Combination therapy for treating cancer using a prmt5 inhibitor and a kras g12d inhibitor

Abstract

The present disclosure relates to the use of compounds as methionine aminopeptidase (MTA)-synergistic PRMT5 inhibitors in combination with K RAS G 12D Methods of inhibiting cancer in a subject with a combination of inhibitors.

Description

[0001] Background of this disclosure

[0002] Cross-reference to related applications

[0003] This application claims the benefit of U.S. Provisional Application No. 63 / 631,023, filed April 8, 2024, the entire contents of which are incorporated herein by reference.

[0004] This disclosure of the field

[0005] This disclosure relates to methods for treating cancer. This disclosure also relates to treating an individual's cancer using a compound that is a protein arginine N-methyltransferase 5 (PRMT5) inhibitor, particularly in combination with an aspartic acid glycine (G12D) inhibitor at codon 12 of the Kirsten rat sarcoma virus oncogene homolog (KRAS).

[0006] Description of related fields

[0007] PRMT5 is a type II arginine methyltransferase, which catalyzes the methylation of arginine methyltransferases. S -Adenosine- L -Methionine (SAM) is transferred to proteins. L -Guidino functional group of arginine residue -nitrogen( - Monomethylation), and catalyzes the transfer of a second methyl group to another. -Nitrogen, producing symmetrical dimethylarginine (sDMA). PRMT5 forms a complex with methylsomal protein 50 (MEP50), which is essential for substrate recognition and orientation, and is also essential for the histone 2A and histone 4 methyltransferase activities catalyzed by PRMT5 (see, for example, Ho et al. (2013)). PLOS ONE 8(2): e57008).

[0008] Homozygous deletion of p16 / CDKN2a is prevalent in cancer, and these mutations often involve the common deletion of adjacent genes, including the gene encoding methionine phosphorylase (MTAP). It is estimated that approximately 15% of all cancers present with homozygous deletion of the MTAP gene (see, for example, Firestone & Schramm (2017)). J. Am. Chem Soc. . 139(39):13754-13760).

[0009] Cells lacking MTAP activity exhibit elevated levels of the MTAP substrate methionine (MTA), a potent inhibitor of PRMT5. Inhibition of PRMT5 activity leads to decreased methylation activity and increased sensitivity of cell proliferation to PRMT5 depletion or loss of activity. Therefore, loss of MTAP activity reduces PRMT5 methylation activity, making cells selectively dependent on PRMT5 activity.

[0010] Kirsten rat sarcoma 2 virus oncogene homolog (“KRas”) is a small GTPase and a member of the Ras oncogene family. KRas acts as a molecular switch that cycles between an inactive (GDP-bound) and an active (GTP-bound) state to transduce upstream cellular signals received from a variety of tyrosine kinases to downstream effectors, thereby regulating a variety of processes, including cell proliferation (see, for example, Alamgeer et al., (2013) Current Opin Pharmcol. 13:394-401).

[0011] The role of activated KRas in malignant tumors was observed more than 30 years ago (see, for example, Santos et al., (1984) Science 223:661-664). Aberrant expression of KRas accounts for 20% of all cancers, and oncogenic KRas mutations that stabilize GTP binding and lead to constitutive activation of KRas and downstream signaling have been reported in 25-30% of lung adenocarcinomas (see, for example, Samatar and Poulikakos (2014) Nat Rev Drug Disc 13(12): 928-942 doi:10.1038 / nrd428). Single nucleotide substitutions leading to missense mutations at codons 12 and 13 of the primary amino acid sequence of KRas account for approximately 40% of KRas-driven mutations in lung adenocarcinomas. KRAS G12D mutations are present in 25.0% of all patients with pancreatic ductal adenocarcinoma, 13.3% of all patients with colorectal cancer, 10.1% of all patients with rectal cancer, 4.1% of all patients with non-small cell lung cancer, and 1.7% of all patients with small cell lung cancer (see, for example, The AACR Project GENIE Consortium, (2017) Cancer Discovery;7(8):818-831. Dataset Version 4).

[0012] The well-known role of KRas in malignant tumors and the frequent occurrence of KRas mutations in various tumor types make KRas an attractive target for the pharmaceutical industry for cancer therapy. Compounds that inhibit KRas activity remain highly desirable and are under investigation, including those that disrupt effectors, such as guanine nucleotide exchange factors (see, for example, Sun et al., (2012) Agnew Chem Int Ed Engl. 51(25):6140-6143 doi: 10.1002 / anie201201358) and recent advances in covalent targeting of the KRas G12C allosteric pocket (see, for example, Ostrem et al., (2013) Nature 503:548-551 and Fell et al., (2018) ACS Med. Chem. Lett.9:1230-1234).

[0013] Despite the importance of PRMT5 for cell survival and its incidence in cancer, effective therapies for inhibiting PRMT5 have remained perplexing. Similarly, despite three decades of large-scale discovery efforts to develop KRas inhibitors for cancer treatment, KRas inhibitors have not yet demonstrated sufficient safety and / or efficacy to gain regulatory approval (see, for example, McCormick (2015) Clin Cancer Res. 21 (8):1797-1801).

[0014] For all the reasons mentioned above, it is necessary to develop and utilize PRMT5 inhibitors and KRAS. G12D Combination therapies using inhibitors are used to treat a wide range of cancers.

[0015] Overview of this disclosure

[0016] One aspect of this disclosure provides a method for treating cancer in an individual. Such a method involves administering a therapeutically effective amount of KRAS to the individual. G12D Inhibitors and therapeutically effective doses of PRMT5 inhibitors.

[0017] This article also provides methods for treating cancer in individuals in need, including determining whether the cancer is associated with a loss of homozygosity for MTAP (e.g., MTAP-related cancer). These methods may optionally also include determining whether the cancer is associated with KRAS. G12D Mutation-related. This type of approach also includes administering a therapeutically effective dose of KRAS to an individual. G12D Inhibitors and therapeutically effective doses of PRMT5 inhibitors.

[0018] These and other features and advantages of the invention can be more fully understood by taking into account the following detailed description of the appended claims. It should be noted that the scope of the claims is defined by the statements therein, and not by the specific discussion of the features and advantages set forth in this specification.

[0019] Detailed description of this disclosure

[0020] Before describing the disclosed methods and substances, it should be understood that the aspects described herein are not limited to the specific embodiments, and thus can certainly be modified. It should also be understood that the terminology used herein is for the purpose of describing specific aspects only, and is not intended to be restrictive unless specifically defined herein.

[0021] As mentioned above, MTAP del and KRAS G12D Gene mutations are prevalent in many cancers. The inventors have advantageously discovered a combination therapy targeting cancers exhibiting both of these characteristics. In one aspect, this disclosure provides a method for treating cancer in an individual, the method comprising administering to the individual a therapeutically effective amount of glycine-to-aspartic acid (KRAS) at codon 12 of the Kirsten rat sarcoma virus oncogene homolog. G12D Inhibitors and therapeutically effective doses of protein arginine N-methyltransferase 5 (PRMT5) inhibitors, wherein the PRMT5 inhibitors are methionine (MTA)-co-PRMT5 inhibitors.

[0022] Combination therapy

[0023] In view of this disclosure, those skilled in the art can configure the methods and compositions described herein to meet desired needs. This disclosure provides improvements in the treatment of cancer in individuals. As used herein, the terms "individual" or "patient" are used interchangeably and refer to any animal, including mammals, and most preferably humans.

[0024] The methods provided herein can be used to treat a variety of cancers, including tumors such as lung, prostate, breast, brain, skin, cervical, and testicular cancers. More specifically, cancers that can be treated with the compositions and methods of the present invention include, but are not limited to, tumor types such as astrocyte, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate, and thyroid cancers and sarcomas. More specifically, these compounds can be used to treat: Heart: sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma, and teratoma; Lung: bronchial protocarcinoma (squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (… Tubular adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, viroma); Small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma); Large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Urogenital tract: Kidney (adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia), Bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), Prostate (adenocarcinoma, sarcoma), Testis (seminomatous seminoma, teratoma, embryonal carcinoma). Fetal carcinoma, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenoma-like tumor, lipoma; Liver: hepatocellular carcinoma, bile duct epithelial carcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Bile duct: gallbladder carcinoma, ampullary carcinoma, bile duct epithelial carcinoma; Bone: osteoblastic sarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondrogenic exophytic tumor). Osteoma, benign chondroma, chondroblastoma, chondromycinous fibroma, osteoid osteoma and giant cell tumor; Nervous system: Skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), Meninges (meningioma, meningeal sarcoma, gliomatosis), Brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pineal tumor), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma and congenital tumors), Spinal cord neurofibroma, meningioma, glioma and sarcoma);Gynecology: Uterus (endometrial cancer), Cervix (cervical cancer, pretumoral cervical dysplasia), Ovary (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenoma, unclassified carcinoma), granulosa-theca cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), Vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), Vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonic rhabdomyosarcoma), Fallopian tubes ( Cancer; Blood: Myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndromes), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); Skin: Malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevi, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and Adrenal glands: Neuroblastoma.

[0025] In some embodiments of the methods disclosed herein, the cancer is MTAP-related cancer. For example, in some embodiments, the cancer comprises MTAP gene homozygosity deletion (MTAP). DEL Individuals can be identified or diagnosed with MTAP-related cancers, where MTAP is measured, for example, using a suitable assay or kit. DEL Alternatively, the individual may be suspected of having MTAP-related cancer, or the individual may have a clinical record indicating that the individual has MTAP-related cancer.

[0026] In some embodiments of the methods disclosed herein, the cancer comprises KRAS G12D Genetic mutation. Individuals can be identified or diagnosed with KRAS. G12D Cancer, in which KRAS is measured using appropriate assays or kits. G12D Mutation. Alternatively, an individual suspected of having KRAS may be at risk. G12D Cancer, or an individual having evidence that they have KRAS G12D Clinical records of cancer.

[0027] As used herein, “KRas G12D” refers to a mutant form of the mammalian KRas protein containing an aspartic acid substitution for glycine at amino acid position 12. The amino acid codon and residue positions of human KRas are assigned based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116: Variantp.Gly12Asp.

[0028] As used herein, "KRas G12D inhibitor" refers to the compounds of the present invention represented by formula (I) as described herein. These compounds are capable of negatively regulating or inhibiting all or part of the enzymatic activity of KRas G12D.

[0029] As used herein, “KRas G12D-related disease or disorder” refers to a disease or disorder that is associated with, mediated by, or has a KRas G12D mutation. A non-limiting example of a KRas G12D-related disease or disorder is KRas G12D-related cancer.

[0030] In some embodiments of the methods disclosed herein, the cancer may further comprise homozygous deletion of the cyclin-dependent kinase inhibitor 2A (CDKN2A) gene. DEL Individuals can be identified or diagnosed with CDKN2A. DEL This deficiency is detected using appropriate assays or kits. Alternatively, individuals suspected of having CDKN2A... DEL Cancer, or an individual having symptoms indicating that they have CDKN2A. DEL Clinical records of cancer.

[0031] In some embodiments of any of the methods or uses described herein, the assay is used to determine whether a patient has MTAP using a sample from an individual (e.g., a biological sample or biopsy sample, such as a paraffin-embedded biopsy sample). DEL and / or KRAS G12D and / or CDKN2A DEL Such assays include, but are not limited to, next-generation sequencing, immunohistochemistry, fluorescence microscopy, lysis FISFI analysis, DNA blotting, protein blotting, FACS analysis, RNA blotting, and PCR-based amplification (e.g., RT-PCR and quantitative real-time RT-PCR). As is well known in the art, assays typically use, for example, at least one labeled nucleic acid probe or at least one labeled antibody or its antigen-binding fragment.

[0032] In some embodiments, the cancer in the methods of this disclosure is selected from lung cancer, pancreatic cancer, colon cancer, head and neck cancer, bladder cancer, esophageal cancer, lymphoma, gastric cancer, skin cancer, breast cancer, and brain cancer.

[0033] In some embodiments, the cancer in the methods of this disclosure is selected from lung cancer, pancreatic cancer, colon cancer, head and neck cancer, esophageal cancer, and melanoma.

[0034] In some embodiments, the cancers in the methods of this disclosure are selected from lung cancer (e.g., mesothelioma or non-small cell lung cancer (NSCLC), including adenocarcinoma and squamous cell carcinoma), pancreatic cancer, colon cancer, head and neck cancer (e.g., squamous cell carcinoma (HNSCC)), bladder cancer, esophageal cancer, lymphoma (e.g., diffuse large B-cell lymphoma), gastric cancer, melanoma, breast cancer, and brain cancer (e.g., glioblastoma multiforme and glioma).

[0035] In some embodiments, the cancer in the methods of this disclosure is selected from lung cancer (e.g., mesothelioma or NSCLC, including adenocarcinoma and squamous cell carcinoma), pancreatic cancer, colon cancer, head and neck cancer (e.g., squamous cell carcinoma (HNSCC)), esophageal cancer, and melanoma.

[0036] In some embodiments, the cancer in the methods of this disclosure is selected from mesothelioma, NSCLC (e.g., adenocarcinoma and squamous cell carcinoma), pancreatic cancer, HNSCC, and colon cancer.

[0037] In one embodiment of the method disclosed herein, the cancer is lung cancer. For example, lung cancer can be NSCLC (e.g., adenocarcinoma and squamous cell carcinoma) or mesothelioma. In one embodiment, the cancer is NSCLC.

[0038] In one embodiment of the method disclosed herein, the cancer is pancreatic cancer.

[0039] In one embodiment of the method disclosed herein, the cancer is colon cancer.

[0040] The PRMT5 inhibitor disclosed herein and / or the KRAS disclosed herein G12D Inhibitors can be provided as pharmaceutical compositions comprising a therapeutically effective amount of such inhibitor and a pharmaceutically acceptable carrier, excipient, and / or diluent. The PRMT5 inhibitors and / or KRAS inhibitors of this disclosure can be formulated by any method well known in the art. G12D Inhibitors, and can be formulated into forms for administration via any route, including but not limited to over-the-counter, oral, sublingual, transdermal, topical, intranasal, intratracheal, or rectal administration. In some embodiments, the PRMT5 inhibitors of this disclosure and / or the KRAS inhibitors of this disclosure... G12C The inhibitor is administered intravenously in a hospital setting. In some alternative embodiments, administration is preferably via oral route.

[0041] The characteristics of the carrier depend on the route of administration. As used herein, the term "pharmaceutically acceptable" means a non-toxic material that is compatible with biological systems such as cells, cell cultures, tissues, or organisms and does not interfere with the bioavailability of the active ingredient. Therefore, the pharmaceutical compositions of this disclosure may include, in addition to inhibitors, diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art. Preparation of pharmaceutically acceptable formulations is described, for example, in Remington's Pharmaceutical Sciences, 18th edition, edited by A. Gennaro, Mack Publishing Co., Easton, Pa., 1990.

[0042] Administer the PRMT5 inhibitor and KRAS disclosed herein at a therapeutically effective dose. G12D Inhibitors. As used herein, the term "therapeutic effective amount" or "effective amount" refers to the amount of an active agent that elicits a biological or pharmaceutical response sought by researchers, physicians, or other clinicians in a tissue, system, individual, or person. Typically, a therapeutically effective amount is sufficient to deliver a biological or pharmaceutical response to an individual without causing serious toxicity. Dosage ranges for active agents can be approximately 0.01–300 mg / kg / day, for example 0.1–100 mg / kg / day, and more commonly 0.5–approximately 25 mg / kg of recipient body weight / day. Typical local dosage ranges are 0.01–3% wt / wt in a suitable carrier.

[0043] In some embodiments of the methods disclosed herein, the therapeutically effective dose of the PRMT5 inhibitor ranges from about 0.01 to 300 mg / kg / day. For example, in some embodiments, the therapeutically effective dose of the PRMT5 inhibitor ranges from about 0.1 to 100 mg / kg / day, or 25 to 100 mg / kg / day, or 50 to 100 mg / kg / day.

[0044] In some implementations, the therapeutically effective amount of a PRMT5 inhibitor is less than 1% of the clinically determined therapeutic amount, such as less than 10%, less than 25%, or less than 50% (e.g., the amount required when administering a PRMT5 inhibitor autologously).

[0045] In some of the implementation methods described herein, the therapeutically effective dose of a PRMT5 inhibitor is administered once daily.

[0046] In some embodiments of the method disclosed herein, KRAS G12D The therapeutically effective dose range for inhibitors is approximately 0.01-300 mg / kg / day. For example, in some implementations, KRAS... G12DThe effective therapeutic dose range for inhibitors is approximately 0.1-100 mg / kg / day, or 0.1-50 mg / kg / day, or 10-100 mg / kg / day, or 10-50 mg / kg / day.

[0047] In some implementations, KRAS G12D The therapeutically effective dose of an inhibitor is less than 1% of the clinically determined therapeutic dose, for example, less than 10%, less than 25%, or less than 50% (e.g., when KRAS is administered autologously). G12D The amount required for inhibitors.

[0048] In some implementations as described herein, KRAS is administered twice daily. G12D The effective therapeutic dose of inhibitors.

[0049] In defining the PRMT5 inhibitors and KRAS of this disclosure G12D Combination therapy for the use of inhibitors is intended to include the sequential administration of each active agent in a regimen that provides the beneficial effects of the combination of drugs (e.g., the PRMT5 inhibitor and KRAS disclosed herein can be used together). G12D The inhibitors are formulated as separate compositions to be administered sequentially, and are also intended to include co-administration of these active agents in a substantially simultaneous manner, for example in a single dosage form having a fixed proportion of these active agents or in multiple or separate dosage forms of each active agent. This disclosure does not limit the order of administration: the PRMT5 inhibitors of this disclosure can be administered with the KRAS of this disclosure. G12D Administer the inhibitor before or after (i.e., sequentially) or simultaneously (i.e., concurrently).

[0050] The methods disclosed herein are useful as first-line treatment. Therefore, in some embodiments of the methods disclosed herein, the individual has not previously received any other first-line therapy.

[0051] The methods disclosed herein can also be used as first-line maintenance or second-line treatment. Therefore, in some embodiments of the methods disclosed herein, the individual has previously completed additional first-line therapy. For example, in some embodiments, the methods disclosed herein can delay cancer progression and recurrence in individuals who have previously completed additional first-line chemotherapy. For example, in some embodiments, the individual has previously completed platinum- and / or taxane-based chemotherapy (e.g., carboplatin, cisplatin, oxaliplatin, paclitaxel, docetaxel, etc.). In some embodiments of the methods disclosed herein, the individual has previously completed additional first-line chemotherapy and has a partial response to such chemotherapy.

[0052] KRAS G12D Inhibitors

[0053] As described above, the method of this disclosure includes applying KRAS. G12DInhibitors. As used in this article, "KRAS" G12D "Inhibitor" refers to compounds as described herein. These compounds are capable of negatively regulating or inhibiting KRAS. G12D All or part of the enzyme activity.

[0054] In some implementations, the KRAS disclosed herein G12D The inhibitor is KRAS disclosed in International Patent Publication No. WO 2022 / 031678, published on February 10, 2022. G12D Any of the inhibitors, which are incorporated in whole by reference.

[0055] In some implementations, the KRAS disclosed herein G12D The inhibitor is KRAS disclosed in International Patent Publication No. WO 2022 / 066646, published on March 31, 2022. G12D Any of the inhibitors, which are incorporated in whole by reference.

[0056] In some implementations, the KRAS disclosed herein G12D The inhibitor is KRAS disclosed in International Patent Publication No. WO 2022 / 098625, published on May 12, 2022. G12D Any of the inhibitors, which are incorporated in whole by reference.

[0057] In some implementations, the KRAS disclosed herein G12D The inhibitor is KRAS disclosed in International Patent Publication No. WO 2021 / 041671 A1, published on March 4, 2021. G12D Any of the inhibitors, which are incorporated in whole by reference.

[0058] In one aspect of this disclosure as described herein, KRAS G12D The inhibitor is a compound of formula (I): Formula (I) Or its pharmaceutically acceptable salt: in: R 1 It can be hydrogen, hydroxyl, halogen, C1-C3 alkyl, C1-C3 cyanoalkyl, C1-C3 hydroxyalkyl, HC(=O)-, -CO2R 5 -CO2N(R) 5 )2 or 5-6 heteroaryl groups; Y or key, O or NR 5 ; R 2 For hydrogen, -N(R) 52. Heterocyclic groups, C1-C6 alkyl groups, -L-heterocyclic groups, -L-aryl groups, -L-heteroaryl groups, -L-cycloalkyl groups, -LN(R) 5 )2, -L-NHC(=NH)NH2, -LC(O)N(R 5 2. -L-C1-C6 haloalkyl, -L-OR 5 -L-(CH2OR) 5 (CH2) n OR 5 -L-NR 5 C(O)-aryl, -L-COOH or -LC(=O)OC1-C6 alkyl, wherein heterocyclic, -L-NR 5 The aryl moiety of the C(O)-aryl group, the heterocyclic moiety of the -L-heterocyclic group, and the cycloalkyl moiety of the -L-cycloalkyl group may optionally be replaced by one or more R groups. 6 Substitution, wherein the aryl or heteroaryl groups of -L-aryl and -L-heteroaryl may optionally be replaced by one or more R 7 replace; Each L is independently a C1-C4 alkylene group, which may optionally be substituted with a hydroxyl group, a C1-C4 hydroxyalkyl group, or a heteroaryl group; R 3 It is aryl or heteroaryl, wherein the aryl or heteroaryl group is optionally surrounded by one or more R 8 replace; R 4 It is hydrogen, halogen, or C1-C3 alkyl; Each R 5 Independently hydrogen or C1-C3 alkyl; Each R 6 Independently, it is a halogen, hydroxyl, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, -NHC(O)phenylSO2F, C1-C3 alkyl-substituted pyrazolyl, aryl C1-C3 alkyl-, tert-butyldimethylsilyloxyCH2-, -N(R 5 2. (C1-C3 alkoxy)C1-C3 alkyl-, (C1-C3 alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)C1-C3 alkoxy, -CH2OC(O)N(R) 5 )2、-CH2NHC(O)OC1-C6 alkyl、-CH2NHC(O)N(R 5 )2、-CH2NHC(O)C1-C6 alkyl、-CH2(pyrazolyl)、-CH2NHSO2C1-C6 alkyl、-CH2OC(O) heterocyclic、-OC(O)N(R 5)2、-OC(O)NH(C1-C3alkyl)O(C1-C3alkyl),-OC(O)NH(C1-C3alkyl)O(C1-C3alkyl)phenyl(C1-C3alkyl)N(CH3)2、-OC(O)NH(C1-C3alkyl)O(C1-C3alkyl)phenyl or-OC(O)heterocyclic,-CH2heterocyclic, wherein the phenyl group of -NHC(O)phenyl or -OC(O)NH(C1-C3alkyl)O(C1-C3alkyl)phenyl is optionally substituted with -C(O)H or OH, and wherein the heterocyclic group of -CH2heterocyclic is optionally substituted with oxy; Q represents a key or an O; Each R 7 Independently, it is a halogen, hydroxyl, HC(=O)-, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, or -N(R) 5 )2; and Each R 8 Independently, it can be halogen, cyano, hydroxy, C1-C4 alkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -S-C1-C3 haloalkyl, C1-C3 alkoxy, hydroxyC1-C3 alkyl, -CH2C(=O)N(R) 5 )2、-C3-C4 ynyl group (NR 5 )2、-N(R 5 2. Deuterated C2-C4 alkynyl, (C1-C3 alkoxy) halo-C1-C3 alkyl- or C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl is optionally substituted with a halogen or a C1-C3 alkyl.

[0059] In one embodiment of the compound of formula (I), R 1 Halogen, hydroxyl, C1-C3 alkyl, C1-C3 cyanoalkyl, C1-C3 hydroxyalkyl, HC(=O)-, -CO2R 5 or -CO2N(R) 5 )2.

[0060] In some implementations, R 1 It is hydrogen.

[0061] In some implementations, R 1 It is a hydroxyl group.

[0062] In another implementation scheme, R 1 -CO2R 5 In some implementations, R 5 It is hydrogen. In another embodiment, R 5It is a C1-C3 alkyl group.

[0063] In another implementation scheme, R 1 -C(O)2N(R) 5 2. In some implementations, each R 5 For hydrogen, each R 5 For independently selected C1-C3 alkyl groups, or an R 5 For hydrogen and the second R 5 It is a C1-C3 alkyl group.

[0064] In one embodiment of the compound of formula (I), Y is a bond.

[0065] In one embodiment of the compound of formula (I), Y is a bond, and R 2 For hydrogen, -N(R) 5 )2 or optionally by one or more R 6 Substituted heterocyclic groups.

[0066] In some embodiments of the compound of formula (I), R 2 -N(R) 5 2. In one implementation scheme, each R 5 For hydrogen. In one implementation, each R 5 For independently selected C1-C3 alkyl groups. In one embodiment, an R 5 For hydrogen and the second R 5 It is a C1-C3 alkyl group. In some embodiments, Y is a bond, and R... 2 -N(R) 5 )2.

[0067] In another implementation scheme, R 2 It is a heterocyclic group. In one embodiment, R 2 It is a heterocyclic group and the heterocyclic group is a nitrogen-containing heterocyclic butyl, pyrrolidinyl, or tetrahydro-2-hydroxyl group. H -Thiam 1,1-dioxide or 1,6-thiam 2 -diazaspiro[3.3]heptyl. In some embodiments, Y is a bond and R 2 It is a heterocyclic group.

[0068] In some implementations, the heterocyclic group is formed by an R 6 Substituted nitrogen-containing heterocyclic butyl groups. In some embodiments, the heterocyclic group is replaced by an R... 6 Substituted nitrogen-containing heterocyclic butyl groups, wherein R 6 It is hydroxyl, hydroxyalkyl or -N(R) 5 2. In some embodiments, the heterocyclic group is formed by two R groups. 6Group-substituted nitrogen-containing heterocyclic butyl groups, wherein R 6 The groups are independently selected from -N(R) 5 )2 and C1-C3 alkyl groups. In some embodiments, Y is a bond, and the heterocyclic group is surrounded by an R 6 Substituted nitrogen-containing heterocyclic butyl groups, wherein R 6 It is hydroxyl, hydroxyalkyl or -N(R) 5 2. In some implementations, Y is the bond, and the heterocyclic group is formed by two R groups. 6 Group-substituted nitrogen-containing heterocyclic butyl groups, wherein R 6 The groups are independently selected from -N(R) 5 )2 and C1-C3 alkyl groups.

[0069] In one embodiment of the compound of formula (I), Y is O.

[0070] In one implementation, Y is O, and R 2 It is a C1-C6 alkyl group, optionally with one or more R 6 Substituted -L-heterocyclic group, -L-heteroaryl group (wherein the heteroaryl moiety is optionally replaced by one or more R groups) 7 Substitution), -L-aryl (wherein the aryl moiety is optionally replaced by one or more R 7 Substitution), -L-cycloalkyl (wherein the cycloalkyl moiety is optionally replaced by one or more R 6 Replacement), -LN(R) 5 )2, -L-NC(=NH)-NH2, -LC(O)N(R 5 2. -L-C1-C6 haloalkyl, -L-COR 5 -L-(CH2OR) 5 (CH2) n OR 5 -L-NR 5 C(O)-aryl.

[0071] In one embodiment of the compound of formula (I), Y is O, and R 2 It is a C1-C6 alkyl group. In some embodiments, the C1-C6 alkyl group is methyl, ethyl, isopropyl, or isobutyl.

[0072] In one embodiment of the compound of formula (I), Y is O, and R 2 For optional use by one or more R 6 Substituted -L-heterocyclic group.

[0073] In one implementation, Y is O, and R 2 The heterocyclic group is a tetrahydropyranyl group optionally substituted with two halogens. In one embodiment, both halogens are fluorine.

[0074] In another implementation, Y is O, and R 2 It is an -L-heterocyclic group, where L is methylene and the heterocyclic group is hexahydro-1- H -pyrrolazinyl, hexahydro-3H-pyrrolazin-3-one, hexahydro-1H-pyrrolo[2,1-c][1,4]oxazinyl, octahydroindazinyl, hexahydropyrrolazine 4(1H)-oxide, aziridine, pyrrolylalkyl, pyrrolidine-2-one, oxacyclobutyl, piperidinyl, 1-azabicyclo[2.2.1]heptyl, morpholinyl, oxa-5-azabicyclo[2.2.1]hept-5-yl, thiaranyl, 6-oxa-2 2 -azaspiro[3.4]octyl, 7-oxa-2 2 -azaspiro[3.5]nonyl, 2',3'dihydrospiro[cyclopropane-1,1'-indene], (2S)-1-azabicyclo[2.2.1]hept-2-yl or tetrahydrofuranyl.

[0075] In some implementations, Y is O, and R 2 It is an -L-heterocyclic group, where L is methylene and the heterocyclic group is hexahydro-1- H -pyrrolizinyl group.

[0076] In some implementations, Y is O, and R 2 It is an -L-heterocyclic group, where L is a methylene group, and the heterocyclic group is optionally decorated with an R group. 6 Substituted hexahydro-1 H -pyrrolizinyl, where R 6 The alkyl group is a halogen, hydroxyl, hydroxyalkyl, C1-C3 haloalkyl, C1-C3 alkyl, C1-C3 alkoxy, phenyl, tert-butyldimethylsilyloxyCH2-, or pyrazolyl, wherein the pyrazolyl group is optionally substituted with a C1-C3 alkyl group. In one embodiment, the C1-C3 haloalkyl group is chloromethyl. In another embodiment, the pyrazolyl group is substituted with a C1-C3 alkyl group. In yet another embodiment, hexahydro-1 H -Pyrrolizin group is surrounded by two R 6 Group substitution, wherein each R 6 The alkyl group is a C1-C3 alkyl group of independent choice. In some embodiments, the heterocyclic group is hexahydro-1. H -pyrrolizinyl group, which is unsubstituted.

[0077] In some implementations, Y is O, and R 2 It is an -L-heterocyclic group, where L is a methylene group, and the heterocyclic group is surrounded by an R group. 6 Substituted nitrogen-containing heterocyclic butyl groups, wherein R 6 It is a C1-C3 alkyl group.

[0078] In some implementations, Y is O, and R 2 It is an -L-heterocyclic group, where L is a methylene group, and the heterocyclic group is surrounded by an R group. 6 Substituted pyrroleyl, wherein R 6 The alkyl group is a C1-C3 hydroxyalkyl, C1-C3 haloalkyl, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 aralkyl, or -Q-phenyl, wherein Q is O and -NHC(O)phenyl. In one embodiment, the phenyl group of -Q-phenyl is substituted with SO2F. In another embodiment, the phenyl group of -NHC(O)phenyl is substituted with SO2F. In one embodiment, the C1-C3 aralkyl group is benzyl.

[0079] In another implementation, Y is 0, and R 2 It is an -L-heterocyclic group, where L is methylene, and the pyrrolidinyl group is separated by two R groups. 6 Group substitution, one of which R 6 It is a C1-C3 alkyl group, and another R 6 It is a C1-C3 alkoxy or halogen.

[0080] In some implementations, Y is O, and R 2 It is an -L-heterocyclic group, where L is a methylene group, and the heterocyclic group is surrounded by an R group. 6 Substituted pyrrolidone-2-one, wherein R 6 It is a C1-C3 alkyl group.

[0081] In some implementations, Y is O, and R 2 It is an -L-heterocyclic group, where L is a methylene group, and the heterocyclic group is surrounded by an R group. 6 Substituted piperidinyl, wherein R 6 It can be acetyl, (C1-C3 alkoxy)C1-C3 alkoxy, or -C(O)CH2Cl.

[0082] In some implementations, Y is O, and R 2 It is an -L-heterocyclic group, where L is a methylene group and the heterocyclic group is (2S)-1-azabicyclo[2.2.1]hept-2-yl.

[0083] In one embodiment of the compound of formula (I), Y is O, and R is... 2 It is an -L-heterocyclic group, wherein L is ethylene or propylene, and the heterocyclic group is morpholino or oxa-5-azabicyclo[2.2.1]hept-5-yl.

[0084] In one embodiment of the compound of formula (I), Y is O, and R 2It is -L-heteroaryl, wherein the heteroaryl moiety is optionally surrounded by one or more R 7 Substitution. In some embodiments, L is ethylene, and the heteroaryl group is benzimidazolyl, which is optionally replaced by one or more R... 7 Replacement. In one implementation, R 7 It is a C1-C4 alkyl group.

[0085] In some implementations, Y is O, and R 2 It is an -L-heteroaryl group.

[0086] In some implementations, Y is O, and R 2 It is -L-heteroaryl, where L is methylene or ethylene. In some embodiments, Y is O, and R... 2 It is -L-heteroaryl, where L is methylene or ethylene, and the heteroaryl group is pyridyl, pyrazolyl, imidazolyl, triazolyl, or 4,5,6,7-tetrahydro-1-yl. H -Indazole, benzimidazole, imidazo[1,2-a]pyridyl or pyrimidinyl.

[0087] In some implementations, Y is O, and R 2 It is -L-heteroaryl, where the heteroaryl group is surrounded by an R 7 Substituted pyridinyl group. In some embodiments, Y is O, and R... 2 It is -L-heteroaryl, where the heteroaryl group is surrounded by an R 7 Substituted pyridinyl group, wherein R 7 Halogen, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkyl, -N(R) 5 )2 or C1-C4 alkoxy.

[0088] In some implementations, Y is O, and R 2 It is -L-heteroaryl, where L is methylene or ethylene, and the heteroaryl group is surrounded by an R. 7 Substituted pyrazolyl group. In some embodiments, Y is O, and R 2 It is -L-heteroaryl, where L is methylene or ethylene, and the heteroaryl group is surrounded by an R. 7 Substituted pyrazol group, wherein R 7 It is a halogen, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkyl, alkoxy, or -N(R) 5 )2.

[0089] In some implementations, Y is O, and R 2 It is -L-heteroaryl, where L is methylene or ethylene, and the heteroaryl group is surrounded by an R. 7The imidazole group is substituted. In some embodiments, Y is O, and R is... 2 It is -L-heteroaryl, where L is methylene or ethylene, and the heteroaryl group is surrounded by an R. 7 Substituted imidazole group, wherein R 7 It is a C1-C4 alkyl, C1-C4 haloalkyl, or C1-C4 hydroxyalkyl.

[0090] In some implementations, Y is O, and R 2 It is -L-heteroaryl, where L is methylene or ethylene, and the heteroaryl group is surrounded by an R. 7 Substituted triazole group. In some embodiments, Y is O, and R... 2 It is -L-heteroaryl, where L is methylene or ethylene, and the heteroaryl group is surrounded by an R. 7 Substituted triazole group, wherein R 7 It is a C1-C4 alkyl group.

[0091] In one embodiment of the compound of formula (I), Y is O, and R 2 It is -L-aryl, wherein the aryl moiety is optionally surrounded by one or more R 7 Substitution. In some embodiments, L is ethylene and the aryl group is phenyl. In one embodiment, the phenyl group is replaced by an R... 7 Substitution. In one embodiment, the phenyl group is replaced by an R 7 Replace, where R 7 It is a halogen. In one embodiment, the phenyl group is reacted with two R... 7 Group substitution. In one embodiment, the phenyl group is replaced by two R groups. 7 Group substitution. In one embodiment, the phenyl group is replaced by two R groups. 7 Group substitution, one of which R 7 It is a hydroxyl group and an R 7 It is HC(=O)-.

[0092] In one embodiment of the compound of formula (I), Y is O, and R 2 It is -L-cycloalkyl, wherein the cycloalkyl moiety is optionally surrounded by one or more R 6 Substitution. In one embodiment, L is methylene. In one embodiment, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, the cyclopropyl and cyclopentyl groups are each replaced by an R group. 6 Replacement. In some embodiments, cyclopropyl and cyclopentyl are each replaced by an R 6 Replace, where R 6 It is a haloalkyl group. In some embodiments, the cyclobutyl and cyclohexyl groups are each separated by two R groups. 6 Group substitution. In some embodiments, the cyclobutyl and cyclohexyl groups are each replaced by two R groups.6 Group substitution, wherein each R 6 The group is halogen.

[0093] In one embodiment of the compound of formula (I), Y is O, and R 2 -LN(R) 5 2. In some embodiments, L is ethylene. In some embodiments, R... 5 It is a C1-C3 alkyl group.

[0094] In one embodiment of the compound of formula (I), Y is O, and R 2 It is -L-NC(=NH)-NH2. In some embodiments, L is ethylene or propylene.

[0095] In one embodiment of the compound of formula (I), Y is O, and R 2 -LC(O)N(R) 5 2. In some embodiments, L is ethylene, and each R 5 It is a C1-C3 alkyl group.

[0096] In one embodiment of the compound of formula (I), Y is O, and R 2 It is an L-C1-C6 haloalkyl group. In some embodiments, L is methylene. In some embodiments, the haloalkyl group is 1,1,3,3-tetrafluoropropyl or trifluoromethyl. In other embodiments, L is ethylene or propylene, and the haloalkyl group is trifluoromethyl.

[0097] In one embodiment of the compound of formula (I), Y is O, and R 2 -L-COR 5 In some embodiments, L is propylidene, and R... 5 It is hydrogen or a C1-C3 alkyl group. In some embodiments, L is propylene, which is substituted with a hydroxyl, hydroxyalkyl, or heteroaryl group, and R... 5 It is hydrogen or a C1-C3 alkyl group. In one embodiment, the heteroaryl group is pyridyl.

[0098] In one embodiment of the compound of formula (I), Y is O, and R 2 -L-(CH2OR) 5 (CH2) n OR 5 In some embodiments, L is methylene, and each R 5 It is independently hydrogen or C1-C3 alkyl, and n is 1 or 2.

[0099] In one embodiment of the compound of formula (I), Y is O, and R 2-L-NR 5 C(O)-aryl. In some embodiments, L is methylene, R... 5 The aryl group is hydrogen. In one embodiment, the aryl group is phenyl. In one embodiment, the phenyl group is converted to an R group. 6 Replace, where R 6 It is -SO2F.

[0100] In one embodiment of the compound of formula (I), R 3 For optional use by one or more R 8 Substituted aryl group. In some embodiments, the aryl group is selected from phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, and 2,3-dihydro-1H-indenyl, wherein each is optionally substituted with one or more R... 8 replace.

[0101] In one implementation, the aryl group is formed by one or more R groups. 8 A phenyl group substituted with a radical. In one embodiment, the aryl group is a phenyl group substituted with one or more R groups. 8 A phenyl group substituted with a radical, wherein the R 8 The group is independently selected from halogens, C1-C3 haloalkyl groups, and -O-C1-C3 haloalkyl groups. In some embodiments, the phenyl group is surrounded by two R groups. 8 Group substitution. In some embodiments, the phenyl group is replaced by two R groups. 8 Group substitution, where two R groups are substituted. 8 The groups are two independently chosen C1-C3 haloalkyl groups or -O-C1-C3 haloalkyl groups and halogens.

[0102] In one embodiment, the aryl group is 2,3-dihydro-1H-indenyl, optionally coupled with one or more R... 8 Substitution. In one embodiment, the aryl group is 2,3-dihydro-1H-indenyl, which is optionally replaced by an R 8 Replacement. In one implementation, R 8 It is a C1-C alkyl group.

[0103] In one implementation, the aryl group is formed by one or more R groups. 8 The naphthyl group is substituted with a group. In one embodiment, the aryl group is substituted with one or more R groups. 8 The group-substituted naphthyl group, said R 8 The groups are independently selected from halogens, cyano, hydroxyl, C1-C3 alkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1-C3 haloalkyl and -O-C1-C3 haloalkyl.

[0104] In one embodiment, the aryl group is a naphthyl group substituted with a hydroxyl group. In another embodiment, the aryl group is a naphthyl group substituted with a halogen. In some embodiments, the halogen is chlorine, fluorine, or bromine. In yet another embodiment, the halogen is chlorine.

[0105] In one embodiment, the aryl group is a naphthyl group substituted with a C1-C3 alkyl group, wherein the C1-C3 alkyl group is methyl or ethyl.

[0106] In one embodiment, the aryl group is a naphthyl group substituted with a C2-C4 alkenyl group. In some embodiments, the C2-C4 alkenyl group is a prop-2-alkenyl group.

[0107] In one embodiment, the aryl group is a naphthyl group substituted with a C2-C4 ynyl group. In some embodiments, the C2-C4 ynyl group is acetylene or prop-2-ynyl.

[0108] In one implementation, the aryl group is formed by one or two R groups. 8 Substituted naphthyl groups, wherein each R 8 The aryl group is halogenated, cyano, hydroxyl, C1-C3 alkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 ynyl, C2-C4 hydroxyynyl, C1-C3 cyanoalkyl, or triazolyl. In one embodiment, the aryl group is formed by two R groups. 8 The group-substituted naphthyl group, said R 8 The groups are independently selected from halogens, hydroxyl groups, C1-C3 alkyl groups, and C2-C4 alkynyl groups.

[0109] In one embodiment of the compound of formula (I), R 3 For optional use by one or more R 8 Substituted heteroaryl groups. In one embodiment, the heteroaryl group is optionally replaced by one or more R groups. 8 The substituted isoquinolinyl, indazole, or benzo[d][1,3]m-dioxacyclopentenyl group. In one embodiment, the heteroaryl group is optionally replaced by one or more R groups. 8 Substituted indazole group. In one embodiment, the heteroaryl group is an indazole group optionally substituted with a C1-C3 alkyl group. In another embodiment, the heteroaryl group is an indazole group optionally substituted with one or more R groups. 8 Substituted isoquinolinyl group. In other embodiments, the heteroaryl group is an isoquinolinyl group optionally substituted with a halogen or a C2-C4 alkynyl group. In some embodiments, the heteroaryl group is optionally substituted with two R groups. 8 The benzo[d][1,3]-dioxanepentenyl group is substituted with a radical. In some embodiments, the heteroaryl group is optionally replaced by two R groups. 8 Group-substituted benzo[d][1,3]m-dioxanepentenyl, wherein each R 8 The groups are independently chosen halogens. In one embodiment, both halogens are gem-difluoro substituted.

[0110] In one embodiment of the compound of formula (I), R 4 It is hydrogen.

[0111] In one embodiment of the compound of formula (I), R 4 It is a halogen. In one embodiment, R 4 It is fluorine. In one embodiment, R 4 It is chlorine.

[0112] In one embodiment of the compound of formula (I), R 4 It is a C1-C3 alkyl group. In one embodiment, R 4 It is a methyl group.

[0113] Non-limiting examples of compounds of formula (I) are selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , 、 , , , , , , , , , , , , , , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、. 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or

[0114] And pharmaceutically acceptable salts thereof. In one embodiment, the compound of formula (I) comprises the dihydrochloride, trihydrochloride, trifluoroacetate, difluoroacetate, and trifluoroacetate of the above-described compounds. The compound of formula (I) or a pharmaceutically acceptable salt thereof may be formulated into a pharmaceutical composition.

[0115] In some embodiments of this disclosure, KRAS G12D Inhibitors are (MRTX-1133) or a pharmaceutically acceptable salt thereof.

[0116] PRMT5 inhibitors

[0117] As described above, PRMT5 inhibitors are also administered using the methods of this disclosure. As used herein, “PRMT5 inhibitor” refers to compounds as described herein. These compounds are capable of negatively regulating or inhibiting all or part of the activity of PRMT5, particularly in vitro or in vivo or in cells expressing elevated levels of MTA in the presence of bound MTA. In some embodiments, the PRMT5 inhibitor is an MTA-co-PRMT5 inhibitor.

[0118] In some embodiments, the PRMT5 inhibitor disclosed herein is any of the PRMT5 inhibitors disclosed in International Patent Publication No. WO 2021 / 050915 A1, published on March 18, 2021, which is incorporated herein by reference in its entirety.

[0119] In some other embodiments, the PRMT5 inhibitor disclosed herein is any of the PRMT5 inhibitors disclosed in International Patent Publication No. WO 2022 / 192745, published on September 15, 2022, which is incorporated herein by reference in its entirety.

[0120] In some other embodiments, the PRMT5 inhibitor disclosed herein is any of the PRMT5 inhibitors disclosed in International Patent Publication No. WO2023 / 081367, published on August 3, 2023, which is incorporated herein by reference in its entirety.

[0121] In some other embodiments, the PRMT5 inhibitor disclosed herein is any of the PRMT5 inhibitors disclosed in International Patent Publication No. WO2023 / 278564, published on January 5, 2023, which is incorporated herein by reference in its entirety.

[0122] For example, the PRMT5 inhibitor in the methods described herein is a compound of formula IIA, IIB, or IIC 1: Formula IIA Formula IIB Formula IIC Or its pharmaceutically acceptable salt, wherein: A is CR 9 Or N; D is (C(R) 9 )2) 1-2 -NH2、 , , , or ; or D is , wherein the methylene group is bonded to E, where E is C; E represents C and CR. 9 Or N; Each L is independently a bond or a C1-C3 alkylene group; W is CR 9 Or N; Each X is independently a bond, O, S, -NR 4 -or-NR 4 C(O)-; Each Z can be independently a bond, -SO-, -SO2-, -CH(OH)-, or -C(O)-; Each R 2 Independently hydroxyl, halogen, cyano, cyanomethyl, -(NR) 4 2. Hydroxylalkyl, alkoxy, -SO2C1-C3alkyl, -X-arylC1-C3alkyl, heteroalkyl, C2-C4 ynyl, -X-haloalkyl, -X-C1-C5alkyl, -Z-C1-C5alkyl, heterocyclic, -XL-cycloalkyl, -Z-cycloalkyl, -X-aryl, -Z-aryl or -X-heteroaryl, wherein the heterocyclic, cycloalkyl, aryl and heteroaryl groups are optionally surrounded by one or more R 5 replace; Each R 4 Independently hydrogen or C1-C3 alkyl; Each R 5 Independently, it is cyano, oxo, halogen, C1-C3 alkyl, hydroxyalkyl, hydroxyl, alkoxy, alkoxy-C1-C3 alkyl, -X-haloalkyl, -Z-cycloalkyl, -X-arc C1-C3 alkyl, -X-arc C1-C3 alkyl substituted with cyano, -XL-cycloalkyl optionally substituted with C1-C3 alkyl or oxo, -XL-heteroaryl optionally substituted with one or more C1-C3 alkyl or oxo, -XL-heterocyclic or -X-aryl optionally substituted with one or more C1-C3 alkyl or oxo. R 6 Hydrogen, halogen, C1-C3 alkyl, haloalkyl, hydroxyl, alkoxy, C1-C3 alkyl-alkoxy, N(R) 9 2. NR 9 C(O)R 9 C(O)R 9 , oxetane and THF; R 7 H or a C1-C3 alkyl group optionally substituted with one or more halogens; R 8 It is H or C1-C3 alkyl; and Each R 9 It is independently H or C1-C3 alkyl, halogen or haloalkyl.

[0123] Implementation scheme 2 provides a PRMT5 inhibitor as a compound of formula IIA in the method of this disclosure: Formula IIA.

[0124] In some embodiments, the PRMT5 inhibitor of the formula IIB compound is used in the method of this disclosure: Formula IIB.

[0125] In some embodiments, the PRMT5 inhibitor of the formula IIC compound is used in the method disclosed herein: Formula IIC.

[0126] In some implementations of formulas IIA, IIB, and IIC, W is CR 9 .

[0127] In some implementations of formulas IIA, IIB, and IIC, A is CR. 9 .

[0128] In some implementations of formulas IIA, IIB, and IIC, E is N.

[0129] In some implementations of formulas IIA, IIB, and IIC, W is CR 9 A is CR 9 And E is N.

[0130] Implementation scheme 9 provides a method for any one of implementation schemes 1-8, wherein R 2 Selected from: benzothiophene, naphthalene, quinoline, chromium, isochromium, dihydrobenzodioxene, indolazine, tetrahydroindolazine, dihydroisobenzofuran, benzene, isoquinolinone, benzodioxane, thienopyridine, tetrahydroindolone, indolazine, dihydroindolazinone, imidazopyridone, thienopyrimidine, thiophene, pyrrolopyrimidinone, thiazopyridone, dihydropyrrolopyridone, isoindolone, and tetrahydroisoquinoline.

[0131] In certain implementations of formulas IIA, IIB, and IIC, each R 5 Independently, it is cyano, oxo, halogen, C1-C3 alkyl, hydroxy, hydroxyalkyl, alkoxy-C1-C3 alkyl, -XL-heterocyclic group optionally substituted with one or more C1-C3 alkyl or oxo, or -XL-cycloalkyl optionally substituted with C1-C3 alkyl or oxo.

[0132] In certain implementations of formulas IIA, IIB, and IIC, R 6Selected from hydrogen, hydroxyl, chlorine, -NHC(O)CH3, -C(O)CF2H, -NH2, -CF2, -CH3, -O-CH2CH3, -CH2-CH2-O-CH3, oxetane and THF.

[0133] In some embodiments of formulas IIA, IIB, and IIC, one of L, X, and Z is a key. In some embodiments, all of L, X, and Z are keys.

[0134] One aspect of this disclosure provides a method wherein the PRMT5 inhibitor is a compound of formula IIIC: Formula IIIC Or its pharmaceutically acceptable salt, wherein A is CR 9 Or N; D is -CH2-NH2. , , , or ; W is CR 9 Or N, where R 9 It is H or C1-C3 alkyl; G, Q, J, and U are independently selected from C(H) and C(R). 5 The condition is that only one or two of G, Q, J, and U can be N; Each R 5 Independently, it is hydroxyl, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkoxy, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl or C1-C3 alkoxy C1-C3 alkyl; R 6 Hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, hydroxyl, C1-C6 alkoxy, C1-C3 alkoxy, C1-C3 alkyl, C3-C6 heterocyclic alkyl, -C(O)-C1-C3 haloalkyl, -N(R 9 )2 or -NR 15 (CO)R 16 , Each R 9 Independently H or C1-C3 alkyl, R 15 It is hydrogen or methyl, and R 16 It is a C1-C3 alkyl group; and R 7 It is a C1-C3 alkyl or a C1-C3 haloalkyl.

[0135] In some implementations of Formula IIIC, A is CH.

[0136] In some implementations of Formula IIIC, W is N.

[0137] In some implementations of Formula IIIC, W is CH.

[0138] In some embodiments of formula IIIC, D is -CH2-NH2.

[0139] In some embodiments, the PRMT5 inhibitor is a compound of formula IIIC having the following formula: .

[0140] In some implementations of Formula IIIC, R 6 Hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, hydroxyl, C1-C6 alkoxy, C1-C3 alkoxy, C1-C3 alkyl, C3-C6 heterocyclic alkyl, -C(O)-C1-C3 haloalkyl, -N(R 9 )2 or -NR 15 (CO)R 16 .

[0141] In some implementations of Formula IIIC, R 6 Hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, hydroxyl, C1-C3 alkoxy, C1-C3 alkoxy-C1-C3 alkyl, C3-C6 heterocyclic alkyl, -C(O)-C1-C3 haloalkyl, -N(R 9 )2 or -NR 15 (CO)R 16 .

[0142] In some implementations of Formula IIIC, R 6 It can be hydrogen, chlorine, fluorine, methyl, ethyl, difluoromethyl, hydroxyl, methoxy, ethoxy, (methoxy)methyl, (ethoxy)methyl, (methoxy)ethyl, (ethoxy)ethyl, oxetanebutyl, tetrahydrofuranyl, -C(O)-difluoromethyl, -NH2 or -NH(CO)CH3.

[0143] In some implementations of Formula IIIC, R 6 Halogen, C1-C6 alkyl, C1-C6 haloalkyl, hydroxyl, C1-C6 alkoxy, C1-C3 alkoxy, C1-C3 alkyl, C3-C6 heterocyclic alkyl, -C(O)-C1-C3 haloalkyl, -N(R 9 )2 or -NR 15 (CO)R 16 .

[0144] In some implementations of Formula IIIC, R 6Halogen, C1-C3 alkyl, C1-C3 haloalkyl, hydroxyl, C1-C3 alkoxy, C1-C3 alkoxy-C1-C3 alkyl, C3-C6 heterocyclic alkyl, -C(O)-C1-C3 haloalkyl, -N(R 9 )2 or -NR 15 (CO)R 16 .

[0145] In some implementations of Formula IIIC, R 6 It can be chlorine, fluorine, methyl, ethyl, difluoromethyl, hydroxyl, methoxy, ethoxy, (methoxy)methyl, (ethoxy)methyl, (methoxy)ethyl, (ethoxy)ethyl, oxetane, tetrahydrofuranyl, -C(O)-difluoromethyl, -NH2 or -NH(CO)CH3.

[0146] In some implementations of Formula IIIC, each G, Q, J, and U is independently C(H).

[0147] In some embodiments of formula IIIC, G, Q, J, and U are independently selected from C(H) and C(R). 5 ).

[0148] In some embodiments of Formula IIIC, G, Q, J, and U are independently selected from C(H) and N.

[0149] In some implementations of Formula IIIC, R 6 It is hydrogen; At least one of G, Q, J, and U is C(R) 5 Furthermore, the remaining G, Q, J, and U are independently selected from C(H) and C(R). 5 ) and N, where each R 5 It is independently a hydroxyl group, a halogen, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C3-C6 cycloalkoxy group, a C3-C6 cycloalkyl group, a C3-C6 heterocycloalkyl group, or a C1-C3 alkoxy group or a C1-C3 alkyl group.

[0150] For example, in some implementations, one or both of G, Q, J, and U are N.

[0151] In some implementations of Formula IIIC, R 6 It is hydrogen; At least one of G, Q, J, and U is C(R) 5 Furthermore, the remaining G, Q, J, and U are independently selected from C(H) and C(R). 5 ), where each R 5It is independently a hydroxyl group, a halogen, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C3-C6 cycloalkoxy group, a C3-C6 cycloalkyl group, a C3-C6 heterocycloalkyl group, or a C1-C3 alkoxy group or a C1-C3 alkyl group.

[0152] For example, in some implementations, at least one of G, Q, J, and U is C(R) 5 ), and the remaining G, Q, J, and U are independently C(H); for example, only one of G, Q, J, and U is C(R). 5 In some implementations, two of G, Q, J, and U are C(R). 5 ), and the remaining G, Q, J, and U are independently C(H). In some embodiments, three of G, Q, J, and U are C(R). 5 ), and the remaining G, Q, J and U are C(H).

[0153] In some embodiments of formula IIIC, G, Q, J, and U are formed together with the attached thiophene: , , , , , , , or .

[0154] In some embodiments of formula IIIC, G, Q, J, and U together with the linked thiophene form benzo[ b ]thiophene.

[0155] In some implementations of Formula IIIC, R 5 (If present) is hydroxyl, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C3-C6 cycloalkoxy, C3-C6 cycloalkyl, C3-C6 heterocyclic alkyl or C1-C3 alkoxy-C1-C3 alkyl.

[0156] In some implementations of Formula IIIC, R 5 (If present) is hydroxyl, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C3-C6 heterocyclic alkyl or C1-C3 alkoxy C1-C3 alkyl.

[0157] In some implementations of Formula IIIC, R 5(If present) is hydroxyl, chlorine, fluorine, methyl, ethyl, methoxy, ethoxy, 2,2-difluoroethoxy, oxetyl, tetrahydrofuranyl, (methoxy)methyl, (ethoxy)methyl, (methoxy)ethyl or (ethoxy)ethyl.

[0158] In some implementations of Formula IIIC, R 7 It is a methyl group.

[0159] In some implementations of Formula IIIC, R 7 It is an ethyl group.

[0160] In some implementations of Formula IIIC, R 7 It is propyl (e.g., isopropyl).

[0161] In some implementations of Formula IIIC, R 7 It is difluoromethyl or trifluoromethyl.

[0162] In some embodiments of formula IIIC, the PRMT5 inhibitor has the following formula: , in G, Q, J, and U together form with the attached thiophene: , , , , , , , or , Each R 5 Independently, it is hydroxyl, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C3-C6 heterocyclic alkyl, or C1-C3 alkoxy-C1-C3 alkyl; and R 6 Hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, hydroxyl, C1-C3 alkoxy, C1-C3 alkoxy-C1-C3 alkyl, C3-C6 heterocyclic alkyl, -C(O)-C1-C3 haloalkyl, -N(R 9 )2 or -NR 15 (CO)R 16 .

[0163] In some embodiments of formula IIIC, the PRMT5 inhibitor has the following formula: , in G, Q, J, and U together form with the attached thiophene: , , , or , Each R 5 Independently, it is hydroxyl, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C3-C6 heterocyclic alkyl, or C1-C3 alkoxy-C1-C3 alkyl; and R 6 Halogen, C1-C3 alkyl, C1-C3 haloalkyl, hydroxyl, C1-C3 alkoxy, C1-C3 alkoxy-C1-C3 alkyl, C3-C6 heterocyclic alkyl, -C(O)-C1-C3 haloalkyl, -N(R 9 )2 or -NR 15 (CO)R 16 .

[0164] In some embodiments of formula IIIC, the PRMT5 inhibitor has the following formula: , in G, Q, J, and U together form with the attached thiophene: , , or , Each R 5 It is independently a hydroxyl group, a halogen, a C1-C3 alkyl group, a C1-C3 haloalkyl group, a C1-C3 alkoxy group, a C1-C3 haloalkoxy group, a C3-C6 heterocyclic alkyl group, or a C1-C3 alkoxy C1-C3 alkyl group.

[0165] In some embodiments of the methods described herein, the PRMT5 inhibitor is: PRMT5 inhibitor is: (IVD) or its pharmaceutically acceptable salt.

[0166] In some implementations, the PRMT5 inhibitor is a compound of formula IIIB: Formula IIIB Or its pharmaceutically acceptable salt, wherein A is CR 9 Or N; D is -CH2-NH2. , , , or ; W is CR9 Or N, where R 9 It is H or C1-C3 alkyl; R 51 It is hydrogen, fluorine, chlorine or methyl, or R 51 and R 52 Together with the atoms to which they are attached, they form C4-C6 heterocyclic alkyl groups (e.g., hydrogen-furanyl); R 52 It is fluorine, chlorine or methyl, or R 52 and R 53 Together with the atoms they are attached to, they form a phenyl group; R 53 It can be hydrogen, fluorine, chlorine, or methyl; R 54 It is hydrogen, halogen, C1-C3 alkyl, or C1-C3 alkoxy; L 5 It can be -O- or -CH2-; R 6 It can be hydrogen, halogen, C1-C6 alkyl, hydroxyl, C1-C6 alkoxy, C1-C3 alkoxy, C1-C3 alkyl, C3-C6 heterocyclic alkyl, -C(O)-C1-C3 haloalkyl or -NR 15 (CO)R 16 , where R 15 It is hydrogen or methyl, and R 16 It is a C1-C3 alkyl group; R 7 It is a C1-C3 alkyl or a C1-C3 haloalkyl.

[0167] In some implementations of Formula IIIB: A is -CH or -CCH3; D is -CH2-NH2; W can be -CH, -CCH3, or N; R 51 R 52 R 53 and R 54 Each is independently selected from hydrogen, fluorine, chlorine, or methyl; L 5 -O-; R 6 It is hydrogen, fluorine, chlorine, or methyl; and R 7 It is a C1-C2 alkyl or a C1-C2 haloalkyl.

[0168] In some implementations of Formula IIIB: A and W are -CH; D is -CH2-NH2; R 51 R52 and R 53 Each is independently selected from hydrogen, fluorine, chlorine, and methyl; R 54 It is hydrogen; L 5 -O-; R 6 It is hydrogen; and R 7 It is a methyl group.

[0169] In some implementations of Formula IIIB: A and W are -CH; D is -CH2-NH2; R 51 and R 52 Each is independently selected from fluorine, chlorine, and methyl; R 53 and R 54 It is hydrogen; L 5 -O-; R 6 It is hydrogen; and R 7 It is a methyl group.

[0170] In some embodiments of Formula IIIB, A is CH.

[0171] In some embodiments of Formula IIIB, W is N.

[0172] In some embodiments of Formula IIIB, W is CH.

[0173] In some embodiments of formula IIIB, D is -CH2-NH2.

[0174] In some embodiments of Formula IIIB, R 54 It can be hydrogen or methyl.

[0175] In some embodiments of Formula IIIB, R 54 It is hydrogen.

[0176] In some embodiments of Formula IIIB, R 54 It is a methyl group.

[0177] In some embodiments of formula IIIB, the PRMT5 inhibitor has the following formula: ,For example .

[0178] In some embodiments of Formula IIIB, L 5 It is -CH2-.

[0179] In some embodiments of Formula IIIB, L 5 It is -O-.

[0180] In some implementations of Formula IIIB, R 6 Hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, hydroxyl, C1-C3 alkoxy, C1-C3 alkoxy-C1-C3 alkyl, C3-C6 heterocyclic alkyl, -C(O)-C1-C3 haloalkyl, -N(R 9 )2 or -NR 15 (CO)R 16 For example, where R 6 It can be hydrogen, chlorine, fluorine, methyl, ethyl, difluoromethyl, hydroxyl, methoxy, ethoxy, (methoxy)methyl, (ethoxy)methyl, (methoxy)ethyl, (ethoxy)ethyl, oxetanebutyl, tetrahydrofuranyl, -C(O)-difluoromethyl, -NH2 or -NH(CO)CH3.

[0181] In some implementations of Formula IIIB, R 6 It is hydrogen, halogen, C1-C6 alkyl, or C1-C6 alkoxy; for example, R 6 It can be hydrogen, halogen, C1-C3 alkyl or C1-C3 alkoxy.

[0182] In some implementations of Formula IIIB, R 6 It can be hydrogen, chlorine, fluorine, methyl, ethyl, methoxy, or ethoxy.

[0183] In some implementations of Formula IIIB, R 6 Halogen, C1-C3 alkyl, C1-C3 haloalkyl, hydroxyl, C1-C3 alkoxy, C1-C3 alkoxy-C1-C3 alkyl, C3-C6 heterocyclic alkyl, -C(O)-C1-C3 haloalkyl, -N(R 9 )2 or -NR 15 (CO)R 16 For example, where R 6 It can be chlorine, fluorine, methyl, ethyl, difluoromethyl, hydroxyl, methoxy, ethoxy, (methoxy)methyl, (ethoxy)methyl, (methoxy)ethyl, (ethoxy)ethyl, oxetane, tetrahydrofuranyl, -C(O)-difluoromethyl, -NH2 or -NH(CO)CH3.

[0184] In some embodiments of Formula IIIB, R 6 It is a halogen, a C1-C6 alkyl, or a C1-C6 alkoxy; for example, R 6 It is a halogen, a C1-C3 alkyl or a C1-C3 alkoxy.

[0185] In some implementations of Formula IIIB, R6 It can be chlorine, fluorine, methyl, ethyl, methoxy, or ethoxy.

[0186] In some embodiments of Formula IIIB, R 7 It is a methyl group.

[0187] In some embodiments of Formula IIIB, R 7 It is an ethyl group.

[0188] In some embodiments of Formula IIIB, R 7 It is propyl (e.g., isopropyl).

[0189] In some embodiments of Formula IIIB, R 7 It is difluoromethyl or trifluoromethyl.

[0190] In some embodiments of Formula IIIB, R 53 It is hydrogen or methoxy; or R is present in the form of hydrogen or methoxy. 53 It is hydrogen.

[0191] In some embodiments of formula IIIB, the PRMT5 inhibitor has the following formula: .

[0192] In some implementations, R 52 It is fluorine, and R 51 It can be hydrogen, fluorine, chlorine, or methyl.

[0193] In some embodiments of Formula IIIB, R 52 It is fluorine, and R 51 It is chlorine.

[0194] In some embodiments of Formula IIIB, R 52 It is fluorine, and R 51 It is methyl or hydrogen (e.g., R). 52 It is fluorine, and R 51 Methyl; or R 52 It is fluorine, and R 51 (For hydrogen).

[0195] In some embodiments of Formula IIIB, R 51 and R 52 Together with the attached atoms, they form a hydrogen furanyl group (e.g. ).

[0196] In some embodiments of Formula IIIB, the PRMT5 inhibitor is... .

[0197] In some embodiments of Formula IIIB, the PRMT5 inhibitor is... (MRTX1719).

[0198] One aspect of this disclosure provides a method wherein the PRMT5 inhibitor is a compound of formula IIIA: Formula IIIA Or its pharmaceutically acceptable salt, wherein A is CR 9 Or N; D is -CH2-NH2. , , , or ; W is CR 9 Or N, where R 9 It is H or C1-C3 alkyl; R 2 for , , or , Where R 56 It can be hydrogen, fluorine, chlorine, or methyl. G, Q, J, and U are independently selected from C(H) and C(R). 5 The condition is that only one or two of G, Q, J, and U can be N; Each R 5 Independently, it is hydroxyl, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkoxy, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl or C1-C3 alkoxy C1-C3 alkyl; R 6 It can be hydrogen, halogen, C1-C6 alkyl, hydroxyl, C1-C6 alkoxy, C1-C3 alkoxy, C1-C3 alkyl, C3-C6 heterocyclic alkyl, -C(O)-C1-C3 haloalkyl or -NR 15 (CO)R 16 , where R 15 It is hydrogen or methyl, and R 16 It is a C1-C3 alkyl group; and R 7 It is a C1-C3 alkyl or a C1-C3 haloalkyl.

[0199] One aspect of this disclosure provides a method wherein the PRMT5 inhibitor is a compound of formula IIIA: Formula IIIA Or its pharmaceutically acceptable salt, wherein A is CR9 Or N; D is -CH2-NH2. , , , or ; W is CR 9 Or N, where R 9 It is H or C1-C3 alkyl; R 2 for , , , or , Where R 56 It can be hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy; R 6 It can be hydrogen, halogen, C1-C6 alkyl, hydroxyl, C1-C6 alkoxy, C1-C3 alkoxy, C1-C3 alkyl, C3-C6 heterocyclic alkyl, -C(O)-C1-C3 haloalkyl or -NR 15 (CO)R 16 , where R 15 It is hydrogen or methyl, and R 16 It is a C1-C3 alkyl group; and R 7 It is a C1-C3 alkyl or a C1-C3 haloalkyl.

[0200] In some implementations of Formula IIIA, A is CH.

[0201] In some implementations of Formula IIIA, W is N.

[0202] In some embodiments of Formula IIIA, W is CH.

[0203] In some embodiments of formula IIIA, D is -CH2-NH2.

[0204] In some embodiments of Formula IIIA, the PRMT5 inhibitor has the following formula: .

[0205] In some implementations of Formula IIIA, R 2 for , or .

[0206] In some embodiments of Formula IIIA, G, Q, J, and U are independently selected from C(H) and C(R). 5 ).

[0207] In some implementations of Formula IIIA, G, Q, J, and U are independently C(H).

[0208] In some embodiments of Formula IIIA, at least one of G, Q, J, and U is C(R) 5 ), and the remaining G, Q, J, and U are independently C(H); for example, only one of G, Q, J, and U is C(R). 5 ).

[0209] In some embodiments of Formula IIIA, U is N, and G, Q, and J are independently selected from C(H) and C(R). 5 ).

[0210] In some embodiments of formula IIIA, G is N, and Q, J, and U are independently selected from C(H) and C(R). 5 ).

[0211] In some implementations of Formula IIIA, R 5 (If present) is hydroxyl, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C3-C6 cycloalkoxy, C3-C6 cycloalkyl, C3-C6 heterocyclic alkyl or C1-C3 alkoxy-C1-C3 alkyl.

[0212] In some implementations of Formula IIIA, R 5 (If present) is hydroxyl, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C3-C6 heterocyclic alkyl or C1-C3 alkoxy C1-C3 alkyl.

[0213] In some implementations of Formula IIIA, R 5 (If present) is hydroxyl, chlorine, fluorine, methyl, ethyl, methoxy, ethoxy, 2,2-difluoroethoxy, oxetyl, tetrahydrofuranyl, (methoxy)methyl, (ethoxy)methyl, (methoxy)ethyl or (ethoxy)ethyl.

[0214] In some implementations of Formula IIIA, R 5 (If present) is a halogen, C1-C6 alkyl, or C1-C6 alkoxy; for example, R 6 It is a halogen, a C1-C3 alkyl or a C1-C3 alkoxy.

[0215] In some implementations of Formula IIIA, R 5(If present) is chlorine, fluorine, methyl, ethyl, methoxy, or ethoxy.

[0216] In some implementations of Formula IIIA, R 56 It can be fluorine, chlorine, or methyl.

[0217] In some implementations of Formula IIIA, R 2 for , or .

[0218] In some implementations of Formula IIIA, R 56 It can be hydrogen, fluorine, chlorine, or methyl.

[0219] In some implementations of Formula IIIA, R 6 Hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, hydroxyl, C1-C3 alkoxy, C1-C3 alkoxy-C1-C3 alkyl, C3-C6 heterocyclic alkyl, -C(O)-C1-C3 haloalkyl, -N(R 9 )2 or -NR 15 (CO)R 16 For example, where R 6 It can be hydrogen, chlorine, fluorine, methyl, ethyl, difluoromethyl, hydroxyl, methoxy, ethoxy, (methoxy)methyl, (ethoxy)methyl, (methoxy)ethyl, (ethoxy)ethyl, oxetanebutyl, tetrahydrofuranyl, -C(O)-difluoromethyl, -NH2 or -NH(CO)CH3.

[0220] In some implementations of Formula IIIA, R 6 It is hydrogen, halogen, C1-C6 alkyl, or C1-C6 alkoxy; for example, R 6 It can be hydrogen, halogen, C1-C3 alkyl or C1-C3 alkoxy.

[0221] In some implementations of Formula IIIA, R 6 It can be hydrogen, chlorine, fluorine, methyl, ethyl, methoxy, or ethoxy.

[0222] In some implementations of Formula IIIA, R 6 Halogen, C1-C3 alkyl, C1-C3 haloalkyl, hydroxyl, C1-C3 alkoxy, C1-C3 alkoxy-C1-C3 alkyl, C3-C6 heterocyclic alkyl, -C(O)-C1-C3 haloalkyl, -N(R 9 )2 or -NR 15 (CO)R 16 For example, where R 6It can be chlorine, fluorine, methyl, ethyl, difluoromethyl, hydroxyl, methoxy, ethoxy, (methoxy)methyl, (ethoxy)methyl, (methoxy)ethyl, (ethoxy)ethyl, oxetanebutyl, tetrahydrofuranyl, -C(O)-difluoromethyl, -NH2 or -NH(CO)CH3.

[0223] In some implementations of Formula IIIA, R 6 It is a halogen, a C1-C6 alkyl, or a C1-C6 alkoxy; for example, R 6 It is a halogen, a C1-C3 alkyl or a C1-C3 alkoxy.

[0224] In some implementations of Formula IIIA, R 6 It can be chlorine, fluorine, methyl, ethyl, methoxy, or ethoxy.

[0225] In some implementations of Formula IIIA, R 7 It is a methyl group.

[0226] In some implementations of Formula IIIA, R 7 It is an ethyl group.

[0227] In some implementations of Formula IIIA, R 7 It is propyl (e.g., isopropyl).

[0228] In some implementations of Formula IIIA, R 7 It is difluoromethyl or trifluoromethyl.

[0229] In some embodiments of the methods described herein, the PRMT5 inhibitor is: (IVA, MRTX9768); (IVB, MRTX7477); ; ; ; ; ; ;or .

[0230] In some embodiments of the methods described herein, the PRMT5 inhibitor is: (IVA) or (IVB), or a pharmaceutically acceptable salt thereof.

[0231] In some embodiments of the methods described herein, the PRMT5 inhibitor is: ; ; ; ; ; ;or .

[0232] In some embodiments of the methods described herein, the PRMT5 inhibitor is: ; ; ; ; ; ;or .

[0233] In some embodiments of the methods described herein, the PRMT5 inhibitor is: .

[0234] In some embodiments as described herein, the PRMT5 inhibitor is... (IVA) or a pharmaceutically acceptable salt, and KRAS G12D The inhibitor is a compound of formula I or a pharmaceutically acceptable salt thereof. For example, in some embodiments, the PRMT5 inhibitor is... (IVA) or a pharmaceutically acceptable salt, and KRAS G12D The inhibitor is MRTX-1133 or a pharmaceutically acceptable salt thereof.

[0235] In some embodiments as described herein, the PRMT5 inhibitor is... (IVB) or a pharmaceutically acceptable salt, and KRAS G12D The inhibitor is a compound of formula I or a pharmaceutically acceptable salt thereof. For example, in some embodiments, the PRMT5 inhibitor is... (IVB) or a pharmaceutically acceptable salt, and KRAS G12D The inhibitor is MRTX-1133 or a pharmaceutically acceptable salt thereof.

[0236] In some embodiments as described herein, the PRMT5 inhibitor is... (IVC) or its pharmaceutically acceptable salt, and KRAS G12D The inhibitor is a compound of formula 1 or a pharmaceutically acceptable salt thereof. For example, in some embodiments, the PRMT5 inhibitor is... (IVC) or its pharmaceutically acceptable salt, and KRAS G12D The inhibitor is MRTX-1133 or a pharmaceutically acceptable salt thereof.

[0237] In some embodiments as described herein, the PRMT5 inhibitor is MRTX1719 or a pharmaceutically acceptable salt thereof, and KRASG12D The inhibitor is MRTX-1133 or a pharmaceutically acceptable salt thereof.

[0238] In some implementations as described herein, the PRMT5 inhibitor is: (IVD) or its pharmaceutically acceptable salt, and KRAS G12D The inhibitor is a compound of formula 1 or a pharmaceutically acceptable salt thereof. For example, in some embodiments as described herein, the PRMT5 inhibitor is: (IVD) or its pharmaceutically acceptable salt, and KRAS G12D The inhibitor is MRTX-1133 or a pharmaceutically acceptable salt thereof.

[0239] definition

[0240] For simplicity, chemical moieties are defined and are referred to throughout as monovalent chemical moieties (e.g., alkyl, aryl, etc.). Nevertheless, such terms can also be used to convey corresponding polyvalent moieties in suitable structural cases that are obvious to those skilled in the art. For example, while the "alkyl" moieties generally refer to monovalent groups (e.g., CH3-CH2-), in some cases the divalent linking moieties can be "alkyl," in which case those skilled in the art will understand that alkyl refers to a divalent group (e.g., -CH2-CH2-), which is equivalent to the term "alkylene". (Similarly, where a divalent moieties are required and described as "aryl," those skilled in the art will understand that the term "aryl" refers to the corresponding divalent arylene moieties.) All atoms should be understood to have the normal valence for bond formation (i.e., carbon 4, N 3, O 2, and S 2, 4, or 6, depending on the oxidation state of S).

[0241] The term "amino" refers to -NH2.

[0242] The term "acetyl" refers to "-C(O)CH3".

[0243] As used herein, the term "acyl" refers to an alkyl carbonyl or aryl carbonyl substituent, wherein the alkyl and aryl moieties are as defined herein.

[0244] As used herein, the term "alkyl" refers to a saturated straight-chain and branched aliphatic group having 1-12 carbon atoms. Therefore, "alkyl" includes C1, C2, C3, C4, C5, C6, C7, C8, C9, C1 ...1, C1, C1, C1, C1, C1, C1, 10 C 11 and C 12 Groups. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl.

[0245] As used herein, the term "alkenyl" refers to an unsaturated straight-chain or branched aliphatic group having 2-12 carbon atoms and one or more carbon-carbon double bonds. Therefore, "alkenyl" includes C2, C3, C4, C5, C6, C7, C8, C9, C16, C17, C18, C19, C16, C19, C10, C11, C12, C13, C14, C15, C16, C17, C18 ... 10 C 11 and C 12 Groups. Examples of alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, pentenyl, and hexenyl.

[0246] As used herein, the term "alkynyl" refers to an unsaturated straight-chain or branched aliphatic group having 2-12 carbon atoms and one or more carbon-carbon triple bonds. Therefore, "alkynyl" includes C2, C3, C4, C5, C6, C7, C8, C9, C16, C17, C18, C19, C16, C19, C10, C11, C12, C13, C14, C15, C16, C17, C18 ... 10 C 11 and C 12 Groups. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, penynyl, and hexynyl.

[0247] "alkylene," "alkenylene," or "yntynyl" refers to an alkyl, alkenyl, or yntyl group as defined above, which is located between and serves to connect the other two chemical groups. Examples of alkylene groups include, but are not limited to, methylene, ethylene, propylene, and butylene. Examples of alkenyl groups include, but are not limited to, vinylene, propenyl, and butenylene. Examples of yntynyl groups include, but are not limited to, ethynylene, propynylene, and butynylene.

[0248] The term "alkoxy" refers to -OC1-C6 alkyl.

[0249] As used herein, the term "cycloalkyl" refers to a saturated and partially unsaturated cyclic hydrocarbon group having 3–12 carbon atoms. Therefore, "cycloalkyl" includes C3, C4, C5, C6, C7, C8, C9, C16, C17, C18, C19, C19, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C1 10 C 11 and C 12 Cyclic hydrocarbon groups. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.

[0250] The term "heteroalkyl" refers to an alkyl group as defined above, wherein one or more carbon atoms in the chain are independently bounded by O, S, or NR. x Replacement, where R x It is hydrogen or a C1-C3 alkyl group. Examples of heteroalkyl groups include methoxymethyl, methoxyethyl, and methoxypropyl.

[0251] "Aryl" is a C6-C group containing 1-3 aromatic rings. 14 The aromatic group. Therefore, "aryl" includes C6, C... 10 C 13 and C14 Cyclic hydrocarbon group. An exemplary aryl group is C6-C. 10 Aryl. Specific aryl groups include, but are not limited to, phenyl, naphthyl, anthracene, and fluorenyl. "Aryl" also includes fused polycyclic (e.g., bicyclic) ring systems, wherein one or more of the fused rings are non-aromatic, provided that at least one ring is aromatic, such as indene.

[0252] "Arylalkyl" or "arylalkyl" comprises an aryl group covalently linked to an alkyl group, wherein the portion is connected to another group via the alkyl moiety. An exemplary arylalkyl group is a -(C1-C6)alkyl (C6-C6)alkyl group. 10 Aryl groups, including but not limited to benzyl, phenethyl, and naphthylmethyl. For example, aryl C1-C3 alkyl groups are aryl groups covalently linked to C1-C3 alkyl groups.

[0253] "Heterocyclic group" or "heterocyclic group" refers to a single or bicyclic (e.g., fused or spiro) ring structure having 3-12 atoms (3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 atoms), for example 4-8 atoms, wherein one or more ring atoms are independently -C(O)-, N, NR. 4 The ring atoms are O or S, and the remaining ring atoms are quaternary carbons or carbonyl carbons. Examples of heterocyclic groups include, but are not limited to, epoxy, ethylene oxide, oxetane, azirne, aziridinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopheneyl, pyrrolidinyl, piperidinyl, piperazine, imidazoalkyl, thiazoalkyl, thioheterobutyl, dithiazoalkyl, trithiazoalkyl, azirnezoalkyl, oxazoalkyl, dioxopentyl, oxazolidinone, decahydroquinolinyl, piperidinone, 4-piperidinone, thiomorpholinyl, dimethylmorpholinyl, and morpholinyl. In particular, compounds having adjacent ring O and / or S atoms are excluded from the scope of this term.

[0254] As used herein, “L-heterocyclic group” refers to a heterocyclic group that is covalently attached to another group via an alkylene linker.

[0255] As used herein, the term "heteroaryl" refers to a group having 5 to 14 ring atoms, preferably 5, 6, 10, 13, or 14 ring atoms; having 6, 10, or 14 π electrons shared in the ring array; and having 1 to 3 heteroatoms, each independently selected from N, O, or S, in addition to a carbon atom. Heteroaryls also include fused polycyclic (e.g., bicyclic) ring systems, wherein one or more of the fused rings are non-aromatic, provided that at least one ring is aromatic and at least one ring contains an N, O, or S ring atom. Examples of heteroaryl groups include acridinel, aziridine octyl, benzimidazolyl, benzofuranyl, benzo[d]oxazol-2(3H)-one, 2H-benzo[b][1,4]oxazin-3(4H)-one, benzothiofuranyl, benzothiophene, benzooxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazole, phenylisooxazolyl, benzoisothiazolyl, benzimidazolinyl, carbazole, 4aH-carbazole, carbolinyl, chromanyl, chromenyl, terolinyl, furanyl, furanyl, and furanyl. Zanyl, imidazolinyl, imidazolyl, 1H-indazole, indoleenyl, dihydroindole, indazinyl, indole, 3H-indole, isobenzofuranyl, isochoryl, isoindazole, isodihydroindole, isoindole, isoquinolinyl, isothiazolyl, isoxazolyl, naphridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolylalkyl, oxazolyl, oxazolylalkyl Pyrimidinyl, phenanthridine, phenanthrolinyl, phenazinyl, phenothiazinyl, phenothiazinyl, phenothiazinyl, phthalazinyl, piperinyl, pteridinyl, purine, pyranyl, pyrazinyl, pyrazolylyl, pyrazolyl, pyridazinyl, pyridoxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyrimidinyl, pyrrolinyl, 2H-pyrroleyl, pyrroleyl, quinazolinyl, quinolinyl, 4H-quinazinyl, quinoxalinyl, quinine Cycloyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thienyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthonyl.

[0256] "L-Heteroarylalkyl" or "L-heteroarylalkyl" refers to a heteroaryl group covalently linked to another group via an alkylene linker. Examples of heteroaryl groups include C1-C6 alkyl groups and heteroaryl groups having 5, 6, 9, or 10 ring atoms. Examples of heteroaryl groups include pyridylmethyl, pyridylethyl, pyrrolithylmethyl, pyrrolithylethyl, imidazolylmethyl, imidazolylethyl, thiazolylmethyl, thiazolylethyl, benzimidazolylmethyl, benzimidazolylethyl, quinazolinylmethyl, quinolinylmethyl, quinolinylethyl, benzofuranylmethyl, dihydroindolylethyl, isoquinolinylmethyl, isoindolylmethyl, cinolinylmethyl, and benzothiophenylethyl. Compounds having adjacent ring O and / or S atoms are specifically excluded from the scope of this term.

[0257] "Arylidene", "heteroarylidene", or "heterocyclic" are divalent aryl, heteroaryl, or heterocyclic groups as defined above, which are located between and used to connect two other chemical groups.

[0258] As used herein, when a part (e.g., cycloalkyl, aryl, heteroaryl, heterocyclic, urea, etc.) is described as “optionally substituted” without specifying the substituents, it means that the group optionally has 1 to 4, preferably 1 to 3, more preferably 1 or 2 non-hydrogen substituents.

[0259] As used in this article, the term "halogen" or "halogenated" refers to chlorine, bromine, fluorine, or iodine.

[0260] The term "haloalkyl" refers to an alkyl chain in which one or more hydrogen atoms are replaced by halogens. Exemplary haloalkyl groups are trifluoromethyl, difluoromethyl, fluorochloromethyl, chloromethyl, and fluoromethyl.

[0261] The term "hydroxyalkyl" refers to -alkylene-OH.

[0262] Example

[0263] The methods of this disclosure are further illustrated by the following examples, but should not be construed as limiting this disclosure to the scope or spirit of the specific methods and compounds described herein.

[0264] MRTX1719 + KRAS G12D Combinatorial research methods: Immunodeficient female mice were implanted with... MTAPE Deletion of homozygosity (GMO) MTAPE DEL )and CRASS G12DA mutant human cancer model was established. Mice were monitored daily for health, and caliper measurements were initiated when tumors became palpable. Tumor volume was measured using the formula 0.5 × L × W², where L represents the length of each tumor and W represents its width. Tumors reached approximately 200–300 mm in diameter. 3 Animals were randomly assigned to receive: A) a mediator; B) an orally administered (PO) PRMT5 inhibitor prepared in 0.5% methylcellulose (4000 cps) / 0.2% Tween 80 in water; C) an intraperitoneally administered (IP) KRAS G12D inhibitor prepared in 10% Captisol in 50 mM citrate buffer at pH 5.0; or D) both a PRMT5 inhibitor and a KRAS G12D inhibitor. Tumor volume was measured twice weekly (n=5 / treatment group). When the mean final treated tumor volume was greater than the initial treated tumor volume, the tumor growth inhibition rate (%TGI) was calculated using the following formula: (1 - (final treated tumor volume - initial treated tumor volume) / (final mediator-treated tumor volume - initial mediator-treated tumor volume)) 100. When the average tumor volume of the ultimately treated tumor is smaller than the initial tumor volume, the percentage regression (% regression) is calculated using the following formula: (-100%) (1 - ((tumor volume after final treatment) / (tumor volume after initial treatment)).

[0265] Example 1

[0266] Following the research methods described above, this embodiment was conducted in immunodeficient female nu / nu mice, which were implanted with 5×10⁻⁶ cells in 50% matrix gel. 6 KP4 pancreatic cancer cells. The PRMT5 inhibitor was MRTX1719, administered at 100 mg / kg once daily (QD). The MRTX1719 used is as described herein.

[0267] The embodiment used CRASS G12D The inhibitor was MRTX1133, administered at 30 mg / kg twice daily (BID). The MRTX1133 used is as described herein.

[0268] The results are shown in Table 1. MTAPE DEL And this KRAS G12D In the pancreatic tumor xenograft KP4 model, the combination of MRTX1719 and MRTX1133 produced greater antitumor activity compared to either inhibitor alone.

[0269] Table 1.

[0270] Example 2

[0271] Based on the research methods described above, this embodiment was performed in immunodeficient female nu / nu mice, which were implanted with 5×10⁻⁶ cells in 50% matrix gel. 6 SU8686 pancreatic cancer cells. The PRMT5 inhibitor was MRTX1719, administered at 100 mg / kg once daily (QD). The MRTX1719 used is as described herein.

[0272] The embodiment used CRASS G12D The inhibitor was MRTX1133, administered at 30 mg / kg twice daily (BID). The MRTX1133 used is as described herein.

[0273] The results are shown in Table 2. MTAPE DEL and KRAS G12D In the pancreatic tumor xenograft SU8686 model, the combination of MRTX1719 and MRTX1133 produced greater antitumor activity compared to either inhibitor alone.

[0274] Table 2.

[0275] It should be understood that the embodiments and implementations described herein are for illustrative purposes only and are intended to inspire those skilled in the art to make various modifications or changes based thereon, which will be incorporated into the spirit and scope of this application and the appended claims. All publications, patents, and patent applications cited herein are incorporated herein by reference for all purposes.

Claims

1. A method for treating individual cancers, which includes: Administer a therapeutically effective dose of glycine-to-aspartic acid (KRAS) at codon 12 of the Kirsten rat sarcoma virus oncogene homolog (KRAS) to an individual. G12D Inhibitors and therapeutically effective doses of methionine (MTA)-co-protein arginine N-methyltransferase 5 (PRMT5) inhibitors.

2. The method of claim 1, wherein the cancer comprises homozygous deletion of the methionine phosphorylase (MTAP) gene.

3. The method of claim 1, wherein the cancer comprises KRAS. G12D Gene mutation.

4. The method of claim 2, wherein the cancer further comprises homozygous deletion of the cyclin-dependent kinase inhibitor 2A (CDKN2A) gene.

5. The method of claim 1, wherein the cancer is lung cancer or pancreatic cancer.

6. The method of claim 1, wherein the cancer is lung cancer, such as non-small cell lung cancer (NSCLC).

7. The method of claim 1, wherein the cancer is pancreatic cancer.

8. The method of claim 1, wherein KRAS G12D Inhibitors are (MRTX-1133) or a pharmaceutically acceptable salt thereof.

9. The method according to claim 1, wherein the PRMT5 inhibitor is: (IVC) or its pharmaceutically acceptable salt.

10. The method according to claim 1, wherein the PRMT5 inhibitor is: (MRTX1719) or a pharmaceutically acceptable salt thereof.

11. The method according to claim 1, wherein the PRMT5 inhibitor is... (IVC) or its pharmaceutically acceptable salt, and KRAS G12D The inhibitor is a compound of formula 1 or a pharmaceutically acceptable salt thereof.

12. The method according to claim 1, wherein the PRMT5 inhibitor is... (IVC) or its pharmaceutically acceptable salt, and KRAS G12D The inhibitor is MRTX-1133 or a pharmaceutically acceptable salt thereof.

13. The method of claim 1, wherein the PRMT5 inhibitor is MRTX1719 or a pharmaceutically acceptable salt thereof, and KRAS G12D The inhibitor is MRTX-1133 or a pharmaceutically acceptable salt thereof.

14. The method according to claim 1, wherein the therapeutically effective dose of the PRMT5 inhibitor ranges from about 0.01 to 300 mg / kg / day.

15. The method of claim 1, wherein the therapeutically effective dose of the PRMT5 inhibitor ranges from about 0.1 to 100 mg / kg / day.

16. The method of claim 1, wherein the therapeutically effective amount of the PRMT5 inhibitor is less than 1% of the clinically determined therapeutic amount, for example less than 10%, less than 25%, or less than 50%.

17. The method according to any one of claims 14-16, wherein a therapeutically effective amount of the PRMT5 inhibitor is administered once daily.

18. The method of claim 1, wherein KRAS G12D The effective therapeutic dose range for inhibitors is approximately 0.01-300 mg / kg / day.

19. The method of claim 1, wherein KRAS G12D The effective therapeutic dose range for inhibitors is approximately 0.1-100 mg / kg / day.

20. The method of claim 1, wherein KRAS G12D The therapeutically effective dose of an inhibitor is less than 1% of the clinically determined therapeutic dose, for example, less than 10%, less than 25%, or less than 50%.

21. The method according to any one of claims 18-20, wherein a therapeutically effective amount of KRAS is administered twice daily. G12D .

22. The method of claim 1, wherein KRAS is applied sequentially. G12D Inhibitors and PRMT5 inhibitors.

23. The method of claim 1, wherein KRAS is applied simultaneously. G12D Inhibitors and PRMT5 inhibitors.

24. The method of claim 1, wherein the individual has previously received or completed first-line chemotherapy.

25. The method of claim 1, wherein the individual has not previously received or completed first-line chemotherapy.

26. The method of claim 24 or claim 25, wherein the first-line chemotherapy is platinum- and / or taxane-based chemotherapy.

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