Combination Therapy Using PRMT5 Inhibitors for the Treatment of Cancer

Abstract

Methods for treating cancer are disclosed herein. More specifically, the present disclosure provides a method for treating cancer in a subject using a compound that is an inhibitor of PRMT5, particularly in combination with a taxane.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 252,995, filed October 06, 2021, the disclosure of which is incorporated herein by reference in its entirety.

[0002] The present disclosure relates to methods of treating cancer. The present disclosure further relates to treating cancer in a subject with a compound that is protein arginine N-methyltransferase 5 (PRMT5), particularly in combination with a taxane. [Background technology]

[0003] PRMT5 is a type II arginine methyltransferase that catalyzes the transfer of a methyl group from S-adenosyl-L-methionine (SAM) to the omega-nitrogen of the guanidino functional group of protein L-arginine residues (omega-monomethylation) and the transfer of a second methyl group to the other omega-nitrogen, resulting in symmetric dimethylarginine (sDMA). PRMT5 forms a complex with methylosomal protein 50 (MEP50), which is required for substrate recognition and orientation, and is also required for PRMT5-catalyzed histone 2A and histone 4 methyltransferase activity (see, e.g., Ho et al. (2013) PLoS ONE 8(2):e57008).

[0004] Homozygous deletions of p16 / CDKN2a are common in cancer, and these mutations are commonly associated with co-deletions of adjacent genes, including the gene encoding methylthioadenosine phosphorylase (MTAP). It is estimated that approximately 15% of all human cancers have homozygous deletions of the MTAP gene (see, e.g., Firestone & Schramm (2017) J. Am. Chem Soc. 139(39):13754-13760).

[0005] Cells lacking MTAP activity have elevated levels of the MTAP substrate, methylthioadenosine (MTA), a potent inhibitor of PRMT5. Inhibiting PRMT5 activity reduces methylation activity and increases the sensitivity of cell proliferation to PRMT5 depletion or loss of activity. Thus, loss of MTAP activity reduces the methylation activity of PRMT5 and renders cells selectively dependent on PRMT5 activity.

[0006] Despite the importance of PRMT5 to cell viability and the prevalence in cancer, effective therapies that inhibit PRMT5 have been elusive, and there remains a need to develop new PRMT5 inhibitor therapies to treat a wide range of cancers. Summary of the Invention

[0007] One aspect of the present disclosure provides a method for treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of a PRMT5 inhibitor together with a therapeutically effective amount of a taxane.

[0008] In certain embodiments, the taxane described elsewhere herein is docetaxel.

[0009] Also provided herein are methods for treating cancer in a subject in need thereof, including determining that the cancer is associated with MTAP homozygous deletion (e.g., is an MTAP-associated cancer).

[0010] These and other features and advantages of the present invention will be more fully understood from the following detailed description taken in conjunction with the appended claims, with the understanding that the claims are defined by the recitations therein, and not by the specific discussion of the features and advantages described herein.

[0011] The accompanying drawings are included to provide a further understanding of the methods of the present disclosure, and are incorporated in and constitute a part of this specification. These drawings illustrate one or more embodiments of the present disclosure, and together with the description, serve to explain the principles and operation of the present disclosure. [Brief description of the drawings]

[0012] [Figure 1] FIG. 1 illustrates the results of Example 1, in which MRTX1719 (PO, QD), docetaxel (IP Q7D), or a combination thereof was administered to mice (n=5 / cohort) bearing H1650 xenograft tumors. Data presented as mean + / - SEM. [Diagram 2] FIG. 1 illustrates the results of Example 2, in which MRTX1719 (oral, QD), docetaxel (IP Q7D), or the combination were administered to mice (n=5 / cohort) bearing H2228 xenograft tumors. Data presented as mean + / - SEM. [Diagram 3] FIG. 1 illustrates the results of Example 3, in which MRTX1719 (oral, QD), docetaxel (IP Q7D), or the combination were administered to A549 xenograft tumor-bearing mice (n=5 / cohort). Data presented as mean + / - SEM. [Figure 4] FIG. 1 illustrates the results of Example 4, in which MRTX1719 (oral, QD), docetaxel (IP Q7D), or the combination were administered to mice (n=5 / cohort) bearing HCC4006 xenograft tumors. Data presented as mean + / - SEM. [Diagram 5] FIG. 1 illustrates the results of Example 5, in which MRTX1719 (oral, QD), docetaxel (IP Q7D), or the combination were administered to SW1573 xenograft tumor-bearing mice (n=5 / cohort). Data presented as mean + / - SEM. [Figure 6] FIG. 1 illustrates the results of Example 6, in which MRTX1719 (oral, QD), docetaxel (IP Q7D), or the combination were administered to mice (n=5 / cohort) bearing LU99 xenograft tumors. Data presented as mean + / - SEM. [Figure 7] FIG. 1 illustrates the results of Example 7, in which MRTX1719 (oral, QD), docetaxel (IP Q7D), or the combination were administered to mice (n=5 / cohort) bearing MIAPaCa-2 xenograft tumors. Data presented as mean + / - SEM. [Figure 8] FIG. 1 illustrates the results of Example 8, in which MRTX1719 (oral, QD), docetaxel (IP Q7D), or the combination were administered to mice (n=5 / cohort) bearing KP4 xenograft tumors. Data presented as mean + / - SEM. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] Before the disclosed processes and materials are described, it is to be understood that the aspects described herein are not limited to particular embodiments, which can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only, and is not intended to be limiting, unless specifically defined herein.

[0014] In view of the present disclosure, the methods and compositions described herein can be adapted by those skilled in the art to meet the desired needs. The present disclosure provides improvements in treating cancer in a subject. As used herein, the terms "subject" or "patient" are used interchangeably and refer to any animal, including mammals, most preferably humans.

[0015] The methods provided herein may be used for the treatment of a wide variety of cancers, including, for example, tumors such as lung cancer, prostate cancer, breast cancer, brain cancer, skin cancer, cervical cancer, testicular cancer, etc. More specifically, cancers that may be treated by the compositions and methods of the present invention include, but are not limited to, tumor types such as astrocytoma, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, head and neck cancer, hepatocellular carcinoma, laryngeal cancer, lung cancer, oral cancer, ovarian cancer, prostate cancer, and thyroid cancer, as well as sarcoma. More specifically, these compounds can be used to treat: cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; lung: bronchogenic carcinoma (squamous cell, small undifferentiated cell, large undifferentiated cell, adenocarcinoma), alveolar (bronchial) carcinoma, bronchial adenoma, sarcoma, lymphoma, perichondrial hamartoma, mesothelioma; gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, cystic sarcoma ... tumors, hamartomas, leiomyomas); genitourinary tract: kidneys (adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testes (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma); liver: liver cancer (hepatocellular carcinoma), bile duct , hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; biliary tract: gallbladder cancer, ampullary cancer, bile duct cancer; bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondral exostosis (osteochondroma), benign chondroma, chondroma endocarcinoma, chondromyxoid fibroma, osteoid osteoma and giant cell tumor;Nervous system: skull (osteoma, hemangioma, granuloma, xanthomas, osteitis deformans), meninges (meningioma, meningeal sarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); gynecology: uterus (endometrial cancer), cervix (cervical cancer, preneoplastic cervical dysplasia), ovary (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa theca cell tumor, Sertoli-Leydig cell tumor, germinoma, malignant aberrant tumor sarcoma), vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tube (carcinoma); hematological: blood (myeloid leukemia (acute and chronic), acute lymphocytic 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, melanocytic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and adrenal gland: neuroblastoma.

[0016] In certain embodiments of the methods of the present disclosure, the cancer is an MTAP-associated cancer. For example, in certain embodiments, the cancer is a MTAP-associated cancer. DEL The subject may be identified or diagnosed as having an MTAP-associated cancer, e.g., DEL is determined using a suitable assay or kit. Alternatively, the subject is suspected of having an MTAP-associated cancer or the subject has clinical records indicating that the subject has an MTAP-associated cancer.

[0017] In certain embodiments of the disclosed methods, the cancer is a cancer characterized by a homozygous deletion of the cyclin-dependent kinase inhibitor 2A (CDKN2A) gene (CDKN2A DEL The subject further includes CDKN2A DEL Alternatively, the subject may be identified or diagnosed as having CDKN2A, where the deletion is determined using a suitable assay or kit. DELThe subject is suspected of having cancer or the subject is DEL Have clinical documentation showing they have cancer.

[0018] In some embodiments of any of the methods or uses described herein, an assay is used to determine subject treatment eligibility using a sample from the subject (e.g., a biological sample or a biopsy sample (e.g., a paraffin-embedded biopsy sample)). Such assays include, but are not limited to, next-generation sequencing, immunohistochemistry, fluorescence microscopy, break-apart FISFI analysis, Southern blotting, Western blotting, FACS analysis, Northern blotting, and PCR-based amplification (e.g., RT-PCR and quantitative real-time RT-PCR). As is well known in the art, the assay is typically performed, for example, using at least one labeled nucleic acid probe or at least one labeled antibody or antigen-binding fragment thereof.

[0019] In certain embodiments, the cancer in the methods of the present 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.

[0020] In certain embodiments, the cancer in the methods of the present disclosure is selected from lung cancer, pancreatic cancer, colon cancer, head and neck cancer, esophageal cancer, and melanoma.

[0021] In certain embodiments, the cancer in the methods of the present disclosure is selected from lung cancer (e.g., mesothelioma or non-small cell lung cancer (NSCLC) including adenocarcinoma and squamous cell), pancreatic cancer, colon cancer, head and neck cancer (such as 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).

[0022] In certain embodiments, the cancer in the methods of the present disclosure is selected from lung cancer (e.g., mesothelioma or NSCLC, including adenocarcinoma and squamous cell), pancreatic cancer, colon cancer, head and neck cancer (e.g., squamous cell carcinoma (HNSCC)), esophageal cancer, and melanoma.

[0023] In certain embodiments, the cancer in the methods of the present disclosure is selected from mesothelioma, NSCLC (e.g., adenocarcinoma and squamous cell), pancreatic cancer, HNSCC, and colon cancer.

[0024] In one embodiment of the method of the present disclosure, the cancer is lung cancer. For example, the lung cancer can be NSCLC (e.g., adenocarcinoma and squamous cell) or mesothelioma. In certain embodiments, the cancer is NSCLC.

[0025] In one embodiment of the methods of the present disclosure, the cancer is pancreatic cancer.

[0026] In one embodiment of the methods of the present disclosure, the cancer is colon cancer.

[0027] In certain embodiments described elsewhere herein, the taxane comprises at least one of docetaxel, paclitaxel, abraxane, and cabazitaxel. For example, in certain embodiments, the taxane is docetaxel or paclitaxel. In various embodiments described elsewhere herein, the taxane is docetaxel.

[0028] As provided above, paclitaxel (CAS Registry Number: 330690-62-4), docetaxel (CAS Registry Number: 114977-28-5), Abraxane (CAS Registry Number: 33069-62-4), and / or cabazitaxel (CAS Registry Number: 18313396-2) are administered in the methods of the present disclosure. For example, docetaxel and paclitaxel are both widely manufactured and distributed, and can be provided in anhydrous form, or as hydrates or solvates thereof. Docetaxel is commercially available and sold in intravenous and injectable forms for administration. As known in the art, Abraxane is an albumin-bound paclitaxel and is widely available.

[0029] As provided above, PRMT5 inhibitors are also administered in the methods of the present disclosure.As used herein, "PRMT5 inhibitors" refers to the compounds of the present disclosure described herein.These compounds can negatively regulate or inhibit all or part of the enzyme activity of PRMT5, particularly in the presence of bound MTA in vitro or in vivo, or in cells expressing elevated levels of MTA.In certain embodiments, the PRMT5 inhibitor is an MTA-cooperative PRMT5 inhibitor.

[0030] In certain embodiments, the PRMT5 inhibitor of the present disclosure is any one of the PRMT5 inhibitors disclosed in International Patent Publication No. 2021 / 050915A1, published on March 18, 2021, and incorporated by reference in their entireties.

[0031] In certain other embodiments, the PRMT5 inhibitor of the present disclosure is any one of the PRMT5 inhibitors disclosed in U.S. Provisional Patent Application No. 63 / 200,521, published on March 11, 2021, and incorporated by reference in its entirety.

[0032] For example, the PRMT5 inhibitor in the disclosed methods described herein is a compound of formula IIA, IIB, or IIC (embodiment 1): [ka] [ka] [ka] or a pharma- ceutically acceptable salt thereof, wherein: A is CR 9 or N, D is (C(R 9 )2) 1-2 -NH2, [ka] [ka] [ka] [ka] or [ka] or D is [ka] wherein the methylene is bonded to E and E is C; E is C, CR 9 , or N, each L is independently a bond or C1-C3 alkylene; W is CR 9 or N, Each X is independently a bond, O, S, or -NR 4 -OR-NR 4 C(O)-, each Z is independently a bond, -SO-, -SO2-, -CH(OH)-, or -C(O)-; Each R 2 are independently hydroxy, halogen, cyano, cyanomethyl, -(NR 4 )2, hydroxyalkyl, alkoxy, -SO2C1-C3 alkyl, -X-(C1-C3 alkyl)-aryl, heteroalkyl, C2-C4 alkynyl, -X-haloalkyl, -X-C1-C5 alkyl, -Z-C1-C5 alkyl, heterocyclyl, -XL-cycloalkyl, -Z-cycloalkyl, -X-aryl, -Z-aryl, or -X-heteroaryl, where heterocyclyl, cycloalkyl, aryl, and heteroaryl are selected from one or more of R 5 and optionally substituted with Each R 4 is independently hydrogen or C1-C3 alkyl; Each R 5 are independently cyano, oxo, halogen, C1-C3 alkyl, hydroxyalkyl, hydroxy, alkoxy, alkoxy-C1-C3 alkyl, -X-haloalkyl, -Z-cycloalkyl, X-(C1-C3 alkyl)-aryl, X-(C1-C3 alkyl)-aryl 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-heterocyclyl optionally substituted with one or more C1-C3 alkyl or oxo, or -X-aryl; R 6 is hydrogen, halogen, C1-C3 alkyl, haloalkyl, hydroxy, alkoxy, C1-C3 alkyl-alkoxy, N(R 9 )2, NR 9 C(O)R 9 , C(O)R 9 , oxetane, and THF; R 7 is H or C1-C3 alkyl optionally substituted with one or more halogens; R 8 is H or C1-C3 alkyl; Each R 9 is independently H or C1-C3 alkyl, halogen, or haloalkyl.

[0033] Embodiment 2 provides the PRMT5 inhibitor in the methods of the disclosure as a compound of formula IIA. [ka]

[0034] Embodiment 3 provides the PRMT5 inhibitor in the methods of the disclosure as a compound of formula IIB. [ka]

[0035] Embodiment 4 provides the PRMT5 inhibitor in the methods of the disclosure as a compound of formula IIC. [ka]

[0036] In the fifth embodiment, W is CR 9 The method according to any one of embodiments 1 to 4 is provided, wherein

[0037] In embodiment 6, A is CR 9 The method according to any one of embodiments 1 to 4 is provided, wherein

[0038] Embodiment 7 provides a method according to any one of embodiments 1 to 4, wherein E is N.

[0039] In the eighth embodiment, W is CR 9 and A is CR 9 and E is N.

[0040] Embodiment 9 is a compound comprising R 2is selected from benzothiophene, naphthalene, quinoline, chroman, isochroman, dihydrobenzodioxin, indorazine, tetrahydroindolazine, dihydroisobenzofuran, benzene, isoquinolinone, benzodioxone, thienopyridine, tetrahydroindolone, indolizine, dihydroindolizinone, imadazopyridinone, thienopyrimidine, thiophene, pyrrolopyrimidinone, thiazolopyridinone, dihydropyrrolidine, isoindalone, and tetrahydroisoquinoline.

[0041] In a tenth embodiment, each R 5 is independently cyano, oxo, halogen, C1-C3 alkyl, hydroxy, hydroxyalkyl, alkoxy-C1-C3 alkyl, -XL-heterocyclyl optionally substituted with one or more C1-C3 alkyl or oxo, -XL-cycloalkyl optionally substituted with C1-C3 alkyl or oxo.

[0042] Embodiment 11 is a compound comprising R 6 is selected from hydrogen, hydroxy, chlorine, -NHC(O)CH3, -C(O)CF2H, -NH2, -CF2, -CH3, -O-CH2CH3, -CH2-CH2-O-CH3, oxetane, and THF.

[0043] Embodiment 12 provides the method of any one of embodiments 1-11, wherein one of L, X, and Z is a bond.

[0044] Embodiment 13 provides the method of embodiment 12, wherein L, X, and Z are all bonds.

[0045] One aspect of the present disclosure is that the PRMT5 inhibitor is a compound of formula (IIIC) (embodiment 14): [ka] or a pharma- ceutically acceptable salt thereof, wherein: A is CR 9 or N, D is -CH2-NH2, [ka] [ka] [ka] [ka] or [ka] and W is CR 9 or N, where R 9 is H or C1-C3 alkyl; G, Q, J, and U are independently C(H), C(R 5 ), and N, with the proviso that only one or two of G, Q, J, and U can be N; Each R 5 are independently hydroxy, 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 alkoxyC1-C3 alkyl; R 6 is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, hydroxy, C1-C6 alkoxy, C1-C3 alkoxyC1-C3 alkyl, C3-C6 heterocycloalkyl, -C(O)-C1-C3 haloalkyl, -N(R 9 )2, or -NR 15 (CO)R 16 and In the formula, each R 9 is independently H or C1-C3 alkyl; R 15 is hydrogen or methyl, R 16 is C1-C3 alkyl; R 7 is C1-C3 alkyl or C1-C3 haloalkyl.

[0046] Embodiment 15 provides the method of embodiment 14, wherein A is CH.

[0047] Embodiment 16 provides the method of embodiment 14 or 15, wherein W is N.

[0048] Embodiment 17 provides the method of embodiment 14 or 15, wherein W is CH.

[0049] Embodiment 18 provides the method of any one of embodiments 14-17, wherein D is -CH2-NH2.

[0050] Embodiment 19 provides a method of the disclosure, wherein the PRMT5 inhibitor is a compound according to embodiment 14 of the following formula: [ka]

[0051] Embodiment 20 is a method for producing a compound according to the present invention 6 is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, hydroxy, C1-C6 alkoxy, C1-C3 alkoxyC1-C3 alkyl, C3-C6 heterocycloalkyl, -C(O)-C1-C3 haloalkyl, -N(R 9 )2, or -NR 15 (CO)R 16 The method according to any one of embodiments 14 to 19 is provided, wherein

[0052] Embodiment 21 is a compound comprising R 6is hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, hydroxy, C1-C3 alkoxy, C1-C3 alkoxyC1-C3 alkyl, C3-C6 heterocycloalkyl, -C(O)-C1-C3 haloalkyl, -N(R 9 )2, or -NR 15 (CO)R 16 The method according to any one of embodiments 14 to 19 is provided, wherein

[0053] Embodiment 22 is a compound comprising R 6 is hydrogen, chloro, fluoro, methyl, ethyl, difluoromethyl, hydroxy, methoxy, ethoxy, (methoxy)methyl, (ethoxy)methyl, (methoxy)ethyl, (ethoxy)ethyl, oxetanyl, tetrahydrofuranyl, -C(O)-difluoromethyl, -NH, or -NH(CO)CH.

[0054] Embodiment 23 is a compound comprising R 6 is halogen, C1-C6 alkyl, C1-C6 haloalkyl, hydroxy, C1-C6 alkoxy, C1-C3 alkoxyC1-C3 alkyl, C3-C6 heterocycloalkyl, -C(O)-C1-C3 haloalkyl, -N(R 9 )2, or -NR 15 (CO)R 16 The method according to any one of embodiments 14 to 19 is provided, wherein

[0055] Embodiment 24 is a method for producing a compound according to the present invention 6 is halogen, C1-C3 alkyl, C1-C3 haloalkyl, hydroxy, C1-C3 alkoxy, C1-C3 alkoxyC1-C3 alkyl, C3-C6 heterocycloalkyl, -C(O)-C1-C3 haloalkyl, -N(R 9 )2, or -NR 15 (CO)R 16 The method according to any one of embodiments 14 to 19 is provided, wherein

[0056] Embodiment 25 is a method for producing a compound according to the present invention 6is chloro, fluoro, methyl, ethyl, difluoromethyl, hydroxy, methoxy, ethoxy, (methoxy)methyl, (ethoxy)methyl, (methoxy)ethyl, (ethoxy)ethyl, oxetanyl, tetrahydrofuranyl, -C(O)-difluoromethyl, -NH, or -NH(CO)CH.

[0057] Embodiment 26 provides the method of any of embodiments 23-25, wherein each G, Q, J, and U is independently C(H).

[0058] Embodiment 27 is an embodiment in which G, Q, J, and U are independently C(H) and C(R 5 The method according to any one of embodiments 23 to 25, wherein the method is selected from the group consisting of:

[0059] Embodiment 28 provides the method of any of embodiments 23-25, wherein G, Q, J, and U are independently selected from C(H) and N.

[0060] Embodiment 29 is R 6 is hydrogen, 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), C(R 5 ), and N, each R 5 is independently hydroxy, 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 alkoxyC1-C3 alkyl.

[0061] Embodiment 30 provides the method of embodiment 29, wherein one or two of G, Q, J, and U are N.

[0062] Embodiment 31 is R6 is hydrogen, 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) and C(R 5 ) and each R 5 is independently hydroxy, 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 alkoxyC1-C3 alkyl.

[0063] Embodiment 32 is an embodiment in which 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), e.g., only one of G, Q, J, and U is C(R 5 32. The method of claim 31, wherein

[0064] Embodiment 33 is an embodiment in which two of G, Q, J, and U are C(R 5 ) and the remaining G, Q, J, and U are independently C(H).

[0065] Embodiment 34 is an embodiment in which three of G, Q, J, and U are C(R 5 ) and the remaining G, Q, J, and U are C(H).

[0066] Embodiment 35 is an embodiment in which G, Q, J, and U, together with the thiophene to which they are attached, represent: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or [ka] The method according to any one of embodiments 14 to 19, further comprising forming

[0067] Embodiment 36 provides the method of embodiment 35, wherein G, Q, J, and U, together with the thiophene to which they are attached, form a benzo[b]thiophene.

[0068] Embodiment 37 is a method for producing a compound according to the present invention 5 The method of any one of embodiments 14-36, wherein, if present, is hydroxy, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C3-C6 cycloalkoxy, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, or C1-C3 alkoxyC1-C3 alkyl.

[0069] Embodiment 38 is directed to R 5The method of any one of embodiments 14-36, wherein, if present, is hydroxy, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C3-C6 heterocycloalkyl, or C1-C3 alkoxyC1-C3 alkyl.

[0070] Embodiment 39 is a method for producing a compound according to the present invention 5 The method of any one of embodiments 14-36, wherein, if present, is hydroxy, chloro, fluoro, methyl, ethyl, methoxy, ethoxy, 2,2-difluoroethoxy, oxetanyl, tetrahydrofuranyl, (methoxy)methyl, (ethoxy)methyl, (methoxy)ethyl, or (ethoxy)ethyl.

[0071] Embodiment 40 is a method for producing a compound according to the present invention 7 The method of any one of embodiments 14-39, wherein is methyl.

[0072] Embodiment 41 is a compound comprising R 7 The method of any one of embodiments 14-39, wherein is ethyl.

[0073] Embodiment 42 is R 7 The method of any one of embodiments 14-39, wherein is propyl (e.g., isopropyl).

[0074] Embodiment 43 is a compound comprising R 7 The method of any one of embodiments 14-39, wherein is difluoromethyl or trifluoromethyl.

[0075] Embodiment 44 is wherein the PRMT5 inhibitor is of the formula: [ka] During the ceremony, G, Q, J, and U together with the thiophene to which they are attached [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or [ka] Forming In the formula, each R 5 are independently hydroxy, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C3-C6 heterocycloalkyl, or C1-C3 alkoxyC1-C3 alkyl; R 6 is hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, hydroxy, C1-C3 alkoxy, C1-C3 alkoxyC1-C3 alkyl, C3-C6 heterocycloalkyl, -C(O)-C1-C3 haloalkyl, -N(R 9 )2, or -NR 15 (CO)R 16 15. The method of embodiment 14, wherein

[0076] Embodiment 45 is wherein the PRMT5 inhibitor is of the formula: [ka] During the ceremony, G, Q, J, and U together with the thiophene to which they are attached [ka] [ka] [ka] [ka] or [ka] Forming In the formula, each R 5 are independently hydroxy, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C3-C6 heterocycloalkyl, or C1-C3 alkoxyC1-C3 alkyl; R 6 is hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, hydroxy, C1-C3 alkoxy, C1-C3 alkoxyC1-C3 alkyl, C3-C6 heterocycloalkyl, -C(O)-C1-C3 haloalkyl, -N(R 9 )2, or -NR 15 (CO)R 16 15. The method of embodiment 14, wherein

[0077] Embodiment 46 is wherein the PRMT5 inhibitor is of the formula: [ka] During the ceremony, G, Q, J, and U together with the thiophene to which they are attached [ka] [ka] [ka] or [ka] Forming In the formula, each R 5 is independently hydroxy, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C3-C6 heterocycloalkyl, or C1-C3 alkoxyC1-C3 alkyl.

[0078] Embodiment 47 is a compound of formula (IIIB): [ka] or a pharma- ceutically acceptable salt thereof, wherein: A is CR 9 or N, D is -CH2-NH2, [ka] [ka] [ka] [ka] or [ka] and W is CR 9 or N, where R 9 is H or C1-C3 alkyl; R 51 is hydrogen, fluoro, chloro, or methyl, or R 51 and R 52 together with the atoms to which they are attached form a C4-C6 heterocycloalkyl (e.g., hydrofuranyl); R 52 is fluoro, chloro, or methyl, or R 52 and R 53 together with the atom to which they are attached to form a phenyl, R 53 is hydrogen, fluoro, chloro, or methyl; R 54 is hydrogen, halogen, C1-C3 alkyl, or C1-C3 alkoxy; L 5 is -O- or -CH2-, R 6 is hydrogen, halogen, C1-C6 alkyl, hydroxy, C1-C6 alkoxy, C1-C3 alkoxyC1-C3 alkyl, C3-C6 heterocycloalkyl, -C(O)-C1-C3 haloalkyl, or -NR 15 (CO)R 16 where R 15 is hydrogen or methyl, R 16 is C1-C3 alkyl; R 7 is C1-C3 alkyl or C1-C3 haloalkyl.

[0079] Embodiment 48 is A is -CH or -CCH3; D is -CH2-NH2, W is -CH, -CCH3, or N; R 51 、 R 52 , R 53 , and R 54 are each independently selected from hydrogen, fluoro, chloro, or methyl; L 5 is -O-, R 6 is hydrogen, fluoro, chloro, or methyl; R 7 is C1-C2 alkyl or C1-C2 haloalkyl.

[0080] Embodiment 49 is A and W are -CH; D is -CH2-NH2, R 51 、 R 52 , and R 53 are each independently selected from hydrogen, fluoro, chloro, and methyl; R 54 is hydrogen, L 5 is -O-, R 6 is hydrogen, R 7 is methyl.

[0081] Embodiment 50 is A and W are -CH; D is -CH2-NH2, R 51 and R 52 are each independently selected from fluoro, chloro, and methyl; R 53 and R 54 is hydrogen, L 5 is -O-, R 6 is hydrogen, R 7is methyl.

[0082] Embodiment 51 provides the method of embodiment 47, wherein A is CH.

[0083] Embodiment 52 provides the method of embodiment 47 or 48, wherein W is N.

[0084] Embodiment 53 provides the method of embodiment 47 or 48, wherein W is CH.

[0085] Embodiment 54 provides the method of any of embodiments 47-50, wherein D is -CH2-NH2.

[0086] Embodiment 55 is directed to R 54 The method of any one of embodiments 47-51, wherein is hydrogen or methyl.

[0087] Embodiment 56 is directed to R 54 The method of any one of embodiments 47-51, wherein is hydrogen.

[0088] Embodiment 57 is directed to R 54 The method of any one of embodiments 47-51, wherein is methyl.

[0089] Embodiment 58 is a method for the preparation of a PRMT5 inhibitor having the formula: [ka] for example, [ka] etc.,

[0090] In embodiment 59, L 5 The method of any one of embodiments 47-55, wherein is -CH2-.

[0091] In embodiment 60, L 5 The method of any one of embodiments 47-55, wherein is -O-.

[0092] Embodiment 61 is a compound comprising R 6 is hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, hydroxy, C1-C3 alkoxy, C1-C3 alkoxyC1-C3 alkyl, C3-C6 heterocycloalkyl, -C(O)-C1-C3 haloalkyl, -N(R 9 )2, or -NR 15 (CO)R 16 For example, R 6 is hydrogen, chloro, fluoro, methyl, ethyl, difluoromethyl, hydroxy, methoxy, ethoxy, (methoxy)methyl, (ethoxy)methyl, (methoxy)ethyl, (ethoxy)ethyl, oxetanyl, tetrahydrofuranyl, -C(O)-difluoromethyl, -NH, or -NH(CO)CH.

[0093] Embodiment 62 is a compound comprising R 6 is hydrogen, halogen, C1-C6 alkyl, or C1-C6 alkoxy, for example, R 6 is hydrogen, halogen, C1-C3 alkyl, or C1-C3 alkoxy.

[0094] Embodiment 63 is a compound comprising R 6 58. The method of any one of embodiments 47-57, wherein is hydrogen, chloro, fluoro, methyl, ethyl, methoxy, or ethoxy.

[0095] Embodiment 64 is directed to R 6 is halogen, C1-C3 alkyl, C1-C3 haloalkyl, hydroxy, C1-C3 alkoxy, C1-C3 alkoxyC1-C3 alkyl, C3-C6 heterocycloalkyl, -C(O)-C1-C3 haloalkyl, -N(R 9 )2, or -NR 15 (CO)R16 For example, R 6 is chloro, fluoro, methyl, ethyl, difluoromethyl, hydroxy, methoxy, ethoxy, (methoxy)methyl, (ethoxy)methyl, (methoxy)ethyl, (ethoxy)ethyl, oxetanyl, tetrahydrofuranyl, -C(O)-difluoromethyl, -NH, or -NH(CO)CH.

[0096] Embodiment 65 is directed to R 6 is halogen, C1-C6 alkyl, or C1-C6 alkoxy, for example, R 6 is halogen, C1-C3 alkyl, or C1-C3 alkoxy.

[0097] Embodiment 66 is directed to R 6 58. The method of any one of embodiments 47-57, wherein is chloro, fluoro, methyl, ethyl, methoxy, or ethoxy.

[0098] Embodiment 67 is directed to R 7 The method of any one of embodiments 47-63, wherein is methyl.

[0099] Embodiment 68 is directed to R 7 The method of any one of embodiments 47-63, wherein is ethyl.

[0100] Embodiment 69 is a method for producing 7 The method of any one of embodiments 47-63, wherein is propyl (e.g., isopropyl).

[0101] Embodiment 70 is a method for producing a compound according to the present invention 7 The method of any one of embodiments 47-63, wherein is difluoromethyl or trifluoromethyl.

[0102] Embodiment 71 is R 53 is hydrogen or methoxy, or R 53The method of any one of embodiments 47-67, wherein is hydrogen.

[0103] Embodiment 72 provides the method of embodiment 47, wherein the PRMT5 inhibitor is of the following formula: [ka]

[0104] Embodiment 73 is R 52 is fluoro and R 51 The method of any one of embodiments 47-69, wherein is hydrogen, fluoro, chloro, or methyl.

[0105] Embodiment 74 is R 52 is fluoro and R 51 The method of any one of embodiments 47-69, wherein is chloro.

[0106] Embodiment 75 is a method for producing 52 is fluoro and R 51 is methyl or hydrogen (e.g., R 52 is fluoro and R 51 is methyl or R 52 is fluoro and R 51 is hydrogen.

[0107] Embodiment 76 is a method for producing 51 and R 52 together with the atom to which they are attached form hydrofuranyl (e.g. [ka] The method of any one of embodiments 47 to 69 is provided, wherein

[0108] Embodiment 77 is a method for treating a PRMT5 inhibitor comprising administering to a patient [ka] The method of any one of embodiments 47 to 76 is provided, wherein

[0109] Embodiment 78 is a method for treating a PRMT5 inhibitor comprising administering to a patient [ka] The method of any one of embodiments 47 to 77 is provided, wherein

[0110] One aspect of the disclosure is that the PRMT5 inhibitor is a compound of formula (IIIA) (embodiment 79): [ka] or a pharma- ceutically acceptable salt thereof, wherein: A is CR 9 or N, D is -CH2-NH2, [ka] [ka] [ka] [ka] or [ka] and W is CR 9 or N, where R 9 is H or C1-C3 alkyl; R 2 but, [ka] [ka] [ka] or [ka] Forming In the formula, R 56 is hydrogen, fluoro, chloro, or methyl; G, Q, J, and U are independently C(H), C(R 5 ), and N, with the proviso that only one or two of G, Q, J, and U can be N; Each R 5 are independently hydroxy, 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 alkoxyC1-C3 alkyl; R 6 is hydrogen, halogen, C1-C6 alkyl, hydroxy, C1-C6 alkoxy, C1-C3 alkoxyC1-C3 alkyl, C3-C6 heterocycloalkyl, -C(O)-C1-C3 haloalkyl, or -NR 15 (CO)R 16 where R 15 is hydrogen or methyl, R 16 is C1-C3 alkyl; R 7 is C1-C3 alkyl or C1-C3 haloalkyl.

[0111] One aspect of the disclosure is that the PRMT5 inhibitor is a compound of formula (IIIA) (embodiment 80): [ka] or a pharma- ceutically acceptable salt thereof, wherein: A is CR 9 or N, D is -CH2-NH2, [ka] [ka] [ka] [ka] or [ka] and W is CR 9 or N, where R 9 is H or C1-C3 alkyl; R 2 but, [ka] [ka] [ka] [ka] or [ka] and In the formula, R 56is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy; R 6 is hydrogen, halogen, C1-C6 alkyl, hydroxy, C1-C6 alkoxy, C1-C3 alkoxyC1-C3 alkyl, C3-C6 heterocycloalkyl, -C(O)-C1-C3 haloalkyl, or -NR 15 (CO)R 16 where R 15 is hydrogen or methyl, R 16 is C1-C3 alkyl; R 7 is C1-C3 alkyl or C1-C3 haloalkyl.

[0112] Embodiment 81 provides the method of embodiment 79 or 80, wherein A is CH.

[0113] Embodiment 82 provides the method of embodiment 79 or 80, wherein W is N.

[0114] Embodiment 83 provides the method of embodiment 79 or 80, wherein W is CH.

[0115] Embodiment 84 provides the method of embodiment 79 or 80, wherein D is -CH2-NH2.

[0116] Embodiment 85 provides the method of embodiment 79 or 80, wherein the compound is of the formula: [ka]

[0117] Embodiment 86 is a method for producing a compound according to the present invention 2 but, [ka] [ka] or [ka] The method according to any one of embodiments 79 and 81 to 85, wherein

[0118] Embodiment 87 is an embodiment in which G, Q, J, and U are independently C(H) and C(R 5 87. The method of embodiment 86, wherein the method is selected from the group consisting of

[0119] Embodiment 88 provides the method of embodiment 86, wherein G, Q, J, and U are independently C(H).

[0120] Embodiment 89 is an embodiment in which 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), e.g., only one of G, Q, J, and U is C(R 5 87. The method of embodiment 86, wherein

[0121] Embodiment 90 is an embodiment in which U is N and G, Q, and J are independently C(H) and C(R 5 87. The method of embodiment 86, wherein the method is selected from the group consisting of

[0122] Embodiment 91 is an embodiment in which G is N and Q, J, and U are independently C(H) and C(R 5 87. The method of embodiment 86, wherein the method is selected from the group consisting of

[0123] Embodiment 92 is R 5 The method of any one of embodiments 79 or 81-91, wherein, if present, is hydroxy, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C3-C6 cycloalkoxy, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, or C1-C3 alkoxyC1-C3 alkyl.

[0124] Embodiment 93 is R 5 The method of any one of embodiments 79 or 81-91, wherein, if present, is hydroxy, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C3-C6 heterocycloalkyl, or C1-C3 alkoxyC1-C3 alkyl.

[0125] Embodiment 94 is R 5 The method of any one of embodiments 79 or 81-91, wherein, if present, is hydroxy, chloro, fluoro, methyl, ethyl, methoxy, ethoxy, 2,2-difluoroethoxy, oxetanyl, tetrahydrofuranyl, (methoxy)methyl, (ethoxy)methyl, (methoxy)ethyl, or (ethoxy)ethyl.

[0126] Embodiment 95 is a method for producing 5 When present, it is halogen, C1-C6 alkyl, or C1-C6 alkoxy, e.g., R 6 The method of any one of embodiments 79 or 81-91, wherein is halogen, C1-C3 alkyl, or C1-C3 alkoxy.

[0127] Embodiment 96 is a method for producing 5 The method of any one of embodiments 79 or 81-91, wherein, if present, is chloro, fluoro, methyl, ethyl, methoxy, or ethoxy.

[0128] Embodiment 97 is R 56 The method of any one of embodiments 79 or 81-91, wherein is fluoro, chloro, or methyl.

[0129] Embodiment 98 is R 2 but, [ka] [ka] or [ka] The method according to any one of embodiments 80 to 85, wherein

[0130] Embodiment 99 is R 56 The method of any one of embodiments 80-85 or 98, wherein is hydrogen, fluoro, chloro, or methyl.

[0131] Embodiment 100 is R 6 is hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, hydroxy, C1-C3 alkoxy, C1-C3 alkoxyC1-C3 alkyl, C3-C6 heterocycloalkyl, -C(O)-C1-C3 haloalkyl, -N(R 9 )2, or -NR 15 (CO)R 16 For example, R 6 is hydrogen, chloro, fluoro, methyl, ethyl, difluoromethyl, hydroxy, methoxy, ethoxy, (methoxy)methyl, (ethoxy)methyl, (methoxy)ethyl, (ethoxy)ethyl, oxetanyl, tetrahydrofuranyl, -C(O)-difluoromethyl, -NH, or -NH(CO)CH.

[0132] Embodiment 101 is R 6 is hydrogen, halogen, C1-C6 alkyl, or C1-C6 alkoxy, for example, R 6 is hydrogen, halogen, C1-C3 alkyl, or C1-C3 alkoxy.

[0133] Embodiment 102 is R 6 99. The method of any one of embodiments 79-99, wherein is hydrogen, chloro, fluoro, methyl, ethyl, methoxy, or ethoxy.

[0134] Embodiment 103 is R6 is hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, hydroxy, C1-C3 alkoxy, C1-C3 alkoxyC1-C3 alkyl, C3-C6 heterocycloalkyl, -C(O)-C1-C3 haloalkyl, -N(R 9 )2, or -NR 15 (CO)R 16 For example, R 6 is hydrogen, chloro, fluoro, methyl, ethyl, difluoromethyl, hydroxy, methoxy, ethoxy, (methoxy)methyl, (ethoxy)methyl, (methoxy)ethyl, (ethoxy)ethyl, oxetanyl, tetrahydrofuranyl, -C(O)-difluoromethyl, -NH, or -NH(CO)CH.

[0135] Embodiment 104 is a method for producing a 6 is halogen, C1-C6 alkyl, or C1-C6 alkoxy, for example, R 6 The method of any one of embodiments 79-99, wherein is halogen, C1-C3 alkyl, or C1-C3 alkoxy.

[0136] Embodiment 105 is a 6 The method of any one of embodiments 79-99, wherein is chloro, fluoro, methyl, ethyl, methoxy, or ethoxy.

[0137] Embodiment 106 is a method for producing a 7 The method of any one of embodiments 79-105, wherein is methyl.

[0138] Embodiment 107 is R 7 The method of any one of embodiments 79-105, wherein is ethyl.

[0139] Embodiment 108 is a method for producing a 7 The method of any one of embodiments 79-105, wherein is propyl (e.g., isopropyl).

[0140] Embodiment 109 is R 7 The method of any one of embodiments 79-105, wherein is difluoromethyl or trifluoromethyl.

[0141] In certain embodiments of the disclosed methods described herein, the PRMT5 inhibitor is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or [ka] It is.

[0142] In certain embodiments of the disclosed methods described herein, the PRMT5 inhibitor is [ka] [ka] [ka] [ka] [ka] [ka] or [ka] It is.

[0143] In certain embodiments of the disclosed methods described herein, the PRMT5 inhibitor is [ka] [ka] [ka] [ka] [ka] [ka] or [ka] It is.

[0144] In certain embodiments of the disclosed methods described herein, the PRMT5 inhibitor is [ka] It is.

[0145] In certain aspects, the disclosure provides a method for treating cancer in a subject, the method comprising administering to the subject: A therapeutically effective amount of docetaxel, [ka] Docetaxel, formula: [ka] The method includes administering a therapeutically effective amount of a PRMT5 inhibitor to a patient.

[0146] The PRMT5 inhibitors of the present disclosure and / or the taxanes of the present disclosure (e.g., docetaxel) may be provided as pharmaceutical compositions comprising a therapeutically effective amount of such inhibitors and pharma- ceutically acceptable carriers, excipients, and / or diluents. The PRMT5 inhibitors of the present disclosure and / or the taxanes of the present disclosure may be formulated by any method known in the art and prepared for administration by any route, including, but not limited to, parenteral, oral, sublingual, transdermal, topical, intranasal, intratracheal, or rectal.

[0147] The characteristics of the carrier will depend on the route of administration. As used herein, the term "pharmaceutical acceptable" refers to a non-toxic material that is compatible with a biological system, such as a cell, cell culture, tissue, or organism, and does not interfere with the effectiveness of the biological activity of the active ingredient. Thus, the pharmaceutical composition of the present disclosure may contain, in addition to the inhibitor, diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art. The preparation of pharmaceutical acceptable formulations is described, for example, in Remington's Pharmaceutical Sciences, 18th Edition, ed. A. Gennaro, Mack Publishing Co., Easton, Pa., 1990.

[0148] The PRMT5 inhibitors and taxanes of the present disclosure are administered in a therapeutically effective amount. As used herein, the phrase "therapeutically effective amount" or "effective amount" refers to an amount of active agent that induces a biological or pharmaceutical response sought in a tissue, system, subject, or human by a researcher, physician, or other clinician. Generally, a therapeutically effective amount is sufficient to deliver a biological or pharmaceutical response to a subject without causing significant toxic effects. The dosage of the active agent is about 1-500 mg / m per day. 2 , e.g., 5 to 400 mg / m per day 2 , more commonly, 10 to about 300 mg / m 2 per kg of recipient body weight per day. 2 Typical topical dosages will be in the range of 0.01 to 10% weight / weight in a suitable carrier.

[0149] In certain embodiments of the disclosed methods, the therapeutically effective amount of the PRMT5 inhibitor is in the range of about 0.01-300 mg / kg per day. For example, in certain embodiments, the therapeutically effective amount of the PRMT5 inhibitor is in the range of about 0.1-100 mg / kg per day, or 25-100 mg / kg per day, or 50-100 mg / kg per day.

[0150] In certain embodiments, the therapeutically effective amount of the PRMT5 inhibitor is less than 1%, e.g., less than 10%, or less than 25%, or less than 50% of the clinically established therapeutic amount (e.g., the amount required when the PRMT5 inhibitor is administered alone).

[0151] In certain embodiments of the disclosed methods, the therapeutically effective amount of taxane is about 1-500 mg / m per day. 2 , e.g., 5 to 400 mg / m per day 2 , more commonly 10–300 mg / m of recipient body weight per day. 2For example, in certain embodiments, the therapeutically effective amount of taxane ranges from about 30 to 300 mg / m per day. 2 (e.g., 50-250 mg / m per day) 2 , or 50 to 200 mg / m 2 , or 50 to 150 mg / m 2 ) range.

[0152] For example, in various embodiments, the taxane can be docetaxel. Thus, in certain embodiments of the methods of the present disclosure, the therapeutically effective amount of docetaxel is about 1-500 mg / m per day. 2 , e.g., 5 to 400 mg / m per day 2 , more commonly 10–300 mg / m of recipient body weight per day. 2 For example, in certain embodiments, the therapeutically effective amount of docetaxel ranges from about 30 to 300 mg / m per day. 2 (e.g., 50-250 mg / m per day) 2 , or 50 to 200 mg / m 2 , or 50 to 150 mg / m 2 ) range.

[0153] In certain embodiments, the therapeutically effective amount of the docetaxel inhibitor is less than 1%, e.g., less than 10%, or less than 25%, or less than 50%, or less than 75% of the clinically established therapeutic amount (e.g., the amount required when docetaxel is administered alone).

[0154] Combination therapy, in defining the use of the PRMT5 inhibitors of the present disclosure and taxanes (e.g., docetaxel), is intended to embrace sequential administration of each agent in a regimen that results in the beneficial effect of the drug combination (e.g., the PRMT5 inhibitors of the present disclosure and the taxanes can be formulated as separate compositions given sequentially), as well as embrace the co-administration of these agents substantially simultaneously, e.g., in a single dosage form having a fixed ratio of these active agents, or in multiple or separate dosage forms for each agent. The present disclosure is not limited to the order of administration: the PRMT5 inhibitors of the present disclosure can be administered either before or after (i.e., sequentially), or simultaneously (i.e., simultaneously) with the administration of the taxanes of the present disclosure.

[0155] The methods of the present disclosure are useful as first line treatments. Thus, in certain embodiments of the methods of the present disclosure, the subject has not previously received another first line therapy.

[0156] The method of the present disclosure is also useful as first-line maintenance or second-line treatment. Thus, in certain embodiments of the method of the present disclosure, the subject has previously completed another first-line therapy. For example, in certain embodiments, the method of the present disclosure can provide delay in the progression and recurrence of cancer in a subject who has previously completed another first-line chemotherapy. For example, in certain embodiments, the subject has previously completed platinum and / or taxane-based chemotherapy (e.g., FOLFIRINOX, carboplatin, cisplatin, oxaliplatin, paclitaxel, docetaxel, etc.). In certain embodiments of the method of the present disclosure, the subject has previously completed another first-line chemotherapy and is partially responsive to such chemotherapy.

[0157] definition For the sake of brevity, chemical moieties are defined and referred to primarily as monovalent chemical moieties (e.g., alkyl, aryl, etc.) throughout. Nevertheless, such terms may also be used to convey corresponding multivalent moieties under appropriate structural circumstances clear to one of skill in the art. For example, an "alkyl" moiety generally refers to a monovalent radical (e.g., CH3-CH2-), but in certain circumstances, a divalent linking moiety may be an "alkyl", in which case one of skill in the art would understand the alkyl to be the divalent radical equivalent to the term "alkylene" (e.g., -CH2-CH2-). Similarly, in situations where a divalent moiety is required and is described as an "aryl", one of skill in the art would understand the term "aryl" to refer to the corresponding divalent moiety, arylene. It is understood that all atoms have their normal valence numbers for bond formation (i.e., 4 for carbon, 3 for N, 2 for O, and 2, 4, or 6 for S depending on the oxidation state of S).

[0158] The term "amino" refers to --NH.sub.2.

[0159] The term "acyl" refers to -C(O)CH3.

[0160] As used herein, the term "acyl" refers to an alkylcarbonyl or arylcarbonyl substituent, where the alkyl and aryl moieties are as defined herein.

[0161] The term "alkyl" as used herein refers to saturated straight and branched chain aliphatic groups having 1 to 12 carbon atoms. Thus, "alkyl" includes C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30, C31, C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, ​​C47, C48, C49, C50, C51, C52, C53, C54, C55, C56, C57 10 , C 11 , and C 12 Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl.

[0162] As used herein, the term "alkenyl" refers to an unsaturated straight or branched chain aliphatic group having one or more carbon-carbon double bonds and having 2 to 12 carbon atoms. Thus, "alkenyl" includes C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30, C31, C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, ​​C47, C48, C49, C50, C51, C52, C53 10 , C 11 , and C 12 Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, and hexenyl.

[0163] The term "alkynyl" as used herein refers to an unsaturated straight or branched chain aliphatic group containing one or more carbon-carbon triple bonds having 2 to 12 carbon atoms. Thus, "alkynyl" includes C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30, C31, C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, ​​C47, C48, C49, C50, C51, C52, C53, C 10 , C 11 , and C 12 Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

[0164] An "alkylene", "alkenylene", or "alkynylene" group is an alkyl, alkenyl, or alkynyl group that is located between and functions to link two other chemical groups, as defined herein above. Examples of alkylene groups include, but are not limited to, methylene, ethylene, propylene, and butylene. Exemplary alkenylene groups include, but are not limited to, ethenylene, propenylene, and butenylene. Exemplary alkynylene groups include, but are not limited to, ethynylene, propynylene, and butynylene.

[0165] The term "alkoxy" refers to -OC1-C6 alkyl.

[0166] The term "cycloalkyl" as used herein refers to saturated and partially unsaturated cyclic hydrocarbon groups having 3 to 12 carbons. Thus, "cycloalkyl" includes C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C210, C220, C23, C24, C25, C26, C27, C28, C29, C30, C31, C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, ​​C47, C48, C49, C50, C51, C52, C53, C54, C55, C56, C57, C 10 , C 11 , and C 12 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.

[0167] The term "heteroalkyl" is as defined herein above, and one or more of the carbon atoms in the chain are independently O, S, or NR x and R x is hydrogen or C1-C3 alkyl. Examples of heteroalkyl groups include methoxymethyl, methoxyethyl, and methoxypropyl.

[0168] An "aryl" group is a C6-C aryl group containing one to three aromatic rings. 14 It is an aromatic moiety. Therefore, "aryl" includes C6, C 10 , C 13 , and C 14 Exemplary aryl groups include C6-C 10 It is an aryl group. Particular aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, and fluorenyl. "Aryl" groups also include fused polycyclic (e.g., bicyclic) ring systems in which one or more of the fused rings are non-aromatic, provided that at least one ring is aromatic, such as indenyl.

[0169] An "aralkyl" or "arylalkyl" group comprises an aryl group covalently bonded to an alkyl group, which in turn is bonded to another group via the alkyl moiety. Exemplary aralkyl groups include, but are not limited to, -(C1-C6)alkyl(C6-C8)alkyl, -(C1 ... 10) aryl. For example, arC1-C3 alkyl is an aryl group covalently linked to a C1-C3 alkyl.

[0170] A "heterocyclyl" or "heterocyclic" group is a mono- or bicyclic (fused or spiro) ring structure having three to twelve atoms (3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 atoms), e.g., four to eight atoms, in which one or more ring atoms are independently selected from -C(O)-, N, NR 4 , O, or S, with the remainder of the ring atoms being quaternary or carbonyl carbons. Examples of heterocyclic groups include, but are not limited to, epoxy, oxiranyl, oxetanyl, azetidinyl, aziridinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, thiazolidinyl, thiatanyl, dithianyl, trithianyl, azathianyl, oxathianyl, dioxolanyl, oxazolidinyl, oxazolidinonyl, decahydroquinolinyl, piperidonyl, 4-piperidonyl, thiomorpholinyl, dimethyl-morpholinyl, and morpholinyl. Specifically excluded from the scope of this term are compounds having adjacent ring O and / or ring S atoms.

[0171] As used herein, "L-heterocyclyl" refers to a heterocyclyl group covalently linked to another group via an alkylene linker.

[0172] 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 pi electrons shared within the cyclic array, and having, in addition to carbon atoms, 1 to 3 heteroatoms, each independently N, O, or S. Heteroaryl also includes fused polycyclic (e.g., bicyclic) ring systems in which one or more of the fused rings is 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 acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzo[d]oxazol-2(3H)-one, 2H-benzo[b][1,4]oxazin-3(4H)-one, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, furanyl, Furazanyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxa Zolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinucinyl Examples include lysinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienoxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl.

[0173] An "L-heteroaralkyl" or "L-heteroarylalkyl" group comprises a heteroaryl group covalently linked to another group via an alkylene linker. Examples of heteroalkyl groups include C1-C6 alkyl groups and heteroaryl groups having 5, 6, 9, or 10 ring atoms. Examples of heteroaralkyl groups include pyridylmethyl, pyridylethyl, pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl, imidazolylethyl, thiazolylmethyl, thiazolylethyl, benzimidazolylmethyl, benzimidazolylethyl, quinazolinylmethyl, quinolinylmethyl, quinolinylethyl, benzofuranylmethyl, indolinylethyl, isoquinolinylmethyl, isoinodylmethyl, cinnolinylmethyl, and benzothiophenylethyl. Compounds having adjacent ring O and / or ring S atoms are specifically excluded from the scope of this term.

[0174] An "arylene," "heteroarylene," or "heterocyclylene" group is a divalent aryl, heteroaryl, or heterocyclyl group, respectively, as defined herein above, that is positioned between and serves to connect two other chemical groups.

[0175] As used herein, when a moiety (e.g., cycloalkyl, aryl, heteroaryl, heterocyclyl, urea, etc.) is described as "optionally substituted" without explicitly reciting substituents, it means that the group optionally has 1 to 4, preferably 1 to 3, and more preferably 1 or 2 non-hydrogen substituents.

[0176] The term "halogen" or "halo" as used herein refers to chlorine, bromine, fluorine, or iodine.

[0177] The term "haloalkyl" refers to an alkyl chain in which one or more hydrogens have been replaced by halogen. Exemplary haloalkyls are trifluoromethyl, difluoromethyl, fluorochloromethyl, chloromethyl, and fluoromethyl.

[0178] The term "hydroxyalkyl" refers to -alkylene-OH. EXAMPLES

[0179] The methods of the present disclosure are further illustrated by the following examples, which are not to be construed as limiting the disclosure in scope or spirit to the particular procedures and compounds described therein.

[0180] Study design: The PRMT5 inhibitors of the present disclosure show selective activity in MTAP-deficient cancers by binding to and inhibiting PRMT5 when bound to the intracellular metabolite MTA.As mentioned above, MTAP is an enzyme in the methionine salvage pathway, and its deletion in cancer cells leads to the accumulation of MTA in these cells.PRMT5 is an essential enzyme required for cell survival, and therefore, the PRMT5 inhibitors of the present disclosure represent a novel approach to selectively treat MTAP-deficient cancers.

[0181] It is highly unlikely that a single mutation will cause cancer, and in most cases, it is multiple mutations that cause cancer to develop.The inventors have found that the use of combination therapy improves the treatment of certain cancers with PRMT5 inhibitors.In particular, the inventors have surprisingly found that combination therapy of PRMT5 inhibitors and taxanes (e.g., docetaxel) provides higher antitumor activity compared to either inhibitor alone.

[0182] Test procedure: Immunocompromised female nu / nu or BALBC / Nude mice were implanted with 3 × 10 6 ~1×10 7 Human cancer cells were implanted subcutaneously. The tumors were approximately 100–150 mm 3The tumor volume was measured using calipers until the tumor volume reached 100%. Animals were randomized to receive A) vehicle (0.5% methylcellulose (4000cps) / 0.2% Tween80 in water), B) PRMT5 inhibitor, C) docetaxel, or D) PRMT5 inhibitor and docetaxel, administered according to the indicated route, schedule, and duration of treatment. Tumor volumes were measured twice weekly (n=5 / treatment group). Mean tumor volumes and standard error of the mean were calculated and plotted in GraphPad for each study day.

[0183] Example 1 This example was carried out according to the test procedure described above. The PRMT5 inhibitor was MRTX1719 administered once daily (QD) at 100 mg / kg. MRTX1719 is (2M)-2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile, and is disclosed as Example 16-8 on page 307 of International Patent Publication No. 2021 / 050915A1, published March 18, 2021, which is incorporated by reference in its entirety.

[0184] The docetaxel used in this example was supplied by Selleck Chemicals, Cat#S1148, Lot6.

[0185] The results are provided in Figure 1 and Table 1. The combination of MRTX1719 and docetaxel resulted in greater antitumor activity, as measured by change in tumor volume over time, compared to either compound alone in this NCI-H1650 model. [Table 1]

[0186] Example 2 Essentially the same procedure was repeated as in Example 1, except for mice bearing NCI-H2228 xenograft tumors. The results are shown in FIG. [Table 2]

[0187] Example 3 Essentially the same procedure was repeated as in Example 1, except for mice bearing A549 xenograft tumors. The results are shown in FIG. [Table 3]

[0188] Example 4 Essentially the same procedure was repeated as in Example 1, except for mice bearing HCC4006 xenograft tumors. The results are shown in FIG. [Table 4]

[0189] Example 5 Essentially the same procedure was repeated as in Example 1, except for mice bearing SW1573 xenograft tumors. The results are shown in FIG. [Table 5]

[0190] Example 6 Essentially the same procedure as in Example 1 was repeated, except for mice bearing LU99 xenograft tumors. The results are shown in FIG. [Table 6]

[0191] Example 7 Essentially the same procedure as in Example 1 was repeated, except for mice bearing MIAPaCa-2 xenograft tumors. The results are shown in FIG. [Table 7]

[0192] Example 8 Essentially the same procedure as in Example 1 was repeated, except for mice bearing KP4 xenograft tumors. The results are shown in Figure 8 and Table 8. [Table 8]

[0193] Without wishing to be bound by theory, the inventors have observed that PRMT5 inhibition, such as by PRMT5 inhibitors as described elsewhere herein, may induce cell death in cancer tissues through DNA damage.Therefore, it has been hypothesized that providing an additional chemotherapeutic agent that also functions to damage DNA in a complementary or orthogonal manner to PRMT5 may help to enhance therapeutic efficacy.In certain embodiments, for example, docetaxel is administered in combination with a PRMT5 inhibitor.As disclosed herein, the combination is surprisingly found to effectively inhibit tumor volume in a synergistic manner.

[0194] It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes will be suggested to those skilled in the art in light thereof and are incorporated within the spirit and scope of this application and the appended claims. All publications, patents, and patent applications cited herein are incorporated by reference herein for all purposes.

Claims

1. A pharmaceutical composition for treating cancer in a subject, comprising a therapeutically effective amount of a taxane and a therapeutically effective amount of a protein arginine N-methyltransferase 5 (PRMT5) inhibitor.

2. The pharmaceutical composition of claim 1, wherein the cancer comprises a homozygous deletion of the methylthioadenosine phosphorylase (MTAP) gene.

3. 2. The pharmaceutical composition of claim 1, wherein the cancer further comprises a homozygous deletion of the cyclin-dependent kinase inhibitor 2A (CDKN2A) gene.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the cancer is lung cancer, pancreatic cancer, colon cancer, head and neck cancer, esophageal cancer, or melanoma.

5. The pharmaceutical composition according to any one of claims 1 to 3, wherein the cancer is lung cancer, pancreatic cancer, head and neck cancer, bladder cancer, esophageal cancer, lymphoma, stomach cancer, skin cancer, breast cancer, brain cancer, liver cancer, or colon cancer.

6. The pharmaceutical composition according to any one of claims 1 to 3, wherein the cancer is lung cancer (e.g., mesothelioma or non-small cell lung cancer (NSCLC) including adenocarcinoma and squamous cell), pancreatic cancer, head and neck cancer, 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).

7. The pharmaceutical composition of claim 1 , wherein the PRMT5 inhibitor is a methylthioadenosine (MTA)-cooperative PRMT5 inhibitor.

8. The PRMT5 inhibitor is 【Chemical 1】 or 【Chemistry 2】 The pharmaceutical composition of claim 1, wherein

9. The PRMT5 inhibitor is 【Chemistry 3】 The pharmaceutical composition of claim 1, wherein

10. The PRMT5 inhibitor is 【Chemistry 4】 The pharmaceutical composition of claim 9, wherein

11. The PRMT5 inhibitor is 【Chemistry 5】 The pharmaceutical composition of claim 1, wherein

12. 12. The pharmaceutical composition of any one of claims 1 and 7 to 11, wherein the therapeutically effective amount of the PRMT5 inhibitor ranges from about 0.01 to 300 mg / kg per day.

13. 12. The pharmaceutical composition of any one of claims 1 and 7 to 11, wherein the therapeutically effective amount of the PRMT5 inhibitor ranges from about 0.1 to 100 mg / kg per day.

14. 12. The pharmaceutical composition of any one of claims 1 and 7 to 11, wherein the therapeutically effective amount of the PRMT5 inhibitor is less than 1%, e.g., less than 10%, or less than 25%, or less than 50% of a clinically established therapeutic amount.

15. 10. The pharmaceutical composition of claim 1, wherein the taxane comprises at least one of docetaxel, paclitaxel, abraxane, and cabazitaxel.

16. 10. The pharmaceutical composition of claim 1, wherein the taxane comprises docetaxel.

17. 17. The pharmaceutical composition of claim 16, wherein the taxane is docetaxel.

18. The therapeutically effective amount of the taxane is about 1 to 500 mg / m per day ２ The pharmaceutical composition according to any one of claims 1 and 15 to 17, wherein the

19. The therapeutically effective amount of the taxane is about 10 to 300 mg / m per day ２ The pharmaceutical composition according to any one of claims 1 and 15 to 17, wherein the

20. 18. The pharmaceutical composition of any one of claims 1 and 15 to 17, wherein the therapeutically effective amount of the taxane is less than 1%, for example less than 10%, or less than 25%, or less than 50% of the clinically established therapeutic amount.

21. The pharmaceutical composition according to claim 1, wherein the taxane and the PRMT5 inhibitor are administered sequentially.

22. The pharmaceutical composition according to claim 1, wherein the taxane and the PRMT5 inhibitor are administered simultaneously.

23. The pharmaceutical composition of claim 1 , wherein the subject has previously undergone or completed first-line chemotherapy.

24. 24. The pharmaceutical composition of claim 23, wherein the first-line chemotherapy is a platinum and / or taxane-based chemotherapy.

25. A therapeutically effective amount of: 【Chemistry 6】 Docetaxel and a therapeutically effective amount of the formula: 【Chemistry 7】 A pharmaceutical composition for treating cancer in a subject, comprising a PRMT5 inhibitor of formula (I):

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