Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/50—Pyridazines; Hydrogenated pyridazines
  • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

• This disclosure relates to methods of treating cancer.
• This disclosure further relates to treating cancer in a subject with compounds that are inhibitors of protein arginine N- methyl transferase 5 (PRMT5), particularly in combination with cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors.
• PRMT5 protein arginine N- methyl transferase 5
• CDK4/6 cyclin-dependent kinase 4 and 6
• PRMT5 is a type II arginine methyltransferase that catalyzes the transfer of a methyl group from S-adenosyl-L-methionine (SAM) to an omega-nitrogen of the guanidino function of protein L-arginine residues (omega-monomethylation) and the transfer of a second methyl group to the other omega-nitrogen, yielding symmetric dimethylarginine (sDMA).
• SAM S-adenosyl-L-methionine
• sDMA symmetric dimethylarginine
• PRMT5 forms a complex with methylosome 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 (e.g., see Ho et al. (2013) PLoS ONE 8(2): e57008).
• MTAP methylthioadenosine phosphorylase
• One aspect of the disclosure provides methods for treating cancer in a subject. Such methods include administering to the subject a therapeutically effective amount of a CDK4/6 inhibitor and a therapeutically effective amount of a PRMT5 inhibitor.
• Also provided herein is a method for treating cancer in a subject in need thereof.
• Such methods include determining that the cancer is associated with MTAP homozygous deletion (e.g., an MTAP-associated cancer). These methods optionally further include determining that the cancer is associated with a CDKN2A homozygous deletion. Such methods further include administering to the subject a therapeutically effective amount of a CDK4/6 inhibitor and a therapeutically effective amount of a PRMT5 inhibitor.
• Figure 1 illustrates the results of the methods of Example 1 in the KRAS G12C and CDKN2A/MTAP DEL lung tumor xenograft LU99 model grown in immunodeficient mice.
• the PRMT5 inhibitor used in this method was MRTX9768 administered at 100 mg/kg twice a day (BID), and the CDK4/6 inhibitor was palbociclib administered at 130 mg/kg once a day (QD). Average tumor volume ⁇ standard error is plotted of the mean at study day as indicated.
• Figure 2 illustrates the results of the methods of Example 2 in the KRAS G12C and CDKN2A/MTAP DEL lung tumor xenograft LU99 model grown in immunodeficient mice.
• the PRMT5 inhibitor used in this method was MRTX7477 administered at 200 mg/kg BID, and the CDK4/6 inhibitor was palbociclib administered at 130 mg/kg QD. Average tumor volume ⁇ standard error is plotted of the mean at study day as indicated.
• Figure 3 illustrates the results of the methods of Example 3 in HCC4006 lung tumor xenograft model.
• the PRMT5 inhibitor used in this method was MRTX1719 administered at 100 mg/kg QD, and the CDK4/6 inhibitor was palbociclib administered at 130 mg/kg QD. Average tumor volume ⁇ standard error is plotted of the mean at study day as indicated.
• Figure 4 illustrates the results of the methods of Example 4 in SW1573 PRMT5-044 lung tumor xenograft model.
• the PRMT5 inhibitor used in this method was MRTX1719 administered at 50 mg/kg QD, and the CDK4/6 inhibitor was palbociclib administered at 130 mg/kg QD. Average tumor volume ⁇ standard error is plotted of the mean at study day as indicated.
• Figure 5 illustrates the results of the methods of Example 5 in H1650 lung tumor xenograft model.
• the PRMT5 inhibitor used in this method was MRTX1719 administered at 100 mg/kg QD, and the CDK4/6 inhibitor was palbociclib administered at 130 mg/kg QD. Average tumor volume ⁇ standard error is plotted of the mean at study day as indicated.
• Figure 6 illustrates the results of the methods of Example 6 in A549 PRMT-034 lung tumor xenograft model.
• the PRMT5 inhibitor used in this method was MRTX1719 administered at 100 mg/kg QD, and the CDK4/6 inhibitor was palbociclib administered at 130 mg/kg QD. Average tumor volume ⁇ standard error is plotted of the mean at study day as indicated.
• Figure 7 illustrates the results of the methods of Example 7 in PANC-05-04 pancreatic tumor xenograft model.
• the PRMT5 inhibitor used in this method was MRTX1719 administered at 100 mg/kg QD, and the CDK4/6 inhibitor was palbociclib administered at 130 mg/kg QD. Average tumor volume ⁇ standard error is plotted of the mean at study day as indicated.
• Figure 8 illustrates the results of the methods of Example 8 in BXPC-3 pancreatic tumor xenograft model.
• the PRMT5 inhibitor used in this method was MRTX1719 administered at 100 mg/kg QD, and the CDK4/6 inhibitor was palbociclib administered at 130 mg/kg QD. Average tumor volume ⁇ standard error is plotted of the mean at study day as indicated.
• Figure 9 illustrates the results of the methods of Example 9 in MKN45 gastric tumor xenograft model.
• the PRMT5 inhibitor used in this method was MRTX1719 administered at 100 mg/kg QD, and the CDK4/6 inhibitor was palbociclib administered at 130 mg/kg QD.
• Average tumor volume ⁇ standard error is plotted of the mean at study day as indicated. DETAILED DESCRIPTION OF THE DISCLOSURE
• the methods and compositions described herein can be configured by the person of ordinary skill in the art to meet the desired need.
• the present disclosure provides improvements in treating cancer in a subject.
• the terms “subject” or “patient” are used interchangeably, refers to any animal, including mammals, and most preferably humans.
• cancers such as lung, prostate, breast, brain, skin, cervical carcinomas, testicular carcinomas, etc. More particularly, cancers that may be treated by the compositions and methods of the invention include, but are not limited to tumor types such as astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate and thyroid carcinomas and sarcomas.
• tumor types such as astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate and thyroid carcinomas and sarcomas.
• these compounds can be used to treat: Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma;
• Gastrointestinal esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi’s sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary tract: kidney (adenocarcinoma, Wilm’s tumor (nephroblastoma), lymphoma, leukemia), bladder and
• Gynecological uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma); Hematologic: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myel
• the cancer is a MTAP- associated cancer.
• the cancer comprises MTAP gene homozygous deletion (MTAP DEL ).
• the subject may be identified or diagnosed as having MTAP-associated cancer where, for example, MTAP DEL is determined using a suitable assay or a kit.
• the subject is suspected of having MTAP-associated cancer or the subject has a clinical record indicating that the subject has MTAP-associated cancer.
• the cancer comprises a cyclin-dependent kinase inhibitor 2A (CDKN2A) gene homozygous deletion (CDKN2A DEL ).
• CDKN2A cyclin-dependent kinase inhibitor 2A
• the subject may be identified or diagnosed as having CDKN2A DEL where the deletion is determined using a suitable assay or a kit.
• the subject is suspected of having the CDKN2A DEL cancer, or the subject has a clinical record indicating that the subject has the CDKN2A DEL cancer.
• the cancer may further comprise a Kirsten rat sarcoma viral oncogene homolog (KRAS) gene mutation, such as glycine-to-cysteine (KRAS G12C ) gene mutation.
• KRAS Kirsten rat sarcoma viral oncogene homolog
• KRAS G12C glycine-to-cysteine gene mutation.
• the subject may be identified or diagnosed as having KRAS G12C cancer where KRAS G12C mutation is determined using a suitable assay or a kit.
• the subject is suspected of having the KRAS G12C cancer or the subject has a clinical record indicating that the subject has the KRAS G12C cancer.
• an assay is used to determine whether the patient has MTAP DEL and/or CDKN2A DEL and/or KRAS G12C using a sample (e.g., a biological sample or a biopsy sample such as a paraffin-embedded biopsy sample) from a subject.
• a sample e.g., a biological sample or a biopsy sample such as a paraffin-embedded biopsy sample
• Such assay includes, but is 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).
• the assays are typically performed, e.g., with at least one labelled nucleic acid probe or at least one labelled antibody or antigen-binding fragment thereof.
• the cancer in the methods of the disclosure is selected from lung cancer, pancreatic cancer, head and neck cancer, bladder cancer, esophageal cancer, lymphoma, stomach cancer, skin cancer, breast cancer, brain cancer, liver cancer, and colon cancer.
• the cancer in the methods of the disclosure is selected from lung cancer, pancreatic cancer, head and neck cancer, bladder cancer, esophageal cancer, lymphoma, stomach cancer, skin cancer, breast cancer, and brain cancer.
• the cancer in the methods of the disclosure is selected from lung cancer (e.g., mesothelioma or non-small cell lung cancer (NSCLC) including adenocarcinoma and squamous cell), pancreatic cancer, head and neck cancer (such as squamous cell carcinoma (HNSCC)), bladder cancer, esophageal cancer, lymphoma (e.g., diffuse large B-cell lymphoma), stomach cancer, melanoma, breast cancer, and brain cancer (e.g., glioblastoma multiforme and glioma).
• lung cancer e.g., mesothelioma or non-small cell lung cancer (NSCLC) including adenocarcinoma and squamous cell
• HNSCC head and neck cancer
• bladder cancer such as squamous cell carcinoma (HNSCC)
• esophageal cancer e.g., lymphoma (e.g., diffuse large B-cell lymph
• the cancer in the methods of the disclosure is selected from mesothelioma, NSCLC (e.g., adenocarcinoma and squamous cell), pancreatic cancer, HNSCC, and bladder cancer.
• NSCLC e.g., adenocarcinoma and squamous cell
• pancreatic cancer e.g., adenocarcinoma and squamous cell
• HNSCC adenocarcinoma and squamous cell
• bladder cancer e.g., adenocarcinoma and squamous cell
• the cancer is lung cancer.
• the lung cancer may be NSCLC (e.g., adenocarcinoma and squamous cell) or mesothelioma.
• NSCLC e.g., adenocarcinoma and squamous cell
• mesothelioma e.g., mesothelioma.
• the cancer is pancreatic cancer.
• the cancer is head and neck cancer.
• the cancer is bladder cancer.
• the CDK4/6 inhibitor is administered in the methods of the disclosure.
• a “CDK4/6 inhibitor” refers to compounds capable of negatively modulating or inhibiting all or a portion of the enzymatic activity of CDK4/6.
• the CDK4/6 inhibitors of the present disclosure interact with and/or irreversibly bind to CDK4/6 resulting in the inhibition of the enzymatic activity of CDK4/6 and blocking the transition from the G1 to the S phase of the cell cycle.
• the CDK4/6 inhibitor also inhibits CDK2, i.e. , it is a CDK 2/4/6 inhibitor.
• the CDK4/6 inhibitor is selected from palbociclib (sold as Ibrance ® , Pfizer Inc., New York, New York), abemaciclib (sold as Verzenio ® , Eli Lilly and Company, Indianapolis, Indiana), ribociclib (sold as Kisqali ® , Novartis Pharmaceuticals,
• the CDK4/6 inhibitor is trilaciclib (sold as CoselaTM, G1 Therapeutics, Inc., Durham, North Carolina).
• the CDK4/6 inhibitor is palbociclib.
• the PRMT5 inhibitor is also administered in the methods of the disclosure.
• a “PRMT5 inhibitor” as used herein refers to compounds of the disclosure as described herein. These compounds are capable of negatively modulating or inhibiting all or a portion of the enzymatic activity of the PRMT5, particularly, in the presence of bound MTA in vitro or in vivo or in cells expressing elevated levels of MTA.
• the PRMT5 inhibitor is a MTA-cooperative PRMT5 inhibitor.
• the PRMT5 inhibitor of the disclosure is any one of the PRMT5 inhibitors disclosed in International patent publication No. WO 2021/050915 A1, published 18 March 2021, incorporated by reference in its entirety.
• the PRMT5 inhibitor of the disclosure is any one of the PRMT5 inhibitors disclosed in U.S. provisional application No. 63/200,521, filed 11 March 2021, incorporated by reference in its entirety.
• the PRMT5 inhibitor in the methods of the disclosure as described herein is a compound of Formula IIA, MB or IIC (Embodiment 1): or a pharmaceutically acceptable salt thereof, wherein: methylene is bonded to E where E is C;
• E is C, CR 9 or N; each L is independently a bond or C 1 -C 3 alkylene;
• W is CR 9 or N; each X is independently a bond, O, S, -NR 4 - or -NR 4 C(0)-; each Z is independently a bond, -SO-, -S0 2 -, -CH(OH)- or -C(O)-; each R 2 is independently hydroxy, halogen, cyano, cyanomethyl, -(NR 4 ) 2 , hydroxyalkyl, alkoxy, -S0 2 CrC 3 alkyl, -X-arCrCsalkyl, heteroalkyl, C 2 -C 4 alkynyl, -X-haloalkyl, -X- C 1 -C 5 alkyl, -Z-C 1 -C 5 alkyl, heterocyclyl, -X-L-cycloalkyl, -Z-cycloalkyl, -X-aryl, -Z-aryl, or -X-heteroaryl, wherein the heterocyclyl,
• R 6 is hydrogen, halogen, C 1 -C 3 alkyl, haloalkyl, hydroxy, alkoxy, C 1 -C 3 alkyl-alkoxy, N(R 9 ) 2 , NR 9 C(0)R 9 , C(0)R 9 , oxetane and THF;
• R 7 is H or C 1 -C 3 alkyl optionally substituted with one or more halogen
• R 8 is H or C 1 -C 3 alkyl; and each R 9 is independently H or C 1 -C 3 alkyl, halogen or haloalkyl.
• Embodiment 2 provides the PRMT5 inhibitor in the methods of the disclosure as a compound of Formula IIA:
• Embodiment 3 provides the PRMT5 inhibitor in the methods of the disclosure as a compound of Formula MB:
• Embodiment 4 provides the PRMT5 inhibitor in the methods of the disclosure as a compound of Formula IIC:
• Embodiment 5 provides the method of any of embodiments 1-4, wherein W is CR 9 .
• Embodiment 6 provides the method of any of embodiments 1-4, wherein A is CR 9 .
• Embodiment 7 provides the method of any of embodiments 1-4, wherein E is N.
• Embodiment 8 provides the method of any of embodiments 1-7, wherein W is CR 9 , A is CR 9 and E is N.
• Embodiment 9 provides the method of any of embodiments 1-8, wherein R 2 is selected from: benzothiophene, naphthalene, quinoline, chromane, isochromane, dihydrobenzodioxine, indolazine, tetrahydroindolazine, dihydroisobenzofuran, benzene, isoquinolinone, benzodioxone, thienopyridine, tetrahydroindolone, indolizine, dihydroindolizinone, imadazopyridinone, thienopyrimidine, thiophene, pyrrolopyrimidinone, thiazolopyridinone, dihydropyrrolizine, isoindalone and tetrahydroisoquinoline.
• R 2 is selected from: benzothiophene, naphthalene, quinoline, chromane, isochromane, di
• Embodiment 10 provides the method of any of embodiments 1-8, wherein each R 5 is independently cyano, oxo, halogen, C1 - C3 alkyl, hydroxy, hydroxyalkyl, alkoxy-C1-C3alkyl, -X-L-heterocyclyl optionally substituted with one or more C1-C3alkyl or oxo, -X-L-cycloalkyl optionally substituted with C1-C3 alkyl or oxo.
• Embodiment 11 provides the method of any of embodiments 1-8, wherein R 6 is selected from hydrogen, hydroxy, chlorine, -NHC(0)CH 3 , -C(0)CF 2 H, -NH 2 , -CF 2 , -CH3, -O- CH 2 CHS, -CH 2 -CH 2 -0-CH 3 , oxetane and THF.
• Embodiment 12 provides the method of any of embodiments 1-11 , where one of L, X and Z is a bond.
• Embodiment 13 provides the method of embodiment 12, wherein all of L, X and Z are bonds.
• PRMT5 inhibitor is a compound of the formula (NIC) (Embodiment 14): or a pharmaceutically acceptable salt thereof, wherein
• W is CR 9 or N, where R 9 is H or C1-C3 alkyl
• G, Q, J and U are independently selected from C(H), C(R 5 ), and N, provided only one or two of G, Q, J, and U can be 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 alkoxyCrCs alkyl;
• R 6 is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, hydroxy, C1-C6 alkoxy, C1-C3 alkoxyCr C 3 alkyl, C 3 -C 6 heterocycloalkyl, -C(0)-C C 3 haloalkyl, -N(R 9 ) 2 , or -NR 15 (CO)R 16 , where each R 9 is independently H or C 1 -C 3 alkyl, R 15 is hydrogen or methyl, and R 16 is C 1 -C 3 alkyl; and R 7 is C 1 -C 3 alkyl or C 1 -C 3 haloalkyl.
• Embodiment 15 provides the method according to embodiment 14, wherein A is CH.
• Embodiment 16 provides the method according to embodiment 14 or 15, wherein W is N.
• Embodiment 17 provides the method according to embodiment 14 or 15, wherein W is CH.
• Embodiment 18 provides the method according to any of embodiments 14-17, wherein D is -CH2-NH2.
• Embodiment 19 provides the method of the disclosure wherein the PRMT5 inhibitor is a compound according to embodiment 14 of the formula:
• Embodiment 20 provides the method according to any of embodiments 14-19, wherein R 6 is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, hydroxy, C1-C6 alkoxy, C1-C3 alkoxyCrC3 alkyl, C3-C6 heterocycloalkyl, -C(0)-CrC3 haloalkyl, -N(R 9 )2, or -NR 15 (CO)R 16 .
• R 6 is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, hydroxy, C1-C6 alkoxy, C1-C3 alkoxyCrC3 alkyl, C3-C6 heterocycloalkyl, -C(0)-CrC3 haloalkyl, -N(R 9 )2, or -NR 15 (CO)R 16 .
• Embodiment 21 provides the method according to any of embodiments 14-19, wherein R 6 is hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, hydroxy, C1-C3 alkoxy, C1-C3 alkoxyCrC3 alkyl, C3-C6 heterocycloalkyl, -C(0)-CrC 3 haloalkyl, -N(R 9 ) 2 , or -NR 15 (CO)R 16 .
• R 6 is hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, hydroxy, C1-C3 alkoxy, C1-C3 alkoxyCrC3 alkyl, C3-C6 heterocycloalkyl, -C(0)-CrC 3 haloalkyl, -N(R 9 ) 2 , or -NR 15 (CO)R 16 .
• Embodiment 22 provides the method according to any of embodiments 14-19, wherein R 6 is hydrogen, chloro, fluoro, methyl, ethyl, difluoromethyl, hydroxy, methoxy, ethoxy, (methoxy)methyl, (ethoxy)methyl, (methoxy)ethyl, (ethoxy)ethyl, oxetanyl, tetrahydrofuranyl, -C(0)-difluoromethyl, -IMH2, or -NH(CO)CH3.
• Embodiment 23 provides the method according to any of embodiments 14-19, wherein R 6 is halogen, C1-C6 alkyl, C1-C6 haloalkyl, hydroxy, C1-C6 alkoxy, C1-C3 alkoxyCr C 3 alkyl, C 3 -Ce heterocycloalkyl, -C(0)-Ci-C 3 haloalkyl, -N(R 9 ) 2 , or -NR 15 (CO)R 16 .
• Embodiment 24 provides the method according to any of embodiments 14-19, wherein R 6 is halogen, C1-C3 alkyl, C1-C3 haloalkyl, hydroxy, C1-C3 alkoxy, C1-C3 alkoxyCr C 3 alkyl, C 3 -C 6 heterocycloalkyl, -C(0)-C C 3 haloalkyl, -N(R 9 ) 2 , or -NR 15 (CO)R 16 .
• Embodiment 25 provides the method according to any of embodiments 14-19, wherein R 6 is chloro, fluoro, methyl, ethyl, difluoromethyl, hydroxy, methoxy, ethoxy, (methoxy) methyl, (ethoxy) methyl, (methoxy)ethyl, (ethoxy) ethyl, oxetanyl, tetrahydrofuranyl, -C(0)-difluoromethyl, -NH 2 , or -NH(CO)CH 3 .
• Embodiment 26 provides the method according to any of embodiments 23-25, wherein each G, Q, J and U is independently C(H).
• Embodiment 27 provides the method according to any of embodiments 23-25, wherein G, Q, J and U are independently selected from C(H) and C(R 5 ).
• Embodiment 28 provides the method according to any of embodiments 23-25, wherein G, Q, J and U are independently selected from C(H) and N.
• Embodiment 29 provides the method according to any of embodiments 14-19, wherein
• 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 selected from C(H), C(R 5 ) and N, wherein 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 alkoxyCrC 3 alkyl.
• Embodiment 30 provides the method according to embodiment 29, wherein one or two of G, Q, J and U is N.
• Embodiment 31 provides the method according to any of embodiments 14-19, wherein
• 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 selected from C(H) and C(R 5 ), wherein 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 alkoxyCrCs alkyl.
• Embodiment 32 provides the method according to embodiment 31 , wherein 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 ).
• Embodiment 33 provides the method according to embodiment 31 , wherein two of G, Q, J, and U is C(R 5 ), and the remaining G, Q, J, and U are independently C(H).
• Embodiment 34 provides the method according to embodiment 31 , wherein three of G, Q, J, and U is C(R 5 ), and the remaining G, Q, J, and U is C(H).
• Embodiment 35 provides the method according to any of embodiments 14-19, wherein G, Q, J, and U together with the thiophene to which they are attached form:
• Embodiment 36 provides the method according to embodiment 35, wherein G, Q, J, and U together with the thiophene ring to which they are attached form a benzo[Jb]thiophene.
• Embodiment 37 provides the method according to any one of embodiments 14-36, wherein R 5 , 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 alkoxyCrCs alkyl.
• Embodiment 38 provides the method according to any one of embodiments 14-36, wherein R 5 , if present, is hydroxy, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C3-C6 heterocycloalkyl, or C1-C3 alkoxyCrCs alkyl.
• Embodiment 39 provides the method according to any one of embodiments 14-36, wherein R 5 , if present, is hydroxy, chloro, fluoro, methyl, ethyl, methoxy, ethoxy, 2,2- difluoroethoxy, oxetanyl, tetrahydrofuranyl, (methoxy) methyl, (ethoxy)methyl, (methoxy)ethyl, or (ethoxy)ethyl.
• Embodiment 40 provides the method according to any one of embodiments 14-39, wherein R 7 is methyl.
• Embodiment 41 provides the method according to any one of embodiments 14-39, wherein R 7 is ethyl.
• Embodiment 42 provides the method according to any one of embodiments 14-39, wherein R 7 is propyl (e.g., isopropyl).
• Embodiment 43 provides the method according to any one of embodiments 14-39, wherein R 7 is difluoromethyl or trifluoromethyl.
• Embodiment 44 provides the method according to embodiment 14, wherein the PRMT5 inhibitor is of the formula: wherein
• 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 alkoxyCrC3 alkyl;
• R 6 is hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, hydroxy, C1-C3 alkoxy, C1-C3 alkoxyCrC3 alkyl, C3-C6 heterocycloalkyl, -C(0)-CrC3 haloalkyl, -N(R 9 )2, or -NR 15 (CO)R 16 .
• Embodiment 45 provides the method according to embodiment 14, wherein the PRMT5 inhibitor is of the formula: wherein
• each R 5 is independently hydroxy, halogen, C1-C 3 alkyl, C1-C 3 haloalkyl, C1-C 3 alkoxy, C1-C 3 haloalkoxy, C 3 -C 6 heterocycloalkyl, or C1-C 3 alkoxyCrC3 alkyl;
• R 6 is halogen, C1-C 3 alkyl, C1-C 3 haloalkyl, hydroxy, C1-C 3 alkoxy, C1-C 3 alkoxyCrCs alkyl, C 3 -C 6 heterocycloalkyl, -C(0)-C C 3 haloalkyl, -N(R 9 ) 2 , or -NR 15 (CO)R 16 .
• Embodiment 46 provides the method according to embodiment 14, wherein the PRMT5 inhibitor is of the formula: wherein
• each R 5 is independently hydroxy, halogen, C1-C 3 alkyl, C1-C 3 haloalkyl, C1-C 3 alkoxy, C1-C 3 haloalkoxy, C 3 -C 6 heterocycloalkyl, or C1-C 3 alkoxyCrCs alkyl.
• Embodiment 47 provides the method of the disclosure wherein the PRMT5 inhibotor is a compound of the formula (NIB): or a pharmaceutically acceptable salt thereof, wherein
• W is CR 9 or N, where R 9 is H or C1-C 3 alkyl
• R 51 is hydrogen, fluoro, chloro, or methyl, or R 51 and R 52 together with 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 atoms to which they are attached form a phenyl;
• R 53 is hydrogen, fluoro, chloro, or methyl
• R 54 is hydrogen, halogen, C 1 -C 3 alkyl, or C 1 -C 3 alkoxy;
• L 5 is -O- or -CH2-
• R 6 is hydrogen, halogen, CrC 6 alkyl, hydroxy, CrC 6 alkoxy, C1-C 3 alkoxyCrCs alkyl, C 3 -C 6 heterocycloalkyl, -C(0)-Ci-C 3 haloalkyl, or -NR 15 (CO)R 16 , where R 15 is hydrogen or methyl, and R 16 is C1-C 3 alkyl;
• R 7 is C 1 -C 3 alkyl or C 1 -C 3 haloalkyl.
• Embodiment 48 provides the method according to embodiment 47, wherein:
• A is -CH or -CCHs
• D is -CH2-NH2
• W is -CH, -CCHs, 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; and R 7 is C1-C2 alkyl or C1-C2 haloalkyl.
• Embodiment 49 provides the method according to embodiment 47 or embodiment 48, wherein:
• 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 -0-
• R 6 is hydrogen; and R 7 is methyl.
• Embodiment 50 provides the method according to any of embodiments 47-49, wherein:
• 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 are hydrogen
• L 5 is -0-
• R 6 is hydrogen; and R 7 is methyl.
• Embodiment 51 provides the method according to embodiment 47, wherein A is CH.
• Embodiment 52 provides the method according to embodiment 47 or 48, wherein W is N.
• Embodiment 53 provides the method according to embodiment 47 or 48, wherein W is CH.
• Embodiment 54 provides the method according to any of embodiments 47-50, wherein D is -CH2-NH2.
• Embodiment 55 provides the method according to any of embodiments 47-51 , wherein R 54 is hydrogen or methyl.
• Embodiment 56 provides the method according to any of embodiments 47-51 , wherein R 54 is hydrogen.
• Embodiment 57 provides the method according to any of embodiments 47-51 , wherein R 54 is methyl.
• Embodiment 58 provides the method according to embodiment 47, where the PRMT5 inhibitor is of the formula:
• Embodiment 59 provides the method according to any of embodiments 47-55, wherein L 5 is - CH 2 -
• Embodiment 60 provides the method according to any of embodiments 47-55, wherein L 5 is -0-.
• Embodiment 61 provides the method according to any of embodiments 47-57, wherein R 6 is hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, hydroxy, C1-C3 alkoxy, C1-C3 alkoxyCrC3 alkyl, C3-C6 heterocycloalkyl, -C(0)-CrC3 haloalkyl, -N(R 9 )2, or -NR 15 (CO)R 16 ; for example, wherein R 6 is hydrogen, chloro, fluoro, methyl, ethyl, difluoromethyl, hydroxy, methoxy, ethoxy, (methoxy)methyl, (ethoxy) methyl, (methoxy)ethyl, (ethoxy)ethyl, oxetanyl, tetrahydrofuranyl, -C(0)-difluoromethyl, -NH2, or -NH(CO)CH3.
• Embodiment 62 provides the method according to any of embodiments 47-57, wherein 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.
• Embodiment 63 provides the method according to any of embodiments 47-57, wherein R 6 is hydrogen, chloro, fluoro, methyl, ethyl, methoxy, or ethoxy.
• Embodiment 64 provides the method according to any of embodiments 47-57, wherein R 6 is halogen, C1-C3 alkyl, C1-C3 haloalkyl, hydroxy, C1-C3 alkoxy, C1-C3 alkoxyCr C3 alkyl, C3-C6 heterocycloalkyl, -C(0)-CrC 3 haloalkyl, -N(R 9 ) 2 , or -NR 15 (CO)R 16 ; for example, wherein R 6 is chloro, fluoro, methyl, ethyl, difluoromethyl, hydroxy, methoxy, ethoxy, (methoxy)methyl, (ethoxy)methyl, (methoxy)ethyl, (ethoxy)ethyl, oxetanyl, tetrahydrofuranyl, -C(0)-difluoromethyl, -NH2, or -NH(CO)CH3.
• Embodiment 65 provides the method according to any of embodiments 47-57, wherein R 6 is halogen, C1-C6 alkyl, or C1-C6 alkoxy; for example, R 6 is halogen, C1-C3 alkyl, or C1-C3 alkoxy.
• Embodiment 66 provides the method according to any of embodiments 47-57, wherein R 6 is chloro, fluoro, methyl, ethyl, methoxy, or ethoxy.
• Embodiment 67 provides the method according to any one of embodiments 47-63, wherein R 7 is methyl.
• Embodiment 68 provides the method according to any one of embodiments 47-63, wherein R 7 is ethyl.
• Embodiment 69 provides the method according to any one of embodiments 47-63, wherein R 7 is propyl (e.g., isopropyl).
• Embodiment 70 provides the method according to any one of embodiments 47-63, wherein R 7 is difluoromethyl or trifluoromethyl.
• Embodiment 71 provides the method according to any of embodiments 47-67, wherein R 53 is hydrogen or methoxy; or wherein R 53 is hydrogen.
• Embodiment 72 provides the method according to embodiment 47, where the PRMT5 inhibitor is of the formula:
• Embodiment 73 provides the method according to any one of embodiments 47-69, wherein R 52 is fluoro, and R 51 is hydrogen, fluoro, chloro, or methyl.
• Embodiment 74 provides the method according to any one of embodiments 47-69, wherein R 52 is fluoro, and R 51 is chloro.
• Embodiment 75 provides the method according to any one of embodiments 47-69, wherein R 52 is fluoro, and R 51 is methyl or hydrogen (for example, R 52 is fluoro and R 51 is methyl; or R 52 is fluoro and R 51 is hydrogen).
• Embodiment 76 provides the method according to any one of embodiments 47-69, wherein R 51 and R 52 together with atoms to which they are attached form a hydrofuranyl [0116] Embodiment 77 provides the method according to any one of embodiments 47-76, wherein the PRMT5 inhibitor
• Embodiment 78 provides the method according to any one of embodiments 47-77, wherein the PRMT5 inhibitor
• PRMT5 inhibitor is a compound of the formula (IMA) (Embodiment 79): or a pharmaceutically acceptable salt thereof, wherein A is CR 9 or N; where R 56 is hydrogen, fluoro, chloro, or methyl,
• G, Q, J and U are independently selected from C(H), C(R 5 ), and N, provided only one or two of G, Q, J, and U can be N; each R 5 is independently hydroxy, halogen, C1-C6 alkyl, C1-C6 haloalkyl, Cr C 6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkoxy, C3-C6 cycloalkyl, C3- C 6 heterocycloalkyl, or C1-C3 alkoxyCrCs alkyl;
• R 6 is hydrogen, halogen, C1-C6 alkyl, hydroxy, C1-C6 alkoxy, C1-C3 alkoxyCrCs alkyl, C3-C6 heterocycloalkyl, -C(0)-Ci-C 3 haloalkyl, or -NR 15 (CO)R 16 , where R 15 is hydrogen or methyl, and R 16 is C1-C3 alkyl; and R 7 is C1-C3 alkyl or C1-C3 haloalkyl.
• PRMT5 inhibitor is a compound of the formula (IIIA) (Embodiment 80): or a pharmaceutically acceptable salt thereof, wherein A is CR 9 or N; where R 56 is 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 alkoxyCrCs alkyl, C3-C6 heterocycloalkyl, -C(0)-CrC 3 haloalkyl, or -NR 15 (CO)R 16 , where R 15 is hydrogen or methyl, and R 16 is C1-C3 alkyl; and R 7 is C1-C3 alkyl or C1-C3 haloalkyl.
• Embodiment 81 provides the method according to embodiment 79 or 80, wherein A is CH.
• Embodiment 82 provides the method according to embodiment 79 or 80, wherein W is N.
• Embodiment 83 provides the method according to embodiment 79 or 80, wherein W is CH.
• Embodiment 84 provides the method according to any of embodiments 79 or 80, wherein D is -CH 2 -NH 2 .
• Embodiment 85 provides the method according to embodiment 79 or 80, which is of the formula:
• Embodiment 87 provides the method according to embodiment 86, wherein G, Q, J and U are independently selected from C(H) and C(R 5 ).
• Embodiment 88 provides the method according to embodiment 86, wherein G, Q, J and U are independently C(H).
• Embodiment 89 provides the method according to embodiment 86, wherein 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 ).
• Embodiment 90 provides the method according to embodiment 86, wherein U is N, and G, Q, and J are independently selected from C(H) and C(R 5 ).
• Embodiment 91 provides the method according to embodiment 86, wherein G is N, and Q, J, and U are independently selected from C(H) and C(R 5 ).
• Embodiment 92 provides the method according to any one of embodiments 79 or 81- 91, wherein R 5 , if present, is hydroxy, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, Cr C3 haloalkoxy, C3-C6 cycloalkoxy, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, or C1-C3 alkoxyCrC 3 alkyl.
• Embodiment 93 provides the method according to any one of embodiments 79 or SI- 91 , wherein R 5 , if present, is hydroxy, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, Cr C3 haloalkoxy, C3-C6 heterocycloalkyl, or C1-C3 alkoxyCrCs alkyl.
• Embodiment 94 provides the method according to any one of embodiments 79 or SI- 91 , wherein R 5 , if present, is hydroxy, chloro, fluoro, methyl, ethyl, methoxy, ethoxy, 2,2- difluoroethoxy, oxetanyl, tetrahydrofuranyl, (methoxy) methyl, (ethoxy)methyl, (methoxy)ethyl, or (ethoxy)ethyl.
• Embodiment 95 provides the method according to any one of embodiments 79 or SI- 91 , wherein R 5 , if present, is halogen, C1-C6 alkyl, or C1-C6 alkoxy; for example, R 6 is halogen, C1-C3 alkyl, or C1-C3 alkoxy.
• Embodiment 96 provides the method according to any one of embodiments 79 or SI- 91 , wherein R 5 , if present, is chloro, fluoro, methyl, ethyl, methoxy, or ethoxy.
• Embodiment 97 provides the method according to any one of embodiments 79 or SI- 91 , wherein R 56 is fluoro, chloro, or methyl.
• Embodiment 98 provides the method according to embodiment 80-85, wherein R 2 is
• Embodiment 99 provides the method according to any of embodiments 80-85 or 98, wherein R 56 is hydrogen, fluoro, chloro, or methyl.
• Embodiment 100 provides the method according to any of embodiments 79-99, wherein R 6 is hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, hydroxy, C1-C3 alkoxy, C1-C3 alkoxyCrCs alkyl, C3-C6 heterocycloalkyl, -C(0)-CrC3 haloalkyl, -N(R 9 )2, or -NR 15 (CO)R 16 ; for example, wherein R 6 is hydrogen, chloro, fluoro, methyl, ethyl, difluoromethyl, hydroxy, methoxy, ethoxy, (methoxy)methyl, (ethoxy) methyl, (methoxy)ethyl, (ethoxy)ethyl, oxetanyl, tetrahydrofuranyl, -C(0)-difluoromethyl, -NH2, or -NH(CO)CH3.
• Embodiment 101 provides the method according to any of embodiments 79-99, wherein 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.
• Embodiment 102 provides the method according to any of embodiments 79-99, wherein R 6 is hydrogen, chloro, fluoro, methyl, ethyl, methoxy, or ethoxy.
• Embodiment 103 provides the method according to any of embodiments 79-99, wherein R 6 is halogen, C1-C3 alkyl, C1-C3 haloalkyl, hydroxy, C1-C3 alkoxy, C1-C3 alkoxyCr C3 alkyl, C3-C6 heterocycloalkyl, -C(0)-CrC 3 haloalkyl, -N(R 9 ) 2 , or -NR 15 (CO)R 16 ; for example, wherein R 6 is chloro, fluoro, methyl, ethyl, difluoromethyl, hydroxy, methoxy, ethoxy, (methoxy)methyl, (ethoxy)methyl, (methoxy)ethyl
• Embodiment 104 provides the method according to any of embodiments 79-99, wherein R 6 is halogen, C1-C6 alkyl, or C1-C6 alkoxy; for example, R 6 is halogen, C1-C3 alkyl, or C1-C3 alkoxy.
• Embodiment 105 provides the method according to any of embodiments 79-99, wherein R 6 is chloro, fluoro, methyl, ethyl, methoxy, or ethoxy.
• Embodiment 106 provides the method according to any one of embodiments 79-105, wherein R 7 is methyl.
• Embodiment 107 provides the method according to any one of embodiments 79-105, wherein R 7 is ethyl.
• Embodiment 108 provides the method according to any one of embodiments 79-105, wherein R 7 is propyl (e.g., isopropyl).
• Embodiment 109 provides the method according to any one of embodiments 79-105, wherein R 7 is difluoromethyl or trifluoromethyl.
• the PRMT5 inhibitor is:
• the PRMT5 inhibitor is: [0151] In certain embodiments of the methods of the disclosure as described herein, the PRMT5 inhibitor is:
• PRMT5 inhibitor is:
• the PRMT5 inhibitor of the disclosure and/or the CDK4/6 inhibitor of the disclosure may be provided as a pharmaceutical composition comprising a therapeutically effective amount of such inhibitor and a pharmaceutically acceptable carrier, excipient, and/or diluents.
• the PRMT5 inhibitor of the disclosure and/or the CDK4/6 inhibitor of the disclosure may be formulated by any method well known in the art and may be prepared for administration by any route, including, without limitation, parenteral, oral, sublingual, transdermal, topical, intranasal, intratracheal, or intrarectal.
• the PRMT5 inhibitor of the disclosure and/or the CDK4/6 inhibitor of the disclosure are administered intravenously in a hospital setting.
• administration may preferably be by the oral route.
• pharmaceutically acceptable means a non-toxic material that is compatible with a biological system such as a cell, cell culture, tissue, or organism, and that does not interfere with the effectiveness of the biological activity of the active ingredient(s).
• pharmaceutical compositions of the 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 pharmaceutically acceptable formulations is described in, e.g., Remington’s Pharmaceutical Sciences, 18 th Edition, ed. A. Gennaro, Mack Publishing Co., Easton, Pa., 1990.
• the PRMT5 inhibitor and the CDK4/6 inhibitor of the disclosure are administered in a therapeutically effective amount.
• therapeutically effective amount refers to the amount of active agent that elicits the biological or medicinal response that is being sought in a tissue, system, subject or human by a researcher, medical doctor or other clinician. In general, the therapeutically effective amount is sufficient to deliver the biological or medicinal response to the subject without causing serious toxic effects.
• a dose of the active agent may be in the range from about 0.01 to 300 mg/kg per day, such as 0.1 to 100 mg/kg per day, more generally 0.5 to about 25 mg/kg body weight of the recipient per day.
• a typical topical dosage will range from 0.01 to 3% wt/wt in a suitable carrier.
• the therapeutically effective amount of the PRMT5 inhibitor is in the range of about 0.01 to 300 mg/kg per day.
• the therapeutically effective amount of the PRMT5 inhibitor is in the range of about 0.1 to 100 mg/kg per day, or 25 to 100 mg/kg per day, or 50 to 100 mg/kg per day.
• the therapeutically effective amount of the PRMT5 inhibitor is less than 1% of, e.g., less than 10%, or less than 25%, or less than 50% of the clinically- established therapeutic amount (e.g., such as the amount required when the PRMT5 inhibitor is administered by itself).
• the therapeutically effective amount of the CDK4/6 inhibitor is in the range of about 0.01 to 300 mg/kg per day.
• the therapeutically effective amount of the CDK4/6 inhibitor is in the range of about 0.1 to 100 mg/kg per day, or 0.1 to 50 mg/kg per day, or 10 to 100 mg/kg per day, or 10 to 50 mg/kg per day.
• the therapeutically effective amount of the CDK4/6 inhibitor is less than 1% of, e.g., less than 10%, or less than 25%, or less than 50% of the clinically- established therapeutic amount (e.g., such as the amount required when the CDK4/6 inhibitor is administered by itself).
• Combination therapy in defining use of PRMT5 inhibitor and the CDK4/6 inhibitor of the present disclosure, is intended to embrace administration of each agent in a sequential manner in a regimen that will provide beneficial effects of the drug combination (e.g., the PRMT5 inhibitor and the CDK4/6 inhibitor of the disclosure can be formulated as separate compositions that are given sequentially), and is intended as well to embrace co administration of these agents in a substantially simultaneous manner, such as in a single dosage form having a fixed ratio of these active agents or in multiple or a separate dosage forms for each agent.
• the disclosure is not limited in the sequence of administration: the PRMT5 inhibitor of the disclosure may be administered either prior to or after (i.e. , sequentially), or at the same time (i.e., simultaneously) as administration of the CDK4/6 inhibitor of the disclosure.
• the methods of disclosure are useful as a first-line treatment.
• the subject has not previously received another first-line of therapy.
• the methods of disclosure are also useful as a first-line maintenance or a second- line treatment.
• the subject has previously completed another first-line of therapy.
• the methods of the disclosure may provide a delay in progression and relapse of cancer in subjects that have previously completed another first-line chemotherapy.
• the subject has previously completed a platinum- and/or taxane-based chemotherapy (e.g., carboplatin, cisplatin, oxaliplatin, paclitaxel, docetaxel, and the like).
• the subject has previously completed another first-line chemotherapy and is in partial response to such chemotherapy.
• chemical moieties are defined and referred to throughout primarily as univalent chemical moieties (e.g., alkyl, aryl, etc.). Nevertheless, such terms may also be used to convey corresponding multivalent moieties under the appropriate structural circumstances clear to those skilled in the art.
• an “alkyl” moiety generally refers to a monovalent radical (e.g.
• a bivalent linking moiety can be “alkyl,” in which case those skilled in the art will understand the alkyl to be a divalent radical (e.g., -CH2-CH2-), which is equivalent to the term “alkylene.”
• alkyl a divalent radical
• aryl a divalent moiety refers to the corresponding divalent moiety, arylene.
• All atoms are understood to have their normal number of valences 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 the S).
• amino refers to -IMH2.
• acetyl refers to “-C(0)CH 3 .
• acyl refers to an alkylcarbonyl or arylcarbonyl substituent wherein the alkyl and aryl portions are as defined herein.
• alkyl refers to saturated straight and branched chain aliphatic groups having from 1 to 12 carbon atoms.
• alkyl encompasses Ci, C2, C 3 , C4, C5, Cs, C7, Cs, Cg, C1 0 , C11 and C12 groups.
• alkyl groups include, without limitation, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl.
• alkenyl as used herein means an unsaturated straight or branched chain aliphatic group with one or more carbon-carbon double bonds, having from 2 to 12 carbon atoms. As such, “alkenyl” encompasses C2, C 3 , C4, C5, Ob, C7, Cs, Cg, C1 0 , Cn and C12 groups. Examples of alkenyl groups include, without limitation, ethenyl, propenyl, butenyl, pentenyl, and hexenyl.
• alkynyl as used herein means an unsaturated straight or branched chain aliphatic group with one or more carbon-carbon triple bonds, having from 2 to 12 carbon atoms.
• alkynyl encompasses C2, C 3 , C4, C5, C 6 , C7, Cs, Cg, C1 0 , Cn and C12 groups.
• alkynyl groups include, without limitation, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.
• alkylene is an alkyl, alkenyl, or alkynyl group, as defined hereinabove, that is positioned between and serves to connect two other chemical groups.
• alkylene groups include, without limitation, methylene, ethylene, propylene, and butylene.
• alkenylene groups include, without limitation, ethenylene, propenylene, and butenylene.
• alkynylene groups include, without limitation, ethynylene, propynylene, and butynylene.
• alkoxy refers to -OCi-Cs alkyl.
• cycloalkyl as employed herein is a saturated and partially unsaturated cyclic hydrocarbon group having 3 to 12 carbons.
• “cycloalkyl” includes C 3 , C4, Cs, Cs, C7, Cs, Cg, C1 0 , C11 and C12 cyclic hydrocarbon groups.
• Examples of cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.
• heteroalkyl refers to an alkyl group, as defined hereinabove, wherein one or more carbon atoms in the chain are independently replaced O, S, or NR X , wherein R x is hydrogen or C1-C3 alkyl.
• heteroalkyl groups include methoxymethyl, methoxyethyl and methoxypropyl.
• An "aryl” group is a C6-C14 aromatic moiety comprising one to three aromatic rings.
• “aryl” includes Ob, Cio, C13, and C14 cyclic hydrocarbon groups.
• An exemplary aryl group is a C6-C10 aryl group.
• Particular aryl groups include, without limitation, phenyl, naphthyl, anthracenyl, and fluorenyl.
• An “aryl” group also includes fused multicyclic (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, such as indenyl.
• An "aralkyl” or “arylalkyl” group comprises an aryl group covalently linked to an alkyl group wherein the moiety is linked to another group via the alkyl moiety.
• An exemplary aralkyl group is -(Ci-Ce)alkyl(C 6 -Cio)aryl, including, without limitation, benzyl, phenethyl, and naphthylmethyl.
• an arCrCsalkyl is an aryl group covalently linked to a C1-C3 alkyl.
• a “heterocyclyl” or “heterocyclic” group is a mono- or bicyclic (fused or spiro) ring structure having from 3 to 12 atoms, (3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 atoms), for example 4 to 8 atoms, wherein one or more ring atoms are independently -C(O)-, N, NR 4 , O, or S, and the remainder of the ring atoms are quaternary or carbonyl carbons.
• heterocyclic groups include, without limitation, 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 S atoms.
• L-heterocyclyl refers to a heterocyclyl group covalently linked to another group via an alkylene linker.
• 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 p electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to three heteroatoms that are each independently N, O, or S.
• Heteroaryl also includes fused multicyclic (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.
• heteroaryl groups include acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzo[d]oxazol- 2(3H)-one, 2/-/-benzo[b][1,4]oxazin-3(4H)-one, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4a/-/-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, furanyl, furazanyl, imidazolinyl, imidazolyl, 1 /-/-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl
• a "L-heteroaralkyl” or “L-heteroarylalkyl” group comprises a heteroaryl group covalently linked to another group via an alkylene linker.
• heteroalkyl groups comprise a Cr Ob alkyl group and a heteroaryl group having 5, 6, 9, or 10 ring atoms.
• heteroaralkyl groups include pyridylmethyl, pyridylethyl, pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl, imidazolylethyl, thiazolylmethyl, thiazolylethyl, benzimidazolylmethyl, benzimidazolylethyl quinazolinylmethyl, quinolinylmethyl, quinolinylethyl, benzofuranylmethyl, indolinylethyl isoquinolinylmethyl, isoinodylmethyl, cinnolinylmethyl, and benzothiophenylethyl. Specifically excluded from the scope of this term are compounds having adjacent ring O and/or S atoms.
• arylene is a bivalent aryl, heteroaryl, or heterocyclyl group, respectively, as defined hereinabove, that is positioned between and serves to connect two other chemical groups.
• halogen or halo as employed herein refers to chlorine, bromine, fluorine, or iodine.
• haloalkyl refers to an alkyl chain in which one or more hydrogens have been replaced by a halogen.
• exemplary haloalkyls are trifluoromethyl, difluoromethyl, flurochloromethyl, chloromethyl, and fluoromethyl.
• hydroxyalkyl refers to -alkylene-OH.
• the PRMT5 inhibitors of the disclosure demonstrate selective activity in MTAP- deleted cancers by binding to and further inhibiting PRMT5 when bound to the intracellular metabolite MTA.
• 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 viability and, as such, the PRMT5 inhibitors of the disclosure represent a novel approach to selectively treat MTAP-deleted cancers.
• a single mutation will likely not cause cancer — most often, it is multiple mutations that are responsible for developing cancer.
• the inventors found the treatment of certain cancers with PRMT5 inhibitors improved with the use of combination therapies. Particularly, the inventors surprisingly found that a combination therapy of PRMT5 inhibitor and CDK4/6 inhibitor provides greater antitumor activity compared to either inhibitor alone.
• MRTX9768 is 2-(4-(4-(aminomethyl)-1-oxo-1 ,2-dihydrophthalazin-6-yl)-1-methyl-1 H-pyrazol-5-yl)-3- fluoro-1-naphthonitrile, disclosed as Example 16-1 at p. 304 of the International patent publication No. WO 2021/050915 A1, published 18 March 2021, incorporated by reference in its entirety.
• the CDK4/6 inhibitor used in this example was palbociclib administered at 130 mg/kg once a day (QD).
• Palbociclib is 6-acetyl-8-cyclopentyl-5-methyl-2-[(5-piperazin-1-ylpyridin-2- yl)amino]pyrido[2,3-d]pyrimidin-7-one, and is sold as Ibrance ® available from Pfizer Inc.,
• Results are provided in Figure 1 and Table 1.
• the combination of MRTX9768 and MRTX849 led to greater antitumor activity compared to either inhibitor alone in this KRAS G12C and CDKN2A/MTAP DEL lung tumor xenograft LU99 model.
• the PRMT5 inhibitor was MRTX7477, administered at 200 mg/kg BID.
• MRTX7477 is 2-(4-(4- (aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-1-naphthonitrile, disclosed as Example 4-147 at p. 226 of the International patent publication No. WO 2021/050915 A1, published 18 March 2021, incorporated by reference in its entirety.
• the CDK4/6 inhibitor used in this example was the same as in Example 1, palbociclib, administered at 130 mg/kg QD.
• Results are provided in Figure 2 and Table 2.
• the combination of MRTX7477 and MRTX849 led to greater antitumor activity compared to either inhibitor alone in this KRAS G12C and CDKN2A/MTAP DEL lung tumor xenograft LU99 model.
• the compound of the disclosure was evaluated in several different lung tumor xenograft models: HCC4006, SW1573 PRMT5-044, H1650, and A549 PRMT-034. This example was carried out substantially according to the study procedure described above, except with mice bearing HCC4006 xenograft tumors, SW1573 PRMT5-044 xenograft tumors, H 1650 xenograft tumors, orA549 PRMT-034 xenograft tumors.
• the PRMT5 inhibitor was MRTX1719, administered at 50 mg/kg QD or at 100 mg/kg QD.
• 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, disclosed as Example 16-8 at p. 307 of the International patent publication No. WO 2021/050915 A1, published 18 March 2021, incorporated by reference in its entirety.
• the CDK4/6 inhibitor used in this example was the same as in Example 1, palbociclib, administered at 130 mg/kg QD.
• the compound of the disclosure was evaluated in a couple of different pancreatic tumor xenograft models: PANC-05-04 and BXPC-3. This example was carried out substantially according to the study procedure described above, except with mice bearing PANC-05-04 xenograft tumors or BXPC-3 xenograft tumors.
• the PRMT5 inhibitor and the CDK4/6 inhibitor used in this example were the same as in Example 3: MRTX1719 was administered at 100 mg/kg QD, and palbociclib was administered at 130 mg/kg QD.
• the compound of the disclosure was evaluated in a gastric tumor xenograft model MKN45, and the results are provided in Figure 9 and Table 9.
• This example was carried out substantially according to the study procedure described above, except with mice bearing MKN45 xenograft tumors.
• the PRMT5 inhibitor and the CDK4/6 inhibitor used in this example were the same as in Example 3: MRTX1719 was administered at 100 mg/kg QD, and palbociclib was administered at 130 mg/kg QD.

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