Combination drugs with PRMT5 inhibitors

Abstract

The present disclosure relates to a combination drug for treating and / or preventing cancer, and methods and uses thereof. More specifically, a combination drug is provided that includes a PRMT5 inhibitor and a cell activity modulator selected from an EGFR inhibitor, a KRAS inhibitor, a KRAS-G12C inhibitor, a MEK inhibitor, a Bcl-2 inhibitor, an SOS1 inhibitor, a PARP inhibitor, a RAF inhibitor, an ERK inhibitor, a CDK4 / 6 inhibitor, a MALT1 inhibitor, a BTK inhibitor, a MAT2A inhibitor, a PI3K inhibitor, an AKT inhibitor, an FGFR inhibitor, a type I PRMT inhibitor, a STING agonist, or an immune checkpoint inhibitor / modulator.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This PCT application claims priority to Indian Provisional Patent Application No. 201921042899, filed on October 22, 2019, the contents of which are incorporated herein by reference in their entirety. All references and products cited in this PCT application, including but not limited to patents, patent applications, and non-patent references, and the disclosures thereof, are hereby incorporated by reference in their entireties.

[0002] Field The present invention relates to a combination medicine for treating cancer. In particular, the present invention relates to a combination medicine for use in the treatment and / or prevention of cancer, comprising a protein arginine N-methyltransferase 5 (PRMT5) inhibitor of formula (I) and at least one tagged drug / cell activity modulator selected from EGFR inhibitors, KRAS inhibitors, KRAS-G12C inhibitors, MEK inhibitors, Bcl-2 inhibitors, SOS1 inhibitors, PARP inhibitors, RAF inhibitors, ERK inhibitors, CDK4 / 6 inhibitors, MALT1 inhibitors, BTK inhibitors, MAT2A inhibitors, PI3K inhibitors, AKT inhibitors, FGFR inhibitors, type I PRMT inhibitors, STING agonists or immune checkpoint inhibitors / modulators, wherein the PRMT5 inhibitor is of formula (I) [ka] or a tautomer, a stereoisomer, a pharma- ceutically acceptable salt, a polymorph thereof, or a solvate thereof. [Background technology]

[0003] background Protein methylation is a common post-translational modification that affects protein activity and interactions with other biomolecules. N-methylation typically occurs on the nitrogen atoms of arginine, lysine, and histidine residues, and there are different families of enzymes that catalyze the methylation reaction, each of which is specific for the amino acid residue that is methylated.

[0004] A family of nine enzymes called protein arginine N-methyltransferases (PRMTs) are responsible for the methylation of the guanidinium group of arginine, which has two terminal nitrogen atoms that can undergo mono- or dimethylation. Depending on the type of dimethylation, the enzymes are further classified as type I or type II. Type I PRMTs catalyze mono- or asymmetric dimethylation, whereas type II enzymes catalyze symmetric dimethylation. Substrates that undergo methylation include histones, Sm ribonucleoprotein, MRE11, and p53-binding protein 1.

[0005] Arginine side chain methylation plays an important role in various cellular functions including transcription activation and repression, mRNA translation, pre-mRNA splicing, protein transport and signal transduction. Methylation also occurs on a wide variety of substrates. PRMT enzymatic activity therefore affects cellular processes such as cell proliferation, repair of damaged DNA, and cell cycle and cell death. PRMT enzyme-mediated hypermethylation has been shown to result in certain disease states such as cancer (Nature Reviews Cancer 2013, 13, p37; Cellular and Molecular Life Sciences 2015, 72, p2041; Trends in Biochemical Sciences 2011, 36, p633).

[0006] Currently, the most studied type II enzyme is PRMT5, which is conserved across eukaryotes. Overexpression of PRMT5 is associated with oncogenesis and reduced patient survival in several human malignancies (Cell Mol Life Sci., 2015, 72, p2041). PRMT5 is a putative oncogene, as it directly interacts with proteins that are often dysregulated or mutated in cancer (Mol Cell Biol, 2008, 28, p6262). PRMT5-mediated transcriptional repression of tumor suppressor genes such as p53, RB-1, ST7, or upregulation of cyclin D1, CDK4, CDK6, eIF 4 E, MITF, FGFR3, has been linked to tumorigenesis in both solid and hematological malignancies. PRMT5 is located in the nucleus and cytoplasm, and its overexpression has been implicated in glioblastoma multiforme (Oncogene, 2017, 36, p263), prostate cancer (Oncogene, 2017, 36, p1223), and pancreatic cancer (Science, 2016, 351, p1214), mantle cell lymphoma (Nature Chemical Biology, 2015, 11, p432), non-Hodgkin's lymphoma and diffuse large B-cell lymphoma (Journal of Biological Chemistry, 2013, 288, p35534), acute myeloid leukemia (Leukemia, 2018, 32, p499), acute lymphoblastic leukemia (AACR; Cancer Research 2017;77(13 Suppl):Abstract nr 1128), multiple myeloma (Leukemia, 2018, 32, p996), non-small cell lung cancer (The Biochemical Journal, 2012, 446, p235), small cell lung cancer (AACR; Cancer Research 2017;77(13 Suppl):Abstract nr DDT02-04), breast cancer (Cell Reports, 2017, 21, p3498), triple negative breast cancer (AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4786), gastric cancer (International Journal of Oncology, 2016, 49, p1195), colorectal cancer (Oncotarget, 2015, 6, p22799), ovarian cancer (J Histochem Cytochem 2013, 61, p206), bladder cancer (Clinical Cancer Research, 2018, CCR-18-1270), hepatocellular carcinoma (Oncology Reports, 2018, 40, p536), melanoma (PLoS One, 2013, 8, e74710; J Clin Invest. 2018, 128, p517), sarcoma (Oncology Letters, 2018, 16, p2161), oropharyngeal squamous cell carcinoma (Oncotarget, 2017, 8, p14847), chronic myeloid leukemia (J Clin Invest, 2016, 126, p3961), epidermal squamous cell carcinoma (Carcinogenesis, 2017, 38, p827), nasopharyngeal carcinoma (Carcinogenesis, 2017, 38, p827), nasopharyngeal carcinoma (Oncology Reports, 2016, 35, p1703), neuroblastoma (Molecular Oncology, 2015, 9, p617), endometrial cancer (Gynecol Oncol., 2016, 140, p145), and cervical cancer (Pharmazie, 2018, 73, p269). These findings led to further studies showing that inhibiting PRMT5 reduces cell proliferation (Molecular and Cellular Biology 2008, 28, p6262, The Journal of Biological Chemistry 2013, 288, p35534).

[0007] Inhibitors of arginine methyltransferase were first disclosed in 2004 by Cheng et al. in the Journal of Biological Chemistry - Vol. 279 (23), p.23892. Since then, various other compounds and substances have been disclosed that have higher selectivity for either type I or type II arginine methyltransferase. Other publications disclosing small molecules as inhibitors for PRMT5 include PCT International Publication Nos. WO2011077133, WO2011079236, WO2014100695, WO2014100716, WO2014100719, WO2014100730, WO2014100734, WO2014128465, WO201414100737, WO201414100739, WO201414100740, WO201414100750, WO201414100760, WO201414100771, WO201414100780, WO201414100791, WO201414100792, WO20141410071, WO20141410071, WO201414100720, WO201414100731, WO201414100732, WO201414100733, WO201414100734, WO201414100735, WO201414100736, WO201414100737, WO2014141 No. 5214, No. WO2015200677, No. WO2015200680, No. WO2015198229, No. WO2016022605, No. WO2016034671, No. WO2 No. 016034673, No. WO2016034675, No. WO2016038550, No. WO2016135582, No. WO2016145150, No. WO2016178870 , WO2018065365, WO2019032859, WO2016089883 , and WO2017032840 and ACS Medicinal Chemistry Letters 2015, 6, p408 , Cell reports 2018, 24(10), p2643-2657; Proceedings of the National Academy, 2019, 116(36), p 17990-18000; Blood Cancer Journal 2019, 33(12), p2898-2911 and Bioorganic & Medicinal Chemistry Letters, 2019, 29(11), p1264-1269. Other publications describing cellular activity modulators are WO2018115380; WO2019051084; Cell Elsevier, 2018,172(3), p578 It is.

[0008] However, there is a need to identify improved pharmaceutical compositions or methods for treating or preventing cancer in subjects in need thereof. Summary of the Invention

[0009] overview The invention described and claimed herein has many attributes and aspects, including but not limited to those described or illustrated or referred to in this Summary. Not intended to be comprehensive, the invention described and claimed herein is not limited to, and is not limited by, the features or embodiments identified in this Summary, which is included for illustrative purposes only and not for limiting purposes.

[0010] In view of the above problems, according to one aspect disclosed in the present specification, the present invention relates to a combination pharmaceutical for use in the treatment and / or prevention of cancer, comprising a PRMT5 inhibitor of formula (I) in combination with at least one tagged agent / cell activity modulator selected from an EGFR inhibitor, a KRAS inhibitor, a KRAS-G12C inhibitor, a MEK inhibitor, a Bcl-2 inhibitor, a SOS1 inhibitor, a PARP inhibitor, a RAF inhibitor, an ERK inhibitor, a CDK4 / 6 inhibitor, a MALT1 inhibitor, a BTK inhibitor, a MAT2A inhibitor, a PI3K inhibitor, an AKT inhibitor, a FGFR inhibitor, a type I PRMT inhibitor, a STING agonist or an immune checkpoint inhibitor / modulator, wherein the PRMT5 inhibitor is represented by formula (I) [ka] or a tautomer, a stereoisomer, a pharma- ceutically acceptable salt, a polymorph thereof, or a solvate thereof.

[0011] According to one aspect disclosed herein, there is provided a pharmaceutical combination for treating and / or preventing cancer in a subject, comprising a PRMT5 inhibitor of formula (I) or a stereoisomer thereof or a pharma- ceutical acceptable salt thereof and at least one tagging agent / modulator selected from an EGFR inhibitor, a KRAS inhibitor, a KRAS-G12C inhibitor, a Bcl-2 inhibitor, a SOS1 inhibitor, a PARP inhibitor, a RAF inhibitor, an ERK inhibitor, a CDK4 / 6 inhibitor, a MALT1 inhibitor, a BTK inhibitor, a MAT2A inhibitor, a PI3K inhibitor, an AKT inhibitor, a BTK inhibitor, a MAT2A inhibitor, a PI3K inhibitor, an AKT inhibitor, a FGFR inhibitor, a type I PRMT inhibitor, a STING agonist or an immune checkpoint inhibitor / modulator, wherein the compound of formula (I) [ka] (In the formula, L1 is -CR a R b -, -NRa -, S and O; Z=CH or N; R a and R b is independently selected from hydrogen, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl; Ring A is as follows [ka] Selected from; R c and R d are selected from substituted or unsubstituted alkyl, or together with the carbon atom to which they are attached form a C3-C6 cycloalkyl ring; R is -NR 4 R 5 , hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted heteroaryl, and substituted or unsubstituted cycloalkyl; R 1 and R 2 form a bond together with the carbon atom to which they are attached to form -C=C-; or R 1 and R 2 together with the carbon atoms to which they are attached form a cyclopropane ring; R 2' and R 2a may be the same or different and are independently selected from hydrogen and substituted or unsubstituted alkyl; R 3 is, for each occurrence, a halogen, cyano, nitro, substituted or unsubstituted alkyl, -OR 6 , -NR 7 R 8 , substituted or unsubstituted cycloalkyl, -C(O)OH, -C(O)O-alkyl, -C(O)R 9 , -C(O)NR 7 R 8 , -NR 7 C(O)R 9 , independently selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclyl; R4 and R 5 is independently selected from hydrogen, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl; R 6 is selected from hydrogen, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl; R 7 and R 8 is independently selected from hydrogen, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl; R 9 is selected from substituted or unsubstituted alkyl and substituted or unsubstituted cycloalkyl; R 10 is selected from hydrogen, halogen, and substituted or unsubstituted alkyl; "n" is an integer between 0 and 4, inclusive; The alkyl group, when substituted, can be oxo (=O), halogen, cyano, cycloalkyl, aryl, heteroaryl, heterocyclyl, -OR 7a , -C(=O)OH, -C(=O)O(alkyl), -NR 8a R 8b , -NR 8a C(=O)R 9a and -C(=O)NR 8a R 8b substituted with 1 to 4 substituents independently selected from: Heteroaryl groups, when substituted, include halogen, nitro, cyano, alkyl, haloalkyl, perhaloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 7a , -NR 8a R 8b , -NR 7a C(=O)R 9a , -C(=O)R 9a , -C(=O)NR 8a R 8b , -SO2-alkyl, -C(=O)OH and -C(=O)O-alkyl; Heterocyclic groups, when substituted, are substituted either on ring carbon atoms or on ring heteroatoms, and when substituted on a ring carbon atom, are substituted with oxo (=O), halogen, cyano, alkyl, cycloalkyl, perhaloalkyl, -OR 7a , -C(=O)NR 8a R 8b , -C(=O)OH, -C(=O)O-alkyl, -N(H)C(=O)(alkyl), -N(H)R 8a and -N(alkyl)2, and when substituted on the ring nitrogen, is alkyl, cycloalkyl, aryl, heteroaryl, -SO2(alkyl), -C(=O)R 9a and -C(=O)O(alkyl), and, when substituted on the ring sulfur, is substituted with one or two oxo (=O) groups; R 7a is selected from hydrogen, alkyl, perhaloalkyl, and cycloalkyl; R 8a and R 8b are each independently selected from hydrogen, alkyl, and cycloalkyl; R 9a is selected from alkyl and cycloalkyl A combination medicine.

[0012] According to another aspect disclosed herein, the PRMT5 inhibitor of formula (I) in the combination pharmaceutical comprises (1S,2R,5R)-3-(2-(2-amino-3-bromoquinolin-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (compound 1); (1S,2R,5R)-3-(2-(2-amino-3-chloroquinolin-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (compound 2); (1S,2R,5R)-3-(2-(2-amino-3-bromoquinolin-7-yl)ethyl)-5-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (compound 3); (1S,2R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-(((2-aminoquinolin-7-yl)thio)methyl)cyclopent-3-ene-1,2-diol (compound 4); (1S,2R,5R)-3-(((2-amino-3-chloroquinolin-7-yl)thio)methyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (compound 5); (1S,2R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-(((2-aminoquinolin-7-yl)(methyl)amino)methyl)cyclopent-3-ene-1,2-diol (compound 6); (1S,2R,5R)-3-(1-(2-amino-3-bromoquinolin-7-yl)propan-2-yl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (compounds 7a and 7b); (1S,2R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-(1-((2-(methylamino)quinolin-7-yl)oxy)ethyl)cyclopent-3-ene-1,2-diol (compounds 8a and 8b); (1S,2R,5R)-3-(((2-amino-3-chloro-5-fluoroquinolin-7-yl)oxy)methyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-methylcyclopent-3-ene-1,2-diol (compound 9); (1S,2R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-(2-(2-(methylamino)quinolin-7-yl)ethyl)cyclopent-3-ene-1,2-diol (compound 10); (1S,2R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-(2-(3-methylimidazo[1,2-a]pyridin-7-yl)ethyl)cyclopent-3-ene-1,2-diol (compound 11); (1S,2R,5R)-3-(((2-amino-3-chloro-5-fluoroquinolin-7-yl)oxy)methyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-4-methylcyclopent-3-ene-1,2-diol (compound 12); (1S,2R,5R)-3-(2-(2-amino-3-chloro-5-fluoroquinolin-7-yl)ethyl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (compound 13); (1S,2R,5R)-3-(2-(2-amino-3-chloro-5-fluoroquinolin-7-yl)ethyl)-5-(4-methyl-1H-pyrrolo[3,2-c]pyridin-1-yl)cyclopent-3-ene-1,2-diol hydrochloride (compound 14); (1S,2R,5R)-3-(2-(2-amino-3-chloro-5-fluoroquinolin-7-yl)ethyl)-5-(1H-pyrrolo[3,2-c]pyridin-1-yl)cyclopent-3-ene-1,2-diol (compound 15); (1S,2R,5R)-3-(2-(2-amino-3-chloro-5-fluoroquinolin-7-yl)ethyl)-5-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (compound 16); (1S,2R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-(((2-aminoquinolin-7-yl)amino)methyl)cyclopent-3-ene-1,2-diol (compound 17); (1S,2R,5R)-3-(((2-amino-3-chloro-5-fluoroquinolin-7-yl)oxy)methyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (compound 18); (1S,2R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-(((2-(methylamino)quinolin-7-yl)oxy)methyl)cyclopent-3-ene-1,2-diol (compound 19); (1S,2R,5R)-3-(1-((2-amino-3-chloro-5-fluoroquinolin-7-yl)oxy)ethyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (compounds 20a and 20b); (1S,2R,5R)-3-(2-(2-amino-3-chloroquinolin-7-yl)ethyl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (compound 21); (1S,2R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-(2-(2-(cyclobutylamino)quinolin-7-yl)ethyl)cyclopent-3-ene-1,2-diol (compound 22); (1S,2R,5R)-3-(2-(2-amino-3-fluoroquinolin-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (compound 23); (1S,2R,5R)-3-(2-(2-amino-3-chloro-5-fluoroquinolin-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (compound 24); (1S,2R,5R)-3-(2-(2-amino-3-chloro-6-fluoroquinolin-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (compound 25); (1S,2R,5R)-3-(2-(2-amino-3-chloro-8-fluoroquinolin-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (compound 26); (1S,2R,5R)-3-(2-(2-amino-3,3-dimethyl-3H-indol-6-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (compound 27); (1S,2R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-(2-(2'-aminospiro[cyclobutane-1,3'-indol]-6'-yl)ethyl)cyclopent-3-ene-1,2-diol (compound 28); (1S,2R,5R)-3-(2-(2-amino-3,5-dichloroquinolin-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (compound 29); (1S,2R,5R)-3-(2-(2-amino-3-chloroquinolin-7-yl)ethyl)-5-(2-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (compound 30); (1S,2R,5R)-3-(2-(2-amino-3-chloro-5-fluoroquinolin-7-yl)ethyl)-5-(4-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (compound 31); (1S,2R,5R)-3-(2-(2-amino-3-chloro-5-fluoroquinolin-7-yl)ethyl)-5-(4-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (compound 32); (1S,2R,5R)-3-(1-(2-amino-3-chloro-5-fluoroquinolin-7-yl)propan-2-yl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (compounds 33a and 33b); (1S,2R,5R)-3-(1-(2-amino-3-chloroquinolin-7-yl)propan-2-yl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (compounds 34a and 34b); (1S,2R,5R)-3-(1-(2-amino-3-chloro-5-fluoroquinolin-7-yl)propan-2-yl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (compounds 35a and 35b); (1S,2R,5R)-3-(1-(2-amino-3-chloro-5-fluoroquinolin-7-yl)propan-2-yl)-2-methyl-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (compounds 36a and 36b); (1S,2R,5R)-3-(2-(2-amino-3-chloro-5-fluoroquinolin-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-methylcyclopent-3-ene-1,2-diol (compound 37); (1S,2R,5R)-3-(1-(2-amino-3-chloro-5-fluoroquinolin-7-yl)propan-2-yl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-methylcyclopent-3-ene-1,2-diol (compound 38); (1S,2R,5R)-3-(2-(2-amino-3-chloro-5-fluoroquinolin-7-yl)ethyl)-2-methyl-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (compound 39); (1S,2R,5R)-3-(2-(2-amino-3-chloro-5-fluoroquinolin-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethylcyclopent-3-ene-1,2-diol (compound 40); (1S,2R,5R)-3-(2-(2-amino-3-chloro-5-fluoroquinolin-7-yl)ethyl)-5-(4-ethyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (compound 41); (1S,2R,5R)-3-(2-(2-amino-3-chloro-5-fluoroquinolin-7-yl)ethyl)-5-(4-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (compound 42); (1S,2R,5R)-3-(2-(2-amino-3-bromo-5-fluoroquinolin-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (compound 43); (1S,2R,5R)-3-(2-(2-amino-3-bromo-5-fluoroquinolin-7-yl)ethyl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (compound 44); (1S,2R,5R)-3-(1-(2-amino-3-bromo-5-fluoroquinolin-7-yl)propan-2-yl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (compounds 45a and 45b); (1S,2R,5R)-3-(2-(2-amino-6-fluoroquinolin-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (compound 46); (1S,2R,5R)-3-(2-(2-amino-5-fluoroquinolin-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (compound 47); (1R,2R,3S,4R,5S)-1-(2-(2-amino-3-chloro-5-fluoroquinolin-7-yl)ethyl)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[3.1.0]hexane-2,3-diol (compound 48); (1R,2R,3S,4R,5S)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-(2-(2-(methylamino)quinolin-7-yl)ethyl)bicyclo[3.1.0]hexane-2,3-diol (compound 49); (1R,2R,3S,4R,5S)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-(2-(2-(isopropylamino)quinolin-7-yl)ethyl)bicyclo[3.1.0]hexane-2,3-diol (compound 50); (1R,2R,3S,4R,5S)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-(2-(2-(cyclobutylamino)quinolin-7-yl)ethyl)bicyclo[3.1.0]hexane-2,3-diol (compound 51); (1R,2R,3S,4R,5S)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-(2-(2-((cyclopropylmethyl)amino)quinolin-7-yl)ethyl)bicyclo[3.1.0]hexane-2,3-diol (compound 52); (1R,2R,3S,4R,5S)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-(2-(2-amino-8-fluoroquinolin-7-yl)ethyl)bicyclo[3.1.0]hexane-2,3-diol (compound 53); (1R,2R,3S,4R,5S)-1-(2-(2-amino-3-methylquinolin-7-yl)ethyl)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[3.1.0]hexane-2,3-diol (compound 54); (1R,2R,3S,4R,5S)-1-(2-(2-amino-3-isopropylquinolin-7-yl)ethyl)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[3.1.0]hexane-2,3-diol (compound 55); (1R,2R,3S,4R,5S)-1-(2-(2-amino-3-(1,1-difluoroethyl)quinolin-7-yl)ethyl)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[3.1.0]hexane-2,3-diol (compound 56); (1R,2R,3S,4R,5S)-1-(2-(2-amino-3-cyclopropylquinolin-7-yl)ethyl)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[3.1.0]hexane-2,3-diol (compound 57); (1R,2R,3S,4R,5S)-1-(2-(2-amino-3-methoxyquinolin-7-yl)ethyl)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[3.1.0]hexane-2,3-diol (compound 58); 2-amino-7-(2-((1R,2R,3S,4R,5S)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,3-dihydroxybicyclo[3.1.0]hexan-1-yl)ethyl)quinoline-3-carbonitrile (compound 59); (1R,2R,3S,4R,5S)-1-(2-(2-amino-3-fluoroquinolin-7-yl)ethyl)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[3.1.0]hexane-2,3-diol (compound 60); (1R,2R,3S,4R,5S)-1-(2-(2-amino-3-chloroquinolin-7-yl)ethyl)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[3.1.0]hexane-2,3-diol (compound 61); (1R,2R,3S,4R,5S)-1-(2-(2-amino-3-chloro-6-fluoroquinolin-7-yl)ethyl)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[3.1.0]hexane-2,3-diol (compound 62); (1R,2R,3S,4R,5S)-1-(2-(2-amino-3-chloro-8-fluoroquinolin-7-yl)ethyl)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[3.1.0]hexane-2,3-diol (compound 63); (1R,2R,3S,4R,5S)-1-(2-(2-amino-3-bromo-6-fluoroquinolin-7-yl)ethyl)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[3.1.0]hexane-2,3-diol (compound 64); (1R,2R,3S,4R,5S)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-(2-(3-methylimidazo[1,2-a]pyridin-7-yl)ethyl)bicyclo[3.1.0]hexane-2,3-diol (compound 65); (1R,2R,3S,4R,5S)-1-(2-(2-amino-3,3-dimethyl-3H-indol-6-yl)ethyl)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[3.1.0]hexane-2,3-diol (compound 66); (1R,2R,3S,4R,5S)-1-(2-(2-amino-3-chloro-5-fluoroquinolin-7-yl)ethyl)-4-(4-amino-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[3.1.0]hexane-2,3-diol (compound 67); (1R,2R,3S,4R,5S)-1-(2-(2-amino-3-chloro-6-fluoroquinolin-7-yl)ethyl)-4-(4-amino-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[3.1.0]hexane-2,3-diol (compound 68); (1R,2R,3S,4R,5S)-1-(2-(2-amino-3-chloro-5-fluoroquinolin-7-yl)ethyl)-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[3.1.0]hexane-2,3-diol (compound 69); (1R,2R,3S,4R,5S)-1-(2-(2-amino-3-chloro-5-fluoroquinolin-7-yl)ethyl)-4-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[3.1.0]hexane-2,3-diol (compound 70); (1R,2R,3S,4R,5S)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-(2-(2'-aminospiro[cyclobutane-1,3'-indol]-6'-yl)ethyl)bicyclo[3.1.0]hexane-2,3-diol (compound 71); (1R,2R,3S,4R,5S)-1-(2-(2-amino-3-bromo-5-fluoroquinolin-7-yl)ethyl)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[3.1.0]hexane-2,3-diol (compound 72); (1R,2R,3S,4R,5S)-1-(2-(2-amino-3-bromoquinolin-7-yl)ethyl)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[3.1.0]hexane-2,3-diol (compound 73); (1R,2R,3S,4R,5S)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-(2-(2-aminoquinolin-7-yl)ethyl)bicyclo[3.1.0]hexane-2,3-diol (compound 74); (1R,2R,3S,4R,5S)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-(2-(2-aminoquinazolin-7-yl)ethyl)bicyclo[3.1.0]hexane-2,3-diol (compound 75); (1S,2R,3S,4R,5S)-1-((S)-1-(2-amino-3-bromoquinolin-7-yl)propan-2-yl)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[3.1.0]hexane-2,3-diol (compounds 76a and 76b); (1S,2R,3S,4R,5S)-1-((S)-2-(2-amino-3-chloro-5-fluoroquinolin-7-yl)-1-cyclopropylethyl)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[3.1.0]hexane-2,3-diol (compounds 77a and 77b); (1S,2R,3S,4R,5S)-1-(1-(2-amino-3-chloro-5-fluoroquinolin-7-yl)propan-2-yl)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[3.1.0]hexane-2,3-diol (compounds 78a and 78b); (1R,2R,3S,4R,5S)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-(2-(2-aminoquinolin-7-yl)propyl)bicyclo[3.1.0]hexane-2,3-diol (compounds 79a and 79b); (1R,2R,3S,4R,5S)-1-(((2-amino-3-bromoquinolin-7-yl)oxy)methyl)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[3.1.0]hexane-2,3-diol (compound 80); (1S,2R,3S,4R,5S)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-(((2-aminoquinolin-7-yl)thio)methyl)bicyclo[3.1.0]hexane-2,3-diol (compound 81); (1R,2R,3S,4R,5S)-1-(2-(2-amino-3-(4-fluorophenyl)quinolin-7-yl)ethyl)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[3.1.0]hexane-2,3-diol (compound 82); (1R,2R,3S,4R,5S)-1-(2-(2-amino-3-(pyridin-3-yl)quinolin-7-yl)ethyl)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[3.1.0]hexane-2,3-diol (compound 83); and (1R,2R,3S,4R,5S)-1-(2-(2-amino-3-(3-methylisoxazol-4-yl)quinolin-7-yl)ethyl)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[3.1.0]hexane-2,3-diol (compound 84) or a pharma- ceutically acceptable salt, hydrate or stereoisomer thereof. The compound is selected from the group consisting of:

[0013] According to another aspect disclosed herein, the PRMT5 inhibitor is (1S,2R,5R)-3-(2-(2-amino-3-chloro-5-fluoroquinolin-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (compound 24) or a pharma- ceutically acceptable salt thereof. According to another aspect disclosed herein, the at least one tagged drug / cell activity modulator is an inhibitor of EGFR or an oncogenic mutant thereof. According to a further aspect disclosed herein, the inhibitor of EGFR is afatinib, osimertinib, erlotinib, or gefitinib. According to another aspect disclosed herein, the at least one tagged drug / cellular activity modulator is an inhibitor of an SOS1 inhibitor. According to a further aspect disclosed herein, the SOS1 inhibitor is BI-3406.

[0014] According to another aspect disclosed herein, the at least one tagged drug / cellular activity modulator is an inhibitor of an ERK inhibitor. According to a further aspect disclosed herein, the ERK inhibitor is ulixertinib, MK-8353 or lavoxertinib. According to another aspect disclosed herein, the at least one tagged drug / cellular activity modulator is an inhibitor of PARP. According to a further aspect disclosed herein, the PARP inhibitor is olaparib, niraparib, rucaparib, or talazoparib (BMN-673). According to another aspect disclosed herein, the at least one tagged drug / cellular activity modulator is an inhibitor of CDK4 / 6. According to a further aspect disclosed herein, the CDK4 / 6 inhibitor is palbociclib, ribociclib, and abemaciclib.

[0015] According to another aspect disclosed herein, the at least one tagged drug / cellular activity modulator is an inhibitor of MALT1. According to a further aspect disclosed herein, the MALT1 inhibitor is MI-2, JNJ-67856633. According to another aspect disclosed herein, the at least one tagged drug / cellular activity modulator is an inhibitor of BTK. According to a further aspect disclosed herein, the BTK inhibitor is ibrutinib, zanubrutinib, or acalabrutinib.

[0016] According to another aspect disclosed herein, the PRMT5 inhibitor compound is administered simultaneously, in parallel, sequentially, sequentially, alternatingly or separately with at least one tagged drug / cellular activity modulator selected from an EGFR inhibitor, a KRAS inhibitor, a KRAS-G12C inhibitor, a Bcl-2 inhibitor, a SOS1 inhibitor, a PARP inhibitor, a RAF inhibitor, an ERK inhibitor, a CDK4 / 6 inhibitor, a MALT1 inhibitor, a BTK inhibitor, a MAT2A inhibitor, a PI3K inhibitor, an AKT inhibitor, a BTK inhibitor, a MAT2A inhibitor, a PI3K inhibitor, an AKT inhibitor, a FGFR inhibitor, a type I PRMT inhibitor, a STING agonist or an immune checkpoint inhibitor / modulator.

[0017] According to another aspect disclosed herein, (a) the compound (1S,2R,5R)-3-(2-(2-amino-3-chloro-5-fluoroquinolin-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (Compound 24) or a pharma- ceutically acceptable salt thereof; (b) Afatinib and 23. A combination pharmaceutical for treating and / or preventing cancer in a subject, comprising:

[0018] According to another aspect disclosed herein, (a) the compound (1S,2R,5R)-3-(2-(2-amino-3-chloro-5-fluoroquinolin-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (Compound 24) or a pharma- ceutically acceptable salt thereof; (b) BI-3406 and 23. A combination pharmaceutical for treating and / or preventing cancer in a subject, comprising:

[0019] According to another aspect disclosed herein, (a) the compound (1S,2R,5R)-3-(2-(2-amino-3-chloro-5-fluoroquinolin-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (Compound 24) or a pharma- ceutically acceptable salt thereof; (b) ulixertinib and 23. A combination pharmaceutical for treating and / or preventing cancer in a subject, comprising:

[0020] According to another aspect disclosed herein, there is provided a method for treating and / or preventing cancer in a human subject in need thereof, comprising administering to the human subject a therapeutically effective amount of any of the pharmaceutical combinations disclosed herein.

[0021] According to another aspect disclosed herein, the cancer is glioblastoma multiforme, prostate cancer, pancreatic cancer, mantle cell lymphoma, non-Hodgkin's lymphoma and diffuse large B-cell lymphoma, acute myeloid leukemia, acute lymphocytic leukemia, multiple myeloma, non-small cell lung cancer, small cell lung cancer, breast cancer, triple-negative breast cancer, gastric cancer, colorectal cancer, ovarian cancer, bladder cancer, hepatocellular carcinoma, melanoma, sarcoma, oropharyngeal squamous cell carcinoma, chronic myeloid leukemia, epidermal squamous cell carcinoma, nasopharyngeal carcinoma, neuroblastoma, endometrial cancer, head and neck cancer, or cervical cancer.

[0022] BRIEF DESCRIPTION OF THE DRAWINGS The drawings form part of the present specification and are included to further demonstrate certain aspects of the embodiments described herein, which may be better understood by reference to one or more of the following drawings in combination with the detailed description. [Brief description of the drawings]

[0023] [Figure 1] 1 shows the in vitro inhibitory effects of a representative combination of the present invention, compound 24 and the PARP inhibitor olaparib, in MIA PaCa-2 cells. [Diagram 2] 1 shows the in vitro inhibitory effects of a representative combination of the present invention, compound 24 and the PARP inhibitor BMN-673, in MDA-MB-231 cells. [Diagram 3] 1 shows the in vitro inhibitory effects of a representative combination of the present invention, compound 24 and the EGFR inhibitor afatinib, in MIA PaCa-2 cells. [Figure 4] 1 shows the in vitro inhibitory effects of a representative combination of the present invention, compound 24 and SOS1 inhibitor BI-3406, in MIA PaCa-2 cells. [Diagram 5] 1 shows the in vitro inhibitory effect of a representative combination of the present invention, compound 24 and the EGFR inhibitor afatinib, in MDA-MB-231 cells. [Figure 6] 1 shows the in vitro inhibitory effects of a representative combination of the present invention, compound 24 and the CDK4 / 6 inhibitor abemaciclib, in MDA-MB-231 cells. [Figure 7] 1 is a line graph showing the in vitro inhibitory effects of a representative combination of the present invention, compound 24 and the KRAS-G12C inhibitor AMG510, in MIA PaCa-2 cells. [Figure 8] 1 is a line graph showing the in vivo efficacy of a representative combination of the present invention, compound 24 and the EGFR inhibitor afatinib, in MIA PaCa-2 xenografts. [Figure 9] 1 is a line graph showing the in vivo efficacy of a representative combination of the present invention, compound 24 and the SOS1 inhibitor BI-3406, in MIA PaCa-2 xenografts. [Figure 10] 1 is a line graph showing the in vivo efficacy of a representative combination of the present invention, compound 24 and the ERK inhibitor ulixertinib (BVD-523), in MIA PaCa-2 xenografts. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0024] Detailed Description This description of exemplary embodiments is intended to be read in conjunction with the accompanying drawings / figures, which are to be considered part of the entire written description. The drawings / figures are not necessarily to scale, and certain features may be exaggerated in scale or shown in somewhat schematic form in the interest of clarity and conciseness.

[0025] Some species of PRMT5 inhibitors (none of which are compounds of formula (I)) can be combined with some cellular activity modulators for the treatment of cancer. Tagged therapeutic agents / cellular activity modulators for the treatment of cancer include PARP inhibitors (Cell Reports 2018, 24, 2643-2657); EGFR inhibitors (Nat Cell Biol. 2011 Feb; 13(2): 174-181; Cancer Medicine, 2019, 8(5), 2414-2428); SOS1 inhibitors (Science, 2019,363(6433),1280-1281); RAF inhibitors (Sci Signal. 2011; 4(190): ra58); ERK inhibitors (Nat Cell Biol. 2011 Feb; 13(2):174-181); CDK4 / 6 inhibitors (Proc Natl Acad Sci US A. 2019; 116(36):17990-18000); MALT1 inhibitors (AACR Annual Meeting 2020; April 27-28, 2020 and June 22-24, 2020);BTK inhibitors (J Clin Oncol 2020, 38(25): 2937);PI3K inhibitors (Leukemia. 2019 May 23. doi: 10.1038 / s41375-019-0489-6;);AKT inhibitors (J Cell Mol Med. 2019; 23(2):1333-1342);FGFR inhibitors (Cancer Res 2015; 21(12); 2684-94);c-Met inhibitors (Sci Signal. 2011; 4(190): ra58; Cancer Medicine 2018; 7(3):869-882).

[0026] The present invention relates to a combination pharmaceutical comprising a PRMT5 inhibitor of formula (I) in combination with at least one tagged drug / cellular activity modulator selected from an EGFR inhibitor, a KRAS inhibitor, a KRAS-G12C inhibitor, a MEK inhibitor, a Bcl-2 inhibitor, a SOS1 inhibitor, a PARP inhibitor, a RAF inhibitor, an ERK inhibitor, a CDK4 / 6 inhibitor, a MALT1 inhibitor, a BTK inhibitor, a MAT2A inhibitor, a PI3K inhibitor, an AKT inhibitor, a FGFR inhibitor, a type I PRMT inhibitor, a STING agonist or an immune checkpoint inhibitor / modulator, wherein the PRMT5 inhibitor is of formula (I) [ka] (In the formula, L1 is -CR a R b -, -NR a -, S and O; Z=CH or N; R a and R b is independently selected from hydrogen, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl; Ring A is as follows [ka] Selected from; R c and R d are selected from substituted or unsubstituted alkyl, or together with the carbon atom to which they are attached form a C3-C6 cycloalkyl ring; R is -NR 4 R 5 , hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted heteroaryl, and substituted or unsubstituted cycloalkyl; R 1 and R 2 form a bond together with the carbon atom to which they are attached to form -C=C-; or R 1 and R 2together with the carbon atoms to which they are attached form a cyclopropane ring; R 2' and R 2a may be the same or different and are independently selected from hydrogen and substituted or unsubstituted alkyl; R 3 is, for each occurrence, a halogen, cyano, nitro, substituted or unsubstituted alkyl, -OR 6 , -NR 7 R 8 , substituted or unsubstituted cycloalkyl, -C(O)OH, -C(O)O-alkyl, -C(O)R 9 , -C(O)NR 7 R 8 , -NR 7 C(O)R 9 , independently selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclyl; R 4 and R 5 is independently selected from hydrogen, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl; R 6 is selected from hydrogen, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl; R 7 and R 8 is independently selected from hydrogen, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl; R 9 is selected from substituted or unsubstituted alkyl and substituted or unsubstituted cycloalkyl; R 10 is selected from hydrogen, halogen, and substituted or unsubstituted alkyl; "n" is an integer between 0 and 4, inclusive; The alkyl or cycloalkyl groups, when substituted, include oxo (=O), halogen, cyano, cycloalkyl, aryl, heteroaryl, heterocyclyl, -OR 7a , -C(=O)OH, -C(=O)O(alkyl), -NR 8a R 8b , -NR 8a C(=O)R9a and -C(=O)NR 8a R 8b substituted with 1 to 4 substituents independently selected from: The aryl or heteroaryl group, if substituted, may be selected from halogen, nitro, cyano, alkyl, haloalkyl, perhaloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 7a , -NR 8a R 8b , -NR 7a C(=O)R 9a , -C(=O)R 9a , -C(=O)NR 8a R 8b , -SO2-alkyl, -C(=O)OH and -C(=O)O-alkyl; Heterocyclyl groups, when substituted, are substituted either on a ring carbon atom or on a ring heteroatom, and when substituted on a ring carbon atom, are substituted with oxo (=O), halogen, cyano, alkyl, cycloalkyl, perhaloalkyl, -OR 7a , -C(=O)NR 8a R 8b , -C(=O)OH, -C(=O)O-alkyl, -N(H)C(=O)(alkyl), -N(H)R 8a and -N(alkyl)2, and when substituted on the ring nitrogen, is alkyl, cycloalkyl, aryl, heteroaryl, -SO2(alkyl), -C(=O)R 9a and -C(=O)O(alkyl), and, when substituted on the ring sulfur, is substituted with one or two oxo (=O) groups; R 7a is selected from hydrogen, alkyl, perhaloalkyl, and cycloalkyl; R 8a and R 8b are each independently selected from hydrogen, alkyl, and cycloalkyl; R 9a is selected from alkyl and cycloalkyl or a tautomer, a stereoisomer, a pharma- ceutically acceptable salt, a polymorph thereof, or a solvate thereof.

[0027] In some embodiments of the present invention, the disclosure includes a pharmaceutical combination comprising a PRMT5 inhibitor of formula (I) in combination with at least one tagged drug / cellular activity modulator selected from an EGFR inhibitor, a KRAS inhibitor, a KRAS-G12C inhibitor, a MEK inhibitor, a Bcl-2 inhibitor, a SOS1 inhibitor, a PARP inhibitor, a RAF inhibitor, an ERK inhibitor, a CDK4 / 6 inhibitor, a MALT1 inhibitor, a BTK inhibitor, a MAT2A inhibitor, a PI3K inhibitor, an AKT inhibitor, a BTK inhibitor, a MAT2A inhibitor, a PI3K inhibitor, an AKT inhibitor, a FGFR inhibitor, a type I PRMT inhibitor, a STING agonist or an immune checkpoint inhibitor / modulator, wherein the PRMT5 inhibitor is (1S,2R,5R)-3-(2-(2-amino-3-bromoquinolin-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (compound 1); (1S,2R,5R)-3-(2-(2-amino-3-chloroquinolin-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (compound 2); (1S,2R,5R)-3-(2-(2-amino-3-bromoquinolin-7-yl)ethyl)-5-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (compound 3); (1S,2R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-(((2-aminoquinolin-7-yl)thio)methyl)cyclopent-3-ene-1,2-diol (compound 4); (1S,2R,5R)-3-(((2-amino-3-chloroquinolin-7-yl)thio)methyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (compound 5); (1S,2R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-(((2-aminoquinolin-7-yl)(methyl)amino)methyl)cyclopent-3-ene-1,2-diol (compound 6); (1S,2R,5R)-3-(1-(2-amino-3-bromoquinolin-7-yl)propan-2-yl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (compounds 7a and 7b); (1S,2R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-(1-((2-(methylamino)quinolin-7-yl)oxy)ethyl)cyclopent-3-ene-1,2-diol (compounds 8a and 8b); (1S,2R,5R)-3-(((2-amino-3-chloro-5-fluoroquinolin-7-yl)oxy)methyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-methylcyclopent-3-ene-1,2-diol (compound 9); (1S,2R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-(2-(2-(methylamino)quinolin-7-yl)ethyl)cyclopent-3-ene-1,2-diol (compound 10); (1S,2R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-(2-(3-methylimidazo[1,2-a]pyridin-7-yl)ethyl)cyclopent-3-ene-1,2-diol (compound 11); (1S,2R,5R)-3-(((2-amino-3-chloro-5-fluoroquinolin-7-yl)oxy)methyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-4-methylcyclopent-3-ene-1,2-diol (compound 12); (1S,2R,5R)-3-(2-(2-amino-3-chloro-5-fluoroquinolin-7-yl)ethyl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (compound 13); (1S,2R,5R)-3-(2-(2-amino-3-chloro-5-fluoroquinolin-7-yl)ethyl)-5-(4-methyl-1H-pyrrolo[3,2-c]pyridin-1-yl)cyclopent-3-ene-1,2-diol hydrochloride (compound 14); (1S,2R,5R)-3-(2-(2-amino-3-chloro-5-fluoroquinolin-7-yl)ethyl)-5-(1H-pyrrolo[3,2-c]pyridin-1-yl)cyclopent-3-ene-1,2-diol (compound 15); (1S,2R,5R)-3-(2-(2-amino-3-chloro-5-fluoroquinolin-7-yl)ethyl)-5-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (compound 16); (1S,2R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-(((2-aminoquinolin-7-yl)amino)methyl)cyclopent-3-ene-1,2-diol (compound 17); (1S,2R,5R)-3-(((2-amino-3-chloro-5-fluoroquinolin-7-yl)oxy)methyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (compound 18); (1S,2R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-(((2-(methylamino)quinolin-7-yl)oxy)methyl)cyclopent-3-ene-1,2-diol (compound 19); (1S,2R,5R)-3-(1-((2-amino-3-chloro-5-fluoroquinolin-7-yl)oxy)ethyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (compounds 20a and 20b); (1S,2R,5R)-3-(2-(2-amino-3-chloroquinolin-7-yl)ethyl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (compound 21); (1S,2R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-(2-(2-(cyclobutylamino)quinolin-7-yl)ethyl)cyclopent-3-ene-1,2-diol (compound 22); (1S,2R,5R)-3-(2-(2-amino-3-fluoroquinolin-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (compound 23); (1S,2R,5R)-3-(2-(2-amino-3-chloro-5-fluoroquinolin-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (compound 24); (1S,2R,5R)-3-(2-(2-amino-3-chloro-6-fluoroquinolin-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (compound 25); (1S,2R,5R)-3-(2-(2-amino-3-chloro-8-fluoroquinolin-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (compound 26); (1S,2R,5R)-3-(2-(2-amino-3,3-dimethyl-3H-indol-6-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (compound 27); (1S,2R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-(2-(2'-aminospiro[cyclobutane-1,3'-indol]-6'-yl)ethyl)cyclopent-3-ene-1,2-diol (compound 28); (1S,2R,5R)-3-(2-(2-amino-3,5-dichloroquinolin-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (compound 29); (1S,2R,5R)-3-(2-(2-amino-3-chloroquinolin-7-yl)ethyl)-5-(2-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (compound 30); (1S,2R,5R)-3-(2-(2-amino-3-chloro-5-fluoroquinolin-7-yl)ethyl)-5-(4-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (compound 31); (1S,2R,5R)-3-(2-(2-amino-3-chloro-5-fluoroquinolin-7-yl)ethyl)-5-(4-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (compound 32); (1S,2R,5R)-3-(1-(2-amino-3-chloro-5-fluoroquinolin-7-yl)propan-2-yl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (compounds 33a and 33b); (1S,2R,5R)-3-(1-(2-amino-3-chloroquinolin-7-yl)propan-2-yl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (compounds 34a and 34b); (1S,2R,5R)-3-(1-(2-amino-3-chloro-5-fluoroquinolin-7-yl)propan-2-yl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (compounds 35a and 35b); (1S,2R,5R)-3-(1-(2-amino-3-chloro-5-fluoroquinolin-7-yl)propan-2-yl)-2-methyl-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (compounds 36a and 36b); (1S,2R,5R)-3-(2-(2-amino-3-chloro-5-fluoroquinolin-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-methylcyclopent-3-ene-1,2-diol (compound 37); (1S,2R,5R)-3-(1-(2-amino-3-chloro-5-fluoroquinolin-7-yl)propan-2-yl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-methylcyclopent-3-ene-1,2-diol (compound 38); (1S,2R,5R)-3-(2-(2-amino-3-chloro-5-fluoroquinolin-7-yl)ethyl)-2-methyl-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (compound 39); (1S,2R,5R)-3-(2-(2-amino-3-chloro-5-fluoroquinolin-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethylcyclopent-3-ene-1,2-diol (compound 40); (1S,2R,5R)-3-(2-(2-amino-3-chloro-5-fluoroquinolin-7-yl)ethyl)-5-(4-ethyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (compound 41); (1S,2R,5R)-3-(2-(2-amino-3-chloro-5-fluoroquinolin-7-yl)ethyl)-5-(4-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (compound 42); (1S,2R,5R)-3-(2-(2-amino-3-bromo-5-fluoroquinolin-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (compound 43); (1S,2R,5R)-3-(2-(2-amino-3-bromo-5-fluoroquinolin-7-yl)ethyl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (compound 44); (1S,2R,5R)-3-(1-(2-amino-3-bromo-5-fluoroquinolin-7-yl)propan-2-yl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (compounds 45a and 45b); (1S,2R,5R)-3-(2-(2-amino-6-fluoroquinolin-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (compound 46); (1S,2R,5R)-3-(2-(2-amino-5-fluoroquinolin-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (compound 47); (1R,2R,3S,4R,5S)-1-(2-(2-amino-3-chloro-5-fluoroquinolin-7-yl)ethyl)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[3.1.0]hexane-2,3-diol (compound 48); (1R,2R,3S,4R,5S)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-(2-(2-(methylamino)quinolin-7-yl)ethyl)bicyclo[3.1.0]hexane-2,3-diol (compound 49); (1R,2R,3S,4R,5S)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-(2-(2-(isopropylamino)quinolin-7-yl)ethyl)bicyclo[3.1.0]hexane-2,3-diol (compound 50); (1R,2R,3S,4R,5S)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-(2-(2-(cyclobutylamino)quinolin-7-yl)ethyl)bicyclo[3.1.0]hexane-2,3-diol (compound 51); (1R,2R,3S,4R,5S)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-(2-(2-((cyclopropylmethyl)amino)quinolin-7-yl)ethyl)bicyclo[3.1.0]hexane-2,3-diol (compound 52); (1R,2R,3S,4R,5S)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-(2-(2-amino-8-fluoroquinolin-7-yl)ethyl)bicyclo[3.1.0]hexane-2,3-diol (compound 53); (1R,2R,3S,4R,5S)-1-(2-(2-amino-3-methylquinolin-7-yl)ethyl)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[3.1.0]hexane-2,3-diol (compound 54); (1R,2R,3S,4R,5S)-1-(2-(2-amino-3-isopropylquinolin-7-yl)ethyl)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[3.1.0]hexane-2,3-diol (compound 55); (1R,2R,3S,4R,5S)-1-(2-(2-amino-3-(1,1-difluoroethyl)quinolin-7-yl)ethyl)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[3.1.0]hexane-2,3-diol (compound 56); (1R,2R,3S,4R,5S)-1-(2-(2-amino-3-cyclopropylquinolin-7-yl)ethyl)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[3.1.0]hexane-2,3-diol (compound 57); (1R,2R,3S,4R,5S)-1-(2-(2-amino-3-methoxyquinolin-7-yl)ethyl)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[3.1.0]hexane-2,3-diol (compound 58); 2-amino-7-(2-((1R,2R,3S,4R,5S)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,3-dihydroxybicyclo[3.1.0]hexan-1-yl)ethyl)quinoline-3-carbonitrile (compound 59); (1R,2R,3S,4R,5S)-1-(2-(2-amino-3-fluoroquinolin-7-yl)ethyl)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[3.1.0]hexane-2,3-diol (compound 60); (1R,2R,3S,4R,5S)-1-(2-(2-amino-3-chloroquinolin-7-yl)ethyl)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[3.1.0]hexane-2,3-diol (compound 61); (1R,2R,3S,4R,5S)-1-(2-(2-amino-3-chloro-6-fluoroquinolin-7-yl)ethyl)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[3.1.0]hexane-2,3-diol (compound 62); (1R,2R,3S,4R,5S)-1-(2-(2-amino-3-chloro-8-fluoroquinolin-7-yl)ethyl)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[3.1.0]hexane-2,3-diol (compound 63); (1R,2R,3S,4R,5S)-1-(2-(2-amino-3-bromo-6-fluoroquinolin-7-yl)ethyl)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[3.1.0]hexane-2,3-diol (compound 64); (1R,2R,3S,4R,5S)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-(2-(3-methylimidazo[1,2-a]pyridin-7-yl)ethyl)bicyclo[3.1.0]hexane-2,3-diol (compound 65); (1R,2R,3S,4R,5S)-1-(2-(2-amino-3,3-dimethyl-3H-indol-6-yl)ethyl)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[3.1.0]hexane-2,3-diol (compound 66); (1R,2R,3S,4R,5S)-1-(2-(2-amino-3-chloro-5-fluoroquinolin-7-yl)ethyl)-4-(4-amino-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[3.1.0]hexane-2,3-diol (compound 67); (1R,2R,3S,4R,5S)-1-(2-(2-amino-3-chloro-6-fluoroquinolin-7-yl)ethyl)-4-(4-amino-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[3.1.0]hexane-2,3-diol (compound 68); (1R,2R,3S,4R,5S)-1-(2-(2-amino-3-chloro-5-fluoroquinolin-7-yl)ethyl)-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[3.1.0]hexane-2,3-diol (compound 69); (1R,2R,3S,4R,5S)-1-(2-(2-amino-3-chloro-5-fluoroquinolin-7-yl)ethyl)-4-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[3.1.0]hexane-2,3-diol (compound 70); (1R,2R,3S,4R,5S)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-(2-(2'-aminospiro[cyclobutane-1,3'-indol]-6'-yl)ethyl)bicyclo[3.1.0]hexane-2,3-diol (compound 71); (1R,2R,3S,4R,5S)-1-(2-(2-amino-3-bromo-5-fluoroquinolin-7-yl)ethyl)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[3.1.0]hexane-2,3-diol (compound 72); (1R,2R,3S,4R,5S)-1-(2-(2-amino-3-bromoquinolin-7-yl)ethyl)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[3.1.0]hexane-2,3-diol (compound 73); (1R,2R,3S,4R,5S)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-(2-(2-aminoquinolin-7-yl)ethyl)bicyclo[3.1.0]hexane-2,3-diol (compound 74); (1R,2R,3S,4R,5S)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-(2-(2-aminoquinazolin-7-yl)ethyl)bicyclo[3.1.0]hexane-2,3-diol (compound 75); (1S,2R,3S,4R,5S)-1-((S)-1-(2-amino-3-bromoquinolin-7-yl)propan-2-yl)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[3.1.0]hexane-2,3-diol (compounds 76a and 76b); (1S,2R,3S,4R,5S)-1-((S)-2-(2-amino-3-chloro-5-fluoroquinolin-7-yl)-1-cyclopropylethyl)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[3.1.0]hexane-2,3-diol (compounds 77a and 77b); (1S,2R,3S,4R,5S)-1-(1-(2-amino-3-chloro-5-fluoroquinolin-7-yl)propan-2-yl)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[3.1.0]hexane-2,3-diol (compounds 78a and 78b); (1R,2R,3S,4R,5S)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-(2-(2-aminoquinolin-7-yl)propyl)bicyclo[3.1.0]hexane-2,3-diol (compounds 79a and 79b); (1R,2R,3S,4R,5S)-1-(((2-amino-3-bromoquinolin-7-yl)oxy)methyl)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[3.1.0]hexane-2,3-diol (compound 80); (1S,2R,3S,4R,5S)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-(((2-aminoquinolin-7-yl)thio)methyl)bicyclo[3.1.0]hexane-2,3-diol (compound 81); (1R,2R,3S,4R,5S)-1-(2-(2-amino-3-(4-fluorophenyl)quinolin-7-yl)ethyl)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[3.1.0]hexane-2,3-diol (compound 82); (1R,2R,3S,4R,5S)-1-(2-(2-amino-3-(pyridin-3-yl)quinolin-7-yl)ethyl)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[3.1.0]hexane-2,3-diol (compound 83); or (1R,2R,3S,4R,5S)-1-(2-(2-amino-3-(3-methylisoxazol-4-yl)quinolin-7-yl)ethyl)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[3.1.0]hexane-2,3-diol (compound 84); and and pharma- ceutically acceptable salts thereof.

[0028] In some embodiments, the pharmaceutical combination comprises the compound (1S,2R,5R)-3-(2-(2-amino-3-chloro-5-fluoroquinolin-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (compound 24) and at least one tagged drug / cellular activity modulator which is an EGFR inhibitor, a KRAS inhibitor, a KRAS-G12C inhibitor, a MEK inhibitor, a Bcl-2 inhibitor, a SOS1 inhibitor, a PARP inhibitor, a RAF inhibitor, an ERK inhibitor, a CDK4 / 6 inhibitor, a MALT1 inhibitor, a BTK inhibitor, a MAT2A inhibitor, a PI3K inhibitor, an AKT inhibitor, a BTK inhibitor, a MAT2A inhibitor, a PI3K inhibitor, an AKT inhibitor, a FGFR inhibitor, a type I PRMT inhibitor, a STING agonist or an immune checkpoint inhibitor / modulator, for use in the treatment and / or prevention of cancer.

[0029] In some embodiments, the pharmaceutical combination comprises at least one PRMT5 inhibitor of Formula 1 and an EGFR inhibitor or an oncogenic mutant thereof. In some embodiments, the EGFR inhibitor is afatinib ((E)-N-[4-(3-chloro-4-fluoroanilino)-7-[(3S)-oxolan-3-yl]oxyquinazolin-6-yl]-4-(dimethylamino)but-2-enamide), osimertinib (N-[2-[2-(dimethylamino)ethyl-methylamino]-4-methoxy-5-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino]phenyl]prop-2-enamide), erlotinib (N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine), and gefitinib (N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholin-4-ylpropoxy)quinazolin-4-amine): [ka] [ka] [ka] [ka]

[0030] In some embodiments, the pharmaceutical combination comprises at least one PRMT5 inhibitor of Formula 1 and an SOS1 inhibitor. In some embodiments, the SOS1 inhibitor is BI-3406 (N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-2-methyl-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-4-amine): [ka]

[0031] In some embodiments, the pharmaceutical combination comprises at least one PRMT5 inhibitor of Formula 1 and an ERK inhibitor. In some embodiments, the ERK inhibitor is ulixertinib (N-[(1S)-1-(3-chlorophenyl)-2-hydroxyethyl]-4-[5-chloro-2-(propan-2-ylamino)pyridin-4-yl]-1H-pyrrole-2-carboxamide), MK-8353 ((S)-N-(3-(6-isopropoxypyridin-3-yl)-1H-indazol-5-yl)-1-(2-(4-(4-(1-methylphenyl)pyridin-3-yl)-1H-indazol-5-yl), The compounds are 1-[(1S)-1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl]-4-[2-[(2-methylpyrazol-3-yl)amino]pyrimidin-4-yl]pyridin-2-one, 1-[(1H)-1,2,4-triazol-3-yl)phenyl]-3,6-dihydropyridin-1(2H)-yl)-2-oxoethyl]-3-(methylthio)pyrrolidine-3-carboxamide and lavoxertinib (1-[(1S)-1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl]-4-[2-[(2-methylpyrazol-3-yl)amino]pyrimidin-4-yl]pyridin-2-one): [ka] [ka] [ka]

[0032] In some embodiments, the pharmaceutical combination comprises at least one PRMT5 inhibitor of Formula 1 and a PARP inhibitor. In some embodiments, the PARP inhibitor is selected from the group consisting of olaparib (4-[[3-[4-(cyclopropanecarbonyl)piperazine-1-carbonyl]-4-fluorophenyl]methyl]-2H-phthalazin-1-one), niraparib ((S)-2-(4-(piperidin-3-yl)phenyl)-2H-indazole-7-carboxamide), rucaparib (6-fluoro-2-[4-(methylaminomethyl)phenyl]-3,10 -diazatricyclo[6.4.1.04,13]trideca-1,4,6,8(13)-tetraen-9-one) and talazoparib (BMN-673) ((11S,12R)-7-fluoro-11-(4-fluorophenyl)-12-(2-methyl-1,2,4-triazol-3-yl)-2,3,10-triazatricyclo[7.3.1.05,13]trideca-1,5(13),6,8-tetraen-4-one): [ka] [ka] [ka] [ka]

[0033] In some embodiments, the pharmaceutical combination comprises at least one PRMT5 inhibitor of formula 1 and a CDK4 / 6 inhibitor. In some embodiments, the CDK4 / 6 inhibitor is palbociclib (6-acetyl-8-cyclopentyl-5-methyl-2-[(5-piperazin-1-ylpyridin-2-yl)amino]pyrido[2,3-d]pyrimidin-7-one), ribociclib (7-cyclopentyl-N,N-dimethyl-2-[(5-piperazin-1-ylpyridin-2-yl)amino]pyrrolo[2,3-d]pyrimidine-6-carboxamide), and abemaciclib (N-[5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-yl]-5-fluoro-4-(7-fluoro-2-methyl-3-propan-2-ylbenzimidazol-5-yl)pyrimidin-2-amine): [ka] [ka] [ka]

[0034] In some embodiments, the pharmaceutical combination comprises at least one PRMT5 inhibitor of Formula 1 and a BTK inhibitor. In some embodiments, the BTK inhibitor is ibrutinib (1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one), zanubrutinib ((7S)-2-(4-phenoxyphenyl)-7-(1-prop-2-enoylpiperidin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide), or acalabrutinib (4-[8-amino-3-[(2S)-1-but-2-ynoylpyrrolidin-2-yl]imidazo[1,5-a]pyrazin-1-yl]-N-pyridin-2-ylbenzamide): [ka] [ka] [ka]

[0035] In some embodiments, the disclosure includes a pharmaceutical combination comprising (a) the compound (1S,2R,5R)-3-(2-(2-amino-3-chloro-5-fluoroquinolin-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol or a pharma- ceutical acceptable salt thereof, and (b) afatinib, for use in the treatment and / or prevention of cancer in a subject in need thereof. In some embodiments, the disclosure includes a pharmaceutical combination comprising (a) the compound (1S,2R,5R)-3-(2-(2-amino-3-chloro-5-fluoroquinolin-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol or a pharma- ceutical acceptable salt thereof, and (b) BI-3406, for use in the treatment and / or prevention of cancer in a subject in need thereof. In some embodiments, the disclosure includes a pharmaceutical combination comprising (a) the compound (1S,2R,5R)-3-(2-(2-amino-3-chloro-5-fluoroquinolin-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol or a pharma- ceutical acceptable salt thereof, and (b) ulixertinib, for use in the treatment and / or prevention of cancer in a subject in need thereof.

[0036] In some embodiments, the present disclosure includes a combination pharmaceutical comprising a PRMT5 inhibitor of formula (I) with an EGFR inhibitor, a KRAS inhibitor, a KRAS-G12C inhibitor, a MEK inhibitor, a Bcl-2 inhibitor, a SOS1 inhibitor, a PARP inhibitor, a RAF inhibitor, an ERK inhibitor, a CDK4 / 6 inhibitor, a MALT1 inhibitor, a BTK inhibitor, a MAT2A inhibitor, a PI3K inhibitor, an AKT inhibitor, a BTK inhibitor, a MAT2A inhibitor, a PI3K inhibitor, an AKT inhibitor, a FGFR inhibitor, a type I PRMT inhibitor, a STING agonist or an immune checkpoint inhibitor / modulator. The PRMT5 inhibitor of formula (I) can be administered simultaneously, in parallel, sequentially, sequentially, alternately or separately with at least one tagged drug / cell activity modulator (e.g., the administration of the PRMT5 inhibitor of formula (I) and at least one tagged drug / cell activity modulator can be performed in any order).

[0037] In some embodiments of the present invention, the disclosure comprises a method of treating and / or preventing cancer in a human subject in need thereof comprising administering to the human subject a therapeutically effective amount of a pharmaceutical combination comprising a PRMT5 inhibitor of formula (I) as defined herein and at least one tagged drug / cellular activity modulator selected from an EGFR inhibitor, a KRAS inhibitor, a KRAS-G12C inhibitor, a MEK inhibitor, a Bcl-2 inhibitor, a SOS1 inhibitor, a PARP inhibitor, a RAF inhibitor, an ERK inhibitor, a CDK4 / 6 inhibitor, a MALT1 inhibitor, a BTK inhibitor, a MAT2A inhibitor, a PI3K inhibitor, an AKT inhibitor, a BTK inhibitor, a MAT2A inhibitor, a PI3K inhibitor, an AKT inhibitor, a FGFR inhibitor, a type I PRMT inhibitor, a STING agonist or an immune checkpoint inhibitor / modulator, thereby treating and / or preventing cancer in the human subject.

[0038] In some embodiments of the present invention, the disclosure comprises a method of treatment and / or prevention of a human subject suffering from cancer, comprising administering to the human subject a therapeutically effective amount of a pharmaceutical combination comprising a PRMT5 inhibitor of formula (I) as defined herein and at least one tagged agent / cellular activity modulator selected from an EGFR inhibitor, a KRAS inhibitor, a KRAS-G12C inhibitor, a MEK inhibitor, a Bcl-2 inhibitor, a SOS1 inhibitor, a PARP inhibitor, a RAF inhibitor, an ERK inhibitor, a CDK4 / 6 inhibitor, a MALT1 inhibitor, a BTK inhibitor, a MAT2A inhibitor, a PI3K inhibitor, an AKT inhibitor, a FGFR inhibitor, a type I PRMT inhibitor, a STING agonist or an immune checkpoint inhibitor / modulator, together with at least one of a pharma- ceutical carrier and a pharma-ceutical acceptable diluent, thereby treating and / or preventing cancer in the human subject.

[0039] In some embodiments, the disclosure comprises a pharmaceutical combination comprising a PRMT5 inhibitor of formula (I) as defined herein and at least one tagged drug / cellular activity modulator selected from an EGFR inhibitor, a KRAS inhibitor, a KRAS-G12C inhibitor, a MEK inhibitor, a Bcl-2 inhibitor, a SOS1 inhibitor, a PARP inhibitor, a RAF inhibitor, an ERK inhibitor, a CDK4 / 6 inhibitor, a MALT1 inhibitor, a BTK inhibitor, a MAT2A inhibitor, a PI3K inhibitor, an AKT inhibitor, a BTK inhibitor, a MAT2A inhibitor, a PI3K inhibitor, an AKT inhibitor, a FGFR inhibitor, a type I PRMT inhibitor, a STING agonist or an immune checkpoint inhibitor / modulator, for use in the treatment and / or prevention of cancer in a subject in need thereof.

[0040] In some embodiments, the disclosure includes a pharmaceutical combination comprising a PRMT5 inhibitor of formula (I) as defined herein and at least one tagged drug / cellular activity modulator selected from an EGFR inhibitor, a KRAS inhibitor, a KRAS-G12C inhibitor, a MEK inhibitor, a Bcl-2 inhibitor, a SOS1 inhibitor, a PARP inhibitor, a RAF inhibitor, an ERK inhibitor, a CDK4 / 6 inhibitor, a MALT1 inhibitor, a BTK inhibitor, a MAT2A inhibitor, a PI3K inhibitor, an AKT inhibitor, a BTK inhibitor, a MAT2A inhibitor, a PI3K inhibitor, an AKT inhibitor, a FGFR inhibitor, a type I PRMT inhibitor, a STING agonist or an immune checkpoint inhibitor / modulator, for use in treating cancer in a subject in need thereof.

[0041] In some embodiments, the disclosure includes a pharmaceutical combination comprising a PRMT5 inhibitor of formula (I) as defined herein and at least one tagged drug / cellular activity modulator selected from an EGFR inhibitor, a KRAS inhibitor, a KRAS-G12C inhibitor, a MEK inhibitor, a Bcl-2 inhibitor, a SOS1 inhibitor, a PARP inhibitor, a RAF inhibitor, an ERK inhibitor, a CDK4 / 6 inhibitor, a MALT1 inhibitor, a BTK inhibitor, a MAT2A inhibitor, a PI3K inhibitor, an AKT inhibitor, a BTK inhibitor, a MAT2A inhibitor, a PI3K inhibitor, an AKT inhibitor, a FGFR inhibitor, a type I PRMT inhibitor, a STING agonist or an immune checkpoint inhibitor / modulator for use in reducing tumor growth rate, reducing tumor size, or alleviating one or more symptoms associated with having a tumor in a subject in need thereof.

[0042] In some embodiments, the disclosure provides a combination of a PRMT5 inhibitor of formula (I) and at least one tagged drug selected from an EGFR inhibitor, a KRAS inhibitor, a KRAS-G12C inhibitor, a MEK inhibitor, a Bcl-2 inhibitor, a SOS1 inhibitor, a PARP inhibitor, a RAF inhibitor, an ERK inhibitor, a CDK4 / 6 inhibitor, a MALT1 inhibitor, a BTK inhibitor, a MAT2A inhibitor, a PI3K inhibitor, an AKT inhibitor, a BTK inhibitor, a MAT2A inhibitor, a PI3K inhibitor, an AKT inhibitor, a FGFR inhibitor, a type I PRMT inhibitor, a STING agonist, or an immune checkpoint inhibitor / modulator. The present invention includes pharmaceutical combinations comprising a therapeutic agent / cell activity modulator and a medicament for treating and / or preventing a variety of cancers, which may or may not include glioblastoma multiforme, prostate cancer, pancreatic cancer, mantle cell lymphoma, non-Hodgkin's lymphoma and diffuse large B-cell lymphoma, acute myeloid leukemia, acute lymphocytic leukemia, multiple myeloma, non-small cell lung cancer, small cell lung cancer, breast cancer, triple negative breast cancer, gastric cancer, colorectal cancer, ovarian cancer, bladder cancer, hepatocellular carcinoma, melanoma, sarcoma, oropharyngeal squamous cell carcinoma, chronic myeloid leukemia, epidermal squamous cell carcinoma, nasopharyngeal carcinoma, neuroblastoma, endometrial cancer, head and neck cancer, and cervical cancer.

[0043] definition General terms used in the formula can be defined as follows, however the stated meanings should not be construed as limiting the scope of the terms themselves.

[0044] As used herein, the description of a numerical range for a variable / variable is intended to be understood to mean that the invention can be practiced with the variable / variable equal to any value within that range. Thus, for a variable / variable that is discrete in nature, the variable / variable can be equal to any integer value in that range, including the endpoints of the numerical range. Similarly, for a variable / variable that is continuous in nature, the variable / variable can be equal to any real value in that range, including the endpoints of the numerical range. As an example, a variable / variable described as having a value of 0 to 2 can be 0, 1, or 2 for a variable / variable that is discrete in nature, and 0.0, 0.1, 0.01, 0.001, or any other real value for a variable / variable that is continuous in nature.

[0045] As used herein, the term "about" is intended to qualify the numerical value it modifies, and indicates a value that is variable within a margin of error. Unless a margin of error, such as a standard deviation for a mean value, is specifically stated, the term "about" refers to a numerical value within ±10% of the number to which the term is attached. Thus, for example, about 50% means within the range of 45% to 55%.

[0046] As used herein, the term "halogen" or "halo" means fluorine, chlorine, bromine, or iodine. As used herein, the term "alkyl" refers to an alkane-derived hydrocarbon group, e.g., (C1-C6)alkyl or (C1-C4)alkyl, containing only carbon and hydrogen atoms in the backbone, no unsaturation, having 1 to 6 carbon atoms and attached to the remainder of the molecule by a single bond, representative groups include, for example, methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, etc. Unless stated to the contrary, all alkyl groups described in this specification or claims may be straight or branched chain.

[0047] As used herein, the term "alkenyl" refers to a hydrocarbon group containing 2-10 carbon atoms and containing at least one carbon-carbon double bond. Non-limiting examples of alkenyl groups include, for example, (C2-C6)alkenyl, (C2-C4)alkenyl, ethenyl, 1-propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like. Unless stated to the contrary, all alkenyl groups described herein or in the claims may be straight or branched chain. As used herein, the term "alkynyl" refers to a hydrocarbon group containing 2-10 carbon atoms and containing at least one carbon-carbon triple bond. Non-limiting examples of alkynyl groups include, for example, (C2-C6)alkynyl, (C2-C4)alkynyl, ethynyl, propynyl, butynyl, and the like. Unless stated to the contrary, all alkynyl groups described herein or in the claims may be straight or branched chain.

[0048] As used herein, the term "haloalkyl" refers to an alkyl group as defined above substituted with one or more halogen atoms as defined above. For example, (C1-C6)haloalkyl or (C1-C4)haloalkyl. Suitably, the haloalkyl may be a monohaloalkyl, dihaloalkyl, or polyhaloalkyl, including perhaloalkyl. A monohaloalkyl may have one iodine, bromine, chlorine, or fluorine atom. Dihaloalkyl and polyhaloalkyl groups may be substituted with two or more of the same or different halogen atoms in combination. Suitably, polyhaloalkyl is substituted with up to 12 halogen atoms. Non-limiting examples of haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, and the like. Perhaloalkyl refers to an alkyl group in which all hydrogen atoms have been replaced with halogen atoms. Unless stated to the contrary, all haloalkyl groups described in this specification or claims may be straight or branched chain.

[0049] As used herein, the term "alkoxy" refers to an alkyl group attached to the remainder of the molecule via an oxygen linkage. Representative examples of such groups are -OCH3 and -OC2H5. Unless otherwise specified, all alkoxy groups described herein or in the claims may be straight or branched chain. As used herein, the term "alkoxyalkyl" refers to an alkoxy group as defined above directly bonded to an alkyl group as defined above, e.g., -CH2-O-CH3, -CH2-O-CH2CH3, -CH2CH2-O-CH3, and the like.

[0050] As used herein, the term "cycloalkyl" refers to a non-aromatic monocyclic or polycyclic ring system having 3 to 12 carbon atoms, e.g., (C 10)cycloalkyl, (C3-C6)cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. Examples of polycyclic cycloalkyl groups include, but are not limited to, perhydronaphthyl, adamantyl, and norbornyl groups, bridged cyclic groups or spiro bicyclic groups such as spiro(4,4)non-2-yl, etc. As used herein, the term "aryl" refers to aromatic groups having 6 to 14 carbon atoms and includes monocyclic, bicyclic and tricyclic aromatic systems, such as phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, and the like.

[0051] As used herein, the terms "heterocycle" or "heterocyclyl ring" or "heterocyclyl", unless otherwise specified, refer to a substituted or unsubstituted non-aromatic 3- to 15-membered ring consisting of carbon atoms and one or more heteroatoms independently selected from N, O, or S. The heterocycle may be a monocyclic ring system, or a bicyclic or tricyclic ring system which may include fused, bridged, or spiro ring systems, and the nitrogen, carbon, oxygen, or sulfur atoms in the heterocycle may be optionally oxidized to various oxidation states. In addition, the nitrogen atom may be optionally quaternized, the heterocycle or heterocyclyl may optionally contain one or more olefinic bonds, and one or two carbon atoms in the heterocycle or heterocyclyl may be interrupted by -CF2-, -C(O)-, -S(O)-, S(O)2, etc. In addition, the heterocycle may be fused to an aromatic ring. Non-limiting examples of heterocycles include azetidinyl, benzopyranyl, chromanyl, decahydroisoquinolyl, indolinyl, isoindolinyl, isochromanyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, oxazolinyl, oxazolidinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, octahydroindolyl, octahydroisoindolyl, perhydroazolyl, and the like. Zepinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, piperidinyl, phenothiazinyl, phenoxazinyl, quinuclidinyl, tetrahydroisoquinolyl, tetrahydrofuryl, tetrahydropyranyl, thiazolinyl, thiazolidinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinylsulfoneindoline, benzodioxole, tetrahydroquinoline, tetrahydrobenzopyran, etc. The heterocycle may be attached by any atom of the heterocycle that results in the creation of a stable structure.

[0052] As used herein, the term "heteroaryl", unless otherwise specified, refers to a substituted or unsubstituted 5-14 membered aromatic heterocycle having one or more heteroatoms independently selected from N, O, or S. Heteroaryl may be a monocyclic, bicyclic, or tricyclic ring system. The heteroaryl ring may be attached by any atom of the heteroaryl ring that results in the creation of a stable structure. Non-limiting examples of heteroaryl rings include oxazolyl, isoxazolyl, imidazolyl, furyl, indolyl, isoindolyl, pyrrolyl, triazolyl, triazinyl, tetrazolyl, thienyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuranyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzothienyl, carbazolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, naphthyridinyl, pteridinyl, purinyl, quinoxalinyl, quinolyl, isoquinolyl, thiadiazolyl, indolizinyl, acridinyl, phenazinyl, phthalazinyl, and the like. The compounds of the present invention may have one or more chiral centers. The absolute stereochemistry at each chiral center may be "R" or "S". The compounds of the present invention include all diastereomers and enantiomers and mixtures thereof. Unless otherwise specified, a reference to a single stereoisomer refers to any of the possible stereoisomers. When the stereoisomeric composition is not specified, it is understood that all possible stereoisomers are included.

[0053] As used herein, the term "stereoisomers" refers to compounds composed of the same atoms bonded by the same bonds, but with different, incompatible three-dimensional structures. The three-dimensional structures are called configurations. As used herein, the term "enantiomers" refers to two stereoisomers whose molecules are non-superimposable mirror images of one another. The term "chiral center" refers to a carbon atom to which four different groups are attached. As used herein, the term "diastereomers" refers to stereoisomers that are not enantiomers. The terms "racemate" or "racemic mixture" refer to a mixture of equal amounts of enantiomers. As used herein, the term "tautomer" refers to a compound that undergoes rapid proton transfer from one atom of the compound to another atom of the compound. Some of the compounds described herein may exist as tautomers that differ in the point of attachment of hydrogen. Individual tautomers and mixtures thereof are encompassed by the compounds of formula (I).

[0054] As used herein, the term "treating" or "treatment" of a condition, disorder, or pathological condition includes (a) preventing or delaying the appearance of clinical symptoms of the developing condition, disorder, or pathological condition in a subject who may be afflicted with or susceptible to the condition, disorder, or pathological condition, but who has not yet experienced or exhibited clinical or subclinical symptoms of the condition, disorder, or pathological condition; (b) inhibiting the condition, disorder, or pathological condition, i.e., arresting or reducing the progression of the disease or at least one clinical or subclinical symptom thereof; (c) alleviating the disease, disorder, or pathological condition, or at least one clinical or subclinical symptom thereof, or (d) palliating the disease, i.e., causing regression or amelioration of the condition, disorder, or pathological condition, or at least one clinical or subclinical symptom thereof.

[0055] As used herein, the terms "treat," "ameliorate," and "inhibit," and terms derived therefrom, as used herein, do not necessarily mean 100% or complete treatment, amelioration, or inhibition. Rather, there are various degrees of treatment, amelioration, and inhibition that one of skill in the art would recognize as likely to have a beneficial or therapeutic effect. In this regard, the disclosed methods can provide any amount or level of treatment, amelioration, or inhibition of a disorder in a mammal. For example, the disorder (including its symptoms or pathology) may be reduced by, for example, 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, or 10%. Furthermore, the treatment, amelioration, or inhibition provided by the methods of the present invention can include the treatment, amelioration, or inhibition of one or more pathologies or symptoms of the disorder (e.g., cancer). Also, for purposes herein, "treatment," "amelioration," or "inhibition" can encompass delaying the onset of the disorder or its symptoms or pathology.

[0056] As used herein, the term "inhibitor" refers to a molecule that binds to an enzyme and inhibits, either partially or completely, the activity of that enzyme. As used herein, the terms "patient" and "subject" are interchangeable and may be taken to mean any living organism that can be treated with the pharmaceutical combinations disclosed herein. The terms "patient" and "subject" include mammals (e.g., primates or humans) and other animals, such as domestic animals (e.g., household pets, including cats and dogs) and non-domestic animals (e.g., wild animals).

[0057] As used herein, "therapeutically effective amount" means the amount of a compound that, when administered to a subject for treating a disease, disorder, or pathological condition, is sufficient to cause the effect for which it is administered in the subject. The "therapeutically effective amount" varies depending on the compound, the route of administration, the disease and its severity, and the age, weight, physical condition, and responsiveness of the subject being treated. As used herein, "pharmaceutical acceptable carrier" refers to an ingredient in a pharmaceutical formulation other than an active ingredient that can be safely administered to a subject. Pharmaceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers, or preservatives. Suitable carriers and diluents include buffered, aqueous solutions, saline, dextrose, glycerol, isotonic saline, such as phosphate buffered saline, isotonic water, and the like, and combinations thereof. In some embodiments, the carrier may include propylene glycol, dimethyl isosorbide, and water, and more specifically, phosphate buffered saline, isotonic water, deionized water, monofunctional alcohols, and symmetric alcohols.

[0058] As used herein, the term "tumor" refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all pre-cancerous and cancerous cells and tissues. The terms "cancer," "cancerous," "cell proliferative disorder," "proliferative disorder," and "tumor" are not mutually exclusive when referred to herein.

[0059] As used herein, the phrase "pharmaceutical acceptable salt" refers to a pharmaceutical acceptable organic or inorganic salt of the compound of the present invention.Exemplary salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate "mesylate", ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1'-methylene-bis(2-hydroxy-3-naphthoate)). A pharmaceutically acceptable salt may contain another molecule, such as an acetate ion, a succinate ion, or other counter ion. In some embodiments, the counter ion is any organic or inorganic moiety that stabilizes the charge on the parent compound. In addition, a pharmaceutically acceptable salt may have more than one charged atom in its structure. In the example where multiple charged atoms are part of the pharmaceutically acceptable salt, it can have multiple counter ions. Thus, a pharmaceutically acceptable salt can have one or more charged atoms and / or one or more counter ions.

[0060] In some embodiments, when the compound of the invention is a base, the desired pharma- ceutically acceptable salt is prepared by any suitable method available in the art, for example, by treating the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, trifluoroacetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an α-hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, and the like.

[0061] In some embodiments, when the compound of the invention is an acid, the desired pharma- ceutically acceptable salt is prepared by any suitable method, for example, by treating the free acid with an inorganic or organic base, such as an amine (primary, secondary, or tertiary), an alkali metal hydroxide or an alkaline earth metal hydroxide, etc. Illustrative examples of suitable salts include, but are not limited to, organic salts derived from amino acids, such as glycine and arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines, such as piperidine, morpholine, and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.

[0062] As used herein, the term "solvate" refers to an association or complex of one or more solvent molecules with a compound of the invention. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.

[0063] composition In some embodiments, EGFR inhibitors that can be used together with the PRMT5 inhibitor of formula (I) may or may not include afatinib, osimertinib, erlotinib, or gefitinib, or any other agent that inhibits the activity of the enzyme EGFR or its oncogenic mutants. In some embodiments, CDK4 / 6 inhibitors that can be used together with the PRMT5 inhibitor of formula (I) may or may not include palbociclib, ribociclib, or abemaciclib, or any other agent that inhibits the activity of the enzymes CDK4 and CDK6. In some embodiments, RAF inhibitors that can be used together with the PRMT5 inhibitor of formula (I) may or may not include dabrafenib, regorafenib, encorafenib or a pan-RAF inhibitor, such as RAF265, or any other agent that inhibits the activity of RAF isoforms (ARAF, BRAF and CRAF).

[0064] In some embodiments, ERK inhibitors that can be used together with the PRMT5 inhibitor of formula (I) may or may not include ulixertinib, MK-8353 or lavoxertinib, or any other agent that inhibits the activity of ERK1 / 2 kinase. In some embodiments, the SOS1 inhibitor that can be used together with the PRMT5 inhibitor of formula (I) may or may not include BI-3406. In some embodiments, MALT1 inhibitors that can be used together with the PRMT5 inhibitor of formula (I) may or may not include MI-2 or JNJ-67856633.

[0065] In some embodiments, BTK inhibitors that can be used together with the PRMT5 inhibitor of formula (I) may or may not include ibrutinib, zanubrutinib, or acalabrutinib. In some embodiments, PI3K inhibitors that can be used together with the PRMT5 inhibitor of Formula (I) may or may not include alpelisib, copanlisib, duvelisib, BEZ-235, gedatolisib, buparisib, or an agent that inhibits the activity of one or more PI3K isoforms (α, β, δ, and γ) or a dual PI3K-mTOR inhibitor. In some embodiments, AKT inhibitors that can be used together with the PRMT5 inhibitor of formula (I) may or may not include GSK690693, AZD5363, or ipatasertib.

[0066] In some embodiments, FGFR inhibitors that can be used together with the PRMT5 inhibitor of formula (I) may or may not include dovitinib, AZD4547, BGJ398, or JNJ42756493. In some embodiments, c-Met inhibitors that can be used together with the PRMT5 inhibitor of formula (I) may or may not include tivantinib, cabozantinib, crizotinib, or capmatinib. In some embodiments, KRAS inhibitors and KRAS-G12C inhibitors that can be used together with the PRMT5 inhibitor of formula (I) may or may not include sotorasib (AMG510), JNJ74699157, or GDC-6036.

[0067] In some embodiments, MEK inhibitors that can be used together with the PRMT5 inhibitor of formula (I) may or may not include cobimetinib, trametinib, SF-2626. In some embodiments, Bcl-2 inhibitors that can be used together with the PRMT5 inhibitor of formula (I) may or may not include navitoclax, venetoclax, AZD-4320, alvocidib hydrochloride, TP-1287, APG-2575. In some embodiments, type I PRMT inhibitors that can be used together with the PRMT5 inhibitor of formula (I) may or may not include GSK-3368715.

[0068] In some embodiments, the MAT2A inhibitor that can be used together with the PRMT5 inhibitor of formula (I) may or may not include AG24512 or AG25696. In some embodiments, STING agonists that can be used together with the PRMT5 inhibitor of Formula (I) may or may not include MK-1454, GSK-532, SYNB-1891, E-7766, or BMS-986301.

[0069] In some embodiments, immune checkpoint inhibitors / modulators (cancer immunotherapeutics) that can be used with the PRMT5 inhibitor of formula (I) may or may not include nivolumab, ipilimumab, pembrolizumab, omburtamab, tremelimumab, pidilizumab, varlilumab, epacadostat, CT-011, AMP-224, and MDX-1106. Checkpoint inhibitors are agents that target checkpoint proteins or derivatives thereof, also referred to as "checkpoint inhibitors." Checkpoint inhibitors may or may not include proteins, polypeptides, amino acid residues, and monoclonal or polyclonal antibodies. PRMT5 inhibitor compounds may be administered with one or more checkpoint inhibitors. Checkpoint inhibitors may, for example, bind to ligands or proteins found in any of the T cell regulator family, for example CD28 / CTLA-4. Targets of checkpoint inhibitors include, but are not limited to, receptors or co-receptors expressed on immune system effector or regulator cells (e.g., T cells) (e.g., CTLA-4; CD8); proteins expressed on the surface of antigen-presenting cells (e.g., proteins expressed on the surface of activated T cells, including PD-1, PD-2, PD-L1, PD-L2, 4-1BB, and OX40); metabolic enzymes or metabolic enzymes expressed on both tumor and tumor-infiltrating cells (e.g., indoleamine (IDO), including isoforms such as IDO1 and IDO2); proteins belonging to the immunoglobulin superfamily (e.g., lymphocyte activation gene 3, also known as LAG3); proteins belonging to the B7 superfamily (e.g., B7-H3 or its homologs). B7 proteins can be found on both activated antigen-presenting cells and T cells.

[0070] method In some embodiments, there is provided the use of a combination drug comprising a PRMT5 inhibitor of formula (I) and at least one tagged drug / cellular activity modulator selected from an EGFR inhibitor, a KRAS inhibitor, a KRAS-G12C inhibitor, a MEK inhibitor, a Bcl-2 inhibitor, a SOS1 inhibitor, a PARP inhibitor, a RAF inhibitor, an ERK inhibitor, a CDK4 / 6 inhibitor, a MALT1 inhibitor, a BTK inhibitor, a MAT2A inhibitor, a PI3K inhibitor, an AKT inhibitor, a BTK inhibitor, a MAT2A inhibitor, a PI3K inhibitor, an AKT inhibitor, a FGFR inhibitor, a type I PRMT inhibitor, a STING agonist or an immune checkpoint inhibitor / modulator or a salt thereof for the manufacture of a medicament for use in the treatment of a disease or pathological condition in which inhibition of PRMT5 protein inhibition is beneficial.

[0071] In some embodiments of the present invention, the disclosure provides a method for the treatment and / or prevention of cancer in a human subject in need thereof, comprising administering to the human subject a combination pharmaceutical composition comprising a PRMT5 inhibitor of formula (I) and at least one tagged drug / cellular activity modulator selected from an EGFR inhibitor, a KRAS inhibitor, a KRAS-G12C inhibitor, a MEK inhibitor, a Bcl-2 inhibitor, a SOS1 inhibitor, a PARP inhibitor, a RAF inhibitor, an ERK inhibitor, a CDK4 / 6 inhibitor, a MALT1 inhibitor, a BTK inhibitor, a MAT2A inhibitor, a PI3K inhibitor, an AKT inhibitor, a BTK inhibitor, a MAT2A inhibitor, a PI3K inhibitor, an AKT inhibitor, a FGFR inhibitor, a type I PRMT inhibitor, a STING agonist or an immune checkpoint inhibitor / modulator. The disease cancer can be glioblastoma multiforme, prostate cancer, pancreatic cancer, mantle cell lymphoma, non-Hodgkin's lymphoma and diffuse large B-cell lymphoma, acute myeloid leukemia, acute lymphocytic leukemia, multiple myeloma, non-small cell lung cancer, small cell lung cancer, breast cancer, triple-negative breast cancer, gastric cancer, colorectal cancer, ovarian cancer, bladder cancer, hepatocellular carcinoma, melanoma, sarcoma, oropharyngeal squamous cell carcinoma, chronic myeloid leukemia, epidermal squamous cell carcinoma, nasopharyngeal carcinoma, neuroblastoma, endometrial cancer or cervical cancer.

[0072] In some embodiments, the present invention provides a method of treating and / or preventing cancer in a subject in need thereof. In some embodiments, the present invention provides a method of slowing tumor growth rate, reducing tumor size, alleviating one or more symptoms associated with having a tumor, or eliminating a tumor in a subject in need thereof. Cancer may or may not include a solid tumor, a leukemia, or a lymphoma.

[0073] Administration In some embodiments, the pharmaceutical combination provided herein may comprise a combination of a PRMT5 inhibitor of formula (I) and at least one tagged drug / cellular activity modulator selected from an EGFR inhibitor, a KRAS inhibitor, a KRAS-G12C inhibitor, a MEK inhibitor, a Bcl-2 inhibitor, a SOS1 inhibitor, a PARP inhibitor, a RAF inhibitor, an ERK inhibitor, a CDK4 / 6 inhibitor, a MALT1 inhibitor, a BTK inhibitor, a MAT2A inhibitor, a PI3K inhibitor, an AKT inhibitor, a BTK inhibitor, a MAT2A inhibitor, a PI3K inhibitor, an AKT inhibitor, a FGFR inhibitor, a type I PRMT inhibitor, a STING agonist or an immune checkpoint inhibitor / modulator, administered by any route appropriate to the pathological condition to be treated. Suitable routes may or may not include oral, parenteral (including subcutaneous, intramuscular, intravenous, intraarterial, intradermal, intrathecal and epidural), intraperitoneal (IP), transdermal, rectal, nasal, topical (including buccal and sublingual), intravaginal, intrapulmonary and intranasal. In some embodiments, for localized therapy, the compound is administered by intratumoral administration, which involves perfusing or otherwise contacting the tumor with the inhibitor. It is understood that the preferred route may vary, for example, depending on the pathological condition of the recipient / subject. In some embodiments, when administered orally, the compound is formulated as a pill, capsule, tablet, etc., together with a pharma- ceutically acceptable carrier and / or excipient. In some embodiments, when administered parenterally, the compound is formulated in an injectable unit dosage form together with a pharma- ceutically acceptable parenteral vehicle, as described herein.

[0074] Suitable doses and dosing regimens can be determined by range finding techniques as a function of the subject's body weight, body volume, body surface area, area of ​​administration, route of administration, and the degree of cancer prognosis of the subject. Generally, treatment is initiated with a dosage that is less than the optimal dose of the composition of the present invention. Thereafter, the dosage is increased in small increments until the optimal effect under the circumstances is reached. The method can include administration of about 0.1 μg to about 50 mg of at least one compound of the present invention per kg body weight of the subject. For example, for a 70 kg patient, a dosage of about 10 μg to about 200 mg of compound can be used, depending on the physiological response of the patient.

[0075] In some embodiments, the dose of a pharma- ceutical active agent described herein for the methods of treating and / or preventing cancer described herein can be about 0.001 to about 1 mg / kg of subject body weight per day, e.g., about 0.001 mg, 0.002 mg, 0.005 mg, 0.010 mg, 0.015 mg, 0.020 mg, 0.025 mg, 0.050 mg, 0.075 mg, 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg, 0.5 mg, 0.75 mg, or 1 mg / kg of body weight per day. Doses of the pharma- ceutical active agents described herein for the methods described can be from about 1 to about 1000 mg / kg body weight of the subject treated per day, e.g., about 1 mg, 2 mg, 5 mg, 10 mg, 15 mg, 0.020 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 250 mg, 500 mg, 750 mg, or 1000 mg / kg body weight per day.

[0076] In some embodiments, within the combination pharmaceuticals for the methods of treating and / or preventing cancer described herein, the dose of the PRMT5 inhibitor of formula (I) is about 1 mg / kg / day, about 2 mg / kg / day, about 5 mg / kg / day, about 10 mg / kg / day, about 15 mg / kg / day, about 20 mg / kg / day, about 25 mg / kg / day, about 30 mg / kg / day, about 35 mg / kg / day, about 40 mg / kg / day, about 45 mg / kg / day, about 50 mg / kg / day, about 60 mg / kg / day, about 70 mg / kg / day, about 80 mg / kg / day, about 90 mg / kg / day, about 100 mg / kg / day, about 125 mg / kg / day, about 150 mg / kg / day, about 175 mg / kg / day, about 200 mg / kg / day, about 250 mg / kg / day or The compound may be administered in a dose of about 300 mg / kg / day, in combination with an EGFR inhibitor, which may be administered in a dose of about 1 mg / kg / day, about 2 mg / kg / day, about 5 mg / kg / day, about 10 mg / kg / day, about 15 mg / kg / day, about 20 mg / kg / day, about 25 mg / kg / day, about 30 mg / kg / day, about 35 mg / kg / day, about 40 mg / kg / day, about 45 mg / kg / day, about 50 mg / kg / day, about 60 mg / kg / day, about 70 mg / kg / day, about 80 mg / kg / day, about 90 mg / kg / day, about 100 mg / kg / day, about 125 mg / kg / day, about 150 mg / kg / day, about 175 mg / kg / day, about 200 mg / kg / day, about 250 mg / kg / day or about 300 mg / kg / day.

[0077] In some embodiments, within the combination pharmaceuticals for the methods of treating and / or preventing cancer described herein, the dose of the PRMT5 inhibitor of formula (I) is about 1 mg / kg / day, about 2 mg / kg / day, about 5 mg / kg / day, about 10 mg / kg / day, about 15 mg / kg / day, about 20 mg / kg / day, about 25 mg / kg / day, about 30 mg / kg / day, about 35 mg / kg / day, about 40 mg / kg / day, about 45 mg / kg / day, about 50 mg / kg / day, about 60 mg / kg / day, about 70 mg / kg / day, about 80 mg / kg / day, about 90 mg / kg / day, about 100 mg / kg / day, about 125 mg / kg / day, about 150 mg / kg / day, about 175 mg / kg / day, about 200 mg / kg / day, about 250 mg / kg / day or It can be administered in a dose of about 300 mg / kg / day, in combination with an SOS1 inhibitor, which can be administered in a dose of about 1 mg / kg / day, about 2 mg / kg / day, about 5 mg / kg / day, about 10 mg / kg / day, about 15 mg / kg / day, about 20 mg / kg / day, about 25 mg / kg / day, about 30 mg / kg / day, about 35 mg / kg / day, about 40 mg / kg / day, about 45 mg / kg / day, about 50 mg / kg / day, about 60 mg / kg / day, about 70 mg / kg / day, about 80 mg / kg / day, about 90 mg / kg / day, about 100 mg / kg / day, about 125 mg / kg / day, about 150 mg / kg / day, about 175 mg / kg / day, about 200 mg / kg / day, about 250 mg / kg / day or about 300 mg / kg / day.

[0078] In some embodiments, within the combination medicines for the methods of treatment and / or prevention of the above diseases or pathological conditions, for the methods of treatment and / or prevention of cancer described herein, the dose of the PRMT5 inhibitor of formula (I) is about 1 mg / kg / day, about 2 mg / kg / day, about 5 mg / kg / day, about 10 mg / kg / day, about 15 mg / kg / day, about 20 mg / kg / day, about 25 mg / kg / day, about 30 mg / kg / day, about 35 mg / kg / day, about 40 mg / kg / day, about 45 mg / kg / day, about 50 mg / kg / day, about 60 mg / kg / day, about 70 mg / kg / day, about 80 mg / kg / day, about 90 mg / kg / day, about 100 mg / kg / day, about 125 mg / kg / day, about 150 mg / kg / day, about 175 mg / kg / day, about 200 mg / kg / day, about 250 mg / kg / day, about 300 mg / kg / day, about 350 mg / kg / day, about 40 mg / kg / day, about 45 mg / kg / day, about 50 mg / kg / day, about 60 mg / kg / day, about 70 mg / kg / day, about 80 mg / kg / day, about 90 mg / kg / day, about 100 mg / kg / day, about 125 mg / kg / day, about 150 mg / kg / day, about 175 mg / kg / day, about 200 mg / kg / day, about 250 mg / kg / day, about 350 mg / kg / day, about 40 ... and about 1 mg / kg / day, about 2 mg / kg / day, about 5 mg / kg / day, about 10 mg / kg / day, about 15 mg / kg / day, about 20 mg / kg / day, about 25 mg / kg / day, about 30 mg / kg / day, about 35 mg / kg / day, about 40 mg / kg / day, about 45 mg / kg / day, about 50 mg / kg / day, about 60 mg / kg / day, about 65 mg / kg / day, about 70 mg / kg / day, about 75 mg / kg / day, about 80 mg / kg / day, about 85 mg / kg / day, about 90 mg / kg / day, about 95 mg / kg / day, about 100 mg / kg / day, about 100 mg / kg / day, about 150 mg / kg / day, about 200 mg / kg / day, about 250 mg / kg / day, about 300 mg / kg / day, The composition can be administered in combination with an ERK inhibitor, which can be administered at a dose of about 70 mg / kg / day, about 80 mg / kg / day, about 90 mg / kg / day, about 100 mg / kg / day, about 125 mg / kg / day, about 150 mg / kg / day, about 175 mg / kg / day, about 200 mg / kg / day, about 250 mg / kg / day, or about 300 mg / kg / day.

[0079] In some embodiments, the pharmaceutical combinations of the present disclosure can be administered systemically, such as by intravenous, intraarterial, or intraperitoneal administration, such that the final circulating concentration of the PRMT5 inhibitor compound of formula (I) is from about 0.001 to about 150 micromolar, or greater, up to 200 micromolar, 300 micromolar, 400 micromolar, 500 micromolar, 600 micromolar, 700 micromolar, 800 micromolar, 900 micromolar, or 1000 micromolar.Final circulating concentrations were (all in micromolar): 0.001, 0.002, 0.003, 0.004, 0.005, 0.006, 0.007, 0.008, 0.009, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6 ,2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8 .2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 109, 109, 9, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 100, 110, 120, 130, 140 or 150 micromolar, or any concentration between any two of the preceding numbers, or higher concentrations as above, and any concentration within the ranges described. Those of skill in the art will recognize the desired dosage for one or more active agents, taking into account the nature of the agent and the principles discussed herein above.

[0080] In some embodiments, the present disclosure provides a PRMT5 inhibitor compound of formula (I): The present invention provides a method for administering at least one tagged drug / cellular activity modulator selected from an EGFR inhibitor, a KRAS inhibitor, a KRAS-G12C inhibitor, a MEK inhibitor, a Bcl-2 inhibitor, a SOS1 inhibitor, a PARP inhibitor, a RAF inhibitor, an ERK inhibitor, a CDK4 / 6 inhibitor, a MALT1 inhibitor, a BTK inhibitor, a MAT2A inhibitor, a PI3K inhibitor, an AKT inhibitor, a FGFR inhibitor, a type I PRMT inhibitor, a STING agonist or an immune checkpoint inhibitor / modulator simultaneously, in parallel, sequentially, in sequence, alternatingly or separately.

[0081] Co-administration of a PRMT5 inhibitor of formula (I) with at least one tagged drug / cell activity modulator selected from EGFR inhibitors, KRAS inhibitors, KRAS-G12C inhibitors, MEK inhibitors, Bcl-2 inhibitors, SOS1 inhibitors, PARP inhibitors, RAF inhibitors, ERK inhibitors, CDK4 / 6 inhibitors, MALT1 inhibitors, BTK inhibitors, MAT2A inhibitors, PI3K inhibitors, AKT inhibitors, BTK inhibitors, MAT2A inhibitors, PI3K inhibitors, AKT inhibitors, FGFR inhibitors, type I PRMT inhibitors, STING agonists or immune checkpoint inhibitors / modulators may allow for improved alleviation or amelioration of one or more symptoms, reduction in duration or extent of disease, delay or slowing of disease progression, improvement, reduction or stabilization of disease state, partial or complete remission, prolonged survival, and / or other beneficial therapeutic outcomes. Such treatments may be administered simultaneously or sequentially in any order with periods between administrations. Those skilled in the art will easily recognize how to administer drugs or therapies simultaneously, alternately or sequentially, and the possible time periods between administrations.When PRMT5 inhibitor compounds are administered at different times than other cell activity modulators described herein, they may be administered, for example, within 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks or 1 month, or any interval between any two of the above periods.Dosages may be administered QD, BID, TID, QID, or in weekly doses, for example QIW, BIW, QW.They may also be administered as needed (PRN) and before bedtime.

[0082] In some embodiments, the treatment according to the present invention may include administering to a human subject a combination pharmaceutical comprising a PRMT5 inhibitor of formula (I) and at least one tagged drug / cell activity modulator selected from an EGFR inhibitor, a KRAS inhibitor, a KRAS-G12C inhibitor, a MEK inhibitor, a Bcl-2 inhibitor, a SOS1 inhibitor, a PARP inhibitor, a RAF inhibitor, an ERK inhibitor, a CDK4 / 6 inhibitor, a MALT1 inhibitor, a BTK inhibitor, a MAT2A inhibitor, a PI3K inhibitor, an AKT inhibitor, a BTK inhibitor, a MAT2A inhibitor, a PI3K inhibitor, an AKT inhibitor, a FGFR inhibitor, a type I PRMT inhibitor, a STING agonist, or an immune checkpoint inhibitor / modulator. For example, the combination pharmaceutical described herein can be used in the manufacture of a medicament for use in promoting the overall health of a subject or reducing one or more side effects of cancer treatment. A person skilled in the art will readily recognize various drugs that may be beneficial to administer, for example, with respect to the disease to be treated.In some embodiments, the PRMT5 inhibitor compound of formula (I) is initially co-administered with at least one tagged drug / cellular activity modulator selected from an EGFR inhibitor, a KRAS inhibitor, a KRAS-G12C inhibitor, a MEK inhibitor, a Bcl-2 inhibitor, a SOS1 inhibitor, a PARP inhibitor, a RAF inhibitor, an ERK inhibitor, a CDK4 / 6 inhibitor, a MALT1 inhibitor, a BTK inhibitor, a MAT2A inhibitor, a PI3K inhibitor, an AKT inhibitor, a BTK inhibitor, a MAT2A inhibitor, a PI3K inhibitor, an AKT inhibitor, a FGFR inhibitor, a type I PRMT inhibitor, a STING agonist, or an immune checkpoint inhibitor / modulator. Thus, administration of the compound of formula (I) may be stopped or tapered while continuing administration of at least one tagged drug / cellular activity modulator selected from an EGFR inhibitor, a KRAS inhibitor, a KRAS-G12C inhibitor, a MEK inhibitor, a Bcl-2 inhibitor, a SOS1 inhibitor, a PARP inhibitor, a RAF inhibitor, an ERK inhibitor, a CDK4 / 6 inhibitor, a MALT1 inhibitor, a BTK inhibitor, a MAT2A inhibitor, a PI3K inhibitor, an AKT inhibitor, a BTK inhibitor, a MAT2A inhibitor, a PI3K inhibitor, an AKT inhibitor, a FGFR inhibitor, a type I PRMT inhibitor, a STING agonist or an immune checkpoint inhibitor / modulator.

[0083] The administration of the PRMT5 inhibitor compound of formula (I) and at least one tagged drug / modulator of cellular activity selected from EGFR inhibitors, KRAS inhibitors, KRAS-G12C inhibitors, MEK inhibitors, Bcl-2 inhibitors, SOS1 inhibitors, PARP inhibitors, RAF inhibitors, ERK inhibitors, CDK4 / 6 inhibitors, MALT1 inhibitors, BTK inhibitors, MAT2A inhibitors, PI3K inhibitors, AKT inhibitors, BTK inhibitors, MAT2A inhibitors, PI3K inhibitors, AKT inhibitors, FGFR inhibitors, type I PRMT inhibitors, STING agonists or immune checkpoint inhibitors / modulators may occur at any time during the progression of the disease or disorder or before or after the onset of the disorder or one or more symptoms of the disease or disorder. In one embodiment, the PRMT5 inhibitor compound of formula (I) and at least one tagged drug / cellular activity modulator selected from EGFR inhibitors, KRAS inhibitors, KRAS-G12C inhibitors, MEK inhibitors, Bcl-2 inhibitors, SOS1 inhibitors, PARP inhibitors, RAF inhibitors, ERK inhibitors, CDK4 / 6 inhibitors, MALT1 inhibitors, BTK inhibitors, MAT2A inhibitors, PI3K inhibitors, AKT inhibitors, FGFR inhibitors, type I PRMT inhibitors, STING agonists or immune checkpoint inhibitors / modulators are administered daily over an extended period of time to aid in the ongoing management of symptoms. In another embodiment, the PRMT5 inhibitor compound of formula (I) and at least one tagged drug / cellular activity modulator selected from EGFR inhibitors, KRAS inhibitors, KRAS-G12C inhibitors, MEK inhibitors, Bcl-2 inhibitors, SOS1 inhibitors, PARP inhibitors, RAF inhibitors, ERK inhibitors, CDK4 / 6 inhibitors, MALT1 inhibitors, BTK inhibitors, MAT2A inhibitors, PI3K inhibitors, AKT inhibitors, FGFR inhibitors, type I PRMT inhibitors, STING agonists or immune checkpoint inhibitors / modulators are administered daily for an extended period of time to prevent or delay the onset of a disease or disorder.

[0084] Synergistic / potentiated combinations The term "synergistic" as used herein refers to a therapeutic combination that is more effective than the additive effect of two or more single agents. The present combination therapy provides "synergistic effects" and can be proven to be "synergistic", i.e., the effect achieved when the active ingredients are used together is greater than the sum of the effects resulting from the use of the compounds separately. Synergistic effects can be achieved when the active ingredients are (1) co-formulated and administered or delivered simultaneously in a combined unit dosage formulation; or (2) delivered alternately as separate formulations. When delivered in alternation therapy, synergistic effects can be achieved when the compounds are administered or delivered sequentially, for example, by different injections in separate syringes. Generally, during alternation therapy, an effective dosage of each active ingredient is administered sequentially, i.e., following each other in time. In some embodiments, synergistic effects are evidenced by the lower toxicity of the composition compared to the same administration of either single ingredient at the same total dosage. For example, when a PRMT5 inhibitor compound of formula (I) is co-administered with a cellular activity modulator described herein, the toxicity of a 50:50 (w / w) composition comprising a PRMT5 inhibitor compound and a cellular activity modulator described herein is less than the toxicity of 100% (w / w) PRMT5 inhibitor compound or 100% (w / w) cellular activity modulator, and the compositions have approximately the same level of efficacy. Without intending to be bound by theory, the inventors have realised that while a PRMT5 inhibitor compound may be metabolised by a first set of metabolic enzymes, at least one tagged drug / cellular activity modulator selected from an EGFR inhibitor, a KRAS inhibitor, a KRAS-G12C inhibitor, a MEK inhibitor, a Bcl-2 inhibitor, a SOS1 inhibitor, a PARP inhibitor, a RAF inhibitor, an ERK inhibitor, a CDK4 / 6 inhibitor, a MALT1 inhibitor, a BTK inhibitor, a MAT2A inhibitor, a PI3K inhibitor, an AKT inhibitor, an FGFR inhibitor, a type I PRMT inhibitor, a STING agonist or an immune checkpoint inhibitor / modulator may be metabolised by a second set of enzymes, such that the first and second sets of enzymes are not entirely the same.The result is that the toxicity of the combination is less than that of the single components of the combination, or the efficacy of the combination is greater than that of the single components of the combination. The rationale for combining two or more anti-cancer therapeutic agents is not only to reduce toxicity and provide greater safety, but also to increase efficacy beyond that provided by a single agent alone. Increased efficacy is one of the advantages of combination therapy. The combination is designed to target cell signaling mechanisms to simultaneously address multiple oncogenic pathways, ultimately resulting in enhanced anti-cancer activity and / or efficacy (inhibition of tumor growth). Analysis of the examples discussed herein demonstrates improved anti-cancer efficacy both in vitro and in vivo, clearly illustrating the advantages of combining compound 24 with other cell activity modulators.

[0085] When measuring in vivo or therapeutic synergy, one measure of synergy is known as "Excess over Highest Single Agent" synergy. Excess over Highest Single Agent synergy occurs when a fixed dose combination is superior to any of its component doses, and is referred to as "excess over highest single agent." An effective amount of a compound (or a pharma- ceutically acceptable salt thereof) in the combination of the present invention may be understood to include an amount sufficient to prevent or inhibit tumor cell proliferation or the progression of cancer metastasis. The therapeutic or pharmacological effectiveness of a dose and administration regimen may also be characterized as the ability to induce, enhance, maintain or prolong remission in patients experiencing a particular tumor.

[0086] Manufacturing and Stability In some embodiments, the formulations of the present invention are substantially pure. By substantially pure, it is meant that the formulation contains less than about 10%, 5% or 1%, preferably less than about 0.1% of any impurity. In some embodiments, the total impurities, including metabolites, of the PRMT5 inhibitor compound of formula (I) are 15% or less. In some embodiments, the total impurities, including metabolites, of the PRMT5 inhibitor compound of formula (I) are 12% or less. In some embodiments, the total impurities, including metabolites, of the PRMT5 inhibitor compound of formula (I) are 11% or less. In other embodiments, the total impurities, including metabolites, of the PRMT5 inhibitor compound of formula (I) are 10% or less.

[0087] In some embodiments, the purity of the formulations of the invention may be measured using a method selected from anion exchange HPLC (AEX-HPLC) or mass spectrometry. Mass spectrometry may include LC / MS or LC / MS / MS. In some embodiments, the method used to measure impurities may include both AEX-HPLC and LC / MS. The sterile composition containing the PRMT5 inhibitor compound of formula (I) of the present invention or its pharma- ceutically acceptable salt is prepared by aseptic processing by dissolving the compound in the formulation vehicle. In one embodiment, the formulation may be sterilized by filtration. The excipients used in the preparation of the formulation of the present invention are widely used in pharmaceutical products and are published in pharmacopoeia standards.

[0088] formulation The PRMT5 inhibitor compound of formula (I) may be present in a pharmaceutical formulation in a substantially isolated form. It is understood that the product may be mixed with a carrier or diluent that does not interfere with the intended purpose of the product and still be considered to be substantially isolated. The product of the present invention may also be in a substantially purified form, in which case the product generally comprises about 80%, 85% or 90%, for example, at least about 88%, at least about 90, 95 or 98% or at least about 99% of the compound of formula (I) or at least one tagged drug / cell activity modulator selected from EGFR inhibitors, KRAS inhibitors, KRAS-G12C inhibitors, MEK inhibitors, Bcl-2 inhibitors, SOS1 inhibitors, PARP inhibitors, RAF inhibitors, ERK inhibitors, CDK4 / 6 inhibitors, MALT1 inhibitors, BTK inhibitors, MAT2A inhibitors, PI3K inhibitors, AKT inhibitors, FGFR inhibitors, type I PRMT inhibitors, STING agonists or immune checkpoint inhibitors / modulators.

[0089] Pharmaceutically acceptable diluents, carriers and / or excipients include those suitable for human pharmaceutical use as well as veterinary use. Suitable carriers and / or excipients will be readily recognized by those skilled in the art, taking into account the properties of the compound of formula (I) or other cellular activity modulator. However, by way of example, diluents, carriers and / or excipients include solutions, solvents, dispersion media, retardants, polymeric and lipid agents, emulsions, and the like. By way of further example, suitable liquid carriers (particularly suitable for injectable solutions) include water, saline, aqueous dextrose solutions, and the like, with isotonic solutions being preferred for intravenous, intrathecal and intracisternal administration, and vehicles such as liposomes are also particularly suitable for administration of the drug.

[0090] In addition, if desired, substances such as wetting agents or emulsifiers, stabilizers or pH buffers, or preservatives may also be present in the pharmaceutical combination of the present invention.In some embodiments, the pharmaceutical combination of the present invention comprises a suitable pharma- ceutical acceptable buffer, such as acetate buffer, citrate buffer, phosphate buffer, borate buffer, and mixtures thereof.In some embodiments, the buffer useful in the present invention comprises boric acid, sodium borate, sodium phosphate (including monobasic phosphate, dibasic phosphate, and tribasic phosphate, such as sodium phosphate monobasic monohydrate and sodium phosphate dibasic heptahydrate), and mixtures thereof.In some embodiments, the preservative may be stabilized chlorine dioxide, cationic polymer, or quaternary ammonium compound. In some embodiments, the pharmaceutical combination may also include wetting agents, nutrients, viscosity builders, antioxidants, and the like, such as disodium ethylenediaminetetraacetate, alkali metal hexametaphosphates, citric acid, sodium citrate, sodium metabisulfite, sodium thiosulfate, N-acetylcysteine, butylated hydroxyanisole, butylated hydroxytoluene, polyvinyl alcohol, polyoxamers, polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxyethylmethylcellulose, and mixtures thereof, and mixtures thereof. In some embodiments, the pharmaceutical formulation of the present invention does not include a preservative.

[0091] In some embodiments, the pharmaceutical combination of the present disclosure is in the form of a sterile injectable preparation, for example, a sterile injectable aqueous or oleaginous suspension. In some embodiments, the suspension is formulated according to the method using suitable dispersing or wetting agents and suspending agents described above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, a solution in 1,3-butanediol prepared as a lyophilized powder. In some embodiments, the acceptable vehicle and solvent used may or may not include water, Ringer's solution (including lactated Ringer's solution), Hartmann's solution, Tyrode's solution, and isotonic sodium chloride solution. In some embodiments, sterile fixed oils are used as a solvent or suspending medium. For this purpose, any non-irritating fixed oil is used, including synthetic mono- or diglycerides. In some embodiments, fatty acids, for example, oleic acid, are used in the preparation of injectables.

[0092] The composition of the present invention may contain any suitable level of the PRMT5 inhibitor compound of formula (I) or at least one tagged drug / cell activity modulator selected from EGFR inhibitors, KRAS inhibitors, KRAS-G12C inhibitors, MEK inhibitors, Bcl-2 inhibitors, SOS1 inhibitors, PARP inhibitors, RAF inhibitors, ERK inhibitors, CDK4 / 6 inhibitors, MALT1 inhibitors, BTK inhibitors, MAT2A inhibitors, PI3K inhibitors, AKT inhibitors, FGFR inhibitors, type I PRMT inhibitors, STING agonists or immune checkpoint inhibitors / modulators, taking into account the dosage form and mode of administration. However, by way of example, the composition used in the present invention may contain about 0.1% to about 99% by weight, preferably about 1% to about 60% by weight, of the PRMT5 inhibitor compound of formula (I), depending on the method of administration.

[0093] In addition to standard diluents, carriers and / or excipients, the compositions according to the invention may be formulated with one or more additional components in such a manner as to enhance the activity or bioavailability of at least one tagged drug / cell activity modulator selected from, for example, a compound of formula (I), an EGFR inhibitor, a KRAS inhibitor, a KRAS-G12C inhibitor, a MEK inhibitor, a Bcl-2 inhibitor, a SOS1 inhibitor, a PARP inhibitor, a RAF inhibitor, an ERK inhibitor, a CDK4 / 6 inhibitor, a MALT1 inhibitor, a BTK inhibitor, a MAT2A inhibitor, a PI3K inhibitor, an AKT inhibitor, an FGFR inhibitor, a type I PRMT inhibitor, a STING agonist or an immune checkpoint inhibitor / modulator, help protect the integrity or increase its half-life or shelf life, allow sustained release upon administration to a subject, or provide other desirable benefits. For example, sustained release vehicles include macromers, poly(ethylene glycol), hyaluronic acid, poly(vinylpyrrolidone) or hydrogels. By way of further example, the compositions may also include preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavors, coating agents, buffers, etc. Those skilled in the art to which this invention pertains will readily identify additional additives that may be desirable for a particular purpose.

[0094] The pharmaceutical combinations described herein may be formulated according to standard techniques as may be found in standard references, e.g., Gennaro AR: Remington: The Science and Practice of Pharmacy, 20th Edition, Lippincott, Williams & Wilkins, 2000. EXAMPLES

[0095] Working Example The following examples are provided to illustrate, but not to limit, the methods described herein. ,Mr Various modifications may be made.

[0096] Example 1: material The compounds of the present disclosure are described in PCT International Publication No. WO2019116302 and can be made and characterized as described herein. As a representative example, the synthesis of compound 24 is as follows.

[0097] 3-Chloro-7-(2-((3aS,4R,6aR)-4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-6-yl)ethyl)-5-fluoroquinolin-2-amine [ka]

[0098] A mixture of 4-chloro-7-((3aS,4R,6aR)-2,2-dimethyl-6-vinyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine (10.01 g, 31.5 mmol) (prepared according to the procedure set out in WO2019116302, p. 116, line 2 to p. 117, line 19) and 9-BBN (9-borabicyclononane) (180 ml, 90 mmol) was heated at 50° C. under a N2 atmosphere for 1.15 hours. The reaction mixture was cooled to room temperature and a solution of tripotassium phosphate (23.88 g, 113 mmol) in water (20 ml) was added and stirred for 30 minutes. Then, a solution of 7-bromo-3-chloro-5-fluoroquinolin-2-amine (6.2 g, 22.50 mmol) in THF (20 ml) was added, followed by dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) (1.467 g, 2.250 mmol). The resulting mixture was stirred at 50° C. for 3 h. The reaction mixture was quenched with water (100 ml) and extracted with EtOAc (200 ml). The layers were separated and the organic layer was washed with brine (100 ml) and dried over sodium sulfate. The organic layer was filtered and concentrated under reduced pressure to give the crude compound. The residue was purified by HPLC using redisep R f Column, Combi Flash (R fPurification on a (200, Teledyne / Isco) apparatus using a gradient elution of ethyl acetate in dichloromethane (0-40%) afforded the title compound (6 g, 51.8%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.64 (s, 1H), 8.18 (d, J = 0.7 Hz, 1H), 7.25 (s, 1H), 7.09 - 7.01 (m, 2H), 6.96 (s, 2H), 6.45 (d, J = 3.7 Hz, 1H), 5.67 (s, 1H), 5.56 - 5.52 (m, 1H), 5.35 (d, J = 5.8 Hz, 1H), 4.52 (d, J = 5.7 Hz, 1H), 3.03 (hept, J = 6.8 Hz, 2H), 2.65 (q, J = 11.9, 8.6 Hz, 2H), 1.38 (s, 3H), 1.29 (s, 3H); LCMS m / z = 515.07 (M+).

[0099] 7-(2-((3aS,4R,6aR)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-6-yl)ethyl)-3-chloro-5-fluoroquinolin-2-amine [ka]

[0100] To a stirred solution of 3-chloro-7-(2-((3aS,4R,6aR)-4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-6-yl)ethyl)-5-fluoroquinolin-2-amine (6 g, 11.66 mmol) in dioxane (60 ml) was added ammonium hydroxide (114 ml, 2916 mmol) at room temperature. The resulting mixture was stirred in a steel bomb at 120° C. for 16 hours. The reaction mixture was diluted with water (100 ml) and extracted with EtOAc (100 ml). The layers were separated and the organic layer was washed with brine (50 ml) and dried over sodium sulfate. The organic layer was filtered and concentrated under reduced pressure to give the crude compound. The residue was purified by HPLC using redisep R f Column, Combi Flash (R f Purification on a (200, Teledyne / Isco) apparatus using a gradient elution of methanol in dichloromethane (0-8%) afforded the title compound (4.05 g, 70.1%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.17 (d, J = 0.7 Hz, 1H), 8.05 (s, 1H), 7.26 (s, 1H), 7.05 (dd, J = 11.1, 1.4 Hz, 1H), 6.97 (d, J = 7.0 Hz, 4H), 6.41 (d, J = 3.5 Hz, 1H), 6.35 (d, J = 3.5 Hz, 1H), 5.53 (d, J = 14.5 Hz, 2H), 5.30 (d, J = 5.7 Hz, 1H), 4.37 (d, J = 5.7 Hz, 1H), 3.02 (h, J = 6.8 Hz, 2H), 2.73 - 2.58 (m, 2H), 1.37 (s, 3H), 1.27 (s, 3H); LCMS m / z = 495.05 (M+).

[0101] (1S,2R,5R)-3-(2-(2-amino-3-chloro-5-fluoroquinolin-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (compound 24) [ka]

[0102] A mixture of 7-(2-((3aS,4R,6aR)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-6-yl)ethyl)-3-chloro-5-fluoroquinolin-2-amine (4.05 g, 8.18 mmol) and TFA (26.5 ml, 344 mmol) was stirred at 0° C. for 5 min under N2 atmosphere. The resulting mixture was stirred at room temperature for 12 h. The reaction mixture was basified with ice-cold sodium bicarbonate solution and extracted with ethyl acetate (100 ml). The layers were separated and the organic layer was washed with brine (50 ml) and dried over anhydrous Na2SO4. The organic layer was filtered and concentrated under reduced pressure to give the crude compound. The residue was purified by HPLC using redisep R f Column, Combi Flash (R f 200, Teledyne / Isco) using gradient elution of methanol in dichloromethane (0-10%) to give 3.6 g of the title compound. This compound was purified again by reverse phase preparative HPLC (YMC Triart C18 50×2.0 mm, 1.9 μm (RFLC-175); Mobile phase A: water:CH3CN (9:1 V / V) + 0.05% NH4OH, Mobile phase B: CH3CN:water (9:1) (V / V) + 0.05% NH4OH; Injection volume: 0.2 μl, Wavelength: 220 nm, Run time: 4.5 min, Flow rate: 0.6 ml / min). The compound obtained after RP preparative HPLC was co-distilled twice with water (12 ml and 5 ml) to give the title compound (2.3 g, 61.8%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.17 (d, J = 0.8 Hz, 1H), 8.03 (s, 1H), 7.22 (s, 1H), 7.01 (dd, J = 11.0, 1.4 Hz, 1H), 6.95 (s, 2H), 6.92 (s, 2H), 6.63 (d, J = 3.5 Hz, 1H), 6.42 (d, J = 3.5 Hz, 1H), 5.50 (t, J = 3.2 Hz, 1H), 5.45 (t, J = 1.7 Hz, 1H), 4.96 (dd, J = 6.3, 3.0 Hz, 2H), 4.45 (t, J = 5.8 Hz, 1H), 3.97 (q, J = 5.5 Hz, 1H), 3.03 - 2.87 (m, 2H), 2.56 (t, J = 7.0 Hz, 2H); LCMS m / z = 454.98 (M+).

[0103] Example 2 - In Vitro Data Compound 24 ((1S,2R,5R)-3-(2-(2-amino-3-chloro-5-fluoroquinolin-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol) was investigated in combination with tagged therapeutic agents in various cell lines in vitro, either in cell viability assays assessed by CellTiter-Glo® (CTG) or colony formation assays (CFA) assessed by crystal violet staining or CCK8 assays. Combination experiments were performed in cell lines MDA-MB-231 (breast cancer, TNBC), MIA PaCa-2 (KRAS-mut pancreatic cancer), OCI-Ly10 (ABC-diffuse large B-cell lymphoma) and OCI-Ly3 (ABC-diffuse large B-cell lymphoma, CARD11 mutant). Both cell lines OCI-Ly10 and OCI-Ly3 were obtained and licensed from the University Health Network (Canada).

[0104] CTG assay: MDA-MB-231 cells were seeded in 96-well white opaque plates at a density of 250 cells / well in culture medium (DMEM+10% FBS) and then incubated overnight under standard cell culture conditions. The next day, cells were treated with compound 24 and the other tagging agents indicated in the figure. Treatment was repeated on day 5 and assays were terminated on day 10. Cell viability was assessed at the end of treatment using CellTiter-Glo® reagent according to the manufacturer's instructions. Luminescence was measured on a BioTek Synergy Neo II plate reader. RLU (relative light units) is directly proportional to the number of actively proliferating cells. % Inhibition = [[(mean vehicle RLU-mean blank RLU)-(mean test RLU-mean blank RLU)] x 100] / [(mean vehicle RLU-mean blank RLU)] NOTE: The blank contains only CTG and medium (no cells). OCI-Ly3 cells were seeded in culture medium (RPMI+10%FBS) at a density of 2000 cells / well in 96-well white opaque plates. Treatment was started on the same day and cells were treated for 4 days. Cell viability was assessed at the end of treatment using CellTiter-Glo® reagent according to the manufacturer's instructions. Luminescence was measured on a BioTek Synergy Neo II plate reader. The effect on cell viability was evaluated for compound 24 in combination with MALT1 inhibitors.

[0105] CCK-8 Assay: OCI-Ly-10 cells were seeded in culture medium (IMDM+20%FBS) at a density of 2000 cells / well in 96-well clear plates and treated with various concentrations of test compounds. Treatment was started on the same day and cells were treated for 7 days. Cell viability was assessed using a CCK-8 kit (Dojindo Laboratories, China) according to the manufacturer's instructions. Plates were read in a colorimeter to detect absorbance (detection at 450 nm; background correction at 650 nm). The effect on cell viability was evaluated for compound 24 in combination with MALT1 inhibitors or in combination with the BTK inhibitor ibrutinib. % Inhibition (after background subtraction) = [(mean vehicle control OD - mean test OD) x 100] / [mean vehicle control OD]

[0106] Colony formation assay: MIA PaCa-2 cells were seeded at a density of 5000 cells / well in 6-well plates or 500 cells / well in 48-well plates and then incubated overnight under standard cell culture conditions. The next day, cells were treated with compound 24 and another tagging drug as indicated in the figure. After 7 days of drug treatment, the medium was removed from each well and the plate was washed with PBS. Colonies were stained with crystal violet solution for 2-5 min. The plate was then carefully washed with tap water and air-dried. For quantification, 1000 μL of decolorizing solution containing 10% glacial acetic acid was added to each well and the crystal violet from the colonies was solubilized for 20-30 min on a plate shaker. After solubilization, the absorbance of the extracted stain was recorded at 590 nm in a BioTek Synergy Neo II plate reader. The absorbance value was directly proportional to colony growth. % Inhibition = [[(mean vehicle abs - mean blank abs) - (mean test abs - mean blank abs)] x 100] / [(mean vehicle abs - mean blank abs)] NOTE: The blank contains only the destaining solution. As shown in Figures 1-7 and further discussed in the "In Vivo Data" section below, combinations of compound 24 with various tagged drugs (e.g., EGFR inhibitors, SOS1 inhibitors, ERK inhibitors, PARP inhibitors, KRAS-G12C inhibitors or CDK4 / 6 inhibitors) showed synergistic or enhanced inhibition of cell viability compared to either drug alone.

[0107] In vivo data Example 3: Compound 24 was combined with the EGFR inhibitor afatinib to perform an in vivo efficacy study in the MIA PaCa-2 human pancreatic cancer xenograft model in nude mice. 6 MIA PaCa-2 cells were injected subcutaneously into nude mice in the presence of PBS and Matrigel at a 1:1 ratio. Tumors grew to approximately 177–178 mm 3 The mean tumor volume ranged from 119 to 232 mm 3 Tumor-bearing mice were randomized when the tumor reached 100%. Mice were divided into the following groups (n=9-10 / group): vehicle control, compound 24 (1 mg / kg; bid), afatinib (12.5 mg / kg; qd), and compound 24 + afatinib (compound 24; 1 mg / kg; bid + afatinib; 12.5 mg / kg; qd). Compound 24 alone and afatinib alone showed tumor growth inhibition % of 48.03 ± 5.75% and 58.68 ± 5.14%, respectively, while the combination of compound 24 and afatinib resulted in tumor growth inhibition of 84.16 ± 1.88%. Furthermore, FIG. 8 shows the surprising in vivo efficacy of compound 24 and the EGFR inhibitor afatinib in MIA PaCa-2 xenografts.

[0108] Example 4: Compound 24 was combined with the SOS1 inhibitor BI-3406 to perform an in vivo efficacy study in the MIA PaCa-2 human pancreatic cancer xenograft model in nude mice. 6 MIA PaCa-2 cells were injected subcutaneously into nude mice in the presence of PBS and Matrigel at a 1:1 ratio. Tumors grew to approximately 155–159 mm 3The mean tumor volume ranged from 107 to 248 mm 3 Tumor-bearing mice were randomized when the tumor reached 15 days of age. Mice were divided into the following groups (n=7-8 / group): vehicle control, compound 24 (1 mg / kg; bid), BI-3406 (50 mg / kg; bid), and compound 24 + BI-3406 (compound 24; 1 mg / kg; bid + BI-3406; 50 mg / kg; bid). Compound 24 alone and BI-3406 alone showed 47.88 ± 12.12% and 47.97 ± 11.91% tumor growth inhibition%, respectively, at day 15, whereas the combination of compound 24 and BI-3406 resulted in 85.98 ± 6.79% tumor growth inhibition at day 15. Furthermore, FIG. 9 shows the surprising in vivo efficacy of compound 24 and the SOS1 inhibitor BI-3406 in MIA PaCa-2 xenografts.

[0109] Example 5: In vivo efficacy studies were performed on compound 24 in combination with the ERK inhibitor ulixertinib (BVD-523) in the MIA PaCa-2 human pancreatic cancer xenograft model in nude mice. MIA PaCa-2 tumor fragments were implanted subcutaneously into nude mice. The tumors were approximately 181–183 mm 3 The mean tumor volume ranged from 54 to 314 mm 3 Tumor-bearing mice were randomized when the tumor reached 100%. Mice were divided into the following groups (n=8-10 / group): vehicle control, compound 24 (1 mg / kg; bid), BVD-523 (25 mg / kg; bid), and compound 24 + BVD-523 (compound 24; 1 mg / kg; bid + BVD-523; 25 mg / kg; bid). Compound 24 alone and BVD-523 alone showed tumor growth inhibition % of 58.83 ± 9.92% and 37.48 ± 9.58%, respectively, while the combination of compound 24 and BVD-523 resulted in tumor growth inhibition of 88.05 ± 6.77%. Additionally, FIG. 10 shows the surprising in vivo efficacy of compound 24 with the ERK inhibitor ulixertinib (BVD-523) in MIA PaCa-2 xenografts.

[0110] It will be understood that the foregoing description is of exemplary embodiments of the present invention and that the present invention is not limited to the specific forms shown. . Essential Changes can be made to the design and layout of the elements.

[0111] The invention described and claimed herein has many attributes and embodiments, including but not limited to those described or illustrated or referred to in this Detailed Description. Not intended to be comprehensive, the invention described and claimed herein is not limited to, and is not limited by, the features or embodiments identified in this Detailed Description, which is included for illustrative purposes only and not for limiting purposes. Those skilled in the art will readily recognize that many of the components and parameters may be modified or altered to some extent or substituted with known equivalents without departing from the scope of the invention. It is understood that such modifications and equivalents are incorporated herein as if individually described. The invention also includes all of the steps, features, compositions and compounds referred to or shown herein, individually or collectively, and any and all combinations of any two or more of such steps or features.

[0112] All patents, publications, scientific articles, websites, and other documents and materials referenced or mentioned in this specification are indicative of the level of skill of those skilled in the art to which the invention pertains, and each such referenced document and material is incorporated herein by reference to the same extent as if it were individually incorporated herein by reference in its entirety or set forth in its entirety herein. Applicants reserve the right to physically incorporate into this specification any and all materials and information from such patents, publications, scientific articles, websites, electronically available information, and other referenced materials or documents. The reference in this specification to any application, patent, and publication is not an admission, nor is it an indication, that they constitute valid prior art or form part of the common general knowledge in any country in the world, and should not be construed as such.

[0113] The specific methods and compositions described herein are representative of preferred embodiments, are exemplary, and are not intended to limit the scope of the invention. Other objects, embodiments, and embodiments will occur to those skilled in the art upon consideration of this specification and are defined by the claims. That's right R BooksIt will be immediately apparent to one skilled in the art that various substitutions and modifications may be made to the invention disclosed herein. The invention illustratively described herein may preferably be practiced in the absence of any element or limitation not specifically disclosed herein as essential. Thus, for example, in each instance herein, any of the terms "comprising," "consisting essentially of," and "consisting of" may be replaced with either of the other two terms herein. Also, terms such as "comprising," "including," "containing," and the like, are to be interpreted expansively and without limitation. The methods and processes illustratively described herein may preferably be performed in different sequences of steps, and are not necessarily limited to the sequence of steps set forth herein or in the claims. Also, as used herein and in the appended claims, the singular forms "a," "an," and "the" are intended to include plural references unless the context clearly dictates otherwise. Under no circumstances should this patent be construed as limited to any particular examples or embodiments or methods specifically disclosed herein. Under no circumstances should this patent be construed as limited by any statements made by any examiner or any other officer or employee of the Patent and Trademark Office unless such statements are specifically and unconditionally expressly adopted in the responsive document by the applicant. Furthermore, titles, headings, and the like are provided to enhance the reader's comprehension of this document and should not be construed as limiting its scope. Any examples, embodiments, or components of embodiments of the invention referred to herein shall be considered non-limiting.

[0114] The terms and expressions employed are used as terms of description rather than limitation, and there is no intention in the use of such terms and expressions to exclude any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention as claimed.Thus, although this has been specifically disclosed by preferred embodiments and optional features, it is understood that modifications and variations of the concepts disclosed herein may be made by those skilled in the art, and that such modifications and variations are considered to be within the scope of the invention as defined by the appended claims. The invention has been described broadly and generically herein. Each of the narrower species and subgeneric groupings falling within the scope of the generic disclosure also form part of the invention. This includes the generic description of the invention with a provisos or negative limitation excluding any particular subject matter from the genus, regardless of whether the omitted material is specifically recited herein. Other embodiments are within the scope of the following claims. Furthermore, when features or embodiments of the invention are described in terms of a Markush group, those of skill in the art will recognize that the invention is also described hereby in terms of any individual members or subgroups of members of that Markush group.

Claims

1. 1. A pharmaceutical combination for treating cancer in a subject, comprising: (a) (1S,2R,5R)-3-(2-(2-amino-3-chloro-5-fluoroquinolin-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (Compound 24) or a pharma- ceutical acceptable salt thereof, and afatinib; (b) (1S,2R,5R)-3-(2-(2-amino-3-chloro-5-fluoroquinolin-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (Compound 24)) or a pharma- ceutically acceptable salt thereof, and BI-3406, and (b) (1S,2R,5R)-3-(2-(2-amino-3-chloro-5-fluoroquinolin-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (Compound 24)) or a pharma- ceutically acceptable salt thereof, and ulixertinib A combination pharmaceutical selected from the group consisting of

2. In the manufacture of a medicament for the treatment of human cancer, (a) (1S,2R,5R)-3-(2-(2-amino-3-chloro-5-fluoroquinolin-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (Compound 24) or a pharma- ceutically acceptable salt thereof, and afatinib; or (b) (1S,2R,5R)-3-(2-(2-amino-3-chloro-5-fluoroquinolin-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (Compound 24)) or a pharma- ceutically acceptable salt thereof, and BI-3406; or (b) (1S,2R,5R)-3-(2-(2-amino-3-chloro-5-fluoroquinolin-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (Compound 24)) or a pharma- ceutically acceptable salt thereof, and ulixertinib Use of.

3. 3. The use according to claim 2, wherein the cancer is glioblastoma multiforme, prostate cancer, pancreatic cancer, mantle cell lymphoma, non-Hodgkin's lymphoma and diffuse large B-cell lymphoma, acute myeloid leukemia, acute lymphocytic leukemia, multiple myeloma, non-small cell lung cancer, small cell lung cancer, breast cancer, triple-negative breast cancer, gastric cancer, colorectal cancer, ovarian cancer, bladder cancer, hepatocellular carcinoma, melanoma, sarcoma, oropharyngeal squamous cell carcinoma, chronic myeloid leukemia, epidermal squamous cell carcinoma, nasopharyngeal carcinoma, neuroblastoma, endometrial cancer, head and neck cancer or cervical cancer.

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