BR-112020011746-B1 - COMPOUND, PHARMACEUTICAL COMPOSITION, AND USE OF SUCH COMPOUND

BR112020011746B1BR 112020011746 B1BR112020011746 B1BR 112020011746B1BR-112020011746-B1

Abstract

The invention relates to substituted bicyclic heterocyclic compounds having formula (I), and their pharmaceutically acceptable salts and pharmaceutical compositions, for the treatment of diseases, disorders or conditions associated with overexpression of the PRMT5 enzyme. The invention also relates to methods of treating diseases, disorders or conditions associated with overexpression of the PRMT5 enzyme.

Inventors

PRATHAP SREEDHARAN NAIR
SANJEEV ANANT KULKARNI
MILIND DATTATRAYA SINDKHEDKAR
VENKATA P. PALLE
RAJENDER KUMAR KAMBOJ
GANESH BHAUSAHEB GUDADE
Sachin Sethi
DIPAK RAYCHAND LAGAD
CHETAN SANJAY PAWAR
MAHADEO BHASKAR TRYAMBAKE
CHAITANYA PRABHAKAR KULKARNI
ANIL KASHIRAM HAJARE
BALASAHEB ARJUN GORE

Assignees

LUPIN LIMITED

Dates

Publication Date: 20260317
Application Date: 20181213
Priority Date: 20171213

Claims (6)

1. COMPOUND OF GENERAL FORMULA (I), A STEREO-ISOMER OR A PHARMACEUTICALLY ACCEPTABLE SALT OF THE SAME, characterized by: The ring A to be selected from: Rc and Rd are selected independently from hydrogen, methyl, and cyclopropyl; Li is selected from -CH2-, -CH(CHs)-, -NH-, -N(CHs)-, S, and O; R3 is selected from F, Cl, Br, CN, -NH2, -NH(CH3), -NHCH(CH3)2, -CH3, cyclopropyl, -CH(CH3)2, -CF2CH3, -OCH3, CF3. R can be selected from hydrogen, -NH2, Cl, -CH(CH3)2, methyl, ethyl, cyclopropyl Ra and Rb are selected independently from hydrogen, methyl, and cyclopropyl; the R2' and R2a groups are selected independently from hydrogen and methyl; R1 and R2, together with the carbon atoms to which they are attached, form a bond to form a -C=C- ring; or the R1 and R2 groups, together with the carbon atoms to which they are attached, form a cyclopropane ring; R10 is selected from hydrogen, -F, and methyl; Z is selected from CH and N; and 'n' is an integer ranging from 1 to 3, inclusive.
2. COMPOUND OF FORMULA (I), A STEREO-ISOMER OR A PHARMACEUTICALLY ACCEPTABLE SALT THEREOF, according to claim 1, characterized in that the compound is selected from: (1S,2R,5R)-3-(2-(2-amino-3-bromoquinoline-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7-yl)cyclopent-3-ene-1,2-diol; (1S,2R,5R)-3-(((2-amino-3-chloroquinoline-7-yl)thio)methyl)-5-(4-amino-7H-pyrrolo[2,3- d]pyrimidine-7-yl)cyclopent-3-ene-1,2-diol;(1S,2R,5R)-3-(1-(2-amino-3-bromoquinoline-7-yl)propane-2-yl)-5-(4-amino-7H- pyrrolo[2,3-d]pyrimidine-7-yl)cyclopent-3-ene-1,2-diol;(1S,2R,5R)-3-(((2-amino-3-chloro-5-fluoroquinoline-7-yl)oxy)methyl)-5-(4-amino-7H- pyrrolo[2,3-d]pyrimidine-7-yl)-2-methylcyclopent-3-ene-1,2-diol (Compound 9);(1S,2R,5R)-3-(1-(2-amino-3-chloro-5-fluoroquinoline-7-yl)propane-2-yl)-5-(4-methyl- 7H-pyrrolo[2,3-d]pyrimidine-7-yl)cyclopent-3-ene-1,2-diol;(1S,2R,5R)-3-(2-(2-amino-3-chloro-5-fluoroquinoline-7-yl)ethyl)-5-(4-methyl-7H- pyrrolo[2,3-d]pyrimidine-7-yl)cyclopent-3-ene-1,2-diol;(1S,2R,5R)-3-(1-((2-amino-3-chloro-5-fluoroquinoline-7-yl)oxy)ethyl)-5-(4-amino-7H- pyrrolo[2,3-d]pyrimidine-7-yl)cyclopent-3-ene-1,2-diol;(1S,2R,5R)-3-(2-(2-amino-3-chloroquinoline-7-yl)ethyl)-5-(4-methyl-7H-pyrrolo[2,3- d]pyrimidine-7-yl)cyclopent-3-ene-1,2-diol;(2-(2-amino-3-fluoroquinoline-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7- yl)cyclopent-3-ene-1,2-diol;(1S,2R,5R)-3-(2-(2-amino-3-chloro-5-fluoroquinoline-7-yl)ethyl)-5-(4-amino-7H- pyrrolo[2,3-d]pyrimidine-7-yl)cyclopent-3-ene-1,2-diol;(1S,2R,5R)-3-(2-(2-amino-3-chloro-6-fluoroquinoline-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7-yl)cyclopent-3-ene-1,2-diol; (1S,2R,5R)-3-(2-(2-amino-3-chloro-8-fluoroquinoline-7-yl)ethyl)-5-(4-amino-7H- pyrrolo[2,3-d]pyrimidine-7-yl)cyclopent-3-ene-1,2-diol;(1S,2R,5R)-3-(2-(2-amino-3,5-dichloroquinoline-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3- d]pyrimidine-7-yl)cyclopent-3-ene-1,2-diol;(1S,2R,5R)-3-(((2-amino-3-chloro-5-fluoroquinoline-7-yl)oxy)methyl)-5-(4-amino-7H- pyrrolo[2,3-d]pyrimidine-7-yl)cyclopent-3-ene-1,2-diol;(1S,2R,5R)-3-(2-(2-amino-3-chloro-5-fluoroquinoline-7-yl)ethyl)-5-(4-isopropyl-7H- pyrrolo[2,3-d]pyrimidine-7-yl)cyclopent-3-ene-1,2-diol;(1S,2R,5R)-3-(2-(2-amino-3-chloro-5-fluoroquinoline-7-yl)ethyl)-5-(4-(1-methyl-1H- pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)cyclopent-3-ene-1,2-diol;(1S,2R,5R)-3-(1-(2-amino-3-chloro-5-fluoroquinoline-7-yl)propane-2-yl)-5-(4-amino- 7H-pyrrolo[2,3-d]pyrimidine-7-yl)cyclopent-3-ene-1,2-diol;(1S,2R,5R)-3-(1-(2-amino-3-chloroquinoline-7-yl)propane-2-yl)-5-(4-amino-7H- pyrrolo[2,3-d]pyrimidine-7-yl)cyclopent-3-ene-1,2-diol;(1S,2R,5R)-3-(2-(2-amino-3-chloro-5-fluoroquinoline-7-yl)ethyl)-5-(4-amino-7H- pyrrolo[2,3-d]pyrimidine-7-yl)-2-methylcyclopent-3-ene-1,2-diol;(1S,2R,5R)-3-(1-(2-amino-3-chloro-5-fluoroquinoline-7-yl)propane-2-yl)-5-(4-amino- 7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-methylcyclopent-3-ene-1,2-diol;(1S,2R,5R)-3-(2-(2-amino-3-chloro-5-fluoroquinoline-7-yl)ethyl)-5-(4-amino-7H- pyrrolo[2,3-d]pyrimidine-7-yl)-2-ethylcyclopent-3-ene-1,2-diol;(1S,2R,5R)-3-(2-(2-amino-3-chloro-5-fluoroquinoline-7-yl)ethyl)-5-(4-ethyl-7H- pyrrolo[2,3-d]pyrimidine-7-yl)cyclopent-3-ene-1,2-diol;(1S,2R,5R)-3-(2-(2-amino-3-chloro-5-fluoroquinoline-7-yl)ethyl)-5-(4-cyclopropyl-7H- pyrrolo[2,3-d]pyrimidine-7-yl)cyclopent-3-ene-1,2-diol;(1S,2R,5R)-3-(2-(2-amino-3-bromo-5-fluoroquinoline-7-yl)ethyl)-5-(4-amino-7H- pyrrolo[2,3-d]pyrimidine-7-yl)cyclopent-3-ene-1,2-diol;(1S,2R,5R)-3-(2-(2-amino-3-bromo-5-fluoroquinoline-7-yl)ethyl)-5-(4-methyl-7H- pyrrolo[2,3-d]pyrimidine-7-yl)cyclopent-3-ene-1,2-diol;(1S,2R,5R)-3-(1-(2-amino-3-bromo-5-fluoroquinoline-7-yl)propane-2-yl)-5-(4- amino-7H-pyrrolo[2,3-d]pyrimidine-7-yl)cyclopent-3-ene-1,2-diol; (1S,2R,5R)-3-(2-(2-amino-3-chloro-5-fluoroquinoline-7-yl)ethyl)-5-(4-methyl-1H- pyrrolo[3,2-c]pyridine-1-yl)cyclopent-3-ene-1,2-diol;(1S,2R,5R)-3-(2-(2-amino-6-fluoroquinoline-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3- d]pyrimidine-7-yl)cyclopent-3-ene-1,2-diol;(1S,2R,5R)-3-(2-(2-amino-5-fluoroquinoline-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3- d]pyrimidine-7-yl)cyclopent-3-ene-1,2-diol;(1R,2R,3S,4R,5S)-1-(2-(2-amino-3-methylquinoline-7-yl)ethyl)-4-(4-amino-7H- pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[3.1.0]hexane-2,3-diol;(1R,2R,3S,4R,5S)-1-(2-(2-amino-3-chloroquinoline-7-yl)ethyl)-4-(4-amino-7H- pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[3.1.0]hexane-2,3-diol;(1R,2R,3S,4R,5S)-1-(2-(2-amino-3-chloro-5-fluoroquinoline-7-yl)ethyl)-4-(4-amino-7H- pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[3.1.0]hexane-2,3-diol;(1R,2R,3S,4R,5S)-1-(2-(2-amino-3-chloro-6-fluoroquinoline-7-yl)ethyl)-4-(4-amino-7H- pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[3.1.0]hexane-2,3-diol;(1R,2R,3S,4R,5S)-1-(2-(2-amino-3-bromo-6-fluoroquinoline-7-yl)ethyl)-4-(4-amino- 7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[3.1.0]hexane-2,3-diol;(1R,2R,3S,4R,5S)-1-(2-(2-amino-3-bromo-5-fluoroquinoline-7-yl)ethyl)-4-(4-ami no-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[3.1.0]hexane-2,3-diol;e(1R,2R,3S,4R,5S)-1-(2-(2-amino-3-bromoquinoline-7-yl)ethyl)-4-(4-amino-7H- pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[3.1.0]hexane-2,3-diol.
3. COMPOUND OF FORMULA (I), A STEREO-ISOMER OR A PHARMACEUTICALLY ACCEPTABLE SALT THEREOF, according to claim 1, characterized in that the compound is selected from: (1S,2R,5R)-3-(2-(2-amino-3-chloro-5-fluoroquinoline-7-yl)ethyl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-yl)cyclopent-3-ene-1,2-diol; (1S,2R,5R)-3-(2-(2-amino-3-chloro-5-fluoroquinoline-7-yl)ethyl)-5-(4-amino-7H- pyrrolo[2,3-d]pyrimidine-7-yl)cyclopent-3-ene-1,2-diol;(1S,2R,5R)-3-(1-(2-amino-3-chloro-5-fluoroquinoline-7-yl)propane-2-yl)-5-(4-amino- 7H-pyrrolo[2,3-d]pyrimidine-7-yl)cyclopent-3-ene-1,2-diol; (1S,2R,5R)-3-(2-(2-amino-3-chloro-5-fluoroquinoline-7-yl)ethyl)-5-(4-amino-7H- pyrrolo[2,3-d]pyrimidine-7-yl)-2-methylcyclopent-3-ene-1,2-diol;(1R,2R,3S,4R,5S)-1-(2-(2-amino-3-chloro-5-fluoroquinoline-7-yl)ethyl)-4-(4-amino-7H- pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[3.1.0]hexane-2,3-diol;(1R,2R,3S,4R,5S)-1-(2-(2-amino-3-chloro-6-fluoroquinoline-7-yl)ethyl)-4-(4-amino-7H- pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[3.1.0]hexane-2,3-diol;(1R,2R,3S,4R,5S)-1-(2-(2-amino-3-bromoquinoline-7-yl)ethyl)-4-(4-amino-7H- pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[3.1.0]hexane-2,3-diol;(1S,2R,5R)-3-(2-(2-amino-3-bromoquinoline-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3- d]pyrimidine-7-yl)cyclopent-3-ene-1,2-diol;(1S,2R,5R)-3-(2-(2-amino-3-chloro-6-fluoroquinoline-7-yl)ethyl)-5-(4-amino-7H- pyrrolo[2,3-d]pyrimidine-7-yl)cyclopent-3-ene-1,2-diol;(1S,2R,5R)-3-(((2-amino-3-chloro-5-fluoroquinoline-7-yl)oxy)methyl)-5-(4-amino-7H- pyrrolo[2,3-d]pyrimidine-7-yl)cyclopent-3-ene-1,2-diol;(1S,2R,5R)-3-(1-(2-amino-3-chloroquinoline-7-yl)propane-2-yl)-5-(4-amino-7H- pyrrolo[2,3-d]pyrimidine-7-yl)cyclopent-3-ene-1,2-diol;(1S,2R,5R)-3-(1-(2-amino-3-chloro-5-fluoroquinoline-7-yl)propane-2-yl)-5-(4-amino- 7H-pyrrolo[2,3-d]pyrimidine-7-yl)cyclopent-3-ene-1,2-diol;(1S,2R,5R)-3-(1-(2-amino-3-chloro-5-fluoroquinoline-7-yl)propane-2-yl)-5-(4-amino- 7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-methylcyclopent-3-ene-1,2-diol;(1R,2R,3S,4R,5S)-1-(2-(2-amino-3-chloroquinoline-7-yl)ethyl)-4-(4-amino-7H- pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[3.1.0]hexane-2,3-diol;(1S,2R,5R)-3-(2-(2-amino-3-bromo-5-fluoroquinoline-7-yl)ethyl)-5-(4-amino-7H- pyrrolo[2,3-d]pyrimidine-7-yl)cyclopent-3-ene-1,2-diol;(1S,2R,5R)-3-(1-(2-amino-3-bromo-5-fluoroquinoline-7-yl)propane-2-yl)-5-(4- amino-7H-pyrrolo[2,3-d]pyrimidine-7-yl)cyclopent-3-ene-1,2-diol;(1S, 2R, 5R) -3- (2- (2-amino-3-bromo-5-fluoroquinoline-7-yl) ethyl) -5- (4-methyl-7H- pyrrolo[2,3-d] pyrimidine-7-yl) cyclopent-3-ene-1,2-diol;(1R,2R,3S,4R,5S)-1-(2-(2-amino-3-bromo-5-fluoroquinoline-7-yl)ethyl)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[3.1.0]hexane-2,3-diol;e (1R,2R,3S,4R,5S)-1-(2-(2-amino-3-bromo-6-fluoroquinoline-7-yl)ethyl)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[3.1.0]hexane-2,3-diol.
4. PHARMACEUTICAL COMPOSITION, characterized by comprising at least one compound as defined in any one of claims 1 to 3, a stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
5. USE OF A COMPOUND, as defined in any one of claims 1 to 3, characterized in that such use is for the preparation of a medicament for the treatment of diseases, disorders, syndromes or conditions associated with the inhibition of PRMT5 in an individual in need of such treatment, wherein the diseases, disorders, syndromes or conditions are cancer.
6. USE, according to claim 5, characterized in that the diseases, disorders, syndromes or conditions are selected from glioblastoma multiforme, prostate cancer, pancreatic cancer, mantle cell lymphoma, non-Hodgkin lymphomas and diffuse large B-cell lymphoma, acute myeloid leukemia, acute lymphoblastic 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, squamous cell carcinoma of the oropharynx, chronic myeloid leukemia, epidermal squamous cell carcinoma, nasopharyngeal carcinoma, neuroblastoma, endometrial carcinoma, and cervical cancer.

Description

FIELD OF THE INVENTION [001] The invention relates to substituted bicyclic heterocyclic compounds having formula (I), and their pharmaceutically acceptable salts and compositions, for the treatment of diseases, disorders or conditions associated with overexpression of the PRMT5 enzyme. The invention also relates to methods for treating diseases, disorders or conditions associated with overexpression of the PRMT5 enzyme. CROSS-REFERENCE WITH RELATED PATENT APPLICATIONS [002] This patent application claims the benefit of Indian provisional patent applications No. IN 201721044886, filed on December 13, 2017, No. IN 201821040029, filed on October 23, 2018, and No. IN 201821024634, filed on July 2, 2018, the contents of which are incorporated herein by reference in their entirety for all purposes. BACKGROUND OF THE INVENTION [003] Protein methylation is a common post-translational modification that affects protein activity and its interaction with other biological molecules. N-methylation typically occurs at the nitrogen atoms of arginine, lysine, and histidine residues, and there are different families of enzymes that catalyze the methylation reaction, each being specific to the amino acid residue that will be methylated. [004] A family of 9 enzymes, called Protein Arginine N-Methyl Transferases (PRMTs), is responsible for the methylation of the guanidinium group of arginine. The guanidinium group of arginine has 2 terminal nitrogen atoms that undergo monomethylation or dimethylation. Depending on the type of dimethylation, the enzymes are further classified as type I or type II. Type I PRMTs catalyze asymmetric monomethylation or dimethylation, while type II enzymes catalyze symmetric dimethylation. Some of the substrates that undergo methylation are histones, Sm ribonucleoproteins, MRE11 binding proteins, and p53. [005] Arginine side chain methylation plays an important role in several cellular functions, including transcriptional activation as well as transcriptional repression, mRNA translation, pre-mRNA maturation, protein trafficking, and signal transduction. It also occurs on numerous substrates. The enzymatic activity of PRMTs, therefore, affects cellular processes such as cell proliferation, repair of damaged DNA, as well as cell cycle and cell death. Enzyme-mediated hypermethylation of PRMTs has been shown to lead to certain disease conditions, such as cancer {Nature Reviews Cancer, 2013, 13, p37; Cellular and Molecular Life Sciences, 2015, 72, p2041; Trends in Biochemical Sciences, 2011, 36, p633}. [006] Currently, the most studied type II enzyme is PRMT5, which is conserved in eukaryotic organisms. PRMT5 overexpression is linked to carcinogenesis and decreased patient survival in several human malignancies (Cell. MoL Life Sci., 2015, 72, p2041). PRMT5 interacts directly with proteins that are frequently deregulated or mutated in cancers, consequently being a putative oncogene (Mol. Cell. Biol., 2008, 28, p6262). PRMT5-mediated transcriptional repression of tumor suppressor genes such as p53, RB-1, ST7, or the upregulation of cyclin DI, CDK4, CDK6, eLF4E, MITF, FGFR3, are associated with oncogenesis in both solid tumors and hematological malignancies. PRMT5 is located in the nucleus as well as in the cytoplasm, and its overexpression has been associated with a wide range of cancers, including, but not limited to, glioblastoma multiforme (Oncogene, 2017, 36, p263), prostate cancer (Oncogene, 2017, 36, p223) and pancreatic cancer (Science, 2016, 351, p214), mantle cell lymphoma (Nature Chemical Biology, 2015, 11, p432), non-Hodgkin lymphomas, and diffuse large B-cell lymphoma (Journal of Biological Chemistry, 2013, 288, p35534), acute myeloid leukemia (Leukemia, 2018, 32, p499), acute lymphoblastic leukemia (Cancer Research, 2017; 77 (13 Suppl.): Abstract nr 1128), multiple myeloma (Leukemia, 2018, 32, p996), non-small cell lung cancer (The Biochemistry Journal, 2012, 446, p235), small cell lung cancer (44C7?; Cancer Research, 2017; 77 (13 Suppl. Abstract nr DDT02-04), breast cancer (Cell Reports, 2017, 21, p3498), triple-negative breast cancer (44C7?; 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 (Onco/Ogy Reports, 2018, 40, p536), melanoma (PLoS One, 2013, 8, e74710; J. Clin. Invest., 2018, 128, p517), sarcoma (Oncology Letters, 2018, 16, p2161), squamous cell carcinoma of the oropharynx (Oncotarget, 2017, 8, p4847), chronic myeloid leukemia (J. Clin. (Invest., 2016, 126, p3961), squamous cell carcinoma of the epidermis (Carcinogenesis, 2017, 38, p827), nasopharyngeal carcinoma (Oncology Reports, 2016, 35, p703), neuroblastoma (Molecular Oncology, 2015, 9, p617), endometrial carcinoma (Gynecol. Oncol., 2016, 140, p45), cervical cancer (P