Substituted bicyclic heterocyclic compounds as PRMT5 inhibitors

Abstract

The invention relates to substituted bicyclic heterocyclic compounds of formula (I), pharmaceutically acceptable salts thereof and pharmaceutical compositions for treating diseases, disorders or conditions associated with the overexpression of PRMT5 5 enzyme. The invention also relates to methods of treating diseases, disorders or conditions associated with the overexpression of PRMT5 enzyme.

Description

SUBSTITUTED BICYCLIC HETEROCYCLIC COMPOUNDS AS PRMT5 INHIBITORS Field of the Invention The invention relates to substituted bicyclic heterocyclic compounds of formula (I), pharmaceutically acceptable salts thereof and pharmaceutical compositions for treating diseases, disorders or conditions associated with the overexpression of PRMT5 enzyme. The invention also relates to methods of treating diseases, disorders or conditions associated with the overexpression of PRMT5 enzyme. Related applications The present application claims the benefit of Indian Provisional Patent Applications Nos. IN 201721044886 filed on December 13, 2017, IN 201821040029 filed on October 23, 2018, and IN 201821024634 filed on July 02, 2018. Background to the invention Methylation of proteins is a common post-translational modification that affects the protein's activity and its interaction with other biological molecules. 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 being specific to the amino acid residue that will be methylated. A family of 9 enzymes, called Protein Arginine N-Methyl Transferases (PRMTs), are responsible for the methylation of the guanidinium group of arginine. The guanidinium group of arginine bears 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 catalyse the monomethylation or the asymmetric dimethylation whereas type II enzymes catalyse the symmetric dimethylation. Some of the substrates that undergo methylation are histones, Sm ribonucleoproteins, MRE11 and p53 binding protein 1. The methylation of arginine side-chains has an important role to play in various cell functions that include transcription activation as well as transcription repression, mRNA translation, pre-mRNA splicing, protein trafficking and signal transduction. It also occurs on myriad substrates. The enzymatic activity of the PRMTs hence affects cellular processes like cell proliferation, repair of damaged DNA as well as cell cycle and cell death. It has been shown that PRMT enzyme-mediated hypermethylation leads to certain disease conditions like cancer (Nature Reviews Cancer 2013, 13, p37; Cellular and Molecular Life Sciences 2015, 72, p2041; Trends in Biochemical Sciences 2011, 36, p633). At present, the most studied type II enzyme is PRMT5, which is conserved across the eukaryotic organisms. Overexpression of PRMT5 is linked with carcinogenesis and decreased patient survival in several human malignancies (Cell Mol Life Sci., 2015, 72, p2041). PRMT5 directly interacts with proteins often dysregulated or mutated in cancers, hence a putative oncogene (Mol Cell Biol, 2008, 28, p6262). PRMT5 mediated transcriptional repression of tumor suppressor genes like p53, RB-1, ST7, or upregulation of Cyclin D1, CDK4, CDK6, eLF4E, MITF, FGFR3 associate with the oncogenesis in both solid tumors and hemaological malignancies. PRMT5 is located in the nucleus as well as the cytoplasm and its overexpression has been linked to a wide range of cancers including, but not limited to, 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 lymphomas 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 3 cancer (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 myelogenous leukemia (J Clin Invest, 2016, 126, p3961), epidermal squamous cell carcinoma (Carcinogenesis, 2017, 38, p827), nasopharyngeal carcinoma (Oncology Reports, 2016, 35, p1703), neuroblastoma (Molecular Oncology, 2015, 9, p617), endometrial carcinoma (Gynecol Oncol., 2016, 140, p145), cervical cancer (Pharmazie, 2018, 73, p269).. These findings have led to further research which show that inhibiting PRMT5 reduces cell proliferation (Molecular and Cellular Biology 2008, 28, p6262, The Journal of Biological Chemistry 2013, 288, p35534). Inhibitors of arginine methyl transferases 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 having greater selectivity towards either type I or type II arginine methyl transferases have been disclosed. Other publications that disclose small molecules as inhibitors in relation to PRMT5 are: WO2011077133, WO2011079236, WO2014100695, WO2014100716, WO2014100719, WO2014100730, WO2014100734, WO2014128465, WO2014145214, WO2015200677, WO2015200680, WO2015198229, WO2016022605, WO2016034671, WO2016034673, WO2016034675, WO2016038550, WO2016135582, WO2016145150, WO2016178870, WO2017032840 and ACS Medicinal Chemistry Letters 2015, 6, p408. Summary of the Invention In accordance with one aspect, the invention provides compound of general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, [Image disponible dans le document PDF, Image available in the PDF document] (l) wherein, L<com:Sub>1< / com:Sub> is selected from -CR<com:Sup>a< / com:Sup>R<com:Sup>b< / com:Sup>-, -NR<com:Sup>a< / com:Sup>-, S, and O; <com:Math><semantics>Z=CH or N;<annotation encoding="application / x-tex">Z=CH \text{ or } N;< / annotation>< / semantics>< / com:Math> R<com:Sup>a< / com:Sup> and R<com:Sup>b< / com:Sup> are independently selected at each occurrence from hydrogen, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl; ring A is selected from, [Image disponible dans le document PDF, Image available in the PDF document] R<com:Sup>c< / com:Sup> and R<com:Sup>d< / com:Sup> are selected from substituted or unsubstituted alkyl or together with the carbon atoms to which they are attached form a C<com:Sub>3< / com:Sub>-C<com:Sub>6< / com:Sub> cycloalkyl ring; R is selected from –NR<com:Sup>4< / com:Sup>R<com:Sup>5< / com:Sup>, hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted heteroaryl and substituted or unsubstituted cycloalkyl; R<com:Sup>1< / com:Sup> and R<com:Sup>2< / com:Sup> together with the carbon atoms to which they are attached form a bond in order to form a <com:Math><semantics>−C=C<annotation encoding="application / x-tex">-C=C< / annotation>< / semantics>< / com:Math>-; or <com:Math><semantics>ℝ1<annotation encoding="application / x-tex">\mathbb{R}^1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>ℝ2<annotation encoding="application / x-tex">\mathbb{R}^2< / annotation>< / semantics>< / com:Math> together with the carbon atoms to which they are attached form a cyclopropane ring; R<com:Sup>2< / com:Sup> and R<com:Sup>2a< / com:Sup> which may be same or different and are independently selected from hydrogen and substituted or unsubstituted alkyl; R<com:Sup>3< / com:Sup> is independently selected at each occurrence from halogen, cyano, nitro, substituted or unsubstituted alkyl, -OR<com:Sup>6< / com:Sup>, -NR<com:Sup>7< / com:Sup>R<com:Sup>8< / com:Sup>, substituted or unsubstituted cycloalkyl, -C(O)OH, -C(O)O-alkyl, -C(O)R<com:Sup>9< / com:Sup>, -C(O)NR<com:Sup>7< / com:Sup>R<com:Sup>8< / com:Sup>, -NR<com:Sup>7< / com:Sup>C(O)R<com:Sup>9< / com:Sup>, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclyl; R<com:Sup>4< / com:Sup> and R<com:Sup>5< / com:Sup> are independently selected from hydrogen, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl; R<com:Sup>6< / com:Sup> is selected from hydrogen, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl; R<com:Sup>7< / com:Sup> and R<com:Sup>8< / com:Sup> are independently selected from hydrogen, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl; R<com:Sup>9< / com:Sup> is selected from substituted or unsubstituted alkyl and substituted or unsubstituted cycloalkyl; R<com:Sup>10< / com:Sup> is selected from hydrogen, halogen, and substituted or unsubstituted alkyl; 'n' is an integer ranging from 0 to 4, both inclusive; when an alkyl group is substituted, it is substituted with 1 to 4 substituents independently selected from oxo (=0), halogen, cyano, cycloalkyl, aryl, heteroaryl, heterocyclyl, -OR<com:Sup>7a< / com:Sup>, <com:Math><semantics>−C(=O)OH<annotation encoding="application / x-tex">-C(=O)OH< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−C(=O)O(alkyl)<annotation encoding="application / x-tex">-C(=O)O(alkyl)< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−NR8aR8b<annotation encoding="application / x-tex">-NR^{8a}R^{8b}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−NR8aC(=O)R9a<annotation encoding="application / x-tex">-NR^{8a}C(=O)R^{9a}< / annotation>< / semantics>< / com:Math>, and <com:Math><semantics>−C(=O)NR8aR8b<annotation encoding="application / x-tex">-C(=O)NR^{8a}R^{8b}< / annotation>< / semantics>< / com:Math>; when the heteroaryl group is substituted, it is substituted with 1 to 4 substituents independently selected from halogen, nitro, cyano, alkyl, haloalkyl, perhaloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR<com:Sup>7a< / com:Sup>, -NR<com:Sup>8a< / com:Sup>R<com:Sup>8b< / com:Sup>, -NR<com:Sup>7a< / com:Sup>C(=O)R<com:Sup>9a< / com:Sup>, -C(=O)R<com:Sup>9a< / com:Sup>, - <com:Math><semantics>C(=O)NR8aR8b<annotation encoding="application / x-tex">C(=O)NR^{8a}R^{8b}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−SO2<annotation encoding="application / x-tex">-SO_2< / annotation>< / semantics>< / com:Math>-alkyl, <com:Math><semantics>−C(=O)OH<annotation encoding="application / x-tex">-C(=O)OH< / annotation>< / semantics>< / com:Math>, and <com:Math><semantics>−C(=O)O<annotation encoding="application / x-tex">-C(=O)O< / annotation>< / semantics>< / com:Math>-alkyl; when the heterocycle group is substituted, it is substituted either on a ring carbon atom or on a ring hetero atom, and when it is substituted on a ring carbon atom, it is substituted with 1 to 4 substituents independently selected from oxo (=0), halogen, cyano, alkyl, cycloalkyl, perhaloalkyl, <com:Math><semantics>−OR7a<annotation encoding="application / x-tex">-OR^{7a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−C(=O)NR8aR8b<annotation encoding="application / x-tex">-C(=O)NR^{8a}R^{8b}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−C(=O)OH<annotation encoding="application / x-tex">-C(=O)OH< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−C(=O)O<annotation encoding="application / x-tex">-C(=O)O< / annotation>< / semantics>< / com:Math>-alkyl, - <com:Math><semantics>N(H)C(=O)(alkyl)<annotation encoding="application / x-tex">N(H)C(=O)(alkyl)< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−N(H)R8a<annotation encoding="application / x-tex">-N(H)R^{8a}< / annotation>< / semantics>< / com:Math>, and <com:Math><semantics>−N(alkyl)2<annotation encoding="application / x-tex">-N(alkyl)_2< / annotation>< / semantics>< / com:Math>; and when the heterocycle group is substituted on a ring nitrogen, it is substituted with substituents independently selected from alkyl, cycloalkyl, aryl, heteroaryl, <com:Math><semantics>−SO2(alkyl)<annotation encoding="application / x-tex">-SO_2(alkyl)< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−C(=O)R9a<annotation encoding="application / x-tex">-C(=O)R^{9a}< / annotation>< / semantics>< / com:Math>, and <com:Math><semantics>−C(=O)O(alkyl)<annotation encoding="application / x-tex">-C(=O)O(alkyl)< / annotation>< / semantics>< / com:Math>; when the heterocycle group is substituted on a ring sulfur, it is substituted with 1 or 2 oxo <com:Math><semantics>(=0)<annotation encoding="application / x-tex">(=0)< / annotation>< / semantics>< / com:Math> group(s); R<com:Sup>7a< / com:Sup> is selected from hydrogen, alkyl, perhaloalkyl, and cycloalkyl; R<com:Sup>8a< / com:Sup> and R<com:Sup>8b< / com:Sup> are each independently selected from hydrogen, alkyl, and cycloalkyl; and R<com:Sup>9a< / com:Sup> is selected from alkyl and cycloalkyl. 6 The details of one or more embodiments of the invention set forth in below are only illustrative in nature and not intended to limit to the scope of the invention. Other features, objects and advantages of the inventions will be apparent from the description and claims. 5 According to one embodiment, the invention provides compounds having the structure of Formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, [Image disponible dans le document PDF, Image available in the PDF document] (II) wherein, Ring A, L<com:Sub>1< / com:Sub>, Z, R<com:Sup>a< / com:Sup>, R<com:Sup>b< / com:Sup>, R<com:Sup>2< / com:Sup>', R, R<com:Sup>2a< / com:Sup>, R<com:Sup>3< / com:Sup>, R<com:Sup>10< / com:Sup> and 'n' are as defined herein above. According to another embodiment, the invention provides compounds having the structure of Formula (III), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, [Image disponible dans le document PDF, Image available in the PDF document] (III) wherein, Ring A, L<com:Sub>1< / com:Sub>, Z, R<com:Sup>a< / com:Sup>, R<com:Sup>b< / com:Sup>, R<com:Sup>2< / com:Sup>, R, R<com:Sup>2a< / com:Sup>, R<com:Sup>3< / com:Sup>, R<com:Sup>10< / com:Sup> and 'n' are as defined herein above. According to one embodiment, the invention provides compounds having the structure of Formula (IV), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, [Image disponible dans le document PDF, Image available in the PDF document] (IV) wherein, <com:Math><semantics>X2<annotation encoding="application / x-tex">X^2< / annotation>< / semantics>< / com:Math> is Br or Cl; L<com:Sub>1< / com:Sub>, R<com:Sup>a< / com:Sup>, R<com:Sup>b< / com:Sup>, R<com:Sup>1< / com:Sup>, R<com:Sup>2< / com:Sup>, R<com:Sup>2< / com:Sup>, R, R<com:Sup>2a< / com:Sup> and R<com:Sup>10< / com:Sup> are as defined herein above. In accordance with an embodiment of the invention, R<com:Sup>c< / com:Sup> and R<com:Sup>d< / com:Sup> are independently selected from substituted or unsubstituted alkyl or R<com:Sup>c< / com:Sup> and R<com:Sup>d< / com:Sup> together with the carbon atom to which they are attached form a cyclobutyl ring. In certain embodiment, Rc and Rd are independently selected from methyl or Rc and Rd together with the carbon atom to which they are attached from a cyclobutyl ring. In any of above embodiments, R<com:Sup>a< / com:Sup> and R<com:Sup>b< / com:Sup> are independently selected from hydrogen, methyl, and cyclopropyl. In any of above embodiments, R<com:Sup>3< / com:Sup> is selected from halogen, cyano, -OR<com:Sup>6< / com:Sup>, -NR<com:Sup>7< / com:Sup>R<com:Sup>8< / com:Sup>, substituted or unsubstituted alkyl, and substituted or unsubstituted aryl. In certain embodiments, R<com:Sup>3< / com:Sup> is independently selected from -F, Cl, Br, CN, -NH<com:Sub>2< / com:Sub>, - NH(CH<com:Sub>3< / com:Sub>), -NHCH(CH<com:Sub>3< / com:Sub>)<com:Sub>2< / com:Sub>, -CH<com:Sub>3< / com:Sub>, cyclopropyl, -CH(CH<com:Sub>3< / com:Sub>)<com:Sub>2< / com:Sub>, -CF<com:Sub>2< / com:Sub>CH<com:Sub>3< / com:Sub>, -OCH<com:Sub>3< / com:Sub>, [Image disponible dans le document PDF, Image available in the PDF document] In any of above embodiments, <com:Math><semantics>R2<annotation encoding="application / x-tex">R^{2}< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R2a<annotation encoding="application / x-tex">R^{2a}< / annotation>< / semantics>< / com:Math> are independently selected from hydrogen and methyl. In any of above embodiments, R is selected from hydrogen, halogen, -NR<com:Sup>4< / com:Sup>R<com:Sup>5< / com:Sup>, and substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl and substituted or unsubstituted heteroaryl. In certain embodiments, R is selected from hydrogen, –NH<com:Sub>2< / com:Sub>, methyl, Chloro, cyclopropyl, [Image disponible dans le document PDF, Image available in the PDF document] and In any of above embodiments, R<com:Sup>4< / com:Sup> and R<com:Sup>5< / com:Sup> are independently selected from hydrogen. In any of above embodiments, R<com:Sup>6< / com:Sup> is selected from substituted and unsubstituted alkyl. In certain embodiments, <com:Math><semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>< / com:Math> is selected from methyl. In any of above embodiments, R<com:Sup>7< / com:Sup> and R<com:Sup>8< / com:Sup> are independently selected from hydrogen, methyl, -CH(CH<com:Sub>3< / com:Sub>)<com:Sub>2< / com:Sub>, -CH<com:Sub>2< / com:Sub>-cyclopropyl, cyclopropyl, and cyclobutyl. In any of above embodiments, <com:Math><semantics>R10<annotation encoding="application / x-tex">R^{10}< / annotation>< / semantics>< / com:Math> is selected from hydrogen, -F, and methyl. In any of above embodiments, n is selected from 1 to 3. According to another embodiment, there are provided compounds having the structure of Formula (I) wherein <com:Math><semantics>L1<annotation encoding="application / x-tex">L_1< / annotation>< / semantics>< / com:Math> is selected from <com:Math><semantics>−CH2<annotation encoding="application / x-tex">-CH_2< / annotation>< / semantics>< / com:Math>-, <com:Math><semantics>−CH(CH3)<annotation encoding="application / x-tex">-CH(CH_3)< / annotation>< / semantics>< / com:Math>-, <com:Math><semantics>−NH<annotation encoding="application / x-tex">-NH< / annotation>< / semantics>< / com:Math>-, <com:Math><semantics>−N(CH3)<annotation encoding="application / x-tex">-N(CH_3)< / annotation>< / semantics>< / com:Math>- S, and O; According to another embodiment, there are provided compounds having the [Image disponible dans le document PDF, Image available in the PDF document] structure of Formula (I) wherein ring A is According to another embodiment, there are provided compounds having the [Image disponible dans le document PDF, Image available in the PDF document] structure of Formula (I) wherein ring A is According to another embodiment, there are provided compounds having the [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] or structure of Formula (I) wherein ring A is R<com:Sup>c< / com:Sup> R<com:Sup>d< / com:Sup> According to another embodiment, there are provided compounds having the structure of Formula (I), wherein ring A is selected from- [Image disponible dans le document PDF, Image available in the PDF document] L1 is selected from -CH2-, -CH(CH3)-, -NH-, -N(CH3)-, S, and O; R<com:Sup>3< / com:Sup> is selected from F, Cl, Br, CN, -NH<com:Sub>2< / com:Sub>, -NH(CH<com:Sub>3< / com:Sub>), -NHCH(CH<com:Sub>3< / com:Sub>)<com:Sub>2< / com:Sub>, -CH<com:Sub>3< / com:Sub>, cyclopropyl, -CH(CH<com:Sub>3< / com:Sub>)<com:Sub>2< / com:Sub>, -CF<com:Sub>2< / com:Sub>CH<com:Sub>3< / com:Sub>, - <com:Math><semantics>OCH3<annotation encoding="application / x-tex">OCH_3< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>CF3<annotation encoding="application / x-tex">CF_3< / annotation>< / semantics>< / com:Math>, [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] selected from hydrogen, -NH<com:Sub>2< / com:Sub>, Cl, -CH(CH<com:Sub>3< / com:Sub>)<com:Sub>2< / com:Sub>, methyl, ethyl, cyclopropyl and R<com:Sup>a< / com:Sup> and R<com:Sup>b< / com:Sup> are independently selected from hydrogen, methyl, and cyclopropyl; R<com:Sup>2< / com:Sup> and R<com:Sup>2a< / com:Sup> are independently selected from hydrogen and methyl; R<com:Sup>10< / com:Sup> is selected from hydrogen, -F, and methyl. The examples 1 to 84 given herein are representative compounds, which are only illustrative in nature and are not intended to limit to the scope of the invention. It should be understood that formula (I) structurally encompasses all tautomers, stereoisomers and isotopes wherever applicable and pharmaceutically acceptable salts that may be contemplated from the chemical structures generally described herein. According to one embodiment, there are provided compounds of formula (I) to (IV) wherein the compound is in the form of the free base or is a pharmaceutically acceptable salt thereof. In another aspect of the invention, there are provided compounds of formula (I) to (IV) or a pharmaceutically acceptable salt thereof for treating the diseases, disorders, syndromes or conditions associated with PRMT5 enzyme. In one embodiment of the present invention, there are provided compounds of formula (I) to (IV), or a pharmaceutically acceptable salt thereof for treating diseases, disorders, syndromes or conditions by inhibition of PRMT5 enzyme. In another aspect of the invention, there are provided compounds of formula (I) to (IV) or a pharmaceutically acceptable salt thereof for use as a medicament. In another aspect of the invention, there are provided compounds of formula (I) to (IV) or a pharmaceutically acceptable salt thereof for use in treating the diseases, disorders, syndromes or conditions associated with PRMT5. In one embodiment of the present invention, there are provided compounds of formula (I) to (IV) or a pharmaceutically acceptable salt thereof for use in treating diseases, disorders, syndromes or conditions by the inhibition of PRMT5. In another aspect of the invention, there is provided a method of inhibiting PRMT5 by using a compound selected from formula (I) to (IV) or a pharmaceutically acceptable salt thereof. In another aspect of the invention, there is provided a method of treating diseases, disorders or conditions associated with PRMT5 by using a compound selected from formula (I) to (IV). In another aspect of the present invention, a method of treating diseases, disorders or conditions is selected from glioblastoma multiforme, prostate cancer, and pancreatic cancer, mantle cell lymphoma, non-Hodgkin's 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 cancer, melanoma, sarcoma, oropharyngeal squamous cell carcinoma, chronic myelogenous leukemia, epidermal squamous cell carcinoma, nasopharyngeal carcinoma, neuroblastoma, endometrial carcinoma, and cervical cancerby using a compound selected from formula (I) to (IV) is provided. In another aspect of the invention, there is provided a use of a compound selected from formula (I) to (IV) or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating, the diseases, disorders or conditions associated with PRMT5. In another aspect, the invention provides a pharmaceutical composition comprising at least one compound of formula (I) to (IV) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. In another aspect, the invention provides a pharmaceutical composition comprising a therapeutically effective amount of compound of formula (I) to (IV) or a pharmaceutically acceptable salt thereof, for use in treating, the diseases, disorders or conditions associated with PRMT5 by administering to the subject in need thereof. In another aspect of the present invention, wherein the use of compounds of formula (I) to (IV) or a pharmaceutically acceptable salt thereof for the diseases, disorders, syndromes or conditions associated by inhibition of PRMT5 are selected from the group consisting of glioblastoma multiforme, prostate cancer, and pancreatic cancer, mantle cell lymphoma, non-Hodgkin's 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 cancer, melanoma, sarcoma, oropharyngeal squamous cell carcinoma, chronic myelogenous leukemia, epidermal squamous cell carcinoma, nasopharyngeal carcinoma, neuroblastoma, endometrial carcinoma, and cervical cancer. In another aspect, the invention provides a pharmaceutical composition comprising a therapeutically effective amount of compound of formula (I) to (IV) or a pharmaceutically acceptable salt thereof, for treating the diseases, disorders or conditions associated with PRMT5 by administering to the subject in need thereof. In another embodiment of the invention the compounds, their stereoisomers or pharmaceutically acceptable salts thereof are: (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 (Compound-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 (Compound-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 (Compound-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-(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(Compound-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 (Compound-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 (Compound-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 (Compound-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-fluoro quinolin-7-yl)propan-2-yl)-5-(4-amino- 7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (Compound-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- dlpyrimidin-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-isopropyl quinolin-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 (Compound-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 (Compound-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 (Compound- 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 (Compound-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-methyl isoxazol-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). In another embodiment of the invention the compounds, their stereoisomer thereof, or a pharmaceutically acceptable salt thereof, are selected from: (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-(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 (Compound-7a and 7b); (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)-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-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)-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 (Compound-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)-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-3,5-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-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(Compound-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 (Compound-34a and 34b); (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)-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-fluoro quinolin-7-yl)propan-2-yl)-5-(4-amino- 7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (Compound-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)-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); [Image disponible dans le document PDF, Image available in the PDF document] In another embodiment of the invention the compounds, their stereoisomer thereof, or a pharmaceutically acceptable salt thereof, are selected from: (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-amino-7H- pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (Compound-24); (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(Compound-33a and 33b); (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); (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)-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-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); (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-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-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)-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 (Compound-34a and 34b); (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); (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); (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-(1-(2-Amino-3-bromo-5-fluoro quinolin-7-yl)propan-2-yl)-5-(4-amino- 7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (Compound-45a); (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); (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); and (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). Detailed description of the invention Definitions and Abbreviations Unless otherwise stated, the following terms used in the specification and claims have the meanings given below. For purposes of interpreting the specification, the following definitions will apply and whenever appropriate, terms used in the singular will also include the plural and vice versa. The terms "halogen" or "halo" means fluorine, chlorine, bromine, or iodine. The term "alkyl" refers to an alkane derived hydrocarbon radical that includes solely carbon and hydrogen atoms in the backbone, contains no unsaturation, has from one to six carbon atoms, and is attached to the remainder of the molecule by a single bond, for example <com:Math><semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics>< / com:Math> alkyl or <com:Math><semantics>(C1−C4)<annotation encoding="application / x-tex">(C_1-C_4)< / annotation>< / semantics>< / com:Math> alkyl, representative groups include <com:Math><semantics>e.g.<annotation encoding="application / x-tex">e.g.< / annotation>< / semantics>< / com:Math>, methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl and the like. Unless set forth or recited to the contrary, all alkyl groups described or claimed herein may be straight chain or branched. The term "alkenyl" refers to a hydrocarbon radical containing from 2 to 10 carbon atoms and including at least one carbon-carbon double bond. Non-limiting Examples of alkenyl groups include, for example <com:Math><semantics>(C2−C6)<annotation encoding="application / x-tex">(C_2-C_6)< / annotation>< / semantics>< / com:Math>alkenyl, <com:Math><semantics>(C2−C4)<annotation encoding="application / x-tex">(C_2-C_4)< / annotation>< / semantics>< / com:Math>alkenyl, ethenyl, 1-propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-l- propenyl, 1-butenyl, 2-butenyl and the like. Unless set forth or recited to the contrary, all alkenyl groups described or claimed herein may be straight chain or branched. The term "alkynyl" refers to a hydrocarbon radical containing 2 to 10 carbon atoms and including at least one carbon-carbon triple bond. Non-limiting Examples of alkynyl groups include, for example <com:Math><semantics>(C2−C6)<annotation encoding="application / x-tex">(C_2-C_6)< / annotation>< / semantics>< / com:Math>alkynyl, <com:Math><semantics>(C2−C4)<annotation encoding="application / x-tex">(C_2-C_4)< / annotation>< / semantics>< / com:Math>alkynyl, ethynyl, propynyl, butynyl and the like. Unless set forth or recited to the contrary, all alkynyl groups described or claimed herein may be straight chain or branched. The term "haloalkyl" refers to an alkyl group as defined above that is substituted by one or more halogen atoms as defined above. For example <com:Math><semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics>< / com:Math> haloalkyl or <com:Math><semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics>< / com:Math> C<com:Sub>4< / com:Sub>)haloalkyl. Suitably, the haloalkyl may be monohaloalkyl, dihaloalkyl or polyhaloalkyl including perhaloalkyl. A monohaloalkyl can have one iodine, bromine, chlorine or fluorine atom. Dihaloalkyl and polyhaloalkyl groups can be substituted with two or more of the same halogen atoms or a combination of different halogen atoms. Suitably, a polyhaloalkyl is substituted with up to 12 halogen atoms. Non-limiting Examples of a haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl and the like. A perhaloalkyl refers to an alkyl having all hydrogen atoms replaced with halogen atoms. Unless set forth or recited to the contrary, all haloalkyl groups described or claimed herein may be straight chain or branched. The term "alkoxy" denotes an alkyl group attached via an oxygen linkage to the rest of the molecule. Representative examples of such groups are -OCH<com:Sub>3< / com:Sub> and -OC<com:Sub>2< / com:Sub>H<com:Sub>5< / com:Sub>. Unless set forth or recited to the contrary, all alkoxy groups described or claimed herein may be straight chain or branched. The term "alkoxyalkyl" refers to an alkoxy group as defined above directly bonded to an alkyl group as defined above, e.g., -CH<com:Sub>2< / com:Sub>-O-CH<com:Sub>3< / com:Sub>, -CH<com:Sub>2< / com:Sub>-O-CH<com:Sub>2< / com:Sub>CH<com:Sub>3< / com:Sub>, - CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>-O-CH<com:Sub>3< / com:Sub> and the like. The term "cycloalkyl" refers to a non-aromatic mono or multicyclic ring system having 3 to 12 carbon atoms, such as <com:Math><semantics>(C3−C10)<annotation encoding="application / x-tex">(C_3-C_{10})< / annotation>< / semantics>< / com:Math> cycloalkyl, <com:Math><semantics>(C3−C6)<annotation encoding="application / x-tex">(C_3-C_6)< / annotation>< / semantics>< / com:Math> cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. Examples of multicyclic cycloalkyl groups include, but are not limited to, perhydronaphththyl, adamantyl and norbornyl groups, bridged cyclic groups or spirobicyclic groups, e.g., spiro(4,4)non-2-yl and the like. The term "aryl" refers to an aromatic radical having 6- to 14- carbon atoms, including monocyclic, bicyclic and tricyclic aromatic systems, such as phenyl, naphthyl, tetrahydronaphthyl, indanyl, and biphenyl and the like. The term "heterocyclic ring" or "heterocyclyl ring" or "heterocyclyl", unless otherwise specified, refers to substituted or unsubstituted non-aromatic 3- to 15- membered ring which consists of carbon atoms and with one or more heteroatom(s) independently selected from N, O or S. The heterocyclic ring may be a mono-, bi- or tricyclic ring system, which may include fused, bridged or spiro ring systems and the nitrogen, carbon, oxygen or sulfur atoms in the heterocyclic ring may be optionally oxidized to various oxidation states. In addition, the nitrogen atom may be optionally quaternized, the heterocyclic ring or heterocyclyl may optionally contain one or more olefinic bond(S), and one or two carbon atoms(S) in the heterocyclic ring or heterocyclyl may be interrupted with <com:Math><semantics>−CF2<annotation encoding="application / x-tex">-CF_2< / annotation>< / semantics>< / com:Math>-, <com:Math><semantics>−C(O)<annotation encoding="application / x-tex">-C(O)< / annotation>< / semantics>< / com:Math>-, <com:Math><semantics>−S(O)<annotation encoding="application / x-tex">-S(O)< / annotation>< / semantics>< / com:Math>-, <com:Math><semantics>S(O)2<annotation encoding="application / x-tex">S(O)_2< / annotation>< / semantics>< / com:Math> etc. In addition heterocyclic ring may also be fused with aromatic ring. Non-limiting Examples of heterocyclic rings include azetidinyl, benzopyranyl, chromanyl, decahydroisoquinolyl, indolinyl, isoindolinyl, isochromanyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, oxazolinyl, oxazolidinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, octahydroindolyl, octahydroisoindolyl, perhydroazepinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, piperidinyl, phenothiazinyl, phenoxazinyl, quinuclidinyl, tetrahydroisquinolyl, tetrahydrofuryl, tetrahydropyranyl, thiazolinyl, thiazolidinyl, thiamorpholinyl, thiamorpholinylsulfoxide, thiamorpholinylsulfoneindoline, benzodioxole, tetrahydroquinoline, tetrahydrobenzopyran and the like. The heterocyclic ring may be attached by any atom of the heterocyclic ring that results in the creation of a stable structure. The term "heteroaryl" unless otherwise specified, refers to a substituted or unsubstituted 5- to 14- membered aromatic heterocyclic ring with one or more heteroatom(S) independently selected from N, O or S. The heteroaryl may be a mono-, bi- 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 a heteroaryl ring 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 invention include all diastereomers and enantiomers and mixtures thereof. Unless specifically mentioned otherwise, reference to one stereoisomer applies to any of the possible stereoisomers. Whenever the stereoisomeric composition is unspecified, it is to be understood that all possible stereoisomers are included. The term "stereoisomer" refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures which are not interchangeable. The three-dimensional structures are called configurations. As used herein, the term "enantiomer" 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 which are not enantiomers. The terms "racemate" or "racemic mixture" refer to a mixture of equal parts of enantiomers. A "tautomer" refers to a compound that undergoes rapid proton shifts from one atom of the compound to another atom of the compound. Some of the compounds described herein may exist as tautomers with different points of attachment of hydrogen. The individual tautomers as well as mixture thereof are encompassed with compounds of formula (I). The term "treating" or "treatment" of a state, disorder or condition includes: (a) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a subject that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition; (b) inhibiting the state, disorder or condition, i.e., arresting or reducing the development of the disease or at least one clinical or subclinical symptom thereof; c) lessening the disease, disorder or condition or at least one of its clinical or subclinical symptoms or (d) relieving the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms. The term "inhibitor" refers to a molecule that binds to an enzyme to inhibit the activity of the said enzyme either partially or completely. The term "subject" includes mammals (especially humans) and other animals, such as domestic animals (e.g., household pets including cats and dogs) and non-domestic animals (such as wildlife). A "therapeutically effective amount" means the amount of a compound that, when administered to a subject for treating a disease, disorder or condition, is sufficient to cause the effect in the subject, which is the purpose of the administration. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the subject to be treated. Pharmaceutically Acceptable Salts The compounds of the invention may form salts with acid or base. The compounds of invention may be sufficiently basic or acidic to form stable nontoxic acid or base salts, administration of the compound as a pharmaceutically acceptable salt may be appropriate. Non-limiting Examples of pharmaceutically acceptable salts are inorganic, organic acid addition salts formed by addition of acids including hydrochloride salts. Non-limiting Examples of pharmaceutically acceptable salts are inorganic, organic base addition salts formed by addition of bases. The compounds of the invention may also form salts with amino acids. Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, for example by reacting sufficiently basic compound such as an amine with a suitable acid. Screening of the compounds of invention for PRMT5 inhibitory activity can be achieved by using various in vitro and in vivo protocols mentioned herein below or methods known in the art. Pharmaceutical Compositions The invention relates to pharmaceutical compositions containing the compounds of the formula (I), or pharmaceutically acceptable salts thereof disclosed herein. In particular, pharmaceutical compositions containing a therapeutically effective amount of at least one compound of formula (I) described herein and at least one pharmaceutically acceptable excipient (such as a carrier or diluent). Preferably, the contemplated pharmaceutical compositions include the compound(s) described herein in an amount sufficient to inhibit PRMT5 to treat the diseases described herein when administered to a subject. The subjects contemplated include, for example, a living cell and a mammal, including human. The compound of the invention may be associated with a pharmaceutically acceptable excipient (such as a carrier or a diluent) or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container. The pharmaceutically acceptable excipient includes pharmaceutical agent that does not itself induce the production of antibodies harmful to the individual receiving the composition, and which may be administered without undue toxicity. Examples of suitable carriers or excipients include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, salicylic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerytritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone. The pharmaceutical composition may also include one or more pharmaceutically acceptable auxiliary agents, wetting agents, emulsifying agents, suspending agents, preserving agents, salts for influencing osmotic pressure, buffers, sweetening agents, flavoring agents, colorants, or any combination of the foregoing. The pharmaceutical composition of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the subject by employing procedures known in the art. The pharmaceutical compositions described herein may be prepared by conventional techniques known in the art. For example, the active compound can be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier, which may be in the form of an ampoule, capsule, sachet, paper, or other container. When the carrier serves as a diluent, it may be a solid, semi-solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound. The active compound can be adsorbed on a granular solid container, for Example, in a sachet. The pharmaceutical compositions may be in conventional forms, for example, capsules, tablets, caplets, orally disintegrating tablets, aerosols, solutions, suspensions or products for topical application. The route of administration may be any route which effectively transports the active compound of the invention to the appropriate or desired site of action. Suitable routes of administration include, but are not limited to, oral, oral inhalation, nasal, pulmonary, buccal, subdermal, intradermal, transdermal, parenteral, rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic (such as with an ophthalmic solution) or topical (such as with a topical ointment). Solid oral formulations include, but are not limited to, tablets, caplets, capsules (soft or hard gelatin), orally disintegrating tablets, dragees (containing the active ingredient in powder or pellet form), troches and lozenges. Tablets, dragees, or capsules having talc and / or a carbohydrate carrier or binder or the like are particularly suitable for oral application. Liquid formulations include, but are not limited to, syrups, emulsions, suspensions, solutions, soft gelatin and sterile injectable liquids, such as aqueous or non- aqueous liquid suspensions or solutions. For parenteral application, particularly suitable are injectable solutions or suspensions, preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil. The pharmaceutical preparation is preferably in unit dosage form. In such form the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as pocketed tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, caplet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form. For administration to subject patients, the total daily dose of the compounds of the invention depends, of course, on the mode of administration. For example, oral administration may require a higher total daily dose, than an intravenous (direct into blood). The quantity of active component in a unit dose preparation may be varied or adjusted from 0.1 mg to 1000 mg by oral administration and 1 µg to 5000 µg by inhalation according to the potency of the active component or mode of administration. Those skilled in the relevant art can determine suitable doses of the compounds for use in treating the diseases and disorders described herein. Therapeutic doses are generally identified through a dose ranging study in subject based on preliminary evidence derived from the animal studies. Doses must be sufficient to result in a desired therapeutic benefit without causing unwanted side effects for the patient. For example, the daily dosage of the PRMT5 inhibitor can range from about 0.1 to about 30.0 mg / kg by oral administration. Mode of administration, dosage forms, suitable pharmaceutical excipients, diluents or carriers can also be well used and adjusted by those skilled in the art. All changes and modifications envisioned are within the scope of the invention. Methods of Treatment The invention provides compound of formula (I) and pharmaceutical compositions thereof as protein arginine methyl transferase-5 (PRMT5) inhibitors for treating the diseases, disorders or conditions associated with overexpression of PRMT5. The invention further provides a method of treating diseases, disorders or conditions associated with overexpression of PRMT5 in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound or a pharmaceutical composition of the invention. In another aspect, the invention relates to a method of treating diseases, disorders or conditions associated with the overexpression of PRMT5. In this method, a subject in need of such treatment is administered a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein. In one embodiment of the present invention, the diseases, disorders, or conditions associated with the overexpression of PRMT5 are cancer. In another embodiment, the invention provides a method of treating cancers, particularly, glioblastoma multiforme, prostate cancer, pancreatic cancer, mantle cell lymphoma, non-Hodgkin's 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 cancer, melanoma, sarcoma, oropharyngeal squamous cell carcinoma, chronic myelogenous leukemia, epidermal squamous cell carcinoma, nasopharyngeal carcinoma, neuroblastoma, endometrial carcinoma, and cervical cancer. It is to be understood that the invention encompasses the compounds of formula (I) or pharmaceutically acceptable salts thereof for use in the treatment of a disease or disorder mentioned herein. It is to be understood that the invention encompasses the compounds of formula (I) or pharmaceutically acceptable salts thereof in the manufacture of a medicament for treating a disease or disorder mentioned herein. General Methods of Preparation The compound of formula described herein may be prepared by techniques known in the art. In addition, the compound of formula described herein may be prepared by following the reaction sequence as depicted in Scheme-1 to Scheme-27. Further, in the following schemes, where specific bases, acids, reagents, solvents, coupling agents, etc., are mentioned, it is understood that other bases, acids, reagents, solvents, coupling agents etc., known in the art may also be used and are therefore included within the scope of the present invention. Variations in reaction conditions, for example, temperature and / or duration of the reaction, which may be used as known in the art, are also within the scope of the present invention. All the isomers of the compound of formula in described in these schemes, unless otherwise specified, are also encompassed within the scope of this invention. Scheme-1: [Image disponible dans le document PDF, Image available in the PDF document] Scheme-1 illustrates the synthesis of compound of formula 10 (when Q<com:Sup>1< / com:Sup> is N, CH or CX, where X can be Cl or Br). Compound of formula 1 (where PG = Protecting group), is prepared by following the procedure reported in Kenneth A. Jacobson et.al; Purinergic Signalling (2015) 11:371–387. Mitsunobu reaction of compound of formula 1 with compound of formula <com:Math><semantics>2(X=−Cl,−Br)<annotation encoding="application / x-tex">2 (X = -Cl, -Br)< / annotation>< / semantics>< / com:Math> using various azo dicarboxylate reagents such as but not limited to DEAD or DIAD in presence of phosphine such as but not limited to PPh<com:Sub>3< / com:Sub> to form the compound of formula 3. Compound of formula 4 is formed upon treatment of compound of formula 3 with fluoride ions such as but not limited to TBAF. Oxidation of compound of formula 4 with oxidising agents such as but not limited to Dess-Martin periodinane can furnish the compound of formula 5. Reagents such as but not limited to methyltriphenylphosphonium bromide in presence of a base such as but not limited to KO<com:Sup>t< / com:Sup>Bu, NaO<com:Sup>t< / com:Sup>Bu, LiHMDS, NaHMDS, or KHMDS when treated with compound of formula 5 affords compound of formula 6. Compound of formula 6a (where R<com:Sup>4< / com:Sup> and R<com:Sup>5< / com:Sup> are defined herein above) upon treatment with compound of formula 6 affords compound of formula 7. Compound of formula 9 can be achieved by hydroboration of compound of formula 7 with suitable boranes such as but not limited to 9-BBN followed by addition of inorganic base such as but not limited to K<com:Sub>3< / com:Sub>PO<com:Sub>4< / com:Sub> or Cs<com:Sub>2< / com:Sub>CO<com:Sub>3< / com:Sub>, in presence of Pd catalyst such as but not limited to <com:Math><semantics>Pd(dppf)Cl2<annotation encoding="application / x-tex">Pd(dppf)Cl_2< / annotation>< / semantics>< / com:Math> or <com:Math><semantics>Pd(PPh3)2Cl2<annotation encoding="application / x-tex">Pd(PPh_3)_2Cl_2< / annotation>< / semantics>< / com:Math> and compound of formula 8 (Y = -Br, - I, which can be prepared by following the procedure reported J. Med. Chem., 2017, 60 (9), 3958-3978). Acetonide deprotection of compound of formula 9 with acids such as but not limited to HCl or TFA affords compound of formula 10. Scheme-2: [Image disponible dans le document PDF, Image available in the PDF document] Scheme-2 illustrates the synthesis of compound of formula 16. This can be achieved by Mitsunobu reaction of compound of formula 1a, which is prepared by following the procedure reported in Kenneth A. Jacobson et.al; Purinergic Signalling (2015) 11:371–387, with compound of formula 2 using various azo dicarboxylate reagents such as but not limited to DIAD in presence of phosphine such as but not limited to PPh<com:Sub>3< / com:Sub> to form the compound of formula 11, which can be further converted to compound of formula 12 upon treatment with fluoride ions such as but not limited to TBAF. Mitsunobu reaction of compound of formula 12 with compound of formula 13 (commercially available or synthesized as per known literature, where <com:Math><semantics>Q1=C<annotation encoding="application / x-tex">Q^1 = C< / annotation>< / semantics>< / com:Math> or N, <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics>< / com:Math> are defined herein above) using various azo dicarboxylate reagents such as but not limited to DIAD in presence of phosphine such as but not limited to PPh<com:Sub>3< / com:Sub> affords the compound of formula 14. Compound of formula 6a upon treatment with compound of formula 14 affords compound of formula 15. Acetonide deprotection of compound of formula 15 with acids such as but not limited to HCl or TFA affords compound of formula 16. Scheme-3: [Image disponible dans le document PDF, Image available in the PDF document] Scheme-3 illustrates the synthesis of compound of formula 21. Compound of formula 17 is formed upon treatment of compound of formula 12 with oxidising agents such as but not limited to Dess-Martin periodinane. Reagents such as but not limited to methyltriphenylphosphonium bromide in presence of a base such as but not limited to KO<com:Sup>t< / com:Sup>Bu, NaO<com:Sup>t< / com:Sup>Bu, LiHMDS, NaHMDS, or KHMDS when treated with compound of formula 17 affords compound of formula 18. Compound of formula 19 can be synthesized by hydroboration of compound of formula 18 with suitable boranes such as but not limited to 9-BBN followed by addition of inorganic base such as but not limited to tripotassium phosphate or Cs<com:Sub>2< / com:Sub>CO<com:Sub>3< / com:Sub>, in presence of Pd catalyst such as but not limited to Pd(dppf)Cl<com:Sub>2< / com:Sub> or <com:Math><semantics>Pd(PPh3)2Cl2<annotation encoding="application / x-tex">Pd(PPh_3)_2Cl_2< / annotation>< / semantics>< / com:Math> and compound of formula 8 (Y = -Br, -I), which was synthesized by following the procedure reported in WO2012002577 A1, followed by N-oxide formation, chlorination with phosphoroxychloride and nucleophilic substitution with PMB-NH<com:Sub>2< / com:Sub> or J. Med. Chem, 2017, 60 (9), 3958-3978). Compound of formula 6a (where R<com:Sup>4< / com:Sup> and R<com:Sup>5< / com:Sup> are defined herein above) upon treatment with compound of formula 19 affords compound of formula 20. Acetonide deprotection of compound of formula 20 with acids such as but not limited to HCl or TFA affords compound of formula 21. 5 Scheme-4: [Image disponible dans le document PDF, Image available in the PDF document] Scheme-4 illustrates the synthesis of compound of formula 27. Compound of formula 22 is formed upon treatment of compound of formula 5 with Grignard reagent such as but not limited to methylmagnesium bromide, ethylmagnesium bromide, cyclopropylmagnesium bromide etc. Compound of formula 22 on oxidation with oxidising agents such as but not limited to Dess-Martin periodinane gives compound of formula 23. Reagents such as but not limited to methyltriphenylphosphonium bromide in presence of base such as but not limited to KO<com:Sup>t< / com:Sup>Bu, NaO<com:Sup>t< / com:Sup>Bu, LiHMDS, NaHMDS, or KHMDS when treated with compound of formula 23 affords compound of formula 24. Compound of formula 25 can be achieved by hydroboration of compound of formula 24 with suitable boranes such as but not limited to 9-BBN followed by addition of inorganic base such as but not limited to tripotassium phosphate or Cs<com:Sub>2< / com:Sub>CO<com:Sub>3< / com:Sub>, in presence of Pd catalyst such as but not limited to <com:Math><semantics>Pd(dppf)Cl2<annotation encoding="application / x-tex">Pd(dppf)Cl_2< / annotation>< / semantics>< / com:Math> or <com:Math><semantics>Pd(PPh3)2Cl2<annotation encoding="application / x-tex">Pd(PPh_3)_2Cl_2< / annotation>< / semantics>< / com:Math> and compound of formula 8 (Y = -Br, -I), which was synthesized by following the procedure reported in WO2012002577 A1, followed by N-oxide formation, chlorination with Phosphoroxychloride, and nucleophilic substitution with PMB-NH<com:Sub>2< / com:Sub> or J.Med.Chem, 2017, 60 (9), 3958-3978). Compound of formula 6a (where R<com:Sub>4< / com:Sub> and R<com:Sub>5< / com:Sub> are defined herein above) upon treatment with compound of formula 25 affords compound of formula 26. Acetonide deprotection of compound of formula 26 with acids such as but not limited to HCl or TFA affords compound of formula 27. Scheme-5: [Image disponible dans le document PDF, Image available in the PDF document] Scheme-5 illustrates the synthesis of compound of formula 32. Compound of formula 28 is formed upon treatment of compound of formula 5 with Wittig reagents such as but not limited to (1-iodoethyl) triphenylphosphonium bromide. Compound of formula 29 can be achieved by Suzuki coupling of compound of formula 28 with suitable inorganic base such as but not limited to tripotassium phosphate or Cs<com:Sub>2< / com:Sub>CO<com:Sub>3< / com:Sub>, in presence of Pd catalyst such as but not limited to Pd(PPh<com:Sub>3< / com:Sub>)<com:Sub>4< / com:Sub>, Pd(dppf)Cl<com:Sub>2< / com:Sub> or Pd(PPh<com:Sub>3< / com:Sub>)<com:Sub>2< / com:Sub>Cl<com:Sub>2< / com:Sub> and compound of formula 8a (Y = -Br, -I). Compound of formula 6a (where <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math> are defined herein above) upon treatment with compound of formula 29 affords compound of formula 30. Hydrogenation of compound of formula 30 affords compound of formula 31. Acetonide deprotection of compound of formula 31 with acids such as but not limited to HCl or TFA affords compound of formula 32. Scheme-6: [Image disponible dans le document PDF, Image available in the PDF document] . . Compound of formula-33 (can be synthesized by following the protocol as mentioned in Med. Chem. Comm.; vol. 4; nb. 5; (2013); p. 822 - 826) upon treatment with iodine in presence of pyridine affords Compound of formula-34, which can be reduced by cerium chloride and sodium borohydride to get compound of formula-35. Mitsunobu reaction using compound of formula-2 with compound of formula-35 provides the compound of formula-36. Halogen of compound of formula-36 on substitution with PMB amine, followed by Suzuki reaction affords the compound of formula-38. TBDMS deprotection of compound of formula-38 followed by tosylation of compound of formula-39 provides compound of formula-40. The tosyl of compound of formula-40 is replaced with compound of formula-13 gives the compound of formula-41, which is further deprotected in acidic condition to get the final compound of formula -42. Scheme-7: [Image disponible dans le document PDF, Image available in the PDF document] Reaction of compound of formula-43 [can be prepared by method reported in <com:Math><semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics>< / com:Math>. Org. Chem. 2014, 79, 8059-8066] with methyl magnesium bromide gives compound of formula-44, with only one stereoisomer with good yield. This when subjected to acetonide shuffling affords compound of formula-46. Mitsunobu reaction using compound of formula 2 with compound of formula-46 yields the compound of formula-47, which can be converted to compound of formula-48 on treating with TBAF. Compound of formula-48 can be oxidized with DMP to afford Compound of formula-49, which can undergo Witting reaction to give compound of formula-50. Compound of formula 51 can be achieved by hydroboration of compound of formula 50 with suitable boranes such as but not limited to 9-BBN followed by addition of inorganic base such as but not limited to K<com:Sub>3< / com:Sub>PO<com:Sub>4< / com:Sub> or Cs<com:Sub>2< / com:Sub>CO<com:Sub>3< / com:Sub>, in presence of Pd catalyst such as but not limited to Pd(dppf)Cl<com:Sub>2< / com:Sub> or Pd(PPh<com:Sub>3< / com:Sub>)<com:Sub>2< / com:Sub>Cl<com:Sub>2< / com:Sub> and compound of formula 8. Compound of formula-51 on treating with aq. ammonia followed by treatment with trifluroacetic acid affords compound of formula-53. Scheme-8: [Image disponible dans le document PDF, Image available in the PDF document] i) Oxidation<com:Br / >ii) Grignard - . deprotection Compound of formula-48 (compound of formula 48a can be synthesized from 48 by oxidation and Grignard reaction) when condensed with compound of formula-13 using Mitsunobu reaction affords compound of formula-54, which can be reacted with ammonia followed by treatment with trifluroacetic acid to provide a compound of formula 56. Scheme-9: [Image disponible dans le document PDF, Image available in the PDF document] 6-Halo-oxindole on treatment with a base, and methyl iodide or diiodopropane or appropriately substituted dihalide provides compound of formula-57. Compound of formula 57 when treated with Lawesson's reagent in hydrocarbon solvent such as but not limited to toluene at 100°C for 3h gives compound of formula-58, which is then treated with sodium hydride followed by methyl iodide in THF to yield compound of formula 59. Compound of formula 59 on treating with 7N ammonia in methanol at 100°C for 16h provides compound of formula-60. Scheme-10: [Image disponible dans le document PDF, Image available in the PDF document] Hydroboration of compound of formula-18 with 9-BBN followed Suzuki coupling with compound of formula-59 in presence of Pd-118 or PdCl<com:Sub>2< / com:Sub>dppf in THF / H<com:Sub>2< / com:Sub>O at 50-70°C for 5-16h provide compound of formula-61, which is then treated with compound of formula- 6a followed by TFA to give compound of formula 63. Scheme-11: [Image disponible dans le document PDF, Image available in the PDF document] Hydroboration of compound of formula-7 with 9-BBN followed Suzuki coupling with compound of formula-59 in presence of Pd-118 or PdCl<com:Sub>2< / com:Sub>dppf in THF / H<com:Sub>2< / com:Sub>O at 50-70°C for 5-16h affords compound of formula-64, which is then treated with compound of formula- 6a followed by TFA to afford compound of formula 66. Scheme-12: [Image disponible dans le document PDF, Image available in the PDF document] Hydroboration of compound of formula-18 with 9-BBN followed Suzuki coupling with compound of formula-67 in presence of Pd-118 in THF / H<com:Sub>2< / com:Sub>O at 50°C for 5-16h affords compound of formula-68, which is when treated with compound of formula-6a followed by TFA affords compound of formula-70. Hydroboration of compound of formula-7 with 9-BBN followed Suzuki coupling with compound of formula-67 in presence of Pd-118 or PdCl<com:Sub>2< / com:Sub>dppf in THF / H<com:Sub>2< / com:Sub>O at 50-70°C for 5-16h affords compound of formula-71, which is when treated with TFA affords compound of formula-72. Scheme-13: [Image disponible dans le document PDF, Image available in the PDF document] Hydroboration of compound of formula-6 with 9-BBN followed by Suzuki coupling of compound of formula 8 in presence of Pd-118 or PdCl<com:Sub>2< / com:Sub>dppf in THF / H<com:Sub>2< / com:Sub>O at 50-70°C for 5-16h affords compound of formula 73, which is when treated with compound of formula- 6a followed by treatment with TFA affords compound of formula 75. Scheme-14: [Image disponible dans le document PDF, Image available in the PDF document] 1 Compound of formula-17 when treated with methylmagnesium bromide in THF gives compound of formula-76, which can be oxidized by DMP in methylene chloride at 0°C to afford compound of formula-77. Addition of methylmagnesium bromide on compound of formula-77 provides compound of formula-78. Dehydration of compound of formula-78 with Martin Sulfurane gives compound of formula-79, which then treated with 9-BBN followed by Suzuki coupling with compound of formula-8 in presence of Pd-118 or PdCl<com:Sub>2< / com:Sub>dppf in THF / H<com:Sub>2< / com:Sub>O at 50-70°C for 5-16h affords compound of formula-80. Treating compound of formula-80 with compound of formula 6a followed by treatment with TFA affords compound of formula-82. Scheme-15: [Image disponible dans le document PDF, Image available in the PDF document] Compound of formula-11 on treatment with trimethylboroxine in presence of tripotassium phosphate, and Pd-118 or PdCl<com:Sub>2< / com:Sub>dppf gives mixture of compound of formula-83 and compound of formula-84. The PG of compound of formula-83 can be deprotected to afford compound of formula-85, which on oxidation with DMP gives compound of formula-86. Wittig reaction of compound of formula-86 provides compound of formula-87. Hydroboration of compound of formula-87 with 9-BBN followed by Suzuki coupling with compound of formula-8 in presence of Pd-118 or PdCl<com:Sub>2< / com:Sub>dppf in THF / H<com:Sub>2< / com:Sub>O at 50-70°C for 5- 16h affords compound of formula-88, which when treated with TFA affords compound of formula-89. Scheme-16: [Image disponible dans le document PDF, Image available in the PDF document] The protecting group of compound of formula-84 can be deprotected to afford compound of formula-90, which on oxidation with DMP gives compound of formula-91. Wittig reaction of compound of formula-91 provides compound of formula-92. Hydroboration of compound of formula-92 with 9-BBN followed by Suzuki coupling with compound of formula-8 in presence of Pd-118 or PdCl<com:Sub>2< / com:Sub>dppf in THF / H<com:Sub>2< / com:Sub>O at 50-70°C for 5-16h affords compound of formula-93, which is then treated with TFA to afford compound of formula 94. Scheme-17: [Image disponible dans le document PDF, Image available in the PDF document] Reductive amination of compound of formula-17 with compound of formula-95 affords compound of formula-96, which is then treated with compound of formula-6a followed by treatment with TFA to afford compound of formula-98. Scheme-18: [Image disponible dans le document PDF, Image available in the PDF document] 15 Compound of formula-12 is treated with TsCl / MsCl in presence of a base to give a compound of formula -99, which is then reacted with compound of formula-100 to yield compound of formula -101. Reaction of compound of formula-101 with compound of formula-6a followed by treatment with TFA affords compound of formula-103. Scheme-19: [Image disponible dans le document PDF, Image available in the PDF document] Compound of formula-99 is reacted with compound of formula-104 in presence of a base such as but not limited to cesium carbonate to afford a compound of formula-105. Substitution reaction of compound of formula-105 with compound of formula-6a followed by treatment with TFA affords compound of formula-107. Scheme-20: [Image disponible dans le document PDF, Image available in the PDF document] The compound of formula-109 can be synthesized by Mitsunobu reaction of compound of formula 1a with compound of formula 108 using various azo dicarboxylate reagents such as but not limited to DIAD in presence of phosphine such as but not limited to PPh<com:Sub>3< / com:Sub>. Compound of formula-109 can be further converted to compound of formula 110 upon treatment with fluoride ions such as but not limited to TBAF. Oxidation followed by Wittig reaction on compound of formula 110 gives compound of formula 112. The aromatic halogen of compound of formula 112 can be converted to alkyl groups such as a methyl group using Pd-118 or PdCl<com:Sub>2< / com:Sub>dppf with trimethylboroxine to afford compound of formula 113. Hydroboration of compound of formula-113 with 9-BBN followed by Suzuki coupling 43 with compound of formula-8 in presence of Pd-118 or PdCl<com:Sub>2< / com:Sub>dppf in THF / H<com:Sub>2< / com:Sub>O at 50-70°C for 5-16h affords compound of formula-114, which when treated with TFA or HCl / MeOH affords compound of formula-115. Scheme-21: [Image disponible dans le document PDF, Image available in the PDF document] Mitsunobu reaction of compound of formula 4 (can be prepared from compound of formula 1 as described in scheme 1) with compound of formula 13 using various azo dicarboxylate reagents such as but not limited to DIAD in presence of phosphine such as but not limited to PPh<com:Sub>3< / com:Sub> provides compound of formula 116. Compound of formula-116 on treating compound of formula 6a followed by treatment with trifluroacetic acid affords compound of formula-118. Scheme-22: [Image disponible dans le document PDF, Image available in the PDF document] Scheme-22 illustrates the synthesis of compound of formula 126. Compound of formula 119 (where PG = Protecting group), is prepared by Simmon Smith reaction. Mitsunobu reaction of compound of formula 119 with compound of formula 2 (<com:Math><semantics>X=−Cl<annotation encoding="application / x-tex">X = -Cl< / annotation>< / semantics>< / com:Math>, -Br) using various azo dicarboxylate reagents such as but not limited to DEAD or DIAD in presence of phosphine such as but not limited to PPh<com:Sub>3< / com:Sub> to form the compound of formula 120. Compound of formula 121 is formed upon treatment of compound of formula 120 with fluoride ions such as but not limited to TBAF. Oxidation of compound of formula 121 with oxidising agents such as but not limited to Dess-Martin periodinane can furnish the compound of formula 122. Reagents such as but not limited to methyltriphenylphosphonium bromide in presence of a base such as but not limited to KOtBu, NaOtBu, LiHMDS, NaHMDS, or KHMDS when treated with compound of formula 122 affords compound of formula 123. Amine of formula 6a (where R<com:Sub>4< / com:Sub> and R<com:Sub>5< / com:Sub> are defined herein above) upon treatment with compound of formula 123 affords compound of formula 124. Compound of formula 125 can be achieved by hydroboration of compound of formula 124 with suitable boranes such as but not limited to 9-BBN followed by addition of inorganic base such as but not limited to K<com:Sub>3< / com:Sub>PO<com:Sub>4< / com:Sub> or Cs<com:Sub>2< / com:Sub>CO<com:Sub>3< / com:Sub>, in presence of Pd catalyst such as but not limited to <com:Math><semantics>Pd(dppf)Cl2<annotation encoding="application / x-tex">Pd(dppf)Cl_2< / annotation>< / semantics>< / com:Math> or <com:Math><semantics>Pd(PPh3)2Cl2<annotation encoding="application / x-tex">Pd(PPh_3)_2Cl_2< / annotation>< / semantics>< / com:Math> and compound of formula 8 (Y = - Br, -I, which can be prepared by following the procedure reported J. Med. Chem., 2017, 60 (9), 3958-3978). Acetonide deprotection of compound of formula 125 with acids such as but not limited to HCl or TFA affords compound of formula 126. Scheme-23: [Image disponible dans le document PDF, Image available in the PDF document] Suzuki coupling of compound of formula 10 with aryl or heteroaryl boronic acid or ester in presence of Pd(PPh<com:Sub>3< / com:Sub>)<com:Sub>4< / com:Sub> or Pd-118 or PdCl<com:Sub>2< / com:Sub>dppf in dioxane at 80-100°C for 5-16h affords compound of formula-127. Scheme-24: [Image disponible dans le document PDF, Image available in the PDF document] Compound of formula-18 when treated with compound of formula-128 using Suzuki coupling affords compound of formula-129. Compound of formula 130 can be achieved by hydroboration of compound of formula 129 with suitable boranes such as but not limited to 9-BBN followed by addition of inorganic base such as but not limited to K<com:Sub>3< / com:Sub>PO<com:Sub>4< / com:Sub> or Cs<com:Sub>2< / com:Sub>CO<com:Sub>3< / com:Sub>, in presence of Pd catalyst such as but not limited to Pd(dppf)Cl<com:Sub>2< / com:Sub> or Pd(PPh<com:Sub>3< / com:Sub>)<com:Sub>2< / com:Sub>Cl<com:Sub>2< / com:Sub> and compound of formula <com:Math><semantics>8(Y=−Br,−I,whichcanbepreparedbyfollowingtheprocedure<annotation encoding="application / x-tex">8 (Y = -Br, -I, which can be prepared by following the procedure< / annotation>< / semantics>< / com:Math> reported J. Med. Chem., 2017, 60 (9), 3958-3978). Acetonide deprotection of compound of formula 130 with acids such as but not limited to HCl or TFA affords compound of formula 131. Scheme-25: [Image disponible dans le document PDF, Image available in the PDF document] 134 Compound of formula-76 when condensed with compound of formula-13 using Mitsunobu reaction affords compound of formula-132, which can be reacted with compound of formula-6a followed by treatment with trifluroacetic acid to provide a compound of formula-134. Scheme-26: [Image disponible dans le document PDF, Image available in the PDF document] Compound of formula-48a when treated DMP in methylene chloride at 0°C to afford compound of formula -135, which when react with methylmagnesium bromide in THF gives compound of formula-136. Dehydration of compound of formula-136 with Martin Sulfurane gives compound of formula-137, which then treated with 9-BBN followed by Suzuki coupling with compound of formula-8 in presence of Pd-118 or PdCl<com:Sub>2< / com:Sub>dppf in THF / H<com:Sub>2< / com:Sub>O at 50-70°C for 5-16h affords compound of formula-138. Treating compound of formula-138 with compound of formula 6a followed by treatment with TFA affords compound of formula-140. Scheme-27: [Image disponible dans le document PDF, Image available in the PDF document] - - - Compound of formula-4 is treated with TsCl / MsCl in presence of a base to give a compound of formula 141. Compound of formula-141 is reacted with compound of formula-104 in presence of a base such as but not limited to cesium carbonate to afford a compound of formula -142. Substitution reaction of compound of formula-142 with compound of formula-6a followed by treatment with TFA affords compound of formula- 144. Abbreviations The following abbreviations may be used herein: <com:Math><semantics>AcOH=Aceticacid<annotation encoding="application / x-tex">AcOH = Acetic acid< / annotation>< / semantics>< / com:Math> Aq.= aqueous ca = about or approximately <com:Math><semantics>NH4Cl=Ammoniumchloride<annotation encoding="application / x-tex">NH_4Cl = Ammonium chloride< / annotation>< / semantics>< / com:Math> 9-BBN = 9-Borabicyclononane BINAP = 2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl <com:Math><semantics>Boc=tert<annotation encoding="application / x-tex">Boc = tert< / annotation>< / semantics>< / com:Math>-Butoxycarbonyl <com:Math><semantics>t<annotation encoding="application / x-tex">t< / annotation>< / semantics>< / com:Math>-Bu or <com:Math><semantics>t<annotation encoding="application / x-tex">t< / annotation>< / semantics>< / com:Math>Bu = <com:Math><semantics>tert<annotation encoding="application / x-tex">tert< / annotation>< / semantics>< / com:Math>-Butyl 47 <com:Math><semantics>Cs2CO3=CesiumCarbonate<annotation encoding="application / x-tex">Cs_2CO_3 = Cesium Carbonate< / annotation>< / semantics>< / com:Math> <com:Math><semantics>CHCl3=Chloroform<annotation encoding="application / x-tex">CHCl_3 = Chloroform< / annotation>< / semantics>< / com:Math> CDCl<com:Sub>3< / com:Sub> = Deuterated chloroform DAST = Diethylaminosulphur trifluoride 5 dba = Dibenzylideneacetone <com:Math><semantics>CH2Cl2<annotation encoding="application / x-tex">CH_2Cl_2< / annotation>< / semantics>< / com:Math> or <com:Math><semantics>DCM=Dichloromethane<annotation encoding="application / x-tex">DCM = Dichloromethane< / annotation>< / semantics>< / com:Math> DMP = Dess Martin Periodinane DEAD = Diethyl azodicarboxylate DIAD = Diisopropyl azodicarboxylate 10 DIPEA = Diisopropylethylamine <com:Math><semantics>DMAP=4<annotation encoding="application / x-tex">DMAP = 4< / annotation>< / semantics>< / com:Math>-Dimethylaminopyridine <com:Math><semantics>DMF=N,N<annotation encoding="application / x-tex">DMF = N, N< / annotation>< / semantics>< / com:Math>-Dimethylformamide DMSO = Dimethylsulphoxide <com:Math><semantics>DMSO−d6=Deuterateddimethylsulphoxide<annotation encoding="application / x-tex">DMSO-d_6 = Deuterated dimethylsulphoxide< / annotation>< / semantics>< / com:Math> 15 <com:Math><semantics>Et=ethyl<annotation encoding="application / x-tex">Et = ethyl< / annotation>< / semantics>< / com:Math> <com:Math><semantics>EtOH=Ethanol<annotation encoding="application / x-tex">EtOH = Ethanol< / annotation>< / semantics>< / com:Math> <com:Math><semantics>EtOAc=Ethylacetate<annotation encoding="application / x-tex">EtOAc = Ethyl acetate< / annotation>< / semantics>< / com:Math> <com:Math><semantics>g=gram<annotation encoding="application / x-tex">g = gram< / annotation>< / semantics>< / com:Math> <com:Math><semantics>H2O2<annotation encoding="application / x-tex">H_2O_2< / annotation>< / semantics>< / com:Math> = Hydrogen peroxide 20 <com:Math><semantics>H2SO4=Sulphuricacid<annotation encoding="application / x-tex">H_2SO_4 = Sulphuric acid< / annotation>< / semantics>< / com:Math> <com:Math><semantics>K2CO3<annotation encoding="application / x-tex">K_2CO_3< / annotation>< / semantics>< / com:Math> = Potassium carbonate KOH = Potassium hydroxide KO<com:Sup>t< / com:Sup>Bu = Potassium tert-butoxide <com:Math><semantics>K3PO4<annotation encoding="application / x-tex">K_3PO_4< / annotation>< / semantics>< / com:Math> = Potassium phosphate 25 KHMDS = Potassium bis(trimethylsilyl)amide LDA = Lithium diisopropylamide LHMDS = Lithium bis(trimethylsilyl)amide LCMS = Liquid chromatography mass spectrometry m-CPBA = meta-chloroperoxybenzoic acid 30 <com:Math><semantics>mg=milligram<annotation encoding="application / x-tex">mg = milligram< / annotation>< / semantics>< / com:Math> <com:Math><semantics>Me=Methyl<annotation encoding="application / x-tex">Me = Methyl< / annotation>< / semantics>< / com:Math> <com:Math><semantics>MeOH=Methanol<annotation encoding="application / x-tex">MeOH = Methanol< / annotation>< / semantics>< / com:Math> MeOD = Deuterated methanol MS = Molecular sieves MsCl = Methanesulphonyl chloride <com:Math><semantics>MgSO4=Magnesiumsulphate<annotation encoding="application / x-tex">MgSO_4 = Magnesium sulphate< / annotation>< / semantics>< / com:Math> 5 NaH = Sodium hydride NaO<com:Sup>t< / com:Sup>Bu = Sodium tert-butoxide NaHCO<com:Sub>3< / com:Sub> = Sodium bicarbonate <com:Math><semantics>Na2SO4=Sodiumsulphate<annotation encoding="application / x-tex">Na_2SO_4 = Sodium sulphate< / annotation>< / semantics>< / com:Math> <com:Math><semantics>Na2S2O3=Sodiumthiosulphate<annotation encoding="application / x-tex">Na_2S_2O_3 = Sodium thiosulphate< / annotation>< / semantics>< / com:Math> 10 <com:Math><semantics>Na2SO3=Sodiumsulphite<annotation encoding="application / x-tex">Na_2SO_3 = Sodium sulphite< / annotation>< / semantics>< / com:Math> NaHMDS = Sodium bis(trimethylsilyl)amide <com:Math><semantics>NMP=N−Methyl−2−pyrrolidone<annotation encoding="application / x-tex">NMP = N-Methyl-2-pyrrolidone< / annotation>< / semantics>< / com:Math> <com:Math><semantics>NBS=N<annotation encoding="application / x-tex">NBS = N< / annotation>< / semantics>< / com:Math>-Bromosuccinimide <com:Math><semantics>NCS=N<annotation encoding="application / x-tex">NCS = N< / annotation>< / semantics>< / com:Math>-Chlorosuccinimide 15 NIS = N-Iodosuccinimide NMO = N-Methylmorpholine-N-oxide NMR = Nuclear magnetic resonance <com:Math><semantics>Ph=phenyl<annotation encoding="application / x-tex">Ph = phenyl< / annotation>< / semantics>< / com:Math> PDC = Pyridinium dichlorochromate 20 <com:Math><semantics>Pd(OAc)2=Palladiumacetate<annotation encoding="application / x-tex">Pd(OAc)_2 = Palladium acetate< / annotation>< / semantics>< / com:Math> <com:Math><semantics>Pd / C=Palladiumoncarbon<annotation encoding="application / x-tex">Pd / C = Palladium on carbon< / annotation>< / semantics>< / com:Math> Pd-118 = [1,1'-Bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) <com:Math><semantics>Pd(PPh3)4=Tetrakis(triphenylphosphine)palladium(0)<annotation encoding="application / x-tex">Pd(PPh_3)_4 = Tetrakis(triphenylphosphine)palladium(0)< / annotation>< / semantics>< / com:Math> POCl<com:Sub>3< / com:Sub> = Phosphorous oxychloride 25 <com:Math><semantics>PdCl2(dppf)=[1,1′−Bis(diphenylphosphino)ferrocene]dichloropalladium(II)<annotation encoding="application / x-tex">PdCl_2(dppf) = [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)< / annotation>< / semantics>< / com:Math> <com:Math><semantics>Pd(PPh3)2Cl2=Bis(triphenylphosphine)palladium(II)dichloride<annotation encoding="application / x-tex">Pd(PPh_3)_2Cl_2 = Bis(triphenylphosphine)palladium(II) dichloride< / annotation>< / semantics>< / com:Math> PCC = Pyridinium chlorochromate <com:Math><semantics>PMB=p−Methoxybenzyl<annotation encoding="application / x-tex">PMB = p-Methoxybenzyl< / annotation>< / semantics>< / com:Math> PTSA = p-Toluenesulphonic acid 30 <com:Math><semantics>Rt=Retentiontime<annotation encoding="application / x-tex">Rt = Retention time< / annotation>< / semantics>< / com:Math> rt = room temperature Sat.= saturated SFC = Supercritical fluid chromatography TLC = Thin layer chromatography TBAF = Tetrabutylammonium fluoride TsCl = p-Toluenesulphonyl chloride TBDMS = tert-Butyldimethylsilyl TBDPS = tert-Butyldiphenylsilyl <com:Math><semantics>Et3N<annotation encoding="application / x-tex">Et_3N< / annotation>< / semantics>< / com:Math> or <com:Math><semantics>NEt3<annotation encoding="application / x-tex">NEt_3< / annotation>< / semantics>< / com:Math> or <com:Math><semantics>TEA=Triethylamine<annotation encoding="application / x-tex">TEA = Triethylamine< / annotation>< / semantics>< / com:Math> TFA = Trifluoroacetic acid THF = Tetrahydrofuran <com:Math><semantics>Ts=p<annotation encoding="application / x-tex">Ts = p< / annotation>< / semantics>< / com:Math>-Toluenesulphonyl p-TsOH = p-Toluenesulphonic acid INTERMEDIATES 7-Bromoquinolin-2-amine [Image disponible dans le document PDF, Image available in the PDF document] The title compound was prepared by following an analogous reaction protocol as described in Cinelli, Maris A et al, Journal of Medicinal Chemistry, 2017, vol. 60, #9, p. 3958 - 3978. 7-Bromo-N-(4-methoxybenzyl)quinolin-2-amine [Image disponible dans le document PDF, Image available in the PDF document] The title compound was prepared by following an analogous reaction protocol as described in Arnould, Jean-Claude et al, WO 2007 / 141473 A1. 7-Bromo-N-methylquinolin-2-amine [Image disponible dans le document PDF, Image available in the PDF document] The title compound was prepared by following same reaction protocol as described in Arnould, Jean-Claude et al, WO 2007 / 141473 A1. 7-Bromo-N-isopropylquinolin-2-amine [Image disponible dans le document PDF, Image available in the PDF document] The title compound was prepared by following an analogous reaction protocol as described in Arnould, Jean-Claude et al, WO 2007 / 141473 A1. 7-Bromo-N-cyclobutylquinolin-2-amine [Image disponible dans le document PDF, Image available in the PDF document] The title compound was prepared by following an analogous reaction protocol as described in Arnould, Jean-Claude et al, WO 2007 / 141473 A1. 7-Bromo-N-(cyclopropylmethyl)quinolin-2-amine [Image disponible dans le document PDF, Image available in the PDF document] The title compound was prepared by following analogous reaction protocol as described in Arnould, Jean-Claude et al, WO 2007 / 141473 A1. 7-Bromo-2-chloro-8-fluoroquinoline [Image disponible dans le document PDF, Image available in the PDF document] The title compound was prepared by following same reaction protocol as described in Aciro, Caroline et al, WO2013 / 185103 A1. 7-Bromo-2-chloro-3-isopropylquinoline [Image disponible dans le document PDF, Image available in the PDF document] The title compound was prepared by following same reaction protocol as described in Vialard, Jorge Eduardo et al, WO2008 / 107478 A1; LCMS m / z= 284.1, 286.1 (M+, M+2; 100%). 2-Amino-4-bromo-6-fluorobenzaldehyde [Image disponible dans le document PDF, Image available in the PDF document] To a stirred solution of 4-bromo-2-fluoro-6-nitrobenzaldehyde (prepared by following same reaction protocol as described in Li, Liansheng et al, WO 2015 / 054572 A1; 4.15g, 16.73 mmol) in ethanol (20ml) & acetic acid (20ml) was added iron powder (2.80 g, 50.2 mmol) at 0°C and stirred the reaction mixture for 1h. The reaction mixture was diluted with ethyl acetate (70ml) and netralized with aq. sat. NaHCO<com:Sub>3< / com:Sub> (100 ml). The resulting emulsion was filtered through celite<com:Sup>TM< / com:Sup>. Layers were separated, organic layer was washed with brine (100 ml) and dried over anhydrous Na<com:Sub>2< / com:Sub>SO<com:Sub>4< / com:Sub>. The organic layer was filtered and concentrated in vacuo to afford (3.36g, 92%) as a light green solid which was used for next step without purification. <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-<com:Math><semantics>d6<annotation encoding="application / x-tex">d_6< / annotation>< / semantics>< / com:Math>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 10.10 (s, 1H), 7.78 – 7.54 (m, 2H), 6.84 (t, <com:Math><semantics>J=1.5 Hz,1H,6.64 (dd,J=11.1,1.8 Hz,1H).<annotation encoding="application / x-tex">J = 1.5 \text{ Hz}, 1\text{H}, 6.64 \text{ (dd}, J = 11.1, 1.8 \text{ Hz}, 1\text{H}).< / annotation>< / semantics>< / com:Math> 1-Chloro-5-iodo-2-methyl-3-nitrobenzene [Image disponible dans le document PDF, Image available in the PDF document] A solution of iodine (10.43g, 41.1mmol), potassium iodate (1.247g, 5.83mmol) in conc. H<com:Sub>2< / com:Sub>SO<com:Sub>4< / com:Sub> (51.4g, 525mmol) was added to a solution of 1-chloro-2-methyl-3-nitrobenzene (5g, 29.1mmol) in conc. H<com:Sub>2< / com:Sub>SO<com:Sub>4< / com:Sub> (51.4g, 525mmol) at 25°C. The resulting mixture was stirred at 25°C for 6h. The reaction mixture was added slowly onto crushed ice and extracted the product with ethyl acetate (75ml). The organic layer was washed with aq.sat.NaHCO<com:Sub>3< / com:Sub> (75ml), aq.sat.Na<com:Sub>2< / com:Sub>S<com:Sub>2< / com:Sub>O<com:Sub>3< / com:Sub> (75ml) and brine (75ml) successively. Dried the organic layer over anhydrous Na<com:Sub>2< / com:Sub>SO<com:Sub>4< / com:Sub>, filtered and concentrated in vacuo to give 9g of crude compound. This residue was purified by combiflash (R<com:Sub>f< / com:Sub>200, Teledyne / Isco) instrument onto a redisep® R<com:Sub>f< / com:Sub> column with elution of petroleum ether to afford the title compound (8.5g, 98%) as a pale yellow oil. <com:Sup>1< / com:Sup>H NMR (400 MHz, Chloroform-d) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.02 (d, J = 1.4 Hz, 1H), 7.96 (d, J = 1.7 Hz, 1H), 2.50 (s, 3H). 2-(Bromomethyl)-1-chloro-5-iodo-3-nitrobenzene [Image disponible dans le document PDF, Image available in the PDF document] To a stirred solution of 1-chloro-5-iodo-2-methyl-3-nitrobenzene (27.5g, 92mmol) in CCl<com:Sub>4< / com:Sub> (280 ml) was added NBS (19.74g, 111mmol) and benzoyl peroxide (2.99g, 9.24 mmol) at 25°C. The resulting mixture was stirred at 80°C for 15h. The solvent was evaporated in vacuo and this residue was purified by combiflash (R<com:Sub>f< / com:Sub>200, Teledyne / Isco) instrument onto a redisep® R<com:Sub>f< / com:Sub> column with gradient elution of (0 to 1%) of ethyl acetate in petroleum ether 52 to afford the title compound (12g, 34.5 %) as an off-white solid. <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-<com:Math><semantics>d6<annotation encoding="application / x-tex">d_6< / annotation>< / semantics>< / com:Math>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.37 – 8.33 (m, 2H), 4.72 (s, 2H). 2-Chloro-4-iodo-6-nitrobenzaldehyde [Image disponible dans le document PDF, Image available in the PDF document] To a stirred solution of 2-(bromomethyl)-1-chloro-5-iodo-3-nitrobenzene (12 g, 31.9) mmol) in acetonitrile (150ml) was added 4-methylmorpholine-N-oxide (9.19 g, 78 mmol) and molecular sieves 4A° (30g) at 25°C. The resulting mixture was stirred at 25°C for 1.5h. Water (75ml) was added, pH was adjusted to 6 by adding 1N HCl. Extracted the product with ethyl acetate (75ml). Layers were separated, organic layer was washed with brine (20ml) and dried over anhydrous Na<com:Sub>2< / com:Sub>SO<com:Sub>4< / com:Sub>. The organic layer was filtered and concentrated in vacuo to give 16.5g of crude compound. This residue was purified by combiflash (R<com:Sub>f< / com:Sub>200, Teledyne / Isco) instrument onto a redisep® R<com:Sub>f< / com:Sub> column with gradient elution (0 to 4%) of ethyl acetate in petroleum ether to afford the title compound (7g, 70.5%) as an off-white solid. <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d<com:Sub>6< / com:Sub>) δ 10.22 (s, 1H), 8.46 (s, 2H). 2-Amino-6-chloro-4-iodobenzaldehyde [Image disponible dans le document PDF, Image available in the PDF document] The title compound was prepared by following an analogous reaction protocol as described in the preparation of 2-amino-4-bromo-6-fluorobenzaldehyde. <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-<com:Math><semantics>d6<annotation encoding="application / x-tex">d_6< / annotation>< / semantics>< / com:Math>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 10.26 (s, 1H), 7.80 – 7.55 (m, 2H), 7.23 (d, <com:Math><semantics>J=1.4<annotation encoding="application / x-tex">J = 1.4< / annotation>< / semantics>< / com:Math> Hz, 1H), 6.99 (d, <com:Math><semantics>J=1.5<annotation encoding="application / x-tex">J = 1.5< / annotation>< / semantics>< / com:Math> Hz, 1H). 1-Fluoro-2-iodo-5-methyl-4-nitrobenzene [Image disponible dans le document PDF, Image available in the PDF document] To a stirred solution of 2-fluoro-4-methyl-5-nitroaniline (2.0 g, 11.75 mmol) in conc.HCl (6.15 ml, 73.8 mmol) was added a solution of sodium nitrite (0.884 g, 12.81 mmol) in water (4ml) in a dropwise manner at 0°C. After stirring for 15mins, the mixture was filtered through a cotton pad and slowly poured into a stirred solution of potassium iodide (6.83 g, 41.1mmol) in water (25ml) at 0°C. The resulting mixture was stirred at 25°C for 16h. The reaction mixture was diluted with ethyl acetate (20ml) and washed with 10% aq.NaOH (50ml), aq.sat.NaHCO<com:Sub>3< / com:Sub> (50ml) successively. Layers were separated, organic layer was washed with brine (50ml) and was dried over anhydrous Na<com:Sub>2< / com:Sub>SO<com:Sub>4< / com:Sub>. The organic layer was filtered and concentrated in vacuo to give 3.1g of crude compound. This residue was purified by combiflash (R<com:Sub>f< / com:Sub>200, Teledyne / Isco) instrument onto a redisep® R<com:Sub>f< / com:Sub> column with petroleum ether as a eluent to afford the title compound (1.7g, 51.5%) of the title compound as an off-white solid. <com:Sup>1< / com:Sup>H NMR (400 MHz, Chloroform-d) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.45 (d, <com:Math><semantics>J=5.7<annotation encoding="application / x-tex">J = 5.7< / annotation>< / semantics>< / com:Math> Hz, 1H), 7.06 (d, 1H), 2.62 (d, <com:Math><semantics>J=0.7<annotation encoding="application / x-tex">J = 0.7< / annotation>< / semantics>< / com:Math> Hz, 3H); GCMS m / z= 281.03 (M+, 50%). 1-(Bromomethyl)-5-fluoro-4-iodo-2-nitrobenzene [Image disponible dans le document PDF, Image available in the PDF document] The title compound was prepared by following an analogous reaction protocol as described in the preparation of 2-(bromomethyl)-1-chloro-5-iodo-3-nitrobenzene. <com:Sup>1< / com:Sup>H NMR (400 MHz, Chloroform-d) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.53 (d, <com:Math><semantics>J=5.6<annotation encoding="application / x-tex">J = 5.6< / annotation>< / semantics>< / com:Math> Hz, 1H), 7.31 (d, <com:Math><semantics>J=7.8<annotation encoding="application / x-tex">J = 7.8< / annotation>< / semantics>< / com:Math> Hz, 1H), 4.80 (s, 2H). 5-Fluoro-4-iodo-2-nitrobenzaldehyde [Image disponible dans le document PDF, Image available in the PDF document] The title compound was prepared by following an analogous reaction protocol as described in the preparation of 2-chloro-4-iodo-6-nitrobenzaldehyde. <com:Sup>1< / com:Sup>H NMR (400 MHz, Chloroform-d) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 10.42 (d, J = 2.3 Hz, 1H), 8.62 (d, J = 5.1 Hz, 1H), 7.60 (d, J = 7.2 Hz, 1H). 2-Amino-5-fluoro-4-iodobenzaldehyde [Image disponible dans le document PDF, Image available in the PDF document] The title compound was prepared by following an analogous reaction protocol as described in the preparation of 2-amino-4-bromo-6-fluorobenzaldehyde. <com:Sup>1< / com:Sup>H NMR (400 MHz, Chloroform-d) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 9.78 (d, <com:Math><semantics>J=0.6<annotation encoding="application / x-tex">J = 0.6< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>7.17−7.13<annotation encoding="application / x-tex">7.17 - 7.13< / annotation>< / semantics>< / com:Math> (m, 2H), <com:Math><semantics>5.98<annotation encoding="application / x-tex">5.98< / annotation>< / semantics>< / com:Math> (s, 2H). 7-Bromo-3-cyclopropylquinoline [Image disponible dans le document PDF, Image available in the PDF document] To a stirred mixture of 2-amino-4-bromobenzaldehyde (2 g, 10.00 mmol) and 2- cyclopropylacetaldehyde (0.841 g, 10.00 mmol) in absolute ethanol (12ml) was added a solution of KOH (0.191 g, 3.40 mmol) in ethanol (12ml) in a dropwise manner under N<com:Sub>2< / com:Sub> atmosphere. The resulting mixture was stirred at 95°C for 5h. The volatiles were evaporated in vacuo and the residue was dissolved in dichloromethane (60 ml) and washed with water (40 ml). Layers were separated, organic layer was washed with brine (50 ml) and dried over anhydrous Na<com:Sub>2< / com:Sub>SO<com:Sub>4< / com:Sub>. The organic layer was filtered and concentrated in vacuo to give 2.5g of crude compound. This residue was purified by combiflash (R<com:Sub>f< / com:Sub>200, Teledyne / Isco) instrument onto a redisep® R<com:Sub>f< / com:Sub> column with gradient elution (0 to 6%) of ethyl acetate in petroleum ether to afford 7-bromo-3-cyclopropylquinoline (1g, 40.3%) as a pale yellow solid. <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.80 (d, <com:Math><semantics>J=2.3<annotation encoding="application / x-tex">J = 2.3< / annotation>< / semantics>< / com:Math> Hz, 1H), 8.17 (d, <com:Math><semantics>J=2.1<annotation encoding="application / x-tex">J = 2.1< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>8.00 (d, J=2.4 Hz, 1H),7.89−7.80 (m, 1H),7.70 (dd, J=8.8,2.1 Hz, 1H),2.15 (tt, J=3.8)<annotation encoding="application / x-tex">8.00 \text{ (d, } J = 2.4 \text{ Hz, } 1\text{H)}, 7.89 - 7.80 \text{ (m, } 1\text{H)}, 7.70 \text{ (dd, } J = 8.8, 2.1 \text{ Hz, } 1\text{H)}, 2.15 \text{ (tt, } J = 3.8)< / annotation>< / semantics>< / com:Math> <com:Math><semantics>8.1,5.1 Hz,1H<annotation encoding="application / x-tex">8.1, 5.1 \text{ Hz}, 1\text{H}< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>1.14−1.03 (m, 2H)<annotation encoding="application / x-tex">1.14 - 1.03 \text{ (m, 2H)}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>0.95−0.81 (m, 2H)<annotation encoding="application / x-tex">0.95 - 0.81 \text{ (m, 2H)}< / annotation>< / semantics>< / com:Math>; LCMS m / z= 247.83, 249.83 (M+, M+2, 100%). 7-Bromo-3-(1,1-difluoroethyl)quinoline [Image disponible dans le document PDF, Image available in the PDF document] A mixture of 1-(7-bromoquinolin-3-yl)ethan-1-one (synthesized by following same reaction protocol as described in Alam, Muzaffar et al, US20120230951 A1; 2.4 g, 9.60 mmol) in diethylaminosulfur trifluoride (2.5 ml, 18.92 mmol) was stirred at 70°C for 16h. The resulting mixture was slowly poured into aq. sat. sodium bicarbonate (50ml) and extracted with dichloromethane (50ml). Layers were separated, organic layer was washed with brine (20ml) and dried over anhydrous Na<com:Sub>2< / com:Sub>SO<com:Sub>4< / com:Sub>. The organic layer was filtered and concentrated in vacuo to give 3.2g of crude compound. This residue was purified by combiflash (R<com:Sub>f< / com:Sub>200, Teledyne / Isco) instrument onto a redisep® R<com:Sub>f< / com:Sub> column with gradient elution (0 to 30%) of ethyl acetate in petroleum ether to afford the title compound (1.7g, 65.1 %) as a pale yellow solid. <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-<com:Math><semantics>d6<annotation encoding="application / x-tex">d_6< / annotation>< / semantics>< / com:Math>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 9.13 (d, <com:Math><semantics>J=2.4<annotation encoding="application / x-tex">J = 2.4< / annotation>< / semantics>< / com:Math> Hz, 1H), 8.71 (s, 1H), 8.34 (d, <com:Math><semantics>J=2.1<annotation encoding="application / x-tex">J = 2.1< / annotation>< / semantics>< / com:Math> Hz, 1H), 8.11 (d, <com:Math><semantics>J=8.7<annotation encoding="application / x-tex">J = 8.7< / annotation>< / semantics>< / com:Math> Hz, 1H), 7.88 (dd, <com:Math><semantics>J=8.7<annotation encoding="application / x-tex">J = 8.7< / annotation>< / semantics>< / com:Math>, 2.0 Hz, 1H), 2.14 (t, <com:Math><semantics>J=19.2<annotation encoding="application / x-tex">J = 19.2< / annotation>< / semantics>< / com:Math> Hz, 3H), LCMS m / z= 271.90, 273.90 (M+1; 100%). 7-Bromo-3-chloro-8-fluoroquinoline [Image disponible dans le document PDF, Image available in the PDF document] To a stirred solution of 7-bromo-8-fluoroquinoline (synthesized by following same reaction protocol as described in Ghergurovich, Jonathan Michael et al, WO2013028447 A1, 3.4 g, 15.04 mmol) in DMF (10ml) was added N-chlorosuccinimide (4.02g, 30.1mmol) at 25°C. The reaction mixture was stirred at 100°C for 16h. The reaction mixture was cooled to 25°C and poured onto ice cold water (100ml) and stirred for 30 minutes. The precipitate was collected by filtration and washed with water. The precipitate was dried in vacuo to afford the title compound (2g, 51%) as an off-white solid. <com:Sup>1< / com:Sup>H NMR (400 MHz, Chloroform-d) δ 8.90 (d, <com:Math><semantics>J=2.3<annotation encoding="application / x-tex">J = 2.3< / annotation>< / semantics>< / com:Math> Hz, 1H), 8.18 (t, <com:Math><semantics>J=1.9<annotation encoding="application / x-tex">J = 1.9< / annotation>< / semantics>< / com:Math> Hz, 1H), 7.72 (dd, <com:Math><semantics>J=8.9<annotation encoding="application / x-tex">J = 8.9< / annotation>< / semantics>< / com:Math>, 6.1 Hz, 1H), 7.48 (dd, <com:Math><semantics>J=8.8,1.5 Hz,1H<annotation encoding="application / x-tex">J = 8.8, 1.5 \text{ Hz}, 1\text{H}< / annotation>< / semantics>< / com:Math>; LCMS m / z= 261.71 (M+; 100%). 7-Bromo-3-chloro-5-fluoroquinoline [Image disponible dans le document PDF, Image available in the PDF document] To a stirred solution of 2-amino-4-bromo-6-fluorobenzaldehyde (3.36 g, 15.41 mmol) in toluene (35 ml) was added 2-chloro-1,1-dimethoxyethane (2.304 g, 18.49 mmol) followed by p-toluene sulfonic acid monohydrate (2.93 g, 15.41 mmol) at 25°C. The resulting mixture was stirred at 110°C using Dean Stark apparatus for 4h under N<com:Sub>2< / com:Sub> atmosphere. The reaction mixture was diluted with ethyl acetate (100ml) and basified with aq.sat.NaHCO<com:Sub>3< / com:Sub> (75ml). Layers were separated, organic layer was washed with brine (20ml) and dried over anhydrous Na<com:Sub>2< / com:Sub>SO<com:Sub>4< / com:Sub>. The organic layer was filtered and concentrated in vacuo to give 1.1g of crude compound. This residue was purified by combiflash (R<com:Sub>f< / com:Sub>200, Teledyne / Isco) instrument onto a redisep® R<com:Sub>f< / com:Sub> column with gradient elution (0 to 2%) of ethyl acetate in petroleum ether to afford the title compound (1.64g, 40.9%) as a light green solid. <com:Sup>1< / com:Sup>H NMR <com:Math><semantics>(400 MHz,Chloroform-d)δ8.88 (d, J=2.4 Hz,1H),8.38 (d, J=2.4 Hz,1H),8.15 (s, 1H),<annotation encoding="application / x-tex">(400 \text{ MHz}, \text{Chloroform-}d) \delta 8.88 \text{ (d, } J = 2.4 \text{ Hz}, 1\text{H)}, 8.38 \text{ (d, } J = 2.4 \text{ Hz}, 1\text{H)}, 8.15 \text{ (s, 1H)},< / annotation>< / semantics>< / com:Math> 7.45 (ddd, <com:Math><semantics>J=9.0<annotation encoding="application / x-tex">J = 9.0< / annotation>< / semantics>< / com:Math>, 3.5, 1.8 Hz, 1H); LCMS m / z=261.76 (M+1, 100%). Intermediates in table-1 were synthesized by following an analogous reaction protocol as was used for the preparation of 7-bromo-3-chloro-5-fluoroquinoline using the appropriate starting materials. Table-1: [Image disponible dans le document PDF, Image available in the PDF document] 7-Bromo-3-chloro-5-fluoroquinoline 1-oxide [Image disponible dans le document PDF, Image available in the PDF document] A mixture of 7-bromo-3-chloro-5-fluoroquinoline (1.64 g, 6.30 mmol) and m-CPBA (2.90 g, 12.59 mmol) in CHCl<com:Sub>3< / com:Sub> (30ml) was heated at 50°C for 16h. The reaction mixture was 5 diluted with chloroform (50ml) and washed with aq.sat. Na<com:Sub>2< / com:Sub>SO<com:Sub>3< / com:Sub> (50ml) followed by aq.sat.NaHCO<com:Sub>3< / com:Sub> (50ml). Layers were separated, organic layer was washed with brine (50ml) and dried over anhydrous Na<com:Sub>2< / com:Sub>SO<com:Sub>4< / com:Sub>. The organic layer was filtered and concentrated in vacuo to give 1.35g of crude compound. This residue was purified by combiflash (R<com:Sub>f< / com:Sub>200, Teledyne / Isco) instrument onto a redisep® R<com:Sub>f< / com:Sub> column with gradient elution (0 to 20%) of ethyl acetate in petroleum ether to afford the title compound (542mg, 31.1%) as a light brown solid. <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-<com:Math><semantics>d6<annotation encoding="application / x-tex">d_6< / annotation>< / semantics>< / com:Math>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.97 (d, <com:Math><semantics>J=1.8<annotation encoding="application / x-tex">J = 1.8< / annotation>< / semantics>< / com:Math> Hz, 1H), 8.46 (s, 1H), 8.17 <com:Math><semantics>−8.10<annotation encoding="application / x-tex">-8.10< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>8.03<annotation encoding="application / x-tex">8.03< / annotation>< / semantics>< / com:Math> (dd, <com:Math><semantics>J=9.5<annotation encoding="application / x-tex">J = 9.5< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>1.9<annotation encoding="application / x-tex">1.9< / annotation>< / semantics>< / com:Math> Hz, 1H); LCMS m / z= 275.83, 277.83 (M+, M+2; 100%). Intermediates in table-2 were synthesized by following an analogous reaction protocol as was used for the preparation of 7-bromo-3-chloro-5-fluoroquinoline 1-oxide using the appropriate starting materials. Table-2: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] 7-Bromo-2,3-dichloro-5-fluoroquinoline [Image disponible dans le document PDF, Image available in the PDF document] To a stirred solution of 7-bromo-3-chloro-5-fluoroquinoline 1-oxide (542 mg, 1.960 mmol) in CHCl<com:Sub>3< / com:Sub> (10 ml) was added POCl<com:Sub>3< / com:Sub> (1.867 ml, 20.03 mmol) at 25°C. The resulting mixture was stirred at 65°C for 2h under N<com:Sub>2< / com:Sub> atmosphere. The reaction mixture was poured onto ice cold water (50ml), carefully basified with solid NaHCO<com:Sub>3< / com:Sub> and extracted the product with dichloromethane (50ml). Layers were separated, organic layer was washed with brine (50ml) and was dried over anhydrous Na<com:Sub>2< / com:Sub>SO<com:Sub>4< / com:Sub>. The organic layer was filtered and concentrated in vacuo to give 1.2g of crude compound. This residue was purified by combiflash (R<com:Sub>f< / com:Sub>200, Teledyne / Isco) instrument onto a redisep® R<com:Sub>f< / com:Sub> column with gradient elution (0 to 10%) of ethyl acetate in petroleum ether to afford the title compound (410mg, 70.9%) as a white solid. <com:Sup>1< / com:Sup>H NMR (400 MHz, Chloroform-d) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.49 – 8.43 (m, 1H), 8.04 (dt, J = 1.9, 1.0 \text{ Hz}, 1\text{H}), 7.45 (dd, J = 8.9, 1.7 \text{ Hz}, 1\text{H}); LCMS m / z = 296.19 (M+1; 100%). Intermediates in table-3 were synthesized by following an analogous reaction protocol as was used for the preparation of 7-bromo-2,3-dichloro-5-fluoroquinoline using the appropriate starting materials. Table-3: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] 7-Bromo-3-chloro-5-fluoroquinolin-2-amine [Image disponible dans le document PDF, Image available in the PDF document] A mixture of 7-bromo-2,3-dichloro-5-fluoroquinoline (410mg, 1.390mmol), aqueous ammonia (9.74 ml, 250 mmol) in dioxane (10ml) was heated at 120°C in a steel bomb for 24h. The reaction mixture was diluted with ethyl acetate (20ml) and washed with water (20ml). Layers were separated, organic layer was washed with brine (20ml) and dried over anhydrous Na<com:Sub>2< / com:Sub>SO<com:Sub>4< / com:Sub>. The organic layer was filtered and concentrated in vacuo to give 1.15g of crude compound. This residue was purified by combiflash (R<com:Sub>f< / com:Sub>200, Teledyne / Isco) instrument onto a redisep® R<com:Sub>f< / com:Sub> column with gradient elution (0 to 30%) of ethyl acetate in petroleum ether to afford the title compound (297 mg, 78%) as a white solid. <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-<com:Math><semantics>d6<annotation encoding="application / x-tex">d_6< / annotation>< / semantics>< / com:Math>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.23 (s, 1H), 7.51 (d, <com:Math><semantics>J=1.9<annotation encoding="application / x-tex">J = 1.9< / annotation>< / semantics>< / com:Math> Hz, 1H), 7.32 (dd, <com:Math><semantics>J=9.5<annotation encoding="application / x-tex">J = 9.5< / annotation>< / semantics>< / com:Math>, 1.9 Hz, 1H), 7.25 (s, 2H); LCMS <com:Math><semantics>m / z=276.83<annotation encoding="application / x-tex">m / z = 276.83< / annotation>< / semantics>< / com:Math> (M+1; 100%). Intermediates in table-4 were synthesized by following an analogous reaction protocol as was used for the preparation of 7-bromo-3-chloro-5-fluoroquinolin-2-amine using the 5 appropriate starting materials. Table-4: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] 7-Bromo-3-chloro-5-fluoro-N-(4-methoxybenzyl)quinolin-2-amine [Image disponible dans le document PDF, Image available in the PDF document] The title compound was prepared by following an analogous reaction protocol as described in Banka, Anna Lindsey et al, WO2012 / 037108 A1 using appropriate starting materials. <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.22 (d, J = 0.8 Hz, 1H), 7.96 (t, J = 6.1 Hz, 1H), 7.58 (dd, <com:Math><semantics>J=1.8,1.0 Hz,1H,7.39−7.28 (m, 3H),6.91−6.82 (m, 2H),4.62 (d, J=6.1 Hz,2H),<annotation encoding="application / x-tex">J = 1.8, 1.0 \text{ Hz}, 1\text{H}, 7.39 - 7.28 \text{ (m, 3H)}, 6.91 - 6.82 \text{ (m, 2H)}, 4.62 \text{ (d, } J = 6.1 \text{ Hz}, 2\text{H)},< / annotation>< / semantics>< / com:Math> <com:Math><semantics>3.71<annotation encoding="application / x-tex">3.71< / annotation>< / semantics>< / com:Math> (s, <com:Math><semantics>3H<annotation encoding="application / x-tex">3H< / annotation>< / semantics>< / com:Math>); LCMS m / z= <com:Math><semantics>397<annotation encoding="application / x-tex">397< / annotation>< / semantics>< / com:Math> (M+1; <com:Math><semantics>100%<annotation encoding="application / x-tex">100\%< / annotation>< / semantics>< / com:Math>). [Image disponible dans le document PDF, Image available in the PDF document] A mixture of 3,7-dibromo-5-fluoroquinolin-2-amine (2.05g, 6.41mmol), Et<com:Sub>3< / com:Sub>N (2.68ml, 19.22mmol), DMAP (0.078g, 0.641mmol) and Boc anhydride (3.12 ml, 13.45 mmol) in THF (25ml) was stirred at 25°C for 16h. The reaction mixture was diluted with ethyl acetate (20ml) and washed with water (20ml). Layers were separated, organic layer was washed with brine (20ml) and dried over anhydrous Na<com:Sub>2< / com:Sub>SO<com:Sub>4< / com:Sub>. The organic layer was filtered and concentrated in vacuo to give 3.9g of crude compound. This residue was purified by combiflash (R<com:Sub>f< / com:Sub>200, Teledyne / Isco) instrument onto a redisep® R<com:Sub>f< / com:Sub> column with gradient elution (0 to 5%) of ethyl acetate in petroleum ether to afford the di-boc compound (2.5g, 75%) as an off-white solid. <com:Sup>1< / com:Sup>H NMR (400 MHz, Chloroform-d) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.65 (d, <com:Math><semantics>J=0.8<annotation encoding="application / x-tex">J = 0.8< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>8.08(q,J=1.2Hz,1H),7.46(dd,J=8.9,1.7Hz,1H),1.42(s,18H).<annotation encoding="application / x-tex">8.08 (q, J = 1.2 Hz, 1H), 7.46 (dd, J = 8.9, 1.7 Hz, 1H), 1.42 (s, 18H).< / annotation>< / semantics>< / com:Math> 2-Amino-7-bromoquinoline-3-carbonitrile. [Image disponible dans le document PDF, Image available in the PDF document] A mixture of 2-amino-4-bromobenzaldehyde (0.448 g, 2.240 mmol), malononitrile (0.222 g, 3.36 mmol) and piperidine (0.111ml, 1.120mmol) in ethanol (10ml) was stirred at 100 °C for 16h. The volatiles were evaporated in vacuo and the residue was purified by combiflash (R<com:Sub>f< / com:Sub>200, Teledyne / Isco) instrument onto a redisep® R<com:Sub>f< / com:Sub> column with gradient elution (0 to 10%) of ethyl acetate in petroleum ether to afford the title compound (0.343g, 61.7%) as an off-white solid. <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) δ 8.71 (s, 1H), 7.74 – 7.65 <com:Math><semantics>(m,2H),7.42 (dd, J=8.6,2.0 Hz,1H),7.20 (s, 2H);LCMS m / z=248,250 (M+, M+2)<annotation encoding="application / x-tex">(m, 2H), 7.42 \text{ (dd, } J = 8.6, 2.0 \text{ Hz}, 1H), 7.20 \text{ (s, 2H)}; LCMS \text{ m / z} = 248, 250 \text{ (M+, M+2)}< / annotation>< / semantics>< / com:Math> 100%). 7-Bromo-N-(4-methoxybenzyl)quinazolin-2-amine [Image disponible dans le document PDF, Image available in the PDF document] The title compound was prepared by following an analogous reaction protocol as described in Li, Liansheng et al, WO2017 / 087528 A1; LCMS m / z= 344.1 (M+, 100%). 7-Bromo-3-fluoroquinolin-2-amine [Image disponible dans le document PDF, Image available in the PDF document] The title compound was prepared by an following analogous reaction protocol as described in Banka, Anna Lindsey et al, WO2012 / 037108 A1. 7-Bromo-3-chloroquinolin-2-amine [Image disponible dans le document PDF, Image available in the PDF document] The title compound was prepared by following an analogous reaction protocol as described in Banka, Anna Lindsey et al, WO2012 / 037108 A1. 7-Bromo-3-chloro-N-(4-methoxybenzyl)quinolin-2-amine [Image disponible dans le document PDF, Image available in the PDF document] The title compound was prepared by following an analogous reaction protocol as described in Banka, Anna Lindsey et al, WO2012 / 037108 A1. 7-Bromo-3-chloro-N,N-bis(4-methoxybenzyl)quinolin-2-amine [Image disponible dans le document PDF, Image available in the PDF document] To a stirred suspension of 7-bromo-3-chloroquinolin-2-amine (2.0 g, 7.77 mmol) in DMF (20 ml) was added NaH (0.932 g, 23.30 mmol) at 0°C. The resulting miture was stirred at 0°C for 15 min. Then 1-(chloromethyl)-4-methoxybenzene (3.65 g, 23.30 mmol) was added dropwise under N<com:Sub>2< / com:Sub> atmosphere. The reaction mixture was then stirred for 16h at 25°C. The reaction mixture was poured into ice water (150 mL) and extarcted with ethyl acetate (150 ml). Layers were separated, organic layer was washed with brine (100ml) and dried over anhydrous Na<com:Sub>2< / com:Sub>SO<com:Sub>4< / com:Sub>. The organic layer was filtered and concentrated in vacuo to give 3.87g of crude compound. This residue was purified by combiflash (R<com:Sub>f< / com:Sub>200, Teledyne / Isco) instrument onto a redisep® R<com:Sub>f< / com:Sub> column with gradient elution (0 to 30%) of ethyl acetate in petroleum ether to afford the title compound (2.2g, 56.9%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.45 (s, 1H), 7.89 (d, J = 1.9 Hz, 1H), 7.77 (d, J <com:Math><semantics>=8.6 Hz,1H,7.56 (dd, J=8.6,2.0 Hz,1H,7.31−7.22 (m, 4H),6.93−6.82 (m, 4H),<annotation encoding="application / x-tex">= 8.6 \text{ Hz}, 1\text{H}, 7.56 \text{ (dd, J} = 8.6, 2.0 \text{ Hz}, 1\text{H}, 7.31 - 7.22 \text{ (m, 4H)}, 6.93 - 6.82 \text{ (m, 4H)},< / annotation>< / semantics>< / com:Math> <com:Math><semantics>4.54<annotation encoding="application / x-tex">4.54< / annotation>< / semantics>< / com:Math> (s, 4H), <com:Math><semantics>3.70<annotation encoding="application / x-tex">3.70< / annotation>< / semantics>< / com:Math> (s, 6H); LCMS m / z= <com:Math><semantics>498.97<annotation encoding="application / x-tex">498.97< / annotation>< / semantics>< / com:Math> (M+1; <com:Math><semantics>100%<annotation encoding="application / x-tex">100\%< / annotation>< / semantics>< / com:Math>). 3-Bromo-7-iodo-N-(4-methoxybenzyl)quinolin-2-amine [Image disponible dans le document PDF, Image available in the PDF document] The title compound was prepared by following an analogous reaction protocol as described in Banka, Anna Lindsey et al, WO2012 / 037108 A1. 6-Bromo-3,3-dimethylindoline-2-thione. [Image disponible dans le document PDF, Image available in the PDF document] The suspension of 6-bromo-3,3-dimethylindolin-2-one (3.5 g, 14.58 mmol), which was synthesized by following an analogous reaction protocol as was reported in WO2015 / 177110, A1 and Lawesson's reagent (7.66 g, 18.95 mmol) in toluene (15 ml) was heated at 100°C for 3h under N<com:Sub>2< / com:Sub> atmosphere. Solvent was evaporated in vacuo and this residue was purified by combiflash (R<com:Sub>f< / com:Sub>200, Teledyne / Isco) instrument onto a redisep® R<com:Sub>f< / com:Sub> column with gradient elution (0-20%) of ethyl acetate in petroleum ether to afford the title compound (3.3g, 88 %) as an off-white solid. <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) δ 12.67 (s, 1H), <com:Math><semantics>7.40<annotation encoding="application / x-tex">7.40< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=7.9<annotation encoding="application / x-tex">J = 7.9< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>7.31<annotation encoding="application / x-tex">7.31< / annotation>< / semantics>< / com:Math> (dd, <com:Math><semantics>J=7.9<annotation encoding="application / x-tex">J = 7.9< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>1.8<annotation encoding="application / x-tex">1.8< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>7.15<annotation encoding="application / x-tex">7.15< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=1.7<annotation encoding="application / x-tex">J = 1.7< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>1.30<annotation encoding="application / x-tex">1.30< / annotation>< / semantics>< / com:Math> <com:Math><semantics>(s,6H)<annotation encoding="application / x-tex">(s, 6H)< / annotation>< / semantics>< / com:Math>; LCMS m / z= 256.89 (M+1; 30%). 6-Bromo-3,3-dimethyl-2-(methylthio)-3H-indole. [Image disponible dans le document PDF, Image available in the PDF document] To a stirred suspension of 6-bromo-3,3-dimethylindoline-2-thione (3 g, 11.71 mmol) in THF (40ml) was added NaH (0.703g, 17.57mmol) at 0°C. The resulting mixture was stirred for 15 min at 0°C. Methyl iodide (1.098 ml, 17.57 mmol) was added and stirred the reaction mixture for 1h at 0°C under N<com:Sub>2< / com:Sub> atmosphere. The reaction mixture was diluted with ethyl acetate (50 ml) and washed with water (50 ml). Layers were separated, organic layer was washed with brine (50 ml) and dried over anhydrous sodium sulphate. The organic layer was filtered and concentrated in vacuo to give 3.5g of crude compound. This residue was purified by combiflash (R<com:Sub>f< / com:Sub>200, Teledyne / Isco) instrument onto a redisep® R<com:Sub>f< / com:Sub> column with gradient elution (0-5%) of ethyl acetate in petroleum ether to afford the title compound <com:Math><semantics>(3.1g,98%)<annotation encoding="application / x-tex">(3.1g, 98\%)< / annotation>< / semantics>< / com:Math> as a white solid. <com:Sup>1< / com:Sup>H NMR <com:Math><semantics>(400 MHz,DMSO−d6)δ7.60 (d, J=1.7 Hz, 1H),<annotation encoding="application / x-tex">(400 \text{ MHz}, DMSO-d6) \delta 7.60 \text{ (d, J} = 1.7 \text{ Hz, 1H)},< / annotation>< / semantics>< / com:Math> <com:Math><semantics>7.41 (d, J = 7.9 Hz, 1H),7.32 (dd, J = 7.9, 1.8 Hz, 1H),2.60 (s, 3H),1.29 (s, 6H);LCMS<annotation encoding="application / x-tex">7.41 \text{ (d, J = 7.9 Hz, 1H)}, 7.32 \text{ (dd, J = 7.9, 1.8 Hz, 1H)}, 2.60 \text{ (s, 3H)}, 1.29 \text{ (s, 6H)}; LCMS< / annotation>< / semantics>< / com:Math> <com:Math><semantics>m / z=269.90(M+;40%)<annotation encoding="application / x-tex">m / z = 269.90 (M+; 40\%)< / annotation>< / semantics>< / com:Math>. 6'-Bromospiro[cyclobutane-1,3'-indoline]-2'-thione. [Image disponible dans le document PDF, Image available in the PDF document] The title compound was prepared by following an analogous reaction protocol as was described in the preparation of 6-bromo-3,3-dimethylindoline-2-thione. LCMS m / z= 267.65 (M+; 20%). 6'-Bromo-2'-(methylthio)spiro[cyclobutane-1,3'-indole] [Image disponible dans le document PDF, Image available in the PDF document] The title compound was prepared by following an analogous reaction protocol as was described in the preparation of 6-bromo-3,3-dimethyl-2-(methylthio)-3H-indole. <com:Sup>1< / com:Sup>H NMR 68 (400 MHz, Chloroform-d) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 7.63 (d, <com:Math><semantics>J=1.7<annotation encoding="application / x-tex">J = 1.7< / annotation>< / semantics>< / com:Math> Hz, 1H), 7.44 (d, <com:Math><semantics>J=7.9<annotation encoding="application / x-tex">J = 7.9< / annotation>< / semantics>< / com:Math> Hz, 1H), 7.32 (dd, <com:Math><semantics>J=7.9<annotation encoding="application / x-tex">J = 7.9< / annotation>< / semantics>< / com:Math> Hz, 1H), 7.32 (dd, <com:Math><semantics>J=7.9<annotation encoding="application / x-tex">J = 7.9< / annotation>< / semantics>< / com:Math> Hz, 1H), 7.32 (dd, <com:Math><semantics>J=7.9<annotation encoding="application / x-tex">J = 7.9< / annotation>< / semantics>< / com:Math> Hz, 1H), 7.32 (dd, <com:Math><semantics>J=7.9<annotation encoding="application / x-tex">J = 7.9< / annotation>< / semantics>< / com:Math> Hz, 1H), 7.32 (dd, <com:Math><semantics>J=7.9<annotation encoding="application / x-tex">J = 7.9< / annotation>< / semantics>< / com:Math> H <com:Math><semantics>=7.9,1.7 Hz,1H<annotation encoding="application / x-tex">= 7.9, 1.7 \text{ Hz}, 1\text{H}< / annotation>< / semantics>< / com:Math>), 2.73 (s, 3H), 2.61 – 2.46 (m, 4H), 2.37 – 2.30 (m, 2H); LCMS m / z= 281.78, 283.78 (M+, M+2; 100%). 6'-Bromospiro[cyclobutane-1,3'-indol]-2'-amine. [Image disponible dans le document PDF, Image available in the PDF document] To stirred solution of 6'-bromo-2'-(methylthio)spiro[cyclobutane-1,3'-indole] (1.2 g, 4.25) mmol) in 7N ammonia in methanol (15ml, 371mmol) was heated at 100°C for 16 h. Solvent was evaporated in vacuo and this residue was purified by combiflash (R<com:Sub>f< / com:Sub>200, Teledyne / Isco) instrument onto a redisep® R<com:Sub>f< / com:Sub> column with gradient elution (0-10%) of methanol in dichloromethane to afford the title compound (650mg, 60.9%) as white solid. <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 7.69 (s, 2H), 7.46 (d, J = 8.2 Hz, 1H), 7.01 (h, J = 1.8) Hz, 2H), <com:Math><semantics>2.63−2.53<annotation encoding="application / x-tex">2.63 - 2.53< / annotation>< / semantics>< / com:Math> (m, 2H), <com:Math><semantics>2.43−2.30<annotation encoding="application / x-tex">2.43 - 2.30< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>2.23−2.09<annotation encoding="application / x-tex">2.23 - 2.09< / annotation>< / semantics>< / com:Math> (m, 3H); LCMS m / z= 250.87 <com:Math><semantics>(M+;100%).<annotation encoding="application / x-tex">(M+; 100\%).< / annotation>< / semantics>< / com:Math> 7-Bromo-3-methylimidazo[1,2-a]pyridine [Image disponible dans le document PDF, Image available in the PDF document] The title compound was prepared by following an analogous reaction protocol as was described in Dubois., Laurent et al, WO 2009 / 112679 A1. 2-(Methylamino)quinolin-7-ol [Image disponible dans le document PDF, Image available in the PDF document] The title compound was prepared by following an analogous reaction protocol as was described in Doherty, Elizabeth M. et.al, Journal of Medicinal Chemistry, 2007, vol. 50, # 15, p. 3515 – 3527. 3-Bromo-N-(4-methoxybenzyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)quinolin-2-amine [Image disponible dans le document PDF, Image available in the PDF document] A mixture of 3-bromo-7-iodo-N-(4-methoxybenzyl)quinolin-2-amine (1.5g, 3.20mmol), bispinacolotodiboron (0.974g, 3.84mmol), [1,1'-bis(diphenylphosphino) ferrocene] dichloropalladium(II), complex with dichloromethane (0.261g, 0.320mmol) and potassium acetate (0.533g, 5.44mmol) in DMSO (50ml) was heated at 80°C for 15min in a preheated oil bath. The reaction mixture was allowed to cool to 25°C, diluted with ethyl acetate (50ml) and poured onto ice-cold water (100ml). Layers were separated, organic layer was washed with brine (50 ml) and dried over anhydrous sodium sulphate. The organic layer was filtered and concentrated in vacuo to give 2.5g of crude compound. This residue was purified by combiflash (R<com:Sub>f< / com:Sub>200, Teledyne / Isco) instrument onto a redisep® R<com:Sub>f< / com:Sub> column with gradient elution (0-7%) of ethyl acetate in petroleum ether to afford the title compound (1.35g, 90%) as an off-white solid. <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-<com:Math><semantics>d6<annotation encoding="application / x-tex">d_6< / annotation>< / semantics>< / com:Math>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.42 (d, <com:Math><semantics>J=0.7<annotation encoding="application / x-tex">J = 0.7< / annotation>< / semantics>< / com:Math> Hz, 1H), 7.86 (d, <com:Math><semantics>J=0.7<annotation encoding="application / x-tex">J = 0.7< / annotation>< / semantics>< / com:Math> Hz, 1H), 7.86 (d, <com:Math><semantics>J=0.7<annotation encoding="application / x-tex">J = 0.7< / annotation>< / semantics>< / com:Math> Hz, 1H), 7.86 (d, <com:Math><semantics>J=0.7<annotation encoding="application / x-tex">J = 0.7< / annotation>< / semantics>< / com:Math> Hz, 1H), 7.86 (d, <com:Math><semantics>J=0.7<annotation encoding="application / x-tex">J = 0.7< / annotation>< / semantics>< / com:Math> Hz, 1H), 7.86 (d, <com:Math><semantics>J=0.7<annotation encoding="application / x-tex">J = 0.7< / annotation>< / semantics>< / com:Math> Hz, <com:Math><semantics>=1.1 Hz,1H,7.65 (d, J=7.9 Hz,1H),7.43 (dd, J=7.9,1.1 Hz,1H),7.40−7.32 (m, 3H),<annotation encoding="application / x-tex">= 1.1 \text{ Hz}, 1\text{H}, 7.65 \text{ (d, } J = 7.9 \text{ Hz}, 1\text{H}), 7.43 \text{ (dd, } J = 7.9, 1.1 \text{ Hz}, 1\text{H}), 7.40 - 7.32 \text{ (m, 3H)},< / annotation>< / semantics>< / com:Math> <com:Math><semantics>6.99−6.74<annotation encoding="application / x-tex">6.99 - 6.74< / annotation>< / semantics>< / com:Math> (m, 2H), <com:Math><semantics>4.62<annotation encoding="application / x-tex">4.62< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=6.0<annotation encoding="application / x-tex">J = 6.0< / annotation>< / semantics>< / com:Math> Hz, 2H), <com:Math><semantics>3.71<annotation encoding="application / x-tex">3.71< / annotation>< / semantics>< / com:Math> (s, 3H), <com:Math><semantics>1.32<annotation encoding="application / x-tex">1.32< / annotation>< / semantics>< / com:Math> (s, 12H); LCMS m / z= 468.89 (M+; 100%). 3-Bromo-2-((4-methoxybenzyl)amino)quinolin-7-ol [Image disponible dans le document PDF, Image available in the PDF document] To a stirred solution of 3-bromo-N-(4-methoxybenzyl)-7-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)quinolin-2-amine (0.35g, 0.746mmol) in THF (20 ml) was added AcOH (0.064ml, 1.119mmol) dropwise at 0°C and stirred for 1h. Aq. H<com:Sub>2< / com:Sub>O<com:Sub>2< / com:Sub> (0.5ml, 1.492mmol) was added slowly at 0°C. The resulting mixture was stirred at 25°C for 5h. The reaction mixture was diluted with ethyl acetate (20ml) and washed with aq.sat.Na<com:Sub>2< / com:Sub>SO<com:Sub>3< / com:Sub> (20ml). Layers were separated, organic layer was washed with brine (20ml) and dried over anhydrous sodium sulphate. The organic layer was filtered and concentrated in vacuo to give 0.41g of crude compound. This residue was purified by combiflash (R<com:Sub>f< / com:Sub>200, Teledyne / Isco) instrument onto a redisep® R<com:Sub>f< / com:Sub> column with gradient elution (0-25%) of ethyl acetate in petroleum ether to afford the title compound (0.13g, 48.5%) as an off-white solid. LCMS <com:Math><semantics>m / z=359.22(M+;100%)<annotation encoding="application / x-tex">m / z = 359.22 (M+; 100\%)< / annotation>< / semantics>< / com:Math>. 3-Chloro-5-fluoro-N-(4-methoxybenzyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)quinolin-2-amine [Image disponible dans le document PDF, Image available in the PDF document] The title compound was synthesized by following an analogous reaction protocol as was described in the preparation of 3-bromo-N-(4-methoxybenzyl)-7-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)quinolin-2-amine. <com:Sup>1< / com:Sup>H NMR (400 MHz, Chloroform-d) δ 1H NMR (400 MHz, Chloroform-d) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.17 (d, J = 0.9 Hz, 1H), 8.07 (s, 1H), 7.41 – 7.36 (m, 2H), <com:Math><semantics>7.29 (dd, J=10.0,0.8 Hz, 1H),6.94−6.89 (m, 2H),5.69 (s, 1H),4.77 (d, J=5.4 Hz, 2H),<annotation encoding="application / x-tex">7.29 \text{ (dd, J} = 10.0, 0.8 \text{ Hz, 1H)}, 6.94 - 6.89 \text{ (m, 2H)}, 5.69 \text{ (s, 1H)}, 4.77 \text{ (d, J} = 5.4 \text{ Hz, 2H)},< / annotation>< / semantics>< / com:Math> 3.83 (s, 3H), 1.29 (s, 12H); LCMS <com:Math><semantics>m / z=443.05<annotation encoding="application / x-tex">m / z = 443.05< / annotation>< / semantics>< / com:Math> (M+; 100%). 3-Chloro-5-fluoro-2-((4-methoxybenzyl)amino)quinolin-7-ol [Image disponible dans le document PDF, Image available in the PDF document] The title compound was synthesized by following an analogous reaction protocol as was described in the preparation of 3-bromo-2-((4-methoxybenzyl)amino)quinolin-7-ol. <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 10.19 (d, J = 1.0 Hz, 1H), 8.02 (s, 1H), 7.55 (t, J = 6.2 Hz, 1H), <com:Math><semantics>7.43−7.28<annotation encoding="application / x-tex">7.43 - 7.28< / annotation>< / semantics>< / com:Math> (m, 2H), <com:Math><semantics>6.91−6.82<annotation encoding="application / x-tex">6.91 - 6.82< / annotation>< / semantics>< / com:Math> (m, 2H), <com:Math><semantics>6.67<annotation encoding="application / x-tex">6.67< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=2.1<annotation encoding="application / x-tex">J = 2.1< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>6.57<annotation encoding="application / x-tex">6.57< / annotation>< / semantics>< / com:Math> (dd, <com:Math><semantics>J=11.7<annotation encoding="application / x-tex">J = 11.7< / annotation>< / semantics>< / com:Math>, 2.2 Hz, 1H), <com:Math><semantics>4.60<annotation encoding="application / x-tex">4.60< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=6.0<annotation encoding="application / x-tex">J = 6.0< / annotation>< / semantics>< / com:Math> Hz, 2H), <com:Math><semantics>3.71<annotation encoding="application / x-tex">3.71< / annotation>< / semantics>< / com:Math> (s, 3H); LCMS m / z= 333.15, 335.15 (M+, M+2; 30%). N2-(4-Methoxybenzyl)quinoline-2,7-diamine. [Image disponible dans le document PDF, Image available in the PDF document] A mixture of 7-bromo-N-(4-methoxybenzyl)quinolin-2-amine (0.6 g, 1.748 mmol), copper(I) iodide (0.033g, 0.175mmol), and N1,N1-dimethylethane-1,2-diamine (0.171ml, 1.748mmol) in AMMONIA (0.757 ml, 35.0 mmol) and DMSO (1ml) at 130°C for 15h. The resulting suspension was cooled to 25°C and saturated aqueous sodium sulphate solution (5mL) was added. The resulting mixture was extracted with ethyl acetate (20ml X 3). The organic layer was separated, dried over MgSO4, filtered and concentrated. This residue was purified by combiflash (R<com:Sub>f< / com:Sub>200, Teledyne / Isco) instrument onto a redisep® R<com:Sub>f< / com:Sub> column with gradient elution (0-5%) of methanol in dichloromethane to afford the title compound (0.18g, 36.9%) as a brown solid. <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) δ 7.55 (d, J <com:Math><semantics>=8.7 Hz,1H,7.34−7.29 (m, 2H),7.25 (d, J=8.4 Hz,1H),7.07 (t, J=5.8 Hz,1H),6.91<annotation encoding="application / x-tex">= 8.7 \text{ Hz}, 1\text{H}, 7.34 - 7.29 \text{ (m, 2H)}, 7.25 \text{ (d, J} = 8.4 \text{ Hz}, 1\text{H)}, 7.07 \text{ (t, J} = 5.8 \text{ Hz}, 1\text{H)}, 6.91< / annotation>< / semantics>< / com:Math> <com:Math><semantics>−6.83<annotation encoding="application / x-tex">-6.83< / annotation>< / semantics>< / com:Math> (m, 2H), <com:Math><semantics>6.56<annotation encoding="application / x-tex">6.56< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=2.2<annotation encoding="application / x-tex">J = 2.2< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>6.52<annotation encoding="application / x-tex">6.52< / annotation>< / semantics>< / com:Math> (dd, <com:Math><semantics>J=8.4<annotation encoding="application / x-tex">J = 8.4< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>2.2<annotation encoding="application / x-tex">2.2< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>6.40<annotation encoding="application / x-tex">6.40< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=8.7<annotation encoding="application / x-tex">J = 8.7< / annotation>< / semantics>< / com:Math> Hz, 1H), 5.32 (s, 2H), 4.49 (d, <com:Math><semantics>J=5.8 Hz<annotation encoding="application / x-tex">J = 5.8 \text{ Hz}< / annotation>< / semantics>< / com:Math>, 2H), 3.72 (s, 3H); LCMS m / z= 280.2 (M+1, 100%). N2-(4-Methoxybenzyl)-N7-methylquinoline-2,7-diamine. [Image disponible dans le document PDF, Image available in the PDF document] A mixture of 7-bromo-N-(4-methoxybenzyl)quinolin-2-amine (0.5 g, 1.457 mmol), methanamine (7.54 ml, 7.28 mmol) and copper (0.046 g, 0.728 mmol) was stirred at 110°C in a sealed tube for 12h. The reaction mixture was diluted with ethyl acetate (20ml) and washed with water (20ml). The organic layer was separated, dried over MgSO<com:Sub>4< / com:Sub>, filtered and concentrated. This residue was purified by combiflash (R<com:Sub>f< / com:Sub>200, Teledyne / Isco) instrument onto a redisep® R<com:Sub>f< / com:Sub> column with gradient elution (0-5%) of methanol in dichloromethane to afford the title compound (0.4g, 94%) as a brown liquid. LCMS m / z= 294.09 (M+1; 100%). S-(2-((4-Methoxybenzyl)amino)quinolin-7-yl) ethanethioate. [Image disponible dans le document PDF, Image available in the PDF document] To a stirred solution of 7-bromo-N-(4-methoxybenzyl)quinolin-2-amine (2g, 5.83mmol), potassium thioacetate (1.331g, 11.65mmol), DIEA (2.035ml, 11.65mmol) and xantphos (0.337g, 0.583mmol) in 1,4-dioxane (20ml) was added Pd<com:Sub>2< / com:Sub>(dba)<com:Sub>3< / com:Sub> (0.534g, 0.583mmol) at 25°C under N<com:Sub>2< / com:Sub> atmosphere. The resulting mixture was stirred at 110°C for 1.5h under microwave condition. The reaction mixture was diluted with ethyl acetate (20ml) and washed with water (20ml). The organic layer was separated, dried over MgSO<com:Sub>4< / com:Sub>, filtered and concentrated. This residue was purified by combiflash (R<com:Sub>f< / com:Sub>200, Teledyne / Isco) instrument onto a redisep® R<com:Sub>f< / com:Sub> column with gradient elution (0-20%) of ethyl acetate in petroleum ether to afford the title compound (0.67g, 34%) as an off-white solid. <com:Sup>1< / com:Sup>H NMR (400 MHz, Chloroform-d) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 7.87 – 7.80 (m, 2H), 7.63 (d, J = 8.3 Hz, 1H), 7.39 – 7.32 (m, 2H), 7.28 – <com:Math><semantics>7.23<annotation encoding="application / x-tex">7.23< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>6.95−6.87<annotation encoding="application / x-tex">6.95 - 6.87< / annotation>< / semantics>< / com:Math> (m, 2H), <com:Math><semantics>6.67<annotation encoding="application / x-tex">6.67< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=9.0<annotation encoding="application / x-tex">J = 9.0< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>5.21<annotation encoding="application / x-tex">5.21< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>4.67<annotation encoding="application / x-tex">4.67< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=5.4<annotation encoding="application / x-tex">J = 5.4< / annotation>< / semantics>< / com:Math> Hz, 2H), 3.82 (s, 3H), 2.47 (s, 3H); LCMS <com:Math><semantics>m / z=339.22<annotation encoding="application / x-tex">m / z = 339.22< / annotation>< / semantics>< / com:Math> (M+1; 100%). 2-((4-Methoxybenzyl)amino)quinoline-7-thiol. [Image disponible dans le document PDF, Image available in the PDF document] To a stirred solution of S-(2-((4-methoxybenzyl)amino)quinolin-7-yl) ethanethioate (0.67g, 1.98 mmol) in 20 mL of ethanol was added KOH (0.33 g, 5.94 mmol) at 25°C. The resulting mixture was stirred at 25°C for 1h. The reaction mixture was quenched with sat.aqueous NH<com:Sub>4< / com:Sub>Cl (20ml) and extracted with ethyl acetate (20ml). The organic layer was separated, dried over MgSO<com:Sub>4< / com:Sub>, filtered and concentrated in vacuo to give the title compound (0.56g, 95%) as a brown solid. <com:Sup>1< / com:Sup>H NMR (400 MHz, Chloroform-d) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 7.77 (d, J = 8.9 Hz, 1H), 7.64 <com:Math><semantics>(d,J=1.8 Hz,1H),7.46(d,J=8.3 Hz,1H),7.37−7.32(m,2H),7.10(dd,J=8.3,1.9 Hz,1.9 Hz)<annotation encoding="application / x-tex">(d, J = 1.8 \text{ Hz}, 1H), 7.46 (d, J = 8.3 \text{ Hz}, 1H), 7.37 - 7.32 (m, 2H), 7.10 (dd, J = 8.3, 1.9 \text{ Hz}, 1.9 \text{ Hz})< / annotation>< / semantics>< / com:Math> 1H), <com:Math><semantics>6.93−6.87<annotation encoding="application / x-tex">6.93 - 6.87< / annotation>< / semantics>< / com:Math> (m, 2H), <com:Math><semantics>6.58<annotation encoding="application / x-tex">6.58< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=8.9<annotation encoding="application / x-tex">J = 8.9< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>5.58<annotation encoding="application / x-tex">5.58< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>4.64<annotation encoding="application / x-tex">4.64< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=5.3<annotation encoding="application / x-tex">J = 5.3< / annotation>< / semantics>< / com:Math> Hz, 2H), <com:Math><semantics>3.82<annotation encoding="application / x-tex">3.82< / annotation>< / semantics>< / com:Math> (s, 3H); LCMS m / z= 297.09 (M+; 100%). S-(2-(Bis(4-methoxybenzyl)amino)-3-chloroquinolin-7-yl) ethanethioate [Image disponible dans le document PDF, Image available in the PDF document] The title compound was synthesized by following an analogous reaction protocol as was described in the preparation of S-(2-((4-methoxybenzyl)amino)quinolin-7-yl) ethanethioate. LCMS <com:Math><semantics>m / z=493.30<annotation encoding="application / x-tex">m / z = 493.30< / annotation>< / semantics>< / com:Math> (M+; 100%). 2-(Bis(4-methoxybenzyl)amino)-3-chloroquinoline-7-thiol [Image disponible dans le document PDF, Image available in the PDF document] To a solution of S-(2-(bis(4-methoxybenzyl)amino)-3-chloroquinolin-7-yl) ethanethioate (300 mg, 0.608 mmol) in ethanol (9 ml) was added KOH (51.2 mg, 0.913 mmol) at 25°C. The mixture was heated at 50°C for 2h. The reaction solution was allowed to cool to 25°C, adjusted pH to 4 with HCl (1N) and concentrated in vacuo to get 0.4g of crude compound, which was triturated with diethyl ether (20ml) to get the title compound <com:Math><semantics>(200 mg,72.9%)<annotation encoding="application / x-tex">(200 \text{ mg}, 72.9\%)< / annotation>< / semantics>< / com:Math> as an off-white solid. LCMS m / z = <com:Math><semantics>450.42<annotation encoding="application / x-tex">450.42< / annotation>< / semantics>< / com:Math> (M+; <com:Math><semantics>100%<annotation encoding="application / x-tex">100\%< / annotation>< / semantics>< / com:Math>). ((3aR,6R,6aS)-6-(4-Chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-6,6a- dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methanol [Image disponible dans le document PDF, Image available in the PDF document] The title compound was prepared by following the same reaction protocol as was described in Kenneth A. Jacobson et.al; Purinergic Signalling (2015) 11:371–387. ((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)methyl 4-methylbenzenesulfonate [Image disponible dans le document PDF, Image available in the PDF document] To a stirred solution of ((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)methanol (0.5 g, 1.554 mmol) in dichloromethane (10ml) was added TEA (0.651 ml, 4.66 mmol), DMAP (0.038 g, 0.311 mmol), followed by a slow addition of p-TsCl (0.355 g, 1.865 mmol) at 0°C and stirred for 10mins. The resulting mixture was stirred at 25°C for 2h. The reaction mixture was diluted with ethyl acetate (20ml) and washed with water (20ml). The organic layer was separated, dried over MgSO<com:Sub>4< / com:Sub>, filtered and concentrated in vacuo to give 0.71g of crude compound. This residue was purified by combiflash (R<com:Sub>f< / com:Sub>200, Teledyne / Isco) instrument onto a redisep® R<com:Sub>f< / com:Sub> column with gradient elution (0-10%) of ethyl acetate in petroleum ether to afford the title compound (0.282g, 38.1%) as a pale yellow liquid. <com:Sup>1< / com:Sup>H NMR (400 MHz, Chloroform- d) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.69 (t, J = 2.8 Hz, 1H), 7.89 – 7.81 (m, 2H), 7.42 – 7.34 (m, 2H), 7.12 (s, 1H), 6.64 <com:Math><semantics>(d,J=3.8 Hz,1H),5.86(d,J=12.4 Hz,2H),5.36(d,J=5.6 Hz,1H),4.90−4.77(m,J=1.86m)<annotation encoding="application / x-tex">(d, J = 3.8 \text{ Hz}, 1H), 5.86 (d, J = 12.4 \text{ Hz}, 2H), 5.36 (d, J = 5.6 \text{ Hz}, 1H), 4.90 - 4.77 (m, J = 1.86 m)< / annotation>< / semantics>< / com:Math> 2H), <com:Math><semantics>4.63<annotation encoding="application / x-tex">4.63< / annotation>< / semantics>< / com:Math> (t, <com:Math><semantics>J=4.5<annotation encoding="application / x-tex">J = 4.5< / annotation>< / semantics>< / com:Math> Hz, <com:Math><semantics>1<annotation encoding="application / x-tex">1< / annotation>< / semantics>< / com:Math>H), <com:Math><semantics>2.52−2.45<annotation encoding="application / x-tex">2.52 - 2.45< / annotation>< / semantics>< / com:Math> (m, <com:Math><semantics>3<annotation encoding="application / x-tex">3< / annotation>< / semantics>< / com:Math>H), <com:Math><semantics>1.45<annotation encoding="application / x-tex">1.45< / annotation>< / semantics>< / com:Math> (s, <com:Math><semantics>3<annotation encoding="application / x-tex">3< / annotation>< / semantics>< / com:Math>H), <com:Math><semantics>1.34<annotation encoding="application / x-tex">1.34< / annotation>< / semantics>< / com:Math> (s, <com:Math><semantics>3<annotation encoding="application / x-tex">3< / annotation>< / semantics>< / com:Math>H); LCMS m / z = 476.17 (M+; 100%). (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]dioxole-6-carbaldehyde [Image disponible dans le document PDF, Image available in the PDF document] To a stirred solution of ((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)methanol (2.50g, 7.77mmol) in CH<com:Sub>2< / com:Sub>Cl<com:Sub>2< / com:Sub> (40ml) at 0°C, was added Dess-Martin Periodinane (3.95 g, 9.32 mmol) portion- wise and stirred for 1h. The reaction mixture was diluted with dichloromethane (50ml) and washed with water (50ml). The organic layer was separated, dried over MgSO<com:Sub>4< / com:Sub>, filtered and concentrated in vacuo to give 2.71g of crude compound. This residue was purified by combiflash (R<com:Sub>f< / com:Sub>200, Teledyne / Isco) instrument onto a redisep® R<com:Sub>f< / com:Sub> column with gradient elution (0-30%) of ethyl acetate in petroleum ether to afford the title compound (2.32g, 93%) as a colorless oil. <com:Sup>1< / com:Sup>H NMR (400 MHz, Chloroform-d) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 10.00 (s, 1H), 8.67 (s, 1H), 7.12 (d, <com:Math><semantics>J=3.6<annotation encoding="application / x-tex">J = 3.6< / annotation>< / semantics>< / com:Math> Hz, 1H), 6.78 (dd, <com:Math><semantics>J=2.6<annotation encoding="application / x-tex">J = 2.6< / annotation>< / semantics>< / com:Math>, 0.9 Hz, 1H), 6.69 (d, <com:Math><semantics>J=3.7<annotation encoding="application / x-tex">J = 3.7< / annotation>< / semantics>< / com:Math> Hz, 1H), 5.97 (dt, <com:Math><semantics>J=2.8,1.4 Hz,1H<annotation encoding="application / x-tex">J = 2.8, 1.4 \text{ Hz}, 1\text{H}< / annotation>< / semantics>< / com:Math>), 5.76 (dd, <com:Math><semantics>J=5.9,1.5 Hz,1H<annotation encoding="application / x-tex">J = 5.9, 1.5 \text{ Hz}, 1\text{H}< / annotation>< / semantics>< / com:Math>), 4.88 (dt, <com:Math><semantics>J=5.9,1.1 Hz,1H<annotation encoding="application / x-tex">J = 5.9, 1.1 \text{ Hz}, 1\text{H}< / annotation>< / semantics>< / com:Math>), 1.54 (s, 3H), 1.40 (s, 3H); LCMS <com:Math><semantics>m / z=320.2<annotation encoding="application / x-tex">m / z = 320.2< / annotation>< / semantics>< / com:Math> (M+1, 100%). 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 [Image disponible dans le document PDF, Image available in the PDF document] To a cooled suspension of methyl(triphenyl)phosphonium bromide (5.03g, 14.07mmol) in THF (30mL) at 0°C, was added 1M KHMDS in THF (14.07mL, 14.07mmol) slowly and stirred for 5 min. The reaction mixture was allowed to warm to 25°C and stirred for 10min. Cooled the reaction mixture to 0°C and slowly added a solution of (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]dioxole-6-carbaldehyde (1.8g, 5.63mmol) in THF (1ml). Stirred the reaction mixture at 25°C for 10min. The reaction mixture was quenched with sat.aqueous NH<com:Sub>4< / com:Sub>Cl (50ml) and extracted with ethyl acetate (50ml). The organic layer was separated, dried over Na<com:Sub>2< / com:Sub>SO<com:Sub>4< / com:Sub>, filtered and concentrated in vacuo to give 2.1g of crude compound. This residue was purified by combiflash (R<com:Sub>f< / com:Sub>200, Teledyne / Isco) instrument onto a redisep® R<com:Sub>f< / com:Sub> column with gradient elution (0-7%) of ethyl acetate in petroleum ether to afford the title compound <com:Math><semantics>(0.81g,45.3%)<annotation encoding="application / x-tex">(0.81g, 45.3\%)< / annotation>< / semantics>< / com:Math> as an off-white solid. <com:Sup>1< / com:Sup>H NMR (400 MHz, Chloroform-d) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.72 (s, 1H), <com:Math><semantics>7.11<annotation encoding="application / x-tex">7.11< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=3.6<annotation encoding="application / x-tex">J = 3.6< / annotation>< / semantics>< / com:Math> Hz, <com:Math><semantics>1H<annotation encoding="application / x-tex">1H< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>6.66−6.57<annotation encoding="application / x-tex">6.66 - 6.57< / annotation>< / semantics>< / com:Math> (m, <com:Math><semantics>2H<annotation encoding="application / x-tex">2H< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>5.94<annotation encoding="application / x-tex">5.94< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=2.6<annotation encoding="application / x-tex">J = 2.6< / annotation>< / semantics>< / com:Math> Hz, <com:Math><semantics>1H<annotation encoding="application / x-tex">1H< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>5.81−5.75<annotation encoding="application / x-tex">5.81 - 5.75< / annotation>< / semantics>< / com:Math> (m, <com:Math><semantics>2H<annotation encoding="application / x-tex">2H< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>5.57 (dd, J=6.0,1.5 Hz, 1H),5.49 (d, J=10.9 Hz, 1H),4.66 (dt, J=6.0,1.0 Hz, 1H),1.52<annotation encoding="application / x-tex">5.57 \text{ (dd, J} = 6.0, 1.5 \text{ Hz, 1H)}, 5.49 \text{ (d, J} = 10.9 \text{ Hz, 1H)}, 4.66 \text{ (dt, J} = 6.0, 1.0 \text{ Hz, 1H)}, 1.52< / annotation>< / semantics>< / com:Math> (s, 3H), 1.40 (s, 3H); LCMS m / z = 318.09 (M+1, 100%). 7-((3aS,4R,6aR)-2,2-Dimethyl-6-vinyl-4,6a-dihydro-3aH-cyclopenta [d] [1,3] dioxol- 4-yl)-4-ethyl-7H-pyrrolo[2,3-d]pyrimidine [Image disponible dans le document PDF, Image available in the PDF document] To a stirred solution 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 (500mg, 1.573mmol) in THF (1ml) and NMP (0.2ml) was added ferric acetylacetonate (55.6 mg, 0.157mmol) at 25°C. 2M Ethylmagnesium chloride in THF (1.573ml, 3.15mmol) was added dropwise and the reaction mixture was stirred for 4h. The reaction mixture was quenched with sat.aqueous NH<com:Sub>4< / com:Sub>Cl (10ml) and extracted with ethyl acetate (10ml). The organic layer was separated, dried over Na<com:Sub>2< / com:Sub>SO<com:Sub>4< / com:Sub>, filtered and concentrated in vacuo to give 0.6g of crude compound. This residue was purified by combiflash (R<com:Sub>f< / com:Sub>200, Teledyne / Isco) instrument onto a redisep® R<com:Sub>f< / com:Sub> column with gradient elution (0-90%) of ethyl acetate in petroleum ether to afford the title compound (0.28g, 57.1%) as an off-white solid. <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) δ 8.71 (s, 1H), 7.35 (d, <com:Math><semantics>J=3.6 Hz<annotation encoding="application / x-tex">J = 3.6 \text{ Hz}< / annotation>< / semantics>< / com:Math>, 1H), 6.73 (d, <com:Math><semantics>J=3.6 Hz<annotation encoding="application / x-tex">J = 3.6 \text{ Hz}< / annotation>< / semantics>< / com:Math>, 1H), 6.60 (dd, <com:Math><semantics>J=17.7<annotation encoding="application / x-tex">J = 17.7< / annotation>< / semantics>< / com:Math>, 10.8 Hz, 1H), <com:Math><semantics>5.88<annotation encoding="application / x-tex">5.88< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=2.7<annotation encoding="application / x-tex">J = 2.7< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>5.83−5.74<annotation encoding="application / x-tex">5.83 - 5.74< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>5.66−5.56<annotation encoding="application / x-tex">5.66 - 5.56< / annotation>< / semantics>< / com:Math> (m, 2H), <com:Math><semantics>5.45−5.37<annotation encoding="application / x-tex">5.45 - 5.37< / annotation>< / semantics>< / com:Math> <com:Math><semantics>(m,1H),4.67 (dd, J=6.0,1.1 Hz,1H),2.99 (q, J=7.6 Hz,2H),1.40 (s, 3H),1.30 (s, 6H);<annotation encoding="application / x-tex">(m, 1H), 4.67 \text{ (dd, } J = 6.0, 1.1 \text{ Hz}, 1H), 2.99 \text{ (q, } J = 7.6 \text{ Hz}, 2H), 1.40 \text{ (s, } 3H), 1.30 \text{ (s, } 6H);< / annotation>< / semantics>< / com:Math> LCMS <com:Math><semantics>m / z=312.21(M+1,100%)<annotation encoding="application / x-tex">m / z = 312.21 (M+1, 100\%)< / annotation>< / semantics>< / com:Math>. 7-((3aS,4R,6aR)-2,2-Dimethyl-6-vinyl-4,6a-dihydro-3aH-cyclopenta[d] [1,3]dioxol-4- yl)-4-isopropyl-7H-pyrrolo[2,3-d]pyrimidine [Image disponible dans le document PDF, Image available in the PDF document] Α solution 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 (1g, 3.15mmol), 2M isopropyl magnesium bromide in THF (5.51 ml, 11.01 mmol) and PdCl<com:Sub>2< / com:Sub>(dppf) (0.230 g, 0.315 mmol) in toluene (10 ml) was heated at 100°C for 30min. After completion of the reaction, the reaction mixture was quenched with methanol and concentrated. This residue was purified by combiflash (R<com:Sub>f< / com:Sub>200, Teledyne / Isco) instrument onto a redisep® R<com:Sub>f< / com:Sub> column with gradient elution (0-2%) of methanol in dichloromethane to afford the title compound (150mg, 14.65%) as an off-white solid. <com:Sup>1< / com:Sup>H NMR (400 MHz, Chloroform-d) δ 8.98 (s, 1H), 7.48 (d, <com:Math><semantics>J=4.0<annotation encoding="application / x-tex">J = 4.0< / annotation>< / semantics>< / com:Math> Hz, 1H), 7.11 (t, <com:Math><semantics>J=1.6<annotation encoding="application / x-tex">J = 1.6< / annotation>< / semantics>< / com:Math> Hz, 1H), 6.86 (d, <com:Math><semantics>J=4.0<annotation encoding="application / x-tex">J = 4.0< / annotation>< / semantics>< / com:Math> Hz, 1H), 3.98 (dt, <com:Math><semantics>J=4.0<annotation encoding="application / x-tex">J = 4.0< / annotation>< / semantics>< / com:Math> Hz, 1H), 3.98 (dt, <com:Math><semantics>J=4.0<annotation encoding="application / x-tex">J = 4.0< / annotation>< / semantics>< / com:Math> Hz, 1H), 3.98 (dt, <com:Math><semantics>J=4.0<annotation encoding="application / x-tex">J = 4.0< / annotation>< / semantics>< / com:Math> Hz, 1H), 3.98 (dt, <com:Math><semantics>J=4.0<annotation encoding="application / x-tex">J = 4.0< / annotation>< / semantics>< / com:Math> Hz, 1H), 3.98 (dt, <com:Math><semantics>J=4.0<annotation encoding="application / x-tex">J = 4.0< / annotation>< / semantics>< / com:Math> H 2.5, 1.2 Hz, 2H), <com:Math><semantics>3.50−3.43<annotation encoding="application / x-tex">3.50 - 3.43< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>2.66<annotation encoding="application / x-tex">2.66< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>2.20<annotation encoding="application / x-tex">2.20< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=2.4<annotation encoding="application / x-tex">J = 2.4< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>2.00<annotation encoding="application / x-tex">2.00< / annotation>< / semantics>< / com:Math> (dd, <com:Math><semantics>J=2.4<annotation encoding="application / x-tex">J = 2.4< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>2.00<annotation encoding="application / x-tex">2.00< / annotation>< / semantics>< / com:Math> (dd, <com:Math><semantics>J=2.4<annotation encoding="application / x-tex">J = 2.4< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>2.00<annotation encoding="application / x-tex">2.00< / annotation>< / semantics>< / com:Math> (dd, <com:Math><semantics>J=2.4<annotation encoding="application / x-tex">J = 2.4< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>2.00<annotation encoding="application / x-tex">2.00< / annotation>< / semantics>< / com:Math> (dd, <com:Math><semantics>J=2.4<annotation encoding="application / x-tex">J = 2.4< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>2.00<annotation encoding="application / x-tex">2.00< / annotation>< / semantics>< / com:Math> (dd 7.2, 1.0 Hz, 2H), 1.44 (dd, <com:Math><semantics>J=6.9<annotation encoding="application / x-tex">J = 6.9< / annotation>< / semantics>< / com:Math>, 3.1 Hz, 6H), 1.28 (s, 6H). 4-Cyclopropyl-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. [Image disponible dans le document PDF, Image available in the PDF document] The title compound was synthesized by following an analogous reaction protocol as was described in the preparation of 7-((3aS,4R,6aR)-2,2-dimethyl-6-vinyl-4,6a-dihydro-3aH- cyclopenta [d] [1,3] dioxol-4-yl)-4-ethyl-7H-pyrrolo[2,3-d]pyrimidine. LCMS m / z = 323.90 (M+; 100%). 1-((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)ethan-1-ol. [Image disponible dans le document PDF, Image available in the PDF document] To a stirred solution of (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]dioxole-6-carbaldehyde (2.30 g, 7.19 mmol) in THF (120ml) at -78°C, was added methylmagnesium bromide (4.80 ml, 14.39 mmol) and the reaction mixture was stirred at same temperature for 3h. The reaction mixture was quenched with a sat. aqueous NH<com:Sub>4< / com:Sub>Cl (50 ml) and extracted with ethyl acetate (50 ml). Layers were separated, the organic layer was washed with brine (50 ml) and dried over anhydrous sodium sulphate. The organic layer was filtered and concentrated in vacuo to give 2.2g of crude compound and this crude residue was purified by combiflash (Rf200, Teledyne / Isco) instrument onto a redisep® Rf column with gradient elution (0 to 20%) of ethyl acetate in petroleum ether to afford the title compound (1.82g, 75%) as a off-white solid. <com:Sup>1< / com:Sup>H NMR (400 MHz, Chloroform-d) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.70 (s, 1H), 7.11 (d, J = 3.7 Hz, 1H), 6.63 (d, <com:Math><semantics>J=3.7 Hz<annotation encoding="application / x-tex">J = 3.7 \text{ Hz}< / annotation>< / semantics>< / com:Math>, 1H), <com:Math><semantics>5.88−5.81 (m, 1H)<annotation encoding="application / x-tex">5.88 - 5.81 \text{ (m, 1H)}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>5.80−5.71 (m, 1H)<annotation encoding="application / x-tex">5.80 - 5.71 \text{ (m, 1H)}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>5.59−5.45 (m, 1H)<annotation encoding="application / x-tex">5.59 - 5.45 \text{ (m, 1H)}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>4.76−4.64 (m, 1H)<annotation encoding="application / x-tex">4.76 - 4.64 \text{ (m, 1H)}< / annotation>< / semantics>< / com:Math> <com:Math><semantics>(m,2H),1.59−1.49(m,6H),1.38(d,J=1.0Hz,3H),1.32−1.23(m,1H);LCMSm / z=1.0Hz,3H(m,2H),1.59−1.49(m,6H),1.38(d,J=1.0Hz,3H),1.32−1.23(m,1H);LCMSm / z=1.0Hz,3H(m,2H),1.59−1.49(<annotation encoding="application / x-tex">(m, 2H), 1.59 - 1.49 (m, 6H), 1.38 (d, J = 1.0 Hz, 3H), 1.32 - 1.23 (m, 1H); LCMS m / z = 1.0 Hz, 3H (m, 2H), 1.59 - 1.49 (m, 6H), 1.38 (d, J = 1.0 Hz, 3H), 1.32 - 1.23 (m, 1H); LCMS m / z = 1.0 Hz, 3H (m, 2H), 1.59 - 1.49 (< / annotation>< / semantics>< / com:Math> 336.2 (M+; 100%). 1-((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)ethan-1-one. [Image disponible dans le document PDF, Image available in the PDF document] To a stirred solution of 1-((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)ethan-1-ol (4.75 g, 14.15 mmol) in dichloromethane (45 ml) at 0 °C, was added Dess-Martin Periodinane (7.20 g, 16.97 mmol) portion-wise and stirred for 30 min. Water (50ml) was added and filtered the reaction mixture through a celite bed, washed with dichloromethane (25ml X 2). Separated the layers and the organic layer was washed with brine (50ml), dried over anhydrous sodium sulphate and concentrated in vacuo to give 4.8g crude compound. This crude residue was purified by combiflash (Rf200, Teledyne / Isco) instrument onto a redisep® Rf column with gradient elution (0 to 50%) of ethyl acetate in petroleum ether to afford the title compound (3.8g, 80%) as an off-white solid. <com:Sup>1< / com:Sup>H NMR (400 MHz, Chloroform-d) δ <com:Math><semantics>8.68<annotation encoding="application / x-tex">8.68< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>7.10<annotation encoding="application / x-tex">7.10< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=3.7<annotation encoding="application / x-tex">J = 3.7< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>6.68<annotation encoding="application / x-tex">6.68< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=3.6<annotation encoding="application / x-tex">J = 3.6< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>6.63<annotation encoding="application / x-tex">6.63< / annotation>< / semantics>< / com:Math> (dt, <com:Math><semantics>J=2.7<annotation encoding="application / x-tex">J = 2.7< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>0.7<annotation encoding="application / x-tex">0.7< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>5.96<annotation encoding="application / x-tex">5.96< / annotation>< / semantics>< / com:Math> (dt, <com:Math><semantics>J=2.8<annotation encoding="application / x-tex">J = 2.8< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>1.5<annotation encoding="application / x-tex">1.5< / annotation>< / semantics>< / com:Math> Hz, <com:Math><semantics>1H<annotation encoding="application / x-tex">1H< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>5.75<annotation encoding="application / x-tex">5.75< / annotation>< / semantics>< / com:Math> (dd, <com:Math><semantics>J=5.9<annotation encoding="application / x-tex">J = 5.9< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>1.6<annotation encoding="application / x-tex">1.6< / annotation>< / semantics>< / com:Math> Hz, <com:Math><semantics>1H<annotation encoding="application / x-tex">1H< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>4.82<annotation encoding="application / x-tex">4.82< / annotation>< / semantics>< / com:Math> (dt, <com:Math><semantics>J=5.9<annotation encoding="application / x-tex">J = 5.9< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>1.1<annotation encoding="application / x-tex">1.1< / annotation>< / semantics>< / com:Math> Hz, 1H), 2.47 (s, 3H), 1.52 (s, 3H), 1.39(s, 3H); LCMS <com:Math><semantics>m / z=334.09<annotation encoding="application / x-tex">m / z = 334.09< / annotation>< / semantics>< / com:Math> (M+; 100%). 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)propan-2-ol. [Image disponible dans le document PDF, Image available in the PDF document] To a stirred solution of 1-((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)ethan-1-one (1.0 g, 3.00 mmol) ) in THF (10 ml) at -20 °C, was added dropwise methyl magnesium bromide (1.498 ml, 4.49 mmol) and stirred the reaction mixture for 30 min at the same temperature. The reaction mixture was quenched with a sat. aqueous NH<com:Sub>4< / com:Sub>Cl (50 ml) and extracted with ethyl acetate (50 ml). Layers were separated, the organic layer was washed with brine (50 ml) and dried over anhydrous sodium sulphate. The organic layer was filtered and concentrated in vacuo to give 1.5g of crude compound and this crude residue was purified by combiflash (Rf200, Teledyne / Isco) instrument onto a redisep® Rf column with gradient elution (0 to 30%) of ethyl acetate in petroleum ether to afford the title compound (850 mg, 81%) as an off-white solid. <com:Sup>1< / com:Sup>H NMR (400 MHz, Chloroform-d) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.69 (s, 1H), 7.09 (d, J = 3.6 Hz, 1H), <com:Math><semantics>6.71−6.60<annotation encoding="application / x-tex">6.71 - 6.60< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>5.82<annotation encoding="application / x-tex">5.82< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>5.78−5.69<annotation encoding="application / x-tex">5.78 - 5.69< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>5.65−5.58<annotation encoding="application / x-tex">5.65 - 5.58< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>4.69<annotation encoding="application / x-tex">4.69< / annotation>< / semantics>< / com:Math> (dt, <com:Math><semantics>J=5.8,1.0 Hz,1H,1.59−1.53 (m, 9H),1.38 (s, 3H);LCMS m / z=350.2 (M+; 100%).<annotation encoding="application / x-tex">J = 5.8, 1.0 \text{ Hz}, 1\text{H}, 1.59 - 1.53 \text{ (m, 9H)}, 1.38 \text{ (s, 3H)}; LCMS \text{ m / z} = 350.2 \text{ (M+; } 100\%).< / annotation>< / semantics>< / com:Math> 4-Chloro-7-((3aS,4R,6aR)-2,2-dimethyl-6-(prop-1-en-2-yl)-3a,6a-dihydro-4H- cyclopenta[d][1,3]dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine. [Image disponible dans le document PDF, Image available in the PDF document] To a stirred solution of 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)propan-2-ol (8.2 g, 23.44) mmol) in dichloromethane (80ml) at 0°C was added Martin's Sulfurane (17.34 g, 25.8 mmol) and the stirred the reaction mixture for 45 min at 25°C. The reaction mixture was quenched with an sat.aq. sodium bicarbonate (100ml), extracted with dichloromethane (100ml). Layers were separated, the organic layer was washed with brine (50 ml) and was dried over anhydrous sodium sulphate. The organic layer was filtered and concentrated in vacuo to give 8.5g of crude compound. This crude residue was purified by combiflash (Rf200, Teledyne / Isco) instrument onto a redisep® Rf column with gradient elution (0 to 30%) of ethyl acetate in petroleum ether to afford the title compound (4.2g, 54.0%) as an off-white solid. <com:Sup>1< / com:Sup>H NMR (400 MHz, Chloroform-d) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.71 (s, 1H), 7.11 (d, J = 3.6 Hz, 1H), <com:Math><semantics>6.63<annotation encoding="application / x-tex">6.63< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=3.6<annotation encoding="application / x-tex">J = 3.6< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>6.00−5.94<annotation encoding="application / x-tex">6.00 - 5.94< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>5.76<annotation encoding="application / x-tex">5.76< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=2.7<annotation encoding="application / x-tex">J = 2.7< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>5.62−5.52<annotation encoding="application / x-tex">5.62 - 5.52< / annotation>< / semantics>< / com:Math> (m, 2H), 5.33 (d, <com:Math><semantics>J=1.7<annotation encoding="application / x-tex">J = 1.7< / annotation>< / semantics>< / com:Math> Hz, 1H), 4.67 (dt, <com:Math><semantics>J=6.0<annotation encoding="application / x-tex">J = 6.0< / annotation>< / semantics>< / com:Math>, 1.0 Hz, 1H), 2.03 (t, <com:Math><semantics>J=1.0<annotation encoding="application / x-tex">J = 1.0< / annotation>< / semantics>< / com:Math> Hz, 3H), 1.52 (s, 3H), 1.40 (s, 3H); LCMS <com:Math><semantics>m / z=332.28<annotation encoding="application / x-tex">m / z = 332.28< / annotation>< / semantics>< / com:Math> (M+; 100%). 7-((3aS,4R,6aR)-2,2-Dimethyl-6-(prop-1-en-2-yl)-4,6a-dihydro-3aH-cyclo penta[d][1,3] dioxol-4-yl)-4-methyl-7H-pyrrolo[2,3-d]pyrimidine [Image disponible dans le document PDF, Image available in the PDF document] To a degassed solution of 4-chloro-7-((3aS,4R,6aR)-2,2-dimethyl-6-(prop-1-en-2-yl)- 3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine (1.000 g, 3.01 mmol) in dioxane (10 ml) and water (1 ml), was added potassium phosphate, tribasic (1.575 g, 9.04 mmol), dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) (0.196 g, 0.301 mmol) and 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (4.21 ml, 30.1 mmol) at 25°C. The resulting mixture was stirred at 100°C for 50min under microwave condition. Solvent was removed and the crude residue was purified by combiflash (Rf200, Teledyne / Isco) instrument onto a redisep® Rf column with gradient elution (0 to 50%) of ethyl acetate in petroleum ether to afford the title compound (0.84g, 90%) as an off-white solid. LCMS <com:Math><semantics>m / z=312.28(M+1;100%)<annotation encoding="application / x-tex">m / z = 312.28 (M+1; 100\%)< / annotation>< / semantics>< / com:Math>. 7-((3aS,4R,6aR)-6-(((tert-Butyldiphenylsilyl)oxy)methyl)-2,2-dimethyl-3a,6a- dihydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-4-methyl-7H-pyrrolo[2,3-d]pyrimidine (A). 7-((3aS,4R,6aR)-6-(((tert-Butyldiphenylsilyl)oxy)methyl)-2,2-dimethyl-3a,6a- dihydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine (B). [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] To a degassed solution of 7-((3aS,4R,6aR)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2- dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-4-chloro-7H-pyrrolo[2,3-d] pyrimidine (5g, 8.93 mmol) in dioxane (80 ml) and water (10ml), was added potassium phosphate tribasic (4.66 g, 26.8 mmol), dichloro[1,1'-bis(di-t-butylphosphino) ferrocene]palladium(II) (0.582 g, 0.893 mmol) and 2,4,6-trimethyl-1,3,5,2,4,6- trioxatriborinane (12.48 ml, 89 mmol) at 25°C. The reaction mixture was heated at 80°C for 8h. The reaction mixture was diluted with ethyl acetate (50 ml) and washed with water (50 ml). Layers were separated and the organic layer was washed with brine (50 ml) and dried over anhydrous sodium sulphate. The organic layer was filtered and concentrated in vacuo to give 4.3g of crude compound. This crude residue was purified by combiflash (Rf200, Teledyne / Isco) instrument onto a redisep® Rf column with gradient elution (0 to 20%) of ethyl acetate in petroleum ether to afford the title compound, A (3.2g, 66%) and B (0.75g, 15.98%) as an off-white solids. <com:Sup>1< / com:Sup>H NMR of A (400 MHz, Chloroform-d) δ 8.83 (s, 1H), 7.71 (tt, <com:Math><semantics>J=6.6<annotation encoding="application / x-tex">J = 6.6< / annotation>< / semantics>< / com:Math>, 1.5 Hz, 4H), 7.48 – 7.37 (m, 6H), 6.91 (d, <com:Math><semantics>J=3.6<annotation encoding="application / x-tex">J = 3.6< / annotation>< / semantics>< / com:Math> Hz, 1H), 6.57 (d, <com:Math><semantics>J=3.6 Hz<annotation encoding="application / x-tex">J = 3.6 \text{ Hz}< / annotation>< / semantics>< / com:Math>, 1H), 5.88 (s, 2H), 5.25 (d, <com:Math><semantics>J=5.7 Hz<annotation encoding="application / x-tex">J = 5.7 \text{ Hz}< / annotation>< / semantics>< / com:Math>, 1H), 4.60 (d, <com:Math><semantics>J=5.7 Hz<annotation encoding="application / x-tex">J = 5.7 \text{ Hz}< / annotation>< / semantics>< / com:Math>, 1H), 4.55 – <com:Math><semantics>4.45<annotation encoding="application / x-tex">4.45< / annotation>< / semantics>< / com:Math> (m, 2H), <com:Math><semantics>2.77<annotation encoding="application / x-tex">2.77< / annotation>< / semantics>< / com:Math> (s, 3H), <com:Math><semantics>1.45<annotation encoding="application / x-tex">1.45< / annotation>< / semantics>< / com:Math> (s, 3H), <com:Math><semantics>1.32<annotation encoding="application / x-tex">1.32< / annotation>< / semantics>< / com:Math> (s, 3H), <com:Math><semantics>1.11<annotation encoding="application / x-tex">1.11< / annotation>< / semantics>< / com:Math> (s, 9H); LCMS m / z = <com:Math><semantics>540.4<annotation encoding="application / x-tex">540.4< / annotation>< / semantics>< / com:Math> (M+1; 100%); <com:Sup>1< / com:Sup>H NMR of B (400 MHz, Chloroform-d) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 7.71 (tt, <com:Math><semantics>J=6.6<annotation encoding="application / x-tex">J = 6.6< / annotation>< / semantics>< / com:Math>, 1.5 Hz, 4H), <com:Math><semantics>7.53−7.35<annotation encoding="application / x-tex">7.53 - 7.35< / annotation>< / semantics>< / com:Math> (m, 6H), 6.98 (d, <com:Math><semantics>J=3.6<annotation encoding="application / x-tex">J = 3.6< / annotation>< / semantics>< / com:Math> Hz, 1H), 6.57 (d, <com:Math><semantics>J=3.6<annotation encoding="application / x-tex">J = 3.6< / annotation>< / semantics>< / com:Math> Hz, 1H), 5.90 (d, <com:Math><semantics>J=14.5<annotation encoding="application / x-tex">J = 14.5< / annotation>< / semantics>< / com:Math> Hz, 2H), 5.26 (d, <com:Math><semantics>J=5.7<annotation encoding="application / x-tex">J = 5.7< / annotation>< / semantics>< / com:Math> Hz, 1H), 4.61 (d, <com:Math><semantics>J=5.7<annotation encoding="application / x-tex">J = 5.7< / annotation>< / semantics>< / com:Math> Hz, 1H), 4.51 (d, <com:Math><semantics>J=9.3<annotation encoding="application / x-tex">J = 9.3< / annotation>< / semantics>< / com:Math> Hz, 2H), 1.46 (s, 3H), 1.33 (s, 3H), 1.28 (s, 2H), 1.11 (s, 9H); LCMS m / z = 526.44 (M+1; 100%). ((3aS,4R,6aR)-2,2-dimethyl-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3a,6a- dihydro-4H-cyclopenta[d][1,3]dioxol-6-yl)methanol [Image disponible dans le document PDF, Image available in the PDF document] To a stirred solution of 7-((3aS,4R,6aR)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2- dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-4-methyl-7H-pyrrolo[2,3- d]pyrimidine (3.20 g, 5.93 mmol) in THF (20 ml), was slowly added TBAF (8.89 ml, 8.89 mmol) at 25°C and stirred the reaction mixture at 25°C for 15h. Volatiles were removed in vacuo and the crude residue was purified by combiflash (R<com:Sub>f< / com:Sub>200, Teledyne / Isco) instrument onto a redisep® R<com:Sub>f< / com:Sub> column with gradient elution (0 to 100%) of ethyl acetate in petroleum ether to afford the title compound (1.5g, 84%) as an off-white solid. <com:Sup>1< / com:Sup>H NMR (400 MHz, Chloroform-d) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.81 (s, 1H), 7.06 (d, <com:Math><semantics>J=3.6<annotation encoding="application / x-tex">J = 3.6< / annotation>< / semantics>< / com:Math> Hz, 1H), 6.55 (d, <com:Math><semantics>J=3.6<annotation encoding="application / x-tex">J = 3.6< / annotation>< / semantics>< / com:Math> Hz, 1H), 5.90 – 5.78 (m, 2H), 5.41 (ddd, <com:Math><semantics>J=5.8<annotation encoding="application / x-tex">J = 5.8< / annotation>< / semantics>< / com:Math>, 1.7, 0.9 Hz, 1H), 4.65 (dt, <com:Math><semantics>J=5.8<annotation encoding="application / x-tex">J = 5.8< / annotation>< / semantics>< / com:Math>, 0.9 Hz, 1H), 4.56 – 4.42 (m, 2H), 3.35 (d, <com:Math><semantics>J=8.2<annotation encoding="application / x-tex">J = 8.2< / annotation>< / semantics>< / com:Math> Hz, 1H), 2.74 (s, 3H), 1.53 (s, 3H), 1.37 (s, 3H); LCMS m / z <com:Math><semantics>=302.21(M+1;100%)<annotation encoding="application / x-tex">= 302.21 (M+1; 100\%)< / annotation>< / semantics>< / com:Math>. (3aS,4R,6aR)-2,2-Dimethyl-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3a,6a- dihydro-4H-cyclopenta[d][1,3]dioxole-6-carbaldehyde. [Image disponible dans le document PDF, Image available in the PDF document] To a stirred solution of 7-((3aS,4R,6aR)-6-(((tert-Butyldiphenylsilyl)oxy)methyl)-2,2- dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine (1.50 g, 4.98 mmol) in dichloromethane (100 ml) at 0°C, was added Dess-Martin Periodinane (2.53 g, 5.97 mmol) portion-wise and stirred for 1h. The reaction mixture was diluted with methylene chloride (50 ml) and washed with water (50 ml). Layers were separated, the organic layer was washed with brine (50 ml) and dried over anhydrous sodium sulphate. The organic layer was filtered and concentrated in vacuo to give a crude compound and this crude residue was purified by combiflash (Rf200, Teledyne / Isco) instrument onto a redisep® Rf column with gradient elution (0 to 30%) of ethyl acetate in petroleum ether to afford the title compound (0.95g, 63.8%) as an off-white solid. <com:Sup>1< / com:Sup>H NMR (400 MHz, Chloroform-d) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 10.00 (s, 1H), 8.80 (s, 1H), 7.02 (d, <com:Math><semantics>J=3.6<annotation encoding="application / x-tex">J = 3.6< / annotation>< / semantics>< / com:Math> Hz, 1H), 6.82 – 6.76 (m, 1H), 6.63 (d, <com:Math><semantics>J=3.6<annotation encoding="application / x-tex">J = 3.6< / annotation>< / semantics>< / com:Math> Hz, 1H), 6.00 (dt, <com:Math><semantics>J=2.7<annotation encoding="application / x-tex">J = 2.7< / annotation>< / semantics>< / com:Math>, 1.4 Hz, 1H), 5.76 (dd, <com:Math><semantics>J=5.9<annotation encoding="application / x-tex">J = 5.9< / annotation>< / semantics>< / com:Math>, 1.5 Hz, 1H), 4.87 (dt, <com:Math><semantics>J=5.9<annotation encoding="application / x-tex">J = 5.9< / annotation>< / semantics>< / com:Math>, 1.1 Hz, 1H), 2.77 (s, 3H), 1.53 (s, 3H), 1.38 (s, 3H); LCMS <com:Math><semantics>m / z=300.15(M+1;100%)<annotation encoding="application / x-tex">m / z = 300.15 (M+1; 100\%)< / annotation>< / semantics>< / com:Math> 7-((3aS,4R,6aR)-2,2-Dimethyl-6-vinyl-3a,6a-dihydro-4H-cyclopenta[d] [1,3]dioxol-4- yl)-4-methyl-7H-pyrrolo[2,3-d]pyrimidine. [Image disponible dans le document PDF, Image available in the PDF document] The title compound was synthesized by following an analogous reaction protocol as was described in the preparation 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. <com:Sup>1< / com:Sup>H NMR (400 MHz, Chloroform-d) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.83 (s, 1H), 7.01 (d, J = 3.6 Hz, 1H), 6.68 – 6.53 (m, 2H), 5.95 (d, <com:Math><semantics>J=2.5 Hz<annotation encoding="application / x-tex">J = 2.5 \text{ Hz}< / annotation>< / semantics>< / com:Math>, 1H), <com:Math><semantics>5.80−5.71 (m, 2H)<annotation encoding="application / x-tex">5.80 - 5.71 \text{ (m, 2H)}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>5.56 (dd, J=6.0,1.4 Hz<annotation encoding="application / x-tex">5.56 \text{ (dd, } J = 6.0, 1.4 \text{ Hz}< / annotation>< / semantics>< / com:Math>, 1H), <com:Math><semantics>5.47 (d, J=10.8 Hz<annotation encoding="application / x-tex">5.47 \text{ (d, } J = 10.8 \text{ Hz}< / annotation>< / semantics>< / com:Math>, 1H), <com:Math><semantics>4.65<annotation encoding="application / x-tex">4.65< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=5.8<annotation encoding="application / x-tex">J = 5.8< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>2.75<annotation encoding="application / x-tex">2.75< / annotation>< / semantics>< / com:Math> (s, 3H), <com:Math><semantics>1.52<annotation encoding="application / x-tex">1.52< / annotation>< / semantics>< / com:Math> (s, 3H), <com:Math><semantics>1.40<annotation encoding="application / x-tex">1.40< / annotation>< / semantics>< / com:Math> (s, 3H); LCMS m / z = 298.5 <com:Math><semantics>(M+1;100%)<annotation encoding="application / x-tex">(M+1; 100\%)< / annotation>< / semantics>< / com:Math>. ((3aS,4R,6aR)-2,2-Dimethyl-4-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3a,6a-dihydro-4H- cyclopenta[d][1,3]dioxol-6-yl)methanol. [Image disponible dans le document PDF, Image available in the PDF document] The title compound was synthesized by following an analogous reaction protocol as was described in the preparation of 7-((3aS,4R,6aR)-6-(((tert-butyldiphenylsilyl)oxy)methyl)- 2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-7H-pyrrolo[2,3- d]pyrimidine. LCMS m / z = <com:Math><semantics>287.90<annotation encoding="application / x-tex">287.90< / annotation>< / semantics>< / com:Math> (M+; <com:Math><semantics>100%<annotation encoding="application / x-tex">100\%< / annotation>< / semantics>< / com:Math>). (3aS,4R,6aR)-2,2-Dimethyl-4-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3a,6a-dihydro-4H- cyclopenta[d][1,3]dioxole-6-carbaldehyde. [Image disponible dans le document PDF, Image available in the PDF document] The title compound was synthesized by following an analogous reaction protocol as was described in the preparation of (3aS,4R,6aR)-2,2-Dimethyl-4-(4-methyl-7H-pyrrolo[2,3- d]pyrimidin-7-yl)-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxole-6-carbaldehyde. <com:Sup>1< / com:Sup>H NMR (400 MHz, Chloroform-d) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 10.01 (s, 1H), 9.04 (s, 1H), 8.93 (s, 1H), 7.11 (d, <com:Math><semantics>J=3.6<annotation encoding="application / x-tex">J = 3.6< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>6.83−6.77<annotation encoding="application / x-tex">6.83 - 6.77< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>6.67<annotation encoding="application / x-tex">6.67< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=3.7<annotation encoding="application / x-tex">J = 3.7< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>6.03<annotation encoding="application / x-tex">6.03< / annotation>< / semantics>< / com:Math> (dt, <com:Math><semantics>J=2.8<annotation encoding="application / x-tex">J = 2.8< / annotation>< / semantics>< / com:Math>, 1.4 Hz, 1H), <com:Math><semantics>5.77<annotation encoding="application / x-tex">5.77< / annotation>< / semantics>< / com:Math> <com:Math><semantics>(dd,J=5.9,1.5Hz,1H),4.89(dt,J=6.0,1.2Hz,1H),1.54(s,3H),1.41(s,3H);<annotation encoding="application / x-tex">(dd, J = 5.9, 1.5 Hz, 1H), 4.89 (dt, J = 6.0, 1.2 Hz, 1H), 1.54 (s, 3H), 1.41 (s, 3H);< / annotation>< / semantics>< / com:Math> LCMS <com:Math><semantics>m / z=286.09(M+;100%)<annotation encoding="application / x-tex">m / z = 286.09 (M+; 100\%)< / annotation>< / semantics>< / com:Math>. 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. [Image disponible dans le document PDF, Image available in the PDF document] The title compound was synthesized by following an analogous reaction protocol as was described in the preparation 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. <com:Sup>1< / com:Sup>H NMR (400 MHz, Chloroform-d) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.97 (d, <com:Math><semantics>J=15.8<annotation encoding="application / x-tex">J = 15.8< / annotation>< / semantics>< / com:Math> Hz, 2H), 7.09 (d, <com:Math><semantics>J=3.7<annotation encoding="application / x-tex">J = 3.7< / annotation>< / semantics>< / com:Math> Hz, 1H), 6.68 – 6.56 (m, 2H), 5.98 (d, <com:Math><semantics>J=2.7<annotation encoding="application / x-tex">J = 2.7< / annotation>< / semantics>< / com:Math> Hz, 1H), 5.82 – 5.72 (m, 2H), 5.60 – 5.54 (m, 1H), 5.52 – 5.44 (m, 1H), 4.66 (dt, <com:Math><semantics>J=5.8<annotation encoding="application / x-tex">J = 5.8< / annotation>< / semantics>< / com:Math>, 1.0 Hz, 1H), 1.52 (s, 3H), 1.40 (s, 3H); LCMS m / z = 284.04 (M+1; 100%). 7-((3aS,4R,6aR)-6-(((tert-Butyldiphenylsilyl)oxy)methyl)-2,2-dimethyl-4,6a-dihydro- 3aH-cyclopenta[d][1,3]dioxol-4-yl)-4-chloro-5-fluoro-7H-pyrrolo[2,3-d] pyrimidine [Image disponible dans le document PDF, Image available in the PDF document] To a stirred solution of (3aS,4S,6aR)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2- dimethyl-3a,6a-dihydro-4H-cyclo penta[d][1,3]dioxol-4-ol (3.5 g, 8.24 mmol) in THF (50 ml) was added 4-chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine (3.54 g, 20.61 mmol, which was synthesized by following the same reaction protocol as was described in WO2005 / 16878, A2), triphenylphosphine (5.40 g, 20.61 mmol), DIAD (4.01 ml, 20.61 mmol) at 0°C and stirred for 30 min. The resulting reaction mixture was stirred at 25°C for 16h. Volatiles were removed in vacuo and the crude residue was purified by combiflash (Rf200, Teledyne / Isco) instrument onto a redisep® Rf column with gradient elution (0 to 10%) of ethyl acetate in petroleum ether to afford the title compound (2.7g, 56.7%) as an off-white solid. LCMS <com:Math><semantics>m / z=577.94<annotation encoding="application / x-tex">m / z = 577.94< / annotation>< / semantics>< / com:Math> (M+; 100%). ((3aR,6R,6aS)-6-(4-Chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl- 6,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methanol [Image disponible dans le document PDF, Image available in the PDF document] The title compound was synthesized by following an analogous reaction protocol as was described in the preparation of 7-((3aS,4R,6aR)-6-(((tert-butyldiphenylsilyl)oxy)methyl)- 2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-7H-pyrrolo[2,3- d]pyrimidine. LCMS <com:Math><semantics>m / z=340.03<annotation encoding="application / x-tex">m / z = 340.03< / annotation>< / semantics>< / com:Math> (M+; 100%). (3aR,6R,6aS)-6-(4-Chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl- 6,6a-dihydro-3aH-cyclopenta[d][1,3]dioxole-4-carbaldehyde [Image disponible dans le document PDF, Image available in the PDF document] The title compound was synthesized by following an analogous reaction protocol as was described in the preparation of (3aS,4R,6aR)-2,2-Dimethyl-4-(4-methyl-7H-pyrrolo[2,3- d]pyrimidin-7-yl)-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxole-6-carbaldehyde. <com:Sup>1< / com:Sup>H NMR <com:Math><semantics>(400 MHz, DMSO-d6)δ9.90 (s, 1H),8.73 (s, 1H),7.80 (d, J=2.0 Hz, 1H),7.10−7.03<annotation encoding="application / x-tex">(400 \text{ MHz}, \text{ DMSO-d6}) \delta 9.90 \text{ (s, 1H)}, 8.73 \text{ (s, 1H)}, 7.80 \text{ (d, J} = 2.0 \text{ Hz, 1H)}, 7.10 - 7.03< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>6.01<annotation encoding="application / x-tex">6.01< / annotation>< / semantics>< / com:Math> (dq, <com:Math><semantics>J=2.7<annotation encoding="application / x-tex">J = 2.7< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>1.4<annotation encoding="application / x-tex">1.4< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>5.57<annotation encoding="application / x-tex">5.57< / annotation>< / semantics>< / com:Math> (dd, <com:Math><semantics>J=6.0<annotation encoding="application / x-tex">J = 6.0< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>1.5<annotation encoding="application / x-tex">1.5< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>4.80<annotation encoding="application / x-tex">4.80< / annotation>< / semantics>< / com:Math> (dt, <com:Math><semantics>J=6.0<annotation encoding="application / x-tex">J = 6.0< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>1.2<annotation encoding="application / x-tex">1.2< / annotation>< / semantics>< / com:Math> Hz, 1H), 1.39 (s, 3H), 1.28 (s, 3H); LCMS <com:Math><semantics>m / z=338.03<annotation encoding="application / x-tex">m / z = 338.03< / annotation>< / semantics>< / com:Math> (M+; 100%). 4-Chloro-7-((3aS,4R,6aR)-2,2-dimethyl-6-vinyl-4,6a-dihydro-3aH-cyclopenta[d] [1,3] dioxol-4-yl)-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine [Image disponible dans le document PDF, Image available in the PDF document] The title compound was synthesized by following an analogous reaction protocol as was described in the preparation 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. <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-<com:Math><semantics>d6<annotation encoding="application / x-tex">d_6< / annotation>< / semantics>< / com:Math>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.71 (s, 1H), 7.66 (d, <com:Math><semantics>J=2.0<annotation encoding="application / x-tex">J = 2.0< / annotation>< / semantics>< / com:Math> Hz, 1H), 6.66 – 6.52 (m, 1H), 5.90 – 5.78 (m, 2H), <com:Math><semantics>5.67−5.55<annotation encoding="application / x-tex">5.67 - 5.55< / annotation>< / semantics>< / com:Math> (m, 2H), <com:Math><semantics>5.47−5.36<annotation encoding="application / x-tex">5.47 - 5.36< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>4.71<annotation encoding="application / x-tex">4.71< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=6.0<annotation encoding="application / x-tex">J = 6.0< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>1.38<annotation encoding="application / x-tex">1.38< / annotation>< / semantics>< / com:Math> (s, 3H), 1.31 (s, 3H); LCMS <com:Math><semantics>m / z=336.03<annotation encoding="application / x-tex">m / z = 336.03< / annotation>< / semantics>< / com:Math> (M+; 100%). 7-((3aS,4R,6aR)-6-(((tert-Butyldiphenylsilyl)oxy)methyl)-2,2-dimethyl-4,6a-dihydro- 3aH-cyclopenta[d][1,3]dioxol-4-yl)-2-chloro-7H-pyrrolo[2,3-d]pyrimidine [Image disponible dans le document PDF, Image available in the PDF document] To a stirred solution of (3aS,4S,6aR)-6-(((tert-Butyldiphenylsilyl)oxy)methyl)-2,2- dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-ol (1.2g, 2.83 mmol) in THF (15ml) was added 2-chloro-7H-pyrrolo[2,3-d]pyrimidine (0.738 g, 4.80 mmol), triphenylphosphine (2.59 g, 9.89 mmol) and DIAD (1.923 ml, 9.89 mmol) slowly at 0°C and stirred for 5mins. The reaction mixture was brought to 25°C and stirred for 1h. Volatiles were removed in vacuo and the crude residue was purified by combiflash (Rf200, Teledyne / Isco) instrument onto a redisep® Rf column with gradient elution (0 to 15%) of ethyl acetate in petroleum ether to afford the title compound (1.1g, 69.5%) as an off-white solid. <com:Sup>1< / com:Sup>H NMR (400 MHz, Chloroform-d) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.84 (s, 1H), 7.70 (ddt, <com:Math><semantics>J=6.6,5.0,1.5<annotation encoding="application / x-tex">J = 6.6, 5.0, 1.5< / annotation>< / semantics>< / com:Math> Hz, 4H), <com:Math><semantics>7.50−7.34<annotation encoding="application / x-tex">7.50 - 7.34< / annotation>< / semantics>< / com:Math> (m, 6H), <com:Math><semantics>6.94<annotation encoding="application / x-tex">6.94< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=3.6<annotation encoding="application / x-tex">J = 3.6< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>6.59<annotation encoding="application / x-tex">6.59< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=3.6<annotation encoding="application / x-tex">J = 3.6< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>5.84<annotation encoding="application / x-tex">5.84< / annotation>< / semantics>< / com:Math> (dt, <com:Math><semantics>J=<annotation encoding="application / x-tex">J =< / annotation>< / semantics>< / com:Math> 19.8, 2.2 Hz, 2H), 5.30 (d, <com:Math><semantics>J=5.7<annotation encoding="application / x-tex">J = 5.7< / annotation>< / semantics>< / com:Math> Hz, 1H), 4.63 (d, <com:Math><semantics>J=5.6<annotation encoding="application / x-tex">J = 5.6< / annotation>< / semantics>< / com:Math> Hz, 1H), 4.57 – 4.42 (m, 2H), 1.43 (s, 3H), 1.33 (s, 3H), 1.10 (s, 9H); LCMS <com:Math><semantics>m / z=560.3<annotation encoding="application / x-tex">m / z = 560.3< / annotation>< / semantics>< / com:Math> (M+; 100). ((3aR,6R,6aS)-6-(2-Chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-6,6a- dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methanol [Image disponible dans le document PDF, Image available in the PDF document] To a stirred solution of 7-((3aS,4R,6aR)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2- dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-2-chloro-7H-pyrrolo[2,3- d]pyrimidine (500 mg, 0.893 mmol) in THF (5 ml) at 0 °C, was added TBAF (1.250 ml, 1.250 mmol) slowly and stirred the reaction mixture at the same temperature for 10 min. The reaction mixture was brought to 25°C and stirred for 30mins. Volatiles were removed in vacuo and the crude residue was purified by combiflash (Rf200, Teledyne / Isco) instrument onto a redisep® Rf column with gradient elution (0 to 40%) of ethyl acetate in petroleum ether to afford the title compound (0.27g, 94%) as a colourless oil. <com:Sup>1< / com:Sup>H NMR (400 MHz, Chloroform-d) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.81 (s, 1H), 7.28 (s, 1H), 7.08 (d, J = 3.7 Hz, 1H), 6.57 (d, J = 3.7 Hz, 1H), <com:Math><semantics>5.92−5.62<annotation encoding="application / x-tex">5.92 - 5.62< / annotation>< / semantics>< / com:Math> (m, 2H), <com:Math><semantics>5.47<annotation encoding="application / x-tex">5.47< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=5.7<annotation encoding="application / x-tex">J = 5.7< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>4.69<annotation encoding="application / x-tex">4.69< / annotation>< / semantics>< / com:Math> (dt, <com:Math><semantics>J=5.6<annotation encoding="application / x-tex">J = 5.6< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>0.9<annotation encoding="application / x-tex">0.9< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>4.59<annotation encoding="application / x-tex">4.59< / annotation>< / semantics>< / com:Math> <com:Math><semantics>−4.37<annotation encoding="application / x-tex">-4.37< / annotation>< / semantics>< / com:Math> (m, 2H), 1.52 (s, 3H), 1.38 (s, 3H); LCMS m / z = 321.09 (M+; 100). (3aR,6R,6aS)-6-(2-Chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-6,6a- dihydro-3aH-cyclopenta[d][1,3]dioxole-4-carbaldehyde [Image disponible dans le document PDF, Image available in the PDF document] The title compound was synthesized by following an analogous reaction protocol as was described in the preparation of (3aS,4R,6aR)-2,2-Dimethyl-4-(4-methyl-7H-pyrrolo[2,3- d]pyrimidin-7-yl)-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxole-6-carbaldehyde. <com:Sup>1< / com:Sup>H NMR (400 MHz, Chloroform-d) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 9.99 (s, 1H), 8.86 (s, 1H), 7.04 (d, <com:Math><semantics>J=3.7<annotation encoding="application / x-tex">J = 3.7< / annotation>< / semantics>< / com:Math> Hz, 1H), 6.75 (dd, <com:Math><semantics>J=2.6,0.9 Hz,1H<annotation encoding="application / x-tex">J = 2.6, 0.9 \text{ Hz}, 1\text{H}< / annotation>< / semantics>< / com:Math>), 6.65 (d, <com:Math><semantics>J=3.7 Hz,1H<annotation encoding="application / x-tex">J = 3.7 \text{ Hz}, 1\text{H}< / annotation>< / semantics>< / com:Math>), 6.00 (dt, <com:Math><semantics>J=2.7,1.4 Hz,1H<annotation encoding="application / x-tex">J = 2.7, 1.4 \text{ Hz}, 1\text{H}< / annotation>< / semantics>< / com:Math>), 5.77 (dd, <com:Math><semantics>J=2.6,0.9 Hz<annotation encoding="application / x-tex">J = 2.6, 0.9 \text{ Hz}< / annotation>< / semantics>< / com:Math>), 6.65 (d, <com:Math><semantics>J=3.7 Hz,1H<annotation encoding="application / x-tex">J = 3.7 \text{ Hz}, 1\text{H}< / annotation>< / semantics>< / com:Math>), 6.00 (dt, <com:Math><semantics>J=2.7,1.4 Hz,1Hz<annotation encoding="application / x-tex">J = 2.7, 1.4 \text{ Hz}, 1\text{Hz}< / annotation>< / semantics>< / com:Math>), 5.7 <com:Math><semantics>=5.9,1.5 Hz,1H,4.88 (dd, J=5.9,1.2 Hz,1H),1.53 (s, 3H),1.40 (s, 3H);LCMSm / z<annotation encoding="application / x-tex">= 5.9, 1.5 \text{ Hz}, 1\text{H}, 4.88 \text{ (dd, } J = 5.9, 1.2 \text{ Hz}, 1\text{H}), 1.53 \text{ (s, 3H)}, 1.40 \text{ (s, 3H)}; LCMS m / z< / annotation>< / semantics>< / com:Math> <com:Math><semantics>=319.90(M+;100).<annotation encoding="application / x-tex">= 319.90 (M+; 100).< / annotation>< / semantics>< / com:Math> 2-Chloro-7-((3aS,4R,6aR)-2,2-dimethyl-6-vinyl-4,6a-dihydro-3aH- cyclopenta[d][1,3]dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine [Image disponible dans le document PDF, Image available in the PDF document] The title compound was synthesized by following an analogous reaction protocol as was described in the preparation 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. <com:Sup>1< / com:Sup>H NMR (400 MHz, Chloroform-d) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.82 (s, 1H), 7.03 (d, <com:Math><semantics>J=3.6<annotation encoding="application / x-tex">J = 3.6< / annotation>< / semantics>< / com:Math> Hz, 1H), 6.64 – 6.53 (m, 2H), 5.93 (d, <com:Math><semantics>J=2.6 Hz<annotation encoding="application / x-tex">J = 2.6 \text{ Hz}< / annotation>< / semantics>< / com:Math>, 1H), <com:Math><semantics>5.81−5.69 (m, 2H)<annotation encoding="application / x-tex">5.81 - 5.69 \text{ (m, 2H)}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>5.60 (dd, J=5.8,1.4 Hz<annotation encoding="application / x-tex">5.60 \text{ (dd, } J = 5.8, 1.4 \text{ Hz}< / annotation>< / semantics>< / com:Math>, 1H), <com:Math><semantics>5.53−5.44 (m, 1H)<annotation encoding="application / x-tex">5.53 - 5.44 \text{ (m, 1H)}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>4.68 (dd, J=5.8,1.1 Hz, 1H),1.45 (s, 6H);LCMS m / z=318.15 (M+; 100).<annotation encoding="application / x-tex">4.68 \text{ (dd, } J = 5.8, 1.1 \text{ Hz, 1H)}, 1.45 \text{ (s, 6H)}; LCMS \text{ m / z} = 318.15 \text{ (M+; 100)}.< / annotation>< / semantics>< / com:Math> 1-((3aS,4R,6aR)-6-(((tert-Butyldiphenylsilyl)oxy)methyl)-2,2-dimethyl-4,6a-dihydro- 3aH-cyclopenta[d][1,3]dioxol-4-yl)-4-chloro-1H-pyrrolo[3,2-c]pyridine [Image disponible dans le document PDF, Image available in the PDF document] To a stirred solution of (3aS,4S,6aR)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2- dimethyl-3a,6a-dihydro-4H-cyclo penta[d][1,3]dioxol-4-ol (0.5 g, 1.178 mmol) in THF (7 ml) at 0°C was added 4-chloro-1H-pyrrolo[3,2-c]pyridine (0.305 g, 2.002 mmol), triphenylphosphine (1.081 g, 4.12 mmol) and DIAD (0.801 ml, 4.12 mmol) slowly and stirred for 5min. The reaction mixture was stirred at 25°C for 16h. Volatiles were removed in vacuo and the crude residue was purified by combiflash (Rf200, Teledyne / Isco) instrument onto a redisep® Rf column with gradient elution (0 to 10%) of ethyl acetate in petroleum ether to afford the title compound (0.3g, 45.6%) as an off-white solid. LCMS <com:Math><semantics>m / z=559.23(M+;100).<annotation encoding="application / x-tex">m / z = 559.23 (M+; 100).< / annotation>< / semantics>< / com:Math> ((3aR,6R,6aS)-6-(4-Chloro-1H-pyrrolo[3,2-c]pyridin-1-yl)-2,2-dimethyl-6,6a- dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methanol [Image disponible dans le document PDF, Image available in the PDF document] To a stirred solution of 1-((3aS,4R,6aR)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2- dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-4-chloro-1H-pyrrolo[3,2-c] pyridine (1.3 g, 2.325 mmol) in THF (13ml) was added TBAF (3.25 ml, 3.25 mmol) at 0°C and stirred for 5mins. The reaction mixture was brought to 25°C and stirred for 1h. Volatiles were removed in vacuo and the crude residue was purified by combiflash (Rf200, Teledyne / Isco) instrument onto a redisep® Rf column with gradient elution (0 to 45%) of ethyl acetate in petroleum ether to afford the title compound (0.5g, 67%) as an off-white solid. LCMS <com:Math><semantics>m / z=319.71<annotation encoding="application / x-tex">m / z = 319.71< / annotation>< / semantics>< / com:Math> (M-1; 100). (3aR,6R,6aS)-6-(4-Chloro-1H-pyrrolo[3,2-c]pyridin-1-yl)-2,2-dimethyl-6,6a- dihydro-3aH-cyclopenta[d][1,3]dioxole-4-carbaldehyde [Image disponible dans le document PDF, Image available in the PDF document] The title compound was synthesized by following an analogous reaction protocol as was described in the preparation of (3aS,4R,6aR)-2,2-Dimethyl-4-(4-methyl-7H-pyrrolo[2,3- d]pyrimidin-7-yl)-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxole-6-carbaldehyde. <com:Sup>1< / com:Sup>H NMR (400 MHz, Chloroform-d) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 10.05 (s, 1H), 8.19 (d, <com:Math><semantics>J=5.8<annotation encoding="application / x-tex">J = 5.8< / annotation>< / semantics>< / com:Math> Hz, 1H), 7.34 (dd, <com:Math><semantics>J=5.9<annotation encoding="application / x-tex">J = 5.9< / annotation>< / semantics>< / com:Math>, 0.9 Hz, 1H), <com:Math><semantics>6.99<annotation encoding="application / x-tex">6.99< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=3.3<annotation encoding="application / x-tex">J = 3.3< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>6.94−6.89<annotation encoding="application / x-tex">6.94 - 6.89< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>6.74<annotation encoding="application / x-tex">6.74< / annotation>< / semantics>< / com:Math> (dd, <com:Math><semantics>J=3.3<annotation encoding="application / x-tex">J = 3.3< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>0.9<annotation encoding="application / x-tex">0.9< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>5.73<annotation encoding="application / x-tex">5.73< / annotation>< / semantics>< / com:Math> <com:Math><semantics>−5.58<annotation encoding="application / x-tex">-5.58< / annotation>< / semantics>< / com:Math> (m, 2H), 4.67 (dt, <com:Math><semantics>J=5.9<annotation encoding="application / x-tex">J = 5.9< / annotation>< / semantics>< / com:Math>, 1.2 Hz, 1H), 1.55 (s, 3H), 1.39 (s, 3H); LCMS m / z = 319.05 (M+; 100). 4-Chloro-1-((3aS,4R,6aR)-2,2-dimethyl-6-vinyl-4,6a-dihydro-3aH-cyclopenta[d][1,3] dioxol-4-yl)-1H-pyrrolo[3,2-c]pyridine [Image disponible dans le document PDF, Image available in the PDF document] The title compound was synthesized by following an analogous reaction protocol as was described in the preparation 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. <com:Sup>1< / com:Sup>H NMR (400 MHz, Chloroform-d) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.14 (d, <com:Math><semantics>J=5.8<annotation encoding="application / x-tex">J = 5.8< / annotation>< / semantics>< / com:Math> Hz, 1H), 7.37 (dd, <com:Math><semantics>J=5.9<annotation encoding="application / x-tex">J = 5.9< / annotation>< / semantics>< / com:Math>, 0.9 Hz, 1H), 7.06 (d, <com:Math><semantics>J=<annotation encoding="application / x-tex">J =< / annotation>< / semantics>< / com:Math> <com:Math><semantics>3.3 Hz<annotation encoding="application / x-tex">3.3 \text{ Hz}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>1H<annotation encoding="application / x-tex">1\text{H}< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>6.70−6.59 (m, 2H)<annotation encoding="application / x-tex">6.70 - 6.59 \text{ (m, 2H)}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>5.91−5.72 (m, 2H)<annotation encoding="application / x-tex">5.91 - 5.72 \text{ (m, 2H)}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>5.55−5.48 (m, 3H)<annotation encoding="application / x-tex">5.55 - 5.48 \text{ (m, 3H)}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>4.59−4.47 (m, 2H)<annotation encoding="application / x-tex">4.59 - 4.47 \text{ (m, 2H)}< / annotation>< / semantics>< / com:Math> 1H), 1.53 (s, 3H), 1.40 (s, 3H); LCMS <com:Math><semantics>m / z=317.15<annotation encoding="application / x-tex">m / z = 317.15< / annotation>< / semantics>< / com:Math> (M+; 100). 1-((3aS,4R,6aR)-2,2-Dimethyl-6-vinyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4- yl)-4-methyl-1H-pyrrolo[3,2-c]pyridine [Image disponible dans le document PDF, Image available in the PDF document] The title compound was synthesized by following an analogous reaction protocol as was described in the preparation of 7-((3aS,4R,6aR)-2,2-dimethyl-6-(prop-1-en-2-yl)-4,6a- dihydro-3aH-cyclo penta[d][1,3] dioxol-4-yl)-4-methyl-7H-pyrrolo[2,3-d]pyrimidine. LCMS m / z = <com:Math><semantics>297.21<annotation encoding="application / x-tex">297.21< / annotation>< / semantics>< / com:Math> (M+; 100). Des chloro dompound i.e. 1-((3aS,4R,6aR)-2,2-dimethyl- 6-vinyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-1H-pyrrolo[3,2-c]pyridine was also formed, which was separated after Suzuki coupling step (Table-6) by reverse phase preparative HPLC. (3aR,6aR)-6-(((tert-Butyldiphenylsilyl)oxy)methyl)-5-iodo-2,2-dimethyl-3a,6a- dihydro-4H-cyclopenta[d][1,3]dioxol-4-one [Image disponible dans le document PDF, Image available in the PDF document] To a stirred solution of (3aR,6aR)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-dimethyl- 3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-one (20 g, 47.3 mmol) and iodine (14.41 g, 56.8 mmol) in dichloromethane (250 ml), was added pyridine (3.45 ml, 42.6 mmol) under nitrogen atmosphere at 0°C and stirred at 25°C for 4h. The reaction mixture was diluted with methylene chloride (100 ml) and washed with a saturated aqueous sodium thiosulfate (100ml). Layers were separated, the organic layer was washed with brine (100 ml) and dried over anhydrous sodium sulphate. The organic layer was filtered and concentrated in vacuo to give 18g of crude compound. This crude residue was purified by combiflash (Rf200, Teledyne / Isco) instrument onto a redisep® Rf column with gradient elution (0 to 20%) of ethyl acetate in petroleum ether to afford the title compound (15 g, 57.8%) as a colorless oil. <com:Sup>1< / com:Sup>H NMR (400 MHz, Chloroform-d) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 7.74 (ddt, <com:Math><semantics>J=17.2,6.5,1.6<annotation encoding="application / x-tex">J = 17.2, 6.5, 1.6< / annotation>< / semantics>< / com:Math> Hz, 4H), <com:Math><semantics>7.58−7.36<annotation encoding="application / x-tex">7.58 - 7.36< / annotation>< / semantics>< / com:Math> (m, 6H), <com:Math><semantics>5.19<annotation encoding="application / x-tex">5.19< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=5.8<annotation encoding="application / x-tex">J = 5.8< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>4.79<annotation encoding="application / x-tex">4.79< / annotation>< / semantics>< / com:Math> (t, <com:Math><semantics>J=5.6<annotation encoding="application / x-tex">J = 5.6< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>4.53−4.33<annotation encoding="application / x-tex">4.53 - 4.33< / annotation>< / semantics>< / com:Math> (m, 2H), 1.45 (s, 3H), 1.35 (s, 3H), 1.08 (s, 9H). (3aS,4R,6aR)-6-(((tert-Butyldiphenylsilyl)oxy)methyl)-5-iodo-2,2-dimethyl-3a,6a- dihydro-4H-cyclopenta[d][1,3]dioxol-4-ol [Image disponible dans le document PDF, Image available in the PDF document] To a stirred solution of (3aR,6aR)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-5-iodo-2,2- dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-one (13.7g, 24.98mmol) in methanol (130 ml), was added cerium (III) chloride heptahydrate (10.24 g, 27.5 mmol) at 0°C and the reaction mixture was stirred for 30min. Sodium borohydride (0.992 g, 26.2 mmol) was added portion-wise and the resulting mixture was stirred at 0°C for 2h under N<com:Sub>2< / com:Sub> atmosphere. The reaction mass was quenched with water (150 ml) and extracted with ethyl acetate (150 ml x 2). The combined organic layer was washed with brine (100 ml), dried over sodium sulfate & concentrated to give 8.5g of crude compound. This residue was purified by combiflash (Rf200, Teledyne / Isco) instrument onto a redisep® Rf column with gradient elution (0 to 20%) of ethyl acetate in petroleum ether to afford the title compound (6 g, 43.6%) as a colorless oil. <com:Sup>1< / com:Sup>H NMR (400 MHz, Chloroform-d) δ 7.84 – 7.62 (m, 4H), <com:Math><semantics>7.48−7.39<annotation encoding="application / x-tex">7.48 - 7.39< / annotation>< / semantics>< / com:Math> (m, 6H), <com:Math><semantics>5.19<annotation encoding="application / x-tex">5.19< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=5.8<annotation encoding="application / x-tex">J = 5.8< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>4.86−4.71<annotation encoding="application / x-tex">4.86 - 4.71< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>4.46−4.71<annotation encoding="application / x-tex">4.46 - 4.71< / annotation>< / semantics>< / com:Math> 4.31 (m, 3H), 2.84 (d, <com:Math><semantics>J=10.3<annotation encoding="application / x-tex">J = 10.3< / annotation>< / semantics>< / com:Math> Hz, 1H), 1.45 (s, 3H), 1.38 – 1.33 (s, 3H), 1.08 (s 9H). 7-((3aS,4S,6aR)-6-(((tert-Butyldiphenylsilyl)oxy)methyl)-5-iodo-2,2-dimethyl-3a,6a- dihydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidine [Image disponible dans le document PDF, Image available in the PDF document] The title compound was synthesized by following an analogous reaction protocol as was described in the preparation of 1-((3aS,4R,6aR)-6-(((tert-butyldiphenylsilyl)oxy)methyl)- 2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-4-chloro-1H-pyrrolo[3,2- c] pyridine. <com:Sup>1< / com:Sup>H NMR (400 MHz, Chloroform-d) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.64 (s, 1H), 7.75 (ddt, J = 20.3, 6.8, 1.5) Hz, 4H), <com:Math><semantics>7.53−7.31<annotation encoding="application / x-tex">7.53 - 7.31< / annotation>< / semantics>< / com:Math> (m, 6H), <com:Math><semantics>6.96<annotation encoding="application / x-tex">6.96< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=3.7<annotation encoding="application / x-tex">J = 3.7< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>6.67<annotation encoding="application / x-tex">6.67< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=3.6<annotation encoding="application / x-tex">J = 3.6< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>5.74−5.62<annotation encoding="application / x-tex">5.74 - 5.62< / annotation>< / semantics>< / com:Math> <com:Math><semantics>(m,2H),4.86−4.80(m,1H),4.54−4.42(m,2H),1.48(s,3H),1.42(s,3H),1.13(s,9H).<annotation encoding="application / x-tex">(m, 2H), 4.86 - 4.80 (m, 1H), 4.54 - 4.42 (m, 2H), 1.48 (s, 3H), 1.42 (s, 3H), 1.13 (s, 9H).< / annotation>< / semantics>< / com:Math> LCMS <com:Math><semantics>m / z=686.33(M+;100)<annotation encoding="application / x-tex">m / z = 686.33 (M+; 100)< / annotation>< / semantics>< / com:Math>. 7-((3aS,4S,6aR)-6-(((tert-Butyldiphenylsilyl)oxy)methyl)-5-iodo-2,2-dimethyl-3a,6a- dihydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-N-(4-methoxybenzyl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine [Image disponible dans le document PDF, Image available in the PDF document] Α mixture of 7-((3aS,4S,6aR)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-5-iodo-2,2- dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-4-chloro-7H-pyrrolo[2,3-d] pyrimidine (1.7 g, 2.478 mmol) and (4-methoxyphenyl)methanamine (3.40 g, 24.78 mmol) in ethanol (1.7 ml) was refluxed for 4h. The reaction mixture was quenched with water (150 ml) and extracted with ethyl acetate (150 ml). The combined organic layer was washed with brine (100 ml), dried over sodium sulfate and concentrated to give 8.5g of crude compound. This residue was purified by combiflash (Rf200, Teledyne / Isco) instrument onto a redisep® Rf column with gradient elution (0 to 40%) of ethyl acetate in petroleum ether to afford the title compound (1.8 g, 92%) as an off white solid. <com:Sup>1< / com:Sup>H NMR (400 MHz, Chloroform-d) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.37 (d, J = 6.4 Hz, 1H), 7.76 (ddt, J = 19.4, 6.8, 1.4 Hz, 4H), 7.52 – 7.32 <com:Math><semantics>(m,8H),7.00−6.88(m,2H),6.67(d,J=3.7Hz,1H),6.42(d,J=3.6Hz,1H),5.71(s,S)<annotation encoding="application / x-tex">(m, 8H), 7.00 - 6.88 (m, 2H), 6.67 (d, J = 3.7 Hz, 1H), 6.42 (d, J = 3.6 Hz, 1H), 5.71 (s, S)< / annotation>< / semantics>< / com:Math> 1H), 5.61 (d, <com:Math><semantics>J=6.2 Hz<annotation encoding="application / x-tex">J = 6.2 \text{ Hz}< / annotation>< / semantics>< / com:Math>, 1H), 4.80 (dd, <com:Math><semantics>J=12.7<annotation encoding="application / x-tex">J = 12.7< / annotation>< / semantics>< / com:Math>, 5.8 Hz, 3H), 4.60 – 4.37 (m, 2H), 3.84 (s, 3H), 3.77 (s, 1H), 1.46 (s, 3H), 1.41 (s, 3H), 1.13 (s, 9H); LCMS <com:Math><semantics>m / z=786.41<annotation encoding="application / x-tex">m / z = 786.41< / annotation>< / semantics>< / com:Math> (M+; 100). 7-((3aS,4R,6aR)-6-(((tert-Butyldiphenylsilyl)oxy)methyl)-2,2,5-trimethyl-3a,6a- dihydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-N-(4-methoxybenzyl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine [Image disponible dans le document PDF, Image available in the PDF document] Α mixture of 7-((3aS,4S,6aR)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-5-iodo-2,2- dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-N-(4-methoxybenzyl)-7H- rrolo[2,3-d] pyrimidin-4-amine (3.2 g, 4.07 mmol), 2,4,6-trimethyl-1,3,5,2,4,6- trioxatriborinane (1.021 g, 8.13 mmol) and potassium Carbonate (2.53 g, 18.30 mmol) in DMF (10 ml) was purged with nitrogen for 10 min in a seal tube. Pd(PPh<com:Sub>3< / com:Sub>)<com:Sub>4< / com:Sub>(0.470 g, 0.407 mmol) was added to reaction mixture and stirred at 80°C for 8h. The reaction mixture was diluted with water (50 ml) and extracted with ethyl acetate (50 ml X 2). The combined organic layer was washed with brine (50 ml), dried over sodium sulfate, concentrated in vacuo to give 3.1g of crude compound. This residue was purified by combiflash (Rf200, Teledyne / Isco) instrument onto a redisep® Rf column with gradient elution (0 to 40%) of ethyl acetate in petroleum ether to afford the title compound (2.7 g., 98 %) as an off-white solid. LCMS <com:Math><semantics>m / z=675.60(M+;100)<annotation encoding="application / x-tex">m / z = 675.60 (M+; 100)< / annotation>< / semantics>< / com:Math>. ((3aS,4R,6aR)-4-(4-((4-Methoxybenzyl)amino)-7H-pyrrolo[2,3-d] pyrimidin-7-yl)- 2,2,5-trimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-6-yl)methanol [Image disponible dans le document PDF, Image available in the PDF document] To a stirred solution of 7-((3aS,4R,6aR)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2,5- trimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-N-(4-methoxybenzyl)-7H- pyrrolo [2,3-d]pyrimidin-4-amine (2.7 g, 4.00 mmol) in THF (40 ml) at 0 °C, was added TBAF (4.80 ml, 4.80 mmol) slowly and stirred for 2h at 25°C. The reaction mixture was diluted with water (50ml) and extracted with ethyl acetate (50 ml x 2). The combined organic layer was washed with brine (50ml), dried over sodium sulfate, filtered and concentrated in vacuo to give 2.2g of crude compound. This residue was purified by combiflash (Rf200, Teledyne / Isco) instrument onto a redisep® Rf column with gradient elution (0 to 100%) of ethyl acetate in petroleum ether to afford the title compound (1.7 g., 97 %) as a colorless oil. <com:Sup>1< / com:Sup>H NMR (400 MHz, Chloroform-d) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 7.69 (ddd, J = 12.0, 8.3, 1.4) Hz, 1H), <com:Math><semantics>7.62−7.41<annotation encoding="application / x-tex">7.62 - 7.41< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>7.41−7.30<annotation encoding="application / x-tex">7.41 - 7.30< / annotation>< / semantics>< / com:Math> (m, 2H), <com:Math><semantics>6.99−6.80<annotation encoding="application / x-tex">6.99 - 6.80< / annotation>< / semantics>< / com:Math> (m, 2H), <com:Math><semantics>6.70<annotation encoding="application / x-tex">6.70< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=3.6<annotation encoding="application / x-tex">J = 3.6< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>6.35<annotation encoding="application / x-tex">6.35< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=3.5<annotation encoding="application / x-tex">J = 3.5< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>5.67<annotation encoding="application / x-tex">5.67< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>5.51<annotation encoding="application / x-tex">5.51< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=5.9<annotation encoding="application / x-tex">J = 5.9< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>4.79<annotation encoding="application / x-tex">4.79< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=5.5<annotation encoding="application / x-tex">J = 5.5< / annotation>< / semantics>< / com:Math> Hz, 2H), <com:Math><semantics>4.60<annotation encoding="application / x-tex">4.60< / annotation>< / semantics>< / com:Math> (dd, <com:Math><semantics>J=5.9<annotation encoding="application / x-tex">J = 5.9< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>0.9<annotation encoding="application / x-tex">0.9< / annotation>< / semantics>< / com:Math> Hz, <com:Math><semantics>1H<annotation encoding="application / x-tex">1H< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>4.45<annotation encoding="application / x-tex">4.45< / annotation>< / semantics>< / com:Math> (s, <com:Math><semantics>2H<annotation encoding="application / x-tex">2H< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>3.83<annotation encoding="application / x-tex">3.83< / annotation>< / semantics>< / com:Math> (s, <com:Math><semantics>3H<annotation encoding="application / x-tex">3H< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>1.61<annotation encoding="application / x-tex">1.61< / annotation>< / semantics>< / com:Math> (t, <com:Math><semantics>J=1.1<annotation encoding="application / x-tex">J = 1.1< / annotation>< / semantics>< / com:Math> Hz, <com:Math><semantics>3H<annotation encoding="application / x-tex">3H< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>1.51<annotation encoding="application / x-tex">1.51< / annotation>< / semantics>< / com:Math> (s, 3H), 1.37 (s, 3H). LCMS <com:Math><semantics>m / z=437.17<annotation encoding="application / x-tex">m / z = 437.17< / annotation>< / semantics>< / com:Math> (M+, 100%). ((3aS,4R,6aR)-4-(4-((4-Methoxybenzyl)amino)-7H-pyrrolo[2,3-d] pyrimidin-7-yl)- 2,2,5-trimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-6-yl)methyl 4- methylbenzeneulfonate [Image disponible dans le document PDF, Image available in the PDF document] To a mixture of ((3aS,4R,6aR)-4-(4-((4-methoxybenzyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)-2,2,5-trimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-6- yl)methanol (100mg, 0.229mmol), DMAP (5.60 mg, 0.046 mmol) and TEA (0.096 ml, 0.687 mmol) in CH<com:Sub>2< / com:Sub>Cl<com:Sub>2< / com:Sub> (10 ml) at 0°C, was added a solution of p-toluene sulphonyl chloride (65.5 mg, 0.344 mmol) in CH<com:Sub>2< / com:Sub>Cl<com:Sub>2< / com:Sub> (1ml) and stirred for 1h at 25°C. The reaction mixture was diluted with water (5 ml) and extracted with ethyl acetate (10 ml x 2). The combined organic layer was washed with brine (10 ml), dried over sodium sulfate, filtered and concentrated in vacuo to give 0.2g of crude compound. This residue was purified by combiflash (Rf200, Teledyne / Isco) instrument onto a redisep® Rf column with gradient elution (0 to 40%) of ethyl acetate in petroleum ether to afford the title compound (0.08 g, 59.1 %) as a colorless oil. Obtained product was used as such for next step without characterization. (3aS,4R,6aS)-5-(((tert-Butyldiphenylsilyl)oxy)methyl)-2,2,4-trimethyl-3a,6a-dihydro- 4H-cyclopenta[d][1,3]dioxol-4-ol [Image disponible dans le document PDF, Image available in the PDF document] To a stirred solution of (3aS,6aS)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-dimethyl- 3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-one (10.0 g, 23.66 mmol) [synthesized by following the same reaction protocol as was described in J. Org. Chem. 2014, 79, 8059–8066] in THF (100ml), was added 3M methyl magnesium bromide in THF (11.85 ml, 35.5 mmol) at 0°C. The reaction mixture was stirred at 0°C for 1h. The reaction mixture was quenched with a saturated aqueous ammonium chloride (100ml) and extracted with ethyl acetate (200ml x 2). The combined organic layer was washed with brine (50 ml), dried over sodium sulfate, filtered and concentrated in vacuo to give 9.8g of crude compound. This residue was purified by combiflash (R<com:Sub>f< / com:Sub>200, Teledyne / Isco) instrument onto a redisep® R<com:Sub>f< / com:Sub> column with gradient elution (0 to 20%) of ethyl acetate in petroleum ether to afford the title compound (8.50g, 82%) as a colorless oil. <com:Sup>1< / com:Sup>H NMR (400 MHz, Chloroform-d) δ 7.72 <com:Math><semantics>−7.67<annotation encoding="application / x-tex">-7.67< / annotation>< / semantics>< / com:Math> (m, 4H), <com:Math><semantics>7.47−7.37<annotation encoding="application / x-tex">7.47 - 7.37< / annotation>< / semantics>< / com:Math> (m, 6H), <com:Math><semantics>5.84<annotation encoding="application / x-tex">5.84< / annotation>< / semantics>< / com:Math> (q, <com:Math><semantics>J=2.0<annotation encoding="application / x-tex">J = 2.0< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>5.11−5.00<annotation encoding="application / x-tex">5.11 - 5.00< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>4.46−<annotation encoding="application / x-tex">4.46 -< / annotation>< / semantics>< / com:Math> 4.28 (m, 3H), 3.51 (s, 1H), 1.47 (s, 3H), 1.42 (s, 3H), 1.26 (s, 3H), 1.09 (s, 9H). (3aS,4S,6aR)-6-(((tert-Butyldiphenylsilyl)oxy)methyl)-2,2,6a-trimethyl-3a,6a- dihydro-4H-cyclopenta[d][1,3]dioxol-4-ol [Image disponible dans le document PDF, Image available in the PDF document] To a stirred solution of (3aS,4R,6aS)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2,4- trimethyl -3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-ol (8.0 g, 18.24 mmol) in anhydrous acetone (80ml), was added p-TsOH·H<com:Sub>2< / com:Sub>O (0.69 g, 3.65 mmol) at 25°C and stirred for 18h. TLC showed 50% conversion. The reaction mixture was then concentrated in vacuo, diluted with methylene chloride (100 ml) and washed with saturated NaHCO<com:Sub>3< / com:Sub> (50 ml). Layers were separated, the organic layer was washed with brine (50 ml) and dried over anhydrous sodium sulphate. The organic layer was filtered and concentrated in vacuo to give 4.5g of crude compound. This residue was purified by combiflash (R<com:Sub>f< / com:Sub>200, Teledyne / Isco) instrument onto a redisep® R<com:Sub>f< / com:Sub> column with gradient elution (0 to 30%) of ethyl acetate in petroleum ether to afford the title compound (3.5g, 43%) as an oil. <com:Sup>1< / com:Sup>H NMR (400 MHz, Chloroform-d) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 7.74 – 7.65 (m, 4H), 7.48 – 7.35 (m, 6H), 5.81 (p, <com:Math><semantics>J=1.6<annotation encoding="application / x-tex">J = 1.6< / annotation>< / semantics>< / com:Math> Hz, 1H), 4.62 – 4.55 (m, 1H), 4.44 – 4.24 (m, 3H), 1.39 (s, 3H), 1.34 (s, 3H), 1.29 (s, 3H), 1.10 (s, 9H). 7-((3aS,4R,6aR)-6-(((tert-Butyldiphenylsilyl)oxy)methyl)-2,2,6a-trimethyl-3a,6a- dihydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidine. [Image disponible dans le document PDF, Image available in the PDF document] The title compound was synthesized by following an analogous reaction protocol as was described in the preparation of 1-((3aS,4R,6aR)-6-(((tert-butyldiphenylsilyl)oxy)methyl)- 2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-4-chloro-1H-pyrrolo[3,2- c] pyridine. <com:Sup>1< / com:Sup>H NMR (400 MHz, Chloroform-d) δ 8.74 (s, 1H), 7.78 – 7.67 (m, 4H), 7.52 <com:Math><semantics>−7.39<annotation encoding="application / x-tex">-7.39< / annotation>< / semantics>< / com:Math> (m, 6H), 6.94 (d, <com:Math><semantics>J=3.6<annotation encoding="application / x-tex">J = 3.6< / annotation>< / semantics>< / com:Math> Hz, 1H), 6.61 (d, <com:Math><semantics>J=3.6<annotation encoding="application / x-tex">J = 3.6< / annotation>< / semantics>< / com:Math> Hz, 1H), 5.94 <com:Math><semantics>−5.86<annotation encoding="application / x-tex">-5.86< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>5.80(q,J=2.4Hz,1H),4.62−4.48(m,2H),4.13(d,J=1.2Hz,1H),1.39(s,3H),1.38<annotation encoding="application / x-tex">5.80 (q, J = 2.4 Hz, 1H), 4.62 - 4.48 (m, 2H), 4.13 (d, J = 1.2 Hz, 1H), 1.39 (s, 3H), 1.38< / annotation>< / semantics>< / com:Math> (s, 3H), 1.36 (s, 3H), 1.13 (s, 9H), LCMS m / z = 574.44 (M+; 100%). ((3aS,4R,6aR)-4-(4-Chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2,6a-trimethyl-3a,6a- dihydro-4H-cyclopenta[d][1,3]dioxol-6-yl)methanol [Image disponible dans le document PDF, Image available in the PDF document] The title compound was synthesized by following an analogous reaction protocol as was described in the preparation of ((3aR,6R,6aS)-6-(2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7- yl)-2,2-dimethyl-6,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methanol. <com:Sup>1< / com:Sup>H NMR (400 MHz, Chloroform-d) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.73 (s, 1H), 7.16 (d, J = 3.6 Hz, 1H), 6.62 (d, J = <com:Math><semantics>3.6 Hz<annotation encoding="application / x-tex">3.6 \text{ Hz}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>1H<annotation encoding="application / x-tex">1\text{H}< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>5.87−5.78 (m, 2H)<annotation encoding="application / x-tex">5.87 - 5.78 \text{ (m, 2H)}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>4.62−4.44 (m, 2H)<annotation encoding="application / x-tex">4.62 - 4.44 \text{ (m, 2H)}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>4.25−4.20 (m, 1H)<annotation encoding="application / x-tex">4.25 - 4.20 \text{ (m, 1H)}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>1.56 (s, 3H)<annotation encoding="application / x-tex">1.56 \text{ (s, 3H)}< / annotation>< / semantics>< / com:Math>, 1.49 (s, 3H), 1.42 (s, 3H); LCMS <com:Math><semantics>m / z=336.15<annotation encoding="application / x-tex">m / z = 336.15< / annotation>< / semantics>< / com:Math> (M+; 100%). (3aS,4R,6aR)-4-(4-Chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2,6a-trimethyl-3a,6a- dihydro-4H-cyclopenta[d][1,3]dioxole-6-carbaldehyde [Image disponible dans le document PDF, Image available in the PDF document] The title compound was synthesized by following an analogous reaction protocol as was described in the preparation of (3aS,4R,6aR)-2,2-dimethyl-4-(4-methyl-7H-pyrrolo[2,3- d]pyrimidin-7-yl)-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxole-6-carbaldehyde. <com:Sup>1< / com:Sup>H NMR <com:Math><semantics>(400 MHz,Chloroform-d)δ10.01 (s, 1H),8.73 (s, 1H),7.09 (d, J=3.6 Hz, 1H),6.78<annotation encoding="application / x-tex">(400 \text{ MHz}, \text{Chloroform-d}) \delta 10.01 \text{ (s, 1H)}, 8.73 \text{ (s, 1H)}, 7.09 \text{ (d, J} = 3.6 \text{ Hz, 1H)}, 6.78< / annotation>< / semantics>< / com:Math> <com:Math><semantics>(dd,J=2.8,1.2Hz,1H),6.69(d,J=3.6Hz,1H),5.99(dd,J=2.8,0.8Hz,1H),4.34(t,J)<annotation encoding="application / x-tex">(dd, J = 2.8, 1.2 Hz, 1H), 6.69 (d, J = 3.6 Hz, 1H), 5.99 (dd, J = 2.8, 0.8 Hz, 1H), 4.34 (t, J)< / annotation>< / semantics>< / com:Math> <com:Math><semantics>=0.8 Hz<annotation encoding="application / x-tex">= 0.8 \text{ Hz}< / annotation>< / semantics>< / com:Math>, 1H), 1.78 (s, 3H), 1.47 (s, 3H), 1.44 (s, 3H), LCMS m / z = 334.22 (M+1; 100%). 4-Chloro-7-((3aS,4R,6aR)-2,2,6a-trimethyl-6-vinyl-3a,6a-dihydro-4H-cyclopenta[d] [1,3] dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine [Image disponible dans le document PDF, Image available in the PDF document] The title compound was synthesized by following an analogous reaction protocol as was described in the preparation 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. <com:Sup>1< / com:Sup>H NMR (400 MHz, Chloroform-d) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.74 (s, 1H), 7.16 (d, J = 3.6 Hz, 1H), 6.62 (d, J = 3.6 Hz, 1H), <com:Math><semantics>6.49 (dd, J=17.6,11.2 Hz,1H),5.94−5.87 (m, 1H),5.85−5.76 (m, 2H),5.47 (dd, J=1.00 m)<annotation encoding="application / x-tex">6.49 \text{ (dd, J} = 17.6, 11.2 \text{ Hz}, 1\text{H}), 5.94 - 5.87 \text{ (m, 1H)}, 5.85 - 5.76 \text{ (m, 2H)}, 5.47 \text{ (dd, J} = 1.00 \text{ m})< / annotation>< / semantics>< / com:Math> 11.2, 1.2 Hz, 1H), 4.15 (d, <com:Math><semantics>J=1.1<annotation encoding="application / x-tex">J = 1.1< / annotation>< / semantics>< / com:Math> Hz, 1H), 1.60 (s, 3H), 1.44 (s, 6H), LCMS m / z = 332.22 (M+1; 100%). 7-((3aS,4R,6aR)-6-(((tert-Butyldiphenylsilyl)oxy)methyl)-2,2,6a-trimethyl-3a,6a- dihydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-4-methyl-7H-pyrrolo[2,3-d]pyrimidine [Image disponible dans le document PDF, Image available in the PDF document] The title compound was synthesized by following an analogous reaction protocol as was described in the preparation of 7-((3aS,4R,6aR)-6-(((tert-butyldiphenylsilyl)oxy)methyl)- 2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-4-methyl-7H-pyrrolo[2,3- d]pyrimidine. <com:Sup>1< / com:Sup>H NMR1 (400 MHz, Chloroform-d) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.86 (s, 1H), 7.73 (ddt, <com:Math><semantics>J=15.2<annotation encoding="application / x-tex">J = 15.2< / annotation>< / semantics>< / com:Math>, 6.7, 1.5 Hz, 4H), <com:Math><semantics>7.52−7.39<annotation encoding="application / x-tex">7.52 - 7.39< / annotation>< / semantics>< / com:Math> (m, 6H), <com:Math><semantics>6.90<annotation encoding="application / x-tex">6.90< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=3.6<annotation encoding="application / x-tex">J = 3.6< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>6.55<annotation encoding="application / x-tex">6.55< / annotation>< / semantics>< / com:Math> (dd, <com:Math><semantics>J=3.7<annotation encoding="application / x-tex">J = 3.7< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>2.3<annotation encoding="application / x-tex">2.3< / annotation>< / semantics>< / com:Math> Hz, 1H), 5.90 (dt, <com:Math><semantics>J=2.9<annotation encoding="application / x-tex">J = 2.9< / annotation>< / semantics>< / com:Math>, 1.5 Hz, 1H), 5.82 (q, <com:Math><semantics>J=2.4<annotation encoding="application / x-tex">J = 2.4< / annotation>< / semantics>< / com:Math> Hz, 1H), 4.54 (dq, <com:Math><semantics>J=6.2<annotation encoding="application / x-tex">J = 6.2< / annotation>< / semantics>< / com:Math>, 1.8 Hz, 2H), 4.14 <com:Math><semantics>(dd,J=6.7,2.1 Hz,1H),1.64 (s, 6H),1.39 (s, 3H),1.36 (d, J=2.1 Hz, 3H),1.12 (s, 9H);<annotation encoding="application / x-tex">(dd, J = 6.7, 2.1 \text{ Hz}, 1\text{H}), 1.64 \text{ (s, 6H)}, 1.39 \text{ (s, 3H)}, 1.36 \text{ (d, } J = 2.1 \text{ Hz, 3H)}, 1.12 \text{ (s, 9H)};< / annotation>< / semantics>< / com:Math> LCMS <com:Math><semantics>m / z=554.32<annotation encoding="application / x-tex">m / z=554.32< / annotation>< / semantics>< / com:Math> (M+, 100%). ((3aS,4R,6aR)-2,2,6a-Trimethyl-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)- 3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-6-yl)methanol [Image disponible dans le document PDF, Image available in the PDF document] The title compound was synthesized by following an analogous reaction protocol as was described in the preparation of ((3aR,6R,6aS)-6-(2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7- yl)-2,2-dimethyl-6,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methanol. <com:Sup>1< / com:Sup>H NMR (400 MHz, Chloroform-d) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.86 (s, 1H), 7.08 (d, <com:Math><semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics>< / com:Math> = 3.7 Hz, 1H), 6.57 (dd, <com:Math><semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics>< / com:Math> <com:Math><semantics>=3.6,1.1 Hz,1H<annotation encoding="application / x-tex">= 3.6, 1.1 \text{ Hz}, 1\text{H}< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>5.86−5.78 (m, 2H)<annotation encoding="application / x-tex">5.86 - 5.78 \text{ (m, 2H)}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>4.59−4.47 (m, 2H)<annotation encoding="application / x-tex">4.59 - 4.47 \text{ (m, 2H)}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>4.23 (dt, J=6.9,0.8 Hz,1H)<annotation encoding="application / x-tex">4.23 \text{ (dt, } J = 6.9, 0.8 \text{ Hz}, 1\text{H)}< / annotation>< / semantics>< / com:Math>, 2.77 (s, 3H), 1.56 (s, 3H), 1.50 (s, 3H), 1.42 (s, 3H); LCMS m / z=316.21 (M+, 100%). (3aS,4R,6aR)-2,2,6a-Trimethyl-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3a,6a- dihydro-4H-cyclopenta[d][1,3]dioxole-6-carbaldehyde [Image disponible dans le document PDF, Image available in the PDF document] The title compound was synthesized by following an analogous reaction protocol as was described in the preparation of (3aS,4R,6aR)-2,2-dimethyl-4-(4-methyl-7H-pyrrolo[2,3- d]pyrimidin-7-yl)-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxole-6-carbaldehyde. <com:Sup>1< / com:Sup>H NMR (400 MHz, Chloroform-d) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 10.01 (s, 1H), 8.87 (s, 1H), 7.03 (d, <com:Math><semantics>J=3.7<annotation encoding="application / x-tex">J = 3.7< / annotation>< / semantics>< / com:Math> Hz, 1H), 6.79 (td, <com:Math><semantics>J=2.8,1.1 Hz,1H<annotation encoding="application / x-tex">J = 2.8, 1.1 \text{ Hz}, 1\text{H}< / annotation>< / semantics>< / com:Math>), 6.67 (d, <com:Math><semantics>J=3.7 Hz,1H<annotation encoding="application / x-tex">J = 3.7 \text{ Hz}, 1\text{H}< / annotation>< / semantics>< / com:Math>), 6.02 (dd, <com:Math><semantics>J=2.9,0.7 Hz,1H<annotation encoding="application / x-tex">J = 2.9, 0.7 \text{ Hz}, 1\text{H}< / annotation>< / semantics>< / com:Math>), 4.33 (d, <com:Math><semantics>J=3.7 Hz,1Hz<annotation encoding="application / x-tex">J = 3.7 \text{ Hz}, 1\text{Hz}< / annotation>< / semantics>< / com:Math>), 4.35 (d, <com:Math><semantics>J=3.7 Hz,1Hz<annotation encoding="application / x-tex">J = 3.7 \text{ Hz}, 1\text{Hz}< / annotation>< / semantics>< / com:Math>), 6.02 (dd, <com:Math><semantics>J=3.7 Hz,1Hz<annotation encoding="application / x-tex">J = 3.7 \text{ Hz}, 1\text{Hz}< / annotation>< / semantics>< / com:Math>), 6.02 0.9 Hz, 1H), 2.82 (s, 3H), 1.78 (s, 3H), 1.47 (s, 3H), 1.44 (s, 3H); LCMS m / z=314.28 (M+, 100%). (4-Methyl-7-((3aS,4R,6aR)-2,2,6a-trimethyl-6-vinyl-3a,6a-dihydro-4H-cyclopenta[d] [1,3] dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine [Image disponible dans le document PDF, Image available in the PDF document] The title compound was synthesized by following an analogous reaction protocol as was described in the preparation 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. <com:Sup>1< / com:Sup>H NMR (400 MHz, Chloroform-d) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.87 (s, 1H), 7.09 (d, <com:Math><semantics>J=3.7<annotation encoding="application / x-tex">J = 3.7< / annotation>< / semantics>< / com:Math> Hz, 1H), 6.60 – 6.44 (m, 2H), 5.94 – 5.75 (m, 3H), 5.45 (dd, <com:Math><semantics>J=11.3<annotation encoding="application / x-tex">J = 11.3< / annotation>< / semantics>< / com:Math>, 1.5 Hz, 1H), <com:Math><semantics>4.21−4.07<annotation encoding="application / x-tex">4.21 - 4.07< / annotation>< / semantics>< / com:Math> (m, 1H), 2.78 (s, 3H), 2.64 (s, 3H), 1.44 (s, 6H); LCMS m / z=312.28 (M+, 100%). 1-((3aR,6R,6aS)-6-(4-Chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2,3a-trimethyl- 6,6a-di hydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)ethanol [Image disponible dans le document PDF, Image available in the PDF document] The title compound was synthesized by following an analogous reaction protocol as was described in the preparation of 1-((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)ethan-1-ol. <com:Sup>1< / com:Sup>H NMR (400 MHz, Chloroform-d) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.73 (d, <com:Math><semantics>J=2.0<annotation encoding="application / x-tex">J = 2.0< / annotation>< / semantics>< / com:Math> Hz, 1H), 7.12 (dd, <com:Math><semantics>J=31.8<annotation encoding="application / x-tex">J = 31.8< / annotation>< / semantics>< / com:Math>, 3.6 Hz, 1H), 6.62 <com:Math><semantics>(t,J=3.3 Hz,1H),5.87−5.76 (m, 2H),4.78−4.68 (m, 2H),4.26−4.20 (m, 1H),1.61<annotation encoding="application / x-tex">(t, J = 3.3 \text{ Hz}, 1\text{H}), 5.87 - 5.76 \text{ (m, 2H)}, 4.78 - 4.68 \text{ (m, 2H)}, 4.26 - 4.20 \text{ (m, 1H)}, 1.61< / annotation>< / semantics>< / com:Math> <com:Math><semantics>(d,J=7.1 Hz,3H),1.54 (s, 6H),1.43 (d, J=3.5 Hz,3H);LCMSm / z=350.22 (M+, 1)<annotation encoding="application / x-tex">(d, J = 7.1 \text{ Hz}, 3H), 1.54 \text{ (s, 6H)}, 1.43 \text{ (d, } J = 3.5 \text{ Hz}, 3H); LCMS m / z=350.22 \text{ (M+, 1)}< / annotation>< / semantics>< / com:Math> 100%). 1-((3aR,6R,6aS)-6-(4-Chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2,3a-trimethyl- 6,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)ethanone [Image disponible dans le document PDF, Image available in the PDF document] The title compound was synthesized by following an analogous reaction protocol as was described in the preparation of 1-((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)ethan-1-one. <com:Math><semantics>1H<annotation encoding="application / x-tex">^{1}H< / annotation>< / semantics>< / com:Math> NMR (400 MHz, Chloroform-d) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.74 (s, 1H), 7.10 (d, <com:Math><semantics>J=3.7<annotation encoding="application / x-tex">J = 3.7< / annotation>< / semantics>< / com:Math> Hz, 1H), 6.74 – 6.56 (m, 2H), 5.95 (d, <com:Math><semantics>J=2.9<annotation encoding="application / x-tex">J = 2.9< / annotation>< / semantics>< / com:Math> Hz, 1H), 4.27 (t, <com:Math><semantics>J=0.9<annotation encoding="application / x-tex">J = 0.9< / annotation>< / semantics>< / com:Math> Hz, 1H), 2.49 (s, 3H), 1.76 (s, 3H), 1.48 (s, 6H); LCMS m / z=348.16 (M+, 100%). 2-((3aR,6R,6aS)-6-(4-Chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2,3a-trimethyl- 6,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)propan-2-ol [Image disponible dans le document PDF, Image available in the PDF document] The title compound was synthesized by following an analogous reaction protocol as was described in the preparation of 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)propan-2-ol. LCMS <com:Math><semantics>m / z=364.22(M+,100%)<annotation encoding="application / x-tex">m / z=364.22 (M+, 100\%)< / annotation>< / semantics>< / com:Math>. 4-Chloro-7-((3aS,4R,6aR)-2,2,6a-trimethyl-6-(prop-1-en-2-yl)-4,6a-dihydro-3aH- cyclopenta[d][1,3]dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine [Image disponible dans le document PDF, Image available in the PDF document] The title compound was synthesized by following an analogous reaction protocol as was described in the preparation of 4-chloro-7-((3aS,4R,6aR)-2,2-dimethyl-6-(prop-1-en-2- yl)-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine. <com:Sup>1< / com:Sup>H NMR (400 MHz, Chloroform-d) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.74 (s, 1H), 7.15 (d, <com:Math><semantics>J=3.6<annotation encoding="application / x-tex">J = 3.6< / annotation>< / semantics>< / com:Math> Hz, 1H), 6.62 (d, <com:Math><semantics>J=3.7<annotation encoding="application / x-tex">J = 3.7< / annotation>< / semantics>< / com:Math> Hz, 1H), 5.84 (d, <com:Math><semantics>J=3.0<annotation encoding="application / x-tex">J = 3.0< / annotation>< / semantics>< / com:Math> Hz, 1H), 5.76 (ddd, <com:Math><semantics>J=12.2<annotation encoding="application / x-tex">J = 12.2< / annotation>< / semantics>< / com:Math>, 2.4, 1.0 Hz, 2H), 5.31 (t, <com:Math><semantics>J=1.6<annotation encoding="application / x-tex">J = 1.6< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>4.15−4.13<annotation encoding="application / x-tex">4.15 - 4.13< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>2.05<annotation encoding="application / x-tex">2.05< / annotation>< / semantics>< / com:Math> (t, <com:Math><semantics>J=1.0<annotation encoding="application / x-tex">J = 1.0< / annotation>< / semantics>< / com:Math> Hz, 3H), <com:Math><semantics>1.61<annotation encoding="application / x-tex">1.61< / annotation>< / semantics>< / com:Math> (s, 3H), <com:Math><semantics>1.43<annotation encoding="application / x-tex">1.43< / annotation>< / semantics>< / com:Math> (s, 6H); LCMS <com:Math><semantics>m / z=346.02(M+,100%)<annotation encoding="application / x-tex">m / z = 346.02 (M+, 100\%)< / annotation>< / semantics>< / com:Math>. 4-Methyl-7-((3aS,4R,6aR)-2,2,6a-trimethyl-6-(prop-1-en-2-yl)-4,6a-dihydro-3aH- cyclopenta[d][1,3]dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine [Image disponible dans le document PDF, Image available in the PDF document] The title compound was synthesized by following an analogous reaction protocol as was described in the preparation of 7-((3aS,4R,6aR)-2,2-dimethyl-6-(prop-1-en-2-yl)-4,6a- dihydro-3aH-cyclo penta[d][1,3] dioxol-4-yl)-4-methyl-7H-pyrrolo[2,3-d]pyrimidine. <com:Sup>1< / com:Sup>H NMR (400 MHz, Chloroform-d) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.87 (s, 1H), 7.06 (d, J = 3.6 Hz, 1H), 6.56 (d, J = 3.6 Hz, 1H), <com:Math><semantics>5.89−5.67<annotation encoding="application / x-tex">5.89 - 5.67< / annotation>< / semantics>< / com:Math> (m, 3H), <com:Math><semantics>5.29<annotation encoding="application / x-tex">5.29< / annotation>< / semantics>< / com:Math> (t, <com:Math><semantics>J=1.6<annotation encoding="application / x-tex">J = 1.6< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>4.14<annotation encoding="application / x-tex">4.14< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=1.3<annotation encoding="application / x-tex">J = 1.3< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>2.76<annotation encoding="application / x-tex">2.76< / annotation>< / semantics>< / com:Math> (s, 3H), <com:Math><semantics>2.05<annotation encoding="application / x-tex">2.05< / annotation>< / semantics>< / com:Math> (t, <com:Math><semantics>J=1.0<annotation encoding="application / x-tex">J = 1.0< / annotation>< / semantics>< / com:Math> Hz, 3H), <com:Math><semantics>1.61<annotation encoding="application / x-tex">1.61< / annotation>< / semantics>< / com:Math> (s, 3H), <com:Math><semantics>1.43<annotation encoding="application / x-tex">1.43< / annotation>< / semantics>< / com:Math> (s, 6H); LCMS m / z=326.28 (M+, 100%). 7-((3aS,4R,6aR)-2,2-dimethyl-6-vinyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4- yl)-4-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine [Image disponible dans le document PDF, Image available in the PDF document] The title compound was synthesized by following an analogous reaction protocol as was described in the preparation of 7-((3aS,4R,6aR)-2,2-dimethyl-6-(prop-1-en-2-yl)-4,6a- dihydro-3aH-cyclo penta[d][1,3] dioxol-4-yl)-4-methyl-7H-pyrrolo[2,3-d]pyrimidine. LCMS <com:Math><semantics>m / z=364.22<annotation encoding="application / x-tex">m / z=364.22< / annotation>< / semantics>< / com:Math> (M+, 100%). (3aS,4R,6aS)-5-(((tert-Butyldiphenylsilyl)oxy)methyl)-4-ethyl-2,2-dimethyl-4,6a- dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ol TBDPSO ... The title compound was synthesized by following an analogous reaction protocol as was described in the preparation of (3aS,4R,6aS)-5-(((tert-Butyldiphenylsilyl)oxy)methyl)- 2,2,4-trimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-ol. <com:Sup>1< / com:Sup>H NMR (400 MHz, Chloroform-d) <com:Math><semantics>δ7.76−7.74<annotation encoding="application / x-tex">\delta 7.76 - 7.74< / annotation>< / semantics>< / com:Math> (m, 2H), <com:Math><semantics>7.73−7.68<annotation encoding="application / x-tex">7.73 - 7.68< / annotation>< / semantics>< / com:Math> (m, 4H), <com:Math><semantics>7.44−7.39<annotation encoding="application / x-tex">7.44 - 7.39< / annotation>< / semantics>< / com:Math> (m, 8H), <com:Math><semantics>5.95<annotation encoding="application / x-tex">5.95< / annotation>< / semantics>< / com:Math> (d, J) <com:Math><semantics>=1.9 Hz,1H,5.01 (ddt,J=5.5,2.9,1.5 Hz,1H),4.43−4.36 (m, 2H),1.49 (s, 3H),<annotation encoding="application / x-tex">= 1.9 \text{ Hz}, 1\text{H}, 5.01 \text{ (ddt}, J = 5.5, 2.9, 1.5 \text{ Hz}, 1\text{H}), 4.43 - 4.36 \text{ (m, 2H)}, 1.49 \text{ (s, 3H)},< / annotation>< / semantics>< / com:Math> 1.43 (s, 3H), 1.10 (s, 9H), 0.74 (t, <com:Math><semantics>J=7.5<annotation encoding="application / x-tex">J = 7.5< / annotation>< / semantics>< / com:Math> Hz, 3H). (3aS,4S,6aR)-6-(((tert-Butyldiphenylsilyl)oxy)methyl)-6a-ethyl-2,2-dimethyl-4,6a- dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ol [Image disponible dans le document PDF, Image available in the PDF document] The title compound was synthesized by following an analogous reaction protocol as was described in the preparation of (3aS,4S,6aR)-6-(((tert-Butyldiphenylsilyl)oxy)methyl)- 2,2,6a-trimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-ol. <com:Sup>1< / com:Sup>H NMR (400 MHz, Chloroform-d) <com:Math><semantics>δ7.72−7.67<annotation encoding="application / x-tex">\delta 7.72 - 7.67< / annotation>< / semantics>< / com:Math> (m, 4H), <com:Math><semantics>7.41<annotation encoding="application / x-tex">7.41< / annotation>< / semantics>< / com:Math> (dddt, <com:Math><semantics>J=15.6,7.9,6.7,2.1<annotation encoding="application / x-tex">J = 15.6, 7.9, 6.7, 2.1< / annotation>< / semantics>< / com:Math> Hz, 6H), <com:Math><semantics>5.92<annotation encoding="application / x-tex">5.92< / annotation>< / semantics>< / com:Math> (p, <com:Math><semantics>J=1.7 Hz<annotation encoding="application / x-tex">J = 1.7 \text{ Hz}< / annotation>< / semantics>< / com:Math>, 1H), 4.52 (s, 1H), 4.43 – 4.35 (m, 2H), 4.22 (ddd, <com:Math><semantics>J=15.6<annotation encoding="application / x-tex">J = 15.6< / annotation>< / semantics>< / com:Math>, 3.0, 2.0 Hz, 1H), <com:Math><semantics>2.71<annotation encoding="application / x-tex">2.71< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>1.79−1.64<annotation encoding="application / x-tex">1.79 - 1.64< / annotation>< / semantics>< / com:Math> (m, 2H), <com:Math><semantics>1.39<annotation encoding="application / x-tex">1.39< / annotation>< / semantics>< / com:Math> (s, 3H), <com:Math><semantics>1.32<annotation encoding="application / x-tex">1.32< / annotation>< / semantics>< / com:Math> (s, 3H), <com:Math><semantics>1.10<annotation encoding="application / x-tex">1.10< / annotation>< / semantics>< / com:Math> (s, 9H), <com:Math><semantics>0.74<annotation encoding="application / x-tex">0.74< / annotation>< / semantics>< / com:Math> (t, <com:Math><semantics>J=7.6<annotation encoding="application / x-tex">J = 7.6< / annotation>< / semantics>< / com:Math> Hz, 3H). 7-((3aS,4R,6aR)-6-(((tert-Butyldiphenylsilyl)oxy)methyl)-6a-ethyl-2,2-dimethyl-4,6a- dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidine [Image disponible dans le document PDF, Image available in the PDF document] The title compound was synthesized by following an analogous reaction protocol as was described in the preparation of 1-((3aS,4R,6aR)-6-(((tert-butyldiphenylsilyl)oxy)methyl)- 2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-4-chloro-1H-pyrrolo[3,2- c] pyridine. <com:Sup>1< / com:Sup>H NMR (400 MHz, Chloroform-d) δ 8.76 (s, 1H), 7.79 – 7.67 (m, 4H), 7.55 <com:Math><semantics>−7.37<annotation encoding="application / x-tex">-7.37< / annotation>< / semantics>< / com:Math> (m, 6H), 6.99 (d, <com:Math><semantics>J=3.6<annotation encoding="application / x-tex">J = 3.6< / annotation>< / semantics>< / com:Math> Hz, 1H), 6.60 (d, <com:Math><semantics>J=3.6<annotation encoding="application / x-tex">J = 3.6< / annotation>< / semantics>< / com:Math> Hz, 1H), 6.03 <com:Math><semantics>−5.96<annotation encoding="application / x-tex">-5.96< / annotation>< / semantics>< / com:Math> (m, 1H), 5.78 (q, <com:Math><semantics>J=2.5<annotation encoding="application / x-tex">J = 2.5< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>4.61−4.43<annotation encoding="application / x-tex">4.61 - 4.43< / annotation>< / semantics>< / com:Math> (m, 2H), <com:Math><semantics>4.25<annotation encoding="application / x-tex">4.25< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=0.9<annotation encoding="application / x-tex">J = 0.9< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>1.75<annotation encoding="application / x-tex">1.75< / annotation>< / semantics>< / com:Math> (q, <com:Math><semantics>J=7.3<annotation encoding="application / x-tex">J = 7.3< / annotation>< / semantics>< / com:Math> Hz, 1H), 1.55 (dq, <com:Math><semantics>J=14.8<annotation encoding="application / x-tex">J = 14.8< / annotation>< / semantics>< / com:Math>, 7.4 Hz, 1H), 1.41 (s, 6H), 1.13 (s, 9H), 0.68 (t, <com:Math><semantics>J=7.4<annotation encoding="application / x-tex">J = 7.4< / annotation>< / semantics>< / com:Math> Hz, 3H); LCMS <com:Math><semantics>m / z=588.21<annotation encoding="application / x-tex">m / z = 588.21< / annotation>< / semantics>< / com:Math> (M+, 100%). ((3aR,6R,6aS)-6-(4-Chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3a-ethyl-2,2-dimethyl- 6,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methanol [Image disponible dans le document PDF, Image available in the PDF document] The title compound was synthesized by following an analogous reaction protocol as was described in the preparation of ((3aR,6R,6aS)-6-(2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7- yl)-2,2-dimethyl-6,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methanol. <com:Sup>1< / com:Sup>H NMR <com:Math><semantics>(400 MHz,Chloroform-d)δ8.74 (s, 1H),7.17 (d, J=3.7 Hz, 1H),6.60 (d, J=3.6 Hz, 1H),<annotation encoding="application / x-tex">(400 \text{ MHz}, \text{Chloroform-}d) \delta 8.74 \text{ (s, 1H)}, 7.17 \text{ (d, } J = 3.7 \text{ Hz, 1H)}, 6.60 \text{ (d, } J = 3.6 \text{ Hz, 1H)},< / annotation>< / semantics>< / com:Math> 5.93 (dq, <com:Math><semantics>J=2.7<annotation encoding="application / x-tex">J = 2.7< / annotation>< / semantics>< / com:Math>, 1.5 Hz, 1H), 5.79 (q, <com:Math><semantics>J=2.2<annotation encoding="application / x-tex">J = 2.2< / annotation>< / semantics>< / com:Math> Hz, 1H), 4.60 – 4.43 (m, 2H), 4.32 (t, <com:Math><semantics>J=<annotation encoding="application / x-tex">J =< / annotation>< / semantics>< / com:Math> <com:Math><semantics>0.8 Hz<annotation encoding="application / x-tex">0.8 \text{ Hz}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>1H<annotation encoding="application / x-tex">1\text{H}< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>1.94 (dq<annotation encoding="application / x-tex">1.94 \text{ (dq}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>J=14.8<annotation encoding="application / x-tex">J = 14.8< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>7.4 Hz<annotation encoding="application / x-tex">7.4 \text{ Hz}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>1H<annotation encoding="application / x-tex">1\text{H}< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>1.74 (dq<annotation encoding="application / x-tex">1.74 \text{ (dq}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>J=14.7<annotation encoding="application / x-tex">J = 14.7< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>7.5 Hz<annotation encoding="application / x-tex">7.5 \text{ Hz}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>1H<annotation encoding="application / x-tex">1\text{H}< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>1.51 (s, 3H)<annotation encoding="application / x-tex">1.51 \text{ (s, 3H)}< / annotation>< / semantics>< / com:Math>, 1.41 (s, 3H), 0.83 (t, <com:Math><semantics>J=7.5<annotation encoding="application / x-tex">J = 7.5< / annotation>< / semantics>< / com:Math> Hz, 3H); LCMS m / z= 350.22 (M+, 100%). (3aR,6R,6aS)-6-(4-Chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3a-ethyl-2,2-dimethyl- 6,6a-dihydro-3aH-cyclopenta[d][1,3]dioxole-4-carbaldehyde [Image disponible dans le document PDF, Image available in the PDF document] The title compound was synthesized by following an analogous reaction protocol as was described in the preparation of (3aS,4R,6aR)-2,2-dimethyl-4-(4-methyl-7H-pyrrolo[2,3- d]pyrimidin-7-yl)-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxole-6-carbaldehyde. <com:Sup>1< / com:Sup>H NMR (400 MHz, Chloroform-d) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 10.02 (s, 1H), 8.75 (s, 1H), 7.09 (d, <com:Math><semantics>J=3.7<annotation encoding="application / x-tex">J = 3.7< / annotation>< / semantics>< / com:Math> Hz, 1H), 6.88 (dd, <com:Math><semantics>J=2.8,1.1 Hz,1H,6.68 (d,J=3.6 Hz,1H),5.98 (dd,J=2.8,1.0 Hz,1H),4.43 (d,J=2.8,1.0 Hz,1H)<annotation encoding="application / x-tex">J = 2.8, 1.1 \text{ Hz}, 1\text{H}, 6.68 \text{ (d}, J = 3.6 \text{ Hz}, 1\text{H}), 5.98 \text{ (dd}, J = 2.8, 1.0 \text{ Hz}, 1\text{H}), 4.43 \text{ (d}, J = 2.8, 1.0 \text{ Hz}, 1\text{H})< / annotation>< / semantics>< / com:Math> 1.0 Hz, 1H), 2.24 (dq, <com:Math><semantics>J=14.9<annotation encoding="application / x-tex">J = 14.9< / annotation>< / semantics>< / com:Math>, 7.5 Hz, 1H), 1.97 (dq, <com:Math><semantics>J=14.8<annotation encoding="application / x-tex">J = 14.8< / annotation>< / semantics>< / com:Math>, 7.4 Hz, 1H), 1.47 (s, 6H), 0.89 (t, <com:Math><semantics>J=7.5<annotation encoding="application / x-tex">J = 7.5< / annotation>< / semantics>< / com:Math> Hz, 3H); LCMS m / z= 348.22 (M+, 100%). 4-Chloro-7-((3aS,4R,6aR)-6a-ethyl-2,2-dimethyl-6-vinyl-4,6a-dihydro-3aH- cyclopenta[d][1,3]dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine [Image disponible dans le document PDF, Image available in the PDF document] The title compound was synthesized by following an analogous reaction protocol as was described in the preparation 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. <com:Sup>1< / com:Sup>H NMR (400 MHz, Chloroform-d) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.75 (s, 1H), 7.16 (d, <com:Math><semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics>< / com:Math> = 3.7 Hz, 1H), 6.60 (d, <com:Math><semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics>< / com:Math> = 3.7 Hz, 1H), 6.56 <com:Math><semantics>−6.36<annotation encoding="application / x-tex">-6.36< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>5.99−5.69<annotation encoding="application / x-tex">5.99 - 5.69< / annotation>< / semantics>< / com:Math> (m, 3H), <com:Math><semantics>5.44<annotation encoding="application / x-tex">5.44< / annotation>< / semantics>< / com:Math> (dd, <com:Math><semantics>J=11.3<annotation encoding="application / x-tex">J = 11.3< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>1.5<annotation encoding="application / x-tex">1.5< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>4.25<annotation encoding="application / x-tex">4.25< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=0.9<annotation encoding="application / x-tex">J = 0.9< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>2.15−1.99<annotation encoding="application / x-tex">2.15 - 1.99< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>1.76<annotation encoding="application / x-tex">1.76< / annotation>< / semantics>< / com:Math> (dq, <com:Math><semantics>J=14.8<annotation encoding="application / x-tex"&g...

Claims

1. A compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, [Image disponible dans le document PDF, Image available in the PDF document] (l) wherein ring A is selected from- [Image disponible dans le document PDF, Image available in the PDF document] L 1 L_1 is selected from − C H 2 -CH_2 -, − C H ( C H 3 ) -CH(CH_3) -, − N H -NH -, − N ( C H 3 ) -N(CH_3) -, S S , and O O ; R 3 is selected from F, Cl, Br, CN, -NH 2 , -NH(CH 3 ), -NHCH(CH 3 ) 2 , -CH 3 , cyclopropyl, -CH(CH 3 ) 2 , -CF 2 CH 3 , -OCH 3 , CF 3 , [Image disponible dans le document PDF, Image available in the PDF document] R is selected from hydrogen, -NH 2 , Cl, -CH(CH 3 ) 2 , methyl, ethyl, cyclopropyl and [Image disponible dans le document PDF, Image available in the PDF document] R a and R b are independently selected from hydrogen, methyl, and cyclopropyl; R c and R d are independently selected from hydrogen, methyl, and cyclobutyl; R 2 and R 2a are independently selected from hydrogen and methyl; R 1 and R 2 together with the carbon atoms to which they are attached form a bond in order to form a − C = C -C=C -; or R 1 R^1 and R 2 R^2 together with the carbon atoms to which they are attached form a cyclopropane ring; R 10 is selected from hydrogen, -F, and methyl; Z is selected from CH and N and n is an integer ranging from 0 to 4, both inclusive.

2. The compound of claim 1 having the structure of Formula (IV), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, [Image disponible dans le document PDF, Image available in the PDF document] (IV) wherein, X 2 X^2 is Br or Cl; and L 1 L_1 , R a R^a , R b R^b , R 1 R^1 , R 2 R^2 , R 2 R^2 , R R , R 2 a R^{2a} and R 10 R^{10} are as defined in claim 1.

3. The compound of formula (I) according to claim 1 or the compound of formula (IV) according to claim 2, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: (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; (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; (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; (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)-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; (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; (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; (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; (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; (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; (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; (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; (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; (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; (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; (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; (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; (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; (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; (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; (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; (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; (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; (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; (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; (1S,2R,5R)-3-(1-(2-Amino-3-bromo-5-fluoro quinolin-7-yl)propan-2-yl)-5-(4-amino- 7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol; (1S,2R,5R)-3-(2-(2-Amino-3-chloro-5-fluoro quinolin-7-yl)ethyl)-5-(4-methyl-1H- pyrrolo[3,2-c]pyridin-1-yl)cyclopent-3-ene-1,2-diol; (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; (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; (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; (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; (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; (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; (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; (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; and (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.

4. The compound of formula (I) according to claim 1 or the compound of formula (IV) according to claim 2, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: (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; (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; (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; (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; (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; (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; (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; (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; (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; (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; (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; (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; (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; (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; (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; (1S,2R,5R)-3-(1-(2-Amino-3-bromo-5-fluoro quinolin-7-yl)propan-2-yl)-5-(4-amino- 7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol; (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; (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; and (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.

5. A pharmaceutical composition comprising at least one compound as defined in any one of claims 1 to 4, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

6. Use of a compound as defined in any one of claims 1 to 4, in the preparation of a medicament for inhibiting PRMT5 in the treatment of a disease, a disorder, a syndrome or a condition associated with overexpression of PRMT5 in a subject in need thereof.

7. Use of a compound as defined in any one of claims 1 to 4, for inhibiting PRMT5 in the treatment of a disease, a disorder, a syndrome or a condition associated with overexpression of PRMT5 in a subject in need thereof.

8. The use of claim 6 or 7, wherein the disease, the disorder, the syndrome or the condition is selected from the group consisting of glioblastoma multiforme, prostate cancer, pancreatic cancer, mantle cell lymphoma, non-Hodgkin's lymphomas, 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 cancer, melanoma, sarcoma, oropharyngeal squamous cell carcinoma, chronic myelogenous leukemia, epidermal squamous cell carcinoma, nasopharyngeal carcinoma, neuroblastoma, endometrial carcinoma, and cervical cancer.

9. The use of claim 6 or 7, wherein the disease, the disorder, the syndrome or the condition is cancer.

10. A compound as defined in any one of claims 1 to 4, for use in inhibiting PRMT5 in the treatment of a disease, a disorder, a syndrome or a condition associated with overexpression of PRMT5 in a subject in need thereof.

11. The compound for use of claim 10, wherein the disease, the disorder, the syndrome or the condition is selected from the group consisting of glioblastoma multiforme, prostate cancer, pancreatic cancer, mantle cell lymphoma, non-Hodgkin's lymphomas, 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 cancer, melanoma, sarcoma, oropharyngeal squamous cell carcinoma, chronic myelogenous leukemia, epidermal squamous cell carcinoma, nasopharyngeal carcinoma, neuroblastoma, endometrial carcinoma, and cervical cancer.

12. The compound for use of claim 10, wherein the disease, the disorder, the syndrome or the condition is cancer.

13. A pharmaceutical composition as defined in claim 5, for use in inhibiting PRMT5 in the treatment of a disease, a disorder, a syndrome or a condition associated with overexpression of PRMT5 in a subject in need thereof.

14. The pharmaceutical composition for use of claim 13, wherein the disease, the disorder, the syndrome or the condition is selected from the group consisting of glioblastoma multiforme, prostate cancer, pancreatic cancer, mantle cell lymphoma, non-Hodgkin's lymphomas, 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 cancer, melanoma, sarcoma, oropharyngeal squamous cell carcinoma, chronic myelogenous leukemia, epidermal squamous cell carcinoma, nasopharyngeal carcinoma, neuroblastoma, endometrial carcinoma, and cervical cancer.

15. The pharmaceutical composition for use of claim 13, wherein the disease, the disorder, the syndrome or the condition is cancer.