OA19533A

OA19533A - Substituted bicyclic heterocyclic compounds as PRMT5 inhibitors.

Info

Publication number: OA19533A
Application number: OA1202000200
Authority: OA
Inventors: Prathap Sreedharan Nair; Ganesh Bhausaheb Gudade; Sachin Sethi; Dipak Raychand Lagad; Chetan Sanjay Pawar; Mahadeo Bhaskar Tryambake; Chaitanya Prabhakar Kulkarni; Anil Kashiram Hajare; Balasaheb Arjun GORE; Sanjeev Anant Kulkarni; Milind Dattatraya Sindkhedkar; Venkata P. Palle; Rajender Kumar Kamboj
Original assignee: Lupin Limited
Priority date: 2017-12-13
Filing date: 2018-12-13
Publication date: 2020-11-13

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 enzyme. The invention also relates to methods of treating diseases, disorders or conditions associated with the overexpression of PRMT5 enzyme.

Description

Méthylation of proteins is a common post-translational modification that affects the proteiris activity and its interaction with other biological molécules. N-methylation typically occurs on the nitrogen atoms of arginine, lysine and histidine residues and there are different familles of enzymes that catalyze the méthylation reaction, each being spécifie to the amino acid residue that will be methylated.

A family of 9 enzymes, called Protein Arginine N-Mefhyl Transferases (PRMTs), are responsible for the méthylation 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 méthylation are histones, Sm ribonucleoproteins, MRE11 and p53 binding protein 1.

The méthylation of arginine side-chains has an important rôle 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 prolifération, repair of damaged DNA as well as cell cycle and cell death. It has been shown that PRMT enzyme-mediated hyperméthylation 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 présent, 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 nucléus 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), ηοπ-small cell lung cancer (The Biochemical Journal, 2012, 446, p235), small cell lung cancer (AACR; Cancer Research 2017;77(13 Suppl):Abstract nr DDT0204), breast cancer (Cell Reports, 2017, 21, p3498), triple négative 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 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), endométrial carcinoma (Gynecol OncoL, 2016, 140, p145), cervical cancer (Pharmazie, 2018, 73, p269).. These findings hâve led to further research which show that inhibiting PRMT5 reduces cell prolifération (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 a/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 hâve been disclosed. Other publications that disclose small molécules as inhibitors in relation to PRMT5 are: WO2011077133, WO2011079236, WO2014100695, WO2014100716, WO2014100719, WO2014100730, WO2014100734, 5 WO2014128465, WO2014145214, WO2015200677, WO2015200680, WO2015198229,

WO2016022605, WO2016034671, WO2016034673, WO2016034675, WO2016038550, WO2016135582, WO2016145150, WO2016178870, WO2017032840 and ACS Médicinal 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 sait thereof,

wherein,

Li is selected from -CR^aR^b-, -NR^a-, S, and O;

Z=GH or N;

R^a and R^b are independently selected at each occurrence from hydrogen, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl;

ring A is selected from,

R^c and R^d are selected from substituted or unsubstituted alkyl or together with the carbon atoms to which they are attached form a C₃-C₆ cycloalkyl ring;

R is selected from -NR⁴R⁵, hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted heteroaryl and substituted or unsubstituted cycloalkyl;

R¹ and R² together with the carbon atoms to which they are attached form a bond in order to form a -C=C-; or R¹ and R² together with the carbon atoms to which they are attached form a cyclopropane ring;

R²' and R^2a which may be same or different and are independently selected from hydrogen and substituted or unsubstituted alkyl;

R³ is independently selected at each occurrence from halogen, cyano, nitro, substituted or unsubstituted alkyl, -OR⁶, -NR⁷R⁸, substituted or unsubstituted cycloalkyl, -C(O)OH, -C(O)O-a!kyl, -C(O)R⁹, -C(O)NR⁷R⁸, -NR⁷C(O)R⁹ substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclyl;

R⁴ and R⁵ are independently selected from hydrogen, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl;

R⁶ is selected from hydrogen, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl;

R⁷ and R⁸ are independently selected from hydrogen, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl;

R⁹ is selected from substituted or unsubstituted alkyl and substituted or unsubstituted cycloalkyl;

R¹⁰is selected from hydrogen, halogen, and substituted or unsubstituted alkyl;

‘ri 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 (=O), halogen, cyano, cycloalkyl, aryl, heteroaryl, heterocyclyl, -OR^7a, C(=O)OH, -C(=O)O(alkyl), -NR^8aR^8b, -NR^8aC(=O)R^9a, and -C(=O)NR^8aR^8b;

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^7a, -NR^8aR^8b, -NR^7aC(=O)R^9a, -C(=O)R^9a, C(=O)NR^8aR^8b, -SO₂-alkyl, -C(=O)OH, and -C(=O)O-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 (=O), halogen, cyano, alkyl, cycloaikyl, perhaloalkyl, -OR^7a, -C(=O)NR^8aR^8b, -C(=O)OH, -C(=O)O-alkyl, N(H)C(=O)(alkyl), -N(H)R^8a, and -N(alkyl)₂; and when the heterocycle group is substituted on a ring nitrogen, it is substituted with substituents independently selected from alkyl. cycloaikyl, aryl, heteroaryl, -SO₂(aikyl), -C(=O)R^9a, and -C(=O)O(alkyi); when the heterocycle group is substituted on a ring sulfur, it is substituted with 1 or 2 oxo (=O) group(s);

R^7a is selected from hydrogen, alkyl, perhaloalkyl, and cycloaikyl;

R^8a and R^8b are each independently selected from hydrogen, alkyl, and cycloaikyl; and

R^9a is selected from alkyl and cycloaikyl.

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 daims.

According to one embodiment, the invention provides compounds having the structure of Formula (II), a stereoisomer thereof, or a pharmaceutically acceptable sait thereof,

wherein,

Ring A, Li, Z, R^a, R^b, R² , R, R^2a, R³, R¹⁰ and ‘ri 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 sait thereof,

wherein,

Ring A, Li, Z, R^a, R^b, R²', R, R^2a, R³, R¹⁰ and ‘ri are as defined herein above.

According to one embodiment, the invention provides compounds having the structure of 5 Formula (IV), a stereoisomer thereof, or a pharmaceutically acceptable sait thereof,

(IV) wherein,

X² is Br or Cl;

Li, R^a, R^b, R¹, R²', R², R, R^2a and R¹⁰ are as defined herein above.

In accordance with an embodiment ofthe invention, R^G and R^d are independently selected from substituted or unsubstituted alkyl or R^c and R^d together with the carbon atom to which they are attached form a cyciobutyl ring.

In certain embodiment, R^c and R^d are independently selected from methyl or R^c and R^d15 together with the carbon atom to which they are attached from a cyciobutyl ring.

In any of above embodiments, R^a and R^b are independently selected from hydrogen, methyl, and cyclopropyl.

In any of above embodiments, R³ is selected from halogen, cyano, -OR⁶, -NR⁷R⁸, substituted or unsubstituted alkyl, and substituted or unsubstituted aryl.

in certain embodiments, R³ is independently selected from -F, Cl, Br, CN, -NH₂, -NH(CH₃), -NHCH(CH₃)₂, -CH₃, cyclopropyl, -CH(CH₃)₂, -CF2CH3, -OCH₃,

In any of above embodiments, R²’ and R^2a are independently selected from hydrogen and methyl.

In any of above embodiments, R is selected from hydrogen, halogen, -NR⁴R⁵, and substituted or unsubstituted alkyl , substituted or unsubstituted cycloalkyl and substituted or unsubstituted heteroaryl.

In certain embodiments, R is selected from hydrogen, -NH₂, methyl, Chloro, cyclopropyl,

In any of above embodiments, R⁴ and R⁵ are independently selected from hydrogen.

In any of above embodiments, R⁶ is selected from substituted and unsubstituted alkyl.

In certain embodiments, R⁶ is selected from methyl.

In any of above embodiments, R⁷ and R⁸ are independently selected from hydrogen, methyl, -CH(CH₃)₂, -CH₂-cyclopropyl, cyclopropyl, and cyclobutyl.

In any of above embodiments, R¹⁰ 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 Li is selected from -CH₂-, -CH(CH₃)-, -NH-, -N(CH₃)- S, and O;

According to another embodiment, there are provided compounds having the structure of Formula (1) wherein ring A is N

According to another embodiment, there are provided compounds having the structure of Formula (I) wherein ring A is N

According to another embodiment, there are provided compounds having the

r structure of Formula (I) wherein ring A is ^RC R^d

According to another embodiment, there are provided compounds having the structure of Formula (I), wherein ring A is selected fromand

L1 is selected from -CH2-, —CH(CH3)-, -NH-, -N(CH3)-, S, and O; R³ is selected from F, Cl, Br, CN, -NH₂, -NH(CH₃), -NHCH(CH₃)₂, -CH₃₁ cyclopropyl, -CH(CH₃)₂, -CF₂CH₃, -OCH₃, CF_3>

\ selected from hydrogen, -NH₂, Cl, -CH(CH₃)2, methyl, ethyl, cyclopropyl and ; R^aand R^b are independently selected from hydrogen, methyl, and cyclopropyl; R² and R^2a are independently selected from hydrogen and methyl; R¹⁰ is selected from hydrogen, -F, and methyl.

The examplesl to 84 given herein are représentative compounds, which are only 15 illustrative in nature and are not intended to limit to the scope of the invention.

it should be understood that formula (I) structuraliy encompasses ail tautomers, stereoisomers and isotopes wherever applicable and pharmaceutically acceptable salts that may be contempîated from the Chemical structures generally described herein.

According to one embodiment, there are provided compounds of formula (I) to (IV) 20 wherein the compound is in the form of the free base or îs a pharmaceutically acceptable sait thereof.

In another aspect of the invention, there are provided compounds of formula (!) to (IV) or a pharmaceutically acceptable sait thereof for treating the diseases, disorders, syndromes or conditions associated with PRMT5 enzyme.

In one embodiment of the présent invention, there are provided compounds of formula (I) to (IV), or a pharmaceutically acceptable sait 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 sait thereof for use as a médicament.

In another aspect of the invention, there are provided compounds of formula (I) to (IV) or a pharmaceutically acceptable sait thereof for use in treating the diseases, disorders, syndromes or conditions associated with PRMT5.

In one embodiment of the présent invention, there are provided compounds of formula (I) to (IV) or a pharmaceutically acceptable sait 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 (!) to (IV) or a pharmaceutically acceptable sait 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 présent invention, a method of treating diseases, disorders or conditions is selected from glioblastoma multiforme, prostate cancer, and pancreatic cancer, mantle ceîl lymphoma, non-Hodgkin’s lymphomas and diffuse large B-ceiï lymphoma, acute myeloid leukemia, acute lymphoblastic leukemia, multiple myeloma, nonsmall cell lung cancer, small cell lung cancer, breast cancer, triple négative 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, endométrial 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 sait thereof, for the manufacture of a médicament 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 sait 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 saltthereof, 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 présent invention, wherein the use of compounds of formula (I) to (IV) or a pharmaceutically acceptable sait 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 myeioid leukemia, acute lymphoblastic leukemia, multiple myeloma, non-smali celï ïung cancer, smail cell lung cancer, breast cancer, triple négative breast cancer, gastric cancer, colorectal cancer, ovarian cancer, bladder cancer, hepatoceilular cancer, melanoma, sarcoma, oropharyngeal squamous cell carcinoma, chronic myelogenous leukemia, epidermal squamous cell carcinoma, nasopharyngeal carcinoma, neuroblastoma, endométrial 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 sait 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[2,3d]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[2,3d]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-7Hpyrrolo[2,3-d]pyrimidin-7-yl)cyc!opent-3-ene-1,2-diol (Compound-3);

(1S,2R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-(((2-aminoquinoiin-7yl)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[2,3d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (Compound-5);

(1S,2R,5R)-5-(4-amino-7H-pynOlo[2,3-d]pyrimidin-7-yl)-3-(((2-aminoquinolin-7yl)(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-7Hpyrrolo[2_l3-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-7Hpyrrolo{2,3-d]pyrimidin-7-yl)-2-methylGyclopent-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)cyGlopent-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[1,2a]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-7Hpyrrolo[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-7Hpyrrolo[2,3-d]pyrimidin-7-y!)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-1Hpyrrolo[3,2-c]pyridin-1-yl)cyclopent-3-ene-1,2-diol hydrochloride (Compound-14);

(1S_i2R_!5R)-3-(2-(2-Amino-3-chloro-5-fluoroquinolin-7-yi)ethyl)-5-(1H-pyrrolo[3,2G]pyridin-1-yl)cyclopent-3-ene-1,2-diol (Compound-15);

(1S_l2R,5R)-3-(2-(2-amino-3-chloro-5-fluoroquinolin-7-yl)ethyl)-5-(7H-pyrrolo[2,3d]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-7yl)amino)methy!)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-7Hpyrrolo[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)quinolin7-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-7Hpyrrolo[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[2,3d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (Compound-21);

(1S,2R,5R)-5-(4-Amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-(2-(2-(cyclobutylamino) quinolin-7-yl)ethyl)cyclopent-3-ene-1,2-diol (Compound-22);

(1S,2R,5R)-3-(2-(2-Amino-3-fluoroquinolin-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3d]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-7Hpyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (Gompound-24);

(1S,2R,5R)-3-(2-(2-amino-3-chloro-6-fluoroquinolin-7-yl)ethyl)-5-(4-amino-7Hpyrrolo[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-7Hpyrrolo[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-7Hpyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (Compound-27);

( 1 S, 2 R,5 R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-(2-(2'aminospiro[cyclobutane-1 .S'-inddj-S'-yOethyOcyclopent-S-ene-l ,2-diol (Compound28);

(1S,2R,5R)-3-(2-(2-amino-3,5-dichloroquinolin-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (Compound-29);

(1S,2R,5R)-3-(2-(2-amino-3-Ghloroquinolin-7-yl)ethyl)-5-(2-amino-7H-pyrrolo[2,3d]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-7Hpyrrolo[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-1Hpyrazol-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-7Hpyrrolo[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-7Hpyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (Compound-34a and 34b);

(1S,2R,5R)-3-(1-(2-Amino-3-Ghloro-5-fluoroquinolin-7-yl)propan-2-yl)-5-(4-methyl-7Hpyrrolo[2,3-d]pyrimidin-7-yl)cyciopent-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-methyi-5-(4methy!-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (Gompound-36a and 36b);

(1S,2R,5R)-3-(2-(2-amino-3-chloro-5-fluoroquinolin-7-yl)ethyl)-5-(4-amino-7Hpyrrolo[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-7Hpyrrolo[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-methyl7H-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-7Hpyrrolo[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-7Hpyrrolo[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-7Hpyrrolo[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-7Hpyrrolo[2,3-d]pyrimidin-7-yl)cyclopeni-3-ene-1,2-diol (Compound-43);

(1S,2R,5R)-3-(2-(2-Amino-3-bromo-5-fluoroquinolin-7-yl)ethyl)-5-(4-methyl-7Hpyrrolo[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-7Hpyrrolo[2,3-d]pyrimidin-7-y!)cyclopent-3-ene-1,2-diol (Compound-45a and 45b);

(1S,2R,5R)-3-(2-(2-Amino-6-fluorOqL!inolin-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (Compound-46);

(1S,2R,5R)-3-(2-(2-amino-5-fîuoroquinolin-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3d]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-7Hpyrrolo[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);

(1 R,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-yi)-1-(2-(2(cyclobutyIamino)quinolin-7-yl)ethyJ)bicyclo [3.1.0]hexane-2,3-diol (Compound-51);

(1R,2R_!3S_J4R,5S)-4-(4-Amino-7H-pyrrolo[2_l3-d]pyrimidin-7-yl)-1-(2-(2((cyclopropyimethyl)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-8fluoroquinolin-7-yl)ethyl)bicyclo [3.1.0]hexane-2,3-diol (Compound-53);

(1R,2R,3S,4R,5S)-1-(2-(2-Amino-3-methylqu!nolin-7-yl)ethyi)-4-(4-amino-7Hpyrrolo[2,3-d]pyrimidin-7-yl) bicyclo[3.1 .Olhexane-Z^-diol (Compound-54);

(1R,2R,3S,4R_i5S)-1-(2-(2-Amino-3-isopropyl quinol!n-7-yl)ethyl)-4-(4-am!no-7Hpyrrolo[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-amino7H-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)eihyl)-4-(4-amino-7Hpyrrolo[2,3-d]pyrimidin-7-y!) 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-7Hpyrrolo[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)-2,3dihydroxybicyclo [3.1.0]hexan-1-yl)ethyl)quinoline-3-carbonitrile(Compound-59);

(1R,2R,3S,4R,5S)-1-(2-(2-Amino-3-fluoroqu!nolin-7-yl)ethyl)-4-(4-amino-7Hpyrrolo[2,3-d]pyrimidin-7-y!)bicyclo[3.1.0]hexane-2,3-diol(Compound-60);

(1R,2R,3S_l4R,5S)-1-(2-(2-Amino-3-chloroquinolin-7-yl)ethyl)-4-(4-amino-7Hpyrrolo[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-7Hpyrrolo[2,3-d]pyrimidin-7-yl) bicyclo[3.1.0]hexane-2,3-dioi(Compound-62);

(1R,2R,3S_l4R_!5S)-1-(2-(2-Amino-3-chloro-8-fiuoroquinolin-7-yl)ethyl)-4-(4-amino-7Hpyrrolo[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-7Hpyrrolo[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-y!)-1-(2-(3methylimidazo[1,2-a]pyridin-7-yl)ethyl) bicyclo[3.1.0]hexane-2,3-diol (Compound-65);

ί (1R,2R,3S,4R,5S)-1-(2-(2-Amino-3,3-dimethyl-3H-indol-6-yl)ethyl)-4-(4-amino-7Hpyrrolo[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-fluoiOquinolin-7-yl)ethyl)-4-(4-amino-6methyl-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-fÎuoroquinolin-7-yl)ethyl)-4-(4-amino-6methyl-7H-pyrrolo[2,3-d] pyrimidin-7-yl)bicyclo[3.1.0]hexane-2,3-diol (Compound-68);

(1R,2R,3S_l4R,5S)-1-(2-(2-amino-3-chloro-5-fluoroquinolin-7-yl)ethyl)-4-(4-methyl-7Hpyrrolo[2,3-d]pyrim!din-7-yl) bicyclo[3.1.0]hexane-2,3-dîol (Compound-69);

(1R_I2R,3S,4R_i5S)-1-(2-(2-Amino-3-chloro-5-fluoroquinolin-7-yl)ethyO-4-(7Hpyrrolo[2,3-d]pyrimidin-7-yl)bicyclo [3.1,0]hexane-2,3-diol (Gompound-70);

(1 R,2R,3S,4R,5S)-4-(4-Amino-7H-pyrrOlo[2,3-d]pyrimjdin-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-7Hpyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[3.1,0]hexane-2,3-diol (Compound-72);

(1R,2R_l3S,4R,5S)-1-(2-(2-Amino-3-bromoquino!in-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-aminoquinolin7-yl)ethyi)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-(2aminoquinazolin-7-yl)ethyl)bicyclo[3.1.0] hexane-2,3-diol (Compound-75);

(1S_l2R,3S,4R_!5S)-1-((S)-1-(2-Amino-3-bromoquinolin-7-yl)propan-2-yl)-4-(4-amino7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[3.1.0]hexane-2,3-diol (Compound-76a and 76b);

(1S,2R_l3S,4R,5S)-1-((S)-2-(2-Amino-3-chloro-5-fluoroquinolin-7-yl)-1cyclopropylethyl)-4-(4-amino-7H-pyrrolo[2_l3-d]pyrimidin-7-yl)biGyclo[3.1.0]hexane-2_!3diol (Compound-77a and 77b);

(1S,2R,3S_l4R,5S)-1-(1-(2-Amino-3-chloro-5-fluoroquinolin-7-yl)propan-2-yl)-4-(4amino-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-aminoquinolin7-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-7Hpyrrolo[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-7yl)thio)methyl) bicyclo [3.1.0] hexane-2,3-diol (Gompound-81);

(1R,2R,3S,4R,5S)-1-(2-(2-Amino-3-(4-fluorophenyl)quinolin-7-yl)ethyl)-4-(4-amino7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[3.1.0]hexane-2,3-diol_ (Gompound-82 );

(1R,2R,3S,4R,5S)-1-(2-(2-Amino-3-(pyridin-3-yl)quinolin-7-yi)ethyl)-4-(4-amino-7Hpyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[3.1.0Jhexane-2,3-diol (Compound-83); and (1R,2R,3S,4R,5S)-1-(2-(2-Amino-3-(3-methyl isoxazol-4-yl)quinolin-7-yl)ethyI)-4-(4amino-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 sait thereof, are selected from:

(1S,2R,5R)-3-(1-(2-Amino-3-bromoquinolin-7-yl)propan-2-yl)-5-(4-amino-7Hpyrrolo[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-7Hpyrrolo[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-7Hpyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (Compound-13);

(1S,2R,5R)-3-(((2-amino-3-Ghloro-5-fluoroquinolin-7-yl)oxy)methyl)-5-(4-amino-7Hpyrrolo[2,3-d]pyrimidin-7-yl)cyc!opent-3-ene-1,2-diol (Compound-18);

(1S,2R,5R)-3-(2-(2-amino-3-chloroquino!in-7-y!)ethyl)-5-(4-methyÎ-7H-pyrro!o[2,3d]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_i3d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (Compound-23);

(1S,2R,5R)-3-(2-(2-amino-3-chIoro-5-fluoroquinolin-7-yl)ethyl)-5-(4-amino-7Hpyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (Compound-24);

(1S,2R,5R)-3-(2-(2-arnino-3-chloro-6-fluoroquinolin-7-yl)ethyl)-5-(4-arnino-7Hpyrrolo[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-7Hpyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-dioi (Compound-26);

(1S,2R,5R)-3-(2-(2-amino-3,5-dichloroquinoîin-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (Compound-29);

(1S,2R,5R)-3-(2-(2-amino-3-chloro-5-fluoÎOquinolin-7-yl)ethyl)-5-(4-isopropyl-7Hpyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (Compound-31);

(1S,2R,5R)-3-(2-(2-amino-3-chIoro-5-fluoroquinolin-7-y!)ethyl)-5-(4-(1-methyl-1Hpyrazol-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-chloroquinolin-7-yl)propan-2-yl)-5-(4-amino-7Hpyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-dioI (Compound-34a and 34b);

(1S,2R,5R)-3-(2-(2-amino-3-chloro-5-fluoroquinoÎin-7-yl)ethyl)-5-(4-amino-7Hpyrrolo[2,3-d]pyrimidin-7-yl)-2-ethylcyclopent-3-ene-1,2-diol (Compound-40);

(1S,2R,5R)-3-(2-(2-Amino-3-bromo-5-fluoroquinolin-7-yl)ethyl)-5-(4-amino-7Hpyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-'l ,2-diol (Compound-43);

(1S,2R,5R)-3-(2-(2-Amino-3-bromo-5-fluoroquinolin-7-yl)ethyl)-5-(4-methyl-7Hpyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (Oompound-44);

(1S,2R,5R)-3-(1-(2-Amino-3-bromo-5-fluoro quinolin-7-yl)propan-2-yl)-5-(4-amino-7Hpyrrolo[2,3-d]pyrimidin-7-yl)cydopent-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[2,3d]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[2,3d]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-7Hpyrrolo[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-7Hpyrrolo[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-chloroquinolin-7-yl)ethyl)-4-(4-amino-7Hpyrrolo[2,3-d]pyrimidin-7-yl)bicyGlo[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-7Hpyrrolo[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-bromo-6-fluoroquinolin-7-yl)ethyl)-4-(4-amino-7Hpyrrolo[2_!3-d]pyrimidin-7-yl)bicyGlo[3.1.0]hexane-2,3-diol(Compound-64);

(1R,2R,3S,4R,5S)-1-(2-(2-Amino-3-bromo-5-fluoroquinolin-7-yl)ethyl)-4-(4-amino-7Hpyrrolo{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-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).

In another embodiment of the invention the compounds, their stereoisomer thereof, or a pharmaceutically acceptable sait thereof, are selected from.

(1S,2R,5R)-3-(2-(2-amino-3-chloro-5-fluoroquinolin-7-yl)ethyl)-5-(4-amino-7Hpyrrolo[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-7Hpyrrolo[2,3-d]pyrim!din-7-yi)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-7Hpyrrolo[2,3-d]pyrimidin-7-yl)-2-methylcyciopent-3-ene-1,2-diol (Compound-37);

(1R,2R,3S,4R,5S)-1-(2-(2-Amino-3-chloro-5-fluoroquinolin-7-y{)ethyl)-4-(4-amino-7Hpyrrolo[2,3-d]pyrimidin-7-yI)bicyclo[3.1.0]hexane-2,3-diol (Compound-48);

(1R_l2R,3S_I4R,5S)-1-(2-(2-Amino-3-bromoquinolin-7-yl)ethyt)-4-(4-amino-7H-pyrrolo [2,3-d]pyrimidin-7-yl)biGycto[3.1.0]hexane-2,3-diol (Compound-73);

(1S,2R,5R)-3-(2-(2-Amino-3-bromoqujnolin-7-yl)ethyl}-5-(4-arnïno-7H pyrrolo[2,3d]pyrimidin-7-yl)Gyclopent-3-ene-1,2-diol (Compound-1);

(1S,2R,5R)-3-(2-(2-amîno-3-chloro-6-fluoroquinol!n-7-yl)ethyl)-5-(4-amino-7Hpyrrolo[2,3-d}pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (Compound-25);

(1S,2R,5R)-3-(((2-amino-3-chtoro-5-fluoroquinolin-7-y1)oxy)methyl)-5-(4-amino-7Hpyrrolo[2,3-d]pyrimîdin-7-yl)cyGlopent-3-ene-1,2-diol (Compound-18);

(1S,2R,5R)-3-(1-(2-amino-3-chioro-5-fIuoroquinofîn-7-yI)propan-2-yI)-5-(4-amino-7Hpyrrolo[2,3-d]pyrimidin-7-yl)-2-methyîcyGlopent-3-ene-1,2-diol (Compound-38);

(1R,2R,3S,4R,5S)-1-(2-(2-Amino-3-chloroquinolin-7-yI)ethyl)-4-(4-amino-7Hpyrroio[2,3-d]pyrimidin-7-yi)bicyclo[3.1.0]hexane-2,3-diol(Compound-61 );

(1S,2R,5R)-3-(2-(2-Amino-3-bromo-5-fluoroquinolin-7-yi)ethyl)-5-(4-amino-7Hpyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (Compound-43);

( 1 S,2R, 5R)-3-( 1 -(2-Amino-3-bromo-5-fluoro quinoîin-7-yl)propan-2-yl)-5-(4-amino-7HpynOlo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-dÎol (Compound-45a);

(1S,2R,5R)-3-(2-(2-Amino-3-bromo-5-fluoroquînolin-7-yl)ethy!)-5-(4-methyl-7Hpyrrolo[2,3-d]pyrimidin-7-yl)cyGlopent-3-ene-1,2-dioi (Compound-44);

(1R,2R_l3S,4R,5S)-1-(2-(2-Amino-3-bromo-5-fluoroquinolin-7-yl)ethyl)-4-(4-amino-7Hpyrrolo[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-7Hpyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[3.1.0]hexane-2,3-diol (Compound-64).

Detailed description of the invention

Définitions and Abbreviations

Unless otherwise stated, the following tenus used in the spécification and daims hâve the meanings given below.

For purposes of interpreting the spécification, the following définitions 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 molécule by a single bond, for example (Ci-C₆)alkyî or (Ci-C₄)alkyl, représentative groups include e.g., methyi, ethyl, npropyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl and the like. Unless set forth or recited to the contrary, ail alkyl groups described or claimed herein may be straight chair, 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 (C2-Ce)alkenyl, (Cs-C^alkenyl, ethenyl, 1-propenyl, 2propenyl (allyl), /so-propenyl, 2-methyl-l- propenyl, 1-butenyl, 2-butenyl and the like. Unless set forth or recited to the contrary, ail 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 (C2-C₆)alkynyl, (Cz-C^alkynyl, ethynyî, propynyl, butynyl and the like. Unless set forth or recited to the contrary, ail 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 (Ci-Cô)haloalkyl or (CiC4)haloalkyl. Suitably, the haloalkyl may be monohaloalkyl, dihaloalkyl or polyhaloalkyl including perhaloalkyl. A monohaloalkyl can hâve 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 fiuoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl and the like. A perhaloalkyl refers to an alkyl having ail hydrogen atoms replaced with halogen atoms. Unless set forth or recited to the contrary, ail haloalkyl groups described or claimed herein may be straight chain or branched.

The term alkoxy dénotés an alkyl group attached via an oxygen linkage to the rest of the molécule. Représentative examples of such groups are -OCH₃ and -OC₂H₅. Unless set forth or recited to the contrary, ail alkoxy groups described or claimed herein may be straight chain or branched.

The term alkoxyalkyl refers to an alkoxy group as defined above directîy bonded to an alkyl group as defined above, e.g., -CH2-O-CH3, -CH2-O-CH2CH3, -CH2CH2-O-CH3 and the like.

The term cycloalkyl refers to a non-aromatic mono or multicyclic ring System having 3 to 12 carbon atoms, such as (C3-Cio)cycloaikyl, (C₃-C₆)cycîoa'ikyl, cyclopropyi, 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 quatemized, the heterocyclic ring or heterocyclyl may optionally contain one or more olefinic bondfS), and one or two carbon atoms(S) in the heterocyclic ring or heterocyclyl may be interrupted with -CF₂-, -C(O)-, S(O)-, S(O)₂ 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, piperazinyi, 4piperidonyl, pyrrolidinyl, piperidinyl, phenothiazinyl, phenoxazinyl, quinuclidinyi, 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 création 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 heteroatomfS) independently selected from N, O or S. The heteroaryl may be a mono-, bior tricyclic ring System. The heteroaryl ring may be attached by any atom of the heteroaryl ring that results in the création of a stable structure. Non-limiting Examples of a heteroaryl ring include oxazolyl, isoxazolyl, imidazolyl, furyl, indolyl, isoindolyl, pyrrolyl, triazolyl, triazinyl, tetrazolyl, thienyl, thiazolyl, isothiazo’yl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuranyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzothienyl, carbazolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, naphthyridinyl, pteridinyl, purinyl, quinoxalinyl, quinolyl, isoquinolyl, thiadiazolyi, indolizinyl, acridinyl, phenazinyl, phthalazinyl and the like.

The compounds of the présent invention may hâve one or more chiral centers. The absolute stereochemistry at each chiral center may be ‘R’ or ‘S’. The compounds of the invention include ail diastereomers and enantiomers and mixtures thereof. Unless specifically mentioned otherwise, référencé to one stereoisomer applies to any of the possible stereoisomers. Whenever the stereoisomeric composition is unspecified, it is to be understood that ail 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 molécules are nonsuperimposable 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 individuai tautomers as weli 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 expérience or display clinical or subclinical symptoms of the State, disorder or condition; (b) inhibiting the State, disorder or condition, Le., 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, Le., causing régression of the State, disorder or condition or at least one of its clinical or subclinical symptoms.

The term inhibitor refers to a molécule 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 animais, such as domestic animais (e.g., household pets including cats and dogs) and non-domestic animais (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 âge, 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 sait may be appropriate. Non-limiting Exampies 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 usina standard procedures well known in the art, for example by reacting sufficiently basse 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 iiving cell and a mammal, including human. The compound of the invention may be associated with a pharmaceutically acceptable excipient (such as a camer 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, sait solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnésium carbonate, sugar, cyclodextrin, amylose, magnésium stéarate, 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 ingrédient 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 exampie, capsules, tablets, capiets, orally disintegrating tablets, aérosols, 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, parentéral, 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, capiets, capsules (soft or 'nard gelatin), orally disintegrating tablets, dragees (containing the active ingrédient 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 particularîy suitable for oral application. Liquid formulations include, but are not limited to, syrups, émulsions, suspensions, solutions, soft gelatin and stérile injectable liquids, such as aqueous or nonaqueous liquid suspensions or solutions. For parentéral application, particularîy suitable are injectable solutions or suspensions, preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.

The pharmaceutical préparation is preferably in unit dosage form. In such form the préparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged préparation, the package containing discrète quantities of préparation, 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 dépends, 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 préparation may be varied or adjusted from 0.1 mg to 1000 mg by oral administration and 1 pg to 5000 pg by inhalation according to the potency of the active component or mode of administration.

Those skilled in the relevant art can détermine suitabie 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 resuit in a desired therapeutic benefit without causing unwanted side effects for the patient. For example, the daily dosage of the PRMT5 inhibitorcan range from about 0.1 to about 30.0 mg/kg by oral administration. Mode of administration, dosage forms, suitabie pharmaceutical excipients, diluents or carriers can also be well used and adjusted by those skilled in the art. AH 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 sait thereof as described herein.

In one embodiment of the présent 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-smail cell lung cancer, small cell lung cancer, breast cancer, triple négative 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, endométrial 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 médicament for treating a disease or disorder mentioned herein.

General Methods of Préparation

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 spécifie 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 présent invention. Variations in reaction conditions, for example, température and/or duration of the reaction, which may be used as known in the art, are also within the scope of the présent invention. Ail 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 :

Scheme-1 illustrâtes the synthesis of compound of formula 10 (when Q¹ 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 2 (X = -Cl, -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 PPh₃ 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'Bu, NaO^fBu, LiHMDS, NaHMDS, or KHMDS when treated with compound of formula 5 affords compound of formula 6. Compound of formula 6a (where R⁴ and R⁵ 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 K3PO4 or CS2CO3, in presence of Pd catalyst such as but not limited to Pd(dppf)CI₂ or PdiPPhahCfeand 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:

Scheme-2 illustrâtes 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 PPhs 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 Q¹ = C or N, R³, R⁷ and R⁸ 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 PPh₃ 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:

Scheme-3 illustrâtes 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‘Bu, NaO’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 Cs₂CO₃, in presence of Pd catalyst such as but not limited to Pd(dppf)CI₂ or Pd(PPh₃)₂CI₂and 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-NH₂ or J. Med. Chem, 2017, 60 (9), 3958-3978). Compound of formula 6a (where R⁴ and R⁵ 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.

Scheme-4:

Scheme-4 illustrâtes 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 méthylmagnésium 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‘Bu, NaOBu, 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 suitabie boranes such as but not limited to 9-BBN followed by addition of inorganic base such as but not limited to tripotassium phosphate or CS2CO3, in presence of Pd catalyst such as but not limited to Pd(dppf)CÎ2 or Pd(PPh₃)2Cl2 and compound of formula 8 (Y - -Br, -ï), which was synthesized by following the procedure reported in WO2012002577 A1, followed by N-oxide formation, chlorination with Phosphoroxychloride , and nucleophilic substitution with PMB-NH₂ or J.Med.Chem, 2017, 60 (9), 3958-3978). Compound of formula 6a (where R4 and R5 are defîned 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:

Scheme-5 illustrâtes the synthesis of compound of formula 32. Compound of formula 28 is formed upon treatment of compound of formula 5 with Wittig reagents such 5 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 CS2CO3, in presence of Pd catalyst such as but not limited to Pd(PPh₃)4 Pd(dppf)CI₂ or Pd(PPh₃)2CI₂and compound of formula 8a (Y = -Br, -I). Compound of formula 6a (where R⁴ and R⁵ are defined herein 10 above) upon treatment with compound of formula 29 affords compound of formula 30. Hydrogénation 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:

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 présence of pyridine affords Compound of formula-34, which can be reduced by cérium 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 formula36. 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 formuia-13 gives the compound of formula-41, which is further deprotected in acidic condition to get the final compound of formula -42.

Scheme-7:

Reaction of compound of formula-43 [can be prepared by method reported in J. Org. Chem. 2014, 79, 8059-8066] with methyl magnésium 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 K3PO4 or Cs₂CO₃, in presence of Pd catalyst such as but not limited to Pd(dppf)CI₂ or Pd(PPh₃)₂CI₂ 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:

Compound of formula-48 (compound of formula 48a can be synthesized from 48 by 5 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:

X=Halogen

Rc and Rd together forms a carbocyclic ring

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:

Hydroboration of compound of formula-18 with 9-BBN followed Suzuki coupling with 5 compound of formula-59 in presence of Pd-118 or PdCI₂dppf in THF/H₂O at 50-70°C for 516h 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 :

Hydroboration of compound of formula-7 with 9-BBN followed Suzuki coupling with compound of formula-59 in presence of Pd-118 or PdCI₂dppf in THF/H₂O at 50-70°C for 516h 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:

Hydroboration of compound of formula-18 with 9-BBN followed Suzuki coupling with compound of formula-67 in presence of Pd-118 in THF/H2O at 50°C for 5-16h affords compound of formula-6S, which is when treated with compound of formula-6a followed by TFA affords compound of formula-70. Hydroboration of compound of formula-7 with 9BBN followed Suzuki coupling with compound of formula-67 in presence of Pd-118 or PdCI₂dppf in THF/H₂O at 50-70°C for 5-16h affords compound of formu!a-71, which is when treated with TFA affords compound of formula-72.

Scheme-13:

Hydroboration of compound of formula-6 with 9-BBN followed by Suzuki coupling of compound of formula 8 in presence of Pd-118 or PdCbdppf in THF/H₂O at 50-70°C for 515 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:

Compound of formula-17 when treated with méthylmagnésium 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 méthylmagnésium bromide on compound of formula-77 provides compound of formula-78. Déhydration 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 PdCI₂dppf in THF/H2O 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:

(R^a‘ = -Me)

Compound of formula-11 on treatment with trimethylboroxine in presence of tripotassium phosphate, and Pd-118 or PdCbdppf 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 PdCbdppf in THF/H2O at 50-70°C for 516h affords compound of formula-88, which when treated with TFA affords compound of formula-89.

Scheme-16:

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 offormula-92. Hydroboration of compound 15 of formula-92 with 9-BBN followed by Suzuki coupling with compound of formula-8 in presence of Pd-118 or PdCbdppf in THF/H2O 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:

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 5 treatment with TFA to afford compound of formuïa-98.

Scheme-18:

103

Compound of formula-12 is treated with TsCI/ MsCI in presence of a base to give a 10 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:

Compound of formula-99 is reacted with compound of formula-104 in presence of a base such as but not limited to césium 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:

R’»

115

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 PPh₃. 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 PdCI₂dppf with trimethylboroxine to afford compound of formula 113. Hydroboration of compound of formula-113 with 9-BBN followed by Suzuki coupling with compound of formula-8 in presence of Pd-118 or PdCI₂dppf in THF/H₂O at 50-70°C for 516h affords compound of formula-114, which when treated with TFA or HCI/MeOH affords compound of formula-115.

Scheme-21:

deprotecdon

118

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 5 reagents such as but not limited to DIAD in presence of phosphine such as but not limited to PPh₃ 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:

Scheme-22 illustrâtes 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 (X = -Cl, -Br) using 15 various azo dicarboxylate reagents such as but not limited to DEAD or DIAD in presence of phosphine such as but not limited to PPh₃ 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, Li'HMDS, NaHMDS, or KHMDS when treated with compound of formula 5 122 affords compound of formula 123. Amine of formula 6a (where R₄ and R₅ 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 K3PO4 or Cs₂CO₃, in presence of Pd catalyst such as but 10 not limited to Pd(dppf)CI₂ or Pd(PPh₃)₂CI₂ and compound of formula 8 (Y = -Br, -I, which can be prepared by following the procedure reported J. Med. Chem., 2017, 60 (9), 39583978). 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:

Suzuki coupling of compound of formula 10 with aryl or heteroaryl boronic acid or ester in presence of Pd(PPh₃)4 or Pd-118 or PdCI₂dppf in dioxane at 80-100°C for 5-16h affords compound of formula-127.

Scheme-24:

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 K3PO4 or Cs₂CO₃, in presence of Pd catalyst such as but not limited to Pd(dppf)CI₂ or Pd(PPh3)₂CI₂ 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 130 with acids such as but not limited to HCl or TFA affords compound of formula

131.

Scheme-25:

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 formuîa-6a followed by treatment with trifluroacetic acid to provide a compound of formula134.

Scheme-26:

48a (R_a=-Me) ¹³⁵ 136 137

Compound of formula-48a when treated DMP in methylene chloride at 0°C to afford compound of formula -135, which when react with méthylmagnésium bromide in THF gives compound of formula-136. Déhydration of compound of formuia-136 with Martin Sulfurane gives compound of formula-137, which then treated with 9-BBN followed by Suzuki 15 coupling with compound of formula-8 in presence of Pd-118 or PdCbdppf in THF/H2O 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 formula140.

Scheme-27:

LG Ο'

Deprotection

Compound of formula-4 is treated with TsCI/

MsCI in of a base to give a presence

R⁵

Proîéction $ compound of formula 141, Compound of formula-141 is reacted with compound of formula104 in presence of a base such as but not limited to césium carbonate to afford a compound of formula -142. Substitution reaction of compound of forrnula-142 with compound of formula-6a followed by treatment with TFA affords compound of formula-144.

Abbreviations

The following abbreviations may be used herein:

AcOH = Acetic acid

Aq.= aqueous ca = about or approximately

NH₄CI = Ammonium chloride

9-BBN = 9-Borabicyclononane

BINAP = 2,2'-Bis(diphenylphosphino)-1,T-binaphthyl

Boc = tert-Butoxycarbonyl f-Bu or ®u = ferf-Butyl

CS2CO3 = Césium Carbonate

CHCh = Chioroform

CDCIs = Deuterated chioroform

DAST = Diethylaminosulphur trifluoride dba = Dibenzylideneacetone

CH2CI2 or DCM = Dichloromethane

DMP = Dess Martin Periodinane

DEAD = Diethy! azodicarboxylate

DIAD = Diisopropyi azodicarboxylate

DI PEA = Diisopropylethylamine

DMAP = 4-Dimethylaminopyridine

DMF = /V,/V-Dimethylformamide

DMSO = Dimethylsulphoxide

DMSO-de = Deuterated dimethylsulphoxide

Et = ethyl

EtOH = Ethanol

EtOAc = Ethyl acetate g = gram

H2O2 = Hydrogen peroxide

H2SO4 = Sulphuric acid

K2CO3 = Potassium carbonate

KOH = Potassium hydroxide

KO‘Bu = Potassium tert-butoxide

K3PO4 = Potassium phosphate

KHMDS = Potassium bis(trimethylsilyl)amide

LDA = Lithium diisopropylamide

LHMDS = Lithium bis(trimethylsilyl)amide

LCMS = Liquid chromatography mass spectrometry m-CPBA = meta-chloroperoxybenzoic acid mg = milligram Me = Methyl

MeOH = Methanol

MeOD = Deuterated methanol

MS = Molecular sieves

MsCI = Methanesulphonyl chloride

MgSO4 = Magnésium sulphate

NaH = Sodium hydride

NaO^fBu = Sodium tert-butoxide

NaHCOs = Sodium bicarbonate

Na₂SO₄ = Sodium sulphate

Na₂S₂O3 = Sodium thiosulphate

Na₂SO₃ = Sodium sulphite

NaHMDS = Sodium bis(trimethylsilyl)amide

NMP = N-Methyl-2-pyrrolidone

NBS = A/-Bromosuccinimide

NCS = N-Chlorosuccinimide

NIS = N-lodosuccinimide

NMO = N-Methylmorpholine-N-oxide

NMR = Nuclear magnetic résonance

Ph = phenyl

PDC = Pyridinium dichlorochromate

Pd(OAc)₂ = Palladium acetate

Pd/C = Palladium on carbon

Pd-118 = [1,T-Bis(di-tert-butylphosphino)fenOcene]dichloropalladium(ll)

Pd(PPh₃)₄ = Tetrakis(triphenylphosphine)palladium(0)

POCIs = Phosphorous oxychloride

PdCI₂(dppf) = [1,T-Bis(diphenylphosphino)ferrocene]dichloropalladium(ll)

Pd(PPh3)₂CI₂ = Bis(triphenylphosphine)palladium(ll) dichloride

PCC = Pyridinium chlorochromate

PMB = p-Methoxybenzyl

PTSA = p-Toluenesulphonic acid

Rt = Rétention time rt = room température

Sat.= saturated

SFC = Supercritical fluid chromatography

TLC = Thin layer chromatography

TBAF = Tetrabutylammonium fluoride

TsCI = p-Toluenesulphonyl chloride

TBDMS = tert-Butyldimethylsilyl

TBDPS = tert-Butyldiphenylsilyl

Et₃N or NEt₃ orTEA = Triethylamine

TFA = Trifluoroacetic acid

THF = Tetrahydrofuran

Ts= p-Toluenesulphonyl p-TsOH = p-Toluenesulphonic acid

INTERMEDIATES

7-Bromoquinolin-2 -amine

The title compound was prepared by following an analogous reaction protocol as described in Cinelli, Maris A et al, Journal of Médicinal Chemistry, 2017, vol. 60, # 9, p. 3958 - 3978.

7-Bromo-N-(4-methoxybenzyl)quinolin-2-amine

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

H

The title compound was prepared by following same reaction protocol as described in 10 Arnould, Jean-Claude et al, WO 2007/141473 A1.

7-Bromo-N-isopropylquinolin-2-amine

N TJ _Br

H

7-Bromo-N-cyclobutylquinolin-2-amîne

H

The title compound was prepared by following an analogous reaction protocol as described in Arnould, Jean-Claude et al, WO 2007/141473 Al.

7-Bromo-N-(cyclopropylmethyi)quinolin-2-amine

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

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-isopropylquînoline

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-6Tluorobenzaldehyde

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 éthanol (20mî) & 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. NaHCO₃ (100 ml). The resulting émulsion was filtered through celite. Layers were separated, organic layer was washed with brine (100 ml) and dried over anhydrous Na₂SO4. 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. ¹H NMR (400 MHz, DMSO-d₆) δ 10.10 (s, 1H), 7.78 - 7.54 (m, 2H), 6.84 (t, J = 1.5 Hz, 1H), 6.64 (dd, J = 11.1, 1.8 Hz, 1H).

1-Chloro-5-iodo-2-methyl-3-nîtrobenzene

Cl

A i

A solution of iodine (10.43g, 41.1 mmol), potassium iodate (1.247g, 5.83mmol) in conc. H2SO4 (51,4g, 525mmol) was added to a solution of 1-chloro-2-methyl-3-nitrobenzene (5g, 29.1 mmol) in conc. H2SO4 (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.NaHCO₃(75ml), aq.sat.Na2S2O3 (75ml) and brine (75ml) successively. Dried the organic layer over anhydrous Na2SO4_ filtered and concentrated in vacuo to give 9g of crude compound. This residue was purified by combiflash (R_f200, Teledyne/isco) instrument onto a redisep® R_fcolumn with elution of petroleum ether to afford the title compound (8.5g, 98%) as a pale yellowoil. ¹H NMR (400 MHz, Chloroform-d) δ 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

CI

To a stirred solution of 1-chloro-5-iodo-2-methyl-3-nitrobenzene (27.5g, 92mmol) in CCI4 (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 (Rf200, Teledyne/isco) instrument onto a redisep® Ri column with gradient elution of (0 to 1%) of ethyl acetate in petroleum ether to afford the title compound (12g, 34.5 %) as an off-white solid. ¹H NMR (400 MHz, DMSOck) δ 8.37 - 8.33 (m, 2H), 4.72 (s, 2H).

2-Chloro-4-iodo-6-nitrobenzaldehyde

Cl

To a stirred solution of 2-(bromomethyI)-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 HCI. Extracted the product with ethyl acetate (75ml). Layers were separated, organic layer was washed with brine (20ml) and dried over anhydrous NasSO^ The organic layer was filtered and concentrated in vacuo to give 16.5g of crude compound. This residue was purified by combiflash (R_f200,

Teledyne/lsco) instrument onto a redisep® Rrcolumn with gradient elution (0 to 4%) of ethyl acetate in petroleum ether to afford the titie compound (7g, 70.5%) as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.22 (s, 1H), 8.46 (s, 2H).

2-Amino-6-chloro-44odobenzaldehyde

Cl i

The titie compound was prepared by following an analogous réaction protocol as described in the préparation of 2-amino-4-bromo-6-fluorobenzaldehyde. ’H NMR (400 MHz, DMSOd₅) δ 10.26 (s, 1H), 7.80 - 7.55 (m, 2H), 7.23 (d, J- 1.4 Hz, 1H), 6.99 (d, J= 1.5 Hz, 1 H).

-Fl uoro-24odo-5-methyM-nitrobenzene

To a stirred solution of 2-fluoro-4-methyl-5-nitroaniline (2.0 g, 11.75 mmol) in conc.HCI (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 mariner at 0°C. After stirring for 15mrns, the mixture was filtered through a cotton pad and slowly poured into a stirred solution of potassium iodide (6.83 g, 41.1 mmol) in water (25ml) at 0°C. The resufting 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,NaHCO₃ (50ml) successivefy, Layers were separated, organic layer was washed with brine (50ml) and was dried over anhydrous NasSO^ The organic layer was filtered and concentrated in vacuo to give 3.1g of crude compound. This residue was purified by combiflash (R_f200, Teledyne/lsco) instrument onto a redisep® R_fcolumn with Petroleum ether as a eluent to afford the titie compound (1,7g, 51.5%) of the titie compound as an off-white solid. 'Ή NMR (400 MHz, Chloroform-d) δ 8.45 (d, J= 5.7 Hz, 1H), 7.06 (d, 1H), 2.62 (d, J = 0.7 Hz, 3H); GCMS m/z=281.03 (M+, 50%).

1-(BromomethyI)-5-fluoro-44odo-2-nitrobenzene

The title compound was prepared by following an analogous reaction protoco! as described in the préparation of 2-(bromomethyl)-1-chloro-5-iodo-3-nitrobenzene. ¹H NMR (400 MHz, Chloroform-d) δ 8.53 (d, J= 5.6 Hz, 1H), 7.31 (d, J= 7.8 Hz, 1H), 4.80 (s, 2H).

5-Fluoro-4-iodo-2-nitrobenzaldehyde

The title compound was prepared by following an analogous reaction protocol as described in the préparation of 2-chloro-4-iodo-6-nitrobenzaldehyde. ¹H NMR (400 MHz, Chloroformd) δ 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-ftuoro-4-iodobenzaldehyde

The title compound was prepared by following an analogous reaction protocol as described in the préparation of 2-amino-4-bromo-6-fluorobenzaldehyde. ¹H NMR (400 MHz, Chloroform-d) δ 9.78 (d, J = 0.6 Hz_v 1 H), 7.17 - 7.13 (m, 2H), 5.98 (s, 2H).

7-Bromo-3-cycIopropylquinoline

To a stirred mixture of 2-amino-4-bromobenzaldehyde (2 g, 10.00 mmol) and 2cyclopropylacetaldehyde (0.841 g, 10.00 mmol) in absolute éthanol (12ml) was added a solution of KOH (0.191 g, 3.40 mmol) in éthanol (12ml) in a dropwise manner under N₂atmosphère. 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 m!) and dried over anhydrous Na₂SO4 The organic layer was filtered and concentrated in vacuo to give 2.5g of crude compound. This residue was purified by combiflash (R_f200, Teledyne/lsco) instrument onto a redisep® R_f 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. ¹H NMR (400 MHz, DMSO-d6) δ 8.80 (d, J~ 2.3 Hz, 1H), 8.17 (d, J= 2.1 Hz, 1H), 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 =

8.1,5.1 Hz, 1H), 1.14 -1.03 (m,2H), 0.95-0.81 (m, 2H); LCMS m/z= 247.83, 249.83 (M+, M+2, 100%).

7-Bromo-3-(1,1-difluoroethyl)quinoline

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 diethylaminosulfurtrifluoride (2.5 ml, 18.92 mmol) was stirred at 70°Cfor 16h. The resulting mixture was slowly poured into aq. sat. sodium bicarbonate (50mî) and extracted with dichloromethane (50ml). Layers were separated, organic layer was washed with brine (20ml) and dried over anhydrous Na₂SO4 The organic layer was filtered and concentrated in vacuo to give 3.2g of crude compound. This residue was purified by combiflash (R_f200, Teledyne/lsco) instrument onto a redisep® R_fcolumn 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. ¹H NMR (400 MHz, DMSO-cfe) δ 9.13 (d, J= 2.4 Hz, 1H), 8.71 (s, 1H), 8.34 (d, J = 2.1 Hz, 1H), 8.11 (d, J = 8.7 Hz, 1H), 7.88 (dd, J = 8.7, 2.0 Hz, 1H), 2.14 (t, J = 19.2 Hz, 3H), LCMS m/z= 271.90, 273.90 (M+1; 100%).

7-Bromo-3-chloro-8-fluoroquino!ine CL —

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°Cfor 16h. The reaction mixture was cooled to 25°C and poured onto ice coid water (100ml) and stirred for 30 minutes. The précipitât© 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. ¹H NMR (400 MHz, Chioroform-^ δ 8.90 (d, J = 2.3 Hz, 1H), 8.18 (t, J= 1.9 Hz, 1H), 7.72 (dd, J=8.9, 6.1 Hz, 1H), 7.48 (dd, J = 8.8, 1.5 Hz, 1H); LCMS m/z= 261.71 (M+; 100%).

7-Bro mo-3-chl o ro-5-f I uoroquino Ii ne

To a stirred solution of 2-amino-4-bromo-6-fluorobenza!dehyde (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-toiuene sulfonic acid monohydrate (2.93 g, 15.41 mmol) at 25°C. The resulting mixture 5 was stirred at 110°C using Dean Stark apparatus for 4h under N₂ atmosphère. The reaction mixture was diluted with ethyî acetate (100ml) and basified with aq.sat.NaHCO₃ (75ml). Layers were separated, organic layer was washed with brine (20ml) and dried over anhydrous Na₂SO₄ The organic layer was filtered and concentrated in vacuo to give 1.1g of crude compound. This residue was purified by combiflash (R_f200, Teledyne/lsco) 10 instrument onto a redisep® R_f column with gradient elution (0 to 2%) of ethyl acetate in Petroleum etherto afford the title compound (1.64g, 40.9%) as a light green solid. ¹H NMR (400 MHz, Chloroform-d) δ 8.88 (d, J= 2.4 Hz, 1H), 8.38 (d, J = 2.4 Hz, 1H), 8.15 (s, 1H), 7.45 (ddd, J= 9.0, 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 15 was used for the préparation of 7-bromo-3-chloro-5-fluoroquinoline using the appropriate starting materials.

Table-1:

Intermediate’s Structure	Starting materials used	¹H NMR and LCMS data
7-Bromo-3-chloro-6fluoroquinoline	2-Amino-4-bromo-5fluorobenzaldehyde, which was synthesized as per US2014/200216 A1.	¹H NMR (400 MHz, Chloroformd) δ 8.81 (s, 1 H), 8.43 - 8.38 (m, 1H), 8.12 - 8.08 (m, 1H), 7.47 (d, J = 8.4 Hz, 1H); LCMS m/z= 261.83 (M+1; 100%).
CI 3,5-Dichloro-7iodoquinoline	2-Amino-6-chloro-4iodobenzaldehyde	¹HNMR (400 MHz, Chloroformd) δ 8.85 (d, J = 2.3 Hz, 1H), 8.50 (dd, J = 2.3, 0.9 Hz, 1H), 8.48 - 8.45 (m, 1H), 7.96 (d, J = 1.6 Hz, 1H).

F J1 3,7-Dibromo-5fluoroquinoline	2-Amino-4-bromo-6fluorobenzaldehyde	Crude was taken as such for the next step
Br^^^^^F T T T N 1 3-Bromo-6-fiuoro-7iodoquinoline	2-Amino-5-fluoro-4iodobenzaldehyde	’H NMR (400MHz, Chloroformd) δ 8.88 (d, J = 2.2 Hz, 1H), 8.61 (d, J = 6.0 Hz, 1H), 8.27 (d, J = 2.3 Hz, 1H), 7.39 (d, J = 7.8 Hz, 1H); LCMS m/z= 351.03, 353.03 (M-1, M+1, 60%).

7-Bromo-3-chloro-5-fluoroquinoline 1-oxide

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 CHCI₃ (30ml) was heated at 50°C for 16h. The reaction mixture was diluted with chloroform (50ml) and washed with aq.sat. Na₂SO₃(50ml) followed by aq.sat.NaHCO₃(50ml). Layers were separated, organic layer was washed with brine (50ml) and dried over anhydrous NazSCk The organic layer was filtered and concentrated in vacuo to give 1.35g of crude compound. This residue was purified by combiflash (R_f200, Teledyne/lsco) instrument onto a redisep® R_f 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. ¹H NMR (400 MHz, DMSO-cfe) δ 8.97 (d, J= 1.8 Hz, 1H), 8.46 (s, 1 H), 8.17 - 8.10 (m, 1H), 8.03 (dd, J = 9.5, 1.9 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 préparation of 7-bromo-3-chloro-5-fluoroquinoline 1-oxide using the 15 appropriate starting materials.

Table-2:

Intermediate’s Structure

Starting materials used

¹H NMR and LCMS data

l© h Ν ^-^^Έγ °θ 7-Bromo-3-methylquinoline 1-oxide	7-Bromo-3-methylquinoline	¹H NMR (400 MHz, DMSO-d6) δ 8.60 (dd, J = 12.2, 1.7 Hz, 2H), 7.97 (d, J = 8.7 Hz, 1H), 7.85 (dd, J = 8.7, 2.0 Hz, 1H), 7.77 (q, J = 1.1 Hz, 1H), 2.40 (d, J = 1.0 Hz, 3H); LCMS m/z= 237.9, 239.9 (M+, M+2, 100%).
N'^-^/ Br 1 O O 7-Bromo-3- cyclopropylquinoline 1-oxîde	7-Bromo-3- cyclopropylquinoline	¹H NMR (400 MHz, DMSO-d6) δ 8.58 (dd, J = 13.9, 1.7 Hz, 2H), 7.93 (d, J = 8.7 Hz, 1H), 7.84 (dd, J = 8.7, 2.1 Hz, 1H), 7.66 (s, 1H), 2.08 (tt, J = 8.4, 5.0 Hz, 1H), 1.12 - 1.04 (m, 2H), 0.95 - 0.87 (m, 2H); LCMS m/z= 263.83, 265.83 (M+, M+2, 100%).
F F-A iSjTI N Br ΟΘ 7-Bromo-3-(1,1difluoroethyl)quinoline 1- oxide	7-Bromo-3-(1,1difluoroethyl) quinoline	LCMS m/z= 289.96 (M+1; 100%).
Γ H 1 L ®jl JL N Br I 7-Bromo-3- methoxyquinoiine 1-oxide	7-Bromo-3-methoxy quinoline, which was synthesized as per Adams, Nicholas David et al, WO2014/008223 A1.	Crude was taken as such for the next step
Cl ^F k® X XC N Br 1 °0 i	7-Bromo-3-chloro-6fluoroquinoline	¹H NMR (400 MHz, DMSO-d6) δ 8.87 (d, J= 1.8 Hz, 1H), 8.75 (d, J = 6.6 Hz, 1 H), 8.14-8.03

7-Bromo-3-chloro-6- fluoroquinoline 1-oxide		(m, 2H); LCMS m/z= 275.77 (M+1; 60%).
u® J N Br i I Οθ F 7-Bromo-3-chloro-8fluoroquinoline 1-oxide	7-Bromo-3-chioro-8fluoroquinoline	¹H NMR (400 MHz, DMSO-d6) δ 8.78 (d, J= 1.5 Hz, 1 H), 8.17 (s, 1H), 7.99 (dd, J = 8.8, 5.7 Hz, 1H), 7.80 (dd, J = 8.8, 1.6 Hz, 1H); LCMS m/z= 277.83 (M+1; 100%).
Cl L © Il ,ι I Οθ 3,5-Dichloro-7-iodoquinoline 1-oxide	U, U” IL./1^1 HUI V / “ iodoquinoline	¹H NMR (400 MHz, DMSO-d6) δ 8.95 (d, J= 1.7 Hz, 1 H), 8.80 (t, J = 1.3 Hz, 1 H), 8.33 (d, J = 1.6 Hz, 1H),8.08(t, J = 1.3 Hz, 1H).
F e° 3,7-Dibromo-5- fluoroquinoline 1-oxide	3,7-Dibromo-5fluoroquinoline	LCMS m/z= 322.0 (M+1; 100%).
^F 1 Oe 3-Bromo-G-fluoro-7- iodoquinoline 1-oxide	3-Bromo-6-fluoro-7iodoquinoiine	¹H NMR (400 MHz, DMSO-d6) 6 8.91 (d, J = 6.0 Hz, 1 H), 8.87 (d, J = 1.5 Hz, 1H), 8.22 (t, J = 1.1 Hz, 1H), 7.92 (d, J = 8.3 Hz, 1H).

7-Bromo-2,3-dichloro-5-fluoroquinoline

F

To a stirred solution of 7-bromo-3-chloro-5-fluoroquinoline 1-oxide (542 mg, 1.960 mmol) in CHCI₃ (10 ml) was added POCh (1.867 ml, 20.03 mmol) at 25°C. The resulting mixture was stirred at 65°C for 2h under N₂ atmosphère The reaction mixture was poured onto ice cold water (50ml), carefuily basified with solid NaHCOs and extracted the product with 5 dichloromethane (50ml). Layers were separated, organic layer was washed with brine (50ml) and was dried over anhydrous Na2SO₄ The organic layer was filtered and concentrated in vacuo to give 1.2g of crude compound. This residue was purified by combiflash (R_f200, Teledyne/lsco) instrument onto a redisep® R_fcolumn with gradient elution (0 to 10%) of ethyî acetate in petroleum etherto afford the titîe compound (410mg, 10 70.9%) as a white solid. ¹H NMR (400 MHz, Chloroform-d) δ 8.49 - 8.43 (m, 1H), 8.04 (dt,

J = 1.9, 1.0 Hz, 1H), 7.45 (dd, J= 8.9, 1.7 Hz, 1H); 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 préparation of 7-bromo-2,3-dichloro-5-fluoroquinoline using the appropriate starting materials.

Table-3:

Intermediate’s Structure	Starting materials used	¹H NMR and LCMS data
CI^N^^ 7-Bromo-2-chloro-3methylquinolîne	7-Bromo-3- methylquinoline 1-oxide	¹H NMR (400 MHz, DMSOd6) δ 8.40 (t, J = 1.0 Hz, 1H), 8.17 (d, J = 2.0 Hz, 1H), 7.94 (d, J = 8.7 Hz, 1H), 7.78 (dd, J = 8.7, 2.0 Hz, 1 H), 2.48 (d, J = 1.0 Hz, 3H); LCMS m/z= 256, 258 (M+, M+2, 100%).
Cl N Br 7-Bromo-2-chloro-3cyclopropyl quinoiine	7-Bromo-3- cyclopropylquinoline 1- oxide	¹H NMR (400 MHz, DMSOd6) δ 8.16 (d, J = 3.0 Hz, 2H), 7.92 (d, J = 8.7 Hz, 1H), 7.77 (dd, J = 8.7, 2.0 Hz, 1Ή), 2.21 (tt, J = 8.4, 5.3 Hz, 1H), 1.10 (dt, J = 8.5, 3.2 Hz, 2H), 0.92 - 0.81 (m, 2H); LCMS m/z= 281.90, 283.90 (M+, M+2, 100%).

CI^N'^^'Br 7-Bromo-2-chloro-3-(1,1difluoro ethyl)quinoline	7-Bromo-3-(1,1- difluoroethyl) quinoline 1oxide	LCMS m/z= 306, 308 (M+, M+2; 100%).
Cl '^N '^^^'Br 7-Bro mo -2-chl oro-3methoxy quinoline	7-Bromo-3- methoxyquinoline 1-oxide	LCMS m/z= 271.69, 273.69
<T T CI^'N^^^Br 7-Bro mo-2,3-dichloro-6fluoro quinoline	7-Bromo-3-chloro-6- fluoroquinoline 1-oxide	¹H NMR (400 MHz, Ch!oroform-d) δ 8.31 (d, J = 6.3 Hz, 1H), 8.23 - 8.18 (m, 1H), 7.48 (d, J = 8.2 Hz, 1H).
CI^N'X^Br F 7-Bromo-2_J3-dichIoro-8- fluoro quinoline	7-Bromo-3-chloro-8- fluoroquinoline 1-oxide	¹H NMR (400 MHz, DMSOd6) δ 8.94 (d, J = 1.6 Hz, 1H), 7.97 (dd, J = 8.9, 6.3 Hz, 1H), 7.83 (dd, J = 8.9, 1.3 Hz, 1H), LCMS m/z= 295.65 (M+1; 100%).
Cl ¹ J! 1 CI^N^^S 2,3_s5-Trichloro-7iodoquinoline	3,5-Dichloro-7iodoquinoline 1-oxide	¹H NMR (400 MHz, Chloroform-d) δ 8,59 (d, J = 0.8 Hz, 1H), 8.38 (dd, J = 1.6, 0.8 Hz, 1H), 7.96 (d, J = 1.5 Hz, 1H).
F 1 Cl _Br 3,7-Dibromo-2-chIoro-5fiuoro quinoline	3,7-Dibromo-5fluoroquinoline 1-oxide	Crude was taken as such for the next step

A 1 1 3-Bromo-2-chloro-6-fluoro7-iodoquinoline

3-Bromo-6-fluoro-7- iodoquinoline 1-oxide

¹H NMR (400 MHz, Chloroform-d) δ 8.54 (dd, J = 5.9, 0.7 Hz, 1H), 8.38 (s, 1H), 7.40 (d, J = 7.6 Hz, 1H).

7-Bromo-3-chl oro-5-f I u oroq u i nolin -2-a mi ne

F i

A mixture of 7-bromo-2,3-dich!oro-5-fluoroquinoline (410mg, 1.390mmol), aqueous 5 ammonia (9.74 ml, 250 mmol) in dioxane (10ml) was heated at 120°C in a Steel bomb for 24h. The reaction mixture was diïuted with ethyl acetate (20ml) and washed with water (20ml). Layers were separated, organic layer was washed with brine (20ml) and dried over anhydrous Na₂SO4 The organic layer was filtered and concentrated in vacuo to give 1.15g of crude compound. This residue was purified by combiflash (Rf200, Teledyne/lsco) 10 instrument onto a redisep® R? 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. ¹H NMR (400 MHz, DMSO-de) δ 8.23 (s, 1H), 7.51 (d, 7= 1.9 Hz, 1H), 7.32 (dd, 7= 9.5, 1.9 Hz, 1H), 7.25 (s, 2H); LCMS m/z= 276.83 (M+1; 100%).

Intermediates in table-4 were synthesized by following an analogous reaction protocol as 15 was used for the préparation of 7-bromo-3-chloro-5-fluoroquino!in-2-amine using the appropriate starting materials.

Table-4:

Intermediate’s Structure	Starting materials used	¹H NMR and LCMS data
H₂N Br F 7-Bromo-8- fluoroquinolin-2-amine	7-Bromo-2-chloro-8fluoroquinoline	¹H NMR (400 MHz, DMSO-d6) δ 7.95 (dd, J = 8.9, 1.8 Hz, 1H), 7.42 (dd, J = 8.7, 1.4 Hz, 1H), 7.35 7.27 (m, 1H), 6.93 (s, 2H), 6.88 6.79 (m, 1H); LCMS m/z= 240.8 (M+; 100%)

H₂N'^N'^-^'Br 7-Bromo-3methyiquïnolin-2-amine	7-Bromo-2-chloro-3methylquinoline	¹H NMR (400 MHz, DMSO-d6) δ 7.75 (t, J = 1.0 Hz, 1H), 7.60 (d, J = 2.0 Hz, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.25 (dd, J = 8.5, 2.0 Hz, 1H), 6.51 (s, 2H), 2.19 (d, J = 1.1 Hz, 3H); LCMS m/z= 237, 239 (M+, M+2, 100%).
H₂N n Br 7-Bromo-3isopropylquinolin-2- amine	7-Bromo-2-chloro-3isopropyl quinoline	LCMS m/z= 265.1, 267.1 (M+, M+2; 100%).
H₂N'^N'^^>^Br 7-Bromo-3- cyclopropylquinolin-2amine	7-Bromo-2-chioro-3cyclopropyl quinoline	¹H NMR (400 MHz, DMSO-d6) δ 7.63 (s, 1H), 7.59 (d, J = 2.0 Hz, 1H), 7.55 (d, J = 8.5 Hz, 1H), 7.24 (dd, J = 8.5, 2.0 Hz, 1H), 6.65 (s, 2H), 1.80 (tdd, J = 8.2, 4.6, 2.9 Hz, 1H), 1.01 - 0.92 (m, 2H), 0.69 0.62 (m, 2H); LCMS m/z= 262.83, 264.83 (M+, M+2, 100%).
F ifYÙ Η₂Ν-^Ν '^'Έγ 7-Bromo-3-(1,1difluoroethyl ) quinolin-2amine	7-Bromo-2-chloro-3- (1,1- difluoroethyl)quinoline	LCMS m/z= 287.96 (M+1, 100%).
\|l \| HaN^N^^^Br 7-Bromo-3- methoxyquinolin-2-aniine	7-Bromo-2-chloro-3methoxyquinoline	LCMS m/z= 253, 255 (M+, M+2; 100%).

H₂N 7-Bromo-3-chIoro-6fluoroquinolin-2-amine	7-Bromo-2,3-dichloro- 6-fluoro quinoline	Ή NMR (400 MHz, DMSO-d6) δ 8.23 (s, 1H), 7.79 (d, J = 6.7 Hz, 1H), 7.67 (dd, J = 9.3, 2.0 Hz, 1H), 6.97 (s, 2H); LCMS m/z= 276.83 (M+1; 100%).
T T j H2N'^'N'^X^^/^'Br F 7-Bromo-3-chioro-8fluoroquinolin-2-amine	7-Bromo-2,3-dichloro- 8-fluoro quinoline	Ή NMR (400 MHz, DMSO-d6) δ 8.32 (d, J = 1.7 Hz, 1H), 7.30 (s, 2H), 7.35 - 7.16 (m, 2H), LCMS m/z= 276.86 (M+1; 100%).
a 1 \|\| i 3,5-Dichloro-7- îodoquinolin-2-amine	2,3,5-Trichloro-7iodoquinoline	Ή NMR (400 MHz, DMSO-d6) δ 8.22 (s, 1H), 7.94 - 7.81 (m, 1H), 7.67 (d, J = 1.6 Hz, 1H), 7.24 (s, 2H).
F Br-. X J । H₂N Br 3,7-Dibromo-5- ffuoroquinolin-2-amine	3,7-Dibromo-2-chloro- 5-fiuoro quinoline	’H NMR (400 MHz, DMSO-d6) δ 8.39 (d, J = 0.7 Hz, 1H), 7.50 (d, J = 1.7 Hz, 1 H), 7.31 (dd, J = 9.5, 1.8 Hz, 1 H), 7.14 (s, 2H); LCMS m/z= 318.96, 320.34, 322.34 (M-1, M+, M+2; 100%).
H₂N ΊΜ 1 3-Bromo-6-fl uoro-7iodoquinoiin-2-amine	3-Bromo-2-chloro-6- fluoro-7-iodoquinoline	¹H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1H), 7.97 (d, J = 5.9 Hz, 1 H), 7.55 (d, J = 8.5 Hz, 1H), 6.82 (s, 2H).

7-Bromo-3-chloro-5-fluoro-N-(4-methoxybenzyl)quinolin-2-amine

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. ¹H NMR (400 MHz, DMSO-d6) δ 8.22 (d, J = 0.8 Hz, 1H), 7.96 (t, J = 6.1 Hz, 1H), 7.58 (dd, 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), 3.71 (s, 3H); LCMS m/z= 397 (M+1; 100%).

A mixture of 3,7-dibromo-5-fluoroquinolin-2-amine (2.05g, 6.41 mmol), Et₃N (2.68ml, 19.22mmol), DMAP(0.078g, 0.641 mmol) 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 Na₂SO₄ The organic layer was filtered and concentrated in vacuo to give 3.9g of crude compound. This residue was purified by combiflash (Rf200, Teledyne/lsco) instrument onto a redisep® Rt 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. ¹H NMR (400 MHz, Chloroform-d) δ 8.65 (d, J = 0.8 Hz, 1H), 8.08 (q, J = 1.2 Hz, 1H), 7.46 (dd, J = 8.9, 1.7 Hz, 1H), 1.42 (s, 18H).

2-Amino-7-bromoquinoline-3-carbonitrile.

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 éthanol (10ml) was stirred at 100 °C for 16h. The volatiles were evaporated in vacuo and the residue was purified by combiflash (Rf200, Teledyne/lsco) instrument onto a redisep® R_f 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. ¹H NMR (400 MHz, DMSO-d6) δ 8.71 (s, 1H), 7.74 - 7.65 (m, 2H), 7.42 (dd, J = 8.6, 2.0 Hz, 1H), 7.20 (s, 2H); LCMS m/z= 248, 250 (M+, M+2, 100%).

7-Bromo-N-(4-methoxybenzyl)quinazolin-2-amine

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

I Tl

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

X χ X

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

The title compound was prepared by following an analogous reaction protocol as described in Banka, Anna Lindsey et al, WO2012/037108 Al.

7-Bro mo-3-chl oro-N. N -bis(4-methoxybenzyi )quinol i n -2-amine

PMB

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 N₂ atmosphère. The reactiohn 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 Na₂SO₄. The organic layer was filtered and concentrated in vacuo to give 3.87g of crude compound. This residue was purified by combiflash (Rf200, Teledyne/lsco) instrument onto a redisep® Rf column with gradient elution (0 to 30%) of ethyl acetate in Petroleum ether to afford the titie compound (2.2g, 56.9%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.45 (s, 1H), 7.89 (d, J = 1.9 Hz, 1H), 7.77 (d, J = 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), 4.54 (s, 4H), 3.70 (s, 6H); LCMS m/z= 498,97 (M+1; 100%).

3-Bromo-7-iodo-N-(4-methoxybenzyl)quinoiin-2-amine

The titie compound was prepared by following an analogous reaction protocol as described in Banka, Anna Lindsey et al, WO2012/037108 AI.

6-Bromo-3,3-dimethylindoline-2-thione.

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, Al and Lawesson's reagent (7.66 g, 18.95 mmol) in toluene (15 ml) was heated at 100^cC for 3h under N₂ atmosphère Solvent was evaporated in vacuo and this residue was purified by combiflash (Rf200, Teledyne/lsco) instrument onto a redisep® Rf column with gradient elution (0-20%) of ethyl acetate in petroleum ether to afford the titie compound (3.3g, 88 %) as an off-white solid. ¹H NMR (400 MHz, DMSO-d6) δ 12.67 (s, 1H), 7,40 (d, J = 7.9 Hz, 1H), 7.31 (dd, J = 7.9, 1.8 Hz, 1H), 7.15 (d, J = 1.7 Hz, 1H), 1.30 (s, 6H); LCMS m/z= 256.89 (M+1; 30%).

6-Bromo-3,3-dimethyl-2-(methylthio)-3H-indole.

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 1 h at 0°C under N₂ atmosphère The réaction 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 (Rf200, Teiedyne/lsco) instrument onto a redisep® R_fcolumn with gradient elution (0-5%) of ethyl acetate in petroleum ether to afford the title compound (3.1g, 98%) as a white solid. ¹H NMR (400 MHz, DMSO-d6) δ 7.60 (d, J = 1.7 Hz, 1H), 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 m/z= 269.90 (M+; 40%).

6'-Bromospiro[cyclobutane-1,3'-indoline]-2'4hione.

The title compound was prepared by following an analogous reaction protocol as was described in the préparation of 6-bromo-3,3-dimethylindoline-2-thione. LCMS m/z= 267.65 (M+; 20%).

6'-Bromo-2'-(methylthio)spiro[cyclobutane-1₅3'-indole]

The title compound was prepared by following an analogous reaction protocol as was described in the préparation of 6-bromo-3,3-dimethyl-2-(methylthio)-3H-indole. ¹H NMR (400 MHz, Chloroform-d) δ 7.63 (d, J = 1.7 Hz, 1H), 7.44 (d, J = 7.9 Hz, 1H), 7.32 (dd, J = 7.9, 1.7 Hz, 1H), 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.

h₂n~4 Ji J]

To stirred solution of 6'-bromo-2'-(methylthio)spiro[cyclobutane-1,3'-indole] (1.2 g, 4.25 mmol) in 7 N ammonia in methanol (15ml, 371 mmol) was heated at 100°C for 16 h. Solvent was evaporated in vacuo and this residue was purified by combiflash (Rf200, Teledyne/lsco) instrument onto a redisep® Rf column with gradient elution (0-10%) of methanol in dichloromethane to afford the title compound (650mg, 60.9%) as white solid. Ή NMR (400 MHz, DMSO-d6) δ 7.69 (s, 2H), 7.46 (d, J = 8.2 Hz, 1H), 7.01 (h, J = 1.8 Hz, 2H), 2.63 - 2.53 (m, 2H), 2.43 - 2.30 (m, 1H), 2.23 - 2.09 (m, 3H); LCMS m/z= 250.87 (M+; 100%).

7-Bromo-3-methylimidazo[1,2-a]pyridine

The title compound was prepared by following an analogous reaction protocol as was described in Dubois., Laurent et al, WO 2009/112679 Al.

2-(Methylamino)quînolin-7-ol

The title compound was prepared by following an analogous reaction protocol as was described in Doherty, Elizabeth M. étal, Journal of Médicinal Chemistry, 2007, vol. 50, # 15, p. 3515-3527.

3-Bromo-N-(4-methoxybenzyl)-7-(4,4_!5,5-tetramethy!-1,3,2-d!Oxaboro!an-2yl)quinolin-2-amine

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] dichÎorôpalladium(ll), complexwith 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 (50m!) and poured onto ice-cold water (100ml). Layers were separated, organic layerwas washed with brine (50 mi) 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 (Rf200, Teiedyne/lsco) instrument onto a redisep® Rf column with gradient elution (0-7%) of ethyi acetate in petroieum ether to afford the titie compound (1.35g, 90%) as an off-white solid. ¹H NMR (400 MHz, DMSO-d_e) δ 8.42 (d, J= 0.7 Hz, 1H), 7.86 (d, J = 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), 6.99-6.74 (m, 2H), 4.62 (d, J= 6.0 Hz, 2H), 3.71 (s, 3H), 1.32 (s, 12H); LCMS m/z= 468.89 (M+; 100%).

3-Bromo-2-((4-methoxybenzyl)amino)quinolin-7-ol

To a stirred solution of 3-bromo-N-(4-methoxybenzyl)-7-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-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 1 h. Aq. H2O2 (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 ethyi acetate (20ml) and washed with aq.sat.Na2SO3(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 (Rf200, Teledyne/lsco) instrument onto a redisep® Rf column with gradient elution (0-25%) of ethyi acetate in petroieum ether to afford the titie compound (0.13g, 48.5%) as an off-white solid. LCMS m/z= 359.22 (M+; 100%).

3-Chloro-5-fluoro-N-(4-methoxybenzyl )-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)quinolin-2-amine

Ci

The titie compound was synthesized by following an analogous reaction protocol as was described in the préparation of 3-bromo-N-(4-methoxybenzyl)-7-(4,4,5,5-tetramethyl-1,3,2dioxaboroian-2-yl)quinolin-2-amine. ¹H NMR (400 MHz, Chloroform-d) δ 1H NMR (400 MHz, Chloroform-d) δ 8.17 (d, J = 0.9 Hz, 1H), 8.07 (s, 1H), 7.41 - 7.36 (m, 2H), 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), 3.83 (s, 3H), 1.29 (s, 12H); LCMS m/z= 443.05 (M+; 100%).

3-Chloro-5-fluoro-2-((4-methoxybenzyl)amino)quinolin-7-ol

F

The title compound was synthesized by following an analogous reaction protocol as was described in the préparation of 3-bromo-2-((4-methoxybenzyl)amino)quinolin-7-oL ¹H NMR (400 MHz, DMSO-d6) δ 10.19 (d, J = 1.0 Hz, 1H), 8.02 (s, 1H), 7.55 (t, J = 6.2 Hz, 1 H), 7.43 - 7.28 (m, 2H), 6.91 - 6.82 (m, 2H), 6.67 (d, J = 2.1 Hz, 1H), 6.57 (dd, J = 11.7, 2.2 Hz, 1H), 4.60 (d, J = 6.0 Hz, 2H), 3.71 (s, 3H); LCMS m/z= 333.15, 335.15 (M+, M+2; 30%).

N2-(4-Methoxybenzyl)quinoline-2,7-diamine.

A mixture of 7-bromo-N-(4-methoxybenzyl)quinolin-2-amine (0.6 g, 1.748 mmol), copper(l) 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 (Rf200, Teledyne/lsco) instrument onto a redisep® R_f column with gradient elution (0-5%) of methanol in dichloromethane to afford the title compound (0.18g, 36.9%) as a brown solid. ¹H NMR (400 MHz, DMSO-d6) δ 7.55 (d, J = 8.7 Hz, 1H), 7.34 - 7.29 (m, 2H), 7.25 (d, J = 8.4 Hz, 1 H), 7.07 (t, J = 5.8 Hz, 1 H), 6.91 - 6.83 (m, 2H), 6.56 (d, J = 2.2 Hz, 1H), 6.52 (dd, J = 8.4, 2.2 Hz, 1H), 6.40 (d, J = 8.7 Hz, 1H), 5.32 (s, 2H), 4.49 (d, J = 5.8 Hz, 2H), 3.72 (s, 3H); LCMS m/z= 280.2 (M+1, 100%).

N2-(4-Methoxybenzyl)-N7-methylquinoline-2,7-d!amine.

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 MgSO₄, filtered and concentrated. This residue was purified by combiflash (Rf200, Teledyne/lsco) instrument onto a redisep® Rf column with gradient elution (0-5%) of méthane! in dichloromethane to afford the titie compound (0.4g, 94%) as a brown liquid. LCMS m/z= 294.09 (M+1; 100%).

S-(2-((4-Methoxybenzyi)amino)quinolin-7-yl) ethanethioate.

Μ N o

H

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 Pd₂(dba)3 (0.534g, 0.583mmol) at 25°C under N₂ atmosphère. 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 MgSO₄, filtered and concentrated. This residue was purified by combiflash (Rf200, Teledyne/lsco) instrument onto a redisep® Rf column with gradient elution (0-20%) of ethyl acetate in petroleum ether to afford the titie compound (0.67g, 34%) as an off-white solid. ¹H NMR (400 MHz, Chloroform-d) δ 7.87 - 7.80 (m, 2H), 7.63 (d, J = 8.3 Hz, 1H), 7.39 - 7.32 (m, 2H), 7.28 7.23 (m, 1H), 6.95 - 6.87 (m, 2H), 6.67 (d, J = 9.0 Hz, 1H), 5.21 (s, 1H), 4.67 (d, J = 5.4 Hz, 2H), 3.82 (s, 3H), 2.47 (s, 3H); LCMS m/z= 339.22 (M+1; 100%).

2-((4-Methoxybenzyl)amino)quinoline-74hîol.

To a stirred solution of S-(2-((4-methoxybenzyl)amino)quinolin-7-yl) ethanethioate (0.67g, 1.98 mmol) in 20 mL of éthanol 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 NH₄CI (20ml) and extracted with ethyl acetate (20ml). The organic layer was separated, dried over MgSO₄, filtered and concentrated in vacuo to give the titie compound (0.56g,

95%) as a brown solid. Ή NMR (400 MHz, Chloroform-d) δ 7.77 (d, J = 8.9 Hz, 1H), 7.64 (d, J = 1.8 Hz, 1 H), 7.46 (d, J = 8.3 Hz, 1 H), 7.37 - 7.32 (m, 2H), 7.10 (dd, J = 8.3, 1.9 Hz,

1H), 6.93-6.87 (m, 2H), 6.58 (d, J = 8.9 Hz, 1H), 5.58 (s, 1H), 4.64 (d, J = 5.3 Hz, 2H), 3.82 (s, 3H); LCMS m/z= 297.09 (M+; 100%).

S-(2-(Bis(4-methoxybenzyl)amino)-3-chloroquinolin-7-yl) ethanethîoate

The title compound was synthesized by following an analogous reaction protocol as was described in the préparation of S-(2-((4-methoxybenzyl)amino)quinolin-7-yl) ethanethîoate. LCMS m/z = 493.30 (M+; 100%).

2-(Bis(4-methoxybenzyl)amino)-3-chloroquînoline-7-thiol

To a solution of solution of S-(2-(bis(4-methoxybenzyl)amino)-3-chloroquinolin-7-yl) ethanethîoate (300 mg, 0.608 mmo!) in éthanol (9 ml) was added KOH (51.2 mg, 0.913 mmoi) at 25°C. The mixture was heated at 50°C for 2h . The réaction 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 (200 mg, 72.9%) as an off-white solid. LCMS m/z = 450.42 (M+; 100%).

(i3?.R,6R,6aS)-6-i4-Chioro-7H-pyrroio[2_!3-d]pyrimidin-7-yij-2_:2-dimeihyi-6,6adihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methanol

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,4R6aR)-4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,6adihydro-4H-cyclopenta[dJ[1,3]dioxol-6-yl)methyl

4-methylbenzenesuIfonate

To a stirred solution of ((3aS,4R,6aR)-4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2dimethyl-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-TsCI (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 MgSO₄, filtered and concentrated in vacuo to give 0.71g of crude compound. This residue was purified by combiflash (R_f200, Teledyne/lsco) instrument onto a redisep® Rtcolumn 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. ¹H NMR (400 MHz, Chloroform-d) δ 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 (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, 2H), 4.63 (t, J = 4.5 Hz, 1 H), 2.52 - 2.45 (m, 3H), 1.45 (s, 3H), 1.34 (s, 3H); LCMS m/z = 476.17 (M+; 100%).

(3aS,4R,6aR)-4-(4-Chloro-7H-pyrrolo[2,3-cl]pyrimidin-7-yl)-2,2-dimethyl-3a,6adihydro-4H-cyclopenta[d][1,3]dioxole-6-carbaidehyde

To a stirred solution of ((3aS,4R,6aR)-4-(4-Chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-6-yl)methanol (2.50g, 7.77mmol) in CH₂CI₂ (40ml) at 0°C, was added Dess-Martin Periodinane (3.95 g, 9.32 mmol) portionwise and stirred for 1h. The reaction mixture was diluted with dichloromethane (50ml) and washed with water(50ml). The organic layer was separated, dried over MgSO₄, filtered and concentrated in vacuo to give 2.71g of crude compound. This residue was purified by combiflash (Rf200, Teledyne/lsco) instrument onto a redisep® R_f column with gradient elution (0-30%) of ethyl acetate in petroleum ether to afford the title compound (2.32g, 93%) as a colorless oil. ¹H NMR (400 MHz, Chloroform-d) δ 10.00 (s, 1H), 8.67 (s, 1H), 7.12 (d, J = 3.6 Hz, 1H), 6.78 (dd, J = 2.6, 0.9 Hz, 1H), 6.69 (d, J = 3.7 Hz, 1H), 5.97 (dt, J = 2.8, 1.4 Hz, 1 H), 5.76 (dd, J = 5.9, 1.5 Hz, 1 H), 4.88 (dt, J = 5.9, 1.1 Hz, 1 H), 1.54 (s, 3H), 1.40 (s, 3H); LCMS m/z = 320.2 (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

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-(4Chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta [d][1,3]dioxole-6-carbaldehyde (1.8g, 5.63mmoî) in THF (1ml). Stirred the reaction mixture at 25°C for 10min. The reaction mixture was quenched with sat.aqueous NH4CI (50ml) and extracted with ethyl acetate (50ml). The organic layer was separated, dried over Na₂SO₄, filtered and concentrated in vacuo to give 2.1g of crude compound. This residue was purified by combiflash (Rf200, Teledyne/lsco) instrument onto a redisep® R_fcolumn with gradient elution (0-7%) of ethyl acetate in Petroleum ether to afford the title compound (0.81g, 45.3%) as an off-white solid. ¹H NMR (400 MHz, Chloroform-d) δ 8.72 (s, 1H), 7.11 (d, J = 3.6 Hz, 1H), 6.66-6.57 (m, 2H)_y 5.94 (d, J = 2.6 Hz, TH), 5.81 - 5.75 (m, 2H), 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 (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-4yi)-4-ethyi-7H-pyrroio[2,3-d]pyrimidine

To a stirred solution of 4-chloro-7-((3aS,4R,6aR)-2,2-dimethyl-6-vinyl-3a_i6a-dihydro-4Hcyclopenta[d][1,3]dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine (500mg, 1.573mmol) in THF (1ml) and NMP (0.2ml) was added ferrie acetyiacetonate (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 NH₄CI (10ml) and extracted with ethyl acetate (10ml). The organic layer was separated, dried over NasSCX filtered and concentrated in vacuo to give 0.6g of crude compound. This residue was purified by combiflash (Rf200, Teledyne/lsco) instrument onto a redssep® R_f 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. ¹H NMR (400 MHz, DMSO-d6) δ 8,71 (s, 1H), 7.35 (d, J = 3.6 Hz, 1H), 6.73 (d, J = 3.6 Hz, 1H), 6.60 (dd, J = 17.7, 10.8 Hz, 1H), 5.88 (d, J = 2.7 Hz, 1H), 5.83 - 5.74 (m, 1H), 5.66 - 5.56 (m, 2H), 5.45 - 5.37 (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); LCMS m/z =312.21 (M+1, 100%).

7-«3aS_I4R,6aR)-2₅2-D!methyl-6-vinyl-4,6a-dihydro-3aH-cyclopenta[d] [1,3]dioxol-4yl)-4-isopropyl-7H-pyrrolo[2,3-d]pyrimidine

A solution of 4-chloro-7-((3aS,4R,6aR)-2,2-dimethyl-6-vinyl-3a,6a-dihydro-4Hcyclopenta[d][1,3]dioxol-4-yi)-7H-pyrrolo[2,3-d]pyrimidine (1g, 3.15mmol), 2M isopropyl magnésium bromide in THF (5.51 ml, 11.01 mmol) and PdCl2(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 (Rf200, Teledyne/lsco) instrument onto a redisep® R_f column with gradient elution (0-2%) of methanol in dichloromethane to afford the title compound (150mg, 14.65%) as an off-white solid. ¹H NMR (400 MHz, Chloroform-d) δ 8.98 (s, 1H), 7.48 (d, J = 4.0 Hz, 1 H), 7.11 (t, J = 1.6 Hz, 1 H), 6.86 (d, J = 4.0 Hz, 1 H), 3.98 (dt, J = 2.5,1.2 Hz, 2H), 3.50 - 3.43 (m, 1H), 2.66 (s, 1H), 2.20 (d, J = 2.4 Hz, 1H), 2.00 (dd, J = 7.2, 1.0 Hz, 2H), 1.44 (dd, 7= 6.9, 3.1 Hz, 6H), 1.28 (s, 6H).

4-Cyclopropyt-7-((3aS,4R,6aR)-2,2-dimethy!-6-vinyl-3a,6a-dihydro-4H-cyclopenta[d] [1,3]dîoxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine.

The title compound was synthesized by following an analogous reaction protocol as was described in the préparation of 7-((3aS,4R,6aR)-2,2-dimethyl-6-vinyl-4,6a-dihydro-3aHcyclopenta [d] [1,3] dioxol-4-yl)-4-ethyI-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_J2-dimethyl-3a₎6adihydro-4H-cyclopenta[d][1,3]dioxol-6-yI)ethan-1-ol.

To a stirred solution of (3aS,4R,6aR)-4-(4-chloro-7H-pyrro!o[2,3-d]pyrimidin-7-yl)-2,2dimethyl-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 méthylmagnésium bromide (4.80 ml, 14.39 mmol) and the reaction mixture was stirred at same température for 3h. The reaction mixture was quenched with a sat. aqueous NH₄CI (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/lsco) 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. ¹H NMR (400 MHz, Chioroform-d) δ 8.70 (s, 1H), 7.11 (d, J = 3.7 Hz, 1H), 6.63 (d, J = 3.7 Hz, 1 H), 5.88 - 5.81 (m, 1 H), 5.80 - 5.71 (m, 1 H), 5.59 - 5.45 (m, 1 H), 4.76 - 4.64 (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 = 336.2 (M+; 100%).

1-((3aS,4R,6aR)-4-(4-Chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,6adihydro-4H-cyclopenta[d][1,3]dioxol-6-yl)ethan-1-one.

To a stirred solution of 1-((3aS,4R,6aR)-4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2dimethyl-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. ¹H NMR (400 MHz, Chloroform-d) δ 8.68 (s, 1H), 7.10 (d, J = 3.7 Hz, 1H), 6.68 (d, J = 3.6 Hz, 1H), 6.63 (dt, J = 2.7, 0.7 Hz, 1H), 5.96 (dt, J = 2.8, 1.5 Hz, 1H), 5.75 (dd, J = 5.9, 1.6 Hz, 1H), 4.82 (dt, J = 5.9, 1.1 Hz, 1H), 2.47 (s, 3H), 1.52 (s, 3H), 1.39(s, 3H); LCMS m/z = 334.09 (M+; 100%).

2-((3aS,4R,6aR)-4-(4-Chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a_J6adihydro-4H-cyclopenta[d][1,3]dioxol-6-yl)propan-2-ol.

To a stirred solution of 1-((3aS,4R,6aR)-4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2dimethyl-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 magnésium bromide (1.498 ml, 4.49 mmol) and stirred the reaction mixture for 30 min at the same température. The reaction mixture was quenched with a sat. aqueous NH₄CI (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. ¹H NMR (400 MHz, Chloroform-d) δ 8.69 (s, 1H), 7.09 (d, J = 3.6 Hz, 1H), 6.71 6.60 (m, 1H), 5.82 (s, 1H), 5.78 - 5.69 (m, 1H), 5.65 - 5.58 (m, 1H), 4.69 (dt, J = 5.8, 1.0 Hz, 1H), 1.59- 1.53 (m, 9H), 1.38 (s, 3H); LCMS m/z = 350.2 (M+; 100%).

4-Chloro-7-{(3aS,4R,6aR)-2,2-dimethyl-6-(prop-1-en-2-yl)-3a,6a-dihydro-4Hcyclopenta[d][1,3]dioxol-4-yl)-7H-pyrrolo[2₃3-d]pyrimidine.

To a stirred solution of 2-((3aS,4R,6aR)-4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2dimethyl-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 Martiris 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/lsco) 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. ¹H NMR (400 MHz, Chloroform-d) δ 8.71 (s, 1H), 7.11 (d, J = 3.6 Hz, 1H), 6.63 (d, J = 3.6 Hz, 1H), 6.00 - 5.94 (m, 1 H), 5.76 (d, J = 2.7 Hz, 1 H), 5.62 - 5.52 (m, 2H), 5.33 (d, J = 1.7 Hz, 1 H), 4.67 (dt, J = 6.0, 1.0 Hz, 1 H), 2.03 (t, J = 1.0 Hz, 3H), 1.52 (s, 3H), 1.40 (s, 3H); LCMS m/z = 332.28 (M+; 100%).

7-((3aS,4R,6aR)-2,2-Dimethyl-6-(prop-1-en-2-yi)-4,6a-dihyclro-3aH-cyclo penta[d][1,3] dioxol-4-yl)-4-methyl-7H-pyrrolo[2,3-d]pyrimidine

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,T-bis(di-t-butylphosphino)ferrocene]palladium(ll) (0.196 g, 0.301 mmol) and 2,4,6-trimethy!-1,3,5,2,4,6-trioxatriborinane (4.21 ml, 30.1 mmol) at25°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/lsco) 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 m/z = 312.28 (M+1; 100%).

7-((3aS,4R_J6aR)-6-(((tert-ButyidiphenylsilyI)oxy)methyl)-2_J2-dimethyl-3a₃6a-dihydro4H-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-dihydro4H-cyclopenta[d][1,3}dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine (B).

To a degassed solution of 7-((3aS,4R,6aR)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2dimethyl-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,T-bis(di-t-butylphosphino) ferrocene]palladium(ll) (0.582 g, 0.893 mmol) and 2,4,6-trimethyî-1,3,5,2,4,6trioxatriborinane (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/lsco) instrument onto a redisep® Rf column with gradient elution (0 to 20%) of ethyl acetate in Petroleum etherto afford the title compound, A (3.2g, 66%) and B (0.75g, 15.98%) as an off-white solids. ¹H NMR of A (400 MHz, Chloroform-d) δ 8.83 (s, 1H), 7.71 (tt, J = 6.6, 1.5 Hz, 4H), 7.48-7.37 (m, 6H), 6.91 (d, J = 3.6 Hz, 1H), 6.57 (d, J = 3.6 Hz, 1 H), 5.88 (s, 2H), 5.25 (d, J = 5.7 Hz, 1 H), 4.60 (d, J = 5.7 Hz, 1 H), 4.55 - 4.45 (m, 2H), 2.77 (s, 3H), 1.45 (s, 3H), 1.32 (s, 3H), 1.11 (s, 9H); LCMS m/z = 540.4 (M+1: 100%); ¹H NMR of B (400 MHz, Chloroform-d) δ 7.71 (tt, J = 6.6, 1.5 Hz, 4H), 7.53 - 7.35 (m, 6H), 6.98 (d, J= 3.6 Hz, 1H), 6.57 (d, J= 3.6 Hz, 1H), 5.90 (d, J = 14.5 Hz, 2H), 5.26 (d, J = 5.7 Hz, 1H), 4.61 (d, J= 5.7 Hz, 1H), 4.51 (d, J = 9.3 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-dîmethyl-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3a_J6adihydro-4H-cyclopenta[d][1,3]dioxol-6-yl)methanol

7S

To a stirred solution of 7-((3aS,4R,6aR)-6-(((tert-butytdiphenylsilyl)oxy)methyl)-2,2dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3}dioxol-4-yl)-4-methyl-7H-pyrrolo[2,3d]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 réaction mixture at 25’0 for 15h. Volatiles were removed in vacuo and the crude residue was purified by combiflash (Rf200, Teiedyne/lsco) instrument onto a redisep® R_f column with gradient elutïon (0 to 100%) of ethyl acetate in petroleum ether to afford the title compound (1.5g, 84%) as an off-white solid. “Ή NMR (400 MHz, Chloroform-d) δ 8.81 (s, 1H), 7.06 (d, J = 3.6 Hz, 1H), 6.55 (d, J = 3.6 Hz, 1H), 5.90 5.78 (m, 2H), 5.41 (ddd, 5.8, 1.7, 0.9 Hz, 1H), 4.65 (dt, J= 5.8, 0.9 Hz, 1H), 4.56 4.42 (m, 2H), 3.35 (d, J = 8.2 Hz, 1H), 2.74 (s, 3H), 1.53 (s, 3H), 1.37 (s, 3H); LCMS m/z = 302.21 (M+1; 100%) .

(3aS,4R,6aR)-2_I2-Dimethyl-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimîdin-7-yl)-3a,6adibydro-4H-cyclopenta[d][1,3]dioxole-6-carbaldehyde.

To a stirred solution of 7-((3aS,4R,6aR)-6-(((tert-Butyldiphenylsilyl)oxy)methyl)-2,2dimethyl-3a,6a-dihydro-4H-cyclopenta(dl[1,3]dioxol-4-yl)-7H-pyrrolo[2,3-dJpyrimidine (1.50 g, 4.98 mmol) in dichtoromethane (100 ml) at 0°C, was added Dess-Martin Periodinane (2.53 g, 5.97 mmol) portion-wise and stirred for Tn. 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 fiitered and concentrated in vacuo to give a crude compound and this crude residue was purified by combiflash (Rf200, Teiedyne/lsco) instrument onto a redisep® Rf column with gradient elutïon (0 to 30%) of ethyl acetate in Petroleum ether to afford the title compound (0.95g, 63.8%) as an off-white solid. ¹H NMR (400 MHz, Chloroform-d) δ 10.00 (s, 1H), 8.80 (s, 1H), 7.02 (d, J = 3.6 Hz, 1H), 6.82 6.76 (m, 1H), 6.63 (d,J= 3.6 Hz, 1 H), 6.00 « J = 2.7, 1.4 Hz, 1 H), 5.76 (dd, J = 5.9,1.5

Hz, 1H), 4.87 (dt, J = 5.9, 1.1 Hz, 1H), 2.77 (s, 3H), 1.53 (s, 3H), 1.38 (s, 3H); LCMS m/z = 300.15 (M+1; 100%)

7-((3aS,4R,6aR)-2_J2-DimethyI-6-vinyl-3a_J6a-dihydro-4H-cyclopenta[d] [1,3]dioxol-4yl)-4-methyl-7H-pyrrolo[2,3-d]pyrimidine.

The titie compound was synthesized by following an analogous reaction protocol as was described in the préparation ©f 4-chioro-7-((3aS,4R,6aR)-2,2-dimethyl-6-vinyl-3a,6adihydro-4H-cyclopenta[d][1,3] dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine. ¹H NMR (400 MHz, Chloroform-d) δ 8.83 (s, 1H), 7.01 (d, J = 3.6 Hz, 1H), 6.68 - 6.53 (m, 2H), 5.95 (d, J = 2.5 Hz, 1 H), 5.80-5.71 (m, 2H), 5.56 (dd, J = 6.0, 1.4 Hz, 1H), 5.47 (d, J = 10.8 Hz, 1 H), 4.65 (d, J = 5.8 Hz, 1H), 2.75 (s, 3H), 1.52 (s, 3H), 1.40 (s, 3H); LCMS m/z = 298.5 (M+1; 100%).

((3aS,4R,6aR)-2,2-Dimethyl-4-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3a,6a-dihydro-4Hcyclopenta[d][1,3]dioxol-6-yl)methanol.

The titie compound was synthesized by following an analogous reaction protocol as was described in the préparation 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 = 287.90 (M+; 100%).

(SaSARjSaR^^-DïnriethyM-CTH-pyrrolo^jS-dlpyrimidin^-ylJ-Sa.ea-dîhydro^Hcyc!openta[d][1,3]dioxo!e-6-carbaldehyde.

The titie compound was synthesized by following an analogous reaction protocol as was described in the préparation of (3aS,4R,6aR)-2,2-Dimethy!-4-(4-methyl-7H-pyrrolo[2,319533

d]pyrimidin-7-yl)-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxole-6-carbaldehyde. ¹H NMR (400 MHz, Chloroform-d) δ 10.01 (s, 1H), 9.04 (s, 1H), 8.93 (s, 1H), 7.11 (d, J= 3.6 Hz, 1 H), 6.83 - 6.77 (m, 1 H), 6.67 (d, J = 3.7 Hz, 1 H), 6.03 (dt, J = 2.8, 1.4 Hz, 1 H), 5.77 (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); LCMS m/z = 286.09 (M+; 100%).

7-((3aS,4R,6aR)-2,2-Dimethy!-6-vinyl-3a,6a-dihydro-4H-cyclopenta[d] [1,3] dioxol-4yl)-7H-pyrro!o[2,3-d]pyrimidine.

The titie compound was synthesized by following an analogous reaction protocol as was described in the préparation of 4-chloro-7-((3aS,4R,6aR)-2,2-dimethyl-6-vinyl-3a,6adihydro-4H-cyclopenta[d][1,3] dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine. ¹H NMR (400 MHz, Chloroform-d) δ 8.97 (d, J = 15.8 Hz, 2H), 7.09 (d, J= 3.7 Hz, 1H), 6.68-6.56 (m, 2H), 5.98 (d, J = 2.7 Hz, 1H), 5.82 - 5.72 (m, 2H), 5.60 - 5.54 (m, 1H), 5.52 - 5.44 (m, 1H), 4.66 (dt, J= 5.8, 1.0Hz, 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-dihydro3aH-cyclopenta[d][1,3]dioxol-4-yl)-4-chloro-5-fluoro-7H-pyrrolo[2,3-d] pyrimidine

To a stirred solution of (3aS,4S,6aR)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-dimethyl3a,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/lsco) instrument onto a redisep® Rf column with gradient elution (0 to 10%) of ethyi acetate in petroieum ether to afford the titie compound (2.7g, 56.7%) as an off-white solid. LCMS m/z = 577.94 (M+; 100%).

((3aR,6R,6aS)-6-(4-Chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethy!6,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methano!

The title compound was synthesized by following an anaiogous reaction protocol as was described in the préparation 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 = 340.03 (M+; 100%).

(3aR_J6R,6aS)-6-(4-Chloro-5-fluoro-7H-pyrrolo[2_J3-d]pyrimidin-7-yl)-2,2-dîmethyl6,6a-dihydro-3aH-cyclopenta[d][1,3]dîoxole-4-carbaldehyde

The title compound was synthesized by following an anaiogous reaction protocol as was described in the préparation of (3aS,4R,6aR)-2,2-Dimethyl-4-(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxole-6-carbaldehyde. ¹H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 8.73 (s, 1H), 7.80 (d, J = 2.0 Hz, 1 H), 7.10 - 7.03 (m, 1 H), 6.01 (dq, J = 2.7, 1.4 Hz, 1 H), 5.57 (dd, J = 6.0, 1.5 Hz, 1 H), 4.80 (dt, J = 6.0, 1.2 Hz, 1H), 1.39 (s, 3H), 1.28 (s, 3H); LCMS m/z = 338.03 (M+; 100%).

4-Chloro-7-((3aS₎4R,6aR)-2,2-dimethyl-6-vinyl-4,6a-dihydro-3aH-cyclopenta[d] [1,3] d.^:oxo!=4=yî)-5“f!uoro-7H=pyrro!o[2,3-d]pyrimidine

The title compound was synthesized by following an anaiogous reaction protocol as was described in the préparation of 4-chloro-7-((3aS,4R,6aR)-2,2-dimethyl-6-vinyl-3a,6a19533 dihydro-4H-cyclopenta[d][1,3] dioxoï-4-yl)-7H-pyrrolo[2,3-d]pyrimidine. ¹H NMR (400 MHz, DMSO-de) δ 8.71 (s, 1H), 7.66 (d, J = 2.0 Hz, 1H), 6.66 - 6.52 (m, 1H), 5.90 - 5.78 (m, 2H), 5.67 - 5.55 (m, 2H), 5.47 - 5.36 (m, 1 H), 4.71 (d, J = 6.0 Hz, 1 H), 1.38 (s, 3H), 1.31 (s, 3H); LCMS m/z = 336.03 (M+; 100%).

7-((3aS,4R,6aR)-6-(((tert-Butyldiphenylsilyl)oxy)methyl)-2_J2-dimethyl-4,6a-dihydro3aH-cyclopenta[d][1,3]dioxo!-4-y!)-2-chloro-7H-pyrrolo[2,3-d]pyrimidine

To a stirred solution of (3aS,4S,6aR)-6-(((tert-Butyldiphenylsilyl)oxy)methyl)-2,2-dimethyl3a,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 omins. 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/lsco) 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. ¹H NMR (400 MHz, Chloroform-d) δ 8.84 (s, 1 H), 7.70 (ddt, J = 6.6, 5.0, 1.5 Hz, 4H), 7.50 - 7.34 (m, 6H), 6.94 (d, J= 3.6 Hz, 1H), 6.59 (d, J = 3.6 Hz, 1H), 5.84 (dt, J = 19.8, 2.2 Hz, 2H), 5.30 (d, J = 5.7 Hz, 1 H), 4.63 (d, J = 5.6 Hz, 1 H), 4.57 - 4.42 (m, 2H), 1.43 (s, 3H), 1.33 (s, 3H), 1.10 (s, 9H); LCMS m/z = 560.3 (M+; 100).

((3aR,6R,6aS)-6-(2-Chloro-7H-pyrro!o[2,3-d]pynmidîn-7-yl)-2,2-dimethyl-6,6adihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methanol

To a stirred solution of 7-((3aS,4R,6aR)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-2-chloro-7H-pyrrolo[2,3d]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 température 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/lsco) 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. ¹H NMR (400 MHz, Chloroform-d) δ 8.81 (s, 1H), 7.28 (s, 1H), 7.08 (d, J = 3.7 Hz, 1H), 6.57 (d, J = 3.7 Hz, TH), 5.92 - 5.62 (m, 2H), 5.47 (d, J = 5.7 Hz, 1 H), 4.69 (dt, J = 5.6, 0.9 Hz, 1 H), 4.59 - 4.37 (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]pyrimîdin-7-yl)-2,2-dimethyl-6,6adihydro-3aH-cyclopenta[d][1,3]dioxole-4-carbaldehyde

The title compound was synthesized by following an analogous reaction protocol as was described in the préparation of (3aS,4R,6aR)-2,2-Dimethyl-4-(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxole-6-carbaldehyde. ¹H NMR (400 MHz, Chloroform-d) δ 9.99 (s, TH), 8.86 (s, 1H), 7.04 (d, J = 3.7 Hz, 1H), 6.75 (dd, J = 2.6, 0.9 Hz, 1H), 6.65 (d, J = 3.7 Hz, 1H), 6.00 (dt, J= 2.7, 1.4 Hz, 1H), 5.77 (dd, J = 5.9, 1.5 Hz, 1H), 4.88 (dd, J- 5.9, 1.2 Hz, 1H), 1.53 (s, 3H), 1.40 (s, 3H); LCMS m/z = 319.90 (M+; 100).

2-Chloro-7-((3aS,4R_J6aR)-2_!2-dimethyl-6-vinyl-4,6a-dihydro-3aHcyclopenta[d][1,3]dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine

The title compound was synthesized by following an analogous reaction protocol as was described in the préparation of 4-chloro-7-((3aS,4R,6aR)-2,2-dimethyl-6-vinyl-3a,6adihydro-4H-cyclopenta[d][1,3] dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine. ¹H NMR (400 MHz, Chloroform-d) δ 8.82 (s, 1H), 7.03 (d, J = 3.6 Hz, 1H), 6.64-6.53 (m, 2H), 5.93 (d, J = 2.6 Hz, 1H), 5.81-5.69 (m, 2H), 5.60 (dd, J= 5.8, 1.4 Hz, 1H), 5.53-5.44 (m, 1H), 4.68 (dd, J=5.8, 1.1 Hz, 1H), 1.45 (s, 6H); LCMS m/z = 318.15 (M+; 100).

1-((3aS,4R,6aR)-6-(((tert-Butyldiphenylsilyl)oxy)methyl)-2,2-dimethyl-4,6a-dihydro3aH-cyclopenta[d][1,3]dioxol-4-yl)-4-chloro-1H-pyrrolo[3_s2-c]pyridine

To a stirred solution of (3aS,4S,6aR)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-dimethyl3a,6a-dihydro-4H-cyclo penta[d][1,3]dioxoi-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) siowly 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/lsco) 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 m/z = 559.23 (M+; 100).

((3aR,6R,6aS)-6-(4-Chloro-1H-pyrrolo[3.,2-c]pyridîn-1-yl)-2,2-dimethyl-6,6a-dihydroSaH-cycÎoperitatdHI.SJdioxoM-yOmetihanol

To a stirred solution of 1-((3aS,4R,6aR)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2dimethy!-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-y!)-4-chloro-1H-pyrro!o[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 1 h. Volatiles were removed in vacuo and the crude residue was purified by combiflash (Rf200, Teledyne/lsco) 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 m/z = 319.71 (M-1: 100).

(3aR,6R,6aS)-6-(4-Chloro-1H-pyrrolo[3_J2-c]pyridin-1-yl)-2,2-dîmethyl-6,6a-dihydro3aH-cyclopenta[d][1,3]dioxole-4-carbaldehyde

The title compound was synthesized by following an analogous reaction protocol as was described in the préparation of (3aS,4R,6aR)-2,2-Dimethyl-4-(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxole-6-carbaldehyde. ¹H NMR (400 MHz, Chloroform-d) δ 10.05 (s, TH), 8.19 (d, J = 5.8 Hz, 1H), 7.34 (dd, J= 5.9, 0.9 Hz, 1H), 6.99 (d, 7= 3.3 Hz, 1H), 6.94-6.89 (m, 1H), 6.74 (dd, 7= 3.3, 0.9 Hz, 1H), 5.73 -5.58 (m, 2H), 4.67 (dt, 7= 5.9, 1.2 Hz, 1H), 1.55 (s, 3H), 1.39 (s, 3H); LCMS m/z = 319.05 (M+; 100).

4-Chioro-1-((3aS,4R_J6aR)-2,2-dimethyl-6-vinyl-4,6a-dihydro-3aH-cyclopenta[d][1_J3] dioxol-4-yl)-1H-pyrrolo[3,2-c]pyridine

The title compound was synthesized by following an analogous reaction protocol as was described in the préparation of 4-chloro-7-((3aS,4R,6aR)-2,2-dimethyI-6-vinyl-3a,6adihydro-4H-cyclopenta[d][1,3] dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine. ¹H NMR (400 MHz, Chloroform-d) δ 8.14 (d, 7= 5.8 Hz, 1H), 7.37 (dd, 7= 5.9, 0.9 Hz, 1H), 7.06 (d, 7= 3.3 Hz, 1H), 6.70 - 6.59 (m, 2H), 5.91 - 5.72 (m, 2H), 5.55 - 5.48 (m, 3H), 4.59 - 4.47 (m, 1H), 1.53 (s, 3H), 1.40 (s, 3H); LCMS m/z = 317.15 (M+; 100).

1-((3aS,4R,6aR)-2_J2-Dîmethyi-6-vinyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxoi-4yl)-4-methyl-1H-pyrrolo[3,2-c]pyridine

The title compound was synthesized by following an analogous reaction protocol as was described in the préparation of 7-((3aS,4R,6aR)-2,2-dimethyl-6-(prop-1-en-2-yl)-4,6adihydro-3aH-cyclo penta[d][1,3] dioxol-4-yl)-4-methyl-7H-pyrroior2,3-d]pyrimidine.

LCMS m/z = 297.21 (M+; 100). Des chloro dompound i.e. 1-((3aS,4R,6aR)-2,2-dimethyl6-vinyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-1 H-pyrrolo[3,2-c]pyridine was also formed, which was separated after Suzuki coupling step (Table-6) by reverse phase préparative HPLC.

(3aR,6aR)-6-(((tert-Butyldiphenylsilyl)oxy)methyl)-5-iodo-2,2-dimethyl-3a,6adihydro-4H-cyclopenta[d][1,3]dioxol-4-one

To a stirred solution of (3aR,6aR)-6-(((tert-butyldiphenylsilyl)oxy)rnethyl)-2,2-dimethyl3a,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 atmosphère 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/lsco) instrument onto a redisep® Rf column with gradient elution (0 to 20%) of ethyl acetate in petroleum etherto afford the title compound (15 g, 57.8%) as a colorless oil. ¹H NMR (400 MHz, Chloroform-d) δ 7.74 (ddt, J = 17.2, 6.5, 1.6 Hz, 4H), 7.58 -7.36(m, 6H), 5.19 (d, J = 5.8 Hz, 1H), 4.79 (t, J= 5.6 Hz, 1H), 4.53-4.33 (m, 2H), 1.45 (s, 3H), 1.35 (s, 3H), 1.08 (s, 9H).

(3aS,4R,6aR)-6-(((tert-ButyÎdîphenyisiiyi)oxy)methyi)-5-iodo-2,2-dimethyl-3a,6adîhydro-4H-cyclopenta[d][1,3]dioxol-4-ol

To a stirred solution of (3aR,6aR)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-5-iodo-2,2dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-one (13.7g, 24.98mmol) in methanol (130 ml), was added cérium (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? atmosphère. 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/lsco) instrument onto a redisep® Rf column with gradient elution (0 to 20%) of ethyl acetate in petroleum ether to afford the titie compound (6 g, 43.6%) as a colorless oiî. ¹H NMR (400 MHz, Chloroform-d) δ 7.84 - 7.62 (m, 4H), 7.48-7.39 (m,6H), 5.19 (d, J =5.8 Hz, 1 H), 4.86-4.71 (m, 1 H), 4.46-4.31 (m, 3H), 2.84 (d, J = 10.3 Hz, 1 H), 1.45 (s, 3H), 1.38 - 1.33 (s, 3H), 1.08 (s 9H).

7-((3aS,4S,6aR)-6-(((tert-Butyldiphenylsîlyl)oxy)methyl)-5-iodo-2,2-dimethyl-3a,6adihydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidine

The titie compound was synthesized by following an analogous reaction protocol as was described in the préparation of 1-((3aS,4R,6aR)-6-(((tert-butyldiphenylsilyl)oxy)methyl)2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3jdioxol-4-yÎ)-4-chloro-1H-pyrrolo[3,2-c] pyridine. ¹H NMR (400 MHz, Chloroform-d) δ 8.64 (s, 1H), 7.75 (ddt, J = 20.3, 6.8, 1.5 Hz, 4H), 7.53 - 7.31 (m, 6H), 6.96 (d, J = 3.7 Hz, 1 H), 6.67 (d, J = 3.6 Hz, 1 H), 5.74 - 5.62 (m, 2H), 4.86 - 4.80 (m, 1 H), 4.54 - 4.42 (m, 2H), 1.48 (s, 3H), 1.42 (s, 3H), 1.13 (s, 9H). LCMS m/z = 686.33 (M+; 100).

7-((3aS,4S,6aR)-6-(((tert-Butyidîphenylsilyl)oxy)methyl)-5-iodo-2,2-dimethyl-3a_s6adihydro-4H-cyclopenta[d][1,3]dioxol-4-yi)-N-(4-methoxybenzyl)-7H-pyrroîo[2,3d]pyrimidin-4-amine

A mixture of 7-((3aS,4S,6aR)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-5-iodo-2,2-dimethyl3a,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 éthanol (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/lsco) instrument onto a redisep® Rf column with gradient elution (0 to 40%) of ethyl acetate in petroleum etherto afford the title compound (1.8 g, 92%) as an off white solid. ¹H NMR (400 MHz, Chloroform-d) δ 8.37 (d, J = 6.4 Hz, 1H), 7.76 (ddt, J = 19.4, 6.8, 1.4 Hz, 4H), 7.52 - 7.32 (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, 1H), 5.61 (d, J = 6.2 Hz, 1H), 4.80 (dd, J = 12.7, 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 m/z = 786.41 (M+; 100).

7-((3aS,4R,6aR)-6-(((tert-Butyldiphenylsilyl)oxy)methyl)-2,2,5-trimethyl-3a,6adihydro-4H-cyclopenta[d][1,3]d!Oxol-4-yl)-N-(4-methoxybenzyl)-7H-pyrrOlo[2,3d]pyrimidin-4-amine

A mixture of 7-((3aS,4S,6aR)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-5-iodo-2,2-dimethyl3a,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(PPhg)4(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/lsco) instrument onto a redisep® Rf column with gradient elution (0 to 40%) of ethyl acetate in Petroleum etherto afford the title compound (2.7 g,, 98 %) as an off-white solid. LCMS m/z = 675.60 (M+; 100).

((3aS,4R,6aR)-4-(4-((4-IVIethoxybenzyl)amîno)-7H-pyrrolo[2,3-d] pyrimidin-7-yl)z^S-trimethyi-Sajea-dihydro^H-cyclopentafdJfljSldioxoi-e-ylJmethanoI

To a stirred solution of 7-((3aS,4R,6aR)-6-(((tert-butyldiphenylsilyl)oxy)methy!)-2,2,5trimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-yÎ)-N-(4-methoxybenzyÎ)-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 ethyi 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/lsco) instrument onto a redisep® Rf column with gradient elution (0 to 100%) of ethyi acetate in petroieum ether to afford the titie compound (1.7 g,, 97 %) as a colorless oil. ¹H NMR (400 MHz, Chloroform-d) δ 7.69 (ddd, J = 12.0, 8.3, 1.4 Hz, 1H), 7.62 - 7.41 (m, 1 H), 7.41 - 7.30 (m, 2H), 6.99 - 6.80 (m, 2H), 6.70 (d, J = 3.6 Hz, 1 H), 6.35 (d, J = 3.5 Hz, 1H), 5.67 (s, 1H), 5.51 (d, J = 5.9 Hz, 1H), 4.79 (d, J = 5.5 Hz, 2H), 4.60 (dd, J = 5.9, 0.9 Hz, 1H), 4.45 (s, 2H), 3.83 (s, 3H), 1.61 (t, J = 1.1 Hz, 3H), 1.51 (s, 3H), 1.37 (s, 3H). LCMS m/z = 437.17 (M+, 100%).

((3aS,4R,6aR)-4-(4-((4-Methoxybenzyl)amino)-7H-pyrrolo[2,3-d] pyrimidin-7-yl)-2₅2₅5trimethyl-3a,6a-d!hydro-4H-cyclopenta[d][1,3]dioxol-6-yl)methyl 4methylbenzeneulfonate

To a mixture of ((3aS,4R,6aR)-4-(4-((4-methoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin7-yl)-2,2,5-trimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-6-yl)methanoi (100mg, 0.229mmol), DMAP (5.60 mg, 0.046 mmol) and TEA (0.096 ml, 0.687 mmol) in CH₂CI₂ (10 ml) at 0°C, was added a solution of p-toluene sulphonyl chloride (65.5 mg, 0.344 mmol) in CH₂Ci₂ (1mi) and stirred for 1h at 25°C. The reaction mixture was diluted with water (5 ml) and extracted with ethyi 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/lsco) instrument onto a redisep® Rf column with gradient elution (0 to 40%) of ethyi acetate in petroieum ether to afford the titie 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)methy!)-2,2,4-trimethyl-3a,6a-dihydro4H-cyclopenta[d][1,3]dioxol-4-ol

To a stirred solution of (3aS.6aS)-5-(((tert-butyldiphenylsiîyl)oxy)methyl)-2,2-dimethyl3a,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 magnésium bromide in THF (11.85 mi, 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 mi), dried over sodium sulfate, filtered and concentrated in vacuo to give 9.8g of crude compound. This residue was purified by combiflash (Rf200, Teledyne/lsco) instrument onto a redisep® R_f 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. ¹H NMR (400 MHz, Chloroform-d) δ 7.72 7.67 (m, 4H), 7.47 - 7.37 (m, 6H), 5.84 (q, J = 2.0 Hz, 1 H), 5.11 - 5.00 (m, 1 H), 4.46 - 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-dihydro4H-cyclopenta[d][1,3]dioxol-4-o!

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-TSOHH2O (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 NaHCOs (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 (Rf200, Teledyne/lsco) instrument onto a redisep® R_f column with gradient elution (0 to 30%) of ethyl acetate in petroleum ether to afford the title compound (3.5g, 43%) as an oil. ¹H NMR (400 MHz, Chloroform-d) δ 7.74 - 7.65 (m, 4H), 7.48 - 7.35 (m, 6H), 5.81 (p, J = 1.6 Hz, 1H), 4.62 4.55 (m, 1 H), 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-Butyldiphenylsiiyl)oxy)methy!)-2,2,6a-trimethyl-3a,6adihydro-4H-cycIopenta[d][1,3]dioxol-4-yl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidine.

The title compound was synthesized by following an analogous reaction protocol as was described in the préparation 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-pynOlo[3,2-c] pyridine. ¹H NMR (400 MHz, Chloroform-d) δ 8.74 (s, 1 H), 7.78 - 7.67 (m, 4H), 7.52 - 7.39 (m, 6H), 6.94 (d, J = 3.6 Hz, 1 H), 6.61 (d, J = 3.6 Hz, 1 H), 5.94 - 5.86 (m, 1 H), 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 (s, 3H), 1.36 (s, 3H), 1.13 (s, 9H), LCMS m/z = 574.44 (M+; 100%).

((3aS₃4R₃6aR)-4-(4-Chloro-7H-pyrroio[2₃3-d]pyrîmidin-7-yl)-2₃2₃6a-trimethyl-3a,6a10 dihydro-4H-cyclopenta[d][1,3]dioxol-6-yl)methanol

The title compound was synthesized by following an analogous reaction protocol as was described in the préparation of ((3aR,6R,6aS)-6-(2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7yl)-2,2-dimethyl-6,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methanol.

¹H NMR (400 MHz, Chloroform-d) δ 8.73 (s, 1H), 7.16 (d, J = 3.6 Hz, 1H), 6.62 (d, J = 3.6 Hz, 1 H), 5.87 - 5.78 (m, 2H), 4.62 - 4.44 (m, 2H), 4.25 - 4.20 (m, 1 H), 1.56 (s, 3H), 1.49 (s, 3H), 1.42 (s, 3H); LCMS m/z = 336.15 (M+; 100%).

(3aS,4R,6aR)-4-(4-Chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2,6a-trimethyl-3a₃6adihydro-4H-cyclopenta[d][1,3]dioxole-6-carbaldehyde

The title compound was synthesized by following an analogous reaction protocol as was described in the préparation of (3aS,4R,6aR)-2,2-dimethyl-4-(4-methyl-7H-pyrrolo[2,3djpyrimidin-7-yl)-3a,6a-dinydro-4H-cycÎopenta[dj[1_!3]dioxoÎe-6-carbaldehyde. ¹H NMR (400 MHz, Chloroform-d) δ 10.01 (s, 1H), 8.73 (s, 1H), 7.09 (d, J = 3.6 Hz, 1H), 6.78 (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 = 0.8 Hz, 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_J4R6aR}-2_J2,6a-trimethyl-6-vinyl-3a,6a-dihydro-4H-cyclopenta[d]

[1,3] dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine

The title compound was synthesized by following an analogous reaction protocol as was described in the préparation of 4-chloro-7-((3aS,4R,6aR)-2,2-dimethyl-6-vinyl-3a,6adihydro-4H-cyclopenta[d][1,3] dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine. ¹H NMR (400 MHz, Chioroform-d) δ 8.74 (s, 1H), 7.16 (d, J = 3.6 Hz, 1H), 6.62 (d, J = 3.6 Hz, 1H), 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 = 11.2, 1.2 Hz, 1H), 4.15 (d, J = 1.1 Hz, 1H), 1.60 (s, 3H), 1.44 (s, 6H), LCMS m/z = 332.22 (M+1; 100%).

7-((3aS_!4R_i6aR)-6-(((tert-Butyldiphenylsilyl)oxy)methyl)-2_J2_J6a-trimethyl-3a,6adihydro-4H-cyciopenta[d][1,3]dioxol-4-yi)-4-methyl-7H-pyrrolo[2₃3-d]pyrimidine

The title compound was synthesized by following an analogous reaction protocol as was described in the préparation 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[2,3djpyrimidine. ¹H NMR1 (400 MHz, Chloroform-d) δ 8.86 (s, 1H), 7.73 (ddt, J = 15.2, 6.7, 1.5 Hz, 4H), 7.52-7.39 (m, 6H), 6.90 (d, J= 3.6 Hz, 1H), 6.55 (dd, J= 3.7, 2.3 Hz, 1H), 5.90 (dt, J= 2.9, 1.5 Hz, 1H), 5.82 (q, J= 2.4 Hz, 1H), 4.54 (dq, J = 6.2, 1.8 Hz, 2H), 4.14 (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); LCMS m/z=554.32 (M+, 100%).

((3aS,4R,6aR)-2,2,6a-Trimethyl-4-(4-methy^-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3a_J6adihydro-4H-cycîopenta[d][1,3]dioxol-6-yl)methanol

The title compound was synthesized by following an analogous reaction protocol as was described in the préparation 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.

¹H NMR (400 MHz, Chloroform-d) δ 8.86 (s, 1 H), 7.08 (d, J = 3.7 Hz, 1 H), 6.57 (dd, J =

3.6, 1.1 Hz, 1H), 5.86 - 5.78 (m, 2H), 4.59 - 4.47 (m, 2H), 4.23 (dt, J = 6.9, 0.8 Hz, 1H), 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-Trimethy!-4-(4-methyl-7H-pyrroio[2,3-d]pyrimidin-7-y!)-3a,6a dihydro-4H-cyclopenta[d][1,3]dioxole-6-carbaldehyde

The title compound was synthesized by following an analogous reaction protocol as was described in the préparation of (3aS,4R,6aR)-2,2-dimethyl-4-(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxole-6-carbaldehyde. ¹H NMR 15 (400 MHz, Chloroform-d) δ 10.01 (s, 1H), 8.87 (s, 1H), 7.03 (d, J = 3.7 Hz, 1H), 6.79 (td, J = 2.8, 1.1 Hz, 1H), 6.67 (d, J = 3.7 Hz, 1H), 6.02 (dd, J= 2.9, 0.7 Hz, 1H), 4.33 (d, J = 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] 20 [1,3] dioxoi-4-yl)-7H-pyrrolo[2,3-d]pyrimidine

The title compound was synthesized by following an analogous reaction protocol as was described in the préparation of 4-chloro-7-((3aS,4R,6aR)-2,2-dimethyl-6-vinyl-3a,6a19533 dihydro-4H-cyclopenta[d][1,3] dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine. ¹H NMR (400 MHz, Chioroform-d) δ 8.87 (s, 1 H), 7.09 (d, J = 3.7 Hz, 1 H), 6.60 - 6.44 (m, 2H), 5.94 - 5.75 (m, 3H), 5.45 (dd, J = 11.3, 1.5 Hz, 1H), 4.21 - 4.07 (m, 1H), 2.78 (s, 3H), 2.64 (s, 3H), 1.44 (s, 6H); LCMS m/z=312.28 (M+, 100%).

1-((3aR_s6R,6aS)-6-(4-Chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2,3a4:rimethyl-6,6a-di hydro-3aH-cyclopenta[d][1,3]dioxol-4-y!)ethano!

The title compound was synthesized by following an analogous reaction protocol as was described in the préparation of 1-((3aS,4R,6aR)-4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7yl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-6-yl)ethan-1-ol. ¹H NMR (400 MHz, Chloroform-d) δ 8.73 (d, J = 2.0 Hz, 1H), 7.12 (dd, J= 31.8, 3.6 Hz, 1H), 6.62 (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 (d, J = 7.1 Hz, 3H), 1.54 (s, 6H), 1.43 (d, J = 3.5 Hz, 3H); LCMS m/z=350.22 (M+, 100%).

1-((3aR,6R,6aS)-6-(4-Chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2,3a-trimethyl-6_J6adihydro-3aH-cyclopenta[d][1,3]dioxol-4-yi)ethanone

The title compound was synthesized by following an analogous reaction protocol as was described in the préparation of 1-((3aS,4R,6aR)-4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7yl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-6-yl)ethan-1-one. ¹H NMR (400 MHz, Chloroform-d) δ 8.74 (s, 1H), 7.10 (d, J = 3.7 Hz, 1H), 6.74 - 6.56 (m, 2H), 5.95 (d, J= 2.9 Hz, 1H), 4.27 (t, J = 0.9 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-6,6adihydro-3aH-cyciopenta[d][1_s3jdioxoi-4-yi)propan-2-oi

The titie compound was synthesized by following an analogous reaction protocol as was described in the préparation of 2-((3aS,4R,6aR)-4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7yl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-6-yl)propan-2-ol. LCMS m/z=364.22 (M+, 100%).

4-Chloro-7-((3aS,4R,6aR)-2,2,6a-trimethyl-6-(prop-1-en-2-yl)-4,6a-dihydro-3aHcyclopenta[d][1,3]dioxol-4-yI)-7H-pyrTo!o(2,3-d]pyrimidine

The titie compound was synthesized by following an analogous reaction protocol as was described in the préparation 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. ¹H NMR (400 MHz, Chloroform-d) δ 8.74 (s, 1H), 7.15 (d, J= 3.6 Hz, 1H), 6.62 (d, 3.7 Hz, 1H), 5.84 (d, J = 3.0 Hz, 1H), 5.76 (ddd, J = 12.2, 2.4, 1.0 Hz, 2H), 5.31 (t, J = 1.6 Hz, 1H), 4.15 4.13 (m, 1H), 2.05 (t, J = 1.0 Hz, 3H), 1.61 (s, 3H), 1.43 (s, 6H); LCMS m/z= 346.02 (M+, 100%).

4-Methyl-7-((3aS_J4R,6aR)-2,2_J6a-trimethyl-6-(prop-1-en-2-yl)-4,6a-dihydro-3aHcyclopenta[d][1,3]dioxol-4-yI)-7H-pyrrolo[2,3-d]pyrimidine

The titie compound was synthesized by following an analogous reaction protocol as was described in the préparation of 7-((3aS,4R,6aR)-2,2-dimethyl-6-(prop-1-en-2-yl)-4,6adihydro-3aH-cyclo penta{d][1,3] dioxol-4-yl)-4-methyl-7H-pyrrolo[2,3-d]pyrimidine. ¹H NMR (400 MHz, Chloroform-d) δ 8.87 (s, 1H), 7.06 (d, J = 3.6 Hz, 1H), 6.56 (d, J = 3.6 Hz, 1H), 5.89 - 5.67 (m, 3H), 5.29 (t, J = 1.6 Hz, 1H), 4.14 (d, J = 1.3 Hz, 1H), 2.76 (s, 3H), 2.05 (t, J = 1.0 Hz, 3H), 1.61 (s, 3H), 1.43 (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“4yl)-4-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimîdine

The title compound was synthesized by following an analogous reaction protocol as was described in the préparation of 7-((3aS,4R,6aR)-2,2-dimethyl-6-(prop-1-en-2-yl)-4,6adihydro-3aH-cyclo penta[d][1,3j dioxol-4-yl)-4-methyl-7H-pyrrolo[2,3-d]pyrimidine. LCMS m/z=364.22 (M+, 100%).

(3aS,4R,6aS)-5-(((tert-Butyldiphenylsilyl)oxy)methyl)-4-ethyl-2,2-dimethyl-4.6adihydro-3aH-cyclopenta[d][1,3]dioxol-4-ol

The title compound was synthesized by following an analogous reaction protocol as was described in the préparation of (3aS,4R,6aS)-5-(((tert-Butyldiphenylsi!yl)oxy)methyl)2,2,4-trimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-ol. ¹H NMR (400 MHz, Chloroform-d) δ 7.76 - 7.74 (m, 2H), 7.73 - 7.68 (m, 4H), 7.44 - 7.39 (m, 8H), 5.95 (d, J = 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), 1.43 (s, 3H), 1.10 (s, 9H), 0.74 (t, J = 7.5 Hz, 3H).

(3aS,4S,6aR)-6-(((tert-Butyldiphenyllsilyl)oxy)methyl)-6a-ethyl-2.2-dimethyl-4,6adihydro-3aH-cyclopenta[d][1,3]dioxol-4-ol

The title compound was synthesized by following an analogous reaction protocol as was described in the préparation of (3aS,4S,6aR)-6-(((tert-Butyldiphenylsilyl)oxy)methyl)2,2,6a-trimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-ol. ¹H NMR (400 MHz, Chloroform-d) δ 7.72 - 7.67 (m, 4H), 7.41 (dddt, J= 15.6,7.9,6.7,2.1 Hz, 6H), 5.92 (p, J = 1.7 Hz, 1H),4.52(s, 1 H), 4.43-4.35 (m, 2H), 4.22 (ddd, J = 15.6,3.0,2.0 Hz, 1 H), 2.71 (s, 1H), 1.79 - 1.64 (m, 2H), 1.39 (s, 3H), 1.32 (s, 3H), 1.10 (s, 9H), 0.74 (t, J = 7.6 Hz, 3H).

7-((3aS,4R_!6aR)-6-(((tert-Butyldiphenylsilyl)oxy)methyl)-6a-ethyl-2,2-dimethyl-4,6adihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidine

The title compound was synthesized by following an analogous reaction protocol as was described in the préparation 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. ¹H NMR (400 MHz, Chloroform-d) δ S.76 (s, 1 H), 7.79 - 7.67 (m, 4H), 7.55 - 7.37 (m, 6H), 6.99 (d, J = 3.6 Hz, 1 H), 6.60 (d, J = 3.6 Hz, 1 H), 6.03 - 5.96 (m, 1 H), 5.78 (q, J = 2.5 Hz, 1H), 4.61 -4.43 (m, 2H), 4.25 (d, J = 0.9 Hz, 1H), 1.75 (q, J = 7.3 Hz, 1H), 1.55 (dq, J = 14.8, 7.4 Hz, 1H), 1.41 (s, 6H), 1.13 (s, 9H), 0.68 (t, J = 7.4 Hz, 3H); LCMS m/z= 588.21 (M+, 100%).

((3aR,6R,6aS)-6-(4-Chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3a-ethyl-2,2-dimethyl6,5a-dihydro-3aH-cyciopenta[d][1,3]dîoxoi^l-4-yi')methanol

The title compound was synthesized by following an analogous reaction protocol as was described in the préparation 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. ¹H NMR (400 MHz, Chloroform-d) δ 8.74 (s, 1H), 7.17 (d, J = 3.7 Hz, 1H), 6.60 (d, J = 3.6 Hz, 1H), 5.93 (dq, J = 2.7, 1.5 Hz, 1H), 5.79 (q, J = 2.2 Hz, 1H), 4.60-4.43 (m, 2H), 4.32 (t, J= 0.8 Hz, 1H), 1.94 (dq, J = 14.8, 7.4 Hz, 1H), 1.74 (dq, J = 14.7, 7.5 Hz, 1H), 1.51 (s, 3H), 1.41 (s, 3H), 0.83 (t, J = 7.5 Hz, 3H); LCMS m/z= 350.22 (M+, 100%).

(3aR,6R,6aS)-6-(4-Chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yi)-3a-ethyl-2,2-dimethyl6,6a-dihydro-3aH-cyclopenta[d][1,3]dîoxole-4-carbaldehyde

The title compound was synthesized by following an anaiogous reaction protocol as was described in the préparation of (3aS,4R,6aR)-2,2-dimethyl-4-(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxole-6-carbaldehyde. ¹H NMR (400 MHz, Chloroform-d) δ 10.02 (s, 1H), 8.75 (s, 1H), 7.09 (d, J= 3.7 Hz, 1H), 6.88 (dd, 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 = 1.0 Hz, 1H), 2.24 (dq, J = 14.9, 7.5 Hz, 1H), 1.97 (dq, J = 14.8, 7.4 Hz, 1H), 1.47 (s, 6H), 0.89 (t, J = 7.5 Hz, 3H); LCMS m/z= 348.22 (M+, 100%).

4-Chioro-7-((3aS₅4R.,6aR)-6a-ethyi-2₅2-dimeïhyi-6-vînyî-4_J6a-dihydro-3aHcyclopenta[d][1,3]dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine

The title compound was synthesized by following an anaiogous reaction protocol as was described in the préparation of 4-chloro-7-((3aS,4R,6aR)-2,2-dimethyl-6-vinyl-3a,6adihydro-4H-cyclopenta[d][1,3] dioxol-4-yi)-7H-pyrrofo[2,3-d]pyrimidine. ¹H NMR (400 MHz, Chloroform-d) δ 8.75 (s, 1H), 7.16 (d, J = 3.7 Hz, 1H), 6.60 (d, J = 3.7 Hz, 1H), 6.56-6.36 (m, 1H), 5.99 = 5.69 (m, 3H), 5.44 (dd, J = 11.3, 1.5 Hz, 1H), 4.25 (d, J = 0.9 Hz, 1H), 2.15 - 1.99 (m, 1H), 1.76 (dq, J= 14.8, 7.5 Hz, 1H), 1.46 (s, 6H), 0.81 (t, J = 7.5 Hz, 3H). LCLCMS m/z= 346.22 (M+, 100%).

((3aR_J3bR,4aS,5R,5aS)-5-(4-Chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyI hexa hydrocyclopropa[3,4]cyclopenta[1,2-d][1,3]dioxol-3b-yl)methanol

The title compound was prepared by an anaiogous reaction protocol as described in WO2006/091905 A1.

«3aR,3bR,4aS,5R,5aS)-5-(4-Chloro-7H-pyrrolo[2,3-d]pyrimîdin-7-yl)-2,2-dimethyI hexahydrocyclopropaES^jcycîopentafl^-dJil’SJdîoxol-Sb-yQmethyl 4-methyl benzenesulfonate

To a stirred solution of ((3aR,3bR,4aS,5R,5aS)-5-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7yl)-2,2-dimethyltetrahydrocyclopropa[3,4]cyclopenta[1,2-d][1,3]dioxol-3b(3aH)yl)methanol (2 g, 5.96 mmol) in CH₂CI₂ (40 ml)at 0°C, was added TEA (2.494 rnl, 17.87 mmol) , DMAP (0.146 g, 1.191 mmol) and followed by p-TsCI (1.363 g, 7.15 mmol) slowly and stirred for 10 min. The reaction mixture was stirred at 25°C for 16h. The reaction mixture was diluted with methylene chloride (100 ml) and washed with water (100 ml). Layers were separated, organic layer was washed with brine (100 ml) and dried over anhydrous Na₂SO₄ The organic layer was filtered and concentrated in vacuo to give 12g of crude compound. This residue was purified by combiflash (R_T-200, Teledyne/lsco) instrument onto a redisep® R_f column with gradient elution (0 to 7%) of ethyi acetate in petroieum ether to afford the titie (0.267g, 9.15%) as an off-white solid. LCMS m/z= 490.17 (M+, 100%).

(3aR,3bS,4aS,5R,5aS)-5-(4-Chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2d!methylhexahydrocyclopropa[3,4]cyclopenta[1,2-d][1,3]dioxo!e-3b-carbaldehyde

The titie compound was synthesized by following an analogous reaction protocol as was described in the préparation of (3aS,4R,6aR)-2,2-dimethyl-4-(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)-3a,6a-dihydro-4H-cyclopenta[dj[1,3]dioxole-6-carbaldehyde. ¹H NMR (400 MHz, Chloroform-d) δ 9.34 (s, 1H), 8.63 (s, 1H), 7.18 (d, J-3.6 Hz, 1H), 6.66 (d, J = 3.6 Hz, 1 H), 5.91 (dd, J = 7.1, 1.2 Hz, 1 H), 5.11 (s, 1 H), 4.82 (dd, J = 7.1, 1.6 Hz, 1 H), 2.34 (ddd, J= 9.4, 6.1, 1.6 Hz, 1H), 1.89 - 1.77 (m, 2H), 1.58 (s, 3H), 1.30 (s, 3H); LCMS m/z =333.9 (M+, 100%).

100

4-Chloro-7-((3aR₎3bS,4aS,5R,5aS)-2,2-dimethyl-3b-vinylhexahydro cyclopropa [3,4] cyclo penta[1,2-d][1,3]dioxoI-5-yl)-7H-pyrrolo[2,3-d]pyrimidine.

To a stirred suspension of methyitriphenylphosphonium bromide (24.62 g, 68.9 mmol) in THF (200 ml), was added 1M KHMDS in THF (68.9 ml, 68.9 mmol) at 25°C and stirred for 10 min. The resulting yellowsuspension was cooled to 0°C and a solution of (3aR,3bS,4aS, 5R,5aS)-5-(4-Chloro-7H-pyrroIo[2,3-djpyrimidin-7-yl)-2,2-dimethylhexahydrocyclopropa [3,4]cyclopenta[1,2-d][1,3]dioxole-3b-carbaldehyde (9.2 g, 27.6 mmol) in THF (80 ml) was added slowly. The reaction mixture was stirred at the same température for 1h. The reaction mixture was quenched with a saturated aq.NH₄CI (200ml) and extracted with ethyl acetate (200 ml). Layers were separated, organic layer was washed with brine (250 ml) and dried over anhydrous Na₂SO4. The organic layer was filtered and concentrated in vacuo to give 11g of crude compound. This residue was purified by combiflash (Rf200, Teledyne/lsco) instrument onto a redisep® R_f column with gradient elution (0 to 20%) of ethyl acetate in petroleum etherto afford the title compound (7g, 77%) as a white solid. ¹H NMR (400 MHz, Chloroform-d) δ 8.68 (s, 1H), 7.23 (d, J = 3.7 Hz, 1H), 6.67 (d, J = 3.6 Hz, 1H), 5.86 (dd, J = 17.3, 10.6 Hz, 1H), 5.39-5.32 (m, 2H), 5.29 (s, 1H), 5.18 (dd, J = 10.6, 0.9 Hz, 1H), 4.59 (dd, J = 7.1, 1.6 Hz, 1H), 1.77 (ddd, J = 9.3, 4.9, 1.6 Hz, 1H), 1.63 (s, 3H), 1.49 (t, J= 5.3 Hz, 1H), 1.27 (s, 3H), 1.18 (ddd, J = 9.3, 5.6, 1.6 Hz, 1H); LCMS m/z =332,28 (M+, 50%).

7-((3aR,3bS_J4aS,5R_i5aS)-2_J2-Dimethyl-3b-vinylhexahydrocyclopropa

[3,4]cyclopenta [1,2-d][1,3]dioxol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine.

A mixture of 4-chloro-7-((3aR,3bS,4aS,5R,5aS)-2,2-dimethyl-3b-vinylhexahydro cyclopropa [3,4] cyclo penta[1,2-d][1,3]dioxol-5-yl)-7H-pyrrolo[2,3-d]pyrimidine (3g, 9.04 mmol) and aq. ammonia (19.57 ml, 904 mmol) in dioxane (6ml) stirred at 130°C in a Steel

101 bomb for 16 h. The reaction mixture was diiuted with ethyl acetate (20ml) and washed with water (20ml). Layers were separated, organic layer was washed with brine (20ml) and dried over anhydrous Na₂SO₄ The organic layer was filtered and concentrated in vacuo to give 4.1g of crude compound. This residue was purified by combiflash (Rf200, Teledyne/lsco) instrument onto a redisep® Rf column with gradient elution (0 to 3%) of methanol in dichloromethane to afford the title compound (2.45g, 87%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.07 (s, 1H), 7.02 (s, 2H), 6.96 (d, J = 3.5 Hz, 1H), 6.62 (d, J = 3.5 Hz, 1H), 5.86 (dd, J= 17.4, 10.7 Hz, 1H), 5.33 (dd, J = 7.2, 1.3 Hz, 1H), 5.23 (dd, J = 17.4, 1.3 Hz, 1H), 5.10-5.01 (m, 2H), 4.50 (dd, J=7.1, 1.6 Hz, 1H), 1.70 (ddd, J=9.3, 4.8, 1.6 Hz, 1H), 1.46 (s, 3H), 1.29 - 1.22 (m, 1H), 1.19 (s, 3H), 1.10 (ddd, J = 9.1, 5.1, 1.5 Hz, 1H); LCMS m/z =313 (M+1, 100%).

7-((3aR,3bS₎4aS_s5R,5aS)-2,2-Dimethyl-3b-vînyIhexahydrocyclopropa

[3,4]cyclopenta [1,2-d][1,3]d!Oxol-5-y!)-4-methyl-7H-pyrrolo[2,3-d]pyrimidîne

To a degassed mixture dioxane (8ml) and water (1ml) in a microwave vial was added 4chloro-7-((3aR,3bS,4aS,5R,5aS)-2,2-dimethyl-3bvinylhexahydrocyclopropa[3,4]cyclopenta [1,2-d][1,3]dioxol-5-yl)-7H-pyrrolo[2,3djpyrimidine (1.00 g, 3.01 mmol, potassium phosphate, tribasic (1.575 g, 9.04 mmol), dichloro[1,T-bis(di-t-butylphosphino)ferrocene] palladium(ll) (0.196 g, 0.301 mmol) and 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (2.107 ml, 15.07 mmol) at 25°C. Stirred the reaction mixture at 100°C for 1h. The reaction mixture was diiuted with ethyl acetate (20ml) and washed with water (20ml). Layers were separated, organic layer was washed with brine (20ml) and dried over anhydrous Na₂SO₄. The organic layer was filtered and concentrated in vacuo to give 1.1g of crude compound. This residue was purified by combiflash (Rf200, Teledyne/lsco) instrument onto a redisep® Rt column with gradient elution (0 to 20%) of ethyl acetate in petroleum ether to afford the title compound (0.66g, 70.3%) as an off white solid. ¹H NMR (400 MHz, Chloroform-d) δ 8.81 (s, 1H), 7.16 (d, J = 3.6 Hz, 1 H), 6.63 (d, J = 3.6 Hz, 1 H), 5.87 (dd, J = 17.3,10.6 Hz, 1 H), 5.37-5.31 (m, 3H), 5.17 (dd, J = 10.6, 0.9 Hz, 1H), 4.58 (dd, J= 7.1, 1.6 Hz, 1H), 2.78 (s, 3H), 1.78 (ddt, J = 9.3, 4.9, 1.8 Hz, 1H), 1.59 (d, J= 1.8 Hz, 3H), 1.50 (td, J = 5.2, 2.7 Hz, 1H), 1.27 (d, J = 2.2 Hz, 3H), 1.19 - 1.14 (m, 1H); LCMS m/z =312.21 (M+1, 100%).

102

Des chlore dompound Le. 7-((3aR,3bS,4aS,5R,5aS)-2,2-dimethyl-3b-vinylhexahydro cyclo propa[3,4]cyclopenta[1,2-d] [1,3]dioxol-5-yl)-7H-pyrrolo[2,3-d]pyrimidine was also formed, which was separated at final step by reverse phase préparative HPLC.

-(S)-1-((3aR,3bR,4aS,5R,5aS)-5-(4-ChlorO-7H-pyrrQlo[2,3-d]pyrimidin-7-yl)-2,2dimethyltetrahydrocyclopropa[3,4]cyclopenta[1,2-d][1,3]dioxol-3b(3aH)-yl)ethan-1oî

To a solution of (3aR,3bS,4aS,5R,5aS)-5-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2dimethyltetrahydrocyclopropa[3,4]cyclopenta[1,2-d][1,3]dioxole-3b(3aH)-carbaldehyde (2.0 g, 5.99 mmol) in tetrahydrofuran (20 ml), was added 1M methyl magnésium bromide in THF (3.00 ml, 8.99 mmol) at 0°C. The reaction mixture was then stirred at 0°C for2h. The reaction mixture was quenched with a sat. aq. ammonium chloride (50ml) and extracted with ethyl acetate (50ml X 2). The combined organic layer was washed with brine (50ml), dried over sodium sulfate, fiitered and concentrated in vacuo to give 2.2g of crude compound. This residue was purified by combiflash (Rf200, Teiedyne/lsco) instrument onto a redisep® R_f column with gradient elution (0 to 30%) of ethyl acetate in petroleum ether to afford the title compound (1.85g, 88%) as an off-white solid. LCMS m/z = 350.03 (M+1; 100%).

1-((3aK,3bS,4aS,5R,5aS)-5-(4-chioro-7H-pyrroio[2,3-d]pyrimidin-7-yi)-2,2-dimethyi tetrahydrocyclopropafS^cyclopentatl^-dHIjSJdioxoI-SblSaHJ-ylJethan-l-one

The title compound was synthesized by following an analogous reaction protocol as was described in the préparation of (3aS,4R,6aR)-2,2-dimethyl-4-(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yï)-3a,6a-dihydro-4H-cyc!openta[dj[1,3]dioxoîe-6-carbaldehyde. LCMS m/z = 348.03 (M+; 100%).

4-Chloro-7-((3aR_I3bS,4aS,5R,5aS)-2,2-d!methy!-3b-vinylhexahydro cyclopropa[3,4] cyclopenta[1,2-d][1,3]dioxol-5-yl)-7H-pyrrolo[2,3-d]pyrimidine.

103

To a stirred suspension of methyltriphenylphosphonium bromide (3.85 g, 10.78 mmol) in THF (40 ml) was added 1M KHMDS in THF (10.78 ml, 10.78 mmol) at 0°C and stirred for 10min. To this yellow suspension was added a solution of 1-((3aR,3bS,4aS,5R,5aS)-5-(4chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl tetra hydrocyclopropa [3,4] cyclopenta[1,2-d][1,3]dioxol-3b(3aH)-yl)ethan-1-one (1.5 g, 4.31 mmol) in THF (20 ml) was added slowly at 0°C. The reaction mixture was stirred at 25°C for 1 h. The reaction mixture was quenched with a saturated aqueous ammonium chloride (50ml) and extracted with ethyl acetate (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 2.2g of crude compound. This residue was purified by combiflash (R_f200, Teledyne/lsco) instrument onto a redisep® R? column with gradient elution (0 to 20%) of ethyl acetate in petroleum ether to afford the title compound (0.7g, 46.9%) as a white solid. LCMS m/z = 346.03 (M+1; 100%).

(R)-((3aR,3bR,4aS,5R,5aS)-5-(4-Chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl )-2,2dimethyl tetrahydrocyclopropa[3,4]cyclopenta[1,2-d][1,3]dioxol-3b(3aH)-yl) (cyclopropyl)methanol

The title compound was synthesized by following an analogous reaction protocol as was described in the préparation of (S)-1-((3aR,3bR,4aS,5R,5aS)-5-(4-chloro-7H-pyrrolo[2,3d]pyrimidin-7-yl)-2,2-dimethyltetrahydrocyclopropa[3,4]cyclopenta[1,2-d][1,3]dioxol3b(3aH)-yl)ethan-1-ol. LCMS m/z = 375.91 (M+; 100%).

((3aR,3bS,4aS,5R,5aS)-5-(4-Chloro-7H-pyrrolG[2,3-d]pyrimidin-7-yl)-2,2-dimethyl tetra hydrocyclopropa[3,4]cyclopenta[1,2-d][1,3]dioxol-3b(3aH)-yl) (cyclopropyl) mëthânonê

104

The title compound was synthesized by following an analogous réaction protocol as was described in the préparation of 1-((3aR,3bS,4aS,5R,5aS)-5-(4-chloro-7H-pyrrolo[2,3djpyrimidin-7-yl)-2,2-dimethyï tetrahydrocyclopropa[3,4]cyciopenta[1,2-d][1,3]dioxol5 3b(3aH)-yl)ethan-1-one. ¹H NMR (400 MHz, DMSO-d6) δ 8.58 (s, 1H), 7.71 (d, J = 3.7

Hz, 1H), 6.72 (d, J = 3.6 Hz, 1H), 5.84 (dd, J- 7.3, 1.2 Hz, 1H), 5.21 (s, 1H), 4.79 (dd, J = 7.3,1.5 Hz, 1 H), 2.09 (s, 1 H), 2.07 - 2.01 (m, 1 H), 1.79 (ddd, J = 9.5, 5.3, 1.4 Hz, 1 H), 1.51 (t, J= 5.5 Hz, 1H), 1.48 (s, 3H), 1.21 (s, 3H), 0.96-0.74 (m, 4H); LCMS m/z = 373.97 (M+; 100%).

4-Ch!oro-7-f(3aR,3bR,4aS_î5R_î5aS)-3b-(1-cyclopropyivinyi)-2,2-dimethylhexahydro cyclopropa[3,4]cyclopenta[1,2-d][1,3]dioxol-5-yl)-7H-pyrrolo[2,3-d]pyrinnidine

The title compound was synthesized by following an analogous reaction protocol as was described in the préparation of 4-chloro-7-((3aR,3bS,4aS,5R,5aS)-2,2-dimethyl-3b15 vinylhexahydro cyciopropa[3,4] cyclopenta[1,2-d][1,3]dioxol-5-yl)-7H-pyrrolo[2,3d]pyrimidine. ¹H NMR (400 MHz, Chloroform-d) δ 8.67 (s, 1H), 7.29 (d, J = 3.6 Hz, 1H), 6.68 (d, J = 3.6 Hz, 1H), 5.37-5.35 (m, 2H), 4.98 (d, J = 0.8 Hz, 1H), 4.80 (s, 1 H), 4.59 (dd, J= 7.5, 1.6 Hz, 1 H), 2.04 (ddd, J = 9.3, 4.7, 1.6 Hz, 1 H), 1.67 (s, 2H), 1.42 (t, J = 5.1 Hz, 1H), 1.27 (s, 6H), 0.75 - 0.69 (m, 2H), 0,56 - 0.52 (m, 2H); LCMS m/z = 372.2 (M+: 20 100%).

4-ChÎoro-7-((3aR_J3bR,4aS,5R,5aS)-3b-((E)-2-îodoprop-1-en-1-yî)-2,2-dimethylhexa hydrocyclopropa[3,4]cyclopenta[1,2-d][1,3]dîoxol-5-yl)-7H-pyrrolo[2,3-d]pyrimidine.

105

To a suspension of (1-iodoethyl)triphenylphosphonium bromide (4.08 g, 7.49 mmol, synthesized by following same réaction protocol as was described in WO2004/9574, A1) in THF (20 ml)), was added NaHMDS (7.49 ml, 7.49 mmol) at -25°C. The resulting red coloured solution was stirred at -25^CC for 10min. A solution of (SâR.SbSAaS.SR.SaSj-ô(4-Chloro-7H-pyrroio[2_J3-d}pyrimidin-7-yl)-2,2-dimethyltetrahydro cyclopropa[3,4] cyclopenta [1,2-d][1,3Jdioxoie-3b(3aH><arbaldehyde (1.00 g, 3.00 mmol) in THF (20 ml) was added at -30°C and stirred for 30mins. The reaction mixture was quenched with sat aq.NH₄CI (20 ml) and extracted with ethyl acetate (20 ml). Layers were separated, organic layer was washed with brine (20 ml) and dried over anhydrous Na₂SO₄ The organic layer was filtered and concentrated in vacuo to give 1.04g of crude compound. This residue was purified by combiflash (Rf200, Teledyne/lsco) instrument onto a redisep® R_f column with gradient elution (0 to 10%) of ethyl acetate in petroleum ether to afford the title compound (0.79g, 55.9%) as an off-white solid. LCMS m/z - 471.80 (M+; 100%).

7-((3aR_!3bR_!4aS,5R_i5aS)-3b-(((tert-ButyIdjphenylsilyl)oxy)methyl)-2_ï2dimethylhexahydro cyciopropa[3,4]cyc!openta[1,2-d][1,3]dîoxol-5-yl)-4-ch!oro-6methy!-7H-pyrrolo[2^-d]pyrimidine

The title compound was synthesized by following an anaiogous reaction protocol as was described in the préparation of 1-((3aS,4R,6aR)-6-(((tert-butytdiphenylsilyl)oxy)methyl)2,2-dimethyl-4,6a-dîhydro-3aH-cyclopenta[dJ1,3]dioxoÎ-4-yf)-4-chloro-1H-pynOlo[3,2-c] pyridine. LCMS m/z = 587.82(M+: 100%).

((3aR,3bR,4aS,5R,5aS)-5-(4-Chtoro-6-methy!-7H-pyrrolo[2_J3-d]pyrirnidin-7-yl)-2,2dimethyltetrahydrocyclopropa[3_J4}cyclopenta[1,2-d][1,3ldioxol-3b(3aH)-yl)methanoI

The title compound was synthesized by following an anaiogous reaction protocol as was described in the préparation of ((3aR,6R,6aS)-6-(2-ch!oro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)2,2-dimethyî-6,6a-dihydro-3aH-cyclopenta[d][1,3jdioxoi-4-y1)rnethanoi. ¹H NMR (400 MHz,

106

DMSO-d6) δ 8.57 (s, 1 H), 6.48 (d, J = 1.1 Hz, 1 H), 5.34 - 5.25 (m, 1 H), 4.98 (s, 1 H), 4.90 (dt, J = 7.4, 1.3 Hz, 1H), 4.66 (t, J= 5.7 Hz, 1H), 3.65 (q, J= 5.8, 5.3 Hz, 2H), 2.57 (s, 3H), 1.54- 1.48 (m, 1H), 1.46 (s, 3H), 1.19 (s, 3H), 0.92 (ddd, J = 9.0, 5.0, 1.3 Hz, 1H), 0.85 (q, J= 4.7, 4.3 Hz, 1H); LCMS m/z = 350.03 (M+; 100%).

(3aR,3bS,4aS,5R,5aS)-5-(4-Chloro-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2dimethyltetrahydrocyclopropa[3,4]cyclopenta[1,2-d][1,3]dîoxole-3b(3aH)carbaldehyde

The title compound was synthesized by following an analogous reaction protocol as was described in the préparation of (3aS,4R,6aR)-2,2-dimethyl-4-(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxole-6-carbaldehyde. LCMS m/z = 348.03 (M+; 100%).

4-Chloro-7-((3aR,3bS,4aS,5R,5aS)-2,2-dimethyl-3b-vinylhexahydro cyclopropa[3,4] cycle penta[1,2-d][1,3]dioxol-5-yl)-6-methyl-7H-pyrrolo[2,3-d]pyrimidine

The title compound was synthesized by following an analogous reaction protocol as was described in the préparation of 4-chloro-7-((3aR,3bS,4aS,5R,5aS)-2,2-dimethyl-3bvinylhexahydro cycîopropa [3,4] cyclo penta[1,2-d][1,3]dioxol-5-yl)-7H-pyrrolo[2,3d]pyrimidine. ¹H NMR (400 MHz, Chloroform-d) δ 8.57 (s, 1H), 6.38 (q, J = 1.1 Hz, 1H), 5.88 (dd, J = 17.3, 10.6 Hz, 1H), 5.64 (dd, J = 7.2, 1.4 Hz, 1H), 5.34-5.23 (m, 1H), 5.10 (dd, J = 10.6, 1.1 Hz, 1H), 5.02 - 4.96 (m, 1H), 4.87 (s, 1H), 2.55 (s, 3H), 1.59 (s, 3H), 1.56-1.51 (m, 1H), 1.30 (s, 3H), 1.29- 1.26 (m, 1 H), 1.19 - 1.12 (m, 1H); LCMS m/z = 346.03 (M+; 100%).

7-((3aR,3bS,4aS,5R,5aS)-2,2-Dimethyl-3b-vinylhexahydrocyclopropa [3,4]cyclo penta [1,2-d][1,3]dioxol-5-yl)-6-methyl-7H-pyrrolo[2,3-d]pyrimîdin-4-amine

107

The title compound was synthesized by following an analogous reaction protocol as was described in the préparation of 7-((3aR,3bS,4aS,5R,5aS)-2,2-dimethyl-3b-vinylhexa hydrocyclopropa [3,4]cyclopenta [1,2-d][1,3]dioxol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4amine. ¹H NMR (400 MHz, DMSO-d6) δ 7.99 (s, 1H), 6.83 (s, 2H), 6.29 (d, J = 1.2 Hz, 1H), 5.87-5.74 (m, 2H), 5.44 (d, J = 7.3 Hz, 1H), 5.19 (dd, J = 17.4, 1.4 Hz, 1H), 5.02 (dd, J = 10.7, 1.3 Hz, 1H), 4.80 (d, J = 7.3 Hz, 1 H), 2.36 (s, 3H), 1.61 (dd, J = 9.0,5.3 Hz, 1H), 1.46 (s, 3H), 1.21 (s, 3H), 1.15-1.08 (m, 2H); LCMS m/z = 327.1 (M+1; 100%).

3-Bromo-7-(2-((3aS,4R,6aR)-4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2dimethyl -3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-6-yl)ethyl)-N-(4methoxybenzyl)quinolin-2-amine

4-Chloro-7-((3aS,4R,6aR)-2,2-dimethyl-6-vinyl-3a,6a-dihydro-4H-cyclo penta[d][1,3]dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine (0.25g, 0.787mmol) in 9-BBN (0.5 molar, 6.29ml, 3.15mmol) was heated at 70°C for2h under N₂ atmosphère. The reaction mixture was cooled to 25°C, then potassium phosphate tribasic (0.685g, 3.93mmol) in water (0.5ml) was added and stirred for 20mins. A solution of 3-bromo-7-iodo-N’(4methoxybenzyl)quinolin-2-amine (0.369g, 0.787mmol) in THF (1ml) was added, followed by PdCI₂(dppf) (0.058g, 0.079mmol). The resulting mixture was stirred at 70°C for 2h. The reaction mixture was diiuted with ethyl acetate (10 ml) and washed with water (10 ml). Layers were separated, organic layer was washed with brine (10 ml) and dried over anhydrous Na₂SO₄ The organic layer was filtered and concentrated in vacuo to give 0.35g of crude compound. This residue was purified by combiflash (R_f200, Teledyne/lsco) instrument onto a redisep® R_f column with gradient elution (0 to 15%) of ethyl acetate in petroleum ether to afford the title compound (0.25g, 48.1%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.65 (s, 1H), 8.37 (s, 1H), 7.60 (d, J = 8.2 Hz, 1H), 7.45 (s, 1H), 7.33 (d, J = 8.5 Hz, 2H), 7.28-7.14 (m, 2H), 6.98 (d, J = 3.7 Hz, 1H), 6.87-6.75 (m, 2H), 6.36 (d, J = 3.6 Hz, 1H), 5.66 (s, 1 H), 5.52 (s, 1H), 5.35 (d, J = 5,7 Hz, 1H), 4.63 (d, J = 6.0

108

Hz, 2H), 4.49 (d, J = 5.7 Hz, 1H), 3.66 (s, 3H), 3.07 - 2.97 (m, 2H), 2.65 - 2.59 (m, 2H), 1.39 (s, 3H), 1.28 (s, 3H).LCMS m/z= 658.89, 661.64 (M-2, M+1, 100%).

Intermediates in table-5 were synthesized by an analogous reaction protocol as was used for the préparation of 3-bromo-7-(2-((3aS,4R,6aR)-4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin7-yl)-2,2-dimethyl -3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-6-yl)ethyl)-N-(4-methoxy benzyl)quinolin-2-amine using the appropriate starting materials.

Table-5:

Structure & IUPAC name-	Intermediates used	¹H NMR & LCMS data
Ν' ^N i H Ο_χΟ 7-(2-((3aS,4R,6aR)-4-(4-chloro-7Hpyrrolo[2,3-djpyrimidin-7-yl)-2,2dimethyl-3a,6a-dihydro-4H- cyclopenta[d][1,3]dioxol-6-yl)ethyl)N-methylquïnolin-2-amine	7-Bromo-N-methyl quinolin-2amine and 4-Chloro-7-((3aS,4R, 6aR)-2,2-dimethyl-6-vinyl3a,6a-dihydro-4Hcyclopenta[d][1,3] dioxol-4-yl)7H-pyrrolo[2,3-d]pyrimidine	LCMS m/z= 476.05 (M+, 100%)
F .· _; . ,N 3-Bromo-7-(2-((3aS,4R,6aR)-4-(4- chloro-5-fluoro-7H-pyrrolo[2,3d]pyrimidin-7-yl)-2,2-dimethyl-3a,6a- dihydro-4H-cyclopenta[d] [1,3 ]dioxol-6-yl)ethyl)-N-(4- methoxybenzyl) quino lin-2-amine	4-Chloro-7-((3aS,4R ,6aR)-2,2dimethyl-6-vinyl-4,6a-dihydro3aH-cyc!openta [d] [1,3] dioxol4-yl)-5-fluoro-7H-pyrrolo[2,3d]pyrimidine and 3-Bromo-7iodo-N-(4methoxybenzyl)quinoiin-2amine	LCMS m/z = 679.85 (M+1, 100%)
^FsAA^/ Vl /Ά\* U AA⁷ Cj t « H₂N' ⁿ 4 _λ °Z^CA Chemical Formula: C25H23CIFN5O2	7-Bromo-3-fluoro quinolin-2amine and 4-Chloro-7-((3aS,4R, 6aR)-2,2-dimethyl-6-vinyl3a,6a-dihydro-4H-	¹H NMR (400 MHz, DMSO-de) δ 8.65 (s, 1H), 7.81 (d, J = 11.9 Hz,1H), 7.60 (d, J= 8.2 Hz, 1H), 7.41 (d, J= 1.6

109

7-(2-((3aS,4R,6aR)-4-(4-chloro-7Hpyrrolo[2,3-d]pyrimidin-7-yl)-2,2dimethyl-3a,6a-dihydro-4Hcyclopenta[d][1,3]dioxol-6-yl)ethyl)3-fluoroquinolin-2-amine	cyclopenta[d][1,3] dioxol-4-yi)- 7H-pyrrolo[2,3-d] pyrimidine	Hz, 1H), 7.19 (dd, J = 8.2, 1.6 Hz, 1H), 6.95 (d, J = 3.7 Hz, 1H), 6.84 - 6.67 (m, 2H), 6.41 (d,J= 3.7 Hz, 1H), 5.66 (s, 1H), 5.52 (s, 1H), 5.34 (d, J =5.7 Hz, 1H), 4.51 (dd, J= 15.1, 5.6 Hz, 1H), 3.18-2.98 (m, 2H), 2.80 - 2.56 (m, 2H), 1.39 (s, 3H), 1.28 (s„ 3H). LCMS m/z = 480.2 (M+, 100%)
pmb~_n ^zn ;—'· _n^n h /\ 3-Bromo-7-(2-((3aS,4R,6aR)-4-(4chloro-7H-pyrrolo[2,3-d]pyrimidin-7yl)-2,2-dimethyl-3a,6a-dihydro-4Hcyclopenta[d][1,3]dioxoÎ-6yl)propyî)N-(4-methoxybenzyI)quinolin-2amine	4-Chloro-7-((3aS,4R, 6aR)-2,2dimethyl-6-(prop-1-en-2-yl)3a,6a-d!hydro-4H-cyc!openta[d] [1,3] dioxol-4-yl)-7H-pyrrolo[2,3d] pyrimidine and 3-Bromo-7iodo-N-(4methoxybenzyI)quinolin-2amine	LCMS m/z = 676.47 (M+1, 100%)
'i____/ γ tt ^N - · H °W° /\ 1- fr> /ZQ«O AO A IA 7LJ [ζ.-μύάΟ,+Λ,υοΓι)-'t-(t-vniui m- / npyrrolo[2,3-d]pyrimidin-7-yl)-2,2- dimethyl-3a,6a-dihydro-4Hcyclopenta[d][1,3]dioxol-6-yl)ethyl)N-cyclobutylquinolin-2-amine	4-Chloro-7-((3aS,4R,6aR)-2,2dimethyl-6-vinyi-3a,6a-dihydro4H-cyclopenta[d][1,3] dioxol-4yl)-7H-pyrrolo[2,3-d]pyrimidine and 7-Bromo-N- cyclobutylquinolin-2-amine	¹H NMR (400 MHz, Chloroform-d) δ 8.65 (s, 1 H), 7.89 (d, J=8.9Hz, 1H), 7.60 - 7.51 (m, 2H), 7.16 (dd, J = 8.1, 1.7 Hz, 1H), 6.65 (d, J= 8.9 Hz, 1H), 6.46 (d, J = 3.7 Hz, 1H), 6.25 (d, J = 3.7 Hz, 1H), 5.77 (s, 1H), 5.44 (t, J= 1.7 Hz, 1H), 5.32 - 5.28 (m, 2H), 4.48 - 4.41 (m,

110

		2H), 3.22 - 3.02 (m, 2H), 2.83 - 2.77 (m, 2H), 2.58 - 2.46 (m, 2H), 2.07 - 1.96 (m, 2H), 1.85 (ddd, J= 10.6, 9.0, 6.4 Hz, 2H), 1.51 (s, 3H), 1.38 (s, 3H); LCmS m/z =515.19 (M1, 100%)
\ \ r ‘ « An - - n^ⁿ H₂N Οχ/θ A 3- Chloro-7-(2-((3aS,4R,6aR)-2,2dimethyl-4-(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)-3a,6a-dihydro-4Hcyclopenta[d][1,3]dioxol-6yl)ethyl)quinolin-2-amine	7-((3aS,4R,6aR)-2,2-dimethyl6-vinyl-3a,6a -dihydro-4H-cyclo penta[d][1,3]dioxol-4-yl)-4methyl-7H-pyrrolo[2,3-d] pyrimidîne & 7-bromo-3-chioro quinolin-2-amine	LCMS m/z= 476.36 (M+, 60%)
An - - ^HA 3-Chloro-7-(2-((3aS,4R,6aR)-4-(4- chloro-7H-pyrrolo[2,3-d]pyrimidin-7yi)-2,2-dimethyi-3a,6a-dihydro-4Hcyclopenta[d][1,3]dioxol-6yi)propyl)quinolin-2-amine	4-Chloro-7-((3aS,4R, 6aR)-2,2dimethyl-6-(prop-1-en-2-yl)-3a, 6a-dihydro-4H-cyclo penta[d][1,3]dioxol-4-yl)-7Hpyrrolo[2,3-d] pyrimidîne & 7bromo-3-chloro quinolin-2- amine	LCMS m/z= 510.2 (M+, 100%)
Boc	F MA Soc and 4-chloro-7-((3aS,4R ,6aR)-2,2d imethy l-6-vi ny l-3a,6a-d i hyd ro4H-cyclopenta[d] [1,3] dioxol-4yï)-7H-pyrrolo[2,3-d] pyrimidîne	¹H NMR (400 MHz, Chioroform-d) δ 8.76 8.62 (m, 2H), 7.76 (s, 4U\ “7 ne /-4-4 1 — A in), ! VUU, U — IU.4, 1.5 Hz, 1H), 6.84 (d, J = 3.7 Hz, 1H), 6.54 (d,J = 3.6 Hz, 1H), 5.81 (s, 1H), 5.55 (s, 1H), 5.37-

111

		5.29 (m, 1H), 4.58 (d, J = 5.7 Hz, 1H), 3.25 3.12 (m, 2H), 2.89 2.72 (m, 2H), 1.51 (s, 3H), 1.45 (s, 9H), 1.43 (s, 9H), 1.38 (s, 3H); LCMS m/z = 760.41 (M+1, 40%).
F Β=-Λ“ d b ^N«> Boc /\^	F Β\ζΐΑχ Boc^ .A. <?Α. N N^^Br Bog and 7-((3aS,4R,6aR)-2,2-dimethyl- 6-viny!-3a,6a -dihydro-4H-cyclo penta[d][1,3]dioxol-4-yl)-4methy!-7H-pyrrolo[2,3d]pyrimidine	¹H NMR (400 MHz, DMSO-de) δ 8.88 (s, 1H), 8.64 (s, 1H), 7.85 (s, 1H), 7.63 (dd, J = 11.0, 1.5 Hz, 1H), 6.80 (d, J = 3.6 Hz, 1H), 6.48 (d, J =3.7 Hz, 1H), 5.65 (s, 1H), 5.56 (s, 1H), 5.37 (d, J =5.6 Hz, 1H), 4.44 (d, J=5.7Hz, 1H), 3.22 - 3.13 (m, 2H), 2.78 - 2.66 (m, 2H), 2.61 (s, 3H), 1.38 (s, 9H), 1.35 (s, 3H), 1.33 (s, 9H), 1.27 (s, 3H); LCMS m/z = 738.61 (M+, 90%), 740.61 (M+2, 100%).
O A Z \^”'O -M / Z A // v-A. o / Z'^ >- ! CÛ o O CÛ	4-Chloro-7-((3aS,4R, 6aR)-2,2dimethyl-6-(prop-1-en-2-yl)-3a_i6a-dihydro-4H-cyclo penta[d][1,3]dioxol-4-yl)-7Hpyrrolo[2,3-d] pyrimidine and F Boc _s .A -A ^A N N Br Boc	LCMS m/z = 796.20 (M+23, 60%).

112

N W y 4-Chloro-7-((3aS,4R,6aR)-2,2dimethyl-6-(2-(3-methylimidazo[1,2a]pyridin-7-yl)ethyî)-3a,6a-dihydro4H-cyclopenta[d][1,3]dioxol-4-yl)7H-pyrrolo[2,3-d]pyrimidine

4-Chloro-1-((3aS,4R, 6aR)-2,2dimethyl-6-vinyl-4,6a-dihydro3aH-cyclopenta[d] [1,3]dioxol-4yl)-1H-pyrrolo[3,2-c]pyrid ine & 7-Bromo-3-methylimidazo[1,2a]pyridine

LCMS m/z=450.04 (M+, 100%)

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

4-Chloro-7-((3aS,4R,6aR)-2,2-dimethyl-6-vinyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol4-yl)-7H-pyrrolo[2,3-d]pyrimidine (0.242g, 0.762mmol) in 9-BBN (0.5 molar, 4.36ml,

2.178mmol) was heated at 50°C for 1h under N₂ atmosphère. The reaction mixture was cooled to 25°C, then potassium phosphate tribasic (0.578g, 2.72mmol) in water (0.5ml) was added and stirred for 20 mins. A solution of 7-bromo-3-chloro-5-fluoroquinoiin-210 amine (0.150g, 0.544mmol) in THF (0.5mî) was added, followed by dichloro[1,T-bis(di-tbutylphosphino)ferrocene]palladium(ll) (0.035g, 0.054mmol). The resulting mixture was stirred at 50°C for 6h. The reaction mixture was diluted with water (10 ml) and extracted with ethyl acetate (10 ml). Layers were separated, organic layer was washed with brine (10 ml) and dried over anhydrous Na₂SO4 The organic layer was filtered and concentrated in vacuo to give 0.345g of crude compound. This residue was purified by combiflash (Rf200, Teledyne/lsco) instrument onto a redisep® Rrcolumn with gradient elution (0 to 35%) of ethyl acetate in petroleum etherto afford the title compound (0.16g, 57.5%) as an off-white solid. ¹H NMR (400 MHz, DMSO-d6) δ 8.64 (s, 1H), 8.18 (s, 1H), 7.25 (s, 1H), 7.09-6.96 (m, 4H), 6.44 (d, J = 3.6 Hz, 1 H), 5.67 (s, 1 H), 5.56-5.51 (m, 1H), 5.35 (d, J = 5.7 Hz, 1H),

4.52 (d, J = 5.7 Hz, 1H), 3.05 - 2.98 (m, 2H), 2.74 - 2.56 (m, 2H), 1.38 (s, 3H), 1.28 (s,

3H); LCMS m/z = 514.2 (M+, 100%).

113

Intermediates in table-6 were synthesized by an analogous reaction protocol as was used for the préparation of 3-chloro-7-(2-((3aS,4R,6aR)-4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin7-yl)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-6-yl)ethyl)-5-fluoroquinolin-2amine using the appropriate starting materials.

Table-6:

Structure & IUPAC name	Intermecliates used	¹H NMR & LCMS data
F _ c CM¹ M A 3-Chloro-7-(2-((3aS,4R,6aR)-4(4-chloro-7H-pyrrolo[2,3d]pyrimidin-7-yl)-2,2-dimethyl3a,6a-dihydro-4Hcyclopenta[d][1,3]dioxol-6yl)ethyl)-6-fluoroquinolin-2-amine	4-Chloro-7-((3aS,4R, 6aR)-2,2-dimethyl-6vinyl-3a,6a-dihydro4H-cyclopenta [d][1,3] dioxol-4-yl)-7Hpyrrolo[2,3-d] pyrimidine and 7Bromo-3-chloro-6fluoroquino!in-2amine	¹H NMR (400 MHz, DMSOd6) δ 8.65 (s, 1H), 8.18 (s, 1H), 7.56 - 7.44 (m, 2H), 7.14 (d, 7= 3.7 Hz, 1H),6.73 (s, 2H), 6.50 (d, 7 = 3.7 Hz, 1H), 5.69 (s, 1H), 5.60 5.52 (m, 1 H), 5.42-5.31 (m, 1H), 4.53 (dd, 7 = 5.7, 2.8 Hz, 1 H), 3.08-3.01 (m, 2H), 2.66-2.62 (m, 2H), 1.39 (s, 3H). 1.28 (s, 3H); LCMS m/z =515 (M+1, 100%).
H Ka A.A Λ 3-3-Ch!oro-7-(2-((3aS,4R,6aR)-4(4-chloro-7H-pymo!o[2,3d]pyrimidin-7-yl)-2,2-dimethyl3a,6a-dihydro-4Hcyclopenta[d][1,3]dioxol-6yl)ethyl)quinolin-2-amine.	4-Chloro-7-((3aS,4R ,6aR)-2,2-dimethyl-6vinyi-3a,6a-dihydro4H-cyclopenta[d] [1,3] dioxol-4-yl)-7Hpyrrolo[2,3-d] pyrimidine and 7Bromo-3chloroquinolin-2amine	¹H NMR (400 MHz, DMSOd6) δ 8.65 (s, 1H), 8.19 (s, 1.H), 7.61 (d, J = 8.2 Hz, 1H), 7.40 (s, 1H), 7.19 (dd, J = 8.1, 1.7 Hz, 1 H), 6.96 (d, J = 3.6 Hz, 1H), 6.72 (s, 2H), 6.41 (d, J = 3.6 Hz, 1 H), 5.66 (s, 1 H), 5.52 (s, 1 H), 5.34 (d, J = 5.7 Hz, 1H), 4.49 (d, J = 5.6 Hz, 1H), 3.10-2.96 (m, 2H), 2.79 - 2.60 (m, 2H), 1.38 (s, 3H), 1.28 (s, 3H); LCMS m/z =496.05 (M+, 100%)
F 'AA'¹ ο o A 3-Chloro-7-(2-((3aS,4R,6aR)-4- (4-chloro-7H-pyrrolo[2,3-	4-ChIoro-7((3aS,4R,6aR)-2,2dimethyl-6-(prop-1en-2-yl)-3a,6adihydro-4H- cycïopenta[dj[1,3]diox	¹H NMR (400 MHz, DMSOd₆) δ 8.64 (d, 7 = 6.1 Hz, 1H), 8.22 - 8.16 (m, 1H), 7.29 - 7.14 (m, 2H), 7.00 6.95 (m, 3H), 6.56 (d, 7= 3.6 Hz, 1H), 5.67 (d, 7= 14.7

115

d]pyrimidin-7-yl)-2,2-dimethyl3a,6a-dihydro-4Hcyclopenta[d][1,3]dioxol-6yl)propyl)-5-fluoroquinolin-2amine	ol-4-yl)-7H- pyrrolo[2,3d]pyrimidine and 7Bromo-3-chloro-5fluoroquinolin-2amine	Hz, 1H), 5.57 (s, 1H), 5.405.34 (m, 1H), 4.54 (dd, J = 15.1, 5.7 Hz, 1H), 3.04 (q, J = 9.6, 7.8 Hz, 1H), 2.87 (s, 2H), 1.30 (d, J=9.7 Hz, 3H), 1.19 (d, 6H); LCMS m/z =528.32 (M+, 100%)
^F\ H₂N ^N A X X / \ 3-Chloro-7-(2-((3aS,4R,6aR)-2,2- dimethyl-4-(4-methyl-7H- pyrroio[2,3-d]pyrimidin-7-yl)- 3a,6a-dihydro-4H- cyclopenta[d][1,3]dioxol-6- yl)ethyl)-5-fluoroquinolin-2-amine	7-((3aS,4R,6aR)-2,2Dimethyl-6-vinyl3a,6a-dihydro-4Hcyclopentafd] [1,3] dioxol-4-yl)-4-methyl 7H-pyrrolo[2,3djpyrimidine and 7Bromo-3-chloro-5fluoroquinolin-2amine	¹H NMR (400 MHz, Chloroform-d) δ 8.83 (s, 1H), 8.22 (d, J=0.8 Hz, 1H), 7.34 (s, 1H), 6.92 (dd, J = 10.6, 1.5 Hz, 1H), 6.68 (d, J = 3.6 Hz, 1H), 6.38 (d, J = 3.6 Hz, 1H), 5.80 (s, 1H), 5.52-5.47 (m, 2H), 4.55 (d, J = 5.7 Hz, 1H), 3.12-3.06 (m, 2H), 2.77 - 2.74 (m, 2H), 2.74 (s, 3H), 1.51 (s, 3H), 1.38 (s, 3H); LCMS m/z =494.3 (M+, 80%)
.../ ν'' ;—( m₂N ô _ô Y X Cl 3-Chloro-7-(2-((3aS,4R,6aR)-4(2-chloro-7H-pyrrolo[2,3d]pyrimidin-7-y!)-2,2-dîmethyl3a,6a-dihydro-4Hcyclopenta[d][1,3]dioxol-6yl)ethyl)quinolin-2-amine	2-Chloro-7((3aS,4R,6aR)-2,2dimethyl-6-vinyi-4,6adihydro-3aHcyclopenta[d][1,3]diox ol-4-yl)-7Hpyrrolo[2,3- d]pyrimidine and 7Bromo-3chloroquinolin-2amine	¹H NMR (400 MHz, Chioroform-d) δ 8.76 (s, 1H), 7.98 (s, 1H), 7.55 (d, J = 8.2 Hz, 2H), 7.22 (dd, J = 8.1, 1.7 Hz, 1 H), 6.52 (d, J = 3.6 Hz, 1 H), 6.28 (d, J=3.7 Hz, 1H), 5.75 (s, 1H), 5.42 (d, J= 2.4 Hz, 1H), 5.34 (d, J = 10.9 Hz, 3H), 4.52 (d, J = 5.6 Hz, 1H), 3.18 - 3.07 (m,2H), 2.81-2.76 (m, 2H), 1.49 (s, 3H), 1.38 (s, 3H); LCMS m/z =496.24 (M+, 60%)

116

'i k \_f γ » H₂N ^N H θ-ν⁰/ \ 3-Chloro-7-(2-((3aS,4R,6aR)-2,2dimethyl-4-(4-methyl-7Hpyrrolo[2,3-d]pyrimidin-7-yl)3a,6a-dihydro-4Hcyclopenta[d][1,3]dioxol-6yi)propyl)-5-fluoroquinolin-2amine	7-((3aS,4R,6aR)-2,2Dimethyl-6-(prop-1en-2-yl)-4,6a-dihydro 3aH-cyclo penta[d] [1,3]dioxol-4-yl)-4methyl-7H-pyrrolo [2,3-d]pyrimidine and 7-Bromo-3-chloro-5fluoroquinolin-2amine	LCMS m/z=508.31 (M+, 100%)
F / \ 3-Chloro-7-(2-((3aS,4R,6aR)-2,2dimethyl-4-(7H-pyrrolo[2,3d]pyrimidin-7-yl)-3a,6a-dihydro4H-cyclopenta[d][1,3]dioxol-6yl)ethyl)-5-fluoroquinoÎin-2-amine	7-((3aS,4R, 6aR)-2,2dimethyl-6-vinyl3a,6a-dihydro-4Hcyclopenta[d][1,3]diox ol-4-yl)-7Hpyrrolo[2,3djpyrimidine and 7Bromo-3-chloro-5fluoroquinolin-2amine	¹H NMR (400 MHz, Chioroform-d) δ 8.93 (d, J = 10.4 Hz, 2H), 8.24 (s, 1H), 7.37 (s, 1H), 6.94 (dd, J = 10.8, 1.4 Hz, 1H), 6.71 (d, J = 3.6 Hz, 1H), 6.37 (d, J = 3.6 Hz, 1H), 5.83 (s, 1H), 5.72 (s, 2H), 5.50 (s, 1H), 5.31 (d, J = 5.7 Hz, 1 H), 4.56 (d, J = 5.7 Hz, 1H), 3.16 3.04 (m,2H), 2.78-2.76 (m, 2H), 1.52 (s, 3H), 1.38 (s, 3H); LCMS m/z=480.2 (M+, 70%)
F »/- >M· 3-Chloro-5-fluoro-7-(2- ((3aS,4R,6aR)-4-(4-isopropyl-7Hpyrrolo[2,3-d]pyrimidin-7-yl)-2,2dimethyl-3a,6a-dihydro-4H-	7-((3aS,4R,6aR)-2,2dimethyl-6-vinyl3a,6a-dihydro-4Hcyciopenta[d][1,3]dïox ol-4-yl)-4-isopropyl7H-pyrrolo[2,3d]pyrimidine & 7- Bromo-3-chloro-5-	LCMS m/z= 522.32 (M+, 100%)

117

cyclopenta[d][1,3] dioxol-6- yl)ethyl)quinolin-2-amtne	fluoroquinoiin-2amine
H,N ^N i °x° 3-Chloro-7-(2-((3aS,4R,6aR)-4- (4-ethyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)-2,2-dimethyl- 3a, 6a-dihyd ro-4 H- cyclopenta[d][1,3]dioxol-6- yl)ethyl)-5-fluoroquinolin-2-amine	7-((3aS,4R,6aR)-2,2dimethyl-6-vinyl3a,6a-dihydro-4Hcyclopenta[d][1,3]diox ol-4-yl)-4-ethyl-7Hpyrrolo[2,3d]pyrimidine & 7- Bromo-3-chloro-5fluoroquinolin-2amine	¹H NMR (400 MHz, DMSOd6) δ 8.68 (s, 1H), 8.18 (s, 1H), 7.25 (s, 1H), 7.05 (dd, J = 11.0, 1.4 Hz, 1H), 6.96 (s, 2H), 6.85 (d, J=3.6 Hz, 1H), 6.49 (d, J=3.6 Hz, 1 H), 5.66 (s, 1 H), 5.52 (s, 1H), 5.34 (d, J = 5.7 Hz, 1H), 4.46 (d, J = 5.6 Hz, 1H), 3.05-2.93 (m, 4H), 2.66 - 2.59 (m, 2H), 1.38 (s, 3H), 1.31 - 1.24 (m, 6H); LCMS m/z =508.31 (M+, 100%)
L H .N ^? M 0^.0 3-Chloro-7-(2-((3aS,4R,6aR)-2,2dimethyl-4-(4-(1-methyl-1 Hpyrazol-4-yl)-7H-pyrrolo[2,3-d] pyrimidin-7-yl)-3a,6a-dihydro-4Hcyclopenta[d] [1,3]dioxol-6- yl)ethyl)-5-fluoroquînolin-2-amine	7-((3aS,4R,6aR)-2,2dimethyl-6-vinyl3a,6a-dihydro-4Hcyclopenta[d][1,3]diox ol-4-yi)-4-(1 -methyl1 H-pyrazol-4-yl)-7Hpyrrolo[2,3d]pyrimidine & 7- Bromo-3-chloro-5fluoroquinolin-2amine	¹H NMR (400 MHz, DMSOd6) δ 8.70 (s, 1 H), 8.60 (s, 1H), 8.23 (s, 1H), 8.19 (s, 1H), 7.27 (s, 1H), 7.10 6.95 (m, 4H), 6.79 (d, J = 3.7 Hz, 1H), 5.70 (s, 1H), 5.55 (s, 1H), 5.36 (d, J = 5.6 Hz, 1 H), 4.50 (d, J = 5.7 Hz, 1H), 3.97 (s, 3H), 3.10-2.94 (m, 2H), 2.71 - 2.60 (m, 2H), 1.39 (s, 3H), 1.29 (s, 3H); LCMS m/z =560.33 (M+, 100%)
X 3-Chloro-7-(2-((3aS,4R,6aR)-4-	4-chloro-7«3aS,4R,6aR)-2,2- dimethyl-6-vinyl- 3a,6a-dihydro-4Hcyclopenta[d][1,3]diox	¹H NMR (400 MHz, DMSOde) δ 8.65 (s, 1H), 8.26 (d, J = 1.6 Hz, 1H), 7.62 (s, 1H), 7.45 (d, J=8.3 Hz, 1 H), 7.27 -7.15(m, 1H), 7.03 (s, 2H),

118

(4-chloro-7H-pyrrolo[2,3d]pyrimidin-7-yl)-2,2-dimethyl3a,6a-dihydro-4Hcyclopenta[d][1,3]dioxol-6yl)ethyl)-8-fluoroquinolin-2-amine	ol-4-yl)-7Hpyrrolo[2,3d]pyrimidine & 7- Bromo-3-chloro-8fluoroquinolin-2amine	6.51 (d, J=3.7Hz, 1H), 5.69 (s, 1 H), 5.55 (s, 1 H), 5.36 (d, J= 5.7 Hz, 1H), 4.54 (d, J = 5.7 Hz, 1H), 3.12 - 3.0 (m, 2H), 2.66 - 2.58 (m, 2H), 1.29 (s, 3H), 1.24 (s, 3H); LCMS m/z =515.57 (M+1, 40%)
l N M A 4-Chloro-7-((3aS,4R,6aR)-6-(2(3,3-dimethyl-2-(methylthio)-3Hindo!-6-y!)ethy!)-2,2-dimethyl3a,6a-dihydro-4H- cyclopenta[d][1,3]dioxol-4-yl)-7Hpyrrolo[2,3-d]pyrimidine	4-chloro-7((3aS,4R,6aR)-2,2dimethyl-6-vinyl3a,6a-dihydro-4Hcyclopenta[d][1,3]diox ol-4-yl)-7H- pyrrolo[2,3d]pyrimidine & 6- Bromo-3,3-dimet‘nyl2-(methylthio)-3Hindole	¹H NMR (400 MHz, DMSOd₆) δ 8.67 (s, 1H), 7.42 7.28 (m,2H), 7.17-6.99 (m, 2H), 6.51 (d, J =3.6 Hz, 1H), 5.68 (s, 1H), 5.53 (s, 1H), 5.36 (d, J=5.7Hz, 1 H), 4.52 (d, J = 5.6 Hz, 1H), 3.07 2.85 (m, 2H), 2.71 -2.56 (m, 5H), 1.38 (s, 3H), 1.29 (d, J = 3.4 Hz, 9H); LCMS m/z =510.31 (M+1, 60%)
A'^ Ν^'^Ν 6-(2-((3aS,4R,6aR)-4-(4-chloro7H-pyrro!o[2,3-d]pyrimidin-7-yl)2,2-dimethyl-3a,6a-dihydro-4Hcyclopenta[d][1,3]dioxol-6yi)ethyÎ)-2'- (methylthio)spiro(cyclobutane- 1,3'-indole]	4-Chloro-1((3aS,4R,6aR)-2,2dimethyl-6-vinyl-4,6adihydro-3aHcyclopenta[d][1,3]diox o!-4-y!)-1Hpyrrolo[3,2-c]pyridine & 6'-Bromo-2'- (methylthio)spiro[cycl obutane-1,3'-indole]	¹H NMR (400 MHz, DMSOd₆) δ 8.66 (s, 1H), 7.61 (d, J = 7.5 Hz, 1H), 7.31 (d, J = 1.4 Hz, 1H), 7.09 (dd, J = 7.6, 1.5 Hz, 1 H), 7.01 (d, J = 3.7 Hz, 1H), 6.46 (d, J= 3.6 Hz, 1H), 5.67 (s, 1H), 5.53 (s, 1H), 5.35 (d, J = 5.6 Hz, 1H), 4.52 (d,J= 5.6 Hz, 1H), 3.02 - 2.86 (m, 2H), 2.69 2.56 (m, 5H), 2.48 - 2.39 (m, 4H), 2.39 - 2.18 (m, 2H), 1.39 (s, 3H), 1.29 (s, 3H);

119

		LCMS m/z =521.19 (M+, 30%)
F H N' ^h ₂N q O / \ 3-Chioro-5-fluoro-7-(2((3aS,4R,6aR)-2,2,6a-trimethyl-4(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)-3a,6a-dihydro4H-cyclopenta[d][1,3]dioxol-6yl)propyl)quinolin-2-amine	4-methyl-7((3aS,4R,6aR)2,2,6a-trimethyl-6(prop-1-en-2-yl)3a,6a-dihydro-4Hcyclopenta[d][1,3]diox ol-4-yl)-7Hpyrrolo[2,3d]pyrimidine and 7bromo-3-chloro-5fluoroquinolin-2amine	LCMS m/z =522.32 (M+, 100%)
^F\ __ A \ / V « Z^N - ' HîN ô 0 3-Chloro-7-(2-((3aS,4R,6aR)-4(4-cyclopropyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)-2,2-dimethyl3a, 6a-d i hy d ro-4 H- cyclopenta[d][1,3]dioxol-6- yl)ethyl)-5-fluoroquinoiin-2-amine	4-Cyclopropyl-7((3aS,4R, 6aR)-2,2dimethyl-6-vinyl3a,6a-dihydro-4Hcyclopenta[d][1,3] dioxol-4-yl)-7Hpyrroio[2,3d]pyrimidine and 7Bromo-3-chloro-5fluoroquinolin-2amine	LCMS m/z=520.14 (M+, 100%)
F θ' 'fN H,A ^N - °\x° A 3- Chloro-7-(2-((3aS,4R,6aR)-4-(4-	4-Ch!oro-7((3aS,4R,6aR)2,2,6a-trimethy!-6vinyl-3a,6a-dihydro4H-cyclopenta[d]	¹H NMR (400 MHz, Chloroform-d) δ 8.72 (s, 1 H), 8.22 (d, J=0.8 Hz, 1H), 7.37 (s, 1H), 6.99 (d, J =3.6 Hz, 1 H), 6.96-6.89 (m, 1H),

120

chloro-7H-pyrrolo[2,3-d]pyrimidin7-yl)-2,2,6a-trimethyl-3a,6adihydro-4H- cyciopenta[d][1,3]dioxol-6- yl)ethyl)-5-fluoroquinolin-2-amine	[1,3]dioxol-4-yl)-7Hpyrrolo[2,3d]pyrimidine & 7-Bromo-3-chloro5-fluoroquinolin-2amine	6.55 (d, J=3.7 Hz, 1 H), 5.76 (s, 1H), 5.58-5.46 (m, 3H), 4.18 - 4.13 (m, 1H), 3.20 3.05 (m, 2H), 2.77-2.62 (m, 2H), 1.50 (s, 3H), 1.44 (s, 3H), 1.42 (s, 3H); LCMS m/z =528.19 (M+, 100%)
F -H. h₂n ô O A 3-Chloro-5-fluoro-7-(2((3aS,4R,6aR)-2,2,6a-trimethyl-4(4-methyl-7H-pyrrolo[2,3-d]pyri midin-7-yl)-3a,6a-dihydro-4Hcyclopenta [d][1,3]dioxol-6- yl)ethyl)quinolin-2-amine	4-Methyl-7((3aS,4R,6aR)2,2,6a-trimethyl-6vinyl-3a,6a-dihydro4H-cyclopenta[d][1,3 ]dioxol-4-yl)-7Hpyrrolo[2,3d]pyrimidine & 7- Bromo-3-chloro-5fiuoroquinolin-2amine	¹H NMR (400 MHz, DMSOcfe) δ 8.68 (s, 1H), 8.18 (s, 1H), 7.27 (s, 1H), 7.12 7.03 (m, 2H), 6.96 (s, 2H), 6.66-6.51 (m, 1H), 5.64 (s, 1H), 5.58 (s, 1H), 4.04 (s, 1H), 3.14 - 3.02 (m, 2H), 2.74-2.59 (m, 5H), 1.39 (s, 3H), 1.30 (d, J =3.5 Hz, 6H) ; LCMS m/z =508.31 (M+, 100%)
Cl \ V A·' \ / । ii hAⁿ ci °x° 3,5-Dichloro-7-(2-((3aS,4R,6aR)4-(4-ch loro-7 H-py rrolo[2,3d]pyrimidin-7-yl)-2,2-dimethyl3a,6a-dihydro-4H- cyclopenta[d][1,3]dioxoI-6yl)ethyl)quinolin-2-amine	4-chloro-7- ((3aS,4R,6aR)-2,2dimethyl-6-vinyl3a,6a-dihydro-4Hcyclopenta[d][1,3]diox ol-4-yl)-7H- pyrrolo[2,3- d]pyrimidine & 3,5Dichloro-7-iodoquin olin-2-amine	LCMS m/z=532.19 (M+1, 90%)

121

F h₂n ⁿ 3-Chloro-7-(2-((3aS,4R,6aR)-4(4-chloro-7H-pyrrolo[2,3- d]pyrimidin-7-yl)-2,2,6a-trimethyl3a,6a-dihydro-4Hcyclopenta[d][1 ,3]δίοχο1-6yl)propyl)-5-fluoroquinolin-2amine	4-chloro-7((3aS,4R,6aR)2,2,6a-trimethyl-6(prop-1-en-2-yl)3a ,6a-d i hyd ro-4 Hcyclopenta[d][1,3]diox ol-4-yl)-7Hpyrrolo[2,3d]pyrimidine & 7- bromo-3-chloro-5fluoroquinolin-2amine	¹H NMR (400 MHz, DMSOd₆) δ 8.66 (s, 1H), 8.14 (s, 1H), 7.25 (s, 1H), 7.07 (dd, J = 11.1, 1.3 Hz, 1H), 7.01 (s, 2H),6.69 (d, J=3.7Hz, 1H), 6.35 (d, J =3.7 Hz, 1H), 5.77 (d, J =2.7 Hz, 1H), 5.60 (d, J = 2.7 Hz, 1 H), 4.01 (s, 1H), 3.10-2.93 (m, 2H), 2.92 2.80 (m, 1H), 1.37 (s, 3H), 1.27 (s, 3H), 1.25 (d, J =6.0 Hz, 3H), 1.11 (s, 3H). LCMS m/z =542.20 (M+, 100%)
^F _X _ i '\ _H M H₂N ο^,Ο 3-chloro-7-(2-((3aS,4R,6aR)-2,2dimethyl-4-(4-methyl-1 Hpyrrolo[3,2-c]pyridin-1-yl)-3a,6adihydro-4H- cyclopenta[d][1,3]dioxol-6- yl)ethyl)-5-fluoroquinolin-2-amine	1-((3aS,4R,6aR)-2,2Dimethyl-6-vinyl3a,6a-dihydro-4Hcyclopenta[d][1,3]diox ol-4-yl)-4-methyl-1 Hpyrrolo[3,2-c]pyridine, 1-((3aS,4R,6aR)-2,2dimethyl-6-vinyl3a,6a-dihydro-4Hcyc-lopenta[d][1,3]diox ol-4-yl)-1Hpyrrolo[3,2-c]pyridine and 7-bromo-3- chloro-5fluoroquinolin-2amine	LCMS m/z =493.36 (M+, 100%)

122

Uo^Kun H J- CM O X	1-((3aS,4R,6aR)-2,2- Dimethyl-6-vinyl3a,6a-dihydro-4Hcyclopenta[d][1,3]diox ol-4-yl)-4-methyl-1 Hpyrrolo[3,2-c]pyridine, 1-((3aS,4R,6aR)-2,2dimethyl-6-vinyl3a,6a-dihydro-4Hcyclopenta[d][1,3]diox ol-4-yl)-1Hpyrrolo[3,2-c]pyridine and 7-bromo-3- chloro-5fluoroquinolin-2amine	LCMS m/z =479.30 (M.+, 100%)
^F _u ^clXxX^rÇY^clh,n ^N /x / k.N °x° 3-Chloro-7-(2-((3aS,4R,6aR)-4(4-ch 1 o ro-7 H-py rrolo[2,3d]pyrimidin-7-yi)-6a-ethyi-2,2dimethyl-3a,6a-dihydro-4Hcyclopenta[d][1,3] dioxol-6- yl)ethyl)-5-fiuoroquinolin-2-amine	4-Chloro-7-((3aS,4R, 6aR)-6a-ethyl-2,2dimethyl-6-vinyl-4,Sari i hyd ro-3a H-cyclo penta[d] [1,3]dioxol-4yi)-7H-pyrrolo[2,3-d] pyrimidine & 7-Bromo- Ο c O-VI 11 Wl fluoroquinolin-2amine	¹H NMR (400 MHz, DMSOd₆) δ 8.70 (s, 1H), 8.18 (s, 1 H), 7.34 (d, J=3.7 Hz, 1H), 7.28 (s, 1H), 7.07 (dd, J = 11.1, 1.4 Hz, 1H), 6.96 (s, 2H), 6.60 (d, J= 3.7 Hz, 1H), 5.79 (s, 1H), 5.58 (d, J =2.3 Hz, 1H),4.23(s, 1H), 3.182.98 (m,2H), 2.67-2.53 (m, 2H), 1.68 - 1.52 (m, 2H), 1.31 (s, 3H), 1.28 (s, 3H), 0.70 - 0.61 (m, 3H); LCMS m/z = 542.3 (M+, 100%)

123

ξ ^Ci ri₂N q A Chemical Formula: C₂₈H₂₉CIFN₅O₂ 3-chloro-5-fluoro-7-(2- ((3aS,4R,6aR)-2,2,6a-trimethyl-4(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)-3a,6a-dihydro4H-cyclopenta[d][1,3]dioxoi-6yl)propyl)quinolin-2-amine

4-methyî-7((3aS,4R,6aR)2,2,6a-trimethyl-6(prop-1-en-2-yl)3a,6a-dihydro-4Hcyclopenta[d][1,3]diox ol-4-yl)-7H- pyrrolo[2,3d]pyrimidine & 7-bromo-3-chloro-5fluoroquinolin-2amine

LCMS m/z = 522.32 (M+, 100%).

7-(2-((3aR,3bR,4aS,5R,5aS)-5-(4-Amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2dimethyltetrahydrocyclopropa[3,4]cyclopenta[1,2-d][1,3]dioxol-3b(3aH)-yI)ethyl)-3chloro-5-fluoroquinoïin-2-amîne

7-((3aR,3bS,4aS,5R,5aS)-2,2-Dimethyl-3b-vinylhexahydrocyclopropa[3,4]cyclopenta[1,2d][1,3]dioxol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (1g, 3.20mmol) in 9-BBN (0.5 molar, 25.6 ml, 12.81 mmol) was heated at 60°C for 1h under N2 atmosphère. The reaction mixture was cooled to 25°C, then potassium phosphate tribasic (3.40g, 16.01mmol) in water (2 ml) was added and stirred for 30 mins. A solution of 7-bromo-3-chloro-510 fluoroquinolin-2-amine (0.882g, 3.20mmoî) in THF (12 ml) was added, followed by PdCI₂(dppf) (0.234g, 0.320mmol). The resulting mixture was stirred at 50°C for 6h. The reaction mixture was diluted with water (10 ml) and extracted with ethyi acetate (10 ml). Layers were separated, organic layer was washed with brine (10 ml) and dried over anhydrous Na₂SO₄ The organic layer was filtered and concentrated in vacuo to give 1.5g of crude compound. This residue was purified by combiflash (Rf200, Teledyne/lsco)

124 instrument onto a redisep® R? column with gradient elution (0 to 5%) of methanol in dichloromethane to afford the title compound (1.3g, 80%) as a pale yellow semisolid. ¹H NMR (400 MHz, DMSO-de) δ 8.16 (s, 1H), 8.08 (s, 1H), 7.22 (s, 1H), 7.12 (d, J = 3.5 Hz, 1H), 7.05 (d, J = 1.4 Hz, 1H), 7.02 (s, 2H), 6.94 5 (s, 2H), 6.61 (d, J = 3.5 Hz, 1H), 5.20 (d, J =7.2 Hz, 1H), 5.01 (s, 1H), 4.52 (dd, J = 7.3,

1.5 Hz, 1H), 2.85 - 2.80 (m, 2H), 2.32 - 2.26 (m, 1H), 1.72 - 1.56 (m, 1H), 1.48 (s, 3H), 1.46 - 1.41 (m, 1H), 1.19 (s, 3H), 0.94 - 0.92 (m, 1H), 0.77 - 0.68 (m, 1H); LCMS m/z =509.06 (M+, 20%).

Intermediates in table-7 were synthesized by an analogous reaction protocol as was used 10 for the préparation of 7-(2-((3aR,3bR,4aS,5R,5aS)-5-(4-amino-7H-pyrroio[2,3-d]pyrimidin7-yl)-2,2-dimethyltetrahydrocyclopropa[3,4]cyclopenta[1,2-d][1,3]dioxol-3b(3aH)-yl)ethyl)3-chloro-5-fluoroquinolin-2-amine using the appropriate starting matériels and at suitable température.

Table-7:

Structure & IUPAC name-	Intermediates used	¹H NMR & LCMS data
,F U y- A y n h₂n ⁿ J 7-(2-((3aR,3bR,4aS,5R,5aS)-5-(4amino-7H-pyrrolo[2,3-d]pyrimidin-7yl)-2,2-dimethyltetra hydrocyclopropa[3,4]cyclopenta[1,2d][1,3]dioxol-3b(3aH)-yl)ethyl)-3chloro-6-fluoroquinolin-2-amine	7- ((3aR,3bS,4aS,5R,5aS) -2,2-Dimethyl-3bvinylhexahydrocyclopro pa [3,4]cyclopenta[1,2d][1,3]dioxol-5-yl)-7Hpy rrolo[2,3-d]pyrim id i n4-amine and 7-Bromo-3chloro-6-fluoroquinolin2-amine	¹H NMR (400 MHz, DMSOd₆) δ 8.16 (s, 1H), 8.07 (s, 1H), 7.50 - 7.40 (m, 2H), 7.14 (d, J = 3.5 Hz, 1H), 7.09-7.01 (m, 3H), 6.67 (s, 1H), 6.62 (dd, J = 6.0, 3.6 Hz, 1 H), 5.20 (d, J =7.2 Hz, 1H), 5.01 (s, 1H), 4.54 (d, J = 7.2 Hz, 1H), 2.97 - 2.76 (m, 2H), 2.30 - 2.20(m, 1H), 1.68 - 1.60 (m, 1H), 1.48 (s, 3H), 1.24 (s, 3H), 1.20 - 1.14 (m, 1H), 0.97 -

125

		0.94 (m, 1H), 0.76 - 0.70 (m, 1H); LCMS m/z =509.06 (M+, 30%)
H₂N^>N N Jn 7-(2-((3aR,3bR,4aS,5R,5aS)-5-(4amino-7H-pyrroio[2,3-d]pyrimidin-7yl)-2,2-dimethyltetra hydrocyclopropa[3,4]cyc!openta[1,2d][1,3]dioxol-3b(3aH)-yl)ethyl)-3chloroquinolin-2-amine	7- ((3aR,3bS,4aS,5R,5aS) -2,2-Dimethyl-3bvinylhexahydrocyclopro pa [3,4]cyclopenta[1 ,2d][1,3]dioxol-5-yl)-7Hpyrrolo[2,3-d]pyrimidin4-amine and 7-Bromo-3chioroquinolin-2-amine	¹H NMR (400 MHz, DMSOd_e) δ 8.15 (s, 1H), 8.08 (s, 1H), 7.58 (d, J = 8.2 Hz, 1H), 7.37 (d, J = 1.6 Hz, 1H), 7.20 - 7.10 (m, 2H), 7.01 (s, 2H), 6.73-6.57 (m, 3H), 5.21 (dd, J = 7.1, 1.3 Hz, 1H), 5.01 (s, 1H), 4.52 (dd, J = 7.3, 1.5 Hz, 1H), 2.86- 2.81 (m, 2H), 2.32 2.21 (m, 1H), 1.69 - 1.65 (m, 1H), 1.48 (s, 3H), 1.471.42 (m, 1 H), 1.20 (s, 3H), 0.97 - 0.91 (m, 1H), 0.80 0.72 (m, 1H); LCMS m/z =491.06 (M+, 100%)
°V° 7-(2-((3aR,3bR,4aS,5R,5aS)-5-(4amino-7H-pyrrolo[2,3-d]pyrimidin-7yl)-2,2-d imethyltetrah ydrocyclopropa[3,4]cyclopenta[1,2d][ 1,3]dioxol-3b(3a H)-yl)etnyl)-3methoxyquinolin-2-amine	7((3aR,3bS,4aS,5R,5aS) -2,2-Dimethyl-3bvinylhexahydrocyciopro pa [3,4]cyclopenta[1,2d][1,3]dioxol-5-yl)-7Hpyrrolo[2,3-d]pyrimidin4-amine and 7-Bromo-3methoxyquinolin-2amine	¹H NMR (400 MHz, DMSOd_s) δ 8.08 (s, 1H), 7.50 (d, J = 8.1 Hz, 1H), 7.40 - 7.24 (m, 2H), 7.18 — 7.05 (m, 2H), 7.01 (s, 2H), 6.61 (d, J = 3.5 Hz, 1H), 6.29 (s, 2H), 5.21 (dd, J = 7.2, 1.3 Hz, 1H), 5.02 (s, 1H), 4.52 (dd, J=7.3, 1.5 Hz, 1H), 3.89(s, 3H), 2.88 - 2.74 (m, 2H), 2.30-2.18 (m, 1H), 1.721.60 (m, 1H), 1.48 (s, 3H), 1.46-1.41 (m, 1H), 1.20 (s, 3H), 0.98 - 0.91 (m, 1H),

126

		0.79-0.73 (m, 1H); LCMS m/z = 487.2 (M+1, 50%)
\ /⁼⁼\ V*^Ν '^^ί^>^/ΝΗ2η₂ν· ^Ν Ν J^N ² °^° /\ 7-(2-((3aR,3bR,4aS,5R,5aS)-5-(4amino-7H-pyrrolo[2,3-d]pyrimidin-7yl)-2,2-dimethyltetra hydrocyciopropa[3,4]cyclopenta[1,2d][1,3]dioxol-3b(3aH)-yl)ethyl)-3isopropylquinolin-2-amine	7((3aR,3bS,4aS,5R,5aS) -2,2-Dimethyl-3bvinylhexahydrocyclopro pa [3,4]cyclopenta[1,2d][1,3]dioxol-5-yl)-7Hpyrrolo[2,3-d]pyrimidin4-amine and 7-Bromo-3isopropylquinolin-2amine	¹H NMR (400 MHz, DMSOd₆) δ 8.08 (s, 1H), 7.83 (s, 1H), 7.60 (d, J = 8.1 Hz, 1H), 7.34 (d, J = 1.5 Hz, 1H), 7.14 (dd, J = 7.6, 2.5 Hz, 2H), 7.02 (s, 2H), 6.69 -6.59 (m, 3H), 5.27-5.16 (m, 1H), 5.01 (s, 1H), 4.53 (dd, J = 7.3, 1.5 Hz, 1H), 3.10 - 3.0 (m, 1H), 2.91 2.76 (m, 2H), 2.32 - 2.19 (m, 1H), 1.72 — 1.60 (m, 1H), 1.48 (s, 3H), 1.45 1.41 (m, 1H), 1.25 - 1.23 (m, 6H), 1.20 (s, 3H), 0.960.91 (m, 1H), 0.77 - 0.73 (m, 1H); LCMS m/z = 499.3 (M+1, 75%)
/\ 7-(2-((3aR,3bR,4aS,5R,5aS)-5-(4amino-7H-pyrrolo[2,3-d]pyrimidin-7yl)-2,2-dimethyltetra hydrocyclopropa[3,4]cyclopenta[1,2d][1,3]dioxol-3b(3aH)-yl)ethyl)-3chloro-8-fluoroquinolin-2-amine	7((3aR,3bS,4aS,5R,5aS) -2,2-Dimethyl-3bvinylhexahydrocyclopro pa [3,4]cyclopenta[1,2d][1,3]dioxol-5-yl)-7Hpyrrolo[2,3-d]pyrimidin4-amine and 7-Bromo-3- ch loro-8-f I uoroq u i nol i n2-amine	LCMS m/z =509.12 (M+, 60%)
i I « ; r i z y-' O Q %......< / ^Λ~Ί 32	7- ((3aR,3bS,4aS,5R,5aS) -2,2-Dimethyl-3bvinylhexahydrocyclopro	¹H NMR (400 MHz, DMSOd6) δ 8.08 (s, 1H), 7.73 (s, 1H), 7.51 (d, J = 8.1 Hz, 1H), 7.34 (d, J = 1.6 Hz,

127

7-(2-((3aR,3bR_!4aS,5R,5aS)-5-(4amino-7H-pyrrolo[2,3-d]pyrimidin-7yl)-2,2-dimethyltetra hydrocyclopropa[3,4]cyclopenta[1,2d][1,3]dioxol-3b(3aH)-yl)ethyÎ)-3methylquinolin-2-amine	pa [3,4]cyclopenta[1,2d][1,3]dioxol-5-yl)-7Hpy rrolo[2,3-d] pyrim id i n4-amine and 7-Bromo-3methylquinolin-2-amine	1H), 7.13 - 7.07 (m, 2H), 7.01 (s, 2H), 6.61 (d, J=3.5 Hz, 1H), 6.40 (s, 2H), 5.21 (d, J = 7.2 Hz, 1H), 5.01 (s, 1H), 4.53 (dd, J = 7.2, 1.4 Hz, 1H), 2.90 - 2.76 (m, 2H), 2.31 - 2.20 (m, 1H), 2.21 (s, 3H), 1.72-1.61 (m, 1H), 1.48 (s, 3H), 1.47 1.41 (m, 1H), 1.23 (s, 3H), 0.97-0.91 (m, 1H), 0.800.73 (m, 1H); LCMS m/z =471.3 (M+1, 90%)
H₂N ^N /X 'A' °x° 7-(2-((3aR,3bR,4aS,5R,5aS)-5-(4amino-7H-pyrroio[2,3-d]pyrimidin-7yl)-2,2-dimethyl tetrahydrocyclopropa[3,4]cyclopenta[1 ,2-d][1,3] dioxol-3b(3aH)-yl)ethyl)-3cyclopropyiquinolin-2-amine	7- ((3aR,3bS,4aS,5R,5aS) -2,2-Dimethyl-3bvinylhexahydrocyclopro pa [3,.4]cyclopenta[1.2d][1,3]dioxol-5-yl)-7Hpy rroio[2,3-d] pyrim id i n4-amine and 7-Bromo-3cyclopropylquinolin-2amine	¹H NMR (400 MHz, DMSOd6) δ 8.07 (s, 1H), 7.59 (s, 1H), 7.52 (d, J = 8.1 Hz, 1H), 7.32 (d, J = 1.6 Hz, 1H), 7.17 - 7.05 (m, 2H), 7.02 (s, 1 H), 6.61 (d, J=3.5 Hz, 1H), 6.46 (s, 2H), 5.21 (d, J =7.2 Hz, 1H), 5.01 (s, 1H), 4.52 (dd, J = 7.3, 1.5 Hz, 1H), 2.90 - 2.73 (m, 2H), 2.30 - 2.18 (m, 1H), 1.86- 1.74 (m, 1H), 1.731.60 (m, 1H), 1.51 - 1.41 (m, 4H), 1.26-1.22 (m, 4H), 1.00-0.90 (m, 3H), 0.790.71 (m, 1H), 0.68 - 0.60 (m, 2H); LCMS m/z = 497.11 (M+1, 15%)
ΊΟ-../ΑA k _XNH₂ H n^n X	7- ((3aR,3bS,4aS,5R,5aS) -2,2-Dimethyl-3b-	¹H NMR (400 MHz, DMSOd6) δ 8.61 (s, 1H), 8.07 (s, 1H), 7.66 (d, J = 8.3 Hz,

128

2-Amino-7-(2- ((3aR,3bR,4aS,5R,5aS)-5-(4-amino7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2dimethyl tetrahydrocydopropa[3,4]cyclopenta[1 ,2-d][1,3] dioxol-3b(3aH)- yl)ethyl)quinoline-3-carbonitrile	vinylhexahydrocyclopro pa [3,4]cydopenta[1,2d][1,3]dioxol-5-yl)-7Hpyrrolo[2,3-d]pyrimidin4-amine and 2-Amino-7bromoquinoline-3carbonitrile	1H), 7.38 (s, 1H), 7.29 7.19 (m, 1H), 7.12 (d, J = 3.5 Hz, 1H), 7.01 (s, 2H), 6.89 (s, 2H), 6.61 (dd, J = 8.7, 3.5 Hz, 1H), 5.21 (d, J = 7.1 Hz, 1H), 5.01 (s, 1H), 4.52 (dd, J = 7.0, 1.6 Hz, 1 H), 2.89 - 2.83 (m, 2H), 2.31 -2.22 (m, 1H), 1.721.60 (m, 1H), 1.48 (s, 3H), 1.45-1.40 (m, 1H), 1.20 (s, 3H), 0.97 - 0.90 (m, 1H), 0.80-0.60 (m, 1H); LCMS m/z =482.36 (M+1, 15%)
^nh2 h₂fAⁿ ' /A A 7-(2-((3aR,3bR,4aS,5R,5aS)-5-(4amino-7H-pyrrolo[2,3-d]pyrimidin-7yl)-2,2-dimethyltetra hydrocydopropa[3,4]cydopenta[1,2d][1,3]dioxol-3b(3aH)-yl)ethyl)-3fiuoroquinolin-2-amine	7((3aR,3bS,4aS,5R,5aS) -2,2-Dimethy!-3bvinylhexahydrocyclopro pa [3,4]cydopenta[1,2d][1,3]dioxol-5-yl)-7Hpyrrolo[2,3-d]pyrimidin- 4-amine and 7-Bromo-3fluoroquinolin-2-amine	¹H NMR (400 MHz, DMSOd6) δ 8.07 (s, 1H), 7.77 (d, J = 11.8 Hz, 1H), 7.57 (d, J = 8.2 Hz, 1H), 7.37 (d, J = 1.6 Hz, 1H), 7.20-7.09 (m, 2H), 7.01 (s, 2H), 6.71 (s, 2H), 6.60 (d, J = 3.5 Hz, 1H), 5.21 (dd, J= 7.2, 1.3 Hz, 1H), 5.02 (s, 1H), 4.52 (dd, J = 7.4, 1.5 Hz, 1H), 2.87-2.77 (m, 2H), 2.31 2.20 (m, 1H), 1.70 - 1.60 (m, 1H), 1.48 (s, 3H), 1.461.43 (m, 1H), 1.20 (s, 3H), 0.96 - 0.92 (m, 1H), 0.82 0.69 (m, 1H); LCMS m/z =475.3 (M+1, 100%)
A Al A’N * o ,0 X	7- ((3aR,3bS,4aS,5R,5aS) -2,2-Dimethyl-3b-	LCMS m/z =522.94 (M+, 15%)

129

7-(2-((3aR,3bR,4aS,5R,5aS)-5-(4amino-6-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)-2,2-dimethyltetra hydrocyclopropa[3,4]cyclopenta[1,2- d][1,3]dioxol-3b(3aH)-yl)ethyl)-3- chloro-5-fluoroquinolin-2-amine	vinylhexahydrocyclopro pa [3,4]cyclopenta[1,2d][1,3]dioxol-5-yl)-6methyl-7H-pyrrolo[2,3d]pyrimidin-4-amine and 7-Bromo-3-chloro-5fluoroquinolin-2-amine
^^F \ A A·-^ yLT y h Η₂Ν^^Ν / i A^N A 7- (2-((3aR,3bR,4aS,5R,5aS)-5-(4amino-6-methyl-7H-pyrrolo[2,3d]pyrimidin-7-y.^!)-2,2-dimethyl tetrahydrocyclopropa[3,4]cyclopenta[1 ,2-d][1,3] dioxol-3b(3aH)-yl)ethyl)-3chloro-6-fluoroquinolin-2-amine	7((3aR,3bS,4aS,5R,5aS) -2,2-Dimethyl-3bvinylhexahydrocyciopro pa [3,4]cyclopenta[1,2d][1,3]dioxol-5-yl)-6methyl-7 H-pyrrolo[2,3d]pyrim!din-4-amine & 7Bromo-3-chloro-6fluoroquinolin-2-amine	LCMS m/z =522.94 (M+, 10%)
^N / ^νΧΧά ^{N H 2} XX nXn 7-((3aR,3bR,4aS,5R,5aS)-2,2dimethyl-3b-(2-(3-methylimidazo[1,2a]pyridin-7-yl)ethyl)hexahydro cyclopropa[3,4]cyclopenta[1,2d][1,3]dioxol-5-yl)-7H-pyrrolo[2,3d]pyrimidin-4-amine	7-((3aR,3bS,4aS_> 5R,5aS)-2,2-Di methyl3b-vinyl hexahydrocyclopropa [3,4]cyc!o penta[1,2d][1,3] dioxol-5-yl)-7Hpyrrolo[2,3-d]pyr imidin4-amine and 7-Bromo-3methy limidazo[1,2- a]pyridine	LCMS m/z=445.3 (M+1, 70%)
B ⁷AX^ ^{N H}2 H tÀ^N i A/N ^H ₂N ô O A 7. (2-((3aR,3bR,4aS,5R,5aS)-5-(4- amino-7H-pyrrolo[2,3-d]pyrimidin-7-	7-((3aR,3bS,4aS, 5R,5aS)-2,2-Di methyl- 3b-vinyl hexahydrocyclopropa [3,4]cyclo penta[1,2- d][1,3] dioxoi-5-yi)-7H-	LCMS m/z= 553.20 (M+, 100%)

130

yl)-2,2-dimethyltetra hydrocyclopropa[3,4]cyclopenta[1,2d][1,3]dioxol-3b(3aH)-yl)ethyl)-3- bromo-6-fluoroquinolin-2-amine	pyrrolo[2,3-d]pyri midin4-amine and 3-Bromo-6-fIuoro-7iodoq uinolin-2-amine
F , Αί Aà (Boc;₂N Ô O A	.«:xA , 7-((3aR,3bS,4aS, 5R,5aS)-2,2-Di methyl3b-vïnyl hexahydrocyclopropa [3,4]cyclo penta[1,2d][1,3] dioxol-5-yl)-7Hpyrro!o[2,3-d]pyri midin4-amine	LCMS m/z = 755.59 (M+2, 100%).

7-(2-((3aR,3bR,4aS,5R,5aS)-5-(4-Amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2dimethyl tetrahydrocyclopropa[3,4]cyclopenta[1,2-d][1,3]dioxol-3b(3aH)-yl)ethyl)-Nisopropyl quinolin-2-amine

7-((3aR,3bS,4aS,5R,5aS)-2,2-Dimethyl-3b-vinylhexahydrocyclopropa[3,4]cyclopenta[1,2d][1,3]dioxol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (150mg, 0.480mmol) in 9-BBN (0.5molar, 3.84mî, 1.921 mmol) was heated at 50°C for 1h under N₂ atmosphère. The reaction mixture was cooled to 25°C, then potassium phosphate tribasic (510 mg, 2.401 10 mmol) in water (0.5ml) was added and stirred for 30 mins. A solution of 7-bromo-Nisopropylquinolin-2-amine (0,127g, 0.480mmol) in THF (3ml) was added, followed by dichloro[1_tT-bis(di-t-butylphosphino)ferrocene]palladium(ll) (6.26 mg, 9,60 pmol). The resulting mixture was stirred at 50°C for 6h. The reaction mixture was diluted with water (10 ml) and extracted with ethyl acetate (10 ml). Layers were separated, organic layer was 15 washed with brine (10 ml) and dried over anhydrous Na₂SO4 The organic layer was filtered and concentrated in vacuo to give 1.5g of crude compound. This residue was purified by combiflash (Rf200, Teledyne/lsco) instrument onto a redisep® R_f column with gradient

131 elution (0 to 10%) of 50% 7N NHa/MeOH in dichloromethane to afford the title compound (0.12g, 50.1%) as a pale yellow semisolid. LCMS m/z=499.2 (M+1, 40%).

Intermediates in table-8 were synthesized by an analogous reaction protocol as was used for the préparation of 7-(2-((3aR,3bR,4aS,5R,5aS)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin5 7-yl)-2,2-dimethyltetrahydrocyclopropa[3,4]cyclopenta[1,2-d][1,3]dioxol-3b(3aH)-yl)ethyl)N-isopropylquinolin-2-amine using the appropriate starting materiais and at suitable température.

Table-8:

Structure & IUPAC name	Intermediates used	¹H NMR & LCMS data
,\ k O i n W-n' ⁿ XI H 0^.0 7-(2-((3aR,3bR,4aS,5R,5aS)-5-(4-amino7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2dimethyltetra hydrocyclopropa[3,4]cyclopenta[1,2d][1,3]dioxol-3b(3aH)-yl)ethyl)-Ncyclobutylquinolin-2-amine	7-((3aR,3bS,4aS,5R, 5aS)-2,2-Dimethyl-3bvinylhexahydrocyclopr opa [3,4]cyclopenta[1,2d][1,3]dioxol-5-yl)-7Hpyrrolo[2,3-d]pyrimidin4-amine and 7-BromoN-cyclobutyIquinolin-2amine	LCMS m/z=511.3 (M+1, 40%)
' N H₂N ^N y i X 7-(2-((3aR,3bR,4aS,5R,5aS)-5-(4-amino7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2dimethyltetra hydrocyclopropa[3,4]cyclopenta[1,2d][ 1,3]dioxo!-3b(3aH)-yl)ethyl)-3-(1, 1difluoroethyl)quinolin-2-amine	7- ((3aR,3bS,4aS,5R,5aS )-2,2-Dimethyl-3bvinylhexahydrocyclopr opa [3,4]cyclopenta[1,2d][1,3]dioxol-5-yl)-7Hpyrrolo[2,3-d]pyrimidin4-amine and 7-Bromo3-(1,1difluoroethyl)quinolin2-amine	¹H NMR (400 MHz, DMSO-cfe) δ 8.15 (s, 1H), 8.08 (d, J= 1.4 Hz, 1H), 7.69 (d, J = 8.2 Hz, 1H), 7.38 (s, 1H), 7.22 7.11 (m, 2H), 7.01 (s, 2H), 6.61 (dd, J = 3.6, 1.4 Hz, 1H), 6.23 (s, 2H), 5.22 (d, J= 7.1 Hz, 1H), 5.02 (s, 1H), 4.53 (d, J = 7.1 Hz, 1H), 2.92-2.78 (m, 2H), 2.32-2.22 (m, 1H), 2.08 (t, J = 19.1 Hz, 3H), 1.74-1.60 (m, 1H),

132

		1.48 (s, 3H), 1.46-1.41 (m, 1H), 1.24 (s, 3H), 0.97-0.92 (m, 1H), 0.79 - 0.71 (m, 1H); LCMS m/z =520.94 (M+, 50%)
N ί, NH₂ z— j 4 N^ \7' ^H ο o ^v Λ 7-(2-((3aR,3bR,4aS,5R,5aS)-5-(4-amino7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2dimethyltetra hydrocyclopropa[3,4]cyclopenta[1,2d][1,3]dioxol-3b(3aH)-yl)ethyl)-N(cyclopropylmethyl)quinolin-2-amine	7- ((3aR,3bS,4aS,5R,5aS )-2,2-Dimethyl-3bvinylhexahydrocyclopr opa [3,4]cyclopenta[1,2d][1,3]dioxol-5-yl)-7Hpyrrolo[2,3-d]pyrimidin4-amme and 7-Bromo- N- (cyclopropylmethyl)qui nolin-2-amine	¹H NMR (400 MHz, DMSO-d6) δ 8.08 (s, 1H), 7.78 (d, J = 8.9 Hz, 1H), 7.51 (d, J = 8.1 Hz, 1H), 7.39 (d, J = 1.6 Hz, 1 H), 7.19-7.05 (m, 3H), 7.02 (s, 2H), 6.73 (d, J = 8.9 Hz, 1H), 6.61 (d, J = 3.6 Hz, 1 H), 5.21 (dd, J = 7.2, 1.3 Hz, 1H), 5.02 (s, 1H), 4.52 (dd, J = 7.3, 1.5 Hz, 1H), 3.26 (t, J = 6.1 Hz, 2H), 2.90-2.74 (m, 2H), 2.34 - 2.22 (m, 1H), 1.75-1.59 (m, 2H), 1.49 (s, 3H), 1.48-1.44 (m, 1H), 1.20 (s, 3H), 0.94 (t, J = 4.6 Hz, 1H), 0.77-0.70 (m, 1H), 0.51 - 0.43 (m, 2H), 0.29 0.22 (m, 2H); LCMS m/z = 511.12 (M+1, 100%)
c—Χχ \^,,r / 'y v / ^N M M θχθ /X 7-((3aR,3bR,4aS,5R,5aS)-3b-(2-(3,3- dimethyl-2-(methylthio)-3H-indol-6-yl)ethyl)- 2,2-dimethyl	7- ((3aR,3bS,4aS,5R,5aS )-2,2-Dimethyl-3bvinylhexahydrocyclopr opa [3,4]cyclopenta[1,2d][1,3]dioxol-5-yl)-7H-	^ήΗ NMR (400 MHz, DMSO-d6) δ 8.08 (s, 1 H), 7.34-7.26 (m, 2H), 7.12 (d, J = 3.5 Hz, 1H), 7.08-6.94 (m, 3H), 6.61 (d, J = 3.5 Hz, 1H), 5.22 - 5.15 (m, 1H), 5.02 (s,

133

hexahydrocyclopropa[3,4]cyclopenta[1,2d][1,3] dioxol-5-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine	py rrolo[2,3-d]pyrimid i n4-amine and 6-Bromo-3,3- dimethyl-2- (methylthio)-3H-indole	1H), 4.52 (dd, J = 7.2, 1.5 Hz, 1H), 2.81 -2.69 (m, 2H), 2.59 (s, 3H), 2.29-2.16 (m, 1H), 1.68 - 1.56 (m, 1H), 1.48 (s, 3H), 1.45-1.41 (m, 1H), 1.27 (s, 6H), 1.20 (s, 3H), 0.94 (t, J = 4.7 Hz, 1H), 0.80-0.71 (m, 1H); LCMS m/z =504.31 (M+1, 100%)
/îAl A^CKa² °x° 6'-(2-((3aR,3bR,4aS,5R,5aS)-5-(4-amino7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2dimethyltetra hydrocyclopropa[3,4]cyclopenta[1,2d][1,3]dioxol-3b(3aH)- yl)ethyl)spiro[cyclobutane-1,3'-indol]-2'amine	7-((3aR,3bS,4aS,5R, 5aS)-2,2- Dimethy i-3bvinylhexahydrocyclopr opa [3,4]cyclopenta [1,2-d][1,3]dioxol-5-yl)7H-pyrrolo[2,3d]pyrimidin-4-amine and 6'-Bromospiro [cyclobutane-1,3'indol]-2'-amine.	LCMS m/z =485.3 (M+1, 70%)

3-Bromo-7-(2-((3aR,3bR,4aS,5R,5aS)-5-(4-chioro-7H-pyrrolo[2,3-d]pyrim!din-7-yl)2,2-dimethyltetrahydrocyclopropa[3,4]cyclopenta[1,2-d][1,3]dioxo!-3b(3aH)yl)ethyl)-N-(4-methoxybenzyl)quinoIin-2>amîne

4-Chloro-7-((3aR,3bS,4aS,5R,5aS)-2,2-dimethyl-3b-vinylhexahydrocyclopropa[3,4]cyclo penta[1,2-d][1,3]dioxol-5-yl)-7H-pyrrolo[2,3-d]pyrimidine (2.9g, 8.74mmol) in 9-BBN (0.5 molar, 87ml, 43.7mmol) was stirred at 70°C for 1h. The reaction mixture was cooled to 25°C, then potassium phosphate tribasic (5.57g, 26.2mmol) in water (45ml) was added and

134 stirred for 30 mins. A solution of 3-bromo-7-iodo-N-(4-methoxybenzyl)quinolin-2-amine (4.72g, 10.05mmol) in THF (60ml) was added, followed by PdCl2(dppf)-CH₂CI₂ (0.357g, 0.437mmol). The resulting mixture was stirred at 70°C for 3h. The reaction mixture was diluted with water (50 ml) and extracted with ethyl acetate (50 ml). Layers were separated, organic layer was washed with brine (50 ml) and dried over anhydrous Na₂SO4 The organic layer was filtered and concentrated in vacuo to give 3.5g of crude compound. This residue was purified by combiflash (Rf200, Teledyne/lsco) instrument onto a redisep® Rtcolumn with gradient elution (0 to 30%) of ethyl acetate in petroleum ether to afford the title compound (3.1 g, 52.5%) as an off-white solid. ¹H NMR (400 MHz, DMSO-cfe) δ 8.68 (s, 1H), 8.33 (s, 1H), 7.73 (d, J = 3.7 Hz, 1H), 7.56 (d, J = 8.2 Hz, 1H), 7.43 (d, J= 1.6 Hz, 1H), 7.37-7.31 (m, 2H), 7.25-7.12 (m, 1H), 7.15 (dd, J = 8.2, 1.6 Hz, 1H), 6.90-6.83 (m, 2H), 6.70 (d, J = 3.7 Hz, 1H), 5.27 (dd, J = 7.2, 1.3 Hz, 1H), 5.12 (s, 1H), 4.71 -4.56 (m, 3H), 3.70 (s, 3H), 2.90 — 2.75 (m, 2H), 2.38 - 2.26 (m, 1 H), 1.63 — 1.58 (m, 1 H), 1.55 1.51 (m, 1H), 1.49 (s, 3H), 1.20 (s, 3H), 0.95 (t, J =4.7 Hz, 1H), 0.79-0.72 (m, 1H); LCMS m/z =674.1 (M-1, 100%).

Intermediates in table-9 were synthesized by an analogous reaction protocol as was used for the préparation of 3-bromo-7-(2-((3aR,3bR,4aS,5R,5aS)-5-(4-chloro-7H-pyrrolo[2,3d]pyrimidin-7-yl)-2,2-dimethyltetrahydrocyclopropa[3,4]cyclopenta[1,2-d][1,3]dioxol3b(3aH)-yl)ethyl)-N-(4-methoxybenzyl)quinolin-2-amine using the appropriate starting materials.

I able-9:

Structure & IUPAC name

Intermediates used ¹H NMR & LCMS data

3-Chioro-7-(2-((3aR,3bS,4aS,5R,5aS)-5-(4chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2dimethyltetrahydrocyciopropa[3,4]cyclopenta [1,2-d][1,3]dioxol-3b(3aH)-yl)propyl)-5-fluoro4-chloro-7- LCMS m/z =662.10 ((3aR,3bR,4aS,5R,5aS)- (M+, 100%)

2,2-dimethyl-3b-(prop-1en-2-yl)hexahydrocyclo propa[3,4]cyclopenta[1,2 -d][1,3]dioxol-5-yl)-7Hpyrrolo[2,3-d]pyrimidine and 7-Bromo-3-chloro-5N-(4-methoxybenzyl)quinolin-2-amine fluoro-N-(419533

135

	methoxybenzyi)quinolin- 2-amine
F ^-7 ΡΜΒ^μ' N ?—t N^N ^H °x° 3-Chloro-7-(2-((3aR,3bS,4aS,5R,5aS)-5-(4chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2dimethyltetrahydrocyclopropa[3,4]cyclopenta [1,2-d][1,3]dioxol-3b(3aH)-yl)-2- cyclopropylethyl)-5-fluoro-N-(4- methoxybenzyl)quinolin-2-amine	4-Chloro-7((3aR,3bR,4aS,5R,5aS)3b-(1-cyclopropyîvinyl)2,2- dimethylhexahydrocyclop ropa[3,4]cyclopenta[1,2d][1,3]dioxol-5-yl)-7Hpy rrol o [2,3-d] pyrimid i ne and 7-Bromo-3-chloro-5- fluoro-N-(4methoxybenzyl)quinolin2-amine	¹H NMR (400 MHz, DMSO-de) δ 8.62 (s, 1H), 8.16 (d, J = 3.6 Hz, 1H), 7.78-7.71 (m, 1H), 7.61 (dd, J = 10.1, 5.1 Hz, 1H), 7.40 - 7.30 (m, 3H), 7.09 - 7.03 (m, 1H), 6.86 (dd, J= 8.6, 3.2 Hz, 2H), 6.78 6.74(m, 1H), 5.53 (t, J =7.2 Hz, 2H), 5.34 (d, J = 7.0 Hz, 1H), 5.16 (s, 1 H), 4.63 (d, J=6.5Hz, 1H), 3.70 (s, 3H), 2.98 - 2.88 (m, 2H), 1.73-1.68 (m, 1H), 1.53 (d, J = 7.4 Hz, 4H), 1.26 1.22 (m, 4H), 0.91 0.86 (m, 1H), 0.630.55 (m, 1H), 0.430.33 (m, 2H), 0.22 0.12 (m, 2H).
U y / γ \i pmb~._n^n j—! n -A H ^X^ 3-Bromo-7-(2-((3aR,3bS,4aS,5R,5aS)-5-(4chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2dimethyltetra hydrocyclopropa[3,4]cyclopenta[1,2-	4-chloro-7- ((3aR,3bR,4aS,5R,5aS)- 2,2-dimethyl-3b-(prop-1en-2-yI)hexahydrocyclo propa[3,4]cyclopenta[1,2 -d][1,3]dioxol-5-yl)-7H- pyrrolo[2,3-d]pyrimidine & 3-Bromo-7-iodo-N-(4-	LCMS m/z = 687.98 (M-1, 80%); 689.98 (M+1, 100%)

136

d][1,3]dioxol-3b(3aH)-yl)propyl)-N-(4methoxybenzyl)quinolin-2-amine methoxybenzyl)quinoBn2-amine

7-(2-((3aR₅3bR,4aS_J5R,5aS)-5-(4-chloro-7H-pyrroIo[2,3-d}pyrimidin-7-yl)-2_J2dimethyltetrahydrocyclopropa[3,4]cyclopenta[1,2-dni,3ldîoxol-3b(3aH)-yl)ethyl)-8fiuoroquinoIin-2-amine

4-chloro-7-((3aR,3bS,4aS,5R,5aS)-2,2-dimethyl-3b-vinylhexahydrocyclopropa[3,4] cyclo penta[1,2-dJ[1,3]dioxoF5-yl>7H-pyrrolo[2,3-d}pyrimid!ne (0.38g, 1.145mmol) in 9-BBN (0.5 moiar, 9.16 mi, 4.58 mmol) was stirred at 70°C for 8h. The réaction mixture was cooled to 25°C, then potassium phosphate tribasic (0.729g, 3.44mmol) in water (6ml) was added and stirred for 30mins. A solution of 7-bromo-8-fluoroquinoîin-2-amine (0.304g, 1.26mmol) in THF (30ml) was added, followed by [1,1-bis(di-tert-butylphosphino) ferrocene] dichloropailadiumni) (0.022g, 0.034mmoî). The resulting mixture was stirred at 70°C for 7h. The reaction mixture was diiuted with water (20 ml) and extracted with ethyl acetate (20 ml). Layers were separated, organic layer was washed with brine (20 ml) and dried over anhydrous Na₂SO4 The organic layer was filtered and concentrated in vacuo to give 0.5g of crude compound. This residue was purified by combiflash (R_f200, Teledyne/lsco) instrument onto a redisep® R_f column with gradient elution (0 to 50%) of ethyl acetate in petroleum ether to afford the title compound (0.12g, 21.21%) as an offwhite solid. ¹H NMR (400 MHz, DMSO-d6) δ 8.67 (s, 1H), 7.87 (d, J = 8.8 Hz, 1 H), 7.75 (d, J = 3.6 Hz, 1H), 7.36 (d, J = 8.1 Hz, TH), 7.14-7.05 (m, 1H), 6.79 -6.70 (m, 2H), 6.64 (s, 2H), 5.27 (d, J = 7.2 Hz, 1H), 5.13 (s, 1H), 4.69 (d, J = 7 2 Hz, 1H), 2.96 - 2.77 (m, 2H), 2.31 - 2.22 (m, 1H), 1.70 - 1.60 (m, 1H), 1.59 - 1.54 (m, 1H), 1.50 (s, 3H), 1.21 (s, 3H), 0.99 (t, J = 4.7 Hz, 1H), 0.83-0.77 (m, 1H); LCMS m/z =494 (M+, 100%)

Intermediates in table-10 were synthesized by an analogous reaction protocol as was used for the préparation of 7-(2-((3aR,3bR,4aS,5R,5aS)-5-(4-ch!oro-7H-pyrrolo[2,3-d]pyrimidin7-yl)-2,2-dimethyÎtetrahydrocyclopropa[3,4jcyciopenta[1,2-d][1_I3jdioxol-3b(3aH)-yl)ethyl)8-fluoroquinolin-2-amïne using the appropriate starting materials and at suitabie température.

Table-10:

137

Structure & IUPAC name	Intermediates used	¹H NMR & LCMS data
PMB~_n-^N '—^!·. N^Jù H 0^0 A 7-(2-((3aR,3bR, 4aS,5R,5aS)-5-(4chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)2,2-dimethyltetrahydrocyclopropa[3,4] cyclopenta[1,2-d][1,3]dioxol-3b(3aH)yl)ethyl)-N-(4-methoxybenzyl)quinolin2-amine	4-Chloro-7((3aR,3bS,4aS,5R,5a S)-2,2-dimethyl-3bvinylhexahydro cyclopropa[3,4]cyclop enta[1,2-d][1,3]dioxol5-yl)-7H-pyrrolo[2,3d]pyrimidine & 7Bromo-N-(4methoxybenzyl)quinol in-2-amine	¹H NMR (400 MHz, Chloroformd) δ 8.68 (s, 1H), 7.82 (d, J = 8.9 Hz, 1H),7.60(d, J= 1.5 Hz, 1H), 7.54 (d, J= 8.1 Hz, 1H), 7.41 7.33 (m, 2H), 7.21 - 7.14 (m, 2H), 6.97 - 6.84 (m, 2H), 6.65 6.57 (m, 2H), 5.23 (dd, J = 7.3, 1.4 Hz, 1H), 5.15 (s, 1H), 4.704.62 (m, 3H), 3.83 (s, 3H), 3.11 - 2.86 (m, 2H), 2.48 - 2.37 (m, 1H), 1.83— 1.76 (m, 1H), 1.55 (s, 3H), 1.50 (dd, J= 4.8, 1.5 Hz, 1H), 1.28 (s, 3H), 1.16 (t, J =5.0 Hz, 1H), 0.86 - 0.78 (m, 1H); LCMS m/z = 596.20 (M+, 100%)
--y h °y° 7-(2-((3aR,3bR,4aS,5R,5aS)-5-(4chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)2,2-dimethyltetrahydrocyclopropa [3,4]cyclopenta[1,2-d][1,3]dioxol3b(3aH)-yl)ethyl)-N-methy!quinolin-2amine	4-Chloro-7((3aR,3bS,4aS,5R,5a S)-2,2-dimethyl-3bvinylhexahydro cyclopropa[3,4]cyclop enta[1,2-d][1,3]dioxol5-yl)-7H-pyrrolo[2,3d]pyrimidine and 7Bromo-Nmethylquinolin-2amine	¹H NMR (400 MHz, DMSO-d_e) δ 8.69 (s, 1H), 7.77 (d, J = 8.9 Hz, 1H), 7.74 (d, J = 3.7 Hz, 1H), 7.51 (d, J =8.1 Hz, 1H), 7.41 (d, J = 1.6 Hz, 1H), 7.07 (dd, J = 8.1, 1.7 Hz, 1H), 6.93 (d, J = 5.9 Hz, 1 H), 6.71 (d, J =3.6 Hz, 1H), 6.67 (d, J = 8.9 Hz, 1H), 5.27 (dd, J =7.2, 1.3 Hz, 1H), 5.13 (s, 1H), 4.67 (dd, J = 7.3, 1.5 Hz, 1H), 2.88 (d, J = 4.7 Hz, 3H), 2.85 - 2.74 (m, 2H), 2.36 - 2.30

138

		(m, 1H), 1.71 - 1.65 (m, 1H), 1.57 - 1.52 (m, 1H), 1.50 (s, 3H), 1.21 (s, 3H), 0.96 (t, J= 4.7 Hz, 1H), 0.82 - 0.76 (m, 1H); LCMS m/z=490.24 (M+, 60%)
u ΧΑ⁷ \fj τ u PMB^A^N 2—! N^/^N X 7-(2-((3aR,3bR,4aS,5R,5aS)-5-(4- chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)2,2-dimethyltetrahydrocyclo propa[3,4] cyclopenta[1,2-d][1,3]dioxol-3b(3aH)yl)ethyi)-N-(4- methoxybenzyl)quinazolin-2-amine	4-Chloro-7((3aR,3bS,4aS,5R,5a S)-2,2-dimethyl-3bvinylhexahydro cyclopropa[3,4]cyclop enta[1,2-d][1,3]dioxol5-yl)-7H-pyrrolo[2,3d]pyrimidine & 7Bromo-N-(4methoxybenzyl)quina zolin-2-amîne	¹H NMR (400 MHz, DMSO-de) δ 9.04 (s, 1H), 8.68 (s, 1H), 7.79 (s, 1H), 7.74 (d, J = 3.7 Hz, 1H), 7.69 (d, J= 8.2 Hz, 1H), 7.35 (s, 1H), 7.30 (d, J = 8.2 Hz, 2H), 7.17 (dd, J = 8.3, 1.6 Hz, 1H), 6.89-6.83 (m, 2H), 6.71 (d, J = 3.7 Hz, 1H), 5.27 (d, J =7.1 Hz, 1H), 5.13 (s, 1H), 4./1 — 4.64 (m, 1H), 4.52 (d, J=6.3Hz, 2H), 3.71 (s, 3H), 2.90 - 2.80 (m, 2H), 2.37-2.27 (m, 1H), 1.671.62 (m, 1H), 1.56 - 1.52 (m, 1H), 1.49 (s, 3H), 1.20 (s, 3H), 0.95 (t, J = 4.6 Hz, 1H), 0.79 0.74 (m, 1H); LCMS m/z =597.3 (M+, 100%)
F -i /=\ -i-A y \\ n . .A/ U Vi7 v V h₂n ^N - K ^N-^N ² °X° 3-Chloro-7-(2-((3aR,3bR,4aS,5R,5aS)2,2-dimethy,^!-5-(4-methy!-7Hpyrrolo[2,3-d] pyrim id i n-7yl)tetrahyd rocycl o propa[3,4]cyclopenta[1,2-d][ 1,3]dioxol3b(3aH)-yl)ethyl)-5-fluoroquinolin-2amine	7((3aR,3bS,4aS,5R,5a S)-2,2-Dimethyl-3bvinylhexahydrocyclop ropa [3,4]cyclopenta[1,2d][1,3]dioxol-5-yl)-4methyl-7Hpyrrolo[2,3- d]pyrimidine and 7Bromo-3-chloro-5-	LCMS m/z =508.19 (M+, 80%)

139 fluoroquinolin-2amine

7-(1-((3aS_l4R,6aR)-4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,6adihydro-4H-cyclopenta[d][1,3]dioxol-6-yl)ethoxy)-N-methylquinolin-2-amine

To a stirred solution of 1-((3aS,4R,6aR)-4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxoI-6-yl)ethan-1-ol (0.2g, 0.596 mmol), 2(methylamino)quinolin-7-ol (0.145g, 0.834mmol) and triphenylphosphine (0.469g, 1.787mmol) at 0°C was added DEAD (0.283ml, 1.787mmol) slowly and stirred for 30min. The resulting mixture was stirred at 25°C for 1h. The solvent was evaporated under reduced pressure and the residue was purified by combiflash (Rf200, Teledyne/lsco) instrument onto a redisep® Rf column with gradient elution (0 to 20%) of ethyl acetate in Petroleum ether to afford the titie compound (0.1g, 34.1%) as an off-white solid. LCMS m/z = 492.2 (M+, 100%).

7-(((3aS,4R,6aR)-4-(4-chioro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyi-3a,6adihydro-4H-cyclopenta[d][1,3]dioxol-6-yl)methoxy)-N-methylquinolin-2-amine

To a stirred solution of ((3aR,6R,6aS)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2dimethyl-6,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methanol (0.25g, 0.777mmol), 2(methylamino)quinolin-7-ol (0.338g, 1.942mmol) and triphenylphosphine (0.611g, 2.331 mmol) in THF (20ml) was added DEAD (0.369ml, 2.331 mmol) dropwise at 0°C. The resulting mixture was stirred at 25°C for 20h. The solvent was evaporated under reduced pressure and the residue was purified by combiflash (Rt200, Teledyne/lsco) instrument onto a redisep® R_f column with gradient elution (0 to 70%) of ethyl acetate in petroleum ether (0.2 g, 53.9 %) as an off-white solid. ¹H NMR (400 MHz, DMSO-d6) δ 8.66 (s, 1H), 7.74 (d, J = 8.8 Hz, 1H), 7.53 (d, J = 1.7 Hz, 1H), 7.51 (d, J = 3.5 Hz, 1H), 7.07 (d, J = 2.5 Hz, 1H), 6.95 (d, J = 5.0 Hz, 1H), 6.85 (dd, J = 8.7, 2.5 Hz, 1H), 6.69-6.51 (m, 2H), 5.87

140 (s, 1H), 5.78 (s, 1H), 5.55 - 5.42 (m, 1H), 5.04-4.85 (m, 2H), 4.74-4.63 (m, 1H), 2.89 (d, J = 4.7 Hz, 3H), 1.49 (s, 3H), 1.24 (s, 3H); LCMS m/z = 479.3 (M+1, 100%).

3-Bromo-7-(((3aR,3bR_J4aS_J5R,5aS)-5-(4-chloro-7H-pyrTolo[2,3-d]pyrimidin-7-yl)-2,2dimethyltetrahydrocyclopropa[3,4]cyciopenta[1,2-d][1,3]dioxol-3b(3aH)yl)methoxy)-N-(4-methoxybenzyl)quinoiin-2 -amine

To a stirred solution of ((3aR,3bR,4aS,5R,5aS)-5-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7yl)-2,2-dimethyltetrahydrocyclopropa[3,4]cyclopenta[1,2-d][1,3]dioxoi-3b(3aH)yl)methanol (0.09g, 0.268mmol), 3-bromo-2-((4-methoxybenzyl)amino)quinolin-7-ol (0.106g, 0.295mmol) and triphenylphosphine (0.176g, 0.670mmol) in THF (8 ml), was added DEAD (0.106ml, 0.670mmol) dropwise at 0°C and stirred for 30 min. The resulting mixture stirred for at 25°C for 14h. The solvent was evaporated under reduced pressure and the residue was purified by combiflash (Rf200, Teledyne/lsco) instrument onto a redisep® Rf column with gradient elution (0 to 60%) of ethyl acetate in petroieum ether (0.12g, 66.1%) as an off-white solid. LCMS m/z= 677.97 (M+1, 100%).

3-Bromo-7-((E)-1-((3aR,3bS,4aS_J5R,5aS)-5-(4-chloro-7H-pyrrolo[2_!3-d]pyrimidîn-7yl)-2,2-dimethyltetrahydrocyc!opropa[3_J4]cyclopenta[1,2-d][1_J3]dioxol-3b(3aH)yl)prop-1-en-2-yl)-N-(4-methoxybenzyi)quinolin-2-amine

A mixture of 4-chloro-7-((3aR,3bR,4aS,5R,5aS)-3b-((E)-2-iodoprop-1-en-1-yl)-2,2dimethylhexahydro cyclopropa[3,4]cyclopenta[1,2-d][1,3]dioxol-5-yl)-7H-pyrrolo[2,3d]pyrimidine (0.12g, 0.254mmol), triphenylphosphine (6.67mg, 0.025mmol), 3-bromo-N(4-methoxybenzyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoIin-2-amine (0.179g, 0.382mmol), sodium carbonate (0.054g, 0.509mmol) and Pd(OAc)2 (2.86mg, 0.013mmol) in DMF (4ml) and water (1 ml) was stirred at 25°C for 16h. The reaction mixture was diluted with water (20 ml) and extracted with ethyl acetate (20 ml). Layers were separated, organic layer was washed with brine (20 ml) and dried over anhydrous Na₂SO₄The organic layer was filtered and concentrated in vacuo to give 0.3g of crude compound. This residue was purified by combiflash (Rf200, Teledyne/lsco) instrument onto a redisep®

141

Rf column with gradient elution (0 to 15%) of ethyl acetate in petroleum ether to afford the title compound (0.13g, 74.4%) as an off-white solid. LCMS m/z = 687.98 (M+1, 100%).

N7-(((3aS,4R_J6aR)-4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidîn-7-yl)-2,2-dimethyl-3a,6adihydro-4H-cyclopenta[d][1,3]dioxol-6-yl)methyI)-N2-(4-methoxybenzyl)quinoline2,7-diamine

To a stirred solution of (3aS,4R,6aR)-4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxole-6-carbaldehyde (0.18g, 0.563mmol) and N2-(4-methoxybenzyl)quinoline-2,7-diamine (0.157g, 0.563mmol) in methanol (5ml) was added acetic acid (0.1 mL) at 25°C and stirred for 2h. Sodium cyanoborohydride (0.106g, 1.689mmoî) was added stirred for 16h. The reaction was quenched by addition of sat. NH4CI (15mL). The reaction mixture was concentrated under reduced pressure and the residue was diluted with ethyl acetate (40mL). The organic phase was washed with water (30ml), saturated aqueous sodium bicarbonate (30ml) and brine (30ml) successively. Dried the organic layer over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give 0.2g of crude compound. This residue was purified by combiflash (Rf200, Teledyne/lsco) instrument onto a redisep® R_f column with gradient elution (0 to 15%) of methanol in dichloromethane to afford the title compound (0.15g, 45.7%) as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d6) δ 8.66 (s, 1H), 7.59 (d, J = 8.8 Hz, 1H), 7.48 (d, J = 3.7 Hz, 1H), 7.30 (m, 3H), 7.10 (t, J = 5.8 Hz, 1H), 6.92-6.86 (m, 2H), 6.65 (dd, J = 8.6, 2.3 Hz, 1H), 6.57 (d, J = 2.2 Hz, 1H), 6.51 (d, J = 3.7 Hz, 1H), 6.45 (d, J = 8.7 Hz, 1H), 5.72 (s, 1H), 5.69 (s, 1H), 5.38 (d, J = 5.7 Hz, 1H), 4.65-4.52 (m, 1H), 4.55 (d, J = 5.8 Hz, 2H), 4.13 - 3.93 (m, 3H), 3.72 (s, 3H), 1.48 (s, 3H), 1.30 (s, 3H); LCMS m/z = 583.4 (M+, 100%).

N7-(((3aS,4R,6aR)-4-(4-chloro-7H-pyrrolo[2_!3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,6adihydro-4H-cyclopenta[d][1,3]dÎoxol-6-yl)methyl)-N2-(4-methoxybenzyl)-N7methylquinoline-2,7-diamine

To a stirred solution of N2-(4-methoxybenzyl)-N7-methylquinoline-2,7-diamine in DMF (2 ml) was added K₂CO₃ (0.058g, 0.420mmol) at 0°C slowly followed by ((3aS,4R,6aR)-4-(4

142 chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yi)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3] dioxol-6-yl)methyl 4-methylbenzenesulfonate (0.1g, 0.210mmol) and stirred the reaction mixture for 10 mins. The resulting mixture was stirred at 25°C for 16h. The reaction mixture was diluted with water (20mi) and extracted with ethyi acetate (20mi). Layers were separated, organic layer was washed with brine (20 ml) and dried over anhydrous Na₂SO₄The organic layer was filtered and concentrated in vacuo to give 0.3g of crude compound. This residue was purified by combiflash (R_f200, Teledyne/lsco) instrument onto a redisep® R_f column with gradient elution (0 to 7%) of ethyi acetate in petroieum ether to afford the titie compound (0.025g, 19.93%) as a colourless oil. LCMS m/z = 597.29 (M+, 80%).

7-(({(3aS,4R,6aR)-4-(4-chioro-7H-pyrrolo[2,3-dJpynmîdin-7-yl)-2,2-dimethyi-3a,6adihydro-4H-cyclopenta[d][1,3]dioxol-6-yl)methyl)thio)-N-(4-methoxybenzyl)quinolin2-amine

H

Toa stirred solution of 2-((4-methoxybenzyl)amino)quinoline-7-thiol (125mg, 0.422mmol) in DMSO (3 ml) at 0°C was added Cs₂CO₃ (302mg, 0.928mmol) and ((3aS,4R,6aR)-4-(4chloro-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 (201 mg, 0.422mmol). The resulting mixture was stirred at 25°C for 3h. The reaction mixture was diiuted with water (20ml) and extracted with ethyi acetate (20ml). Layers were separated, organic layer was washed with brine (20 ml) and dried over anhydrous Na -SO.·. The organic layer was filtered and concentrated in vacuo to give 0.3g of crude compound. This residue was purified by combiflash (Rf200, Teledyne/lsco) instrument onto a redisep® R_f column with gradient elution (0 to 20%) of ethyi acetate in petroieum ether to afford the titie compound (0.112g, 44.3%) as an offwhite solid. ¹H NMR (400 MHz, DMSO-d6) δ 8.60 (s, 1H), 7.85 (d, J = 8.9 Hz, 1H), 7.60 7.48 (m, 3H), 7.33 - 7.26 (m, 2H), 7.19 (dd, J = 8.3, 1.9 Hz, 1H), 6.85 - 6.79 (m, 3H), 6.48 (d, J = 3.7 Hz, 1H), 6.06 (d, J = 3.6 Hz, 1H), 5.72 (s, 1H), 5.65 (s, 1H), 5.43 (d, J = 5.7 Hz, 1H), 4.54 (d, J = 5.7 Hz, 2H), 4.48 (d, J = 5.7 Hz, 1H), 4.22 (d, J = 15.3 Hz, 1H), 3.77 3.70 (m, 1H), 3.68 (s, 3H), 1.43 (s, 3H), 1.28 (s, 3H); LCMS m/z = 600.21 (M+, 100%).

3-Chioro-7-(1-((3aS,4R,6aR)-4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-6-yl)ethoxy)-5-fluoro-N-(4methoxybenzyl)quino!in-2-amine

143

To a stirred solution of 1-((3aS,4R,6aR)-4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-6-yl)ethan-1-ol (0.7g, 2.085mmol), 3chloro-5-fluoro-2-((4-methoxybenzyl)amino)quinolin-7-ol (0.416g, 1.251 mmol) and triphenylphosphine (1.640g, 6.25mmol) in THF (10ml), was added DEAD (0.990 ml, 6.25 mmol) dropwise at 0°C and stirred for 30mins. The resulting mixture stirred at 25°C for 16h. The solvent was evaporated under reduced pressure and this residue was purified by combiflash (R_f200, Teledyne/lsco) instrument onto a redisep® R_f column with gradient elution (0 to 15%) of ethyl acetate in petroleum ether to afford the title compound (0.5g, 36.9 % yield) as an off-white solid. LCMS m/z = 650.3 (M+, 100%).

3-chloro-7-(((3aS,4R,6aR)-4-(4-chÎoro-7H-pyrrolo[2,3-d]pyrimîdîn-7-yl)-2,2-dimethyl3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-6-yl)methoxy)-5-fluoro-N-(4methoxybenzyl)quino!in-2-ani!ne

Césium carbonate (558 mg, 1.713 mmol) was addd to a solution of ((3aS,4R,6aR)-4-(4chloro-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 (272 mg, 0.571 mmol) and 3-chloro-5fiuoro-2-((4-methoxybenzyl)amino) quinolin-7-ol (190 mg, 0.571 mmol) in DMF (4 mi) at 0°C and stirred at 25°C for 1h. Ice cold water (20ml) was added to the reaction mixture and stirred for 10 minutes, precipitated solid was filtered, washed with water and dried under vacuum to afford the title compound (300 mg, 83%) as a brown solid. ¹H NMR (400 MHz, DMSO-d6) δ 8.64 (s, 1H), 8.11 (s, 1H), 7.65 (t, J = 6.1 Hz, 1H), 7.50 (d, J = 3.7 Hz, 1 H), 7.36 - 7.30 (m, 2H), 6.94 (d, J = 2.3 Hz, 1 H), 6.89 - 6.79 (m, 3H), 6.60 (d, J = 3.7 Hz, 1H), 5.87 (s, 1H), 5.78 (s, 1H), 5.48 (d, J = 5.7 Hz, 1H), 5.05-4.89 (m, 2H), 4.70 (d, J = 5.7 Hz, 1H), 4.64 (d, J = 6.1 Hz, 2H), 3.71 (s, 3H), 1.45 (s, 3H), 1.30 (s, 3H); LCMS m/z =636.34 (M+, 100%).

Intermediates in table-11 were synthesized by an analogous reaction protocol as was used for the préparation of 3-chloro-7-(((3aS,4R,6aR)-4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-719533

144 yi)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-6-yl)methoxy)-5-fluoro-N-(4methoxybenzyl)quinolin-2-amine using the appropriate starting materials and at suitable température.

Table-11:

Structure & IUPAC name	Intermediates used	¹H NMR & LCMS data
F /A I /A ^H Λ AA^o \ T Y « PMB-._n ^z'N c i N^^N H V Λ 3-Chloro-5-f luoro- N-(4- methoxybenzyl)-7-(((3aS,4R,6aR)-4(4-((4-methoxybenzyl)amino)-7Hpyrrolo[2,3-d]pyrimidin-7-yl)-2,2,5trimethyl-3a,6a-dihydro-4Hcyclopenta[d][1,3]dioxol-6yl)methoxy)quinolin-2-amine	((3aS,4R,6aR)-4-(4-((4methoxybenzyl)amino)7H-pyrrolo[2,3d]pyrimidin-7-yl)-2,2,5trimethyl-3a,6a-dihydro4H- cyclopenta[d][1,3]dioxol6-yl)methyl 4- methylbenzenesulfonate & 3-chloro-5-fluoro-2((4- methoxybenzyl)amino)q l ΗΓίΛΐϊΛ-Ύ-Λΐ MH IVHI J^- l VI	LCMS m/z=751.61 (M+, 100%).
A{ N PMB °y° /\ 3-Chloro-7-((((3aS,4R,6aR)-4-(4ch!oro-7H-pyrrolo[2,3-d]pyrimidin-7yl)-2,2-dimethyl-3a,6a-dihydro-4Hcyclopenta[d][1,3]dioxol-6yl)methyl)thio)-N,N-bis(4methoxybenzyl)quinolin-2-amine	((3aS,4R,6aR)-4-(4- chloro-7H-pyrrolo[2,3d]pyrimidin-7-yl)-2,2dimethyl-3a,6a-dihydro- 4H- cyclopenta[d][1,3]dioxol6-yl)methyl 4- methylbenzenesulfonate & 2-(bis(4- methoxybenzyl)amino)- 3-chloroquinoline-7-thiol	¹H NMR (400 MHz, DMSO-d6) δ 8.53 (s, 1H), 8.41 (s, 1H), 7.74 (d, J = 8.6 Hz, 1H), 7.67 (d, J = 1.8 Hz, 1H), 7.43 (dd, J = 8.5, 1.9 Hz, 1H), 7.26 - 7.20 (m, 4H), 6.81 - 6.75 (m, 4H), 6.38 (d, J = 3.7 Hz, 1H), 5.98 (d, J = 3.6 Hz, 1H), 5.72 (s, 1H), 5.63 (s, 1H), 5.44 (d, J = 5.7 Hz, 1 H), 4.57-4.42 (m, 5H), 4.28 (d, J = 15.4

145

		Hz, 1 H), 3.82-3.76 (m, 1H), 3.64 (s, 6H), 1.42 (s, 3H), 1.28 (s, 3H); LCMS m/z =754.49 (M+, 100%)
\ XA^s ! \ « An ; ; N'-À PMBHN Ô 0 7-((((3aR,3bS,4aS,5R,5aS)-5-(4- chloro-7H-pyrrolo[2,3-d]pyrimidin-7yi)-2,2- dimethyltetrahydrocyclopropa[3,4]cyc lopenta[1,2-d][1,3]dioxol-3b(3aH)yl)methyl)thio)-N-(4- methoxybenzyl)quinolin-2-amine	((3aR,3bR,4aS,5R,5aS) -5-(4-chloro-7Hpyrrolo[2,3-d]pyrimidin7-yl)-2,2dimethyltetrahydrocyclo propa[3,4]cyclopenta[1, 2-d][1,3]dioxol-3b(3aH)yl)methyl 4- methylbenzenesulfonate & 2-((4- methoxybenzyl)amino)q uinoline-7-thiol	¹H NMR (400 MHz, Chloroform-d) δ 8.68 (s, 1H), 7.76 (d, J = 8.9 Hz, 1H), 7.64 (d, J= 1.8 Hz, 1 H), 7.48 (d, J = 8.3 Hz, 1H), 7.39 (d, J = 3.6 Hz, TH), 7.37 - 7.32 (m, 2H), 7.20 (dd, J = 8.4, 1.9 Hz, 1 H), 6.93 — 6.87 (m, 2H), 6.59 (d, J = 8.8 Hz, 1 H), 6.55 (d, J = 3.6 Hz, 1H), 5.39 (dd, J = 7.2, 1.5 Hz, 1H), 5.21 (s, 1H), 4.65 (d, J = 5.3 Hz, 2H), 4.64-4.60 (m, 1H), 3.82 (s, 3H), 3.62 (d, J = 13.3 Hz, 1H), 3.43 (d, J = 13.3 Hz, 1H), 1.76 - 1.73 (m, 1H), 1.60 (s, 3H), 1.331.30 (m, 1H), 1.26 (s, 3H), 1.12 - 1.06 (m, 1H); LCMS m/z = 614.21 (M+, 100%)

3-Chloro-7-(((3aS_!4R₃6aR)-4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2,6atrimethyl-3a,6a-dihydro-4H-cyclopenta[d][1_J3]dioxol-6-yl)methoxy)-5-fluoro-N-(4methoxybenzyl)quinolin-2-amine

146

To a stirred solution of ((3aS,4R,6aR)-4-(4-chloro-7H-pynOlo[2,3-d]pyrimidin-7-yl)-2,2,6atrimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-6-yl) methanol (250 mg, 0.745 mmol) and 3-chloro-5-fluoro-2-((4-methoxybenzyl)amino)quinolin-7-ol (297 mg, 0.S93 mmol) in toluene (2 ml) was added triphenyi phosphine (234 mg, 0.893 mmol) and stirred for 5 minutes then added DEAD (0.118 ml, 0.745 mmol) dropwise at 25°C and reaction mixture was stirred at 90°C for 2 hours. The volatiles were removed in vacuo and obtained 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 (420mg, 87%) as a off-white solid. ¹H NMR (400 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.12 (s, 1H), 7.69 (t, J = 6.1 Hz, 1H), 7.48 (d, J = 3.7 Hz, 1H), 7.42 - 7.36 (m, 1H), 7.36 - 7.30 (m, 2H), 6.97 (d, J = 2.2 Hz, 1 H), 6.88 - 6.86 (m, 2H), 6.62 (d, J = 3.6 Hz, 1 H), 5.86 (d, J = 2.8 Hz, 1H), 5.68 (d, J = 2.5 Hz, 1H), 5.08 (d, J = 15.5 Hz, 1H), 4.89 (d, J = 15.5 Hz, 1H), 4.65 (d, J = 6.0 Hz, 2H), 4.25 (s, 1H), 3.70 (s, 3H), 1.55 (s, 3H), 1.41 (s, 3H), 1.34 (s, 3H); LCMS m/z =650,34 (M+, 100%).

7-(2-((3aS_ï4R,6aR)-4-(4-Amino-7H-pyrrolo[2_J3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,6adihydro-4H-cyclopenta[d][1,3]dioxol-6-y!)ethyI)-N-methylquinolin-2-amine

A mixture of 7-(2-((3aS,4R,6aR)-4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-6-yl)ethyl)-N-methylquinolin-2-amine (0.100 g, 0.210 mmol) in dioxane (3 ml) was added aq. ammonia (0.227 ml, 10.50 mmol) at 25°C and stirred the reaction mixture at 130°C for 16h. The reaction mixture was diluted with brine (20m,¹) and extracted with ethyl acetate (20ml). Layers were separated, the organic layer was dried over anhydrous Na₂SO₄ , filtered and concentrated in vacuo to give 0.15g of crude compound. The obtained residue was purified by combiflash (Rf200, Teledyne/isco) instrument onto a redisep® R_f column with gradient elution (0 to 5%) of methanol in dicholomethane to afford the title compound (0.07g, 73%) as an off-white solid. LCMS m/z= 457.2 (M+1; 40%).

147

Intermediates in table-12 were synthesized by an anaiogous reaction protocol as was used for the préparation of 7-(2-((3aS,4R,6aR)-4-(4-Amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-6-yl)ethyl)-N-methylquinolin-2-amine using the appropriate starting materials (Instead of aq.NH₃, 7N NH₃ in MeOH could also be 5 used).

Table-12

Srtucture & IUPAC name	Intermediate used	¹H NMR & LCMS data
^N 7-(2-((3aS,4R,6aR)-4-(4-Amino-7Hpyrrolo[2,3-d]pyrimidin-7-yl)-2,2dimethyl-3a,6a-dihydro-4H- cyclopenta[d][1,3]d ioxol-6-yl)ethy I)N-cyclobutylquinolin-2-amine	7-(2-((3aS,4R,6aR)-4-(4Chloro-7H-pyrrolo[2,3d]pyrimidin-7-yl)-2,2dimethyl-3a,6a-dihydro4H- cyclopenta[d][1,3]dioxol6-yl)ethyl)-Ncyclobuty!quinolin-2amine	¹H NMR (400 MHz, Chloroform-d) δ 8.35 (s, 1 H), 7.86 (d, J = 8.9 Hz, 1H), 7.58 - 7.53 (m, 2H), 7.15 (dd, J = 8.2, 1.7 Hz, 1H), 6.62 (d, J = 8.9 Hz, 1H), 6.31 (d, J = 3.6 Hz, 1H), 6.09 (d, J = 3.6 Hz, 1H), 5.75 (s, 1H), 5.51 - 5.45 (m, 2H), 5.26 (d, J = 6.0 Hz, 1H), 5.15 (s, 2H), 4.47 (d, J = 5.7 Hz, 1H), 4.45 - 4.37 (m, 1H), 3.19 - 3.01 (m, 2H), 2.87 - 2.68 (m, 2H), 2.57 2.46 (m, 2H), 2.02 - 1.93 (m, 2H), i §ΰ_·{ vg /m 2H) 1 50 (s 3 H) 1.37 (s, 3H); LCMS m/z= 497.3 (M+1; 70%).
h₂n' ⁿ } ί À °y° 7-(2-((3aS,4R,6aR)-4-(4-Amino-7Hpyrrolo[2,3-d]pyrimidin-7-yl)-2,2dimethyl-3a,6a-dihydro-4H- cyclopenta[d][1,3]dioxol-6-yl)ethyl)3-fluoroquinolin-2-amine	7-(2-((3aS,4R,6aR)-4-(4Chloro-7H-pyrrolo[2,3d]pyrimidin-7-yl)-2,2dimethyl-3a,6a-dihydro4H- cyclopenta[d][1,3]dioxol6-yl)ethyl)-3fluoroquinolin-2-amine	¹H NMR (400 MHz, DMSO-d6) δ 8.05 (s, 1H), 7.79 (d, J = 11.8 Hz, 1H), 7.60 (d, J = 8.2 Hz, 1H), 7.41 (s, 1H), 7.19 (d, J = 8.2 Hz, 1H), 6.96 (s, 2H), 6.72 (s, 2H), 6.35 6.31 (m, 2H), 5.54 (s, 1H), 5.50 (s, 1 H), 5.29 (d, J = 5.9 Hz, 1 H), 4.35 (d, J = 5.7 Hz, 1H), 3.10 - 2.93 (m, 2H), 2.70 - 2.60 (m, 2H), 1.37

148

		(s, 3H), 1.24 (s, 3H); LCMS m/z= 461.3 (M+1; 60%).
_Ηχ ⁿ H k,^N X 7-(2-((3aS,4R,6aR)-4-(4-Amino-7Hpyrro!o[2,3-d]pyrimidin-7-yl)-2,2dimethyl-3a,6a-dihydro-4H- cycÎopenta[d][1,3]dioxol-6-yÎ)ethyl)3-chloroquinolin-2-amine	3-Chloro-7-(2((3aS,4R,6aR)-4-(4chloro-7H-pyrro!o[2,3d]pyrimidin-7-yl)-2,2dimethyl-3a,6a-dihydro4H- cyclopenta[d][1,3]dioxol6-yl)ethyl)quinolin-2amine	¹H NMR (400 MHz, DMSO-d6) δ 8.17 (s, 1H), 8.05 (s, 1H), 7.61 (d, J = 8.3 Hz, 1H), 7.41 (d, J = 1.6 Hz, 1H), 7.19 (dd, J = 8.2, 1.7 Hz, 1H), 6.98 (s, 2H), 6.69 (s, 2H), 6.41 (d, J = 3.6 Hz, 1H), 6.35 (d, J = 3.5 Hz, 1H), 5.55 (s, 1H), 5.51 (s, 1H), 5.29 (d, J = 5.7 Hz, 1H), 4.36 (d, J = 5.7 Hz, 1H), 3.09 2.94 (m, 2H), 2.72-2.56 (m, 2H), 1.37 (s, 3H), 1.28 (s, 3H); LCMS m/z= 477.05 (M+; 20%).
PMB-_nX^N ? i ^H °x° 7-(2-((3aS,4R,6aR)-4-(4-Amino-7Hpyrrolo[2,3-d]pyrimidin-7-yl)-2,2dimethyl-3a,6a-dihydro-4Hcyclopenta[d][1,3]dioxo!-6-yl)ethyl)3-bromo-N'-(4- methoxybenzyl)quinolin-2-amine	3-Bromo-7-(2((3aS,4R,6aR)-4-(4chloro-7H-pyrrolo[2,3d]pyrimidin-7-yl)-2,2dimethyl-3a,6a-dihydro4H- cyclopenta[d][1,3]dioxol6-y!)ethyl)-N-(4methoxybenzyl)quinolin2-amine	¹H NMR (400 MHz, DMSO-d6) δ 8.35 (s, 1H), 8.07 (s, 1H), 7.60 (d, J = 8.2 Hz, 1H), 7.45 (s, 1H), 7.38 - 7.31 (m, 2H), 7.22 - 7.16 (m, 2H), 7.01 (s, 2H), 6.88 - 6.82 (m, 2H), 6.52 (d, J = 3.5 Hz, 1 H), 6.40 (d, J = 3.6 Hz, 1H), 5.56 (s, 1H), 5.52 (s, 1H), 5.30 (d, J = 5.7 Hz, 1 H), 4.66 - 4.61 (m, 2H), 4.38 (d, J = 5.6 Hz, 1H), 3.69 (s, 3H), 3.06 - 2.93 (m, 2H), 2.70 - 2.59 (m, 2H), 1.38 (s, 3H), 1.27 (s, 3H); LCMS m/z= 641.97 (M+; 60%).
ξ _ό ' ' A 7-(2-((3aS,4R,6aR)-4-(4-AminoTHpyrro!o[2,3-d]pyrimidi n-7-yl)-2,2dimethyl-3a,6a-dihydro-4H-	3-Chloro-7-(2- ((3aS,4R,6aR)-4-(4chloro-7H-pyrrolo[2,3d]pyrimidin-7-yl)-2,2dimethyl-3a,6a-dihydro4H- cyclopenta[d][1,3]dioxol-	¹H NMR (400 MHz, DMSO-d6) δ 8.17 (d, J = 0.7 Hz, 1H), 8.05 (s, 1H), 7.26 (s, 1H), 7.05 (dd, J = 11.1, 1.4 Hz, 1H), 7.01 -6.91 (m, 4H), 6.41 (d, J = 3.5 Hz, 1H), 6.35 (d, J = 3.5 Hz, 1H), 5.54 (s, 1H), 5.51 (s, 1H), 5.30 (d, J = 5.7 Hz,

149

cyclopenta[d][1,3]dioxol-6-yl)ethyl)- 3-chloro-5-fluoroquinolin-2-amine	6-yl)ethyl)-5- fluoroquinolin-2-amine	1H), 4.37 (d, J = 5.7 Hz, 1H), 3.07 - 2.95 (m, 2H), 2.71 - 2.56 (m, 2H), 1.37 (s, 3H), 1.27 (s, 3H); LCMS m/z= 495.05 (M+; 40%).
ô J A 7-(2-((3aS,4R,6aR)-4-(4-Amino-7Hpyrroio[2,3-d]pyrimidin-7-yl)-2,2dimethyl-3a,6a-dihydro-4H- cyclopenta[d][1,3]dioxol-6-yl)ethyl)3-bromo-5-fluoroquinolin-2-amine	s i 7 a j i' A c?	¹H NMR (400 MHz, DMSO-d6) δ 8.34 (s, 1H), 8.05 (s, 1H), 7.25 (s, 1H), 7.04 (dd, J = 11.0, 1.4 Hz, 1H), 6.97 (s, 2H), 6.86 (s, 2H), 6.43 (d, J = 3.5 Hz, 1H), 6.37 (d, J = 3.5 Hz, 1H), 5.55 (s, 1H), 5.51 (s, 1H), 5.30 (d, J = 5.7 Hz, 1H), 4.38 (d, J = 5.7 Hz, 1H), 3.08 2.95 (m, 2H), 2.71 -2.58 (m, 2H), 1.37 (s, 3H), 1.28 (s, 3H); LCMS m/z = 541.20 (M+2; 100%)
_zF ^{Cl ν}Οα ^NHî '- nÀ °x° 7-(2-((3aS,4R,6aR)-4-(4-Amino-7Hpyrrolo[2,3-d]pyrimidin-7-yl)-2,2dimethyl-3a,6a-dihydro-4Hcyclopenta[d][1,3]dioxol-6-yl)ethyl)3-chloro-6-fluoroquinolin-2-amine	3-Chloro-7-(2((3aS,4R,6aR)-4-(4chloro-7H-pyrrolo[2,3d]pyrimidin-7-yl)-2,2dimethy!-3a,6a-dihydro4H- cyclopenta[d][1,3]dioxol6-yl)ethyl)-6fluoroquinolin-2-amine	¹H NMR (400 MHz, DMSO-d6) δ 8.17 (s, 1H), 8.06 (s, 1H), 7.53 7.44 (m, 2H), 6.99 (s, 2H), 6.71 (s, 2H), 6.52 (d, J = 3.5 Hz, 1H), 6.40 (d, J = 3.5 Hz, 1H), 5.57 (s, 1H), 5.55 (s, 1H), 5.32 (d, J = 5.7 Hz, 1H), 4.40 (d, J = 5.7 Hz, 1H), 3.12 - 2.99 (m, 2H), 2.70 - 2.56 (m, 2H), 1.36 (s, 3H), 1.28 (s, 3H); LCMS m/z= 494.99 (M+; 20%).
L ΐ i N^A °x° 7-(2-((3aS,4R,6aR)-4-(4-Amino-7Hpyrrolo[2,3-djpyrim id i n-7-yl)-2,2dimethyl-3a,6a-dihydro-4Hcyclopenta[dl[1,3]dioxol-6-yl)ethyl)3-chloro-8-fluoroquinolin-2-amine	3-Ch!oro-7-(2((3aS,4R,6aR)-4-(4chloro-7H-pyrrolo[2,3d]pyrimidin-7-yl)-2,2dimethyl-3a,6a-dihydro4H- cyclopenta[d][1,3]dioxol6-yl)ethyl)-8fluoroquinolin-2-amine	i nus m/?= Αας -ίη /μ+· 7n%> i i u — tw. w ynu ; t w / .

150

Cl H NT ^nZ J ί X·'’ ^H2^N Q^O 7-(2-((3aS,4R,6aR)-4-(4-Amino-7H- pyrrolo[2,3-d]pyrimidin-7-yi)-2,2dimethyl-3a,6a-dihydro-4Hcyclopenta[d][1,3]dioxol-6-yl)ethyl)3,5-dichloroquinolin-2-amtne	3,5-DichIoro-7-(2((3aS,4R,6aR)-4-(4- chloro-7H-pyrrolo[2,3- d]pyrimidin-7-yl)-2,2dimethyl-3a,6a-dihydro- 4H- cyclopenta[d][1,3]dioxol- 6-yl)ethyl)quinolin-2- amine	LCMS m/z= 511.2 (M+; 100%).
\—Z ί V, S i Ν^ζΐΊ °x° 7-((3aS,4R,6aR)-2,2-Dimethyl-6-(2(3-methylimidazo[1,2-a]pyridin-7yl)ethyl)-3a,6a-dihydro-4Hcyclopenta[d][1,3]dioxol-4-yl)-7Hpyrrolo[2,3-d]pyrimidin-4-amine	4-Chloro-7- ((3aS,4R,6aR)-2,2dimethyl-6-(2-(3methylimidazo[1,2a]pyridin-7-yl)ethyl)3a,6a-dihydro-4Hcyciopenta[d][1,3]dioxol4-yi)-7H-pyrrolo[2,3d]pyrimidine	¹H NMR (400 MHz, DMSO-d6) δ 8.19 (d, J = 7.0 Hz, 1H), 8.04 (s, 1H), 7.43 (s, 1H), 7.31 (d, J = 1.1 Hz, 1H), 6.98 (s, 2H), 6.91 (dd, J = 7.1, 1.7 Hz, 1 H), 6.44 (d, J = 3.5 Hz, 1H), 6.35 (d, J = 3.5 Hz, 1H), 5.55 (s, 1H), 5.50 (s, 1H), 5.32 (d, J = 5.6 Hz, 1H), 4.38 (d, J = 5.7 Hz, 1 H), 3.02-2.91 (m, 2H), 2.71 - 2.57 (m, 2H), 2.45 (d, J = 1.0 Hz, 3H), 1.38 (s, 3H), 1.28 (s, 3H); LCMS m/z= 430.98 (M+; 30%).
H,N V=N °x° 7-((3aS,4R,6aR)-6-(2-(2-Amino-3,3dimethyl-3H-indol-6-yl)ethyi)-2,2dimethyl-3a,6a-dihydro-4Hcyclopenta[d][1,3]dioxol-4-yi)-7Hpyrrolo[2,3-d]pyrimidin-4-amine	4-chloro-7- ((3aS,4R,6aR)-6-(2-(3,3dimethyl-2-(methylthio)3H-indol-6-yl)ethyl)-2,2dimethyl-3a,6a-dihydro4H- cyclopenta[d][1,3]dioxol4-yl)-7 H-py rrolo[2,3d]pyrimidine	¹H NMR (400 MHz, DMSO-d6) δ 9.42 (s, 2H), 8.06 (s, 1H), 7.32 (d, J = 7.6 Hz, 1H), 7.10 - 6.95 (m, 4H), 6.45 (s, 2H), 5.56 (s, 1H), 5.51 (s, 1H), 5.28 (d, J = 5.6 Hz, 1 H), 4.37 (d, J = 5.7 Hz, 1 H), 3.02 - 2.84 (m, 2H), 2.65 - 2.54 (m, 2H), 1.46 (s, 6H), 1.36 (s, 3H), 1.28 (s, 3H); LCMS m/z= 459.36 (M+1; 20%).

151

αΑαχ ζ-·α^χ^^ ^Ν Η 1 ν^Α X 6'-(2-((3aS,4R,6aR)-4-(4-Amino-7Hpyrrolo[2,3-d]pyrimidin-7-yl)-2,2dimethyl-3a,6a-dihydro-4Hcyclopenta[d][1,3]dioxoi-6yl)ethyl)spiro [cyclobutane-1,3'- indoi]-2’-amine	6'-(2-((3aS,4R,6aR)-4-(4chloro-7H-pyrrolo[2,3d]pyrimîdin-7-yl)-2,2dimethyl-3a,6a-dihydro4H-cyclopenta[d][1,3] dioxol-6-yl)ethyl)-2'(methylthio)spiro[cyclobu tane-1,3'-indole]	¹H NMR (400 MHz, DMSO-d6) δ 8.06 (s, 1 H), 7.64 (d, J = 7.6 Hz, 1H), 7.09 - 6.97 (m, 4H), 6.47 6.40 (m, 2H), 5.55 (s, 1H), 5.50 (s, 1 H), 5.28 (d, J = 5.7 Hz, 1 H), 4.37 (d, J = 5.6 Hz, 1H), 2.99 - 2.87 (m, 2H), 2.83 - 2.71 (m, 2H), 2.64 - 2.53 (m, 2H), 2.36 - 2.29 (m, 2H), 2.27-2.16 (m, 2H), 1.37 (s, 3H), 1.28 (s, 3H); LCMS m/z= 472.3 (M+2; 100%).
Ay A ,νπ, N ^N ; i N^N °x° 7-(((3aS,4R,6aR)-4-(4-Amino-7Hpyrrolo[2,3-d]pyrimidin-7-yl)-2,2dimethyl-3a,6a-dihydro-4Hcyclopenta[d][1,3]dioxol-6- yl)methoxy)-N-methylquinolin-2amine	7-(((3aS,4R,6aR)-4-(4Chloro-7H-pyrrolo[2,3d]pyrimidin-7-yl)-2,2dimethyl-3a,6a-dihydro4H-cyclopenta[d][1,3] dioxol-6-yl)methoxy)-Nmethyiquinolin-2-amine	¹H NMR (400 MHz, DMSO-d6) δ 8.08 (s, 1H), 7.80 (d, J = 8.9 Hz, 1 H), 7.57 (d, J = 8.7 Hz, 1 H), 7.15 (s, 1H), 7.06 (s, 2H), 6.90 (dd, J = 8.6, 2.4 Hz, 1H), 6.86 (d, J = 3.6 Hz, 1H), 6.64 (d, J = 8.9 Hz, 1H), 6.52 (d, J = 3.6 Hz, 1H), 5.84 (s, 1H), 5.65 (s, 1H), 5.42 (d, J = 5.6 Hz, 1H), 4.93 (s, 2H), 4.53 (d, J = 5.7 Hz, 1H), 2.93 (d, J = 4.8 Hz, 3H), 1.46 (s, 3H), 1.30 (s, 3H); LCMS m/z= 459.40 (M+1; 30%).
F PMB.uX'N' N An H AA X 7-(((3aS,4R,6aR)-4-(4-.Amino-7Hpyrrolo[2,3-d]pyrimidin-7-yl)-2,2dimethyl-3a,6a-dihydro-4Hcyclopenta[d][1,3]dioxol-6- yl)methoxy)-3-chloro-5-fluoro-N-(4methoxybenzyl)quinolin-2-amine	3-Chloro-7- (((3aS,4R,6aR)-4-(4chloro-7H-pyrrolo[2,3d]pyrimidin-7-yl)-2,2d i methyl-3a ,6a-d i hydro4H-cyclopenta[d][1,3] dioxol-6-yl)methoxy)-5fluoro-N-(4- methoxybenzyl)quinolin2-amine	n iwirx ινιπζ., u 8.11 (s, 1H), 8.07 (s, 1H), 7.67 (t, j = 6.2 Hz, 1H), 7.36 - 7.31 (m, 2H), 7.01 (s, 2H), 6.94 (d, J = 2.2 Hz, 1 H), 6.90 - 6.81 (m, 4H), 6.51 (d, J = 3.6 Hz, 1H), 5.83 (s, 1H), 5.65 (s, 1H), 5.42 (d, J = 5.7 Hz, 1H), 4.94 (q, J = 15.3 Hz, 2H), 4.65 (d, J = 6.1 Hz, 2H), 4.55 (d, J = 5.7 Hz, 1H), 3.70 (s, 3H), 1.43

152

		(s, 3H), 1.29 (s, 3H); LCMS m/z= 617.34 (M+; 100%).
ΡΜΒ-_ΝΆ Η A aJ Η O^Ô N7-(((3aS,4R,6aR)-4-(4-Amino-7Hpyrrolo[2,3-d]pyrimidin-7-yl)-2,2dimethyl-3a,6a-dihydro-4Hcyclopenta[d][1,3]dioxol-6yl)methyl)-N2-(4methoxybenzy!)quinoline-2,7diamine	N7-(((3aS,4R,6aR)-4-(4Chloro-7H-pyrrolo[2,3d]pyrimidin-7-yl)-2,2dimethyl-3a,6a-dihydro4H-cyclopenta[d][1,3] dioxol-6-yl)methyl)-N2(4methoxybenzyl)quinoline -2,7-diamine	LCMS m/z= 564.40 (M+1: 100%).
' y ⁿ^ⁿ N7-(((3aS,4R,6aR)-4-(4-Amino-7Hpyrrolo[2,3-d]pyrimidin-7-yl)-2,2dimethyl-3a,6a-dihydro-4Hcyclopenta[d][1 ,3]dioxol-6yl)methyl)-N2-(4-methoxybenzyl)N7-methyiquinoline-2,7-diamine	N7-(((3aS,4R,6aR)-4-(4Chloro-7H-pyrrolo[2,3d]pyrimidin-7-yl)-2,2dimethyl-3a,6a-dihydro4H- cyclopenta[d][1,3]dioxol6-y I ) methy l)- N2-(4methoxybenzyl)-N7methylquinoline-2,7diamine	LCMS m/z= 576.95 (M-1; 100%).
u. AA's \ j ï Y ΡΜΒ-_μ ^λ N .· - N<A H Ο_χΟ 7-((((3aS,4R,6aR)-4-(4-Amino-7Hpyrrolo[2,3-d]pyrimidin-7-yl)-2,2dimethyl-3a,6a-dihydro-4Hcyclopenta[d][1,3]dioxo!-6- yl)methyl)thio)-N-(4- methoxybenzyl)quinolin-2-amine	7-((((3aS,4R,6aR)-4-(4- Chloro-7H-pyrrolo[2,3d]pyrimidin-7-yl)-2,2dimethyl-3a,6a-dihydro4H- cyciopenta[d][1,3jdioxoi6-y 1 ) methy l)th io)- N-(4methoxybenzyl)quinolin2-amine	¹H NMR (400 MHz, DMSO-d6) δ 8.03 (s, 1H), 7.84 (d, J = 8.9 Hz, 1H), 7.57 (d, J = 8.3 Hz, 1H), 7.49 (s, 2H), 7.36 - 7.26 (m, 2H), 7.18 (d, J = 8.4 Hz, 1H), 6.96 (s, 2H), 6.84 (d, J = 8.2 Hz, 2H), 6.82 6.76 (m, 1 H), 6.16 (s, 1 H), 6.01 (s, 1H), 5.76 (s, 2H), 5.71 (s, 1H), 5.54 (s, 1H), 5.38 (s, 1H), 4.55 (s, 1H), 4,34 (d, J = 5.5 Hz, 1H), 4.19 (d, J = 15.2 Hz, 1H), 3.70 (s, 3H),

153

		1.42 (s, 3H), 1.27 (s, 3H); LCMS m/z= 580.83 (M+; 100%).
A XXs va Y» (PMB)₂N ^N N^N X 7- ((((3aS,4R,6aR)-4-(4-Amino-7Hpyrrolo[2,3-d]pyrimidin-7-yl)-2,2dimethyl-3a,6a-dihydro-4Hcyclopenta[d][1,3]dioxol-6- y l)methy l)thio)-3-chloro-N, N-bis(4methoxybenzyl)quinolin-2-amine	3-Chloro-7- ((((3aS,4R,6aR)-4-(4chloro-7H-pyrrolo[2,3d]pyrimidin-7-yl)-2,2dimethyl-3a,6a-dihydro4H- cyclopenta[d][1,3]dioxol6-yl)methyl)thio)-N,Nbis(4- methoxybenzyl)quinoiin2-amine	LCMS m/z= 735.61 (M+; 80%).
H₂N ^N z i fA-A °\z° Ύ X nh₂ 7-(2-((3aS,4R,6aR)-4-(2-Amino-7Hpyrrolo[2,3-d]pyrimidin-7-yl)-2,2dimethyi-3a,6a-d!hydro-4Hcyclopenta[d][1,3]dioxol-6-yl)ethyl)3-chloroquinolin-2-amine	3-Chloro-7-(2((3aS,4R,6aR)-4-(2chloro-7H-pyrrolo[2,3d]pyrimidin-7-yl)-2,2d i methyl-3a ,6a-d i hyd ro4H- cyciopenia[a][1,3jdioxoî~ 6-yl)ethyl)quinolin-2amine	¹H NMR (400 MHz, DMSO-d6) δ 8.43 (s, 1H), 8.17 (s, 1H), 7.61 (d, J = 8.3 Hz, 1H), 7.40 (d, J = 1.5 Hz, 1H), 7.28 (s, 2H), 7.19 (dd, J = 8.3, 1.7 Hz, 1H), 6.69 (s, 2H), 6.23 (d, J = 3.7 Hz, 1H), 6.03 (d, J = 3.6 Hz, 1H), 5.46 (s, 1H), 5.43 (s, 1H), 5.33 (d, J = 5.7 Hz, 1H), 4.36 (d, J = 5.6 Hz, 1H), 3.10 2.93 (m, 2H), 2.67 - 2.56 (m, 2H), 1.36 (s, 3H), 1.28 (s, 3H); LCMS m/z= 476.98 (M+; 100%).
F PMEU^N M X,N m Ô Ω X 7-(2-((3aS,4R,6aR)-4-(4-Amino-5fluoro-7H-pyrrolo[2,3-d]pyrimidin-7yl)-2,2-dimethyl-3a,6a-dihydro-4Hcyclopenta[d][1,3]dioxol-6-yl)ethyl)-	3-Bromo-7-(2((3aS,4R,6aR)-4-(4chloro-5-fluoro-7Hpyrrolo[2,3-d]pyrimidin-7yl)-2,2-dimethyl-3a,6adihydro-4H- cyclopenta[d][1,3]dioxol6-yl)ethyl)-N-(4-	¹H NMR (400 MHz, DMSO-d6) δ 8.35 (s, 1H), 8.06 (s, 1H), 7.60 (d, J = 8.3 Hz, 1H), 7.45 (s, 1H), 7.36 - 7.31 (m, 2H), 7.21 - 7.16 (m, 2H), 6.95 (s, 2H), 6.86 - 6.82 (m, 2H), 6.35 (d, J = 2.1 Hz, 1H), 5.58 (s, 1H), 5.48 (s, 1H), 5.28 (d, J = 5.6 Hz, 1H), 4.37 (d, J = 5.6 Hz, 1H), 4.27 (d, J = 4.1 Hz, 2H), 3.68

154

3-bromo-N-(4- methoxybenzyl)quinolin-2-amine	methoxybenzyl)quinolin- 2-amine	(s, 3H), 3.05 - 2.97 (m, 2H), 2.67 -2.57 (m, 2H), 1.36 (s, 3H), 1.27 (s, 3H); LCMS m/z= 660.97 (M+1; 25%).
ciaAi Λ /A⁷ \ / v « h n ^N ; - ⁿ^ⁿ ri₂N ₀ 0 A 7-(2-((3aS,4R,6aR)-4-(4-Amino-7Hpyrrolo[2,3-d]pyrimidin-7-yi)-2,2dimethyl-3a,6a-dihydro-4Hcyclopenta[d][1,3]dioxol-6yl)propyl)-3-chloroquinolin-2-amine	3-Chloro-7-(2((3aS,4R,6aR)-4-(4chloro-7H-pyrrolo[2,3d]pyrimidin-7-yl)-2,2dimethyl-3a,6a-dihydro4H- cyclopenta[d][1,3]dioxol6-yl)propyl)quinolin-2amine	Diastereomeric mixture was separated by chiral préparative HPLC. Run Time (min): 10.00, Injection Volume: 5.00 pL Wavelength: 225nm HEX_0.1 %DEA_I PA_DCM_60_4 0_A_C_1.2ML_10MIN Flow Rate: 1.2 ml/min. Column : CHIRALPAK IA CRL-027 OLD Column Temp: 25.0 °C Mobile Phase A: HEX_0.1%DEA Mobile Phase C: IPA:DCMMobile Phase B: NA Mobile Phase D: NA Disstereomer^- 1 1H NMR (400 MHz, DMSO-d6) δ 8.17 (s, 1H), 8.04 (s, 1H), 7.61 (d, J = 8.2 Hz, 1H), 7.38 (s, 1H), 7.16 (dd, J = 8.1, 1.6 Hz, 1H), 6.98 (s, 2H), 6.67 (s, 2H), 6.32 (d, J = 3.5 Hz, 1H), 6.29 (d, J = 3.6 Hz, 1 H), 5.55 (s, 1H), 5.52 (s, 1H), 5.41 (d, J = 5.8 Hz, 1H), 4.35 (d, J = 5.8 Hz, 1 H), 3.12 - 3.03 (m, 1 H), 2.96 - 2.90 (m, 1H), 2.88 - 2.81 (m, 1H), 1.31 (s, 3H), 1.27 (s, 3H), 1.17 (d, J = 6.8 Hz, 3H); LCMS m/z= 491.36 (M+; 80%). Diastereomer-2

155

		1H NMR (400 MHz, DMSO-d6) δ 8.17 (s, 1H), 8.06 (s, 1H), 7.61 (d, J = 8.2 Hz, 1H), 7.36 (s, 1H), 7.15 (dd, J = 8.3, 1.6 Hz, 1H), 6.97 (s, 2H), 6.67 (s, 2H), 6.56 (d, J = 3.6 Hz, 1H), 6.44 (d, J = 3.6 Hz, 1H), 5.60 - 5.56 (m, 1H), 5.52 (d, J = 2.5 Hz, 1H), 5.34 (d, J = 5.7 Hz, 1 H), 4.40 (d, J = 5.7 Hz, 1 H), 3.13 - 3.04 (m, 1H), 2.93 (q, J = 7.2 Hz, 1 H), 2.83 (d, J = 10.0 Hz, 1 H), 1.40 (s, 3H), 1.28 (s, 3H), 1.14 (d, J = 6.8 Hz, 3H); LCMS m/z= 491.36 (M+; 80%).
PMB-nTv ₂ nTz^N H °_v° Λ 7-(2-((3aS,4R,6aR)-4-(4-Amino-7Hpyrrolo[2,3-d]pyrimidin-7-yl)-2,2dimethyl-3a,6a-dihydro-4Hcyclopenta[d][1,3]dioxol-6yl)propyl)-3-bromo-N-(4methoxybenzyl)quinolin-2-amine	3-Bromo-7-(2((3aS,4R,6aR)-4-(4chloro-7H-pyrrolo[2,3d]pyrimidin-7-yÎ)-2,2dimethyl-3a,6a-dihydro4H- cyclopenta[d][1,3]dioxol6-yl)propyî)-N-(4methoxybenzyl)quinolin2-amine	Diastereomeric mixture was separated by chiral préparative HPLC. Run Time (min): 10.00 Injection Volume: 5.00 pL.Wavelength: 251 nm, HEX_0.1%DEA_IPA- DCM_50_50_A_C_1,0ML_1 OMI N_251nm Flow Rate: 1.0 ml/min. Column : CHIRALPAK IG CRL071 Column Temp: 25.0 °C. Mobile Phase A: HEX_0.1%DEA Mobile Phase C: IPA-DCM_1-1, Mobile Phase B: NA Mobile Phase D: NA Diastereomer-1: ¹H NMR (400 MHz, DMSO-d6) δ 8.36 (s, 1H), 8.07 (s, 1H), 7.60 (d, J = 8.2 Hz, 1 H), 7.41 (d, J = 1.4 Hz, 1 H), 7.37

156

		- 7.33 (m, 2H), 7.19 - 7.13 (m, 2H), 6.99 (s, 2H), 6.87 - 6.83 (m, 2H), 6.63 (d, J = 3.6 Hz, 1H), 6.46 (d, J = 3.5 Hz, 1H), 5.59 (s, 1H), 5.53 (s, 1H), 5.32 (d, J = 5.7 Hz, 1H), 4.65 (d, J = 6.0 Hz, 2H), 4.40 (d, J = 5.8 Hz, 1H), 3.69 (s, 3H), 3.Γ1 - 3.04 (m, 1H), 2.86 - 2.76 (m, 2H), 1.41 (s, 3H), 1.28 (s, 3H), 1.14 (d, J = 6.5 Hz, 3H); LCMS m/z= 657.47 (M+2; 45%). Diastereomer-2: ¹H NMR (400 MHz, DMSO-d6) δ 8.35 (s, 1 H), 8.05 (s, 1H), 7.60 (d, J = 8.1 Hz, 1H), 7.42 (s, 1H), 7.33 (d, J = 8.5 Hz, 2H), 7.18 - 7.13 (m, 2H), 7.00 (s, 2H), 6.84 (d, J = 8.6 Hz, 2H), 6.43 (d, J = 3.6 Hz, 1H), 6.38 (d, J = 3.5 Hz, 1H), 5.55 (s, 1H), 5.52 (s, 1H), 5.42 (d, J = 5.7 Hz, 1H), 4.63 (d, J = 6.0 Hz, 2H), 4.38 (d, J = 5.7 Hz, 1H), 3.69 (s, 3H), 3.10 - 3.05 (m, 1H), 2.96 - 2.90 (m, 2H), 1.32 (s, 3H), 1.27 (s, 3H), 1.16 (d, J — 6.8 Hz, 3H); LCMS m/z= 655.47 (M+; 35%).
F N À h₂n 0^,0 /'-(2-((3aS,4R,6aR)-4-(4-Amino-7Hpyrrolo[2,3-d]pyrimidin-7-yl)-2,2dimethyl-3a,6a-dihydro-4Hcyclopenta[d][1,3]dioxol-6-	3-Chloro-7-(2((3aS,4R,6aR)-4-(4chloro-7H-pyrrolo[2,3d]pyrimidin-7-yl)-2,2dimethyl-3a,6a-dihydro4H- cyclopenta[d][1,3]dioxol6-yl)propyl)-5fluoroquinolin-2-amine	LCMS m/z= 509.3 (M+; 60%).

157

yI)propyl)-3-chloro-5-fluoroquinolin2-amine
F h₂n °A° 7-(2-((3aS,4R,6aR)-4-(4-Amino-7Hpyrrolo[2,3-d]pyrimidin-7-yl)-2,2dimethyl-3a,6a-dihydro-4Hcyclopenta[d][1,3]dioxol-6- yl)propyl)-3-bromo-5-fluoroquinolin2-amine	s ^βγ αΑΑΑυ Ά^! Λ	Diastereomeric mixture was separated by chiral préparative HPLC. Run Time (min): 15.00, Injection Volume: 10.00 pL, Wavelength: 254nm, Flow Rate: 1.50 ml/min, Column Temp: 30.0 °C, Instrument Method: ACN_DEA_100_B_1,5ML_15MI N_254NM, Column : CHIRALPAK OX-H CRL-061, Mobile Phase A: NA, Mobile Phase B: ACN_0.1%DEA Diastereomer-1: LCMS m/z = 553.20, 555.20 (M+;M+2; 100%) Diastereomer-2: ¹H NMR (400 MHz, DMSO-d6) δ 8.35 (s, 1H), 8.06 (s, 1H), 7.20 (s, 1H), 7.00 6.96 (m, 3H), 6.86 (s, 2H), 6.57 (d, J = 3.5 Hz, 1H), 6.45 (d, J = 3.5 Hz, 1H), 5.57 (s, 1H), 5.53 (s, 1 H), 5.34 (d, J = 5.8 Hz, 1 H), 4.41 (d, J = 5.7 Hz, 1H), 3.09 - 3.01 (m, 2H), 2.85 - 2.83 (m, 1 H), 1.40 (s, 3H), 1.28 (s, 3H), 1.15 (d, J = 6.0 Hz, 3H); LCMS m/z = 555.20 (M+2; 100%)
T Z A-²,.........( /) [I / ^xo à ZI /	7-(1-((3aS,4R,6aR)-4-(4- Chloro-7H-pyrrolo[2,3d]pyrimidin-7-yi)-2,2dimethyl-3a,6a-dihydro-	LCMS m/z= 473.11 (M+1; 20%).

158

7-(1-((3aS,4R,6aR)-4-(4-Amino-7Hpyrrolo[2,3-d]pyrim idi n-7-yl)-2,2dimethyl-3a,6a-dihydro-4Hcyclopenta[d][1,3]dioxol-6yl)ethoxy)-N-methylquinolin-2amine	4H- cyclopenta[d][1,3]dioxol- 6-yi)ethoxy)-N- methylquinolin-2-amine
ξ y \ / γ 'À h₂n ⁿ d o Λ 7-(2-((3aS,4R,6aR)-4-(4-Amino-7Hpyrrolo[2,3-d]pyrimidin-7-yl)-2,2,6atrimethyÎ-3a,6a-dihydro-4Hcyclopenta[d][1,3]dioxol-6-yl)ethyl)3-chloro-5-fluoroquinolin-2-amine	3-Chloro-7-(2((3aS,4R,6aR)-4-(4chloro-7H-pyrrolo[2,3d]pyrimidin-7-yl)-2,2,6atrimethyl-3a,6a-dihydro- 4H- cyclopenta[d][1,3]dioxoi6-yl)ethyl)-5fluoroquinolin-2-amine	¹H NMR (400 MHz, DMSO-d6) δ 8.17 (d, J = 0.7 Hz, 1H), 8.09 (s, 1H), 7.27 (s, 1H), 7.09-7.01 (m, 3H), 6.95 (s, 2H), 6.65 (d, J = 3.5 Hz, 1H), 6.47 (d, J = 3.5 Hz, 1H), 5.63 - 5.58 (m, 1H), 5.49 - 5.44 (m, 1H), 4.00 (d, J = 0.9 Hz, 1H), 3.06 (t, J = 7.6 Hz, 2H), 2.70 2.59 (m, 1 H), 2.59 - 2.53 (m, 1 H), 1.39 (s, 3H), 1.30 (s, 3H), 1.28 (s, 3H); LCMS m/z= 509.2 (M+; 90%).
V A- 7—⁷ \ / V « fl '' M'_;A h₂n / d ô A 7-(2-((3aS,4R,6aR)-4-(4-Amino-7Hpyrrolo[2,3-d]pyrimidin-7-yl)-6aethyl-2,2-dimethyl-3a,6a-dihydro4H-cyclopenta[d][1,3]dioxol-6yl)ethyl)-3-chloro-5-fluoroquinolin-2amine	3-Chloro-7-(2((3aS,4R,6aR)-4-(4chloro-7H-pyrrolo[2,3d]pyrimidin-7-yi)-6aethyi-2,2-dimethyl-3a,6adihydro-4H- cyclopenta[d][1,3]dioxol6-yl)eîhyl)-5fluoroquinolin-2-amine	A NMR (400 MHz, DMSO-d6) δ 8.18 (s, 1H), 8.09 (s, 1H), 7.28 (s, 1H), 7.06 (dd, J = 11.1, 1.4 Hz, 1H), 6.99 (s, 2H), 6.95 (s, 2H), 6.68 (d, J = 3.5 Hz, 1H), 6.45 (d, J = 3.5 Hz, 1H), 5.73 (d, J = 2.3 Hz, 1 H), 5.47 - 5.43 (m, 1 H), 4.09 (s, 1H), 3.07 (t, J = 7.6 Hz, 2H), 2.70 - 2.54 (m, 2H), 1.84 (dq, J = 14.9, 7.4 Hz, 1H). 1.59 (dq, J = 14.7, 7.4 Hz, 1H), 1.31 (s, 3H), 1.27 (s, 3H), 0.68 (t, J = 7.4 Hz, 3H); LCMS m/z= 523.44 (M+; 95%).

159

F \ / T « H₂N ^N ΐ lM ² °X° 7-(2-((3aS,4R,6aR)-4-(4-Amino-7Hpyrrolo[2,3-d]pyrimidin-7-yl)-2,2,6atrimethyl-3a,6a-dihydro-4Hcyclopenta[d][1,3]dioxol-6yl)propyl)-3-ch!oro-5-fluoroquinolin2-amine	3-C.hloro-7-(2((3aS,4R,6aR)-4-(4chloro-7H-pyrrolo[2,3d]pyrimidin-7-yl)-2,2,6atrimethyl-3a,6a-dihydro4H- cyclopenta[d][1,3]dioxol6-yl)propyl)-5fluoroquinolin-2-amine	Diaste.reomer-1: ¹H NMR (400 MHz, DMSO-d6) δ 8.20 (s, 1H), 8.06 (s, 1H), 7.26 (s, 1H), 7.06 (dd, J= 11.1, 1.4 Hz, 1H), 6.96 (s, 4H), 6.21 (d, J = 3.5 Hz, 1 H), 5.97 (d, J = 3.6 Hz, 1H), 5.69 (d, J = 2.6 Hz, 1H), 5.45 (d, J = 2.7 Hz, 1H), 3.86 (s, 1H), 3.10-2.97 (m, 2H), 2.93 - 2.84 (m, 1 H), 1.36 (s, 3H), 1.27 (s, 3H), 1.24 (d, J = 3.0 Hz, 3H), 1.19 (s, 3H); LCMS m/z= 523.32 (M+; 50%). Note- Only desired isomer was isolated
PMB-m-An —) i n^N H 0 O A 7-(((3aS,4R,6aR)-4-(4-Amino-7Hpyrrolo[2,3-d]pyrimidin-7-yl)-2,2,6atrimethyl-3a,6a-dihydro-4Hcyciopenta[d][1,3]dioxoî-6- y I ) methoxy)-3-ch I o ro-5-f luoro- N-(4methoxybenzyl)quinolin-2-amine	3-Chloro-7- (((3aS,4R,6aR)-4-(4chloro-7H-pyrrolo[2,3d]pyrimidin-7-yl)-2,2,6atrimethyl-3a,6a-dihydro4H- cyclopenta[d][1,3]dioxol6 -y i ) methoxy)-5-fluoro- N(4- methoxybenzyl)quinolin2-amine	LCMS m/z= 631.30 (M+; 60%).
A AJ \ I, PMB-kAN b i Ν^/^Ν ^H °x° z'-(1-((3aS,4R,6aR)-4-(4-Amino7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2dimethyl-3a,6a-dihydro-4Hcyclopenta[d][1,3]dioxol-6-	3-Chloro-7-(1- ((3aS,4R,6aR)-4-(4chloro-7H-pyrroio[2,3d]pyrimidin-7-yl)-2,2- dimeihyl-3a,6a-dihydro- 4H- çyclopenta[d]F1,3]dioxol6-yl)ethoxy)-5-fluoro-N(4-	Diastereomer-1 LCMS m/z= 631.34 (M+; 100%). Diastereomer-2 LCMS m/z= 631.34 (M+; 100%).

160

yl)ethoxy)-3-chloro-5-fluoro-N-(4methoxybenzyl)quinolin-2-amine	methoxybenzyl)quinolin- 2-amine
'' i l PMBHN ^N ; i N_;z ⁿ X 7-(2-((3aR,3bR,4aS,5R,5aS)-5-(4amino-7H-pyrrolo[2,3-d]pyrimidin-7yl)-2,2- d i methyl hexa hyd rocyclop ropa[3,4]c yclopenta[1,2-d][1,3]dioxol-3byl)ethyl)-3-bromo-N-(4- methoxybenzyl)quinolin-2-amïne	3-bromo-7-(2((3aR,3bR,4aS,5R,5aS)5-(4-chloro-7H- pyrrolo[2,3-d]pyrimidin-7yi)-2,2- dimethylhexahydrocyclop ropa[3,4]cyclopenta[1,2d][1,3]dioxol-3b-yl)ethyl)N-(4methoxybenzyl)quinolin2-amine	¹H NMR (400 MHz, DMSO-d6) δ 8.33 (s, 1H), 8.08 (s, 1H), 7.57 (d, J = 8.2 Hz, 1H), 7.43 (d, J = 1.6 Hz, 1 H), 7.37 - 7.31 (m, 2H), 7.19 (t, J = 6.1 Hz, 1H), 7.16 (dd, J = 8.2, 1.6 Hz, 1H), 7.14 (d, J = 3.5 Hz, 1H), 7.03 (s, 2H), 6.90 6.84 (m, 2H), 6.61 (d, J = 3.5 Hz, 1H), 5.21 (d, J = 7.3 Hz, 1H), 5.01 (s, 1H), 4.62 (d, J = 6.1 Hz, 2H), 4.51 (dd, J = 7.4, 1.5 Hz, 1 H), 3.71 (s, 3H), 2.88—2.79 (m, 2H), 2.36 - 2.24 (m, 1 H), 1.67 1.58 (m, 1H), 1.48 (s, 3H), 1.46 -1.41 (m, 1 H), 1.19 (s, 3H), 0.92 (t, J = 4.7 Hz, 1H), 0.74 - 0.68 (m, 1H); LCMS m/z = 656.2 (M+1; 40%).
PMBHN' ^N ' Ô Ô ^N-A 7-((E)-1-((3aR,3bS,4aS,5R,5aS)-5(4-amino-7H-pyrrolo[2,3d]pyrimidin-7-y 1)-2,2- dimethyltetrahydrocyclopropa[3,4]cy clopenta[1,2-d][1,3]dioxol-3b(3aH)yl)prop-1-en-2-yl)-3-bromo-N-(4methoxybenzyl)quinolin-2-amine	3-bromo-7-((E)-1((3aR,3bS,4aS,5R,5aS)5-(4-chloro-7Hpyrrolo[2,3-d]pyrimidin-7yi)-2,2dimethyltetrahydrocyclop ropa[3,4]cyclopenta[1,2d][1,3]dioxol-3b(3aH)yl)prop-1-en-2-yl)-N-(4methoxybenzyl)quinolin2-amine	¹H NMR (400 MHz, DMSO-d6) δ 8.38 (s, 1H), 8.08 (s, 1H), 7.64 (s, 1H), 7.58 (d, J = 8.3 Hz, 1H), 7.45 - 7.40 (m, 1H), 7.33 (d, J = 8.4 Hz, 2H), 7.16 (d, J = 3.6 Hz, 1H), 7.12 (t, J = 6.0 Hz, 1 H), 7.01 (s, 2H), 6.87 (d, J = 8.6 Hz, 2H), 6.63 (d, J = 3.5 Hz, 1H), 6.17 (s, 1H), 5.26 (d, J = 6.9 Hz, 1H), 4.94 (s, 1H), 4.70 (dd, J = 14.7, 6.0 Hz, 1H), 4.59 (dd, J = 14.7, 6.0 Hz, 1H), 4.48 (d, J = 6.9 Hz, 1H), 3.71 (s, 3H), 2.12 (s, 3H), 1.51 (s, 3H), 1.46-1.39 (m, TH),

161

		1.19 (s, 3H), 0.90 (t, J = 5.1 Hz, 1H), 0.26 - 0.18 (m, 1H); LCMS m/z = 668.97 (M+1; 30%).
PMB-_nÀn )—( A N ^H V 7-(2-((3aR,3bS,4aS,5R,5aS)-5-(4amino-7H-pyrrolo[2,3-d]pyrimidin-7yl)-2,2- dimethyltetrahydrocyclopropa[3,4]cy clopenta[1,2-d][1,3]dioxol-3b(3aH)yl)propyl)-3-chloro-5-fluoro-N-(4methoxybenzyÎ)quinoiin-2-amine	3-chloro-7-(2((3aR,3bS,4aS,5R,5aS)5-(4-chloro-7H- pyrrolo[2,3-d]pyrimidin-7yl)-2,2- di methy Itetrahyd rocy clop ropa[3,4]cyclopenta[1,2d][1,3]dioxol-3b(3aH)yl)propyl)-5-fluoro-N-(4methoxybenzyl)quinolin2-amine	Diastereomeric mixture was separated by chiral préparative HPLC. Wavelength: 225nm, Instrument Method: H EX-0.1 % D EAJ PADCM_50_50_ A_C_1.2ML_8MIN Flow Rate: 1.2 ml/min, Column CHIRALPAK IG CRL-071 Column Temp: 25°C, Mobile Phase A: HEX_0.1%DEA Mobile Phase C: IPA-DCM, Mobile Phase B: NA Mobile Phase D: NA First Diastereomer: LCMS m/z = 643.09(M+; 30%). Second Diastereomer: LCMS m/z = 643.09(M+; 30%).
aAVA k/\*N X.,,-^nh2 V \^-r / L ρμβ-^ν A n^A ^H °x° 7-(2-((3aR,3bS,4aS,5R,5aS)-5-(4amino-7H-pyrrolo[2,3-d]pyrimidin-7yl)-2,2- dimethyltetrahydrocyclopropa[3,4]cy clopenta[1,2-d][1,3]dioxol-3b(3aH)yl)-2-cyclopropylethyl)-3-chloro-5fluoro-N-(4-methoxybenzyi)quinolin2-amine	3-chloro-7-(2((3aR,3bS,4aS,5R,5aS)5-(4-chloro-7H- pyrrolo[2,3-d]pyrimidin-7yl)-2,2- d i methy Itetrahyd rocyclop ropa[3,4]cyclopenta[1,2d][1,3]dioxol-3b(3aH)-yl)2-cyclopropylethyl)-5fluoro-N-(4- methoxybenzyl)quinolin2-amine	LCMS m/z = 669.10(M+; 20%).

162


A, AA''·'' \ u PMBHN ^N c i N^N °x° 7-(2-((3aR,3bS,4aS,5R,5aS)-5-(4amino-7H-pyrrolo[2,3-d]pyrimidin-7yi)-2,2- dimethyltetrahydrocyclopropa[3,4]cy clopenta[1,2-d][1,3]dioxol-3b(3aH)yl)propyl)-3-bromo-N-(4methoxybenzyl)quino!in-2-amine	3-Bromo-7-(2((3aR,3bS,4aS,5R,5aS)5-(4-chloro-7H- pyrrolo[2,3-d]pyrimidin-7yl)-2,2- dimethyltetrahydrocyclop ropa[3,4]cyclopenta[1,2d][1,3]dioxol-3b(3aH)yl)propyl)-N-(4methoxybenzyl)quinolin2-amine	LCMS m/z = 670.97(M+1; 20%).
îAwtaT PMBHN ^N ; i 0 0 X 7- (2-((3aR,3bR,4aS,5R,5aS)-5-(4amino-7H-pyrrolo[2,3-d]pyrimidin-7yl)-2,2- dimethyltetrahydrocyclopropa[3,4]cy clopenta[1,2-d][1 ,3]dioxôi-3b(3aH)yl)ethyl)-N-(4- methoxybenzyl)quinazolin-2-amine	7-(2- ((3aR,3bR,4aS,5R,5aS)5-(4-chloro-7H- pyrrolo[2,3-d]pyrimidin-7yi)-2,2- dimethyltetrahydrocyclop ropa[3,4]cyclopenta[1,2d][1,3]dioxol-3b(3aH)y!)ethyl)-N-(4methoxybenzyî)quinazoii n-2-amine	¹H NMR (400 MHz, DMSO-d6) δ 9.04 (s, 1 H), 8.07 (s, 1 H), 7.79 (t, J = 6.3 Hz, 1H), 7.69 (d, J = 8.2 Hz, 1H), 7.35 (s, 1H), 7.30 (d, J = 8.2 Hz, 2H), 7.17 (dd, J = 8.2, 1.6 Hz, 1H), 7.13 (d, J = 3.5 Hz, 1 H), 7.01 (s, 2H), 6.90 - 6.84 (m, 2H), 6.61 (d, J = 3.5 Hz, 1H), 5.21 (d, J = 7.1 Hz, 1H), 5.01 (s, 1 H), 4.57 - 4.48 (m, 3H), 3.71 (s, 3H), 2.91 - 2.80 (m, 2H), 2.35 2.24 (m, 1H), 1.69 - 1.58 (m, 1 H), 1.48 (s, 3H), 1.47 -1.42 (m, 1H), 1.20 (s, 3H), 0.93 (t, J = 4.7 Hz, 1H), 0.75 - 0.69 (m, 1H); LCMS m/z = 578.3 (M+1; 90%).
:F ^!CX-z ^{n H 2} '/''-μ'''Ύ' \ * 1 h h₂n ⁿ ' .· - AÂ A 7- (2-((3aR,3bR,4aS,5R,5aS)-5-(4-	7-(2- ((3aR,3bR,4aS,5R,5aS)- 5-(4-Chioro-7H- pyrrolo[2_!3-d]pyrimidin-7-	¹H NMR (400 MHz, DMSO-d6) δ 8.07 (s, 1H), 7.88 (d, J = 8.9 Hz, 1H), 7.36 (d, J = 8.2 Hz, 1H), 7.13 (d, J = 3.7 Hz, 1H), 7.09 (t,

163

amino-7H-pyrroiop,3-d]pynmidin-7yl)-2,2- d i methy ltetrahydrocydopropa[3,4}cy clopenta[1,2-d][1,3]dioxol-3b(3aH)yl)ethyl)-8-fluoroquinolin-2-amine	yl)-2,2- dîmethyftetrahydrocyctop ropa(3,4]cyctopenta[1,2d][1,3]dioxol-3b(3aH)~ y0ethyl)-84luoroquinoün2-amine	J = 7.4 Hz, 1H), 7.00 (s, 2H), 6.75 (d, J = 8.9 Hz, 1 H), 6.65 (s, 2H), 6.61 (d, J = 3.5 Hz, 1H), 5.21 (d, J = 7.2 Hz, 1H), 5.01 (s, 1H), 4.55 (d, J = 7.2 Hz, 1H), 2.93 - 2.79 (m, 2H), 2.29 - 2.20 (m, 1H), 1.68 - 1.58 (m, 1H), 1.49 (s, 3H), 1.47 - 1.43 (m, 1 H), 1.21 (s, 3H), 0.96 (t, J = 4.8 Hz, 1H), 0.75 (dd, J = 9.0, 5.0 Hz, 1H); LCMS m/z = 475.2 (M+1; 30%).
Ν'Ά M H O A 7- (2-((3aR,3bR,4aS,5R,5aS)-5-(4- amino-7H-pyrrolo[2,3-d}pyrimidtn-7yl)-2,2- dimethylhexahydrocyclopropap,4]c yclopenta[1,2-d][1,3]dîoxoi-3byl)ethyl)-N-methylquinolin-2-amine	7-(2- ((3aR,3bR,4aS,5R,5aS)5-(4-chtoro-7H- pyrrokj[2,3-d}pyrimidm-7yD-2,2- dimeihylhexahydrocyctop ropa[3,4]cydopema[1 ,2d][1,3]dioxoi-3b-yl)ethyl)N-methyiquinoiin-2amine	NMR (400 MHz, DMSO-d6) δ §.08 (s, TH), 7.84 (d, J = 8.9 Hz, 1H), 7.55 (d, J = 8.1 Hz, 1H), 7.46 <s, 1 H), 7.16 - 7.10 (m, 2H), 7.06 (s, 2H), 6.72 (d, J = 8.9 Hz, 1HL 6.62 (d, J = 3.5 Hz, 1H), 5.22 (d, J = 7.2 Hz, 1H), 5.02 (s, 1H)_S 4.52 (dd, J = 7.3, 1.5 Hz, 1H)_t 2.91 (d, J = 4.7 Hz, 3H), 2.88 - 2.77 (m, 2H), 2.32 - 2.24 (m, 1H), 1.70 - 1.61 (m, 1H), 1.49 (s, 3H), 1.48-1.44 (m, 1H), 1.20 (s, 3H), 0.94 (t, J = 4.7 Hz, 1H), 0.74 (dd, J = 9.2, 5.0 Hz, 1H); LCMS m/z = 471.23 (M+1; 15%).
TAo^îrA’' PMBHN ^N θ AA A 7- (((3aR,3bR,4aS,5R,5aS)-5-(4- amino-7H-pyrrolo[2,3-d]pynmidin=7yl)-2,2-	3-bromo-7- («3aR, 3bR,4aS,5R,5aS) -5-(4-chloro-7H- py rrolo[2,3-d]pyrimidin-7- yi)-2,2- dimethyltetrahydrocydop	⁴H NMR (400 MHz, DMSO-d6) δ 8.30 (s, 1H), 8.09 (s, 1H), 7.64 7.59 (m, 1H), 7.38 (d, J = 3.6 Hz, 1H), 7.37 - 7.31 (m, 2H), 7.16 (t, J = 5.9 Hz, 1H), 7.04 (s, 2H), 7.00 (d, J = 2.5 Hz, 1H), 6.97 -

164

d imethyltetrahyd rocy clopro pa [3,4]cy clopenta[1,2-d][1,3]dioxol-3b(3aH)yl)methoxy)-3-bromo-N-(4methoxybenzyl)quinolin-2-amine	ropa[3,4]cyclopenta[1,2- d][1,3]dioxol-3b(3aH)- yl)methoxy)-N-(4methoxybenzyl)quinolin2-amine	6.92 (m, 1H), 6.91 - 6.84 (m, 2H), 6.65 (d, J = 3.6 Hz, 1H), 5.30 (d, J = 7.1 Hz, 1H), 5.14 (s, 1H), 4.63 (d, J = 6.0 Hz, 2H), 4.50 (d, J = 7.1 Hz, 1 H), 4.35 (d, J = 10.5 Hz, 1H), 4.21 (d, J = 10.5 Hz, 1H), 3.71 (s, 3H), 1.78 -1.71 (m, 1H), 1.48 (s, 3H), 1.18 (s, 3H), 1.11-1.06 (m, 1 H), 0.88 _ A OQ fU'.· 1 ΓΆΛΟ — — \hi, ii ly, uOivî^ hvî. — 659.3 (M+2; 100%).
/A PMBHN ' ô 0 /\ 7-((((3aR,3bS,4aS,5R,5aS)-5-(4amino-7H-pyrrolo[2,3-d]pyrimidin-7y!)-2,2- dimethyltetrahydrocyclopropa[3,4]cy clopenta[1,2-d][1,3]dioxol-3b(3aH)yl)methyl)thio)-N-(4- methoxybenzyl)quinolin-2-amine	7- ((((3aR,3bS,4aS,5R,5aS) -5-(4-chloro-7H- pyrrolo[2,3-d]pyrimidin-7y!)-2,2- dimethyltetrahydrocyciop ropa[3,4]cyclopenta[1,2d][1,3]dioxol-3b(3aH)yl)methyl)thio)-N-(4methoxybenzyl)quinolin2-amine	¹H NMR (400 MHz, DMSO-d6) δ 8.09 (s, 1H), 7.80 (d, J = 8.9 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.46 (t, J = 5.7 Hz, 1H), 7.41 (d, j = i a H? 1 μη 7 _ i r™ 2H), 7.23 (d, J = 3.5 Hz, 1H), 7.12 (dd, J = 8.3, 1.9 Hz, 1H), 7.01 (s, 2H), 6.91 - 6.86 (m, 2H), 6.75 (d, J = 8.9 Hz, 1 H), 6.58 (d, J = 3.5 Hz, 1 H), 5.23 (dd, J = 7.3, 1.4 Hz, 1 H), 5.03 (s, 1 H), 4.55 (d, J = 5.7 Hz, 2H), 4.51 (dd, J = 7.4, 1.5 Hz, 1 H), 3.72 (s, 3H), 3.67 (d, J = 12.6 Hz, 1H), 3.32 (d, J = 12.7 Hz, 1H), 1.71 - 1.63 (m, 1H), 1.47 (s, 3H), 1.17 (s, 3H), 1.06 (t, J = 4.8 Hz, 1H), 1.01 0.95 (m, 1H); LCMS m/z = 595.21 (M+;70%)
H,N Ύ \ / v \\ -· i O 0 /\	7- ((3aR,3bR,4aS,5R,5aS)- 3b-(2-(3,3-dimethyl-2- (methylthio)-3H-indoi-6-	¹H NMR (400 MHz, DMSO-d6) δ 8.07 (s, 1H), 7.18 (d, J = 7.5 Hz, TH), 7.11 (d, J = 3.6 Hz, 1H), 7.01 (s, 2H), 6.94 (s, 1H), 6.88

165

7-((3aR,3bR,4aS,5R,5aS)-3b-(2-(2amino-3,3-dimethyl-3H-indol-6yl)ethyl)-2,2- dimethylhexahydrocyclopropa[3,4]c yclopenta[1,2-d][ 1,3]dioxol-5-yl)-7Hpyrrolo[2,3-d]pyrimidin-4-amine	yl)ethyl)-2,2- d i methy I hexa hyd rocyciop ropa[3,4]cyclopenta[1,2d][1,3]dioxol-5-yl)-7H- pyrrolo[2,3-d]pyrimidin-4amine	(d, J = 7.6 Hz, 1H), 6.61 (d, J = 3.5 Hz, 1H), 5.18 (d, J = 7.2 Hz, 1H), 5.00 (s, 1H), 4.52 (d, J = 7.1 Hz, 1H), 2.77 - 2.65 (m, 2H), 2.22-2.12 (m, 1H), 1.66-1.55 (m, 1H), 1.47 (s, 3H), 1.44 (dd, J = 9.2, 4.3 Hz, 1H), 1.36 (s, 3H), 1.24 (s, 3H), 1.19 (s, 3H), 0.93 (t, J = 4.7 Hz, 1 H), 0.75 (dd, J = 9.1, 5.0 Hz, 1H); LCMS m/z = 473.4 (M+1; 80%)
C yX PMBHN''^N q b 7-(2-((3aR,3bR,4aS,5R,5aS)-5-(4amino-7H-pyrrolo[2,3-d]pyrimidin-7yi)-2,2- dimethylhexahydrocyclopropa[3,4]c yclopenta[1,2-d][1,3]dioxol-3byi)ethyl)-N-(4- methoxybenzyl)quinolin-2-amine	7-(2- ((3aR,3bR,4aS,5R,5aS)5-(4-chloro-7H- pyrrolo[2,3-d]pyrimidin-7yi)-2,2- dimethylhexahydrocyclop ropa[3,4]cyclopenta[1,2d][1,3]dioxol-3b-yl)ethyl)N-(4- methoxybenzyl)quinolin2-amine	Ή NMR (400 MHz, Chloroformd) δ 8.34 (s, 1 H), 7.87 (d, J = 8.9 Hz, 1H), 7.63 (s, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.35 (d, J = 8.5 Hz, 2H), 7.22 (d, J = 8.1 Hz, 1H), 6.97 (d, J = 3.6 Hz, 1 H), 6.91 (d, J = 8.7 Hz, 2H), 6.65 (d, J = 9.0 Hz, 1 H), 6.39 (d, J = 3.6 Hz, 1 H), 5.25 (s, 2H), 5.19 (d, J = 7.1 Hz, 1H), 5.14 (s, 1H), 4.67-4.62 (m, 3H), 3.82 (s, 3H), 3.06-2.93 (m, 2H), 2.41 - 2.36 (m, 1H), 2.06 2.01 (m, 1H), 1.60 (s, 3H), 1.51 (dd, J = 8.7, 4.2 Hz, 1 H), 1.28 (s, 3H), 1.15 (t, J = 4.8 Hz, 1 H), 0.78 (dd, J = 5.5, 3.2 Hz, 1H); LCMS m/z = 577.5 (M+1; 60%)

7-(1-((3aR,3bR,4aS,5R,5aS)-5-(4-Amino-7H-pyrrolo[2,3-d]pyrîmidin-7-yl)-2,2dimethyltetrahydrocyclopropa[3,4]cyclopenta[1,2-d][1,3]dioxol-3b(3aH)-yl)propan2-yl)-N-(4-methoxybenzyl)quinolin-2-amine

166

A mixture of 7-((E)-1-((3aR,3bS,4aS,5R,5aS)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)2,2-dimethyltetrahydrocyclopropa[3,4]cyclopenta[1,2-d][1,3]dioxol-3b(3aH)-yl)prop-1-en2-yl)-3-bromo-N-(4-methoxybenzyl)quinolin-2-amine (0.05g, 0.075 mmol), ammonium formate (0.331 g, 5.24 mmoi) and Pd/'C (0.024 g, 0.225 mmoi) in EtOH (15 m!) was heated at 75°C for 8h. The reaction mixture was cooled 25°C, filtered through celite and concentrated in vacuo to get 0.06g of crude compound. The obtained residue was purified by combiflash (R_f200, Teledyne/lsco) instrument onto a redisep® R_f column with gradient elution (0 to 5%) of methanol in dichloromethane to afford the title compound (0.042g, 95%) as an off-white solid. LCMS m/z = 591.29 (M+1, 100%).

Examples

Example-1:

(1S,2R,5R)-3-(2-(2-Amino-3-bromoquinolin-7-vl)ethyl)-5-(4-amino-7H

Pvrrolo[2.3-dlpyrimidin-7-y0cvclopent-3-ene-1,2-diol (Compound-1 )

The mixture of 7-(2-((3aS,4R,6aR)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-6-yl)ethyi)-3-bromo-N-(4-methoxy benzyl)quinolin-2-amine (0.220 g, 0.343 mmol) in TFA (3.96 ml, 51.4 mmol) was stirred at 50°C for 1.5h. The resulting mixture was concentrated in vacuo and obtained residue was dissolved in MeOH (5ml). K₂CO₃ (0.142 g, 1.029 mmol) was added and stirred the reaction mixture at 50°C for 1.5h. Reaction mixture was filtered and filtrate was concentrated under reduced pressure to get 0.27g of crude compound. This residue was purified by combiflash (R_f200, Teledyne/lsco) instrument onto a redisep® R_f column with gradient elution (0 to 7%) of methanol in dichioromethane to afford the title compound (0.03g, 18%) as an off-white solid. ^ήΗ NMR (400 MHz, DMSO-d6) δ 8.35 (s, 1H), 8.06 (s, 1H), 7.61 (d, J = 8.2 Hz, 1H), 7.36 (d, J = 1.6 Hz, 1H), 7.16 (dd, J = 8.2, 1.7 Hz, 1H), 7.08 (s, 2H), 6.67 (d, J = 3.5 Hz, 1H), 6.61 (s, 2H), 6.45 (d, J = 3.5 Hz, 1H), 5.50 (d, J = 4.4 Hz, 1H), 5.44 (t, J = 1.7 Hz, 1H), 498 (d, J = 6,4 Hz, 2H), 4.45 (t, J = 5.9 Hz, 1H), 3,97 (d, J = 5.0 Hz, 1H), 3,04 - 2.87 (m, 2H), 2.61 - 2.53 (m, 2H); LCMS m/z = 483.01 (M+2, 90%).

Examples in table-13 Vv-ere synthesized by following an analogous reaction protocol as -was used for the préparation of (1S,2R,5R)-3-(2-(2-amino-3-bromoquinolin-7-yl)ethyl)-5-(419533

167 amino-/H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol using the appropriate starting materials (Instead of TFA, 3N HCI/MeOH could also be used).

Table-13

Structure & IUPAC name	Intermediate used	¹H NMR & LCMS data
Compound-2 H,N ^N 7 i NîA ² HO OH (1 S,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	7-(2-((3aS,4R,6aR)-4- (4-amino-7H-pyrrolo[2,3d]pyrimidin-7-yl)-2,2dimethyl-3a,6a-dihydro4H- cyclopenta[d][1,3]dioxol6-yl)ethyl)-3-chloro-N-(4methoxybenzyl)quinolin2-amine	¹H NMR (400 MHz, DMSO-d6) δ 8.17 (s, 1H), 8.09 (s, 1H), 7.61 (d, J = 8.2 Hz, 1H), 7.37 (s, 1H), 7.29 (s, 2H), 7.16 (dd, J = 8.3, 1.7 Hz, 1H), 6.75 - 6.66 (m, 3H), 6.49 (d, J = 3.6 Hz, 1H), 5.50 (d, J = 4.4 Hz, 1H), 5.43 (d, J = 1.9 Hz, 1H), 5.01 (d, J = 6.7 Hz, 2H), 4.45 (t, J = 5.9 Hz, 1H), 3.96 (d, J = 5.0 Hz, 1H), 2.94 (ddt, J = 21.4, 14.1, 7.2 Hz, 2H), 2.58 - 2.55 (m, 2H); LCMS m/z = 436.92 (M+, 20%)
Compound-3 F U \ / Y h h «An _v ^h2™ ho oh (1 S,2R,5R)-3-(2-(2-amino-3- bromoquinolin-7-yl)ethyl)-5-(4- amino-5-fluoro-7H-pyrrolo[2,3d]pyrimidin-7-yl)cyclopent-3-ene1,2-diol	7-(2-((3aS,4R,6aR)-4(4-amino-5-fluoro-7Hpyrrolo[2,3-d]pyrimidin7-yl)-2,2-dimethyl-3a,6adihydro-4Hcyciopenta[dj[1,3jdioxoi6-yl)ethyl)-3-bromo-N(4- methoxybenzyl)quinolin2-amine	¹H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1H), 8.08 (s, 1H), 7.63 (d, J = 8.2 Hz, 1H), 7.37 (s, 1H), 7.18 (dd, J = 8.2, 1.6 Hz, 3H), 6.72 (d, J = 27.4 Hz, 2H), 6.55 (d, J = 2.1 Hz, 1H), 5.54 (s, 1H), 5.40 (q, J’ = 1.7 Hz, 1H), 5.10 - 4.91 (m, 2H), 4.43 (d, J = 5.7 Hz, 1H), 3.92 (q, J = 5.2 Hz, 1 H), 3.04 - 2.87 (m, 2H) 2.65 - 2.52 (m, 2H),; LCMS m/z = 501 (M+1, 30%)
Compound-4	7-((((3aS,4R,6aR)-4-(4amino-7H-pyrrolo[2,3djpyrimidin-7-yi)-2,2dimethyl-3a,6a-dihydro-	¹H NMR (400 MHz, DMSO-d6) δ 8.00 (s, 1 H), 7.86 (d, J = 8.8 Hz, 1H), 7.56 (d, J = 8.3 Hz, 1H), 7.40 (d, J = 1.8 Hz, 1H), 7.15 (dd, J =

168

V Ά/ ^s V ft Μ N ' '' Ν -V^-' N Η₂Ν HO oh (1 S,2R,5R)-5-(4-amino-7Hpy rrol o [2,3-d] pyrim id i n-7-y 1 )- 3(((2-aminoquinolin-7- yl)thio)methyl)cyclopent-3-ene1,2-diol	4H- cyclopenta[d][1,3]dioxol6-yl)methyl)thio)-N-(4methoxybenzyl)quinolin2-amine	8.3, 1.9 Hz, 1H), 6.89 (s, 2H), 6.72 (d, J = 8.8 Hz, 1H), 6.48 (s, 2H), 6.26 (d, J = 3.5 Hz, 1H), 6.21 (d, J = 3.6 Hz, 1H), 5.57 (s, 1H), 5.49 (s, 1H), 5.11 (d, J = 5.5 Hz, 1H), 5.04 (d, J = 6.4 Hz, 1H), 4.58 (s, 1H), 4.01 (d, J = 14.7 Hz, 1H), 3.88 - 3.81 (m, 1H), 3.75 - 3.66 (m, 1 H); LCMS m/z = 420.85 (M+, 100%)
Compound-5 Hz/ ⁿ H N (1 S,2R,5R)-3-(((2-amino-3- chloroquinolin-7-yl)thio)methyl)-5(4-amino-7H-pyrrolo[2,3d]pyrimidin-7-yl)cyclopent-3-ene- 1,2-diol	7-((((3aS,4R,6aR)-4-(4amino-7H-pyrrolo[2,3d]pyrimidin-7-yl)-2,2dimethyl-3a,6a-dihydro4H- cyclopenta[d][1,3]dioxol6-yl) methyl)thio)-3chloro-N,N-bis(4methoxybenzyl)quinolin2-amine	¹H NMR (400 MHz, DMSO-d6) δ 8.19 (s, 1H), 8.00 (s, TH), 7.62 (d, J = 8.4 Hz, 1H), 7.43 (s, 1H), 7.23 (dd, J = 8.4, 1.9 Hz, 1H), 6.94 (s, 2H), 6.82 (s, 2H), 6.28 (q, J = 3.5 Hz, 2H), 5.61 (s, 1 H), 5.50 (s, 1 H), 5.09 (dd, J = 24.6, 6.5 Hz, 2H), 4.57 (t, J = 6.0 Hz, 1H), 4.04 (d, J = 14.9 Hz, 1 H), 3.87 (q, J = 5.7 Hz, 1H), 3.74 (d, J = 15.0 Hz, 1H); LCMS m/z = 455.50 (M+, 50%)
Compound-6 \ „NH, ^H2N ' ho' 6h AV (1 S,2R,5R)-5-(4-amino-7H- py rrolo[2,3-d] pyrimidin-7-yl)-3- (((2-aminoquinolin-7-	N7-(((3aS,4R,6aR)-4-(4amino-7H-pyrrolo[2,3d]pyrimidin-7-yl)-2,2dimethyl-3a,6a-dihydro4H- cyclopenta[d][1,3]dioxol6-yl)methyl)-N2-(4methoxybenzyl)-N7-	¹H NMR (400 MHz, DMSO-d6) δ 8.02 (s, 1H), 7.65 (d, J = 8.7 Hz, 1H), 7.39 (d, J = 8.8 Hz, 1H), 6.95 - 6.86 (m, 3H), 6.81 (dd, J = 8.9, 2.6 Hz, 1H), 6.61 (d, J = 2.5 Hz, 1H), 6.49 (d, J = 3.5 Hz, 1H), 6.41 (d, J = 8.7 Hz, 1H), 6.09 (s, 2H), 5.51 (s, 1H), 5.41 (d, J = 1.9 Hz, 1H), 5.06 (dd, J = 6.5, 2.5 Hz, 2H),

169

yl)(methyl)amino)methyl)cyclopen t-3-ene-1,2-diol	methylquinoüne-2,7diamine	4.44 (t, J = 6.0 Hz, 1H), 4.17 (d, J = 4.9 Hz, 2H), 4.11 - 4.04 (m, 1 H), 3.05 (s, 3H); LCMS m/z = 417.10 (M+, 100%)
Compound-7a and 7b N A'·,' ^{N H}' .h₂n^ⁿ ₂ k An HO OH (1S,2R,5R)-3-(1-(2-Amino-3- bromoquinolin-7-yl)propan-2-yl)5-(4-amino-7H-pyrrolo[2,3d]pyrimidin-7-yl)cyclopent-3-ene1,2-diol	7-(2-((3aS,4R,6aR)-4- (4-amino-7H-pyrrolo[2,3d]pyrimidin-7-yl)-2,2dimethyl-3a,6a-dihydro4H- cyclopenta[d][1,3]dioxol6-yl)propyl)-3-bromo-N(4-methoxybenzyl) quinolin-2-amine	First Diastereomer(Compound7a): ¹H NMR (400 MHz, DMSOd6) δ 8.35 (s, 1H), 8.05 (s, 1H), 7.60 (d, J = 8.2 Hz, 1H), 7.33 (s, 1H), 7.13 (d, J = 8.4 Hz, 1H), 6.93 (s, 2H), 6.78 (d, J = 3.6 Hz, 1H), 6.59 (s, 2H), 6.49 (d, J = 3.6 Hz, 1H), 5.53 (d, J = 4.5 Hz, 1H), 5.42 (s, 1H), 5.01 -4.88 (m, 2H), 4.46 (t, J = 5.8 Hz, 1H), 3.99 (t, J = 7.8 Hz, 1H), 3.03 (dd, J = 11.9, 4.4 Hz, 1H), 2.73 (q, J = 10.6, 8.9 Hz, 2H), 1.24 (s, 3H); LCMS m/z = 497.30 (M+2, 100%) Second GUI 1 IGH 1 ipuui lli l VJ ). Il NMR (400 MHz, DMSO-d6) δ 8.36 (s, 1H), 8.05 (s, 1H), 7.61 (d, J = 8.2 Hz, 1H), 7.33 (s, 1H), 7.21 - 7.02 (m, 3H), 6.61 (s, 2H), 6.50 (d, J = 3.5 Hz, 1H), 6.43 (d, J = 3.6 Hz, 1H), 5.52 (d, J = 5.0 Hz, 1H), 5.35 (s, 1H), 5.00 (s, 1H), 4.91 (d, J = 6.4 Hz, 1 H), 4.56 (s, 1 H), 3.90 (d, J = 5.8 Hz, 1 H), 3.07-2.99 (m, 1 H), 2.83 - 2.74 (m, 2H) 1.09 (d, J = 5.8 Hz, 3H); LCMS m/z = 495.24 (M+, 40%)

170

(Compound-8a and 8b) À., \__! fi' Y N ^N } i N^ⁿ H HO OH (1 S,2R,5R)-5-(4-Amino-7H- pyrrolo[2,3-d]pyrimidin-7-yl)-3-(1((2-(methylamino) quinoîin-7yl)oxy)ethyl)cyclopent-3-ene-1,2- diol

7-(1-((3aS,4R,6aR)-4-(4- amino-7H-pyrro!o [2,3- d]pyrimidin-7-yl)-2,2- d i methyl-3a ,6a-di hyd ro- 4H-cyclopenta [d] [1,3] dioxol-6-yi)ethoxy)-N- methyl quinolin-2-amine

Diastereomeric mixture was separated by chiral préparative HPLC. W&velength: 225 nm, Instrument Method: I PA_0.1 % DEA_MeOH_ 0.1 %DEA_50_50_0.7ML_12MI N, Flow Rate: 0.70 ml/min Column : CHIRALPAK IB CRL043 OLD, Column Temp: 30°C,Mobile Phase A: IPA_0.1%DEA, Mobile Phase B: MeOH_0.1%DEA First Diastereomer (Compound8a): ¹H NMR. (400 MHz, DMSOd6) δ 8.04 (s, 1H), 7.73 (d, J = 8.8 Hz, 1H), 7.49 (d, J = 8.7 Hz, 1H), 7.00 (d, J = 2.5 Hz, 1H), 6.92 (d, J = 4.2 Hz, 2H), 6.84 6.80 (m, 2H), 6.57 (d, J = 8.8 Hz, 1H), 6.44 (d, J = 3.5 Hz, 1H), 5.70 (t, J = 1.7 Hz, 1H), 5.60 5.56 (m, 1 H), 5.21 (d, J = 6.7 Hz, 1H), 5.14-5.08 (m, 1H), 5.044.99 (m, 1H), 4.62 - 4.58 (m, 1H), 4.15-4.11 (m, 1 H), 3.19 3.16(m, 1H),2.90 (d,J = 4.7Hz, 3H), 1.54 (d, J = 6.3 Hz, 3H); LCMS m/z = 433.04 (M+1, 30%) Second Diastereomer(Cornpound-8b); ¹H NMR (400 MHz, DMSO-cfô) δ 8.02 (s, 1H), 7.73 (d, J = 8.9

171

		Hz, 1 H), 7.49 (d, J = 8.7 Hz, 1H), 7.04 (d, J = 2.5Hz, 1H), 6.94 (d, J = 3.5 Hz, 3H), 6.81 (dd, J = 8.7,2.5 Hz, 1 H), 6.57 (d, J =8.8 Hz, 1H), 6.54 (d, J = 3.6 Hz, 1H),5.72(t, J= 1.5 Hz, 1 H), 5.57 (d, J = 5.0 Hz, 1H), 5.26 (d, J = 6.7 Hz, 1H), 5.15 (s, 1H), 5.10 (s, 1H), 4.48 (s, 1 H),4.36 (d, J = 4.2 Hz, 1H), 3.94 (d, J = 5.8 Hz, 1H), 2.91 (d, J = 4.7 Hz, 3H), 1.57 (d, J = 6.5 Hz, 3H); LCMS (m/z) =433.04 (M+, 30%).
Compound-9 F ^A'^ t /~^A-.nO^,nh₂ u. ΛΑο \ / AA h₂n' ⁿ *< ζ N (1 S,2R,5R)-3-(((2-amino-3- chloro-5-fluoroquinolin-7- yl)oxy)methyl)-5-(4-amino-7Hpyrrolo[2,3-d]pyrimidin-7-yl)-2methylcyclopent-3-ene-1,2-diol	7-(((3aS,4R,6aR)-4-(4amino-7H-pyrrolo[2,3- d1nwrimîHin-7-wh-9 9 Aa- trimethyl-3a,6a-dihydro- 4H- cyclopenta[d][1,3]dioxol-6yl)methoxy)-3-chloro-5fluoro-N-(4- methoxybenzyl)quinolin-2amine	¹H NMR (400 MHz, DMSO-d6) δ 8.37 (s, 1H),8.14(s, 1 H), 7.71 (d, J = 3.7 Hz, 1 H), 7.07 (s, 2H), 6.97 (d, J = 3.6 Hz, 1 H), 6.90 (d, J = 2.2 Hz, 1H), 6.79 (dd, J = 11.5, 2.2 Hz, 1H), 5.61 (s, 2H), 4.89 - 4.77 (m, 2H), 4.76 - 4.63 (m, 3H), 1.82 (s, 3H); LCMS m/z = 471.07 (M+, 100%)
Compound-10 La \ / A ft n ^N 7—n^n H HO OH (1 S,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	7-(2-((3aS,4R,6aR)-4-(4amino-7H-pyrrolo[2,3d]pyrimidin-7-yl)-2,2dimethyl-3a,6a-dihydro4H- cyclopenta[d][1,3]dioxol-6yl)ethyl)-N-methylquinolin2-amine	¹H NMR (400 MHz, DMSO-d6) δ 8.03 (s, 1H), 7.79 (d, J = 8.9 Hz, 1 H), 7.54 (d, J = 8.0 Hz, 1 H), 7.39 (s, 1H), 7.07 (dd, J = 8.1, 1.6 Hz, 1 H), 6.93 (s, 2H), 6.72 6.64 (m, 2H), 6.41 (d, J = 3.5 Hz, 1H), 5.51 (s, 1H), 5.43 (d, J = 1.9 Hz, 1H), 4.95 (dd, J = 10.7, 6.5 Hz, 2H), 4.45 (t, J = 6.0 Hz, 1H), 4.01 -3.90 (m, 1H), 3.12 -

172

		3.08 (m, 2H), 2.90 (d, J = 4.7 Hz, 3H), 2.60-2.52 (m, 2H); LCMS m/z= 416.48 (M+, 60%)
Compound-11 k ( / A \\ N^ r i N^N HÔ OH (1 S,2R,5R)-5-(4-amino-7H- pyrrolo[2,3-d]pyrimidin-7-yl)-3-(2{3-methylimidazo[1,2-a]pyridin-7yl)ethyl)cyclopent-3-ene-1,2-diol	7-((3aS,4R,6aR)-2,2dimethyl-6-(2-(3methylimidazo[1,2a]pyridin-7-yl)ethyl)-3a,6adihydro-4H- cyclopenta[d][1,3]dioxol-4yl)-7H-pyrrolo[2,3d]pyrimidin-4-amine	¹H NMR (400 MHz, DMSO-d6) δ 8.20 (d, J = 7.0 Hz, 1H), 8.03 (s, 1H), 7.39 (s, 1H), 7.32 (s, 1H), 7.00 - 6.86 (m, 3H), 6.66 (d, J = 3.5 Hz, 1H), 6.42 (d, J = 3.5 Hz, 1 H), 5.53 - 5.41 (m, 2H), 4.98 (d, J = 6.4 Hz, 2H), 4.46 (t, J = 6.0 Hz, 1H), 3.98 (q, J = 5.5 Hz, 1 H), 3.40 (d, J = 7.0 Hz, 2H), 2.99 - 2.82 (m, 2H), 2.45 (s, 3H); LCMS m/z= 390.91 (M+, 90%)
Compound-12 ξ h₂A ⁿ _H0 'qH (1 S,2R,5R)-3-(((2-amino-3chloro-5-fluoroquinolin-7yi)oxy)methyl)-5-(4-amino-7Hpyrrolo[2,3-d]pyrimidin-7-yl)-4methylcyclopent-3-ene-1,2-diol	3-chloro-5-fluoro-N-(4methoxybenzyl)-7(((3aS,4R,6aR)-4-(4-((4methoxybenzyl)amino)7H-pyrrolo[2,3d]pyrimidin-7-yl)-2,2,5trimethyl-3a,6a-dihydro4H- cyclopenta[d][1,3]dioxol-6yl)methoxy)quinolin-2amine	LCMS m/z = 471.23 (M+, 60%)
Compound-13	3-chloro-7-(2((3aS,4R,6aR)-2,2dimethyl-4-(4-methyl-7H-	’H NMR (400 MHz, DMSO-d6) δ 8.62 (s, 1 H), 8.18 (s, 1 H), 7.22 (s, 1H), 7.13 - 6.90 (m, 4H),

173

F ciAX'L N^z^N HjN HÔ OH (1 S,2R,5R)-3-(2-(2-amino-3- ch!oro-5-fluoroquinolin-7- yl)ethy!)-5-(4-methy I-7 Hpyrrolo[2,3-d]pyrimidin-7yl)cyclopent-3-ene-1,2-diol	pyrrolo[2,3-d]pyrimidin-7yl)-3a,6a-dihydro-4Hcyclopenta[d][1,3jdioxol-6yl)ethyl)-5-fluoroquinolin2-amine	6.55 (d, J = 3.6 Hz, 1 H), 5.61 (d, J = 4.4 Hz, 1H), 5.46 (t, J = 1.7 Hz, 1H), 5.02 (dd, J = 6.5, 4.3 Hz, 2H), 4.47 (t, J = 6.0 Hz, 1H), 4.08 - 3.98 (m, 1 H), 3.04 - 2.85 (m, 2H), 2.63 (s, 3H), 2.60 2.54 (m, 2H); LCMS m/z = 454.17 (M+, 100%)
Compound-14 > AIhCI HO OH (1 S,2R,5R)-3-(2-(2-amino-3- chloro-5-fluoroquinolin-7- yl)ethy!)-5-(4-methyl-1 Hpyrrolo[3,2-c]pyridin-1yl)cyclopent-3-ene-1,2-diol hydrochloride	3-chloro-7-(2((3aS,4R,6aR)-2,2dimethyl-4-(4-methyl-1 Hpyi i iuii î~ i’yij“ 3a,6a-dihydro-4Hcyclopenta[d][1,3]dioxo!-6yl)ethyl)-5-fluoroquinolin2-amine	¹H NMR (400 MHz, DMSO-d6) δ 14.95 (s, 1H), 8.41 (s, TH), 8.26 (t, J = 5.9 Hz, 1H), 7.94 (d, J = 6.9 Hz, 1H), 7.53 (d, J = 3.5 Hz, 1H), 7.43 - 7.29 (m, 2H), 7.29 - 7.03 (m, 3H), 5.64 (s, 1H), 5.58 (d, J = 5.3 Hz, 1H), 4.41 (d, J = 5.6 Hz, 1H), 3.88 (t, J = 5.6 Hz, 1 H), 3.10 - 2.99 (m, 2H)), 2.93 (s, 3H), 2.62-2.50 (m, 2H); LCMS m/z= 453.11 (M+1, 100%)
Compound-15 F ^c:''^ HO' bH AÀ (1 S,2R,5R)-3-(2-(2-Amino-3chloro-5-fluoroquinolin-7yl)ethyl)-5-(1 H-pyrrolo[3,2c]pyridin-1 -y!)cyclopent-3-ene- 1,2-diol	3-Chloro-7-(2((3aS,4R,6aR)-2,2dimethyl-4-(1H- py rrolo[3,2-c] py ridin-1 -y I)3a,6a-dihydro-4H- cyclopenta[d][1,3]dioxol-6yl)ethyl)-5-fluoroquinolin2-amine	¹H NMR (400 MHz, DMSO-d6) δ 8.91 (s, 1 H), 8.20 (s, 1 H), 8.09 (d, J = 6.2 Hz, 1H), 7.49 (d, J = 6.1Hz, 1H), 7.24 (s, 1H), 7.11 (d, J = 3.3 Hz, 1H), 7.07-7.01 (m, 1H), 6.98 (s, 2H), 6.60 (d, J = 3.3 Hz,1H), 5.58 (d, J = 1.8 Hz, 1H), 5.39 (s, 1H), 5.18 (dd, J = 17.2, 6.7 Hz, 2H), 4.41 (t, J = 5.4 Hz, 1H), 3.84(q, J = 5.9 Hz, 1H), 3.11 - 2.91 (m, 2H),

174

		2.68 - 2.58 (m, 2H); LCMS (m/z) =439.23 (M+, 100%).
Compound-16 F AvArJ Xn ; > NiA ^h2ⁿ ho oh (1 S,2R,5R)-3-(2-(2-amino-3chloro-5-fluoroquinolin-7yl)ethyl)-5-(7H-pyrrolo[2,3d]pyrimidin-7-yl)cyclopent-3-ene- 1,2-diol	3-chloro-7-(2((3aS,4R,6aR)-2,2dimethyl-4-(7Hpyrrolo[2,3-d]pyrimidin-7yl)-3a,6a-dihydro-4Hcyclopenta[d][1,3]dioxol-6yl)ethyl)-5-fluoroquinolin2-amine	¹H NMR (400 MHz, DMSO-d6) 5 8.98 (s, 1 H), 8.76 (s, 1 H), 8.18 (s, 1 H), 7.22 (s, 1 H), 7.11 (d, J = 3.6 Hz, 1H), 7.02 (dd, J = 11.1, 1.4 Hz, 1H), 6.96 (s, 2H), 6.49 (d, J = 3.6 Hz, 1H), 5.65 (s, 1H), 5.47 (d, J= 1.9 Hz, 1 H), 5.03 (d, J = 6.4 Hz, 2H), 4.48 (t, J = 6.1 Hz, 1H), 4.06 - 4.02 (m, 1H), 3.02 - 2.93 (m, 2H), 2.60 - 2.55 (m, 2H) ; LCMS m/z= 440.17 (M+, 60%)
Compound-17 h₂n HO OH (1 S,2R,5R)-5-(4-amino-7Hpyrrolo[2,3-d]pyrimidin-7-yl)-3(((2-aminoquinolin-7- yl)amino)methyl)cyclopent-3-ene1,2-diol	N7-(((3aS,4R,6aR)-4-(4- amino-7H-pyrrolo[2,3d]pyrimidin-7-yl)-2,2dimethyl-3a,6a-dihydro4H-cyclo penta[d][1,3]dioxol-6- yl)methyl) -N2-(4- methoxybenzyl) quinoline2,7-diamine	¹H NMR (400 MHz, DMSO-d6) 5 8.04 (s, 1H), 7.60 (d, J = 8.6 Hz, 1 H), 7.29 (d,J = 8.6 Hz, 1H), 6.96 - 6.91 (m, 3H), 6.64 (dd, J = 8.7, 2.3 Hz, 1H), 6.51 (d, J = 3.5 Hz, 1H), 6.48 (d, J = 2.2 Hz, 1H), 6.37 (d, J = 8.6 Hz, 1H), 6.20 (t, J = 5.6 Hz, 1H), 6.08 (s, 2H), 5.61 (q, J = 1.8 Hz, 1H), 5.55 (s, 1 H), 5.09 - 5.04 (m, 2H), 4.52 (t, J = 5.9 Hz, 1H), 4.11 (q, J = 5.8 Hz, 1H), 3.90 (s, 2H); LCMS m/z= 404.16 (M+, 100%)
Compound-18 F Ci-AAVi. U A-Xo \ J Y U ^H2 ho oh	7-(((3aS,4R,6aR)-4-(4Amino-7H-pyrrolo[2,3d]pyrimidin-7-yl)-2,2dimethyl-3a,6a-dihydro4H-cyclopenta[d] [1,3] dioxol-6-yl)methoxy)-3-	¹H NMR (400 MHz, DMSO-d6) 5 8.58 (bs, 2H), 8.32 (s, 1H), 8.11 (s, 1 H), 7.32 (d, J = 3.6 Hz, 1H), 6.99 (bs, 2H), 6.89 - 6.83 (m, 2H), 6.81 (d, J = 2.3 Hz, 1 H), 5.82 (q, J= 1.8 Hz, 1 H), 5.63 (d,

175

(1S,2R,5R)-3-(((2-amino-3chloro-5-fluoroquinolin-7yl)oxy)methyl)-5-(4-amino-7Hpyrrolo[2,3-d]pyrimidin-7yl)cyclopent-3-ene-1,2-diol	chloro-5-fluoro-N-(4methoxybenzyl)quinolin-2amine	J = 5.2 Hz, 1H), 5.27 (bs, 2H), 4.93-4.80 (m, 2H), 4.56 (d, J = 5.7 Hz, 1H), 4.21 (t, J = 5.6 Hz, 1H); LCMS m/z= 457.17 (M+, 70%)
Compound-19 /Xi k \ Γ γ f q HO OH (1 S,2R,5R)-5-(4-amino-7Hpyrrolo[2,3-d]pyrimidin-7-yl)-3- ///O i ►ν'Λΐ.Πι tl <» »·νΛ t i i îr> λΙ îr% 7 i içii lyiai » hi iU^uii ινιιΠ-1 - yl)oxy)methyl)cyclopent-3-ene1,2-diol	7-(((3aR,6R,6aS)-6-(4- amino-7H-pyrroio[2,3d]pyrimidin-7-yl)-2,2d i methy I-6,6a-d i hyd ro3aH- cyclopenta[d][1,3]dioxol-4yl)methoxy)-N- methylquinolin-2-amine	¹H NMR (400 MHz, DMSO-d6) δ 8.12 (s, 1H), 8.00 (d, J = 8.9 Hz, 1 H), 7.69 (d, J = 8.8 Hz, 1 H), 7.40 (d, J = 13.8 Hz, 3H), 7.12 (d, J = 3.7 Hz, 1H), 7.03 (d, J = 8.9 Hz, 1H), 6.80 (d, J = 9.0 Hz, 1H), 6.64 (d, J = 3.5 Hz, 1H), 5.82 (d, J = 2.0 Hz, 1H), 5.61 (s, 1H), 5.30 - 5.08 (m, 2H), 4.86 (s, 2H), 4.60 (t, J = 5.6 Hz, 1H), 4.28 - 4.04 (m, 2H) 3.05 (d, J = 4.6 Hz, 3H); LCMS m/z= 419.16 (M+, 100%)
Compound-20a and 20b r ' /=> 0Η.γ·'γ ,οΎ² V Λ/'^Ό \ / y 5 U'N < i N'. À HzN HO' PH (1S,2R,5R)-3-(1-((2-amino-3- chloro-5-fluoroquinolin-7yl)oxy)ethyl)-5-(4-amino-7Hpyrrolo[2,3-d]pyrimidin-7yl)cyclopent-3-ene-1,2-diol	7-(1-((3aS,4R,6aR)-4-(4amino-7H-pyrrolo[2,3d]pyrimidin-7-yl)-2,2dimethyl-3a,6a-dihydro4H- cyclopenta[d][1,3]dioxol-6yl)ethoxy)-3-chloro-5fluoro-N-(4- methoxybenzyl)quinolin-2amine	Diastereomeric mixture was separated by chiral préparative HPLC. First Diastereomer (Compound20a): ¹H NMR (400 MHz, DMSO-d6) δ 8.12 (s, 1H), 7.92 (s, 1H), 7.36 (d, J = 3.6 Hz, 1H), 7.16 (d, J = 3.5 Hz, 1 H), 6.83 (s, 2H), 6.65 - 6.35 (m, 3H), 5.96 (t, J = 9.7 Hz, 1H), 5.82 - 5.54 (m, 2H), 5.07-4.91 (m, 2H), 4.61 4.36 (m, 2H), 4.18 (dd, J = 9.6, 4.8 Hz, 1H), 1.65 (ddd, J = 26.6, 6.9, 2,5 Hz, 3H); LCMS m/z= 471.23 (M+, 90%)

176

		Second Diastereomer (Compound-20b): ¹H NMR (400 MHz, DMSO-d6) δ 8.08 (s, 1H), 8.01 (s, 1 H), 6.93 (s, 5H), 6.87 6.75 (m, 2H), 6.54 (d, J = 3.6 Hz, 1H), 5.62 (d, J = 1.6 Hz, 1H), 5.53 - 5.49 (m, 1 H), 5.26 (d, J = 5.9Hz, 1H), 5.23-5.13 (m, 2H), 4.55 (t, J = 5.7 Hz, 1H), 4.15 4.00 (m, 1 H), 1.57 (d, J = 6.5 Hz, 3H); LCMS m/z= 471.23 (M+, 80%)
Compound-21 /=\ ν A/ U r « H₂N c -, N ho Oh (1 S,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	3-chloro-7-(2((3aS,4R,6aR)-2,2d i methy l-4-(4-methy I-7 Hpyrrolo[2,3-d]pyrimidin-7yl)-3a,6a-dihydro-4Hcyciopenta[dj[1,3]dioxo!-6yl)ethyl)quinolin-2-amine	¹H NMR (400 MHz, DMSO-d₆) δ 8.62 (s, 1H), 8.17 (s, 1H), 7.61 (d, J =8.3 Hz, 1H), 7.44 (s, 1H), 7.37 (s, 1H), 7.17 (d, J=8.2Hz, 1H), 7.02 (d, J = 3.6 Hz, 1H), 6.70 (s, 2H), 5.62 (s, 1H), 5.45 (s, 1H), 5.04 (s, 2H), 4.47 (d, J = 5.5 Hz, 1H), 4.14-3.91 (m, 1H), 3.06 - 2.87 (m, 2H) 2.58 (d, J = 32.3 Hz, 5H); LCMS m/z= 436.23 (M+, 90%)
Compound-22 '^Χ'Ν N c -, ’J N H HO OH Chemical Formula: Cas^eNsOs (1 S,2R,5R)-5-(4-Amino-7H- pyrrolo[2,3-d]pyrimidin-7-yl)-3-(2- (2-(cycIobutylamino) quinolin-7- yl)ethyl)cyclopent-3-ene-1,2-diol	7-(2-((3aS,4R,6aR)-4-(4Amino-7H-pyrrolo[2,3d]pyrim!din-7-y!)-2,2dimethyl-3a,6a-dihydro4H-cyclo penta[d][1,31 dioxol-6-yl)ethyl)-N-cyclo butylquinolin-2-amine	¹H NMR (400 MHz, DMSO-d6) δ 8.15 (s, 1H), 8.05 (d, J = 9.1 Hz, 1H), 7.77 - 7.51 (m, 4H), 7.24 (d, J = 8.1 Hz, 1H), 6.82 (dd, J = 17.2, 6.4 Hz, 2H), 6.57 (d, J = 3.6 Hz, 1H), 5.53 (s, 1H), 5.45 (s, 1 H), 5.03 (s, 2H), 4.55 4.43 (m, 2H), 4.01 (t, J = 5.2 Hz, 1 H), 3.06 - 2.87 (m, 2H), 2.59 2.54 (m, 2H), 2.41 (d, J = 8.7 Hz, 2H), 2.01 (q, J = 9.8 Hz, 2H),

177

1.76 (q, J = 9.4 Hz, 2H); LCMS m/z= 457.3 (M+, 90%)

Example-2:

(1S.2R,5R)-3-(2-(2-Amino-3-fluoroquinolin-7-vDethyl)-5-(4-amino-7HPvrrolo[2,3-dlpyrimidin-7-vl)cvclopent-3-ene-1,2-diol (Compound-23)

The mixture of 7-(2-((3aS,4R,6aR)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2dimethyl-3a,6a-dihydro-4H-cyc!opentard][1,3]dioxo!-6-yl)ethyl)-3-fluoroquinoïin-2-amine (0.060 g, 0.130 mmol) in TFA (1.004 ml, 13.03 mmol) was stirred at 25°C for 6h under N₂atmosphère. The reaction mixture was basified with ice cold solution of aq.sat.NaHCO₃(20ml) and extracted with ethyl acetate (20 ml). Layers were separated, organic layer was washed with brine (20 ml) and dried over anhydrous Na₂SO₄. The organic layer was filtered and concentrated in vacuo to give 0.12g of crude compound. This residue was purified by combiflash (Rf200, Teledyne/lsco) instrument onto a redisep® Rf column with gradient elution (0 to 10%) of methanol in dichloromethane to afford the title compound (25 mg, 45.6 % yield) as an off-white solid. ¹H NMR (400 MHz, DMSO-d6) δ 8.05 (d, J = 7.3 Hz, 1H), 7.79 (d, J = 11.8 Hz, 1H), 7.59 (d, J = 8.2 Hz, 1H), 7.37 (s, 1H), 7.16 (d, J = 8.3 Hz, 1H), 6.99 (s, 2H), 6.74 (s, 2H), 6.58 (d, J = 3.5 Hz, 1H), 6.40 (d, J = 3.5 Hz, 1 H), 5.50 (d, J = 9.5 Hz, 1H), 5.42 (d, J = 1.9 Hz, 1H), 4.97 (dd, J = 6.6, 3.1 Hz, 2H), 4.45 (t, J = 6.0 Hz, 1H), 3.95 (q, J = 5.5 Hz, 1 H), 3.04 - 2.85 (m, 2H), 2.60 - 2.53 (m, 2H); LCMS m/z= 420.92 (M+, 100%).

Examples in table-14 were synthesized by following an analogous reaction protocol as was used for the préparation of (1S,2R,5R)-3-(2-(2-amino-3-fluoroquinolin-7-yl)ethyl)-5-(4amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol using the appropriate starting materials (Instead of TFA, aq.TFA or FeCh.DCM could also be used at appropriate forrtrioro+i iroA IWI I UlUI

Table-14

Structure & IUPAC name

Intermediate used

Ή NMR & LCMS data

178

Compound-24 \ \ / V i Ai '—- n_2/ ⁿ H₂N ho oh (1 S,2R,5R)-3-(2-(2-amino-3chloro-5-fluoroquinolin-7- yl)ethyl)-5-(4-amino-7H- py rro! o[2,3-d] pyrimidin-7 - yl)cyclopent-3-ene-1,2-diol	7-(2-((3aS,4R,6aR)-4(4-amino-7Hpyrrolo[2,3-d]pyrimidin7-yl)-2,2-dimethyl3a,6a-dihydro-4Hcyclopenta[d][1,3]dioxol -6-yl)ethyl)-3-chloro-5fluoroquinolin-2-amine	¹H NMR (400 MHz, DMSO-d6) δ 8.17 (d, J = 0.8 Hz, 1H), 8.03 (s, 1H), 7.22 (s, 1H), 7.01 (dd, J = 11.0, 1.4 Hz, 1H), 6.95 (s, 2H), 6.92 (s, 2H), 6.63 (d, J = 3.5 Hz, 1H), 6.42 (d, J = 3.5 Hz, 1H), 5.50 (t, J = 3.2 Hz, 1H), 5.45 (t, J = 1.7 Hz, 1H), 4.96 (dd, J = 6.3, 3.0 Hz, 2H), 4.45 (t, J = 5.8 Hz, 1H), 3.97 (q, J = 5.5 Hz, 1H), 3.03 2.87 (m, 2H), 2.56 (t, J = 7.0 Hz, 2H); LCMS m/z= 454.98 (M+, 40%)
Compound-25 F /= x r γ » ^HîN HÔ OH (1 S,2R,5R)-3-(2-(2-amino-3chloro-6-fluoroquinolin-7yl)ethyl)-5-(4-amino-7Hpyrroio[2,3-d]pyrimidin-7yi)cyclopent-3-ene-1,2-diol	7-(2-((3aS,4R,6aR)-4(4-amino-7Hpyrrolo[2,3-d]pyrimidin7-yl)-2,2-dimethyl- 3 a, 6 a- d i hy d ro-4 Hcyclopenta[d][1,3]dioxol -6-yl)ethyl)-3-chloro-6fluoroquinolin-2-amine	A NMR (400 MHz, DMSO-cfe) δ 8.17 (s, 1H), 8.03 (s, 1H), 7.53 - 7.30 (m, 2H), 6.97 (s, 2H), 6.75 - 6.55 (m, 3H), 6.44 (d, J = 3.6 Hz, 1 H), 5.57 - 5.31 (m, 2H), 4.98 (dd, J = 6.4, 1.8 Hz, 2H), 4.45 (t, J = 6.0 Hz, 1 H), 3.98 (q, J = 5.6 Hz, 1 H), 2.98 (q, J = 6.7 Hz, 2H), 2.59 - 2.52 (m, 2H); LCMS m/z= 455.10 (M+, 90%)
Compound-26 y Aa Y S H-N ^N t F HO OH (1S,2R,5R)-3-(2-(2-amino-3- chloro-8-fluoroquinolin-7yl)ethyl)-5-(4-amino-7Hpyrrolo[2,3-d]pyrimidin-7yl)cyclopent-3-ene-1,2-diol	7-(2-((3aS,4R,6aR)-4(4-amino-7Hpyrrolo[2,3-d]pyrimidin7-yl)-2,2-dimethyl- 3a.6a-dihvdro-4H---,---- „ ... cyclopenta[d][1,3]dioxol -6-yl)ethyl)-3-chloro-8fluoroquinolin-2-amine	A NMR (400 MHz, DMSO-d6) δ 8.24 (d, J = 1.6 Hz, 1 H), 8.04 (s, 1 H), 7.44 (d, J = 8.3 Hz, 1H), 7.17 (dd, J = 8.3, 6.5 Hz, 1H), 7.00 (bs, 4H), 6.66 (d, J = 3.6 Hz, 1H), 6.44 (d, J = 3.5 Hz, 1H), 5.51 (d, J = 4.5 Hz, 1 H), 5.42 (d, J = 1.8 Hz, 1 H), 4.96 (dd, J = 6.6, 4.8 Hz, 2H), 4.44 (t, J = 5.9 Hz, 1 H), 3.98 (q, J = 5.6 Hz, 1 H), 2.98 (d, J = 8.3 Hz, 2H), 2.49 - 2.40 (m, 2H); LCMS m/z= 455.05 (M+, 100%)
Compound-27	7-((3aS,4R,6aR)-6-(2(2-amino-3,3-dimethyl3H-indol-6-yl)ethyl)-2,2-	A NMR (400 MHz, DMSO-d6) δ 8.04 (s, 1 H), 7.02 (d, J = 7.3 Hz, 1 H), 6.97 - 6.85 (m, 4H), 6.81 (d, J = 1.4 Hz, 1H), 6.67

179

/Χ'¹i n X>^nh2 h,nA Ay A y y y v ~ ^N H M (1S,2R,5R)-3-(2-(2-amino-3,3dimethyl-3H-indol-6-yl)ethyl)-5(4-amino-7H-pyrrolo[2,3d]pyrimidin-7-yl)cyclopent-3ana-1,2-dioi	dimethyl-3a,6a-dihydro4H- cyclopenta[d][1,3]dioxol -4-yl)-7H-pyrrolo[2,3d]pyrimidin-4-amine	(dd, J = 7.4, 1.5 Hz, 1 H), 6.63 (d, J = 3.5 Hz, 1H), 6.46 (d, J = 3.5 Hz, 1H), 5.55 5.46 (m, 1H), 5.42 (t, J = 1.7 Hz, 1H), 4.95 (s, 2H), 4.44 (d, J = 5.5 Hz, 1H), 3.93 (q, J = 4.8 Hz, 1 H), 2.87 - 2.62 (m, 2H), 2.49-2.41 (m, 2H), 1.30-1.17 (m, 6H); LCMS m/z= 418.41 (M+, 100%)
Compound-28 \_j ^7 ^N e----_r N ,N HO OH (1 S,2R,5R)-5-(4-amino-7Hpyrrolo[2,3-d]pyrimidin-7-yl)-3- (2-(2'-aminospiro[cyclobutane- 1,3'-indol]-6'- yl)ethyl)cyclopent-3-ene-1,2diol	6'-(2-((3aS,4R,6aR)-4- (4-amino-7H- pyrrolo[2,3-d]pyrimid in7-yi)-2,2-dimetnyï3a,6a-dihydro-4Hcyclopenta[d][1,3]dioxol -6- yl)ethyl)spiro[cyclobutan e-1,3'-indol]-2'-amine	¹H NMR (400 MHz, DMSO-d6) δ 8.04 (s, 1H), 7.39 (d, J = 7.3 Hz, 1H), 7.07 (s, 2H), 6.92 (s, 2H), 6.77 (d, J = 1.4 Hz, 1H), 6.71 (dd, J ^Ξ 7.5, 1.5 Hz, 1H), 6.62 (d, J = 3.5 Hz, 1H), 6.45 (d, J = 3.5 Hz, 1H), 5.49 (d, J = 4.3 Hz, 1H), 5.41 (d, J = 1.9 Hz, 1 H), 4.93 (d, J = 5.9 Hz, 2H), 4.45 (d, J = 5.5 Hz, 1H), 3.93 (q, J = 5.3 Hz, 1 H), 2.87 - 2.64 (m, 2H), 2.62 - 2.49 (m, 4H), 2.40 - 2.30 (m, 1 H), 2.24 - 2.13 (m, 3H); LCMS m/z= 431.23 (M+, 50%)
Compound-29 Ci M, H₂N HO oh (1S,2R,5R)-3-(2-(2-amino-3,5- dichloroquinolin-7-yl)ethyl)-5(4-amino-7H-pyrroio[2,3d]pyrimidin-7-yl)cyclopent-3ene-1,2-diol	7-(2-((3aS,4R,6aR)-4(4-amino-7Hpyrrolo[2,3-d]pyrimidin7-yl)-2,2-dimethyl3a,6a-dihydro-4Hcyclopenta[d][1,3]dioxol -6-yl)ethyl)-3,5dichloroquinolin-2amine	¹H NMR (400 MHz, DMSO-d6) δ 8.20 (s, 1H), 8.03 (s, 1H), 7.35 (d, J = 8.7 Hz, 2H), 7.14 - 6.88 (m, 4H), 6.62 (d, J = 3.5 Hz, 1H), 6.43 (d, J = 3.6 Hz, 1H), 5.49 (s, 1H), 5.43 (s, 1H), 4.98 (dd, J = 11.2, 6.4 Hz, 2H), 4.46 (t, J = 5.9 Hz, 1H), 3.96 (q, J = 5.5 Hz, 1H), 3.04-2.85 (m, 2H), 2.62 - 2.56 (m, 2H); LCMS m/z= 471.30 (M+, 50%)

180

Compound-30 ci./X'/ _Λ k=\ Tl ^HK ^N In HO OH ''T nh₂ (1S,2R,5R)-3-(2-(2-amino-3- chloroquinolin-7-yl)ethyl)-5-(2amino-7H-pyrrolo[2,3d]pyrimidin-7-y!)cyclopent-3ene-1,2-diol	7-(2-((3aS,4R,6aR)-4- (2-amino-7H- pyrrolo[2,3-d]pyrimidin- 7-yl)-2,2-dimethyl- 3a,6a-dihydro-4Hcyclopenta[d][1,3]dioxol -6-yl)ethyl)-3- chloroquinolin-2-amine	¹H NMR (400 MHz, DMSO-d₆) δ 8.69 (s, 1H), 8.37 (s, 1H), 7.69 (d, J = 8.2 Hz, 1H), 7.42 (s, 1H), 7.26 (d, J = 8.3 Hz, 1H), 6.95 (d, 7 = 3.9 Hz, 1H), 6.46 (d, J = 3.8 Hz, 1H), 5.42 (dd, J= 10.5, 3.3 Hz, 2H), 5.30 - 4.81 (m, 2H), 4.47 (d, J = 5.5 Hz, 1 H), 4.22 - 3.88 (m, 1 H), 3.09 - 2.87 (m, 2H) 2.57 (d, J = 7.7 Hz, 2H); LCMS m/z= 437.21 (M+1,70%)
Compound-31 F ^H2^{N N} _HO' >_OH ΝΐΧ· (1 S,2R,5R)-3-(2-(2-amino-3chloro-5-fluoroquinolin-7yl)ethyl)-5-(4-isopropyl-7Hpyrrolo[2,3-d]pyrimidin-7yl)cyclopent-3-ene-1,2-diol	3-chloro-5-fluoro-7-(2((3aS,4R,6aR)-4-(4isopropy!-7H- py rrolo [2,3-d] pyrim id i n7-yl)-2,2-dimethyl3a,6a-dihydro-4Hcyclopenta[d][1,3]dioxol -6-yl)ethyl)quinolin-2amine	¹H NMR (400 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.18 (s, 1H), 7.22 (s, 1H), 7.05 (d, J = 3.7 Hz, 1H), 7.02 (dd, J = 11.0, 1.4 Hz, 1H), 6.96 (s, 2H), 6.57 (d, J = 3.6 Hz, 1H), 5.63 (d, J = 4.5 Hz, 1H), 5.46 (d, J = 1.8 Hz, 1 H), 5.01 (d, J = 6.5 Hz, 2H), 4.47 (t, J = 6.1 Hz, 1H), 4.10 - 3.98 (m, 1H), 3.40 (dt, J = 13.9, 6.9 Hz, 1 H), 3.04 - 2.89 (m, 2H), 2.57 (d, J = 8.3 Hz, 2H), 1.32 (d, J = 2.1 Hz, 3H), 1.30 (d, J = 2.1 Hz, 3H); LCMS m/z= 483.92 (M+, 30%)
Compound-32 h,n ⁿ M (1S,2R,5R)-3-(2-(2-amino-3- chloro-5-fluoroquinolin-7-	3-chîoro-7-(2((3aS,4R,6aR)-2,2dimethyl-4-(4-(1-methyl1H-pyrazol-4-yl)-7Hpyrrolo[2,3-d]pyrimidin7-yl)-3a,6a-dihydro-4Hcyclopenta[d][1,3]dioxol -6-yl)ethyl)-5fluoroquinolin-2-amine	¹H NMR (400 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.62 (s, 1H), 8.21 (d, J = 19.9 Hz, 2H), 7.26 - 7.17 (m, 2H), 7.03 (dd, J = 11.0, 1.4 Hz, 2H), 6.98 (s, 1 H), 6.87 (d, J = 3.7 Hz, 1H), 5.66 (d, J = 4.6 Hz, 1H), 5.50 (t, J = 1.7 Hz, 1H), 5.04 (d, J = 6.1 Hz, 2H), 4.48 (s, 1 H), 4.08 (d, J = 5.4 Hz, 1H), 3.97 (s, 3H), 3.06 - 2.88 (m, 2H),

181

y l)ethy 1)-5-(4-( 1 -methyl-1Hpyrazol-4-yl)-7H-pyrrolo[2,3d]pyrimidin-7-yl)cyclopent-3ene-1,2-diol		2.60 - 2.55 (m, 2H); LCMS m/z= 520.32 (M+, 100%)
Compound-33a and 33b F \ \ Z Y \\ An - ί nA ^h2ⁿ ho oh (1S,2R,5R)-3-(1-(2-amino-3- chloro-5-fluoroquinolin-7yl)propan-2-yl)-5-(4-amino-7Hpyrrolo[2,3-d]pyrimidin-7yl)cyc!opent-3-e.ne-1,2-diol	7-(2-((3aS,4R,6aR)-4(4-amino-7Hpyrrolo[2,3-d]pyrimidin7-yl)-2,2-dimethyl3a,6a-dihydro-4Hcyclopenta[d][1,3]dioxol -6-yl)propyl)-3-chloro-5fluoroquinolin-2-amine	Diastereomeric mixture was separated by chiral préparative HPLC. First Diastereomer(Compound-33a) : ¹H NMR (400 MHz, DMSO-d6) δ 8.18 (s, 1H), 8.03 (s, 1H), 7.18 (s, 1H), 7.146.83 (m, 5H), 6.50 (d, J = 3.5 Hz, 1H), 6.42 (d, J = 3.5 Hz, 1H), 5.51 (d, J = 5.1 Hz, 1 H), 5.36 (d, J = 1.8 Hz, 1 H), 5.00 (d, J = 6.8 Hz, 1H), 4.89 (d, J = 6.2 Hz, 1H), 4.56 (t, J = 5.8 Hz, 1H), 3.91 (d, J = 5.5 Hz, 1H), 3.08-2.94 (m, 1H), 2.79 (d, J = 9.3 Hz, 2H), 1.09 (d, J = 6.7 Hz, 3H); LCMS m/z= 469.36 (M+, 30%) Second Diastereomer (Compound-33b) : ¹H NMR (400 MHz, DMSO-d6) δ 8.18 (s, 1H), 8.05 (s, 1H), 7.19 (s, 1H), 7.086.86 (m, 5H), 6.78 (d, J = 3.5 Hz, 1H), 6.50 (d, J = 3.5 Hz, 1H), 5.56 - 5.47 (m, 1H), 5.43 (t, J = 1.4 Hz, 1H), 4.97 (t, J = 5.5 Hz, 2H), 4.51 - 4.42 (m, 1 H), 3.98 (q, J = 6.1, 5.3 Hz, 1 H), 3.09-2.96 (m, 1H), 2.75 (s, 2H), 1.08 (d, J = 6.3 Hz, 3H); LCMS m/z= 469.36 (M+, 30%)
Compound-34a and 34b ^clAO~AyA_v“· h₂n ^N X nJn HO OH	7-(2-((3aS,4R,6aR)-4- (4-amino-7H- pyrrolo[2,3-d]pyrimidin- 7-y I )-2,2-d imethy I3a,6a-dihydro-4Hcyclopenta[d][1,3]dioxol	Diastereomeric mixture was separated by chiral préparative HPLC. First Diastereomer (Compound-34a) : ¹H NMR (400 MHz, DMSO-d6) δ 8.17 (s, 1H), 8.03 (s, 1H), 7.60 (d, J = 8.2 Hz, 1H), 7.33 (d, J = 1.5 Hz, 1H), 7.13 (dd, J

182

(1 S,2R,5R)-3-(1-(2-amino-3chloroquinolin-7-yl)propan-2yl)-5-(4-amino-7H-pyrrolo[2,3d]pyrimidin-7-yl)cyclopent-3ene-1,2-diol	-6-yl)propyl)-3- chloroquinolin-2-amine	= 8.2, 1.6 Hz, 1H), 6.94 (s, 2H), 6.67 (s, 2H), 6.47 (d, J = 3.5 Hz, 1 H), 6.39 (d, J = 3.5 Hz, 1 H), 5.56 - 5.46 (m, 1 H), 5.35 (d, J = 1.8 Hz, 1H), 4.98 (d, J = 6.7 Hz, 1H), 4.88 (d, J = 6.3 Hz, 1H), 4.57 (t, J = 5.9 Hz, 1H), 3.90 (q, J = 5.7 Hz, 1H), 3.10 2.96 (m, 1 H), 2.84 - 2.73 (m, 2H), 1.13 1.09 (m, 3H); LCMS m/z= 451.2 (M+, 100%) Second Diastereomer(Compound-34b) : ¹H NMR (400 MHz, DMSO-d6) δ 8.17 (s, 1H), 8.05 (s, 1H), 7.60 (d, J = 8.2 Hz, 1H), 7.34 (d, J = 1.6 Hz, 1H), 7.13 (dd, J = 8.2, 1.6 Hz, 1H), 6.94 (s, 2H), 6.77 (d, J = 3.6 Hz, 1 H), 6.67 (s, 2H), 6.49 (d, J = 3.5 Hz, 1H), 5.59 - 5.49 (m, 1H), 5.47 5.38 (m, 1H), 4.95 (t, J = 7.2 Hz, 2H), 4.47 (t, J = 6.0 Hz, 1H), 3.98 (q, J = 5.5 Hz, 1H), 3.04 (dd, J = 12.0, 4.5 Hz, 1H), 2.82 - 2.64 (m, 2H), 1.07 (d, J = 6.3 Hz, 3H); LCMS m/z= 452.98 (M+1, 80%)
Compound-35a and 35b HjN HÔ OH (1S,2R,5R)-3-(1-(2-Amino-3chloro-5-fluoroquinolin-7yl)propan-2-yl)-5-(4-methyl7H-pyrrolo[2,3-d]pyrimidin-7yl)cyclopent-3-ene-1,2-diol	3-chloro-7-(2((3aS,4R,6aR)-2,2d imethy I-4- (4- me thy I7H-pyrrolo[2,3d]pyrimidin-7-yi)-3a,6adihydro-4Hcyclopenta[d][1,3]dioxol -6-yl)propyl)-5fluoroquinolin-2-amine	Diastereomeric mixture was separated by chiral préparative HPLC. First Diastereomer (Compound-35a): ¹H NMR (400 MHz, DMSO-d6) δ 8.63 (s, TH), 8.18 (s, 1H), 7.27 - 7.12 (m, 2H), 6.96 (s, 3H), 6.64 (d, J = 3.6 Hz, 1H), 5.64 (d, J = 4.9 Hz, 1H), 5.46 (d, J = 2.0 Hz, 1H), 5.01 (dd, J = 6.5, 3.4 Hz, 2H), 4.46 (t, J = 5.9 Hz, 1H), 4.03 (q, J = 5.7 Hz, 1H), 3.02 (q, J = 9.1 Hz, 1 H), 2.86 2.68 (m, 2H), 2.64 (s, 3H), 1.09 (d, J = 7.0 Hz, 3H); LCMS m/z = 468.36 (M+, 80%)

183

		Second Diastereomer (Compound-35b): ¹H NMR (400 MHz, DMSO-d6) δ 8.60 (s, 1H), 8.19 (s, 1H), 7.19 (s, 1H), 7.04 6.89 (m, 4H), 6.52 (d, J = 3.6 Hz, 1H), 5.63 (d, J = 5.0 Hz, 1H), 5.39 (d, J = 1.8 Hz, 1H), 5.08 - 5.00 (m, 1H), 4.95 (d, J = 6.2 Hz, 1H), 4.58 (t, J = 5.9 Hz, 1H), 3.98 (dt, J = 6.8, 5.4 Hz, 1H), 3.03 (q, J = 10.1 Hz, 1 H), 2.81 (s, 2H), 2.62 (s, 3H), 1.11 (d, J = 5.3 Hz, 3H); LCMS m/z = 468.36 (M+, 80%)
Compound-36a and 36b ajXWX A 5Ί* “^^N (1 S,2R,5R)-3-(1 -(2-amino3-chloro-5-fluoroquinolin-7yl)propan-2-yl)-2-methyl-5(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)cyclopent3-ene-1,2-diol	3-chloro-5-fluoro-7-(2((3aS,4R,6aR)-2,2,6atrimethyl-4-(4-methyl7H-pyrrolo[2,3d]pyrimidin-7-yl)-3a,6adihydro-4H- cyclopenta[d][1,3]dioxol -6-yl)propyl)quinolin-2amine	Diastereomeric mixture was separated by chiral préparative HPLC. First Diastereomer(Compound 36a): ¹H NMR (400 MHz, DMSO-d6) δ 8.63 (s, 1H), 8.19 (s, 1H), 7.22 - 7.12 (m, 2H), 7.03 - 6.90 (m, 3H), 6.66 (d, J = 3.7 Hz, 1 H), 5.64 - 5.54 (m, 2H), 5.05 (d, J = 7.1 Hz, 1H), 4.49 (s, 1H), 3.66 (t, J = 6.5 Hz, 1H), 2.96 (dd, J = 13.2, 7.1 Hz, 1H), 2.85 -2.68 (m, 2H), 2.65 (s, 3H), 1.24 (s, 3H), 1.13 (d, J = 6.5 Hz, 3H); LCMS m/z= 482.2 (M+, 40%) Second Diastereomer (Compound 36b): ¹H NMR (400 MHz, DMSO-d6) δ 8.64 (s, TH), 8.17 (s, 1H), 7.43 (d, J = 3.6 Hz, 1H), 7.21 (s, 1H), 7.00 (dd, J = 11.1, 1.3 Hz, 1 H), 6.95 (s, 2H), 6.69 (d, J = 3.6 Hz, 1 H), 5.68 - 5.61 (m, 1 H), 5.46 (d, J = 1.4 Hz, 1H), 5.18 (d, J = 7.3 Hz, 1 H), 4.63 (s, 1H), 3.90 (t, J = 6.9 Hz, 1H), 3.23 - 3.16 (m, 1H), 2.73 (s, 2H), 2.65 (s, 3H), 1.42 (s, 3H), 0.99 (d, J = 6.6 Hz, 3H); LCMS m/z= 482.2 (M+, 40%).

184

Compound-37 ξ Hz N ⁿ 5 i N^ⁿ HO OH (1 S,2R,5R)-3-(2-(2-amino-3chloro-5-fluoroquinolin-7yl)ethyl)-5-(4-amino-7Hpyrrolo[2,3-d]pyrimidin-7-yl)-2- methyÎcyciopènt-3-ene-1,2-dioi	7-(2-((3aS,4R,6aR)-4(4-amino-7Hpyrrolo[2,3-d]pyrimidin7-yl)-2,2,6a-trimethyl3a,6a-dihydro-4Hcyclopenta[d][1,3]dioxol -6-yl)ethyI)-3-chloro-5fluoroquinolin-2-amine	¹H NMR (400 MHz, DMSO-d6) δ 8.17 (s, 1H), 8.12 (s, 1H), 7.34 (s, 2H), 7.22 (s, 1 H), 7.07 - 6.92 (m, 4H), 6.65 - 6.57 (m, 1H), 5.56-5.41 (m, 2H), 5.15-4.99 (m, 1H), 4.62 (s, 1H), 3.83 (d, J = 6.0 Hz, 1 H), 2.99 - 2.86 (m, 2H), 2.46 - 2.31 (m, 2H), 1.27 (s, 3H); LCMS m/z= 469.30 (M+, 40%)
Compound-38 fi Y AA \ / v v ^HA ’ HÔ oh (1S,2R,5R)-3-(1-(2-amino-3- chloro-5-fluoroquinolin-7yl)propan-2-yl)-5-(4-amino-7HpyrroIo[2,3-d]pyrimidin-7-yl)-2methylcyclopent-3-ene-1,2-diol	7-(2-((3aS,4R,6aR)-4(4-amino-7Hpyrrolo[2,3-d]pyrimidin7-yl)-2,2,6a-trimethyi3a ,6a-d i hyd ro-4 Hcyclopenta[d][1,3]dioxol -6-yl)propyl)-3-chloro-5f!uoroquino!in-2-amine	First Diastereomer: ¹H NMR (400 MHz, DMSO-d6) δ 8.18 (s, 1H), 8.04 (s, 1H), 7.18 (s, 1H), 7.01 -6.90 (m, 5H), 6.70 (d, J = 3.6 Hz, 1H), 6.47 (d, J = 3.5 Hz, 1H), 5.55 (d, J = 1.7 Hz, 1H), 5.47 (d, J = 5.9 Hz, 1 H), 5.06 (d, J = 7.0 Hz, 1H), 4.44 (s, 1H), 3.63 (dd, J = 7.0, 5.8 Hz, 1H), 2.97 (dd, J = 12.9, 6.7 Hz, 1 H), 2.82 - 2.68 (m, 2H), 1.24 (s, 3H), 1.11 (s, 3H); LCMS m/z= 482.67 (M+, 80%)
Compound-39 F^ H 4 ( ^Ha^N HO OH (1 S,2R,5R)-3-(2-(2-amino-3- chloro-5-fluoroquinolin-7- yl)ethyl)-2-methyl-5-(4-methyl-	3-chloro-5-fluoro-7-(2((3aS,4R,6aR)-2,2,6atrimethyl-4-(4-methyl7H-pyrrolo[2,3d]pyrimidin-7-yl)-3a,6ad i hyd ro-4 Hcyclopenta[d][1,3]dioxol -6-yl)ethyl)q uinolin-2amine	¹H NMR (400 MHz, DMSO-d6) δ 8.63 (s, 1H), 8.17 (s, 1H), 7.38 (d, J = 3.7 Hz, 1H), 7.22 (s, 1H), 7.02 (dd, J = 11.0, 1.5 Hz, 1H), 6.96 (s, 2H), 6.67 (d, J = 3.5 Hz, 1 H), 5.64 - 5.57 (m, 1 H), 5.50 - 5.45 (m, 1H), 5.07 (d, J = 7.3 Hz, 1H), 4.65 (s, 1H), 3.89 (dd, J = 7.4, 6.1 Hz, 1H), 2.94 (t, J = 7.8 Hz, 2H), 2.64 (s, 3H), 2.57 2.53 (m, 2H), 1.28 (s, 3H); LCMS m/z= 468.36 (M+, 60%)

185

7H-pyrroîo[2,3-d]pyrimidin-7yl)cyclopent-3-ene-1,2-diol
Compound-40 ξ ^c Oa^H2 h₂iXⁿ /Ή AÀ ² HO OH (1S,2R,5R)-3-(2-(2-amino-3chloro-5-fluoroquinolin-7yl)ethyl)-5-(4-amino-7Hpyrrolo[2,3-d]pyrimidin-7-yl)-2ethylcyclopent-3-ene-1,2-diol	7-(2-((3aS,4R,6aR)-4- (4-amino-7H- pyrrolo[2,3-d]pyrimidin- 7-yl)-6a-ethyl-2,2- dimethyl-3a,6a-dihydro4H- cyclopenta[d][1,3]dioxol -6-yl)ethyl)-3-chloro-5fluoroquinolin-2-amine	¹H NMR (400 MHz, DMSO-d6) δ 8.16 (s, 1H), 8.05 (s, 1H), 7.22 (s, 1H), 7.07 6.89 (m, 6H), 6.56 (d, J = 3.6 Hz, 1 H), 5.57 - 5.43 (m, 2H), 5.04 (d, J = 7.6 Hz, 1 H), 4.56 (s, 1 H), 3.95 (t, J = 6.4 Hz, 1 H), 2.94 (t, J = 8.0 Hz, 2H), 2.48 - 2.42 (m, 2H), 1.69 (dq, J = 14.4, 7.2 Hz, 1 H), 1.56 (dq, J = 14.4, 7.2 Hz, 1H), 0.85 (t, J = 7.2 Hz, 3H); LCMS m/z= 482.67 (M+, 80%)
Compound-41 L î n.a ^h2ⁿ hô oh (1 S,2R,5R)-3-(2-(2-amino-3- chloro-5-fluoroquinolin-7- yl)ethyl)-5-(4-ethyl-7H- pyrrolo[2,3-d]pyrimidin-7yl)cyclopent-3-ene-1,2-diol	3-chloro-7-(2((3aS,4R,6aR)-4-(4ethyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)-2,2d i methy l-3a ,6a-d i hyd ro4H- cyclopenta[d][1,3]dioxol -6-yl)ethyl)-5fluoroquinolin-2-amine	¹H NMR (400 MHz, DMSO-d6) δ 8.66 (s, 1H), 8.18 (s, 1H), 7.22 (s, 1H), 7.11 6.91 (m, 4H), 6.56 (d, J = 3.6 Hz, 1H), 5.63 (s, 1H), 5.46 (d, J = 1.9 Hz, 1H), 5.02 (dd, J = 6.5, 4.3 Hz, 2H), 4.47 (t, J = 6.0 Hz, 1 H), 4.08 - 4.00 (m, 1 H), 2.96 (q, J = 7.7 Hz, 4H), 2.57 (d, J = 7.2 Hz, 2H), 1.31 (d, J = 7.6 Hz, 3H); LCMS m/z= 468.08 (M+, 100%)
Compound-42 ξ A \ Aa~Aaⁿ 7..A AA''- A/ r » H₂N -, N,A HO OH	3-Chloro-7-(2((3aS,4R,6aR)-4-(4cyclopropyl-7Hpyrrolo[2,3-d]pyrimi din7-yl)-2,2-dimethyl3a,6a-dihydro-4Hcyclopenta[d][1,3]dioxol	¹H NMR (400 MHz, DMSO-d6) δ 8.63 (s, 1H), 8.27 (s, 1H), 7.30 (d, J = 36.5 Hz, 3H), 7.18 (d, J = 3.7 Hz, 1H), 7.08 (d, J = 10.9 Hz, 1H), 6.76 (d, J = 3.7 Hz, 1H), 5.62 (d, J = 3.7 Hz, 1H), 5.47 (d, J = 1.9 Hz, 1 H), 4.47 (d, J = 5.5 Hz, 1 H), 4.06 (t, J = 5.2 Hz, 1 H), 3.07 - 2.88 (m, 2H), 2.62

186

(1 S,2R,5R)-3-(2-(2-amino-3chloro-5-fluoroquinolin-7yl)ethyl)-5-(4-cyclopropyl-7H- py rrol o[2,3- d] pyrim id i n-7yl)cyciopent-3-ene-1,2-diol	-6-yi) ethyl)-5- fluoroquinolin-2-amine	- 2.54 (m, 3H) 1.27 - 1.14 (m, 4H); LCMS m/z= 479.86 (M+, 100%)
Compound-43 ^N N^N nO OH — (1 S,2R,5R)-3-(2-(2-Amino-3- bromo-5-fluoroquinolin-7- yl)ethyi)-5-(4-amino-7Hpyrroloi2,3-d]pyrimidin-7yl)cyclopent-3-ene-1,2-diol	7-(2-((3aS,4R,6aR)-4(4-amino-7Hpyrroio[2,3-d]pyrimidin7-yl)-2,2-dimethyl3a,.6a-dihydro-4Hcyclopenta[d][1,3]dioxol -6-yl)ethyl)-3-bromo-5fluoroquinolin-2-amine	¹H NMR (400 MHz, DMSO-d6) δ 8.34 (s, 1H), 8.04 (s, 1H), 7.21 (s, 1H), 7.06 6.94 (m, 3H), 6.86 (s, 2H), 6.65 (d, J = 3.5 Hz, 1 H), 6.43 (d, J = 3.5 Hz, 1 H), 5.49 (d, J = 4.4 Hz, 1H), 5.45 (t, J = 1.7 Hz, 1H), 4.96 (dd, J = 6.5, 2.1 Hz, 2H), 4.45 (t, J = 6.0 Hz, 1H), 3.97 (q, J = 5.5 Hz, 1 H), 3.04 - 2.86 (m, J = 7.4 Hz, 2H), 2.55 (d, J = 6.4 Hz, 2H); LCMS m/z= 499.30, 501.24 (M+, M+2, 100%)
Compound-44 P A /- + \ / ν ή h A^N <- - Hz·' HO Oh (1 S,2R,5R)-3-(2-(2-Amino-3- bromo-5-fluoroquinolin-7- yl)ethyl)-5-(4-methyl-7H- pyrrolo[2,3-d]pyrimidin-7yl)cyclopent-3-ene-1,2-diol		¹H NMR (400 MHz, DMSO-d6) δ 8.61 (s, 1H), 8.34 (s, 1H), 7.21 (s, 1H), 7.06 (d, J = 3.6 Hz, 1H), 7.02 - 6.98 (m, 1H), 6.87 (s, 2H), 6.54 (d, J = 3.6 Hz, 1H), 5.61 (t, J = 3.3 Hz, 1H), 5.46 (q, J = 1.6 Hz, 1H), 5.01 (dd, J = 6.5, 5.2 Hz, 2H), 4.47 (t, J = 6.0 Hz, 1H), 4.08 - 3.99 (m, 1H), 3.07 - 2.86 (m, 2H), 2.62 (s, 3H), 2.57 (t, J = 8.3 Hz, 2H); LCMS m/z= 498.24, 500.24 (M+, M+2, 100%).
Compound-45a and 45b	7-(2-((3aS,4R,6aR)-4(4-amino-7Hpyrrolo[2,3-d]pyrimidin7-yl)-2,2-dimethyl-	First Diastereomer(Compound 45a): ¹H NMR (400 MHz, DMSO-d6) δ 8.34 (s, 1H), 8.03 (s, 1H), 7.18 (s, 1H), 7.11 6.68 (m, 5H), 6.52 (d, J = 3.7 Hz, 1H),

187

ξ η,νΆ ₄ ·, nXn HO OH A/ (1S,2R,5R)-3-(1-(2-Amino-3- bromo-5-fluoro quinolin-7- yl)propan-2-yl)-5-(4-amino-7Hpyrrolo[2,3-d]pyrimidin-7yl)cyclopent-3-ene-1,2-diol

3a,6a-dihydro-4Hcyclopenta[d][1,3]dioxol -6-y I ) propy l)-3-bromo-5fluoroquinoiin-2-amine

6.41 (d, J = 3.4 Hz, 1H), 5.51 (d, J = 4.8 Hz, 1 H), 5.37 (s, 1 H), 5.00 (d, J = 7.1 Hz, 1H), 4.89 (d, J = 6.2 Hz, 1H), 4.56 (s, 1 H), 3.91 (d, J = 6.2 Hz, 1 H), 3.01 (d, J = 7.4 Hz, 1H), 2.88-2.71 (m, 2H), 1.10 (d, J = 7.1, Hz, 3H). LCMS m/z= 514.19 (M+1, 100%) Second Diastereomer (Compound 45b): 1H NMR (400 MHz, DMSO-d6) δ 8.34 (s, 1H), 8.04 (s, 1H), 7.18 (s, 1H), 7.02 6.92 (m, 3H), 6.86 (s, 2H), 6.78 (d, J = 3.5 Hz, 1 H), 6.50 (d, J = 3.5 Hz, 1 H), 5.52 (d, J = 4.8 Hz, 1 H), 5.43 (s, 1 H), 4.97 (dd, J = 6.5, 3.6 Hz, 2H), 4.46 (t, J = 6.1 Hz, 1 H), 3.98 (q, J = 5.6 Hz, 1 H), 3.01 (d, J = 9.0 Hz, 1H), 2.84 - 2.65 (m, 2H), 1.07 (d, J = 5.9 Hz, 3H). LCMS m/z= 514.19 (M+1, 100%)

ExampIe-3:

(1S,2R,5R)-3-(2-(2-Amino-6-fluoroquinolin-7-vl)ethyl)-5-(4-amino-7Hpyrrolo[2,3-dlpyrimidin-7-yl)cyclopent-3-ene-1,2-diol (Compound-46 )

F

The mixture of (1S,2R,5R)-3-(2-(2-amino-3-chloro-6-fluoroquinolin-7-yl)ethyl)-5-(4-amino7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (311mg, 0.684mmol) and palladium hydroxide (168mg, 0.239mmol) in éthanol (40ml) was stirred at 25°C for 8h under hydrogen atmosphère (60 psi). The resulting mixture was filtered through celite and filtrate was concentrated in vacuo to give 0.32g of crude compound. Obtained residue was purified by combiflash (Rf200, Teledyne/lsco) instrument onto a redisep® R_f column with gradient elution (0 to 10%) of methanolic ammonia in dichloromethane to afford the titie compound

188 (7mg, 2.4% yield) as an off-white solid. ¹H NMR (400 MHz, DMSO-d6) δ 8.03 (s, 1H), 7.85 (d, J = 8.8 Hz, 1H), 7.40 (t, J = 9.3 Hz, 2H), 6.91 (s, 2H), 6.75 (d, J = 8.8 Hz, 1H), 6.65 (d, J = 3.6 Hz, 1H), 6.43 (d, J = 3.6 Hz, 1H), 6.36 (s, 2H), 5.51 (s, 1H), 5.45 (s, 1H), 4.97 (d, J - 6.3 Hz, 2H), 4.46 (s, 1H), 3.97 (d, J = 5.7 Hz, 1H), 3.05 - 2.88 (m, 2H), 2.48 - 2.26 (m, 2 H).

LCMS m/z= 420.98 (M+, 50%).

Example-4:(1S,2R,5R)-3-(2-(2-amino-5-fluoroquinolin-7-yl)ethyl)-5-(4-amino-7HPYrrolof2,3-dlpyrimidin-7-vl)cyclopent-3-ene-1,2-diol (Compound-47 )

The mixture of (1S,2R,5R)-3-(2-(2-amino-3-chloro-5-fluoroquinolin-7-yl)ethyl)-5-(4-amino7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (30 mg, 0.066 mmol), Pd-C (1.755 mg, 1.649 pmol) and ammonium formate (16.63mg, 0.264mmol) in MeOH (2 ml) was stirred at 78°C for 8h. The resulting mixture was filtered through celite and filtrate was concentrated in vacuo to give 0.32g of crude compound. Obtained residue was purified by combiflash (R_f200, Teledyne/lsco) instrument onto a redisep® R_f column with gradient elution (0 to 10%) of methanolic ammonia in dichloromethane to afford the title compound (9mg, 32.5%) as an off-white solid. ¹H NMR (400MHz, DMSO-d6) D 8.03 (s, 1H), 7.97 (d, J = 9.0 Hz, 1H), 7.15 (s, 1H), 6.94-6.87 (m, 3H), 6.77 (d, J = 9.0 Hz, 1H), 6.64-6.59 (m, 3H), 6.41 (d, J = 3.5 Hz, 1H), 5,49 (d, J = 3.9 Hz, 1H), 5.44 (t, J = 1,7 Hz, 1H), 4.97 (d, J = 5.5 Hz, 2H), 4.46 (s, 1H), 3.96 (q, J = 5.3 Hz, 1H), 3.00-2.86 (m, 2H), 2.54 (d, J = 10.1 Hz, 2H); LCMS m/z= 420.98 (M+, 90%).

Example-5: (1R.2R,3S,4R,5S)-1-(2-(2-Amino-3-chloro-5-fluoroquinolin-7-yl)ethyl)-4-(4amino-7H-pyrrolo[2,3-dlpyrimidin-7-vl)bicyclo[3.1.0]hexane-2,3-diol (Compound-48)

TFA (44.3 ml, 575 mmol) was added to 7-(2-((3aR,3bR,4aS,bR,5aS)-5-(4-amino-7Hpyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl tetrahydrocyclopropa[3,4]cyclopenta[1,2

d][1,3]dioxol-3b(3aH)-yl)ethyl)-3-chloro-5-fluoro quinolin-2-amine (4.5g, 8.84 mmol) at 0°C.

189

The resulting mixture was stirred at 25°C for 16h under N₂ atmosphère The solvent was removed in vacuo at 30°C. The obtained residue was dissolved with ethyl aceate (100ml) and basified with aq.sat. NaHCOs. Layers were separated, organic layer was washed with brine (50ml) and dried over anhydrous Na₂SO₄ The organic layer was fiïtered and 5 concentrated in vacuo to give 5.1g of crude compound. This residue was purified by combiflash (R_f200, Teledyne/lsco) instrument onto a redisep® Rf column with gradient elution (0 to 10%) of methanol in dichloromethane to afford the title compound (2.8g, 67.5%) as a light Brown solid. ¹H NMR (400 MHz, DMSO-d6) δ 8.16 (s, 1H), 8.07 (s, 1H), 7.21 (s, 1H), 7.04 (d, J = 3.6 Hz, 1H), 7.03 - 6.99 (m, 1H), 6.99 - 6.90 (m, 4H), 6.58 (d, J 10 = 3.5 Hz, 1H), 5.12 (d, J = 3.8 Hz, 1H), 4.90 (s, 1H), 4.52 (d, J = 4.1 Hz, 2H), 3.72 (s, 1H),

2.96-2.80 (m, 2H), 2.14 (ddd, J = 16.1, 11.3, 5.3 Hz, 1H), 1.84 (ddd, J = 13.7, 11.2, 5.6 Hz, 1H), 1.24 (d, J = 5.3 Hz, 2H), 0.57 (q, J = 5.9 Hz, 1H); LCMS m/z= 469.23 (M+1, 50%).

Examples in table-15 were synthesized by following an analogous reaction protocol as was used for the préparation of (1R,2R,3S,4R,5S)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)15 1-(2-(2-aminoquinoiin-7-yl)êthyl)bicyclo[3.1.0]hêxanê-2,3-diol using the appropriate starting materials.

Table-: 15

Structure & IUPAC name	Intermediate used	¹H NMR & LCMS data
Compound-49 ^ΝχΧγ ^{N H2} -Yn' X i nXn H HO OH (1 R,2R,3S,4R,5S)-4-(4-Amino-7Hpyrrolo[2,3-d]pyrimidin-7-yl)-1-(2(2-(methylamino)quinolin-7yl)ethyl)bicyclo [3.1.0] hexane-2,3diol	7-(2- ((3aR,3bR,4aS,5R,5aS)- 5-(4-Amino-7H- pyrrolo[2,3-d]pyrimidin-7- yi)-2,2- dimethylhexahydrocyclopr opa [3,4]cyclopenta[1,2d][1,3]dioxol-3b-yl)ethyl)N-methylquinolin-2-amine	¹H NMR (400 MHz, DMSO-d6) δ 8.09 (s, 1H), 7.91 (d, J = 9.0 Hz, 1H), 7.60 (d, J = 8.1 Hz, 1H), 7.52(s, 1H), 7.16 (d, J = 8.2 Hz, 1H), 7.12 - 7.03 (m, 2H), 6.77 (d, J = 9.0 Hz, 1H), 6.61 (d, J = 3.5 Hz, 1H), 5.12 (d, J = 4.5 Hz, 1 H), 4.91 (s, 1H), 4.53 (d, J = 7.0 Hz, 2H), 3.74 (t, J = 5.0 Hz, 1 H), 2.95 (d, J = 4.8 Hz, 3H), 2.87 - 2.84 (m, 2H), 2.21 - 2.05 (m, 1 H), 1.88 (ddd, J = 13.7, 11.5, 5.5 Hz, 1H),

190

		1.32 -1.19 (m, 2H), 0.61 - 0.58 (m, 1H); ; LCMS m/z =431.06 (M+1; 60 %).
Compound-50 ⁿ Xv ^{n h}2 \ X Y''- / \ u Λν^Λν 2 i Ά^Ν ^z H HO OH (1 R,2R,3S,4R,5S)-4-(4-Amino-7Hpyrroio[2,3-d]pyr!m!din-7-yî)-1-(2(2-(isopropylamino)quinolin-7yl)ethyl)bicyc!o [3.1,0]hexane-2,3diol.	7-(2((3aR,3bR,4aS,5R,5aS)5-(4-Amino-7Hpyrrolo[2,3-d]pyrimidin-7yl)-2,2dîmethyltetrahydrocyclopr opa [3,4]cyclopenta[1,2d][1,3]dioxol-3b(3aH)yi)ethyl)-Nisopropylquinolin-2-amine.	¹H NMR (400 MHz, DMSO-d6) δ 8.13 (s, 1H), 7.99 (s, 1H), 7.70-7.53 (m, 2H), 7.27 (d, J = 38.6 Hz, 3H), 7.10 (d, J = 3.6 Hz, 1H), 6.83 (d, J = 9.0 Hz, 1H), 6.66 (d, J = 3.5 Hz, 1H), 5.14 (d, J = 4.4 Hz, 1H), 4.91 (d, J = 1.3 Hz, 1 H), 4.54 (d, J = 3.2 Hz, 2H), 4.31 - 4.18 (m, 1 H) 3.75 (s, 1 H), 3.03 - 2.80 (m, 2H), 2.14 (ddd, J = 17.0, 11.9, 6.1 Hz, 1H), 1.94 - 1.79 (m, 1H), 1.27- 1.23 (m, 8H), 0.640.54 (m, 1H); LCMS m/z = 459.3 (M+1; 100%).
Compound-51 m m H HO OH (1 R,2R,3S,4R,5S)-4-(4-Amino-7Hpyrrolo[2,3-d]pyrimidin-7-yl)-1-(2(2-(cyclobutylamino)quinolin-7yl)ethyl)bicyclo [3.1.0]hexane-2,3diol.	7-(2((3aR,3bR,4aS,5R,5aS)5-(4-Amino-7Hpyrrolo[2,3-d]pyrimidin-7yl)-2,2dimethyltetrahydrocyclopr opa [3,4]cyclopenta[1,2d][1,3]dioxol-3b(3aH)yl)ethyÎ)-N-cyclobutyl quinolin-2-amine.	¹H NMR (400 MHz, DMSO-d6) δ 8.13 (s, 1H), 7.96 (d, J = 9.2 Hz, 1H), 7.62 (d, J = 8.1 Hz, 1H), 7.52 (s, 1H), 7.29 (s, 1H), 7.19 (d, J = 8.4 Hz, 1H), 7.10 (d, J = 3.6 Hz, 1 H), 6.77 (d, J = 9.1 Hz, 1H), 6.65 (d, J = 3.5 Hz, 1H), 5.13 (d, J = 4.5 Hz, 1H), 4.91 (d, J = 1.3 Hz, 1H), 4.574.45 (m, 3H), 3.75 (s, 1H), 3.17 (s, 1H), 2.95 - 2.85 (m, 2H), 2.45-2.33 (m, 2H), 2.13 (ddd, J = 13.4, 11.3, 5.2 Hz, 1H),

191

		2.06 - 1.81 (m, 2H), 1.74 (ddd, J = 15.3, 10.1, 7.1 Hz, 2H), 1.33 - 1.21 (m, 2H), 0.64 - 0.55 (m, 1H); LCMS m/z = 471.3 (M+1; 100%).
Compound-52 h HO OH (1 R,2R,3S,4R,5S)-4-(4-Amino-7Hpyrrolo[2,3-d]pyrimidin-7-yfM-(2(2-((cyclopropylmethyf)amino) quinolin-7-yl) ethyl)bicyclo[3.1.0]hexane-2,3-dioî	7-(2((3aR,3bR,4aS,5R,5aS)5-(4-Amino-7Hpyrrolo[2,3-d]pyrirmdin-7yl)-2,2- dimethyhetrahydrocydopr opa [3,4]cyclopentafl ,2- d][1,3Jdioxol-3b(3aH)yl)ethyl)-N-(<^ciopropyt methyî)quinolfn-2-amâïe.	Ή NMR (400 MHz, DMSO-d6) e 8.10 (s, 1H), 7.89 (d, J = 9.0 Hz, 1H), 7.58 (d, J = 8.1 Hz, 1H), 7.46 (s, 1H), 7.18 - 7.04 (m, 4H), 6.81 (d, J = 9.0 Hz, 1H), 6.61 (d, J = 3.5 Hz, 1H), 5.12 (d, J = 4.4 Hz, 1H), 4.91 (d, J = 1.2 Hz, 1H), 4.53 (d, J = 5.6 Hz, 2H), 3.74 (t, J = 4.8 Hz, 1H), 3.31 - 3.28 (m, 1H), 2.94 -2.83(m, 2H), 2.12 (ddd, J = 13.7, 11.5, 5.2 Hz, 1H), 1.88 (ddd. J = 13.7, 11.5, 5.4 Hz, 1H), 1.28-1.23 (m, 3H), 1.19 — 1.08(m, 1 H), 0.59 (q, J = 5.9 Hz, 1H), 0.53 - 0.45 (m, 2H), 0.33 - 0.22 (m,2H); LCMS m/z = 471.05(M+1; 90%).
Compound-53 AaAy· ^NA „_d i» (1 R,2R,3S,4R,5S)-4-(4-Arnino-7Hpyrrolo[2,3-d]pyrimidin-7-yI)-1-(2(2-amino-8-fluoroquinolin-7- yl)ethyl)bicyclo [3.1 .OJhexane-2,3diol.	7-(2((3aR,3bR,4aS,5R,5aS)5-(4-Amino-7Hpyrrolo[2,3-d}pyrimidin-7yi)-2,2- dimethyltetrahydrocydopr opa (3,4]cyck>penta[1,2d](1,3]d^oxo^-3b(3aH)yl)ethyΓ)-8-flu£WΌqu^noîin2-amine.	H NMR (400 MHz, DMSO-d6) δ 8.10 (s, 1H), 7.90 (dd, J = 9.0, 1.6 Hz, 1H), 7.38 (d, J = 8.2 Hz, 1H), 7.30 - 7.00 (m, 4H), 6.77 (d, J = 9.1 Hz, 3H), 6.62 (d, J = 3.6 Hz, 1H), 5.15 (d, J = 4.5 Hz, 1H), 4.91 (s, 1H), 4.53 (d, J = 3.0 Hz, 2H), 3.75 (s, 1H), 2.97 (ld, J = 12.6, 5.1 Hz, 1H), 2.84 (td, J= 12.6, 5.3 Hz, 1H), 2.19 - 2.01 (m, 1H), 1.82 (td, J =

192

		12.7, 5.2 Hz, 1H), 1.28 (d, J = 3.5 Hz, 2H), 0.63 - 0.54 (m, 1H); LCMS m/z = 435.04 (M+1; 40 %).
Compound-54 . N - '- N ^H2^N hô oh (1 R,2R,3S,4R,5S)-1 -(2-(2-Amino3-methylquinolin-7-yl)ethyl)-4-(4amino-7H-pyrrolo[2,3-d]pyrimidin7-yl) bicyclo[3.1.0]hexane-2,3-dioî.	7-(2((3aR,3bR,4aS,5R,5aS)5-(4-Amino-7Hpyrrolo[2,3-d]pyrimidin-7yl)-2,2- d i methyltetrahydrocyciopr opa [3,4]cyclopenta[1,2d][1,3]dioxol-3b(3aH)yl)ethyl)-3-methylquinolin2-amine.	¹H NMR (400 MHz, DMSO-d6) δ 8.07 (s, 1H), 7.71 (s, 1H), 7.51 (d, J = 8.2 Hz, 1H), 7.33 (d, J = 1.6 Hz, 1H), 7.08 (dd, J = 8.2, 1.7 Hz, 1H), 7.03 (d, J = 3.6 Hz, 1H), 6.98 (s, 2H), 6.58 (d, J = 3.5 Hz, 1 H),6.36 (s, 2H), 5.12 (d, J = 4.5 Hz, TH), 4.90 (d, J = 1.2 Hz, 1 H), 4.59 - 4.46 (m, 2H), 3.72 (t, J = 5.2 Hz,1H), 2.92 - 2.83 (m, 2H), 2.20 (d, J = 1.1 Hz, 3H), 2.10 (ddd, J = 12.7, 11.0, 5.2 Hz, 1H), 1.88 (ddd, J = 13.8, 11.5, 5.5 Hz, 1H), 1.23 (d, J = 3.5 Hz, 2H), 0.58 (q, J = 5.5 Hz, 1H); LCMS m/z = 431.08 (M+1; 100%).
Compound-55 1 H,hJ ^N ,-'---N X ² HO OH (1R,2R,3S,4R,5S)-1-(2-(2-Amino- 3-isopropyl quinolin-7-yl)ethyl)-4-(4amino-7H-pyrrolo[2,3-d]pyrimidin7-yl)bicyclo[3.1.0]hexane-2,3-diol.	7-(2- ((3aR,3bR,4aS,5R,5aS)5-(4-amino-7H- pyrrolo[2,3-d]pyrimidin-7yl)-2,2- d i methy Itetrahy d rocyclo pr opa[3,4]cyclopenta[1,2d][1,3]dioxol-3b(3aH)y!)ethyl)-3- isopropylquinolin-2-amine	¹H NMR (400 MHz, DMSO-d6) δ 8.09 (d, J = 6.3 Hz, 2H), 7.74 (d, J = 8.2 Hz, 3H), 7.45 (s, 1H), 7.30(dd, J = 8.1, T5 Hz, 1H), 7.07 (dd, J = 9.1, 3.6 Hz, 3H), 6.61 (d, J = 3.5 Hz, 1H), 5.16 (d, J = 4.5 Hz,1H), 4.90 (d, J = 1.2 Hz, 1 H), 4.53 (d, J = 7.5 Hz, 2H), 3.74 (t, J = 5.1 Hz, 1H), 3.10 (p, J = 6.7 Hz, 1H), 3.01 2.83 (m, 2H), 2.14 (ddd, J = 15.8, 12.1, 6.4 Hz, TH), 1.85 (ddd, J = 13.6, 11.1, 5.9 Hz,

193

		1H), 1.26 (d, J = 6.6 Hz, 8H), 0.56 (q, J = 6.0 Hz, 1H); LCMS m/z =459.3 (M+; 40%).
Compound-56 FJ. \ a··.^ H₂N ^N A^N ² HO OH (1 R,2R_l3S_>4R_!5S)-1-(2-(2’Amiπo- 3-(1,1 -difluoroethyl) quinolin-7- yl)ethyl)-4-(4-amino-7H-pyrrolo [2,3-d] pyrimidin-7- yl)bicyclo[3.1,0jhexane-2,3-dioL	7-(2- ((3aR,3bR,4aS,5R,5aS)5-(4-Amino-7Hpyrrolo[2,3-d]pyrimtdin-7yi)-2,2dimethyltetrahydrocyclo propa [3,4]cyclopenta[1,2d][1,3]dioxoi-3b(3aH)yl)ethy 1)-3-( 1,1 -difluoro ethyl)quinolin-2-amine.	A NMR (400 MHz, DMSO-d6) δ 8.15 (s, 1H), 8.09 (s, 1H), 7.70 (d, J = 8.1 Hz, 1H), 7.38 (s, 1H), 7.21 - 7.15 (m, 1H), 7.10-7.00 (m, 3H), 6.61 (d, J = 3.6 Hz, 1H), 6.25 (s, 2H), 5.11 (d, J = 4.5 Hz, 1H), 4.91 (s, 1 H), 4.53 (d, J = 7.5 Hz, 2H), 3.74 (t, J = 5.2 Hz, 1H), 2.83 2.91 (m, 2H), 2.18 - 1.98 (m, 4H), 1.88 (td, J = 12.4, 5.5 Hz, 1H), 1.28- 1.25 (m, 2H), 0.58 (q, J = 5.9 Hz, 1H); LCMS m/z = 481.2 (M+1; 90%).
Compound-57 a^h2 X rï μ κι ^N ; i A A ^KsN HO OH (1 R,2R,3S,4R,5S)-1-(2-(2-Amino3-cycÎopropyÎquinolin-/-yl)ethyl)-4(4-amino-7H-pyrrolo[2_:3d]pyrim!din-7-y!) bicyclo[3.1,0]hexane-2,3-diol.	7-(2- ((3aR,3bR,4aS,5R,5aS)- 5-(4-Amino-7H- pyrrolo[2,3-d]pyrimidin-7y!)-2,2- d i methy Itetrahydrocyclo propa[3,4]cyclopenta[1,2d][1,3]dioxol-3b(3aH)yl)ethyl)-3-cyclopropyl quinolin-2-amine.	A NMR (400 MHz, DMSO-d6) δ 8.09 (s, 1H), 7.91 (s, 1H), 7.80 (s, 2H), 7.67 (d, J = 8.2 Hz, 1 H), 7.44 (s, 1 H), 7.27 (dd, J = 8.2, 1.5 Hz, 1H), 7.11 (s, 2H), 7.06 (d, J = 3.5 Hz, 1H), 6.61 (d, J = 3.5 Hz, 1H), 5.17 (d, J = 4.5 Hz, 1 H), 4.90 (d, J = 1.2 Hz, 1H), 4.53 (d, J =4.3 Hz, 2H), 3.73 (s, 1H), 2.95 - 2.87 (m, 2H), 2.12 (ddd, J = 13.8, 11.0, 5.4 Hz, 1H), 1.90 - 1.74 (m, 2H), 1.23 (d, J = 3.4 Hz, 2H), 1.08 - 0.96 (m, 2H), 0.78 - 0.68 (m, 2H), 0.55 (q, J = 5.8 Hz, 1H); LCMS m/z = 457.13 (M+; 50%).

194

Compound-58 Η,Ν^^ - Ν^Α ² HO ΟΗ (1R,2R,3S,4R,5S)-1-(2-(2-Amino- 3-methoxyquinolin-7-yl)ethyi)-4-(4amino-7H-pyrrolo[2,3-d]pyrimidin7-yl)bicycio[3.1.0]hexane-2,3-diol.	7-(2- ((3aR,3bR,4aS,5R,5aS)- 5-(4-Amino-7H- pyrrolo[2,3-d]pyrimidin-7yi)-2,2- d i methy Itetrahy d rocy ci o propa[3,4]cyclopenta[1,2d][1,3]dioxol-3b(3aH)- yl)ethyi)-3- methoxyquinolin-2-amine.	¹H NMR (400 MHz, DMSO-d6) δ 8.08 (s, 1H), 7.54 (d, J = 8.1 Hz, 1H), 7.40 - 7.31 (m, 2H), 7.15-7.05 (m, 3H), 7.04 (d, J = 3.5 Hz, 1H), 6.67 (d, J = 18.5 Hz, 2H), 6.60 (d, J =3.5 Hz, 1H), 5.12 (d, J = 4.5 Hz, 1H), 4.90 (d, J = 1.3 Hz, 1H), 4.52 (d, J = 5.8 Hz, 2H), 3.91 (s, 3H), 3.79 - 3.66 (m, 1 H), 2.90 - 2.80 (m, 2H), 2.09 (ddd, J = 13.7, 11.2, 5.4 Hz, 1H), 1.88 (ddd, J = 13.8, 11.5, 5.7 Hz, 1H), 1.24 (d, J = 5.2 Hz, 2H), 0.58 (q, J = 5.8 Hz, 1H). ); LCMS m/z = 447 ni (M+1; 90%).
Compound-59 ' - ho oh 2-amino-7-(2-((1R,2R,3S,4R,5S)-4(4-Amino-7H-pyrrolo[2,3d]pyrimidin-7-yl)-2,3- dihydroxybicyclo [3.1.0]hexan-1yl)ethyl)quinolîne-3-carbonitriie.	2-amino-7-(2((3aR,3bR,4aS,5R,5aS)5-(4-Amino-7Hpyrro!o[2,3-d]pyrimidin-7yl)-2,2-dimethyltetra hydrocyclopropa[3,4]cycio penta[1,2-d][1,3]dioxol3b(3aH)-yi)ethyl) quinoline-3-carbonitrile.	¹H NMR (400 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.06 (d, J = 2.3 Hz, 1H), 7.66 (d, J = 8.3 Hz, 1H), 7.37(s, 1H), 7.22 (dd, J = 8.3, 1.6 Hz, 1H), 7.03 (d, J = 3.6 Hz, 1H), 6.97 (s, 2H), 6.89 (s, 2H), 6.58 (d, J =3.5 Hz, 1H), 5.11 (d, J = 4.5 Hz, 1H), 4.90 (s, 1H), 4.57 -4.48 (m, 2H), 3.73 (t, J = 5.3 Hz, 1H), 3.0 2.81 (m, 2H), 2.21 -2.04(m, 1H) 1.93-1.81 (m, 1H), 1.261.23 (m, 2H), 0.57 (q, J = 5.9 Hz, 1H); LCMS m/z = 442.23 (M+1; 80%).
Compound-60	7-(2- ((3aR,3bR,4aS,5R,5aS)- 5-(4-Amino-7H-	¹H NMR (400 MHz, DMSO-d6) δ 8.15 (s, 1H), 7.78 (d, J = 11.8 Hz, 1H), 7.58 (d, J = 8.2 Hz,

195

AN h<5 ÔH (1 R,2R,3S,4R,5S)-1-(2-(2-Amino- 3-fluoroquinolin-7-yl)ethyl)-4-(4- amino-7H-pyrroio[2,3-d]pyrimidin7-yl)bicyclo[3.1,0]hexane-2,3-diol.	pyrrolo[2,3-d]pyrimrdin-7yi)-2,2dimethyltetrahydrocyclo propa[3,4]cyclopenta[1,2d][1 ^SJdioxol-SbiSaH)yl)ethyl)-3-fluoroquinolin2-amine.	1H), 7.49 (s, 2H), 7.37 (d, J = 1.6 Hz, 1H), 7.15 (dd, J = 8.2, 1.6 Hz, 1 H), 7.11 (d, J = 3.6 Hz, 1H), 6.77 (s, 2H), 6.67 (d, J = 3.6 Hz, 1H),5.14(d, J = 4.3 Hz, 1H), 4.90 (d, J = 1.3 Hz, 1H), 4.54 (d, J = 8.9 Hz, 2H), 3.74 (d, J = 5.5 Hz, 1 H), 2.92 - 2.82 (m, 2H), 2.10 (ddd, J = 13.8, 11.2, 5.4 Hz, 1H), 1.87 (ddd, J = 13.8, 11.6, 5.6 Hz, 1H), 1.27 - 1.23 (m,2H), 0.63-0.55 (m, 1H). ); LCMS m/z = 435.3 (M+; 80%).
Compound-61 ^CIV'^ vLT r « H₂N ^N - A ,N HO OH (1 R,2R,3S,4R,5S)-1-(2-(2-Amino3-ch!oroquino!in-7-yl)ethy!)-4-(4amino-7H-pyrrolo[2,3-d]pyrimidin7-yl)bicyclo[3.1.0]hexane-2,3-dio!,	7-(2- ((3aR,3bR,4aS,5R,5aS)5-(4-Amino-7Hpyrrolo[2,3-d]pyrimidin-7yl)-2,2- dimethyltetrahydrocyclo propa[3,4]cyclopenta[1,2d][ 1,3]dioxOf-3b(3aH)yl)ethyl)-3-chloroquinolin2-amine.	¹H NMR (400 MHz, DMSO-d6) δ 8.15 (s, 1H), 8.07 (s, 1H), 7.58 (d, J = 8.2 Hz, 1 H), 7.36 (s, 1H), 7.15(dd. J = 8.2, 1.6 Hz, 1H), 7.08 - 6.89 (m, 3H), 6.66 (s, 2H), 6.58 (d, J = 3.5 Hz, 1H), 5.11 (d, J = 4.5 Hz,1H), 4.90 (s, 1H), 4.55 4.50 (m, 2H), 3.73 (t, J = 5.3 Hz, 1H), 2.96 - 2.80 (m, 2H), 2.11 (ddd, J = 13.7, 11.3, 5.3 Hz, 1H), 1.87 (ddd, J = 13.9, 11.6, 5.6 Hz, 1H), 1.26 - 1.23 (m, 2H), 0.58 (q, J = 5.9 Hz, 1 H); LCMS m/z = 451.3 (M+1 ; 80%).
Compound-62	7-(2- ((3aR,3bR,4aS,5R,5aS)- 5-(4-Amino-7H- pyrrolo[2,3-d]pyrimidin-7-	¹H NMR (400 MHz, DMSO-d6) δ 8.15 (d, J = 6.2 Hz, 2H), 7.56 -7.35 (m, 4H), 7.13 (d, J = 3.6 Hz,1H), 6.68 (d, J = 3.1 Hz,

196

F ^NH2 h₂n^{x n} JA X I HO OH (1R,2R,3S,4R,5S)-1-(2-(2-Amino- 3-chloro-6-fluoroquinolin-7yl)ethyl)-4-(4-amino-7H-pyrrolo[2,3d]pyrimidin-7-yl) bicyclo[3.1.0]hexane-2,3-diol.	yi)-2,2- d i methyltetrahyd rocyclo propa[3,4]cyclopenta[1,2d][1,3]dioxol-3b(3aH)yl)ethyl)-3-chloro-6fluoroquinolin-2-amine.	3H), 5.16 (s, 1H), 4.91 (s, 1H), 4.53 (d, J = 7.2 Hz, 2H), 3.75 (s, 1H), 2.98 (t, J= 12.0 Hz, 1H), 2.91 -2.78 (m, 1H), 2.13 (q, J = 8.2, 4.7 Hz, 1H), 1.89 1.76 (m, 1H), 1.25 (d,J = 11.4 Hz, 2H), 0.59 (q, J = 6.0 Hz, TH); LCMS m/z = 451.3 (M+1; 80%).
Compound-63 k /A viy Y « Η,Ν ^N L ^{2 F} HO OH (1 R,2R,3S,4R,5S)-1-(2-(2-Amino- 3-chloro-8-fluoroquinolin-7- yl)ethyl)-4-(4-amino-7H-pyrrolo[2,3d]pyrimidin-7- yl)bicyclo[3.1.0]hexane-2,3-diol.	7-(2((3aR,3bR,4aS,5R,5aS)- 5-(4-Amino-7H- pyrrolo[2,3-d]pyrimidin-7yi)-2,2- d i methyltetrahyd rocyclo propa[3,4]cyclopenta[1,2d][1,3jdioxoi-3b(3aH)yl)ethyl)-3-chloro-8fluoroquinolin-2-amine.	X NMR (400 MHz, DMSO-d6) δ 8.23 (s, 1H), 8.07 (s, 1H), 7.42 (d, J = 8.3 Hz, 1H), 7.17 (t, J = 7.4 Hz, 1H), 7.04 (d, J = 3.6 Hz, 1H), 7.01 - 6.92 (m, 4H), 6.58 (d, J = 3.5 Hz, 1H), 5.16 (d, J = 4.6 Hz, 1 H), 4.90 (s, 1 H), 4.59 - 4.44 (m, 2H), 3.73 (t, J = 5.4 Hz, 1H), 3.09 - 2.92 (m, 1H), 2.92 - 2.77 (m, 1H) 2.13 (t, J = 7.2 Hz, 1H), 1.87-1.74 (m, 1 H), 1.27 (t, J = 6.5 Hz, 2H), 0.58 (d, J = 5.6 Hz, 1 H); LCMS m/z = 468.68 (M+; 80%).
Compound-64 F y k/AXA ^N\Av^NH2 H₂N ^N n N HO OH (1R,2R,3S,4R,5S)-1-(2-(2-amino-3bromo-6-fluoroquino!În-7-yl)ethyl)4-(4-amino-7H-pyrrolo[2,3d]pyrimidin-7- yl)bicyclo[3.1,0]hexane-2,3-diol.	7-(2- /maR ^hP SP SaRk 5-(4-Amino-7Hpyrrolo[2,3-d]pyrimidin-7yi)-2,2dimethyltetrahydrocycfo propa[3,4]cyclopenta[1,2d][1,3]dioxol-3b(3aH)yl)ethyl)-3-bromo-6fluoroquino!in-2-amine.	¹H NMR (400 MHz, DMSO-d6) δ 8.35 (s, 1H), 8.24 (s, 1H), 7.96 (d, J = 30.9 Hz, 2H), 7.45 (t, J = 8.4Hz, 1H), 7.24 (d, J = 3.6 Hz, 1H),6.80(d, J = 3.5 Hz, 1H), 6.60 (s, 1H), 5.17 (s, 1H), 4.91 (d, J = 4.0 Hz,1H), 4.53 (s, 1H), 4.40 (d, J = 6.8 Hz, 1H), 3.78 (d, J = 6.4 Hz, 1H), 3.042.80(m, 2H), 2.15 (s, 1H), 1.82

197

		(s, 1H), 1.30 - 1.27 (m, 2H), 0.60 - 0.55 (m, 1H); LCMS m/z = 514.19 (M+1; 80%).
Compound-65 < αΧ^*Ύα'^n?NH2H XJ HO OH (1 R,2R,3S,4R,5S)-4-(4-Amino-7Hpyrrolo[2,3-d]pyrimidin-7-yl)-1-(2(3-methylimidazo[1,2-a]pyridin-7yl)ethyl) bicyclo[3.1,0]hexane-2,3diol.	7((3aR,3bR,4aS,5R,5aS)2,2-Dimethyl-3b-(2-(3methylimidazo[1,2a]pyridin-7yl)ethyl)hexahydrocyclo propa[3,4]cyclopenta[1,2d][1,3]dioxol-5-yl)-7Hpyrrolo[2,3-d]pyrimidin-4amine.	¹H NMR (400 MHz, DMSO-d6) δ 8.16 (d, J = 6.9 Hz, 1H), 8.07 (s, 1H), 7.36 (s, 1H), 7.28 (s, 1H), 7.08 - 6.85 (m, 4H), 6.58 (d, J = 3.4 Hz, 1H), 5.12 (d, J = 4.5 Hz, 1H), 4.90 (s, 1H), 4.52 (s, 2H), 3.72 (s, 1H), 3.29 (s, 1H), 2.95-2.75 (m, 2H), 2.61 2.53 (m, 1 H), 2.44 (s, 3H), 2.21 -2.03 (m, 1H), 1.97-1.74 (m, 1H), 0.61 — 0.47 (m, 1H); LCMS m/z = 405.16 (M+1; 100%).
Compound-66 J \ A k „NH₂ η,νΆ AA^ / AA ' N V_J T b c i N-A HO OH (1 R,2R,3S,4R,5S)-1-(2-(2-Amino- 3,3-dimethyl-3H-indol-6-yi)ethyl)-4(4-amino-7H-pyrrolo[2,3- d]pyrimidin-7-yl) bicyclo[3.1.0]hexane-2,3-diol.	7- ((3aR,3bR,4aS,5R,5aS)3b-(2-(2-Amino-3,3- d i methyl-3 H-i ndoi-6yl)ethyl)-2,2dimethylhexahydrocyclo propa[3,4]cyclopenta[1,2d][1,3]dioxol-5-yl)-7H- pyrrolo[2,3-d]pyrimidin-4amine.	¹H NMR (400 MHz, DMSO-d6) δ 8.06 (s, 1H), 7.09 (d, J = 7.4 Hz, 1H), 7.01 (d, J = 3.6 Hz, 1H), 6.98 (s, 2H), 6.87 (d, J = 1.4 Hz, 1H), 6.79 - 6.74 (m, 1H), 6.58 (d, J = 3.5 Hz, 1H), 5.11 (s, 1H), 4.90 (d, J = 1.2 Hz, 1H), 4.49 (s, 2H), 3.71 (s, 1H), 2.82 - 2.59 (m, 2H), 2.091.96 (m, 1H), 1.81 (td, J = 12.7, 5.3 Hz, 1H), 1.30 (s, 6H), 1.26 - 1.19 (m, 2H), 0.63-0.51 (m, 1H); LCMS m/z = 433.40 (M+1; 80%).
Compound-67	7-(2- ((3aR,3bR,4aS,5R,5aS)5-(4-Amino-6-methyl-7Hpyrroîo[2,3-d]pyrimidin-7-	¹H NMR (400 MHz, DMSO-d6) δ 8.15 (s, 1H), 8.03 (s, 1H), 7.18 (s, 1H), 7.06 - 6.87 (m, 5H), 6.36 -6.29 (m, 1H), 4.93

198

F _χ η/Λ Fi Χγ ² HO OH (1 R,2R,3S,4R,5S)-1-(2-(2-Amino3-chloro-5-fluoroquinolin-7yl)ethyl)-4-(4-amino-6-methyl-7Hpyrrolo[2,3-d] pyrimidin-7- yl)bicyclo[3.1.0]hexane-2,3-diol.	yl)-2,2-dimethyltetra hydrocyclopropa[3,4]cyclo penta[1,2-d][1,3}dioxol3b(3aH)-yl)ethyl)-3-chloro5-fluoroquinolin-2-amine.	(d, J = 5.4 Hz, 1H), 4.74 (t, J = 6.7 Hz, 1 H), 4.51 (d, J = 6.6 Hz, 1H), 4.41 (d, J = 3.4Hz, 1H), 4.28 (s, 1H), 2.95 (td, J = 12.6, 11.3, 4.9 Hz, 1H), 2.82 (td, J = 12.8, 12.1, 5.7 Hz, 1H), 2.38 (s,3H), 2.14 - 1.98 (m, 1H), 1.79 (ddd, J = 13.6, 11.3, 5.8 Hz, 1H), 0.99 - 0.79 (m, 2H), 0.58 (dd, J = 8.4,4.7 Hz, 1H); LCMS m/z = 485.05 (M+2; 40%).
Compound-68 Va V \Y y Ύ H,N ^N i i ^NY ² HO OH (1 R,2R,3S,4R,5S)-1-(2-(2-Amino3-chloro-6-fluoroquinolin-7yl)ethyl)-4-(4-amino-6-methyl-7Hpyrrolo[2,3-d] pyrimidin-7- yl)bicyclo[3.1.0]hexane-2,3-diol.	7-(2- ((3aR,3bR,4aS,5R,5aS)5-(4-Amino-6-methyl-7Hpyrrolo[2,3-d]pyrimidin-7yl)-2,2-dimethyltetra hydrocyclo propa[3,4]cyclopenta[1,2d][1,3]dioxol-3b(3aH)yl)ethyl)-3-chloro-6fluoroquinolin-2-amine.	¹H NMR (400 MHz, DMSO-d6) δ 8.15 (s, 1H), 8.01 (s, 1H), 7.46 - 7.39 (m, 2H), 6.94 (s, 2H), 6.67 (s, 2H), 6.32 (d, J = 1.2 Hz, 1H), 4.98 - 4.91 (m, 1 H),4.76 (t, J = 6.7 Hz, 1H), 4.53 (d, J = 6.6 Hz, 1H), 4.42 (d, J = 3.4 Hz, 1H), 4.28 (s, 1H), 3.08-2.94 (m, 1H), 2.84 (td, J = 13.3, 12.7, 5.3 Hz, 1H), 2.43 -2.37 (m, 3H), 2.04 (dq, J = 19.8, 7.7, 6.3 Hz, 1H), 1.86 1.72 (m, 1H), 1.32 - 1.26 (m, 2H), 0.59 (dd, J = 8.3, 4.7 Hz, 1 H); LCMS m/z = 482.30 (M; 80%).
Compound-69 ciY\1 z*YY-nΧγ \ \'^F 1 V « ,. . γΝ - - N<Y 2 HO OH (1R,2R,3S,4R,5S)-1-(2-(2-amino-3-	3-Chloro-7-(2((3aR,3bR,4aS,5R,5aS)2,2-dimethyl-5-(4-methyl- 7H-pyrro!o [2,3- d]pyrimidin-7yl)tetrahydrocyclo	A mixture of two compound was separated by reverse phase HPLC to afford compound X and compound Y as shown be!ow.¹H NMR (400 MHz, DMSO-d6) δ 8.66 (s, 1 H),

199

chloro-5-fluoroquinolin-7-yi)ethyl)- 4-(4-methyl-7H-pyrrolo[2,3- d]pyrimidin-7-yl) bicyclo[3.1.0]hexane-2,3-diol.	propa[3,4]cyclopenta[1,2d][1,3]dioxol-3b(3aH)yl)ethyl)-5-fluoroquinolin2-amine.	8.16 (s, 1H), 7.43 (d, J = 3.7 Hz, 1H), 7.21 (s, 1H), 7.00 (dd, J = 11.1, 1.4 Hz, 1H), 6.93(s, 2H), 6.70 (d, J = 3.6 Hz, 1H), 5.16 (s, 1H), 4.99 (d, J = 1.4 Hz, 1H), 4.56 (d, J = 6.5 Hz, 2H), 3.80 (d, J = 5.8 Hz, 1H), 2.97 - 2.80 (m, 2H), 2.65 (s, 3H), 2.22-2.09 (m, 1H), 1.91 -1.81 (m, 1H), 1.31-1.25 (m, 2H), 0.60 (q, J = 5.8 Hz, 1H) ); LCMS m/z = 468.2 (M+1; 80%).
Compound-70 F ^clYrl /AvO·. x AA⁷ A/ \ W ; i N^N ² HO OH (1R,2R,3S,4R,5S)-1-(2-(2-Amino- 3-chloro-5-fluoroquinolin-7y!)ethy!)-4-(7H-pyrro!o[2,3d]pyrimidin-7-yl)bicyclo [3.1.0]hexane-2,3-diol.	3-Chloro-7-(2((3aR,3bR,4aS,5R,5aS)2,2-dimethyi-5-(7Hpyrrolo[2,3-d]pyrimidin-7yl)tetrahydrocyclo propa [3,4]cyclopenta[1,2d][ 1,3]dioxoi-3b(3aH)yl)ethyl)-5-fluoroquinolin2-amine.	X NMR (400 MHz, DMSO-d6) δ 9.02 (s, 1H), 8.81 (s, 1H), 8.16 (s, 1H), 7.51 (d, J = 3.7 Hz, 1H), 7.22 (s, 1H), 7.03 6.98 (m,1H), 6.92 (bs, 2H), 6.67 (d, J = 3.6 Hz, 1H), 5.02 (d, J = 1.5 Hz, 1H), 4.56 (d, J = 6.7 Hz, 1 H), 3.81 (d, J = 6.4 Hz, 1H), 2.87 (ddd,J = 19.0, 14.0, 8.5 Hz, 2H), 2.20 - 2.10 (m, 1H), 1.88 (d, J = 10.5 Hz, 1H), 1.32 - 1.26 (m, 2H), 0.64- 0.58 (m, 1H); LCMS m/z = 454.11 (M+1; 40%).
Compound-71 η,νΆ· \ u ² _N- \' >\| N HO OH (1 R,2R_l3S,4R_l5S)-4-(4-Amiπo-7H- pyrrolo[2,3-d]pyrimidin-7-yl)-1-(2- (2'-aminospiro[cyclobutane1,3‘-	6^!-(2((3aR,3bR,4aS,5R,5aS)- 5-(4-Amino-7H- pyrrolo[2,3-d]pyrimidin-7- yi)-2,2- dimethyitetrahydrocyciopr opa [3,4]cyclopenta[1,2-	¹H NMR (400 MHz, DMSO-d6) δ 8.07 (s, 1H), 7.68 (d, J = 7.7 Hz, 1H), 7.22 - 7.07 (m, 4H), 7.07 - 6.96 (m, 3H) 6.59 (d, J = 3.5 Hz, 1H), 5.14 (d, J = 4.6Hz, 1H), 4.89 (s, 1H), 4.51 (d, J = 7.2 Hz, 1H), 3.74 (t, J = 5.4 Hz,

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indol]-6’-yl) ethyl)bicyclo[3.1.0]hexane-2,3-diol.	d][1,3]dioxol-3b(3aH)- yl)ethyl)spîro[cyclobutane1,3'-indol]-2'-amine.	1H), 2.79 (dd, J = 24.0, 14.1 Hz, 3H), 2.35 (d, J = 12.3 Hz, 2H), 2.20 (d, J = 9.9 Hz, 1H), 2.04 (d, J = 17.8 Hz, 1H), 1.87 -1.74 (m, 1H), 1.26-1.18 (m, 5H), 0.60 - 0.50 (m, 1H); LCMS m/z = 445.03 (M+1; 90%).
Compound-72 F Br - \ Ky ^v \^r/ ..· - N N ^H2^N hô oh (1R,2R,3S,4R,5S)-1-(2-(2-Amino- 3-bromo-5-fluoroquinolin-7yl)ethyl)-4-(4-amino-7H-pyrrolo[2,3d]pyrimidin-7- yl)bicyclo[3.1.0]hexane-2,3-diol	k» Λ	¹H NMR (400 MHz, DMSO-d6) d 8.33 (s, 1H), 8.08 (s, 1H), 7.20 (s. 2H), 7.17 - 6.96 (m, 3H), 6.84 (s, 2H), 6.60 (d, J = 3.5 Hz, 1 H), 5.11 (d, J = 4.5 Hz, 1H), 4.90 (d, J = 1.2 Hz, 1H), 4.52 (d, J = 2.7 Hz, 2H), 3.72 (s, 1H), 3.00 - 2.74 (m, 2H), 2.14 (s, 1H), 1.90 - 1.76 (m, 1H). 1.42 - 1.28 (m, 1H), 0.91 - 0.75 (m, 1 H), 0.57 (q, J = 5.9 Hz, 1H); LCMS m/z = 514.19, 516.19 (M+, M+2, 100%).

Example-6: (1R,2R,3S,4R,5S)-1-(2-(2-Amino-3-bromoquinolin-7-vDethyl)-4-(4-amino-7Hpyrrolo [2.3-dlpyrimidin-7-yl)bicyclo(3.1.0]hexane-2,3-diol (Compound-73)

7-(2-((3aR,3bR,4aS,5R,5aS)-5-(4-Amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl hexahydrocyclopropa[3,4]cyclopenta[1,2-d][1,3]dioxol-3b-yl)ethyl)-3-bromo-N-(4-methoxy benzyl)quinolin-2-amine (2.6g, 3.97mmol) in TFA (55.0 ml, 714 mmol) was stirred at 50®C for 1 h under N₂ atmosphère. The resulting mixture was concentrated in vacuo and obtained residue was dissolved in MeOH (50ml). K2CO3 (0.982 g, 7.10mmol) was added and stirred

201 the reaction mixture at 60°C for 1h. The reaction mixture was filtered, and fiitrate was concentrated under reduced pressure to get 2.7g of crude compound. This residue was purified by combiflash (Rf200, Teledyne/lsco) instrument onto a redisep® R_f column with gradient elution (0 to 9%) of met'nanol in dichloromethane to afford the title compound 5 (1,35g, 77%) as a white solid. ¹H NMR (400 MHz, DMSO-de): δ 8.34 (s, 1H), 8.12 (s, 1H),

7.58 (d, J= 8.3 Hz, 1H), 7.36 (d, J = 1.6 Hz, 1H), 7.26 (s 2H), 7 15 (dd J = 8 2 1 7 Hz 1H), 7.09 (d, J = 3.5 Hz, 1H), 6.64 (d, J = 3.5 Hz, 1H), 6.60 (s, 2H), 5.13 (d, J = 4.6 Hz, 1H), 4.97-4.83 (m, 1H), 4.53 (d, J = 3.9 Hz, 2H), 3.74 (s, 1H), 2.94-2.81 (m, 2H), 2.11 (dt, J= 11.2, 6.5 Hz, 1H), 1.87 (ddd, J = 13.9, 11.5, 5.6 Hz, 1H), 1.33-1.12 (m, 2H); 0.60 10 - 0.57 (m, 1 H). LCMS m/z= 494.99, 496.99 (M+, M+2; 100%).

Examples in table-16 were synthesized by following an analogous reaction protocol as was used for the préparation of (1R,2R,3S,4R,5S)-1-(2-(2-amino-3-bromoquinolin-7-yl)ethyl)4-(4-amino-7H-pynOlo [2,3-d]pyrimidin-7-yï)bicyclo[3.1.0]hexane-2,3-diol using the appropriate starting materials.

Table-16:

Srtucture & IUPAC name	Intermediate used	¹H NMR & LCMS data
Compound-74 i / ί V, c - N-^N HO OH (1 R,2R,3S,4R,5S)-4-(4-Amino-7Hpyrrolo[2,3-d]pyrimidin-7-yl)-1-(2- (2-aminoquinoIin-7- yf)ethyl)bicyclo[3.1.0]hexane-2,3diol	7-(2-((3aR,3bR,4aS,5R,5aS)5-(4-Amino-7 H-pyrrolo[2,3dlpyrimidin-7-yl)-2_î2-dimethyl hexahydrocyclopropa [3,4] cyclopenta[1,2-d][1,3]dioxol3b-yl)ethyl)quinolin-2-amine	¹H NMR (400 MHz, DMSO-d6) δ 8.07 (s, 1 H), 7.82 (d, J = 8.8 Hz, 1 H), 7.52 (d, J = 8.2 Hz, 1 H), 7.30 (d, J = 1.6 Hz, 1H), 7.08 - 7.02 (m, 2H), 6.97 (s, 2H), 6.68 (d, J = 8.8 Hz, 1 H), 6.58 (d, J = 3.5 Hz, 1 H), 6.34 (s, 2H), 5.11 (d, J = 4.5 Hz, 1H), 4.91 (d, J = 1.2 Hz, 1H), 4.55 - 4.49 (m, 2H), 3.73 (t, J = 5.2 Hz, 1H), 2.91 - 2.78 (m, 2H), 2.10 (ddd, J = 13.6, 11.3, 5.3 Hz, 1H), 1.92 - 1.85 (m, 1H), 1.28 -1.24 (m, 2H), 0.59 (td, J = 6.6, 3.2 Hz, 1H); LCMS m/z= 418.17 (M+2; 40%).
Compound-75	N-(7-(2-((1 R,2R,3S,4R,5S)-4(4-Amino-7 H-py rrolo[2,3-	¹H NMR (400 MHz, DMSO-d6) δ 9.04 (s, 1H), 8.16 (s, 1H), 7.71 (d, J

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ΥΥ'Α^{N Hz}h2n^{z N} c - LZN HO OH (1 R,2R,3S,4R,5S)-4-(4-amino-7Hpyrrolo[2,3-d]pyrimidin-7-yl)-1-(2(2-aminoquinazolin-7- yl)ethyl)bicyclo[3.1.0] hexane-2,3diol.	d]pyrimidin-7-yl)-2,3dihydroxybicyclo[3.1,0]hexan1-yl)ethyl)quinazolin-2-yl)~ 2,2,2-trifl uoroacetamide.	= 8.2 Hz, 1H), 7.53 (s, 2H), 7.28 (s, 1H), 7.15 (dd, J = 11.1, 5.8 Hz, 2H), 6.83 (s, 2H), 6.69 (d, J = 3.6 Hz, 1 H), 5.14 (s, 1H), 4.90 (s, 1H), 4.55 (s, 2H), 3.75 (s, 1H), 2.99 - 2.79 (m, 2H), 2.11 (d, J = 15.9 Hz, 1H), 1.87 (q, J = 10.9, 8.1 Hz, 1H), 1.29-1.23 (m, 2H), 0.61 - 0.56 (m, 1H); LCMS m/z = 418.10 (M+1; 80%).
Compound-76a and 76b ^ΒΓ NH? H₂N^Zn / X_ZN HO OH (1S,2R,3S,4R,5S)-1-((S)-1-(2- Amino-3-bromoquinolin-7yl)propan-2-yl)-4-(4-amino-7Hpyrrolo[2,3-d]pyrimidin-7yl)bicyclo[3.1,0]hexane-2,3-diol.	7-(2-((3aR,3bS,4aS,5R,5aS)5-(4-Amino-7H-pyrrolo[2,3d]pyrimidin -7-yl)-2,2- dimethyltetrahydrocyclo propa[3,4]cyclopenta[1,2d][1,3] dioxol-3b(3aH)- yl)propyl)-3-bromo-N-(4methoxybenzyl) quinolin-2amine.	Diastereomeric mixture was separated by chiral préparative HPLC. Wavelength: 225nm, Instrument Method: HEX-0.1 %DEA_I PA- DCM_A_C_40_60_1.2ML_10ΜΙΝ Flow Rate: 1.2 ml/min, Column : CHIRALPAK IA CRL-025 Column Temp: 25°C, Mobile Phase A: HEX_0.1%DEA Mobile Phase C: IPA-DCM_1-1, Mobile Phase B: NA Mobile Phase D: NA First Diastereomer (Compound 76a): ¹H NMR (400 MHz, DMSO-d6) δ 8.33 (s, 1H), 8.06 (s, 1H), 7.58 (d, J = 8.2 Hz, 1H), 7.33 (s, 1H), 7.12 (d, J = 8.4 Hz, 1H), 7.01 - 6.87 (m, 3H), 6.64-6.47 (m, 3H), 5.13 (d, J - o.z nz, in), 4.ou (u, j - z.^ nz, 1 H), 4.61 (t, J = 6.7 Hz, 1 H), 4.47 (d, J = 7.2 Hz, 1 H), 3.96 - 3.85 (m, 1 H), 3.22 (dd, J = 13.2, 3.9 Hz, 1H), 2.94 -2.88(m. 1 H), 1.97-1.83 (m, 1 H), 1.31 -1.21 (m, 2H), 0.79 (d, J = 6.8

203

		Hz, 3H), 0.67 - 0.59 (m, 1 H); LCMS m/z = 510.94 (M+2; 40%) Second Diastereomer (Compound 76b): ¹H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 1H), 8.06 (s, 1H), 7.57 (d, J = 8.2 Hz, 1H), 7.32 (s, 1H), 7.11 (dd, J= 8.2, 1.6 Hz,1H), 7.07 (d, J = 3.6 Hz, 1H), 6.97 (s, 2H), 6.58 (d, J = 3.5 Hz, 1H), 6.55 (s, 2H), 5.15 (d, J = 5.1 Hz, 1H), 4.80 (d, J = 2.6 Hz,1H)_t 4.64 (t, J= 7.0 Hz, 1H), 4.43 (d, J = 7.3 Hz, 1H), 3.97 - 3.88 (m, 1H), 3.07-2.97 (m, 1 H), 2.97-2.88 (m, 1H), 1.70- 1.55(m, 1H), 1.31 1.21 (m, 2H), 0.98 (d, J = 6.8 Hz, 3H), 0.61 -0.52 (m, 1H); LCMS m/z = 510.94 (M+2; 40%)
Compound-77a and 77b F ^-7 h₂n^ⁿ' M n^À ² HO OH (1 S,2R,3S,4R,5S)-1 -((S)-2-(2- Amino-3-chloro-5-fluoroquinolin-7yl)-1-cyclopropylethyl)-4-(4-amino7H-pyrrolo[2,3-d]pyrimidin-7yl)bicyclo[3.1,0]hexane-2,3-diol.	7-(2-((3aR,3bS,4aS,5R,5aS)5-(4-Amino-7H-pyrrolo[2,3d]pyrimidin -7-yi)-2,2- dimethyltetrahydrocyclo propafS, 4]cydopenta[l ,2d][1,3] dioxol-3b(3aH)-yl)-2cyclopropyl ethyi)-3-chloro-5fluoro-N-(4meihoxybenzyi)quinoîin-2amine.	Diastereomeric mixture was separated by chiral préparative HPLC. Wavelength: 225 nm, Instrument Method: MeOH_0.1%DEA_ 100_10ML_12MIN Flow Rate: 1.00 ml/min Column : CHIRALPAK IE CRL-042 Column Temp: 30°C, Mobile Phase A: MEOH_0.1%DEA, Mobile Phase . k s a D. iNM First Diastereomer (Compound 77a): ¹H NMR (400 MHz, DMSOd6) δ 8.39 (s, 1H), 8.16 (s, 1 H), 8.04 (s, TH), 7.28 (s, TH), 7.05 (dd, J = 11.3, 1.3 Hz, 1 H), 6.93 (dd, J = 11.6,

204

		8.0 Hz, 4H), 6.52 (d, J = 3.5 Hz, 1Ή), 5.28 - 5.08 (m, 1H), 4.82 (d, J = 2.8 Hz, 1H>, 4.61 (d, J = 6.7 Hz, 1H), 3.86 (s, 1H), 2.90 (dd, J = 13.3, 8.5 Hz, 1H), 2.77 (q, J = 7.2 Hz, 2H), 2.68 (q, J = 1.8 Hz, 1H), 1.37 (dd, J = 8.8, 4.0 Hz, 1H), 1.27 - 1.01 (m, 3H), 0.66 (dd, J = 8.6, 4.9 Hz, 1H), 0.46 (s, 1H), 0.26 - 0.17 (m, 1H), η AHi i™ 1U\ I P MO — U. 1U “ U.U ! V ¹ h ^{1 1} v» 1 1 — 509.4 (M+1; 50%) Second Diastereomer (Compound 77b): ¹H NMR (400 MHz, DMSO-d6) δ 8.15 (s, 1H), 8.05 (s, 1H), 7.31 7.17 (m, 2H), 7.08 - 6.81 (m, 5H), 6.59 (d, J = 3.5 Hz, 1H), 5.18 (s, 1H), 4.82 (dd, J = 9.3, 4.6 Hz, 2H), 4.54 (s, 1 H), 3.92 (d, J = 6.7 Hz, 1H), 3.16 (q, J = 6.5 Hz, 1H), 2.99 - 2.89 (m, 1H), 1.22 - 1.06 (m, 4H), 0.57 (q, J = 8.5, 7.9 Hz, 1H), 0.50 - 0.34 (m, 1H), 0.26 (ddd, J = 13.1,8.4, 4.7 Hz, 2H), 0.06 (dd, J = 9.4, 4.7 Hz, 1H) ; LCMS m/z = 509.4 (M+1; 50%)
Compound-78a and 78b F ^Cl k nQy ^NHz ^Hz ho Oh (1S,2R,3S,4R,5S)-1-(1-(2-Amino-3chloro-5-fluoroquinolin-7-yl)propan2-yl)-4-(4-amino-7H-pyrrolo[2,3d]pyrimidin-7- yl)bicyclo[3.1,0]hexane-2,3-diol.	N-(7-(2-(( 1 S,2R,3S,4R,5S)-4(4-Amino-7H-pyrrolo[2,3d]pyrimidin -7-yl)-2,3- dihydroxybicyclo [3.1.0] hexan-1 -yl)propyl)-3-chloro5-fluoroquinolin-2-yl)-2,2,2trifluoroacetamide.	First Diastereomer(Compound78a): ¹H NMR (400 MHz, DMSOd6) δ 8.15 (s, 2H), 8.06 (s, 1 H), 7.17 (s, 1 H), 7.07 (d, J = 3.6 Hz, 1 H), 7.04 - 6.90 (m, 4H), 6.58 (d, J = 3.5 Hz, 1H), 5.16 (d, J = 5.1 Hz, 1H), 4.79 (d, J = 2.6 Hz, 1H), 4.63 (t, J = 7.1 Hz, 1H), 4.45 (d, J = 7.3 Hz, 1H), 3.93 (d, J = 6.9 Hz, 1H), 2.99 (dd, J = 13.3. 4.9 Hz, 1 H), 2.61 (d, J =11.2

205

		Hz, 1 H), 1.63 (s, 1 H), 1.17 (d, J = 5.8 Hz, 2H), 0.99 (d, J = 6.7 Hz, 3H), 0.57 (d, J = 4.3 Hz, 1H>; LCMS m/z = 485.03 (M+2; 40%) Second Diastereomer (Compound78b): ¹H NMR (400 MHz, DMSO-d6) δ 8.16 (s, 1H), 8.08 (s, 1H), 7.19 (s, 1H), 7.10 (s, 2H), 6.98 (dd, J = 10.0, 2.2 Hz, 2H), 6.92 (s, 2H), 6.56 (d, J = 3.6 Hz, 1H), 5.13 (d, J = 5.3 Hz, 1H), 4.80 (d, J = 2.9 Hz, 1H), 4.61 (t, J = 6.7 Hz, 1H), 4.48 (d, J = 7.1 Hz, 1H), 3.90 (s, 1H), 3.21 (dd, J = 13.3, 4.1 Hz, 1H), 2.68 (p, J = 1.9 Hz, 1H), 2.36-2.32 (m, 1H), 1.17 (t, J = 4.3 Hz, 2H), 0.79 (d, J = 6.8 Hz, 3H), 0.63 (dd, J = 8.6, 4.7 Hz, 1 H); LCMS m/z = 483.02 (M+; 90%)
Compound-79a and 79b Η,ΐ/^ '· i L nA HO OH (1 R,2R,3S,4R,5S)-4-(4-Amino-7Hpyrrolo[2,3-d]pyrimidin-7-yl)-1 -(2(2-aminoquinolin-7-yl)propyl) bicyclo(3.1.0]hexane-2,3-diol.	7-(1-((3aR,3bR,4aS,5R,5aS)5-(4-Amino-7H-pyrroio[2,3d]pyrimidin -7-yl)-2,2- dimethyltetrahydrocyclo propa[3,4]cyclopenta[1,2- d][1,3] dioxol-3b(3aH)- yl)propan-2-yl)-N-(4methoxybenzyî)quinolin-2- amine.	Diastereomeric mixture was separated by chiral préparative HPLC. Wavelength: 225 nm, Instrument Method: MeOH_0.1 %DEA_A_1.0ML_10ΜΙΝ Flow Rate: 1.00 ml/min, Column : CHIRALPAK IB CRL-043 Column Temp: 30°C, Mobile Phase A: MeOH_0.1%DEA,Mobile Phase B: NA First Diastereomer(Compound 79a): ¹H NMR (400 MHz, DMSOd6) δ 8.13 - 8.03 (m, 2H), 7.66 (d, J = 8.2 Hz, 1H), 7.53 - 7.43 (m, 3H) 7.31 (d, J= 8.3 Hz, 1H), 7.03 (s, 2H),

206

		6.93 (d, J = 3.5 Hz, 1H), 6.84 (d, J = 9.1 Hz, 1H), 6.56 (d, J = 3.5 Hz, 1H), 5.15 (d, J = 4.7 Hz, 1H), 4.76 (d, J = 1.4 Hz, 1H), 4.49 - 4.32 (m, 2H), 3.70 (t, J = 5.5 Hz, 1H), 3.30 - 3.18 (m, 1H), 2.25 (dd, J = 14.1, 4.8 Hz, 1H), 1.82 (dd, J = 14.2, 9.1 Hz, 1H), 1.31 - 1.22 (m, 4H), 1.02 - 0.91 (m, 1H), 0.64 (dd, J = 8.5, 4.7 Hz, 1H); LCMS m/z = 430.92 (M+1; 90%). Second Diastereomer(Compound 79a): Ή NMR (400 MHz, DMSOd6) δ 8.02 (d, J = 13.7 Hz, 2H), 7.64 (d, J = 8.2 Hz, 1H), 7.37 (d, J = 1.6 Hz, 1H), 7.21 (dd, J = 8.2, 1.6 Hz, 3H), 6.98 (s, 2H), 6.81 (d, J = 9.0 Hz, 1H), 6.69 (d, J = 3.6 Hz, 1H), 6.42 (d, J = 3.5 Hz, 1H), 5.16 (d, J = 4.8 Hz, 1H), 4.83 (d, J = 1.7 Hz, 1H), 4.47 (d, J = 2.4 Hz, 2H), 3.68 (s, 1H), 2.37 - 2.27 (m, 1 H), 1.68 - 1.57 (m, 1 H), 1.39 - 1.26 (m, 5H), 1.04 (dd, J = 8.6, 3.8 Hz, 1H), 0.69 - 0.60 (m, 1H); LCMS m/z = 430.98 (M+1; 90%)
Compound-80 . /=\ V s A k AA k-AX® \ / ΥΥ M-M N ' ( i V. '~ - ΑΖ* HO OH (1R,2R,3S,4R,5S)-1-(((2-Amino-3bromoquinolin-7-yl)oxy)methyl)-4(4-amino-7H-pyrrolo[2,3- d]pynmidin-7- yl)bicyclo[3.1.0]hexane-2,3-diol.	N-(7-((( 1 R,2R,3S,4R,5S)-4(4-Amino-7H-pyrrolo[2,3d]py rimidin-7-y l)-2,3dihydroxybicyclo[3.1.0]hexan1-yl)methoxy)-3bromoquinolin-2-yl)-2,2,2trifluoroacetamide.	NMR (400 MHz, DMSO-d6) δ 9.39 (bs, 2H), 8.45 - 8.36 (m, 3H), 7.83 - 7.62 (m, 2H), 7.03-7.14 (m, 3H), 6.99 (d, J = 3.6 Hz, 1H), 5.28 (s, 1H), 5.05 (s, 1H), 4.86 (s, 1H), 4.71 - 4.57 (m, 2H),3.93 (d, J = 10.4 Hz, 1H), 3.72 (d, J = 6.4 Hz, 1H), 1.62 (d, J = 8.6 Hz, 1H), 1.53 (t, J =

207

		4.4 Hz, 1H), 0.90- 0.82 (m, 1H); LCMS m/z = 499.2 (M+2; 40%).
Compound-81 \ X s Γ V « J N-, A ™ HO OH (1 S,2R,3S,4R,5S)-4-(4-Amino-7H- pyrrolo[2,3-d]pyrimidin-7-yl)-1-(((2- aminoquinolin-7-yl)thio)methyl) bicycio [3.1.0] hexane-2,3-diol.	7-((((3aR,3bS,4aS,5R,5aS)5-(4-Amino-7H-pyrrolo[2,3d]pyrimidin-7-yl)-2,2dimethyltetra hydrocycio propa [3,4]cyclopenta[1,2d][1,3]dioxol-3b(3aH)yl)methyl)thio)-N-(4methoxybenzyl)quinolin-2amine.	¹H NMR (400 MHz, DMSO-d6) δ 8.05 (s, 1 H), 7.82 (d, J = 8.8 Hz, 1 H), 7.53 (d, J = 8.4 Hz, 1H), 7.38(d, J = 1.8 Hz, 1 H), 7.16 (d, J = 3.5 Hz, 1H), 7.13 (dd, J = 8.4, 1.9 Hz, 1H), 6.96 (s, 2H), 6.67 (d, J = 8.8Hz, 1H), 6.52 (d, J = 3.5 Hz, 1 H), 6.44 (s, 2H), 5.21 -5.11 (m, 1H), 4.90 (s, 1 H), 4.68 (d, J = 7.1 Hz,1H), 4.57 (s, 1H), 3.71 3.60 (m, 2H), 3.38 (d, J = 13.5 Hz, 1 H), 1.43- 1.38 (m, 2H), 0.84 -0.77 (m,1H); LCMS m/z = 435.10 (M+2; 90%).

Example-7: (1R,2R,3S,4R,5S)-1-(2-(2-Amino-3-(4-fluorophenyl)quinolin-7-yl)ethyl)-4-(4amino-7H-pyrrolo[2,3-dlpyrimidin-7-vl)bicyclof3.1.0lhexane-2.3-diol (Compound-82 )

In a sealed tube, the mixture of (1R,2R,3S,4R,5S)-1-(2-(2-amino-3-bromoquinolin-7yl)ethyl)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[3.1.0]hexane-2,3-diol (100 mg, 0.202 mmol), K2CO3 (84mg, 0.606mmol), (4-fluorophenyl)boronic acid (42.4mg, 0.303mmoî) in dioxane (10mi) was deggassed for 10min with nitrogen at25^QC. PdCÎ2(dppf)19533

208

CH2CÎ2adduct (16.49mg, 0.020mmol) was added and stirred the reaction mixture at 100°C for 16h. The resulting mixture was filtered through cellite and filtrate was concentred in vacuo to get 0.15g of crude compound.. This residue was purified by combiflash (Rf200, Teledyne/lsco) instrument onto a redisep® R_f column with gradient elution (0 to 8%) of 5 methanol in dichloromethane to afford the title compound (0.025g, 93.81%) as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.07 (s, 1H), 7.78 (s, 1H), 7.68 - 7.50 (m, 3H), 7.43 -7.24 (m, 3H), 7.13 (dd, J = 8.2, 1.7 Hz, 1H), 7.05 (d, J= 3.6 Hz, 1H), 6.97 (s, 2H), 6.59 (d, J = 3.5 Hz, 1 H), 5.96 (s, 2H), 5.11 (d, J = 4.5 Hz, 1 H), 4.97 - 4.81 (m, 1 H), 4.58 - 4.39 (m, 2H), 3.74 (t, J = 5.5 Hz, 1H), 3.04-2.72 (m, 2H), 2.18-2.09 (m, 1H), 1.90 (td, J = 10 12.5, 5.6 Hz, 1H), 1.34 - 1.16 (m, 2H), 0.64 - 0.54 (m, 1H); LCMS m/z= 511.09 (M+1;

90%).

Examples in table-17 were synthesized by following an analogous reaction protocol as was used for the préparation of (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 using the 15 appropriate starting materials.

Table-17

Srtucture & IUPAC name	Intermediate used	¹H NMR & LCMS data
Compound-83 \ / r h ^N X -, N N HO OH (1 R,2R,3S,4R,5S)-1-(2-(2-Amino3-(pyridin-3-yi)quinolin-7-yl)ethyl)4-(4-amino-7H-pyrrolo[2,3- d]pyrimidin-7- yl)bicyclo[3.1.0]hexane-2,3-diol.	(1 R,2R, 3S,4R, 53)-1-(2- (2-Amino-3bromoquinolin-7y l)ethy l)-4-(4-amino-7 Hpyrrolop, 3-d]pyrimtdin7yl)bicyclo[3.1.0]hexane2,3-diol.	¹H NMR (400 MHz, DMSO-d₆) δ 8.07 (s, 1 H), 7.78 (s, 1 H), 7.68 7.50 (m, 3H), 7.43 - 7.24 (m, 3H), 7.13 (dd, J = 8.2, 1.7 Hz, 1H), 7.05 (d, J = 3.6 Hz, 1H), 6.97 (s, 2H), 6.59 (d, J = 3.5 Hz, 1H), 5.96 (s, 2H), 5.11 (d, J = 4.5 Hz, 1H), 4.97 - 4.81 (m, 1 H), 4.58 - 4.39 (m, 2H), 3.74 (t, J = 5.5 Hz, 1 H), 3.04 - 2.72 (m, 2H), 2.18-2.09 (m, 1 H), 1.90 (td, J = 12.5, 5.6 Hz, 1 H), 1.34 - 1.16 (m, 2H), 0.64 - 0.54 (m, 1H); LCMS m/z= 494.2(M+1;30%)

209

Compound-84 nX U AA /AA ' / li H₂N ⁿ <· ·-> N .N ² HO OH (1R,2R,3S,4R,5S)-1-(2-(2-Amino3-(3-methyl isoxazol-4-yî)quinolin7-yi)ethyî)-4-(4-amino-7Hpyrrolo[2,3-d]pyrimidin-7yl)bicyc!o[3.1.0]hexane-2,3-diol.

(1R,2R,3S,4R,5S)-1-(2(2-Amino-3bromoquinolin-7yl)ethyl)-4-(4-amino-7Hpyrrolo[2,3-d]pyrimidin-7yl)bicyclo[3.1.0]hexane2,3-diol

¹H NMR (400 MHz, DMSO-d6) δ 9.01 (s, 1 H), 8.07 (s, 1 H), 7.85 (s, 1H), 7.59 (d, J = 8.2 Hz, 1H), 7.37 (d, J = 1.5 Hz, 1 H), 7.13 (dd, J = 8.2, 1.6 Hz, 1H), 7.04 (d, J = 3.6 Hz, 1H), 6.97 (s, 2H), 6.58 (d, J = 3.5 Hz, 1H), 6.15(s,2H), 5.12 (d, J = 4.1 Hz, 1H), 4.59 - 4.47 (m, 2H), 3.74 (d, J = 5.2 Hz, 1H), 3.00-2.77 (m, 3H), 2.22 (s, 3H), 1.89(ddd, J= 13.9, 11.4, 5.7 Hz, 1 H), 1.30 - 1.25 (m, 2H), 0.90 0.80 (m, 1H), 0.59 (q, J = 5.8 Hz, 1H); 498.07 (M+1;100%)

Biological Examples

Biochemical assay protocol 1

Inhibitory effect of compounds on PRMT5 was assessed using HTRF détection 5 technology in biochemical assay. Biotinylated H4R3 (residues 1-21) was used as a substrate. Compounds were pre-incubated with 15-25 ng PRMT5;MEP50 perweïî of a 384well plate for 30 min at room température in the assay buffer containing 20 mM Bicine, pH 7.6, 25 mM NaCI, 2 mM DTT, 0.01% Chicken albumin and 0.01% Tween-20. Reaction was initiated by adding 1 μΜ of SAM and 50 nM biotinylated H4R3. Total assay volume was 15 uL Reaction was continued for 120 min at room température, Then détection solution containing Streptavidin-Eu cryptate, anti-rabbit lgG-XL-665, Histone H4R3 Dimethyl Symmetric (H4R3me2s) Polyclonal Antibody, ail prepared in HTRF détection buffer was added and further incubated for 30 min at room température. HTRF signal was recorded in PHERAStar microplate reader. Ratio of signal obtained at 665 nm and 620 nm was used to compute the percent inhibition of compound as foliows % Inhibition = 100-((Test Ratio - Négative control Ratio)/(Positive control Ratio Négative control Ratio)*100) where

Positive control = PRMT5 + SAM + H4R3

Négative control = PRMT5 + H4R3

210

Biochemical assav protocol 2

Inhibitory effect of compounds on PRMT5 was assessed using HTRF détection technology in biochemical assay. Biotinylated H4R3 (residues 1-21) was used as a substrate. Compounds were pre-incubated with 2.5 ng PRMT5:MEP50 per well of a 384well plate for 30 min at room température in the assay buffer containing 20 mM Bicine, pH 7.6,25 mM NaCI, 2 mM DTT, 0.01% Chicken albumin and 0.01% Tween-20. Reaction was initiated by adding 1 μΜ of SAM and 50 nM biotinylated H4R3. Total assay volume was 15 uL. Reaction was continued for 4 h at room température. Then détection solution containing Streptavidin-Eu cryptate, anti-rabbit lgG-XL-665, Histone H4R3 Dimethyl Symmetric (H4R3me2s) Polyclonal Antibody, ail prepared in HTRF détection buffer was added and further incubated for 30 min at room température. HTRF signal was recorded in PHERAStar microplate reader. Ratio of signal obtained at 665 nm and 620 nm was used to compute the percent inhibition of compound as follows % Inhibition = 100-((Test Ratio - Négative control Ratio)/(Positive control Ratio Négative control Ratio)*100) where

Positive control = PRMT5 + SAM + H4R3

Négative control = PRMT5 + H4R3

Activity Range	Compound numbers
IC50 300pM to 950pM	43, 26, 35b, 47, 21, 38, 34b, 34a, 7a, 13, 37, 18, 33b, 33a, 76a, 23, 25, 24, 48, 1, 61, 73, 44, 2, 15, 36a, 45a, 45b, 35a

SDMA inhibition assav

Protocol

Z-138 cells (ATCC, CRL-3001™) were seeded at a density of 1 million cells/well in transparent, fiat bottomed tissue culture grade 48-well plates. Cells were treated with various concentration of test compounds for a period of 48 h. Cell lysate was prepared using 1X CST Lysis buffer (Cell Signaling Technology, USA) and 500 ng/well/50 pl_ of lysate in pH 9.6 carbonate buffer was coated on 96-well Maxisorb plate and incubated overnight at 4°C. The plate was washed twice in 1 x PBS containing 0.05% Tween 20 and blocked in 1% BSA for 1 h at ambient température. Further, the plate was incubated first with primary antibody (anti-SDMA antibody; CST#13222s) at ambient température for 2 h

211 and then with HRP-conjugated secondary antibody at ambient température for 1 h with 2 intermittent washing steps in between.

For luminiscence based détection, HRP substrates (substrate A + substrate B in a 1:1 proportion) were added followed by luminiscence reading after 30 min in Synergy™ 2 5 reader (Biotek, USA).

For absorbance based détection, TMB substrate was added followed by addition of STOP solution (2N H2SO4) post colour development and absorbance (excitation 450 nm and émission 540 nm) was measured in Synergy™ 2 reader (Biotek, USA).

% inhibition of SDMA was calculated relative to the vehicle control samples containing 10 media with 0.1 % DMSO alone as per the formula below.

(Avg, of Untreated Control — Avg. of Test) X 100

Avg. of Untreated control

The IC50 values of individual compounds were calculated with Non Linear Régression Analysis using Graph Pad Prism (Graph Pad software, Inc, USA).

Activity Range	Compound numbers
IC₅₀ IpM to 1nM	7b, 13, 37, 33b, 46, 76b, 23, 24, 2, 48, 1, 61, 73, 47, 38, 34b, 30, 41, 31, 72, 29, 34a, 21, 35a, 26, 43.
ICso1.1nM to 50nM	32, 64, 33a, 76a, 25, 62, 35b.

Anticancer activity assav

Z-138 cells were seeded at a density of 2000-3000 cells per well in culture media (IMDM + 10% FBS). PANC-1 (ATCC, CRL-1469™) and MIA PaCa-2 (ATCC, CRL-1420™) 20 cells were seeded at a density of 200-300 cells per well in culture media (DMEM + 10% FBS). Cells were seeded in opaque, fiat bottomed tissue culture grade 96-well plates and Z-138 cells (suspension) were seeded and treated on the same day with various concentrations of test compounds. PANC-1 and MIA PaCa-2 cells, being adhèrent, were kept for overnight seulement at standard cell culture conditions (37°C, 5% CO2). On the 25 following day, cells were treated with various concentrations of test compounds. Cells were treated with test compounds for a period of 96 h, 7 days and 10 days, for Z-138 cells, PANC-1 cells and MIA PaCa-2 cells, respectively. Cell viability was assessed using

212

CelITiterGIo™ (Promega, USA) as per manufacturées instructions. Relative Light Units (RLU) were read in Synergy^TM2 reader (Biotek, USA). The assay measures cellular ATP as an indicator of cell viability. RLU is proportional to the number of viable cells in the respective well.

% inhibition of cell viability was calculated relative to the vehicle control samples containing media with 0.1% DMSO alone as per the formula below.

(Avg. of Untreated Control - Ανα. of Test) X 100

Avg. of Untreated control

The IC50 values of individual compounds were calculated with Non Linear 10 Régression Analysis using Graph Pad Prism (Graph Pad software, Inc, USA).

Anti-cancer Assay (Z-138)

Activity Range	Compound numbers
IC₅oO.1pM to 100pM	43, 35a, 47, 21, 40, 38, 34a , 13, 37, 18, 33b, 46, 76b, 24, 2, 48, 1, 54, 61, 73, 34b, 7a, 25, 33a, 44, 72.
ÎCso 101pM to 1 nM	26,64, 39, 7b, 76a, 62, 20b

Anti-cancer assay (Panc-1)

Activity Range	Compound numbers
IC50 300pM to 20nM	41,47, 64, 40, 21, 38, 34b, 34a, 7b, 13, 37, 33b , 46,25,24, 48,61, 73, 18, 30, 7a, 2, 1, 54, 35a, 43
îCsq 20nM to 100nM	39, 29, 33a, 76b, 62

Anti-cancer assay (MiaPaCa-2)

Activity Range

Compound numbers

213

IC₅o 1pM to 40nM

21, 38, 34b, 34a, 13, 37, 33b, 25, 24, 2, 48, 1,61, 73, 18, 30, 40,64,62, 33a, 35a, 43,26

In vivo efficacy experiments

Tumor xenograft for mantle ceil lymphoma was established by injection of cells into the right flank of female NOD.CB17-Prkdc<scid>/J mice with an âge between 7-11 weeks purchased from The Jackson Laboratory, USA. Ali animal study proposais were reviewed and approved by the Institutional Animal Ethics Committee (IAEC) prior to initiation of expérimentation.

Z-138 xenograft

For Z-138 xenograft mouse model, Z-138 cells (ATCC® CRL-3001 ™) were grown in IMDM medium supplemented with 10% FBS. Cells were incubated under standard conditions at 37°C and 5% CO2. For generating tumors, Z-138 cells in IMDM medium were mixed with Matrigel (Corning® Matrigel® Basement Membrane Matrix) in a ratio of 1:1. 10 x 10⁶ cells) in a volume of 200 pL were injected subcutaneously in each mouse to establish tumors. Mice were randomized into treatment groups of 8-10 mice, once tumors reached an average volume between 100 to 120 mm³. Treatment was initiated on day of randomization and continued until end of the study, The Vehicle and test compound treatment groups were administered respective treatments orally, using gavage tubing, at an application volume of 10 mUkg per mouse twice a day.

Mice were housed in individually ventilated cages (IVC) at room température of 22+3°C, humidity 50+20% and 12/12 h light/dark cycle. Ail the experimental activities were carriedout inside the biosafety cabinets to ensure sterility.

Tumor size was measured with Digimatic Vernier caliper (Mitutoyo, Japan) when the tumors became palpable. Tumor volume (T. V.) is calculated by using the formula:

Tumor volume (mm3) = (L xW2)/2

Where, L: Length of tumor, W: Width of tumor in millimeter

Percent tumor growth inhibition (% TGI) is calculated using the formula:

% TGI = [1- (Tf - Ti)/(Cf - Ci)] x 100

Where, Tf and Ti, are the final and initial tumor volumes (test compound), and Cf and Ci are the final and initial mean tumor volumes (vehicle group), respectively.

214

Percent tumor régression is calculated as:

% TR: (Ti - Tf)/(Ti) χ 100

Where, Tf and Ti, are the final and initial tumor volumes, respectively.

The compounds 24, 33b, and 13 were tested for tumor growth inhibition in Z-138xenograft 5 model using assay procedure given above; the % of tumor growth inhibition after 38 days at 1 mg/kg dose was found to be 100% and tumor régression was 67-74%. The compound48 was tested at 5 mg/kg dose, it showed 100% tumor growth inhibition and 63% tumor régression.

Claims

1. A compound having the general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable sait thereof,

15 wherein,

Li is selected from -CR^aR^b-, -NR^a-, S, and O;

Z is selected from CH and N;

R‘ and R- are independently selected at each occurrence tram hydrogen substituted or unsubstituted alkyl, and substituted or unsubstituted cydoalkyl;

ring A is selected from,

R' and R» are selected from substituted or unsubstituted alkyl or together with the carbon atoms to which they are attached form a CrC. cydoalkyl ring;

216

R is selected from -NR⁴R⁵, hydrogen, halogen, substituted or unsubstituted alkyi, substituted or unsubstituted alkoxy, substituted or unsubstituted heteroaryl and substituted or unsubstituted cycloalkyl;

R² and R^2a which may be same or different and are independently selected from hydrogen and substituted or unsubstituted alkyi;

R³ is independently selected at each occurrence from halogen, cyano, nitro, substituted or unsubstituted alkyi, -OR⁶, -NR⁷R⁸, substituted or unsubstituted cycloalkyl, -C(O)OH, -C(O)O-alkyl, -C(O)R⁹, -C(O)NR⁷R⁸, -NR⁷C(O)R⁹ substituted or unsubstituted aryï, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclyl;

R⁴ and R⁵ are independently selected from hydrogen, substituted or unsubstituted alkyi, and substituted or unsubstituted cycloalkyl;

R^s is selected from hydrogen, substituted or unsubstituted alkyi, and substituted or unsubstituted cycloalkyl;

R' and R⁸ are independently selected from hydrogen, substituted or unsubstituted alkyi, and substituted or unsubstituted cycloalkyl;

R⁹ is selected from substituted or unsubstituted alkyi and substituted or unsubstituted cycloalkyl;

R¹⁰ is selected from hydrogen, halogen, and substituted or unsubstituted alkyi;

‘n’ is an integer ranging from 0 to 4, both inclusive;

when an alkyi group is substituted, it is substituted with 1 to 4 substituants independently selected from oxo (=O), halogen, cyano, cycloalkyl, aryl, heteroaryl, heterocyclyl, -OR⁷³, -C(=O)OH, -C(=O)O(aikyi), -NR^8aR^eb, -NR^8aC(=O)R⁹³, and C(=O)NR⁸³R^8b;

when the heteroaryl group is substituted, it is substituted with 1 to 4 substituents independently selected from halogen, nitro, cyano, alkyi, haloalkyl, perhaloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR^7a, -NR⁸³R^8b, -NR^7aC(=O)R^9a, C(=O)R^9a,-C(=O)NR^8aR^8b, -SO₂-alkyl, -C(=O)OH, and -C(=O)O-alkyl;

21Ί 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 (=O), halogen, cyano, alkyl, cycloaikyl, perhaloalkyl, -OR^7a,-C(=O)NR^SaR^8b, -C(=O)OH, C(=O)O-alkyl, -N(H)C(=O)(alkyl), -N(H)R^8a, and -N(alkyl)2; and when the heterocycle group is substituted on a ring nitrogen, it is substituted with substituents independently selected from alkyl, cycloaikyl, aryl, heteroaryl, -SO₂(alkyl), C(=O)R^9a, and-C(=O)O(alkyl); when the heterocycle group is substituted on a ring sulfur, it is substituted with 1 or 2 oxo (=O) group(s);

R^7a is selected from hydrogen, alkyl, perhaloalkyl, and cycloaikyl;

R^9a is selected from alkyl and cycloaikyl.

2. The compound of claim 1 having the structure of Formula (II), a stereoisomer thereof, or a pharmaceutically acceptable sait thereof,

wherein,

Ring A, Z, Li, R^a, R^D, R²’, R, R^2a, R³, R¹⁰ and ^!n’ are as defined herein above.

3. The compound of claim 1 having the structure of Formula (III), a stereoisomer thereof, or a pharmaceutically acceptable sait thereof,

(III)

213 wherein,

Ring A, Z, Li, R^a, R^b, R²', R, R^2a, R³, R¹⁰ and ‘n’ are as defined herein above.

4. The compound of claim 1 having the structure of Formula (IV), a stereoisomer thereof, or a pharmaceutically acceptable sait thereof,

HO OH (IV) wherein,

X² is Br or Cl;

U, R^a, R^b, R¹ ,R²’, R², R, R^2a and R¹⁰ are as defined herein above.

The compound of claim 1 to 3, wherein ring A is selected from-

6. The compound of claim 1 to 4, wherein Li is selected from -CH₂-, -CH(CH₃)-, -NH, -N(CH₃)-, S, and O.

7. The compound of claim 1 to 3, wherein R³ is selected from F, Cl, Br, CN, -NH₂, -

NH(CH₃), -NHCH(CH₃)₂, -CH₃, cyclopropyl, -CH(CH₃)₂, -CF2CH3, -OCH₃, CF₃,

The compound of claim 1 to 4, wherein R is selected from hydrogen, -NH2, Cl, fi \

1! ,N

CH(CH₃)₂, methyl, ethyl, cyclopropyl and

2iq

9. The compound of claim 1 to 4, wherein R^a and R^b are independently selected from hydrogen, methyl, and cyclopropyl.

10. The compound of claim 1 to 4, wherein R²’ and R^2a are independently selected from hydrogen and methyl.

11. The compound of claim 1 to 4, wherein R¹⁰ is selected from hydrogen, -F, and methyl.

12. The compound of claim 1, wherein ring A is selected from-

L1 is selected from -CH2-, -CH(CH3)-, -NH-, -N(CH3)-, S, and O; R³ is selected from F, Cl, Br, CN, -NH₂, -NH(CH₃), -NHCH(CH₃)_2> -CH_3> cyclopropyl, -CH(CH₃)_2>-CF2CH3, -OCH3, CF₃, . _ ΎΊ n p—<>-HN_XJ y

Y y <Τί r / nY

X, R is selected from hydrogen, -NH₂, Cl, -CH(CH₃)₂. methyl, ethyl,

JLp^N cyclopropyl and ; R^a and R^b are independently selected from hydrogen, methyl, and cyclopropyl; R²’ and R^2a are independently selected from hydrogen and methyl; R¹⁰ is selected from hydrogen, -F, and methyl.

13. The compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable sait thereof, as claimed in any one of preceding daims, wherein the compound is selected from:

(1S,2R,5R)-3-(2-(2-Amino-3-bromoquinolin-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol;

(1S,2R,5R)-3-(((2-amino-3-chloroquinoiin-7-yl)thio)methyt)-5-(4-amino-7Hpyrrolo[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-7Hpyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol;

12.0 ( 1 S,2R, 5RJ-3-(((2-amino-3-chioro-5-fluoroquinoîin-7-y!)oxy)methyl)-5-(4-amino7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-methylcyclopent-3-ene-1,2-diol (Compound-9);

(1S,2R,5R)-3-(1-(2-Amino-3-chlorO5-fluoroquinolin-7-yJ)propan-2-yl)-5-(4-methyl7H-pyrrolo[2,3-dJpyrimidin-7-yl)cyclopent-3-ene-1,2-diol;

(1S,2R,5R)-3-(2-(2-amino-3-chlori>5-fluoroquinolin-7-yl)ethyl)-5-(4-rriethyl-7Hpyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol;

(1S,2R,5R)-3-(1-((2-amino-3-chloro-5-fluoroquinor!n-7-yl)oxy)ethyl)-5-(4-amino7H-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[2,3d]pyrimidin-7-yl)cyc!opent-3-ene-1,2-diol;

(2-(2-Amino-3-fluoroquinoiin-7-y0ethyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7yl)cyclopent-3-ene-1,2-diol;

(1S,2R,5R)-3-(2-(2-amino-3-chloro-5-fiuorOquinolin-7-yl)ethyl)-5-(4-amino-7Hpyrrolo[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-7Hpyrrolo[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-7Hpyrrolo[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-7Hpyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol;

(1S,2R,5R)-34((2-amino-3-chloro-5-fluoroquinolin-7-yl)oxy)methyl)-5-(4-arnino7H-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-7Hpyrrolo[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-methyHHpyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-sne-1,2-diol;

(1S,2R,5R)-3-(1-(2-amino-3-chloro-5-fluoroquinolin-7-yl)propan-2-yl)-5-(4-amino7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol;

(1S,2R,5R)-3-(1-(2-arnino-3-chloroquinolin-7-yl)propan-2-yl)-5-(4-amino-7Hpyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol;

22 i (1S_j2R_!5R)-3-(2-(2-amino-3-chioro-5-fluoroquinoIin-7-yÎ)ethyl)-5-(4-amino-7HpyrTolo[2,3-d]pyrimidin-7-yt)-2-methyîcyctopent-3-en^ (1S,2R,5R)-3-(1-(2-amino-3-chIon>-5-fluoroquîncfin-7-yI)propan-2-yl)-5-(4-amino7H-pyrrolo[2,3-d)pyrimidin-7-yl)-2-rnethylcydopent-3-ene-1,2-diol;

(1S,2R,5R)-3-(2-(2-amino-3-chlon>5-fluoroquinogn-7-yi)ethyl)-5-(4-amino-7Hpyrrolo[2,3-d]pyrimidin-7-yl)-2-ethylcydopent-3-ene-1,2-diol;

(TS,2R,5R)-3-(2-(2-amino-3-dilorcb5-fluoroquinoljn-7-yl)ethyl)-5-(4-ethyl-7Hpyrrolo[2,3-d]pyrimidin-7-yl)cydopent-3-ene-1,2-diol;

( 1 S, 2 R, 5 R)-3-(2-(2-amino-3-chloro-5-fluoroqufnolin-7-yl)ethyl)-5-(4-cyclopropy I7H-pyrrolo[2,3-d]pynmidin-7-yl)cydopent-3-ene-1,2-diol;

(1S,2R,5R)-3-(2-(2~Amino-3-bromo-5-fiuoroquinolin-7-yl)ethyl)-5-(4-amino-7Hpyrrolo[2,3-d]pyrimidtn-7-yl)cyclopent-3-ene-1,2-diol;

(1S,2R,5R}-3“(2-(2-AmirK)-3-bromO“5-fluoroquinoWn-7-yl)ethyl)-5-(4-methyl-7Hpyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-dioi;

(1S,2R,5R)-3-(1-(2-Arnkx>3-bromo-5-fluoro quinoIin-7-yl)propan-2-yl)-5-(4-amino7H-pyrrolo[2,3-d)pyrimidin-7-yl)cydopent-3-ene-1_J2-diol;

( 1 S,2R, 5R)-3-(2-(2-Amino-3-chloro-5-fluoro quinolin-7-yl)ethy!)-5-(4-methyl-1Hpyrrolo[3,2-cjpyridin-1 -yl)cydopent-3-ene-1,2-diol;

(1S,2R,5R)-3-(2-(2-AmsTO“6“fluoroquinoIin-7-yi)ethy!)-5-(4-amino-7H-pyrrolo[2,3d]pyrimidin-7-yl)cydopent-3-ene-1,2-diol;

(1S,2R,5R>3-(2-(2-amino-5-fluoroquinolin-7-yl)ethyl>5-(4-amino-7H-pyrrolo[2,3d]pyrimidin-7-yl)cydopent-3-ene-1,2-diol;

(1R_:2R,3S,4R,5S)-1-(2-(2-Am!nO“3-methylquinolin-7-y!)ethyl)-4-(4-amino-7Hpyrrolo[2,3-d]pyrimidin-7-yl) bicydop. 1.0]hexane-2,3-diol;

(1R,2R,3S,4R_!5S)-1-(2-(2-Amfno3-chloroquindin-7-yl)ethyl)-4-(4-amino-7Hpyrrolo[2,3-d]pyrimidin-7-yl)bicydo[3.1 .OJhexane-2,3-diol;

(1R,2R,3S,4R,5S)-1-(2-(2-AmirK>3-ditoro-5-fluoroquinolin-7-yl)ethyl)-4-(4-amino7H-pyrrolo[2,3-d]pyrimidin-7-yl) bîcydo[3.1.0]hexane-2,3-diol;

(1R,2R,3S_î4R_>5S)-1-(2-(2-Amino-3-chloro-6-fluoTOquino!!r_l-7-yÎ)ethyl)-4-(4-amino7H-pyrrolo[2,3-d]pyrimidin-7-yl) bicydo[3.1,0]hexane-2,3-diol;

222 (1R,2R,3S,4R,5S)-1-(2-(2-amino-3-bromo-6-fluoroquinolin-7-yI)ethyl)-4-(4-amino7H-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)ethyi)-4-(4-amino7H-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-7Hpyrrolo [2,3-d]pyrimidin-7-yl)bicyclo [3.1,0]hexane-2,3-diol.

14. The compound of formula (i), a stereoisomer thereof, or a pharmaceutically acceptable sait thereof, as claimed in any one of preceding claims, wherein the compound is selected from:

(1S,2R,5R)-3-(2-(2-amino-3-chloro-5-fluoroquinolin-7-yl)ethyl)-5-(4-methyl-7Hpyrrolo[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-7Hpyrrolo[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-7Hpyrrolo[2,3-d]pyrimidin-7-yl)-2-methylcyclopent-3-ene-1,2-diol;

(1 R,2R,3S,4R,5S)-1-(2-(2-Amino-3-chloro-5-fluoroquinolin-7-yl)ethyl)-4-(4-amino7H-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-amino7H-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-7Hpyrrolo [2,3-d]pyrimidin-7-yl)bicyclo [3.1.0]hexane-2,3-diol;

(1S,2R,5R)-3-(2-(2-amino-3-chloro-6-fluoroquinolin-7-yl)ethyl)-5-(4-amino-7Hpyrrolo[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-amino7H-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-7Hpyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol;

223 (1S,2R,5R)-3-(1-(2-amino-3-chîoro-5-fluoroquinolin-7-yl)propan-2-yl)-5-(4-amino7H-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-amino7H-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-7Hpyrrolo[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-7Hpyrrolo[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-y!)propan-2-yl)-5-(4-amino7H-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-7Hpyrrolo[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-amino7H-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-amino7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[3.1.0]hexane-2,3-diol.

15. A pharmaceutical composition comprising at least one compound of any one of the daims 1 to 14, a stereoisomer thereof, or a pharmaceutically acceptable sait thereof, and a pharmaceutically acceptable carrier.

16. A method fortreating the diseases, disorders, syndromes or conditions associated by inhibition of PRMT5 enzyme to a subject in need thereof, comprising administering to the subject, an effective amount of compound as claimed in claim 1 to 14, or their pharmaceutically acceptable sait thereof.

17. A method as claimed in claim 16, wherein the said diseases, disorders, syndromes or conditions associated by inhibition of PRMT5 enzyme is glioblastoma multiforme, prostate cancer, pancreatic cancer, mantle ceîl lymphoma, non-Hodgkin’s lymphomas and diffuse large B-cell lymphoma, acute myeloid leukemia, acute lymphoblastic leukemia, multiple myeloma, non-smal! cell lung cancer, smal! cell lung cancer, breast cancer, triple négative breast cancer, gastric cancer, colorectal cancer, ovarian cancer, bladder cancer, hepatocellular cancer, melanoma, sarcoma, oropharyngea! squamous cell carcinoma, chronic myelogenous leukemia, epidermal squamous cell carcinoma, nasopharyngeal carcinoma, neuroblastoma, endometria! carcinoma, and cervical cancer.

224-

18. A method as claimed in claim 16, wherein the said diseases, disorders, syndromes or conditions associated by inhibition of PRMT5 enzyme is cancer

19. Use of a compound, of any one of claim 1 to 14, in the préparation of médicament for treating the diseases, disorders, syndromes or conditions associated by inhibition of PRMT5 in a subject in need thereof.

20. The use as claimed in claim 19, wherein the diseases, disorders, syndromes or conditions associated by inhibition of PRMT5 are selected from the group consisting of 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 négative 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, neuroblastome, endométrial carcinoma, and cervical cancer.

21. The use as claimed in claim 19, wherein the diseases, disorders, syndromes or conditions associated by inhibition of PRMT5 is cancer.