RU2814198C2 - Rmt5 inhibitors - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof. In formula (I): X represents either CH₂ or O; Y represents either CH₂, NH or O; R¹ and R⁷ are taken together to form a five-membered carbon ring, optionally substituted with 1–3 halogens, or a five-membered heterocycloalkyl ring containing one O atom; R² represents either H, OH, CH₃, CHF₂ or F; R³ represents H, halogen, NH₂, NHCH ₃, OH, OCH_3, C_1-4 alkyl, optionally substituted with 1–3 halogens or OH, or C_3-5cycloalkyl, optionally substituted either with 1–3 halogens or OH; R⁵ is either H, NH₂ or NHR⁶; and R⁴ is either H, halogen, CH₃, CHF₂ or CF₃; or R⁴ and R⁵, taken together with the carbon atoms to which they are attached, combine to form a 5-membered heterocycloalkyl containing one N atom, the said heterocycloalkyl being optionally substituted with one to four substituents independently selected from halogen, CH₃, CF₃ and CF₂H; R⁶ when present is either CH₃, C₂H₅, CH₂CH₂CH₃, CH(CH₃)₂, CH₂CHF₂, CH₂CF₃ or CH₂-cyclopropyl; R⁸ represents H, halogen, C_1-4 alkyl, optionally substituted with 1–3 halogens, C_3-5 cycloalkyl, optionally substituted with 1–3 halogens, or phenyl, optionally substituted with 1–3 halogens; R¹⁰ represents H, C_1-6 alkyl, NH₂ or halogen. Also the following is proposed: a compound of formula Ia, a compound selected from a group of individual compounds, and a composition including the above compounds.

EFFECT: proposed compounds are PRMT5 inhibitors and can be used to treat cancer, sickle cell disease and mutations associated with hereditary persistence of fetal hemoglobin (HPFH).

18 cl, 26 tbl, 137 ex

Description

Prerequisites for creating the invention

PRMT5 (also known as JBP1, SKB1, lBP72, SKB1his, and HRMTIL5) is a type II arginine methyltransferase and was first identified through a two-hybrid search for Janus tyrosine kinase-interacting proteins (Jak2) ( Pollack et al., 1999 ). PRMT5 plays an important role in the control and modulation of gene transcription. Among other things, PRMT5 is known to symmetrically methylate histone H3 at Arg-8 (a different site from the site methylated by PRMT4) and histone H4 at Arg-3 (the same site that is methylated by PRMT1). PRMT5 has been reported to have various functions, including but not limited to influencing cell viability, stemness, DNA damage repair, and RNA splicing (Clarke et al., Mol Cell (2017), Chiang et al., Cell Rep (2017) , Gerhart et al., Sci Rep (2018)). Specifically, PRMT5 inhibition induces alternative splicing of the p53 negative regulator, MDM4, resulting in increased expression of the short isoform of MDM4 (MDM4-S), decreased expression of the full-length isoform (MDM4-FL), and increased p53 activity (Gerhart el al Sci Rep (2018) ). Most of the physiological functions of p53 are attributed to its role as a transcriptional activator in response to DNA damaging agents. p53 status is wild type in approximately half of human cancers. These include 94% of cervical cancers, 87% of hematologic malignancies, 85% of bone and endocrine gland cancers, and 75% of primary breast cancers. Restoring p53 in cancer cells harboring wild-type p53 through inhibitory mechanisms that suppress its function leads to growth arrest and apoptosis and is considered a potentially effective means of tumor suppression.

In response to DNA damage caused by various agents, including doxorubicin, camptothecin and UV light, as well as in response to treatment with nutlin-3, knockdown of PRMT5 leads to an increase in the sub-G1 population and a concomitant decrease in the number of G1 cells and, in the presence of p53, significant increase in apoptosis. Knockdown of PRMT5 also resulted in increased levels of p21, a key p53 target gene that regulates cell cycle arrest during the p53 response, and MDM2, a p53 E3 ubiquitin ligase, but not PUMA, NOXA, AlP1, and APAF1, which are p53 target genes associated with apoptosis.

Knockdown of PRMT5 (but not PRMT1 or CARM1/PRMT4) results in decreased p53 stabilization, decreased basal p53 levels, decreased p53 oligomerization, and decreased expression of elF4E, a major component of the translational machinery involved in the binding of ribosomes to mRNA. Indeed, elF4E is a potent oncogene that has been shown to promote malignant transformation in vitro and cancer formation in humans.

The role of PRMT5 in the DNA damage response has been studied by groups reporting a role for PRMT5 in the regulation of high-fidelity homologous recombination-mediated DNA repair in both solid (Clarke et al., Mol Cell (2017)) and hematological tumor models (Hamard et al. al., Cell Rep (2018)).

PRMT5 is aberrantly expressed in approximately half of human cancers, further linking this mechanism to cancer. PRMT5 overexpression has been observed in patient tissue samples and cell lines of prostate cancer (Gu et al., 2012), lung cancer (Zhongping et al., 2012), melanoma (Nicholas et al., 2012), and breast cancer (Powers et al. ., 2011), colorectal cancer (Cho et al., 2012), gastric cancer (Kim et al., 2005), esophageal and lung carcinoma (Aggarwal et al., 2010), as well as B-cell lymphomas and leukemias (Wang , 2008). Moreover, increased expression of PRMT5 in melanoma, breast cancer, and colorectal cancer has been demonstrated to correlate with poor prognosis.

Lymphoid malignancies, including chronic lymphocytic leukemia (CLL), are associated with PRMT5 overexpression. PRMT5 is overexpressed (at the protein level) in the nucleus and cytosol in a number of patient-derived Burkitt lymphoma cell lines; mantle cell lymphoma (MCL); EBV-transformed lymphoma in vitro; leukemia cell lines; and B-CLL compared with normal CD19+ B cells (Pal et al., 2007; Wang et al., 2008). Interestingly, despite increased PRMT5 protein levels in these tumor cells, PRMT5 mRNA levels are decreased (2- to 5-fold). PRMT5 mRNA translation, however, is enhanced in lymphoma cells, resulting in increased PRMT5 levels (Pal et al., 2007; Wang et al., 2008).

In addition to genomic alterations, CLL, like almost all cancers, has aberrant epigenetic abnormalities characterized by global hypomethylation and hotspots of repressive hypermethylation at promoters, including tumor suppressor genes. While the role of epigenetics in the origin and progression of CLL remains unclear, epigenetic changes appear to occur early in the disease, and specific DNA methylation patterns are associated with worse prognosis (Chen et al., 2009; Kanduri et al., 2010 ). Global symmetric methylation of histones H3R8 and H4R3 is increased in transformed lymphoid cell lines and clinical MCL samples (Pal et al., 2007), which correlates with PRMT5 overexpression observed in a large number of lymphoid cancer cell lines and clinical MCL samples.

Therefore, PRMT5 is a target for the identification of new therapeutic agents for the treatment of cancer.

Hemoglobin is the main protein of red blood cells and is essential for transporting oxygen from the lungs to the tissues. In adults, the most common type of hemoglobin is a tetramer called hemoglobin A, consisting of two α and two β subunits. In infants, the hemoglobin molecule consists of two α chains and two γ chains. Gamma chains are gradually replaced by β subunits as the child grows. The developmental switch in the human β-like globin gene subtype from fetal (γ) to adult (β), which begins at birth, marks the onset of the hemoglobinopathies β-thalassemia or sickle cell disease (SCD). In β-thalassemia, adult chains are not formed. In SCD, a point mutation in the coding sequence of the β-globin gene results in the production of a protein with altered polymerization properties. The observation that increased β-globin gene expression in adults (in the setting of hereditary persistence of fetal hemoglobin (HPFH) mutations) significantly alleviates the clinical severity of β-thalassemia and SCD has prompted the search for therapeutic strategies to reverse γ-globin gene silencing. To date, this has been achieved through pharmacological induction using compounds that broadly affect epigenetic modifications, including DNA methylation and histone deacetylation. The development of more targeted therapies depends on identifying the molecular mechanisms underlying fetal globin gene silencing. These mechanisms remain unclear despite extensive research on HPFH mutations and significant progress in many other aspects of globin gene regulation.

PRMT5 plays a critical role in triggering coordinated repressive epigenetic events that begin with histone H4 arginine 3 dimethylation (H4R3me2s) and culminate in DNA methylation and transcriptional silencing of γ genes ( Rank et al., 2010 ). An integral part of the synchronous establishment of repressive markers is the assembly of a PRMT5-dependent complex containing the DNA methyltransferase DNMT3A and other repressor proteins (Rank et al., 2010). DNMT3A is directly recruited to bind to the PRMT5-induced H4R3me2s mark, and loss of this mark due to shRNA-mediated knockdown of PRMT5 or forced expression of a mutant form of PRMT5 lacking methyltransferase activity results in a marked increase in γ gene expression and complete abolition of DNA methylation at γ -promoter. Treatment of human erythroid progenitors with nonspecific methyltransferase inhibitors (Adox and MTA) also resulted in increased γ gene expression (He Y, 2013). Thus, PRMT5 inhibitors have potential as therapeutic agents for hemoglobinopathies such as β-thalassemia or sickle cell disease (SCD).

The present inventors have developed compounds that inhibit PRMT5 activity and may therefore be useful in the treatment of conditions ameliorated by inhibition of PRMT5 activity.

The essence of the invention

Compounds of formula I

and pharmaceutically acceptable salts, esters and prodrugs thereof, which are PRMT5 inhibitors. Also provided are methods for preparing compounds of Formula I, pharmaceutical compositions comprising compounds of Formula I, and methods of using these compounds for the treatment of cancer, sickle cell disease, and mutations associated with hereditary persistence of fetal hemoglobin (HPFH).

Detailed Description of the Invention

The invention is a compound of the formula

or pharmaceutically acceptable salts thereof, wherein

X represents CH ₂ or O;

Y represents CH ₂ , NH or O;

Z ¹ represents CR ⁴ or N;

Z ² , Z ³ , Z ⁴ and Z ⁵ are independently selected from N or CR ⁹ ;

A ¹ represents CH or N;

A ² represents CR ¹⁰ or N;

A ³ represents CH or N;

A ⁴ represents CR ⁸ or N;

R ¹ , R ² and R ⁷ are:

i) R ¹ represents H, CCH or C _1-3 alkyl, optionally substituted with 1-2 halogens; and R ² is H, halogen, OH, CH ₃ , NH ₂ , NHCH ₃ , CH ₂ OH, CH ₂ F or CHF ₂ , and R ⁷ is H, provided that R ¹ and R ² cannot both be H; or

ii) R ¹ and R ⁷ are taken together to form a five-membered carbon ring, optionally substituted with 1-3 halogens, or a five-membered heterocycloalkyl ring containing one O atom, and R ² represents H, OH, CH ₃ , CHF ₂ or F;

R ³ is H, halogen, NH ₂ , NHCH ₃ , CN, OH, OCH _{3 ,} C _1-4 alkyl, optionally substituted with 1-3 halogens or OH, or C _3-5 cycloalkyl, optionally substituted with 1-3 halogens or OH;

R ⁵ is H, NH ₂ or NHR ⁶ ; and R ⁴ , when present, is H, halogen, CH ₃ , CHF ₂ or CF ₃ ; or

R ⁴ and R ⁵ taken together with the carbon atoms to which they are attached combine to form a 5-membered heterocycloalkyl containing one N atom, said heterocycloalkyl being optionally substituted with one to four substituents independently selected from halogen, CH ₃ , CF ₃ or CF ₂ H;

R ⁶ when present is CH ₃ , C ₂ H ₅ , CH ₂ CH ₂ CH ₃ , CH(CH ₃ ) ₂ , CH ₂ CHF ₂ , CH ₂ CF ₃ or CH ₂ -cyclopropyl;

R ⁸ when present is H, halogen, C _1-4 alkyl, optionally substituted with 1-3 halogens, C _3-5 cycloalkyl, optionally substituted with 1-3 halogens, or aryl, optionally substituted with 1-3 halogens;

each R ⁹ , when present, is independently selected from H or halogen; And

R ¹⁰ when present is H, C _1-6 alkyl, NH ₂ or halogen.

An embodiment of the invention of a compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (Ia);

or pharmaceutically acceptable salts thereof, wherein

X represents CH ₂ or O;

Y represents CH ₂ , NH or O;

Z ¹ represents CR ⁴ or N;

Z ² represents CH or N;

Z ³ represents CH or N;

Z ⁴ represents CH or N;

A ¹ represents CH or N;

A ² represents CH, N, CNH ₂ or CCH ₃ ;

A ³ represents CH or N;

A ⁴ represents CR ⁸ or N;

R ¹ , R ² and R ⁷ are:

i) R ¹ represents H, CCH or C _1-3 alkyl, optionally substituted with 1-2 halogens; and R ² is H, halogen, OH, CH ₃ , NH ₂ , NHCH ₃ , CH ₂ OH, CH ₂ F or CHF ₂ , and R ⁷ is H, provided that R ¹ and R ² cannot both be H; or

ii) R ¹ and R ⁷ are taken together to form a five-membered ring, and R ² is H, OH, CH ₃ , CHF ₂ or F;

R³ represents H, halogen, CH₃, C₂H₅, cyclopropyl, NH₂, NHCH₃,CN,CF₃, OH, OCH₃ or CHF₂;

R ⁴ , when present, is H, halogen, CH ₃ , CHF ₂ or CF ₃ ; and R ⁵ is H, NH ₂ or NHR ⁶ ; or

^R4 and ^R5 , taken together with the carbon atoms to which they are attached, combine to form a 5-membered heterocycloalkyl containing one N atom, said heterocycloalkyl being optionally substituted with one to four substituents independently selected from halogen, _CH3 , CF ₃ or CF ₂ H;

R ⁶ when present is CH ₃ , C ₂ H ₅ , CH ₂ CH ₂ CH ₃ , CH(CH ₃ ) ₂ , CH ₂ CHF ₂ , CH ₂ CF ₃ or CH ₂ -cyclopropyl; And

R ⁸ when present is H, C _1-4 alkyl or halogen.

An embodiment of the invention of a compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (Ib);

In one sub-embodiment of the invention of formula Ib, X is CH ₂ or O.

In another sub-embodiment of the invention of formula Ib, X is CH ₂ .

In another sub-embodiment of the invention of formula Ib, X is O.

In one sub-embodiment of the invention of formula Ib, Y is CH ₂ , NH or O.

In another sub-embodiment of the invention of formula Ib, Y represents CH ₂ .

In another sub-embodiment of the invention of formula Ib, Y is O.

In one sub-embodiment of the invention of formula Ib, W is CR ¹¹ R ¹¹ or O.

In one sub-embodiment of the invention of formula Ib, W is O, CHF, CF ₂ or CH ₂ .

In one sub-embodiment of the invention of formula Ib, W is CHF.

In one sub-embodiment of the invention of formula Ib, W is CF ₂ .

In another sub-embodiment of the invention of formula Ib, W represents O.

In another sub-embodiment of the invention of formula Ib, W is CH ₂ .

In a sub-embodiment of the invention, formulas Ib Z ² , Z ³ , Z ⁴ and Z ⁵ are independently selected from N or CR ⁹ .

In one sub-embodiment of the invention of formula Ib, A ² is CR ¹⁰ or N.

In another sub-embodiment of the invention of formula Ib, A ² is N, CH, CNH ₂ , CF, CCl or CCH ₃ .

In another sub-embodiment of the invention of formula Ib, A ² represents CH, CCl or CF.

In one sub-embodiment of the invention of formula Ib, R ² is H, OH, CH ₃ , CHF ₂ or F.

In another sub-embodiment of the invention of formula Ib, R ² represents H.

In one sub-embodiment of the invention R³ represents H, halogen, NH₂, NHCH₃, CN, OH, OCH₃, C_1-4alkyl, optionally substituted with 1-3 halogens or OH or C_3-5cycloalkyl, optionally substituted with 1-3 halogens or OH.

In another sub-embodiment of the invention of formula Ib, R ³ is NH ₂ , Cl, OCH ₃ or CH ₃ .

In another sub-embodiment of the invention of formula Ib, R ³ is NH ₂ or CH ₃ .

In one sub-embodiment of the invention of formula Ib, R ⁴ is H, halogen, CH ₃ , CHF ₂ or CF ₃ .

In another sub-embodiment of the invention of formula Ib, R ⁴ represents H.

In another sub-embodiment of the invention of formula Ib, R ⁴ is halogen.

In another sub-embodiment of the invention of formula Ib, R ⁴ represents H, Cl, F or Br.

In one sub-embodiment of the invention of formula Ib, R ⁵ is H, NH ₂ or NHR ⁶ .

In one sub-embodiment of the invention of formula Ib, R ⁶ , when present, is CH ₃ , C ₂ H ₅ , CH ₂ CH ₂ CH ₃ , CH(CH ₃ ) ₂ , CH ₂ CHF ₂ , CH ₂ CF ₃ or CH ₂ - cyclopropyl.

In one sub-embodiment of the invention of formula Ib, each R ¹¹ , when present, is independently selected from H or halogen.

In another sub-embodiment of the invention of formula Ib, R ⁵ represents H.

In another sub-embodiment of the invention of formula Ib, R ⁵ represents NH ₂ .

In one sub-embodiment of the invention of formula Ib, R ⁸ is H, halogen, C _1-4 alkyl, optionally substituted with 1-3 halogens, C _3-5 cycloalkyl, optionally substituted with 1-3 halogens, or aryl, optionally substituted with 1-3 halogens .

In another sub-embodiment of the invention of formula Ib, R ⁸ is H, CH ₃ or F.

In one sub-embodiment of the invention of formula Ib, each R ⁹ , when present, is independently selected from H or halogen.

In one sub-embodiment of the invention of formula Ib, each R ⁹ , when present, is independently selected from H, F or Cl.

In another sub-embodiment of the invention of formula Ib, R ⁹ , when present, represents H.

In another sub-embodiment of the invention of formula Ib, R ⁹ , when present, represents F.

In another sub-embodiment of the invention of formula Ib, R ⁹ , when present, represents Cl.

In one sub-embodiment of the invention of formula Ib, R ¹⁰ , when present, represents H, NH ₂ , C _1-6 alkyl or halogen.

In another sub-embodiment of the invention of formula Ib, R ¹⁰ represents H.

In another sub-embodiment of the invention of formula Ib, R ¹⁰ is CH ₃ .

In another sub-embodiment of the invention of formula Ib, R ¹⁰ represents F.

An embodiment of the invention of a compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (Ic);

In one sub-embodiment of the invention of formula Ic, X is CH ₂ or O.

In one sub-embodiment of the invention of formula Ic, Y is CH ₂ , NH or O.

In one sub-embodiment of the invention of formula Ic W is CH ₂ or O _.

In one sub-embodiment of the invention of formula Ic R ² represents H, OH, CH ₃ , CHF ₂ or F.

In another sub-embodiment of the invention of formula Ic R ² represents H.

In one sub-embodiment of the invention of formula Ic R ³ is H, halogen, CH ₃ , C ₂ H ₅ , cyclopropyl, NH ₂ , NHCH ₃ , CN, CF ₃ , OH, OCH ₃ or CHF ₂ .

In another sub-embodiment of the invention of formula Ic R ³ represents CH ₃ , Cl, NH ₂ or OCH ₃ .

In one sub-embodiment of the invention of formula Ic R ⁴ represents H, halogen, CH ₃ , CHF ₂ or CF ₃ .

In another sub-embodiment of the invention of formula Ic, R ⁴ represents H or halogen.

In another sub-embodiment of the invention of formula Ic, R ⁴ is H or Br.

In one sub-embodiment of the invention of formula Ic R ⁵ represents H, NH ₂ or NHR ⁶ .

In another sub-embodiment of the invention of formula Ic R ⁵ represents H or NH ₂ .

In another sub-embodiment of the invention of formula Ic R ⁵ represents NH ₂ .

In one sub-embodiment of the invention for formula Ic, R ⁴ and R ⁵ , taken together with the carbon atoms to which they are attached, combine to form a 5-membered heterocycloalkyl containing one N atom, wherein said heterocycloalkyl is optionally substituted with one to four substituents, regardless selected from halogen, CH ₃ , CF ₃ or CF ₂ H.

In one sub-embodiment of the invention of formula Ic R ⁶ when present is CH ₃ , C ₂ H ₅ , CH ₂ CH ₂ CH ₃ , CH(CH ₃ ) ₂ , CH ₂ CHF ₂ , CH ₂ CF ₃ or CH ₂ - cyclopropyl.

In another sub-embodiment of the invention of formula Ic, R ⁶ when present is CH ₃ .

In one sub-embodiment of the invention of formula Ic R ⁸ represents H, C _1-4 alkyl or halogen.

In one sub-embodiment of the invention of formula Ic, R ⁸ is H.

A sub-embodiment of the invention of a compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (Id);

.

In one sub-embodiment of the invention of formula Id X is CH ₂ or O.

In one sub-embodiment of the invention of formula Id Y is CH ₂ , NH or O.

In one sub-embodiment of the invention of formula Id, R ¹ is H, CCH or C _1-3 alkyl, optionally substituted with 1-2 halogens, and R ² is H, halogen, OH, CH _3, NH ₂ , NHCH ₃ , CH ₂ OH, CH ₂ F or CHF ₂ , while R ¹ and R ² cannot be H at the same time.

In another sub-embodiment of the invention of formula Id, R ¹ is H, CH ₃ , CCH, CH ₂ F or CHF ₂ , and R ² is H or CH ₃ , and R ¹ and R ² cannot both be H.

In another sub-embodiment of the invention of formula Id, R ¹ is H, CH ₃ or CCH, and R ¹ and R ² cannot simultaneously be H.

In another sub-embodiment of the invention of the formula Id, R ² represents H or CH ₃ , and R ¹ and R ² cannot simultaneously be H.

In one sub-embodiment of the invention of formula Id R ³ is H, halogen, CH ₃ , C ₂ H ₅ , cyclopropyl, NH ₂ , NHCH ₃ , CN, CF ₃ , OH, OCH ₃ or CHF ₂ .

In another sub-embodiment of the invention of the formula Id R ³ represents H, CH ₃ , NH ₂ , Cl, OH or OCH ₃ .

In another sub-embodiment of the invention of the formula Id R ³ represents CH ₃ , Cl, OCH ₃ or NH ₂ .

In one sub-embodiment of the invention of formula Id R ⁴ represents H, halogen, CH ₃ , CHF ₂ or CF ₃ .

In another sub-embodiment of the invention of formula Id R ⁴ represents H or halogen.

In another sub-embodiment of the invention of formula Id R ⁴ represents H or Br.

In one sub-embodiment of the invention of the formula Id R ⁵ represents H, NH ₂ or NHR ⁶ .

In another sub-embodiment of the invention of the formula Id R ⁵ represents H or NH ₂ .

In another sub-embodiment of the invention of the formula Id R ⁵ represents NH ₂ .

In one sub-embodiment of the invention of the formula Id R ⁶ when present is CH ₃ , C ₂ H ₅ , CH ₂ CH ₂ CH ₃ , CH(CH ₃ ) ₂ , CH ₂ CHF ₂ , CH ₂ CF ₃ or CH ₂ - cyclopropyl.

In another sub-embodiment of the invention of the formula Id R ⁶ represents CH ₃ .

In one sub-embodiment of the invention of formula Id R ⁸ represents H, C _1-4 alkyl or halogen.

In another sub-embodiment of the invention of formula Id R ⁸ represents H.

In an embodiment of the invention, the compound of formula I is:

(1R,2S,3R,5R)-5-(((2-amino-3-bromoquinolin-7-yl)oxy)methyl)-3-(4-chloro-7H-pyrrolo[2,3-d]pyrimidine -7-yl)-1-methylcyclopentane-1,2-diol,

(1R,2S,3R,5R)-5-(((2-amino-3-bromoquinolin-7-yl)oxy)methyl)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidine -7-yl)-1-methylcyclopentane-1,2-diol,

(2R,3S,4R,5R)-2-(((2-amino-3-bromoquinolin-7-yl)oxy)methyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidine -7-yl)-3-ethynyltetrahydrofuran-3,4-diol,

(2R,3S,4R,5R)-2-(2-(2-amino-3-bromoquinolin-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)-2,3-dimethyltetrahydrofuran-3,4-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)oxy)-2-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)hexahydro-2H-cyclopenta[b]furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)oxy)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)hexahydro-2H-cyclopenta[b]furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)oxy)-2-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)hexahydro-2H-cyclopenta[b]furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)hexahydro-2H-cyclopenta[b]furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)hexahydro-2H-cyclopenta[b]furan-3,3a-diol,

(2R,3S,4R,5R)-2-(((2-amino-3-bromoquinolin-7-yl)oxy)methyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidine -7-yl)-3-methyltetrahydrofuran-3,4-diol,

(2R,3S,4R,5R)-2-{[(2-amino-3-bromoquinolin-7-yl)oxy]methyl}-5-(4-chloro-7H-pyrrolo[2,3-d]pyrimidine -7-yl)-3-methyltetrahydrofuran-3,4-diol,

(2R,3S,4R,5R)-2-(((2-amino-3-bromoquinolin-7-yl)oxy)methyl)-5-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidine -7-yl)-2-methyltetrahydrofuran-3,4-diol,

(2R,3S,4R,5R)-2-(((2-amino-3-bromoquinolin-7-yl)oxy)methyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidine -7-yl)-2-methyltetrahydrofuran-3,4-diol,

(2 R ,3 S ,4 R ,5 R )-2-(((2-amino-3-bromoquinolin-7-yl)oxy)methyl)-5-(4-amino-7 H -pyrrolo[2, 3-d]pyrimidin-7-yl)-3-methyltetrahydrofuran-3,4-diol,

(1 S ,2 R ,3 S ,5 R )-3-[2-(2-amino-3-bromo-7-quinolinyl)ethyl]-5-(4-amino-7 H -pyrrolo[2,3 - d ]pyrimidin-7-yl)-3-methyl-1,2-cyclopentanediol,

(1S,2R,3aR,4S,6aR)-4-((2-amino-3-fluoroquinolin-7-yl)methyl)-2-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)hexahydropentalene-1,6a(1H)-diol,

(1S,2R,3aR,4S,6aR)-4-((2-amino-3-chloroquinolin-7-yl)methyl)-2-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)hexahydropentalene-1,6a(1H)-diol,

(1S,2R,3aR,4R,6aR)-4-((2-amino-3-fluoroquinolin-7-yl)methyl)-2-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)hexahydropentalene-1,6a(1H)-diol,

(1S,2R,3aR,4S,6aR)-4-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)hexahydropentalene-1,6a(1H)-diol,

(2R,3R,3aS,6S,6aR)-6-[(2-amino-3,8-difluoroquinolin-7-yl)methyl]-2-(4-amino-7H-pyrrolo[2,3-d] pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-[(2-amino-3-chloro-5-fluoroquinolin-7-yl)methyl]-2-(4-amino-7H-pyrrolo[2,3- d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-[(2-amino-3-chloro-8-fluoroquinolin-7-yl)methyl]-2-(4-methyl-7H-pyrrolo[2,3- d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-(difluoromethyl)quinolin-7-yl)methyl)-2-(4-methyl-7H-pyrrolo[2,3-d ]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3,5-difluoroquinolin-7-yl)methyl)-2-(4-amino-5-fluoro-7H-pyrrolo[2, 3-d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((6-amino-7-fluoro-1,5-naphthyridin-3-yl)methyl)-2-(4-methyl-7H-pyrrolo[2, 3-d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-chloro-8-fluoroquinolin-7-yl)methyl)-2-(4-amino-7H-pyrrolo[2,3- d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-[(2-amino-3,6-difluoroquinolin-7-yl)methyl]-2-(4-amino-7H-pyrrolo[2,3-d] pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((7-amino-6-chloro-1,8-naphthyridin-2-yl)methyl)-2-(4-amino-7H-pyrrolo[2, 3-d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-[(2-amino-3,5-difluoroquinolin-7-yl)methyl]-2-(4-amino-7H-pyrrolo[2,3-d] pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol,

(1S,2R,3aR,4S,6aR)-4-((2-amino-3-fluoroquinolin-7-yl)methyl)-2-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)hexahydropentalene-1,6a(1H)-diol,

(1S,2R,3aR,4S,6aR)-2-(4-amino-2-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-4-((2-amino-3- chloroquinolin-7-yl)methyl)hexahydropentalene-1,6a(1H)-diol,

(1S,2R,3aR,4S,6aR)-2-(4-amino-2-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-4-((2-amino-3- fluoroquinolin-7-yl)methyl)hexahydropentalene-1,6a(1H)-diol,

(1S,2R,3aR,4S,6aR)-4-((2-amino-3-fluoroquinolin-7-yl)methyl)-2-(4-amino-5-fluoro-7H-pyrrolo[2,3- d]pyrimidin-7-yl)hexahydropentalene-1,6a(1H)-diol,

(1S,2R,3aR,4S,6aR)-4-((2-amino-3-chloroquinolin-7-yl)methyl)-2-(4-amino-5-fluoro-7H-pyrrolo[2,3- d]pyrimidin-7-yl)hexahydropentalene-1,6a(1H)-diol,

(1S,2R,3aR,4S,6aR)-4-[(2-amino-3,5-difluoroquinolin-7-yl)methyl]-2-(4-amino-5-methyl-7H-pyrrolo[2, 3-d]pyrimidin-7-yl)hexahydropentalene-1,6a(1H)-diol,

(1S,2R,3aR,4S,6aR)-4-[(2-amino-3-chloro-5-fluoroquinolin-7-yl)methyl]-2-(4-amino-5-methyl-7H-pyrrolo[ 2,3-d]pyrimidin-7-yl)hexahydropentalene-1,6a(1H)-diol,

(1S,2R,3aR,4S,6aR)-2-(4-amino-2-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-4-((2-amino-3- bromoquinolin-7-yl)methyl)hexahydropentalene-1,6a(1H)-diol,

(1S,2R,3aR,4S,6aR)-4-((2-amino-3-fluoroquinolin-7-yl)methyl)-2-(4-amino-5-methyl-7H-pyrrolo[2,3- d]pyrimidin-7-yl)hexahydropentalene-1,6a(1H)-diol,

(1S,2R,3aR,4S,6aR)-4-((2-amino-3-chloroquinolin-7-yl)methyl)-2-(4-amino-5-methyl-7H-pyrrolo[2,3- d]pyrimidin-7-yl)hexahydropentalene-1,6a(1H)-diol,

(1S,2R,3aR,4S,6aR)-4-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(4-amino-5-methyl-7H-pyrrolo[2,3- d]pyrimidin-7-yl)hexahydropentalene-1,6a(1H)-diol,

(1S,2R,3aR,4S,6aR)-4-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)hexahydropentalene-1,6a(1H)-diol,

(1S,2R,3aR,4S,6aR)-4-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(4-amino-5-fluoro-7H-pyrrolo[2,3- d]pyrimidin-7-yl)hexahydropentalene-1,6a(1H)-diol,

(2R,3R,3aS,6S,6aR)-6-[(2-amino-3-bromoquinolin-7-yl)methyl]-2-[4-amino-5-(difluoromethyl)-7H-pyrrolo[2, 3-d]pyrimidin-7-yl]hexahydro-3aH-cyclopenta[b]furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-fluoroquinolin-7-yl)methyl)-2-(4-amino-5-fluoro-2-methyl-7H-pyrrolo[ 2,3-d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-2-(4-amino-2-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-6-((2-amino-3- fluoroquinolin-7-yl)methyl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)oxy)-2-(2-amino-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol dihydrochloride,

(2R,3R,3aS,6S,6aR)-2-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-6-[(2-amino-3- chloroquinolin-7-yl)methyl]hexahydro-3aH-cyclopenta[b]furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-2-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-6-[(2-amino-3- fluoroquinolin-7-yl)methyl]hexahydro-3aH-cyclopenta[b]furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-[(2-amino-3-bromoquinolin-7-yl)oxy]-2-(4-amino-5-phenyl-7H-pyrrolo[2,3- d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-2-(4-amino-5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-6-[(2-amino-3- fluoroquinolin-7-yl)methyl]hexahydro-3aH-cyclopenta[b]furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-2-[4-amino-5-(difluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-6-[(2-amino- 3-fluoroquinolin-7-yl)methyl]hexahydro-3aH-cyclopenta[b]furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-[(2-amino-3-bromoquinolin-7-yl)oxy]-2-(4-amino-5-cyclopropyl-7H-pyrrolo[2,3- d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-[(2-amino-3-fluoroquinolin-7-yl)methyl]-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)-5,5-difluorohexahydro-3aH-cyclopenta[b]furan-3,3a-diol,

(2R,3R,3aS,5S,6S,6aR)-6-[(2-amino-3-fluoroquinolin-7-yl)methyl]-2-(4-amino-7H-pyrrolo[2,3-d] pyrimidin-7-yl)-5-fluorohexahydro-3aH-cyclopenta[b]furan-3,3a-diol,

(2R,3R,3aS,5S,6S,6aR)-2-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-6-[(2-amino- 3-fluoroquinolin-7-yl)methyl]-5-fluorohexahydro-3aH-cyclopenta[b]furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)oxy)-2-(4-amino-5-fluoro-7H-pyrrolo[2,3- d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-6-((2-((2,2,2- trifluoroethyl)amino)quinolin-7-yl)oxy)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-6-((2-((cyclopropylmethyl)amino)quinoline- 7-yl)oxy)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-fluoroquinolin-7-yl)methyl)-2-(4-amino-5-fluoro-7H-pyrrolo[2,3- d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)oxy)-2-(4-amino-5-methyl-7H-pyrrolo[2,3- d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-2-(4-amino-2-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-6-((2-amino-3- bromoquinolin-7-yl)methyl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-fluoroquinolin-7-yl)methyl)-2-(4-amino-5-methyl-7H-pyrrolo[2,3- d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-2-(4-amino-2-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-6-((2-amino-3- bromoquinolin-7-yl)oxy)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-chloroquinolin-7-yl)oxy)-2-(4-amino-5-methyl-7H-pyrrolo[2,3- d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-fluoroquinolin-7-yl)oxy)-2-(4-amino-5-methyl-7H-pyrrolo[2,3- d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-chloroquinolin-7-yl)methyl)-2-(4-amino-5-methyl-7H-pyrrolo[2,3- d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-chloroquinolin-7-yl)methyl)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-chloroquinolin-7-yl)methyl)-2-(4-amino-5-fluoro-7H-pyrrolo[2,3- d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)oxy)-2-(4-amino-5-ethyl-7H-pyrrolo[2,3- d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(4-amino-5-methyl-7H-pyrrolo[2,3- d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-fluoroquinolin-7-yl)oxy)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-chloroquinolin-7-yl)oxy)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-fluoroquinolin-7-yl)oxy)-2-(4-amino-5-fluoro-7H-pyrrolo[2,3- d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-chloroquinolin-7-yl)oxy)-2-(4-amino-5-fluoro-7H-pyrrolo[2,3- d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-6-((2,3-dihydro-1H-pyrrolo[ 2,3-b]quinolin-7-yl)oxy)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-(trifluoromethyl)quinolin-7-yl)methyl)-2-(4-amino-7H-pyrrolo[2,3-d ]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-[(2-amino-3-bromoquinolin-7-yl)oxy]-2-[4-(hydroxymethyl)-7H-pyrrolo[2,3-d] pyrimidin-7-yl]hexahydro-3aH-cyclopenta[b]furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-[(2-amino-3-bromoquinolin-7-yl)oxy]-2-[4-(2-hydroxypropan-2-yl)-7H-pyrrolo[ 2,3-d]pyrimidin-7-yl]hexahydro-3aH-cyclopenta[b]furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)oxy)-2-(4-(difluoromethyl)-7H-pyrrolo[2,3-d] pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)oxy)-2-(2,4-dimethyl-7H-pyrrolo[2,3-d] pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(2,4-dimethyl-7H-pyrrolo[2,3-d] pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)oxy)-2-(4-amino-5-ethyl-7H-pyrrolo[2,3- d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(4-isopropyl-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(5-fluoro-4-methyl-7H-pyrrolo[2,3- d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)oxy)-2-(7H-pyrrolo[2,3-d]pyrimidin-7-yl) hexahydro-3aH-cyclopenta[b]furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-fluoroquinolin-7-yl)oxy)-2-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(4-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-(trifluoromethyl)quinolin-7-yl)methyl)-2-(4-methyl-7H-pyrrolo[2,3-d ]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2,3-dihydro-1H-pyrrolo[2,3-b]quinolin-7-yl)oxy)-2-(4-methyl-7H- pyrrolo[2,3-d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-fluoroquinolin-7-yl)methyl)-2-(2,4-dimethyl-7H-pyrrolo[2,3-d] pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-chloroquinolin-7-yl)methyl)-2-(2,4-dimethyl-7H-pyrrolo[2,3-d] pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(4-(methylamino)-7H-pyrrolo[2,3-d] pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol,

(1R,2S,3R,5R)-5-(((2-amino-3-bromoquinolin-7-yl)oxy)methyl)-1-methyl-3-(4-(methylamino)-7H-pyrrolo[2 ,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)oxy)-2-(4-(methylamino)-7H-pyrrolo[2,3-d] pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-fluoroquinolin-7-yl)methyl)-2-(4-(methylamino)-7H-pyrrolo[2,3-d] pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(5-fluoro-4-(methylamino)-7H-pyrrolo[2, 3-d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol,

(1S,2R,3aR,4S,6aR)-4-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(4-(methylamino)-7H-pyrrolo[2,3-d] pyrimidin-7-yl)hexahydropentalene-1,6a(1H)-diol,

(2R,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-methyl-2-((quinolin-7-yloxy)methyl) tetrahydrofuran-3,4-diol,

(2R,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-methyl-2-((quinolin-7-yloxy)methyl) tetrahydrofuran-3,4-diol,

(1S,2R,3R,5R)-3-(((2-amino-3-bromoquinolin-7-yl)oxy)methyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidine -7-yl)-3-methylcyclopentane-1,2-diol,

(1S,2R,3R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-(((2-aminoquinolin-7-yl)oxy)methyl )-3-methylcyclopentane-1,2-diol,

(1S,2R,5R)-3-(2-(2-amino-3-bromoquinolin-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7- yl)-3-(fluoromethyl)cyclopentane-1,2-diol,

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

(2R,3R,3aS,6S,6aR)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-6-((2-aminoquinolin-7-yl)oxy) hexahydro-2H-cyclopenta[b]furan-3,3a-diol,

(1R,2S,3R,5R)-5-(((2-aminoquinolin-7-yl)oxy)methyl)-1-methyl-3-(7H-pyrrolo[2,3-d]pyrimidin-7-yl )cyclopentane-1,2-diol,

(1R,2S,3R,5R)-5-(((2-amino-3-methylquinolin-7-yl)oxy)methyl)-1-methyl-3-(4-methyl-7H-pyrrolo[2,3 -d]pyrimidin-7-yl)cyclopentane-1,2-diol,

(2R,3R,3aS,6S,6aR)-6-((2-aminoquinolin-7-yl)methyl)-2-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl) hexahydro-2H-cyclopenta[b]furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(4-amino-5-fluoro-7H-pyrrolo[2,3- d]pyrimidin-7-yl)hexahydro-2H-cyclopenta[b]furan-3,3a-diol,

(1S,2R,3S,5R)-3-(2-(2-amino-3-bromoquinolin-7-yl)ethyl)-3-methyl-5-(4-methyl-7H-pyrrolo[2,3- d]pyrimidin-7-yl)cyclopentan-1,2-diol,

(1S,2R,3S,5R)-3-(2-(2,3-dihydro-1H-pyrrolo[2,3-b]quinolin-7-yl)ethyl)-3-methyl-5-(4- methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol,

(1R,2S,3R,5R)-5-(((2-amino-3-bromoquinolin-7-yl)oxy)methyl)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidine -7-yl)-1,5-dimethylcyclopentane-1,2-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-chloroquinolin-7-yl)oxy)-2-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)hexahydro-2H-cyclopenta[b]furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-aminoquinolin-7-yl)oxy)-2-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl) hexahydro-2H-cyclopenta[b]furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)oxy)-2-(2-amino-4-methyl-7H-pyrrolo[2,3- d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-(difluoromethyl)quinolin-7-yl)oxy)-2-(4-methyl-7H-pyrrolo[2,3-d ]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol,

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

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

(1R,2S,3S,4R)-1-(2-(2-amino-3-bromoquinolin-7-yl)ethyl)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)-2-methylcyclopentane-1,2,3-triol,

(1S,2R,3aR,4S,6aR)-4-((2-amino-3-bromoquinolin-7-yl)oxy)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)hexahydropentalene-1,6a(1H)-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-fluoroquinolin-7-yl)amino)-2-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-fluoroquinolin-7-yl)methyl)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)-6a-methylhexahydro-3aH-cyclopenta[b]furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-chloroquinolin-7-yl)methyl)-2-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-fluoroquinolin-7-yl)methyl)-2-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-fluoroquinolin-7-yl)methyl)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-methylquinolin-7-yl)methyl)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol,

(1S,2R,3S,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-(2-(2,3-dihydro-1H-pyrrolo[ 2,3-b]quinolin-7-yl)ethyl)-3-methylcyclopentane-1,2-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(2-amino-4-methyl-7H-pyrrolo[2,3- d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-(difluoromethyl)quinolin-7-yl)oxy)-2-(4-amino-7H-pyrrolo[2,3-d ]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol,

(2R,3R,3aS,6R,6aR)-6-((2-amino-3-bromoquinolin-7-yl)oxy)-2-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)oxy)-2-(2-amino-5-fluoro-7H-pyrrolo[2,3- d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol,

(2R,3R,3aS,6R,6aR)-6-((2-amino-3-chloroquinolin-7-yl)methyl)-2-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol,

(3aS,4S,5R)-1-((2-amino-3-bromoquinolin-7-yl)methyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl) tetrahydro-1H-cyclopenta[c]furan-3a,4(3H)-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)tetrahydrofuro[3,4-b]furan-3,3a(4H)-diol,

(2R,3R,3aS,6R,6aR)-6-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)tetrahydrofuro[3,4-b]furan-3,3a(4H)-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(4-amino-5-methyl-7H-pyrrolo[2,3- d]pyrimidin-7-yl)tetrahydrofuro[3,4-b]furan-3,3a(4H)-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)tetrahydrofuro[3,4-b]furan-3,3a(4H)-diol or

(2 R ,3 R ,3a S ,6 S ,6a R )-6-((2-amino-3-(difluoromethyl)quinolin-7-yl)methyl)-2-(4-amino-7 H -pyrrolo [2,3- d ]pyrimidin-7-yl)hexahydro- 2H -cyclopenta[ b ]furan- 3,3a- diol,

or a pharmaceutically acceptable salt thereof.

Reference to compounds of formula I includes reference to formula Ia, Ib, Ic or Id and all sub-embodiments thereof, as described below.

In one embodiment, the present invention is a composition for the treatment of cancer comprising a compound of formula I, Ia, Ib, Ic or Id or a pharmaceutically acceptable salt thereof.

In one embodiment, the present invention is a composition for the treatment of cancer comprising a compound of formula I, Ia, Ib, Ic or Id or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

In one embodiment, the present invention is a composition for the treatment of hemoglobinopathies, such as β-thalassemia or sickle cell disease (SCD), comprising a compound of formula I, Ia, Ib, Ic or Id or a pharmaceutically acceptable salt thereof.

In one embodiment, the present invention is a composition for the treatment of hemoglobinopathies, such as β-thalassemia or sickle cell disease (SCD), comprising a compound of formula I, Ia, Ib, Ic or Id or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

In yet another embodiment, the present invention is a method of treating cancer, comprising administering to a patient in need thereof a compound of formula I, Ia, Ib, Ic or Id, or a pharmaceutically acceptable salt thereof.

In yet another embodiment, the present invention includes a method of treating hemoglobinopathies such as β-thalassemia or sickle cell disease (SCD), comprising administering to a patient in need thereof a compound of formula I, Ia, Ib, Ic or Id, or a pharmaceutically acceptable salt thereof.

In yet another embodiment, the present invention is a method of treating cancer, comprising administering to a patient in need thereof a compound of formula I, Ia, Ib, Ic or Id, or a pharmaceutically acceptable salt thereof.

In yet another embodiment, the present invention is a method of treating cancer, comprising administering to a patient in need thereof a compound of formula I, Ia, Ib, Ic or Id, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

In yet another embodiment, the present invention is a method of treating hemoglobinopathies such as β-thalassemia or sickle cell disease (SCD), comprising administering to a patient in need thereof a compound of formula I, Ia, Ib, Ic or Id, or a pharmaceutically acceptable salt thereof.

In yet another embodiment, the present invention is a method of treating hemoglobinopathies such as β-thalassemia or sickle cell disease (SCD), comprising administering to a patient in need thereof a compound of formula I, Ia, Ib, Ic or Id or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

In yet another embodiment, the present invention is a method of treating cancer, comprising administering to a patient in need thereof a composition comprising a compound of formula I, Ia, Ib, Ic or Id, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

In yet another embodiment, the present invention is a method of treating hemoglobinopathies, such as β-thalassemia or sickle cell disease (SCD), comprising administering to a patient in need thereof a composition comprising a compound of formula I, Ia, Ib, Ic or Id or a pharmaceutical thereof an acceptable salt; and a pharmaceutically acceptable carrier.

In yet another embodiment, the present invention provides the use of a compound of formula I, Ia, Ib, Ic or Id or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of cancer.

In yet another embodiment, the present invention provides the use of a compound of formula I, Ia, Ib, Ic or Id or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of hemoglobinopathies such as β-thalassemia or sickle cell disease (SCD).

In yet another embodiment, the present invention includes the use of compounds of formula I, Ia, Ib, Ic or Id for the preparation of a medicament for the treatment of cancer or hemoglobinopathies such as β-thalassemia or sickle cell disease (SCD).

In yet another embodiment, the use of compounds of formula I, Ia, Ib, Ic or Id for the preparation of a medicament for the treatment of cancer is provided. In yet another embodiment, the use of compounds of formula I, Ia, Ib, Ic or Id is provided for the preparation of a medicament for the treatment of hemoglobinopathies such as β-thalassemia or sickle cell disease (SCD). In a sub-embodiment, the cancer is heart cancer, lung cancer, gastrointestinal cancer, genitourinary cancer, liver cancer, bone cancer, nervous system cancer, gynecological cancer, hematological cancer, skin cancer, or adrenal cancer.

In yet another embodiment, the present invention includes compounds of formula I, Ia, Ib, Ic or Id for use in the treatment of cancer or hemoglobinopathies such as β-thalassemia or sickle cell disease (SCD). In another embodiment, the present invention includes compounds of formula I, Ia, Ib, Ic or Id for use in the treatment of heart cancer, lung cancer, gastrointestinal cancer, genitourinary cancer, liver cancer, bone cancer, nervous system cancer, gynecological cancer, hematological cancer, skin cancer or adrenal cancer.

In one embodiment, a compound disclosed herein is selected from the group consisting of compounds illustrated herein, such as Examples 1-137, or pharmaceutically acceptable salts thereof.

The term "composition" is intended to cover a product comprising the specified ingredients in the specified amounts, as well as any product that results, directly or indirectly, from the combination of the specified ingredients in the specified amounts. The term “anticancer agent” means a drug (drug or pharmaceutically active ingredient) for the treatment of cancer. The term “antineoplastic agent” means a drug (drug or pharmaceutically active ingredient) for the treatment of cancer (ie, a chemotherapeutic agent). The term “at least one” means one or more than one. The meaning of “at least one” when referring to the number of compounds of the invention is independent of the meaning when referring to the number of chemotherapeutic agents. The term “chemotherapeutic agent” means a drug (drug or pharmaceutically active ingredient) for the treatment of cancer (ie, antineoplastic agent). The term “compound”, when referring to antineoplastic agents, includes agents that are antibodies. The term “sequentially” means one after the other. The term “effective amount” means “therapeutically effective amount”. The term “therapeutically effective amount” means that amount of an active compound or pharmaceutical agent that produces a biological or medical response in a tissue, system, animal, or human being desired to be achieved by a researcher, veterinarian, physician, or other clinician. Thus, for example, in the methods of treating cancer described herein, an “effective amount” (or a “therapeutically effective amount”) means that amount of a compound (or drug) or exposure that results in: (a) a reduction, relief, or the disappearance of one or more symptoms caused by the cancer, (b) reduction in tumor size, (c) elimination of the tumor, and/or (d) long-term stabilization of the tumor disease (growth arrest). Also, for example, an effective amount or therapeutically effective amount of a PRMT5 inhibitor (ie, a compound of the invention) is an amount that results in a decrease in PRMT5 activity. The term “administering a cancer treatment” or “treating cancer” refers to administration to a mammal that has a cancerous condition, and refers to an effect that alleviates the cancerous condition by killing cancer cells, and also refers to an effect that results in growth inhibition and/or cancer metastasis.

The invention also provides a pharmaceutical composition comprising an effective amount of at least one compound of formula I, Ia, Ib, Ic or Id and a pharmaceutically acceptable carrier. The invention also provides a pharmaceutical composition comprising an effective amount of at least one compound of formula I, Ia, Ib, Ic or Id and an effective amount of at least one other pharmaceutically active ingredient (such as, for example, a chemotherapeutic agent) and a pharmaceutically acceptable carrier.

The invention also provides a method of inhibiting PRMT5 in a patient in need of such treatment, comprising administering to said patient an effective amount of at least one compound of formula I, Ia, Ib, Ic or Id. The invention also provides a method for treating cancer in a patient in need of such treatment, said method comprising administering to said patient an effective amount of at least one compound of formula I, Ia, Ib, Ic or Id. The invention also provides a method for treating cancer in a patient in need of such treatment, said method comprising administering to said patient an effective amount of at least one compound of formula I, Ia, Ib, Ic or Id in combination with an effective amount of at least one chemotherapeutic agent. facilities. The methods of the invention involve administering a pharmaceutical composition comprising at least one compound of the invention and a pharmaceutically acceptable carrier. The invention also provides any of the above methods for treating cancer, wherein the cancer is colorectal. The invention also provides any of the above methods for treating cancer, where the cancer is melanoma. The methods of treating cancer described herein may not necessarily involve administering an effective amount of radiation (ie, the methods of treating cancer described herein may not necessarily involve the use of radiation therapy).

Methods for treating cancer described herein include methods for treating cancer that include administering a therapeutically effective amount of a compound of the present invention in combination with radiation therapy and/or in combination with a second compound selected from the following: an estrogen receptor modulator, an androgen receptor modulator, retinoid receptor modulator, cytotoxic-cytostatic agent, antiproliferative agent, prenyl-protein transferase inhibitor, HMG-CoA reductase inhibitor, HIV protease inhibitor, reverse transcriptase inhibitor, angiogenesis inhibitor, PPAR-γ agonists, PPAR-δ agonists, innate multidrug resistance inhibitor, antiemetic, agent useful in the treatment of anemia, agent useful in the treatment of neutropenia, immunoenhancing agent, inhibitor of cell proliferation and survival signals, bisphosphonate, aromatase inhibitor, siRNA therapeutic agent, γ-secretase and/or NOTCH inhibitors, agents that antagonize receptor tyrosine kinases (RTKs), an agent that antagonizes cell cycle checkpoint, and any of the therapeutic agents disclosed herein.

In any of the methods for treating cancer described herein, unless otherwise indicated, the methods may optionally include administering an effective amount of radiation therapy. Regarding radiation therapy, γ-irradiation is preferred.

Thus, another example of the invention is directed to a method of treating cancer in a patient in need of such treatment, said method comprising administering an effective amount of a compound of formula I, Ia, Ib, Ic or Id. Another example of the invention is directed to a method of treating cancer in a patient in need of such treatment, the method comprising administering to said patient an effective amount of a compound of formula I, Ia, Ib, Ic or Id and an effective amount of at least one chemotherapeutic agent.

Methods for safely and effectively administering most of these chemotherapeutic agents are known to those skilled in the art. In addition, their introduction is described in the reference literature. For example, the administration of many chemotherapy drugs is described in the Physician's Desk Reference (PDR), e.g., 1996 edition (Medical Economics Company, Montvale, NJ 07645-1742, USA), Physician's Desk Reference, ^56th edition, 2002 (published by Medical Economics company , Inc. Montvale, NJ 07645-1742), Physician's Desk Reference, ^57th edition, 2003 (published by Thompson PDR, Montvale, NJ 07645-1742), Physician's Desk Reference, ^60th edition, 2006 (published by Thompson PDR, Montvale, NJ 07645 -1742) and the Physician's Desk Reference, ^64th Edition, 2010 (published by PDR Network, LLC at Montvale, NJ 07645-1725), currently available through www.pdr.net; the disclosure of which is incorporated herein by reference.

If the patient is responsive or stable after completing a cycle of therapy, the cycle of therapy may be repeated as determined by a qualified clinician. After completion of the treatment cycles, the patient may continue taking the compounds of the invention at the same dose that was administered in accordance with the treatment protocol. This maintenance dose may continue to be given until the patient progresses or can no longer tolerate the dose (in which case the dose may be reduced and the patient may continue on the reduced dose).

Those skilled in the art will appreciate that the actual dosages and administration protocols used in the methods of the invention may vary at the discretion of the skilled clinician. The actual dose used may vary depending on the needs of the patient and the severity of the condition being treated. Determining the appropriate dosage for a particular situation is within the competence of those skilled in the art. The decision to change dosages and administration protocols may be made after consideration by a qualified clinician of factors such as the patient's age, condition, and size, as well as the severity of the cancer being treated and the patient's response to treatment.

The amount and frequency of administration of the compound of formula (1) and chemotherapeutic agents will be adjusted in accordance with the judgment of the treating clinician (physician), taking into account factors such as the age, condition and size of the patient, as well as the severity of the cancer being treated.

The chemotherapy agent can be administered in accordance with therapeutic protocols well known in the art. Those skilled in the art will appreciate that the administration of a chemotherapeutic agent may vary depending on the cancer being treated and the known effects of the chemotherapeutic agent on that disease. In addition, in accordance with the knowledge of a qualified clinician, therapeutic protocols (eg, numbers of doses and times of administration) may be varied based on the observed effects of the administered therapeutic agents on the patient and in consideration of the observed responses of the cancer to the administered therapeutic agents.

Initial administration can be carried out in accordance with established protocols known in the art, and then, based on the observed effects, the skilled clinician can adjust the dosage, routes of administration and timing of administration.

The specific choice of chemotherapy agent will depend on the diagnosis of the treating physicians and their assessment of the patient's condition and the appropriate treatment protocol.

Determining the order of administration and the number of repeat administrations of a chemotherapy agent during a treatment protocol is within the skill of a qualified physician after evaluating the cancer being treated and the patient's condition.

Thus, based on their experience and knowledge, the practitioner can modify each chemotherapy administration protocol to suit the individual needs of the patient as treatment continues. All such modifications are within the scope of the present invention.

The treating physician will consider the patient's overall well-being as well as more specific indications, such as relief of cancer-related symptoms (eg, pain), inhibition of tumor growth, actual tumor shrinkage, or inhibition of metastasis, when assessing the effectiveness of treatment at the administered dosage. Tumor size can be measured by standard methods such as radiological studies such as computed tomography or magnetic resonance imaging, and serial measurements can be used to judge whether tumor growth has slowed or even reverted. Relief of disease-related symptoms, such as pain, and improvement in general condition can also be used to evaluate the effectiveness of treatment.

The compounds, compositions and methods provided herein are useful for the treatment of cancer. Cancers that can be treated with the compounds, compositions and methods disclosed herein include, but are not limited to: (1) Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; (2) pulmonary: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma, non-small cell; (3) gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, VIPoma), small intestine (adenocarcinoma , lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), colon (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), (4) genitourinary tract: kidney (adenocarcinoma, Wilms tumor [nephroblastoma ], lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate gland (adenocarcinoma, sarcoma), male gonads (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma , fibroadenoma, adenomatoid tumors, lipoma); (5) liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; (6) bones: osteosarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronphroma (ostoechondral exostoses), benign chondroma, chondroma roblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; (7) nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma [pinealoma], glioblastoma multiforme, oligodendroglioma , schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); (8) gynecological: uterus (endometrial carcinoma), cervix (cervical carcinoma, cervical preneoplastic dysplasia), ovaries (ovarian carcinoma [serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma], granulosa thecal cell tumors, Sertoli cell tumors -Leydig, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonic rhabdomyosarcoma), fallopian tube carcinoma), breast; (9) hematological: (myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelomonocytic (CMML), myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma [malignant lymphoma]; (10) skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles (dysplastic nevi), lipoma, angioma, dermatofibroma, keloids, psoriasis; and (11) adrenal glands: neuroblastoma. Examples of cancers that can be treated with the compounds, compositions and methods of the invention include thyroid cancer, anaplastic thyroid carcinoma, epidermal cancer, head and neck cancer (eg, squamous cell carcinoma of the head and neck), sarcoma, tetracarcinoma, hepatoma and multiple myeloma. Thus, the term "cancer cell" as used herein includes a cell affected by any of the above conditions.

In the treatment of breast cancer (eg, postmenopausal and premenopausal breast cancer, eg, hormone-dependent breast cancer), a compound of formula (1) can be used with an effective amount of at least one anti-hormonal agent selected from the group consisting of the following: ( a) aromatase inhibitors, (b) antiestrogens and (c) LHRH analogues; and, optionally, an effective amount of at least one chemotherapeutic agent. Examples of aromatase inhibitors include, but are not limited to: Anastrozole (eg, Arimidex), Letrozole (eg, Femara), Exemestane (Aromasin), Fadrozole, and Formestane (eg, Lentaron). Examples of antiestrogens include, but are not limited to: Tamoxifen (eg, Nolvadex), Fulvestrant (eg, Faslodex), Raloxifene (eg, Evista) and Acolbifene. Examples of LHRH analogs include, but are not limited to: Goserelin (eg, Zoladex) and Leuprolide (eg, Leuprolide Acetate, such as Lupron or Lupron Depot). Examples of chemotherapy agents include, but are not limited to: Trastuzumab (eg, Herceptin), Gefitinib (eg, Iressa), Erlotinib (eg, Erlotinib HCl, such as Tarceva), Bevacizumab (eg, Avastin), Cetuximab (eg, Erbitux), and Bortezomib (eg, Velcade).

In one example of the invention, the cancer to be treated is colorectal cancer (such as, for example, colon adenocarcinoma and colon adenoma). Thus, another example of the invention is directed to a method of treating colorectal cancer in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a compound of formula I, Ia, Ib, Ic or Id, or a pharmaceutically acceptable salt thereof. Another example of the invention is directed to a method of treating colorectal cancer in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a compound of formula I, Ia, Ib, Ic or Id, or a pharmaceutically acceptable salt thereof, and an effective amount of at least one chemotherapy agent.

In one example of the invention, the cancer being treated is melanoma. Thus, another example of the invention is directed to a method of treating melanoma in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a compound of formula I, Ia, Ib, Ic or Id, or a pharmaceutically acceptable salt thereof. Another example of the invention is directed to a method of treating melanoma in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a compound of formula I, Ia, Ib, Ic or Id, or a pharmaceutically acceptable salt thereof, and an effective amount of at least one chemotherapeutic agent.

The compounds of the invention are also useful for the preparation of a drug that is useful in the treatment of cancer.

The compounds of the invention are also useful in combination with therapeutic, chemotherapeutic and anticancer agents. Combinations of the compounds disclosed herein with therapeutic, chemotherapeutic and anticancer agents are within the scope of the invention. Examples of such tools can be found in Cancer Principles and Practice of Oncology by V. T. Devita and S. Hellman (editors), ^9th edition (May 16, 2011), Lippincott Williams & Wilkins Publishers. One of ordinary skill in the art will be able to determine which combinations of agents will be useful based on the particular characteristics of the drugs and the particular type of cancer. Such agents include the following: estrogen receptor modulators, programmed cell death protein 1 (PD-1) inhibitors, programmed cell death ligand 1 (PD-L1) inhibitors, androgen receptor modulators, retinoid receptor modulators, cytotoxic/cytostatic agents, antiproliferative agents, inhibitors prenyl protein transferases, HMG-CoA reductase inhibitors and other angiogenesis inhibitors, HIV protease inhibitors, reverse transcriptase inhibitors, cell proliferation and survival signaling inhibitors, bisphosphonates, aromatase inhibitors, siRNA therapeutics, γ-secretase inhibitors, agents that counteract receptor tyrosine kinases (RTKs), and agents that affect cell cycle checkpoints. The compounds of the invention are particularly useful when administered concomitantly with radiation therapy.

The term “estrogen receptor modulators” refers to compounds that interfere with or inhibit the binding of estrogen to the receptor, regardless of the mechanism. Examples of estrogen receptor modulators include, but are not limited to, tamoxifen, raloxifene, idoxifene, LY353381, LY117081, toremifene, fulvestrant, 4-[7-(2,2-dimethyl-1-oxopropoxy-4-methyl-2-[4- [2-(1-piperidinyl)ethoxy]phenyl]-2H-1-benzopyran-3-yl]-phenyl-2,2-dimethylpropanoate, 4,4'-dihydroxybenzophenone-2,4-dinitrophenyl-hydrazone and SH646.

PD-1 inhibitors include pembrolizumab (lambrolizumab), nivolumab, and MPDL3280A. PDL-1 inhibitors include atezolizumab, avelumab, and durvalumab.

The term “androgen receptor modulators” refers to compounds that interfere with or inhibit the binding of androgens to the receptor, regardless of the mechanism. Examples of androgen receptor modulators include finasteride and other 5α-reductase inhibitors, nilutamide, flutamide, bicalutamide, liarozole and abitrateron acetate.

The term “retinoid receptor modulators” refers to compounds that interfere with or inhibit the binding of retinoids to the receptor, regardless of the mechanism. Examples of such retinoid receptor modulators include bexarotene, tretinoin, 13-cis-retinoic acid, 9-cis-retinoic acid, α-difluoromethylornithine, ILX23-7553, trans-N-(4'-hydroxyphenyl)retinamide and N-4-carboxyphenyl retinamide .

“Cytotoxic/cytostatic agents” refer to compounds that cause cell death or inhibit cell proliferation, preferably by directly interfering with cell function, or inhibit or interfere with cellular miosis, including alkylating agents, tumor necrosis factors, intercalators, hypoxia-activated compounds, inhibitors microtubule/microtubule stabilizing agents, mitotic kinesin inhibitors, histone deacetylase inhibitors, inhibitors of kinases involved in mitotic progression, inhibitors of kinases involved in growth factor and cytokine signaling pathways, antimetabolites, biological response modifiers, hormonal/antihormonal therapeutics, hematopoietic growth factors, targeted monoclonal antibody therapeutics, topoisomerase inhibitors, proteasome inhibitors, ubiquitin ligase inhibitors and aurora kinase inhibitors.

Examples of cytotoxic/cytostatic agents include, but are not limited to, sertenef, cachectin, ifosfamide, tasonermine, lonidamine, carboplatin, altretamine, prednimustine, dibromodulcytol, ranimustine, fotemustine, nedaplatin, oxaliplatin, temozolomide, heptaplatin, estramustine, improsulfan tosylate, trophosphamide, neem Ustin , dibrospidium chloride, pumitepa, lobaplatin, satraplatin, profiromycin, cisplatin, irofulven, dexifosfamide, cis-aminedichloro(2-methyl-pyridine)platinum, benzylguanine, glufosfamide, GPX100, (trans, trans, trans)-bis-mu-(hexane -1,6-diamine)-mu-[diamine-platinum(II)]bis[diamine(chloro)platinum(II)]tetrachloride, diarisidinylspermine, arsenic trioxide, 1-(11-dodecylamino-10-hydroxyundecyl)-3, 7-dimethylxanthine, zorubicin, idarubicin, daunorubicin, bisantrene, mitoxantrone, pyrarubicin, pinafide, valrubicin, amrubicin, antineoplaston, 3'-deamino-3'-morpholino-13-deoxo-10-hydroxycarminomycin, annamycin, galarubicin, elinafid, MEN10755, 4-demethoxy-3-deamino-3-aziridinyl-4-methylsulfonyl-daunorubicin (see. WO 00/50032), Raf kinase inhibitors (such as Bay43-9006) and mTOR inhibitors (such as Wyeth's CCI-779).

An example of a hypoxia-activated compound is tirapazamine.

Examples of proteasome inhibitors include, but are not limited to, lactacystin and MLN-341 (Velcade).

Examples of microtubule inhibitors/microtubule-stabilizing agents include paclitaxel, vindesine sulfate, 3',4'-didehydro-4'-deoxy-8'-norvincaleucoblastin, docetaxol, rhizoxin, dolastatin, mivobulin isethionate, auristatin, cemadotin, RPR109881, BMS184476, vinflunine , cryptophycin, 2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl)benzene sulfonamide, anhydrovine blastine, TDX258, epothilones (see, for example, US Patent Nos. 6284781 and 6288237) and BMS188797. In one example, epothilones are not included in microtubule inhibitors/microtubule stabilizing agents.

Some examples of topoisomerase inhibitors include topotecan, hycaptamine, irinotecan, rubitecan, 6-ethoxypropionyl-3',4'-O-exo-benzylidene-carthreusin, 9-methoxy-N,N-dimethyl-5-nitropyrazolo[3,4,5 -kl]acridine-2-(6H)propanamine, 1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo[de]pyrano[3' ,4':b,7]-indolizino[1,2b]quinoline-10,13(9H,15H)dione, lurtothecan, 7-[2-(N-isopropylamino)ethyl]-(20S)camptothecin, BNP1350, BNPI1100 , BN80915, BN80942, etoposide phosphate, teniposide, sobuzoxane, 2'-dimethylamino-2'-deoxy-etoposide, GL331, N-[2-(dimethylamino)ethyl]-9-hydroxy-5,6-dimethyl-6H-pyrido [4,3-b]carbazole-1-carboxamide, asulacrine, (5a, 5aB,8aa,9b)-9-[2-[N-[2-(dimethylamino)ethyl]-N-methylamino]ethyl]-5 -[4-hydroxy-3,5-dimethoxyphenyl]-5,5a,6,8,8a,9-hexohydrofuro(3',4':6,7)naphtho(2,3-d)-1,3- dioxol-6-one, 2,3-(methylenedioxy)-5-methyl-7-hydroxy-8-methoxybenzo[c]-phenanthridinium, 6,9-bis[(2-aminoethyl)amino]benzo[g]isoguinoline- 5,10-dione, 5-(3-aminopropylamino)-7,10-dihydroxy-2-(2-hydroxyethylaminomethyl)-6H-pyrazolo[4,5,1-de]acridin-6-one, N-[1 -[2(diethylamino)ethylamino]-7-methoxy-9-oxo-9H-thioxanthen-4-ylmethyl]formamide, N-(2-(dimethylamino)ethyl)acridine-4-carboxamide, 6-[[2-( dimethylamino)ethyl]amino]-3-hydroxy-7H-indeno[2,1-c]quinolin-7-one and dimesna.

Examples of inhibitors of mitotic kinesins and, in particular, human mitotic kinesin KSP are described in publications WO03/039460, WO03/050064, WO03/050122, WO03/049527, WO03/049679, WO03/049678, WO04/039774, WO03/07 9973, WO03/ 099211, WO03/105855, WO03/106417, WO04/037171, WO04/058148, WO04/058700, WO04/126699, WO05/018638, WO05/019206, WO05/019205, WO05/018 547, WO05/017190, US2005/0176776. In one example, mitotic kinesin inhibitors include, but are not limited to, KSP inhibitors, MKLP1 inhibitors, CENP-E inhibitors, MCAK inhibitors, and Rab6-KIFL inhibitors.

Examples of “histone deacetylase inhibitors” include, but are not limited to, SAHA, TSA, oxamflatin, PXD101, MG98 and scriptaid. Other histone deacetylase inhibitors can be found in the following document: Miller, TA et al. J. Med. Chem. 46(24):5097–5116 (2003).

“Inhibitors of kinases involved in mitotic progression” include, but are not limited to, aurora kinase inhibitors, Polo-like kinase (PLK) inhibitors; particularly PLK-1 inhibitors, bub-1 inhibitors and bub-R1 inhibitors. An example of an “aurora kinase inhibitor” is VX-680 (tosasertib).

“Antiproliferative agents” include antisense RNA and DNA oligonucleotides such as G3139, ODN698, GEM231 and INX3001, and antimetabolites such as enocytabine, carmofur, tegafur, pentostatin, doxifluridine, trimetrexate, fludarabine, capecitabine, halocitabine, cytarabine oxophosphate, fosteabine sodium hydrate , raltitrexed, paltitrexide, emitefur, thiazofurin, decitabine, nolatrexed, pemetrexed, nelzarabine, 2'-deoxy-2'-methylidenecytidine, 2'-fluoromethylene-2'-deoxycytidine, N-[5-(2,3-dihydro-benzofuryl )sulfonyl]-N'-(3,4-dichlorophenyl)urea, N6-[4-deoxy-4-[N2-[2(E),4(E)-tetradecadienoyl]glycylamino]-L-glycero-B-L- manno-heptopyranosyl]adenine, aplidine, ecteinascidin, troxacitabine, 4-[2-amino-4-oxo-4,6,7,8-tetrahydro-3H-pyrimidino[5,4-b][1,4]thiazine- 6-yl-(S)-ethyl]-2,5-thienoyl-L-glutamic acid, aminopterin, 5-fluorouracil, alanosine, 11-acetyl-8-(carbamoyloxymethyl)-4-formyl-6-methoxy-14 ester -oxa-1,11-diazatetracyclo(7.4.1.0.0)-tetradeca-2,4,6-trien-9-ylacetic acid, swainsonine, lometrexol, dexrazoxane, methioninase, 2'-cyano-2'-deoxy-N4 -palmitoyl-1-B-D-arabinofuranosyl cytosine, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone and trastuzumab.

Examples of therapeutic agents specifically delivered by monoclonal antibodies include those therapeutic agents that contain cytotoxic substances or radioisotopes attached to a monoclonal antibody specific for a cancer cell or specific for a target cell. Examples include Bexxar.

The term “HMG-CoA reductase inhibitors” refers to inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase. Examples of HMG-CoA reductase inhibitors that can be used include, but are not limited to, lovastatin (MEVACOR®; see US Patent Nos. 4,231,938, 4,294,926 and 4,319,039), simvastatin (ZOCOR®; see US Patent Nos. 4,444,784, 4,820,850 and 4916239), pravastatin (PRAVACHOL®; see US Patent Nos. 4346227, 4537859, 4410629, 5030447 and 5180589), fluvastatin (LESCOL®; see US Patent Nos. 5354772, 4911165, 4929437, 518 9164, 5118853, 5290946 and 5356896 ), atorvastatin (LIPITOR®; see US Patent Nos. 5273995, 4681893, 5489691 and 5342952), rosuvastatin (CRESTOR® Superseding US Patent RE37,314) and cerivastatin (also known as rivastatin and BAYCHOL®; see US Patent No. 5177080 ). The structural formulas of these and additional HMG-CoA reductase inhibitors that can be used in the methods of the invention are described on page 87 of M. Yalpani, "Cholesterol Lowering Drugs", Chemistry & Industry , pp. 85-89 (February 5, 1996) and in US Pat. Nos. 4,782,084 and 4,885,314. The term HMG-CoA reductase inhibitor as used herein includes all pharmaceutically acceptable lactone and open acid forms (i.e., where the lactone ring is opened to form a free acid ), as well as salt and ester forms of compounds that have HMG-CoA reductase inhibitory activity, and therefore the use of such salts, esters, open acid and lactone forms is included within the scope of the invention.

“Prenyl protein transferase inhibitor” refers to a compound that inhibits any one or any combination of prenyl protein transferase enzymes, including farnesyl protein transferase (FPTase), geranylgeranyl protein transferase type I (GGPTase-I), and geranylgeranyl protein transferase type-II (GGPTase-I). II, also called Rab GGPTase).

Examples of prenyl protein transferase inhibitors can be found in the following publications and patents: WO 96/30343, WO 97/18813, WO 97/21701, WO 97/23478, WO 97/38665, WO 98/28980, WO 98/29119, WO 95 /32987, US Patent Nos. 5420245, 5523430, 5532359, 5510510, 5589485 and 5602098, European Patent Application Publication 0 618 221, European Patent Application Publication 0 675 112, European Patent Application Publication 0 604 181, publication of European patent application 0 696 593 , WO 94/19357, WO 95/08542, WO 95/11917, WO 95/12612, WO 95/12572, WO 95/10514, US Patent No. 5661152, WO 95/10515, WO 95/10516, WO 95/24612, WO 95/34535, WO 95/25086, WO 96/05529, WO 96/06138, WO 96/06193, WO 96/16443, WO 96/ 21701, WO 96/21456, WO 96/22278, WO 96/24611, WO 96/24612, WO 96/05168, WO 96/05169, WO 96/00736, US Patent No. No. 5571792, WO 96/17861, WO 96/33159, WO 96/34850, WO 96/34851, WO 96/30017, WO 96/30018, WO 96/30362, WO 96/30363, WO 96/31111, WO 96/ 31477, WO 96/31478, WO 96/31501, WO 97/00252, WO 97/03047, WO 97/03050, WO 97/04785, WO 97/02920, WO 97/17070, WO 97/23478, WO 97/ 26246, WO 97/30053, WO 97/44350, WO 98/02436 and US Patent No. 5532359. For an example of the role of a prenyl protein transferase inhibitor on angiogenesis, see European J. of Cancer , Vol. 35, No. 9, pp.1394-1401 (1999).

The term “angiogenesis inhibitors” refers to compounds that inhibit the formation of new blood vessels, regardless of the mechanism. Examples of angiogenesis inhibitors include, but are not limited to, tyrosine kinase inhibitors such as Flt-1 (VEGFR1) and Flk-1/KDR (VEGFR2) receptor tyrosine kinase inhibitors, epidermal growth factor, fibroblast or platelet growth factor inhibitors, MMP (matrix metalloproteinase) inhibitors ), integrin blockers, interferon-α, interleukin-12, pentosan polysulfate, cyclooxygenase inhibitors, including non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin and ibuprofen, and selective cyclooxygenase-2 inhibitors such as celecoxib and rofecoxib ( PNAS , Vol. 89, p. 7384 (1992); JNCI , Vol. 69, p. 475 (1982); Arch. Opthalmol ., Vol. 108, p. 573 (1990); Anat. Rec ., Vol. 238, p 68 (1994); FEBS Letters , Vol. 372, p. 83 (1995); Clin, Orthop . Vol. 313, p. 76 (1995); J. Mol. Endocrinol ., Vol. 16, p. 107 ( 1996); Jpn. J. Pharmacol ., Vol. 75, p. 105 (1997); Cancer Res. , Vol. 57, p. 1625 (1997); Cell , Vol. 93, p. 705 (1998); Intl J. Mol. Med ., Vol. 2, p. 715 (1998); J Biol. Chem ., Vol. 274, p. 9116 (1999)), steroidal anti-inflammatory drugs (such as corticosteroids, mineralocorticoids, dexamethasone, prednisone, prednisolone, methylpred, betamethasone), carboxyamidotriazole, combretastatin A-4, squalamine, 6-O-chloroacetyl-carbonyl)-fumagillol, thalidomide, angiostatin, troponin-1, angiotensin II antagonists (see Fernandez et al., J. Lab. Clin. Med . 105:141-145 (1985)) and anti-VEGF antibodies (see Nature Biotechnology , Vol. 17, pp. 963-968 (October 1999); Kim et al., Nature , 362 , 841-844 (1993); WO 00/44777; and WO 00/61186).

Other therapeutic agents that modulate or inhibit angiogenesis and which may also be used in combination with the compounds of the invention include agents that modulate or inhibit the coagulation and fibrinolytic systems (reviewed in Clin. Chem. La. Med . 38:679-692 (2000)). Examples of such agents that modulate or inhibit the coagulation and fibrinolysis pathways include, but are not limited to, heparin (see Thromb. Haemost . 80:10-23 (1998)), low molecular weight heparins, and carboxypeptidase U inhibitors (also known as active inhibitors). thrombin-activated fibrinolysis inhibitor [TAFIa]) (see Thrombosis Res . 101:329-354 (2001)). TAFIa inhibitors are described in US Ser. Nos. 60/310927 (filed August 8, 2001) and 60/349925 (filed January 18, 2002).

“Cell cycle checkpoint agents” refer to compounds that inhibit protein kinases that transmit cell cycle checkpoint signals, thereby sensitizing the cancer cell to DNA-damaging agents. Such agents include inhibitors of ATR, ATM, the CHK1 and CHK2 kinases and inhibitors of cdk and cdc kinases, and specific examples are 7-hydroxystaurosporine, flavopiridol, CYC202 (Cyclacel) and BMS-387032.

“Agents that antagonize receptor tyrosine kinases (RTKs)” refer to compounds that inhibit RTKs, and therefore mechanisms involved in tumorigenesis and tumor progression. Such agents include inhibitors of c-Kit, Eph, PDGF, Flt3 and c-Met. Other agents include RTK inhibitors described in Bume-Jensen and Hunter, Nature , 411:355-365, 2001.

“Cell proliferation and survival signaling inhibitors” refer to compounds that inhibit signal transduction cascades downstream of a cell surface receptor. Such agents include serine/threonine kinase inhibitors (including, but not limited to, Akt inhibitors, such as those described in WO 02/083064, WO 02/083139, WO 02/083140, US 2004-0116432, WO 02/083138, US 2004-0102360 , WO 03/086404, WO 03/086279, WO 03/086394, WO 03/084473, WO 03/086403, WO 2004/041162, WO 2004/096131, WO 2004/096129, WO 2004/0961 35, WO 2004/096130 , WO 2005/100356, WO 2005/100344, US 2005/029941, US 2005/44294, US 2005/43361, 60/734188, 60/652737, 60/670469), Raf kinase inhibitors (for example BAY-43-9006 ) , MEK inhibitors (eg CI-1040 and PD-098059), mTOR inhibitors (eg Wyeth CCI-779) and PI3K inhibitors (eg LY294002).

As described above, combinations with NSAIDs focus on the use of NSAIDs that are potent COX-2 inhibitory agents. For the purposes of this description, an NSAID is effective if it has an IC ₅₀ value for COX-2 inhibition of 1 μM or less, measured in a cellular or microsomal assay.

The invention also covers combinations with NSAIDs that are selective COX-2 inhibitors. For the purposes of this specification, NSAIDs that are selective inhibitors of COX-2 are defined as having a specificity for inhibiting COX-2 of at least 100 times that of COX-1, as measured by the ratio of COX-2 IC ₅₀ to IC ₅₀ for COX-1 determined by cellular or microsomal assay. Such compounds include, but are not limited to, those disclosed in US Patent No. 5474995, US Patent No. 5861419, US Patent No. 6001843, US Patent No. 6020343, US Patent No. 5409944, US Patent No. 5436265, US Patent No. 5536752, US Patent No. No. 5550142, US Patent No. 5604260, US Patent No. 5698584, US Patent No. 5710140, WO 94/15932, US Patent No. 5344991, US Patent No. 5134142, US Patent No. 5380738, US Patent No. 5393790, US Patent No. No. 5466823, US Patent No. 5,633,272 and U.S. Patent No. 5,932,598, all of which are incorporated herein by reference.

COX-2 inhibitors that are particularly useful in the treatment method of the invention are: 3-phenyl-4-(4-(methylsulfonyl)phenyl)-2-( 5H )-furanone; and 5-chloro-3-(4-methylsulfonyl)phenyl-2-(2-methyl-5-pyridinyl)pyridine; or a pharmaceutically acceptable salt thereof.

Compounds that are described as specific COX-2 inhibitors and therefore useful in the present invention include, but are not limited to, the following: rofecoxib, etoricoxib, parecoxib, BEXTRA® and CELEBREX® or a pharmaceutically acceptable salt thereof.

Other examples of angiogenesis inhibitors include, but are not limited to, endostatin, ukrain, ranpirnase, IM862, 5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro[2, 5]oct-6-yl(chloroacetyl)carbamate, acetyldinanaline, 5-amino-1-[[3,5-dichloro-4-(4-chlorobenzoyl)phenyl]methyl]-1H-1,2,3-triazol- 4-carboxamide, CM101, squalamine, combretastatin, RPI4610, NX31838, sulfated mannopentaose phosphate, 7,7-(carbonyl-bis[imino-N-methyl-4,2-pyrrolocarbonylimino[N-methyl-4,2-pyrrole]- carbonylimino]-bis-(1,3-naphthalene disulfonate) and 3-[(2,4-dimethylpyrrol-5-yl)methylene]-2-indolinone (SU5416).

The above term “integrin blockers” refers to compounds that selectively antagonize, inhibit or antagonize the binding of a physiological ligand to an α _v β ₃ integrin, compounds that selectively antagonize, inhibit or antagonize the binding of a physiological ligand to an α _v β ₅ integrin, compounds that antagonize, inhibit or antagonize physiological ligand binding to both α _v β ₃ integrin and α _v β ₅ integrin, and to compounds that antagonize, inhibit or antagonize the activity of specific integrin(s) expressed on capillary endothelial cells. _The term _also refers to _{antagonists of αvβ6} , _αvβ8 , _α1β1 , _α2β1 , _{α5β1 , α6β1} and _{α6β4 integrins . The term} also refers to antagonists _{of any} combination of _{αvβ3 , αvβ5 , αvβ6} , _αvβ8 , _α1β1 , _{α2β1 , α5β1 , α6β1} and _{α6β 4} integrins.

Some specific examples of tyrosine kinase inhibitors include N-(trifluoromethylphenyl)-5-methylisoxazole-4-carboxamide, 3-[(2,4-dimethylpyrrol-5-yl)methylidenyl)indolin-2-one, 17-(allylamino)-17- demethoxygeldanamycin, 4-(3-chloro-4-fluorophenylamino)-7-methoxy-6-[3-(4-morpholinyl)propoxy]quinazoline, N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy) -4-quinazolinamine, BIBX1382, 2,3,9,10,11,12-hexahydro-10-(hydroxymethyl)-10-hydroxy-9-methyl-9,12-epoxy-1H-diindolo[1,2,3 -fg:3',2',1'-kl]pyrrolo[3,4-i][1,6]benzodiazocin-1-one, SH268, genistein, STI571, CEP2563, 4-(3-chlorophenylamino)-5 ,6-dimethyl-7H-pyrrolo[2,3-d]pyrimidinemethane sulfonate, 4-(3-bromo-4-hydroxyphenyl)amino-6,7-dimethoxyquinazoline, 4-(4'-hydroxyphenyl)amino-6,7 -dimethoxyquinazoline, SU6668, STI571A, N-4-chlorophenyl-4-(4-pyridylmethyl)-1-phthalazinamine and EMD121974.

Combinations with compounds other than anticancer compounds are also covered by the methods of the invention. For example, combinations of the inventive compounds with PPAR-γ agonists (ie PPAR-gamma) and PPAR-δ agonists (ie PPAR-delta) are useful in the treatment of certain malignant diseases. PPAR-γ and PPAR-δ are peroxisome proliferator-activated nuclear receptors γ and δ. The expression of PPAR-γ on endothelial cells and its involvement in angiogenesis are described in the literature (see J. Cardiovasc. Pharmacol. 1998; 31:909-913; J. Biol. Chem. 1999; 274:9116-9121; Invest. Ophthalmol Vis Sci 2000;41:2309-2317). PPAR-γ agonists have recently been shown to inhibit the angiogenic response to VEGF in vitro; both troglitazone and rosiglitazone maleate inhibit the development of retinal neovascularization in mice ( Arch. Ophthamol. 2001; 119:709–717). Examples of PPAR-γ agonists and PPAR-γ/α agonists include, but are not limited to, thiazolidinediones (such as DRF2725, CS-011, troglitazone, rosiglitazone and pioglitazone), fenofibrate, gemfibrozil, clofibrate, GW2570, SB219994, AR-H039242, JTT-501, MCC-555, GW2331, GW409544, NN2344, KRP297, NP0110, DRF4158, NN622, GI262570, PNU182716, DRF552926, 2-[(5,7-dipropyl-3-trifluoromethyl-1,2-benzisoxazole-6- yl)oxy]-2-methylpropionic acid (disclosed in USSN 09/782856) and 2(R)-7-(3-(2-chloro-4-(4-fluorophenoxy)phenoxy)propoxy)-2-ethylchroman-2 -carboxylic acid (disclosed in USSN 60/235708 and 60/244697).

Another example of the present invention is the use of the compounds disclosed herein in combination with gene therapy for the treatment of cancer. For a review of genetic strategies for treating cancer, see Hall et al., ( Am. J. Hum. Genet . 61:785-789, 1997) and Kufe et al., (Cancer Medicine, 5th Ed, pp 876-889, BC Decker, Hamilton 2000). Gene therapy can be used to deliver any tumor suppressor gene. Examples of such genes include, but are not limited to, p53, which can be delivered via recombinant virus-mediated gene transfer (see, e.g., US Pat. No. 6,069,134), a uPA/uPAR antagonist ("Adenovirus-Mediated Delivery of a uPA /uPAR Antagonist Suppresses Angiogenesis-Dependent Tumor Growth and Dissemination in Mice," Gene Therapy, August 1998;5(8):1105-13) and interferon gamma ( J. Immunol . 2000;164:217-222).

The compounds of the invention can also be administered in combination with an inhibitor of innate multidrug resistance (MDR), in particular MDR associated with high levels of expression of transport proteins. Such MDR inhibitors include p-glycoprotein (P-gp) inhibitors such as LY335979, XR9576, OC144-093, R101922, VX853 and PSC833 (valspodar).

The compound of the present invention can be used in conjunction with antiemetics for the treatment of nausea or vomiting, including acute, delayed, late phase and expectant vomiting, which may result from the use of a compound of the present invention alone or with radiation therapy. To prevent or treat vomiting, the compound of the present invention can be used in conjunction with other antiemetics, especially neurokinin-1 receptor antagonists, 5HT3 receptor antagonists such as ondansetron, granisetron, tropisetron and zatisetron, GABAB receptor agonists such as baclofen, corticosteroid such as Decadron (dexamethasone), Kenalog, Aristocort, Nasalide, Preferid, Benecorten or others, such as those disclosed in US Patent Nos. 2789118, 2990401, 3048581, 3126375, 3929768, 3996359, 3928326 and 3749712, antidopaminergic chemical agent such as phenothiazines (eg , prochlorperazine, fluphenazine, thioridazine and mesoridazine), metoclopramide or dronabinol. In yet another example, combination therapy with an antiemetic selected from a neurokinin-1 receptor antagonist, a 5HT3 receptor antagonist, and a corticosteroid is disclosed for the treatment or prevention of emesis that may occur following administration of the compounds of the invention.

Neurokinin-1 receptor antagonists for use with the compounds of the present invention are described in detail, for example, in US Patent Nos. 5162339, 5232929, 5242930, 5373003, 5387595, 5459270, 5494926, 5496833, 5637699, 5719147 ; European patent publications Nos. EP 0 360 390, 0 394 989, 0 428 434, 0 429 366, 0 430 771, 0 436 334, 0 443 132, 0 482 539, 0 498 069, 0 499 313, 0 5 12 901, 0 512 902, 0 514 273, 0 514 274, 0 514 275, 0 514 276, 0 515 681, 0 517 589, 0 520 555, 0 522 808, 0 528 495, 0 532 456, 0 533 280, 0 536 817, 0 545 478, 0 558 156, 0 577 394, 0 585 913.0 590 152, 0 599 538, 0 610 793, 0 634 402, 0 686 629, 0 693 489, 0 694 535 , 0 699 655, 0 699 674, 0 707 006, 0 708 101, 0 709 375, 0 709 376, 0 714 891, 0 723 959, 0 733 632 and 0 776 893; International patent publications PCT Nos. WO 90/05525, 90/05729, 91/09844, 91/18899, 92/01688, 92/06079, 92/12151, 92/15585, 92/17449, 92/20661, 92/20676 , 92/21677, 92/22569, 93/00330, 93/00331, 93/01159, 93/01165, 93/01169, 93/01170, 93/06099, 93/09116, 93/10073, 93/14084, 9 3 /14113, 93/18023, 93/19064, 93/21155, 93/21181, 93/23380, 93/24465, 94/00440, 94/01402, 94/02461, 94/02595, 94/03429, 94/034 45 , 94/04494, 94/04496, 94/05625, 94/07843, 94/08997, 94/10165, 94/10167, 94/10168, 94/10170, 94/11368, 94/13639, 94/13663, 9 4 /14767, 94/15903, 94/19320, 94/19323, 94/20500, 94/26735, 94/26740, 94/29309, 95/02595, 95/04040, 95/04042, 95/06645, 95/078 86 , 95/07908, 95/08549, 95/11880, 95/14017, 95/15311, 95/16679, 95/17382, 95/18124, 95/18129, 95/19344, 95/20575, 95/21819, 9 5 /22525, 95/23798, 95/26338, 95/28418, 95/30674, 95/30687, 95/33744, 96/05181, 96/05193, 96/05203, 96/06094, 96/07649, 96/105 62 , 96/16939, 96/18643, 96/20197, 96/21661, 96/29304, 96/29317, 96/29326, 96/29328, 96/31214, 96/32385, 96/37489, 97/01553, 9 7 /01554, 97/03066, 97/08144, 97/14671, 97/17362, 97/18206, 97/19084, 97/19942 and 97/21702; and in UK Patent Publications Nos. 2,266,529, 2,268,931, 2,269,170, 2,269,590, 2,271,774, 2,292,144, 2,293,168, 2,293,169 and 2,302,689. The preparation of such compounds is described in detail in the above patents and publications, which are incorporated herein by reference.

In one example, the neurokinin-1 receptor antagonist for use with the compounds of the present invention is selected from: 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S )-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine or a pharmaceutically acceptable salt thereof, which is described in US Patent No. 5,719,147.

The compound of the invention can also be administered with an agent useful in the treatment of anemia. Such an anemia treatment agent is, for example, a continuous erythropoiesis receptor activator (such as epoetin alfa).

The compound of the invention can also be administered with an agent useful in the treatment of neutropenia. Such an agent for the treatment of neutropenia, for example, is a hematopoietic growth factor that regulates the production and function of neutrophils, such as human granulocyte colony-stimulating factor (G-CSF). Examples of G-CSF include filgrastim.

The compound of the invention can also be administered with an immunoenhancing agent such as levamisole, isoprinosine and Zadaxin.

The compound of the invention may also be useful for the treatment or prevention of cancer in combination with P450 inhibitors including: xenobiotics, quinidine, tyramine, ketoconazole, testosterone, quinine, metyrapone, caffeine, phenelzine, doxorubicin, troleandomycin, cyclobenzaprine, erythromycin, cocaine, furafilin, cimetidine , dextromethorphan, ritonavir, indinavir, amprenavir, diltiazem, terfenadine, verapamil, cortisol, itraconazole, mibefradil, nefazodone and nelfinavir.

The compound of the invention may also be useful for the treatment or prevention of cancer in combination with Pgp and/or BCRP inhibitors, including: cyclosporine A, PSC833, GF120918, Cremophor EL, fumitremorgin C, Ko132, Ko134, Iressa, Imatinib mesylate, EKI-785, Cl1033, novobiocin, diethylstilbestrol, tamoxifen, resperpine, VX-710, tryprostatin A, flavonoids, ritonavir, saquinavir, nelfinavir, omeprazole, quinidine, verapamil, terfenadine, ketoconazole, nifidepine, FK506, amylodarone, XR9576, indinavir, ampre navir, cortisol, testosterone , LY335979, OC144-093, erythromycin, vincristine, digoxin and talinolol.

The compound of the invention may also be useful for the treatment or prevention of cancer, including bone cancer, in combination with bisphosphonates (meant to include bisphosphonates, diphosphonates, bisphosphonic acids and diphosphonic acids). Examples of bisphosphonates include, but are not limited to: etidronate (Didronel), pamidronate (Aredia), alendronate (Fosamax), risedronate (Actonel), zoledronate (Zometa), ibandronate (Boniva), incadronate or cimadronate, clodronate, EB-1053, minodronate , neridronate, pyridronate and tiludronate, including any and all pharmaceutically acceptable salts, derivatives, hydrates and mixtures thereof.

The compound of the invention may also be useful for the treatment or prevention of breast cancer in combination with aromatase inhibitors. Examples of aromatase inhibitors include, but are not limited to: anastrozole, letrozole and exemestane.

The compound of the invention may also be useful for the treatment or prevention of cancer in combination with siRNA-based therapeutics.

The compounds of the invention can also be administered in combination with γ-secretase inhibitors and/or inhibitors of NOTCH signaling. Such inhibitors include those described in WO 01/90084, WO 02/30912, WO 01/70677, WO 03/013506, WO 02/36555, WO 03/093252, WO 03/093264, WO 03/093251, WO 03/ 093253, WO 2004/039800, WO 2004/039370, WO 2005/030731, WO 2005/014553, USSN 10/957,251, WO 2004/089911, WO 02/081435, WO 02/081433, W O 03/018543, WO 2004/ 031137, WO 2004/031139, WO 2004/031138, WO 2004/101538, WO 2004/101539 and WO 02/47671 (including LY-450139).

The compound of the invention may also be useful for the treatment or prevention of cancer in combination with PARP inhibitors.

The compound of the invention may also be useful for the treatment of cancer in combination with the following therapeutic agents: pembrolizumab (Keytruda®), abarelix (Plenaxis depot®); aldesleukin (Prokine®); Aldesleykin (Proleukin®); Alemtuzumab (Campath®); alitretinoin (Panretin®); allopurinol (Zyloprim®); altretamine (Hexalen®); amifostine (Ethyol®); anastrozole (Arimidex®); arsenic trioxide (Trisenox®); asparaginase (Elspar®); azacitidine (Vidaza®); bevacuzimab (Avastin®); bexarotene capsules (Targretin®); bexarotene gel (Targretin®); bleomycin (Bleoxane®); bortezomib (Velcade®); intravenous busulfan (Busulfex®); oral busulfan (Myleran®); calusterone (Methosarb®); capecitabine (Xeloda®); carboplatin (Paraplatin®); carmustine (BCNU®, BiCNU®); carmustine (Gliadel®); carmustine with Polypheprosan 20 Implant (Gliadel Wafer®); celecoxib (Celebrex®); cetuximab (Erbitux®); chlorambucil (Leukeran®); cisplatin (Platinol®); cladribine (Leusstatin®, 2-CdA®); clofarabine (Clolar®); cyclophosphamide (Cytoxane®, Neosar®); cyclophosphamide (Cytoxane Injection®); cyclophosphamide (Cytoxane tablets®); cytarabine (Cytosar-U®); cytarabine liposomal (DepoCyt®); dacarbazine (DTIC-Dome®); dactinomycin, actinomycin D (Cosmegen®); Darbepoetin alfa (Aranesp®); daunorubicin liposomal (Danuoxaome®); daunorubicin, daunomycin (Daunorubicin®); daunorubicin, daunomycin (Cerubidine®); denileukin-diftitox (Ontak®); dexrazoxane (Zinecard®); docetaxel (Taxotere®); doxorubicin (Adriamycin PFS®); doxorubicin (Adriamycin®, Rubex®); doxorubicin (Adriamycin PFS Injection®); doxorubicin liposomal (Doxil®); dromostanolone propionate (Dromostanolone®); dromostanolone propionate (Masterone for injection®); Elliott's B Solution®; epirubicin (Ellence®); Epoetin alfa (epogen®); erlotinib (Tarceva®); estramustine (Emcyt®); etoposide phosphate (Etopophos®); etoposide, VP-16 (Vepesid®); exemestane (Aromasin®); Filgrastim (Neupogen®); floxuridine (intra-arterial) (FUDR®); fludarabine (Fludara®); fluorouracil, 5-FU (Adrucil®); fulvestrant (Faslodex®); gefitinib (Iressa®); gemcitabine (Gemzar®); gemtuzumab ozogamicin (Mylotarg®); goserelin acetate (Zoladex Implant®); goserelin acetate (Zoladex®); histrelin acetate (Histrelin implant®); hydroxyurea (Hydrea®); Ibritumomab Tiuxetan (Zevalin®); idarubicin (Idamycin®); ifosfamide (IFEX®); imatinib mesylate (Gleevec®); interferon alpha 2a (Roferon A®); Interferon alpha-2b (Intron A®); irinotecan (Camptosar®); lenalidomide (Revlimid®); letrozole (Femara®); leucovorin (Wellcovorin®, Leucovorin®); Leuprolide Acetate (Eligard®); levamisole (Ergamisol®); lomustine, CCNU (CeeBU®); meclorethamine, nitrogen mustard (Mustargen®); megestrol acetate (Megace®); melphalan, L-PAM (Alkeran®); mercaptopurine, 6-MP (Purinethol®); mesna (Mesnex®); mesna (Mesnex tabs®); methotrexate®; methoxsalene (Uvadex®); mitomycin C (Mutamycin®); mitotane (Lysodren®); mitoxantrone (Novantrone®); nandrolone phenpropionate (Durabolin-50®); nelarabine (Arranon®); Nofetumomab (Verluma®); Opredvekin (Neumega®); oxaliplatin (Eloxatin®); paclitaxel (Paxene®); paclitaxel (Taxol®); paclitaxel protein-bound particles (Abraxane®); palifermin (Kepivance®); pamidronate (Aredia®); pegademase (Adagen (Pegademase Bovine)®); pegaspargase (Oncaspar®); Pegfilgrastim (Neulasta®); pemetrexed disodium (Alimta®); pentostatin (Nipent®); pipobroman (Vercyte®); plicamycin, mithramycin (Mithracin®); porfimer sodium (Photofrin®); procarbazine (Matulane®); quinacrine (Atabrine®); rasburicase (Elitek®); Rituximab (Rituxan®); Ridaforolimus; sargramostim (Leukine®); Sargramostim (Prokine®); sorafenib (Nexavar®); streptozocin (Zanosar®); sunitinib maleate (Sutent®); talc (Sclerosol®); tamoxifen (Nolvadex®); temozolomide (Temodar®); teniposide, VM-26 (Vumon®); testolactone (Teslac®); thioguanine, 6-TG (Thioguanine®); thiotepa (Thioplex®); topotecan (Hycamtin®); toremifene (Fareston®); Tositumomab (Bexxar®); Tositumomab/I-131 tositumomab (Bexxar®); Trastuzumab (Herceptin®); tretinoin, ATRA (Vesanoid®); Nitrogen Mustard (Uracil Mustard Capsules®); valrubicin (Valstar®); vinblastine (Velban®); vincristine (Oncovin®); vinorelbine (Navelbine®); vorinostat (Zolinza®) and zoledronate (Zometa®).

In one example, the angiogenesis inhibitor that can be used as the second compound is selected from a tyrosine kinase inhibitor, an epidermal growth factor inhibitor, a fibroblast growth factor inhibitor, a platelet-derived growth factor inhibitor, an MMP (matrix metalloproteinase) inhibitor, an integrin blocker, interferon-α, interleukin- 12, pentosan polysulfate, cyclooxygenase inhibitor, carboxyamidotriazole, combretastatin A-4, squalamine, 6-O-chloroacetyl-carbonyl)-fumagillol, thalidomide, angiostatin, troponin-1 or anti-VEGF antibody. In one example, the estrogen receptor modulator is tamoxifen or raloxifene.

Thus, the scope of the invention covers the use of the compounds claimed according to the invention in combination with a second compound selected from the following: estrogen receptor modulator, androgen receptor modulator, retinoid receptor modulator, cytotoxic/cytostatic agent, antiproliferative agent, prenyl-protein transferase inhibitor, HMG-CoA inhibitor reductase, HIV protease inhibitor, reverse transcriptase inhibitor, angiogenesis inhibitor, PPAR-γ agonists, PPAR-δ agonists, innate multidrug resistance inhibitor, antiemetic, agent useful in the treatment of anemia, agent useful in the treatment of neutropenia, immunoenhancing agent, inhibitor cell proliferation and survival signaling, a bisphosphonate, an aromatase inhibitor, an siRNA therapeutic, γ-secretase and/or NOTCH inhibitors, agents that antagonize receptor tyrosine kinases (RTKs), an agent that antagonizes cell cycle checkpoint, and any of the therapeutics mentioned above.

Also included within the scope of the claims is a method of treating cancer which includes administering a therapeutically effective amount of a compound of the present invention in combination with radiation therapy and/or in combination with a second compound selected from the following: estrogen receptor modulator, androgen receptor modulator, retinoid receptor modulator, cytotoxic /cytostatic agent, antiproliferative agent, prenyl-protein transferase inhibitor, HMG-CoA reductase inhibitor, HIV protease inhibitor, reverse transcriptase inhibitor, angiogenesis inhibitor, PPAR-γ agonists, PPAR-δ agonists, innate multidrug resistance inhibitor, antiemetic agent, agent, useful in the treatment of anemia, an agent useful in the treatment of neutropenia, an immunoenhancing agent, an inhibitor of cell proliferation and survival signals, a bisphosphonate, an aromatase inhibitor, a siRNA therapeutic agent, γ-secretase and/or NOTCH inhibitors, agents that antagonize receptor tyrosine kinases (RTKs) ), an agent that antagonizes the cell cycle checkpoint, and any of the therapeutic agents listed above.

Another example of the invention is a method of treating cancer that includes administering a therapeutically effective amount of a compound of the present invention in combination with paclitaxel or trastuzumab.

The invention also covers a method of treating or preventing cancer which includes administering a therapeutically effective amount of a compound of the present invention in combination with a COX-2 inhibitor.

The therapeutic combination disclosed herein may be used in combination with one or more other active agents, including, but not limited to, other anticancer agents that are used to prevent, treat, control, alleviate, or reduce the risk of a particular disease or condition (eg , cell proliferative disorders). In one embodiment, a compound disclosed herein is used in combination with one or more other anticancer agents for use in the prevention, treatment, control, amelioration, or risk reduction of a particular disease or condition in which the compounds disclosed herein are beneficial. Such other active agents can be administered in the manner and in amounts conventionally used for these agents, prior to, concurrently, or sequentially with the administration of a compound of the invention.

The invention also includes a pharmaceutical composition useful for the treatment or prevention of cancer, which includes a therapeutically effective amount of a compound of the present invention and a second compound selected from the following: an estrogen receptor modulator, an androgen receptor modulator, a retinoid receptor modulator, a cytotoxic/cytostatic agent, an antiproliferative agent, prenyl protein transferase inhibitor, HMG-CoA reductase inhibitor, HIV protease inhibitor, reverse transcriptase inhibitor, angiogenesis inhibitor, PPAR-γ agonist, PPAR-δ agonist, cell proliferation and survival signaling inhibitor, bisphosphonate, aromatase inhibitor, siRNA therapeutic , γ-secretase and/or NOTCH inhibitors, agents that antagonize receptor tyrosine kinases (RTKs), an agent that antagonizes cell cycle checkpoint, and any of the therapeutic agents listed above.

When any variable appears in any component more than once, its definition in each case is independent of all other cases. In addition, combinations of substituents and variables are permitted only if such combinations result in stable compounds. Lines drawn in ring systems from substituents indicate that the indicated bond can be attached to any of the substituted ring atoms. If the ring system is bicyclic, the bond is expected to be attached to any of the suitable atoms on any ring of the bicyclic moiety.

It will be understood that those of ordinary skill in the art can select substituents and substitution patterns in the compounds of the present invention to provide compounds that are chemically stable and that can be easily synthesized by methods known in the art, as well as those described below, from readily available starting materials. If the substituent itself is substituted by more than one group, it is understood that the multiple groups may be on the same carbon atom or on different carbon atoms, as long as a stable structure is obtained. Also, “optionally substituted” means optional substitution with specified groups, radicals or moieties.

The present invention includes compounds of structural formula I, Ia, Ib, Ic or Id, as well as pharmaceutically acceptable salts, as well as salts that are not pharmaceutically acceptable when used as precursors of the free compounds or their pharmaceutically acceptable salts or in other synthetic manipulations .

The compounds of the present invention can be administered in the form of a pharmaceutically acceptable salt. The term “pharmaceutically acceptable salt” refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic or organic bases and inorganic or organic acids. Salts of the basic compounds encompassed by the term “pharmaceutically acceptable salt” refer to non-toxic salts of the compounds of the invention, which are typically prepared by reacting the free base with a suitable organic or inorganic acid. Representative salts of the alkali compounds of the present invention include, but are not limited to, the following: acetate, ascorbate, adipate, alginate, aspirate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, 4-bromobenzenesulfonate, butyrate, camphorate, camphorsulfonate, camsilate, carbonate, chloride, clavulanate, citrate, cyclohexyl amidosulfonate, cyclopentane propionate, diethyl acetate, digluconate, dihydrochloride, dodecyl sulfonate, edetate, edisilate, estolate, esilate, ethanesulfonate, formate, fumarate, gluceptate, glucoheptanoate, gluconate, glucuonate, glutamate, glycerophosphate, glycollylarsanilate, hemisulfate, heptanoate, hexanoate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, 2-hydroxyethanesulfonate, hydroxynaphthoate, iodide, isonicotinate, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, methyl sulfo nat, mucinate, 2-naphthalene sulfonate, napsylate, nicotinate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, pectinate, persulfate, phosphate/diphosphate, pimelic acid salt, phenylpropylpropionate, polygalacturonate, propionate, salicylate, stearate , sulfate, subacetate, succinate, tannate, tartrate, theoclate, thiocyanate, tosylate, triethiodide, trifluoroacetate, trifluoromethylsulfonate, p-toluenesulfonate, undeconate, valerate, etc.

In addition, if the compounds of the present invention carry an acid moiety, suitable pharmaceutically acceptable salts thereof include, but are not limited to, salts derived from inorganic bases including aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganese , manganese, potassium, sodium, zinc, etc. Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium salts.

With basic reactants such as hydroxides, carbonates, bicarbonates, alkoxides and ammonia, organic bases, or alternatively basic amino acids, compounds of formula I, Ia, Ib, Ic or Id form stable alkali metal, alkaline earth metal or optionally substituted ammonium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, cyclic amines, dicyclohexylamines and basic ion exchange resins such as arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethanolamine, diethylamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, ornithine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine , triethanolamine, triethylamine, trimethylamine, tripropylamine, trometamol, tromethamine, etc. Also included are basic nitrogen-containing groups which can be quaternized with agents such as lower alkyl halides such as methyl, ethyl, propyl and butyl chloride, bromides and iodides; dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides such as benzyl and phenethyl bromides, and others.

The preparation of pharmacologically acceptable salts from compounds of formula I, Ia, Ib, Ic or Id capable of forming salts, including their stereoisomeric forms, is carried out by known methods, for example, by mixing a compound of the present invention with an equivalent amount and a solution containing the desired acid, base or the like, and then collecting the desired salt by filtering the salt or distilling off the solvent. The compounds of the present invention and their salts can form solvates with a solvent such as water, ethanol or glycerol. The compounds of the present invention can form an acid addition salt and a base salt simultaneously depending on the type of side chain substituent.

The present invention covers all stereoisomeric forms of the compounds of formula I, Ia, Ib, Ic or Id. The centers of asymmetry that are present in compounds of formula I, Ia, Ib, Ic or Id can all independently have an (R) configuration or an (S) configuration. When bonds to a chiral carbon are depicted as straight lines in the structural formulas, it should be understood that both configurations (R) and (S) of the chiral carbon, and therefore both enantiomers and mixtures thereof, are covered by the formulas. Likewise, when the name of a compound is given without the chiral designation of the chiral carbon, it is understood that both the (R) and (S) configurations of the chiral carbon, and therefore the individual enantiomers and mixtures thereof, are covered by that name. The preparation of specific stereoisomers or mixtures thereof may be indicated in the examples in which such stereoisomers or mixtures were prepared, but this does not in any way limit the inclusion of all stereoisomers and mixtures thereof within the scope of the invention.

The invention includes all possible enantiomers and diastereomers and mixtures of two or more stereoisomers, for example mixtures of enantiomers and/or diastereomers, in all proportions. Thus, the enantiomers are the subject of the invention in enantiomerically pure form, both levorotatory and dextrorotatory antipodes, in the form of racemates and in the form of mixtures of the two enantiomers in all proportions. In the case of cis/trans isomerism, the invention includes both the cis form and the trans form, as well as mixtures of these forms in all proportions. If desired, the preparation of individual stereoisomers can be accomplished by separating the mixture by conventional methods, such as chromatography or crystallization, using stereochemically homogeneous starting materials for the synthesis, or by stereoselective synthesis. Optionally, derivatization can be performed before stereoisomer separation. Separation of a mixture of stereoisomers can be carried out at an intermediate step during the synthesis of a compound of formula I, Ia, Ib, Ic or Id, or it can be carried out on the final racemic product. Absolute stereochemistry can be determined by x-ray crystallography of crystalline products or crystalline intermediates, which are optionally derivatized using a reagent containing a stereogenic center of known configuration. When the compounds of the invention are capable of tautomerization, all individual tautomers, as well as mixtures thereof, are included within the scope of the invention. The present invention includes all such isomers, as well as salts, solvates (including hydrates) and solvated salts of such racemates, enantiomers, diastereomers and tautomers, and mixtures thereof.

In the compounds of the invention, the atoms may exhibit their natural isotopic abundance, or one or more atoms may be artificially enriched in a particular isotope having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present invention is intended to include all suitable isotopic variants specifically and generally of the compounds described. For example, the different isotopic forms of hydrogen (H) include protium ( ^1H ) and deuterium ( ^2H ). Protium is the predominant isotope of hydrogen found in nature. Deuterium enrichment may provide certain therapeutic benefits, such as increased in vivo half-life or reduced dosage requirements, or may provide a compound used as a standard for characterizing biological samples. Isotopically enriched compounds can be prepared without undue experimentation by conventional methods well known to those skilled in the art, or by methods similar to those described in the General Preparation Schemes and Examples presented herein, using appropriate isotopically enriched reagents and/ or intermediate compounds.

In addition, the compounds of the present invention may exist in amorphous form and/or in one or more crystalline forms, and thus all amorphous and crystalline forms and mixtures thereof of compounds of formula I, Ia, Ib, Ic or Id are intended to be included within the scope of the present invention. In addition, some of the compounds of the present invention can form solvates with water (ie, hydrate) or common organic solvents. Such solvates and hydrates, especially pharmaceutically acceptable solvates and hydrates of the compounds of the present invention, are also included within the scope of the invention, along with unsolvated and anhydrous forms.

The present invention includes compounds of structural formula I, Ia, Ib, Ic or Id or any other general structural formula or the specific compound described or claimed herein and is intended to cover the specific compound or compounds falling within the scope of the claim or embodiment.

The present invention includes compounds of structural formula I, Ia, Ib, Ic or Id, as well as salts thereof, especially pharmaceutically acceptable salts, solvates of such compounds and solvated salt forms thereof, where such forms are possible unless otherwise indicated.

Except as specified herein, the term “alkyl” is intended to include saturated aliphatic hydrocarbon groups, both branched and straight chain, having a specified number of carbon atoms. The description uses commonly used abbreviations for alkyl groups, for example methyl may be represented by common abbreviations including "Me" or CH ₃ , or by a symbol that represents an extended bond as an end group, e.g. , ethyl can be represented as “Et” or CH ₂ CH ₃ , propyl can be represented as “Pr” or CH ₂ CH ₂ CH ₃ , butyl can be represented as “Bu” or CH ₂ CH ₂ CH ₂ CH ₃ , and etc. “C _1-4 alkyl” (or “C ₁ -C ₄ alkyl”), for example, means straight or branched chain alkyl groups, including all isomers having the specified number of carbon atoms. For example, structures

have equivalent meanings. C _1-4 alkyl includes n-, iso-, sec- and tert-butyl, n- and isopropyl, ethyl and methyl. If the number is not specified, 1-4 carbon atoms are assumed for linear or branched alkyl groups.

“CCH” refers to the carbon atom linked by a triple bond to CH.

Also in the case where a carboxylic acid group (-COOH) or an alcohol group is present in the compounds of the present invention, pharmaceutically acceptable esters of carboxylic acid derivatives such as methyl, ethyl or pivaloyloxymethyl, or acyl alcohol derivatives such as O-acetyl may be used. O-pivaloyl, O-benzoyl and O-aminoacyl. Included are such esters and acyl groups as are known in the art to modify solubility or hydrolysis characteristics for use as sustained release or prodrug compositions.

Celite® Diatomaceous Earth (Fluka) is diatomaceous earth and may be called "celite".

"Cycloalkyl" refers to a non-aromatic ring system containing from about 3 to about 5 ring carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl.

"Heterocycle" refers to a saturated, partially unsaturated or aromatic ring moiety having at least one ring heteroatom and at least one ring carbon atom. In one embodiment, the heteroatom is oxygen, sulfur or nitrogen. A heterocycle containing more than one heteroatom may contain different heteroatoms. Heterocyclyl moieties include both monocyclic and polycyclic (eg, bicyclic) ring moieties. Bicyclic ring moieties include fused, spirocyclic and bridged bicyclic rings and may include one or more heteroatoms on any of the rings. The ring attached to the rest of the molecule may or may not contain a heteroatom. Any ring of a bicyclic heterocycle may be saturated, partially unsaturated, or aromatic. The heterocycle can be attached to the rest of the molecule through a ring carbon atom, a ring oxygen atom, or a ring nitrogen atom. Non-limiting examples of heterocycles are described below.

"Heterocycloalkyl" refers to a stable cyclic group containing carbon atoms and 1 to 3 heteroatoms independently selected from S, N or O. The term "heterocycloalkyl" is intended to include both substituted and unsubstituted heterocycloalkyl groups. Heterocycloalkyl groups may be substituted with 1-4 groups such as halogen, CH ₃ , CF ₃ or CF ₂ H. The term "heterocycloalkyl" covers 5-membered rings having one carbon-carbon double bond or one carbon-nitrogen double bond in the ring (eg 2-pyrrolinyl, 3-pyrrolinyl, etc.).

"Aryl" refers to an aromatic monocyclic or polycyclic ring moiety containing from 6 to 14 ring carbon atoms, or more specifically, from 6 to 10 ring carbon atoms. Monocyclic aryl rings include, but are not limited to, phenyl and naphthyl. Multicyclic rings include, but are not limited to, naphthyl and bicyclic rings where the phenyl is fused to a C _5-7 cycloalkyl or C _5-7 cycloalkenyl ring. Aryl groups may optionally be substituted with one or more substituents as defined herein. Bonding can occur through any of the carbon atoms of any ring.

"Heteroaryl" refers to an aromatic monocyclic or polycyclic ring moiety comprising ring carbon atoms and 1-4 ring heteroatoms present in an aromatic ring system, where each heteroatom is independently selected from S, N or O. Heteroaryl bicyclic ring systems may include one or more heteroatoms in one or both rings.

In some embodiments, the heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms present in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 -membered heteroaryl"). In some embodiments, the heteroaryl group is a 5-8 membered aromatic ring system containing ring carbon atoms and 1-4 ring heteroatoms present in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 -membered heteroaryl"). In some embodiments, the heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms present in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 -membered heteroaryl"). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, each heteroaryl group is independently optionally substituted, such as unsubstituted ("unsubstituted heteroaryl") or substituted ("substituted heteroaryl") with one or more substituents. In some embodiments, the heteroaryl group is an unsubstituted 5-14 membered heteroaryl. In some embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl.

Examples of 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl and thiophenyl. Examples of 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl and isothiazolyl. Examples of 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Examples of 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Examples of 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Examples of 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl and pyrazinyl. Examples of 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Examples of 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Examples of 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl and purinyl. Examples of 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

“Optionally substituted” refers to “unsubstituted or substituted” and, therefore, the general structural formulas described herein cover compounds containing the specified optional substituent(s) as well as compounds that do not contain the optional substituent(s). Each substituent is defined independently each time it appears in the definitions of the overall structural formula.

The term "substituted" means that one or more hydrogen atoms of the designated atoms are replaced by a selection from a specified group, provided that the normal valences of the atoms under existing conditions are not exceeded and that the substitution results in a stable compound. Combinations of substituents and/or variables are permitted only if such combinations result in stable compounds.

If the compounds of formula I, Ia, Ib, Ic or Id simultaneously contain acidic and basic groups in the molecule, the invention also includes, in addition to the salt forms indicated, internal salts or betaines (zwitterions). Salts can be prepared from compounds of formula I, Ia, Ib, Ic or Id by conventional methods known to one skilled in the art, for example by combination with an organic or inorganic acid or base in a solvent or dispersant medium, or by anion or cation exchange from other salts. The present invention also includes all salts of compounds of formula I, Ia, Ib, Ic or Id which, due to their low physiological compatibility, are not directly suitable for use in pharmaceutical preparations, but can be used, for example, as intermediates for chemical reactions or for the preparation physiologically acceptable salts.

The invention also includes derivatives of compounds of formula I, Ia, Ib, Ic or Id, acting as prodrugs and solvates. Any pharmaceutically acceptable modification of a prodrug of a compound of the invention that results in conversion in vivo to a compound within the scope of the invention is also within the scope of the invention. Prodrugs, after administration to a patient, are converted in the body by normal metabolic or chemical processes, such as hydrolysis in the blood, into a compound of formula I, Ia, Ib, Ic or Id. Such prodrugs include prodrugs that exhibit increased bioavailability, tissue specificity and/or cellular delivery to improve drug absorption of a compound of formula I, Ia, Ib, Ic or Id. The effect of such prodrugs may result from modification of physicochemical properties such as lipophilicity, molecular weight, charge and other physicochemical properties that determine drug permeability. For example, esters may optionally be prepared by esterifying an accessible carboxylic acid group or by forming an ester on an accessible hydroxy group in a compound. Labile amides can be prepared in a similar manner. Pharmaceutically acceptable esters or amides of the compounds of the present invention can be prepared to act as prodrugs that can be hydrolyzed back to an acid (or -COO ^- depending on the pH of the fluid or tissue where the conversion occurs) or hydroxyl form, particularly in vivo, and as such are included within the scope of the invention. Examples of pharmaceutically acceptable prodrug modifications include, but are not limited to, -C _1-6 alkyl ethers and -C _1-6 alkyl substituted phenyl ethers.

When any variable appears more than once in any component or formula I, its definition in each occurrence is independent of its definition in each other occurrence. In addition, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

Unless otherwise specified, the term "halogen" means fluorine, chlorine, bromine or iodine.

Where the ring atoms are represented by variables such as “X”, e.g.

variables are defined by specifying the atom located at the variable position of the ring, without depicting the ring bonds associated with that atom. For example, when X in the above ring is nitrogen, the definition will show "N" and will not show the bonds associated with it, for example, will not show "=N-". Likewise, when X is a carbon atom substituted with bromide, the definition will show "C-Br" and will not show the bonds associated with it, e.g.

.

The invention also includes derivatives of compounds of formula I, Ia, Ib, Ic or Id, acting as prodrugs and solvates. Prodrugs, after administration to a patient, are converted in the body by normal metabolic or chemical processes, such as hydrolysis in the blood, into a compound of formula I, Ia, Ib or Ic. Such prodrugs include prodrugs that exhibit increased bioavailability, tissue specificity and/or cellular delivery to improve drug absorption of a compound of formula I, Ia, Ib or Ic. The effect of such prodrugs may result from modification of physicochemical properties such as lipophilicity, molecular weight, charge and other physicochemical properties that determine drug permeability.

The invention also relates to medicinal products containing at least one compound of formula I, Ia, Ib, Ic or Id and/or a pharmaceutically acceptable salt of a compound of formula I, Ia, Ib, Ic or Id and/or optionally a stereoisomeric form of a compound of formula I, Ia, Ib, Ic or Id, or a pharmaceutically acceptable salt of a stereoisomeric form of a compound of formula I, Ia, Ib, Ic or Id, together with a pharmaceutically acceptable carrier, additive and/or other active and auxiliary substances.

The drugs of the invention can be administered by oral, inhalation, rectal or transdermal routes or by subcutaneous, intra-arterial, intraperitoneal or intravenous injection. Oral administration is preferred. It is possible to use compounds of formula I, Ia, Ib, Ic or Id to coat stents and other surfaces in contact with blood in the body.

The invention also relates to a method for producing a medicinal product, which includes preparing a suitable form for administration comprising at least one compound of formula I, Ia, Ib, Ic or Id, using a pharmaceutically acceptable carrier and, optionally, other suitable active substances, additives or excipients.

Suitable solid or galenic dosage forms are, for example, granules, powders, coated tablets, tablets, (micro)capsules, suppositories, syrups, juices, suspensions, emulsions, drops or injections and sustained-release preparations for the preparation of which uses conventional excipients such as carriers, disintegrants, binders, coating agents, swelling agents, glidants or lubricants, flavorings, sweeteners and solubilizers. Commonly used excipients that may be listed include magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, lactose, gelatin, starch, cellulose and its derivatives, animal and vegetable oils such as cod liver oil, sunflower, peanut or sesame oil, polyethylene glycol and solvents such as, for example, sterile water and mono- or polyhydric alcohols such as glycerin.

The dosage regimen using the compounds is selected according to a variety of factors, including the type, species, age, body weight, sex and health status of the patient; the severity of the condition being treated; method of administration; the patient's kidney and liver function; and the particular compound or salt thereof used. A normally trained physician or veterinarian can easily determine and prescribe the effective amount of drug needed to prevent, counteract, or stop the progression of the disease.

Oral dosages of the compounds, when used for the indicated effects, will range from about 0.01 mg per kg body weight per day (mg/kg/day) to about 30 mg/kg/day, preferably 0.025-7.5 mg/kg /day, more preferably 0.1-2.5 mg/kg/day and most preferably 0.1-0.5 mg/kg/day (unless otherwise stated, amounts of active ingredients are based on the free base). For example, a patient weighing 80 kg should receive between about 0.8 mg/day and 2.4 g/day, preferably 2-600 mg/day, more preferably 8-200 mg/day, and most preferably 8-40 mg/day. kg/day. A suitably prepared drug for once daily administration will therefore contain between 0.8 mg and 2.4 g, preferably between 2 mg and 600 mg, more preferably between 8 mg and 200 mg and most preferably 8 mg and 40 mg, for example, 8 mg, 10 mg, 20 mg and 40 mg. Preferably, the compounds may be administered in divided doses two, three or four times daily. For twice daily administration, the suitably prepared drug will contain between 0.4 mg and 4 g, preferably between 1 mg and 300 mg, more preferably between 4 mg and 100 mg and most preferably 4 mg and 20 mg, e.g. mg, 5 mg, 10 mg and 20 mg.

When administered intravenously, the patient will receive the active ingredient in quantities sufficient to deliver from about 0.01 mg/kg body weight per day (mg/kg/day) to about 30 mg/kg/day, preferably 0.025-7.5 mg/day. kg/day, more preferably 0.1-2.5 mg/kg/day and even more preferably 0.1-0.5 mg/kg/day. Such amounts can be administered in a variety of suitable ways, for example large volumes of low concentrations of the active ingredient over one extended period of time or several times a day, low volumes of high concentrations of the active ingredient over a short period of time, for example once a day. Typically, a conventional composition for intravenous administration can be prepared which contains a concentration of the active ingredient of about 0.01 to 1.0 mg/ml, for example 0.1 mg/ml, 0.3 mg/ml and 0.6 mg/ml , and which is administered in amounts per day from 0.01 ml/kg of the patient's body weight to 10.0 ml/kg of the patient's body weight, for example 0.1 ml/kg, 0.2 ml/kg, 0.5 ml/kg . In one example, a patient weighing 80 kg receiving 8 mL twice daily of an intravenous formulation having an active ingredient concentration of 0.5 mg/mL receives 8 mg of active ingredient per day. Buffers may be glucuronic acid, L-lactic acid, acetic acid, citric acid, or any pharmaceutically acceptable acid/conjugate base with reasonable buffering capacity in the pH range suitable for intravenous administration. The selection of the appropriate buffer and pH of the composition depending on the solubility of the administered drug can easily be made by one skilled in the art.

The compounds of the present invention can be prepared using reactions as shown in the following reaction schemes, in addition to other standard manipulations that are known from the literature or illustrated in experimental procedures. Therefore, the illustrative reaction schemes below are not limited to the compounds listed or to any particular substituents used for illustrative purposes. The numbering of substituents shown in reaction schemes does not necessarily correlate with the numbering used in the claims, and often for clarity a single substituent is shown attached to a compound where multiple substituents are not necessarily allowed as defined in formulas I, Ia, Ib, Ic or Id which are given above.

Methods for preparing the compounds of the present invention

General methods

The compounds of the present invention can be easily prepared from known compounds or commercially available compounds, for example, by known methods described in published documents, and prepared by the production methods described below. The present invention is not limited to the production methods described below. The invention also includes methods for preparing the compounds of the invention.

It should be noted that when a compound of structural formula I, Ia, Ib, Ic or Id has a reactive group such as a hydroxyl group, amino group, carboxyl group or thiol group as a substituent, such group can be adequately protected by a protecting group at each step reaction, and the protecting group can be removed at an appropriate stage. The procedure for such introduction and removal of the protecting group can suitably be determined depending on the group to be protected and the type of protecting group, and such introduction and removal is carried out, for example, using the procedures described in the review section of Greene, T.W., et. al., “Protective Groups in Organic Synthesis", 2007, 4th Ed., Wiley, New York, or Kocienski, P., "Protecting Groups” 1994, Thieme.

It should be noted that if there is a discrepancy between the chemical name and the structure, the structure takes precedence.

The scope of the present invention is not limited to the specific embodiments disclosed in the examples, which are intended to illustrate certain aspects of the invention, and any embodiments that are functionally equivalent are within the scope of this invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the relevant art and are intended to come within the scope of the appended claims.

All solvents used were commercially available and were used without further purification. Reactions were typically carried out using anhydrous solvents under an inert nitrogen atmosphere.

The starting materials used were either available from commercial sources or prepared according to procedures described in the literature and had experimental data as stated.

The abbreviations used are traditional in the art and are as follows .

ACN acetonitrile AcOH acetic acid ADDP 1,1’-(azodicarbonyl)dipiperidine AIBN α,α’-azoisobutyronitrile Ar aryl Atm. atmosphere Vodn. water 9-BBN 9-borabicyclo(3.3.1)nonane BBN borabicyclo(3.3.1)nonane BnBr benzyl bromide BOC butyloxycarbonyl B.S.A. bovine serum albumin Bz benzoyl ºC degrees Celsius conc. concentration CDCl ₃ deuterated chloroform CD ₃ OD deuterated methanol CO carbon monoxide _{Cs2CO3 _} cesium carbonate CuBrMe _2S copper bromide dimethyl sulfide DAST diethylaminosulfur trifluoride DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCA dichloroacetic acid DCE 1,2-dichloroethane DCM dichloromethane DDQ 2,3-dichloro-5,6-dicyano- p -benzoquinone DIAD diisopropyl azodicarboxylate DIEA N,N-diisopropylethylamine DEAD di-tert-butyl azodicarboxylate DMAP 4-(dimethylamino)pyridine DMF N,N-dimethylformamide DMSO dimethyl sulfoxide DMP Dess-Martin periodinan DMTr 4,4'-dimethoxytrityl dppf 1,1’-bis(diphenylphosphino)ferrocene DTT dithiothreitol Eq. equivalent (molar) EDC N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide EtOAc ethyl acetate EtOH ethanol G gram h hour(hours) HATU N -[(dimethylamino)-1 H -1,2,3-triazolo-[4,5- b ]pyridin-1-ylmethylene]- N -methylmethanaminium hexafluorophosphate N -oxide HCl hydrochloric acid HMPA hexamethylphosphoramide HPLC high performance liquid chromatography IBX 2-iodoxybenzoic acid Im imidazole LCMS liquid chromatography and mass spectrometry LiHMDS lithium bis(trimethylsilyl)amide M molar m-CPBA meta-chloroperoxybenzoic acid MeCN acetonitrile MeOH methanol MePPh ₃ Br methyltriphenylphosphonium bromide MS mass spectrometry MTBE methyl tert- butyl ether mmol millimoles mg milligram min minutes ml milliliter(milliliters) N normal NaBH ₄ sodium borohydride NaH sodium hydride _NaHCO3 bicarbonate of soda NaOH sodium hydroxide _{Na2SO4 _} sodium sulfate NH ₄ HCO ₃ ammonium bicarbonate _NH4Cl ammonium chloride nM nanomolar NMO N -methylmorpholine- N -oxide NMP N -methyl-2-pyrrolidone NMR nuclear magnetic resonance OTIPS triisopropylsilyl ether P(n-Bu) ₃ triphenylphosphine PDC pyridinium dichromate _PdCl2 (dppf) [1,1-bis(diphenylphosphine)ferrocene]dichloropalladium(II) Pd(PPh ₃ ) ₄ tetrakis(triphenylphosphine)palladium(0) Ph phenyl Ph ₃ P/PPh3 triphenylphosphine PMP p-methoxybenzyl POCl ₃ phosphorus(V) oxychloride Pol polymer-linked psi ² psi pTsOH p -toluenesulfonic acid py pyridine rt room temperature Rh(nbd) ₂ BF ₄ bis(norbornadiene)rhodium(I) tetrafluoroborate RuPhos Pd G3 (2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate sat. saturated SFH supercritical fluid chromatography S.M. starting material _SOCl2 thionyl chloride t-BuOK potassium tert-butoxide TBAF tetrabutylammonium fluoride TBAI tetrabutylammonium iodide TBDPS tert- butyldiphenylsilyl TBDPSO tert- butyldiphenylsilyl ether TBDPSCl tert- butyl(chloro)diphenylsilane TBHP tert-butyl hydroperoxide TEA triethylamine Tf triphlil T.F.A. trifluoroacetic acid THF tetrahydrofuran TIPS triisopropylsilyl TIPSOTf triisopropylsilyl trifluoromethanesulfonate TLC thin layer chromatography TMS trimethylsilyl TMSOTf trimethylsilyl trifluoromethanesulfonate TsCl toluenesulfonyl chloride TsOH p-toluenesulfonic acid Prep-TLC preparative TLC µl microliter Xantphos Pd G3 methanesulfonato[4,5-bis(diphenylphosphino)-9,9-dimethylxanthene](2'-amino-1,1'-biphenyl-2-yl)palladium(II) about. volume

General synthesis schemes

Although the present invention has been described in connection with the specific examples set forth above, many alternatives, modifications and variations thereof will be apparent to those skilled in the art. In some cases, the order of steps in reaction schemes may be varied to facilitate a reaction, or to avoid unwanted reaction products. All such alternatives, modifications and variations are intended to be within the spirit and scope of the present invention. The starting materials and intermediates are obtained from commercial sources, prepared by known methods, or otherwise illustrated.

Unless otherwise specified, all variables have the meaning defined above. In all general schemes, Ar means aryl or heteroaryl.

Scheme 1 :

As shown in Scheme 1, suitable ArOH in the presence of PPh ₃ and DIAD was reacted with the compound of formula 1 , followed by deprotection using TFA, giving the compound of formula 2 .

Scheme 2 :

As shown in Scheme 2, the leaving group on the nucleobase was replaced using an ammonia source to give the compound of formula 4 .

Scheme 3 :

Scheme 3 describes a three-step sequence for selective protection of the nucleobase and the 2′-alcohol, resulting in the 3′-alcohol 8 . The 3'-alcohol was then oxidized followed by selective deprotection of the 5'-alcohol to produce ketone 10 . TMS acetylene was added to ketone 10 followed by the Mitsunobu reaction with an appropriately substituted aromatic or heteroaromatic alcohol to give ester 14 . Deprotection in steps 8 and 9 provided the compound of formula 16 .

Scheme 4 :

Scheme 4 shows the preparation of 3,4-disubstituted methyl ribose by first converting the alcohol17to iodide18, followed by restoration to obtain a connection19. DDQ-mediated removal of naphthyl followed by oxidation of the resulting alcohol yielded the ketone21. Ketone processing21 methyllithium gave a tertiary alcohol22,which was treated with p-toluenesulfonic acid to produce triol23. After epoxide formationin situ by treatment with tributylphosphine and ADDP, the appropriately substituted nucleobase was added under alkaline conditions to produce a diol25. Diol25 then protected with 2,2-dimethoxypropane followed by deprotection of the silyl protecting group by treatment with TBAF to give the alcohol27. Alcohol27oxidized to aldehyde28 followed by olefination to produce olefin29.Treatment with an ammonia source gave compoundthirty.Finally, formation of the alkyl boronate and then the Suzuki coupling reaction gave the compound of formula32.

Scheme 5 :

As shown in Scheme 5, after the formation of acetonide in the presence of 2,2-dimethoxypropane and p-toluenesulfonic acid followed by the formation of tosylate under alkaline conditions, yielding tosylate37. Substitution of the tosylate with an appropriately substituted aryl or heteroaryl alcohol gave the ester38,which was subjected to a deprotection procedure under acidic conditions to produce a triol39. After epoxide formationin situ by treatment with tributylphosphine and ADDP, an appropriately substituted nucleobase (Base) is added under alkaline conditions to give a compound of formula41.

Scheme 6 :

As shown in diagram 6, alcohol42oxidized to ketone43, olefination, formation of an alkyl boronate followed by palladium-catalyzed coupling with an appropriately substituted aryl or heteroaryl iodide gave the compound46. Acid-mediated deprotection, formation of the epoxide in situ and then addition of an appropriately substituted nucleobase (Base) under alkaline conditions gave a compound of formula49.

Scheme 7:

As shown in Scheme 7, the formation of acetonide and silyl ether gave alcohol 52 . Following oxidation and addition of methylmagnesium bromide, acid-mediated acetonide deprotection and acetate formation were performed in a single reaction vessel to yield compound 55 . Lewis acid-catalyzed addition of an appropriately substituted nucleobase afforded compound 56 . Reduction of the iodide followed by deprotection of the silyl group gave compound 58 . Activation of the alcohol as a tosylate leaving group followed by substitution with an appropriately substituted aryl or heteroaryl alcohol provided the compound of formula 60 .

Scheme 8:

As shown in Scheme 8, one of the ketals in compound 61 was selectively deprotected and then converted to olefin 63 . Formation of the alkyl boronate, palladium-catalyzed coupling with an appropriately substituted aryl or heteroaryl iodide, removal of the remaining ketal protecting group, followed by addition of an appropriately substituted nucleobase afforded the compound of formula 66 .

Scheme 9:

Compounds of formulas 68 and 69 can be prepared in the following sequence (Scheme 9). Compound 68 is prepared from 67 by aminolysis using ammonia, and compound 69 is prepared from 67 by aminolysis using methylamine.

Scheme 10 :

Compounds of formula 75 can be prepared in the following sequence (Scheme 10). Triflate 71 is first prepared, followed by aromatic amine substitution to give compound 72 . Displacement of chloride with ammonia, formation of an alkyl boronate, palladium-catalyzed cross-coupling, and eventual acid deprotection yielded compound 75 .

Diagram 11:

Compounds of formula 88 can be prepared in the following sequence shown in Scheme 11. Alcohol 76 is oxidized to aldehyde 77 by treatment with Dess-Martin periodinane, followed by treatment with vinyl magnesium bromide to yield allylic alcohol 78 . Alcohol 78 is treated with triphenylsilyl chloride , followed by a cobalt-catalyzed Pauson-Hand reaction to form bicyclic enone 80. Enone 80 is reduced with sodium borohydride and treated with acetic anhydride to give allyl acetate 82 . Allyl acetate 82 is subjected to palladium-catalyzed allylic alkylation conditions in the presence of an appropriately substituted nucleobase (Base) to give compound 83 . The resulting olefin is subjected to dihydroxylation using osmium tetroxide to give 84 . After deprotection of the silyl ether and formation of the acetonide, oxidation with Dess-Martin periodinane and olefination are carried out to obtain the exocyclic olefin 86 . Formation of an alkyl boronate followed by palladium-catalyzed cross-coupling with an aryl or heteroaryl halide gave compound 87 . Deprotection of the acetonide with acid gave compound 88 .

Scheme 12:

Compounds of formula 97 can be prepared in the following sequence shown in Scheme 12. Allyl acetate 82 was subjected to palladium-catalyzed allylic alkylation conditions in the presence of an appropriately substituted nucleobase ( 89 ) to give compound 90 . The resulting olefin was dihydroxylated using osmium tetroxide to give 91 . After deprotection of the silyl ether and formation of the acetonide, oxidation with Dess-Martin periodinane and olefination were carried out to obtain the exocyclic olefin 94 . Formation of an alkyl boronate followed by palladium-catalyzed cross-coupling with an aryl or heteroaryl bromide gave compound 95 . Substitution of ammonia for the chloride followed by deprotection of the acetonide with acid gave compound 97 .

Diagram 13:

The compounds of formula 102 can be prepared in the following sequence shown in Scheme 13. The substituted aminonucleobase 99 was subjected to a BOC protection procedure. Compound 98 was subjected to a Mitsunobu reaction to introduce a protected nucleobase ( 100 ) to form compound 101 . Acid-mediated deprotection gave compound 102 .

Diagram 14:

Compounds of formula 115 can be prepared in the following sequence shown in Scheme 14. Quinoline iodide 103 was subjected to Stille reaction conditions to give olefin 104 . Subsequent ozonolysis and addition of Grignard vinyl gave alcohol 106 . Alkylation gave enone 107 , which was subjected to a cobalt-catalyzed Pauson-Hand reaction to give enone 108 . Reduction and formation of carbonate gave carbonate 110 . Palladium-catalyzed allylic alkylation gave bicycle 111 . Dihydroxylation of the olefin and acetonide protection gave ketal 113 . Subsequent replacement of the chloride with ammonia and deprotection with acid gave compound 115 .

Diagram 15:

Compounds of formula 126 can be prepared in the following sequence, shown in Scheme 15. Sugar 116 was oxidized with Dess-Martin periodinane to produce ketone 117 . Addition of Grignard vinyl followed by benzyl protection yielded olefin 119 , which was then ozonolyzed and reduced to produce alcohol 120 . Selective acetonide deprotection yielded triol 121 , which was subjected to oxidative cleavage and cyclization to yield lactol 122 . Wittig homologation yielded olefin 123 , which was then subjected to palladium-catalyzed cyclization/arylation to yield bicycle 124 . Global deprotection with BCl ₃ followed by nucleobase installation gave compound 126 .

Diagram 16:

Compounds of formula 130 can be prepared in the following sequence, shown in Scheme 16. Chromatographic purification of compound 124 gave bicycle 127 . Global deprotection with BCl ₃ followed by nucleobase installation gave compound 129 . Substitution of ammonia for chloride gave compound 130 .

SYNTHESIS OF INTERMEDIATES

Scheme for the synthesis of intermediate 1

Intermediate 1: (( 3aR , 4R , 6R , 6aS )-6-(4-chloro- 7H- pyrrolo[2,3- d ]pyrimidin-7-yl)-2,2,3a- trimethyltetrahydro- 3aH -cyclopenta[ d ][1,3]dioxol-4-yl)methanol

Step 1: To a mixture of ( 1R , 4S )-2-azabicyclo[2.2.1]hept-5-en-3-one (50 g, 458 mmol), di-tert- butyl dicarbonate (120 g, 550 mmol) and N,N -dimethylpyridin-4-amine (5.6 g, 45.8 mmol) in DCM (500 ml) triethylamine (69.5 g, 687 mmol) was added at 25°C. The reaction mixture was stirred for 2 hours at 25°C. The reaction was quenched with saturated aqueous NaHCO ₃ (1500 ml) and extracted with EtOAc (2000 ml x 3). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with 0-20% ethyl acetate in petroleum ether to give ( 1R , 4S ) -tert- butyl-3-oxo-2-azabicyclo[2.2.1]hept-5-ene-2 -carboxylate. MS: 154 (M-55).

Step 2: To a solution of ( 1R , 4S ) -tert- butyl 3-oxo-2-azabicyclo[2.2.1]hept-5-ene-2-carboxylate (40 g, 191 mmol) in THF (400 ml) Add phenylhypobromoselenoite (49.6 g, 210 mmol) to THF (1.0 L) dropwise at -78°C under argon. The mixture was stirred for 2 hours at -78°C and then the temperature was slowly raised to 25°C. The reaction mixture was stirred at 25°C for 16 hours. The reaction was quenched with saturated aqueous NaHCO ₃ (500 ml) and extracted with DCM (500 ml x 3). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with 1%-20% ethyl acetate in petroleum ether to give ( 1R , 4R ) -tert- butyl 5-bromo-3-oxo-6-(phenylselanyl)-2-azabicyclo[2.2 .1]heptane-2-carboxylate (a mixture of two isomers). MS: 390/392 (M-55/M-53). ^1H NMR (400 MHz, DMSO- d6 ) isomer 1: δ 7.73-7.59 (m, _2H ), 7.44-7.26 (m, 3H), 4.65 (t, J = 4.0 Hz, 1H), 4.38 (s, 1H), 3.55 (t, J =3.4 Hz, 1H), 3.05 (sq, J =1.8 Hz, 1H), 2.29-2.16 (m, 1H), 2.04 (dt, J = 11.1, 1.4 Hz, 1H), 1.31 (s, 9H). isomer 2: δ 7.73-7.59 (m, 2H), 7.44-7.26 (m, 3H), 4.73 (t, J =2.0 Hz, 1H), 4.33 ( dd, J =3.6, 2.0 Hz, 1H), 4.24 (t, J =3.1 Hz, 1H), 3.05 (sq., J =1.8 Hz, 1H), 2 .42 (dq., J = 10.7, 1.9 Hz, 1H), 2.29-2.16 (m, 1H), 1.36 (s, 9H).

Step 3: To a solution of (1 R ,4 R ) -tert- butyl 5-bromo-3-oxo-6-(phenylselanyl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (33 g, 74.1 mmol) to DCM (150 ml) was added 3-chloroperbenzoic acid (20.1 g, 82 mmol) in several portions at -78°C under argon. The resulting mixture was stirred for 2 hours at -78°C. The reaction was quenched with saturated aqueous NaHCO ₃ (100 ml) and extracted with DCM (300 ml x 3). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated under reduced pressure to give the crude product ( 1R , 4R ) -tert- butyl 5-bromo-3-oxo-6-(phenylseleninyl)-2-azabicyclo[2.2.1]heptane-2-carboxylate. MS: 462/464 (M+1/M+3).

Step 4: To a stirred mixture of (1 R ,4 R ) -tert- butyl 5-bromo-3-oxo-6-(phenylseleninyl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (127 g, 274 mmol ) to DCE (1000 ml) was added triethylamine (76 ml, 549 mmol) at 25°C. The resulting mixture was stirred for 6 hours at 80°C. The reaction mixture was cooled to room temperature and quenched with water (500 ml). The organic layers were separated, washed with brine (100 ml x 2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness. The residue was purified by column chromatography on silica gel, eluted with a mixture of 0-10% ethyl acetate in petroleum ether to give ( 1R , 4R ) -tert- butyl 5-bromo-3-oxo-2-azabicyclo[2.2.1]hept-5- ene-2-carboxylate. ¹ H NMR (400 MHz, DMSO- d6 ) δ 7.20 7.20 (d, J =2.6 Hz, 1H), 4.96 (t, J =2.6 Hz, 1H) _, 3, 42 (t, J =2.8 Hz, 1H), 2.40 (t, J =1.8 Hz, 2H), 1.44 (s, 9H).

Step 5 (Method A): To a stirred solution of ( 1R , 4R ) -tert- butyl 5-bromo-3-oxo-2-azabicyclo[2.2.1]hept-5-ene-2-carboxylate (15 g, 52.1 mmol) in toluene (50 ml) was added Pd(PPh ₃ ) ₄ (6.0 g, 5.2 mmol) and tetramethylstannane (28.9 ml, 208 mmol) at 25°C. The mixture was stirred for 6 hours at 100°C in a hermetically sealed tube. The reaction mixture was quenched with saturated NaHCO ₃ solution (200 ml) and extracted with EtOAc (300 ml x 3). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and the filtrate was concentrated to dryness. The residue was purified by silica gel column chromatography, eluted with 0-3% EtOAc in petroleum ether/DCM (v:v, 5/1) to give ( 1R , 4S ) -tert- butyl 5-methyl-3- oxo-2-azabicyclo[2.2.1]hept-5-ene-2-carboxylate. ^1H NMR (300 MHz, DMSO- d6 ) δ 6.51-6.42 (m, 1H) _, 4.78 (p, J = 2.2 Hz, 1H), 3.12 (d, J = 2.8 Hz, 1H), 2.25 (d, J = 8.4 Hz, 1H), 2.12-2.10 (m, 1H), 1.87 (s, 3H), 1.40 ( s, 9H).

Step 5 (Method B): To a stirred solution of ( 1R , 4R ) -tert- butyl 5-bromo-3-oxo-2-azabicyclo[2.2.1]hept-5-ene-2-carboxylate (26 g, 90 mmol) in THF (250 ml), dimethylzinc (1 M in toluene, 180 ml, 180 mmol) was added dropwise and bis( tri-tert -butylphosphine)palladium(0) (0.92 g, 1.8 mmol) at 0°C. The resulting mixture was stirred for 16 hours at 20°C. The reaction was quenched with saturated aqueous NH ₄ Cl (400 ml) and extracted with DCM (500 ml x 2). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-3% EtOAc in petroleum ether and DCM (v/v = 5:1) to give ( 1R , 4S ) -tert- butyl 5-methyl-3- oxo-2-azabicyclo[2.2.1]hept-5-ene-2-carboxylate. ^1H NMR (400 MHz, DMSO- d6 ) δ 6.53-6.47 (m, _1H ), 4.82-4.80 (m, 1H), 3.16-3.14 (m, 1H ), 2.28 (dt, J = 8.4, 1.8 Hz, 1H), 2.12-2.10 (m, 1H), 1.90 (s, 3H), 1.43 (s, 9H).

Stage 6:To solution (1R,4S)-tert-butyl 5-methyl-3-oxo-2-azabicyclo[2.2.1]hept-5-ene-2-carboxylate (5 g, 22.4 mmol) intBuOH (25 ml)/water (25 ml) was added 4-methylmorpholine 4-oxide (5.25 g, 44.8 mmol) at 0°C under argon. Osmium(VIII) oxide (18.5 mL, 22.4 mmol, 4% in aq) was then added dropwise at 0°C. The mixture was stirred for 16 hours at room temperature. The reaction was quenched by adding a saturated aqueous solution of Na₂S₂O₃ (30 ml), then extracted with EtOAc (30 ml x 4). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated dry. The residue was purified by silica gel column chromatography and eluted with 0-70% ethyl acetate in petroleum ether. Fractions containing the desired product were combined and concentrated under reduced pressure to give (1R,4S,5R.6S)-tert-butyl 5,6-dihydroxy-5-methyl-3-oxo-2-azabicyclo[2.2.1]heptane-2-carboxylate.¹H NMR (300 MHz, DMSO-d ₆) δ 5.54 (d,J=5.7 Hz, 1H), 4.96 (s, 1H), 4.04 (s, 1H), 3.49-3.37 (m, 1H), 2.37 (d,J=2.4 Hz, 1H), 2.11 (dd,J=10.5, 1.8 Hz, 1H), 1.98-1.80 (m, 1H), 1.45 (s, 9H), 1.21 (s, 3H).

Step 7: (1 R ,4 S ,5 R ,6 S ) -tert -butyl 5,6-dihydroxy-5-methyl-3-oxo-2-azabicyclo[2.2.1] heptane-2-carboxylate (1 .4 g, 5.4 mmol) was co-evaporated with anhydrous toluene (10 ml x 3) and then redissolved in acetone (10 ml). To this solution was added 4-methylbenzenesulfonic acid (0.094 g, 0.5 mmol), followed by the addition of 2,2-dimethoxypropane (2.83 g, 27.2 mmol) at room temperature. The resulting mixture was stirred at ambient temperature for 1 hour. The mixture was neutralized with saturated aqueous NaHCO ₃ solution to pH 7. The mixture was concentrated to dryness. The crude product was purified by silica gel column chromatography and eluted with 10-50% ethyl acetate in petroleum ether to give (3 aS ,4 R ,7 S ,7 a R ) -tert- butyl 2,2,7a-trimethyl-6-oxotetrahydro-4 ,7-methano[1,3]dioxolo[4,5- c ]pyridine-5( 6H )-carboxylate. ^1H NMR (400 MHz, Chloroform- d ) δ 4.39 (t, J =1.6 Hz, 1H), 4.21 (d, J =1.5 Hz, 1H), 2.71 (sq. , J =1.6 Hz, 1H), 2.23-2.19 (m, 1H), 2.07-2.00 (m, 1H), 1.61 (s, 3H), 1.53 ( s, 9H), 1.49 (s, 3H), 1.48 (s, 3H).

Step 8: To a solution of ( 3aS , 4R , 7S , 7aR ) -tert- butyl 2,2,7a-trimethyl-6-oxotetrahydro-4,7-methano[1,3]dioxolo[4,5- c]pyridine-5( 6H )-carboxylate (2.9 g, 9.8 mmol) in MeOH (58 ml) was added NaBH ₄ (0.74 g, 19.5 mmol) at 0°C. The mixture was stirred for 2 hours at 0°C. The reaction mixture was quenched with saturated aqueous NH ₄ Cl (50 ml) and extracted with ethyl acetate (60 ml x 3). The combined organic layers were concentrated to dryness. The residue was purified by silica gel column chromatography and eluted with 0-40% EtOAc in petroleum ether. The collected fractions were combined and concentrated in vacuo to give tert- butyl (( 3aS , 4R , 6R , 6aR )-6-(hydroxymethyl)-2,2,6a-trimethyltetrahydro- 3aH- cyclopenta[ d ][1 ,3]dioxol-4-yl)carbamate. ^1H NMR (300 MHz, DMSO- d6 ) 7.05 (brs, 1H), 4.49 ₍ t, J =5.0 Hz, 1H), 3.86 (d, J =2.8 Hz, 1H), 3.77-3.74 (m, 1H), 3.55-3.44 (m, 1H), 3.31-3.25 (m, 1H), 2.07-1, 97 (m, 1H), 2.21-2.14 (m, 1H), 1.40 (s, 9H), 1.40-1.39 (m, 1H), 1.38 (s, 3H) , 1.25 (s, 3H), 1.23 (s, 3H).

Step 9: Tert- butyl (( 3aS , 4R , 6R , 6aR )-6-(hydroxymethyl)-2,2,6a - trimethyltetrahydro- 3aH- cyclopenta[ d ][1,3]dioxol- 4-yl)carbamate (3.5 g, 11.6 mmol) was dissolved in HCl (30 ml, 4 M in methanol). The resulting solution was stirred at ambient temperature for 2 hours. The solution was concentrated to give the crude product ( 1R , 2S , 3R , 5R )-3-amino-5-(hydroxymethyl)-1-methylcyclopentane-1,2- hydrochloride diol. ^1H NMR (300 MHz, DMSO- d6 ) δ 8.21 (brs, 3H), 5.21 ( _brs , 1H), 4.60-4.31 (m, 2H), 3, 52 (d, J =9.0 Hz, 1H), 3.44 (dd, J =10.5, 5.1 Hz, 1H), 3.32-3.19 (m, 2H), 2.18 -2.07 (m, 1H), 2.00-1.76 (m, 1H), 1.46-1.36 (m, 1H), 1.10 (s, 3H).

Step 10: To a stirred mixture of ( 1R , 2S , 3R , 5R )-3-amino-5-(hydroxymethyl)-1-methylcyclopentane-1,2-diol hydrochloride (1.85 g, 9.4 mmol ) and 4,6-dichloro-5-(2,2-diethoxyethyl)pyrimidine (2.73 g, 10.3 mmol) to 2-propanol (40 ml) was added N -ethyl- N -isopropylpropan-2-amine ( 2.42 g, 18.7 mmol) at 25°C. The reaction mixture was stirred for 16 hours at 100°C. The reaction mixture was cooled to room temperature and concentrated to dryness. The residue was purified by silica gel column chromatography (0-15% MeOH in DCM) to give ( 1R , 2S , 3R , 5R )-3-((6-chloro-5-(2,2-diethoxyethyl)pyrimidine- 4-yl)amino)-5-(hydroxymethyl)-1-methylcyclopentane-1,2-diol. MS: 390 (M+1). ^1H NMR (400 MHz, DMSO- d6 ) δ 8.15 (s, 1H), _6.79 (d, J =7.5 Hz, 1H), 4.68-4.56 (m, 2H) , 4.50-4.40 (m, 1H), 4.37-4.30 (m, 1H), 4.01 (s, 1H), 3.76-3.58 (m, 2H), 3 .50-3.39 (m, 4H), 3.35-3.25 (m, 1H), 2.92-2.90 (m, 2H), 2.25-2.18 (m, 1H) , 1.94-1.85 (m, 1H), 1.31-1.24 (m, 1H), 1.21-1.02 (m, 9H).

Step 11: To a stirred solution of (1 R ,2 S ,3 R ,5 R )-3-((6-chloro-5-(2,2-diethoxyethyl)pyrimidin-4-yl)amino)-5-(hydroxymethyl )-1-methylcyclopentane-1,2-diol (10 g, 25.6 mmol) in 1,4-dioxane (80 ml) was added dropwise with an aqueous solution of HCl (20 ml, 80 mmol, 4 M in water) at room temperature. The resulting mixture was stirred for 0.5 hours at 50°C. The mixture was then cooled to 0°C in an ice bath and neutralized with saturated aqueous NaHCO ₃ to pH ~ 8-9. The resulting mixture was concentrated to dryness and the residue was purified by silica gel column chromatography, eluting with 0-10% MeOH in DCM to give ( 1R , 2S , 3R , 5R )-3-(4-chloro- 7H -pyrrolo[ 2,3- d ]pyrimidin-7-yl)-5-(hydroxymethyl)-1-methylcyclopentane-1,2-diol. MS: 298 (M+1). ^1H NMR (400 MHz, DMSO- d6 ) δ 8.62 (s, 1H), _7.89 (d, J =3.6 Hz, 1H), 6.71 (d, J =3.6 Hz , 1H), 5.10 (sq., J =9.6 Hz, 1H), 4.86 (d, J =7.2 Hz, 1H), 4.73 (t, J =4.8 Hz, 1H), 4.27 (s, 1H), 4.05 (dd, J =9.6, 7.2 Hz, 1H), 3.54-3.51 (m, 2H), 2.41-2 .33 (m, 1H), 2.05-1.95 (m, 1H), 1.73-1.66 (m, 1H), 1.21 (s, 3H).

Step 12: ( 1R , 2S , 3R , 5R )-3-(4-chloro- 7H -pyrrolo[2,3- d ]pyrimidin-7-yl)-5-(hydroxymethyl)-1- Methylcyclopentane-1,2-diol (2.03 g, 6.8 mmol) was co-evaporated with anhydrous toluene (10 ml x 3) and then redissolved in acetone (20 ml). To this solution was added 4-methylbenzenesulfonic acid (0.12 g, 0.68 mmol) followed by 2,2-dimethoxypropane (3.55 g, 34.1 mmol). The resulting mixture was stirred at 25°C for 1 hour. Then the solution was neutralized with a saturated aqueous solution of NaHCO ₃ to pH ~7-8. The resulting mixture was extracted with EtOAc (30 ml x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with 0-70% ethyl acetate in petroleum ether to give (( 3aR , 4R , 6R , 6aS )-6-(4-chloro- 7H -pyrrolo[2,3- d ]pyrimidin-7-yl)-2,2,3a-trimethyltetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-4-yl)methanol. MS: 338 (M+1). ^1H NMR (400 MHz, DMSO- d6 ) δ 8.67 (s, 1H), _7.94 (d, J =3.6 Hz, 1H), 6.74 (d, J =3.6 Hz , 1H), 5.20-5.10 (m, 1H), 4.56 (t, J =5.2 Hz, 1H), 4.41 (d, J =4.4 Hz, 1H), 3 .64 (dt, J =10.5, 5.2 Hz, 1H), 3.54-3.35 (m, 1H), 2.44-2.26 (m, 2H), 2.28-2 .11 (m, 1H), 1.49 (s, 6H), 1.26 (s, 3H).

Scheme for the synthesis of intermediate 2

Intermediate 2: (3R,3aS,6R,6aR)-2-methoxyhexahydro-3aH-cyclopenta[b]furan-3,3a,6-triol

Stage 1:To a solution of (3aR,5S,6S,6aR)-5-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyltetrahydrofuro[2,3-d][1 ,3]dioxol-6-ol (500 g, 1.92 mol) in MeCN (2.50 L) at 25°C, IBX (807 g, 2.88 mol) was slowly added at 20~25°C. The reaction mixture was stirred at 85~90°C for 3 hours. The mixture was filtered and concentrated. Crude product (3aR,5R,6aS)-5-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyldihydrofuro[2,3-d][1,3 ]dioxol-6(5H)-one was used in the next step without further purification.¹H NMR (400 MHz, CDCl₃) δ: 6.14 (d,J=4.4 Hz, 1H), 4.31-4.45 (m, 3H), 4.00-4.06 (m, 2H), 1.46 (s, 3H), 1.43 (s, 3H), 1.34 (s, 6H).

Step 2: To a solution of (3aR,5R,6aS)-5-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyldihydrofuro[2,3-d][ 1,3]dioxol-6(5H)-one (500 g, 1.94 mol) in anhydrous THF (2.50 L) cooled to 0~5°C, add vinyl magnesium bromide (1 M, 3.87 L) , maintaining the temperature at 0~5°C. The reaction mixture was heated to 15~20°C and stirred for 0.5 hour. The reaction mixture was quenched by pouring the mixture into an aqueous solution of NH ₄ Cl (10 L) at 0~5°C. The aqueous phase was extracted with MTBE (3 L x 3). The combined organic phase was washed with brine (2 L), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica, petroleum ether/ethyl acetate=1/0 to 5/1) to give (3aR,5R,6aR)-5-((R)-2,2-dimethyl-1,3-dioxolane- 4-yl)-2,2-dimethyl-6-vinyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol.

Step 3: To a solution of NaH (105 g, 2.62 mol, 60% dispersion in mineral oil) in DMF (2.75 L) at 15~20°C was added (3aR,5R,6aR)-5-((R )-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyl-6-vinyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol (375 g, 1 .31 mol) in DMF (1 L) dropwise at 15~20°C. The reaction mixture was stirred at 55~60°C for 1 hour, then BnBr (336 g, 1.96 mol, 233 ml) was added. The reaction mixture was stirred at 15~20°C for another 5 hours. The reaction was quenched by pouring the mixture into ice water (1.5 L). The resulting mixture was extracted with ethyl acetate (2 L × 3). The combined organic phase was washed with aqueous NaHCO ₃ (1.5 L), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. Crude product (3aR,5R,6R,6aR)-6-(benzyloxy)-5-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyl-6- vinyltetrahydrofuro[2,3-d][1,3]dioxole was used without further purification.

Stage 4: To a solution of (3aR,5R,6R,6aR)-6-(benzyloxy)-5-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyl-6- vinyltetrahydrofuro[2,3-d][1,3]dioxole (400 g, 1.06 mol) in EtOAc (2 L) at 15~20°C added periodic acid (250 g, 1.09 mol) and the resulting mixture was stirred for 1 hour. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica, petroleum ether/ethyl acetate=20/1 to 0/1) to give (3aR,5S,6R,6aR)-6-(benzyloxy)-2,2-dimethyl-6-vinyltetrahydrofuro[2 ,3-d][1,3]dioxol-5-carbaldehyde.¹H NMR (400 MHz, CDCl₃) δ: 9.58 (s, 1H), 7.26-7.43 (m, 5H), 5.97 (d,J=3.20 Hz, 1H), 5.78-5.76 (m, 1H), 5.38-5.54 (m, 2H), 4.59-4.73 (m, 4H), 1.62 (s, 3H), 1.40 (s, 3H)

Stage 5: To the suspension [Rh(nbd)₂]BF₄ (6.14 g, 16.4 mmol) in DCE (60 ml) at 15~20°C under N atmosphere₂ 1,2-bis(diphenylphosphino)benzene (6.10 g, 13.7 mmol) was added. The suspension was degassed under reduced pressure, purged with H₂ three times and H₂ bubbled through the solution for 0.25 hours. The reaction mixture was again purged with N₂ for 0.25 hour to remove H_2.(3aR,5S,6R,6aR)-6-(benzyloxy)-2,2-dimethyl-6-vinyltetrahydrofuro[2,3-d][1,3]dioxol-5-carbaldehyde (50.0 g, 164 mmol) in DCE (60 ml) was added dropwise to the resulting solution at 15~20°C under N atmosphere₂. The mixture was stirred at 75~80°C for 12 hours. The mixture was filtered and the solvent was removed to give crude (3aR,4aS,7aS,7bR)-7a-(benzyloxy)-2,2-dimethylhexahydro-5H-cyclopenta[4,5]furo[2,3-d][1,3 ]dioxol-5-one.¹H NMR: (400 MHz, CDCl₃) δ: 7.5-7.25 (m, 5H), 5.94 (m, 1H), 4.69 (m, 1H), 4.63-4.57 (m, 2H), 4.18 (s, 1H), 2.40-2.56 (m, 3H), 1.68-1.74 (m, 1H), 1.61 (s, 3H), 1.40 (s, 3H)

Step 6: NaBH ₄ (37.3 g, 986 mmol) was added to a mixture of (3aR,4aS,7aS,7bR)-7a-(benzyloxy)-2,2-dimethylhexahydro-5H-cyclopenta[4,5]furo[2 ,3-d][1,3]dioxol-5-one (150 g, 493 mmol) in MeOH (750 ml) at 0~5°C. The mixture was stirred at 0~5°C for 1 hour. The residue was poured into ice water (250 ml) and the aqueous phase was extracted with ethyl acetate (250 ml x 3). The combined organic phases were washed with brine (125 ml), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica, petroleum ether/ethyl acetate=20/1 to 0/1) to give (3aR,4aR,5R,7aR,7bR)-7a-(benzyloxy)-2,2-dimethylhexahydro-5H-cyclopent [4,5]furo[2,3-d][1,3]dioxol-5-ol. ^1H NMR: (400 MHz, CDCl ₃ ) δ: 7.33-7.40 (m, 5H), 5.88 (d, J= 3.6 Hz, 1H), 4.65 (d, J= 10.8 Hz, 1H), 4.56 (d, J= 3.2 Hz, 1H), 4.45-4.51 (m, 2H), 4.18-4.29 (m, 1H), 2.06-2.26 (m, 3H), 1.66-1.77 (m, 1H), 1.66-1.77 (m, 1H), 1.62 (s, 3H), 1. 41 (s, 3H)

Step 7: To a solution of TsOH (10.8 g, 62.7 mmol) in MeOH (150 ml) at 15~20°C was added 3aR,4aR,5R,7aR,7bR)-7a-(benzyloxy)-2,2 -dimethylhexahydro-5H-cyclopenta[4,5]furo[2,3-d][1,3]dioxol-5-ol (30.0 g, 97.9 mmol). The mixture was stirred at 15~20°C for 12 hours. The reaction mixture was poured into ice water (16 ml) and neutralized with aqueous Na ₂ CO ₃ solution (25 ml). The aqueous phase was extracted with ethyl acetate (100 ml x 4). The combined organic fractions were washed with brine (100 ml), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica, petroleum ether/ethyl acetate=20/1 to 0/1) to give (3R,3aS,6R,6aR)-3a-(benzyloxy)-2-methoxyhexahydro-2H-cyclopenta[b]furan -3,6-diol. ^1H NMR: (400 MHz, CDCl ₃ ) δ: 7.26-7.40 (m, 5H), 4.93-5.03 (m, 1H), 4.52-4.76 (m, 1H ), 4.33-4.45 (m, 1H), 4.00-4.19 (m, 1H), 3.78-3.97 (m, 1H), 3.46 (d, J= 7 .6 Hz, 3H), 2.98-3.04 (m, 1H), 2.20-2.34 (m, 1H), 1.82-2.12 (m, 4H).

Stage 8: Pd(OH)₂/C (1.70 g, 2.42 mmol, 20 wt% load) was added to (3R,3aS,6R,6aR)-3a-(benzyloxy)-2-methoxyhexahydro-2H-cyclopenta[b]furan-3 ,6-diol (17.0 g, 60.7 mmol) in MeOH (150 ml) at 15~20°C under N atmosphere₂ followed by the addition of acetic acid (2.98 g, 49.5 mmol, 2.83 ml). The suspension was degassed under reduced pressure and purged with H₂ repeatedly. The mixture was then stirred under H atmosphere₂ (50 psi²(3.515 kg/cm²)) at 50~55°C for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure to give (3R,3aS,6R,6aR)-2-methoxyhexahydro-3aH-cyclopenta[b]furan-3,3a,6-triol.¹H NMR: (400 MHz, CDCl₃) δ: 5.00 (d,J=4.0 Hz, 1H), 4.94 (d,J=2.0 Hz, 1H), 4.22-4.18 (m, 1H), 4.16-4.13 (m, 2H), 3.76-3.83 (m, 1H), 3.47 (d,J=13.8 Hz, 3H), 2.14-1.96 (m, 2H), 1.81-1.62 (m, 2H).

Scheme for the synthesis of intermediate 3

Intermediate 3: 3-bromo-7-(((3aS,4R,6R,6aR)-6-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2, 4-trimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)-N-(4-methoxybenzyl)quinolin-2-amine

Step 1: To a solution of ((3aS,4R,6R,6aR)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2,4-trimethyltetrahydrofuro[3, 4-d][1,3]dioxol-4-yl)methanol (95.0 mg, 0.280 mmol) in methanol (1.0 ml) was added to LiOMe (106 mg, 2.80 mmol). The reaction mixture was stirred at room temperature for 20 minutes and then diluted with water (10 ml). The resulting mixture was extracted with DCM (10 ml) and the organic layers were dried over Na ₂ SO ₄ . The organic solvent was removed under reduced pressure to give ((3aS,4R,6R,6aR)-6-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2,4-trimethyltetrahydrofuro [3,4-d][1,3]dioxol-4-yl)methanol. The product was used in the next step without further purification. MS: 336 (M+1). 1H NMR (500 MHz, CDCl ₃ ) δ 8.43 (s, 1H), 7.07 (d, J =3.6 Hz, 1H), 6.89 (dd, J =12.1, 1.7 Hz, 1H), 6.51 (d, J =3.6 Hz, 1H), 5.74 (d, J =5.7 Hz, 1H), 5.35 (t, J =5.8 Hz, 1H), 5.01 (d, J =5.9 Hz, 1H), 4.12 (s, 3H), 3.80 (dd, J =12.2, 1.7 Hz, 1H), 3, 63 (t, J =12.2 Hz, 1H), 1.65 (s, 3H), 1.37 (s, 3H), 1.35 (s, 3H).

Step 2: To a solution of ((3aS,4R,6R,6aR)-6-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2,4-trimethyltetrahydrofuro[3, 4-d][1,3]dioxol-4-yl)methanol (94.0 mg, 0.280 mmol), 3-bromo-7-iodo-N-(4-methoxybenzyl)quinolin-2-amine (75.0 mg, 0.160 mmol), copper iodide (3.05 mg, 0.0160 mmol) and 1,10-phenanthroline (5.77 mg, 0.0320 mmol) in dioxane (0.250 ml) was added cesium carbonate (78.0 mg , 0.240 mmol). The resulting mixture was stirred at 110°C for 23 hours. The reaction mixture was directly purified by flash column chromatography (EtOAc in hexanes, 0-25%) to give 3-bromo-7-(((3aS,4R,6R,6aR)-6-(4-methoxy-7H-pyrrolo[2 ,3-d]pyrimidin-7-yl)-2,2,4-trimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)-N-(4-methoxybenzyl)quinoline-2 -amine in the form of a solid. MS: 676/678 (M+1/M+3). ¹ H-NMR (500 MHz, Chloroform-d) δ 8.51 (s, 1H), 8.01 (s, 1H), 7.42 (d, J=8.8 Hz, 1H), 7.36 (d, J =8.6 Hz, 2H), 7.32 (d, J =3.7 Hz, 1H), 7.06 (d, J =2.4 Hz, 1H), 6.90 (d , J =8.7 Hz, 2H), 6.81 (dd, J =8.8, 2.5 Hz, 1H), 6.49 (d, J =3.7 Hz, 1H), 6.44 (d, J =3.7 Hz, 1H), 5.56 (t, J =5.1 Hz, 1H), 5.44 (dd, J =6.1, 3.8 Hz, 1H), 5 .00 (d, J =6.2 Hz, 1H), 4.72 (d, J =5.1 Hz, 2H), 4.21 (d, J =9.7 Hz, 1H), 4.09 (s, 3H), 4.05 (d, J =9.7 Hz, 1H), 3.81 (s, 3H), 1.71 (s, 3H), 1.55 (s, 3H), 1 .42 (s, 3H).

Scheme for the synthesis of intermediate 4

Intermediate 4 : (3a'R,4'R,6'S,6a'S)-4'-methyl-4'-vinyltetrahydro-4'H-spiro[cyclohexane-1,2'-cyclopenta[d][1,3] dioxol]-6'-ol

Step 1 : A 10 L 4 neck round bottom flask, purged and maintained under an inert nitrogen atmosphere, was charged with D-ribofuranose (970 g, 6.46 mol), cyclohexanone (6.4 L) and 4-methylbenzene-1-sulfonic acid. acid (22.8 g, 132 mmol). The resulting solution was stirred overnight at 25°C. The resulting solution was extracted with 5 L of ethyl acetate and the organic layers were combined. The organic layers were washed with 5 L of saturated aqueous NaHCO ₃ and 5 L of H ₂ O. The organic layers were dried over sodium sulfate. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/petroleum ether (1:1)) to give 2,3- O -1,1-cyclohexanediyl-D-ribofuranose.

Step 2 : A 20 L 4 neck round bottom flask, purged and maintained under an inert nitrogen atmosphere, was charged with MePPh ₃ Br (1.83 kg, 5.13 mol) and tetrahydrofuran (12.7 L). t-BuOK (657 g, 5.86 mol) was then added at 0°C after 15 min. To this mixture was added 2,3- O -1,1-cyclohexanediyl-D-ribofuranose (422 g, 1.83 mol) at 0 ^° C. The resulting solution was stirred for 1 hour at 25°C. The reaction was quenched by adding 20 L of water. The resulting solution was extracted with 20 L of ethyl acetate and the organic layers were combined and dried over sodium sulfate. The resulting mixture was filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography (EtOAc/petroleum ether (1:3)) to give (R)-1-((2R,3S)-3-vinyl-1,4-dioxaspiro[4,5]decane-2 -yl)ethane-1,2-diol.

Step 3 : A 20 L 4-neck round bottom flask, purged and maintained under an inert nitrogen atmosphere, was charged with (R)-1-((2R,3S)-3-vinyl-1,4-dioxaspiro[4,5]decane -2-yl)ethane-1,2-diol (630 g, 2.76 mol) and dichloromethane (8.19 L). A solution of sodium periodate (588 g, 2.75 mol) in water (4.41 L) was then added dropwise. The resulting mixture was stirred for 30 minutes at 25°C. The solids were filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using ethyl acetate/petroleum ether (1:10). Fractions containing the product were combined and concentrated under reduced pressure to give (2S,3S)-3-vinyl-1,4-dioxaspiro[4,5]decane-2-carbaldehyde.

Step 4 : A 20 L 4-neck round bottom flask, purged and maintained under an inert nitrogen atmosphere, was charged with (2S,3S)-3-vinyl-1,4-dioxaspiro[4,5]decane-2-carbaldehyde (637 g , 3.25 mol) and tetrahydrofuran (7.96 l). Bromo(ethenyl)magnesium (4.88 L, 1 M in THF) was then added dropwise with stirring at 0°C. The resulting mixture was stirred for 10 minutes at 0°C and then warmed to room temperature and left to stir for another 1 hour at 25°C. The reaction was quenched by adding 7 L of saturated aqueous NH ₄ Cl solution. The resulting solution was extracted with 7 L of ethyl acetate and the combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using ethyl acetate/petroleum ether (1:50) to give (R)-1-((2S,3R)-3-vinyl-1,4-dioxaspiro[4,5]decane-2 -yl)prop-2-en-1-ol.

Step 5 : A 20 L 4-neck round bottom flask, purged and maintained under an inert nitrogen atmosphere, was charged with (R)-1-((2S,3R)-3-vinyl-1,4-dioxaspiro[4,5]decane -2-yl)prop-2-en-1-ol (400 g, 1.78 mol), dichloromethane (12.8 L) and Grubbs catalyst (24.3 g). The mixture was stirred for 24 hours at 25°C. PDC (1.34 kg, 3.57 mol) and 4 Å molecular sieves (400 g) were added to the mixture. The resulting mixture was stirred for 4 hours at 25°C. The solids were filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica column chromatography (EtOAc/petroleum ether (1:40)) to give (3a 'S ,6a 'S )-3a',6a'-dihydro- 4'H -spiro[cyclohexane-1,2' -cyclopenta[ d ][1,3]dioxol]-4'-one.

Step 6 : A 10-L 4-neck round bottom flask, purged and maintained under an inert nitrogen atmosphere, was charged with (3a 'S ,6a 'S )-3a',6a'-dihydro- 4'H- spiro[cyclohexane-1, 2'-cyclopenta[ d ][1,3]dioxol]-4'-one (246 g, 1.27 mol) and tetrahydrofuran (3.44 L). Methyl lithium (1.74 L, 2.79 mol, 1.6 M in diethyl ether) was added dropwise to this stirred mixture at -78 ^° C. The mixture was stirred for 30 minutes at -78 ^° C, then allowed to warm to room temperature and continued stirring for another 1 hour at 25°C. The reaction was quenched by adding 3 L of saturated aqueous NH ₄ Cl solution. The resulting solution was extracted with 3 L of ethyl acetate and the organic layers were combined and dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography (EtOAc/petroleum ether (1:20)) to give (3a 'S , 4'R ,6a 'S )-4'-methyl-4',6a'-dihydro- 3a'H -spiro[cyclohexane-1,2'-cyclopenta[ d ][1,3]dioxol]-4'-ol.

Step 7 : A 10 L 3-neck round bottom flask, purged and maintained under an inert nitrogen atmosphere, was charged with (3a' S ,4' R ,6a' S )-4'-methyl-4',6a'-dihydro-3a ' H -spiro[cyclohexane-1,2'-cyclopenta[ d ][1,3]dioxol]-4'-ol (192 g, 913 mmol), dichloromethane (3.84 L), 4 Å molecular sieves (192 d), PDC (688 g, 1.83 mol) and acetic anhydride (747 g, 7.3 mol). The mixture was stirred overnight at 25°C. The reaction was quenched by adding 1 L of saturated aqueous Na ₂ CO ₃ solution. The resulting solution was extracted with 1 L of dichloromethane and the combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography (EtOAc/petroleum ether (1:50)) to give ( 3a'R , 6a'R )-6'-methyl-3a',6a'-dihydro- 4'H -spiro[cyclohexane -1,2'-cyclopenta[ d ][1,3]dioxol]-4'-one.

Step 8 : A 2 L 3 neck round bottom flask, purged and maintained under an inert nitrogen atmosphere, was charged with CuBrMe ₂ S (8.43 g, 41.1 mmol) and tetrahydrofuran (627 ml). Bromo(ethenyl)magnesium (548 ml, 2 M in THF, 548 mmol) was then added dropwise with stirring at -78°C. To this mixture was added HMPA (294 g, 1.64 mol) at -78 ^° C, then ( 3a'R , 6a'R )-6'-methyl-3a',6a'-dihydro- 4'H -spiro[ cyclohexane-1,2'-cyclopenta[ d ][1,3]dioxol]-4'-one (57.0 g, 274 mmol) and chlorotrimethylsilane (148 g, 1.36 mol). The resulting mixture was stirred for 3 hours at -78 ^o C. The reaction was quenched by adding 500 ml of a saturated aqueous solution of NH ₄ Cl. The resulting mixture was extracted with 1 L of ethyl acetate, the combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography (EtOAc/petroleum ether (1:100)) to give ( 3a'R , 6'R , 6a'R )-6'-methyl-6'-vinyltetrahydro- 4'H- spiro[ cyclohexane-1,2'-cyclopenta[ d ][1,3]dioxol]-4'-one.

Step 9 : A 2-L, 3-neck round bottom flask, purged and maintained under an inert nitrogen atmosphere, was charged with (3a' R ,6' R ,6a' R )-6'-methyl-6'-vinyltetrahydro-4' H - spiro[cyclohexane-1,2'-cyclopenta[ d ][1,3]dioxol]-4'-one (32.2 g, 136 mmol) and methanol (966 ml). To this mixture was added CeCl ₃ .7H ₂ O (50.8 g) at -30°C, then NaBH ₄ (10.3 g, 273 mmol). The resulting mixture was stirred for 15 minutes at -30°C, then allowed to warm to room temperature and stirring was continued for another 30 minutes at 25°C. The reaction was quenched by adding 1 L of ethyl acetate/petroleum ether (1:1). Solid particles were filtered off. The filtrate was concentrated under reduced pressure. The residue was purified by silica column chromatography (EtOAc/petroleum ether (1:70)) to give (3a'R,4'R,6'S,6a'S)-4'-methyl-4'-vinyltetrahydro-4'H-spiro[ cyclohexane-1,2'-cyclopenta[d][1,3]dioxol]-6'-ol. ¹ H NMR (300 MHz, CDCl ₃ ) δ 5.72-5.66 (m, 1H), 5.03-4.99 (m, 2H), 4.45 (t, J =6.0 Hz, 1H), 4.32 (d, J = 5.5 Hz, 1H), 4.03-3.99 (m, 1H), 2.51 (d, J = 10.0 Hz, 1H), 1, 98-1.94 (m, 1H), 1.72-1.52 (m, 9H), 1.43-1.38 (m, 2H), 1.12 (s, 3H).

Scheme for the synthesis of intermediate 5

Intermediate 5 : 4-chloro-5-(difluoromethyl)-7H-pyrrolo[2,3-d]pyrimidine

Step 1 : To a solution of benzo[ d ]thiazole-2-thiol (50 g, 300 mmol) in 1,4-dioxane (125 ml) and water (125 ml) was added potassium hydroxide (30 g, 540 mmol) at 0° C. The resulting mixture was bubbled with an excess amount of chlorodifluoromethane for 5 hours. The reactor was sealed and the mixture was stirred at room temperature for 8 hours, then concentrated under reduced pressure. The residue was purified by silica column chromatography (neutralized with triethylamine) (0-30% ethyl acetate/hexane) to give 2-((difluoromethyl)thio)benzo[ d ]thiazole. MS: 218 (M+1). ^1H -NMR (300 MHz, Chloroform- d ) δ 8.05-8.02 (m, 1H), 7.89-7.86 (m, 1H), 7.67-7.41 (m, 3H ). ¹⁹ F-NMR (282 MHz, Chloroform- d ) δ -93.20 (s, CF ₂ H).

Step 2: To a solution of 2-((difluoromethyl)thio)benzo[ d ]thiazole (11.1 g, 51 mmol) in ACN/CCl ₄ /water (v:v:v = 1:1:2 , 222 ml) added sodium periodate (34.2 g, 160 mmol) and ruthenium(III) chloride trihydrate (33 mg, 0.13 mmol) in portions. The resulting solution was stirred at room temperature for 3 hours. The mixture was diluted with water (800 ml) and extracted with DCM (1500 ml). The organic phase was washed with brine (800 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica column chromatography (0-20% ethyl acetate/DCM) to give 2-((difluoromethyl)sulfonyl)benzo[ d ]thiazole. MS: 250 (M+1). ^1H -NMR (400 MHz, Chloroform- d ) δ 8.38-8.33 (m, 1H), 8.15-8.06 (m, 1H), 7.76-7.69 (m, 2H ), 6.62 (t, J= 52 Hz, 1H). ¹⁹ F-NMR (376 MHz, Chloroform- d ) δ -121.39 (s, CF ₂ H).

Stage 3: To a solution of 2-((difluoromethyl)sulfonyl)benzo[d]thiazole (116.5 g, 467 mmol) in ethanol (700 ml) sodium borohydride was added (26.5 g, 700 mmol) in portions at room temperature under argon. The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The crude material was triturated with hexane (600 ml x 3) at room temperature to obtain sodium difluoromethanesulfinate. ¹H-NMR (400 MHz, Methanol-d ₄) δ 5.14 (t,J=56 Hz, 1H). ¹⁹F-NMR (376 MHz, Methanol-d ₄) δ -128.92 (s, CF₂H).

Step 4: To a solution of 4-chloro- 7H -pyrrolo[2,3- d ]pyrimidine (10 g, 65.1 mmol) in DCM (150 ml) and water (60 ml) was added sodium difluoromethanesulfinate (27 g, 195 mmol) and TFA (10.0 ml, 130 mmol) in portions at 0°C. To this mixture was added dropwise tert- butyl hydroperoxide (5.5M in decane, 59 mL, 330 mmol) and the resulting mixture was stirred at room temperature for 5 days, then quenched with sodium bicarbonate (2 M aq, 110 mL). The mixture was extracted with DCM (200 ml x 3). The combined organic layers were washed with brine (200 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The product was purified by column chromatography (0-20% ethyl acetate/hexane) to give 4-chloro-5-(difluoromethyl) -7H -pyrrolo[2,3- d ]pyrimidine. MS: 204 (M+1). ¹ H-NMR (400 MHz, DMSO- d ₆ ) δ 13.40 (br.s, 1H), 8.73 (s, 1H), 7.31 (t, J =54 Hz, 1H), 7, 00-7.00 (m, 1H). ¹⁹ F-NMR (376 MHz, DMSO- d ₆ ) δ -112.14 (s, CF ₂ H).

Scheme for the synthesis of intermediate 6

Intermediate 6: 2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)propan-2-ol

Methyl 7H-pyrrolo[2,3-d]pyrimidine-4-carboxylate (0.52 g, 2.9 mmol) dissolved in tetrahydrofuran (12 ml) was purged with nitrogen and cooled to -78°C. Methyl magnesium bromide (1.4 M, 4.6 mL, 6.5 mmol) was added to the solution and the reaction mixture was warmed to room temperature and stirred for 1 hour. After 2 hours, additional methyl magnesium bromide (1.4 M, 4.6 ml, 6.5 mmol) was added at -78°C and the reaction mixture was stirred for 18 hours and warmed to room temperature. The reaction was quenched with a saturated aqueous solution of ammonium chloride and stirred for 1 hour at room temperature. The organic layers were separated, washed with brine, dried over sodium sulfate, and the solvents were removed under reduced pressure to give 2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)propan-2-ol, which was used without further cleaning. MS: 178 (M+1).

Scheme for the synthesis of intermediate 7

Intermediate 7: 4-Chloro-5-cyclopropyl- 1H -pyrrolo[2,3- d ]pyrimidine

Step 1 : Triethylamine (12.5 mL, 89.0 mmol) and (2-(chloromethoxy)ethyl)trimethylsilane (7.60 ml, 42.9 mmol) at 0°C. The mixture was warmed to room temperature and stirred overnight. The mixture was treated with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under reduced pressure and purified by silica column chromatography (0-10% EtOAc/DCM) to give 4-chloro-5-iodo-7-{[2-( trimethylsilyl)ethoxy]methyl}-7 H -pyrrolo[2,3- d ]pyrimidine. MS: 410 (M+1). ^1H NMR (500 MHz, DMSO- d6 ) δ 8.69 (s, 1H), _8.13 (s, 1H), 5.60 (s, 2H), 3.57-3.45 (m, 2H), 0.87-0.75 (m, 2H), -0.10 (s, 9H).

Step 2 : Mixture of 4-chloro-5-iodo-7-{[2-(trimethylsilyl)ethoxy]methyl} -7H- pyrrolo[2,3- d ]pyrimidine (12.2 g, 29.8 mmol), potassium cyclopropyl trifluoroborate (5.29 g, 35.7 mmol), cesium carbonate (29.1 g, 89.0 mmol) and [(di(1-adamantyl)-butylphosphine)-2-(2′-amino-1, 1′-biphenyl)]palladium(II) methanesulfonate (2.17 g, 2.98 mmol) in toluene (135 ml)/water (13.5 ml) was purged with nitrogen and then stirred at 100°C for 10 hours. The mixture was cooled to room temperature, diluted with EtOAc and washed with water and brine. The organic layer was dried over sodium sulfate, concentrated and purified by silica column chromatography (0-20% EtOAc/DCM) to give 4-chloro-5-cyclopropyl-7-{[2-(trimethylsilyl)ethoxy]methyl} -7H -pyrrolo[2,3- d ]pyrimidine. MS: 324 (M+1).

Step 3 : To a stirred solution of 4-chloro-5-cyclopropyl-7-{[2-(trimethylsilyl)ethoxy]methyl} -7H- pyrrolo[2,3- d ]pyrimidine (7.35 g, 22.7 mmol ) to DCM (91 ml) was added TFA (14.0 ml, 182 mmol). The mixture was stirred at 32°C overnight. The mixture was cooled to room temperature, concentrated, diluted with EtOAc and washed with saturated sodium bicarbonate solution. The organic layer was dried over sodium sulfate, concentrated and purified by silica gel chromatography (0-100% EtOAc in DCM) to give (4-chloro-5-cyclopropyl- 7H- pyrrolo[2,3- d ]pyrimidin-7-yl) methanol. MS: 224 (M+1). ^1H NMR (500 MHz, DMSO- d6 ) δ 8.59 (s, 1H), _7.49-7.38 (m, 1H), 6.73-6.59 (m, 1H), 5, 53 (d, J =4.6 Hz, 2H), 2.20-2.09 (m, 1H), 1.00-0.85 (m, 2H), 0.71-0.59 (m, 2H).

Step 4 : Ammonia (7 N in MeOH , 58.6 ml, 410 mmol). The solution was allowed to stir for 10 minutes, concentrated and purified by silica column chromatography (0-100% EtOAc/DCM) to give 4-chloro-5-cyclopropyl- 1H- pyrrolo[2,3- d ]pyrimidine. MS: 194 (M+1). ^1H NMR (600 MHz, DMSO- d6 ) δ 12.23 (s, 1H), 8.51 (s, 1H), _7.34 (d, J =0.8 Hz, 1H), 2.17 -2.09 (m, 1H), 0.91-0.86 (m, 2H), 0.68-0.62 (m, 2H).

Scheme for the synthesis of intermediate 8.

Intermediate 8: 7-bromo-3,5-difluoroquinoline-2-amine

Step 1 : Methyl 2-amino-4-bromo-6-fluorobenzoate (5.0 g, 20 mmol) was dissolved in THF (40 ml) under nitrogen and cooled to 0°C. Lithium aluminum hydride (1M in THF, 40.3 mL, 40.3 mmol) was added dropwise to the stirred solution. The reaction mixture was stirred for 3 hours and cooled to 0°C. The reaction was quenched by sequentially adding dropwise water (2 ml), sodium hydroxide (1N in water, 3 ml) and water (6 ml). Magnesium sulfate was then added and stirred for 30 minutes. The solution was filtered through a pad of Celite® and the solvent was removed under reduced pressure. The residue was purified by silica column chromatography (0-30% DCM/3:1 EtOAc/EtOH) to give (2-amino-4-bromo-6-fluorophenyl)methanol. MS: 202/204 (M-18/M-16).

Step 2 : Manganese(IV) oxide (4.27 g, 49.1 mmol) was added to a stirred solution of (2-amino-4-bromo-6-fluorophenyl)methanol (2.7 g, 12.27 mmol) in DCM (61 ml). The reaction mixture was stirred for 18 hours at 40°C. The reaction mixture was filtered through a pad of Celite® and washed with EtOAc and the solvent was removed to give 2-amino-4-bromo-6-fluorobenzaldehyde, which was used without further purification. MS: 218/220 (M+1/M+3).

Step 3 : 2-Amino-4-bromo-6-fluorobenzaldehyde (1.20 g, 5.50 mmol) was dissolved in DMSO (11 ml). 2-fluoroacetonitrile (1.2 mL, 22 mmol) and potassium hydroxide (0.055 mL, 0.83 mmol) were added to the stirred solution. The reaction mixture was then stirred at 80°C for 18 hours. The reaction mixture was then diluted with EtOAc, added to water and left to stir for several minutes. The aqueous layer was separated and washed with EtOAc. The combined organic layers were dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The material was purified by silica column chromatography (0-100% EtOAc/Hexane) to give 7-bromo-3,5-difluoroquinoline-2-amine. MS: 259/261 (M+1/M+3). ^1H NMR (DMSO-d6) δ: 7.89 (d, J =11 Hz, 1H), 7.52 (s, 1H), 7.32 (dd, J =10, 1 Hz, 1H), 7 .28 (s, 2H)

Intermediates 9-10: Intermediates 9-10 (shown in Table 1) were synthesized using the protocol described for intermediate 8, making appropriate substitutions of aryl ether in step 1 or benzyl alcohol in step 2 or aryl aldehyde in step 3 The substitution reagents and starting material used were commercially purchased, synthesized as described above, or synthesized by known methods described in the literature.

Table 1 Intermediate connection Structure Name MS 9 7-bromo-3,8-difluoroquinoline-2-amine 259/261 (M+1/M+3) 10 7-bromo-3,6-difluoroquinoline-2-amine 259/261 (M+1/M+3)

Scheme for the synthesis of intermediate 11

Intermediate 11: 7-bromo-3-chloro-8-fluoroquinoline-2-amine

The flask containing 2-amino-4-bromo-3-fluorobenzaldehyde (1.8 g, 8.3 mmol) and iron powder (4.6 g, 80 mmol) was purged with nitrogen, charged with THF (16.5 ml), trichloroacetonitrile (1.2 ml, 12 mmol) and heated to 65°C overnight. The reaction mixture was cooled to room temperature, filtered and washed with EtOAc. The organic layers were concentrated under reduced pressure and the residue was purified by silica column chromatography (0-100% EtOAc/DCM). Fractions containing the product were concentrated under reduced pressure. The residue was dissolved in THF (50 ml), N-propyldiethanolamine-functionalized silica gel (0.84 mmol/g) was charged and left to stir overnight. The silica gel was filtered through a pad of Celite® and washed with THF (50 ml). The organic layers were concentrated under reduced pressure to give 7-bromo-3-chloro-8-fluoroquinoline-2-amine. MS: 275/277 (M+1/M+3). ^1H NMR (500 MHz, DMSO-d6) δ 8.32 (s, 1H), 7.48-7.45 (m, 1H), 7.41 (m, 1H), 7.26 (br.s , 2H).

Intermediate 12: Intermediate 12 in Table 2 was synthesized using the protocol described for intermediate 11, making appropriate aryl aldehyde substitution. The replacement starting material was purchased commercially, synthesized as described above, or synthesized by known methods described in the literature.

table 2 Intermediate connection Structure Name MS 12 7-bromo-3-chloro-5-fluoroquinoline-2-amine 275/277 (M+1/M+3)

Scheme for the synthesis of intermediate 13

Intermediate 13: 4-chloro-5-(difluoromethyl)-7-(( 3aR , 4R , 5aR , 8aR )-2,2-dimethyl-6-methylenehexahydrocyclopenta[2,3]furo[3,4 -d][1,3]dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine

Step 1 : To a stirred solution of ( 3R , 3aS , 6aR )-3a-(benzyloxy)-6-methylenehexahydro- 2H- cyclopenta[ b ]furan-2,3-diol (1.0 g, 3.8 mmol) in anhydrous acetonitrile (60 ml) was added dropwise ( E )-diazen-1,2-diylbis(piperidin-1-ylmethanone) (1.54 g, 6.1 mmol) at 0°C under argon followed by by adding tributylphosphine (1.4 ml, 5.7 mmol). The resulting mixture was stirred at 35°C for 1 hour. In a separate container to the stirred solution of 4-chloro-5-(difluoromethyl) -7H- pyrrolo[2,3- d ]pyrimidine (1.1 g, 5.3 mmol ) in anhydrous acetonitrile (25 mL), DBU (0.86 mL, 5.7 mmol) was added under argon at room temperature. The resulting mixture was stirred at room temperature for 30 minutes. The DBU solution was transferred to the above epoxy-containing solution using a syringe. The resulting mixture was stirred at 35°C for 16 hours. The reaction mixture was quenched by adding saturated aqueous ammonium chloride (150 ml) and extracted with ethyl acetate (100 ml x 3). The combined organic layer was washed with brine (100 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The product was purified by silica column chromatography (0-30% ethyl acetate/petroleum ether) to give ( 2R , 3R , 3aS , 6aR )-3a-(benzyloxy)-2-(4-chloro-5-(difluoromethyl )-7 H -pyrrolo[2,3- d ]pyrimidin-7-yl)-6-methylenehexahydro-2 H -cyclopenta[ b ]furan-3-ol. MS: 448(M+1). ^1H NMR (300 MHz, DMSO- d6 ) δ 8.84 (s, 1H), 7.61-7.21 (m, 7H), _6.16 (d, J =8.1 Hz, 1H) , 5.77 (d, J =6.3 Hz, 1H), 5.21-5.14 (m, 3H), 4.94 (d, J =12.0 Hz, 1H), 4.72- 4.66 (m, 2H), 2.85-2.75 (m, 1H), 2.59-2.54 (m, 1H), 2.28-2.25 (m, 1H), 2. 07-2.00 (m, 1H). ^19F NMR (282 MHz, DMSO- d6 ) δ -109.36 (d, 1F), -114.08 (d, 1F) _.

Step 2 : To a solution of ( 2R , 3R , 3aS , 6aR )-3a-(benzyloxy)-2-(4-chloro-5-(difluoromethyl) -7H- pyrrolo[2,3- d ]pyrimidine -7-yl)-6-methylenehexahydro- 2H -cyclopenta[ b ]furan-3-ol (1.79 g, 4.00 mmol) in DCM (20 ml) was added boron trichloride (1M in DCM, 8.0 ml, 8.0 mmol) at -78°C in an argon atmosphere. The mixture was then stirred at -78°C for 2 hours. Triethylamine (2.2 ml, 16 mmol) was added carefully at -78°C to quench the reaction and the mixture was stirred at -78°C for 0.5 hours. The mixture was poured into saturated aqueous sodium bicarbonate solution (100 ml) at 0°C. The mixture was extracted with 200 ml of ethyl acetate. The organic phase was washed with water (30 ml) and brine (60 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica column chromatography (0-50% ethyl acetate/petroleum ether) to give ( 2R , 3R , 3aS , 6aR )-2-(4-chloro-5-(difluoromethyl )-7 H -pyrrolo[2,3- d ]pyrimidin-7-yl)-6-methylenehexahydro-2 H -cyclopenta[ b ]furan-3,3a-diol. MS: 358(M+1). ^1H NMR (400 MHz, DMSO- d6 ) δ 8.81 (s, 1H), _7.59-7.09 (m, 2H), 6.07-6.04 (m, 1H), 5. 50-5.47 (m, 1H), 5.31 (d, J= 4.4 Hz, 1H), 5.14-5.09 (m, 2H), 4.94-4.89 (m, 1H), 4.40 (d, J =4.0 Hz, 1H), 2.80-2.67 (m, 1H), 2.51-2.41 (m, 1H), 2.13-2 .06 (m, 1H), 1.71-1.65 (m, 1H). ^19F NMR (376 MHz, DMSO- d6 ) δ -108.88 (d, 1F), -114.52 (d, 1F) _.

Step 3 : To a mixture of (2 R ,3 R ,3a S ,6a R )-2-(4-chloro-5-(difluoromethyl)-7 H -pyrrolo[2,3- d ]pyrimidin-7-yl)- 6-methylenehexahydro- 2H -cyclopenta[ b ]furan-3,3a-diol (670 mg, 1.87 mmol) in acetone (12 ml) was added 2,2-dimethoxypropane (1.2 ml, 9.4 mmol) and 4-methylbenzenesulfonic acid (32 mg, 0.19 mmol) in portions at ambient temperature. The reaction mixture was stirred at ambient temperature for 16 hours. The mixture was concentrated under reduced pressure and the residue was purified by silica column chromatography (0-30% ethyl acetate/petroleum ether) to give 4-chloro-5-(difluoromethyl)-7-( (3aR,4R,5aR,8aR)-2,2-dimethyl-6-methylenehexahydrocyclopenta[2,3]furo[3,4-d][1,3]dioxol-4-yl)-7H-pyrrolo[2, 3-d]pyrimidine. MS: 398(M+1). ^1H NMR (300 MHz, _Methanol-d4 ) δ 8.74 (s, 1H), 7.40-7.05 (m, 2H), 6.27 (d, J =4.5 Hz, 1H) , 5.76 (d, J = 4.2 Hz, 1H), 5.09-5.06 (m, 2H), 4.63 (s, 1H), 2.94-2.72 (m, 2H ), 2.57-2.50 (m, 1H), 2.19-2.08 (m, 1H), 1.62 (s, 3H), 1.44 (s, 3H). ^19F NMR (282 MHz, _Methanol-d4 ) δ -112.94 (d, 1F), -115.23 (d, 1F).

Scheme for the synthesis of intermediate 14

Intermediate 14: 7-((3a R ,4 R ,5a R ,8a R )-2,2-dimethyl-6-methylenehexahydrocyclopenta[2,3]furo[3,4- d ][1,3]dioxol- 4-yl)-4-methyl-7 H -pyrrolo[2,3- d ]pyrimidine

Step 1: ( 3R , 3aS , 6R , 6aR )-2-methoxyhexahydro- 2H -cyclopenta[ b ]furan- 3,3a ,6-triol (2 g, 10 mmol) was co-evaporated with anhydrous toluene (5 ml × 3) and then dissolved again in acetone (50 ml). To this solution was added 4-methylbenzenesulfonic acid (0.091 g, 0.53 mmol) followed by 2,2-dimethoxypropane (2.74 g, 26.3 mmol). The resulting mixture was stirred at ambient temperature for 1 hour. The pH of the resulting solution was adjusted to 8 with saturated aqueous NaHCO ₃ solution (50 ml) at 0°C. The resulting mixture was extracted with EtOAc (150 ml x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica column chromatography (EtOAc/petroleum ether) to give (3aR,5aR,6R,8aR)-4-methoxy-2,2-dimethylhexahydrocyclopenta[2,3]furo[3,4-d][1, 3]dioxol-6-ol. MS: 248.20 (M+NH ₄ ). ^1H NMR (300 MHz, DMSO- d6 ) δ 4.96 (s, 1H) _, 4.41 (d, J= 5.1 Hz, 1H), 4.17 (s, 1H), 4.10 (d, J= 6.0 Hz, 1H), 3.88-3.79 (m, 1H), 3.33 (s, 3H), 2.04-1.92 (m, 1H), 1, 76-1.62 (m, 3H), 1.39 (s, 3H), 1.31 (s, 3H). The column was then eluted with 45-50% EtOAc in petroleum ether to give (3aR,5aR,6R,8aR)-4-methoxy-2,2-dimethylhexahydrocyclopenta[2,3]furo[3,4-d][1,3 ]dioxol-6-ol. MS: 248 (M+NH ₄ ). ^1H NMR (300 MHz, DMSO- d6 ) δ 4.92 (d, J= 4.2 Hz, 1H) _, 4.72 (d, J= 6.0 Hz, 1H), 4.35 (d , J =4.2 Hz, 1H), 4.00 (d, J = (5.4 Hz, 1H), 3.91-3.82 (m, 1H), 3.35 (s, 3H), 2.09-1.97 (m, 1H), 1.83-1.62 (m, 2H), 1.52-1.43 (m, 1H), 1.40 (s, 3H), 1. 31 (s, 3H).

Step 2: To a mixture of sodium hydride (60% wt. dispersion in mineral oil, 0.88 g, 22 mmol) in anhydrous THF (20 ml) was added tetrabutylammonium iodide (0.67 g, 1.8 mmol) at ambient temperature in an argon atmosphere. The mixture was cooled to 0°C and a solution of (3aR,5aR,6R,8aR)-4-methoxy-2,2-dimethylhexahydrocyclopenta[2,3]furo[3,4-d][1,3]dioxol-6- was added ol (4.2 g, 18 mmol) in THF (15 ml). The mixture was stirred for 0.5 h at ambient temperature. A solution of (bromomethyl)benzene (2.6 mL, 22 mmol) in THF (5 mL) was added to the mixture at 0°C. The resulting mixture was stirred at ambient temperature for 12 hours. The reaction mixture was quenched with saturated aqueous NH ₄ Cl (100 ml) at 0°C. The resulting mixture was extracted with EtOAc (2 x 300 ml). The combined organic layers were washed with saturated aqueous NaHCO ₃ (100 ml) and brine (100 ml). The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica column chromatography (0%-10% EtOAc/petroleum ether) to give ( 3aR , 4S , 5aR , 6R ,8aR)-6-(benzyloxy)-4-methoxy-2,2 -dimethylhexahydrocyclopenta[2,3]furo[3,4-d][1,3]dioxole. MS: 343(M+Na). ^1H NMR (300 MHz, DMSO- d6 ) δ 7.33-7.25 (m, 5H) _, 4.96-4.94 (m, 1H), 4.59 (d, J =11.7 Hz, 1H), 4.42 (d, J =11.7 Hz, 1H), 4.34 (d, J =6.0 Hz, 1H), 4.19-4.17 (m, 1H), 3.77-3.70 (m, 1H), 3.24 (s, 3H), 2.04-1.97 (m, 1H), 1.85-1.64 (m, 3H), 1. 38 (s, 3H), 1.29 (s, 3H).

Step 3 : To a solution of (3a R ,4 S ,5a R ,6 R ,8a R )-6-(benzyloxy)-4-methoxy-2,2-dimethylhexahydrocyclopenta[2,3]furo[3,4- d ] [1,3]dioxole (5.7 g, 18 mmol) in acetonitrile (150 ml) and water (100 ml) was added a concentrated aqueous solution of hydrochloric acid (8.6 ml, 103 mmol) dropwise at ambient temperature. The reaction mixture was stirred at 90°C for 1 hour. The pH of the resulting solution was adjusted to 7 using 1 M aq. NaOH at 0°C. The mixture was concentrated under reduced pressure. The residue was purified by silica column chromatography (0-10% Methanol/DCM) to give ( 3R , 3aS , 6R , 6aR )-6-(benzyloxy)hexahydro- 2H- cyclopenta[ b ]furan-2, 3,3 a -triol. MS: 284 (M+NH ₄ ).

Stage 4: To the stirred mixture (3R,3aS.6R,6aR)-6-(benzyloxy)hexahydro-2H-cyclopenta[b]furan-2,3,3a-triol (1.7 g, 6.4 mmol) in anhydrous acetonitrile (100 ml), tributylphosphine (2.55 ml, 10 mmol) was added under argon followed by the addition of (E)-diazen-1,2-diylbis(piperidin-1-ylmethanone) (2.4 g, 9.6 mmol) at room temperature. The resulting mixture was stirred at room temperature for 30 minutes. The resulting epoxide-containing solution was used directly without any further processing. A separate round bottom flask was loaded with 4-methyl-7 solutionH-pyrrolo[2,3-d]pyrimidine (1.7 g, 13 mmol) in anhydrous DMF (25 ml). To this mixture was added sodium hydride (60% wt. dispersion in mineral oil) (0.77 g, 19 mmol) at 0° C. under argon atmosphere. The suspension was stirred at room temperature for 30 minutes and then transferred into the previously prepared epoxide-containing solution using a syringe. The resulting mixture was stirred at room temperature for 1 hour. The reaction was quenched by adding saturated aqueous ammonium chloride (100 ml) and extracted with EtOAc (3 x 100 ml). The combined organic layers were washed with brine (100 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase column chromatography on C18 (0-95% 5 mM aq. NH₄HCO₃/ACN) receiving (2R,3R,3aS.6R,6aR)-6-(benzyloxy)-2-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)hexahydro-2H-cyclopenta[b]furan-3.3a-diol. MS: 382(M+1).¹H-NMR (300 MHz, DMSO-d ₆) δ 8.69 (s, 1H), 7.74 (d,J=3.6 Hz, 1H), 7.36-7.25 (m, 5H), 6.73 (d,J=3.9 Hz, 1H), 6.16 (d,J=8.4 Hz, 1H), 5.41 (d,J=6.9 Hz, 1H), 5.24 (s, 1H), 4.55-4.50 (m, 2H), 4.27-4.19 (m, 2H), 3.92-3, 86 (m, 1H), 2.67 (s, 3H), 2.02-1.98 (m, 3H), 1.60-1.52 (m, 1H).

Stage 5: To mixture (2R,3R,3aS.6R,6aR)-6-(benzyloxy)-2-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)hexahydro-2H-cyclopenta[b]furan-3.3a-diol (2.4 g, 6.3 mmol) in 2,2-dimethoxypropane (50 ml) was added 4-methylbenzenesulfonic acid (0.11 g, 0.63 mmol) under argon at ambient temperature. The mixture was stirred at 70°C for 48 hours. The mixture was quenched with saturated aqueous NaHCO₃(50 ml) and then extracted with DCM (100 ml x 3). The combined organic layers were dried over anhydrous Na₂SO₄, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica column chromatography (0-60% EtOAc/Petroleum ether) to give 7-((3aR,4R.5aR.6R,8aR)-6-(benzyloxy)-2,2-dimethylhexahydrocyclopenta[2,3]furo[3,4-d][1,3]dioxol-4-yl)-4-methyl-7H-pyrrolo[2,3-d]pyrimidine. MS: 422(M+1).¹H-NMR (400 MHz, DMSO-d ₆) δ 8.71 (s, 1H), 7.79 (d,J=4.0 Hz, 1H), 7.33-7.23 (m, 5H), 6.81 (d,J=3.6 Hz, 1H), 6.32 (d,J=4.4 Hz, 1H), 5.15 (d,J=4.8 Hz, 1H), 4.51 (sq.,J=12.0 Hz, 2H), 4.42 (d,J=4.4 Hz, 1H), 3.93-3.87 (m, 1H), 2.67 (s, 3H), 2.47-2.41 (m, 1H), 2.03-1, 99 (m, 1H), 1.95-1.83 (m, 2H), 1.55 (s, 3H), 1.36 (s, 3H).

Step 6 : To a solution of 7-((3aR,4R,5aR,6R,8aR)-6-(benzyloxy)-2,2-dimethylhexahydrocyclopenta[2,3]furo[3,4-d][1,3]dioxol -4-yl)-4-methyl-7H-pyrrolo[2,3-d]pyrimidine (1.2 g, 2.9 mmol) in anhydrous MeOH (35 ml) under argon was added wet Raney Ni (8 g, 50% by weight in water) at ambient temperature. The resulting mixture was stirred at 60°C for 5 hours. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The product was purified by silica column chromatography (0-100% EtOAc/petroleum ether) to give ( 3aR , 4R , 5aR , 6R , 8aR )-2,2-dimethyl-4-(4-methyl-7 H -pyrrolo[2,3- d ]pyrimidin-7-yl)hexahydrocyclopenta[2,3]furo[3,4- d ][1,3]dioxol-6-ol. MS: 332(M+1). ¹ H-NMR (400 MHz, DMSO- d6 ) δ 8.70 (s, 1H), _7.83 (d, J =4.0 Hz, 1H), 6.83 (d, J =4.0 Hz, 1H), 6.29 (d, J =4.4 Hz, 1H), 5.10 (d, J =4.8 Hz, 1H), 4.92 (d, J =6.0 Hz, 1H), 4.15 (d, J =4.8 Hz, 1H), 3.98-3.94 (m, 1H), 2.68 (s, 3H), 2.43-2.35 (m , 1H), 1.90-1.84 (m, 3H), 1.55 (s, 3H), 1.36 (s, 3H).

Stage 7: To mixture (3aR,4R.5aR.6R,8aR)-2,2-dimethyl-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)hexahydrocyclopenta[2,3]furo[3,4-d][1,3]dioxol-6-ol (2.0 g, 6.04 mmol) in DCM (60 ml) was added Dess-Martin periodinane (4.6 g, 11 mmol) at 25°C under argon. The resulting mixture was stirred at 25°C for 1.5 hours. The mixture was quenched by adding a saturated aqueous solution of NaHCO₃(150 ml) and extracted with EtOAc (3 x 250 ml). The combined organic layers were dried over anhydrous Na₂SO₄, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica column chromatography (0-100% EtOAc/Petroleum ether to give (3aR,4R.5aS,8aS)-2,2-dimethyl-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrocyclopenta[2,3]furo[3,4-d][1,3]dioxol-6(5aH)-she. MS: 330 (M+1).¹H-NMR (400 MHz, DMSO-d ₆ ) δ 8.67 (s, 1H), 7.63 (d,J=3.6 Hz, 1H), 6.75 (d,J=3.6 Hz, 1H), 6.36 (d,J=2.4 Hz, 1H), 5.51 (d,J=2.8 Hz, 1H), 4.56 (s, 1H), 2.96-2.82 (m, 1H), 2.78-2.59 (m, 5H), 2.42-2, 34 (m, 1H), 1.57 (s, 3H), 1.46 (s, 3H).

Stage 8: To a mixture of bromo(methyl)triphenylphosphorane (5.8, 16 mmol) in THF (30 ml) was addedn-butyllithium (2.5 M in hexane, 6 ml, 15 mmol) at -10°C under argon. The resulting mixture was stirred at -10°C for 0.5 hours. A solution of (3a) was added dropwise to this mixtureR,4R.5aS,8aS)-2,2-dimethyl-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrocyclopenta[2,3]furo[3,4-d][1,3]dioxol-6(5aH)-one (1.9 g, 5.8 mmol) in THF (30 ml) at -10°C. The resulting mixture was stirred at -10°C for 1 hour. The mixture was quenched by adding a saturated aqueous solution of NH₄Cl (150 ml), then extracted with DCM (3 x 200 ml). The combined organic layers were dried over anhydrous Na₂SO₄, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica column chromatography (0-60% EtOAc/Petroleum ether) to give 7-((3aR,4R.5aR,8aR)-2,2-dimethyl-6-methylenehexahydrocyclopenta[2,3]furo[3,4-d][1,3]dioxol-4-yl)-4-methyl-7H-pyrrolo[2,3-d]pyrimidine. 328(M+1).¹H-NMR (400 MHz, DMSO-d ₆ ) δ 8.70 (s, 1H), 7.68 (d,J=3.6 Hz, 1H), 6.80 (d,J=3.6 Hz, 1H), 6.32 (d,J=4.0 Hz, 1H), 5.27 (d,J=4.0 Hz, 1H), 5.13-5.11 (m, 2H), 4.61 (s, 1H), 2.67 (s, 3H), 2.61-2.40 (m, 3H), 2.05-1.95 (m, 1H), 1.56 (s, 3H), 1.38 (s, 3H).

Scheme for the synthesis of intermediate 15

Intermediate 15: 7-(( 3aR , 4R , 5aR , 8aR )-2,2-dimethyl-6-methylenehexahydrocyclopenta[2,3]furo[3,4- d ][1,3]dioxol- 4-yl)-7 H -pyrrolo[2,3- d ]pyrimidin-4-amine

Step 1 : To a stirred solution of ( 3aR , 5S , 6R , 6aR )-5-(( R )-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyltetrahydrofuro[ 2,3- d ][1,3]dioxol-6-ol (200 g, 768 mmol) in DCM (1000 ml) was added pyridinium dichromate (170 g, 760 mmol) and acetic anhydride (220 ml, 2.3 mol ) at room temperature. The resulting mixture was stirred at 40°C for 2 hours. The mixture was concentrated under reduced pressure and the residue was purified by silica column chromatography (10-40% EtOAc/petroleum ether to give ( 3aR , 5R , 6aS )-5-( ( R )-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyldihydrofuro[2,3- d ][1,3]dioxol-6( 3aH )-one MS: 276 (M+NH ₄ ). ¹ H NMR (400 MHz, Chloroform- d ) δ 6.11 (d, J = 4.5 Hz, 1H), 4.42-4.31 (m, 2H), 4 .10-3.95 (m, 2H), 3.44-3.39 (m, 1H), 1.46-1.41 (m, 6H), 1.31 (s, 6H).

Step 2 : To a stirred solution of ( 3aR , 5R , 6aS )-5-(( R )-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyldihydrofuro[2,3 - d ][1,3]dioxol-6( 3aH )-one (160 g, 600 mmol) in THF (1500 ml) added vinylmagnesium bromide (1 M in THF, 900 ml, 900 mmol) at -78°C in argon atmosphere. The resulting mixture was stirred at room temperature for 2 hours. The mixture was quenched with a saturated aqueous solution of NH ₄ Cl (500 ml). The mixture was extracted with EtOAc (3 x 1000 ml). The combined organic layers were washed with brine (1000 ml), dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica column chromatography (1-15% EtOAc/petroleum ether) to give (3a R ,5 R ,6 R ,6a R )-5-(( R )-2,2- dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyl-6-vinyltetrahydrofuro[2,3- d ][1,3]dioxol-6-ol. MS: 304(M+ _NH4 ). ^1H NMR (400 MHz, DMSO- d6 ) δ 5.81 (d, J =3.6 Hz, 1H) _, 5.77-5.67 (m, 1H), 5.40-5.36 ( m, 1H), 5.29-5.26 (m, 1H), 5.24-5.19 (m, 1H), 4.20-4.16 (m, 1H), 4.08-4, 06 (m, 1H), 4.02-3.96 (m, 1H), 3.79-3.69 (m, 2H), 1.49 (s, 3H), 1.36-1.20 ( m, 9H).

Step 3 : Sodium hydride (60% wt dispersion in mineral oil, 28 g, 700 mmol) was suspended in anhydrous DMF (1000 ml) under argon and the mixture was cooled to 0°C. A solution of (3a R ,5 R ,6 R ,6a R )-5-(( R )-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyl-6- was added dropwise vinyltetrahydrofuro[2,3- d ][1,3]dioxol-6-ol (133 g, 465 mmol) in anhydrous DMF (300 ml) for 45 min. The mixture was stirred at 50°C for 1 hour, then cooled to 0°C. Bromomethylbenzene (160 g, 930 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with saturated aqueous NH ₄ Cl (1300 ml) and extracted with EtOAc (3 x 1000 ml). The combined organic layers were washed with brine (2000 ml), dried over anhydrous Na ₂ SO ₄ , filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica column chromatography (1-20% EtOAc/petroleum ether) to give ( 3aR , 5R , 6R , 6aR )-6-(benzyloxy)-5-(( R )-2,2- dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyl-6-vinyltetrahydrofuro[2,3- d ][1,3]dioxole. MS: 394(M+ _NH4 ). ^1H NMR (300 MHz, DMSO- d6 ) δ 7.40-7.24 (m, 5H), _5.89 (d, J= 3.3 Hz, 1H), 5.86-5.76 ( m, 1H), 5.49-5.36 (m, 2H), 4.79 (d, J= 3.6 Hz, 1H), 4.55-4.46 (m, 2H), 4.14 -4.02 (m, 2H), 3.90-3.85 (m, 1H), 3.74-3.69 (m, 1H), 1.50 (s, 3H), 1.30 (s , 3H), 1.27 (s, 3H), 1.24 (s, 3H).

Stage 4: (3aR,5R.6R,6aR)-6-(benzyloxy)-5-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyl-6-vinyltetrahydrofuro[2,3-d][1,3]dioxole (130 g, 350 mmol) was dissolved in 80% aqueous acetic acid (900 ml) and the reaction mixture was stirred at 50°C for 2 hours. The reaction mixture was concentrated under reduced pressure and co-evaporated with toluene (2 × 300 ml). The residue was partitioned between EtOAc (1000 ml) and saturated aqueous NaHCO₃ (900 ml). The organic phase was combined and concentrated under reduced pressure to give 1-((3aR,5R.6R,6aR)-6-(benzyloxy)-2,2-dimethyl-6-vinyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)ethane-1,2-diol. The product was used without further purification. MS: 354 (M+NH₄).

Step 5 : To a stirred solution of 1-((3a R ,5 R ,6 R ,6a R )-6-(benzyloxy)-2,2-dimethyl-6-vinyltetrahydrofuro[2,3- d ][1,3] dioxol-5-yl)ethane-1,2-diol (60 g, 180 mmol) in THF (100 ml) was added to a solution of sodium periodate (60 g, 270 mmol) in water (100 ml). The reaction mixture was stirred at room temperature for 1 hour. Water (200 ml) was added and the resulting mixture was extracted with DCM (3 x 300 ml). The combined organic layers were washed with brine (800 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica column chromatography (10-30% EtOAc/petroleum ether to give ( 3aR , 5S , 6R , 6aR )-6-(benzyloxy)-2,2-dimethyl- 6-vinyltetrahydrofuro[2,3- d ][1,3]dioxole-5-carbaldehyde MS: 322(M+ _NH4 ) ^1H NMR (400 MHz, Chloroform- d ) δ 9.58 (s, 1H ), 7.42-7.28 (m, 5H), 6.01-5.97 (m, 1H), 5.81-5.74 (m, 1H), 5.55-5.41 (m , 2H), 4.75-4.62 (m, 4H), 1.62 (s, 3H), 1.41 (s, 3H).

Step 6 : Bis(norbornadiene)rhodium(I) tetrafluoroborate (0.74 g, 2.0 mmol) and 1,2-bis(diphenylphosphino)benzene (1.1 g, 2.4 mmol) were suspended in DCE (70 ml ). The mixture was stirred at room temperature in an argon atmosphere for 10 minutes. Hydrogen was then bubbled through the solution for 10 minutes, then purged with argon again for 20 minutes. (3a R ,5 S ,6 R ,6a R )-6-(benzyloxy)-2,2-dimethyl-6-vinyltetrahydrofuro[2,3- d ][1,3]dioxol-5 was added dropwise to the resulting solution -carbaldehyde (6 g, 20 mmol) in DCE (120 ml) and the mixture was stirred for 20 hours at 75°C. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica column chromatography (1-15% EtOAc/petroleum ether) to give (3aR , 4aS , 7aS , 7bR )-7a-(benzyloxy)-2,2- dimethyltetrahydro- 3aH -cyclopenta[4,5]furo[2,3- d ][1,3]dioxol-5( 4aH )-one. MS: 322(M+ _NH4 ). ^1H NMR (300 MHz, Chloroform- d ) δ 7.40-7.31 (m, 5H), 5.96 (d, J= 3.6 Hz, 1H), 4.77 (d, J= 10 .8 Hz, 1H), 4.67-4.61 (m, 2H), 4.19 (s, 1H), 2.58-2.43 (m, 3H), 1.82-1.68 ( m, 1H), 1.66 (s, 3H), 1.42 (s, 3H).

Step 7 : To a stirred mixture of bromo(methyl)triphenylphosphorane (28.3 g, 79 mmol) in THF (109 ml) was added n -butyllithium (2.5 M in hexane, 28 ml, 71 mmol) dropwise at -60° C in an argon atmosphere. The resulting mixture was stirred at room temperature for 0.5 hours. Then ( 3aR , 4aS , 7aS , 7bR )-7a-(benzyloxy)-2,2-dimethyltetrahydro- 3aH- cyclopent was added dropwise to the resulting solution [4,5]furo[2,3- d ][1,3]dioxol-5( 4aH )-one (8.6 g, 28.3 mmol) in THF (110 ml) via syringe at -60° C. The reaction mixture was stirred at room temperature for 2 hours. The mixture was quenched with saturated aqueous brine (200 ml) at 0°C. The mixture was extracted with EtOAc (3 x 300 ml). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica column chromatography (0-30% EtOAc/petroleum ether) to give (3aR,4aR,7aR,7bR)-7a-(benzyloxy)-2,2-dimethyl-5-methylenehexahydro-5H-cyclopent[4 ,5]furo[2,3-d][1,3]dioxole. ¹ H-NMR (400 MHz, DMSO- d6 ) δ 7.34-7.25 (m, 5H) _, 5.87 (d, J =4.0 Hz, 1H), 5.23-5.22 (m, 1H), 5.10-5.09 (m, 1H), 4.68 (d, J =3.6 Hz, 1H), 4.59 (d, J =11.2 Hz, 1H) , 4.51 (d, J =11.2 Hz, 1H), 4.44 (s, 1H), 2.49-2.39 (m, 2H), 2.22-2.16 (m, 1H ), 1.63-1.55 (m, 1H), 1.51 (s, 3H), 1.32 (s, 3H).

Stage 8: To (3aR,4aR,7aR,7bR)-7a-(benzyloxy)-2,2-dimethyl-5-methylenehexahydro-5H-cyclopenta[4,5]furo[2,3-d][1,3]dioxole (6.8 g, 22 mmol) a solution of TFA (45 ml) in water (11 ml) was added at 0°C. The resulting mixture was stirred at room temperature for 0.25 h. The mixture was neutralized with 2 M aqueous NaOH, then extracted with EtOAc (4 x 200 ml). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-70% EtOAc in petroleum ether) to give (3R,3aS,6aR)-3a-(benzyloxy)-6-methylenehexahydro-2H-cyclopenta[b]furan-2,3-diol in the form of a mixture of two diastereomers at the anomeric center in a ratio of 5:4. ¹H-NMR (400 MHz, DMSO-d ₆ ) δ 7.37-7.24 (m, 5H), 6.51-6.06 (m, 1H), 5.25-4.87 (m, 4H), 4.68-4.36 (m , 3H), 3.87-3.76 (m, 1H), 2.57-2.33 (m, 2H), 2.10-1.72 (m, 2H).

Step 9 : To a stirred solution of ( 3R , 3aS , 6aR ) -3a- (benzyloxy)-6-methylenehexahydro- 2H- cyclopenta[ b ]furan-2,3-diol (5.0 g, 19 mmol ) in anhydrous acetonitrile (63 ml) under argon, ( E )-diazen-1,2-diylbis(piperidin-1-ylmethanone) (7.2 g, 29 mmol) in acetonitrile (63 ml) was added dropwise through a syringe to for 0.5 minutes at room temperature. Tributylphosphine (7.6 mL, 31 mmol) was added via syringe over 5 minutes at room temperature. The reaction solution was stirred at room temperature for about 5 minutes. The reaction mixture was stirred at 46°C for 3 hours. The resulting epoxide-containing mixture was used directly. In parallel, a solution of 4-chloro-7 H -pyrrolo[2,3- d ]pyrimidine (5.6 g, 36 mmol) in anhydrous acetonitrile (30 ml) and DBU (5.2 ml, 34 mmol) was charged into a separate round-bottom flask. ) at room temperature in an argon atmosphere. The resulting mixture was stirred at room temperature for 30 minutes. The DBU-containing solution was then transferred into the above mixture containing the epoxy intermediate using a syringe at room temperature under argon. The resulting mixture was stirred at 46°C for 2 hours and then concentrated under reduced pressure. The residue was purified by silica column chromatography (0-30% EtOAc/petroleum ether) to give ( 2R , 3R , 3aS , 6aR )-3a-(benzyloxy)-2-(4-chloro- 7H -pyrrolo [2,3- d ]pyrimidin-7-yl)-6-methylenehexahydro-2 H -cyclopenta[ b ]furan-3-ol. MS: 398(M+1). ¹ H-NMR (400 MHz, DMSO- d6 ) δ 8.71 (s, 1H), _7.96 (d, J =4.0 Hz, 1H), 7.45-7.28 (m, 5H ), 6.80 (d, J =3.6 Hz, 1H), 6.30 (d, J =8.0 Hz, 1H), 5.83 (d, J =6.8 Hz, 1H), 5.14 (d, J =16.0 Hz, 2H), 4.92 (d, J =12.0 Hz, 1H), 4.71 (d, J =11.6 Hz, 1H), 4, 67 (s, 1H), 4.61-4.58 (m, 1H), 2.84-2.78 (m, 1H), 2.56-2.51 (m, 1H), 2.19- 2.13 (m, 1H), 2.09-2.04 (m, 1H).

Step 10 : To a solution of ( 2R , 3R , 3aS , 6aR )-3a-(benzyloxy)-2-(4-chloro- 7H- pyrrolo[2,3- d ]pyrimidin-7-yl)- 6-methylenehexahydro- 2H- cyclopenta[ b ]furan-3-ol (690 mg, 1.7 mmol) in DCM (10 ml) was added dropwise with trichloroborane (1 M in DCM, 3.5 ml, 3.5 mmol ) at -78°C in an argon atmosphere. The resulting solution was stirred at -78°C for 3 hours. The reaction mixture was quenched by adding TEA (1.0 ml, 7.0 mmol), then stirred at -78°C for 0.5 hours. The reaction solution was poured into saturated aqueous NaHCO ₃ solution (150 ml) at 0°C with vigorous stirring. The mixture was extracted with EtOAc (3 x 200 ml). The organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The crude residue was purified by silica column chromatography (0-10% MeOH/DCM) to give ( 2R , 3R , 3aS , 6aR )-2-(4-chloro- 7H -pyrrolo[2,3- d ]pyrimidin-7-yl)-6-methylenehexahydro- 2H -cyclopenta[ b ]furan- 3,3a -diol. MS: 308(M+1). ¹ H-NMR (400 MHz, DMSO- d6 ) δ 8.72 (s, 1H), _7.95 (d, J =4.0 Hz, 1H), 6.78 (d, J =4.0 Hz, 1H), 6.21 (d, J =8.0 Hz, 1H), 5.52 (d, J =7.2 Hz, 1H), 5.38 (s, 1H), 5.12- 5.07 (m, 2H), 4.44-4.34 (m, 2H), 2.78-2.69 (m, 1H), 2.51-2.42 (m, 1H), 2. 08-2.03 (m, 1H), 1.72-1.64 (m, 1H).

Step 11 : To a mixture of ( 2R , 3R , 3aS , 6aR )-2-(4-chloro- 7H -pyrrolo[2,3- d ]pyrimidin-7-yl)-6-methylenehexahydro- 2H -cyclopenta[ b ]furan- 3,3a -diol (720 mg, 2.3 mmol) in 2,2-dimethoxypropane (2 ml) was added 4-methylbenzenesulfonic acid (40 mg, 0.23 mmol) at ambient temperature . The mixture was stirred for 16 hours at ambient temperature. The reaction mixture was quenched with NaHCO ₃ (200 mg) at ambient temperature. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica column chromatography (0-30% EtOAc/petroleum ether) to give 4-chloro-7-(( 3aR , 4R , 5aR , 8aR )-2,2-dimethyl-6-methylenehexahydrocyclopenta[ 2,3]furo[3,4- d ][1,3]dioxol-4-yl)-7 H -pyrrolo[2,3- d ]pyrimidine. MS: 348 (M+1). ¹ H-NMR (400 MHz, DMSO- d6 ) δ 8.72 (s, 1H), _7.87 (d, J =4.0 Hz, 1H), 6.79 (d, J =4.0 Hz, 1H), 6.36 (d, J =3.6 Hz, 1H), 5.30 (d, J =3.6 Hz, 1H), 5.15-5.14 (m, 2H), 4.68 (s, 1H), 2.58-2.41 (m, 3H), 2.04-1.93 (m, 1H), 1.57 (s, 3H), 1.39 (s, 3H).

Step 12 : K 4-chloro-7-((3a R ,4 R ,5a R ,8a R )-2,2-dimethyl-6-methylenehexahydrocyclopenta[2,3]furo[3,4- d ][1, 3]dioxol-4-yl)-7 H -pyrrolo[2,3- d ]pyrimidine (2.7 g, 7.76 mmol) was added 1,4-dioxane (18 ml) and concentrated aqueous ammonia (28% wt., 18 ml) at room temperature. The reaction container was sealed and stirred at 90°C for 16 hours. The mixture was concentrated under reduced pressure. The residue was purified by silica column chromatography (0-10% MeOH/DCM) to give 7-(( 3aR , 4R , 5aR , 8aR )-2,2-dimethyl-6-methylenehexahydrocyclopenta[2,3]furo [3,4- d ][1,3]dioxol-4-yl)-7 H -pyrrolo[2,3- d ]pyrimidin-4-amine. MS: 329 (M+1). ¹ H-NMR (400 MHz, DMSO- d6 ) δ 8.09 (s, 1H) _, 7.29 (d, J =3.6 Hz, 1H), 7.10 (s, 2H), 6, 64 (d, J =3.6 Hz, 1H), 6.20 (d, J =4.4 Hz, 1H), 5.19 (d, J =4.0 Hz, 1H), 5.13- 5.11 (m, 2H), 4.55 (s, 1H), 2.63-2.42 (m, 3H), 2.01-1.96 (m, 1H), 1.55 (s, 3H), 1.38 (s, 3H).

Scheme for the synthesis of intermediate 16:

Intermediate 16: (3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)oxy)hexahydro-3aH-cyclopenta[b]furan-2,3,3a-triol

Step 1 : To a solution of (3aR,5aR,6R,8aR)-4-methoxy-2,2-dimethylhexahydrocyclopenta[2,3]furo[3,4-d][1,3]dioxol-6-ol (5, 0 g, 22 mmol) to DCM (40 ml) was added 4-dimethylaminopyridine (2.9 g, 24 mmol) at room temperature. Triethylamine (2.4 g, 24 mmol) was added dropwise to the mixture, followed by p-toluene sulfonyl chloride (6.2 g, 33 mmol). The reaction mixture was stirred at 25°C for 16 hours. The resulting mixture was quenched with saturated aqueous NH ₄ Cl (100 ml) and extracted with DCM (100 ml x 3). The combined organic layers were washed with brine (100 ml) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica column chromatography (0-27% ethyl acetate/petroleum ether) to give (3aR,5aR,6R,8aR)-4-methoxy-2,2-dimethylhexahydrocyclopenta[2,3]furo[3,4-d ][1,3]dioxol-6-yl 4-methylbenzenesulfonate. MS: 402 (M+NH ₄ ). ¹ H-NMR (400 MHz, DMSO- d6 ) δ 7.84-7.82 (m, 2H) _, 7.52-7.49 (m, 2H), 4.87 (d, J =4, 0 Hz, 1H), 4.77-4.72 (m, 1H), 4.40 (d, J= 4.0 Hz, 1H), 3.93 (d, J = 5.2 Hz, 1H) , 3.24 (s, 3H), 2.44 (s, 3H), 2.13-2.08 (m, 1H), 1.91-1.86 (m, 1H), 1.78-1 .57 (m, 2H), 1.36 (s, 3H), 1.28 (s, 3H).

Step 2 : Mixture of 2-amino-3-bromoquinolin-7-ol (2.0 g, 8.2 mmol) and (3aR,5aR,6R,8aR)-4-methoxy-2,2-dimethylhexahydrocyclopenta[2,3 ]furo[3,4-d][1,3]dioxol-6-yl 4-methylbenzenesulfonate (3.0 g, 7.8 mmol) was co-evaporated with anhydrous toluene (10 ml each, three times) and redissolved in NMP (10 ml). Cesium carbonate (7.6 g, 23 mmol) was added to this solution at ambient temperature. The resulting mixture was stirred at 90°C for 1.5 hours. The reaction mixture was filtered and the filtrate was purified by reverse phase column chromatography on C18 (0-95% 5 mM aq. NH ₄ HCO ₃ /MeCN) to obtain 3-bromo-7 -(((3aR,5aR,6S,8aR)-4-methoxy-2,2-dimethylhexahydrocyclopenta[2,3]furo[3,4-d][1,3]dioxol-6-yl)oxy)quinoline- 2-amine. MS: 451/453 (M+1/M+3). ¹ H-NMR (400 MHz, DMSO- d6 ) δ 8.30 (s, 1H), _7.60 (d, J =8.4 Hz, 1H), 6.91-6.86 (m, 2H ), 6.62 (s, 2H), 4.95 (d, J= 4.4 Hz, 1H), 4.66 (d, J =4.0 Hz, 1H), 4.54 (d, J =4.4 Hz, 1H), 4.19-4.18 (m, 1H), 3.37 (s, 3H), 2.26-1.98 (m, 4H), 1.36 (s, 3H), 1.28 (s, 3H).

Step 3 : 3-bromo-7-(((3aR,5aR,6S,8aR)-4-methoxy-2,2-dimethylhexahydrocyclopenta[2,3]furo[3,4-d][1,3]dioxol- 6-yl)oxy)quinolin-2-amine (4.9 g, 11 mmol) was dissolved in 0.4 M aq. HCl in MeCN/H ₂ O (3:2, v/v) (120 ml) at 0°C. The resulting mixture was stirred at 90°C for 3 hours in a hermetically sealed test tube. The reaction mixture was cooled to 0°C. The pH value of the solution was adjusted to 7 ~ 8 using 2 M aq. NaOH. The resulting mixture was concentrated under reduced pressure and the residue was purified by reverse phase column chromatography on AQ-C18 (0-95% 5 mM aq NH ₄ HCO ₃ /MeCN) to give (3R,3aS,6S,6aR)-6-(( 2-amino-3-bromoquinolin-7-yl)oxy)hexahydro-3aH-cyclopenta[b]furan-2,3,3a-triol. MS: 397/399 (M+1/M+3). ^1H NMR (400 MHz, _Methanol - d4 ) δ 8.22-8.21 (m, 1H), 7.57-7.54 (m, 1H), 7.12-7.03 (m, 1H ), 6.98-6.94 (m, 1H), 5.35-5.20 (m, 1H), 4.94-4.64 (m, 1H), 4.36-4.18 (m , 1H), 3.80-3.62 (m, 1H), 2.36-2.02 (m, 4H).

Intermediates 17-21: Intermediates 17-21 in Table 3 were synthesized using the protocol described for intermediate 16 (Scheme for the synthesis of intermediate 16), making the appropriate substitution of 2-amino-3-bromoquinolin-7-ol in step 2. The replacement starting material was purchased commercially, synthesized as described above, or synthesized by known methods described in the literature.

Table 3 Intermediate connection Structure Name MS 17 (3 R ,3a S ,6 S ,6a R )-6-[(2-amino-3-chloroquinolin-7-yl)oxy]hexahydro-3a H -cyclopenta[ b ]furan-2,3,3a-triol 353 (M+1) 18 (3 R ,3a S ,6 S ,6a R )-6-[(2-amino-3-fluoroquinolin-7-yl)oxy]hexahydro-3a H -cyclopenta[ b ]furan-2,3,3a-triol 337 (M+1) 19 (3R,3aS,6S,6aR)-6-((2-((2,2,2-trifluoroethyl)amino)quinolin-7-yl)oxy)hexahydro-3aH-cyclopenta[b]furan-2,3, 3a-triol 401 (M+1) 20 (3R,3aS,6S,6aR)-6-((2-((cyclopropylmethyl)amino)quinolin-7-yl)oxy)hexahydro-3aH-cyclopenta[b]furan-2,3,3a-triol 373 (M+1) 21 (3R,3aS,6S,6aR)-6-((2,3-dihydro-1H-pyrrolo[2,3-b]quinolin-7-yl)oxy)hexahydro-3aH-cyclopenta[b]furan-2, 3,3a-triol 345 (M+1)

Scheme for the synthesis of intermediate 22

Intermediate 22: (3R,3aS,6S,6aR)-6-[(2-amino-3-chloroquinolin-7-yl)methyl]hexahydro-3aH-cyclopenta[b]furan-2,3,3a-triol

Step 1: To a solution of (3a R ,5a R ,6 R ,8a R )-4-methoxy-2,2-dimethylhexahydrocyclopenta[2,3]furo[3,4- d ][1,3]dioxol-6- ol (2.0 g, 8.7 mmol) in anhydrous DCM (43 ml) at 0°C under nitrogen, DMP (4.4 g, 10 mmol) was added in one portion. The mixture was stirred at room temperature overnight. The mixture was diluted with DCM (40 ml) and treated with saturated aqueous sodium bicarbonate (80 ml) and sodium thiosulfate (10 g, 63 mmol). The resulting mixture was stirred for 10 minutes at room temperature. The organic layer was separated and the aqueous phase was extracted with DCM (40 ml x 3). The combined organic layers were washed with brine (80 mL), dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography (0-60% EtOAc/hexane) to give (3aR,5aS,8aS)-4-methoxy-2,2-dimethyltetrahydrocyclopenta[2,3]furo[3,4-d][1 ,3]dioxol-6(5aH)-one. ^1H NMR (600 MHz, DMSO- d6 ) δ 4.97 (s, 1H), 4.39 (s, 1H), _4.15 (s, 1H), 3.09 (s, 3H), 2 .50-2.46 (m, 1H), 2.46-2.40 (m, 1H), 2.40-2.29 (m, 2H), 1.38 (s, 3H), 1.36 (c, 3H).

Step 2: To a solution of methyltriphenylphosphonium bromide (5.26 g, 14.7 mmol) in anhydrous THF (23 ml) at -78°C under argon was added n-butyllithium (5.52 ml, 2.5 M in hexane, 13.8 mmol) drop by drop. The mixture was stirred at room temperature for 0.5 hours. A solution of (3aR,5aS,8aS)-4-methoxy-2,2-dimethyltetrahydrocyclopenta[2,3]furo[3,4-d][1,3] was added dropwise ]dioxol-6(5aH)-one (1.05 g, 4.6 mmol), dissolved in anhydrous THF (23 ml), at -78°C. The reaction mixture was stirred at room temperature for 1 hour. The reaction was quenched with saturated aqueous ammonium chloride (50 ml) at 0°C. The mixture was extracted with EtOAc (2 x 30 mL) and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography (0-40% EtOAc/hexane) to give ( 3aR , 4S , 5aR , 8aR )-4-methoxy-2,2-dimethyl-6-methylidenehexahydrocyclopent[2,3] furo[3,4- d ][1,3]dioxole.

Step 3: Into an oven-dried flask containing ( 3aR , 4S , 5aR , 8aR )-4-methoxy-2,2-dimethyl-6-methylidenehexahydrocyclopenta[2,3]furo[3,4- d ] [1,3]dioxole (533 mg, 2.4 mmol) dissolved in THF (6 ml), 9-BBN (24 ml, 0.5 M in THF, 12 mmol) was added dropwise at 0°C under argon. ). The reaction mixture was warmed to room temperature and stirred overnight. The mixture was cooled to 0°C and treated with tribasic potassium phosphate (12 ml, 1 M in water, 12 mmol). The mixture was then stirred for 30 minutes at room temperature. In a separate vessel, a mixture of 7-bromo-3-chloroquinoline-2-amine (910 mg, 3.5 mmol), THF (18 ml) and (2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′- biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (200 mg, 0.24 mmol) was purged with nitrogen for 5 min. A stirred mixture of quinoline was added to the vessel containing the boronate. This reaction mixture was heated at 50°C for 1.5 hours. The mixture was cooled to room temperature and partitioned between brine and EtOAc. The aqueous phase was extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography (0-50% EtOAc/hexane) to give 3-chloro-6-{[(3aR,5aR,6S,8aR)-4-methoxy-2,2-dimethylhexahydrocyclopent[2,3] furo[3,4-d][1,3]dioxol-6-yl]methyl}quinolin-2-amine. MS: 405 (M+1).

Step 4: Into a vessel containing 3-chloro-6-{[(3aR,5aR,6S,8aR)-4-methoxy-2,2-dimethylhexahydrocyclopenta[2,3]furo[3,4-d][1, 3]dioxol-6-yl]methyl}quinolin-2-amine (600 mg, 1.48 mmol) dissolved in acetonitrile (6 ml), water (4 ml) and HCl (355 µl, 37% in water, 4.33 mmol). The mixture was heated at 80°C for 2.5 hours and then stirred overnight at room temperature. The mixture was cooled to 0°C and quenched with saturated aqueous sodium bicarbonate (364 mg, 4.3 mmol). The aqueous layer was extracted with EtOAc and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (3R,3aS,6S,6aR)-6-[(2-amino-3-chloroquinoline -7-yl)methyl]hexahydro-3aH-cyclopenta[b]furan-2,3,3a-triol. MS: 351 (M+1). ^1H NMR (DMSO-d6) δ: 8.14 (s, 1H), 7.57 (d, J =8.2 Hz, 1H), 7.34 (s, 1H), 7.13 (dd, J =8.2, 1.4 Hz, 1H), 6.65 (s, 2H), 5.96 (d, J =6.6 Hz, 1H), 5.16 (dd, J =6.6 , 4.0 Hz, 1H), 4.66 (d, J= 7.6 Hz, 1H), 4.46 (s, 1H), 3.92 (d, J = 4.6 Hz, 1H), 3.48 (dd, J =7.5, 4.0 Hz, 1H), 2.82 (dd, J =13.4, 8.4 Hz, 1H), 2.66 (dd, J =13, 4, 6.7 Hz, 1H), 2.26-2.12 (m, 1H), 1.83-1.73 (m, 1H), 1.62 (dt, J = 12.6, 6, 6 Hz, 1H), 1.57-1.46 (m, 1H), 1.31 (sq.d, J = 12.1, 7.1 Hz, 1H).

Intermediates 23-25: Intermediates 23-25 in Table 4 were synthesized using the protocol described for intermediate 22, making the appropriate substitution of 7-bromo-3-chloroquinoline-2-amine in step 3. The starting material used for replacement was purchased commercially route, synthesized as described above, or synthesized by known methods described in the literature.

Table 4 Intermediate connection Structure Name MS 23 (3R,3aS,6S,6aR)-6-[(2-amino-3-fluoroquinolin-7-yl)methyl]hexahydro-3aH-cyclopenta[b]furan-2,3,3a-triol 335 (M+1) 24 (3R,3aS,6S,6aR)-6-[(2-amino-3-bromoquinolin-7-yl)methyl]hexahydro-3aH-cyclopenta[b]furan-2,3,3a-triol 395/397 (M+1/M+3) 25 (3R,3aS,6S,6aR)-6-((2-amino-3-(trifluoromethyl)quinolin-7-yl)methyl)hexahydro-3aH-cyclopenta[b]furan-2,3,3a-triol 385 (M+1)

Scheme for the synthesis of intermediate 26

Intermediate 26: ( 3R,3aS,5R,6S,6aR )-6-((2-amino-3-fluoroquinolin-7-yl)methyl)-5-fluorohexahydro- 2H- cyclopenta[ b ]furan-2, 3,3 a -triol

Step 1 : To a mixture of Nysted's reagent (6.37 g, 14.0 mmol) in anhydrous THF (40 ml) was added boron trifluoride diethyl etherate (1.8 ml, 14.0 mmol) dropwise at 0°C under argon. The mixture was stirred at 0°C for 5 minutes. A solution of ( 3aR,4aS,7aS,7bR )-7a-(benzyloxy)-6-fluoro-2,2-dimethyltetrahydro- 3aH -cyclopenta[4,5]furo[2,3-d][1,3] was added dioxol-5( 4aH )-one (1.5 g, 4.7 mmol) in anhydrous THF (35 ml) at 0°C. The resulting mixture was stirred at ambient temperature for 15 hours. The reaction mixture was quenched by adding saturated aqueous NaHCO ₃ (40 ml) at 0°C and then partitioned between EtOAc/H ₂ O (250 ml/50 ml). The organic layer was separated and the aqueous layer was again extracted with EtOAc (100 ml). The combined organic layers were washed with water (150 ml) and brine (2 x 100 ml). The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica column chromatography (0-10% EtOAc/petroleum ether) to give ( 3aR,4aR,6R,7aR,7bR )-7a-(benzyloxy)-6-fluoro-2,2-dimethyl-5-methylenehexahydro -3a H -cyclopenta[4,5]furo[2,3-d][1,3]dioxole. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.38-7.29 (m, 5H), 5.99 (d, J = 3.6 Hz, 1H), 5.68-5.64 (m , 2H), 5.57-5.39 (m, 1H), 4.78 (s, 1H), 4.72 (d, J =10.8 Hz, 1H), 4.64 (d, J = 4.0 Hz, 1H), 4.57 (d, J =10.8 Hz, 1H), 2.79-2.72 (m, 1H), 1.96-1.85 (m, 1H), 1.67 (s, 3H), 1.43 (s, 3H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ) δ -169.53 (s, 1F). The chromatographic step also gave ( 3aR,4aR,6S,7aR,7bR )-7a-(benzyloxy)-6-fluoro-2,2-dimethyl-5-methylenehexahydro-3a H -cyclopenta[4,5]furo[2,3 -d][1,3]dioxole. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.45-7.44 (m, 2H), 7.44-7.27 (m, 3H), 5.87 (d, J = 3.6 Hz , 1H), 5.72 (dd, J = 4.4, 1.6 Hz, 2H), 5.58-5.42 (m, 1H), 4.85 (s, 1H), 4.66 ( dd, J =17.2, 10.4 Hz, 2H), 4.61 (d, J =4.0 Hz, 1H), 2.67-2.56 (m, 1H), 2.02-1 .89 (m, 1H), 1.66 (s, 3H), 1.42 (s, 3H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ) δ -164.53 (s, 1F).

Step 2 : To a solution of ( 3aR,4aR,6R,7aR,7bR )-7a-(benzyloxy)-6-fluoro-2,2-dimethyl-5-methylenehexahydro-3a H -cyclopenta[4,5]furo[2, 3-d][1,3]dioxole (180 mg, 0.562 mmol) in anhydrous THF (0.5 mL) was added dropwise with 9-BBN in THF (0.5 M, 6.7 mL, 3.4 mmol) at 0°C under argon and the mixture was stirred at 70°C for 1.5 hours. The mixture was cooled to 0°C and a solution of K ₃ PO ₄ (1M in aq, 716 mg, 3.37 mmol) was added. The resulting mixture was stirred for 0.5 h at ambient temperature. A solution of 7-bromo-3-fluoroquinoline-2-amine (122 mg, 0.51 mmol) in 3.5 ml of anhydrous THF and Pd(dppf)Cl ₂ (41.1 mg, 0.056 mmol) was then added to the mixture. The mixture was heated to 80°C in a microwave reactor for 3.0 hours. The organic layer was separated and the aqueous layer was extracted with EtOAc (150 ml x 2). The combined organic layers were washed with water (50 ml) and brine (80 ml). The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica column chromatography (0-25% EtOAc/petroleum ether) to give 7-((( 3aR,4aR,5S,6R,7aR,7bR )-7a-(benzyloxy)-6-fluoro-2,2 -dimethylhexahydro-3a H -cyclopenta[4,5]furo[2,3-d][1,3]dioxol-5-yl)methyl)-3-fluoroquinolin-2-amine. MS 483 (M+1). ^1H -NMR (400 MHz, Chloroform- d ) δ 7.62-7.54 (m, 3H), 7.35-7.33 (m, 4H), 7.31-7.28 (m, 2H ), 6.02 (d, J =3.6 Hz, 1H), 5.51 (s, 2H), 5.09-4.93 (m, 1H), 4.72-4.67 (m, 2H), 4.54 (d, J =4.0 Hz, 1H), 4.45 (d, J =10.8 Hz, 1H), 3.14-3.11 (m, 2H), 2, 60-2.41 (m, 2H), 2.20-2.07 (m, 1H), 1.62 (s, 3H), 1.44 (s, 3H). ¹⁹ F-NMR (376 MHz, Chloroform- d ) δ -137.96 (s, 1F), -182.37 (s, 1F).

Step 3 : To a mixture of 7-((( 3aR,4aR,5S,6R,7aR,7bR )-7a-(benzyloxy)-6-fluoro-2,2-dimethylhexahydro-3a H -cyclopenta[4,5]furo[ 2,3- d ][1,3]dioxol-5-yl)methyl)-3-fluoroquinolin-2-amine (180 mg, 0.37 mmol) in MeOH (16 ml) and THF (2 ml) added Pd (OH) ₂ /C (20% wt., 500 mg, 0.71 mmol) at ambient temperature in an argon atmosphere. The suspension was degassed in vacuo and purged with H ₂ several times and then stirred under H ₂ at 1 atm at ambient temperature for 6 hours. The mixture was filtered and the filter cake was washed with MeOH/concentrated aqueous ammonia (10:1) three times (10 ml each). The filtrate was concentrated under reduced pressure. The residue was purified by silica column chromatography (0-10% MeOH/DCM) to give ( 3aR,4aR,5S,6R,7aR,7bR )-5-((2-amino-3-fluoroquinolin-7-yl)methyl) -6-fluoro-2,2-dimethylhexahydro-3a H -cyclopenta[4,5]furo[2,3- d ][1,3]dioxol-7 a -ol. MS: 393(M+1).

Stage 4:(3aR,4aR,5S,6R,7aR,7bR)-5-((2-amino-3-fluoroquinolin-7-yl)methyl)-6-fluoro-2,2-dimethylhexahydro-3aH-cyclopenta[4,5]furo[2,3-d][1,3]dioxol-7a-ol (40 mg, 0.10 mmol) was dissolved in TFA and H₂O (2.0 ml, TFA/H₂O=1:1) at 0°C and the mixture was stirred at ambient temperature for 1.0 h. The mixture was co-evaporated with toluene (3 x 15.0 ml) to dryness. The resulting residue was purified by reverse phase column chromatography on C18 (0-95% 5 mM aq. NH₄HCO₃/ACN) with receiving (3R,3aS,5R,6S,6aR)-6-((2-amino-3-fluoroquinolin-7-yl)methyl)-5-fluorohexahydro-2H-cyclopenta[b]furan-2,3,3a-triol. MS: 353(M+1). ¹H-NMR (300 MHz, CD₃OD) δ 7.70 (d,J=11.4 Hz, 1H), 7.60-7.52 (m, 2H), 7.29 (d,J=8.1 Hz, 1H), 5.37 (d,J=4.2 Hz, 1H), 5.08-4.95 (m, 1H), 4.31-3.71 (m, 2H), 3.10-2.98 (m, 2H), 2, 45-2.29 (m, 2H), 2.08-1.93 (m, 1H). ¹⁹F-NMR (282 MHz, CD₃OD) δ -139.28 to -139.34 (m, 1F), -186.24 to -189.90 (m, 1F).

Scheme for the synthesis of intermediate 27

Intermediate 27: ( 3R,3aS,6S,6aR )-6-((2-amino-3-fluoroquinolin-7-yl)methyl)-5,5-difluorohexahydro- 2H- cyclopenta[ b ]furan-2, 3,3 a -triol

Step 1 : To a mixture of (3aR,4aS,7aS,7bR)-7a-(benzyloxy)-2,2-dimethylhexahydro-5H-cyclopenta[4,5]furo[2,3-d][1,3]dioxol- 5-one (3.0 g, 9.9 mmol) in toluene (40 ml) was added triethylamine (46.6 ml, 340 mmol) at ambient temperature under argon. The reaction mixture was heated to 100°C, then treated with tert- butyldimethylsilyl trifluoromethanesulfonate (5.21 g, 20 mmol). The resulting mixture was stirred at 100°C for 30 minutes. After completion of the reaction, the mixture was cooled to room temperature, diluted with toluene (300 ml) and washed with saturated aqueous NaHCO ₃ solution (300 ml). The organic layer was dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica column chromatography (0-15% EtOAc/petroleum ether) to give ((( 3aR,4aS,7aR,7bR )-7 a -(benzyloxy)-2,2-dimethyl-4 a ,7,7 a ,7 b -tetrahydro-3a H -cyclopenta[4,5]furo[2,3- d ][1,3]dioxol-5-yl)oxy)( tert- butyl)dimethylsilane. ¹ H-NMR (300 MHz, DMSO- d6 ) δ 7.36-7.26 (m, 5H), _5.85 (d, J =3.3 Hz, 1H), 4.81-4.79 (m, 1H), 4.64-4.56 (m, 3H), 4.46 (s, 1H), 2.70-2.64 (m, 1H), 2.37-2.31 (m , 1H), 1.51 (s, 3H), 1.35 (s, 3H), 0.91 (s, 9H), 0.18 (s, 6H).

Stage 2: To the mixture (((3aR,4aS,7aR,7bR)-7a-(benzyloxy)-2,2-dimethyl-4a,7,7a.7b-tetrahydro-3aH-cyclopenta[4,5]furo[2,3-d][1,3]dioxol-5-yl)oxy)(tert-butyl)dimethylsilane (4.0 g, 9.6 mmol) in anhydrous DMF (70 ml) was added 1-(chloromethyl)-4-fluoro-1,4-diazabicyclo[2.2.2]octane-1,4-diium tetrafluoroborate (3.72 g, 10.5 mmol) at ambient temperature under argon. The resulting mixture was stirred at ambient temperature for 2 hours. The reaction mixture was diluted with toluene (200 ml) and washed with water (3 x 50 ml). The combined organic layer was dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica column chromatography (0-60% EtOAc/petroleum ether) to give (3aR,4aS,7aS,7bR)-7a-(benzyloxy)-6-fluoro-2,2-dimethyltetrahydro-3aH-cyclopenta[4,5]furo[2,3-d][1,3]dioxol-5(4aH)-she.¹H NMR (400 MHz, DMSO-d ₆) δ 7.20-7.05 (m, 5H), 5.88-5.67 (m, 1H), 4.62-4.49 (m, 1H), 4.44-4.40 (m , 3H), 3.85-3.83 (m, 1H), 2.13-1.94 (m, 2H), 1.28-1.26 (m, 3H), 1.16-1.14 (m, 3H).

Step 3 : To a mixture of ( 3aR,4aS,7aS,7bR )-7a-(benzyloxy)-6-fluoro-2,2-dimethyltetrahydro- 3aH- cyclopenta[4,5]furo[2,3- d ][1 ,3]dioxol-5( 4aH )-one (2.0 g, 6.2 mmol) in toluene (10 ml) was added triethylamine (21.4 g, 210 mmol) at ambient temperature under argon. The reaction mixture was heated to 100°C, then treated with tert- butyldimethylsilyl trifluoromethanesulfonate (3.28 g, 12.4 mmol). The resulting mixture was stirred at 100°C for 30 minutes. After completion of the reaction, the mixture was cooled to room temperature, diluted with water (150 ml) and extracted with EtOAc (3 x 150 ml). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica column chromatography (0-10% EtOAc/petroleum ether) to give ((( 3aR,4aS,7aR,7bR )-7a-(benzyloxy)-6-fluoro-2,2-dimethyl-4a,7 ,7a,7b-tetrahydro-3a H -cyclopenta[4,5]furo[2,3- d ][1,3]dioxol-5-yl)oxy)( tert- butyl)dimethylsilane. ^1H -NMR (400 MHz, DMSO- d6 ) δ 7.17-7.07 (m, 5H), _5.70-5.56 (m, 1H), 4.52-4.42 (m, 3H), 4.39-4.32 (m, 1H), 2.68 (d, J =16.0 Hz, 1H), 2.51 (d, J =16.4 Hz, 1H), 1, 30-1.29 (m, 3H), 1.16-1.15 (m, 3H), 0.72 (s, 9H), -0.04 (s, 6H).

Step 4 : To a mixture of ((( 3aR,4aS,7aR,7bR )-7a-(benzyloxy)-6-fluoro-2,2-dimethyl- 4a , 7,7a , 7b- tetrahydro- 3aH -cyclopent [4,5]furo[2,3- d ][1,3]dioxol-5-yl)oxy)( t- butyl)dimethylsilane (2.6 g, 6.0 mmol) in anhydrous DMF (60 ml) 1-(chloromethyl)-4-fluoro-1,4-diazabicyclo[2.2.2]octane-1,4-diium tetrafluoroborate (2.53 g, 7.2 mmol) was added at 25°C under argon. The resulting mixture was stirred at 25°C for 2 hours. The reaction mixture was diluted with water (300 ml) and extracted with EtOAc (3 x 300 ml). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica column chromatography (0-50% EtOAc/petroleum ether) to give ( 3aR,4aS,7aS,7bR )-7a-(benzyloxy)-6,6-difluoro-2,2-dimethyltetrahydro- 3aH- cyclopenta[4,5]furo[2,3- d ][1,3]dioxol-5( 4aH )-one. ¹ H-NMR (400 MHz, Chloroform- d ) δ 7.42-7.34 (m, 5H), 5.96 (d, J = 3.6 Hz, 1H), 4.78 (d, J = 10.4 Hz, 1H), 4.62 (d, J =3.6 Hz, 1H), 4.54 (d, J =10.8 Hz, 1H), 4.38 (d, J =4, 8 Hz, 1H), 2.90-2.77 (m, 1H), 2.47-2.38 (m, 1H), 1.61 (s, 3H), 1.46 (s, 3H).

Step 5 : To a stirred solution of Nysted's reagent (36.9 g, 16.2 mmol, 20 wt% in THF) in THF (22 ml) was added boron trifluoride diethyl etherate (2.29 g, 16.2 mmol) at 0° C in an argon atmosphere. The mixture was stirred at 0°C for 5 minutes. A solution of ( 3aR,4aS,7aS,7bR )-7a-(benzyloxy)-6,6-difluoro-2,2-dimethyltetrahydro-3a H -cyclopenta[4,5]furo[2,3-d] was added dropwise to the mixture ][1,3]dioxol-5( 4aH )-one (1.1 g, 3.2 mmol) in anhydrous THF (33 ml) at 0°C. The resulting mixture was stirred at ambient temperature for 4 hours. The reaction mixture was quenched with saturated aqueous NaHCO ₃ solution (50 ml) at 0°C. The resulting mixture was extracted with EtOAc (2 x 100 ml). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (EtOAc:petroleum ether=1:3) to give ( 3aR,4aR,7aR,7bR )-7a-(benzyloxy)-6,6-difluoro-2,2-dimethyl-5-methylenehexahydro- 3aH -cyclopenta[4,5]furo[2,3-d][1,3]dioxole. ¹ H-NMR (400 MHz, DMSO- d6 ) δ 7.37-7.26 (m, 5H) _, 5.97 (d, J =3.6 Hz, 1H), 5.87-5.84 (m, 2H), 4.77 (d, J =4.0 Hz, 1H), 4.70-4.69 (m, 1H), 4.63 (d, J =11.2 Hz, 1H) , 4.53 (d, J =11.2 Hz, 1H), 2.98 (t, J =16.0 Hz, 1H), 2.35-2.23 (m, 1H), 1.53 ( s, 3H), 1.34 (s, 3H).

Step 6 : ( 3aR,4aR,7aR,7bR )-7a-(benzyloxy)-6,6-difluoro-2,2-dimethyl-5-methylenehexahydro- 3aH- cyclopenta[4,5]furo[2,3- d][1,3]dioxole (170 mg, 0.50 mmol) was dissolved in 9-BBN (6.029 mL, 3.01 mmol, 0.5 M in THF) at ambient temperature under argon. The resulting solution was stirred at 50°C for 1 hour. The mixture was cooled to 0°C and treated with a solution of K ₃ PO ₄ (533 mg, 2.50 mmol) in 3.5 ml water. The mixture was stirred for 0.5 h at ambient temperature, then a solution of 7-bromo-3-fluoroquinoline-2-amine (97 mg, 0.40 mmol) in 5.0 ml anhydrous THF and Pd(dppf) was added to the mixture. Cl ₂ (37 mg, 0.05 mmol). The mixture was heated to 80°C in a microwave reactor for 3 hours. The mixture was cooled to room temperature, diluted with water (40 ml) and extracted with EtOAc (3 x 80 ml). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (EtOAc:petroleum ether=1:2) to give 7-((( 3aR,4aR,5S,7aR,7bR )-7a-(benzyloxy)-6,6-difluoro-2,2-dimethylhexahydro- 3a H -cyclopenta[4,5]furo[2,3-d][1,3]dioxol-5-yl)methyl)-3-fluoroquinolin-2-amine. MS: 501 (M+1). ¹ H-NMR (400 MHz, Chloroform- d ) δ 7.61 (s, 1H), 7.55 (d, J =3.6 Hz, 1H), 7.52 (s, 1H), 7.36 -7.25 (m, 6H), 5.99 (d, J =3.6 Hz, 1H), 5.61 (s, 2H), 4.68 (d, J =10.4 Hz, 1H) , 4.62 (d, J =3.6 Hz, 1H), 4.48 (d, J =10.8 Hz, 1H), 4.39 (dd, J =6.4 Hz, 3.2 Hz , 1H), 3.16-3.05 (m, 2H), 2.87-2.74 (m, 2H), 2.32-2.21 (m, 1H), 1.56 (s, 3H ), 1.42 (s, 3H).

Stage 7: To solution 7-(((3aR,4aR,5S,7aR,7bR)-7a-(benzyloxy)-6,6-difluoro-2,2-dimethylhexahydro-3aH-cyclopenta[4,5]furo[2,3-d][1,3]dioxol-5-yl)methyl)-3-fluoroquinolin-2-amine (290 mg, 0.58 mmol) in anhydrous DCM (6 .0 ml) BCl was added dropwise₃ (1 M in DCM, 1.7 ml, 1.74 mmol) at -78°C under argon. The resulting mixture was stirred at -78°C for 2 hours. The reaction mixture was quenched by adding triethylamine (0.32 ml, 2.3 mmol) and the resulting mixture was maintained at -78°C for 0.5 hours. The reaction mixture was then poured into saturated aqueous NaHCO solution₃(30 ml) at 0°C and the resulting mixture was stirred at 0°C for an additional 0.5 h. The resulting mixture was extracted with EtOAc (3 x 200 ml). The combined organic layers were dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase column chromatography on C18 (0-95% 5 mM aq. NH₄HCO₃/MeCN) with receiving (3R,3aS,6S,6aR)-6-((2-amino-3-fluoroquinolin-7-yl)methyl)-5,5-difluorohexahydro-2H-cyclopenta[b]furan-2,3,3a-triol. MS: 371(M+1). ¹H-NMR (300 MHz, DMSO-d ₆ ) δ 7.81 (d,J=12.0 Hz, 1H), 7.61 (d,J=8.1 Hz, 1H), 7.41 (s, 1H), 7.19 (d,J=8.1 Hz, 1H), 6.81-6.75 (m, 2H), 6.21 (d,J=7.2 Hz, 1H), 5.26-5.22 (m, 1H), 5.01-4.95 (m, 2H), 4.00-3.99 (m, 1H), 3, 66-3.62 (m, 1H), 2.97-2.66 (m, 3H), 2.42-2.09 (m, 2H).

Scheme for the synthesis of intermediate 28

Intermediate 28: ((3aR,4R,6R,6aR)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2,3a-trimethyltetrahydrofuro[3,4 -d][1,3]dioxol-4-yl)methanol

Step 1: A solution of 4-chloro-5iodo-7H-pyrolo[2,3-d]pyrimidine (1.417 g, 5.07 mmol) in anhydrous ACN (10 ml) was stirred with BSA (1.25 ml, 5.07 mmol ) at room temperature for 15 minutes. Add (3R,4R,5R)-5-((benzoyloxy)methyl)-4-methyltetrahydrofuran-2,3,4-triyl triacetate (2 g, 5.07 mmol) in ACN (20 ml) followed by TMSOTf ( 1.84 ml, 10.1 mmol) and the reaction mixture was stirred for another 10 minutes at room temperature, then for 3 hours at 80°C. The reaction mixture was cooled to room temperature and diluted with EtOAc (40 ml). The reaction mixture was then washed with saturated aqueous NaHCO ₃ (2 x 30 mL) and brine (2 x 30 mL) and dried. The residue was purified by silica gel column chromatography (PE/Et ₂ O) to give (2R,3R,4R,5R)-2-((benzoyloxy)methyl)-5-(4-chloro-5-iodo-7H-pyrrolo[2 ,3-d]pyrimidin-7-yl)-3-methyltetrahydrofuran-3,4-diyl diacetate. MS: 614 (M+1)

Step 2: To a stirred solution of (2R,3R,4R,5R)-2-((benzoyloxy)methyl)-5-(4-chloro-3-iodo-1H-indol-1-yl)-3-methyltetrahydrofuran-3 ,4-diyl diacetate (4.6 g, 7.5 mmol) in anhydrous THF (45 ml), isopropylmagnesium chloride-lithium chloride complex (7.21 ml, 9.37 mmol) was added dropwise over 5 minutes at -78 °C. The mixture was stirred at -78°C for 20 minutes and then quenched by dropwise addition of i-PrOH (0.808 ml, 10.5 mmol) at -78°C. The reaction mixture was poured into a mixture of ice and saturated aqueous NH ₄ Cl and extracted with DCM. The organic layers were combined, dried and concentrated under reduced pressure to give (2R,3R,4R,5R)-2-((benzoyloxy)methyl)-5-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)-3-methyltetrahydrofuran-3,4-diyl diacetate as an oil. MS: 489 (M+1)

Step 3: At 0°C, sodium methoxide (7.75 ml, 3.87 mmol) was added to a stirred solution of (2R,3R,4R,5R)-2-((benzoyloxy)methyl)-5-(4-chloro- 1H-indol-1-yl)-3-methyltetrahydrofuran-3,4-diyl diacetate (3.15g, 6.46 mmol) in MeOH (100 ml). The mixture was stirred at 0°C for 1 hour and then at room temperature for 2 hours. The reaction mixture was quenched using Dowex to pH=6. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (0-10% MeOH/DCM) to give (2R,3S,4R,5R)-5-(4-chloro-7H-pyrrolo[2,3-d ]pyrimidin-7-yl)-2-(hydroxymethyl)-3-methyltetrahydrofuran-3,4-diol in the form of a foamy substance. MS: 300 (M+1)

Step 4: Mixture of (2R,3S,4R,5R)-5-(4-chloro-1H-indol-1-yl)-2-(hydroxymethyl)-3-methyltetrahydrofuran-3,4-diol (443 mg, 1 .48 mmol), p-toluenesulfonic acid monohydrate (562 mg, 2.96 mmol) and 2,2-dimethoxypropane (1.844 μL, 14.78 mmol) in acetone (35 ml) were stirred at 65°C overnight. The reaction mixture was extracted with DCM and the organic phase was washed with saturated aqueous NaHCO ₃ solution. The organic phase was dried, concentrated under reduced pressure and the residue was purified by reverse phase HPLC (C18, ACN/water) to give ((3aR,4R,6R,6aR)-6-(4-chloro-7H-pyrrolo[2,3- d]pyrimidin-7-yl)-2,2,3a-trimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol in the form of a foamy substance. MS: 363 (M+24)

Scheme for the synthesis of intermediate 29

Intermediate 29: 7-bromo-3-(difluoromethyl)quinoline-2-amine

Step 1 : To DMF (16 ml) was added POCl ₃ (48.8 ml, 523 mmol) dropwise via cannula over 30 minutes at 0°C and the reaction mixture was stirred for a further 30 minutes at this temperature. N-(3-bromophenyl)acetamide (16 g, 75 mmol) was then added to the mixture and the reaction mixture was stirred at 80°C for 2 hours. The solvent was then removed under reduced pressure to obtain a crude residue, which was diluted with 200 ml of saturated aqueous solution NaHCO ₃ and extracted with 1000 ml EtOAc. The organic phase was washed with water (600 ml), brine (300 ml), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluted with 20% EtOAc/PE) to give 7-bromo-2-chloroquinoline-3-carbaldehyde as a solid. 7-Bromo-2-chloroquinoline-3-carbaldehyde (1.8 g, 6.65 mmol) was then co-evaporated with toluene (5 ml) three times. To a solution of 7-bromo-2-chloroquinoline-3-carbaldehyde (1.8 g, 6.65 mmol) in DCM (27 ml) was added DAST (1.76 ml, 13.31 mmol) at 0°C and the mixture then stirred at 50°C for 1.5 hours. The reaction mixture was diluted with 50 ml saturated aqueous NaHCO ₃ solution at 0°C and extracted with 250 ml EtOAc. The organic phase was washed with water (100 ml), brine (100 ml), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluted with 30% DCM/PE) to give 7-bromo-2-chloro-3-(difluoromethyl)quinoline as a solid. MS: 292/294 (M+1/M+3).

Step 2 : Solution of 7-bromo-2-chloro-3-(difluoromethyl)quinoline (960 mg, 3.28 mmol) and (4-methoxyphenyl)methanamine (2.144 ml, 16.41 mmol) in 1,4-dioxane ( 10 ml) was stirred at room temperature in a hermetically sealed test tube. The reaction mixture was then heated at 90°C for 16 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (eluted with 20% EtOAc/PE) to give 7-bromo-3-(difluoromethyl)-N- (4-methoxybenzyl)quinoline-2-amine as a solid. MS: 393/395 (M+1/M+3).

Step 3: A solution of 7-bromo-3-(difluoromethyl)-N-(4-methoxybenzyl)quinolin-2-amine (200 mg, 0.509 mmol) in TFA (15 ml) was stirred at 50°C under argon for 3 hours . The reaction mixture was then diluted with 100 ml saturated aqueous NaHCO ₃ solution at 0°C and extracted with 200 ml EtOAc. The organic phase was washed with water (50 ml), brine (50 ml), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluted with 20% EtOAc/PE) to give 7-bromo-3-(difluoromethyl)quinoline-2-amine as a solid. MS: 273/275 (M+1/M+3).

Scheme for the synthesis of intermediate 30

Intermediate 30: (3R,3aS,5S,6S)-6-((2-amino-3-fluoroquinolin-7-yl)methyl)-5-fluorohexahydro-2H-cyclopenta[b]furan-2,3,3a -triol

Step 1: To a solution of (3aR,4aR,6S,7aR,7bR)-7a-(benzyloxy)-6-fluoro-2,2-dimethyl-5-methylenehexahydro-3aH-cyclopenta[4,5]furo[2,3 -d][1,3]dioxole (190 mg, 0.593 mmol) in anhydrous THF (0.5 mL) was added dropwise with 9-BBN (7.12 mL, 0.5 M in THF, 3.56 mmol) at room temperature in an argon atmosphere. The mixture was stirred at 70°C for 1.5 hours. The mixture was then cooled to 0°C and a solution of K ₃ PO ₄ (755 mg, 3.56 mmol) in 2.5 ml H ₂ O was added. The resulting mixture was stirred for further for 0.5 hours at room temperature. A solution of 7-bromo-3-fluoroquinoline-2-amine (129 mg, 0.534 mmol) in anhydrous THF (3 mL) and Pd(dppf)Cl ₂ (43.4 mg, 0.059 mmol) was then added to the mixture. The resulting reaction mixture was microwaved at 80°C for 3 hours. The organic layer was then separated and the aqueous layer was again extracted with EtOAc (60 ml x 2). The combined organic layers were washed with H ₂ O (60 ml) and brine (60 ml), dried over anhydrous Na ₂ SO ₄ , filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica gel (eluted with 0-25% EtOAc/PE) to give 7-(((3aR,4aR,5S,6S,7aR,7bR)-7a-(benzyloxy)-6-fluoro-2 ,2-dimethylhexahydro-3aH-cyclopenta[4,5]furo[2,3-d][1,3]dioxol-5-yl)methyl)-3-fluoroquinolin-2-amine in the form of a solid. MS: 483 (M+1). ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 7.81 (d, J=11.7 Hz, 1H), 7.61 (d, J=8.1 Hz, 1H), 7.47- 7.36 (m, 5H), 7.34-7.29 (m, 1H), 7.15-7.12 (m, 1H), 6.76 (brs, 2H), 5.86 ( d, J=3.9 Hz, 1H), 5.42-5.34 (m, 1H), 4.68-4.65 (m, 2H), 4.57 (d, J=11.1 Hz , 1H), 4.22 (s, 1H), 3.02 (dd, J=14.1, 6.9 Hz, 1H), 2.86-2.78 (m, 1H), 2.70- 2.64 (m, 2H), 2.08-1.90 (m, 1H), 1.40 (s, 3H), 1.30 (s, 3H).

Step 2: 7-(((3aR,4aR,5S,6S,7aR,7bR)-7a-(benzyloxy)-6-fluoro-2,2-dimethylhexahydro-3aH-cyclopenta[4,5]furo[2,3 -°mmol) was dissolved in TFA and H ₂ O (12.0 ml, 1:1 TFA/H ₂ O) at 0°C and the mixture was then stirred at room temperature for 1 hour. The mixture was co-evaporated with toluene (3 × 20 ml) under reduced pressure.The residue was purified by silica gel column chromatography (eluted with 1-10% MeOH/DCM) to give (3R,3aS,5S,6S)-6-((2-amino-3-fluoroquinoline-7- yl)methyl)-3a-(benzyloxy)-5-fluorohexahydro-2H-cyclopenta[b]furan-2,3-diol as a solid MS: 443 (M+1).

Step 3: To a solution of (3R,3aS,5S,6S)-6-((2-amino-3-fluoroquinolin-7-yl)methyl)-3a-(benzyloxy)-5-fluorohexahydro-2H-cyclopenta[b] furan-2,3-diol (650 mg, 1.47 mmol) in anhydrous DCM (20 ml) added BCl ₃ (4.41 ml, 1M in DCM, 4.41 mmol) dropwise at -78°C in atmosphere argon. The resulting solution was stirred at -78°C for 1 hour. The reaction mixture was then quenched with triethylamine (0.819 ml, 5.88 mmol) and stirred at -78°C for 0.5 hour. The reaction mixture was poured into ice-cold saturated aqueous NaHCO ₃ (50 ml) at 0°C and stirring was continued for 0.5 h. The mixture was then extracted with EtOAc (3 x 200 ml). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated under reduced pressure and the resulting residue and the entire aqueous phase were purified using RP-Combi-Flash at room temperature (ACN/water with 5 mM NH ₄ CO ₃ modifier) to give (3R,3aS,5S,6S)-6- ((2-amino-3-fluoroquinolin-7-yl)methyl)-5-fluorohexahydro-2H-cyclopenta[b]furan-2,3,3a-triol as a solid. MS: 353 (M+1). ¹ H NMR (300 MHz, CD ₃ OD) δ 7.71 (d, J=11.4 Hz, 1H), 7.61 (d, J=8.1 Hz, 1H), 7.50 (s, 1H), 7.25 (d, J=8.1 Hz, 1H), 5.29-5.21 (m, 1H), 5.03-4.97 (m, 1H), 4.39-4 .20 (m, 1H), 3.82-3.67 (m, 1H), 3.06-2.99 (m, 2H), 2.68-2.40 (m, 1H), 2.33 -2.05 (m, 2H).

Scheme for the synthesis of intermediate 31

Intermediate 31: 7-bromo-3-fluoro-1,5-naphthyridine-2-amine

Step 1 : 3-amino-5-bromopicolinaldehyde (1000 mg, 4.97 mmol) was dissolved in DMSO (10 ml), 2-fluoroacetonitrile (1108 µl, 19.9 mmol), 15M potassium hydroxide (100 µl, 1, 49 mmol) and heated to 80°C for 2 hours. The reaction mixture was poured into 10 ml of water, diluted with EtOAc (30 ml) and filtered through Celite. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography (0-100% EtOAc/CH ₂ Cl ₂₎ to give 7-bromo-3-fluoro-1,5-naphthyridin-2-amine as a solid. MS: 242/244 (M+1/3).

Scheme for the synthesis of intermediate 32

Intermediate 32: 7-bromo-3-chloro-1,8-naphthyridine-2-amine

Step 1 : A mixture of 2-amino-6-bromonicotinaldehyde (2.6 g, 12.9 mmol) and iron powder (7.22 g, 129 mmol) was degassed under nitrogen and then charged with THF (26 ml). Trichloroacetonitrile (1.95 mL, 19.4 mmol) was added and the mixture was stirred for 2 hours at room temperature. The reaction mixture was refluxed at 65°C overnight. The reaction mixture was cooled to room temperature and filtered through Celite with 10 g of silica gel. The mixture was concentrated under reduced pressure and the residue was purified by silica column chromatography (0-50% 3:1 EtOAc:EtOH/hexane with 1% aqueous NH ₄ OH modifier). The resulting solid was washed with 2 x 10 ml of cold Et ₂ O to give 7-bromo-3-chloro-1,8-naphthyridin-2-amine as a solid, which was used without further purification. MS: 258/260 (M+1/3).

Scheme for the synthesis of intermediate 33

Intermediate 33 : di-tert-butyl (4-methyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)imidodicarbonate

Step 1: To a solution of 4-methyl-7H-pyrrolo[2,3-d]pyrimidin-2-amine (0.5 g, 3.4 mmol) in acetonitrile (8.5 ml)/DCM (8.5 ml ) di-tert-butyl dicarbonate (2.6 g, 12 mmol) and 4-dimethylaminopyridine (0.082 g, 0.68 mmol) were added. The solution was stirred for 18 hours at room temperature. The reaction mixture was concentrated and purified by silica column chromatography (0-60% EtOAc/hexane) to give tert-butyl 2-[bis(tert-butoxycarbonyl)amino]-4-methyl-7H-pyrrolo[2,3-d] pyrimidine 7-carboxylate as a solid. MS: 449 (M+1).

Step 2: To a solution of tert-butyl 2-[bis(tert-butoxycarbonyl)amino]-4-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carboxylate (0.6 g, 1.34 mmol) triethylamine (1.87 mL, 13.4 mmol) was added to MeOH (2.2 mL) at room temperature. The reaction mixture was then heated to 60°C and stirred for 18 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica column chromatography (0-100% EtOAc/hexane) to give di-tert-butyl (4-methyl- 7H -pyrrolo[2,3- d ]pyrimidin-2-yl)imidodicarbonate. MS: 349 (M+1).

Scheme for the synthesis of intermediate 34

Intermediate 34 : 2-chloro-5-fluoro- 1H -pyrrolo[2,3- d ]pyrimidine

Selectfluor (1.16 g, 3.27 mmol) and AcOH (1. 1 ml). The mixture was heated at 70°C overnight. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with EtOAc and washed with water (2×). The solution was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica (20-50% EtOAc/hexane) to give 2-chloro-5-fluoro- 1H -pyrrolo[2,3- d ]pyrimidine. MS: 172 (M+1).

Scheme for the synthesis of intermediate 35

Intermediate 35 : bis(2-methyl-2-propanyl)7H-pyrrolo[2,3-d]pyrimidin-2-ylimidodicarbonate

Step 1 : To a stirred solution of 7H-pyrrolo[2,3-d]pyrimidin-2-amine (500 mg, 3.73 mmol) in acetonitrile (9 ml) and dichloromethane (9 ml) was added Boc anhydride (2.85 g, 13.1 mmol) and DMAP (91 mg, 0.75 mmol). The reaction mixture was stirred overnight. The mixture was concentrated under reduced pressure and the residue was purified by silica column chromatography (0-40% EtOAc in Hex) to give 2-methyl-2-propanyl 2-(bis{[(2-methyl-2-propanyl)oxy]carbonyl} amino) -7H -pyrrolo[2,3- d ]pyrimidine-7-carboxylate. MS: 435 (M+1).

Step 2 : To a stirred solution of 2-methyl-2-propanyl 2-(bis{[(2-methyl-2-propanyl)oxy]carbonyl}amino)-7 H -pyrrolo[2,3- d ]pyrimidine-7- carboxylate (1.52 g, 3.50 mmol) in MeOH (17.5 ml) was added TEA (4.88 ml, 35.0 mmol). The solution was refluxed for 2.5 hours. The mixture was cooled to room temperature, concentrated under reduced pressure and purified by silica gel chromatography (0-60% EtOAc in Hex) to give bis(2-methyl-2-propanyl) 7H-pyrrolo[2,3-d]pyrimidine-2-ylimidodicarbonate. MS: 335 (M+1). ^1H NMR (500 MHz, DMSO- d6 ) δ 12.23 (s, 1H), 8.98 (s, 1H), _7.62 (d, J =3.5 Hz, 1H), 6.63 (d, J =3.5 Hz, 1H), 1.38 (s, 18H).

Scheme for the synthesis of intermediate 36

Intermediate 36: tert- butyl 7-bromo-2,3-dihydro-1H-pyrrolo[2,3-b]quinoline-1-carboxylate

Step 1: To a solution of 4-(1,3-dioxoisoindolin-2-yl)butanoic acid (7.73 g, 33.1 mmol), HATU (15.1 g, 39.8 mmol) and DIEA (17.4 ml, 99 mmol) to DMF (50 ml) was added 3-bromoaniline (5.7 g, 33.1 mmol) at 15°C. The mixture was stirred for 0.5 h. Water (500 ml) was added and the mixture was extracted with EtOAc (200 ml x 3). The combined organic layers were washed with brine (200 mL) and concentrated under reduced pressure. The residue was purified by filtration using EtOAc to give N-(3-bromophenyl)-4-(1,3-dioxoisoindolin-2-yl)butanamide as a solid. MS:387/389 (M+1/M+3)

Step 2: DMF (2.70 ml, 34.9 mmol) was added dropwise to POCl ₃ (19.02 ml, 204 mmol) at 5°C (temperature maintained at 5-15°C) and the reaction mixture was stirred for 15 minutes. N-(3-bromophenyl)-4-(1,3-dioxoisoindolin-2-yl)butanamide (9 g, 23.24 mmol) was added to the reaction mixture and heated to 80°C for 12 hours. The mixture was cooled to room temperature and poured into water (200 ml) and the pH was adjusted to 9. The mixture was extracted with EtOAc (100 ml x 3) and the combined organic layers were concentrated under reduced pressure. The residue was purified by filtration with EtOAc to give 2-(2-(7-bromo-2-chloroquinolin-3-yl)ethyl)isoindoline-1,3-dione as a solid. MS: 415/417 (M+1/M+3)

Step 3: Hydrazine hydrate (0.905 ml, 18.2 mmol) was added dropwise to 2-(2-(7-bromo-2-chloroquinolin-3-yl)ethyl)isoindoline-1,3-dione (6.3 g , 15.2 mmol) in butan-1-ol (60 ml) at 80°C. The reaction mixture was stirred at 100°C for 12 hours. The reaction mixture was concentrated under reduced pressure to obtain 7-bromo-2,3-dihydro-1H-pyrrolo[2,3-b]quinoline as a solid. MS: 249/251 (M+1/M+3)

Step 4: 7-Bromo-2,3-dihydro-1H-pyrrolo[2,3-b]quinoline (100 g, 0.401 mol) was added to a 5 L 4 neck round bottom flask that was purged and maintained under an inert nitrogen atmosphere. and di-tert-butyl dicarbonate (400 g, 1.83 mol). The resulting solution was stirred for 12 hours at 100°C. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica column chromatography (1:10 ethyl acetate/petroleum ether) to give tert- butyl 7-bromo-2,3-dihydro-1H-pyrrolo[2,3-b]quinoline-1-carboxylate as a solid. . MS: 349/351 (M+1/M+3).

Scheme for the synthesis of intermediate 37

Intermediate 37: (3aS,4R,5aR,6S,8aR)-2,2-dimethyl-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)hexahydro-5H-pentaleno [1,6a-d][1,3]dioxol-6-ol

Step 1: Dess-Martin periodinane (14 g, 33 mmol) was added to a flask containing a solution of pent-4-yn-1-ol (2.4 mL, 25 mmol) in DCM (200 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was slowly poured into a beaker containing a stirred solution comprising saturated aqueous sodium bicarbonate and saturated aqueous sodium thiosulfate. The mixture was poured into a separatory funnel and extracted. The organic layers were combined, dried over magnesium sulfate, filtered through a pad of Celite® and concentrated under reduced pressure to give pent-4-ynal, which was used in the next step without further purification.

Step 2: THF (200 ml) was added to the flask containing crude pent-4-ynal. The reaction mixture was cooled to 0°C in an argon atmosphere. Vinyl magnesium bromide (50 ml, 1M, 50 mmol) was added and the reaction mixture was stirred at 0°C for 70 minutes. The reaction mixture was then poured into a separatory funnel containing saturated aqueous ammonium chloride and extracted with EtOAc. The organic layers were combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give hept-1-en-6-yn-3-ol, which was used in the next step without further purification.

Step 3: To a flask containing crude hept-1-en-6-yn-3-ol in DCM (200 ml), add pyridine (6.0 ml, 74 mmol), DMAP (4.58 g, 37.5 mmol) and triphenylchlorosilane (11.5 g, 37.5 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was then poured into a separatory funnel containing saturated aqueous ammonium chloride and extracted. The organic layers were combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was then purified by silica column chromatography (0-10% EtOAc/hexane) to give (hept-1-en-6-yn-3-yloxy)triphenylsilane. ^1H NMR (600 MHz, CDCl ₃ ) δ 7.65-7.61 (m, 6H), 7.45-7.41 (m, 3H), 7.39-7.35 (m, 6H), 5.85-5.78 (m, 1H), 5.06-4.99 (m, 2H), 4.42 (sq., J =6.2 Hz, 1H), 2.27-2.15 (m, 2H), 1.87-1.78 (m, 2H), 1.77-1.70 (m, 1H).

Step 4: To a flask containing a solution of (hept-1-en-6-yn-3-yloxy)triphenylsilane (4.72 g, 12.8 mmol) in DCM (250 ml), add dicobalt octacarbonyl (5.25 g , 14.6 mmol) in an argon atmosphere. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then concentrated under reduced pressure and the residue was dissolved in acetonitrile (500 ml). The reaction mixture was then heated to 83°C under argon overnight. The reaction mixture was then concentrated under reduced pressure, triturated with ether, filtered through a pad of Celite® and then the filtrate was concentrated under reduced pressure. The residue was purified by silica column chromatography (10-30% EtOAc/hexane) followed by chiral SPC (R, R'-Welk-O1 column, 20% MeOH aq/0.1% NH ₄ OH in CO ₂ ) to give (6R,6aR)-6-((triphenylsilyl)oxy)-4,5,6,6a-tetrahydropentalen-2(1H)-one. ^1H NMR (600 MHz, CDCl ₃ ) δ 7.65-7.61 (m, 6H), 7.47-7.43 (m, 3H), 7.42-7.37 (m, 6H), 5.80-5.78 (m, 1H), 3.93 (sq., J = 8.8 Hz, 1H), 3.18-3.12 (m, 1H), 2.83-2.74 (m, 1H), 2.49-2.41 (m, 1H), 2.37 (dd, J =18.1, 6.2 Hz, 1H), 2.21-2.10 (m, 2H ), 1.73 (dd, J =18.1, 3.1 Hz, 1H).

Step 5: THF was added to a flask containing (6R,6aR)-6-((triphenylsilyl)oxy)-4,5,6,6a-tetrahydropentalen-2(1H)-one (7.13 g, 18 mmol) (100 ml) and methanol (80 ml). The solution was cooled in a dry ice/MeCN bath and then cerium(III) chloride heptahydrate (6.70 g, 18.0 mmol) was added. The reaction mixture was stirred in a bath for 20 minutes, then sodium borohydride (0.817 g, 22 mmol) was added. The reaction mixture was stirred in a cooling bath for another 20 minutes, then removed from the bath. Then after 5 minutes the reaction mixture was poured into a separatory funnel containing EtOAc and 3:2:1 saturated ammonium chloride:water:saturated saline solution (200 ml). The aqueous layer was separated and washed twice with EtOAc. The combined organic layers were then dried over sodium sulfate, filtered through Celite® and concentrated under reduced pressure. Crude (2R,6S,6aS)-6-((triphenylsilyl)oxy)-1,2,4,5,6,6a-hexahydropentalen-2-ol was directly used in the next step.

Step 6: To a flask containing crude (2R,6S,6aS)-6-((triphenylsilyl)oxy)-1,2,4,5,6,6a-hexahydropentalen-2-ol in DCM (120 ml) was added pyridine (2.9 ml, 36 mmol), DMAP (2.86 g, 23.4 mmol) and acetic anhydride (2.2 ml, 23 mmol). The reaction mixture was stirred at room temperature for three days. The reaction was then quenched with saturated aqueous ammonium chloride (80 ml). The organic layer was separated on a phase separator, concentrated under reduced pressure and purified by silica column chromatography (0-10% EtOAc/hexane) to give (2R,6S,6aS)-6-((triphenylsilyl)oxy)-1,2, 4,5,6,6a-hexahydropentalene-2-yl acetate. ^1H NMR (600 MHz, CDCl ₃ ) δ 7.66-7.62 (m, 6H), 7.46-7.42 (m, 3H), 7.41-7.37 (m, 6H), 5.82-5.77 (m, 1H), 5.24-5.20 (m, 1H), 3.93 (sq., J =8.0 Hz, 1H), 2.98-2.91 (m, 1H), 2.49-2.43 (m, 1H), 2.40-2.32 (m, 1H), 2.20-2.12 (m, 1H), 2.09-2 .04 (m, 2H), 1.99 (s, 3H), 1.14-1.08 (m, 1H).

Step 7: Into a flask containing allylpalladium(II) chloride dimer (1.66 g, 4.45 mmol), dppf (6.36 g, 11.1 mmol), 4-methyl-7H-pyrrolo[2,3- d]pyrimidine (4.44 g, 33.4 mmol) and potassium t- butoxide (3.74 g, 33.4 mmol), THF (100 ml) was added under argon. The solution was stirred at room temperature for 10 minutes. A solution of (2R,6S,6aS)-6-((triphenylsilyl)oxy)-1,2,4,5,6,6a-hexahydropentalen-2-yl acetate (9.8 g, 22 mmol) in THF (100 ml) and the reaction mixture was heated to 40°C overnight. The reaction mixture was then cooled to room temperature, filtered through Celite® and concentrated under reduced pressure. The residue was purified by silica column chromatography (10-50% EtOAc/hexane) to give 4-methyl-7-((2R,6S,6aS)-6-((triphenylsilyl)oxy)-1,2,4,5, 6,6a-hexahydropentalen-2-yl)-7H-pyrrolo[2,3-d]pyrimidine. MS: 514 (M+1). ^1H NMR (600 MHz, CDCl ₃ ) δ 8.75 (s, 1H), 7.65-7.58 (m, 6H), 7.43-7.38 (m, 3H), 7.38- 7.31 (m, 6H), 7.05 (d, J =3.7 Hz, 1H), 6.54 (d, J =3.6 Hz, 1H), 6.15 (s, 1H), 5.23-5.19 (m, 1H), 3.99 (sq., J = 7.9 Hz, 1H), 3.17-3.11 (m, 1H), 2.78 (s, 3H ), 2.63-2.58 (m, 1H), 2.49-2.42 (m, 1H), 2.29-2.22 (m, 1H), 2.20-2.12 (m , 2H), 1.22-1.15 (m, 1H).

Step 8: Into a flask containing a solution of 4-methyl-7-((2R,6S,6aS)-6-((triphenylsilyl)oxy)-1,2,4,5,6,6a-hexahydropentalen-2-yl) -7H-pyrrolo[2,3-d]pyrimidine (13.2 g, 25.7 mmol) in THF (300 ml), water (150 ml) was added. The solution was cooled to 0°C, then NMO (6.02 g, 51.4 mmol) was added followed by osmium(VIII) oxide (7.8 ml, 4% in water, 1.3 mmol). The reaction mixture was stirred overnight and the bath was left to warm naturally. The reaction was quenched with a saturated aqueous sodium sulfite solution (60 ml) and stirring was continued at room temperature for 30 minutes. The reaction mixture was then poured into a separatory funnel containing water and 25% IPA/chloroform. The aqueous layer was separated and washed two more times with 25% IPA/chloroform. The combined organic layers were dried over sodium sulfite, filtered through Celite® and concentrated under reduced pressure to give crude (1S,2R,3aR,4S,6aR)-2-(4-methyl-7H-pyrrolo[2,3-d]pyrimidine -7-yl)-4-((triphenylsilyl)oxy)hexahydropentalene-1,6a(1H)-diol. This crude product was used directly in the next step.

Step 9: Into a flask containing crude (1S,2R,3aR,4S,6aR)-2-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-4-((triphenylsilyl) oxy)hexahydropentalene-1,6a(1H)-diol, DCM (200 ml) was added followed by 2,2-dimethoxypropane (35 ml, 290 mmol) and p-toluenesulfonic acid monohydrate (17.1 g, 90 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction was quenched with saturated aqueous sodium bicarbonate (100 ml). The organic layer was separated using a phase separator and concentrated under reduced pressure. The residue was purified by silica column chromatography (50-100% EtOAc/hexane to 100% 3:1 EtOAc:EtOH)) to give (3aS,4R,5aR,6S,8aR)-2,2-dimethyl-4-(4 -methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)hexahydro-5H-pentaleno[1,6a-d][1,3]dioxol-6-ol. MS: 330 (M+1).

Intermediate 38: Intermediate 38 in Table 5 was synthesized using the protocol described for intermediate 37, making the appropriate substitution of 4-methyl-7H-pyrrolo[2,3-d]pyrimidine in step 7. The starting material used for replacement was purchased commercially route, synthesized as described above, or synthesized by known methods described in the literature.

Table 5 Intermediate connection Structure Name MS 38 (3aS,4R,5aR,6S,8aR)-4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethylhexahydro-5H-pentaleno[1,6a- d][1,3]dioxol-6-ol 350 (M+1)

Intermediate 39: Intermediate 39 in Table 6 was synthesized using the protocol described for intermediate 13, making the appropriate substitution of 4-chloro-5-(difluoromethyl) -7H- pyrrolo[2,3- d ]pyrimidine in step 1. The replacement starting material was purchased commercially, synthesized as described above, or synthesized by known methods described in the literature.

Table 6 Intermediate connection Structure Name MS 39 4-chloro-7-((3a R ,4 R ,5a R ,8a R )-2,2-dimethyl-6-methylenehexahydrocyclopenta[2,3]furo[3,4- d ][1,3]dioxol- 4-yl)-5-fluoro-2-methyl-7 H -pyrrolo[2,3- d ]pyrimidine 380 (M+1)

EXAMPLES

The following experimental procedures detail the preparation of specific examples of the present invention. The examples are presented for illustrative purposes only and are not intended to limit the scope of the invention in any way.

Example 1

(1 R ,2 S ,3 R ,5 R )-5-(((2-amino-3-bromoquinolin-7-yl)oxy)methyl)-3-(4-chloro-7 H -pyrrolo[2, 3- d ]pyrimidin-7-yl)-1-methylcyclopentane-1,2-diol

Step 1: Mixture of (( 3aR , 4R , 6R , 6aS )-6-(4-chloro- 7H- pyrrolo[2,3- d ]pyrimidin-7-yl)-2,2,3a- trimethyltetrahydro- 3aH -cyclopenta[ d ][1,3]dioxol-4-yl)methanol (1.2 g, 3.6 mmol), 2-amino-3-bromoquinolin-7-ol (0.934 g, 3. 91 mmol) and triphenylphosphine (1.86 g, 7.10 mmol) were co-evaporated with anhydrous toluene (three times, 10 ml each) and then redissolved in anhydrous THF (20 ml). The reaction mixture was cooled to 0°C and ( E )-diisopropyldiazene-1,2-dicarboxylate (1.44 g, 7.10 mmol) was added dropwise at 0°C. The mixture warmed to room temperature naturally, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-10% MeOH in DCM). Fractions containing the desired product were combined and concentrated under reduced pressure to obtain a crude solid. The crude material was then purified by reverse phase column chromatography (0-100% 5 mM aq NH ₄ HCO ₃ /acetonitrile) to give 3-bromo-7-(((3a R ,4 R ,6 R ,6a S )-6 -(4-chloro- 7H -pyrrolo[2,3- d ]pyrimidin-7-yl)-2,2,3a-trimethyltetrahydro- 3aH- cyclopenta[ d ][1,3]dioxol-4-yl) methoxy)quinoline-2-amine. MS 558, 560 (M+1, M+3). ^1H NMR (400 MHz, DMSO- d6 ) δ 8.68 (d, J =1.2 Hz, 1H), 8.28 (s, 1H), 7.96 (d _, J =3.6 Hz , 1H), 7.58 (d, J =8.8 Hz, 1H), 6.98 (d, J =2.4 Hz, 1H), 6.90 (dd, J =9.2, 2, 4 Hz, 1H), 6.76 (d, J =3.6 Hz, 1H), 6.53 (s, 2H), 5.40-5.13 (m, 1H), 4.51 (d, J =4.0 Hz, 1H), 4.27 (dd, J =10.0, 6.0 Hz, 1H), 4.12 (t, J =8.8 Hz, 1H), 2.72- 2.66 (m, 1H), 2.49-2.45 (m, 1H), 2.42-2.36 (m, 1H), 1.60 (s, 3H), 1.51 (s, 3H), 1.30 (s, 3H).

Step 2: To a solution of 3-bromo-7-(((3a R ,4 R ,6 R ,6a S )-6-(4-chloro-7 H -pyrrolo[2,3- d ]pyrimidin-7-yl )-2,2,3a-trimethyltetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-4-yl)methoxy)quinolin-2-amine (430 mg, 0.769 mmol) in water (8 ml) added TFA (8 ml) at room temperature. The reaction mixture was stirred at 25°C for 4 hours. The reaction mixture was cooled to 0°C. The pH was adjusted to pH 7-8 with saturated aqueous sodium bicarbonate (50 ml). The resulting mixture was extracted with EtOAc (50 ml x 5) and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-15% MeOH in DCM) to give ( 1R , 2S , 3R , 5R )-5-(((2-amino-3-bromoquinolin-7-yl)oxy) methyl)-3-(4-chloro- 7H -pyrrolo[2,3- d ]pyrimidin-7-yl)-1-methylcyclopentane-1,2-diol. MS 518, 520 (M+1, M+3). ^1H NMR (400 MHz, DMSO- d6 ) δ 8.60 (s, 1H), 8.28 (s, 1H), 7.93 ₍ d, J =4.0 Hz, 1H), 7.58 (d, J =8.8 Hz, 1H), 6.97 (s, 1H), 6.93 (d, J =8.8 Hz, 1H), 6.71 (d, J =3.6 Hz , 1H), 6.51 (brs, 2H), 5.13 (sq, J =9.2 Hz, 1H), 4.99 (d, J =7.2 Hz, 1H), 4, 51 (s, 1H), 4.21-4.11 (m, 3H), 2.47-2.39 (m, 2H), 1.82-1.75 (m, 1H), 1.26 ( s, 3H).

Example 2

(1 R ,2 S ,3 R ,5 R )-5-(((2-amino-3-bromoquinolin-7-yl)oxy)methyl)-3-(4-amino-7 H -pyrrolo[2, 3- d ]pyrimidin-7-yl)-1-methylcyclopentane-1,2-diol

(1 R ,2 S ,3 R ,5 R )-5-(((2-amino-3-bromoquinolin-7-yl)oxy)methyl)-3-(4- chloro-7H - pyrrolo[2,3- d ]pyrimidin-7-yl)-1-methylcyclopentane-1,2-diol (350 mg, 0.675 mmol), 1,4-dioxane (3 ml) and NH ₃ H ₂ O (5 ml; 25%-28% w/w) at room temperature. The reaction mixture was tightly sealed and then stirred at 90°C for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse phase HPLC (0-45% acetonitrile/water) to give ( 1R , 2S , 3R , 5R )-5-(((2-amino-3-bromoquinolin-7-yl)oxy) methyl)-3-(4-amino- 7H -pyrrolo[2,3- d ]pyrimidin-7-yl)-1-methylcyclopentane-1,2-diol. MS 499, 501 (M+1, M+3). ^1H NMR (400 MHz, DMSO- d6 ) δ 8.28 (s, 1H), 8.02 (s, 1H), 7.58 ₍ d, J =8.7 Hz, 1H), 7.30 (d, J =3.6 Hz, 1H), 6.96-6.89 (m, 4H), 6.57-6.53 (m, 3H), 4.97-4.91 (m, 2H ), 4.41 (s, 1H), 4.19-4.10 (m, 3H), 2.45-2.37 (m, 2H), 1.72-1.66 (m, 1H), 1.24 (s, 3H).

Example 3

(2 R ,3 S ,4 R ,5 R )-2-(((2-amino-3-bromoquinolin-7-yl)oxy)methyl)-5-(4-amino-7 H -pyrrolo[2, 3- d ]pyrimidin-7-yl)-3-ethynyltetrahydrofuran-3,4-diol

Step 1: ( 2R , 3R , 4S , 5R )-2-(4-amino- 7H -pyrrolo[2,3- d ]pyrimidin-7-yl)-5-(hydroxymethyl)tetrahydrofuran-3 ,4-diol (2 g, 7.5 mmol) was co-evaporated with anhydrous pyridine (10 ml x 3) and then resuspended in anhydrous pyridine (30 ml) at ambient temperature under argon. To this suspension was added chlorotrimethylsilane (5.71 g, 52.6 mmol) in one portion at 0°C and the mixture was maintained at ambient temperature for 1 hour. Benzoyl chloride (1.58 g, 11.3 mmol) was then added to the mixture at 0°C. After stirring at ambient temperature for 2 hours, the resulting mixture was quenched with H ₂ O (8 ml) at 0°C. An aqueous solution of NH ₃ (15 mL, 25-28 wt%) was then added dropwise at 0°C, followed by stirring at ambient temperature for 30 min. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica column chromatography (6% MeOH in DCM) to give N- (7-(( 2R , 3R , 4S , 5R )-3,4-dihydroxy-5 -(hydroxymethyl)tetrahydrofuran-2-yl)-7 H -pyrrolo[2,3- d ]pyrimidin-4-yl)benzamide. MS: 371 (M+1). ^1H NMR (300 MHz, DMSO- d6 ) δ 11.12 (s, 1H), 8.59 (s, 1H), 8.10-8.00 (m, 2H) _, 7.71 (d, J =3.8 Hz, 1H), 7.63 (t, J =7.3 Hz, 1H), 7.53 (dd, J =8.3, 6.6 Hz, 2H), 6.67 ( d, J =3.8 Hz, 1H), 6.22 (d, J =6.1 Hz, 1H), 5.35 (d, J =6.4 Hz, 1H), 5.15 (d, J =4.8 Hz, 1H), 5.06 (t, J =5.4 Hz, 1H), 4.41 (dd, J =5.9 Hz, 1H), 4.10 (dd, J = 4.5 Hz, 1H), 3.91 (d, J =3.7 Hz, 1H), 3.69-3.47 (m, 2H).

Step 2: N -(7-((2 R ,3 R ,4 S ,5 R )-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-7 H -pyrrolo[2,3- d ]pyrimidin-4-yl)benzamide (2.1 g, 5.7 mmol) was co-evaporated with anhydrous pyridine (10 ml x 3) and then resuspended in anhydrous pyridine (15 ml) at ambient temperature under argon. To this suspension was added 4,4'-(chloro(phenyl)methylene)bis(methoxybenzene) (2.11 g, 6.24 mmol) in one portion at ambient temperature and the mixture was maintained at ambient temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica column chromatography (EtOAc in petroleum ether) to give N -(7-((2 R ,3 R ,4 S ,5 R )-5-((bis(4- methoxyphenyl)(phenyl)methoxy)methyl)-3,4-dihydroxytetrahydrofuran-2-yl)-7 H -pyrrolo[2,3- d ]pyrimidin-4-yl)benzamide as a solid. MS: 673 (M+1). ^1H -NMR (300 MHz, DMSO- d6 ) δ 11.13 (s, 1H), 8.59 (s, 1H), _8.15-7.94 (m, 2H), 7.68-7 .48 (m, 4H), 7.37 (d, J =7.6 Hz, 2H), 7.31-7.15 (m, 7H), 6.84 (dd, J =8.7, 1 .6 Hz, 4H), 6.65 (d, J =3.7 Hz, 1H), 6.25 (d, J =5.0 Hz, 1H), 5.47 (d, J =5.9 Hz, 1H), 5.19 (d, J =5.6 Hz, 1H), 4.46 (dd, J =5.5 Hz, 1H), 4.20 (dd, J =5.2 Hz, 1H), 3.99 (d, J =7.1 Hz, 1H), 3.71 (s, 6H), 3.23-3.19 (m, 2H).

Stage 3: N-(7-((2R,3R,4S,5R)-5-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-3,4-dihydroxytetrahydrofuran-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzamide (2.36 g, 3.51 mmol), (2R,4S)-4-isopropyl-2-methoxy-3-((R)-2-methyl-1-(1-methyl-1H-imidazol-2-yl)propyl)oxazolidine (0.20 g, 0.70 mmol) andN-ethyl-Nα-isopropylpropan-2-amine hydrochloride (0.017 g, 0.105 mmol) was co-evaporated with anhydrous toluene (10 ml x 3) and then resuspended in anhydrous THF (21 ml) under argon. Added to the suspensionN-ethyl-N-isopropylpropan-2-amine (2.13 g, 16.5 mmol) in one serving at 0°C. Triisopropylsilyl trifluoromethanesulfonate (4.62 g, 15.1 mmol) in DCM (10 ml) was then added at 0°C. The reaction mixture was stirred at ambient temperature for 40 minutes. The reaction mixture was then quenched with water (10 ml) and extracted with EtOAc (2 x 100 ml). United organic layers were washed with saturated aqueous NaHCO solution₃ (50 ml) and brine (2 x 50 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica column chromatography (25% EtOAc in petroleum ether) to giveN-(7-((2R,3R,4R,5R)-5-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-4-hydroxy-3-((triisopropylsilyl)oxy)tetrahydrofuran-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzamide. MS: 829 (M+1).¹H NMR (300 MHz, DMSO-d ₆) δ 11.10 (s, 1H), 8.55 (s, 1H), 8.19-7.95 (m, 2H), 7.68-7.48 (m, 4H), 7.45- 7.35 (m, 2H), 7.25 (dd,J=7.2, 5.4 Hz, 7H), 6.89-6.80 (m, 4H), 6.68 (d,J=3.7 Hz, 1H), 6.32 (d,J=5.6 Hz, 1H), 5.11 (d,J=6.1 Hz, 1H), 4.77 (t,J=5.4 Hz, 1H), 4.26-4.06 (m, 2H), 3.71 (s, 6H), 3.28-3.17 (m, 2H), 0.98-0, 87 (m, 12H), 0.82 (d,J=6.4 Hz, 9H).

Step 4: N -(7-((2 R ,3 R ,4 R ,5 R )-5-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-4-hydroxy-3-((triisopropylsilyl )oxy)tetrahydrofuran-2-yl)-7 H -pyrrolo[2,3- d ]pyrimidin-4-yl)benzamide (1.95 g, 2.35 mmol) was co-evaporated with anhydrous pyridine (10 ml x 3) and then resuspended in anhydrous DCM (30 ml) at ambient temperature under argon. Dess-Martin periodinane (2.49 g, 5.88 mmol) and pyridine (0.65 g, 8.2 mmol) were added to this suspension at ambient temperature. The resulting mixture was then stirred at 0°C for 2 hours. The reaction mixture was quenched with saturated aqueous NaHCO ₃ (10 ml) and then extracted with EtOAc (100 ml x 2). The combined organic layers were washed with brine (100 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give crude N -(7-(( 2R , 3S , 5R )-5-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-4-oxo-3-( (triisopropylsilyl)oxy)tetrahydrofuran-2-yl)-7 H -pyrrolo[2,3- d ]pyrimidin-4-yl)benzamide, which was used directly in the next step. MS: 827 (M+1).

Step 5: To a solution of N -(7-((2 R ,3 S ,5 R )-5-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-4-oxo-3-((triisopropylsilyl) oxy)tetrahydrofuran-2-yl)-7 H -pyrrolo[2,3- d ]pyrimidin-4-yl)benzamide (2.27 g, 2.74 mmol) in DCM (40 ml) was added 2,2-dichloroacetic acid (3.18 g, 24.7 mmol) at ambient temperature and then stirred for 30 minutes. Triethylsilane (31.9 g, 274 mmol) was added to this suspension. After stirring for another 10 minutes, pyridine (1.5 ml) was added to the mixture. The mixture was then concentrated under reduced pressure and the residue was purified by silica column chromatography (30% EtOAc in petroleum ether) to give N- (7-(( 2R , 3S , 5R )-5-(hydroxymethyl)-4-oxo -3-((triisopropylsilyl)oxy)tetrahydrofuran-2-yl)-7 H -pyrrolo[2,3- d ]pyrimidin-4-yl)benzamide. MS: 525 (M+1). ^1H NMR (400 MHz, DMSO- d6 ) δ 11.20 (s, 1H), 8.65 (s, 1H), _8.14-8.04 (m, 2H), 7.89 (d, J =3.8 Hz, 1H), 7.71-7.62 (m, 1H), 7.61-7.53 (m, 2H), 6.84 (d, J =3.8 Hz, 1H ), 6.53 (d, J =8.3 Hz, 1H), 5.39 (br, 1H), 5.00 (d, J =8.3 Hz, 1H), 4.44 (t, J =2.8 Hz, 1H), 3.74-3.70 (m, 2H), 0.91-0.87 (m, 12H), 0.78-0.73 (m, 9H).

Step 6: Cerium(III) chloride (3.04 g, 12.4 mmol) was dried at 140°C under reduced pressure for 1 hour. The resulting powder was cooled under argon. Anhydrous THF (20 ml) was added. The resulting mixture was cooled to -78°C and ((trimethylsilyl)ethynyl)lithium (24.7 ml, 12.4 mmol) was added. The reaction mixture was stirred for 1 hour at -78°C. Then a cooled solution (-78°C) of N -(7-((2 R ,3 S ,5 R )-5-(hydroxymethyl)-4-oxo-3-((triisopropylsilyl)oxy)tetrahydrofuran-2- yl) -7H -pyrrolo[2,3- d ]pyrimidin-4-yl)benzamide (1.08 g, 2.06 mmol) in anhydrous THF (20 ml) and stirring was continued for 2 hours. The reaction was quenched with saturated aqueous solution of ammonium chloride (40 ml). The mixture was diluted with EtOAc (300 ml) and washed with water (100 ml x 2). The organic fraction was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by reverse phase HPLC (0-95% 5 mM aq. NH ₄ HCO ₃ /acetonitrile) to give N -(7-((2 R ,3 R ,4 R ,5 R )- 4-hydroxy-5-(hydroxymethyl)-3-((triisopropylsilyl)oxy)-4-((trimethylsilyl)ethynyl)tetrahydrofuran-2-yl)-7 H -pyrrolo[2,3- d ]pyrimidin-4-yl )benzamide. MS: 623 (M+1). ^1H NMR (300 MHz, DMSO- d6 ) δ 11.08 (s, 1H), 8.56 (s, 1H), _8.06-8.03 (m, 2H), 7.80 (d, J =3.8 Hz, 1H), 7.69-7.41 (m, 3H), 6.71 (d, J =3.7 Hz, 1H), 6.29 (d, J =7.1 Hz, 1H), 5.80 (s, 1H), 5.18 (t, J =4.6 Hz, 1H), 4.98 (d, J =7.2 Hz, 1H), 3.98 ( t, J =3.2 Hz, 1H), 3.87-3.60 (m, 2H), 0.85-0.70 (m, 21H), 0.14 (s, 9H).

Step 7: To a mixture of N -(7-((2 R ,3 R ,4 R ,5 R )-4-hydroxy-5-(hydroxymethyl)-3-((triisopropylsilyl)oxy)-4-((trimethylsilyl) ethynyl)tetrahydrofuran-2-yl)-7 H -pyrrolo[2,3- d ]pyrimidin-4-yl)benzamide (250 mg, 0.401 mmol) in THF (8 ml) was added 2-amino-3-bromoquinoline-7 -ol (115 mg, 0.482 mmol) and triphenylphosphine (368 mg, 1.41 mmol) under argon. ( E )-Diisopropyl diazene-1,2-dicarboxylate (203 mg, 1.00 mmol) was then added dropwise at 0°C. The mixture was stirred at ambient temperature for 12 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica column chromatography (50% EtOAc in petroleum ether) to give N- (7-(( 2R , 3R , 4R , 5R )-5-(((2-amino-3-bromoquinoline- 7-yl)oxy)methyl)-4-hydroxy-3-((triisopropylsilyl)oxy)-4-((trimethylsilyl)ethynyl)tetrahydrofuran-2-yl)-7 H -pyrrolo[2,3- d ]pyrimidin- 4-yl)benzamide. MS: 843/845 (M+1/M+3).

Step 8: To a mixture of N -(7-((2 R ,3 R ,4 R ,5 R )-5-(((2-amino-3-bromoquinolin-7-yl)oxy)methyl)-4-hydroxy -3-((triisopropylsilyl)oxy)-4-((trimethylsilyl)ethynyl)tetrahydrofuran-2-yl)-7 H -pyrrolo[2,3- d ]pyrimidin-4-yl)benzamide (90 mg, 0.11 mmol) in pyridine (3 ml), triethylamine (1.08 g, 10.7 mmol) and triethylamine trihydrofluoride (860 mg, 5.33 mmol) were added at ambient temperature. Stirring was then continued at ambient temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica column chromatography (90% EtOAc in petroleum ether) to give N- (7-(( 2R , 3R ,4 S ,5 R )-5-(((2-amino-3-bromoquinolin-7-yl)oxy)methyl)-4-ethynyl-3,4-dihydroxytetrahydrofuran-2-yl)-7 H -pyrrolo[2, 3- d ]pyrimidin-4-yl)benzamide. MS: 615/617 (M+1/M+3). ^1H NMR (300 MHz, CD ₃ OD) δ 8.57 (s, 1H), 8.21 (s, 1H), 8.06-8.00 (m, 2H), 7.73 (d, J =3.8 Hz, 1H), 7.68-7.60 (m, 1H), 7.58 (d, J =4.2 Hz, 1H), 7.56-7.53 (m, 1H) , 7.52-7.32 (m, 1H), 7.10-7.00 (m, 2H), 6.88 (d, J =3.8 Hz, 1H), 6.50 (d, J =7.4 Hz, 1H), 4.94 (d, J =7.4 Hz, 1H), 4.54-4.41 (m, 3H), 3.15 (s, 1H).

Step 9: To a mixture of N -(7-((2 R ,3 R ,4 S ,5 R )-5-(((2-amino-3-bromoquinolin-7-yl)oxy)methyl)-4-ethynyl -3,4-dihydroxytetrahydrofuran-2-yl)-7 H -pyrrolo[2,3- d ]pyrimidin-4-yl)benzamide (40 mg, 0.065 mmol) in MeOH (2 ml) was added sodium methanolate (17.6 mg, 0.325 mmol) at ambient temperature. Stirring was then continued at ambient temperature for 16 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by reverse phase column chromatography (ACN/water with 5 mM aq NH ₄ HCO ₃ modifier) to give (2 R , 3 S , 4 R ,5 R )-2-(((2-amino-3-bromoquinolin-7-yl)oxy)methyl)-5-(4-amino-7 H -pyrrolo[2,3- d ]pyrimidine-7 -yl)-3-ethynyltetrahydrofuran-3,4-diol. MS: 511/513 (M+1/M+3). ^1H NMR (300 MHz, DMSO- d6 ) δ 8.30 (s, 1H) _, 8.10 (s, 1H), 7.60 (d, J =9.5 Hz, 1H), 7.45 (d, J =3.7 Hz, 1H), 7.22 (br.s, 2H), 6.95-6.93 (m, 2H), 6.76-6.60 (m, 3H), 6.22 (s, 1H), 6.16 (d, J =7.5 Hz, 1H), 5.95 (d, J =7.3 Hz, 1H), 4.74 (t, J =7 .3 Hz, 1H), 4.35-4.29 (m, 3H), 3.61 (s, 1H).

Example 4

(2 R ,3 S ,4 R ,5 R )-2-(2-(2-amino-3-bromoquinolin-7-yl)ethyl)-5-(4-amino-7 H -pyrrolo[2,3 - d ]pyrimidin-7-yl)-2,3-dimethyltetrahydrofuran-3,4-diol

Step 1: To a stirred solution of ((3a R ,5 R ,6 S ,6a R )-5-(( tert- butyldiphenylsilyloxy)methyl)-2,2-dimethyl-6-(naphthalene-2-ylmethoxy)-tetrahydrofuro[ 3,2- d ][1,3]dioxol-5-yl)methanol (12 g, 20 mmol) and imidazole (5.44 g, 80 mmol) in toluene (240 ml) was added PPh ₃ (21 g, 80 mmol) at 25°C in an argon atmosphere. Then I ₂ (10.1 g, 40 mmol) was added to the mixture in portions at 60°C. The resulting mixture was stirred at 80°C for 14 hours. The reaction mixture was cooled to 0°C, quenched with saturated aqueous Na ₂ S ₂ O ₃ (200 ml) and diluted with EtOAc (300 ml). The organic layer was washed with H ₂ O (150 ml), saturated aqueous NaHCO ₃ (150 ml x 2) and brine (150 ml). The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10-40% EtOAc/petroleum ether) to give tert- butyl((( 3aR , 5R , 6S , 6aR )-5-(iodomethyl)-2,2-dimethyl-6 -(naphthalen-2-ylmethoxy)-tetrahydrofuro[3,2- d ][1,3]dioxol-5-yl)methoxy)diphenylsilane. MS: 726 (M+NH ₄ ). ^1H NMR (300 MHz, DMSO- d6 ): δ 7.92-7.68 (m, 4H), 7.60-7.25 ( _m , 13H), 5.68 (d, J =3, 6 Hz, 1H), 4.98-4.82 (m, 2H), 4.71 (d, J = 12.3 Hz, 1H), 4.41 (d, J = 2.4 Hz, 1H) , 3.87 (d, J =12.0 Hz, 1H), 3.71-3.50 (m, 3H), 1.50 (s, 3H), 1.27 (s, 3H), 0, 81 (s, 9H).

Step 2: Tert- butyl (((3a R ,5 R ,6 S ,6a R )-5-(iodomethyl)-2,2-dimethyl-6-(naphthalene-2-ylmethoxy)-tetrahydrofuro[3,2- d ][1,3]dioxol-5-yl)methoxy)diphenylsilane (10.6 g, 14.6 mmol) (co-evaporated with freshly distilled toluene (10 ml x 3)) was dissolved in 200 ml toluene. ( Z )-3,3'-(diazen-1,2-diyl)bis(2,2-dimethyl-3-oxopropanenitrile) (615 mg, 3.85 mmol) and ( n -Bu) _3SnH (11 g , 37 mmol) was added at 60°C under argon in one portion; the temperature was then raised to 120°C and the reaction mixture was stirred at this temperature for 3 hours. The reaction mixture was cooled to room temperature and diluted with EtOAc (300 ml). The organic layer was washed with H ₂ O (150 ml), saturated aqueous NaHCO ₃ (150 ml x 2) and brine (150 ml). The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (14% EtOAc/petroleum ether) to give tert- butyldiphenyl((( 3aR , 5R , 6S , 6aR )-2,2,5-trimethyl-6-(naphthalene-2- ylmethoxy)-tetrahydrofuro[3,2- d ][1,3]dioxol-5-yl)methoxy)silane. MS: 600 (M+NH ₄ ). ^1H NMR (300 MHz, DMSO- d6 ): δ 7.91-7.84 (m, 4H) _, 7.56-7.49 (m, 7H), 7.45-7.34 (m, 6H), 5.70 (d, J =3.9 Hz, 1H), 4.94-4.83 (m, 2H), 4.67 (d, J =12.3 Hz, 1H), 4, 16 (d, J =5.1 Hz, 1H), 3.41 (dd, J =21.0, 9.0 Hz, 2H), 1.52 (s, 3H), 1.30 (s, 3H ), 1.26 (s, 3H), 0.82 (s, 9H).

Step 3: To a solution of tert- butyldiphenyl(((3a R ,5 R ,6 S ,6a R )-2,2,5-trimethyl-6-(naphthalene-2-ylmethoxy)tetrahydrofuro[2,3- d ][ 1,3]dioxol-5-yl)methoxy)silane (5 g, 8.6 mmol) in DCM (50 ml) and water (12.5 ml) was added DDQ (3.90 g, 17.2 mmol) at ambient temperature. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with saturated aqueous NaHCO ₃ (100 ml) and extracted with DCM (100 ml x 3). The combined organic layers were washed with saturated aqueous NaHCO ₃ (150 ml), dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography (1-20% EtOAc/petroleum ether) to give ( 3aR , 5R , 6S , 6aR )-5-((( t- butyldiphenylsilyl)oxy)methyl) -2,2,5-trimethyltetrahydrofuro[2,3- d ][1,3]dioxol-6-ol. MS: 460 (M+NH ₄ ). ^1H NMR (300 MHz, DMSO- d6 ) δ 7.61-7.42 (m, 10H) _, 5.65 (d, J =3.6 Hz, 1H), 5.11 (d, J = 6.6 Hz, 1H), 4.57 (t, J = 4.8 Hz, 1H), 4.16 (t, J = 6.0 Hz, 1H), 3.49-3.40 (m, 2H), 1.48 (s, 3H), 1.25 (s, 3H), 1.14 (s, 3H), 0.99 (s, 9H).

Step 4: To a stirred solution of (3a R ,5 R ,6 S ,6a R )-5-((( tert- butyldiphenylsilyl)oxy)methyl)-2,2,5-trimethyltetrahydrofuro[2,3- d ][1 ,3]dioxol-6-ol (3.5 g, 7.91 mmol) in DCM (80 ml) was added pyridine (2.24 ml, 27.7 mmol) and Dess-Martin periodinane (6.71 g, 15 .8 mmol) at 0°C. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with saturated aqueous NaHCO ₃ (50 ml) and extracted with EtOAc (80 ml x 3). The combined organic layers were washed with saturated aqueous NaHCO ₃ (80 ml) and brine (100 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (1-24% EtOAc/petroleum ether) to give ( 3aR , 5R , 6aS )-5-((( t- butyldiphenylsilyl)oxy)methyl)-2 ,2,5-trimethyldihydrofuro[2,3- d ][1,3]dioxol-6(3aH)-one. MS: 458 (M+NH ₄ ). ^1H NMR (300 MHz, Chloroform- d ) δ 7.68-7.65 (m, 2H), 7.59-7.56 (m, 2H), 7.45-7.36 (m, 6H) , 6.27 (d, J =4.5 Hz, 1H), 4.53 (d, J =4.5 Hz, 1H), 3.66-3.55 (m, 2H), 1.51 ( s, 3H), 1.44 (s, 3H), 1.26 (s, 3H), 1.00 (s, 9H).

Step 5: To a stirred solution of ( 3aR , 5R , 6aS )-5-((( tert- butyldiphenylsilyl)oxy)methyl)-2,2,5-trimethyldihydrofuro[2,3- d ][1,3] dioxol-6( 3aH )-one (3 g, 6.8 mmol) in THF (25 ml) was added dropwise at _- 78°C. The resulting mixture was stirred at -78°C for 2 hours. The reaction mixture was quenched with saturated aqueous NH ₄ Cl (50 ml) and extracted with diethyl ether (100 ml x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (1-14% EtOAc/petroleum ether) to give ( 3aR ,5R , 6S , 6aR )-5-((( tert- butyldiphenylsilyl)oxy)methyl )-2,2,5,6-tetramethyltetrahydrofuro[2,3- d ][1,3]dioxol-6-ol. MS: 479 (M+Na). ^1H NMR (400 MHz, DMSO- d6 ) δ 7.64-7.43 (m, 10H), 5.71(d, J =4.4 _Hz , 1H), 4.58 (s, 1H) , 4.26 (d, J =4.4 Hz, 1H), 3.55-3.44 (m, 2H), 1.49 (s, 3H), 1.29 (s, 3H), 1, 24 (s, 3H), 1.12 (s, 3H), 1.00 (s, 9H).

Step 6: To a solution of (3a R ,5 R ,6 S ,6a R )-5-((( tert- butyldiphenylsilyl)oxy)methyl)-2,2,5,6-tetramethyltetrahydrofuro[2,3- d ][ 1,3]dioxol-6-ol (2.3 g, 5.04 mmol) in 1,4-dioxane (40 ml) and water (10 ml) was added 4-methylbenzenesulfonic acid (0.173 g, 1.01 mmol) at room temperature. The resulting mixture was stirred at 80°C for 2 hours. The reaction mixture was cooled to room temperature and quenched with saturated aqueous NaHCO ₃ (50 ml) and extracted with EtOAc (50 ml x 3). The combined organic layers were washed with saturated aqueous NaHCO ₃ (50 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (10-40% EtOAc/petroleum ether) to give ( 3R , 4S , 5R )-5-((( t- butyldiphenylsilyl)oxy)methyl)-4 ,5-dimethyltetrahydrofuran-2,3,4-triol. MS: 439 (M+Na). ^1H NMR (400 MHz, DMSO- d6 ) δ 7.75-7.39 (m, 10H) _, 5.65 (d, J =7.6 Hz, 1H), 5.04-5.01 ( m, 1H), 4.66 (d, J =8.8 Hz, 1H), 4.35 (s, 1H), 4.06-4.01 (m, 2H), 3.40 (s, 1H ), 1.22 (s, 3H), 1.04 (s, 3H), 0.98 (s, 9H).

Step 7: To a stirred solution of ( 3R , 4S , 5R )-5-((( tert- butyldiphenylsilyl)oxy)methyl)-4,5-dimethyltetrahydrofuran-2,3,4-triol (1.45 g, 3.5 mmol) (co-evaporated with anhydrous MeCN 6 ml × 3) in acetonitrile (20 ml) was added tributylphosphine (1.13 g, 5.6 mmol) and ( E )-diazen-1,2-diylbis(piperidine- 1-ylmethanone) (1.41 g, 5.6 mmol) at ambient temperature under argon. The reaction mixture was stirred for 1 hour at room temperature. The resulting mixture containing (1S,3R,4S,5R)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-3,4-dimethyl-2,6-dioxabicyclo[3,1,0]hexane-4- ol, was used directly in the next step without processing or purification.

Step 8: NaH (418 mg, 10.4 mmol) was added to a stirred solution of 4-chloro- 7H -pyrrolo[2,3- d ]pyrimidine (1.07 g, 6.96 mmol) in DMF (4 mL) at 0°C. The reaction mixture was stirred at room temperature for 0.5 hours. A solution of (1 S ,3 R ,4 S ,5 R )-3-((( tert- butyldiphenylsilyl)oxy)methyl)-3,4- dimethyl-2,6-dioxabicyclo[3,1,0]hexan-4-ol (~3.5 mmol) in MeCN (20 ml) (from the previous step) at room temperature. The resulting mixture was stirred at room temperature for 0.5 h. The reaction mixture was quenched with saturated aqueous NaHCO ₃ (35 ml) and extracted with EtOAc (50 ml x 3). The combined organic layers were washed with water (100 ml) and brine (50 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (1-24% EtOAc/petroleum ether) to give ( 2R , 3S , 4R , 5R )-2-((( tert- butyldiphenylsilyl)oxy)methyl )-5-(4-chloro- 7H -pyrrolo[2,3- d ]pyrimidin-7-yl)-2,3-dimethyltetrahydrofuran-3,4-diol. MS: 552 (M+1). ^1H NMR (300 MHz, DMSO- d6 ) δ 8.58 (s, 1H), _7.68-7.34 (m, 11H), 6.51 (d, J =3.6 Hz, 1H) , 6.15 (d, J =8.4 Hz, 1H), 5.44 (d, J =7.2 Hz, 1H), 4.87 (s, 1H), 4.65-4.60 ( m, 1H), 3.82 (d, J =10.8 Hz, 1H), 3.57 (d, J =11.1 Hz, 1H), 1.34 (s, 3H), 1.18 ( s, 3H), 1.06 (s, 9H).

Stage 9:To solution (2R,3S,4R,5R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-5-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,3-dimethyltetrahydrofuran-3,4-diol (600 mg, 1.09 mmol) in acetone (50 ml) was added 2,2-dimethoxypropane (1.13 g, 10.9 mmol ) and 4-methylbenzenesulfonic acid (19 mg, 0.11 mmol) at room temperature. The reaction mixture was stirred at 40°C for 5 hours. The reaction mixture was quenched with a saturated aqueous solution of NaHCO₃ (40 ml) and acetone was removed under reduced pressure. The aqueous phase was extracted with EtOAc (50 ml x 3). The combined organic layers were washed with brine (50 ml), dried over anhydrous Na₂SO₄And filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (0-40% EtOAc/petroleum ether) to give 7-((3aR,4R.6R,6aS)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2,6,6a-tetramethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidine. MS: 592 (M+1).¹H NMR (400 MHz, CDCl₃) δ 8.66 (s, 1H), 7.65-7.53 (m, 5H), 7.55-7.45 (m, 1H), 7.49-7.28 (m, 5H), 6.48 (d,J=3.7 Hz, 1H), 6.30 (d,J=2.7 Hz, 1H), 5.15 (d,J=2.8 Hz, 1H), 3.64 (d,J=10.8 Hz, 1H), 3.54 (d,J=10.8 Hz, 1H), 1.66 (s, 3H), 1.53 (s, 6H), 1.46 (s, 3H), 1.08 (s, 9H).

Step 10: To a solution of 7-((3a R ,4 R ,6 R ,6a S )-6-((( tert- butyldiphenylsilyl)oxy)methyl)-2,2,6,6a-tetramethyltetrahydrofuro[3,4- d ][1,3]dioxol-4-yl)-4-chloro-7 H -pyrrolo[2,3- d ]pyrimidine (416 mg, 0.702 mmol) in tetrahydrofuran (5 ml) under argon was added tetrabutylammonium fluoride ( 1 M in THF, 2.11 ml, 2.11 mmol) at room temperature. The reaction solution was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (0-20% MeOH/DCM) to give (( 3aS , 4R , 6R , 6aR )-6-(4-chloro- 7H -pyrrolo[2,3- d ] pyrimidin-7-yl)-2,2,3a,4-tetramethyltetrahydrofuro[3,4- d ][1,3]dioxol-4-yl)methanol. MS: 354 (M+1). ^1H NMR (400 MHz, CDCl ₃ ) δ 8.69 (s, 1H), 7.41 (d, J= 3.7 Hz, 1H), 6.67 (d, J =3.7 Hz, 1H ), 6.10 (d, J =5.1 Hz, 1H), 5.14 (d, J =5.1 Hz, 1H), 4.84 (dd, J =8.9, 3.8 Hz , 1H), 3.74-3.55 (m, 2H), 1.71 (s, 6H), 1.59 (s, 3H), 1.38 (s, 3H).

Stage 11:To a solution of oxalyl dichloride (201 mg, 1.6 mmol) in anhydrous DCM (5 ml) was added DMSO (309 mg, 3.96 mmol) dropwise at -78°C under argon. The resulting solution was stirred at -78°C for 0.5 hours. Then the solution ((3a) was added dropwise to this reaction systemS,4R.6R,6aR)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2,3a,4-tetramethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol (140 mg, 0.40 mmol) in anhydrous DCM (5 ml) at -78°C. The resulting solution was stirred at -78°C for an additional 0.5 h. TEA (400 mg, 4 mmol) was then added at -78°C. The resulting solution was stirred for 0.5 h at -78°C. The reaction solution was quenched with H₂O (5 ml) at 0°C and diluted with DCM (30 ml). The organic layer was washed with saturated aqueous NaHCO solution₃ (40 ml), saturated saline (30 ml), dried over anhydrous Na₂SO₄And filtered. The filtrate was concentrated under reduced pressure to give (3aS,4S.6R,6aR)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2,3a,4-tetramethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbaldehyde, which was used directly in the next step without further purification. MS: 352 (M+1).¹H NMR (400 MHz, CDCl₃) δ 9.52 (s, 1H), 8.68 (s, 1H), 7.46 (d,J=3.7 Hz, 1H), 6.73 (d,J=3.7 Hz, 1H), 6.34 (d,J=2.3 Hz, 1H), 5.29 (d,J=2.3 Hz, 1H), 1.73 (s, 3H), 1.67 (s, 3H), 1.51 (s, 3H), 1.49 (s, 3H).

Step 12: To a solution of methyltriphenylphosphonium bromide (395 mg, 1.11 mmol) in anhydrous tetrahydrofuran (5 ml) was added n -BuLi (2.5 M in THF, 0.411 ml, 1.03 mmol) dropwise at -10°C in an argon atmosphere. The reaction mixture was stirred at room temperature for 0.5 hours. Then a solution of ( 3aS , 4S , 6R , 6aR )-6-(4-chloro- 7H -pyrrolo[2, 3- d ]pyrimidin-7-yl)-2,2,3a,4-tetramethyltetrahydrofuro[3,4- d ][1,3]dioxol-4-carbaldehyde (139 mg, 0.396 mmol) in anhydrous tetrahydrofuran (8 ml ) at -10°C. The reaction mixture was stirred for 1 hour at room temperature. The reaction mixture was quenched with a saturated aqueous solution of NH ₄ Cl (20 ml) at 0°C. The reaction solution was diluted with EtOAc (100 ml), washed with H ₂ O (20 ml) and brine (30 ml), dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-30% EtOAc/petroleum ether) to give 4-chloro-7-(( 3aR , 4R , 6R , 6aS )-2,2,6,6a-tetramethyl-6 -vinyltetrahydrofuro[3,4- d ][1,3]dioxol-4-yl)-7 H -pyrrolo[2,3- d ]pyrimidine. MS: 350 (M+1). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.72 (s, 1H), 7.42 (d, J =3.7 Hz, 1H), 6.70 (d, J =3.7 Hz, 1H ), 6.50 (d, J =2.5 Hz, 1H), 5.88 (dd, J =17.3, 11.0 Hz, 1H), 5.21 (dd, J =17.3, 1.3 Hz, 1H), 5.13 (dd, J =11.0, 1.3 Hz, 1H), 4.89 (d, J =2.5 Hz, 1H), 1.66 (s, 3H), 1.58 (s, 3H), 1.55 (s, 3H), 1.47 (s, 3H).

Step 13: 4-chloro-7-((3a R ,4 R ,6 R ,6a S )-2,2,6,6a-tetramethyl-6-vinyltetrahydrofuro[3,4 - d ][1,3]dioxol-4-yl)-7 H -pyrrolo[2,3- d ]pyrimidine (50 mg, 0.143 mmol), 1,4-dioxane (8 ml) and NH ₃ H ₂ O (8 ml, 25%-28% wt.) at room temperature. The mixture was tightly sealed and then stirred at 90°C for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-10% MeOH/DCM) to give 7-(( 3aR , 4R , 6R , 6aS )-2,2,6,6a-tetramethyl-6-vinyltetrahydrofuro[3, 4- d ][1,3]dioxol-4-yl)-7 H -pyrrolo[2,3- d ]pyrimidin-4-amine. MS: 331 (M+1). ^1H NMR (400 MHz, CDCl ₃ ) δ 8.38 (s, 1H), 7.15 (d, J =3.7 Hz, 1H), 6.49 (d, J =2.6 Hz, 1H ), 6.46 (d, J =3.7 Hz, 1H), 5.89 (dd, J =17.3, 11.0 Hz, 1H), 5.33 (s, 2H), 5.23 (dd, J =17.3, 1.4 Hz, 1H), 5.12 (dd, J =11.0, 1.4 Hz, 1H), 4.82 (d, J =2.5 Hz, 1H), 1.65 (s, 3H), 1.57 (s, 3H), 1.54 (s, 3H), 1.45 (s, 3H).

Step 14: To a solution of 7-((3a R ,4 R ,6 R ,6a S )-2,2,6,6a-tetramethyl-6-vinyltetrahydrofuro[3,4- d ][1,3]dioxol-4 -yl) -7H- pyrrolo[2,3- d ]pyrimidin-4-amine (20 mg, 0.061 mmol) in anhydrous THF (1.0 mL) was added 9-BBN in THF (0.605 mL, 0.303 mmol, 0 .5 M) dropwise at 0°C in an argon atmosphere. The reaction solution was stirred at 50°C for 1 hour. The resulting solution was directly used in the next step.

Step 15: To the resulting solution was added tribasic potassium phosphate (64.3 mg, 0.303 mmol) in water (0.2 ml) dropwise at 0°C under argon atmosphere. The reaction solution was stirred at room temperature for 0.5 h. 3-Bromo-7-iodo- N- (4-methoxybenzyl)quinoline-2-amine (31.3 mg, 0.067 mmol) in tetrahydrofuran was accordingly added to this reaction system (0.3 ml) and complex 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride with dichloromethane (4.95 mg, 6.06 µmol) at room temperature. The reaction mixture was heated at 70°C for 2 h under microwave irradiation. The reaction mixture was then cooled to room temperature, diluted with water (5 ml) and extracted with EtOAc (2 x 20 ml). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (developed with 10% MeOH in DCM) to give 7-(2-(( 3aS , 4R , 6R , 6aR )-6-(4-amino- 7H -pyrrolo[2, 3- d ]pyrimidin-7-yl)-2,2,3a,4-tetramethyltetrahydrofuro[3,4- d ][1,3]dioxol-4-yl)ethyl)-3-bromo- N- (4- methoxybenzyl)quinoline-2-amine. MS: 673/675 (M+1/M+3). ^1H NMR (400 MHz, _CDCl3 ) δ 8.35 (s, 1H), 8.05 (s, 1H), 7.43-7.29 (m, 4H), 7.19 (d, J = 3.7 Hz, 1H), 6.93 (d, J =8.6 Hz, 2H), 6.74 (d, J =8.1 Hz, 1H), 6.47 (d, J =3, 7 Hz, 1H), 6.34 (d, J = 2.4 Hz, 1H), 5.65-5.54 (m, 1H), 5.40-5.29 (m, 2H), 4, 77 (d, J =5.0 Hz, 2H), 3.84 (s, 3H), 2.76-2.68 (m, 1H), 2.55-2.45 (m, 1H), 2 .05-1.93 (m, 1H), 1.87-1.76 (m, 1H), 1.66 (s, 3H), 1.63 (s, 3H), 1.54 (s, 3H ), 1.51 (s, 3H).

Step 16: Solution 7-(2-(( 3aS , 4R , 6R , 6aR )-6-(4-amino- 7H -pyrrolo[2,3- d ]pyrimidin-7-yl)-2 ,2,3a,4-tetramethyltetrahydrofuro[3,4- d ][1,3]dioxol-4-yl)ethyl)-3-bromo- N- (4-methoxybenzyl)quinolin-2-amine (40 mg, 0.059 mmol) in TFA (2 mL, 26.0 mmol) was stirred at 60°C for 1 hour. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give the crude product N -(7-(2-(( 2R , 3S , 4R , 5R )-5-(4-amino- 7H -pyrrolo[2,3- d ]pyrimidin-7-yl)-3,4-dihydroxy-2,3-dimethyltetrahydrofuran-2- yl)ethyl)-3-bromoquinolin-2-yl)-2,2,2-trifluoroacetamide, which was used directly in the next step without further purification.

Step 17: To a solution of crude N -(7-(2-((2 R ,3 S ,4 R ,5 R )-5-(4-amino-7 H -pyrrolo[2,3- d ]pyrimidine-7 -yl)-3,4-dihydroxy-2,3-dimethyltetrahydrofuran-2-yl)ethyl)-3-bromoquinolin-2-yl)-2,2,2-trifluoroacetamide (calculated as 0.059 mmol) in methanol (3 ml ) K ₂ CO ₃ (24.6 mg, 0.178 mmol) was added at room temperature. The reaction mixture was stirred at 60°C for 1 hour. The solid was filtered and washed with MeOH (0.5 ml). The filtrate was concentrated under reduced pressure and the residue was purified by reverse phase column chromatography (ACN/water with 5 mM NH ₄ HCO ₃ modifier) to give (2 R ,3 S ,4 R ,5 R )-2-(2-(2- amino-3-bromoquinolin-7-yl)ethyl)-5-(4-amino- 7H -pyrrolo[2,3- d ]pyrimidin-7-yl)-2,3-dimethyltetrahydrofuran-3,4-diol in form of a solid. MS: 513/515 (M+1/M+3). ^1H NMR (400 MHz, DMSO- d6 ) δ 8.33 (s, 1H), 8.06 (s, 1H), 7.58 ₍ d, J= 8.0 Hz, 1H), 7.38 (d, J= 4.0 Hz, 1H), 7.30 (s, 1H), 7.08 (d, J= 8.4 Hz, 1H), 7.01 (lat s, 2H), 6 .64 (d, J = 3.6 Hz, 1H), 6.58 (br.s, 2H), 6.03 (d, J = 8.0 Hz, 1H), 5.29 (br.s, 1H), 4.79-4.77 (m, 1H), 4.72 (s, 1H), 2.66-2.59 (m, 2H), 2.20-2.15 (m, 1H) , 1.70-1.63 (m, 1H), 1.25 (s, 3H), 1.17 (s, 3H).

Example 5

(2 R ,3 R ,3a S ,6 S ,6a R )-6-((2-amino-3-bromoquinolin-7-yl)oxy)-2-(4-chloro-7 H -pyrrolo[2, 3- d ]pyrimidin-7-yl)hexahydro- 2H -cyclopenta[ b ]furan- 3,3a- diol

Step 1: ( 3R , 3aS , 6R , 6aR )-2-methoxyhexahydro- 2H -cyclopenta[ b ]furan- 3,3a ,6-triol (2 g, 10 mmol) was co-evaporated with anhydrous toluene (5 ml × 3) and then dissolved again in acetone (50 ml). To this solution was added 4-methylbenzenesulfonic acid (0.091 g, 0.53 mmol) followed by 2,2-dimethoxypropane (2.74 g, 26.3 mmol). The resulting mixture was stirred at ambient temperature for 1 hour. The pH of the resulting solution was adjusted to 8 with saturated aqueous NaHCO ₃ solution (50 ml) at 0°C. The resulting mixture was extracted with EtOAc (150 ml x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica column chromatography (EtOAc/petroleum ether) to give (3aR,5aR,6R,8aR)-4-methoxy-2,2-dimethylhexahydrocyclopenta[2,3]furo[3,4-d][1, 3]dioxol-6-ol. MS: 248.20 (M+NH ₄ ). ^1H NMR (300 MHz, DMSO- d6 ) δ 4.96 (s, 1H) _, 4.41 (d, J= 5.1 Hz, 1H), 4.17 (s, 1H), 4.10 (d, J= 6.0 Hz, 1H), 3.88-3.79 (m, 1H), 3.33 (s, 3H), 2.04-1.92 (m, 1H), 1, 76-1.62 (m, 3H), 1.39 (s, 3H), 1.31 (s, 3H). The column was then eluted with 45-50% EtOAc in petroleum ether to give (3aR,5aR,6R,8aR)-4-methoxy-2,2-dimethylhexahydrocyclopenta[2,3]furo[3,4-d][1,3 ]dioxol-6-ol. MS: 248 (M+NH ₄ ). ^1H NMR (300 MHz, DMSO- d6 ) δ 4.92 (d, J= 4.2 Hz, 1H) _, 4.72 (d, J= 6.0 Hz, 1H), 4.35 (d , J =4.2 Hz, 1H), 4.00 (d, J = (5.4 Hz, 1H), 3.91-3.82 (m, 1H), 3.35 (s, 3H), 2.09-1.97 (m, 1H), 1.83-1.62 (m, 2H), 1.52-1.43 (m, 1H), 1.40 (s, 3H), 1. 31 (s, 3H).

Step 2: To a solution of (3aR,5aR,6R,8aR)-4-methoxy-2,2-dimethylhexahydrocyclopenta[2,3]furo[3,4-d][1,3]dioxol-6-ol (748 mg , 3.25 mmol) to DCM (30 ml) was added N,N -dimethylpyridin-4-amine (437 mg, 3.57 mmol) at room temperature. Triethylamine (362 mg, 3.57 mmol) was then added followed by 4-methylbenzene-1-sulfonyl chloride (929 mg, 4.87 mmol). The reaction mixture was stirred for 16 hours at 25°C. The resulting mixture was quenched with saturated aqueous NH ₄ Cl (200 ml) and extracted with DCM (100 ml x 3). The combined organic layers were washed with brine (200 ml) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica column chromatography (EtOAc/petroleum ether) to give (3aR,5aR,6R,8aR)-4-methoxy-2,2-dimethylhexahydrocyclopenta[2,3]furo[3 ,4-d][1,3]dioxol-6-yl 4-methylbenzenesulfonate. MS: 402 (M+NH ₄ ). ¹ H NMR (300 MHz, Chloroform- d ) δ 7.85-7.81 (m, 2H), 7.35-7.32 (m, 2H), 4.94 (d, J = 4.2 Hz , 1H), 4.74-4.67 (m, 1H), 4.35 (d, J =4.2 Hz, 1H), 4.15 (d, J =5.1 Hz, 1H), 3 .38 (s, 3H), 2.44 (s, 3H), 2.18-1.75 (m, 4H), 1.49 (s, 3H), 1.37 (s, 3H).

Step 3: To a solution of (3aR,5aR,6R,8aR)-4-methoxy-2,2-dimethylhexahydrocyclopenta[2,3]furo[3,4-d][1,3]dioxol-6-yl 4-methylbenzenesulfonate (400 mg, 1.04 mmol) and 2-amino-3-bromoquinolin-7-ol (249 mg, 1.04 mmol) (azeotroped with toluene 2 ml x 3) in NMP (5 ml) was added Cs ₂ CO ₃ (1.02 g, 3.12 mmol). The reaction mixture was stirred at 90°C for 2 hours in an argon atmosphere. The reaction mixture was cooled to room temperature and quenched with saturated aqueous NH ₄ Cl (60 ml) and extracted with DCM (60 ml x 3). The combined organic layers were washed with brine (60 mL) and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica column chromatography (EtOAc/petroleum ether). The product was further purified by reverse phase HPLC (ACN/water) to give 3-bromo-7-(((3aR,5aR,6S,8aR)-4-methoxy-2,2-dimethylhexahydrocyclopenta[2,3]furo[3, 4-d][1,3]dioxol-6-yl)oxy)quinoline-2-amine. MS: 451/453 (M+1/M+3). ^1H NMR (300 MHz, Chloroform- d ) δ 8.06 (s, 1H), 7.46 (d, J= 9.0 Hz, 1H), 7.06 (d, J= 2.4 Hz, 1H), 6.95 (dd, J= 8.7, 2.4 Hz, 1H), 5.28 (s, 2H), 4.93 (d, J= 4.2 Hz, 1H), 4, 66 (d, J= 4.2 Hz, 1H), 4.63-4.50 (m, 2H), 3.49 (s, 3H), 2.45-2.33 (m, 1H), 2 .26-2.14 (m, 2H), 2.01-1.88 (m, 1H), 1.55 (s, 3H), 1.44 (s, 3H).

Stage 4:Solution of 3-bromo-7-(((3aR,5aR,6S,8aR)-4-methoxy-2,2-dimethylhexahydrocyclopenta[2,3]furo[3,4-d][1,3]dioxol-6- yl)oxy)quinoline-2-amine (315 mg, 0.698 mmol) in HCl (10 ml, 4.00 mmol, 0.4 M in MeCN/H₂O=3:2 (v/v)) was stirred at 90°C for 2 hours. The reaction mixture was quenched with a saturated aqueous solution of NaHCO₃ (50 ml) and extracted with DCM (50 ml x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na₂SO₄And filtered. The filtrate was concentrated under reduced pressure. The combined residue was purified by reverse phase HPLC (ACN/water) to give (3R,3aS.6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)oxy)hexahydro-2H-cyclopenta[b]furan-2,3,3a-triol. MS: 397/399 (M+1/M+3).¹H NMR (300 MHz, Methanol-d ₄) δ 8.20 (s, 1H), 7.56-7.52 (m, 1H), 7.11 (d,J=2.4 Hz, 1H), 7.02 (d,J=2.4 Hz, 1H), 6.97-6.92 (m, 1H), 5.34 (d,J=4.2 Hz, 1H), 5.20 (d,J=3.0 Hz, 1H), 4.76-4.74 (m, 1H), 4.64-4.62 (m, 1H), 4.36 (s, 1H), 4.18 (s, 1H), 3.79 (d,J=4.2 Hz, 1H), 3.63 (d,J=3.3 Hz, 1H), 2.46-1.81 (m, 4H).

Step 5: To a stirred solution of ( 3R , 3aS , 6S , 6aR )-6-((2-amino-3-bromoquinolin-7-yl)oxy)hexahydro- 2H- cyclopenta[ b ]furan-2 ,3,3a-triol (240 mg, 0.604 mmol) in anhydrous MeCN (10 ml) was added tributylphosphine (0.241 ml, 0.967 mmol) followed by the addition of ( E )-diazen-1,2-diylbis(piperidin-1-ylmethanone) (229 mg, 0.906 mmol) at room temperature. The reaction mixture was stirred at ambient temperature for 20 minutes and a solution containing crude (1aS,2aR,3S,5aR,5bR)-3-((2-amino-3-bromoquinolin-7-yl)oxy)hexahydro-5aH- cyclopenta[b]oxyreno[2,3-d]furan-5a-ol was concentrated under reduced pressure. The product was used in the next step without purification.

Stage 6:To a stirred solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (184 mg, 1.20 mmol) in anhydrous DMF (4 ml), sodium hydride (72 mg, 1.8 mmol) was added at 0°C. The suspension was stirred at room temperature for 30 minutes, then the suspension was transferred to a solution containing crude (1aS,2aR,3S,5aR,5bR)-3-((2-amino-3-bromoquinolin-7-yl)oxy)hexahydro- 5aH-cyclopenta[b]oxyreno[2,3-d]furan-5a-ol in ACN (4 ml), via syringe. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with a saturated aqueous solution of NH₄Cl (50 ml) and extracted with DCM (50 ml x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na₂SO₄And filtered. The filtrate was concentrated under reduced pressure and the residue was purified by reverse phase HPLC (ACN/water with 5 mM aq. ammonium bicarbonate). The crude product was further purified by preparative TLC, developed with DCM:MeOH=10:1 (v:v) (rf=0.6) to give (2R,3R,3aS.6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)oxy)-2-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)hexahydro-2H-cyclopenta[b]furan-3.3a-diol. MS: 532/534 (M+1/M+3).¹H NMR (300 MHz, DMSO-d ₆) δ 8.72 (s, 1H), 8.27 (s, 1H), 8.18 (d,J=3.9 Hz, 1H), 7.57 (d,J=8.7 Hz, 1H), 6.88-6.83 (m, 3H), 6.61 (lat, 2H), 6.17 (d,J=8.4 Hz, 1H), 5.53 (d,J=7.2 Hz, 1H), 5.44 (s, 1H), 4.67 (d,J=4.8 Hz, 1H), 4.48 (t,J=7.8 Hz, 1H), 4.15 (s, 1H), 2.51-2.50 (m, 1H), 2.10-1.95 (m, 3H).

Example 6

(2 R ,3 R ,3a S ,6 S ,6a R )-6-((2-amino-3-bromoquinolin-7-yl)oxy)-2-(4-amino-7 H -pyrrolo[2, 3- d ]pyrimidin-7-yl)hexahydro- 2H -cyclopenta[ b ]furan- 3,3a- diol

Step 1: Solution (2 R ,3 R ,3a S ,6 S ,6a R )-6-((2-amino-3-bromoquinolin-7-yl)oxy)-2-(4-chloro-7 H - pyrrolo[2,3- d ]pyrimidin-7-yl)hexahydro- 2H -cyclopenta[ b ]furan-3,3a - diol (55 mg, 0.10 mmol), 1,4-dioxane (15 ml) and NH ₃ ^. H ₂ O (15 ml) was stirred in a sealed tube at 90°C for 10 hours. The reaction mixture was concentrated under reduced pressure and the residue was diluted with a saturated aqueous solution of NH ₄ Cl (30 ml). The mixture was extracted with DCM (25 ml x 5). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica column chromatography (MeOH/DCM) to give ( 2R ,3R, 3aS , 6S , 6aR )-6-((2-amino-3-bromoquinoline-7 -yl)oxy)-2-(4-amino-7 H -pyrrolo[2,3- d ]pyrimidin-7-yl)hexahydro-2 H -cyclopenta[ b ]furan-3,3 a -diol. MS: 513/515 (M+1/M+3). ^1H NMR (400 MHz, DMSO- d6 ) δ 8.26 (s, 1H), 8.09 (s, 1H), 7.57 ₍ d, J =8.8 Hz, 1H), 7.50 (d, J =3.6 Hz, 1H), 7.05 (br.s, 2H), 6.87-6.83 (m, 2H), 6.66 (d, J =4.0 Hz, 1H), 6.53 (brs, 2H), 6.02 (d, J =8.8 Hz, 1H), 5.36 (d, J =7.2 Hz, 1H), 5.31 ( s, 1H), 4.60 (d, J =4.8 Hz, 1H), 4.40 (t, J =7.6 Hz, 1H), 4.08 (s, 1H), 2.52- 2.50 (m, 1H), 2.07-1.99 (m, 3H).

Example 7

(2 R ,3 R ,3a S ,6 S ,6a R )-6-((2-amino-3-bromoquinolin-7-yl)oxy)-2-(4-methyl-7 H -pyrrolo[2, 3-d]pyrimidin-7-yl)hexahydro- 2H -cyclopenta[b]furan-3,3a-diol

Step 1: To a stirred solution of (3 R ,3a S ,6 S ,6a R )-6-((2-amino-3-bromoquinolin-7-yl)oxy)hexahydro-2 H -cyclopenta[b]furan-2 ,3,3a-triol (1.0 g, 2.5 mmol) in anhydrous MeCN (30 ml) under argon was added ( E )-diazen-1,2-diylbis(piperidin-1-ylmethanone) (1.13 g, 4.53 mmol) and tributylphosphine (1.20 ml, 4.78 mmol) at 25°C. The resulting mixture was stirred at 25°C for 40 minutes. This solution was used in the next step without isolation or characterization.

Step 2: To a stirred solution of 4-methyl- 7H -pyrrolo[2,3-d]pyrimidine (0.671 g, 5.04 mmol) (co-evaporated with anhydrous toluene 10 ml x 3, then used) in anhydrous DMF (12 ml) sodium hydride (0.302 g, 7.56 mmol) was added at 0°C. The suspension was stirred at room temperature for 30 minutes. The suspension was transferred via syringe at ambient temperature into the solution from the previous step, which contained ( 1aS , 2aR , 3S , 5aR , 5bR )-3-((2-amino-3-bromoquinolin-7-yl)oxy )hexahydro-1a H -cyclopenta[b]oxyreno[2,3-d]furan-5a-ol (calculated as ~2.52 mmol). The resulting mixture was stirred at room temperature for 30 minutes. The reaction was quenched with saturated aqueous NH ₄ Cl (40 ml) and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (0-100% acetonitrile/water with 5 mM ammonium bicarbonate modifier) to give ( 2R , 3R , 3aS , 6S , 6aR )-6-((2-amino- 3-bromoquinolin-7-yl)oxy)-2-(4-methyl- 7H -pyrrolo[2,3-d]pyrimidin-7-yl)hexahydro- 2H- cyclopenta[b]furan-3,3a- diol as a solid. MS: 512/514 (M+1/M+3). ^1H NMR (400 MHz, DMSO- d6 ) δ 8.70 (s, 1H), 8.26 (s, 1H), 7.95 ₍ d, J =4.0 Hz, 1H), 7.57 (d, J =8.8 Hz, 1H), 6.88-6.83 (m, 3H), 6.52 (brs, 2H), 6.15 (d, J =8.4 Hz, 1H), 5.45 (d, J =7.2 Hz, 1H), 5.39 (s, 1H), 4.64 (d, J =4.8 Hz, 1H), 4.48 (t, J =8.0 Hz, 1H), 4.14 (s, 1H), 2.69 (s, 3H), 2.56-2.50 (m, 1H), 2.10-1.99 (m , 3H).

Example 8

(2 R ,3 R ,3a S ,6 S ,6a R )-6-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(4-methyl-7 H -pyrrolo[2, 3- d ]pyrimidin-7-yl)hexahydro- 2H -cyclopenta[ b ]furan-3,3a-diol

Stage 1:To a solution of oxalyl dichloride (1.47 ml, 17.4 mmol) in anhydrous DCM (20 ml) was added DMSO (3.08 ml, 43.4 mmol) in anhydrous DCM (2 ml) at -78°C under argon. The reaction mixture was stirred at -65°C for 0.5 hours. A solution of (3aR,5aR,6R,8aR)-4-methoxy-2,2-dimethylhexahydrocyclopenta[2,3]furo[3,4- d][1,3]dioxol-6-ol (1.0 g, 4.34 mmol) in anhydrous DCM (10 ml) at -65°C. The solution was stirred for another 0.5 h at -65°C. At this temperature, TEA (6.05 mL, 43.4 mmol) was added to the reaction mixture. The resulting solution was stirred for 0.5 h at -65°C. The reaction was quenched with H₂O (50 ml) at 0°C and extracted with DCM (100 ml × 3). The combined organic layers were washed with saturated aqueous NaHCO₃ (40 ml) and saturated saline (30 ml), dried over anhydrous Na₂SO₄And filtered. The filtrate was concentrated under reduced pressure to give (3aR,5aS,8aS)-4-methoxy-2,2-dimethyltetrahydrocyclopenta[2,3]furo[3,4-d][1,3]dioxol-6(5aH)-one , which was azeotroped with toluene (10 ml x 3) and used directly in the next step without purification.¹H NMR (400 MHz, DMSO-d ₆) δ 5.77 (d,J=1.6 Hz, 1H), 4.98 (d,J=1.6 Hz, 1H), 4.40 (d,J=1.6 Hz, 1H), 4.16 (s, 1H), 3.10 (s, 3H), 2.50-2.30 (m, 3H), 1.39 (s, 3H), 1 .37 (s, 3H).

Stage 2:To a solution of methyltriphenylphosphonium bromide (4.34 g, 12.2 mmol) in anhydrous THF (20 ml) was addedn-BuLi (2.5 M in THF) (4.52 mL, 11.3 mmol) dropwise at -60°C under argon. The reaction mixture was stirred at room temperature for 0.5 hours. Then a solution of (3aR,5aS,8aS)-4-methoxy-2,2-dimethyltetrahydrocyclopenta[2,3]furo[3,4-d][1] was added dropwise ,3]dioxol-6(5aH)-one (1.8 g, crude, 4.3 mmol) in anhydrous THF (20 ml) at -60°C. The reaction mixture was stirred at room temperature for 1 hour. The reaction was quenched with a saturated aqueous solution of NH₄Cl (50 ml) at 0°C. The mixture was extracted with EtOAc (200 ml x 2) and the combined organic layers were washed with brine (50 ml), dried over anhydrous Na₂SO₄And filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/petroleum ether) to give (3aR,5aR,8aR)-4-methoxy-2,2-dimethyl-6-methylenehexahydrocyclopenta[2,3]furo[3,4-d][1 ,3]dioxole.¹H NMR (400 MHz, Chloroform-d) δ 5.17 (s, 1H), 5.07 (s, 1H), 5.02 (t,J=1.1 Hz, 1H), 4.64 (s, 1H), 4.30 (t,J=1.1 Hz, 1H), 3.29 (s, 3H), 2.75-2.59 (m, 1H), 2.44-2.33 (m,1H), 2.23-2, 09 (m, 1H), 2.15-2.05 (m, 1H), 1.51 (s, 3H), 1.41 (s, 3H).

Step 3: To a solution of (3aR,5aR,8aR)-4-methoxy-2,2-dimethyl-6-methylenehexahydrocyclopenta[2,3]furo[3,4-d][1,3]dioxole (300 mg, 1 mmol) in anhydrous THF (3 mL), 9-BBN (0.5 M in THF, 13.3 mL, 6.63 mmol) was added dropwise at 0 °C under argon. The reaction mixture was stirred at 50°C for 1 hour. This solution was used in the next step without characterization.

Step 4: To the solution containing the borane intermediate from the previous step was added a solution of potassium phosphate tribasic (1.41 g, 6.63 mmol) in water (3 ml) at 0°C under argon. The reaction mixture was stirred at room temperature for 0.5 h. A solution of 3-bromo-7-iodo- N- (4-methoxybenzyl)quinoline-2-amine (684 mg, 1.46 mmol) and complex 1,1' was added -bis(diphenylphosphino)ferrocene-palladium(II) dichloride with dichloromethane (108 mg, 0.133 mmol) in THF (5 ml) at room temperature. The reaction mixture was stirred at 50°C for 1.5 hours. The reaction mixture was cooled to room temperature and partitioned between brine (80 ml) and EtOAc (100 ml). The aqueous phase was back-extracted with EtOAc (100 ml x 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica column chromatography (EtOAc/petroleum ether) to give 3-bromo-7-(((3aR,5aR,8aR)-4-methoxy-2,2-dimethylhexahydrocyclopenta[2,3]furo[3,4 -d][1,3]dioxol-6-yl)methyl)-N-(4-methoxybenzyl)quinolin-2-amine. The crude product was used directly in the next step without further purification. MS: 569/571 (M+1/M+3).

Step 5: Solution of 3-bromo-7-(((3aR,5aR,8aR)-4-methoxy-2,2-dimethylhexahydrocyclopenta[2,3]furo[3,4-d][1,3]dioxol-6 -yl)methyl)-N-(4-methoxybenzyl)quinolin-2-amine (890 mg crude, 1.33 mmol) in HCl (0.4 M in MeCN/H ₂ O (3:2, v/v .), 10 ml, 4 mmol) was stirred at 90°C for 1 hour. The reaction mixture was cooled to 0°C and quenched with saturated aqueous Na ₂ CO ₃ (60 ml) and extracted with EtOAc (100 ml x 3) . The combined organic layers were washed with brine (60 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH/DCM) to give ( 3R , 3aS , 6aR )-6-((3-bromo-2-((4-methoxybenzyl)amino)quinolin-7-yl)methyl) hexahydro- 2H -cyclopenta[ b ]furan-2,3,3a-triol. MS: 515/517 (M+1/M+3). ^1H NMR (400 MHz, DMSO- d6 ) δ 8.33 (s, 1H) _, 7.57 (d, J =8.3 Hz, 1H), 7.35 (d, J =8.4 Hz , 3H), 7.13 (d, J= 7.5 Hz, 2H), 6.88 (d, J = 8.2 Hz, 2H), 5.93 (d, J= 6.5 Hz, 1H ), 5.20-5.12 (m, 1H), 4.64 (t, J =8.1 Hz, 3H), 4.46 (d, J =8.1 Hz, 1H), 3.93 (d, J =4.7 Hz, 1H), 3.72 (d, J = 1.1 Hz, 3H), 3.49 (dd, J =7.5, 4.1 Hz, 1H), 2 .87-2.76 (m, 1H), 2.65 (dd, J =13.6, 7.0 Hz, 1H), 2.20-1.19 (m, 5H).

Step 6: To a stirred solution of (3 R ,3a S ,6a R )-6-((3-bromo-2-((4-methoxybenzyl)amino)quinolin-7-yl)methyl)hexahydro- 2H -cyclopenta[ b ]furan-2,3,3a-triol (250 mg, 0.486 mmol) in anhydrous MeCN (9 ml) was added tributylphosphine (176 mg, 0.869 mmol) followed by the addition of ( E )-diazen-1,2-diylbis(piperidine -1-ylmethanone) (206 mg, 0.815 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 hour and the solution was used directly in the next step without characterization.

Step 7: Sodium hydride (60% dispersion in mineral oil) (58, 2 mg, 1.46 mmol) at 0°C. The suspension was stirred at room temperature for 30 minutes. The suspension was transferred to the solution from the previous step containing the epoxy intermediate via a syringe and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 ml) and extracted with EtOAc (40 ml x 3) . The combined organic layers were washed with brine (40 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (MeOH/DCM) to give (2R,3R,3aS,6aR)-6-((3-bromo-2-((4-methoxybenzyl)amino)quinolin-7-yl)methyl)-2- (4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol. MS: 630/632 (M+1/M+3). ^1H NMR (400 MHz, DMSO- d6 ) δ 8.69 (s, _1H ), 8.32 (d, J= 6.0 Hz, 1H), 8.02 (s, 1H), 7.54 (d, J =8.2 Hz, 1H), 7.33 (d, J =8.4 Hz, 2H), 7.14-7.04 (m, 3H), 6.91-6.80 ( m, 4H), 6.03(d, J =8.1 Hz, 1H), 5.30 (d, J =7.0 Hz, 1H), 5.12 (s, 1H), 4.61 ( d, J =6.2 Hz, 2H), 4.22 (t, J =7.6 Hz, 1H), 4.04 (d, J =6.6 Hz, 1H), 3.72 (s, 3H), 2.83 (dd, J= 13.7, 7.2 Hz, 1H), 2.69 (s, 3H), 2.65 (s, 1H), 2.37-2.22 (m , 1H), 1.99-1.93 (m, 1H), 1.55 (d, J =6.5 Hz, 2H).

Step 8: Solution of (2R,3R,3aS,6aR)-6-((3-bromo-2-((4-methoxybenzyl)amino)quinolin-7-yl)methyl)-2-(4-methyl-7H- pyrrolo[2,3-d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol (150 mg, 0.21 mmol) in TFA (2 ml) was stirred at 60°C in for 1 hour. The reaction mixture was quenched with saturated aqueous NaHCO ₃ (50 ml) and extracted with EtOAc (50 ml x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC on silica (MeOH/DCM) to give the crude product as a solid. The crude product was further purified by reverse phase HPLC (ACN/water with 5 mM ammonium bicarbonate modifier) to give ( 2R , 3R , 3aS ,6S, 6aR )-6-((2-amino-3-bromoquinoline -7-yl)methyl)-2-(4-methyl-7 H -pyrrolo[2,3- d ]pyrimidin-7-yl)hexahydro-2 H -cyclopenta[ b ]furan-3,3a-diol. MS: 510/512 (M+1/M+3). ^1H NMR (400 MHz, DMSO- d6 ) δ 8.69 (s, 1H), 8.30 (s, 1H), 7.87 ₍ d, J =3.6 Hz, 1H), 7.54 (d, J =8.4 Hz, 1H), 7.27 (s, 1H), 7.08 (dd, J =8.4, 1.6 Hz, 1H), 6.82 (d, J = 3.6 Hz, 1H), 6.53 (br.s, 2H), 6.01 (d, J = 8.0 Hz, 1H), 5.30 (d, J = 6.8 Hz, 1H) , 5.11 (s, 1H), 4.22 (t, J= 7.6 Hz, 1H), 4.00 (d, J = 5.6 Hz, 1H), 2.83 (dd, J = 13.6, 7.8 Hz, 1H), 2.70 (s, 3H), 2.64 (dd, J =13.6, 7.6 Hz, 1H), 2.35-2.24 (m , 1H), 1.97 (dd, J = 12.4, 5.6 Hz, 1H), 1.79-1.68 (m, 2H), 1.55 (dt, J = 12.4, 6 ,4 Hz, 1H).

Example 9

(2 R ,3 R ,3a S ,6S,6a R )-6-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(4-amino-7 H -pyrrolo[2,3 - d ]pyrimidin-7-yl)hexahydro-2 H -cyclopenta[ b ]furan-3,3a-diol

Step 1: To a stirred solution of (3 R ,3a S ,6a R )-6-((3-bromo-2-((4-methoxybenzyl)amino)quinolin-7-yl)methyl)hexahydro- 2H -cyclopenta[ b ]furan-2,3,3a-triol (70 mg, 0.14 mmol) in anhydrous MeCN (3 ml) was added ( E )-diazen-1,2-diylbis(piperidin-1-ylmethanone) (51.4 mg, 0.204 mmol) in MeCN (0.3 ml) dropwise at 0°C under argon. Tributylphosphine (0.054 mL, 0.22 mmol) was then added dropwise at 0°C. The reaction mixture was then stirred at 35°C for 1 hour. The resulting solution was used directly in the next step without further purification.

Step 2: To a stirred suspension of 4-chloro- 7H -pyrrolo[2,3- d ]pyrimidine (39.0 mg, 0.254 mmol) in anhydrous ACN (3 mL) was added DBU (0.039 mL, 0.26 mmol) at room temperature in an argon atmosphere. The resulting solution was stirred at room temperature for 30 minutes. The solution from the previous step was then transferred through a syringe at room temperature under an argon atmosphere. The resulting mixture was stirred at 35°C for 2 hours. The reaction was quenched with brine (20 ml) and extracted with EtOAc (50 ml x 3). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica column chromatography (MeOH/DCM) to give ( 2R , 3R , 3aS , 6S , 6aR )-6-((3-bromo-2-((4-methoxybenzyl)amino)quinoline -7-yl)methyl)-2-(4-chloro-7 H -pyrrolo[2,3- d ]pyrimidin-7-yl)hexahydro-2 H -cyclopenta[ b ]furan-3,3a-diol. MS: 650/652 (M+1/M+3). ^1H NMR (400 MHz, DMSO- d6 ) δ 8.71 (d, J =1.6 Hz, 1H), 8.32 (s, 1H), 8.12 (d _, J =4.0 Hz , 1H), 7.55 (d, J =8.3 Hz, 1H), 7.37-7.29 (m, 4H), 7.10-7.05 (m, 1H), 6.86 ( d, J =8.2 Hz, 2H), 6.84-6.79 (m, 1H), 6.04 (d, J =8.0 Hz, 1H), 5.37 (brs, 1H ), 4.61 (d, J =6.0 Hz, 2H), 4.22 (d, J =8.0 Hz, 1H), 4.08-4.01 (m, 1H), 3.72 (s, 3H), 2.83 (dd, J = 13.6, 7.6 Hz, 1H), 2.64 (dd, J = 14.6, 7.6 Hz, 1H), 2.37- 2.26 (m, 2H), 1.96 (dd, J =12.4, 6.0 Hz, 1H), 1.85-1.75 (m, 1H), 1.71-1.63 ( m, 1H), 1.56-1.50 (m, 1H).

Step 3: Solution of (2 R ,3 R ,3a S ,6 S ,6a R )-6-((3-bromo-2-((4-methoxybenzyl)amino)quinolin-7-yl)methyl)-2- (4-chloro- 7H -pyrrolo[2,3- d ]pyrimidin-7-yl)hexahydro- 2H -cyclopenta[ b ]furan-3,3a-diol (60 mg, 0.09 mmol) in TFA ( 2 ml, 30 mmol) was stirred at 60°C for 1 hour. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with EtOAc (100 ml) and washed with saturated aqueous NaHCO ₃ solution (20 ml). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica column chromatography (MeOH/DCM) to give ( 2R , 3R , 3aS , 6S , 6aR )-6-((2-amino-3-bromoquinolin-7-yl)methyl)- 2-(4-chloro- 7H- pyrrolo[2,3- d ]pyrimidin-7-yl)hexahydro- 2H -cyclopenta[ b ]furan-3,3a-diol. MS: 530/532 (M+1/M+3). ^1H NMR (400 MHz, DMSO- d6 ) δ 8.72 (s, 1H), 8.31 (s, 1H), 8.11 ₍ d, J =4.0 Hz, 1H), 7.55 (d, J =8.4 Hz, 1H), 7.29 (s, 1H), 7.10 (dd, J =8.4, 1.6 Hz, 1H), 6.83 (d, J = 4.0 Hz, 1H), 6.57-6.51 (m, 3H), 6.03 (d, J =8.0 Hz, 1H), 5.39 (d, J =6.8 Hz, 1H), 5.17 (s, 1H), 4.24 (t, J =7.6 Hz, 1H), 4.05 (d, J =5.6 Hz, 1H), 2.84 (dd, J =13.6, 8.0 Hz, 1H), 2.71-2.60 (m, 1H), 2.37-2.15 (m, 1H), 2.03-1.92 (m, 1H), 1.88-1.63 (m, 1H), 1.62-1.49 (m, 1H).

Step 4: (2 R , 3 R , 3a S , 6 S , 6a R )-6-((2-amino-3-bromoquinolin-7-yl)methyl)-2- (4-chloro- 7H- pyrrolo[2,3- d ]pyrimidin-7-yl)hexahydro- 2H -cyclopenta[ b ]furan-3,3a-diol (30 mg, 0.06 mmol), 1, 4-dioxane (5 ml) and NH ₃ ·H ₂ O (9 ml) at room temperature. The vessel was sealed and the reaction mixture was stirred at 90°C for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (ACN/water with 5 mM ammonium bicarbonate modifier) to give ( 2R , 3R , 3aS ,6S, 6aR )-6-((2-amino-3-bromoquinoline-7 -yl)methyl)-2-(4-amino-7 H -pyrrolo[2,3- d ]pyrimidin-7-yl)hexahydro-2 H -cyclopenta[ b ]furan-3,3a-diol. MS: 511/513 (M+1/M+3). ^1H NMR (400 MHz, DMSO- d6 ) δ 8.30 (s, 1H), 8.09 (s, 1H), 7.54 ₍ d, J =8.4 Hz, 1H), 7.43 (d, J =4.0 Hz, 1H), 7.28 (s, 1H), 7.09 (d, J =8.4 Hz, 1H), 7.03 (brs, 2H), 6 .67 (d, J =3.6 Hz, 1H), 6.54 (br.s, 2H), 5.88 (d, J =8.0 Hz, 1H), 5.23 (d, J = 7.2 Hz, 1H), 5.04 (s, 1H), 4.13 (t, J =7.6 Hz, 1H), 3.95 (d, J =6.0 Hz, 1H), 2 .82 (dd, J =13.2, 8.0 Hz, 1H), 2.62 (dd, J =14.4, 7.2 Hz, 1H), 2.24-2.22 (m, 1H ), 1.96-1.92 (m, 1H), 1.70-1.68 (m, 2H), 1.57-1.51 (m, 1H).

Example 10 and 11

(2R,3S,4R,5R)-2-(((2-amino-3-bromoquinolin-7-yl)oxy)methyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidine -7-yl)-3-methyltetrahydrofuran-3,4-diol (Example 10)

And

(2 R ,3 S ,4 R ,5 R )-2-{[(2-amino-3-bromoquinolin-7-yl)oxy]methyl}-5-(4-chloro-7 H- pyrrolo[2, 3- d ]pyrimidin-7-yl)-3-methyltetrahydrofuran-3,4-diol (Example 11)

Step 1: A solution of (5R,6S)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1, 3]dioxol-6-ol (951 g, 5 mol) in pyridine (7 L) and tert-butyl(chloro)diphenylsilane (1.4 kg, 5.1 mol). The resulting solution was stirred overnight at room temperature. The mixture was diluted with MeOH (600 ml) and then concentrated under reduced pressure. The residue was diluted with EtOAc, washed with HCl (0.5 M in aq), saturated sodium bicarbonate solution and brine. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give (5R,6S)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-dimethyltetrahydrofuro[2,3-d][1. 3]dioxol-6-ol as an oil, which was used in the next step without further purification.

Step 2: A solution of (5R,6S)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-dimethyltetrahydrofuro[2] was charged into a 20-L, 4-neck round bottom flask, which was purged and maintained under an inert nitrogen atmosphere. ,3-d][1,3]dioxol-6-ol (2.1 kg, 5 mol) in DCM (15 L) and Dess-Martin periodinane (3.18 kg, 7.50 mol). The resulting solution was stirred overnight at room temperature. The reaction was quenched by adding saturated aqueous sodium bicarbonate and the solution was concentrated under reduced pressure. The residue was diluted with diethyl ether and the mixture was filtered. The filtrate was concentrated under reduced pressure to give (5R)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-dimethyldihydrofuro[2,3-d][1,3]dioxol-6(5H)-one as an oil, which was used in the next step without further purification.

Step 3: A solution of (5R)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-dimethyldihydrofuro[2,3] was charged into a 20 L 4-neck round bottom flask, which was purged and maintained under an inert nitrogen atmosphere -d][1,3]dioxol-6(5H)-one (2.1 kg, 5 mol) in THF (10 L). To this mixture was added methylmagnesium chloride (1.84 L, 3.0 M in THF) dropwise with stirring at 0 ^° C. The resulting solution was stirred for 1 hour at room temperature. The reaction mixture was then quenched by adding saturated aqueous ammonium chloride. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (5R,6R)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2,6-trimethyltetrahydrofuro[2 ,3-d][1,3]dioxol-6-ol as an oil, which was used in the next step without further purification. ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.73-7.70 (m, 4H), 7.46-7.39 (m, 6H), 5.79 (d, J= 3.8 Hz, 1H), 4.16-4.10 (m, 2H), 3.92 (dd, J =6.4, 4.5 Hz, 1H), 3.85-3.84 (m, 2H), 2 .56 (s, 1H), 2.07 (s, 1H), 1.38 (s, 3H), 1.28 (t, J =7.1 Hz, 2H), 1.14 (s, 3H) , 1.09 (s, 8H).

Step 4: A solution of (5R,6R)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2,6-trimethyltetrahydrofuro was charged into a 20-L, 4-neck round bottom flask, which was purged and maintained under an inert nitrogen atmosphere. [2,3-d][1,3]dioxol-6-ol (2.2 kg, 5 mol) in AcOH (10 L). To this mixture was added sulfuric acid (49.2 g, 502 mmol) dropwise with stirring at 10°C, followed by the addition of acetic anhydride (2.04 kg, 20.0 mol) dropwise with stirring at 10°C. The resulting solution was stirred for 3 hours at room temperature. The mixture was concentrated under reduced pressure and then diluted with EtOAc. The resulting mixture was washed with saturated aqueous sodium bicarbonate and then with saturated saline. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography (eluting with 1:1 ethyl acetate/petroleum ether) to give (3R,4R,5R)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-4-methyltetrahydrofuran-2,3. 4-triyl triacetate as an oil.

Step 5: A 5-L, 4-neck round bottom flask, purged and maintained under an inert nitrogen atmosphere, was charged with 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (420 g, 1503 mmol), BSA (305 g, 7.11 mol), solution of (3R,4R,5R)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-4-methyltetrahydrofuran-2,3,4-triyl triacetate (795 g, 1 .50 mol) in MeCN (7 L) and trimethylsilyl trifluoromethanesulfonate (668 g, 3.00 mol). The resulting solution was stirred for 6 hours at 80°C. The mixture was cooled to room temperature, concentrated under reduced pressure and diluted with EtOAc. The resulting mixture was washed with saturated aqueous sodium bicarbonate and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography (EtOAc/petroleum ether) to give (2R,3R,4R,5R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-5-(4-chloro-5-iodo- 7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-methyltetrahydrofuran-3,4-diyl diacetate as an oil. MS: 748 (M+1).

Step 6: A solution of (2R,3R,4R,5R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-5-( 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-methyltetrahydrofuran-3,4-diyl diacetate (225 g, 300 mmol) in tetrahydrofuran (2.2 L ). The solution was cooled to -78°C and isopropylmagnesium chloride-lithium chloride complex (54.6 g, 376 mmol) was added dropwise and the solution was stirred for 2 hours at -78°C. The mixture was quenched by dropwise addition of iPrOH (25.2 g, 420 mmol) at -78°C. This cold reaction mixture was poured into a mixture of ice and saturated aqueous ammonium chloride. The mixture was extracted with DCM (2×) and the combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give (2R,3R,4R,5R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)- 5-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-methyltetrahydrofuran-3,4-diyl diacetate as an oil, which was used as such without further purification.

Step 7: A solution of (2R,3R,4R,5R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-5-( 4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-methyltetrahydrofuran-3,4-diyl diacetate (186 g, 299 mmol) in THF (1.8 L) and AcOH (90 g, 1.5 mol). TBAF (600 mL, 2.00 eq., 1.0 M in THF) was added dropwise with stirring at room temperature, and the solution was stirred for 2 hours at room temperature. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica column chromatography (MeOH/DCM) to give (2R,3R,4R,5R)-5-(4-chloro-7H-pyrrolo[2,3-d]pyrimidine- 7-yl)-2-(hydroxymethyl)-3-methyltetrahydrofuran-3,4-diyl diacetate as a solid. MS: 384 (M+1).

Step 8: Mixture of (2R,3R,4R,5R)-5-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(hydroxymethyl)-3-methyltetrahydrofuran-3, 4-diyl diacetate (542 mg, 1.41 mmol), TEA (0.59 ml, 4.2 mmol) and DMAP (34.5 mg, 0.28 mmol) were dissolved in DCM (11 ml). 4-toluenesulfonyl chloride (538 mg, 2.8 mmol) was added at 0°C and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with DCM and washed with water. The aqueous layer was extracted with DCM (2×). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography (EtOAc/hexane) to give (2R,3R,4R,5R)-5-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3- methyl 2-((tosyloxy)methyl)tetrahydrofuran-3,4-diyl diacetate, which was used as such without further purification. MS: 538 (M+1).

Step 9: To a solution of (2R,3R,4R,5R)-5-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-methyl-2-((tosyloxy)methyl )tetrahydrofuran-3,4-diyl diacetate (380 mg, 0.71 mmol) and 2-amino-3-bromoquinolin-7-ol (169 mg, 0.71 mmol) in DMF (5 ml) were added at 0°C cesium carbonate (460 mg, 1.4 mmol). The mixture was stirred at room temperature overnight and then quenched with water. The precipitate was collected by filtration, washed with water and dried under reduced pressure to give ( 2R , 3R , 4R , 5R )-2-{[(2-amino-3-bromoquinolin-7-yl)oxy]methyl}-5 -(4-chloro- 7H -pyrrolo[2,3- d ]pyrimidin-7-yl)-3-methyltetrahydrofuran-3,4-diyl diacetate as a solid. MS: 604/606 (M+1/M+3).

Step 10: To a solution of (2 R ,3 R ,4 R ,5 R )-2-{[(2-amino-3-bromoquinolin-7-yl)oxy]methyl}-5-(4-chloro-7 H -pyrrolo[2,3- d ]pyrimidin-7-yl)-3-methyltetrahydrofuran-3,4-diyl diacetate (372 mg, 0.62 mmol) dissolved in dioxane (4 ml), ammonium hydroxide (4 ml) was added , 51.8 mmol, 30% in aq). The mixture was heated at 85°C overnight. The mixture was cooled to room temperature and the reaction mixture was concentrated under reduced pressure. The residue was purified by mass initiated reverse phase HPLC (ACN/water with 0.1% TFA modifier) to give:

Example 10: (2R,3S,4R,5R)-2-(((2-amino-3-bromoquinolin-7-yl)oxy)methyl)-5-(4-amino-7H-pyrrolo[2,3- d]pyrimidin-7-yl)-3-methyltetrahydrofuran-3,4-diol. MS: 501/503 (M+1/M+3). ^1H NMR (600 MHz, DMSO- d6 ) δ 8.72-8.34 (m, _3H ), 8.03-7.40 (m, 3H), 7.15-7.03 (m, 2H ), 6.94 (d, J =3.0 Hz, 1H), 6.16 (d, J =7.9 Hz, 1H), 5.65-4.96 (m, 2H), 4.40 -4.35 (m, 1H), 4.29-4.18 (m, 4H), 1.27 (s, 3H).

Example 11: ( 2R , 3S , 4R , 5R )-2-{[(2-amino-3-bromoquinolin-7-yl)oxy]methyl}-5-(4-chloro- 7H- pyrrolo [2,3- d ]pyrimidin-7-yl)-3-methyltetrahydrofuran-3,4-diol. MS: 520/522 (M+1/M+3). ^1H NMR (600 MHz, DMSO- d6 ) δ 8.73-8.62 (m, 2H), 8.13 (s, 1H), 7.93 ₍ d, J =3.4 Hz, 1H) , 7.76 (d, J =8.7 Hz, 1H), 7.18-7.11 (m, 2H), 6.73 (d, J =3.5 Hz, 1H), 6.25 ( d, J =8.0 Hz, 1H), 4.51-4.44 (m, 2H), 4.33-4.20 (m, 5H), 1.28 (s, 3H).

Example 12

(2R,3S,4R,5R)-2-(((2-amino-3-bromoquinolin-7-yl)oxy)methyl)-5-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidine -7-yl)-2-methyltetrahydrofuran-3,4-diol

Solution of 3-bromo-7-(((3a S ,4 R ,6 R ,6a R )-6-(4-methoxy-7 H -pyrrolo[2,3-d]pyrimidin-7-yl)-2, 2,4-trimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy) -N- (4-methoxybenzyl)quinolin-2-amine (30 mg, 0.04 mmol) in TFA ( 1.0 ml) was stirred at 40°C for 3 days. The reaction mixture was concentrated in vacuo and the residue was purified by reverse phase HPLC (ACN/water with 0.1% TFA modifier) to give ( 2R , 3S , 4R , 5R )-2-(((2-amino-3 -bromoquinolin-7-yl)oxy)methyl)-5-(4-methoxy- 7H -pyrrolo[2,3-d]pyrimidin-7-yl)-2-methyltetrahydrofuran-3,4-diol, TFA salts, in the form of a solid. MS: 516/518 (M+1/M+3). ¹ H-NMR (600 MHz, DMSO- d6 ) δ 8.66 (br, 1H), 8.43 (s, 1H), 7.75 ₍ d, J= 8.2 Hz, 1H), 7, 63-7.59 (m, 1H), 7.16-7.09 (m, 2H), 6.59-6.54 (m, 1H), 6.23 (d, J= 6.6 Hz, 1H), 4.88-4.81 (m, 1H), 4.27-4.19 (m, 2H), 4.11 (d, J =9.9 Hz, 1H), 4.03 (s , 3H), 1.36 (s, 3H).

Example 13

(2R,3S,4R,5R)-2-(((2-amino-3-bromoquinolin-7-yl)oxy)methyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidine -7-yl)-2-methyltetrahydrofuran-3,4-diol

A solution of (2 R ,3 S ,4 R ,5 R )-2-(((2-amino-3-bromoquinolin-7-yl)oxy)methyl)-5-(4-methoxy-7 H -pyrrolo[2 ,3-d]pyrimidin-7-yl)-2-methyltetrahydrofuran-3,4-diol TFA salt (10 mg, 0.019 mmol) in 30% ammonia in water (3 ml) was stirred at 150°C for 4 h in microwave reactor. The reaction mixture was concentrated under reduced pressure and the residue was purified by chiral SFC (DIOL column, 35%/65% methanol/CO ₂ ) to give (2R,3S,4R,5R)-2-(((2-amino-3-bromoquinoline- 7-yl)oxy)methyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-methyltetrahydrofuran-3,4-diol as a solid. MS: 501/503 (M+1/M+3). ¹ H-NMR (500 MHz, CD ₃ OD) δ 8.22 (s, 1H), 8.09 (s, 1H), 7.58 (d, J= 9.0 Hz, 1H), 7.35 (d, J =3.7 Hz, 1H), 7.06-6.98 (m, 2H), 6.60 (d, J =3.3 Hz, 1H), 6.27 (d, J = 6.7 Hz, 1H), 4.87-4.82 (m, 1H), 4.39 (d, J =5.4 Hz, 1H), 4.20 (d, J =10.2 Hz, 1H), 4.12 (d, J =10.2 Hz, 1H), 1.48 (s, 3H).

Example 14

(2 R ,3 S ,4 R ,5 R )-2-(2-(2-amino-3-bromoquinolin-7-yl)ethyl)-5-(4-amino-7 H -pyrrolo[2,3 -d]pyrimidin-7-yl)-3-methyltetrahydrofuran-3,4-diol

Stage 1:IN A 500 ml round bottom flask was loaded (3aR,5R,6aR)-5-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol (10.0 g, 38.4 mmol), which was then dissolved in DCM (100 ml). Dess-Martin periodinane (32.6 g, 77 mmol) was then added portionwise and the cloudy white reaction mixture was stirred at room temperature for 80 minutes. DCM (100 ml) was added and the reaction mixture was stirred at room temperature overnight. The reaction was quenched with saturated aqueous sodium bicarbonate and saturated aqueous sodium thiosulfate. After stirring for 1 hour, the layers were extracted and the organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure to give crude (3aR,5S,6aS)-5-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyldihydrofuro[2,3-d][1,3]dioxol-6(3aH) - it is in the form of an oil, which was used directly in the next step without further purification.¹H-NMR (600 MHz, CDCl₃) δ 6.14 (d,J=4.5 Hz, 1H), 4.39-4.38 (m, 1H), 4.38-4.34 (m, 2H), 4.04-4.01 (m, 2H), 1, 46 (s, 3H), 1.43 (s, 3H), 1.35-1.32 (m, 6H).

Step 2: Crude ( 3aR , 5R , 6aS )-5-(( S )-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyldihydrofuro[2, 3-d][1,3]dioxol-6( 3aH )-one (7.42 g, max. 28.7 mmol), was again filled with argon and then toluene (100 ml) was added. The solution was cooled to 0°C and then methyl magnesium chloride (3.0 M in THF, 14.4 mL, 43.2 mmol) was added dropwise under argon. After 5 minutes, the reaction mixture was removed from the ice bath and allowed to warm to room temperature, stirring overnight. The reaction mixture was poured into a separatory funnel containing saturated ammonium chloride solution and extracted with EtOAc. The organic layers were combined and washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give ( 3aR , 5R , 6R , 6aR )-5-(( S )-2,2-dimethyl-1 ,3-dioxolan-4-yl)-2,2,6-trimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol as a solid, which was used in the next step without further purification. ¹ H-NMR (600 MHz, CDCl ₃ ) δ 5.70 (d, J =3.6 Hz, 1H), 4.17 (d, J =3.7 Hz, 1H), 4.12-4, 08 (m, 2H), 3.95-3.91 (m, 1H), 3.78 (d, J =7.4 Hz, 1H), 2.67 (s, 1H), 1.59 (s , 3H), 1.45 (s, 3H), 1.36 (s, 3H), 1.35 (s, 3H), 1.28 (s, 3H).

Step 3: The flask was loaded with (3a R ,5 R ,6 R ,6a R )-5-(( S )-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2,6- trimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol (5.82 g, 21.2 mmol) and acetonitrile (100 ml) was added. Sulfuric acid (10 mL, 188 mmol) was then added as a 5% vol. solution. in water and the reaction mixture was stirred at room temperature for 4.5 hours. The reaction mixture was poured into a separatory funnel containing saturated sodium bicarbonate solution and extracted with EtOAc. The organic layers were combined and washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give ( S )-1-(( 3aR , 5R , 6R , 6aR )-6-hydroxy-2,2 ,6-trimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)ethane-1,2-diol as a solid, which was used in the following reaction without further purification. ¹ H-NMR (600 MHz, CDCl ₃ ) δ 5.73 (d, J =3.7 Hz, 1H), 4.16 (d, J =3.7 Hz, 1H), 3.85-3, 81 (m, 2H), 3.75 (d, J =8.4 Hz, 1H), 3.72-3.68 (m, 1H), 2.87 (s, 1H), 2.53 (s , 1H), 2.02 (s, 1H), 1.59 (s, 3H), 1.36 (s, 3H), 1.33 (s, 3H).

Step 4: Into a flask containing a solution of crude ( S )-1-(( 3aR , 5R , 6R , 6aR )-6-hydroxy-2,2,6-trimethyltetrahydrofuro[2,3-d][1 ,3]dioxol-5-yl)ethane-1,2-diol (1.24 g, 5.30 mmol) in toluene (100 ml), imidazole (1.44 g, 21.2 mmol) and triphenylphosphine were added successively (5.56 g, 21.2 mmol). The flask was cooled to 0°C and then iodine (4.04 g, 15.9 mmol) was added. The ice bath was allowed to warm naturally and the solution was then stirred at room temperature under argon for four days. The reaction mixture was poured into a separatory funnel containing 1M NaOH and extracted with EtOAc. The organic layers were combined and washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography (0-10-20-30% EtOAc/hexane) to give ( 3aR , 5R , 6R , 6aR )-2,2,6-trimethyl-5-vinyltetrahydrofuro[2, 3-d][1,3]dioxol-6-ol as a solid. ¹ H-NMR (600 MHz, CDCl ₃ ) δ 5.84-5.76 (m, 2H), 5.40 (dt, J = 17.3, 1.5 Hz, 1H), 5.29 (dt , J =10.7, 1.4 Hz, 1H), 4.21 (d, J =5.9 Hz, 1H), 4.17 (d, J =3.9 Hz, 1H), 2.63 (s, 1H), 1.59 (s, 3H), 1.37 (s, 3H), 1.12 (s, 3H).

Step 5: The vessel was loaded with (3a R ,5 R ,6 R ,6a R )-2,2,6-trimethyl-5-vinyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol (200 mg, 0.999 mmol) and 9-BBN (0.5M in THF, 6 mL, 3.00 mmol) and stirred at 50°C for 2 h under argon. The reaction mixture was cooled to room temperature and potassium triphosphate (2M in aq, 2.5 mL, 5.00 mmol) was added. The mixture was stirred vigorously at room temperature for 30 minutes and then a solution of 3-bromo-7-iodo- N- (4-methoxybenzyl)quinoline-2-amine (609 mg, 1.298 mmol) and 1,1'-bis( diphenylphosphino)ferrocene-palladium(II) dichloride with dichloromethane (82 mg, 0.100 mmol) in THF (3 ml). The head of the vessel was purged with argon and the reaction mixture was stirred at 50°C overnight. The reaction mixture was then diluted with DCM and water and passed through a phase separator. The organic layers were combined and concentrated under reduced pressure. The residue was purified by silica column chromatography (0-60% EtOAc/hexane) to give ( 3aR , 5R , 6R , 6aR )-5-(2-(3-bromo-2-((4-methoxybenzyl) amino)quinolin-7-yl)ethyl)-2,2,6-trimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol in the form of a solid. MS: 543/545 (M+1/M+3).

Step 6: Into a vessel containing (3a R ,5 R ,6 R ,6a R )-5-(2-(3-bromo-2-((4-methoxybenzyl)amino)quinolin-7-yl)ethyl)- 2,2,6-trimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol (353.2 mg, 0.650 mmol), water (5 ml) was added followed by pure formic acid (5 ml, 130 mmol). The resulting solution was heated at 50°C overnight. The reaction mixture was cooled to room temperature and then poured into a separatory funnel containing water and extracted with 25% isopropanol/chloroform. The organic layers were combined and dried over sodium sulfate, filtered and concentrated under reduced pressure to give ( 2S , 3R , 4S , 5R )-5-(2-(3-bromo-2-((4-methoxybenzyl)amino )quinolin-7-yl)ethyl)-4-methyltetrahydrofuran-2,3,4-triol as a solid, which was used in the next step without further purification. MS: 503/505 (M+1/M+3).

Step 7: In a vessel, 4-chloro-7 H -pyrrolo[2,3-d]pyrimidine (405 mg, 2.64 mmol) was dissolved in DMF (8 ml). Sodium hydride (106 mg, 2.64 mmol) was then added. The mixture was stirred at room temperature under argon for 75 minutes. At the same time, a solution of crude (3 R ,4 S ,5 R )-5-(2-(3-bromo-2-((4-methoxybenzyl)amino)quinolin-7-yl)ethyl)-4- methyltetrahydrofuran-2,3,4-triol (532 mg, 1.06 mmol) in acetonitrile (18 ml). Tri- n -butylphosphine (0.45 mL, 1.80 mmol) was then added followed by 1,1'-(azodicarbonyl)dipiperidine (400 mg, 1.58 mmol). The reaction mixture was stirred at room temperature for 25 minutes, then additional 1,1'-(azodicarbonyl)dipiperidine (130 mg) was added. After 20 minutes, tri- n -butylphosphine (0.5 ml) was added again. This mixture was stirred at room temperature for another 15 minutes. A solution containing 4-chloro- 7H -pyrrolo[2,3-d]pyrimidine and sodium hydride was then drawn into a syringe and added to the solution originally containing ( 3R , 4S , 5R )-5-(2- (3-bromo-2-((4-methoxybenzyl)amino)quinolin-7-yl)ethyl)-4-methyltetrahydrofuran-2,3,4-triol. This combined reaction mixture was stirred at room temperature under argon overnight. The reaction mixture was then poured into a separatory funnel containing water and extracted with EtOAc. The organic layers were combined, washed with water twice and then with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography (20-90% EtOAc/hexane) to give ( 2R , 3S , 4R , 5R )-2-(2-(3-bromo-2-((4-methoxybenzyl) amino)quinolin-7-yl)ethyl)-5-(4-chloro- 7H -pyrrolo[2,3-d]pyrimidin-7-yl)-3-methyltetrahydrofuran-3,4-diol as a solid, which was used directly in the next step. MS: 638/640 (M+1/M+3).

Step 8: A solution of (2 R ,3 S ,4 R ,5 R )-2-(2-(3-bromo-2-((4-methoxybenzyl)amino)quinolin-7-yl)ethyl)- was added to the vessel 5-(4-chloro- 7H -pyrrolo[2,3-d]pyrimidin-7-yl)-3-methyltetrahydrofuran-3,4-diol (114 mg, 0.178 mmol) in ammonia (7 M in MeOH, 10 ml, 70.0 mmol) and dioxane (2 ml). This solution was heated at 130°C for 4 hours in a microwave reactor. The entire solution was then concentrated under reduced pressure to give ( 2R , 3S , 4R , 5R )-5-(4-amino- 7H -pyrrolo[2,3-d]pyrimidin-7-yl)-2- (2-(3-bromo-2-((4-methoxybenzyl)amino)quinolin-7-yl)ethyl)-3-methyltetrahydrofuran-3,4-diol, which was used in the next step without further purification. MS: 619/621 (M+1/M+3).

Step 9: Into a flask containing crude ( 2R , 3S , 4R , 5R )-5-(4-amino- 7H -pyrrolo[2,3-d]pyrimidin-7-yl)-2-( 2-(3-bromo-2-((4-methoxybenzyl)amino)quinolin-7-yl)ethyl)-3-methyltetrahydrofuran-3,4-diol (110 mg, 0.178 mmol), DCM (9 mL) was added. Trifluoroacetic acid (1 mL, 12.98 mmol) was then added and the reaction mixture was stirred at room temperature overnight. TFA (5 ml) was added and the reaction mixture was stirred at room temperature for an additional 1 hour. TFA (2 ml) was added and the reaction mixture was refluxed for 7 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure. The residue was purified by mass initiated reverse phase HPLC (ACN/water with 0.1% TFA modifier) to give ( 2R , 3S , 4R , 5R )-2-(2-(2-amino-3-bromoquinoline -7-yl)ethyl)-5-(4-amino-7 H -pyrrolo[2,3-d]pyrimidin-7-yl)-3-methyltetrahydrofuran-3,4-diol as a solid TFA salt. MS: 499/501 (M+1/M+3). ¹ H-NMR (600 MHz, DMSO- d6 ) δ 8.64 (s, 1H), 8.39 (s, 1H), _7.74 (d, J =3.7 Hz, 1H), 7, 71 (d, J =8.2 Hz, 1H), 7.39 (s, 1H), 7.25 (d, J =8.0 Hz, 1H), 7.00 (d, J =3.7 Hz, 1H), 6.10 (d, J =7.7 Hz, 1H), 4.31 (d, J =7.7 Hz, 1H), 3.81 (dd, J =11.4, 2 .9 Hz, 1H), 2.81 (ddd, J =13.8, 9.2, 4.7 Hz, 1H), 2.67 (dt, J =13.8, 8.1 Hz, 1H) , 2.07-1.99 (m, 1H), 1.88-1.81 (m, 1H), 1.20 (s, 3H).

Example 15

(1 S ,2 R ,3 S ,5 R )-3-[2-(2-amino-3-bromo-7-quinolinyl)ethyl]-5-(4-amino-7 H -pyrrolo[2,3 - d ]pyrimidin-7-yl)-3-methyl-1,2-cyclopentanediol

Stage 1: To a stirred solution of (3a'R,4'R,6'S,6a'S)-4'-methyl-4'-vinyltetrahydro-4'H-spiro[cyclohexane-1,2'-cyclopenta[d][1,3]dioxol ]-6'-ol (3.8 g, 16 mmol) in DCM (80 ml) was added pyridine (6.45 ml, 80 mmol). The mixture was cooled to 0°C and treated with trifluoromethanesulfonic anhydride in DCM (23.92 mL, 23.92 mmol) for 10 min. The mixture was stirred at 0°C for 30 minutes and treated with water (5 ml). The organic layers were separated and washed with brine. The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure. Toluene (10 ml) was added to the residue and concentrated to give (3a'R,4'S.6'R,6a'R)-6'-methyl-6'-vinyltetrahydro-3a'H-spiro[cyclohexane-1,2'-cyclopenta[d][1,3]dioxol]-4'-yl trifluoromethanesulfonate as an oil. The residue was used in the next step without further purification.

Step 2 : Sodium hydride ( 0.893 g, 22.3 mmol). The mixture was stirred at this temperature for 30 minutes. In a separate flask (3a' R ,4' S ,6' R ,6a' R )-6'-methyl-6'-vinyltetrahydro-3a' H -spiro[cyclohexane-1,2'-cyclopenta[ d ][1 ,3]dioxol]-4'-yl trifluoromethanesulfonate (5.90 g, 15.9 mmol) was dissolved in DMF (10 ml). This solution was slowly added to the sodium salt solution over 10 minutes. The resulting mixture was warmed to room temperature and stirred overnight. The mixture was cooled to 0°C and treated with water. The mixture was diluted with EtOAc (500 ml) and washed with water (3x) and brine. The organic layer was dried over sodium sulfate, concentrated and purified by silica column chromatography (0-20% EtOAc/DCM) to give 4-chloro-7-((3a'R,4'R,6'R,6a'S)-4 '-methyl-4'-vinyltetrahydro-4'H-spiro[cyclohexane-1,2'-cyclopenta[d][1,3]dioxol]-6'-yl)-7H-pyrrolo[2,3-d] pyrimidine. MS: 374 (M+1). ¹ H-NMR (500 MHz, DMSO- d6 ) δ 8.66 (s, 1H), _8.03 (d, J =3.2 Hz, 1H), 6.73 (d, J =3.2 Hz, 1H), 6.00 (dd, J =17.4, 10.7 Hz, 1H), 5.32-5.26 (m, 1H), 5.10-4.99 (m, 3H) , 4.63 (d, J =7.5 Hz, 1H), 2.46 (m, 1H), 2.08 (dd, J =12.7, 7.2 Hz, 1H), 1.75- 1.71 (m, 2H), 1.63-1.28 (m, 8H), 1.17 (s, 3H).

Step 3 : To a stirred solution of 4-chloro-7-((3a'R,4'R,6'R,6a'S)-4'-methyl-4'-vinyltetrahydro-4'H-spiro[cyclohexane-1,2 '-cyclopenta[d][1,3]dioxol]-6'-yl)-7H-pyrrolo[2,3-d]pyrimidine (910 mg, 2.43 mmol) in 1,4-dioxane (4 ml) added ammonium hydroxide (28%, 4 ml) in a microwave vessel. The reaction mixture was heated to 160°C for 5 hours in a microwave reactor. The mixture was cooled to room temperature and diluted with EtOAc and water. The aqueous layer was extracted with EtOAc. The organic layers were combined and washed with brine, dried over sodium sulfate and concentrated under reduced pressure to give 7-((3a'R,4'R,6'R,6a'S)-4'-methyl-4'-vinyltetrahydro-4 'H-spiro[cyclohexane-1,2'-cyclopenta[d][1,3]dioxol]-6'-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine. The crude product was used in the next step without further purification. MS: 355 (M+1). ^1H NMR (500 MHz, DMSO- d6 ) δ 8.06 (s, 1H) _, 7.37 (d, J =2.8 Hz, 1H), 6.99 (s, 2H), 6.57 (d, J =2.8 Hz, 1H), 5.98 (dd, J =17.4, 10.7 Hz, 1H), 5.18-4.93 (m, 4H), 4.59 ( d, J =7.6 Hz, 1H), 2.37 (dd, J =12.3 Hz, 1H), 2.00-1.95 (m, 1H), 1.74-1.28 (m , 10H), 1.14 (s, 3H).

Step 4 : To 7-((3a'R,4'R,6'R,6a'S)-4'-methyl-4'-vinyltetrahydro-4'H-spiro[cyclohexane-1,2'-cyclopenta[d] [1,3]dioxol]-6'-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (300 mg, 0.846 mmol) was added with 9-BBN (0.5 M in THF, 6. 77 ml, 3.39 mmol). The mixture was heated to 50°C for 1 hour, cooled to room temperature, treated with tribasic potassium phosphate (898 mg, 4.23 mmol) and water (0.9 ml) and left to stir for 30 minutes. The mixture was treated with THF (1 ml), 3-bromo-7-iodoquinoline-2-amine (266 mg, 0.762 mmol) and PdCl ₂ (dppf) (61.9 mg, 0.085 mmol), purged with nitrogen for 5 minutes and heated to 50°C for 3 hours. The mixture was cooled to room temperature, diluted with EtOAc and washed with water and brine. The organic layers were combined and dried over sodium sulfate, concentrated and purified by silica column chromatography (0-10% MeOH/DCM) to give 7-(2-((3a'S,4'R,6'S,6a'R)-4'-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-6'-methyltetrahydro-4'H-spiro[cyclohexane-1,2'-cyclopenta[d][1,3]dioxol]-6'-yl)ethyl)-3-bromoquinoline-2-amine in the form of a solid. MS: 577/579 (M+1/M+3). ¹ H-NMR (500 MHz, DMSO- d6 ) δ 8.32 (s, 1H), 8.06 (s, 1H), 7.57 ₍ d, J =8.1 Hz, 1H), 7, 38 (s, 1H), 7.32 (s, 1H), 7.12 (d, J =8.1 Hz, 1H), 6.99 (s, 2H), 6.57 (s, 3H), 5.14-5.07 (m, 1H), 4.98-4.94 (m, 1H), 4.52 (d, J =7.5 Hz, 1H), 2.75-2.65 ( m, 2H), 2.20 (dd J =12.4 Hz, 1H), 2.05-2.00 (m, 1H), 1.78-1.28 (m, 12H), 1.14 ( s, 3H).

Step 5 : K 7-(2-((3a'S,4'R,6'S,6a'R)-4'-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-6 '-methyltetrahydro-4'H-spiro[cyclohexane-1,2'-cyclopenta[d][1,3]dioxol]-6'-yl)ethyl)-3-bromoquinoline-2-amine (320 mg, 0.399 mmol ) HCl (4M in MeOH, 10 ml) was added. The mixture was stirred overnight and then heated at 50°C for 5 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure and purified by reverse phase column chromatography (ACN/water with 0.1% TFA modifier) to give ( 1S,2R,3S,5R)-3-[2-(2-amino-3-bromo-7-quinolinyl)ethyl]-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7 -yl)-3-methyl-1,2-cyclopentanediol as TFA salt. MS: 497/499 (M+1/M+3). ^1H NMR (500 MHz, DMSO- d6 ) δ 9.17 (brs, 1H), 8.72 (s, 1H), 8.65 ( _brs , 1H), 8.37 (s, 1H), 8.27 (br.s, 2H), 7.76 (d, J =8.1 Hz, 1H), 7.70 (d, J =3.2 Hz, 1H), 7.46 ( s, 1H), 7.34 (d, J =8.1 Hz, 1H), 6.94 (d, J =3.1 Hz, 1H), 5.00 (dd J =8.8 Hz, 1H ), 4.89 (brs, 2H), 4.39-4.34 (m, 1H), 3.79 (d, J =5.9 Hz, 1H), 2.85-2.68 ( m, 2H), 1.96-1.70 (m, 4H), 1.12 (s, 3H).

Example 16

(1S,2R,3aR,4S,6aR)-4-((2-amino-3-fluoroquinolin-7-yl)methyl)-2-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)hexahydropentalene-1,6a(1H)-diol

Step 1: Into a flask containing (3aS,4R,5aR,6S,8aR)-2,2-dimethyl-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)hexahydro- 5H-pentaleno[1,6a-d][1,3]dioxol-6-ol (6.0 g, 18 mmol), DCM (200 ml) was added followed by Dess-Martin periodinane (10.25 g, 23 .68 mmol). The reaction mixture was stirred at room temperature overnight. The reaction was quenched 1:1 with saturated aqueous sodium bicarbonate: saturated aqueous sodium thiosulfate (160 ml) with vigorous stirring. The organic layer was separated using a phase separator and concentrated under reduced pressure. Crude (3aS,4R,5aS,8aR)-2,2-dimethyl-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)hexahydro-6H-pentaleno[1,6a- d][1,3]dioxol-6-one was used directly in the following reaction.

Step 2: Methyltriphenylphosphonium bromide (21.91 g, 60.1 mmol) was added to the flask followed by THF (100 ml) under argon. The mixture was cooled to 0°C and then n BuLi (22 ml, 2.5M, 55 mmol) was added. The reaction mixture was removed from the cooling bath and left to vigorously stir at room temperature under argon for 30 minutes. Then the reaction mixture was again cooled to 0°C and a solution of (3aS,4R,5aS,8aR)-2,2-dimethyl-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl) was added )hexahydro-6H-pentaleno[1,6a-d][1,3]dioxol-6-one (5.96 g, 18.2 mmol) in THF (100 ml). After addition, the reaction mixture was removed from the cooling bath and left to stir at room temperature for 70 minutes. The reaction mixture was poured into a separatory funnel containing EtOAc and saturated ammonium chloride. The aqueous layer was separated and washed twice with EtOAc. The organic layers were combined, dried over magnesium sulfate, filtered through Celite® and concentrated under reduced pressure. The crude material was subjected to silica column chromatography (10-100% EtOAc/hexane) to give 7-((3aS,4R,5aR,8aR)-2,2-dimethyl-6-methylenehexahydro-5H-pentaleno[1,6a- d][1,3]dioxol-4-yl)-4-methyl-7H-pyrrolo[2,3-d]pyrimidine. MS: 326 (M+1). ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.76 (s, 1H), 7.24 (d, J =3.4 Hz, 1H), 6.55 (d, J =3.4 Hz, 1H ), 5.16-5.10 (m, 1H), 5.00-4.97 (m, 1H), 4.87 (s, 1H), 4.80 (d, J =5.3 Hz, 1H), 3.08 (t, J =9.1 Hz, 1H), 2.73 (s, 3H), 2.71-2.61 (m, 2H), 2.58-2.51 (m , 1H), 2.32-2.24 (m, 2H), 2.15-2.08 (m, 1H), 1.58 (s, 3H), 1.36 (s, 3H).

Stage 3:Into a flask containing 7-((3aS,4R,5aR,8aR)-2,2-dimethyl-6-methylenehexahydro-5H-pentaleno[1,6a-d][1,3]dioxol-4-yl)-4 -methyl-7H-pyrrolo[2,3-d]pyrimidine (1.22 g, 3.7 mmol), THF (20 ml) was added. A solution of 9-BBN (23.0 mL, 0.5 M in THF, 11.5 mmol) was then added under argon. The reaction mixture was then stirred at room temperature under argon overnight. Potassium triphosphate (9.5 ml, 2M in water, 19 mmol) was then added and the reaction mixture was stirred at room temperature for 30 minutes. A solution of 7-bromo-3-fluoroquinolin-2-amine (1.345 g, 5.60 mmol) and methanesulfonato(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2'-methylamino) was then added -1,1'-biphenyl-2-yl)palladium(II) (0.312 g, 0.373 mmol) in THF (10 ml) and the reaction mixture was heated to 50°C for 2 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The crude material was purified by silica column chromatography (80-100% EtOAc/hexane to 100% 3:1 EtOAc:EtOH), then chiral SFC (OJ-H column, 30% MeOH aq/0.1% NH₄OH to CO₂) to give 7-(((3aS,4R,5aR,6S,8aR)-2,2-dimethyl-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)hexahydro- 5H-pentaleno[1,6a-d][1,3]dioxol-6-yl)methyl)-3-fluoroquinolin-2-amine. MS: 488 (M+1).

Stage 4:Into a flask containing 7-(((3aS,4R,5aR,6S,8aR)-2,2-dimethyl-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)hexahydro -5H-pentaleno[1,6a-d][1,3]dioxol-6-yl)methyl)-3-fluoroquinolin-2-amine (2.03 g, 4.17 mmol), add DCM (50 ml) , water (16 ml) and trifluoroacetic acid (40 ml, 520 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was then concentrated under reduced pressure and purified by mass initiated reverse phase HPLC (ACN/water with 0.1% NH₄OH modifier) to give (1S,2R,3aR,4S,6aR)-4-((2-amino-3-fluoroquinolin-7-yl)methyl)-2-(4-methyl-7H-pyrrolo[2,3 -d]pyrimidin-7-yl)hexahydropentalene-1,6a(1H)-diol. MS: 448 (M+1).¹H NMR (600 MHz, DMSO) δ 8.60 (s, 1H), 7.82 (d,J=3.6 Hz, 1H), 7.75 (d,J=11.8 Hz, 1H), 7.55 (d,J=8.2 Hz, 1H), 7.29 (s, 1H), 7.10 (d,J=8.6 Hz, 1H), 6.71 (d,J=3.6 Hz, 1H), 6.67 (s, 2H), 4.84-4.74 (m, 2H), 4.67 (s, 1H), 3.95 (dd,J=10.2, 7.4 Hz, 1H), 2.76-2.66 (m, 2H), 2.65 (s, 3H), 2.49-2.42 (m, 1H), 2, 18 (sq.,J=9.4 Hz, 1H), 1.88-1.78 (m, 3H), 1.71-1.64 (m, 1H), 1.64-1.55 (m, 1H), 1, 49-1.43 (m, 1H).

Examples 17-18: Examples 17-18 in Table 7 were synthesized in the same manner as described in Example 16, replacing 7-bromo-3-fluoroquinoline-2-amine with a suitable aryl halide in step 3. Substitution reagents and starting material purchased commercially, synthesized as described above, or synthesized by known methods described in the literature.

Table 7 Etc. Structure Name MS 17 (1S,2R,3aR,4S,6aR)-4-((2-amino-3-chloroquinolin-7-yl)methyl)-2-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)hexahydropentalene-1,6a(1H)-diol 464 (M+1) 18 (1S,2R,3aR,4R,6aR)-4-((2-amino-3-fluoroquinolin-7-yl)methyl)-2-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)hexahydropentalene-1,6a(1H)-diol 448 (M+1)

Examples 19: Example 19 in Table 8 was synthesized in the same manner as described in Example 16, replacing step 3 with step 1 in Example 25 and replacing 7-bromo-3,5-difluoroquinoline-2-amine with a suitable aryl halide. The reagents and starting material used for substitution were purchased commercially, synthesized as described above, or synthesized by known methods described in the literature.

Table 8 Etc. Structure Name MS 19 (1S,2R,3aR,4S,6aR)-4-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)hexahydropentalene-1,6a(1H)-diol 508/510 (M+1/M+3)

Examples 20-24: Examples 20-24 in Table 9 were synthesized in the same manner as described in steps 3-4 of Example 16, substituting 7-((3aS,4R,5aR,8aR)-2,2-dimethyl-6-methylenehexahydro -5H-pentaleno[1,6a-d][1,3]dioxol-4-yl)-4-methyl-7H-pyrrolo[2,3-d]pyrimidine is a suitable exo-olefin, and 7-bromo-3- fluoroquinoline-2-amine with a suitable aryl halide, and then performing chiral resolution by SFC, if necessary, based on the substituted exo-olefin. The reagents and starting material used for substitution were purchased commercially, synthesized as described above, or synthesized by known methods described in the literature.

Table 9 Etc. Structure Name MS 20 (2 R ,3 R ,3a S ,6 S ,6a R )-6-[(2-amino-3,8-difluoroquinolin-7-yl)methyl]-2-(4-amino-7 H -pyrrolo[ 2,3- d ]pyrimidin-7-yl)hexahydro-3a H -cyclopenta[ b ]furan-3,3a-diol 469 (M+1) 21 (2 R ,3 R ,3a S ,6 S ,6a R )-6-[(2-amino-3-chloro-5-fluoroquinolin-7-yl)methyl]-2-(4-amino-7 H - pyrrolo[2,3- d ]pyrimidin-7-yl)hexahydro-3a H -cyclopenta[ b ]furan-3,3a-diol 485 (M+1) 22 (2 R ,3 R ,3a S ,6 S ,6a R )-6-[(2-amino-3-chloro-8-fluoroquinolin-7-yl)methyl]-2-(4-methyl-7 H - pyrrolo[2,3- d ]pyrimidin-7-yl)hexahydro-3a H -cyclopenta[ b ]furan-3,3a-diol 484 (M+1) 23 (2R,3R,3aS,6S,6aR)-6-((2-amino-3-(difluoromethyl)quinolin-7-yl)methyl)-2-(4-methyl-7H-pyrrolo[2,3-d ]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol 482 (M+1) 24 (2R,3R,3aS,6S,6aR)-6-((2-amino-3,5-difluoroquinolin-7-yl)methyl)-2-(4-amino-5-fluoro-7H-pyrrolo[2, 3-d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol 487 (M+1)

Example 25

(2R,3R,3aS,6S,6aR)-6-((6-amino-7-fluoro-1,5-naphthyridin-3-yl)methyl)-2-(4-methyl-7H-pyrrolo[2, 3-d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol, 3HCl

Step 1: Into a vessel containing 7-((3aR,4R,5aR,8aR)-2,2-dimethyl-6-methylenehexahydrocyclopenta[2,3]furo[3,4-d][1,3]dioxol-4 -yl)-4-methyl-7H-pyrrolo[2,3-d]pyrimidine (0.070 g, 0.214 mmol), THF (2.047 mL) was added followed by 9-BBN (0.5 M in THF, 1.37 ml, 0.684 mmol). The reaction mixture was stirred at room temperature under argon overnight. An aqueous solution of potassium triphosphate (1 M, 1.155 mL, 1.155 mmol) was then added and the reaction mixture was stirred vigorously at room temperature for 1 hour. A solution of 7-bromo-3-fluoro-1,5-naphthyridin-2-amine ( 0.078 g, 0.321 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.016 g, 0.021 mmol) in THF (1.01 ml) and the reaction mixture was heated to 50°C for 2 h The reaction mixture was cooled to room temperature and poured into a separatory funnel containing water and EtOAc. After extraction, the aqueous layer was washed with EtOAc (x2). The organic layers were combined, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The material was purified by mass initiated reverse phase HPLC (ACN/water with 0.1% TFA modifier) to give 7-(((3aR,4R,5aR,6S,8aR)-2,2-dimethyl-4-(4 -methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)hexahydrocyclopenta[2,3]furo[3,4-d][1,3]dioxol-6-yl)methyl)-3-fluoro -1,5-naphthyridin-2-amine as TFA salt. MS: 491 (M+1).

Step 2: To a solution of 7-(((3aR,4R,5aR,6S,8aR)-2,2-dimethyl-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl) hexahydrocyclopenta[2,3]furo[3,4-d][1,3]dioxol-6-yl)methyl)-3-fluoro-1,5-naphthyridin-2-amine (0.117 g, 0.239 mmol) in MeOH (11.9 mL), hydrochloric acid (2 M, 11.9 mL, 23.9 mmol) was added dropwise. The reaction mixture was stirred for 90 minutes at room temperature. The temperature was raised to 40°C and the mixture was left to stir for 18 hours. The reaction mixture was divided into two separate vessels and concentrated under reduced pressure to give (2R,3R,3aS,6S,6aR)-6-((6-amino- 7-fluoro-1,5-naphthyridin-3-yl)methyl)-2-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan- 3,3a-diol, 3HCl. MS: 451 (M+1). ^1H NMR (499 MHz, DMSO- d6 ) δ 9.19 (s, 1H), _8.66 (d, J =1.4 Hz, 1H), 8.34 (d, J =3.8 Hz , 1H), 8.20 (d, J =10.8 Hz, 1H), 8.10 (s, 1H), 7.32 (d, J =3.8 Hz, 1H), 6.12 (d , J =8.2 Hz, 1H), 4.21 (d, J =8.2 Hz, 1H), 4.10 (d, J =5.9 Hz, 1H), 3.02-2.91 (m, 3H), 2.87-2.80 (m, 1H), 2.45-2.35 (m, 1H), 2.05-1.95 (m, 1H), 1.89-1 .79 (m, 1H), 1.78-1.70 (m, 1H), 1.62-1.52 (m, 1H).

Examples 26-29: Examples 26-29 in Table 10 were synthesized in the same manner as described in steps 1-2 of Example 25, replacing 7-((3aS,4R,5aR,8aR)-2,2-dimethyl-6-methylenehexahydro -5H-pentaleno[1,6a-d][1,3]dioxol-4-yl)-4-methyl-7H-pyrrolo[2,3-d]pyrimidine is a suitable exo-olefin, and 7-bromo-3- fluoroquinoline-2-amine with a suitable aryl halide and then performing chiral resolution by SFC, if necessary, based on the exo-olefin used. The reagents and starting material used for substitution were purchased commercially, synthesized as described above, or synthesized by known methods described in the literature.

Table 10 Etc. Structure Name MS 26 (2R,3R,3aS,6S,6aR)-6-((2-amino-3-chloro-8-fluoroquinolin-7-yl)methyl)-2-(4-amino-7H-pyrrolo[2,3- d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol 485 (M+1) 27 (2 R ,3 R ,3a S ,6 S ,6a R )-6-[(2-amino-3,6-difluoroquinolin-7-yl)methyl]-2-(4-amino-7 H -pyrrolo[ 2,3- d ]pyrimidin-7-yl)hexahydro-3a H -cyclopenta[ b ]furan-3,3a-diol 469 (M+1) 28 (2R,3R,3aS,6S,6aR)-6-((7-amino-6-chloro-1,8-naphthyridin-2-yl)methyl)-2-(4-amino-7H-pyrrolo[2, 3-d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol trihydrochloride 468 (M+1) 29 (2 R ,3 R ,3a S ,6 S ,6a R )-6-[(2-amino-3,5-difluoroquinolin-7-yl)methyl]-2-(4-amino-7 H -pyrrolo[ 2,3- d ]pyrimidin-7-yl)hexahydro-3a H -cyclopenta[ b ]furan-3,3a-diol 469 (M+1)

Example 30

(1S,2R,3aR,4S,6aR)-4-((2-amino-3-fluoroquinolin-7-yl)methyl)-2-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)hexahydropentalene-1,6a(1H)-diol

Step 1: Into a flask containing 1,1'-bis(diphenylphosphino)ferrocene (1.6 g, 2.8 mmol), sodium tert-butoxide (0.96 g, 8.4 mmol), 4-chloro-5 -fluoro-7H-pyrrolo[2,3-d]pyrimidine (1.4 g, 8.4 mmol) and allyl palladium chloride dimer (0.42 g, 1.1 mmol) were added with argon-degassed THF (55 ml). This mixture was stirred at room temperature for 15 minutes. A solution of (2R,6S,6aS)-6-((triphenylsilyl)oxy)-1,2,4,5,6,6a-hexahydropentalen-2-yl acetate (2.47 g, 5.61 mmol) in degassed solution was then added THF (23 ml). The reaction mixture was stirred under argon at 40°C for 3 hours. The mixture was quenched with water and extracted with EtOAc (2x). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography (0-15% EtOAc/hexane) to give 4-chloro-5-fluoro-7-((2R,6S,6aS)-6-((triphenylsilyl)oxy)-1,2. 4,5,6,6a-hexahydropentalen-2-yl)-7H-pyrrolo[2,3-d]pyrimidine. MS: 552 (M+1).

Step 2: Into a flask containing a solution of 4-chloro-5-fluoro-7-((2R,6S,6aS)-6-((triphenylsilyl)oxy)-1,2,4,5,6,6a-hexahydropentalene- 2-yl)-7H-pyrrolo[2,3-d]pyrimidine (1.36 g, 2.46 mmol) in THF (59 ml), water (29 ml) was added. The solution was cooled to 0°C and NMO (0.58 g, 4.9 mmol) and osmium(VIII) oxide (0.75 ml, 4% in water, 0.12 mmol) were added. The ice bath was allowed to warm naturally while stirring the reaction mixture overnight. The reaction was quenched with saturated aqueous sodium sulfite (40 ml) and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was poured into a separatory funnel containing water and EtOAc. After separation, the aqueous layer was washed twice with EtOAc and then once with 3:1 chloroform:IPA. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (1S,2R,3aR,4S,6aR)-2-(4-chloro-5-fluoro-7H-pyrrolo[2,3-d] pyrimidin-7-yl)-4-((triphenylsilyl)oxy)hexahydropentalene-1,6a(1H)-diol. This material was used crude directly in the next step without further purification.

Step 3: Into a flask containing (1S,2R,3aR,4S,6aR)-2-(4-chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-4-( (triphenylsilyl)oxy)hexahydropentalene-1,6a(1H)-diol (1.4 g, 2.4 mmol) dissolved in acetone (24 ml), sulfuric acid (0.126 ml, 2.36 mmol) was added under argon . The mixture was stirred at room temperature for 4 hours. The reaction mixture was then cooled to 0°C and quenched with sodium hydroxide (0.3 ml, 10 M in water, 3 mmol). The material was diluted with water (20 ml) and extracted with EtOAc (3x) and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography (50% EtOAc/hexane) to give (3aS,4R,5aR,6S,8aR)-4-(4-chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine -7-yl)-2,2-dimethylhexahydro-5H-pentaleno[1,6a-d][1,3]dioxol-6-ol. MS: 368 (M+1). ^1H NMR (600 MHz, CDCl ₃ ) δ 8.60 (s, 1H), 7.05 (d, J =2.6 Hz, 1H), 4.91-4.85 (m, 1H), 4 .70 (d, J =7.2 Hz, 1H), 4.11-4.08 (m, 1H), 2.59-2.52 (m, 2H), 2.41-2.34 (m , 1H), 2.25-2.19 (m, 1H), 2.13-2.06 (m, 1H), 2.06-1.93 (m, 2H), 1.59 (s, 3H ), 1.38 (s, 3H).

Step 4: To a solution of (3aS,4R,5aR,6S,8aR)-4-(4-chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethylhexahydro -5H-pentaleno[1,6a-d][1,3]dioxol-6-ol (270 mg, 0.734 mmol) in anhydrous DCM (5 ml) at 0°C under nitrogen was added Dess-Martin periodinane (374 mg , 0.881 mmol) per serving. The mixture was stirred at room temperature overnight. The reaction was quenched with a saturated aqueous solution of sodium bicarbonate (10 ml) and 1 g of Na ₂ S ₂ O ₃ . The resulting mixture was stirred for 10 minutes at room temperature. The organic layer was separated and the aqueous phase was extracted with DCM (10 ml x 3). The combined organic layers were washed with brine (10 mL), dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography (0-60% EtOAc/hexane) to give (3aS,4R,5aS,8aR)-4-(4-chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine -7-yl)-2,2-dimethylhexahydro-6H-pentaleno[1,6a-d][1,3]dioxol-6-one. MS: 366 (M+1).

Step 5: Methyltriphenylphosphonium bromide (781 mg, 2.14 mmol) was added to the vessel, followed by THF (3.3 ml) under argon. The mixture was cooled to 0°C and then n BuLi (650 μl, 2.5 M, 1.624 mmol) was added dropwise. The reaction mixture was removed from the ice bath and left to stir vigorously at room temperature for 30 minutes. Then the reaction mixture was again cooled to 0°C and a solution of (3aS,4R,5aS,8aR)-4-(4-chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl) was added dropwise )-2,2-dimethylhexahydro-6H-pentaleno[1,6a-d][1,3]dioxol-6-one (238 mg, 0.650 mmol) in THF (3.3 ml). The reaction mixture was removed from the ice bath and left to stir at room temperature for 70 minutes. The reaction was quenched with saturated aqueous ammonium chloride (10 ml) at 0°C. The mixture was extracted with EtOAc (2 x 10 mL) and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography (0-50% EtOAc/hexane) to give 4-chloro-7-((3aS,4R,5aR,8aR)-2,2-dimethyl-6-methylenehexahydro-5H-pentaleno[1 ,6a-d][1,3]dioxol-4-yl)-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine. MS: 364 (M+1).

Step 6: Into an argon-purged vessel containing 4-chloro-7-((3aS,4R,5aR,8aR)-2,2-dimethyl-6-methylenehexahydro-5H-pentaleno[1,6a-d][1,3 ]dioxol-4-yl)-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine (201.6 mg, 0.554 mmol), THF (4 ml) was added. A solution of 9-BBN (3.4 mL, 1.700 mmol, 0.5 M in THF) was then added. The reaction mixture was stirred overnight at room temperature under an argon cylinder. Potassium triphosphate (1.4 mL, 2.80 mmol, 2 M aq) was then added and the reaction mixture was stirred vigorously for ~35 min. Potassium tert-butoxide (0.1 mL, 0.100 mmol) was then added followed by rapid addition of a solution of chloro[di(1-adamantyl)-N-butylphosphine)-2-(2-aminobiphenyl)] palladium(II) (60 mg, 0.085 mmol) and 7-bromo-3,5-difluoroquinoline-2-amine (215 mg, 0.831 mmol) in THF (4 ml). The reaction mixture was heated to 50 degrees in an argon atmosphere for 4 hours 40 minutes. The reaction mixture was cooled to room temperature and diluted with DCM and water. The mixture was passed through a phase separator. The organic layer was concentrated under reduced pressure and the crude material was subjected to flash chromatography on silica gel (20-40-60% EtOAc/hexane) followed by chiral SFC (OJ-H column, 15% MeOH aq/0.1% NH ₄ OH modifier in CO2) to give 7-(((3aS,4R,5aR,6S,8aR)-4-(4-chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2 ,2-dimethylhexahydro-5H-pentaleno[1,6a-d][1,3]dioxol-6-yl)methyl)-3,5-difluoroquinolin-2-amine in the form of a foamy substance.

Step 7: Into a vessel containing 7-(((3aS,4R,5aR,6S,8aR)-4-(4-chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl) -2,2-dimethylhexahydro-5H-pentaleno[1,6a-d][1,3]dioxol-6-yl)methyl)-3,5-difluoroquinolin-2-amine (21.4 mg, 0.039 mmol), ammonia (l ml, 7 M in MeOH, 7 mmol) was added. The vessel was sealed and the reaction mixture was heated at 140°C in a microwave reactor for 5 hours. The mixture was then concentrated under reduced pressure to give 7-(((3aS,4R,5aR,6S,8aR)-4-(4-amino-5 -fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethylhexahydro-5H-pentaleno[1,6a-d][1,3]dioxol-6-yl)methyl)- 3,5-difluoroquinoline-2-amine, which was used crude without further purification in the following reaction.

Step 8: Into a vessel containing 7-(((3aS,4R,5aR,6S,8aR)-4-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl) -2,2-dimethylhexahydro-5H-pentaleno[1,6a-d][1,3]dioxol-6-yl)methyl)-3,5-difluoroquinolin-2-amine (21 mg, 0.039 mmol), added DCM (600 µl), water (190 µl) and then TFA (454 µl, 5.89 mmol). The mixture was stirred at room temperature for 3 hours. The reaction mixture was then directly concentrated under reduced pressure. The residue was purified by mass initiated reverse phase HPLC (ACN/water gradient with 0.1% NH ₄ OH modifier) to give (1S,2R,3aR,4S,6aR)-4-((2-amino-3,5- difluoroquinolin-7-yl)methyl)-2-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)hexahydropentalene-1,6a(1H)-diol. MS: 485 (M+1). ¹ H NMR (600 MHz, DMSO) δ 8.69 (s, 2H), 8.29 (s, 1H), 7.98 (d, J =11.1 Hz, 1H), 7.87 (s, 1H), 7.68 (s, 2H), 7.19 (s, 1H), 7.06 (d, J =11.0 Hz, 1H), 4.84-4.77 (m, 1H), 3.76 (d, J =10.3 Hz, 1H), 2.79-2.66 (m, 2H), 2.49-2.42 (m, 1H), 2.16 (sq., J =9.0 Hz, 1H), 1.82 (dd, J =12.2, 5.8 Hz, 1H), 1.78-1.69 (m, 2H), 1.69-1.63 ( m, 1H), 1.63-1.54 (m, 1H), 1.48-1.41 (m, 1H).

Examples 31-34: Examples 31-34 in Table 11 were synthesized in the same manner as described in Example 30, replacing 4-chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine with a suitable nucleobase in step 1, and replacing step 6 with step 3 in Example 16, where a suitable aryl halide is used to replace the 7-bromo-3,5-difluoroquinoline-2-amine. The reagents and starting material used for substitution were purchased commercially, synthesized as described above, or synthesized by known methods described in the literature.

Table 11 Etc. Structure Name MS 31 (1S,2R,3aR,4S,6aR)-2-(4-amino-2-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-4-((2-amino-3- chloroquinolin-7-yl)methyl)hexahydropentalene-1,6a(1H)-diol 2,2,2-trifluoroacetate 479 (M+1) 32 (1S,2R,3aR,4S,6aR)-2-(4-amino-2-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-4-((2-amino-3- fluoroquinolin-7-yl)methyl)hexahydropentalene-1,6a(1H)-diol 2,2,2-trifluoroacetate 463 (M+1) 33 (1S,2R,3aR,4S,6aR)-4-((2-amino-3-fluoroquinolin-7-yl)methyl)-2-(4-amino-5-fluoro-7H-pyrrolo[2,3- d]pyrimidin-7-yl)hexahydropentalene-1,6a(1H)-diol 467 (M+1) 34 (1S,2R,3aR,4S,6aR)-4-((2-amino-3-chloroquinolin-7-yl)methyl)-2-(4-amino-5-fluoro-7H-pyrrolo[2,3- d]pyrimidin-7-yl)hexahydropentalene-1,6a(1H)-diol 483 (M+1)

Examples 35-42: Examples 35-42 in Table 12 were synthesized in the same manner as described in Example 30, replacing 4-chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine with a suitable nucleobase in step 1 and replacing step 6 step 1 in example 25, where a suitable aryl halide is used to replace the 7-bromo-3,5-difluoroquinoline-2-amine. The reagents and starting material used for substitution were purchased commercially, synthesized as described above, or synthesized by known methods described in the literature.

Table 12 Etc. Structure Name MS 35 (1 S ,2 R ,3a R ,4 S ,6a R )-4-[(2-amino-3,5-difluoroquinolin-7-yl)methyl]-2-(4-amino-5-methyl-7 H -pyrrolo[2,3- d ]pyrimidin-7-yl)hexahydropentalene-1,6a( 1H )-diol 481 (M+1) 36 (1 S ,2 R ,3a R ,4 S ,6a R )-4-[(2-amino-3-chloro-5-fluoroquinolin-7-yl)methyl]-2-(4-amino-5-methyl -7H -pyrrolo[2,3- d ]pyrimidin-7-yl)hexahydropentalene-1,6a( 1H )-diol 497 (M+1) 37 (1S,2R,3aR,4S,6aR)-2-(4-amino-2-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-4-((2-amino-3- bromoquinolin-7-yl)methyl)hexahydropentalene-1,6a(1H)-diol 523/525 (M+1/M+3) 38 (1S,2R,3aR,4S,6aR)-4-((2-amino-3-fluoroquinolin-7-yl)methyl)-2-(4-amino-5-methyl-7H-pyrrolo[2,3- d]pyrimidin-7-yl)hexahydropentalene-1,6a(1H)-diol 463 (M+1) 39 (1S,2R,3aR,4S,6aR)-4-((2-amino-3-chloroquinolin-7-yl)methyl)-2-(4-amino-5-methyl-7H-pyrrolo[2,3- d]pyrimidin-7-yl)hexahydropentalene-1,6a(1H)-diol 479 (M+1) 40 (1S,2R,3aR,4S,6aR)-4-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(4-amino-5-methyl-7H-pyrrolo[2,3- d]pyrimidin-7-yl)hexahydropentalene-1,6a(1H)-diol 523/525 (M+1/M+3) 41 (1S,2R,3aR,4S,6aR)-4-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)hexahydropentalene-1,6a(1H)-diol 2,2,2-trifluoroacetate 509/511 (M+1/M+3) 42 (1S,2R,3aR,4S,6aR)-4-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(4-amino-5-fluoro-7H-pyrrolo[2,3- d]pyrimidin-7-yl)hexahydropentalene-1,6a(1H)-diol 527/529 (M+1/M+3)

Examples 43-44: Examples 43-44 in Table 13 were synthesized using the protocols described in steps 6-8 of Example 30, replacing 7-bromo-3,5-difluoroquinoline-2-amine with the appropriate aryl halide in step 6. Used for Substitution reagents and starting material were purchased commercially, synthesized as described above, or synthesized by known methods described in the literature.

Table 13 Etc. Structure Name MS 43 (2 R ,3 R ,3a S ,6 S ,6a R )-6-[(2-amino-3-bromoquinolin-7-yl)methyl]-2-[4-amino-5-(difluoromethyl)-7 H -pyrrolo[2,3- d ]pyrimidin-7-yl]hexahydro-3a H -cyclopenta[ b ]furan-3,3a-diol 561/563 (M+1/M+3) 44 (2R,3R,3aS,6S,6aR)-6-((2-amino-3-fluoroquinolin-7-yl)methyl)-2-(4-amino-5-fluoro-2-methyl-7H-pyrrolo[ 2,3-d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol 2,2,2-trifluoroacetate 484 (M+1)

Example 45

(2R,3R,3aS,6S,6aR)-2-(4-amino-2-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-6-((2-amino-3- fluoroquinolin-7-yl)methyl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol

Step 1: To 2-fluoro-7H-pyrrolo[2,3-d]pyrimidin-4-amine (500 mg, 3.29 mmol) dissolved in DCM (8 ml) and acetonitrile (8 ml) was added di- tert-butyl dicarbonate (2.5 g, 12 mmol) and DMAP (80 mg, 0.66 mmol). The solution was stirred at room temperature for 1 hour. The mixture was then concentrated under reduced pressure and the residue was purified by silica column chromatography (0-30% EtOAc/hexane) to give tert- butyl 4-[bis( tert- butoxycarbonyl)amino]- 2-fluoro- 7H -pyrrolo[2,3- d ]pyrimidine-7-carboxylate. MS: 453 (M+1). ^1H NMR (600 MHz, CDCl ₃ ) δ 7.64 (d, J =4.1 Hz, 1H), 6.48 (d, J =4.1 Hz, 1H), 1.69 (s, 9H ), 1.44 (s, 18H).

Step 2: To a solution of tert- butyl 4-[bis( tert- butoxycarbonyl)amino]-2-fluoro- 7H -pyrrolo[2,3- d ]pyrimidine-7-carboxylate (1.35 g, 2.98 mmol ) in MeOH (15 ml) was added TEA (4.15 ml, 29.8 mmol) at room temperature. The reaction mixture was heated to 60°C and stirred overnight. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica column chromatography (0-60% EtOAc/hexane) to give di-tert-butyl (2-fluoro- 7H -pyrrolo[2,3- d ]pyrimidin-4-yl)imidodicarbonate. MS: 353 (M+1). ¹ H NMR (600 MHz, CDCl ₃ ) δ 9.34 (s, 1H), 7.28 (dd, J =3.5, 2.3 Hz, 1H), 6.50 (dd, J =3, 6, 2.0 Hz, 1H), 1.47 (s, 18H).

Step 3: Into a vessel containing (3R,3aS,6S,6aR)-6-((2-amino-3-fluoroquinolin-7-yl)methyl)hexahydro-3aH-cyclopenta[b]furan-2,3,3a -triol (100 mg, 0.299 mmol) dissolved in anhydrous acetonitrile (5 ml), 1,1'-(azodicarbonyl)dipiperidine (113 mg, 0.45 mmol) was added followed by tri -butylphosphine (120 μl, 0.48 mmol) at room temperature. The mixture was stirred for 1 hour. In a separate vessel containing di-tert-butyl (2-fluoro- 7H -pyrrolo[2,3- d ]pyrimidin-4-yl)imidodicarbonate (211 mg, 0.598 mmol) dissolved in anhydrous acetonitrile (1 ml), DBU (90 μl, 0.60 mmol) was added. The mixture was stirred for 30 minutes at room temperature. The mixture was then added to the mixture containing the previously formed epoxide, and the reaction mixture was stirred for 2.5 hours at room temperature. The mixture was then filtered and purified by mass initiated reverse phase HPLC (ACN/water with 0.1% NH ₄ OH modifier) to give di-tert-butyl (7-{(2 R ,3 R ,3a S ,6 S , 6a R )-6-[(2-amino-3-fluoroquinolin-7-yl)methyl]-3,3a-dihydroxyhexahydro-2 H -cyclopenta[ b ]furan-2-yl}-2-fluoro-7 H - pyrrolo[2,3- d ]pyrimidin-4-yl)imidodicarbonate. MS: 669 (M+1).

Step 4: K di-tert-butyl (7-{(2 R ,3 R ,3a S ,6 S ,6a R )-6-[(2-amino-3-fluoroquinolin-7-yl)methyl]-3 ,3a-dihydroxyhexahydro- 2H -cyclopenta[ b ]furan-2-yl}-2-fluoro- 7H -pyrrolo[2,3- d ]pyrimidin-4-yl)imidodicarbonate (97 mg, 0.14 mmol) dissolved in DCM (3 ml), TFA (1.1 ml, 14.5 mmol) was added. The mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure. The residue was purified by mass initiated reverse phase HPLC (ACN/water gradient with 0.1% NH ₄ OH modifier) to give (2R,3R,3aS,6S,6aR)-2-(4-amino-2-fluoro-7H -pyrrolo[2,3-d]pyrimidin-7-yl)-6-((2-amino-3-fluoroquinolin-7-yl)methyl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol. MS: 469 (M+1). ^1H NMR (600 MHz, DMSO) δ 7.75 (d, J =11.8 Hz, 1H), 7.59 (s, 2H), 7.54 (d, J =8.2 Hz, 1H) , 7.40 (d, J =3.7 Hz, 1H), 7.30 (s, 1H), 7.09 (d, J =8.2 Hz, 1H), 6.78-6.62 ( m, 3H), 5.72 (d, J =8.1 Hz, 1H), 5.26 (d, J =7.0 Hz, 1H), 5.08 (s, 1H), 4.09 ( t, J =7.5 Hz, 1H), 3.96 (d, J =5.7 Hz, 1H), 2.82 (dd, J =13.6, 7.8 Hz, 1H), 2, 62 (dd, J =13.6, 7.2 Hz, 1H), 2.28-2.20 (m, 1H), 1.92 (dd, J =12.7, 6.0 Hz, 1H) , 1.76-1.64 (m, 2H), 1.55-1.48 (m, 1H).

Example 46: Example 45 in Table 14 was synthesized using the Mitsunobu protocol described in step 3 of the synthesis of Example 45, followed by the TFA deprotection procedure described in step 4 of Example 45. Di-tert-butyl (2-fluoro-7 H -pyrrolo[2,3- d ]pyrimidin-4-yl)imidodicarbonate and (3R,3aS,6S,6aR)-6-((2-amino-3-fluoroquinolin-7-yl)methyl)hexahydro-3aH- The cyclopenta[b]furan-2,3,3a-triol in the Mitsunobu sequence was replaced with the appropriate nucleobase and triol, respectively. The reagents and starting material used for substitution were purchased commercially, synthesized as described above, or synthesized by known methods described in the literature.

Table 14 Etc. Structure Name MS 46 (2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)oxy)-2-(2-amino-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol dihydrochloride 513/515 (M+1/M+3)

Examples 47-48: Examples 47-48 in Table 15 were synthesized in the same manner as described in Example 45, replacing 2-fluoro-7H-pyrrolo[2,3-d]pyrimidin-4-amine with a suitable nucleobase in step 1, and (3R,3aS,6S,6aR)-6-((2-amino-3-fluoroquinolin-7-yl)methyl)hexahydro-3aH-cyclopenta[b]furan-2,3,3a-triol with a suitable triol in step 3 The reagents and starting material used for substitution were purchased commercially, synthesized as described above, or synthesized by known methods described in the literature.

Table 15 Etc. Structure Name LCMS 47 (2 R ,3 R ,3a S ,6 S ,6a R )-2-(4-amino-2-chloro-7 H -pyrrolo[2,3- d ]pyrimidin-7-yl)-6-[( 2-amino-3-chloroquinolin-7-yl)methyl]hexahydro-3a H -cyclopenta[ b ]furan-3,3a-diol 501 (M+1) 48 (2 R ,3 R ,3a S ,6 S ,6a R )-2-(4-amino-2-chloro-7 H -pyrrolo[2,3- d ]pyrimidin-7-yl)-6-[( 2-amino-3-fluoroquinolin-7-yl)methyl]hexahydro-3a H -cyclopenta[ b ]furan-3,3a-diol 485 (M+1)

Examples 49-66: Examples 49-66 in Table 16 were synthesized using the Mitsunobu protocol described in step 3 of the synthesis of Example 45, followed by the aminolysis protocol described in step 7 of Example 30. Di-tert-butyl (2-fluoro-7 H -pyrrolo[2,3- d ]pyrimidin-4-yl)imidodicarbonate and (3R,3aS,6S,6aR)-6-((2-amino-3-fluoroquinolin-7-yl)methyl)hexahydro-3aH- The cyclopenta[b]furan-2,3,3a-triol in the Mitsunobu sequence was replaced with the appropriate nucleobase and triol, respectively. The reagents and starting material used for substitution were purchased commercially, synthesized as described above, or synthesized by known methods described in the literature.

Table 16 Etc. Structure Name MS 49 (2 R ,3 R ,3a S ,6 S ,6a R )-6-[(2-amino-3-bromoquinolin-7-yl)oxy]-2-(4-amino-5-phenyl-7 H - pyrrolo[2,3- d ]pyrimidin-7-yl)hexahydro-3a H -cyclopenta[ b ]furan-3,3a-diol 589/591 (M+1/M+3) 50 (2 R ,3 R ,3a S ,6 S ,6a R )-2-(4-amino-5-cyclopropyl-7 H -pyrrolo[2,3- d ]pyrimidin-7-yl)-6-[( 2-amino-3-fluoroquinolin-7-yl)methyl]hexahydro-3a H -cyclopenta[ b ]furan-3,3a-diol 491 (M+1) 51 (2 R ,3 R ,3a S ,6 S ,6a R )-2-[4-amino-5-(difluoromethyl)-7 H -pyrrolo[2,3- d ]pyrimidin-7-yl]-6- [(2-amino-3-fluoroquinolin-7-yl)methyl]hexahydro-3a H -cyclopenta[ b ]furan-3,3a-diol 501 (M+1) 52 (2 R ,3 R ,3a S ,6 S ,6a R )-6-[(2-amino-3-bromoquinolin-7-yl)oxy]-2-(4-amino-5-cyclopropyl-7 H - pyrrolo[2,3- d ]pyrimidin-7-yl)hexahydro-3a H -cyclopenta[ b ]furan-3,3a-diol 553/555 (M+1/M+3) 53 (2 R ,3 R ,3a S ,6 S ,6a R )-6-[(2-amino-3-fluoroquinolin-7-yl)methyl]-2-(4-amino-7 H -pyrrolo[2, 3- d ]pyrimidin-7-yl)-5,5-difluorohexahydro-3a H -cyclopenta[ b ]furan-3,3a-diol 487 (M+1) 54 (2 R ,3 R ,3a S ,5 S ,6 S ,6a R )-6-[(2-amino-3-fluoroquinolin-7-yl)methyl]-2-(4-amino-7 H -pyrrolo [2,3- d ]pyrimidin-7-yl)-5-fluorohexahydro-3a H -cyclopenta[ b ]furan-3,3a-diol 469 (M+1) 55 (2 R ,3 R ,3a S ,5 S ,6 S ,6a R )-2-(4-amino-5-fluoro-7 H -pyrrolo[2,3- d ]pyrimidin-7-yl)-6 -[(2-amino-3-fluoroquinolin-7-yl)methyl]-5-fluorohexahydro-3a H -cyclopenta[ b ]furan-3,3a-diol, 2,2,2-trifluoroethanol 487 (M+1) 56 (2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)oxy)-2-(4-amino-5-fluoro-7H-pyrrolo[2,3- d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol 531/533 (M+1/M+3) 57 (2R,3R,3aS,6S,6aR)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-6-((2-((2,2,2- trifluoroethyl)amino)quinolin-7-yl)oxy)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol 517 (M+1) 58 (2R,3R,3aS,6S,6aR)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-6-((2-((cyclopropylmethyl)amino)quinoline- 7-yl)oxy)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol 489 (M+1) 59 (2R,3R,3aS,6S,6aR)-6-((2-amino-3-fluoroquinolin-7-yl)methyl)-2-(4-amino-5-fluoro-7H-pyrrolo[2,3- d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol 469 (M+1) 60 (2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)oxy)-2-(4-amino-5-methyl-7H-pyrrolo[2,3- d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol 527/529 (M+1/M+3) 61 (2R,3R,3aS,6S,6aR)-2-(4-amino-2-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-6-((2-amino-3- bromoquinolin-7-yl)methyl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol 525/527 (M+1/M+3) 62 (2R,3R,3aS,6S,6aR)-6-((2-amino-3-fluoroquinolin-7-yl)methyl)-2-(4-amino-5-methyl-7H-pyrrolo[2,3- d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol 2,2,2-trifluoroacetate 465 (M+1) 63 (2R,3R,3aS,6S,6aR)-2-(4-amino-2-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-6-((2-amino-3- bromoquinolin-7-yl)oxy)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol 527/529 (M+1/M+3) 64 (2R,3R,3aS,6S,6aR)-6-((2-amino-3-chloroquinolin-7-yl)oxy)-2-(4-amino-5-methyl-7H-pyrrolo[2,3- d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol 2,2,2-trifluoroacetate 483 (M+1) 65 (2R,3R,3aS,6S,6aR)-6-((2-amino-3-fluoroquinolin-7-yl)oxy)-2-(4-amino-5-methyl-7H-pyrrolo[2,3- d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol 2,2,2-trifluoroacetate 467 (M+1) 66 (2R,3R,3aS,6S,6aR)-6-((2-amino-3-chloroquinolin-7-yl)methyl)-2-(4-amino-5-methyl-7H-pyrrolo[2,3- d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol 481 (M+1)

Examples 67-70: Examples 67-70 in Table 17 were synthesized using the Mitsunobu protocol described in step 3 of the synthesis of example 45, followed by the aminolysis protocol described in step 11 of examples 10 & 11. Di-tert-butyl (2-fluoro -7 H -pyrrolo[2,3- d ]pyrimidin-4-yl)imidodicarbonate and (3R,3aS,6S,6aR)-6-((2-amino-3-fluoroquinolin-7-yl)methyl)hexahydro- The 3aH-cyclopenta[b]furan-2,3,3a-triol in the Mitsunobu sequence was replaced with the appropriate nucleobase and triol, respectively. The reagents and starting material used for substitution were purchased commercially, synthesized as described above, or synthesized by known methods described in the literature.

Table 17 Etc. Structure Name MS 67 (2R,3R,3aS,6S,6aR)-6-((2-amino-3-chloroquinolin-7-yl)methyl)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol 467 (M+1) 68 (2R,3R,3aS,6S,6aR)-6-((2-amino-3-chloroquinolin-7-yl)methyl)-2-(4-amino-5-fluoro-7H-pyrrolo[2,3- d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol 485 (M+1) 69 (2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)oxy)-2-(4-amino-5-ethyl-7H-pyrrolo[2,3- d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol 541/543 (M+1/M+3) 70 (2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(4-amino-5-methyl-7H-pyrrolo[2,3- d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol 2,2,2-trifluoroacetate 525/527 (M+1/M+3)

Examples 71-75: Examples 71-75 in Table 18 were synthesized using the Mitsunobu protocol described in step 3 of the synthesis of example 45, followed by the aminolysis protocol described in step 12 of intermediate 15. Di-tert-butyl (2-fluoro- 7 H -pyrrolo[2,3- d ]pyrimidin-4-yl)imidodicarbonate and (3R,3aS,6S,6aR)-6-((2-amino-3-fluoroquinolin-7-yl)methyl)hexahydro-3aH The -cyclopenta[b]furan-2,3,3a-triol in the Mitsunobu sequence was replaced with the appropriate nucleobase and triol, respectively. The reagents and starting material used for substitution were purchased commercially, synthesized as described above, or synthesized by known methods described in the literature.

Table 18 Etc. Structure Name MS 71 (2R,3R,3aS,6S,6aR)-6-((2-amino-3-fluoroquinolin-7-yl)oxy)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol 453 (M+1) 72 (2R,3R,3aS,6S,6aR)-6-((2-amino-3-chloroquinolin-7-yl)oxy)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol 469 (M+1) 73 (2R,3R,3aS,6S,6aR)-6-((2-amino-3-fluoroquinolin-7-yl)oxy)-2-(4-amino-5-fluoro-7H-pyrrolo[2,3- d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol 471 (M+1) 74 (2R,3R,3aS,6S,6aR)-6-((2-amino-3-chloroquinolin-7-yl)oxy)-2-(4-amino-5-fluoro-7H-pyrrolo[2,3- d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol 487 (M+1) 75 (2R,3R,3aS,6S,6aR)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-6-((2,3-dihydro-1H-pyrrolo[ 2,3-b]quinolin-7-yl)oxy)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol 461 (M+1)

Example 76: Example 76 in Table 19 was synthesized using the Mitsunobu protocol described in step 7 of the synthesis of example 14, followed by the aminolysis protocol described in step 12 of intermediate 15. 4-chloro- 7H -pyrrolo[2,3-d ]pyrimidine and (3 R ,4 S ,5 R )-5-(2-(3-bromo-2-((4-methoxybenzyl)amino)quinolin-7-yl)ethyl)-4-methyltetrahydrofuran-2,3 The ,4-triol in the Mitsunobu sequence was replaced with the appropriate nucleobase and triol, respectively. The reagents and starting material used for substitution were purchased commercially, synthesized as described above, or synthesized by known methods described in the literature.

Table 19 Etc. Structure Name MS 76 (2R,3R,3aS,6S,6aR)-6-((2-amino-3-(trifluoromethyl)quinolin-7-yl)methyl)-2-(4-amino-7H-pyrrolo[2,3-d ]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol 501 (M+)

Examples 77-84: Examples 77-84 in Table 20 were synthesized using the Mitsunobu protocol described in step 3 of the synthesis of Example 45. Di-tert-butyl (2-fluoro- 7H- pyrrolo[2,3- d ]pyrimidine-4 -yl)imidodicarbonate and (3R,3aS,6S,6aR)-6-((2-amino-3-fluoroquinolin-7-yl)methyl)hexahydro-3aH-cyclopenta[b]furan-2,3,3a-triol in the sequence, Mitsunobu was replaced by the appropriate nucleobase and triol, respectively. The reagents and starting material used for substitution were purchased commercially, synthesized as described above, or synthesized by known methods described in the literature.

Table 20 Etc. Structure Name MS 77 (2 R ,3 R ,3a S ,6 S ,6a R )-6-[(2-amino-3-bromoquinolin-7-yl)oxy]-2-[4-(hydroxymethyl)-7 H -pyrrolo[ 2,3- d ]pyrimidin-7-yl]hexahydro-3a H -cyclopenta[ b ]furan-3,3a-diol 528/530 (M+1/M+3) 78 (2 R ,3 R ,3a S ,6 S ,6a R )-6-[(2-amino-3-bromoquinolin-7-yl)oxy]-2-[4-(2-hydroxypropan-2-yl) -7 H -pyrrolo[2,3- d ]pyrimidin-7-yl]hexahydro-3a H -cyclopenta[ b ]furan-3,3a-diol 556/558 (M+1/M+3) 79 (2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)oxy)-2-(4-(difluoromethyl)-7H-pyrrolo[2,3-d] pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol 548/550 (M+1/M+3) 80 (2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)oxy)-2-(2,4-dimethyl-7H-pyrrolo[2,3-d] pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol 2,2,2-trifluoroacetate 526/528 (M+1/M+3) 81 (2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(2,4-dimethyl-7H-pyrrolo[2,3-d] pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol 524/526 (M+1/M+3) 82 (2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)oxy)-2-(4-amino-5-ethyl-7H-pyrrolo[2,3- d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol 2,2,2-trifluoroacetate 526/528 (M+1/M+3) 83 (2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(4-isopropyl-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol 538/540 (M+1/M+3) 84 (2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(5-fluoro-4-methyl-7H-pyrrolo[2,3- d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol 528/530 (M+1/M+3)

Examples 85-91: Examples 85-91 in Table 21 were synthesized using the Mitsunobu protocol described in step 7 of the synthesis of Example 14. 4-chloro- 7H -pyrrolo[2,3-d]pyrimidine and ( 3R , 4S , 5 R )-5-(2-(3-bromo-2-((4-methoxybenzyl)amino)quinolin-7-yl)ethyl)-4-methyltetrahydrofuran-2,3,4-triol in the Mitsunobu sequence was replaced by a suitable nucleobase and triol, respectively. The reagents and starting material used for substitution were purchased commercially, synthesized as described above, or synthesized by known methods described in the literature.

Table 21 Etc. Structure Name MS 85 (2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)oxy)-2-(7H-pyrrolo[2,3-d]pyrimidin-7-yl) hexahydro-3aH-cyclopenta[b]furan-3,3a-diol 498/500 (M+1/M+3) 86 (2R,3R,3aS,6S,6aR)-6-((2-amino-3-fluoroquinolin-7-yl)oxy)-2-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol 452 (M+1) 87 (2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(4-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol 536/538 (M+1/M+3) 88 (2R,3R,3aS,6S,6aR)-6-((2-amino-3-(trifluoromethyl)quinolin-7-yl)methyl)-2-(4-methyl-7H-pyrrolo[2,3-d ]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol 500 (M+1) 89 (2R,3R,3aS,6S,6aR)-6-((2,3-dihydro-1H-pyrrolo[2,3-b]quinolin-7-yl)oxy)-2-(4-methyl-7H- pyrrolo[2,3-d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol 460 (M+1) 90 (2R,3R,3aS,6S,6aR)-6-((2-amino-3-fluoroquinolin-7-yl)methyl)-2-(2,4-dimethyl-7H-pyrrolo[2,3-d] pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol 464 (M+1) 91 (2R,3R,3aS,6S,6aR)-6-((2-amino-3-chloroquinolin-7-yl)methyl)-2-(2,4-dimethyl-7H-pyrrolo[2,3-d] pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol 480 (M+1)

Example 92

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(4-(methylamino)-7H-pyrrolo[2,3-d] pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol

Step 1: Into a vessel containing (2R,3R,3aS,6S,6aR)-6-((3-bromo-2-((4-methoxybenzyl)amino)quinolin-7-yl)methyl)-2-(4 -chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)hexahydro-2H-cyclopenta[b]furan-3,3a-diol (102 mg, 0.157 mmol), dissolved in dioxane (3000 µl), add methylamine (2.0 M in THF, 6.26 mL, 12.5 mmol) at room temperature. The mixture was sealed and heated at 70°C for 6 hours. The mixture was concentrated under reduced pressure to give (2R,3R,3aS,6S,6aR)-6-((3-bromo-2-((4-methoxybenzyl)amino )quinolin-7-yl)methyl)-2-(4-(methylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)hexahydro-2H-cyclopenta[b]furan-3,3a-diol in the form of a foamy substance. MS: 645/647 (M+1/M+3).

Step 2: K (2R,3R,3aS,6aR)-6-((3-bromo-2-((4-methoxybenzyl)amino)quinolin-7-yl)methyl)-2-(4-(methylamino)- 7H-pyrrolo[2,3-d]pyrimidin-7-yl)hexahydro-2H-cyclopenta[b]furan-3,3a-diol (101 mg, 0.156 mmol) dissolved in DCM (1304 μL) was added with TFA ( 1300 µl, 16.87 mmol) at room temperature. The mixture was stirred for 5.5 hours at 40°C and then the heat was turned off and the reaction mixture was left to stir at room temperature overnight. The reaction mixture was heated at 40°C for 2 hours. The mixture was concentrated under reduced pressure and purified by mass initiated reverse phase column chromatography (ACN:water with 0.1% NH ₄ OH modifier) to give (2R,3R,3aS, 6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(4-(methylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)hexahydro -2H-cyclopenta[b]furan-3,3a-diol as a solid. MS: 525/527 (M+1/M+3). 1H NMR (600 MHz, DMSO-d6) δ 8.31 (s, 1H), 8.19 (s, 1H), 7.55 (d, J=8.2 Hz, 2H), 7.45 (d , J=3.6 Hz, 1H), 7.28 (s, 1H), 7.09 (dd, J=8.2, 1.4 Hz, 1H), 6.67 (d, J=3, 6 Hz, 1H), 6.57 (s, 2H), 5.90 (d, J=8.1 Hz, 1H), 5.25 (d, J=7.1 Hz, 1H), 5.07 (s, 1H), 4.15 (t, J=7.4 Hz, 1H), 3.96 (d, J=5.7 Hz, 1H), 2.99 (d, J=4.5 Hz , 3H), 2.86-2.79 (m, 1H), 2.66-2.58 (m, 1H), 2.29-2.22 (m, 1H), 1.98-1.91 (m, 1H), 1.78-1.65 (m, 2H), 1.58-1.49 (m, 1H).

Examples 93-97: Examples 93-97 in Table 22 were synthesized in the same manner as described in steps 1-2 of Example 92, replacing (2R,3R,3aS,6S,6aR)-6-((3-bromo-2- ((4-methoxybenzyl)amino)quinolin-7-yl)methyl)-2-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)hexahydro-2H-cyclopenta[b]furan- 3,3a-diol is a suitable chloro-nucleobase. The reagents and starting material used for substitution were purchased commercially, synthesized as described above, or synthesized by known methods described in the literature.

Table 22 Etc. Structure Name MS 93 (1R,2S,3R,5R)-5-(((2-amino-3-bromoquinolin-7-yl)oxy)methyl)-1-methyl-3-(4-(methylamino)-7H-pyrrolo[2 ,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol 513/515 (M+1/M+3) 94 (2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)oxy)-2-(4-(methylamino)-7H-pyrrolo[2,3-d] pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol 527/529 (M+1/M+3) 95 (2R,3R,3aS,6S,6aR)-6-((2-amino-3-fluoroquinolin-7-yl)methyl)-2-(4-(methylamino)-7H-pyrrolo[2,3-d] pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol 465 (M+1) 96 (2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(5-fluoro-4-(methylamino)-7H-pyrrolo[2, 3-d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol 543/545 (M+1/M+3) 97 (1S,2R,3aR,4S,6aR)-4-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(4-(methylamino)-7H-pyrrolo[2,3-d] pyrimidin-7-yl)hexahydropentalene-1,6a(1H)-diol 523/525 (M+1/M+3)

Example 98

(2R,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-methyl-2-((quinolin-7-yloxy)methyl) tetrahydrofuran-3,4-diol

Step 1: Solution of ((3aS,4R,6R,6aR)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2,4-trimethyltetrahydrofuro[3,4 -d][1,3]dioxol-4-yl)methanol (400 mg, 1.18 mmol), quinolin-7-ol (205 mg, 1.41 mmol) and triphenylphosphine (1578 mg, 3.06 mmol) stirred in anhydrous THF (12 ml) under nitrogen atmosphere. DIAD (0.572 mL, 2.94 mmol) was added dropwise at 0°C. The mixture was stirred at room temperature overnight. The reaction mixture was filtered and washed with MeOH. The filtrate was concentrated under reduced pressure and purified by silica column chromatography (EtOAc/PE 0-50% followed by MeOH/DCM 0-5%) to give 7-(((3aS,4R,6R,6aR)-6-(4 -chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2,4-trimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)quinoline in the form solid matter. Then to a stirred solution of 7-(((3aS,4R,6R,6aR)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2,4-trimethyltetrahydrofuro[ 3,4-d][1,3]dioxol-4-yl)methoxy)quinoline (100 mg, 0.214 mmol) in dioxane (1 ml) added ammonia (28% in water) (1 ml, 12.94 mmol) and the mixture was stirred at 120°C for 8.5 hours. The reaction mixture was evaporated under reduced pressure and purified by reverse phase HPLC (ACN/water) to give 7-((3aR,4R,6R,6aS)-2,2. 6-trimethyl-6-((quinolin-7-yloxy)methyl)tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- amine in solid form. MS: 448 (M+1).

Step 2: To the compound 7-((3aR,4R,6R,6aS)-2,2,6-trimethyl-6-((quinolin-7-yloxy)methyl)tetrahydrofuro[3,4-d][1,3 ]dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (11 mg, 0.025 mmol) the previously prepared mixture of TFA (70 μl, 0.909 mmol)/water (150 μl) was added at 0 °C. The resulting suspension was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse phase HPLC (MeCN/water) to give (2R,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-methyl -2-((quinolin-7-yloxy)methyl)tetrahydrofuran-3,4-diol as a solid. MS: 408 (M+1). ^1H NMR (400 MHz, _Methanol-d4 ) δ 8.79 (dd, J =4.5, 1.7 Hz, 1H), 8.32 (d, J =6.7 Hz, 1H), 8 .10 (s, 1H), 7.91 (d, J =9.0 Hz, 1H), 7.48-7.37 (m, 5H), 6.62 (d, J =3.7 Hz, 1H), 6.30 (d, J =6.7 Hz, 1H), 4.45 (d, J =5.5 Hz, 1H), 4.32-4.21 (m, 2H), 1, 53 (s, 3H).

Example 99: Example 99 in Table 23 was synthesized following Steps 1-2 of Example 98 described above starting from intermediate 28.

Table 23 Etc. Structure Name MS 99 (2R,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-methyl-2-((quinolin-7-yloxy)methyl) tetrahydrofuran-3,4-diol 408 (M+1)

Example 100

(1S,2R,3R,5R)-3-(((2-amino-3-bromoquinolin-7-yl)oxy)methyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidine -7-yl)-3-methylcyclopentane-1,2-diol

Step 1: To a solution of lithium bis(trimethylsilyl)amide (73.9 ml, 73.9 mmol) at -70°C was added a solution of (1S,4R)-methyl 4-((tert-butoxycarbonyl)amino)cyclopent-2- encarboxylate (8 g, 33.2 mmol) in THF (8 ml) for 2 minutes at -70°C. The resulting solution was stirred at -70°C for 30 minutes, then iodomethane (3.67 ml, 59.0 mmol) was added over 5 minutes. The reaction mixture was heated to -25°C and maintained at this temperature for 2 hours. The resulting mixture was diluted with saturated aqueous NaHCO ₃ (200 ml) and extracted with EtOAc (3 x 200 ml). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica column chromatography (16.6% EtOAc/PE) to give (1S,4R)-methyl 4-((tert-butoxycarbonyl)amino)-1-methylcyclopent-2-enecarboxylate in in the form of oil. MS: 199 (M-56).

Step 2: To a stirred mixture of (1S,4R)-methyl 4-((tert-butoxycarbonyl)amino)-1-methylcyclopent-2-enecarboxylate (7.1 g, 27.8 mmol) in THF (100 ml) was added tetrahydroborate lithium (27.8 ml, 55.6 mmol) at 0°C under argon. The resulting mixture was heated to 25°C and stirred for 16 hours. The reaction mixture was quenched with MeOH (50 ml), diluted with saturated aqueous NH ₄ Cl (300 ml) and then extracted with EtOAc (3 x 200 ml). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and recrystallized from PE (100 ml). The solid was collected by filtration and dried under reduced pressure to obtain tert-butyl ((1R,4S)-4-(hydroxymethyl)-4-methylcyclopent-2-en-1-yl)carbamate as a solid. MS: 228 (M+1).

Step 3: Mixture of tert-butyl ((1R,4S)-4-(hydroxymethyl)-4-methylcyclopent-2-en-1-yl)carbamate (7.84 g, 34.5 mmol) and HCl (4 M in dioxane, 80 ml) was stirred at 25°C for 2 hours. The solution was then concentrated under reduced pressure and the residue was triturated with ether (200 ml). The solid was collected, washed with ether (100 ml) and dried to give ((1S,4R)-4-amino-1-methylcyclopent-2-en-1-yl)methanol hydrochloride as a solid. MS: 128 (M+1).

Step 4: To a stirred mixture of ((1S,4R)-4-amino-1-methylcyclopent-2-en-1-yl)methanol hydrochloride (5.5 g, 32.6 mmol) in 2-propanol (120 ml) 2-(4,6-dichloropyrimidin-5-yl)acetaldehyde (6.85 g, 35.9 mmol) and triethylamine (6.60 g, 65.2 mmol) were added at 25°C under argon. The resulting mixture was stirred at 82°C for 16 hours. The reaction mixture was quenched with water (250 ml) and extracted with ethyl acetate (3 x 200 ml). The combined organic layers were washed with brine (200 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica column chromatography (25-32% EtOAc/PE) to give ((1S,4R)-4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidine- 7-yl)-1-methylcyclopent-2-en-1-yl)methanol in the form of a solid. MS: 264 (M+1).

Step 5: To a solution of ((1S,4R)-4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-methylcyclopent-2-en-1-yl)methanol ( 300 mg, 1.138 mmol) in THF (5 ml) was added sodium phenolate (660 mg, 5.69 mmol) at 0°C under argon. The reaction mixture was stirred at 66°C for 12 hours. The reaction mixture was quenched with saturated aqueous NH ₄ Cl (100 ml) and extracted with EtOAc (3 x 100 ml). The combined organic layers were washed with brine (100 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica column chromatography (0-60% EtOAc/PE) to give ((1S,4R)-1-methyl-4-(4-phenoxy-7H-pyrrolo[2,3- d]pyrimidin-7-yl)cyclopent-2-en-1-yl)methanol as a solid. MS: 322 (M+1).

Step 6: To a solution of ((1S,4R)-1-methyl-4-(4-phenoxy-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-2-en-1-yl)methanol (260 mg, 0.809 mmol) in DMF (1 ml) were added 1H-imidazole (116 mg, 1.699 mmol) and tert-butylchlorodiphenylsilane (289 mg, 1.052 mmol) in one portion at 0°C under argon. The reaction mixture was stirred at 25°C for 1.5 hours. The reaction mixture was quenched with saturated aqueous NH ₄ Cl (150 ml) and extracted with EtOAc (3 x 100 ml). The combined organic layers were washed with brine (100 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica column chromatography (10-20% EtOAc/PE) to give 7-((1R,4S)-4-(((tert-butyldiphenylsilyl)oxy)methyl)-4-methylcyclopent -2-en-1-yl)-4-phenoxy-7H-pyrrolo[2,3-d]pyrimidine in the form of a solid. MS: 560 (M+1).

Step 7: To a stirred solution of 7-((1R,4S)-4-(((tert-butyldiphenylsilyl)oxy)methyl)-4-methylcyclopent-2-en-1-yl)-4-phenoxy-7H-pyrrolo[ 2,3-d]pyrimidine (260 mg, 0.464 mmol) in THF (4 ml) was added with pyridine (4 ml, 49.5 mmol) and osmium(VIII) oxide (1.299 ml, 0.511 mmol) at 0°C atmosphere argon. The resulting mixture was stirred at the same temperature for 1 hour. The reaction mixture was quenched with saturated aqueous Na ₂ S ₂ O ₃ (25 ml) and extracted with EtOAc (5 x 20 ml). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was dissolved in tBuOH (3.00 ml) and water (3 ml) and sodium hydrogen sulfite (5.52 mg, 0.053 mmol) was added at 25°C under a stream of air. The resulting mixture was stirred for 20 minutes. The reaction mixture was diluted with saturated aqueous NaHSO ₃ (25 ml) and extracted with EtOAc (3 x 25 ml). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate and filtered. The crude residue was purified by silica column chromatography (0-70% EtOAc/PE) to give (3R,5R)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-3-methyl-5-(4-phenoxy- 7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol as an oil. MS: 594 (M+1).

Step 8: To a stirred solution of (3R,5R)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-3-methyl-5-(4-phenoxy-7H-pyrrolo[2,3-d]pyrimidine-7 -yl)cyclopentane-1,2-diol (2.2 g, 3.71 mmol) in anhydrous acetone (12 ml) was added 4-methylbenzenesulfonic acid (0.064 g, 0.371 mmol) and 2,2-dimethoxypropane (1.93 g, 18.5 mmol). The resulting mixture was stirred at 25°C for 3 hours. EtOAc (300 ml) and saturated aqueous NaHCO ₃ (100 ml) were added to the solution, the organic layer was concentrated under reduced pressure, and the residue was purified by silica column chromatography (0-30% EtOAc/PE) to give 7-((3aS,4R,6R,6aR)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2,6-trimethyltetrahydro-3aH-cyclopenta[d][1, 3]dioxol-4-yl)-4-phenoxy-7H-pyrrolo[2,3-d]pyrimidine in the form of a foamy substance. MS: 634 (M+1).

Step 9: To a stirred solution of 7-((3aS,4R,6R,6aR)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2,6-trimethyltetrahydro-3aH-cyclopenta[d][1, 3]dioxol-4-yl)-4-phenoxy-7H-pyrrolo[2,3-d]pyrimidine (650 mg, 1.025 mmol) in THF (5 ml) was added tetrabutylammonium fluoride (1 M in THF, 3.08 ml , 3.08 mmol) at 25°C. The resulting mixture was stirred at 25°C for 2 hours. A saturated aqueous solution of NaHCO ₃ (100 ml) and EtOAc (250 ml) was added to the solution, then the organic layer was concentrated under reduced pressure and the residue was purified by column chromatography (0-70% EtOAc/ PE) to give ((3aR,4R,6R,6aS)-2,2,4-trimethyl-6-(4-phenoxy-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro-3aH- cyclopenta[d][1,3]dioxol-4-yl)methanol in the form of a foamy substance. MS: 396 (M+1).

Step 10: To a stirred mixture of ((3aR,4R,6R,6aS)-2,2,4-trimethyl-6-(4-phenoxy-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro- 3aH-cyclopenta[d][1,3]dioxol-4-yl)methanol (270 mg, 0.683 mmol) in 1,4-dioxane (6 ml) was added 3-bromo-7-iodo-N-(4-methoxybenzyl )quinoline-2-amine (256 mg, 0.546 mmol), 1,10-phenanthroline (19.7 mg, 0.109 mmol), copper(I) iodide (10.4 mg, 0.055 mmol) and cesium carbonate (267 mg, 0.819 mmol). The resulting mixture was stirred at 110°C for 18 hours. The mixture was concentrated under reduced pressure and the residue was purified by silica column chromatography (0-30% EtOAc/PE) to give 3-bromo-N-(4-methoxybenzyl)-7- (((3aR,4R,6R,6aS)-2,2,4-trimethyl-6-(4-phenoxy-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro-3aH-cyclopenta[d ][1,3]dioxol-4-yl)methoxy)quinolin-2-amine in the form of a solid. MS: 736/738 (M+1/M+3).

Step 11: 3-bromo-N-(4-methoxybenzyl)-7-(((3aR,4R,6R,6aS)-2,2,4-trimethyl-6-(4-phenoxy-7H-pyrrolo[2, 3-d]pyrimidin-7-yl)tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methoxy)quinolin-2-amine (230 mg, 0.312 mmol) was dissolved in 2,2,2 -trifluoroacetic acid (5 ml, 67.3 mmol), then the solution was stirred at 60°C for 2 hours. The solution was co-evaporated with toluene five times to give (1S,2R,3R,5R)-3-(((2 -amino-3-bromoquinolin-7-yl)oxy)methyl)-3-methyl-5-(4-phenoxy-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol . MS: 576/578 (M+1/M+3).

Step 12: To a solution of (1S,2R,3R,5R)-3-(((2-amino-3-bromoquinolin-7-yl)oxy)methyl)-3-methyl-5-(4-phenoxy-7H- pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol (230 mg, 0.299 mmol) in 2-propanol (2 ml) added ammonia to i -PrOH(NH ₃ / i -PrOH 5 :1) (5 ml, 0.299 mmol) at -50°C, the resulting mixture was stirred at 130°C for 64 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (ACN/water) to give (1S,2R ,3R,5R)-3-(((2-amino-3-bromoquinolin-7-yl)oxy)methyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl )-3-methylcyclopentane-1,2-diol as a solid. MS: 499/501 (M+1/M+3). 1H-NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 8.03 (s, 1H), 7.59 (d, J=9.2 Hz, 1H), 7.31 ( d, J=3.6 Hz, 1H), 6.98-6.92 (m, 2H), 6.89 (brs, 2H), 6.55 (d, J=3.2 Hz, 1H ), 6.51 (br.s, 2H), 5.03-4.96 (m, 1H), 4.85 (d, J=6.8 Hz, 1H), 4.75 (d, J= 4.8 Hz, 1H), 4.56-4.50 (m, 1H), 4.03 (d, J=9.2 Hz, 1H), 3.97-3.91 (m, 2H), 1.93 (d, J=9.6 Hz, 2H), 1.19 (s, 3H).

Example 101

(1S,2R,3R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-(((2-aminoquinolin-7-yl)oxy)methyl )-3-methylcyclopentane-1,2-diol

Step 1: To a solution of (1S,2R,3R,5R)-3-(((2-amino-3-bromoquinolin-7-yl)oxy)methyl)-5-(4-amino-7H-pyrrolo[2, 3-d]pyrimidin-7-yl)-3-methylcyclopentane-1,2-diol (26 mg, 0.052 mmol) in MeOH (3 ml) was added Pd/C (10%) (20 mg) at 25°C. The mixture was stirred under a hydrogen atmosphere at 25°C for 30 minutes, the mixture was filtered and the filtrate was purified by reverse phase flash column chromatography (ACN/water) to give (1S,2R,3R,5R)-5-(4-amino- 7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-(((2-aminoquinolin-7-yl)oxy)methyl)-3-methylcyclopentane-1,2-diol as a solid. MS: 421 (M+1). ¹ H-NMR (300 MHz, DMSO-d6) δ 8.00 (s, 1H), 7.76 (d, J=9.0 Hz, 1H), 7.50 (d, J=8.7 Hz , 1H), 7.28 (d, J=3.6 Hz, 1H), 6.91-6.80 (m, 4H), 6.57-6.52 (m, 2H), 6.26 ( br.s, 2H), 5.01-4.92 (m, 1H), 4.82 (d, J=6.6 Hz, 1H), 4.71 (d, J=4.8 Hz, 1H ), 4.53-4.46 (m, 1H), 3.98 (d, J=9.6 Hz, 1H), 3.91-3.89 (m, 2H), 1.91-1, 88 (m, 2H), 1.16 (s, 3H).

Example 102

(1S,2R,5R)-3-(2-(2-amino-3-bromoquinolin-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7- yl)-3-(fluoromethyl)cyclopentane-1,2-diol

Step 1: To a stirred mixture of (1R,2S,3R,5R)-3-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-(hydroxymethyl)cyclopentane-1,2 -diol (4.0 g, 14.1 mmol) (azeotroped with toluene 3x) in pyridine (40 ml) was added 1-(chloro(4-methoxyphenyl)(phenyl)methyl)-3-methoxybenzene (5.25 g, 15.5 mmol) at room temperature in an argon atmosphere. The resulting mixture was stirred for approximately 3 hours at room temperature. The reaction mixture was quenched with MeOH (25 ml). The mixture was azeotroped with toluene and the residue was purified by silica column chromatography (1-10% MeOH/DCM) to give (1S,2R,3R,5R)-3-((bis(4-methoxyphenyl)(phenyl)methoxy) methyl)-5-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol as a solid. MS: 586 (M+1). ¹ H-NMR (300 MHz, DMSO- d6 ) δ 8.59 (s, 1H), _7.81 (d, J =3.6 Hz, 1H), 7.44-7.41 (m, 2H ), 7.35-7.24 (m, 7H), 6.92-6.90 (m, 4H), 6.68 (d, J =3.6 Hz, 1H), 4.98-4, 93 (m, 2H), 4.79 (d, J =3.6 Hz, 1H), 4.28-4.26 (m, 1H), 3.89-3.87 (m, 1H), 3 .75 (s, 6H), 3.20-3.17 (m, 1H), 3.09-3.05 (m, 1H), 2.32-2.26 (m, 2H), 1.76 -1.69 (m, 1H).

Step 2: To the stirred mixture of (1S,2R,3R,5R)-3-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-5-(4-chloro-7H-pyrrolo[2,3-d ]pyrimidin-7-yl)cyclopentan-1,2-diol (6.0 g, 10.2 mmol) (azeotroped with toluene 3x) in DMF (80 ml) was added sodium hydride (60% in mineral oil) ( 1.64 g, 41.0 mmol) at 0°C under argon. The resulting mixture was stirred for about 30 minutes at 0°C, then tetrabutylammonium iodide (1.89 g, 5.12 mmol) and (bromomethyl)benzene (5.25 g, 30.7 mmol) were added. The resulting mixture was warmed to room temperature and stirred for 3 hours. The reaction mixture was quenched with saturated aqueous NH ₄ Cl (150 ml) and extracted with EtOAc (3 x 200 ml). The combined organic fractions were washed with brine (3 x 100 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica column chromatography (0-50% EtOAc/PE) to give 7-((1R,2S,3R,4R)-2,3-bis(benzyloxy)-4-(( bis(4-methoxyphenyl)(phenyl)methoxy)methyl)cyclopentyl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidine as a solid. MS: 766 (M+1). ¹ H-NMR (300 MHz, DMSO- d6 ) δ 8.46 (s, 1H), _7.75 (d, J =3.9 Hz, 1H), 7.38-7.08 (m, 17H ), 6.91-6.84 (m, 6H), 6.61 (d, J =3.6 Hz, 1H), 5.20-5.10 (m, 1H), 4.61-4, 48 (m, 2H), 4.39-4.35 (m, 1H), 4.27-4.19 (m, 2H), 3.93-3.91 (m, 1H), 3.71 ( s, 6H), 3.15-3.11 (m, 2H), 2.50-2.40 (m, 1H), 2.30-2.20 (m, 1H), 1.82-1, 72 (m, 1H).

Step 3: To a stirred solution of 7-((1R,2S,3R,4R)-2,3-bis(benzyloxy)-4-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)cyclopentyl)-4- chloro-7H-pyrrolo[2,3-d]pyrimidine (6.0 g, 7.83 mmol) in DCM (50 ml) was added with water (1.411 g, 78 mmol) and 2,2-dichloroacetic acid (6% DCA in DCM) (9.09 g, 70.5 mmol) at room temperature under argon. The resulting mixture was stirred for 15 minutes at this temperature. Triethylsilane (18.21 g, 157 mmol) was then added and the resulting mixture was stirred for 50 minutes at this temperature. The reaction mixture was quenched with pyridine (11.2 g, 141 mmol) at 0°C and stirred for 15 minutes. The mixture was azeotroped with toluene and the residue was purified by silica column chromatography (0-50% EtOAc/PE) to give ((1R,2R,3S,4R)-2,3-bis(benzyloxy)-4-(4- chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl)methanol in the form of a solid. MS: 464 (M+1). ¹ H-NMR (300 MHz, DMSO- d6 ) δ 8.56 (s, 1H), _7.86 (d, J =3.6 Hz, 1H), 7.39-7.27 (m, 5H ), 7.15-7.11 (m, 3H), 6.94-6.91 (m, 2H), 6.66 (d, J =3.6 Hz, 1H), 5.36-5, 14 (m, 1H), 4.86-4.84 (m, 1H), 4.67-4.52 (m, 2H), 4.45-4.41 (m, 1H), 4.35- 4.30 (m, 1H), 4.29-4.25 (m, 1H), 4.03-3.97 (m, 1H), 3.49-3.47 (m, 2H), 2. 31-2.27 (m, 2H), 1.74-1.68 (m, 1H).

Step 4: To a stirred solution of ((1R,2R,3S,4R)-2,3-bis(benzyloxy)-4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl )methanol (3.1 g, 6.68 mmol) in DCM (25 ml) was added Dess-Martin periodinane (5.67 g, 13.4 mmol) at 0°C under argon. The resulting mixture was stirred for 15 minutes at 0°C, then the reaction mixture was warmed to room temperature and stirred for 1 hour. The reaction mixture was quenched with saturated aqueous NaHCO ₃ (20 ml) and extracted with EtOAc (3 x 100 ml). The combined organic fractions were washed with brine (3 x 40 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica column chromatography (0-50% EtOAc/PE) to give (1S,2R,3S,4R)-2,3-bis(benzyloxy)-4-(4-chloro- 7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentanecarbaldehyde as a solid. MS: 462 (M+1). ¹ H-NMR (400 MHz, DMSO- d6 ) δ 9.79 (s, 1H), 8.57 (s, 1H), 7.85 ₍ d, J =3.6 Hz, 1H), 7, 43-7.33 (m, 5H), 7.18-7.13 (m, 3H), 6.96-6.93 (m, 2H), 6.70 (d, J = 3.6 Hz, 1H), 5.35-5.28 (m, 1H), 4.75-4.64 (m, 2H), 4.51-4.49 (m, 2H), 4.35-4.23 ( m, 2H), 3.32-3.28 (m, 1H), 2.49-2.33 (m, 2H).

Step 5: To a stirred solution of (1S,2R,3S,4R)-2,3-bis(benzyloxy)-4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentanecarbaldehyde ( 2.4 g, 5.20 mmol) in dioxane (20 ml) was added potassium carbonate (18.8 ml, 37.7 mmol) and formaldehyde (1.01 ml, 5.20 mmol) at 25°C under argon . The resulting mixture was stirred for 16 hours at 25°C. The reaction mixture was quenched by adding aqueous HCl (1 M, 20 ml) to adjust to pH=7 at 0°C. The solvent was removed from the mixture under reduced pressure. The residue was dissolved in ethanol (20 ml), then sodium borohydride (0.236 g, 6.23 mmol) was added at 0°C under argon. The reaction mixture was stirred at 0°C for approximately 2 hours. The reaction mixture was quenched with aqueous HCl (1 M, 20 ml, to adjust to pH=7) at 0°C, then water (50 ml) was added and the mixture was extracted with EtOAc (3 x 100 ml). The combined organic fractions were washed with brine (3 x 50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica column chromatography (0-80% EtOAc/PE) to give ((2R,3S,4R)-2,3-bis(benzyloxy)-4-(4-chloro-7H -pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,1-diyl)dimethanol in the form of a solid. MS: 494 (M+1). ¹ H-NMR (300 MHz, DMSO- d6 ) δ 8.54 (s, 1H), _7.83 (d, J =3.6 Hz, 1H), 7.38-7.29 (m, 5H ), 7.12-7.08 (m, 3H), 6.91-6.88 (m, 2H), 6.64 (d, J =3.6 Hz, 1H), 5.29-5, 19 (m, 1H), 4.89-4.85 (m, 1H), 4.73-4.69 (m, 1H), 4.61-4.59 (m, 1H), 4.55- 4.49 (m, 1H), 4.48-4.46 (m, 1H), 4.39-4.35 (m, 1H), 4.31-4.27 (m, 1H), 4. 09-4.07 (m, 1H), 3.61-3.51 (m, 4H), 2.08-2.00 (m, 1H), 1.71-1.63 (m, 1H).

Step 6: To a stirred solution of ((2R,3S,4R)-2,3-bis(benzyloxy)-4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1 ,1-diyl)dimethanol (1.2 g, 2.429 mmol) (azeotroped with toluene 3x) in DCM (30 ml) was added triethylamine (0.737 g, 7.29 mmol) at 0°C under argon. (Chloro(4-methoxyphenyl)methylene)dibenzene (0.788 g, 2.55 mmol) was then added at this temperature, then the reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was quenched with a saturated aqueous solution of NH ₄ Cl (40 ml) and extracted with EtOAc (3 x 100 ml). The combined organic fractions were washed with brine (3 x 50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica column chromatography (0-80% EtOAc/PE) to give a mixture of ((1S,2R,3S,4R)-2,3-bis(benzyloxy)-4-(4- chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-(((4-methoxyphenyl)diphenylmethoxy)methyl)cyclopentyl)methanol and ((1R,2R,3S,4R)-2,3 -bis(benzyloxy)-4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-(((4-methoxyphenyl)diphenylmethoxy)methyl)cyclopentyl)methanol as a solid . MS: 766 (M+1). ¹ H NMR mixture (two regioisomers) (400 MHz, DMSO- d ₆ ) δ 8.57-8.52 (m, 1H), 7.82 (d, J = 3.6 Hz, 1H), 7.43 -7.24 (m, 15H), 7.13-7.06 (m, 5H), 6.88-6.84 (m, 4H), 6.66 (d, J = 3.6 Hz, 1H ), 5.14-5.08 (m, 2H), 4.96-4.40 (m, 4H), 4.29-4.12 (m, 2H), 3.77-3.74 (m , 5H), 3.39-3.36 (m, 1H), 3.21-3.19 (m, 1H), 2.09-2.00 (m, 1H), 1.86-1.80 (m, 1H).

Step 7: To a stirred mixture of ((1S,2R,3S,4R)-2,3-bis(benzyloxy)-4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)- 1-(((4-methoxyphenyl)diphenylmethoxy)methyl)cyclopentyl)methanol (1.45 g, 0.473 mmol) and ((1R,2R,3S,4R)-2,3-bis(benzyloxy)-4-(4 -chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-(((4-methoxyphenyl)diphenylmethoxy)methyl)cyclopentyl)methanol (1.45 g, 1.42 mmol) (azeotroped distillation with toluene 3x) in DMF (15 ml) was added sodium hydride (60% in mineral oil) (0.227 g, 5.68 mmol) at 0°C under argon. The resulting mixture was stirred for approximately 30 minutes at 0°C, then tetrabutylammonium iodide (0.262 g, 0.710 mmol) and (bromomethyl)benzene (0.728 g, 4.26 mmol) were added. The resulting mixture was warmed to room temperature and stirred for 3 hours. The reaction mixture was quenched with saturated aqueous NH ₄ Cl (20 ml) and extracted with EtOAc (3 x 100 ml). The combined organic fractions were washed with brine (3 x 50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica column chromatography (0-80% EtOAc/PE) to give a mixture of 7-((1R,2S,3R,4S)-2,3-bis(benzyloxy)-4-( (benzyloxy)methyl)-4-(((4-methoxyphenyl)diphenylmethoxy)methyl)cyclopentyl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidine as a solid and 7-((1R,2S, 3R,4R)-2,3-bis(benzyloxy)-4-((benzyloxy)methyl)-4-(((4-methoxyphenyl)diphenylmethoxy)methyl)cyclopentyl)-4-chloro-7H-pyrrolo[2,3 -d]pyrimidine as a solid. MS: 856 (M+1).

Step 8: 7-((1R,2S,3R,4S)-2,3-bis(benzyloxy)-4-((benzyloxy)methyl)-4-(((4-methoxyphenyl)diphenylmethoxy)methyl)cyclopentyl)- 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1.00 g, 0.292 mmol) and 7-((1R,2S,3R,4R)-2,3-bis(benzyloxy)-4-( (benzyloxy)methyl)-4-(((4-methoxyphenyl)diphenylmethoxy)methyl)cyclopentyl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1.00 g, 0.876 mmol) was dissolved in AcOH ( 20 ml) and water (2.5 ml) at room temperature. The temperature was then raised to 40°C and the reaction mixture was stirred for about 4 hours. The mixture (azeotroped with 3x toluene) was concentrated under reduced pressure and the residue was purified by silica column chromatography (0-80% EtOAc/PE) to give the mixture ((1R,2R,3S,4R)-2,3-bis(benzyloxy)-1-((benzyloxy)methyl)-4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-7- yl)cyclopentyl)methanol as a solid and ((1S,2R,3S,4R)-2,3-bis(benzyloxy)-1-((benzyloxy)methyl)-4-(4-chloro-7H-pyrrolo[ 2,3-d]pyrimidin-7-yl)cyclopentyl)methanol as a solid. MS: 584 (M+1). ^1H -NMR mixture of two regioisomers (300 MHz, DMSO- d6 ) δ 8.51-8.49 (m, 1H) _, 7.78-7.66 (m, 1H), 7.37-7.26 (m, 10H), 7.11-7.07 (m, 3H), 6.89-6.86 (m, 2H), 6.59-6.54 (m, 1H), 5.26-5 .16 (m, 1H), 4.74-4.24 (m, 8H), 4.09-4.07 (m, 1H), 3.66-3.50 (m, 4H), 2.08 -1.97 (m, 1H), 1.79-1.71 (m, 1H).

Step 9: To the stirred mixture of ((1S,2R,3S,4R)-2,3-bis(benzyloxy)-1-((benzyloxy)methyl)-4-(4-chloro-7H-pyrrolo[2,3- d]pyrimidin-7-yl)cyclopentyl)methanol (500 mg, 0.642 mmol) and ((1R,2R,3S,4R)-2,3-bis(benzyloxy)-1-((benzyloxy)methyl)-4- (4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl)methanol (500 mg, 0.214 mmol) (azeotroped with toluene 3x) in DCM (10 ml) was added DAST (310 mg , 1.93 mmol) at 0°C in an argon atmosphere. The resulting mixture was stirred for approximately 16 hours at room temperature. The mixture was quenched with saturated aqueous NaHCO ₃ (25 ml) and extracted with EtOAc (3 x 50 ml). The combined organic fractions were washed with brine (3 x 25 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by preparative TLC (50% EtOAc/PE) to give 7-((1R,2S,3R,4S)-2,3-bis(benzyloxy)-4-((benzyloxy)methyl)- 4-(fluoromethyl)cyclopentyl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidine as an oil. MS: 586 (M+1). ¹ H-NMR (400 MHz, DMSO- d6 ) δ 8.51 (s, 1H), _7.74 (d, J =3.6 Hz, 1H), 7.39-7.33 (m, 10H ), 7.15-7.06 (m, 3H), 6.90-6.87 (m, 2H), 6.61 (d, J =3.6 Hz, 1H), 5.30-5, 20 (m, 1H), 4.80-4.75 (m, 2H), 4.63-4.57 (m, 5H), 4.52-4.48 (m, 1H), 4.33- 4.29 (m, 1H), 4.15 (d, J =4.2 Hz, 1H), 3.63-3.61 (m, 2H), 2.10-1.89 (m, 2H) .

Stage 10: To a stirred mixture of 7-((1R,2S,3R,4S)-2,3-bis(benzyloxy)-4-((benzyloxy)methyl)-4-(fluoromethyl)cyclopentyl)-4-chloro-7H-pyrrolo[ 2,3-d]pyrimidine (395 mg, 0.674 mmol) (azeotroped with toluene 3x) in DCM (6 ml) was added trichloroborane (1 M in DCM) (6.74 ml, 6.74 mmol) at -80 °C in argon atmosphere. The resulting mixture was stirred for approximately 60 minutes at -80°C. The reaction mixture was quenched with a saturated aqueous solution of NaHCO₃ (5 ml). The mixture was purified by reverse phase column chromatography (ACN/water with 5 mM NH₄HCO₃ modifier) to obtain (1S,2R,3S,5R)-5-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-(fluoromethyl)-3-(hydroxymethyl)cyclopentane -1,2-diol as a solid. MS: 316 (M+1).¹H-NMR (300 MHz, DMSO-d ₆ ) δ 8.63 (s, 1H), 7.92 (d,J=3.6 Hz, 1H), 6.71 (d,J=3.6 Hz, 1H), 5.18-5.04 (m, 2H), 4.94-4.92 (m, 2H), 4.73-4.34 (m, 3H), 3, 90-3.87 (m, 1H), 3.55-3.45 (m, 2H), 2.04-1.96 (m, 1H), 1.70-1.62 (m, 1H).

Step 11: To a stirred mixture of (1S,2R,3S,5R)-5-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-(fluoromethyl)-3-(hydroxymethyl )cyclopentane-1,2-diol (178 mg, 0.564 mmol) (azeotroped with toluene 3x) in acetone (5 ml) was added 4-methylbenzenesulfonic acid (9.71 mg, 0.056 mmol) at 0°C under argon . The resulting mixture was stirred for approximately 5 minutes at 0°C, then 2,2-dimethoxypropane (294 mg, 2.82 mmol) was added at this temperature. The resulting mixture was warmed to room temperature and stirred for 3 hours. The reaction mixture was quenched with saturated aqueous NaHCO ₃ (10 ml) and extracted with EtOAc (3 x 30 ml). The combined organic fractions were washed with brine (3 x 10 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica column chromatography (0-80% EtOAc/PE) to give ((3aR,4S,6R,6aS)-6-(4-chloro-7H-pyrrolo[2,3- d]pyrimidin-7-yl)-4-(fluoromethyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methanol as a solid. MS: 356 (M+1). ¹ H-NMR (400 MHz, DMSO- d6 ) δ 8.67 (s, 1H), _8.01 (d, J =3.6 Hz, 1H), 6.75 (d, J =3.6 Hz, 1H), 5.29-5.23 (m, 1H), 5.18 (t, J =4.2 Hz, 1H), 5.04 (t, J =6.8 Hz, 1H), 4.68-4.60 (m, 2H), 4.56-4.48 (m, 1H), 3.53-3.45 (m, 2H), 2.24-2.15 (m, 2H ), 1.50 (s, 3H), 1.24 (s, 3H).

Step 12: To a stirred solution of oxalyl dichloride (0.103 ml, 1.22 mmol) in anhydrous DCM (5 ml) was added (methylsulfinyl)methane (0.174 ml, 2.445 mmol) at -78°C under argon atmosphere, the mixture was stirred for 0. 5 hours at -78°C. Then a solution of ((3aR,4S,6R,6aS)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-4-(fluoromethyl)-2, was added dropwise to the mixture. 2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methanol (145 mg, 0.408 mmol) in anhydrous DCM (3 ml) at -78°C. The mixture was stirred for another 0.5 h at -78°C. At this temperature, triethylamine (0.568 mL, 4.08 mmol) was added to the reaction mixture, and the resulting mixture was stirred for 0.5 h at room temperature. The reaction was quenched with H ₂ O (10.0 ml) at 0°C and extracted with DCM (20 ml). The combined organic layers were washed with saturated aqueous NaHCO ₃ (10 x 3 ml), brine (10 ml), dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated under reduced pressure to give (3aR,4R,6R,6aS)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-4-(fluoromethyl)-2,2 -dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-carbaldehyde as an oil. MS: 354 (M+1).

Step 13: Bromo(methyl)triphenylphosphorane (367 mg, 1.03 mmol) was dissolved in THF (4 ml) at -30°C under argon, then butyllithium (2.5 M in hexane) (0.382 ml, 0.954 mmol) added dropwise at this temperature. The reaction mixture was stirred at -10°C for approximately 30 minutes. Then (3aR,4R,6R,6aS)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-4-(fluoromethyl)-2,2-dimethyltetrahydro-3aH- cyclopenta[d][1,3]dioxole-4-carbaldehyde (130 mg, 0.367 mmol) in THF (2 ml) at -30°C. The reaction mixture was stirred for approximately 1 hour at room temperature. The reaction mixture was quenched by adding saturated aqueous NH ₄ Cl (10 ml) at -40°C and extracted with EtOAc (3 x 30 ml). The combined organic fractions were washed with brine (3 x 10 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by preparative TLC (2:1=PE:EtOAc) to give 4-chloro-7-((3aS,4R,6S,6aR)-6-(fluoromethyl)-2,2-dimethyl- 6-vinyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine. MS: 352 (M+1). ¹ H-NMR (300 MHz, DMSO- d6 ): δ 8.67 (s, 1H), 8.00 (d, J =3.6 Hz, 1H) _, 6.73 (d, J =3, 6 Hz, 1H), 6.06-5.96 (m, 1H), 5.31-5.08 (m, 4H), 4.79-4.77 (m, 1H), 4.65-4 .58 (m, 1H), 4.49-4.42 (m, 1H), 2.49-2.44 (m, 2H), 1.48 (s, 3H), 1.24 (s, 3H ).

Step 14: 4-chloro-7-((3aS,4R,6S,6aR)-6-(fluoromethyl)-2,2-dimethyl-6-vinyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4 -yl)-7H-pyrrolo[2,3-d]pyrimidine (100 mg, 0.284 mmol) was dissolved in 5 ml of dioxane and ammonia hydrate (28% in water) (5 ml, 36.4 mmol) in a sealed tube . The reaction mixture was stirred at 90°C for about 16 hours. The mixture was concentrated under reduced pressure and the residue was purified by reverse phase column chromatography (ACN/water with 5 mM NH ₄ HCO ₃ modifier) to give 7-((3aS,4R,6S ,6aR)-6-(fluoromethyl)-2,2-dimethyl-6-vinyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin- 4-amine as a solid. MS: 333 (M+1). ^1H NMR (300 MHz, DMSO- d6 ): δ 8.07 (s, 1H), 7.36 ( _d , J =3.6 Hz, 1H), 6.99 (s, 2H), 6. 58 (d, J =3.6Hz, 1H), 6.07-5.98 (m, 1H), 5.26-5.17 (m, 3H), 5.08-5.04 (m, 1H ), 4.77-4.74 (m, 1H), 4.68-4.52 (m, 1H), 4.49-4.42 (m, 1H), 2.39-2.35 (m , 2H), 1.48 (s, 3H), 1.25 (s, 3H).

Step 15: Under argon 7-((3aS,4R,6S,6aR)-6-(fluoromethyl)-2,2-dimethyl-6-vinyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4- yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (20 mg, 0.060 mmol) was dissolved in 9-BBN (0.5 M in THF, 0.602 mL, 0.301 mmol) at room temperature and the mixture was stirred for 1 hour at 60°C. The mixture was cooled to 0°C and a solution of K ₃ PO ₄ (63.9 mg, 0.301 mmol) in 0.30 ml H ₂ O was added. The mixture was stirred for 0.5 h at room temperature. A solution of 3-bromo-7-iodo-N-(4-methoxybenzyl)quinoline-2-amine (28.2 mg, 0.060 mmol) in 0.90 ml anhydrous THF and Pd(dppf)Cl ₂ (7 .37 mg, 9.03 µmol), respectively. The resulting mixture was microwaved at 70°C for 3 hours. The organic layer was separated and concentrated under reduced pressure. The crude product was purified by preparative TLC (DCM/MeOH=15:1) to give 7-(2-((3aR,6R,6aS)-6-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7 -yl)-4-(fluoromethyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)ethyl)-3-bromo-N-(4-methoxybenzyl)quinoline-2 -amine in the form of a solid. MS: 675/677 (M+1/M+3).

Step 16: Under argon 7-(2-((3aR,6R,6aS)-6-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-4-(fluoromethyl)- 2,2-Dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)ethyl)-3-bromo-N-(4-methoxybenzyl)quinolin-2-amine (45 mg, 0.067 mmol) was dissolved in a solution of TFA in H ₂ O (2.0 ml, TFA/H ₂ O=1:1) at ambient temperature. The reaction mixture was stirred for 1 hour at 50°C. The reaction mixture was azeotroped with 3x toluene to remove TFA. The crude product was purified by reverse phase column chromatography (ACN/water with 5 mM NH ₄ HCO ₃ modifier). The product was further purified by preparative HPLC (ACN/water with 6.3 mM NH ₄ HCO ₃ modifier) to obtain the desired product (1S,2R,5R)-3-(2-(2-amino-3-bromoquinolin-7-yl) ethyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-(fluoromethyl)cyclopentane-1,2-diol as a solid. MS: 515/517 (M+1/M+3). ¹ H-NMR (300 MHz, DMSO- d6 ) δ 8.34 (s, 1H), 8.04 (s, 1H), 7.60 ₍ d, J =8.1 Hz, 1H), 7, 36 (s, 1H), 7.28 (d, J =3.6 Hz, 1H), 7.17-7.14 (m, 1H), 6.92 (brs, 2H), 6.58 -6.53 (m, 3H), 4.95-4.83 (m, 3H), 4.79-4.38 (m, 3H), 3.85 (t, J = 4.2 Hz, 1H ), 2.86-2.69 (m, 2H), 2.01-1.76 (m, 4H).

Example 103

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

Step 1: Under argon, DMSO (1249 mg, 15.99 mmol) was added to a solution of oxalyl dichloride (1015 mg, 7.99 mmol) in anhydrous DCM (10 mL) at -78°C. The mixture was stirred for 0.5 h at -78°C. Then a solution of ((3aR,4R,6R,6aS)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2,3a-trimethyltetrahydro- 3aH-cyclopenta[d][1,3]dioxol-4-yl)methanol (900 mg, 2.66 mmol) in anhydrous DCM (10 ml) at -78°C. The mixture was stirred for another 0.5 h at -78°C. At this temperature, TEA (2.70 mg, 26.6 mmol) was added to the reaction mixture and the resulting mixture was stirred for 0.5 h at -78°C. The reaction was quenched with H ₂ O (10 ml) at 0°C. The mixture was extracted with DCM (50 ml), washed with saturated aqueous NaHCO ₃ (3 x 30 ml), brine (30 ml). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated under reduced pressure to give the crude product (3aR,4S,6R,6aS)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2,3a-trimethyltetrahydro -3aH-cyclopenta[d][1,3]dioxole-4-carbaldehyde as a solid. MS: 336 (M+1).

Step 2: To a stirred solution of methyltriphenylphosphonium bromide (2.7 g, 7.50 mmol) in anhydrous THF (4.0 mL) was added n -BuLi (2.5 M in THF, 2.79 mL, 6.97 mmol) dropwise at -10°C in an argon atmosphere. The reaction mixture was stirred for 0.5 h at room temperature. Then a solution of (3aR,4S,6R,6aS)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2,3a-trimethyltetrahydro-3aH-cyclopent was added to the mixture [d][1,3]dioxol-4-carbaldehyde (900 mg, 2.68 mmol) in anhydrous THF (6.0 ml) at -10°C. The mixture was stirred for 1.5 hours at room temperature. The reaction mixture was diluted with DCM (50 ml) and washed with water (50 ml) and brine (50 ml). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified by silica column chromatography (EtOAc/PE 0-30%) to give 4-chloro-7-((3aS,4R,6R,6aR)-2,2,6a-trimethyl-6- vinyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine in the form of a solid. MS: 334 (M+1).

Step 3: 4-chloro-7-((3aS,4R,6R,6aR)-2,2,6a-trimethyl-6-vinyltetrahydro-3aH-cyclopenta[d][1,3]dioxol- 4-yl)-7H-pyrrolo[2,3-d]pyrimidine (800 mg, 2.40 mmol), 1,4-dioxane (12 ml) and NH ₃ •H ₂ O (25%, 16 ml) at room temperature. The mixture was tightly sealed and then stirred at 90°C for 16 hours. The reaction mixture was then concentrated under reduced pressure. The residue was purified by silica column chromatography (0-10% MeOH/DCM) to give 7-((3aS,4R,6R,6aR)-2,2,6a-trimethyl-6-vinyltetrahydro-3aH-cyclopenta[d][ 1,3]dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine in the form of a solid. MS: 315 (M+1).

Step 4: To a stirred solution of 7-((3aS,4R,6R,6aR)-2,2,6a-trimethyl-6-vinyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-7H -pyrrolo[2,3-d]pyrimidin-4-amine (100 mg, 0.32 mmol) in anhydrous THF (0.5 ml) was added 9-BBN (0.5 M in THF, 3.18 ml, 1 .59 mmol) dropwise at 0°C in an argon atmosphere. The reaction solution was stirred at 50°C for 1 hour. A solution of tribasic potassium phosphate (336 mg, 1.581 mmol) in water (1 ml) was added dropwise to the reaction solution at 0°C. The reaction solution was stirred at room temperature for 0.5 h. A solution of 3-bromo-7-iodo-N-(4-methoxybenzyl)quinoline-2-amine (163 mg, 0.348 mmol) in THF (1 ml) was added and the complex 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride with dichloromethane (25.8 mg, 0.032 mmol) at room temperature. The resulting reaction mixture was microwaved at 70°C for 2 hours. The reaction mixture was cooled to room temperature, diluted with water (5 ml) and extracted with EtOAc (2 x 20 ml). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified using a Combi-flash system (Column: AQ-C18 column, 80 g, 60Å, 40-60 µm; Mobile phase A: water, Mobile phase B: MeCN; Flow rate: 50 ml/min; Gradient: 20% B to 90% B in 60 minutes (80% retention 5 min)) to give 7-(2-((3aR,4S,6R,6aS)-6-(4-amino-7H-pyrrolo[2 ,3-d]pyrimidin-7-yl)-2,2,3a-trimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)ethyl)-3-bromo-N-(4-methoxybenzyl )quinoline-2-amine in the form of a solid. MS: 657/659 (M+1/M+3).

Step 5: Solution of 7-(2-((3aR,4S,6R,6aS)-6-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2,3a- trimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)ethyl)-3-bromo-N-(4-methoxybenzyl)quinolin-2-amine (40 mg, 0.061 mmol) in TFA (2 ml , 26.0 mmol) was stirred at 60°C for 1 hour. TFA was removed under reduced pressure to give the crude product N-(7-(2-((1S,2R,3S,4R)-4-(4-amino -7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,3-dihydroxy-2-methylcyclopentyl)ethyl)-3-bromoquinolin-2-yl)-2,2,2-trifluoroacetamide as an oil . A mixture of N-(7-(2-((1S,2R,3S,4R)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,3-dihydroxy- 2-methylcyclopentyl)ethyl)-3-bromoquinolin-2-yl)-2,2,2-trifluoroacetamide (40 mg, 0.067 mmol) and K ₂ CO ₃ (28 mg, 0.202 mmol) in methanol (3 ml) were stirred at 60°C for 1 hour. The mixture was filtered and washed with MeOH (0.5 ml). The filtrate was concentrated under reduced pressure and the residue was purified by reverse phase column chromatography (ACN/water) to give (1R,2S,3R,5S)-5-(2-(2-amino-3-bromoquinolin-7-yl)ethyl) -3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-methylcyclopentane-1,2-diol as a solid. MS: 497/499 (M+1/M+3). ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.32 (s, 1H), 8.03 (s, 1H), 7.58 (d, J=8.0 Hz, 1H), 7, 32 (s, 1H), 7.25 (d, J=3.6 Hz, 1H), 7.11 (d, J=8.0 Hz, 1H), 6.87 (brs, 2H), 6.55-6.54 (m, 3H), 4.85 (d, J=6.8 Hz, 1H), 4.80-4.77 (m, 1H), 4.18 (s, 1H) , 3.98-3.94 (m, 1H), 2.78-2.73 (m, 1H), 2.59-2.50 (m, 1H), 2.32-2.27 (m, 1H), 1.91-1.83 (m, 2H), 1.63-1.57 (m, 2H), 1.15 (s, 3H).

Example 104

(2R,3R,3aS,6S,6aR)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-6-((2-aminoquinolin-7-yl)oxy) hexahydro-2H-cyclopenta[b]furan-3,3a-diol

Step 1: To a solution of (2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)oxy)-2-(4-amino-7H-pyrrolo[2,3 -d]pyrimidin-7-yl)hexahydro-2H-cyclopenta[b]furan-3,3a-diol (45 mg, 0.088 mmol) in MeOH (6 ml) added dihydroxypalladium on carbon (18.5 mg, 0.026 mmol) at ambient temperature. The resulting mixture was stirred at 25°C for 30 minutes under a hydrogen atmosphere (1.2 atm). The reaction mixture was then filtered and the filtrate was concentrated under reduced pressure and the residue was purified by reverse phase HPLC (ACN/water with 0.05% TFA modifier). The product-containing fractions were collected and the pH of the solution was adjusted to 7~8 using NH ₃ •H ₂ O (25%). The solution was then concentrated under reduced pressure and further purified by reverse phase column chromatography (ACN/water with 5 mM NH ₄ HCO ₃ modifier) to give (2R,3R,3aS,6S,6aR)-2-(4-amino-7H- pyrrolo[2,3-d]pyrimidin-7-yl)-6-((2-aminoquinolin-7-yl)oxy)hexahydro-2H-cyclopenta[b]furan-3,3a-diol as a solid. MS: 435 (M+1). ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 8.09 (s, 1H), 7.76 (d, J=9.0 Hz, 1H), 7.52-7.49 (m, 2H ), 7.05 (br.s, 2H), 6.80-6.75 (m, 2H), 6.66 (d, J=3.3 Hz, 1H), 6.55 (d, J= 8.7 Hz, 1H), 6.30 (br.s, 2H), 6.02 (d, J=8.4 Hz, 1H), 5.36 (d, J=7.2 Hz, 1H) , 5.30 (s, 1H), 4.59 (d, J=4.5 Hz, 1H), 4.40 (t, J=7.8 Hz, 1H), 4.09-4.08 ( m, 1H), 2.50-2.48 (m, 1H), 2.07-1.98 (m, 3H).

Example 105

(1R,2S,3R,5R)-5-(((2-aminoquinolin-7-yl)oxy)methyl)-1-methyl-3-(7H-pyrrolo[2,3-d]pyrimidin-7-yl )cyclopentane-1,2-diol

Step 1: To a solution of (1R,2S,3R,5R)-5-(((2-amino-3-bromoquinolin-7-yl)oxy)methyl)-3-(4-chloro-7H-pyrrolo[2, 3-d]pyrimidin-7-yl)-1-methylcyclopentane-1,2-diol (20 mg, 0.039 mmol) in MeOH (4 ml) was added triethylamine (7.80 mg, 0.077 mmol) and anhydrous Pd/C ( 10 mg) (10% Pd/C) in argon atmosphere. The resulting mixture was stirred at room temperature under a hydrogen atmosphere (~1 atm) for 4 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase HPLC (ACN/water with 10 mM NH ₄ HCO ₃ modifier) to give (1R,2S,3R,5R)-5-(((2-aminoquinolin-7-yl)oxy)methyl)-1 -methyl-3-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol as a solid. MS: 406 (M+1). ^1H -NMR (400 MHz, DMSO- _d6 ): δ 8.98 (s, 1H), 8.75 (s, 1H), 7.80-7.76 (m, 2H), 7.52 ( d, J=8.8 Hz, 1H), 6.94 (d, J=2.4 Hz, 1H), 6.84 (dd, J=8.8, 2.4 Hz, 1H), 6, 68 (d, J=3.6 Hz, 1H), 6.58 (d, J=8.8 Hz, 1H), 6.30 (brs, 2H), 5.14 (sq, J= 9.6 Hz, 1H), 4.95 (d, J=6.8 Hz, 1H), 4.48 (s, 1H), 4.23-4.10 (m, 3H), 2.48- 2.37 (m, 2H), 1.80-1.73 (m, 1H), 1.26 (s, 3H).

Example 106

(1R,2S,3R,5R)-5-(((2-amino-3-methylquinolin-7-yl)oxy)methyl)-1-methyl-3-(4-methyl-7H-pyrrolo[2,3 -d]pyrimidin-7-yl)cyclopentane-1,2-diol

Step 1: To a mixture of (1R,2S,3R,5R)-5-(((2-amino-3-bromoquinolin-7-yl)oxy)methyl)-3-(4-chloro-7H-pyrrolo[2, 3-d]pyrimidin-7-yl)-1-methylcyclopentane-1,2-diol (20 mg, 0.039 mmol) and Pd(PPh ₃ ) ₄ (4.45 mg, 3.86 μmol) in anhydrous THF (1 ml) trimethylaluminum (2 M in toluene, 0.058 ml, 0.116 mmol) was added dropwise at room temperature under argon. The mixture was stirred at 100°C for 2 hours. After cooling to ambient temperature, the mixture was carefully poured into aqueous HCl (1 M, 10 ml). The mixture was partitioned between EtOAc (40 ml) and H ₂ O (10 ml). The aqueous layer was concentrated under reduced pressure. The residue was purified by reverse phase HPLC (ACN/water with 10 mM NH ₄ HCO ₃ modifier) to give (1R,2S,3R,5R)-5-(((2-amino-3-methylquinolin-7-yl)oxy) methyl)-1-methyl-3-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol as a solid. MS: 434 (M+1). ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 8.60 (s, 1H), 7.71 (d, J=3.6 Hz, 1H), 7.63 (s, 1H), 7 .48 (d, J=8.4 Hz, 1H), 6.95 (d, J=2.0 Hz, 1H), 6.84 (dd, J=8.4, 2.0 Hz, 1H) , 6.71 (d, J=3.6 Hz, 1H), 6.12 (br.s, 2H), 5.10 (sq., J=9.6 Hz, 1H), 4.91 (d , J=7.2 Hz, 1H), 4.45 (s, 1H), 4.21-4.09 (m, 3H), 2.64 (s, 3H), 2.46-2.37 ( m, 2H), 2.17 (s, 3H), 1.79-1.72 (m, 1H), 1.26 (s, 3H).

Example 107

(2R,3R,3aS,6S,6aR)-6-((2-aminoquinolin-7-yl)methyl)-2-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl) hexahydro-2H-cyclopenta[b]furan-3,3a-diol

Step 1: To a solution of (2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(4-methyl-7H-pyrrolo[2,3 -d]pyrimidin-7-yl)hexahydro-2H-cyclopenta[b]furan-3,3a-diol (20 mg, 0.039 mmol) in MeOH (5 ml) was added triethylamine (3.97 mg, 0.039 mmol) and anhydrous Pd/C (10 mg) (10% Pd/C) under argon. The resulting mixture was stirred at room temperature under a hydrogen atmosphere (1.2 atm) for 30 minutes. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase HPLC (ACN/water with 10 MM NH ₄ HCO ₃ modifier) to give (2R,3R,3aS,6S,6aR)-6-((2-aminoquinolin-7-yl)methyl)-2- (4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)hexahydro-2H-cyclopenta[b]furan-3,3a-diol as a solid. MS: 432 (M+1). ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 8.69 (s, 1H), 7.87 (d, J=3.6 Hz, 1H), 7.79 (d, J=8, 8 Hz, 1H), 7.48 (d, J=8.0 Hz, 1H), 7.22 (s, 1H), 7.00 (dd, J=8.0, 1.6 Hz, 1H) , 6.82 (d, J=3.6 Hz, 1H), 6.66 (d, J=8.8 Hz, 1H), 6.31 (br.s, 2H), 6.01 (d, J=8.0 Hz, 1H), 5.29 (d, J=7.2 Hz, 1H), 5.11 (s, 1H), 4.22 (t, J=7.6 Hz, 1H) , 4.01 (d, J=5.6 Hz, 1H), 2.84-2.78 (m, 1H), 2.69 (s, 3H), 2.63-2.58 (m, 1H ), 2.28-2.25 (m, 1H), 1.98-1.94 (m, 1H), 1.80-1.68 (m, 2H), 1.58-1.53 (m , 1H).

Example 108

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(4-amino-5-fluoro-7H-pyrrolo[2,3- d]pyrimidin-7-yl)hexahydro-2H-cyclopenta[b]furan-3,3a-diol

Step 1: Into an oven-dried, argon-cooled vessel containing (3R,3aS,6aR)-6-((3-bromo-2-((4-methoxybenzyl)amino)quinolin-7-yl)methyl)hexahydro-2H -cyclopenta[b]furan-2,3,3a-triol (132.5 mg, 0.257 mmol) dissolved in anhydrous acetonitrile (2.5 ml), 1,1'-(azodicarbonyl)dipiperidine (97 mg, 0.386) was added mmol) followed by the addition of tri-n-butylphosphine (103 μL, 0.411 mmol) at room temperature. The mixture was stirred for 1 hour. In a separate oven-dried and argon-cooled vessel containing 4-chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine (88 mg, 0.514 mmol) dissolved in anhydrous acetonitrile ( 2.5 ml), DBU (78 µl, 0.514 mmol) was added. The mixture was stirred at room temperature for 30 minutes and this suspension was transferred into the first solution through a syringe. The reaction mixture was stirred at room temperature under argon for 7.5 hours and then quenched with water and extracted with EtOAc (3x). The combined organic layers were then washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography (0-50% 3:1 EtOAc:EtOH in hexane) to give (2R,3R,3aS,6aR)-6-((3-bromo-2-((4-methoxybenzyl)amino )quinolin-7-yl)methyl)-2-(4-chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)hexahydro-2H-cyclopenta[b]furan-3,3a -diol in the form of oil. MS: 668 (M+1).

Step 2: Into a vessel containing (2R,3R,3aS,6aR)-6-((3-bromo-2-((4-methoxybenzyl)amino)quinolin-7-yl)methyl)-2-(4-chloro -5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)hexahydro-2H-cyclopenta[b]furan-3,3a-diol (138 mg, 0.206 mmol), add ammonia (7 M in MeOH, 2.5 ml, 17.50 mmol). The vessel was sealed and heated at 140°C in a microwave reactor for 5 hours. The mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (0-70% 3:1 EtOAc:EtOH in hexane) to give (2R,3R,3aS ,6aR)-2-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-6-((3-bromo-2-((4-methoxybenzyl)amino) quinolin-7-yl)methyl)hexahydro-2H-cyclopenta[b]furan-3,3a-diol as a solid. MS: 649 (M+1).

Step 3: K (2R,3R,3aS,6aR)-2-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-6-((3-bromo- 2-((4-methoxybenzyl)amino)quinolin-7-yl)methyl)hexahydro-2H-cyclopenta[b]furan-3,3a-diol (68 mg, 0.105 mmol) dissolved in DCM (875 µl) was added TFA (348 μL, 4.516 mmol) at room temperature and stirred for 4 hours. TFA (500 μL, 6.489 mmol) was added to the reaction mixture and stirred overnight at room temperature. The mixture was heated to 40°C for 8 hours. The reaction mixture was concentrated under reduced pressure and purified by mass initiated reverse phase HPLC (ACN/water with 0.1% NH ₄ OH modifier) to give (2R,3R,3aS,6S ,6aR)-6-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl) hexahydro-2H-cyclopenta[b]furan-3,3a-diol as a solid. MS: 668 (M+1). 1H NMR (600 MHz, DMSO-d6) δ 8.32 (s, 1H), 8.10 (s, 1H), 7.55 (d, J=8.3 Hz, 1H), 7.51 (d , J=1.7 Hz, 1H), 7.29 (s, 1H), 7.12-6.98 (m, 3H), 6.59 (s, 2H), 5.94 (dd, J= 8.2, 1.5 Hz, 1H), 5.28 (d, J=7.0 Hz, 1H), 5.09 (s, 1H), 4.01 (t, J=7.5 Hz, 1H), 3.94 (d, J=5.8 Hz, 1H), 2.85-2.79 (m, 1H), 2.65-2.59 (m, 1H), 2.28-2 .20 (m, 1H), 1.95-1.89 (m, 1H), 1.79-1.69 (m, 1H), 1.69-1.62 (m, 1H), 1.54 -1.47 (m, 1H).

Example 109

(1S,2R,3S,5R)-3-(2-(2-amino-3-bromoquinolin-7-yl)ethyl)-3-methyl-5-(4-methyl-7H-pyrrolo[2,3- d]pyrimidin-7-yl)cyclopentane-1,2-diol

Step 1: 4-chloro-7-((3a'R,4'R,6'R,6a'S)-4'-methyl-4'-vinyltetrahydro-4'H-spiro[cyclohexane-1, 2'-cyclopenta[d][1,3]dioxol]-6'-yl)-7H-pyrrolo[2,3-d]pyrimidine (0.075 g, .2 mmol), Pd on solid support (0.077 g, 0.020 mmol), THF (1 ml) and dimethylzinc (2 M in PhMe, 0.5 ml, 1.0 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was carefully quenched with IPA, then MeOH was added dropwise. The reaction mixture was filtered through a pad of Celite, washed with DCM/EtOAc, then concentrated under reduced pressure to give 4-methyl-7-((3a'R,4'R,6'R,6a'S)-4'-methyl-4 '-vinyltetrahydro-4'H-spiro[cyclohexane-1,2'-cyclopenta[d][1,3]dioxol]-6'-yl)-7H-pyrrolo[2,3-d]pyrimidine. MS: 354 (M+1).

Stage 2: 4-methyl-7-((3a'R,4'R,6'R,6a'S)-4'-methyl-4'-vinyltetrahydro-3a'H-spiro[cyclohexane-1,2'-cyclopenta) was added to the vessel [d][1,3]dioxol]-6'-yl)-7H-pyrrolo[2,3-d]pyrimidine (70.7 mg, 0.2 mmol), THF (1 ml) and 9-BBN ( 0.5 M in THF, 1 ml, 0.500 mmol). The reaction mixture was heated to 50°C for 2 hours, then cooled to room temperature. Another portion of 9-BBN (0.5 M in THF, 1 ml, 0.5 mmol) was added and the reaction mixture was heated to 50°C overnight. The reaction mixture was cooled to room temperature and quenched with K₃P.O.₄ (2 M in water, 0.75 ml, 1.50 mmol) under nitrogen. 3-Bromo-N-(2,4-dimethoxybenzyl)-7-iodoquinoline-2-amine (100 mg, 0.20 mmol), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) was added to a separate vessel. (16.3 mg, 0.020 mmol) in THF (0.5 ml). This suspension was added to the first reaction vessel and the mixture was heated to 50°C overnight. The reaction mixture was cooled to room temperature and diluted with EtOAc, DCM and water. The organic and aqueous layers were separated by passing through a phase separator, and the organic layer was concentrated under reduced pressure to give 3-bromo-N-(2,4-dimethoxybenzyl)-7-(2-((3a'R,4'S,6'R ,6a'S)-4'-methyl-6'-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro-4'H-spiro[cyclohexane-1,2'-cyclopenta[ d][1,3]dioxol]-4'-yl)ethyl)quinoline-2-amine. MS: 726/728 (M+1/M+3).

Step 3: Solution of 3-bromo-N-(2,4-dimethoxybenzyl)-7-(2-((3a'R,4'S,6'R,6a'S)-4'-methyl-6'-(4-methyl -7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro-4'H-spiro[cyclohexane-1,2'-cyclopenta[d][1,3]dioxol]-4'-yl)ethyl )quinoline-2-amine (0.2 mmol) in THF (1 ml), water (0.3 ml, 16.7 mmol) and TFA (0.7 ml, 9.09 mmol) was stirred at room temperature for nights. The reaction mixture was then heated to 50°C for 3 hours. Another portion of TFA (1 ml, 13 mmol) was added at room temperature and the reaction mixture was heated to 50°C for 3 hours. The reaction mixture was concentrated under reduced pressure and the mass was purified - initiated reverse phase HPLC (ACN/water with 0.1% NH ₄ OH modifier) to obtain (1S,2R,3S,5R)-3-(2-(2-amino-3-bromoquinolin-7-yl) ethyl)-3-methyl-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol as a solid. MS: 496/498 (M+1/M+3). ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.29 (s, 1H), 8.03 (s, 1H), 7.59 (d, J=9.2 Hz, 1H), 7, 31 (d, J=3.6 Hz, 1H), 6.98-6.92 (m, 2H), 6.89 (lat, 2H), 6.55 (d, J=3.2 Hz , 1H), 6.51 (br.s, 2H), 5.03-4.96 (m, 1H), 4.85 (d, J=6.8 Hz, 1H), 4.75 (d, J=4.8 Hz, 1H), 4.56-4.50 (m, 1H), 4.03 (d, J=9.2 Hz, 1H), 3.97-3.91 (m, 2H ), 1.93 (d, J=9.6 Hz, 2H), 1.19 (s, 3H).

Example 110: Example 110 in Table 24 was synthesized using step 2 followed by steps 1 & 3 of example 109. 4-methyl-7-((3a'R,4'R,6'R,6a'S)-4'-methyl -4'-vinyltetrahydro-3a'H-spiro[cyclohexane-1,2'-cyclopenta[d][1,3]dioxol]-6'-yl)-7H-pyrrolo[2,3-d]pyrimidine at the stage 2 was replaced with a suitable exo-olefin. The reagents and starting material used for substitution were purchased commercially, synthesized as described above, or synthesized by known methods described in the literature.

Table 24 Etc. Structure Name MS 110 (1S,2R,3S,5R)-3-(2-(2,3-dihydro-1H-pyrrolo[2,3-b]quinolin-7-yl)ethyl)-3-methyl-5-(4- methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol 444 (M+1)

Example 111

(1R,2S,3R,5R)-5-(((2-amino-3-bromoquinolin-7-yl)oxy)methyl)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidine -7-yl)-1,5-dimethylcyclopentane-1,2-diol

Step 1: A mixture of 3-bromo-N-(4-methoxybenzyl)-7-(((3aR,4R,6R,6aS)-2,2,4-trimethyl-6-(4-phenoxy-7H- pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methoxy)quinolin-2-amine (100 mg, 0.136 mmol) at 50% aqueous TFA solution (1 ml). The reaction mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and the residue was purified by preparative TLC (DCM:MeOH=17:1) to give (1S,2R,3R,5R)-3-(((3-bromo -2-((4-methoxybenzyl)amino)quinolin-7-yl)oxy)methyl)-3-methyl-5-(4-phenoxy-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane -1,2-diol as a solid. MS: 696/698 (M+1/M+3).

Stage 2: To a stirred solution of (1S,2R,3R,5R)-3-(((3-bromo-2-((4-methoxybenzyl)amino)quinolin-7-yl)oxy)methyl)-3-methyl-5-( 4-phenoxy-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol (60 mg, 0.086 mmol), N-ethyl-N-isopropylpropan-2-amine chloride (0.428 mg , 2.58 µmol) and (2R,4S)-4-isopropyl-2-methoxy-3-((R)-2-methyl-1-(1-methyl-1H-imidazol-2-yl)propyl)oxazolidine (49 mg, 0.172 mmol) in THF (0.2 ml) was added DIEA (0.045 ml, 0.258 mmol) and tert-butyldimethylsilyl trifluoromethanesulfonate (34.2 mg, 0.129 mmol) at 0°C under argon. The resulting mixture was stirred at room temperature for 2 hours. The reaction was quenched with 10 ml of water and extracted with EtOAc (15 ml x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE/EtOAc=3:1 to give (1R,2R,4R,5S)-2-(((3-bromo-2-((4-methoxybenzyl)amino)quinolin-7-yl)oxy )methyl)-5-((tert-butyldimethylsilyl)oxy)-2-methyl-4-(4-phenoxy-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentanol as an oil. MS: 810 /812 (M+1/M+3).¹H-NMR (300 MHz, Chloroform-d) δ 8.46 (s, 1H), 8.05 (s, 1H), 7.50-7.44 (m, 3H), 7.40-7.38 (m, 2H), 7.33-7 .30 (m, 1H), 7.29-7.25 (m, 4H), 6.99-6.91 (m, 3H), 6.54 (d,J=3.6 Hz, 1H), 5.60-5.58 (m, 1H), 5.31-5.22 (m, 1H), 4.91-4.86 (m, 1H), 4, 77 (s, 2H), 4.08-4.04 (m, 3H), 3.84 (s, 3H), 2.83-2.82 (m, 1H), 2.49-2.41 ( m, 1H), 2.22-2.14 (m, 1H), 1.34 (s, 3H), 0.79 (s, 9H), - 0.14 (s, 3H), - 0.38 (c, 3H).

Step 3: To a stirred solution of (1R,2R,4R,5S)-2-(((3-bromo-2-((4-methoxybenzyl)amino)quinolin-7-yl)oxy)methyl)-5-(( tert-butyldimethylsilyl)oxy)-2-methyl-4-(4-phenoxy-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentanol (20 mg, 0.025 mmol) in DCM (0.5 ml) Dess-Martin periodinane (20.92 mg, 0.049 mmol) was added in one portion at 0°C under argon. The mixture was stirred at 0°C for 2 hours. The reaction was quenched with 5 ml of saturated aqueous Na ₂ S ₂ O ₃ and extracted with EtOAc (5 ml x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give (2R,4R,5S)-2-(((3-bromo-2-((4-methoxybenzyl)amino)quinolin-7-yl) oxy)methyl)-5-((tert-butyldimethylsilyl)oxy)-2-methyl-4-(4-phenoxy-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentanone. MS: 808/810 (M+1/M+3)

Step 4: A portion of cerium(III) chloride (37.0 mg, 0.150 mmol) was dried at 140°C in vacuum for 1 hour. The resulting powder was cooled under argon. Anhydrous THF (0.25 mL) was added and then methyl lithium (1.6 M in ether, 0.094 mL, 0.150 mmol) was added to the mixture at -78°C. The mixture was stirred at this temperature for 1 hour. Then a cooled solution of (2R,4R,5S)-2-(((3-bromo-2-((4-methoxybenzyl)amino)quinolin-7-yl)oxy) was quickly added methyl)-5-((tert-butyldimethylsilyl)oxy)-2-methyl-4-(4-phenoxy-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentanone (20.22 mg, 0.025 mmol ) in THF (0.25 ml) and the resulting mixture was continued to stir at this temperature for 6 hours. The reaction was quenched with saturated aqueous NH ₄ Cl (5 ml) and the mixture was extracted with EtOAc (5 ml x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE/EA=4:1) to give (1R,2R,4R,5S)-2-(((3-bromo-2-((4-methoxybenzyl)amino)quinolin-7-yl) oxy)methyl)-5-((tert-butyldimethylsilyl)oxy)-1,2-dimethyl-4-(4-phenoxy-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentanol as an oil. MS: 824/826 (M+1/M+3). ¹ H-NMR (400 MHz, Chloroform- d ) δ 8.41 (s, 1H), 8.08 (s, 1H), 7.53 (d, J = 8.8 Hz, 1H), 7.49 -7.44 (m, 3H), 7.41-7.38 (m, 2H), 7.28-7.24 (m, 4H), 6.98-6.93 (m, 4H), 6 .52 (d, J =3.2 Hz, 1H), 5.63-5.60 (m, 1H), 5.43-5.36 (m, 1H), 4.86 (d, J =8 ,8 Hz, 1H), 4.79 (s, 2H), 4.17 (d, J =9.2 Hz, 1H), 3.97 (d, J =9.2 Hz, 1H), 3, 84 (s, 3H), 2.40-2.32 (m, 2H), 1.27 (s, 3H), 1.22 (s, 3H), 0.78 (s, 9H), 0.03 (s, 3H), -0.04 (s, 3H).

Stage 5: To a stirred solution of (1R,2R,4R,5S)-2-(((3-bromo-2-((4-methoxybenzyl)amino)quinolin-7-yl)oxy)methyl)-5-((tert-butyldimethylsilyl )oxy)-1,2-dimethyl-4-(4-phenoxy-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentanol (35 mg, 0.042 mmol) in THF (2 ml) was added TBAF ( 1 M in THF, 0.084 ml, 0.084 mmol) at 0°C. The mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with a saturated aqueous solution of NH₄Cl (20 ml) and extracted with EtOAc (30 ml x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified by preparative TLC (PE:EA=1:1) to give (1R,2S,3R,5R)-5-(((3-bromo-2-((4-methoxybenzyl)amino)quinoline -7-yl)oxy)methyl)-1,5-dimethyl-3-(4-phenoxy-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol as a solid . MS: 710/712 (M+1/M+3).¹H-NMR (400 MHz, DMSO-d ₆ ) δ 8.31 (s, 1H), 8.24 (s, 1H), 7.67 (d,J=3.6 Hz, 1H), 7.60 (d,J=8.8 Hz, 1H), 7.49-7.45 (m, 2H), 7.35-7.25 (m, 5H), 7.15-7.12 (m, 1H), 7. 07 (s, 1H), 6.94 (d,J=8.4 Hz, 1H), 6.88 (d,J=8.0 Hz, 2H), 6.52-6.51 (m, 1H), 5.19-5.14 (m, 1H), 4.99 (d,J=7.6 Hz, 1H), 4.67 (d,J=6.0 Hz, 2H), 4.56 (t,J=8.8 Hz, 1H), 4.38 (s, 1H), 4.14-4.11 (m, 1H), 3.96-3.94 (m, 1H), 3.71 (s, 3H), 2.17-2.11 (m, 1H), 2.05-2.02 (m, 1H), 1.19-1.16 (m, 6H).

Stage 6: A solution of (1R,2S,3R,5R)-5-(((3-bromo-2-((4-methoxybenzyl)amino)quinolin-7-yl)oxy)methyl)-1,5-dimethyl-3-( 4-phenoxy-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol (17 mg, 0.024 mmol) in TFA (1 ml) was stirred at 50°C for 3 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by preparative TLC (DCM:MeOH=12:1) to give (1R,2S,3R,5R)-5-(((2-amino-3-bromoquinolin-7-yl)oxy )methyl)-1,5-dimethyl-3-(4-phenoxy-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol as a solid. MS: 590/592 (M+1/M+3).¹H-NMR (400 MHz, DMSO-d ₆ ) δ 8.29 (s, 1H), 8.21 (s, 1H), 7.66 (d,J=3.6 Hz, 1H), 7.60 (d,J=8.8 Hz, 1H), 7.50-7.45 (m, 2H), 7.31-7.28 (m, 1H), 7.26-7.24 (m, 2H), 7. 03-7.02 (m, 1H), 6.96-6.94 (m, 1H), 6.54 (br.s, 2H), 6.52 (d,J=3.6 Hz, 1H), 5.15 (sq.,J=9.6 Hz, 1H), 5.00 (d,J=7.2 Hz, 1H), 4.57-4.53 (m, 1H), 4.39 (s, 1H), 4.13 (d,J=9.6 Hz, 1H), 3.93 (d,J=9.6 Hz, 1H), 2.21-2.02 (m, 2H), 1.17-1.16 (m, 6H).

Step 7: (1R,2S,3R,5R)-5-(((2-amino-3-bromoquinolin-7-yl)oxy)methyl)-1,5-dimethyl-3-(4-phenoxy-7H- pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentan-1,2-diol (13 mg, 0.022 mmol) was dissolved in NH ₃ (liquid)/ i- PrOH (v:v = 5:1) ) (10 ml) at ambient temperature in a sealed tube. The reaction mixture was then stirred at 130°C for 48 hours. The reaction mixture was concentrated under reduced pressure and purified by reverse phase HPLC (ACN/water with 10 mmol NH ₄ HCO ₃ modifier) to give (1R,2S,3R,5R)- 5-(((2-amino-3-bromoquinolin-7-yl)oxy)methyl)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1,5- dimethylcyclopentane-1,2-diol in the form of a solid. MS: 513/515 (M+1/M+3). ¹ H-NMR (400 MHz, DMSO- d6 ) δ 8.30 (s, 1H), 7.93 (s, 1H), 7.60 ₍ d, J =8.8 Hz, 1H), 7, 27 (d, J =3.2 Hz, 1H), 7.01 (s, 1H), 6.96-6.85 (m, 3H), 6.60-6.51 (m, 3H), 5 .02-4.95 (m, 2H), 4.49 (d, J =8.8 Hz, 1H), 4.30 (s, 1H), 4.26 (d, J =9.2 Hz, 1H), 4.12 (d, J =9.2 Hz, 1H), 2.01-1.94 (m, 2H), 1.21 (s, 6H).

Examples 112 and 113

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-chloroquinolin-7-yl)oxy)-2-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)hexahydro-2H-cyclopenta[b]furan-3,3a-diol & (2R,3R,3aS,6S,6aR)-6-((2-aminoquinolin-7-yl)oxy)-2-( 4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)hexahydro-2H-cyclopenta[b]furan-3,3a-diol

Step 1: To a stirred solution of (2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)oxy)-2-(4-methyl-7H-pyrrolo[2, 3-d]pyrimidin-7-yl)hexahydro-2H-cyclopenta[b]furan-3,3a-diol (200 mg, 0.390 mmol) in EtOH (20 ml) was added monocopper(I) monocopper(III) oxide (84 mg, 0.586 mmol), tetramethyl ammonium chloride (428 mg, 3.90 mmol) and (S)-pyrrolidine-2-carboxylic acid (135 mg, 1.17 mmol) at ambient temperature. The mixture was stirred at 110°C overnight. The resulting mixture was concentrated under reduced pressure and the residue was purified by reverse phase column chromatography (ACN/water with 5 mM NH ₄ HCO ₃ modifier) to give (2R,3R,3aS,6S,6aR)-6-((2-amino-3 -chloroquinolin-7-yl)oxy)-2-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)hexahydro-2H-cyclopenta[b]furan-3,3a-diol in the form solid matter. MS: 468 (M+1). ¹ H-NMR (400 MHz, _Methanol-d4 ) δ 8.69 (s, 1H), 8.00 (s, 1H), 7.75 (d, J =3.6 Hz, 1H), 7, 55 (d, J =8.8 Hz, 1H), 6.99-6.94 (m, 2H), 6.82 (d, J =3.6 Hz, 1H), 6.18 (d, J =8.0 Hz, 1H), 4.78 (d, J =4.8 Hz, 1H), 4.64 (d, J =8.0 Hz, 1H), 4.35-4.33 (m , 1H), 2.76 (s, 3H), 2.59-2.49 (m, 1H), 2.28-2.19 (m, 3H). ¹ H-NMR (400 MHz, DMSO- d6 ) δ 8.70 (s, 1H), 8.09 (s, 1H), 7.96 ₍ d, J =3.6 Hz, 1H), 7, 57 (d, J =8.8 Hz, 1H), 6.88-6.84 (m, 3H), 6.62 (brs, 2H), 6.15 (d, J =8.4 Hz , 1H), 5.46 (d, J =7.2 Hz, 1H), 5.40 (s, 1H), 4.64 (d, J =5.6 Hz, 1H), 4.48 (t , J =7.6 Hz, 1H), 4.13-4.12 (m, 1H), 2.69 (s, 3H), 2.56-2.54 (m, 1H), 2.08- 2.01 (m, 3H). Also producing (2R,3R,3aS,6S,6aR)-6-((2-aminoquinolin-7-yl)oxy)-2-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7 -yl)hexahydro-2H-cyclopenta[b]furan-3,3a-diol as a solid. MS: 434 (M+1). ¹ H-NMR (400 MHz, _Methanol-d4 ) δ 8.66 (s, 1H), 7.80 (d, J =8.8 Hz, 1H), 7.73 (d, J =3.6 Hz, 1H), 7.52 (d, J =8.8 Hz, 1H), 6.95 (d, J =2.0 Hz, 1H), 6.88 (dd, J =8.4, 2 .4 Hz, 1H), 6.81 (d, J =3.6 Hz, 1H), 6.63 (d, J =8.4 Hz, 1H), 6.16 (d, J =8.0 Hz, 1H), 4.76 (d, J =5.2 Hz, 1H), 4.62 (d, J =8.0 Hz, 1H), 4.32 (s, 1H), 2.75 ( s, 3H), 2.57-2.47 (m, 1H), 2.26-2.18 (m, 3H). ¹ H-NMR (400 MHz, DMSO- d6 ) δ 8.69 (s, 1H), _7.95 (d, J =3.6 Hz, 1H), 7.76 (d, J =8.8 Hz, 1H), 7.51 (d, J =8.4 Hz, 1H), 6.84-6.76 (m, 3H), 6.55 (d, J =8.8 Hz, 1H), 6.30 (br.s, 2H), 6.15 (d, J =8.4 Hz, 1H), 5.46 (d, J =7.2 Hz, 1H), 5.39 (s, 1H ), 4.62 (d, J =5.2 Hz, 1H), 4.47 (t, J =7.6 Hz, 1H), 4.13 (s, 1H), 2.69 (s, 3H ), 2.56-2.54 (m, 1H), 2.08-1.97 (m, 3H).

Example 114

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)oxy)-2-(2-amino-4-methyl-7H-pyrrolo[2,3- d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol

Step 1: Into an oven-dried, argon-cooled 2-5 mL microwave vial containing (3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)oxy)hexahydro-3aH -cyclopenta[b]furan-2,3,3a-triol (0.086 g, 0.217 mmol) dissolved in anhydrous acetonitrile (4.3 ml), 1,1'-(azodicarbonyl)dipiperidine (0.082 g, 0.325 mmol) was added followed by the addition of tri-n-butylphosphine (0.087 mL, 0.346 mmol) at room temperature. The mixture was stirred for 1 hour and then this solution was used directly without characterization because the product was unstable. In a separate oven-dried, argon microwave-cooled vial containing di-tert-butyl (4-methyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)carbamate (0.151 g, 0.433 mmol) dissolved in anhydrous acetonitrile (1.0 ml), DBU (0.065 ml, 0.433 mmol) was added. The mixture was stirred at room temperature for 30 minutes and this suspension was transferred to the mixture described above through a syringe. The combined reaction mixture was stirred at room temperature under argon for 4 hours. The reaction was quenched with water and extracted with EtOAc (3×), the organic layer was washed with brine and dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (0-100% EtOAc/Hex) to give di-tert-butyl (7-{(2 R ,3 R ,3a S ,6 S ,6a R )-6-[(2-amino-3 -bromoquinolin-7-yl)oxy]-3,3a-dihydroxyhexahydro-2 H -cyclopenta[ b ]furan-2-yl}-4-methyl-7 H -pyrrolo[2,3- d ]pyrimidin-2-yl )imidodicarbonate. MS: 727/729 (M+1/M+3).

Step 2: K di-tert-butyl (7-{(2 R ,3 R ,3a S ,6 S ,6a R )-6-[(2-amino-3-bromoquinolin-7-yl)oxy]-3 ,3a-dihydroxyhexahydro- 2H -cyclopenta[ b ]furan-2-yl}-4-methyl- 7H -pyrrolo[2,3- d ]pyrimidin-2-yl)imidodicarbonate (0.04 g, 0.055 mmol) dissolved in DCM (1.10 mL), 2,2,2-trifluoroacetic acid (0.127 mL, 1.649 mmol) was added. The mixture was stirred for 6 hours at room temperature. The mixture was concentrated under reduced pressure and purified by mass initiated reverse phase HPLC (ACN/water with 0.1% NH ₄ OH modifier) to give (2R,3R,3aS,6S,6aR)-6-((2-amino- 3-bromoquinolin-7-yl)oxy)-2-(2-amino-4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3, 3a-diol, TFA salt, as a solid. MS: 527/529 (M+1/M+3). ^1H NMR (499 MHz, DMSO- d6 ) δ 9.55-9.19 (m, 3H) _, 9.15 (d, J = 15.5 Hz, 1H), 8.42 (d, J = 13.9 Hz, 1H), 8.05 (d, J = 25.0 Hz, 1H), 7.29 (s, 1H), 7.27 (s, 2H), 6.21 (d, J = 113.4 Hz, 2H), 4.79-4.46 (m, 2H), 4.42-4.24 (m, 2H), 3.85 (d, J = 20.8 Hz, 1H), 3.52-3.38 (m, 1H), 3.20-3.10 (m, 1H), 2.98 (d, J =30.6 Hz, 3H), 1.90 (s, 1H) , 1.80-1.63 (m, 1H).

Example 115

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-(difluoromethyl)quinolin-7-yl)oxy)-2-(4-methyl-7H-pyrrolo[2,3-d ]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol

Step 1: To a stirred mixture of (3aR,4R,5aR,6R,8aR)-2,2-dimethyl-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)hexahydrocyclopenta[2 ,3]furo[3,4-d][1,3]dioxol-6-ol (100 mg, 0.302 mmol) in DCM (1.5 ml) and pyridine (0.3 ml) was added trifluoromethanesulfonic anhydride (128 mg , 0.453 mmol) at 0°C in an argon atmosphere. The resulting mixture was stirred for 1 hour at 0°C. The reaction mixture was quenched with saturated aqueous NaHCO ₃ (10 ml), extracted with EtOAc (25 ml x 3). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica column chromatography (0-50% EtOAc/PE) to give (3aR,4R,5aR,6R,8aR)-2,2-dimethyl-4-(4-methyl-7H-pyrrolo[2,3 -d]pyrimidin-7-yl)hexahydrocyclopenta[2,3]furo[3,4-d][1,3]dioxol-6-yl trifluoromethanesulfonate as an oil. MS: 464 (M+1). ¹ H-NMR (300 MHz, DMSO- d6 ) δ 8.76 (s, 1H), _7.85 (d, J =3.6 Hz, 1H), 6.90 (d, J =3.9 Hz, 1H), 6.30 (d, J =5.1 Hz, 1H), 5.34 (d, J =4.8 Hz, 1H), 4.91 (d, J =3.6 Hz, 1H), 4.54-4.52 (m, 1H), 2.71 (s, 3H), 2.65-2.50 (m, 1H), 2.45-2.13 (m, 3H) , 1.59 (s, 3H), 1.40 (s, 3H).

Stage 2: To a stirred mixture of (3aR,4R,5aR,6R,8aR)-2,2-dimethyl-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)hexahydrocyclopenta[2,3] furo[3,4-d][1,3]dioxol-6-yl trifluoromethanesulfonate (100 mg, 0.216 mmol), 3-(difluoromethyl)-2-((4-methoxybenzyl)amino)quinolin-7-ol (71 .3 mg, 0.216 mmol) Cs was added to NMP (3 ml)₂CO₃ (211 mg, 0.647 mmol) at 25°C under argon. The resulting mixture was stirred at 25°C for 2 hours. The reaction mixture was diluted with water (50 ml) and extracted with DCM (50 ml x 3). The combined organic layers were dried over anhydrous Na₂SO₄, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (ACN/water with 5 mM NH₄HCO₃modifier) to obtain 3-(difluoromethyl)-7-(((3aR,4R,5aR,6S,8aR)-2,2-dimethyl-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidine -7-yl)hexahydrocyclopenta[2,3]furo[3,4-d][1,3]dioxol-6-yl)oxy)-N-(4-methoxybenzyl)quinolin-2-amine in the form of a solid. MS: 644 (M+1).¹H-NMR (300 MHz, DMSO-d ₆ ) δ 8.73 (s, 1H), 8.16 (s, 1H), 7.88 (d,J=3.6 Hz, 1H), 7.72 (d,J=8.7 Hz, 1H), 7.38-7.19 (m, 2H), 7.09-6.83 (m, 7H), 6.32 (d,J=4.8 Hz, 1H), 5.35 (d,J=5.1 Hz, 1H), 4.85-4.84 (m, 1H), 4.69-4.61 (m, 2H), 4.41-4.39 (m, 1H), 3, 72 (s, 3H), 2.70 (s, 3H), 2.60-2.16 (m, 4H), 1.55 (s, 3H), 1.41 (s, 3H).

Stage 3: K 3-(difluoromethyl)-7-(((3aR,4R,5aR,6S,8aR)-2,2-dimethyl-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidine-7- yl)hexahydrocyclopenta[2,3]furo[3,4-d][1,3]dioxol-6-yl)oxy)-N-(4-methoxybenzyl)quinolin-2-amine (100 mg, 0.155 mmol) was added TFA (5 ml) at 25°C. The resulting mixture was stirred for 1.5 hours at 50°C. The reaction mixture was azeotroped with toluene five times (20 mL) to remove TFA. The residue was added to water (5 ml) and TFA (5 ml) at 25°C. The mixture was stirred for 16 hours at 25°C. The mixture was azeotroped with toluene five times (20 mL) to remove TFA and water. The residue was purified by reverse phase column chromatography (ACN/water with 5 mM NH₄HCO₃ modifier) to give (2R,3R,3aS,6S,6aR)-6-((2-amino-3-(difluoromethyl)quinolin-7-yl)oxy)-2-(4-methyl-7H-pyrrolo[2 ,3-d]pyrimidin-7-yl)hexahydro-2H-cyclopenta[b]furan-3,3a-diol as a solid. MS: 484 (M+1).¹H-NMR (300 MHz, DMSO-d ₆ ) δ 8.70 (s, 1H), 8.14 (s, 1H), 7.96 (d,J=3.6 Hz, 1H), 7.70 (d,J=8.7 Hz, 1H), 7.27-6.84 (m, 4H), 6.45 (lats, 2H), 6.16 (d,J=8.4 Hz, 1H), 5.47 (d,J=7.2 Hz, 1H), 5.41 (s, 1H), 4.66 (d,J=5.4 Hz, 1H), 4.51-4.46 (m, 1H), 4.14 (s, 1H), 2.72 (s, 3H), 2.54-2.50 (m, 1H), 2.10-1.96 (m, 3H).

Example 116

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

Stage 1 : Under a protective layer of argon to the mixture ((3a R ,4 R ,6 R ,6a S )-6-(4-chloro-7 H -pyrrolo[2,3- d ]pyrimidin-7-yl)-2 ,2-dimethyltetrahydro- 3aH -cyclopenta[ d ][1,3]dioxol-4-yl)methanol (1.0 g, 3.09 mmol) in anhydrous DCM (20 ml) was added Dess-Martin periodinane (2, 62 g, 6.18 mmol) at 0°C. The resulting mixture was stirred at room temperature for 1.5 hours. The reaction mixture was quenched with saturated aqueous Na ₂ S ₂ O ₃ (20 ml) at 0°C and extracted with DCM (2 x 60 ml). The combined organic layers were washed successively with saturated aqueous NaHCO ₃ (60 mL) and brine (60 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica column chromatography (0-33% EtOAc/PE) to give ( 3aR , 4S , 6R , 6aS )-6-(4-chloro- 7H -pyrrolo[2,3- d ] pyrimidin-7-yl)-2,2-dimethyltetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-4-carbaldehyde as an oil. MS: 322 (M+1). ¹ H-NMR (400 MHz, DMSO- d6 ) δ 9.75 (s, 1H), 8.65 (s, 1H), 7.92 ₍ d, J =4.0 Hz, 1H), 6, 73 (d, J =3.6 Hz, 1H), 5.22-5.16 (m, 1H), 5.11 (dd, J =6.8, 4.8 Hz, 1H), 4.97 (dd, J =7.2, 5.2 Hz, 1H), 3.19-3.14 (m, 1H), 2.54-2.46 (m, 2H), 1.51 (s, 3H ), 1.27 (s, 3H).

Step 2 : Compound ( 3aR , 4S , 6R , 6aS )-6-(4-chloro- 7H -pyrrolo[2,3- d ]pyrimidin-7-yl)-2,2-dimethyltetrahydro-3a H -cyclopenta[ d ][1,3]dioxole-4-carbaldehyde (1.9 g, 5.91 mmol) was dissolved in 1,4-dioxane (60 ml) at room temperature. Then, aqueous formaldehyde (37 wt% in water, 0.701 mL, 7.09 mmol) and aqueous potassium carbonate (2M, 14.76 mL, 29.5 mmol) were added at room temperature. The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was neutralized with aqueous AcOH (50% wt) and then extracted with EtOAc (3 x 200 ml). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in EtOH (60 ml) and treated with sodium tetrahydroborate (0.107 g, 2.83 mmol) at 0°C. The reaction mixture was stirred at 0°C for 3 hours. The mixture was then concentrated under reduced pressure. The resulting residue was diluted with water (50 ml). The pH of the mixture was adjusted to 7 with an aqueous solution of AcOH (50% wt). The mixture was then extracted with EtOAc (3 x 200 ml). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (9:10:1 DCM/EtOAc/MeOH) to give (( 3aR , 6R , 6aS )-6-(4-chloro- 7H -pyrrolo[2,3- d ] pyrimidin-7-yl)-2,2-dimethyltetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-4,4-diyl)dimethanol in the form of a foamy substance. MS: 354 (M+1). ¹ H-NMR (400 MHz, DMSO- d6 ) δ 8.67 (s, 1H), _8.01 (d, J =3.6 Hz, 1H), 6.74 (d, J =3.6 Hz, 1H), 5.27-5.20 (m, 1H), 4.95 (t, J =6.4 Hz, 1H), 4.89 (t, J =5.2 Hz, 1H), 4.63 (d, J =7.2 Hz, 1H), 4.50 (t, J =5.6 Hz, 1H), 3.60-3.49 (m, 3H), 3.44-3 .40 (m, 1H), 2.26-2.23 (m, 1H), 2.06-1.92 (m, 1H), 1.48 (s, 3H), 1.22 (s, 3H ).

Step 3 : To a solution of (( 3aR , 6R , 6aS )-6-(4-chloro- 7H -pyrrolo[2,3- d ]pyrimidin-7-yl)-2,2-dimethyltetrahydro- 3aH -cyclopenta[ d ][1,3]dioxol-4,4-diyl)dimethanol (2.5 g, 7.07 mmol) in DCM (26 ml) was added triethylamine (2.95 ml, 21.20 mmol) and TBDPS-Cl (3.63 mL, 14.13 mmol) at 0°C under argon. The reaction mixture was then stirred at room temperature for 16 hours. The resulting solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-30% EtOAc/PE) to give (( 3aR , 4S , 6R , 6aS )-4-((( tert- butyldiphenylsilyl)oxy)methyl)-6-(4 -chloro-7 H -pyrrolo[2,3- d ]pyrimidin-7-yl)-2,2-dimethyltetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-4-yl)methanol in the form of a foamy substance . MS: 592 (M+1). ¹ H-NMR (400 MHz, DMSO- d6 ) δ 8.60 (s, 1H), _7.90 (d, J =3.6 Hz, 1H), 7.67-7.64 (m, 4H ), 7.49-7.41 (m, 6H), 6.70 (d, J =3.6 Hz, 1H), 5.24-5.17 (m, 1H), 5.01 (t, J =6.8 Hz, 1H), 4.73 (d, J =7.2 Hz, 1H), 4.60 (brs, 1H), 3.77 (d, J =10.0 Hz, 1H), 3.70 (d, J =11.2 Hz, 1H), 3.62-3.58 (m, 2H), 2.29-2.24 (m, 1H), 2.20-2 .14 (m, 1H), 1.47 (s, 3H), 1.22 (s, 3H), 1.05 (s, 9H). ((3a R ,4 R ,6 R ,6a S )-4-((( tert- butyldiphenylsilyl)oxy)methyl)-6-(4-chloro-7 H -pyrrolo[2,3- d ]pyrimidine) was also prepared -7-yl)-2,2-dimethyltetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-4-yl)methanol in the form of a foamy substance. MS: 592 (M+1). ^1H NMR (400 MHz, DMSO- d6 ) δ 8.49 (s, 1H), _7.80 (d, J =3.6 Hz, 1H), 7.53-7.51 (m, 4H) , 7.29-7.24 (m, 6H), 6.56 (d, J =3.6 Hz, 1H), 5.04-4.99 (m, 1H), 4.87 (lat.s , 1H), 4.77 (t, J =6.4 Hz, 1H), 4.44 (d, J =6.4 Hz, 1H), 3.62 (d, J =10.0 Hz, 1H ), 3.51 (d, J =10.4 Hz, 1H), 3.46 (d, J =10.4 Hz, 1H), 3.38 (d, J =10.4 Hz, 1H), 2.13-2.10 (m, 1H), 1.93-1.87 (m, 1H), 1.13 (s, 3H), 1.00 (s, 3H), 0.81 (s, 9H).

Step 4 : To a stirred solution of ((3 aR ,4 R ,6 R ,6 aS )-4-((( tert- butyldiphenylsilyl)oxy)methyl)-6-(4-chloro- 7H -pyrrolo[2,3 - d ]pyrimidin-7-yl)-2,2-dimethyltetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-4-yl)methanol (1.7 g, 2.87 mmol) in toluene (50 mL), triphenylphosphine (3.01 g, 11.5 mmol), 1H -imidazole (782 mg, 11.5 mmol) and diiodine (1.46 g, 5.74 mmol) were added at room temperature under argon. The mixture was then stirred at 120°C for 3 hours. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (0-40% EtOAc/PE) to give 7-((3 aS ,4 R ,6 R ,6 aR )-6-((( tert- butyldiphenylsilyl)oxy)methyl)-6-(iodomethyl)-2,2-dimethyltetrahydro- 3aH -cyclopenta[ d ][1,3]dioxol-4-yl)-4-chloro -7 H -pyrrolo[2,3- d ]pyrimidine as an oil. MS: 702 (M+1). ^1H NMR (400 MHz, _Methanol-d4 ) δ 8.63 (s, 1H), 7.82-7.78 (m, 4H), 7.70 (d, J =3.6 Hz, 1H) , 7.50-7.45 (m, 6H), 6.74 (d, J =3.6 Hz, 1H), 5.16-5.10 (m, 1H), 5.08-5.04 (m, 1H), 4.68 (d, J =7.2 Hz, 1H), 3.96 (d, J =11.2 Hz, 1H), 3.75 (t, J =10.0 Hz , 2H), 3.63 (d, J =11.2 Hz, 1H), 2.63-2.57 (m, 1H), 2.40-2.23 (m, 1H), 1.33 ( s, 3H), 1.27 (s, 3H), 1.09 (s, 9H).

Stage 5: To a stirred solution 7-((3aS,4R.6R.6aR)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-6-(iodomethyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1.6 g, 2.28 mmol) in 1,4-dioxane (40 ml), sodium phenolate (661 mg, 5.70 mmol) was added at room temperature under argon. The reaction mixture was stirred at 80°C overnight. The reaction mixture was then directly purified by silica gel column chromatography (0-40% EtOAc/PE) to give 7-((3aS,4R.6R.6aR)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-6-(iodomethyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-4-phenoxy-7H-pyrrolo[2,3-d]pyrimidine in oil form. MS: 760 (M+1). ¹H NMR (400 MHz, DMSO-d ₆) δ 8.43 (s, 1H), 7.78-7.72 (m, 6H), 7.51-7.47 (m, 10H), 6.62 (d,J=3.6 Hz, 1H), 5.22-5.16 (m, 1H), 5.09 (t,J=6.4 Hz, 1H), 4.61 (d,J=6.8 Hz, 1H), 3.85 (d,J=11.2 Hz, 1H), 3.77-3.70 (m, 2H), 3.63 (d,J=11.2 Hz, 1H), 2.56-2.54 (m, 1H), 2.31-2.28 (m, 1H), 1.24 (s, 3H), 1.19 (s, 3H), 1.03 (s, 9H).

Step 6 : To a stirred solution of 7-((3 aS ,4 R ,6 R ,6 aR )-6-((( tert- butyldiphenylsilyl)oxy)methyl)-6-(iodomethyl)-2,2-dimethyltetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-4-yl)-4-phenoxy-7 H -pyrrolo[2,3- d ]pyrimidine (1.6 g, 2.11 mmol) in EtOAc (20 ml ) and ethanol (20 ml) was added dihydroxypalladium on carbon (20 wt.%, 1600 mg, 2.28 mmol) at room temperature under nitrogen atmosphere. The suspension was degassed in vacuo and purged with H ₂ several times, then the mixture was stirred under an H ₂ atmosphere (1-2 atm) at 25°C for 30 minutes. The mixture was then filtered through a pad of Celite and the filtrate was concentrated under reduced pressure to give 7-((3 aS ,4 R ,6 S ,6 aR )-6-((( t- butyldiphenylsilyl)oxy)methyl)-2,2,6 -trimethyltetrahydro- 3aH- cyclopenta[ d ][1,3]dioxol-4-yl)-4-phenoxy- 7H -pyrrolo[2,3- d ]pyrimidine as an oil. MS: 634 (M+1). ¹ H-NMR (400 MHz, DMSO- d6 ) δ 8.41 (s, 1H), _7.79 (d, J =2.7 Hz, 1H), 7.72-7.68 (m, 4H ), 7.51-7.46 (m, 8H), 7.34-7.27 (m, 3H), 6.58 (d, J =2.7 Hz, 1H), 5.22-5, 11 (m, 1H), 5.06 (t, J =4.8 Hz, 1H), 4.52 (d, J =5.1 Hz, 1H), 3.71 (d, J =7.8 Hz, 1H), 3.61 (d, J =7.8 Hz, 1H), 2.50-2.44 (m, 1H), 2.15-2.02 (m, 1H), 1.30 (s, 3H), 1.29 (s, 3H), 1.20 (s, 3H), 1.03 (s, 9H).

Step 7 : To a stirred solution of 7-(( 3aS , 4R , 6S , 6aR )-6-((( tert- butyldiphenylsilyl)oxy)methyl)-2,2,6-trimethyltetrahydro- 3aH -cyclopenta[ d ][1,3]dioxol-4-yl)-4-phenoxy-7 H -pyrrolo[2,3- d ]pyrimidine (1.1 g, 1.74 mmol) in THF (10 ml) added tetrabutylammonium fluoride (1M in THF) (3.47 mL, 3.47 mmol) at room temperature under argon. The reaction mixture was stirred at 45°C overnight. Once complete, the solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (0-40% EtOAc/PE) to give (( 3aR , 4S , 6R , 6aS )-2,2,4-trimethyl-6- (4-phenoxy-7 H -pyrrolo[2,3- d ]pyrimidin-7-yl)tetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-4-yl)methanol as a solid. MS: 396 (M+1). ¹ H-NMR (300 MHz, DMSO- d6 ) δ 8.37 (s, 1H), _7.80 (d, J =3.9 Hz, 1H), 7.51-7.46 (m, 2H ), 7.34-7.26 (m, 3H), 6.56 (d, J =3.6 Hz, 1H), 5.24-5.18 (m, 1H), 5.02 (t, J =6.3 Hz, 1H), 4.57 (t, J =4.8 Hz, 1H), 4.49 (d, J =7.2 Hz, 1H), 3.55-3.51 ( m, 1H), 3.42-3.37 (m, 1H), 2.42-2.35 (m, 1H), 2.05-1.97 (m, 1H), 1.47 (s, 3H), 1.23 (s, 3H), 1.16 (s, 3H).

Step 8 : To a stirred solution of (( 3aR , 4S , 6R , 6aS )-2,2,4-trimethyl-6-(4-phenoxy- 7H -pyrrolo[2,3- d ]pyrimidine-7 -yl)tetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-4-yl)methanol (520 mg, 1.315 mmol) in DCM (10 ml) was added Dess-Martin periodinane (837 mg, 1.97 mmol ) at room temperature in an argon atmosphere. The reaction mixture was stirred at this temperature for 30 minutes. The resulting mixture was quenched with saturated aqueous NaHCO ₃ (1M, 20 ml) and the mixture was extracted with DCM (3 x 30 ml). The combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was then concentrated under reduced pressure to obtain crude ( 3aR , 4R , 6R , 6aS )-2,2,4-trimethyl-6-(4-phenoxy- 7H- pyrrolo[2,3- d ]pyrimidine -7-yl)tetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-4-carbaldehyde was used directly in the next step.

Step 9 : To a stirred mixture of bromo(methyl)triphenylphosphorane (1.32 g, 3.68 mmol) in THF (20 ml) was added n-butyllithium (2.5 M in hexane, 1.37 ml, 3.42 mmol) at -60 ^o C in an argon atmosphere. The reaction mixture was warmed to room temperature and maintained for ~30 minutes. Then, crude (3 aR ,4 R ,6 R ,6 aS )-2,2,4-trimethyl-6-(4-phenoxy- 7H- pyrrolo[2,3- d ]pyrimidine- 7-yl)tetrahydro- 3aH -cyclopenta[ d ][1,3]dioxol-4-carbaldehyde (1.315 mmol) in THF (5 ml) at -40°C under argon. The resulting mixture was stirred at room temperature for 3 hours. The reaction was quenched with saturated aqueous NH ₄ Cl (20 ml) at -40°C and extracted with EtOAc (3 x 50 ml). The combined organic fractions were washed with brine (3 x 20 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (0-40% EtOAc/PE) to give 4-phenoxy-7-((3 aS ,4 R ,6 S ,6 aR )-2,2,6 -trimethyl-6-vinyltetrahydro- 3aH -cyclopenta[ d ][1,3]dioxol-4-yl) -7H- pyrrolo[2,3- d ]pyrimidine as a solid. MS: 392 (M+1). ¹ H-NMR (400 MHz, DMSO- d6 ) δ 8.36 (s, 1H), _7.81 (d, J =3.6 Hz, 1H), 7.50-7.46 (m, 2H ), 7.32-7.25 (m, 3H), 6.55 (d, J =3.6 Hz, 1H), 6.20-6.13 (m, 1H), 5.20-5, 12 (m, 3H), 5.04 (dd, J =5.2, 7.2 Hz, 1H), 4.50 (d, J =7.2 Hz, 1H), 2.39-2.32 (m, 2H), 1.47 (s, 3H), 1.23 (s, 3H), 1.22 (s, 3H).

Step 10 : 4-phenoxy-7-(( 3aS , 4R , 6S , 6aR )-2,2,6-trimethyl-6-vinyltetrahydro- 3aH- cyclopenta[ d ][1,3]dioxol- 4-yl) -7H- pyrrolo[2,3- d ]pyrimidine (272 mg, 0.695 mmol) was dissolved in 1,4-dioxane (15 ml) in a sealed tube and then the mixture was treated with concentrated NH ₃ H ₂ O (28% wt., 15 ml). The resulting mixture was heated at 120°C for 16 hours. Volatiles were removed under reduced pressure and the residue was purified by preparative TLC (1:1 PE:EtOAc) to give 7-((3 aS ,4 R ,6 S ,6 aR )- 2,2,6-trimethyl-6-vinyltetrahydro- 3aH -cyclopenta[ d ][1,3]dioxol-4-yl)-7H - pyrrolo[2,3- d ]pyrimidin-4-amine as a solid substances. MS: 315 (M+1). ¹ H-NMR (400 MHz, DMSO- d6 ) δ 8.06 (s, 1H), _7.38 (d, J =3.6 Hz, 1H), 6.97 (br s, 2H), 6.57 (d, J =3.6 Hz, 1H), 6.18-6.11 (m, 1H), 5.17-5.08 (m, 2H), 5.08-5.04 ( m, 1H), 4.98 (dd, J = 4.8, 7.2 Hz, 1H), 4.47 (d, J = 6.8 Hz, 1H), 2.33-2.20 (m , 2H), 1.45 (s, 3H), 1.22 (s, 3H), 1.20 (s, 3H).

Stage 11: In a 20 ml microwave tube containing 7-((3aS,4R.6S.6aR)-2,2,6-trimethyl-6-vinyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (174 mg, 0.553 mmol), 9-borabicyclo[3.3.1]nonane (0.5 M in THF, 4.43 mL, 2.21 mmol) was added at room temperature under argon. The reaction mixture was heated at 60°C for 1 hour. The mixture was cooled to 0°C upon completion. To this mixture was added a solution of potassium phosphate (587 mg, 2.77 mmol) in water (1.3 ml) at 0°C. After stirring at room temperature for 30 minutes, Pd(dppf)Cl was added₂ (41 mg, 0.055 mmol) and a solution of 7-bromo-3-fluoroquinoline-2-amine (147 mg, 0.608 mmol) in THF (4 ml). The resulting mixture was microwaved at 80°C for 2 hours. The reaction mixture was then diluted with water (20 ml) and the mixture was extracted with EtOAc (3 x 50 ml). The combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by preparative TLC (20:1 EtOAc:MeOH) to give 7-(2-((3aR,4R.6R.6aS)-6-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2,4-trimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)ethyl)-3-fluoroquinoline-2-amine in the form of a solid. MS: 477 (M+1). ¹H-NMR (400 MHz, DMSO-d ₆) δ 8.06 (s, 1H), 7.78 (d,J=11.6 Hz, 1H), 7.60 (d,J=8.4 Hz, 1H), 7.38-7.36 (m, 2H), 7.14 (d,J=8.4 Hz, 1H), 6.97 (br.s, 2H), 6.71 (br.s, 2H), 6.57 (d,J=3.6 Hz, 1H), 5.05-5.02 (m, 2H), 4.44 (d,J=4.0 Hz, 1H), 2.77-2.70 (m, 2H), 2.27-2.22 (m, 1H), 2.15-2.09 (m, 1H), 1, 88-1.73 (m, 2H), 1.46 (s, 3H), 1.25 (s, 3H), 1.21 (s, 3H).

Step 12: 7-(2-((3aR,4R,6R,6aS)-6-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2,4-trimethyltetrahydro -4H-cyclopenta[d][1,3]dioxol-4-yl)ethyl)-3-fluoroquinoline-2-amine (129.4 mg, 0.272 mmol) in TFA (2.72 ml) and water (2, 72 ml) was stirred overnight at 40°C. The reaction mixture was then concentrated under reduced pressure and the residue was purified by mass initiated HPLC (ACN/water with 0.1% TFA modifier) to give (1S,2R,3R,5R)-3-(2-(2-amino-3- fluoroquinolin-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-methylcyclopentane-1,2-diol, TFA salt, as an oil. MS: 437 (M+1). ^1H NMR (DMSO- _d6 ) δ: 8.36 (s, 1H), 8.10 (d, J=11.2 Hz, 2H), 7.79-7.64 (m, 2H), 7 .44 (s, 1H), 7.29 (d, J=8.1 Hz, 1H), 7.24 (s, 1H), 7.14 (s, 1H), 7.04 (s, 1H) , 6.96 (d, J=3.6 Hz, 1H), 5.11-5.03 (m, 1H), 5.02-4.79 (m, 1H), 4.65-4.53 (m, 1H), 3.66 (d, J=4.2 Hz, 1H), 2.80 (td, J=12.7, 4.3 Hz, 1H), 2.67 (td, J= 12.6, 4.3 Hz, 1H), 2.15 (dd, J=13.5, 10.4 Hz, 1H), 1.88 (td, J=12.9, 4.6 Hz, 1H ), 1.67 (td, J=12.9, 4.6 Hz, 1H), 1.60 (dd, J=13.5, 8.9 Hz, 1H), 1.27 (s, 3H) .

Example 117

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

Step 1: (1R,4S)-tert-butyl 5-methyl-3-oxo-2-azabicyclo[2.2.1]hept-5-ene-2-carboxylate (1 g, 4.48 mmol) was dissolved in 4 M HCl/MeOH (10 ml) and the reaction mixture was heated to reflux and stirred at this temperature for 2 hours. The solvent was then removed under reduced pressure to obtain crude (1S,4R)-methyl 4-amino-2-methylcyclopent- 2-enecarboxylate hydrochloride, which was used directly in the next step.

Step 2: To a stirred solution of (1S,4R)-methyl 4-amino-2-methylcyclopent-2-enecarboxylate hydrochloride (859 mg, 4.48 mmol) in 5:1 acetone:H ₂ O (12 ml) was added sodium bicarbonate (753 mg, 8.96 mmol) and di-tert-butyl dicarbonate (1076 mg, 4.93 mmol). The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was diluted with 100 ml water and extracted with 100 ml EtOAc. The organic phase was then washed with 100 ml of saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (3:1 PE/EtOAc) to give (1S,4R)-methyl 4-(( t- butoxycarbonyl)amino)-2-methylcyclopent-2-enecarboxylate as an oil. ^1H NMR (400 MHz, Chloroform-d) δ 5.58-5.52 (m, 1H), 5.04 (s, 1H), 4.72 (s, 1H), 3.75 (s, 3H ), 3.32-3.24 (m, 1H), 2.53 (dt, J=13.9, 8.5 Hz, 1H), 1.90 (dt, J=13.9, 3.2 Hz, 1H), 1.77 (sq., J=1.3 Hz, 3H), 1.46 (s, 9H).

Step 3: To a stirred solution of (1S,4R)-methyl 4-(( tert- butoxycarbonyl)amino)-2-methylcyclopent-2-enecarboxylate (4.3 g, 16.84 mmol) in THF (80 ml) was added 1M lithium bis(trimethylsilyl)amide in THF (38.7 ml, 38.7 mmol, 1M) at -78°C and the reaction mixture was stirred at -78°C for 0.5 h. Iodomethane (2, 63 g, 18.53 mmol) at -78°C and the resulting mixture was stirred at -20°C for 2 hours. The reaction was quenched with saturated aqueous NH ₄ Cl (100 ml) and extracted with EtOAc (120 ml x 3) . The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20-25% EtOAc/PE) to give (1S,4R)-methyl 4-((tert-butoxycarbonyl)amino)-1,2-dimethylcyclopent-2-enecarboxylate as an oil. ^1H NMR (300 MHz, Chloroform-d) δ 5.49 (p, J= 1.5 Hz, 1H), 5.03 (s, 1H), 4.69 (s, 1H), 3.72 ( s, 3H), 2.21-2.15 (m, 2H), 1.69 (t, J= 1.5 Hz, 3H), 1.46 (s, 9H), 1.31 (s, 3H ).

Step 4: To a stirred solution of (1S,4R)-methyl 4-((tert-butoxycarbonyl)amino)-1,2-dimethylcyclopent-2-enecarboxylate (3.1 g, 11.5 mmol) in THF (50 ml) add lithium borohydride (2M in THF, 11.5 ml, 23.02 mmol) dropwise at 0°C. The reaction mixture was then stirred at room temperature for 16 hours. The mixture was quenched with water (100 ml) and extracted with EtOAc (100 ml x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (18-22% EtOAc/PE) to give tert- butyl ((1R,4S)-4-(hydroxymethyl)-3,4-dimethylcyclopent-2-en-1-yl)carbamate as solid matter. ¹ H NMR (400 MHz, Chloroform-d) δ 5.47 (s, 1H), 4.58 (d, J=8.7 Hz, 1H), 3.54 (d, J=10.5 Hz, 1H), 3.31 (d, J=10.5 Hz, 1H), 2.13 (dd, J=13.8, 8.7 Hz, 1H), 1.76 (dd, J=13.8 , 3.0 Hz, 1H), 1.66 (d, J=1.5 Hz, 3H), 1.45 (s, 9H), 1.00 (s, 3H).

Step 5: To a stirred solution of tert- butyl ((1R,4S)-4-(hydroxymethyl)-3,4-dimethylcyclopent-2-en-1-yl)carbamate (550 mg, 2.279 mmol) in 1:1 t BuOH :H ₂ O (6 ml) was added 4-methylmorpholine 4-oxide (534 mg, 4.56 mmol) at room temperature. The mixture was then cooled to 0°C and 4% osmium(VIII) oxide in water (1.88 g, 0.296 mmol) was added at 0°C. The reaction mixture was stirred at 0°C for 16 hours. The reaction was quenched with 50 ml of saturated aqueous sodium thiosulfate and extracted with 50 ml of EtOAc. The organic layer was washed with 50 ml of water and 50 ml of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel (1:1 PE/EtOAc) to give tert- butyl ((1R,2S,3R,4R)-2,3-dihydroxy-4-(hydroxymethyl)-3,4-dimethylcyclopentyl)carbamate as solid matter. Then tert- butyl ((1R,2S,3R,4R)-2,3-dihydroxy-4-(hydroxymethyl)-3,4-dimethylcyclopentyl)carbamate (530 mg, 1.93 mmol) was dissolved in HCl in MeOH (4M , 10 ml) and the reaction mixture was stirred at 25°C for 2 hours. The solvent was removed under reduced pressure to obtain the crude product, which was used directly in the next step. Then to a stirred solution of (1R,2S,3R,5R)-3-amino-5-(hydroxymethyl)-1,5-dimethylcyclopentane-1,2-diol hydrochloride (402 mg, 1.9 mmol) in i -PrOH ( 6 mL) DIEA (0.664 mL, 3.80 mmol) and 4,6-dichloro-5-(2,2-diethoxyethyl)pyrimidine (554 mg, 2.09 mmol) were added at room temperature. The reaction mixture was heated to 100°C and stirred at this temperature for 8 hours. The solvent was then removed under reduced pressure and the resulting crude residue was purified by silica gel column chromatography (eluting with EtOAc) to give (1R,2S,3R,5R)- 3-((6-chloro-5-(2,2-diethoxyethyl)pyrimidin-4-yl)amino)-5-(hydroxymethyl)-1,5-dimethylcyclopentane-1,2-diol as an oil. MS: 404 (M+1).

Step 6: To a stirred solution of (1R,2S,3R,5R)-3-((6-chloro-5-(2,2-diethoxyethyl)pyrimidin-4-yl)amino)-5-(hydroxymethyl)-1, 5-dimethylcyclopentane-1,2-diol (230 mg, 0.569 mmol) in dioxane (3 ml) was added with HCl in water (4M, 0.285 ml, 1.139 mmol) at room temperature. The resulting mixture was heated to 50°C and stirred at this temperature for 15 minutes. The reaction mixture was quenched with 20 ml saturated aqueous sodium bicarbonate and extracted with EtOAc (3 x 20 ml). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give (1R,2S,3R,5R)-3-(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-7- yl)-5-(hydroxymethyl)-1,5-dimethylcyclopentane-1,2-diol as a solid. MS: 312 (M+1).

Step 7: To a stirred solution of (1R,2S,3R,5R)-3-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-(hydroxymethyl)-1,5- dimethylcyclopentane-1,2-diol (540 mg, 1.73 mmol) in acetone (15 ml) added 4-methylbenzenesulfonic acid (30 mg, 0.173 mmol) and 2,2-dimethoxypropane (1.80 gg, 17.3 mmol ) at 0°C. The reaction mixture was stirred at 25°C for 16 hours. The mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (54% EtOAc/PE) to give ((3aR,4R,6R,6aS)-6-(4-chloro -7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2,3a,4-tetramethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methanol in the form of an oil. MS: 352 (M+1).

Step 8: To a stirred solution of oxalyl chloride (0.30 ml, 3.41 mmol) in DCM (8 ml) was added dropwise DMSO (0.484 ml, 6.82 mmol) at -78°C and the resulting mixture was stirred at -78° C for 0.5 h. Then ((3aR,4R,6R,6aS)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2 ,3a,4-tetramethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methanol (400 mg, 1.137 mmol) in DCM (3 ml) and the reaction mixture was continued to stir at -78°C for a further for 0.5 h. TEA (1.585 mL, 11.37 mmol) was then added at -78°C and the reaction mixture was warmed to room temperature and stirred at this temperature for 1 h. Then 100 mL of saturated aqueous ammonium chloride was added and the mixture was extracted with EtOAc (2 x 100 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give crude (3aR,4S,6R,6aS)-6-(4-chloro-7H-pyrrolo[2,3d]pyrimidin-7-yl) -2,2,3a,4-tetramethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-carbaldehyde, which was used directly in the next step.

Step 9: To a stirred solution of methyltriphenylphosphonium bromide (1.14 g, 3.18 mmol) in THF (8 ml) add n-butyllithium (2.5M in hexane, 0.455 ml, 1.14 mmol) dropwise at -20° C. The resulting mixture was heated to room temperature and stirred for 1 hour. Then a solution of (3aR,4S,6R,6aS)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl) was added dropwise )-2,2,3a,4-tetramethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-carbaldehyde (398 mg, 1.14 mmol) in THF (3 ml) at -20°C. The resulting mixture was then heated to 25°C and stirred for 2 hours. The mixture was diluted with 100 ml EtOAc and washed with 100 ml water and 100 ml brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (3:1 PE/EtOAc) to give 4-chloro-7-((3aS,4R,6R,6aR)-2,2,6,6a-tetramethyl-6-vinyltetrahydro-3aH-cyclopent [d][1,3]dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine as an oil. MS: 348 (M+1).

Step 10: In a 25 ml hermetically sealed tube containing a solution of 4-chloro-7-((3aS,4R,6R,6aR)-2,2,6,6a-tetramethyl-6-vinyltetrahydro-3aH-cyclopenta[d] [1,3]dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine (250 mg, 0.719 mmol) in dioxane (5 ml), added 28% wt. NH ₃ in H ₂ O (25 ml). The resulting mixture was heated to 90°C and stirred for 16 hours. The solvent was removed under reduced pressure to give crude 7-((3aS,4R,6R,6aR)-2,2,6,6a-tetramethyl-6-vinyltetrahydro-3aH -cyclopenta[d][1,3]dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, which was used directly in the next step.

Stage 11:IN A 10 ml round bottom flask was charged with 7-((3aS,4R,6R,6aR)-2,2,6,6a-tetramethyl-6-vinyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl) -7H-pyrrolo[2,3-d]pyrimidin-4-amine (70 mg, 0.213 mmol) and 9-BBN (0.5M in THF, 2.13 mL, 1.07 mmol) at room temperature under argon . The resulting mixture was heated to 50°C and stirred for 1 hour. To this crude reaction mixture was added a solution of tribasic potassium phosphate (226 mg, 1.07 mmol) in water (0.2 ml) at 0°C and the resulting mixture was heated to 50°C and stirred for 0.5 h. Then a solution of 3-bromo-7-iodo-N-(4-methoxybenzyl)quinoline-2-amine (110 mg, 0.234 mmol) in THF (0.2 ml) was added and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (15.59 mg, 0.021 mmol) at room temperature and the resulting mixture was heated to 50°C and stirred for 1 hour. The mixture was diluted with 30 ml EtOAc and washed with 30 ml water and 30 ml saturated saline solution. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (10% MeOH/DCM) to give 7-(2-((3aR,6R,6aS)-6-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl) -2,2,3a,4-tetramethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)ethyl)-3-bromo-N-(4-methoxybenzyl)quinolin-2-amine as a solid substances. MS: 671/673 (M+1/M+3).

Stage 12:IN A 10-ml round bottom flask was loaded with 7-(2-((3aR,6R,6aS)-6-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2,3a, 4-tetramethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)ethyl)-3-bromo-N-(4-methoxybenzyl)quinolin-2-amine (80 mg, 0.119 mmol) and TFA ( 2 ml) at room temperature in an argon atmosphere. The resulting mixture was then heated to 50°C and stirred for 40 minutes. The solvent was removed under reduced pressure. The resulting crude material was purified by reverse phase column chromatography (ACN/water at 5 mM to give (1R,2S,3R)-5-(2-(2-amino-3-bromoquinolin-7-yl)ethyl)-3-( 4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1,5-dimethylcyclopentane-1,2-diol as a solid MS: 511/513 (M+1/M+3 ).¹H-NMR (300 MHz, DMSO-d₆) δ 8.33 (s, 1H), 8.04 (s, 1H), 7.58 (d, J=8.4 Hz, 1H), 7.36 (s, 1H), 7.18-7 ,13 (m, 2H), 6.89 (br.s, 2H), 6.54-6.53 (m, 3H), 4.90 (d, J=6.9 Hz, 1H), 4, 81 (sq., J=9.0 Hz, 1H), 4.41-4.36 (m, 1H), 4.09 (s, 1H), 2.68-2.65 (m, 2H), 2.08-1.90 (m, 3H), 1.66-1.63 (m, 1H), 1.09 (s, 6H).

Example 118

(1R,2S,3S,4R)-1-(2-(2-amino-3-bromoquinolin-7-yl)ethyl)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)-2-methylcyclopentane-1,2,3-triol

Step 1: To a stirred solution of (1R,4S)-4-hydroxycyclopent-2-en-1-yl acetate (5.68 g, 40.0 mmol), 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (9.20 g, 59.9 mmol) and triphenylphosphine (36.7 g, 140 mmol) in THF (80 ml) added (E)-diisopropyldiazene-1,2-dicarboxylate (20.20 g, 100 mmol) to argon atmosphere at 0°C. The resulting mixture was stirred at room temperature for 16 hours. The solution was concentrated under reduced pressure and the resulting residue was purified by silica column chromatography (0-80% EtOAc/PE) to give (1R,4R)-4-(4-chloro-7H -pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-2-en-1-ylacetate as a solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.66 (s, 1H), 7.66 (d, J=3.7 Hz, 1H), 6.69 (d, J=3.6 Hz , 1H), 6.32-6.19 (m, 2H), 6.09 (ddt, J=7.4, 4.9, 1.9 Hz, 1H), 6.03-5.92 (m , 1H), 2.53 -2.32 (m, 2H), 2.05 (s, 3H).

Step 2: To a stirred solution of (1R,4R)-4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-2-en-1-ylacetate (8.6 g, 31.0 mmol) in DCM (20 ml), ammonia in MeOH (200 ml, 7M, 1400 mmol) was added and the resulting mixture was stirred at room temperature for 16 hours. The solution was concentrated under reduced pressure and the resulting residue was purified by silica column chromatography (0-15% MeOH/DCM) to give (1R,4R)-4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-2-enol as a solid. MS: 236 (M+1).

Step 3: To a solution of (1R,4R)-4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-2-enol (350 mg, 1.49 mmol) in anhydrous DCM (7 ml) was added Dess-Martin periodinane (945 mg, 2.23 mmol) at 0°C under argon. The resulting mixture was stirred at 25°C for 16 hours. The reaction mixture was then cooled to 0°C, quenched with saturated aqueous sodium bicarbonate (5 ml) and diluted with DCM (100 ml). The solution was then filtered through Celite. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica column chromatography (20-35% EtOAc/PE) to give (R)-4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-7- yl)cyclopent-2-enone in the form of a solid. MS: 234 (M+1).

Step 4: To a stirred solution of (R)-4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-2-enone (870 mg, 3.72 mmol) in DCM ( 3 ml) and pyridine (3 ml), a solution of diiodine (1.60 g, 6.33 mmol) in DCM (3 ml) and pyridine (3 ml) was added at 0°C. The resulting mixture was stirred at room temperature for 16 hours. DCM (30 ml) and sodium thiosulfate solution (60 ml, 1 M) were then added to the solution, and the organic layer was concentrated under reduced pressure. The resulting residue was purified by silica column chromatography (0-80% EtOAc/PE) to give (R)-4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-iodocyclopent -2-enone as a solid. MS: 360 (M+1).

Step 5: To a stirred solution of (R)-4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-iodocyclopent-2-enone (2.9 g, 8.07 mmol) in N -methyl-2-pyrrolidinone (25 ml), copper (I) iodide (0.614 g, 3.23 mmol), triphenylarsine (0.99 g, 3.23 mmol), dichlorobis(benzonitrile) palladium (II) was added ) (1.24 g, 3.23 mmol) and tetramethylstannane (14.4 g, 81 mmol). The resulting mixture was then stirred at 80°C under argon for 2 hours. The mixture was cooled and purified by silica column chromatography (0-70% EtOAc/PE). The isolated material was then dissolved in DCM (100 ml) and washed with water (60 ml x 4). The organic layer was concentrated under reduced pressure and the resulting residue was washed with 30:1 PE/EtOAc (40 ml) and then filtered to give (R)-4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-7 -yl)-2-methylcyclopent-2-enone in the form of a solid. MS: 248 (M+1).

Step 6: To a mixture of (R)-4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-methylcyclopent-2-enone (900 mg, 3.63 mmol) and NMO (851 mg, 7.27 mmol) in THF (90 ml), water (9.0 ml) and acetone (9.0 ml) was added dropwise osmium(VIII) oxide in H ₂ O (9.25 ml, 4 wt.%, 3.63 mmol) at room temperature (15°C) under argon. The reaction mixture was then stirred for 15 hours at room temperature. The reaction mixture was quenched with saturated sodium thiosulfate solution (60 ml) under argon and stirred for 20 minutes at 0°C. The resulting mixture was then diluted with EtOAc/H ₂ O (600 ml/200 ml). The organic layer was separated and washed with H ₂ O (200 ml) and brine (2 x 200 ml), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting crude material was purified by silica column chromatography (0-60% EtOAc/PE) to give (2S,3S,4R)-4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl )-2,3-dihydroxy-2-methylcyclopentanone in the form of a solid. MS: 282 (M+1).

Step 7: To a mixture of (2S,3S,4R)-4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,3-dihydroxy-2-methylcyclopentanone (500 mg, 1.78 mmol) and 4-methylbenzenesulfonic acid (61.1 mg, 0.355 mmol) in anhydrous acetone (25 ml) was added 2,2-dimethoxypropane (2.77 g, 26.6 mmol) dropwise at room temperature under atmosphere argon. The reaction mixture was stirred for 15 hours at 30°C. The reaction mixture was then quenched with saturated sodium bicarbonate solution (20 ml) at 0°C. The resulting mixture was diluted with EtOAc/H ₂ O (200 ml/30 ml) and the organic layer was separated, washed with brine (80 ml), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica column chromatography (0-25% EtOAc/PE) to give (3aS,6R,6aS)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl) -2,2,3a-trimethyldihydro-3aH-cyclopenta[d][1,3]dioxol-4(5H)-one in the form of a solid. MS: 322 (M+1).

Step 8: Cerium(III) chloride (2.45 g, 9.95 mmol) was suspended in THF (15 ml) and stirred for 0.5 h at room temperature under argon. Ethynyltrimethylsilane (977 mg, 9.95 mmol) in anhydrous THF (10 mL) was added to a second flame-dried round bottom flask. The TMS-acetylene solution and the flask containing CeCl ₃ were cooled to -78°C. n -BuLi (3.98 mL, 2.5 M in hexane, 9.95 mmol) was added dropwise to the TMS-acetylene solution via a syringe. Both mixtures were stirred for 20 minutes and then the lithium TMS acetylide solution was transferred through the cannula into the rapidly stirred CeCl ₃ suspension. The mixture was stirred for 0.5 h at -78°C. (3aS,6R,6aS)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2,3a-trimethyldihydro-3aH-cyclopenta[d][1,3 ]dioxol-4(5H)-one (400 mg, 1.243 mmol), dissolved in anhydrous THF (15 ml), was cooled to -78°C and transferred through a cannula into a flask containing cerium acetylide salt. The resulting mixture was stirred for 2 hours at -78°C. The reaction was quenched with saturated ammonium chloride solution (40 ml) at 0°C and diluted with EtOAc/H ₂ O (200 ml/80 ml). The organic layer was separated and washed with saturated sodium bicarbonate (100 ml) and brine (100 ml). The organic layer was then dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (0-18% EtOAc/PE) to give (3aS,4S,6R,6aS)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2 ,2,3a-trimethyl-4-((trimethylsilyl)ethynyl)tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-ol as a solid. MS: 420 (M+1).

Step 9: To a solution of (3aS,4S,6R,6aS)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2,3a-trimethyl-4-( (trimethylsilyl)ethynyl)tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-ol (220 mg, 0.524 mmol) in anhydrous THF (5 ml), cooled to 0°C, added dropwise TBAF (1 .05 ml, 1 M in THF, 1.048 mmol) under argon. The reaction mixture was stirred for 1 hour at 0°C. The solvent was then removed under reduced pressure. The resulting residue was purified by silica column chromatography (0-20% EtOAc/PE) to give (3aS,4S,6R,6aS)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-7- yl)-4-ethynyl-2,2,3a-trimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-ol as a solid. MS: 348 (M+1).

Step 10: (3aS,4S,6R,6aS)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-4-ethynyl-2,2,3a-trimethyltetrahydro-3aH -cyclopenta[d][1,3]dioxol-4-ol (170 mg, 0.489 mmol) was dissolved in NH ₃ (15 ml, 20% in i PrOH) at -70°C. The reaction mixture was stirred for 15 h at 90°C in a hermetically sealed tube. The solvent was then removed under reduced pressure. The resulting residue was purified by silica column chromatography (0-8% MeOH/DCM) to give (3aS,4S,6R,6aS)-6-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7- yl)-4-ethynyl-2,2,3a-trimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-ol as a solid. MS: 329 (M+1).

Step 11: Solution of (3aS,4S,6R,6aS)-6-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-4-ethynyl-2,2,3a-trimethyltetrahydro- 3aH-cyclopenta[d][1,3]dioxol-4-ol (150 mg, 0.457 mmol) in anhydrous MeOH (4 ml) was reduced under hydrogen using Lindlar catalyst (22.5 mg, 10.57 μmol). The reaction mixture was stirred for 2.5 hours at 30°C. The reaction mixture was then filtered through Celite and the filtrate was concentrated under reduced pressure. The resulting residue was purified by chiral HPLC (EtOH/hexane with 8 mM NH ₃ -MeOH modifier) to give (3aS,4S,6R,6aS)-6-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7 -yl)-2,2,3a-trimethyl-4-vinyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-ol as an oil. MS: 331 (M+1).

Step 12: Under argon (3aS,4S,6R,6aS)-6-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2,3a-trimethyl-4- vinyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-ol (70 mg, 0.212 mmol) was dissolved in a solution of 9-BBN (2.12 mL, 0.5 M in THF, 1.06 mmol) at room temperature and the mixture was stirred for 1 hour at 60°C. The reaction mixture was then cooled to 0°C and a solution of K ₃ PO ₄ (183 mg, 1.059 mmol) in H ₂ O (2 ml) was added. The mixture was stirred for 0.5 h at room temperature. Then a solution of 3-bromo-7-iodo-N-(4-methoxybenzyl)quinoline-2-amine (99 mg, 0.212 mmol) and Pd(dppf)Cl ₂ (26.0 mg, 0.032 mmol) in anhydrous THF (2.5 ml). The resulting mixture was microwaved at 70°C for 2 hours. The mixture was concentrated under reduced pressure and the resulting residue was dissolved in EtOAc (100 ml) and then washed with H ₂ O (30 ml) and brine (2 x 30 ml). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting crude mixture was purified by silica column chromatography (0-3% MeOH/DCM) to give (3aS,4S,6R,6aS)-6-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7 -yl)-4-(2-(3-bromo-2-((4-methoxybenzyl)amino)quinolin-7-yl)ethyl)-2,2,3a-trimethyltetrahydro-3aH-cyclopenta[d][1, 3]dioxol-4-ol in the form of a solid. MS: 673/675 (M+1/M+3).

Step 13: Under argon (3aS,4S,6R,6aS)-6-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-4-(2-(3-bromo- 2-((4-methoxybenzyl)amino)quinolin-7-yl)ethyl)-2,2,3a-trimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-ol (100 mg, 0.148 mmol) dissolved in TFA (3.0 ml, 38.9 mmol) at room temperature. The reaction mixture was stirred for 4 hours at 60°C. The mixture was then evaporated under reduced pressure. The resulting residue was co-evaporated with toluene (3 × 90 ml). This residue was then purified by reverse phase column chromatography (ACN/water). The product was further purified by reverse phase HPLC (ACN/water with 10 mM NH ₄ HCO ₃ modifier) to give (1R,2S,3S,4R)-1-(2-(2-amino-3-bromoquinolin-7-yl) ethyl)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-methylcyclopentane-1,2,3-triol as a solid. MS: 513/515 (M+1/M+3). ¹ H-NMR (400 MHz, DMSO-d ₆ +10% D ₂ O) δ 8.66 (s, 1H), 8.36 (s, 1H), 7.75 (d, J=8.4 Hz , 1H), 7.62 (d, J=3.6 Hz, 1H), 7.50 (s, 1H), 7.33 (d, J=8.0 Hz, 1H), 7.00-6 .97 (m, 1H), 5.06 (dd, J=9.6, 18.4Hz, 1H), 4.06 (d, J=8.8 Hz, 1H), 2.96-2.77 (m, 2H), 2.23-2.12 (m, 2H), 1.98-1.81 (m, 2H), 1.38 (s, 3H).

Example 119

(1S,2R,3aR,4S,6aR)-4-((2-amino-3-bromoquinolin-7-yl)oxy)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)hexahydropentalene-1,6a(1H)-diol 2,2,2-trifluoroacetate

Step 1: In an oven-dried and argon-purged vessel with (3aS,4R,5aR,6S,8aR)-4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2, 2-dimethylhexahydro-5H-pentaleno[1,6a-d][1,3]dioxol-6-ol (141.4 mg, 0.404 mmol) was added with 3-bromo-7-iodo-N-(4-methoxybenzyl)quinoline -2-amine (379 mg, 0.808 mmol), 1,10-phenanthroline (29.1 mg, 0.162 mmol), copper iodide (15.40 mg, 0.081 mmol) and cesium carbonate (395 mg, 1.213 mmol). The solids were dissolved in xylene (4 ml) and the reaction mixture was heated to 140°C for 18 hours under argon. The reaction mixture was then slowly cooled to room temperature. The reaction mixture was filtered through Celite and then concentrated under reduced pressure. The residue was purified by silica column chromatography (20-35-80% EtOAc/hexane) to give 3-bromo-7-(((3aS,4R,5aR,6S,8aR)-4-(4-chloro-7H-pyrrolo [2,3-d]pyrimidin-7-yl)-2,2-dimethylhexahydro-3aH-pentaleno[1,6a-d][1,3]dioxol-6-yl)oxy)-N-(4-methoxybenzyl) )quinoline-2-amine in the form of a solid. MS: 690/692 (M+1/M+3).

Step 2: Into a vessel with 3-bromo-7-(((3aS,4R,5aR,6S,8aR)-4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)- 2,2-dimethylhexahydro-3aH-pentaleno[1,6a-d][1,3]dioxol-6-yl)oxy)-N-(4-methoxybenzyl)quinolin-2-amine (37.4 mg, 0.054 mmol ) ammonia (3.5 mL, 24.50 mmol, 7N in MeOH) was added. The reaction mixture was heated in a microwave oven at 140°C for 5 hours. The reaction mixture was then concentrated under reduced pressure to obtain crude 7-(((3aS,4R,5aR,6S,8aR)-4-(4-amino-7H- pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethylhexahydro-3aH-pentaleno[1,6a-d][1,3]dioxol-6-yl)oxy)-3-bromo-N -(4-methoxybenzyl)quinolin-2-amine was directly used in the next step.

Step 3: Into a vessel containing crude 7-(((3aS,4R,5aR,6S,8aR)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2, 2-dimethylhexahydro-3aH-pentaleno[1,6a-d][1,3]dioxol-6-yl)oxy)-3-bromo-N-(4-methoxybenzyl)quinolin-2-amine (25 mg, 0.037 mmol ), DCM (0.5 mL) was added followed by TFA (0.4 mL, 5.19 mmol). The reaction mixture was stirred at 40°C for 75 minutes. Water (0.1 ml) was then added along with additional DCM (0.1 ml) and the reaction mixture was stirred at 40°C for a total of 2.5 hours. DCM (0.2 ml), TFA was then added again (0.3 ml) and water (0.1 ml) and the reaction mixture was heated to 40°C for an additional 2 hours. Finally, anisole (100 μl, 0.915 mmol) was added and the reaction mixture was stirred at 40°C for 1 h. The reaction mixture was concentrated under reduced pressure, dissolved in DMSO, filtered and subjected to mass initiated reverse phase HPLC (MeCN/water with 0.1% TFA modifier) to give (1S,2R,3aR,4S,6aR)- 4-((2-amino-3-bromoquinolin-7-yl)oxy)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)octahydropentalene-1,6a-diol, TFA salts, in solid form. MS: 511/513 (M+1/M+3). ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 8.72 (s, 1H), 8.37 (s, 1H), 7.82 (d, J=3.6 Hz, 1H), 7.78 (d, J=8.9 Hz, 1H), 7.07 (dd, J=8.9, 2.0 Hz, 1H), 6.98-6.94 (m, 2H), 4.96- 4.89 (m, 1H), 4.56 (d, J=4.2 Hz, 1H), 4.05 (d, J=10.5 Hz, 1H), 2.58-2.52 (m , 1H), 2.36-2.27 (m, 2H), 2.09-2.03 (m, 1H), 1.98-1.87 (m, 2H), 1.75-1.67 (m, 1H).

Example 120

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-fluoroquinolin-7-yl)amino)-2-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol

Step 1: To a mixture of (3aR,4R,5aR,6R,8aR)-2,2-dimethyl-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)hexahydrocyclopent[2, 3]furo[3,4-d][1,3]dioxol-6-ol (200 mg, 0.604 mmol) and triphenylphosphine (317 mg, 1.21 mmol) in toluene (2.5 ml) was added isoindoline-1 ,3-dione (178 mg, 1.21 mmol) at room temperature. The mixture was then cooled to 0°C and DIAD (0.235 mL, 1.21 mmol) was added dropwise. The resulting mixture was stirred for 1.5 hours at 80°C. The reaction mixture was then concentrated under reduced pressure and the resulting residue was purified by preparative TLC (1:1 EtOAc:PE) to give 2-((3aR,4R,5aR,6S,8aR)-2,2-dimethyl-4-(4-methyl -7H-pyrrolo[2,3-d]pyrimidin-7-yl)hexahydrocyclopenta[2,3]furo[3,4-d][1,3]dioxol-6-yl)isoindolin-1,3-dione in form of a solid. MS: 461 (M+1).

Step 2: To a stirred solution of 2-((3aR,4R,5aR,6S,8aR)-2,2-dimethyl-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl) hexahydrocyclopent[2,3]furo[3,4-d][1,3]dioxol-6-yl)isoindoline-1,3-dione (220 mg, 0.478 mmol) in MeOH (1.5 ml) added hydrazine hydrate (598 mg, 9.56 mmol). The resulting solution was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the resulting solid was suspended in DCM (30 ml). The mixture was filtered and the filtrate was concentrated under reduced pressure to give (3aR,4R,5aR,6S,8aR)-2,2-dimethyl-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl )hexahydrocyclopent[2,3]furo[3,4-d][1,3]dioxol-6-amine in the form of an oil. MS: 331 (M+1).

Step 3: To a stirred solution of (3aR,4R,5aR,6S,8aR)-2,2-dimethyl-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)hexahydrocyclopent[2 ,3]furo[3,4-d][1,3]dioxol-6-amine (40 mg, 0.097 mmol) and 7-bromo-N-(2,4-dimethoxybenzyl)-3-fluoroquinolin-2-amine (41.7 mg, 0.107 mmol) in THF (0.5 ml) was added Xantphos Pd G3 (4.59 mg, 4.84 µmol) and sodium 2-methylpropan-2-olate (27.9 mg, 0.291 mmol) . The resulting mixture was stirred at 50°C for 16 hours. The reaction was quenched with saturated aqueous ammonium chloride (25 ml) and extracted with EtOAc (3 x 40 ml). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by preparative TLC (2:1 EtOAc:PE) to give N2-(2,4-dimethoxybenzyl)-N7-((3aR,4R,5aR,6S,8aR)-2,2-dimethyl -4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)hexahydrocyclopenta[2,3]furo[3,4-d][1,3]dioxol-6-yl)- 3-fluoroquinoline-2,7-diamine in the form of a solid. MS: 641 (M+1).

Step 4: N2-(2,4-dimethoxybenzyl)-N7-((3aR,4R,5aR,6S,8aR)-2,2-dimethyl-4-(4-methyl-7H-pyrrolo[2,3-d ]pyrimidin-7-yl)hexahydrocyclopenta[2,3]furo[3,4-d][1,3]dioxol-6-yl)-3-fluoroquinolin-2,7-diamine (58 mg, 0.091 mmol) was dissolved in TFA (2 ml, 26.0 mmol). The resulting solution was stirred at 50°C overnight. The reaction mixture was then co-evaporated with toluene (2 x 5 ml) under reduced pressure. The resulting residue was purified by reverse phase column chromatography (ACN/water with 5 mM NH ₄ HCO ₃ modifier). The product was further purified by preparative TLC (10:1 DCM/MeOH) followed by reverse phase column chromatography (ACN/water with 5 mM NH ₄ HCO ₃ modifier) to give (2R,3R,3aS,6S,6aR)-6-( (2-amino-3-fluoroquinolin-7-yl)amino)-2-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)hexahydro-2H-cyclopenta[b]furan-3 ,3a-diol as a solid. MS: 451 (M+1). ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 8.69 (s, 1H), 7.92 (d, J=3.6 Hz, 1H), 7.53 (d, J=12.0 Hz, 1H), 7.32 (d, J=8.7 Hz, 1H), 6.83 (d, J=3.6 Hz, 1H), 6.69 (d, J=7.8 Hz, 1H), 6.42-6.36 (m, 3H), 6.8 (d, J=4.5 Hz, 1H), 6.11 (d, J=8.1 Hz, 1H), 5, 38 (d, J=7.2 Hz, 1H), 5.23 (s, 1H), 4.42 (d, J=7.8 Hz, 1H), 3.96 (s, 1H), 3, 55-3.53 (m, 1H), 2.69 (s, 3H), 2.50-2.49 (m, 1H), 2.07-2.02 (m, 2H), 1.94- 1.90 (m, 1H).

Example 121

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-fluoroquinolin-7-yl)methyl)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)-6a-methylhexahydro-3aH-cyclopenta[b]furan-3,3a-diol

Step 1: To a solution of (S)-2-methyl-CBS-oxazaborolidine (1.788 g, 6.45 mmol) in THF (31 ml) was added borane-THF complex (6.45 ml, 1M in THF, 6.45 mmol ) drop by drop at 0°C. The reaction mixture was stirred for 30 minutes at 0°C. A solution of 2-methylcyclopent-2-enone (3.1 g, 32.2 mmol) in THF (25 ml) and borane-THF complex (22.57 ml, 1M in THF, 22.57 mmol) were added dropwise at the same time 0°C. The reaction mixture was slowly warmed to room temperature and stirred for 1.5 hours. The reaction mixture was carefully quenched by adding 180 ml of water at 0°C. The mixture was stirred for 0.5 h at room temperature and then extracted with DCM (200 ml). The organic extract was washed with saturated aqueous ammonium chloride (100 ml) and saturated brine (100 ml), dried with anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain (R)-2-methylcyclopent-2-enol as an oil. which was used in the next step without further purification.

Step 2: To a stirred solution of (R)-2-methylcyclopent-2-enol (1 g, 10.19 mmol) in DCM (10 ml) was added DMAP (1.867 g, 15.28 mmol) and triethylamine (1.562 ml, 11 .21 mmol) at 0°C in an argon atmosphere. Acetic anhydride (2.08 g, 20.4 mmol) was then added slowly. The mixture was stirred at 0°C for 1 hour. The mixture was quenched with H ₂ O (50 ml) and extracted with DCM (60 ml x 2). The combined organic layers were washed with brine (40 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica column chromatography (0-15% EtOAc/PE) to give (R)-2-methylcyclopent-2-en-1-yl acetate as an oil. A solution of (R)-2-methylcyclopent-2-en-1-yl acetate (700 mg, 4.99 mmol) in THF (8 mL) was then added to lithium diisopropylamide (3.99 mL, 2 M in THF/heptane, 7. 99 mmol) at -78°C for 3 minutes. A solution of tert- butylchlorodimethylsilane (1.43 g, 9.49 mmol) in THF (2 ml) was then added and the mixture was stirred at -78°C for 20 minutes. The reaction mixture was warmed to room temperature and stirred for an additional 2 hours. The solution was then refluxed overnight, cooled to 0°C and treated with concentrated HCl (2 ml). The mixture was stirred at 0°C for 1 hour. The reaction mixture was then partitioned between diethyl ether (40 ml) and water (20 ml). The aqueous layer was extracted with diethyl ether (30 ml). The combined organic layers were dried with anhydrous sodium sulfate and filtered. The filtrate was then concentrated under reduced pressure and the residue was purified by silica column chromatography (0-30% EtOAc/PE) to give (R)-2-(2-methylcyclopent-2-en-1-yl)acetic acid as an oil. ^1H NMR (400 MHz, DMSO- _d6 ) δ 12.04 (s, 1H), 5.36-5.34 (m, 1H), 5.26 (s, 1H), 2.77-2, 75 (m, 1H), 2.46-2.41 (m, 1H), 2.30-1.91 (m, 3H), 1.64 (s, 3H), 1.51-1.46 ( m, 1H).

Step 3: To a solution of (R)-2-(2-methylcyclopent-2-en-1-yl)acetic acid (10 g, 71.3 mmol) in tert- butyl alcohol (100 ml) was added tetraoxotungsten(X) hydride (1.78 g, 7.13 mmol) and hydrogen peroxide (18.2 ml, 30% in water, 178 mmol). The resulting suspension was stirred at 80°C for 30 minutes and then the reaction mixture was cooled to 0°C, then quenched with saturated aqueous sodium thiosulfate (100 ml). The mixture was stirred for 1 hour at room temperature and diluted with EtOAc (200 ml). The organic phases were separated and the aqueous layer was extracted with EtOAc (4 x 100 ml). The combined organic phases were washed with brine (100 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography (0-60% EtOAc/PE) to give (3aR,6S,6aS)-6-hydroxy-6a-methylhexahydro-2H-cyclopenta[b]furan-2-one as an oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 5.09 (d, J=4.4 Hz, 1H), 3.89-3.86 (m, 1H), 3.03-2.87 ( m, 1H), 2.46-2.41 (m, 1H), 2.29-2.29 (m, 1H), 2.11-1.99 (m, 1H), 1.83-1. 72 (m, 1H), 1.59-1.48 (m, 1H), 1.40-1.23 (m, 4H).

Step 4: To a stirred solution of (3aR,6S,6aS)-6-hydroxy-6a-methylhexahydro-2H-cyclopenta[b]furan-2-one (6 g, 38.4 mmol) in DMF (40 ml) was added 1H -imidazole (7.85 g, 115 mmol) and tert- butylchlorodiphenylsilane (12.7 g, 46.1 mmol) at 0°C under argon. The resulting mixture was stirred at 25°C for 16 hours. The reaction mixture was then quenched with saturated aqueous Na ₂ CO ₃ (100 ml) and extracted with EtOAc (200 ml x 2). The combined organic layers were washed with water (2 x 100 ml), then brine (100 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica column chromatography (0-15% EtOAc/PE) to give (3aR,6S,6aS)-6-((tert-butyldiphenylsilyl)oxy)-6a-methylhexahydro-2H- cyclopenta[b]furan-2-one in oil form. MS: 395 (M+1). ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 7.65-7.60 (m, 4H), 7.56-7.37 (m, 6H), 4.11 (t, J=5, 6 Hz, 1H), 2.97-2.88 (m, 1H), 2.57-2.51 (m, 1H), 2.28-2.23 (m, 1H), 2.05-1 .96 (m, 1H), 1.61-1.48 (m, 1H), 1.46-1.39 (m, 4H), 1.32-1.19 (m, 1H), 1.04 (s, 9H).

Step 5: To a solution of (3aR,6S,6aS)-6-((tert-butyldiphenylsilyl)oxy)-6a-methylhexahydro-2H-cyclopenta[b]furan-2-one (13 g, 32.9 mmol) in THF (40 ml) chlorotrimethylsilane (17.9 g, 165 mmol) was added at -78°C. Lithium bis(trimethylsilyl)amide (49.4 mL, 1M in THF, 49.4 mmol) was added dropwise over 5 minutes. The resulting mixture was stirred at -78°C for 30 minutes. A solution of phenyl hypochloroselenoite (7.57 g, 39.5 mmol) in THF (15 ml) was added to the reaction mixture and the mixture was stirred at -78°C for 2 hours. The reaction mixture was then quenched with saturated aqueous ammonium chloride (100 ml) and extracted with EtOAc (150 ml x 3). The combined organic layers were washed with brine (100 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain crude (3R,3aS,6S,6aS)-6-((tert-butyldiphenylsilyl)oxy)-6a-methyl-3-(phenylselanyl)hexahydro-2H-cyclopenta[b]furan-2- it is in the form of oil, which was used directly in the next stage.

Step 6: To a solution of crude (3R,3aS,6S,6aS)-6-((tert-butyldiphenylsilyl)oxy)-6a-methyl-3-(phenylselanyl)hexahydro-2H-cyclopenta[b]furan-2-one ( 18.08 g, 32.9 mmol) in DCM (250 ml) was added hydrogen peroxide (18.7 g, 30% in water, 165 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The mixture was then concentrated under reduced pressure and the resulting residue was purified by silica column chromatography (1-20% EtOAc/PE) to give (6S,6aS)-6-((tert-butyldiphenylsilyl )oxy)-6a-methyl-4,5,6,6a-tetrahydro-2H-cyclopenta[b]furan-2-one in the form of an oil. MS: 410 (M+NH ₄ ). ^1H NMR (400 MHz, DMSO- _d6 ) δ 7.64-7.59 (m, 4H), 7.52-7.39 (m, 6H), 5.82-5.81 (m, 1H ), 3.85 (t, J=8.8 Hz, 1H), 2.86-2.67 (m, 1H), 2.44-2.30 (m, 1H), 2.11-2, 01 (m, 1H), 1.97-1.84 (m, 1H), 1.52 (s, 3H), 1.05 (s, 9H).

Step 7: Solution of (6S,6aS)-6-((tert-butyldiphenylsilyl)oxy)-6a-methyl-4,5,6,6a-tetrahydro-2H-cyclopenta[b]furan-2-one (8 g, 20.4 mmol) in MeCN (20 ml) was suspended in a solution of 2-hydroxypropane-1,2,3-tricarboxylic acid (7.83 g, 40.8 mmol) in water (15 ml). Potassium osmate(VI) dihydrate (0.375 g, 1.02 mmol) was then added followed by 4-methylmorpholine N -oxide (4.77 mL, 50 wt% in water, 22.4 mmol). The reaction mixture was stirred at room temperature for 16 hours. Water (100 ml) was then added to the reaction mixture and the mixture was extracted with EtOAc (150 ml x 3). The combined organic layers were washed with brine (100 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica column chromatography (1-50% EtOAc/PE) to give (3R,3aS,6S,6aR)-6-((tert-butyldiphenylsilyl)oxy)-3,3a- dihydroxy-6a-methylhexahydro-2H-cyclopenta[b]furan-2-one as an oil. MS: 444 (M+NH ₄ ). ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 7.66-7.61 (m, 4H), 7.52-7.41 (m, 6H), 5.99 (d, J=7, 2 Hz, 1H), 5.22 (s, 1H), 4.23 (t, J=7.5 Hz, 1H), 4.07 (d, J=7.2 Hz, 1H), 1.87 -1.68 (m, 2H), 1.65-1.51 (m, 2H), 1.35 (s, 3H), 1.05 (s, 9H).

Step 8: To a stirred solution of (3R,3aS,6S,6aR)-6-((tert-butyldiphenylsilyl)oxy)-3,3a-dihydroxy-6a-methylhexahydro-2H-cyclopenta[b]furan-2-one (7 g, 16.4 mmol) and chlorobis(cyclooctene)iridium(I) dimer (0.147 g, 0.164 mmol) in DCM (13 ml), diethylsilane (2.17 g, 24.6 mmol) was added dropwise under argon at room temperature temperature. The resulting solution was stirred at room temperature for 2 hours. Solid tetrabutylammonium fluoride trihydrate (5.18 g, 16.4 mmol) was then added to the reaction mixture. The mixture was stirred at room temperature for 16 hours. The reaction mixture was then quenched with saturated aqueous sodium bicarbonate (100 ml) and extracted with DCM (3 x 100 ml). The combined organic layers were washed with brine (100 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica column chromatography (1-50% EtOAc/PE) to give (3R,3aS,6S,6aR)-6-((tert-butyldiphenylsilyl)oxy)-6a-methylhexahydro- 2H-cyclopenta[b]furan-2,3,3a-triol as an oil. MS: 446 (M+NH ₄ ).

Step 9: To a stirred solution of (3R,3aS,6S,6aR)-6-((tert-butyldiphenylsilyl)oxy)-6a-methylhexahydro-2H-cyclopenta[b]furan-2,3,3a-triol (5,5 g, 12.8 mmol) in anhydrous MeCN (260 ml) under argon was added (E)-diazen-1,2-diylbis(piperidin-1-ylmethanone) (4.86 g, 19.3 mmol) at 0° C followed by the addition of tributylphosphine (5.13 mL, 20.5 mmol) at 0°C. The resulting mixture was stirred at 35°C for approximately 1 hour. Separately, to a stirred solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (3.74 g, 24.4 mmol) in anhydrous MeCN (25 ml ) DBU (3.48 mL, 23.1 mmol) was added under argon at room temperature. The solution was stirred at room temperature for 30 minutes and then this solution was transferred into the reaction mixture initially containing the triol using a syringe and the resulting reaction mixture was stirred at 35°C for 1 hour. The reaction mixture was quenched with saturated aqueous ammonium chloride (100 ml ) and extracted with EtOAc (3 x 200 ml). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by reverse phase column chromatography (ACN/water with 5 mM NH ₄ HCO ₃ modifier) to give (2R,3R,3aS,6S,6aR)-6-((tert-butyldiphenylsilyl)oxy) -2-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-6a-methylhexahydro-2H-cyclopenta[b]furan-3,3a-diol as a solid. MS: 564 (M+1).

Step 10: To a solution of (2R,3R,3aS,6S,6aR)-6-((tert-butyldiphenylsilyl)oxy)-2-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl )-6a-methylhexahydro-2H-cyclopenta[b]furan-3,3a-diol (4 g, 7.09 mmol) in acetone (40 ml) was added 4-methylbenzenesulfonic acid (0.122 g, 0.709 mmol) and 2.2 -dimethoxypropane (7.38 g, 70.9 mmol) at ambient temperature under argon. The mixture was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure and the resulting residue was purified by silica column chromatography (0-20% EtOAc/PE) to give 7-((3aR,4R,5aR,6S,8aS)- 6-((tert-butyldiphenylsilyl)oxy)-2,2,5a-trimethylhexahydrocyclopenta[2,3]furo[3,4-d][1,3]dioxol-4-yl)-4-chloro-7H-pyrrolo [2,3-d]pyrimidine as a solid. MS: 604 (M+1).

Step 11: To a solution of 7-((3aR,4R,5aR,6S,8aS)-6-((tert-butyldiphenylsilyl)oxy)-2,2,5a-trimethylhexahydrocyclopenta[2,3]furo[3,4-d ][1,3]dioxol-4-yl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (3.8 g, 6.29 mmol) in THF (20 ml) under argon was added fluoride tetrabutylammonium (12.6 ml, 1M in THF, 12.6 mmol) at 0°C. The reaction mixture was then stirred at room temperature for 16 hours and concentrated under reduced pressure. The resulting residue was purified by silica column chromatography (0-50% EtOAc/PE). The product was further purified by preparative SFC (CHIRALPAK IF, 40% 8 mM NH ₃ in MeOH in CO ₂ ) to give (3aR,4R,5aR,6S,8aS)-4-(4-chloro-7H-pyrrolo[2,3- d]pyrimidin-7-yl)-2,2,5a-trimethylhexahydrocyclopenta[2,3]furo[3,4-d][1,3]dioxol-6-ol as a solid. MS: 366 (M+1).

Step 12: Dess-Martin periodinane (696 mg, 1.640 mmol) was added portionwise to the stirred solution of (3aR,4R,5aR,6S,8aS)-4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidine -7-yl)-2,2,5a-trimethylhexahydrocyclopenta[2,3]furo[3,4-d][1,3]dioxol-6-ol (400 mg, 1.093 mmol) in DCM (15 ml) at 0°C. The reaction mixture was then stirred at room temperature for 2 hours. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (100 ml) and extracted with EtOAc (100 ml x 3). The combined organic layers were washed with brine (100 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica column chromatography (1-30% EtOAc/PE) to give (3aR,4R,5aS,8aS)-4-(4-chloro-7H-pyrrolo[2,3- d]pyrimidin-7-yl)-2,2,5a-trimethyltetrahydrocyclopenta[2,3]furo[3,4-d][1,3]dioxol-6(5aH)-one in the form of a solid. MS: 364 (M+1).

Step 13: To a mixture of Nysted's reagent (4.51 g, 20% in THF, 1.98 mmol) in anhydrous THF (20 ml) was added TiCl ₄ (1.98 ml, 1M in DCM, 1.98 mmol) dropwise at 0°C in an argon atmosphere. The mixture was stirred at 0°C for 5 minutes. Then a solution of (3aR,4R,5aS,8aS)-4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2,5a-trimethyltetrahydrocyclopenta[2,3]furo was added [3,4-d][1,3]dioxol-6(5aH)-one (360 mg, 0.990 mmol) in anhydrous THF (10 ml) at 0°C. The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was then quenched with saturated sodium bicarbonate solution (100 ml) at 0°C. The resulting mixture was diluted with EtOAc (100 ml) at room temperature and extracted, and the aqueous layer was then extracted again with EtOAc (100 ml x 2). The combined organic layers were washed with H ₂ O (80 ml) and brine (80 ml), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica column chromatography (1-20% EtOAc/PE) to give 4-chloro-7-((3aR,4R,5aR,8aS)-2,2,5a-trimethyl-6-methylenehexahydrocyclopent[2, 3]furo[3,4-d][1,3]dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine in the form of a solid. MS: 362 (M+1).

Step 14: To a mixture of 4-chloro-7-((3aR,4R,5aR,8aS)-2,2,5a-trimethyl-6-methylenehexahydrocyclopenta[2,3]furo[3,4-d][1,3 ]dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine (240 mg, 0.663 mmol) in 1,4-dioxane (8 ml) was added ammonia hydrate (8 ml, 28% wt., 0.663 mmol ) at room temperature. The reaction mixture was then stirred at 90°C for 15 h in a sealed tube. The solvent was removed under reduced pressure and the resulting residue was purified by silica column chromatography (1-10% MeOH/DCM) to give 7-((3aR,4R,5aR,8aS)-2,2,5a-trimethyl-6-methylenehexahydrocyclopenta[ 2,3]furo[3,4-d][1,3]dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine as a solid. MS: 343 (M+1).

Step 15: 7-((3aR,4R,5aR,8aS)-2,2,5a-trimethyl-6-methylenehexahydrocyclopenta[2,3]furo[3,4-d][1,3]dioxol-4-yl )-7H-pyrrolo[2,3-d]pyrimidin-4-amine (200 mg, 0.584 mmol) was co-evaporated with THF (3 ml) three times. A solution of 9-BBN (5.84 mL, 0.5 M in THF, 2.92 mmol) was then added at room temperature under argon. The reaction solution was stirred at 60°C for 1 hour. A solution of potassium phosphate (620 mg, 2.92 mmol) in water (2.9 ml) was added dropwise at 0°C under argon. The reaction solution was stirred at room temperature for 0.5 h. Then 7-bromo-3-fluoroquinoline-2-amine (148 mg, 0.613 mmol) in THF (2.9 ml) and [1,1'-bis( diphenylphosphino)ferrocene]dichloropalladium(II) (42.7 mg, 0.058 mmol) at room temperature. The reaction mixture was microwaved at 80°C for 2.5 hours. The reaction mixture was then cooled to room temperature, diluted with water (20 ml) and extracted with EtOAc (3 x 50 ml). The combined organic layers were concentrated under reduced pressure and the resulting residue was purified by reverse phase HPLC (ACN/water with 5 mM NH ₄ HCO ₃ modifier) to give 7-(((3aR,4R,5aR,6S,8aS)-4-(4 -amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2,5a-trimethylhexahydrocyclopenta[2,3]furo[3,4-d][1,3]dioxol-6-yl )methyl)-3-fluoroquinoline-2-amine in the form of a solid. MS: 505 (M+1).

Step 16: Into a 40 ml vial containing a solution of 7-(((3aR,4R,5aR,6S,8aS)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl) -2,2,5a-trimethylhexahydrocyclopenta[2,3]furo[3,4-d][1,3]dioxol-6-yl)methyl)-3-fluoroquinolin-2-amine (130 mg, 0.258 mmol) in DCM (5 ml), water (1.2 ml) was added followed by TFA (4 ml, 51.9 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was then concentrated under reduced pressure. The residue was dissolved in DMSO/NH ₄ OH, filtered and subjected to mass initiated reverse phase HPLC (ACN/water with 0.1% NH ₄ OH modifier) to give (2R,3R,3aS,6S,6aR)-6- ((2-amino-3-fluoroquinolin-7-yl)methyl)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-6a-methylhexahydro-3aH-cyclopenta[b ]furan-3,3a-diol in the form of a solid. MS: 465 (M+1). ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 8.09 (s, 1H), 7.74 (d, J=11.8 Hz, 1H), 7.54 (d, J=8.2 Hz , 1H), 7.44 (d, J=3.7 Hz, 1H), 7.28 (s, 1H), 7.07 (d, J=8.5 Hz, 1H), 7.04 (s , 2H), 6.69-6.63 (m, 3H), 5.85 (d, J=8.2 Hz, 1H), 5.34 (d, J=7.0 Hz, 1H), 4 .84 (s, 1H), 4.15 (t, J=7.6 Hz, 1H), 2.84 (dd, J=13.5, 4.8 Hz, 1H), 2.57-2, 51 (m, 1H), 1.89 (dd, J=11.7, 5.5 Hz, 1H), 1.87-1.80 (m, 1H), 1.64-1.55 (m, 1H), 1.52-1.40 (m, 2H), 1.17 (s, 3H).

Example 122

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-chloroquinolin-7-yl)methyl)-2-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol

Step 1: To a solution of (3aR,5aR,8aR)-4-methoxy-2,2-dimethyl-6-methylenehexahydrocyclopenta[2,3]furo[3,4-d][1,3]dioxole (123 mg, 0.544 mmol) in anhydrous THF (2 mL), a solution of 9-BBN (5.44 mL, 0.5 M in THF, 2.72 mmol) was added dropwise at 0°C under argon. The reaction mixture was then stirred at 52°C for 1 hour. The reaction mixture was cooled to room temperature. A solution of tribasic potassium phosphate (576 mg, 2.71 mmol) in water (0.2 ml) was added dropwise to the reaction mixture at 0°C under argon. The reaction mixture was stirred at room temperature for 0.5 h. 7-Bromo-3-chloroquinoline-2-amine (140 mg, 0.543 mmol) in THF (0.3 ml) and 1,1'-bis(diphenylphosphino) complex were added )ferrocene-palladium(II) dichloride with dichloromethane (44.3 mg, 0.054 mmol) at room temperature. The reaction mixture was microwaved at 70°C for 2 hours. The reaction mixture was then cooled to room temperature, diluted with water (15 ml) and extracted with EtOAc (2 x 20 ml). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by preparative TLC (eluting with 20% EtOAc/PE) to give 3-chloro-7-(((3aR,4S,5aR,8aR)-4-methoxy-2,2-dimethylhexahydrocyclopenta[ 2,3]furo[3,4-d][1,3]dioxol-6-yl)methyl)quinolin-2-amine as a solid. MS: 405 (M+1).

Step 2: To a solution of 3-chloro-7-(((3aR,4S,5aR,8aR)-4-methoxy-2,2-dimethylhexahydrocyclopenta[2,3]furo[3,4-d][1,3] Dioxol-6-yl)methyl)quinolin-2-amine (100 mg, 0.247 mmol) in water (6 mL) and acetonitrile (9 mL) were added with concentrated HCl (0.5 mL, 6.00 mmol) at room temperature. The solution was stirred at 90°C for 1 hour. The reaction solution was cooled to 0°C and then sodium bicarbonate (500 mg) was added portionwise. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica column chromatography (0-10% MeOH/DCM) to give (3R,3aS,6aR)-6-((2-amino-3-chloroquinolin-7-yl)methyl)hexahydro-2H-cyclopenta[ b]furan-2,3,3a-triol as a solid. MS: 351 (M+1).

Step 3: To a stirred solution of (3R,3aS,6aR)-6-((2-amino-3-chloroquinolin-7-yl)methyl)hexahydro-2H-cyclopenta[b]furan-2,3,3a-triol ( 60 mg, 0.171 mmol) in anhydrous MeCN (1 ml) under argon, (E)-diazen-1,2-diylbis(piperidin-1-ylmethanone) (64.7 mg, 0.257 mmol) was added dropwise to MeCN (0 .5 ml) at 0°C. Tributylphosphine (0.068 ml, 0.274 mmol) in MeCN (0.5 ml) was then added dropwise at 0°C. The resulting solution was stirred at 30°C for ~1 hour. Separately, to a stirred solution of 4-methyl-7H-pyrrolo[2,3-d]pyrimidine (43.3 mg, 0.325 mmol) in anhydrous DMF (1 ml) was added NaH (12.31 mg, 60% in mineral oil, 0.308 mmol) at room temperature. The suspension was stirred at room temperature for 30 minutes, then the suspension was transferred into the solution initially containing the triol through a syringe. The resulting reaction mixture was stirred at room temperature for 1 hour. The reaction was quenched with water (10 ml) and extracted with EtOAc (2 x 10 ml). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (ACN/water with 10 mM NH ₄ HCO ₃ modifier) to give (2R,3R,3aS,6S,6aR)-6-((2-amino-3-chloroquinolin-7-yl) methyl)-2-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)hexahydro-2H-cyclopenta[b]furan-3,3a-diol as a solid. MS: 466 (M+1). ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.69 (s, 1H), 8.12 (s, 1H), 7.88 (d, J=3.6 Hz, 1H), 7, 54 (d, J=8.0 Hz, 1H), 7.28 (s, 1H), 7.08 (dd, J=8.4, 1.6 Hz, 1H), 6.82 (d, J =3.6 Hz, 1H), 6.64 (br.s, 2H), 6.00 (d, J=8.4 Hz, 1H), 5.31 (d, J=6.8 Hz, 1H ), 5.12 (s, 1H), 4.22 (t, J=8.0 Hz, 1H), 4.00 (d, J=6.0 Hz, 1H), 2.85-2.79 (m, 1H), 2.69 (s, 3H), 2.65-2.60 (m, 1H), 2.33-2.25 (m, 1H), 1.98-1.93 (m , 1H), 1.80-1.67 (m, 2H), 1.58-1.51 (m, 1H).

Example 123

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-fluoroquinolin-7-yl)methyl)-2-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol

Step 1: To a solution of (3aR,5aR,8aR)-4-methoxy-2,2-dimethyl-6-methylenehexahydrocyclopenta[2,3]furo[3,4-d][1,3]dioxole (245 mg, 1 .08 mmol) in anhydrous THF (2.5 mL), a solution of 9-BBN (8.66 mL, 0.5 M in THF, 4.33 mmol) was added dropwise at 0°C under argon. The reaction solution was stirred at 55°C for 1 hour. To this reaction solution was added a solution of K ₃ PO ₄ (1.15 g, 5.40 mmol) in water (2 ml) at 0° C. under an argon atmosphere. The reaction mixture was stirred at room temperature for 0.5 h. Then a solution of 7-bromo-3-fluoroquinoline-2-amine (273 mg, 1.13 mmol) in THF (2 ml) and Pd(dppf)Cl ₂ ( 119 mg, 0.162 mmol) at room temperature. The reaction mixture was stirred at 75°C for 1.5 hours. The reaction mixture was then concentrated under reduced pressure and the residue was purified by preparative TLC (2:1 EtOAc/PE) to give 3-fluoro-7-(((3aR,4S,5aR ,8aR)-4-methoxy-2,2-dimethylhexahydrocyclopenta[2,3]furo[3,4-d][1,3]dioxol-6-yl)methyl)quinolin-2-amine in the form of a solid. MS: 389 (M+1).

Step 2: Solution of 3-fluoro-7-(((3aR,4S,5aR,8aR)-4-methoxy-2,2-dimethylhexahydrocyclopenta[2,3]furo[3,4-d][1,3]dioxol -6-yl)methyl)quinolin-2-amine (300 mg, 0.772 mmol) in 0.4 M aqueous HCl in MeCN/H ₂ O (3:2) (6 ml, 2,400 mmol) was stirred at 90°C for 1 hour. The reaction solution was then cooled to 0°C and quenched with saturated aqueous Na ₂ CO ₃ (60 ml) and extracted with EtOAc (100 ml x 3). The combined organic layers were washed with brine (60 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica column chromatography (0-10% MeOH/DCM) to give (3R,3aS,6aR)-6-((2-amino-3-fluoroquinolin-7-yl)methyl)hexahydro-2H-cyclopent [b]furan-2,3,3a-triol as a solid. MS: 335 (M+1).

Step 3: To a stirred solution of (3R,3aS,6aR)-6-((2-amino-3-fluoroquinolin-7-yl)methyl)hexahydro-2H-cyclopenta[b]furan-2,3,3a-triol ( 0.067 g, 0.2 mmol) in anhydrous MeCN (3 ml) was added tributylphosphine (0.077 g, 0.38 mmol) followed by the addition of (E)-diazen-1,2-diylbis(piperidin-1-ylmethanone) (0.091 g , 0.36 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. Separately, NaH (0.024 g) was added to a stirred solution of 4-methyl-7H-pyrrolo[2,3-d]pyrimidine (0.053 g, 0.400 mmol) in anhydrous DMF (2 mL). , 60% in mineral oil, 0.600 mmol) at 0°C. The suspension was stirred at room temperature for 30 minutes. The suspension was then transferred into the solution initially containing the triol via a syringe. The resulting reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then quenched with saturated ammonium chloride solution (30 ml) and extracted with EtOAc (40 ml x 3). The combined organic layers were washed with brine (40 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by preparative TLC (1:1 DCM/MeOH). The product was further purified by reverse phase column chromatography (ACN/water with 5 mM NH ₄ HCO ₃ modifier) to give (2R,3R,3aS,6S,6aR)-6-((2-amino-3-fluoroquinolin-7-yl )methyl)-2-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)hexahydro-2H-cyclopenta[b]furan-3,3a-diol as a solid. MS: 450 (M+1). ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.69 (s, 1H), 7.87 (d, J=4.0 Hz, 1H), 7.74 (d, J=11.6 Hz, 1H), 7.52 (d, J=8.0 Hz, 1H), 7.28 (s, 1H), 7.07 (d, J=8.0 Hz, 1H), 6.82 ( d, J=3.6 Hz, 1H), 6.66 (br.s, 2H), 6.01 (d, J=8.0 Hz, 1H), 5.31 (d, J=7.2 Hz, 1H), 5.12 (s, 1H), 4.22 (d, J=7.6 Hz, 1H), 4.01 (d, J=6.0 Hz, 1H), 2.84- 2.79 (m, 1H), 2.69 (s, 3H), 2.67-2.59 (m, 1H), 2.28-2.22 (m, 1H), 1.98-1, 94 (m, 1H), 1.76-1.69 (m, 2H), 1.58-1.53 (m, 1H).

Example 124

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-fluoroquinolin-7-yl)methyl)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol

Step 1: To a stirred solution of (3R,3aS,6aR)-6-((2-amino-3-fluoroquinolin-7-yl)methyl)hexahydro-2H-cyclopenta[b]furan-2,3,3a-triol ( 0.100 g, 0.3 mmol) in anhydrous MeCN (4.5 ml) was added tributylphosphine (0.115 g, 0.57 mmol) followed by the addition of (E)-diazen-1,2-diylbis(piperidin-1-ylmethanone) ( 0.136 g, 0.54 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. Separately, sodium hydride was added to a stirred solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (0.092 g, 0.60 mmol) in anhydrous DMF (2 mL). (0.036 g, 60% in mineral oil, 0.90 mmol) at 0°C. The suspension was stirred at room temperature for 30 minutes. The suspension was then transferred into the solution initially containing the triol via a syringe. The resulting reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with saturated ammonium chloride solution (40 ml) and extracted with EtOAc (100 ml x 3). The combined organic layers were washed with brine (40 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by preparative TLC (1:1 PE/EtOAc) to give (2R,3R,3aS,6aR)-6-((2-amino-3-fluoroquinolin-7-yl)methyl)- 2-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)hexahydro-2H-cyclopenta[b]furan-3,3a-diol as a solid. MS: 470 (M+1).

Step 2: To a mixture of (2R,3R,3aS,6aR)-6-((2-amino-3-fluoroquinolin-7-yl)methyl)-2-(4-chloro-7H-pyrrolo[2,3-d ]pyrimidin-7-yl)hexahydro-2H-cyclopenta[b]furan-3,3a-diol (70 mg, 0.149 mmol) in dioxane (8 ml), ammonia hydrate (8 ml, 28%, 0.050) was added in a sealed test tube mmol) at room temperature. The reaction mixture was then heated at 95°C for 16 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by preparative TLC (10:1 DCM/MeOH). The product was further purified by reverse phase column chromatography (ACN/water with 5 mM NH ₄ HCO ₃ modifier) to give (2R,3R,3aS,6S,6aR)-6-((2-amino-3-fluoroquinolin-7-yl )methyl)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)hexahydro-2H-cyclopenta[b]furan-3,3a-diol as a solid. MS: 451 (M+1). ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.09 (s, 1H), 7.74 (d, J=12.0 Hz, 1H), 7.53 (d, J=8.4 Hz, 1H), 7.44 (d, J=3.6 Hz, 1H), 7.29 (s, 1H), 7.09-7.05 (m, 3H), 6.68-6.66 (m, 3H), 5.88 (d, J=8.4 Hz, 1H), 5.25-5.20 (m, 1H), 5.07-5.05 (m, 1H), 4, 13 (d, J=8.0 Hz, 1H), 3.95 (d, J=5.6 Hz, 1H), 2.84-2.79 (m, 1H), 2.67-2.58 (m, 1H), 2.29-2.13 (m, 1H), 1.96-1.92 (m, 1H), 1.74-1.68 (m, 2H), 1.57-1 .49 (m, 1H).

Example 125

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-methylquinolin-7-yl)methyl)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol

Step 1: (2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(4-amino-7H-pyrrolo[2] was added to the microwave test tube ,3-d]pyrimidin-7-yl)hexahydro-2H-cyclopenta[b]furan-3,3a-diol (40 mg, 0.078 mmol), 2,4,6-trimethyl-1,3,5,2, 4,6-trioxatriborinane (19.6 mg, 0.156 mmol), PdCl ₂ (dppf) (14.4 mg, 0.020 mmol), K ₂ CO ₃ in water (0.96 ml, 2M, 1.92 mmol) and DMF (2 ml) at room temperature under argon. The reaction mixture was microwave irradiated for 1 hour at 130°C. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by reverse phase column chromatography (ACN/water with 5 mM NH ₄ HCO ₃ modifier). The product was further purified by preparative HPLC (ACN/water with 10 mM NH ₄ HCO ₃ modifier) to give (2R,3R,3aS,6S,6aR)-6-((2-amino-3-methylquinolin-7-yl)methyl) -2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)hexahydro-2H-cyclopenta[b]furan-3,3a-diol as a solid. MS: 447 (M+1). ^1H -NMR (400 MHz, DMSO- _d6 ) δ 8.10 (s, 1H), 7.65 (s, 1H), 7.47-7.45 (m, 2H), 7.25 (s , 1H), 7.06 (broads, 2H), 7.00 (dd, J=8.0, 1.2 Hz, 1H), 6.68 (d, J=4.0 Hz, 1H) , 6.16 (broads, 2H), 5.90 (d, J=8.4 Hz, 1H), 5.25 (d, J=7.2 Hz, 1H), 5.07 (s, 1H), 4.14 (t, J=7.6 Hz, 1 H), 3.97 (d, J=5.6 Hz, 1 H), 2.84-2.79 (m, 1 H) , 2.63-2.58 (m, 1H), 2.28-2.22 (m, 1H), 2.19 (s, 3H), 1.95 (dd, J=12.0, 4, 4 Hz, 1H), 1.75-1.70 (m, 2H), 1.56-1.51 (m, 1H).

Example 126

(1S,2R,3S,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-(2-(2,3-dihydro-1H-pyrrolo[ 2,3-b]quinolin-7-yl)ethyl)-3-methylcyclopentane-1,2-diol

Step 1: To a solution of 7-((3a'R,4'R,6'R,6a'S)-4'-methyl-4'-vinyltetrahydro-4'H-spiro[cyclohexane-1,2'-cyclopenta[d ][1,3]dioxol]-6'-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (223 mg, 0.63 mmol) in THF (1 ml) was added a solution of 9-BBN (3.16 ml, 0.5 M in THF, 1.58 mmol) under nitrogen and the mixture was heated to 50°C for several hours and then cooled to room temperature and quenched with K ₃ PO ₄ (~3 ml , 2 M in water). The mixture was stirred for 15 minutes and the organic layer was separated from the aqueous layer. To a mixture of RuPhos-Pd-G3 (12.4 mg, 0.015 mmol) and tert-butyl 7-bromo-2,3-dihydro-1H-pyrrolo[2,3-b]quinoline-1-carboxylate (56.9 mg , 0.16 mmol) THF (0.4 ml) was added under nitrogen atmosphere. Then, one third of the above organic layer of a solution of 7-((3a'R,4'S,6'R,6a'S)-4'-(2-((1R,5R)-9-borabicyclo[3.3.1]nonane-9) was simultaneously introduced -yl)ethyl)-4'-methyltetrahydro-3a'H-spiro[cyclohexane-1,2'-cyclopenta[d][1,3]dioxol]-6'-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-amine (1.39 ml, 0.15 mmol) and K ₃ PO ₄ (0.37 ml, 2 M in water, 0.74 mmol). An additional vessel wash with borane solution was added to the reaction vessel with THF (0.3 mL). The resulting mixture was heated to 50°C overnight and then cooled to room temperature. The reaction mixture was diluted with DCM and water. The organic and aqueous layers were separated. The combined organic layers were concentrated under reduced pressure. The residue was again dissolved in THF (0.5 ml), water (0.5 ml, 27.8 mmol) and TFA (0.5 ml, 6.5 mmol) and the resulting mixture was heated to 50°C for two hours and then cooled to room temperature and concentrated under reduced pressure. The residue was purified by mass initiated reverse phase HPLC (MeCN/H ₂ O with 0.1% NH ₄ OH modifier) to give (1S,2R,3S,5R)-5-(4-amino-7H-pyrrolo[2, 3-d]pyrimidin-7-yl)-3-(2-(2,3-dihydro-1H-pyrrolo[2,3-b]quinolin-7-yl)ethyl)-3-methylcyclopentane-1,2- diol as a solid. MS: 445 (M+1). ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 8.05 (s, 1H), 7.61 (s, 1H), 7.47 (d, J=8.1 Hz, 1H), 7.30 -7.24 (m, 2H), 7.13 (s, 1H), 7.09-6.98 (m, 1H), 6.92 (s, 2H), 6.54 (d, J=3 .5 Hz, 1H), 4.93-4.83 (m, 2H), 4.59 (d, J=5.5 Hz, 1H), 4.40 (sq., J=6.2 Hz, 1H), 3.78 (t, J=5.8 Hz, 1H), 3.57 (t, J=7.8 Hz, 2H), 3.10 (t, J=7.5 Hz, 2H) , 2.72 (td, J=12.9, 5.8 Hz, 1H), 2.62 (td, J=13.3, 12.9, 5.7 Hz, 1H), 1.88 (dd , J=12.8, 8.8 Hz, 1H), 1.84-1.70 (m, 3H), 1.11 (s, 3H).

Example 127

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(2-amino-4-methyl-7H-pyrrolo[2,3- d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol

Step 1: Into an oven-dried and argon cooled 2-5 mL microwave vial containing (3R,3aS,6S,6aR)-6-[(2-amino-3-bromoquinolin-7-yl)methyl]hexahydro-3aH -cyclopenta[b]furan-2,3,3a-triol (70 mg, 0.177 mmol) dissolved in anhydrous MeCN (3 ml), 1,1'-(azodicarbonyl)dipiperidine (67.0 mg, 0.266 mmol) was added followed by the addition of tri- n -butylphosphine (70.8 µl, 0.283 mmol) at room temperature. The mixture was stirred for 1 hour. In a separate oven-dried and argon-cooled vessel containing di-tert-butyl (4-methyl- 7H -pyrrolo[2,3- d ]pyrimidin-2-yl)imidodicarbonate (93 mg, 0.266 mmol) dissolved in anhydrous acetonitrile (1 ml), DBU (53.4 μl, 0.354 mmol) was added. The mixture was stirred at room temperature for 30 minutes and then this suspension was transferred through a syringe to the mixture described above, initially containing the triol. The reaction mixture was maintained for 30 minutes at room temperature, then heated to 40°C for ~4 hours. The mixture was then cooled to room temperature, quenched with water and extracted with EtOAc (3×). The combined organic layers were then washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography (0-100% EtOAc:hexane) to give di-tert-butyl (7-{(2R,3R,3aS,6S,6aR)-6-[(2-amino-3-bromoquinoline -7-yl)methyl]-3,3a-dihydroxyhexahydro-2H-cyclopenta[b]furan-2-yl}-4-methyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)imidodicarbonate in the form solid matter. MS: 725/727 (M+1/M+3).

Step 2: To a solution of di-tert-butyl (7-{(2R,3R,3aS,6S,6aR)-6-[(2-amino-3-bromoquinolin-7-yl)methyl]-3,3a-dihydroxyhexahydro -2H-cyclopenta[b]furan-2-yl}-4-methyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)imidodicarbonate (39.8 mg, 0.055 mmol) in DCM (1.10 ml) TFA 20 equivalents was added and the reaction mixture was stirred overnight at room temperature. The mixture was then concentrated under reduced pressure and the residue was purified by mass initiated reverse phase HPLC (MeCN:H ₂ O gradient with 0.1% NH ₄ OH) to give (2R,3R,3aS,6S,6aR)-6-(( 2-amino-3-bromoquinolin-7-yl)methyl)-2-(2-amino-4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b] furan-3,3a-diol as a solid. MS: 525/527 (M+1/M+3). ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 8.31 (s, 1H), 7.55 (d, J=8.2 Hz, 1H), 7.32 (d, J=3.8 Hz , 1H), 7.28 (s, 1H), 7.09 (dd, J=8.2, 1.4 Hz, 1H), 6.55 (s, 2H), 6.51 (d, J= 3.8 Hz, 1H), 6.18 (s, 2H), 5.82 (d, J=8.2 Hz, 1H), 5.27 (d, J=6.9 Hz, 1H), 5 .03 (s, 1H), 4.08-4.03 (m, 1H), 3.91 (d, J=5.7 Hz, 1H), 2.83-2.78 (m, 1H), 2.64-2.59 (m, 1H), 2.45 (s, 3H), 2.28-2.21 (m, 1H), 1.97-1.93 (m, 1H), 1. 72-1.67 (m, 2H), 1.57-1.49 (m, 1H).

Example 128

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-(difluoromethyl)quinolin-7-yl)oxy)-2-(4-amino-7H-pyrrolo[2,3-d ]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol

Step 1: To a stirred solution of ( 3R , 3aS , 6R , 6aR )-6-(benzyloxy)hexahydro- 2H -cyclopenta[ b ]furan-2,3,3a - triol (3.4 g, 12.8 mmol) in anhydrous MeCN (170 ml) was added dropwise tributylphosphine (5.10 ml, 20.4 mmol) in MeCN (70 ml) at 0°C under argon atmosphere. (E)-diazen-1,2-diylbis(piperidin-1-ylmethanone) (4.83 g, 19.2 mmol) in MeCN (70 ml) was then added dropwise at 0°C under argon. The resulting mixture was stirred at 40°C for 30 minutes. Separately, to a stirred solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (3.67 g, 23.88 mmol) in anhydrous MeCN (35 mL) was added dropwise DBU (3.62 mL, 24. 01 mmol) at 0°C in an argon atmosphere. The resulting solution was stirred at 30°C for 1 hour. This solution was then transferred into the solution initially containing triol through a syringe for 1 minute. The resulting reaction mixture was stirred at 39°C for 2 hours. The reaction mixture was diluted with EtOAc (200 ml), washed with water (2 x 100 ml) and washed with brine (100 ml). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by reverse phase HPLC (ACN/water with 0.05% NH ₄ HCO ₃ ) to give (2R,3R,3aS,6R,6aR)-6-(benzyloxy)-2-(4 -chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)hexahydro-2H-cyclopenta[b]furan-3,3a-diol as a solid. MS: 402 (M+1).

Step 2: To a solution of (2R,3R,3aS,6R,6aR)-6-(benzyloxy)-2-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)hexahydro-2H- cyclopent[b]furan-3,3a-diol (8.6 g, 15.2 mmol, 71% wt) in 2,2-dimethoxypropane (100 ml) was added 4-methylbenzenesulfonic acid (0.262 g, 1.52 mmol ) at room temperature in an argon atmosphere. The mixture was stirred at 70°C for 16 hours. The reaction mixture was then cooled to room temperature and quenched with saturated aqueous sodium bicarbonate (10 ml). The mixture was concentrated under reduced pressure and the resulting residue was purified by silica column chromatography (0-50% EtOAc/PE) to give 7-((3aR,4R,5aR,6R,8aR)-6-(benzyloxy)-2,2- dimethylhexahydrocyclopenta[2,3]furo[3,4-d][1,3]dioxol-4-yl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidine as an oil. MS: 442 (M+1).

Step 3: To a solution of 7-((3aR,4R,5aR,6R,8aR)-6-(benzyloxy)-2,2-dimethylhexahydrocyclopenta[2,3]furo[3,4-d][1,3]dioxol -4-yl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (5 g, 10.75 mmol) in dioxane (60 ml) was added ammonium hydroxide (120 ml, 28%, 872 mmol) at room temperature. The mixture was tightly capped and stirred at 90°C for 16 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica column chromatography (0-10% MeOH/DCM) to give 7-((3aR,4R,5aR, 6R,8aR)-6-(benzyloxy)-2,2-dimethylhexahydrocyclopenta[2,3]furo[3,4-d][1,3]dioxol-4-yl)-7H-pyrrolo[2,3-d ]pyrimidin-4-amine in the form of a solid. MS: 423 (M+1).

Step 4: To a mixture of 7-((3aR,4R,5aR,6R,8aR)-6-(benzyloxy)-2,2-dimethylhexahydrocyclopenta[2,3]furo[3,4-d][1,3]dioxol -4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (339 mg, 0.722 mmol) in MeOH (40 ml) was added palladium hydroxide on carbon (1.78 g, 20%, 50% in water, 2.53 mmol) at room temperature under argon. The suspension was degassed in vacuo and purged with H ₂ several times. The reaction mixture was stirred under H ₂ (2 atm) at room temperature for 2 hours. The mixture was filtered through a pad of Celite and the filtrate was concentrated under reduced pressure to give (3aR,4R,5aR,6R,8aR)-4-(4-amino -7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethylhexahydrocyclopenta[2,3]furo[3,4-d][1,3]dioxol-6-ol as a solid . MS: 333 (M+1).

Step 5: To a stirred mixture of (3aR,4R,5aR,6R,8aR)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethylhexahydrocyclopenta[2, 3]furo[3,4-d][1,3]dioxol-6-ol (170 mg, 0.512 mmol) in DCM (5 ml) and pyridine (0.5 ml) was added trifluoromethanesulfonic anhydride (188 mg, 0.665 mmol ) at 0°C in an argon atmosphere. The resulting mixture was stirred for 2 hours at 0°C. The reaction mixture was then quenched with saturated NaHCO ₃ solution (30 ml), extracted with EtOAc (30 ml x 3) and the combined organic layers were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative TLC (1:1 PE:EtOAc) to give (3aR,4R,5aR,6R,8aR)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl) -2,2-dimethylhexahydrocyclopenta[2,3]furo[3,4-d][1,3]dioxol-6-yl trifluoromethanesulfonate as a solid. MS: 465 (M+1).

Step 6: To a stirred solution of (3aR,4R,5aR,6R,8aR)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethylhexahydrocyclopenta[2, 3]furo[3,4-d][1,3]dioxol-6-yl trifluoromethanesulfonate (90 mg, 0.194 mmol) and 2-amino-3-(difluoromethyl)quinolin-7-ol (44.8 mg, 0.213 mmol) in NMP (0.5 ml) was added Cs ₂ CO ₃ (95 mg, 0.291 mmol) at 25°C under argon. The resulting mixture was stirred for 2 hours at 25°C. The reaction mixture was purified by reverse phase column chromatography (ACN/water with 5 mM NH ₄ HCO ₃ modifier) to give 7-(((3aR,4R,5aR,6S,8aR)-4-(4-amino-7H-pyrrolo[ 2,3-d]pyrimidin-7-yl)-2,2-dimethylhexahydrocyclopenta[2,3]furo[3,4-d][1,3]dioxol-6-yl)oxy)-3-(difluoromethyl) quinoline-2-amine in the form of a solid. MS: 525 (M+1).

Step 7: Into a vessel containing 7-(((3aR,4R,5aR,6S,8aR)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2 -dimethylhexahydrocyclopenta[2,3]furo[3,4-d][1,3]dioxol-6-yl)oxy)-3-(difluoromethyl)quinolin-2-amine (50 mg, 0.095 mmol), add TFA ( 1 ml) and water (1 ml) at 25°C. The resulting mixture was stirred at 25°C for 16 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by reverse phase column chromatography (ACN/water with 5 mM NH ₄ HCO ₃ modifier) to give (2R,3R,3aS,6S, 6aR)-6-((2-amino-3-(difluoromethyl)quinolin-7-yl)oxy)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)hexahydro- 2H-cyclopenta[b]furan-3,3a-diol as a solid. MS: 485 (M+1). ¹ H-NMR (400 MHz, CD ₃ OD) δ 8.10-8.09 (m, 2H), 7.65 (d, J=8.8 Hz, 1H), 7.41 (d, J= 3.6 Hz, 1H), 7.00-6.95 (m, 2H), 6.86-6.63 (m, 2H), 6.04 (d, J=8.4 Hz, 1H), 4.77 (d, J=4.8 Hz, 1H), 4.49 (d, J=8.4 Hz, 1H), 4.30 (s, 1H), 2.53-2.43 (m , 1H), 2.26-2.16 (m, 3H).

Example 129

(2R,3R,3aS,6R,6aR)-6-((2-amino-3-bromoquinolin-7-yl)oxy)-2-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol

Step 1: Into a vessel containing (3aR,4R,5aR,6R,8aR)-2,2-dimethyl-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)hexahydrocyclopenta[ 2,3]furo[3,4-d][1,3]dioxol-6-ol (50 mg, 0.15 mmol), 3-bromo-N-(2,4-dimethoxybenzyl)-7-iodoquinoline- 2-amine (113 mg, 0.23 mmol), 4-(pyrrolidin-1-yl)pyridine (26.8 mg, 0.181 mmol), copper iodide (2.87 mg, 0.015 mmol), tribasic potassium phosphate (128 mg, 0.60 mmol), toluene (754 μl) was added and the reaction mixture was heated to 120°C overnight. The reaction mixture was filtered, concentrated under reduced pressure and the residue was purified by silica column chromatography (10-100% EtOAc/CH ₂ Cl ₂ ) to give 3-bromo-N-(2,4-dimethoxybenzyl)-7-(((3aR ,4R,5aR,6R,8aR)-2,2-dimethyl-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)hexahydrocyclopenta[2,3]furo[3,4 -d][1,3]dioxol-6-yl)oxy)quinoline-2-amine in the form of a solid. MS: 702/704 (M+1/M+3).

Step 2: To a solution of 3-bromo-N-(2,4-dimethoxybenzyl)-7-(((3aR,4R,5aR,6R,8aR)-2,2-dimethyl-4-(4-methyl-7H- pyrrolo[2,3-d]pyrimidin-7-yl)hexahydrocyclopenta[2,3]furo[3,4-d][1,3]dioxol-6-yl)oxy)quinolin-2-amine (64 mg, 0.091 mmol) in CH ₂ Cl ₂ (911 µl) was added TFA (1.40 ml, 18.2 mmol) and 1 drop of water. The reaction mixture was heated to 50°C for 4 hours. The solution was concentrated under reduced pressure and the residue was purified by reverse phase HPLC (MeCN/water with 0.1% TFA modifier) to give (2R,3R,3aS,6R,6aR)- 6-((2-amino-3-bromoquinolin-7-yl)oxy)-2-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b] furan-3,3a-diol as a solid. MS: 512/514 (M+1/M+3). ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.63 (s, 1H), 8.24 (s, 1H), 7.78 (d, J=3.8 Hz, 1H), 7.51 (d, J=8.9 Hz, 1H), 6.94 (d, J=2.2 Hz, 1H), 6.86 (dd, J=8.8, 2.4 Hz, 1H), 6 .77 (d, J=3.7 Hz, 1H), 6.54 (s, 2H), 6.14 (d, J=8.2 Hz, 1H), 5.46 (d, J=7, 0 Hz, 1H), 5.39 (s, 1H), 4.84 (dt, J=8.8, 5.8 Hz, 1H), 4.41 (d, J=5.3 Hz, 1H) , 4.33 (t, J=7.6 Hz, 1H), 2.64 (s, 3H), 2.25 (d, J=4.1 Hz, 1H), 2.22-2.12 ( m, 1H), 2.11-2.03 (m, 1H), 1.73-1.64 (m, 1H).

Example 130

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)oxy)-2-(2-amino-5-fluoro-7H-pyrrolo[2,3- d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol

Step 1: Pyridine (20.4 µl, 0.252 mmol), DIAD (103 µl, 0.529 mmol) and tri-n-butylphosphine (126 µl, 0.503 mmol). (3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)oxy)hexahydro-3aH-cyclopenta[b]furan-2,3,3a-triol (100 mg, 0.252 mmol) in one serving. The mixture was left to stir for 2 hours. The mixture was diluted with water and extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica column chromatography (0-20% MeOH/DCM) to give (2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)oxy)-2 -(2-chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol. MS: 550/552 (M+1/M+3)

Step 2: Mixture of (2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)oxy)-2-(2-chloro-5-fluoro-7H-pyrrolo[ 2,3-d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol (55.1 mg, 0.1 mmol) in 1,4-dioxane (1 ml) and hydroxide ammonium (1 ml, 7.19 mmol) was microwaved to 100°C for 2 hours. The mixture was concentrated under reduced pressure and the residue was purified by silica column chromatography (0-15% MeOH/DCM). The product was further purified by mass initiated reverse phase HPLC (MeCN/water with 0.1% TFA modifier) to give (2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinoline-7- yl)oxy)-2-(2-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol as a solid substances. MS: 531/533 (M+1/M+3). ^1H NMR (500 MHz, DMSO- d6 ) δ 8.68 (s, 1H), 8.63 (s, 1H), 7.74 ₍ d, J =8.8 Hz, 1H), 7.59 (s, 1H), 7.25-6.72 (m, 5H), 5.99 (d, J =8.5 Hz, 1H), 4.63 (d, J =5.0 Hz, 1H) , 4.23 (d, J =8.5 Hz, 2H), 4.03 (s, 2H), 2.13-1.90 (m, 3H).

Example 131

(2R,3R,3aS,6R,6aR)-6-((2-amino-3-chloroquinolin-7-yl)methyl)-2-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol

Step 1: To a mixture of chloro(1,5-cyclooctadiene)iridium(I) dimer (18.10 mg, 0.035 mmol) and DPPE (28.0 mg, 0.070 mmol) in CH ₂ Cl ₂ (3.01 ml) was added 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (281 µl, 1.76 mmol) under N ₂ atmosphere. The mixture was degassed and refilled three times with N ₂ . After stirring for 20 minutes at 25°C, 7-((3aR,4R,5aR,8aR)-2,2-dimethyl-6-methylenehexahydrocyclopenta[2,3]furo[3,4-d][1 ,3]dioxol-4-yl)-4-methyl-7H-pyrrolo[2,3-d]pyrimidine (230 mg, 0.703 mmol) in CH ₂ Cl ₂ (3.01 ml) under N ₂ atmosphere. The mixture was degassed and refilled with N ₂ three times and the resulting mixture was stirred at 25°C for 15 hours. The reaction mixture was cooled to 0°C, quenched with 4 ml MeOH, concentrated under reduced pressure and the residue was purified by silica column chromatography ( 10-100% EtOAc/DCM) to give 7-((3aR,4R,5aR,8aR)-2,2-dimethyl-6-((4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2-yl)methyl)hexahydrocyclopenta[2,3]furo[3,4-d][1,3]dioxol-4-yl)-4-methyl-7H-pyrrolo[2,3-d]pyrimidine in the form resin. MS: 456 (M+1).

Step 2: Into a vessel containing 7-bromo-3-chloroquinoline-2-amine (50.9 mg, 0.198 mmol), 7-((3aR,4R,5aR,8aR)-2,2-dimethyl-6-( (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)hexahydrocyclopenta[2,3]furo[3,4-d][1,3]dioxol-4-yl) -4-methyl-7H-pyrrolo[2,3-d]pyrimidine (75 mg, 0.165 mmol), PdCl ₂ (dppf)-CH ₂ Cl ₂ adduct (26.9 mg, 0.033 mmol), THF (2, 75 ml), water (549 µl) and thallium(I) ethoxide (35.0 µl, 0.49 mmol) was loaded. The reaction mixture was heated for 72 hours at 65°C. The reaction mixture was diluted with EtOAc, filtered, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography (10-100% EtOAc/DCM) to give 3-chloro-7-(((3aR,4R,5aR,8aR)-2,2-dimethyl-4-(4-methyl-7H -pyrrolo[2,3-d]pyrimidin-7-yl)hexahydrocyclopenta[2,3]furo[3,4-d][1,3]dioxol-6-yl)methyl)quinolin-2-amine, which was used without additional cleaning. MS: 506 (M+1).

Step 3: 3-chloro-7-(((3aR,4R,5aR,8aR)-2,2-dimethyl-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl) hexahydrocyclopenta[2,3]furo[3,4-d][1,3]dioxol-6-yl)methyl)quinolin-2-amine (10 mg, 0.012 mmol) was dissolved in CH ₂ Cl ₂ (3 ml). A drop of water was added followed by TFA (0.457 mL, 5.93 mmol). The reaction mixture was heated to 50°C for 2 h and the reaction mixture was concentrated under reduced pressure and subjected to SFC separation into (Whelk-O (R, R), 21 × 250 MeOH aq/0.1% NH ₄ OH 35% modifier in CO ₂ ) to give (2R,3R,3aS,6R,6aR)-6-((2-amino-3-chloroquinolin-7-yl)methyl)-2-(4-methyl-7H-pyrrolo[2, 3-d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol as a solid MS: 466 (M+1). ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.64 (s, 1H), 8.14 (s, 1H), 7.80 (d, J=3.8 Hz, 1H), 7.58 (d, J=8.2 Hz, 1H), 7.32 (s, 1H), 7.10 (d, J=8.1 Hz, 1H), 6.77 (d, J=3.7 Hz , 1H), 6.66 (s, 2H), 6.01 (d, J=8.1 Hz, 1H), 5.47 (s, 1H), 5.31 (s, 1H), 4.33 (d, J=8.1 Hz, 1H), 3.92 (m, 1H), 2.86 (dd, J=13.9, 8.2 Hz, 1H), 2.71 (dd, J= 13.9, 8.2 Hz, 1H), 2.66 (s, 3H), 2.35 (m, 1H), 2.12-1.93 (m, 2H), 1.92-1.81 (m, 1H), 1.60 (m, 1H).

Example 132

(3aS,4S,5R)-1-((2-amino-3-bromoquinolin-7-yl)methyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl) tetrahydro-1H-cyclopenta[c]furan-3a,4(3H)-diol

Step 1: To a stirred solution of 3-bromo-7-iodo-N-(4-methoxybenzyl)quinoline-2-amine (3 g, 6.39 mmol) in THF (18.0 ml) was added allyltributylstannane (2.18 ml , 7.03 mmol) and Pd(PPh ₃ ) ₄ (0.739 g, 0.639 mmol) at room temperature in an argon atmosphere. The resulting mixture was heated to 95°C and stirred for 6 hours. The reaction was quenched by adding water (200 ml) and extracted with ethyl acetate (250 ml x 2). The organic layer was washed with brine (200 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography (5-30% hexane/(3:1) ethyl acetate:ethanol) to give 7-allyl-3-bromo-N-(4-methoxybenzyl)quinoline-2-amine as an oil. MS: 383/ 385 (M+1/M+3).

Step 2: In a round bottom flask equipped with a magnetic stirrer, 7-allyl-3-bromo-N-(4-methoxybenzyl)quinoline-2-amine (1 g, 2.61 mmol) was dissolved in DCM (52.2 mL). The flask was placed in a dry ice-acetone bath and connected to an ozonizer. Air was passed through an ozonizer and bubbled into the flask. The reaction was monitored every 5 minutes by LCMS, while the ozonizer was stopped and the reaction mixture was bubbled with air for 5 minutes, then an aliquot was taken. When the starting material was completely consumed and the appropriate mass of ozonide was observed, triphenylphosphane (1.369 g, 5.22 mmol) was added to the cold reaction mixture and the reaction flask was removed from the cooling bath and stirred for an additional 30 minutes. The reaction was quenched with water (10 ml), extracted with DCM (10 ml) and the organic phase was washed with brine (10 ml). The organic layers were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to give 2-(3-bromo-2-((4-methoxybenzyl)amino)quinolin-7-yl)acetaldehyde, which was used in the next step without further purification .

Step 3: To a stirred solution of 2-(3-bromo-2-((4-methoxybenzyl)amino)quinolin-7-yl)acetaldehyde (5 g, 13.0 mmol) in THF (130 ml) was added vinyl magnesium bromide dropwise (20.8 ml, 1M in THF, 20.8 mmol) at 0°C and stirred for 1 hour. The reaction was quenched with saturated ammonium chloride solution (200 ml) and extracted with ethyl acetate (300 ml x 2). The organic layer was washed with brine (200 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography (0-30% hexane/3:1 ethyl acetate:ethanol) to give 1-(3-bromo-2-((4-methoxybenzyl)amino)quinolin-7-yl)but-3 -en-2-ol. MS: 413/415 (M+1/M+3).

Step 4: Solution of 1-(3-bromo-2-((4-methoxybenzyl)amino)quinolin-7-yl)but-3-en-2-ol (1.5 g, 3.63 mmol) in anhydrous THF (36.3 ml) was cooled in an ice bath. Sodium hydride (363 mg, 9.08 mmol) was then added under nitrogen. After stirring for 15 minutes, a solution of 3-bromoprop-1-yne (0.61 mL, 5.44 mmol) in toluene was added dropwise. The resulting reaction mixture was slowly warmed to room temperature overnight. The reaction was quenched with saturated aqueous ammonium chloride and the mixture was extracted with ethyl acetate. The organic phase was separated, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica column chromatography (0-30% hexane/3:1 ethyl acetate:ethanol) to give 3-bromo-N-(4-methoxybenzyl)-7-(2-(prop-2-yn-1- yloxy)but-3-en-1-yl)quinolin-2-amine in the form of a solid. MS: 451/453 (M+1/M+3).

Step 5: To a vessel containing dicobalt octacarbonyl (80 mg, 0.233 mmol) was added a solution of 3-bromo-N-(4-methoxybenzyl)-7-(2-(prop-2-yn-1-yloxy)but-3 -en-1-yl)quinolin-2-amine (700 mg, 1.55 mmol) in toluene (15.5 ml) under argon. The reaction mixture was then heated to 100°C in a Parr CO apparatus at a CO pressure of ~70 psi (4.9 kg/cm ² ) for 20 hours ^. The reaction mixture was cooled to room temperature, diluted with diethyl ether, passed through a pad of Celite and then concentrated under reduced pressure to give crude 3-((3-bromo-2-((4-methoxybenzyl)amino)quinolin-7-yl)methyl) -3a,4-dihydro-1H-cyclopenta[c]furan-5(3H)-one, which was used as such in the next step without further purification.

Step 6: Solution of 3-((3-bromo-2-((4-methoxybenzyl)amino)quinolin-7-yl)methyl)-3a,4-dihydro-1H-cyclopenta[c]furan-5(3H)- she (500 mg, 1.04 mmol) in THF (20 ml) and MeOH (10 ml) was cooled to -40°C in a dry ice/acetonitrile bath. Cerium(III) chloride heptahydrate (389 mg, 1.04 mmol) was added. The mixture was stirred cold for 20 minutes. Sodium tetrahydroborate (79 mg, 2.09 mmol) was then added. The reaction mixture was then vigorously cold stirred for 40 minutes. The reaction mixture was removed from the bath and after a few minutes was quenched by pouring into a separatory funnel containing ethyl acetate (100 ml) and 3:2:1 saturated ammonium chloride:water:saturated saline (70 ml). After extraction, the aqueous layer was washed again with ethyl acetate (100 ml×2). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (0-50% hexane/3:1 ethyl acetate:ethanol) to give 3-((3-bromo-2-((4-methoxybenzyl)amino)quinolin-7-yl)methyl )-3,3a,4,5-tetrahydro-1H-cyclopenta[c]furan-5-ol. MS: 481/483 (M+1/M+3).

Step 7: To a solution of 3-((3-bromo-2-((4-methoxybenzyl)amino)quinolin-7-yl)methyl)-3,3a,4,5-tetrahydro-1H-cyclopenta[c]furan- 5-ol (140 mg, 0.291 mmol) in DCM (20 ml) added pyridine (0.071 ml, 0.872 mmol), N,N-dimethylpyridin-4-amine (71.1 mg, 0.582 mmol) and di-tert-butyl dicarbonate (127 mg, 0.582 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into a separatory funnel containing saturated ammonium chloride solution and DCM. After extraction, the organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting crude material was purified by silica column chromatography (0-5-10% EtOAc/hexane) to give 3-((3-bromo-2-((4-methoxybenzyl)amino)quinolin-7-yl)methyl)-3 ,3a,4,5-tetrahydro-1H-cyclopenta[c]furan-5-yl tert-butyl carbonate. MS: 581/583 (M+1/M+3).

Step 8: Into a vessel containing N,N'-((1R,2R)-cyclohexane-1,2-diyl)bis(2-(diphenylphosphanyl)benzamide) (3.56 mg, 5.16 µmol), tetrabutylammonium difluorotriphenyl silicate (9.28 mg, 0.017 mmol), 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (5.28 mg, 0.034 mmol) and Pd ₂ dba ₃ (1.575 mg, 1.720 µmol), anhydrous THF was added (1 ml). This mixture was stirred at room temperature for 15 minutes. Then a solution of 3-((3-bromo-2-((4-methoxybenzyl)amino)quinolin-7-yl)methyl)-3,3a,4,5-tetrahydro-1H-cyclopenta[c]furan-5- yl tert-butyl carbonate (10 mg, 0.017 mmol) in anhydrous THF (1 ml). The reaction mixture was stirred under argon at room temperature overnight. The mixture was poured into a separatory funnel containing water (10 ml) and extracted with ethyl acetate (15 ml x 2). The combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography (0-50% EtOAc/hexane) to give 3-bromo-7-((5-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)- 3,5,6,6a-tetrahydro-1H-cyclopenta[c]furan-1-yl)methyl)-N-(4-methoxybenzyl)quinolin-2-amine. MS: 616/618 (M+1/M+3).

Step 9: To a solution of 3-bromo-7-((5-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3,5,6,6a-tetrahydro-1H-cyclopenta [c]furan-1-yl)methyl)-N-(4-methoxybenzyl)quinolin-2-amine (160 mg, 0.259 mmol) in THF (2 ml) and water (1 ml) was added 4-methylmorpholine 4-oxide (60.8 mg, 0.519 mmol) and osmium(VIII) oxide solution (407 μl, 0.052 mmol). The mixture was stirred at room temperature overnight. The reaction was quenched with 40% aqueous sodium bisulfite (3 ml) and stirred for 15 minutes and then extracted with chloroform containing 25% isopropyl acetate (5 ml x 2). The combined organic layers were washed with water (3 ml) and then brine (3 ml), dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give 1-((3-bromo-2-((4-methoxybenzyl)amino)quinolin-7-yl)methyl)-5-(4-chloro-7H-pyrrolo[2,3-d ]pyrimidin-7-yl)tetrahydro-1H-cyclopenta[c]furan-3a,4(3H)-diol, which was used in the next step without further purification.

Step 10: To a solution of 1-((3-bromo-2-((4-methoxybenzyl)amino)quinolin-7-yl)methyl)-5-(4-chloro-7H-pyrrolo[2,3-d]pyrimidine -7-yl)tetrahydro-1H-cyclopenta[c]furan-3a,4(3H)-diol (16 mg, 0.025 mmol) to DCM (5 ml) was added 4-methylbenzenesulfonic acid monohydrate (14.0 mg, 0.074 mmol ) and 2,2-dimethoxypropane (30 µl, 0.244 mmol) under argon. The reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into a separatory funnel containing saturated aqueous ammonium chloride (10 ml) and extracted with DCM (10 ml x 2). The organic layers were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to give 3-bromo-7-((4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2 ,2-dimethyltetrahydro-5H,8H-furo[3',4':1,5]cyclopenta[1,2-d][1,3]dioxol-6-yl)methyl)-N-(4-methoxybenzyl) quinoline-2-amine, which was used in the next step without further purification.

Step 11: Into a vessel containing 3-bromo-7-((4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-5H,8H-furo [3',4':1,5]cyclopenta[1,2-d][1,3]dioxol-6-yl)methyl)-N-(4-methoxybenzyl)quinolin-2-amine (16 mg, 0.023 mmol), ammonia (1 mL, 7M in MeOH, 7.00 mmol) was added. The vessel was sealed and the reaction mixture was heated in a microwave oven for 4 hours at 140°C. The reaction mixture was then concentrated under reduced pressure and the residue was purified by silica column chromatography (10-60% hexane/3:1 ethyl acetate:ethanol). The product was further purified using SPC (MeOH aq/0.1% NH ₄ OH, 35% modifier in CO ₂ ) to give 7-(((3aS,4R,8aS)-4-(4-amino-7H-pyrrolo [2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-5H,8H-furo[3',4':1,5]cyclopenta[1,2-d][1,3]dioxol -6-yl)methyl)-3-bromo-N-(4-methoxybenzyl)quinoline-2-amine. MS: 671/ 673 (M+1/M +3).

Step 12: Into a flask containing 7-(((3aS,4R,8aS)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-5H ,8H-furo[3',4':1,5]cyclopenta[1,2-d][1,3]dioxol-6-yl)methyl)-3-bromo-N-(4-methoxybenzyl)quinoline- 2-amine (2 mg, 2.16 µmol), TFA (121 µl, 1.57 mmol) was added and the reaction mixture was stirred at 45°C for 3 hours. The crude material was concentrated under reduced pressure and the residue was purified by mass-initiated reverse -phase HPLC (MeCN/water with 0.1% TFA modifier) to give (3aS,4S,5R)-1-((2-amino-3-bromoquinolin-7-yl)methyl)-5-(4-amino -7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro-1H-cyclopenta[c]furan-3a,4(3H)-diol, TFA salt, as a solid. MS: 511/513 (M+1/M+3). ¹ H NMR (499 MHz, DMSO-d ₆ ) δ 8.31 (s, 1H), 8.00 (s, 1H), 7.57 (d, J=8.2 Hz, 1H), 7.36 (s, 1H), 7.25 (d, J=3.6 Hz, 1H), 7.14 (d, J=6.9 Hz, 1H), 6.89 (s, 2H), 6.56 (s, 2H), 6.50 (d, J=3.5 Hz, 1H), 5.02 (d, J=7.0 Hz, 1H), 4.99 (s, 1H), 4.92 -4.80 (m, 1H), 4.24 (dd, J=10.5, 7.1 Hz, 1H), 4.00 (sq, J=6.7 Hz, 1H), 3.76 (sq., J=9.3 Hz, 2H), 3.05 (dd, J=13.5, 7.6 Hz, 1H), 2.91 (dd, J=13.3, 6.3 Hz , 1H), 2.28-2.19 (m, 1H), 1.99-1.87 (m, 1H), 1.59-1.44 (m, 1H).

Examples 133 and 134

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)tetrahydrofuro[3,4-b]furan-3,3a(4H)-diol and

(2R,3R,3aS,6R,6aR)-6-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)tetrahydrofuro[3,4-b]furan-3,3a(4H)-diol

Step 1: DMP (61.6 g, 145 mmol) was added portionwise to a solution of diacetone-D-glucose (25 g, 97 mmol) in DCM (300 ml) at 0°C. The reaction mixture was then warmed to room temperature and stirred overnight. The reaction mixture was then cooled to 0°C and saturated sodium bicarbonate solution (100 ml) was added, followed by saturated sodium sulfite solution (100 ml). The reaction mixture was stirred for 30 minutes at room temperature and the layers were separated. The aqueous layers were extracted with DCM (1 x 200 ml), the combined organic layers were then dried over sodium sulfate, filtered and concentrated under reduced pressure to give ( 3aR , 5R , 6aS )-5-(( R )-2,2- dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyldihydrofuro[2,3-d][1,3]dioxol-6(3aH)-one, which was used in the next step without further purification.

Stage 2: a 500-ml 3-neck flask equipped with a magnetic stirrer, temperature sensor, dropping funnel and septum was heated with a technical hair dryer in a vacuum, the laboratory glassware was cooled to room temperature and loaded (3a R ,5 R ,6a S )-5- (( R )-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyldihydrofuro[2,3-d][1,3]dioxol-6(3aH)-one (20 g , 77 mmol) and toluene (309 ml). The solution was cooled to 0°C and vinyl magnesium chloride (58 ml, 1.6M, 93 mmol) was added dropwise at such a rate that the temperature did not exceed 5°C. After addition was complete, the reaction mixture was warmed to room temperature and stirred for 3 hours. The mixture was quenched with saturated aqueous ammonium chloride (250 ml) and then diluted with EtOAc (500 ml). The layers were separated and the organic layer was washed with brine (2 x 250 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give ( 3aR , 5R , 6R , 6aR )-5-(( R )- 2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyl-6-vinyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol, which was used in the next step without additional cleaning.

Step 3: Solution of ( 3aR , 5R , 6R , 6aR )-5-(( R )-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyl-6- vinyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol (18.0 g, 62.8 mmol) in THF (165 ml) was cooled to 0°C and sodium hydride (6.28 g, 157 mmol). The reaction mixture was stirred for 30 minutes at 0°C and then for 30 minutes at room temperature. TBAI (2.32 g, 6.28 mmol) was then added followed by benzyl bromide (14.9 mL, 125 mmol) and the reaction mixture was stirred at room temperature overnight. The mixture was cooled to 0°C and quenched with saturated ammonium chloride solution (200 ml). The mixture was diluted with EtOAc (200 ml) and the layers were separated. The combined organic layers were washed with brine (2 x 200 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography (0%-100% EtOAc/hexane) to give ( 3aR , 5R , 6R , 6aR )-6-(benzyloxy)-5-(( R )-2,2- dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyl-6-vinyltetrahydrofuro[2,3-d][1,3]dioxole. ¹ H NMR (600 MHz, CDCl ₃ ) δ 7.43 (d, J = 7.5 Hz, 2H), 7.37-7.32 (m, 2H), 7.31-7.26 (m, 1H), 5.89 (dd, J =18.0, 11.4 Hz, 1H), 5.85 (d, J =3.6 Hz, 1H), 5.49 (d, J =11.4 Hz, 1H), 5.32 (d, J =18.0 Hz, 1H), 4.71 (d, J =11.4 Hz, 1H), 4.65 (d, J =3.6 Hz, 1H), 4.63 (d, J =11.4 Hz, 1H), 4.34 (d, J =5.7 Hz, 1H), 4.19 (dd, J =5.9 Hz, 1H) , 4.01-3.94 (m, 2H), 1.64 (s, 3H), 1.45 (s, 3H), 1.41 (s, 3H), 1.36 (s, 3H).

Step 4: Solution of ( 3aR , 5R , 6R , 6aR )-6-(benzyloxy)-5-(( S )-2,2-dimethyl-1,3-dioxolan-4-yl)-2, 2-dimethyl-6-vinyltetrahydrofuro[2,3-d][1,3]dioxole (1000 mg, 2.66 mmol) and pyridine (0.645 ml, 7.97 mmol) in DCM (20 ml) were cooled to -78 °C and a stream of ozone (Triogen ozonator using compressed air) was passed through the solution for 10 minutes. The vessel was purged with air and heated to room temperature. The reaction mixture was cooled to -78°C and ozone was passed through it for another 10-15 minutes. The vessel was purged with air and heated to 0°C. The crude material was diluted with MeOH (20 ml) and sodium borohydride (502 mg, 13.3 mmol) was added at 0°C. The reaction mixture was stirred at this temperature for 3 hours. The reaction was quenched by adding NaOH solution (1M, 50 ml), stirred for 5 minutes and diluted with EtOAc (200 ml). The organic layer was washed with brine (3 x 50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give (( 3aR , 5R , 6R , 6aR )-6-(benzyloxy)-5-( ( S )-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-yl)methanol, which was used in the following stage without additional purification.

Step 5: Sulfuric acid (0.348 ml, 5% v/v aqueous solution, 6.53 mmol) was added to the solution of ( 3aR , 5R , 6R , 6aR )-6-(benzyloxy)-5-( ( R )-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyl-6vinyltetrahydrofuro[2,3-d][1,3]dioxole (6.15 g, 16.3 mmol) in MeCN (30 ml) at room temperature and the reaction mixture was stirred for 2 hours. The reaction mixture was made basic with a minimal amount of sodium hydroxide and then magnesium sulfate was added. The suspension was filtered and concentrated under reduced pressure to give (R)-1-((3aR,5R,6R,6aR)-6-(benzyloxy)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d] [1,3]dioxol-5-yl)ethane-1,2-diol, which was used crudely without further purification.

Step 6: A solution of sodium periodate (277 mg, 1.30 mmol) in water was cooled to 0°C, then a solution of ( R )-1-((3a R ,5 R ,6 R ,6a R )-6 was added dropwise -(benzyloxy)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)ethane-1,2-diol (315 mg, 0.925 mmol) in MeOH (2 ml). The reaction mixture was stirred for 1 hour at 0°C and then warmed to room temperature and stirred overnight. The reaction mixture was cooled to 0°C and ethylene glycol (1 ml, 17.9 mmol) was added. The reaction mixture was stirred for 5 minutes, then saturated sodium sulfite solution (50 ml) was added and the reaction mixture was warmed to room temperature. The mixture was diluted with EtOAc (100 ml) and the organic layer was washed with brine (3 x 200 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure to give ( 3aR , 4aS , 7aR , 7bR )-7a- (benzyloxy)-2,2-dimethylhexahydrofuro[3',4':4,5]furo[2,3-d][1,3]dioxol-5-ol, which was used without further purification.

Step 7: Potassium tert-butoxide (183 mg, 1.63 mmol) was added portionwise to a suspension of methyltriphenylphosphonium bromide (611 mg, 1.71 mmol) in THF (4 ml) at room temperature. The reaction mixture was stirred at room temperature for 3 hours, then the solution was cooled to 0°C, a solution of (3a R ,4a S ,7a R ,7b R )-7a-(benzyloxy)-2,2dimethylhexahydrofuro[3',4' :4,5]furo[2,3-d][1,3]dioxol-5-ol (251 mg, 0.814 mmol) and the reaction mixture was stirred for 2 hours. The mixture was quenched with saturated aqueous ammonium chloride (10 ml) and the mixture was extracted with EtOAc (1 x 50 ml). The combined organic layers were washed with brine (2 x 50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography (0%-100% EtOAc/hexane) to give (( 3aR , 5R , 6R , 6aR )-6-(benzyloxy)-2,2-dimethyl-5-vinyltetrahydrofuro[ 2,3-d][1,3]dioxol-6-yl)methanol. ¹ H NMR (600 MHz, CDCl ₃ ) δ 7.40 (d, J=7.3 Hz, 2H), 7.37-7.33 (m, 2H), 7.31-7.27 (m, 1H), 5.94 (dd, J=17.2, 10.8, 5.3 Hz, 1H), 5.82 (d, J=3.9 Hz, 1H), 5.49 (dt, J =17.3, 1.6 Hz, 1H), 5.30 (dt, J=10.8, 1.5 Hz, 1H), 4.79 (d, J=11.1 Hz, 1H), 4 .74 (d, J=11.1 Hz, 1H), 4.73-4.70 (m, 1H), 4.68 (d, J=3.9 Hz, 1H), 3.80 (d, J=12.1 Hz, 1H), 3.69 (d, J=12.1 Hz, 1H), 1.63 (s, 3H), 1.39 (s, 3H).

Step 8: Into a vessel containing 3-bromo-N-(2,4-dimethoxybenzyl)-7-iodoquinoline-2-amine (1.62 g, 3.26 mmol), tris(dibenzylideneacetone)dipalladium(0) (75 mg, 0.08 mmol), sodium tert-butoxide (310 mg, 3.3 mmol) and bis(2-diphenylphosphinophenyl)ether (88 mg, 0.16 mmol), added ((3aR,5R,6R,6aR) -6-(benzyloxy)-2,2-dimethyl-5-vinyltetrahydrofuro[2,3-d][1,3]dioxol-6-yl)methanol (500 mg, 1.63 mmol) as a solution in THF ( 8.16 ml). The reaction mixture was heated to 65°C overnight. The reaction was quenched with water and then extracted with DCM twice. The combined DCM layer was dried with Na ₂ SO ₄ and concentrated under reduced pressure to give 7-(((3aR,4aR,7aR,7bR)-7a-(benzyloxy)-2,2-dimethylhexahydrofuro[3',4':4 ,5]furo[2,3-d][1,3]dioxol-5-yl)methyl)-3-bromo-N-(2,4-dimethoxybenzyl)quinolin-2-amine. MS: 677/679 (M+1/M+3).

Step 9: Boron trichloride (0.79 ml, 0.79 mmol) was added to a solution of 7-(((3aR,4aR,7aR,7bR)-7a-(benzyloxy)-2,2-dimethylhexahydrofuro[3',4' :4,5]furo[2,3-d][1,3]dioxol-5-yl)methyl)-3-bromo-N-(2,4-dimethoxybenzyl)quinolin-2-amine (107 mg, 0 .16 mmol) in DCM (8 ml) at -78°C. The reaction mixture was stirred for 15 minutes then heated to 0°C and stirred for 30 minutes. The reaction was quenched by adding THF and a saturated aqueous solution of NaHCO ₃ (4:1). All solvent was evaporated under reduced pressure and the crude material was purified by mass initiated reverse phase HPLC (MeCN/water with 0.1% NH ₄ OH modifier) to give (3R,3aS,6aR)-6-((2-amino-3 -bromoquinolin-7-yl)methyl)tetrahydrofuro[3,4-b]furan-2,3,3a(4H)-triol. MS: 397/399 (M+1/M +3).

Step 10: Into a vessel containing (3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)methyl)tetrahydrofuro[3,4-b]furan-2,3,3a (4H)-triol (20 mg, 0.050 mmol), 1,1'-(azodicarbonyl)dipiperidine (19 mg, 0.076 mmol) was added in anhydrous acetonitrile (750 µl), followed by trin -butylphosphine (20 µl, 0 .08 mmol) at room temperature. The mixture was stirred for 1 hour. In a separate oven-dried vial containing 4-methyl-7H-pyrrolo[2,3-d]pyrimidine (13 mg, 0.10 mmol) dissolved in anhydrous DMF (250 μl) was added NaH (4.0 mg, 0.10 mmol). This mixture was stirred for 30 minutes at room temperature and then added to the mixture originally containing the triol described above. The resulting reaction mixture was then stirred at room temperature overnight. The reaction mixture was directly purified by preparative HPLC (MeCN/water with 0.1% TFA modifier) to obtain two isomers: (2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl )methyl)-2-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuro[3,4-b]furan-3,3a(4H)-diol as TFA salt. MS: 512/514 (M+1/M+3). ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 8.96 (s, 1H), 8.80 (s, 1H), 8.00 (s, 1H), 7.77 (d, J=8, 3 Hz, 1H), 7.55 (s, 1H), 7.41 (d, J=8.2 Hz, 1H), 7.07 (s, 1H), 6.25 (d, J=8, 0 Hz, 1H), 4.37 (d, J=8.0 Hz, 1H), 4.32-4.30 (m, 1H), 4.14-4.08 (m, 1H), 3, 99 -3.95 (m, 1H), 3.42 -3.36 (m, 1H), 3.08-3.03 (m, 2H), 2.82 (s, 3H) and (2R,3R ,3aS,6R,6aR)-6-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl) tetrahydrofuro[3,4-b]furan-3,3a(4H)-diols in the form of TFA salt. (MS: 512/514 (M+1/M+3). ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 8.85 (s, 1H), 8.75 (s, 1H), 7.92 (s, 1H), 7.77 (d, J=8.1 Hz, 1H), 7.54 (s, 1H), 7.38 (d, J=7.8 Hz, 1H), 6.97 (s, 1H), 6.21 (d, J=7.6 Hz, 1H), 4.46 (d, J=7.6 Hz, 1H), 4.32-4.25 (m, 1H) , 4.23-4.20 (m, 1H), 3.99 -3.97 (m, 1H), 3.88-3.86 (m, 1H), 3.13-3.04 (m, 2H), 2.76 (s, 3H).

Example 135

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(4-amino-5-methyl-7H-pyrrolo[2,3- d]pyrimidin-7-yl)tetrahydrofuro[3,4-b]furan-3,3a(4H)-diol

Step 1: Crude 7-(((3aR,4aR,7aR,7bR)-7a-(benzyloxy)-2,2-dimethylhexahydrofuro[3',4':4,5]furo[2,3-d][1 ,3]dioxol-5-yl)methyl)-3-bromo-N-(2,4-dimethoxybenzyl)quinolin-2-amine (1.1 g, 1.6 mmol) was purified by silica column chromatography (0- 40% EtOAc/hexane) to give 7-(((3aR,4aR,5S,7aR,7bR)-7a-(benzyloxy)-2,2-dimethylhexahydrofuro[3',4':4,5]furo[2, 3-d][1,3]dioxol-5-yl)methyl)-3-bromo-N-(2,4-dimethoxybenzyl)quinolin-2-amine as a solid. MS: 677/679 (M+1/M+3). ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.03 (s, 1H), 7.65 (s, 1H), 7.44 (d, J=8.2 Hz, 1H), 7.40-7 .27 (m, 6H), 7.18 (d, J=7.9 Hz, 1H), 6.52 (d, J=2.3 Hz, 1H), 6.47 (dd, J=8, 3, 2.3 Hz, 1H), 6.06 (d, J=3.6 Hz, 1H), 5.85 (s, 1H), 4.76-4.73 (m, 2H), 4, 70 (d, J=3.6 Hz, 1H), 4.53 (d, J=2.2 Hz, 1H), 4.49 (d, J=10.5 Hz, 1H), 4.27 ( td, J=7.1, 2.2 Hz, 1H), 4.19-4.11 (m, 2H), 3.93 (d, J=10.3 Hz, 1H), 3.90 (s , 3H), 3.82 (s, 3H), 3.18 -3.11 (m, 2H), 1.64 (s, 3H), 1.46 (s, 3H).

Step 2: Boron trichloride (5 ml, 5.1 mmol) was added to a solution of 7-(((3aR,4aR,5S,7aR,7bR)-7a-(benzyloxy)-2,2-dimethylhexahydrofuro[3',4' :4,5]furo[2,3-d][1,3]dioxol-5-yl)methyl)-3-bromo-N-(2,4-dimethoxybenzyl)quinolin-2-amine (690 mg, 1 .02 mmol) in DCM (20 ml) at -78°C. The reaction mixture was stirred for 15 minutes, then heated to 0°C and stirred for 30 minutes. The reaction was quenched by adding THF and saturated aqueous NaHCO ₃ solution (8 ml: 2 ml). The mixture was concentrated under reduced pressure and the residue was purified by reverse phase HPLC (MeCN/water with 0.1% NH ₄ OH modifier) to give (3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinoline- 7-yl)methyl)tetrahydrofuro[3,4-b]furan-2,3,3a(4H)-triol. MS: 397/399 (M+1/M+3).

Step 3: Into a vessel containing (3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)methyl)tetrahydrofuro[3,4-b]furan-2,3,3a (4H)-triol (20 mg, 0.05 mmol) in anhydrous acetonitrile (750 µl), 1,1'-(azodicarbonyl)dipiperidine (19 mg, 0.076 mmol) was added followed by trin -butylphosphine (20 µl, 0.08 mmol) at room temperature. The mixture was stirred for 1 hour. In a separate oven-dried vial containing 4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (17 mg, 0.1 mmol) in anhydrous acetonitrile (250 µl) , DBU (15 μL, 0.10 mmol) was added. This mixture was stirred for 30 minutes at room temperature and then added to the mixture originally containing the triol described above. The resulting mixture was stirred at room temperature overnight. The reaction mixture was then directly purified by reverse phase HPLC (MeCN/water with 0.1% TFA modifier) to give (2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl )methyl)-2-(4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuro[3,4-b]furan-3,3a(4H)-diol, TFA salts, in solid form. MS: 546/548 (M+1/M+3).

Step 4: Ammonia in methanol (2 mL, 7M, 14 mmol) was added to the microwave vessel containing (2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)methyl )-2-(4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuro[3,4-b]furan-3,3a(4H)-diol, TFA salt (16 mg, 0.029 mmol). The reaction mixture was heated at 145°C for 5 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by mass initiated reverse phase HPLC (MeCN/water with 0.1% NH ₄ OH modifier) to give (2R,3R,3aS,6S,6aR)-6-((2- amino-3-bromoquinolin-7-yl)methyl)-2-(4-amino-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuro[3,4-b]furan- 3,3a(4H)-diol as a solid. MS: 527/529 (M+1/M+3). ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 8.32 (s, 1H), 8.08 (s, 1H), 7.56 (d, J=8.3 Hz, 1H), 7.35 (s, 1H), 7.15-7.13 (m, 2H), 6.69 (s, 2H), 6.59 (s, 2H), 6.06 (d, J=8.2 Hz, 1H), 5.54 (d, J=6.7 Hz, 1H), 5.49 (s, 1H), 4.17-4.12 (m, 2H), 4.08-3.99 (m , 1H), 3.92 (d, J=9.0 Hz, 1H), 3.37-3.35 (m, 1H), 3.01-2.89 (m, 2H), 2.40 ( s, 3H).

Example 136: Example 136 in Table 25 was synthesized in the same manner as described in steps 1-4 of Example 135, replacing 4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine with a suitable nucleobase. The reagents and starting material used for substitution were purchased commercially, synthesized as described above, or synthesized by known methods described in the literature.

Table 25 Etc. Structure Name MS 136 (2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)tetrahydrofuro[3,4-b]furan-3,3a(4H)-diol 513/515 (M+1/M+3)

Example 137

(2 R ,3 R ,3a S ,6 S ,6a R )-6-((2-amino-3-(difluoromethyl)quinolin-7-yl)methyl)-2-(4-amino-7 H -pyrrolo [2,3- d ]pyrimidin-7-yl)hexahydro- 2H -cyclopenta[ b ]furan- 3,3a -diol

Stage 1: (2 R ,3 R ,3a S ,6a R )-2-(4-chloro-7 H -pyrrolo[2,3- d ]pyrimidin-7-yl)-6-methylenehexahydro was loaded into a hermetically sealed test tube -2H- cyclopenta[ b ]furan-3,3a-diol (200 mg, 0.650 mmol), 1,4-dioxane (3 ml) and concentrated ammonia hydrate (28 wt%, 3 ml) at room temperature. The mixture was tightly capped and then stirred at 90°C for 16 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica column chromatography (30% MeOH/DCM) to give ( 2R , 3R , 3aS ,6a R )-2-(4-amino- 7H -pyrrolo[2,3- d ]pyrimidin-7-yl)-6-methylenehexahydro- 2H- cyclopenta[ b ]furan-3,3a - diol as an oil . MS: 289 (M+1). ^1H NMR (300 MHz, DMSO- d6 ) δ 8.08 (s, 1H), _7.31 (d, J= 3.9 Hz, 1H), 7.04 (brs, 2H), 6 .63 (d, J= 3.6 Hz, 1H), 6.06 (d, J= 8.1 Hz, 1H), 5.37 (d, J= 7.2 Hz, 1H), 5.25 (s, 1H), 5.10-5.06 (m, 2H), 4.31-4.23 (m, 2H), 2.65-2.61 (m, 1H), 2.50-2 .40 (m, 1H), 2.07-2.02 (m, 1H), 1.72-1.61 (m, 1H).

Step 2: Compound ( 2R , 3R , 3aS , 6aR )-2-(4-amino- 7H -pyrrolo[2,3- d ]pyrimidin-7-yl)-6-methylenehexahydro- 2H - Cyclopenta[ b ]furan-3,3a-diol (60 mg, 0.208 mmol) was co-evaporated with THF three times (2 ml each). The mixture was then treated with 9-BBN (2289 μL, 0.5 M in THF, 1.15 mmol) at room temperature under argon. The mixture was stirred at 50°C for 1 hour. A solution of K ₃ PO ₄ (220 mg, 1.04 mmol) in water (1 ml) at 0° C was then added to this reaction mixture and stirring was continued at room temperature for 0 .5 h. A solution of 7-bromo-3-(difluoromethyl)quinoline-2-amine (56.6 mg, 0.207 mmol) in THF (3 ml) was then added followed by PdCl ₂ (dppf) (15.2 mg, 0.021 mmol). The resulting reaction mixture was microwaved at 70°C for 2 hours. The mixture was concentrated under reduced pressure and the resulting residue was purified by reverse phase column chromatography (ACN/water with 5 mM NH ₄ HCO ₃ modifier). The product was further purified by reverse phase HPLC (ACN/water with 10 mM NH ₄ HCO ₃ modifier) to give (2 R ,3 R ,3a S ,6 S ,6a R )-6-((2-amino-3-( difluoromethyl)quinolin-7-yl)methyl)-2-(4-amino-7 H -pyrrolo[2,3- d ]pyrimidin-7-yl)hexahydro-2 H -cyclopenta[ b ]furan-3,3 a -diol in the form of a solid. MS: 483 (M+1). ¹ H-NMR (400 MHz, DMSO- d6 ) δ 8.17 (s, 1H) _, 8.09 (s, 1H), 7.67 (d, J= 8.4 Hz, 1H), 7, 45 (d, J= 3.6 Hz, 1H), 7.29 (s, 1H), 7.26-7.00 (m, 4H), 6.68 (d, J= 3.6 Hz, 1H ), 6.45 (br.s, 2H), 5.89 (d, J= 8.0 Hz, 1H), 5.26 (d, J= 6.8 Hz, 1H), 5.08 (s , 1H), 4.13 (t, J= 7.6 Hz, 1H), 3.96 (d, J= 5.6 Hz, 1H), 2.84 -2.81 (m, 1H), 2 .66-2.65 (m, 1H), 2.30-2.23 (m, 1H), 1.97-1.93 (m, 1H), 1.71-1.68 (m, 2H) , 1.58-1.51 (m, 1H).

PRMT5-MEP50 enzyme methylation assay

The PRMT5-MEP50 biochemical assay is a direct measurement of the methylation activity of the enzyme complex on a short peptide substrate derived from the N-terminus of histone H4. The methylation experiment was carried out with the recombinant PRMT5-MEP50 protein complex. The inhibitory effect of small molecules was assessed by the effectiveness of the compounds to inhibit this reaction (EC ₅₀ ).

In this assay, the potency (EC ₅₀ ) of each compound was determined based on a twenty-point (1:2 serial dilution; highest compound concentration of 100,000 nM) titration curve using the following outlined procedure. To each well of a white ProxiPlus 384-well plate, 100 nL of compound (1% DMSO in a final assay volume of 10 µL) was added followed by 8 µL of 1x assay buffer (50 mM Bicine pH 8.0, 1 mM DTT, 0.004% Tween20.0 .01% BSA) containing 1.25 nM full-length (FL)-PRMT5-MEP50 enzyme complex (recombinant proteins from baculovirus-transfected Sf21 cells: FL-PRMT5; MW=73837 kDa and FL-MEP50; MW=38614) and 1 µl 150 µM S-(5'-Adenosyl)-L-Methionine Chloride (SAM). The plates were sealed and placed in a 37°C humidified chamber for 60 minutes to pre-incubate with compound. Each reaction was then initiated by adding 1 μl of 1x assay buffer containing 750 nM biotinylated H4R3(Mel) peptide. The final reaction mixture in each 10 μL well consisted of 1.0 nM PRMT5-MEP50, 75 nM biotinylated peptide, and 15 μM SAM. Methylation reactions were carried out for 150 minutes in a sealed plate at 37°C. Reactions were immediately quenched by adding 1 μl of 5% formic acid. The plates were then frozen and sent to SAMDITM Tech Inc. to determine the percentage of conversion from H4R3(Me1) to H4R3(Me2). Dose-response curves were obtained by plotting percent effect (% product conversion; Y-axis) vs. Log10 of compound concentration (X-axis). EC ₅₀ values were determined by nonlinear regression according to models for either sigmoidal (4 parameters) or biphasic (7 parameters) dose-response curves.

PRMT5 target cell (TE) binding assay

The PRMT5 TE assay is a biomarker assay to identify compounds that inhibit symmetric arginine dimethylation (SDMA) of PRMT5 substrates. The following substrates are described for PRMT5: Histone H2A and H4 R3, Histone H3 R2, Histone H3 R8, Sm splicing proteins, ribosomal protein RPS10, p53, FEN1, nucleoplasmin, nucleolin, EGFR and EBNA. The assay focuses on the detection of symmetrically dimethylated nuclear proteins using high-throughput imaging technology. Detection of the expression of symmetrically dimethylated nuclear proteins is carried out using a mixture of primary rabbit monoclonal antibodies to SDMA (CST 13222), which in turn are recognized by an Alexafluor 488 dye-conjugated anti-rabbit IgG secondary antibody. The IN Cell Analyzer 2200 or Opera-Phenix measures the intensity of the nuclear fluorescent dye Alexafluor 488, which is directly related to the level of expression of symmetrically dimethylated nuclear proteins at the single-cell level. AF488 nuclear dye intensities are compared to the mean of DMSO-treated cells (MIN) to represent the percent inhibition for each compound-treated well.

In this assay, the cellular potency (EC50) of each compound was determined from a ten-point (1:3 serial dilution; highest compound concentration of 10,000 nM) titration curve using the following outlined procedure. Each well of a BD falcon collagen-coated black/clear bottom 384-well plate was seeded with 4,000 MCF-7 cells in 30 μL medium and allowed to attach for 5 hours. The medium was ATCC-formulated Eagle's minimal essential medium, catalog no. 30-2003. The following components were added to the basic medium: 0.01 mg/ml human recombinant insulin; fetal bovine serum to a final concentration of 10%. An additional 30 μl of medium containing 2x compounds was added to each well. Cells were treated for 3 days in a 37°C CO ₂ incubator. On day 3, cells were fixed with Cytofix reagent, permeabilized with 0.4% Triton-X-100/Cytofix, and washed with Ca/Mg-free D-PBS. Cells were blocked with Licor Odessey blocking reagent for 1 hour at room temperature, then incubated with anti-SDMA antibody (1:1000) at 4°C overnight. 1° antibody was removed, followed by three washes with DPBS without Ca/Mg and 0.05% Tween20. Hoechst (5 μg/ml), Cell Mask deep dye (1:2000), and Alexa488-conjugated goat anti-rabbit IgG (2 μg/ml) were added for 1 hour at room temperature. A final wash step was performed (three washes), then the plate was sealed for imaging on an In Cell Analyzer 2200 or Opera-Phenix. Images from the analyzer were loaded into Columbus for image analysis. IC ₅₀ values were determined using the 4-parameter robust fit method based on the percentage of fluorescence vs. (Log10) concentrations of the compound.

Representative compounds of the present invention were tested using the assay protocol described in this example. The results are presented in Table 26 below.

Table 26
When only one EC ₅₀ value is shown, the data were fit to a 4-parameter single-phase sigmoidal model. When two EC50 values are shown, the data were fit to a 7-parameter biphasic model Etc. No. Enzyme methylation assay (EC ₅₀ or EC ₅₀ 1, nM; E.C. ₅₀ 2, nM) TE Analysis (EC ₅₀ , nM) 1 0.5; 56 18.0 2 0.5 0.7 3 0.8; 193 20.0 4 2.4; 288 186.0 5 0.8 19.0 6 0.6 1.2 7 0.7 4.8 8 0.5 0.5 9 0.3 1.3 10 0.5; 22 6.4 eleven 0.9; 501 131.0 12 33; 20890 10000.0 13 0.5; 89 14.0 14 1.3; 182 17.0 15 0.8 0.5 16 0.4 0.9 17 0.3 0.9 18 0.4; 228.5 10.6 19 0.4 1.1 20 0.5 18.6 21 0.8 0.5 22 1.0 30.0 23 0.4 1.5 24 0.4 1.3 25 11.0; 8913.0 258.2 26 1.1 4.0 27 0.4 2.8 28 0.8 13.0 29 0.3 1.7 thirty 0.7 0.8 31 0.4 0.8 32 0.4 0.8 33 0.6 0.4 34 0.3 0.3 35 0.5 0.8 36 0.5 1.4 37 0.3 0.6 38 0.3 0.6 39 0.3 0.3 40 0.4 0.7 41 0.7 2.9 42 0.3 0.3 43 0.4 1.0 44 0.4 8.8 45 0.3 1.2 46 0.5 16.8 47 0.2 1.4 48 0.5 1.7 49 0.5 13.0 50 0.3 0.7 51 1.2 2.8 52 0.5 75.5 53 0.3 4.5 54 0.3 8.1 55 0.5; 190.5 3.9 56 0.2 1.2 57 0.7; 142.9 2.1 58 0.4 1.0 59 0.6 4.6 60 0.4 1.5 61 0.5 3.2 62 0.5 3.7 63 0.4 5.6 64 0.3 16.2 65 0.2; 199.5 178.6 66 0.3 0.9 67 0.8 1.2 68 0.5 1.1 69 1.1 103.0 70 0.4 1.0 71 1.6 9.0 72 0.9 1.2 73 0.4 2.0 74 0.3 1.0 75 0.7 5.0 76 0.9 8.6 77 2.0; 242.7 185.7 78 13.3; 1.19 5993.0 79 2.9 52.5 80 2.9 97.0 81 0.7 3.9 82 0.7; 75.9 87.2 83 1.2 41.1 84 0.6 7.5 85 1.2; 245.5 32.4 86 0.5; 63.8 37.5 87 0.5 22.9 88 0.2 25.3 89 1.3 4.4 90 0.9 42.2 91 0.4 6.3 92 0.5 9.9 93 0.5; 109.6 3.5 94 0.8 5.3 95 2.8 47.0 96 0.8 11.1 97 0.4 1.3 98 3.4; 2570.0 271.7 99 1.7, 1884.0 202.4 100 0.6; 32.0 7.4 101 0.3 1.0 102 0.3 2.0 103 0.4; 40.7 12.4 104 3.8 7.0 105 0.3; 21.9 0.9 106 0.3 0.5 107 0.2 0.5 108 0.2 0.9 109 0.7 5.9 110 0.9 39.6 111 30.6; 2661.0 2330.0 112 0.6 4.0 113 1.1 1.8 114 1.4 4.4 115 0.4; 255.1 13.6 116 2.4; 660.7 53.7 117 1.0 8.5 118 3.2; 1585.0 103.4 119 1.0; 116.1 180.0 120 0.6 2.0 121 0.4 1.0 122 0.6 2.5 123 1.0 13.1 124 0.3 2.3 125 0.8 0.7 126 0.6 2.9 127 0.7 0.8 128 0.7 15.5 129 33.9; 31620.0 10000.0 130 0.6 134.9 131 0.6 21.3 132 3.9; 3311.0 236.3 133 0.8 2.7 134 3.5 35.8 135 0.4 0.6 136 0.5 0.4 137 0.5 0.8

Claims (203)

1. Compound of formula I or a pharmaceutically acceptable salt thereof, wherein X represents CH ₂ or O; Y represents CH ₂ , NH or O; R ¹ and R ⁷ are taken together to form a five-membered carbon ring, optionally substituted with 1-3 halogens, or a five-membered heterocycloalkyl ring containing one O atom; R ² represents H, OH, CH ₃ , CHF ₂ or F; R ³ represents H, halogen, NH ₂ , NHCH ₃ , OH, OCH _{3 ,} C _1-4 alkyl, optionally substituted with 1-3 halogens or OH, or C _3-5 cycloalkyl, optionally substituted with 1-3 halogens or OH; R ⁵ is H, NH ₂ or NHR ⁶ ; And R ⁴ is H, halogen, CH ₃ , CHF ₂ or CF ₃ ; or ^R4 and ^R5 , taken together with the carbon atoms to which they are attached, combine to form a 5-membered heterocycloalkyl containing one N atom, said heterocycloalkyl being optionally substituted with one to four substituents independently selected from halogen, _CH3 , CF ₃ and CF ₂ H; R ⁶ when present is CH ₃ , C ₂ H ₅ , CH ₂ CH ₂ CH ₃ , CH(CH ₃ ) ₂ , CH ₂ CHF ₂ , CH ₂ CF ₃ or CH ₂ -cyclopropyl; R ⁸ represents H, halogen, C _1-4 alkyl, optionally substituted with 1-3 halogens, C _3-5 cycloalkyl, optionally substituted with 1-3 halogens, or phenyl, optionally substituted with 1-3 halogens; And R ¹⁰ represents H, C _1-6 alkyl, NH ₂ or halogen. 2. Compound of formula Ia or a pharmaceutically acceptable salt thereof, wherein X represents CH ₂ or O; Y represents CH ₂ , NH or O; R ¹⁰ represents H, C _1-6 alkyl, NH ₂ or halogen; R ¹ and R ⁷ are taken together to form a five-membered ring; R ² represents H, OH, CH ₃ , CHF ₂ or F; R ³ is H, halogen, CH ₃ , C ₂ H ₅ , cyclopropyl, NH ₂ , NHCH ₃ , CF ₃ , OH, OCH ₃ or CHF ₂ ; R ⁴ is H, halogen, CH ₃ , CHF ₂ or CF ₃ ; And R ⁵ is H, NH ₂ or NHR ⁶ ; or ^R4 and ^R5 , taken together with the carbon atoms to which they are attached, combine to form a 5-membered heterocycloalkyl containing one N atom, said heterocycloalkyl being optionally substituted with one to four substituents independently selected from halogen, _CH3 , CF ₃ and CF ₂ H; R ⁶ when present is CH ₃ , C ₂ H ₅ , CH ₂ CH ₂ CH ₃ , CH(CH ₃ ) ₂ , CH ₂ CHF ₂ , CH ₂ CF ₃ or CH ₂ -cyclopropyl; And R ⁸ represents H, C _1-4 alkyl or halogen. 3. Compound according to claim 1 of formula Ib or a pharmaceutically acceptable salt thereof, wherein X represents CH ₂ or O; Y represents CH ₂ , NH or O; W represents CR ¹¹ R ¹¹ or O; R ² represents H, OH or CH ₃ ; R ³ represents H, halogen, OH, NH ₂ , NHCH ₃ , OCH _{3 ,} C _1-4 alkyl, optionally substituted with 1-3 halogens or OH, or C _3-5 cycloalkyl, optionally substituted with 1-3 halogens or OH; R ⁴ is H, halogen, CH ₃ , CHF ₂ or CF ₃ ; R ⁵ is H, NH ₂ or NHR ⁶ ; R ⁸ represents H, halogen, C _1-4 alkyl, optionally substituted with 1-3 halogens, C _3-5 cycloalkyl, optionally substituted with 1-3 halogens, or phenyl, optionally substituted with 1-3 halogens; R ¹⁰ represents H, C _1-6 alkyl, NH ₂ or halogen; And each R ¹¹ , when present, is independently selected from H and halogen. 4. A compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein R ⁴ is H, F, Cl, Br, CF ₃ , CHF ₂ or CH ₃ . 5. A compound according to claim 3 or 4 or a pharmaceutically acceptable salt thereof, where R ¹⁰ represents H, NH ₂ , F, Cl, CH ₃ . 6. A compound according to claim 3, 4 or 5 or a pharmaceutically acceptable salt thereof, where R ³ represents NH ₂ , Cl, OCH ₃ , CH ₂ OH, CHF ₂ , C(CH ₃ ) ₂ OH, CH ₂ CH ₃ , CH(CH ₃ ) ₂ , cyclopropyl, NHCH ₃ or CH ₃ . 7. A compound according to claim 3, 4, 5 or 6 or a pharmaceutically acceptable salt thereof, where R ⁸ represents H, CH ₃ , CH ₂ CH ₃ , cyclopropyl, CHF ₂ or F. 8. A compound according to claim 3, 4, 5, 6 or 7, or a pharmaceutically acceptable salt thereof, wherein R ⁵ is NH ₂ , NHCH ₂ CF ₃ or NHCH ₂ cyclopropyl. 9. A compound according to claim 3, 4, 5, 6, 7 or 8, or a pharmaceutically acceptable salt thereof, wherein W is O, CHF, CF ₂ or CH ₂ . 10. Compound according to claim 1 of formula Ic or a pharmaceutically acceptable salt thereof, wherein X represents CH ₂ or O; Y represents CH ₂ , NH or O; W represents CH ₂ or O; R ² represents H, OH, CH ₃ or CH ₂ F; R ³ is H, halogen, CH ₃ , C ₂ H ₅ , cyclopropyl, NH ₂ , NHCH ₃ , CF ₃ , OH, OCH ₃ or CHF ₂ , CH ₂ OH, C(CH ₃ ) ₂ OH CH ₂ CH ₃ or CH(CH ₃ ) ₂ ; R ⁴ is H, halogen, CH ₃ , CHF ₂ or CF ₃ ; R ⁵ is H, NH ₂ or NHR ⁶ ; or ^R4 and ^R5 , taken together with the carbon atoms to which they are attached, combine to form a 5-membered heterocycloalkyl containing one N atom, said heterocycloalkyl being optionally substituted with one to four substituents independently selected from halogen, _CH3 , CF ₃ and CF ₂ H; R ⁶ when present is CH ₃ , C ₂ H ₅ , CH ₂ CH ₂ CH ₃ , CH(CH ₃ ) ₂ , CH ₂ CHF ₂ , CH ₂ CF ₃ or CH ₂ -cyclopropyl; And R ⁸ represents H, C _1-4 alkyl or halogen. 11. The compound according to claim 10 or a pharmaceutically acceptable salt thereof, where R ² represents H. 12. A compound according to claim 10 or 11 or a pharmaceutically acceptable salt thereof, where R ³ represents CH ₃ , Cl, OCH ₃ , CH ₂ OH, C(CH ₃ ) ₂ OH, CHF ₂ , CH ₂ CH ₃ , CH( CH ₃ ) ₂ , cyclopropyl or NH ₂ . 13. A compound according to claim 10, 11 or 12 or a pharmaceutically acceptable salt thereof, where R ⁴ represents H, Cl, F, CH ₃ , CHF ₂ , CF ₃ or Br. 14. A compound according to claim 10, 11, 12 or 13 or a pharmaceutically acceptable salt thereof, wherein R ⁵ is NH ₂ , NHCH ₂ CF ₃ or NHCH ₂ cyclopropyl. 15. The compound according to claim 10, 11, 12, 13 or 14 or a pharmaceutically acceptable salt thereof, where R ⁸ represents H. 16. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is: (2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)oxy)-2-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)hexahydro-2H-cyclopenta[b]furan-3,3a-diol, (2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)oxy)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)hexahydro-2H-cyclopenta[b]furan-3,3a-diol, (2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)oxy)-2-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)hexahydro-2H-cyclopenta[b]furan-3,3a-diol, (2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)hexahydro-2H-cyclopenta[b]furan-3,3a-diol, (2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)hexahydro-2H-cyclopenta[b]furan-3,3a-diol, (1S,2R,3aR,4S,6aR)-4-((2-amino-3-chloroquinolin-7-yl)methyl)-2-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)hexahydropentalene-1,6a(1H)-diol, (1S,2R,3aR,4R,6aR)-4-((2-amino-3-fluoroquinolin-7-yl)methyl)-2-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)hexahydropentalene-1,6a(1H)-diol, (1S,2R,3aR,4S,6aR)-4-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)hexahydropentalene-1,6a(1H)-diol, (2R,3R,3aS,6S,6aR)-6-((2-amino-3-(difluoromethyl)quinolin-7-yl)methyl)-2-(4-methyl-7H-pyrrolo[2,3-d ]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol, (1S,2R,3aR,4S,6aR)-2-(4-amino-2-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-4-((2-amino-3- chloroquinolin-7-yl)methyl)hexahydropentalene-1,6a(1H)-diol, (1S,2R,3aR,4S,6aR)-2-(4-amino-2-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-4-((2-amino-3- fluoroquinolin-7-yl)methyl)hexahydropentalene-1,6a(1H)-diol, (1S,2R,3aR,4S,6aR)-4-((2-amino-3-fluoroquinolin-7-yl)methyl)-2-(4-amino-5-fluoro-7H-pyrrolo[2,3- d]pyrimidin-7-yl)hexahydropentalene-1,6a(1H)-diol, (1S,2R,3aR,4S,6aR)-4-((2-amino-3-chloroquinolin-7-yl)methyl)-2-(4-amino-5-fluoro-7H-pyrrolo[2,3- d]pyrimidin-7-yl)hexahydropentalene-1,6a(1H)-diol, (1S,2R,3aR,4S,6aR)-2-(4-amino-2-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-4-((2-amino-3- bromoquinolin-7-yl)methyl)hexahydropentalene-1,6a(1H)-diol, (1S,2R,3aR,4S,6aR)-4-((2-amino-3-fluoroquinolin-7-yl)methyl)-2-(4-amino-5-methyl-7H-pyrrolo[2,3- d]pyrimidin-7-yl)hexahydropentalene-1,6a(1H)-diol, (1S,2R,3aR,4S,6aR)-4-((2-amino-3-chloroquinolin-7-yl)methyl)-2-(4-amino-5-methyl-7H-pyrrolo[2,3- d]pyrimidin-7-yl)hexahydropentalene-1,6a(1H)-diol, (1S,2R,3aR,4S,6aR)-4-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(4-amino-5-methyl-7H-pyrrolo[2,3- d]pyrimidin-7-yl)hexahydropentalene-1,6a(1H)-diol, (1S,2R,3aR,4S,6aR)-4-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)hexahydropentalene-1,6a(1H)-diol, (1S,2R,3aR,4S,6aR)-4-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(4-amino-5-fluoro-7H-pyrrolo[2,3- d]pyrimidin-7-yl)hexahydropentalene-1,6a(1H)-diol, (2R,3R,3aS,6S,6aR)-6-[(2-amino-3-bromoquinolin-7-yl)methyl]-2-[4-amino-5-(difluoromethyl)-7H-pyrrolo[2, 3-d]pyrimidin-7-yl]hexahydro-3aH-cyclopenta[b]furan-3,3a-diol, (2R,3R,3aS,6S,6aR)-6-((2-amino-3-fluoroquinolin-7-yl)methyl)-2-(4-amino-5-fluoro-2-methyl-7H-pyrrolo[ 2,3-d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol, (2R,3R,3aS,6S,6aR)-2-(4-amino-2-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-6-((2-amino-3- fluoroquinolin-7-yl)methyl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol, (2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)oxy)-2-(2-amino-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol dihydrochloride, (2R,3R,3aS,6S,6aR)-2-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-6-[(2-amino-3- chloroquinolin-7-yl)methyl]hexahydro-3aH-cyclopenta[b]furan-3,3a-diol, (2R,3R,3aS,6S,6aR)-2-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-6-[(2-amino-3- fluoroquinolin-7-yl)methyl]hexahydro-3aH-cyclopenta[b]furan-3,3a-diol, (2R,3R,3aS,6S,6aR)-6-[(2-amino-3-bromoquinolin-7-yl)oxy]-2-(4-amino-5-phenyl-7H-pyrrolo[2,3- d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol, (2R,3R,3aS,6S,6aR)-2-(4-amino-5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-6-[(2-amino-3- fluoroquinolin-7-yl)methyl]hexahydro-3aH-cyclopenta[b]furan-3,3a-diol, (2R,3R,3aS,6S,6aR)-2-[4-amino-5-(difluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-6-[(2-amino- 3-fluoroquinolin-7-yl)methyl]hexahydro-3aH-cyclopenta[b]furan-3,3a-diol, (2R,3R,3aS,6S,6aR)-6-[(2-amino-3-bromoquinolin-7-yl)oxy]-2-(4-amino-5-cyclopropyl-7H-pyrrolo[2,3- d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol, (2R,3R,3aS,6S,6aR)-6-[(2-amino-3-fluoroquinolin-7-yl)methyl]-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)-5,5-difluorohexahydro-3aH-cyclopenta[b]furan-3,3a-diol, (2R,3R,3aS,5S,6S,6aR)-6-[(2-amino-3-fluoroquinolin-7-yl)methyl]-2-(4-amino-7H-pyrrolo[2,3-d] pyrimidin-7-yl)-5-fluorohexahydro-3aH-cyclopenta[b]furan-3,3a-diol, (2R,3R,3aS,5S,6S,6aR)-2-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-6-[(2-amino- 3-fluoroquinolin-7-yl)methyl]-5-fluorohexahydro-3aH-cyclopenta[b]furan-3,3a-diol, (2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)oxy)-2-(4-amino-5-fluoro-7H-pyrrolo[2,3- d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol, (2R,3R,3aS,6S,6aR)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-6-((2-((2,2,2- trifluoroethyl)amino)quinolin-7-yl)oxy)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol, (2R,3R,3aS,6S,6aR)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-6-((2-((cyclopropylmethyl)amino)quinoline- 7-yl)oxy)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol, (2R,3R,3aS,6S,6aR)-6-((2-amino-3-fluoroquinolin-7-yl)methyl)-2-(4-amino-5-fluoro-7H-pyrrolo[2,3- d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol, (2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)oxy)-2-(4-amino-5-methyl-7H-pyrrolo[2,3- d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol, (2R,3R,3aS,6S,6aR)-2-(4-amino-2-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-6-((2-amino-3- bromoquinolin-7-yl)methyl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol, (2R,3R,3aS,6S,6aR)-6-((2-amino-3-fluoroquinolin-7-yl)methyl)-2-(4-amino-5-methyl-7H-pyrrolo[2,3- d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol, (2R,3R,3aS,6S,6aR)-2-(4-amino-2-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-6-((2-amino-3- bromoquinolin-7-yl)oxy)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol, (2R,3R,3aS,6S,6aR)-6-((2-amino-3-chloroquinolin-7-yl)oxy)-2-(4-amino-5-methyl-7H-pyrrolo[2,3- d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol, (2R,3R,3aS,6S,6aR)-6-((2-amino-3-fluoroquinolin-7-yl)oxy)-2-(4-amino-5-methyl-7H-pyrrolo[2,3- d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol, (2R,3R,3aS,6S,6aR)-6-((2-amino-3-chloroquinolin-7-yl)methyl)-2-(4-amino-5-methyl-7H-pyrrolo[2,3- d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol, (2R,3R,3aS,6S,6aR)-6-((2-amino-3-chloroquinolin-7-yl)methyl)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol, (2R,3R,3aS,6S,6aR)-6-((2-amino-3-chloroquinolin-7-yl)methyl)-2-(4-amino-5-fluoro-7H-pyrrolo[2,3- d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol, (2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)oxy)-2-(4-amino-5-ethyl-7H-pyrrolo[2,3- d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol, (2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(4-amino-5-methyl-7H-pyrrolo[2,3- d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol, (2R,3R,3aS,6S,6aR)-6-((2-amino-3-fluoroquinolin-7-yl)oxy)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol, (2R,3R,3aS,6S,6aR)-6-((2-amino-3-chloroquinolin-7-yl)oxy)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol, (2R,3R,3aS,6S,6aR)-6-((2-amino-3-fluoroquinolin-7-yl)oxy)-2-(4-amino-5-fluoro-7H-pyrrolo[2,3- d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol, (2R,3R,3aS,6S,6aR)-6-((2-amino-3-chloroquinolin-7-yl)oxy)-2-(4-amino-5-fluoro-7H-pyrrolo[2,3- d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol, (2R,3R,3aS,6S,6aR)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-6-((2,3-dihydro-1H-pyrrolo[ 2,3-b]quinolin-7-yl)oxy)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol, (2R,3R,3aS,6S,6aR)-6-((2-amino-3-(trifluoromethyl)quinolin-7-yl)methyl)-2-(4-amino-7H-pyrrolo[2,3-d ]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol, (2R,3R,3aS,6S,6aR)-6-[(2-amino-3-bromoquinolin-7-yl)oxy]-2-[4-(hydroxymethyl)-7H-pyrrolo[2,3-d] pyrimidin-7-yl]hexahydro-3aH-cyclopenta[b]furan-3,3a-diol, (2R,3R,3aS,6S,6aR)-6-[(2-amino-3-bromoquinolin-7-yl)oxy]-2-[4-(2-hydroxypropan-2-yl)-7H-pyrrolo[ 2,3-d]pyrimidin-7-yl]hexahydro-3aH-cyclopenta[b]furan-3,3a-diol, (2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)oxy)-2-(4-(difluoromethyl)-7H-pyrrolo[2,3-d] pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol, (2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)oxy)-2-(2,4-dimethyl-7H-pyrrolo[2,3-d] pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol, (2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(2,4-dimethyl-7H-pyrrolo[2,3-d] pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol, (2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)oxy)-2-(4-amino-5-ethyl-7H-pyrrolo[2,3- d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol, (2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(4-isopropyl-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol, (2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(5-fluoro-4-methyl-7H-pyrrolo[2,3- d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol, (2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)oxy)-2-(7H-pyrrolo[2,3-d]pyrimidin-7-yl) hexahydro-3aH-cyclopenta[b]furan-3,3a-diol, (2R,3R,3aS,6S,6aR)-6-((2-amino-3-fluoroquinolin-7-yl)oxy)-2-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol, (2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(4-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol, (2R,3R,3aS,6S,6aR)-6-((2-amino-3-(trifluoromethyl)quinolin-7-yl)methyl)-2-(4-methyl-7H-pyrrolo[2,3-d ]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol, (2R,3R,3aS,6S,6aR)-6-((2,3-dihydro-1H-pyrrolo[2,3-b]quinolin-7-yl)oxy)-2-(4-methyl-7H- pyrrolo[2,3-d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol, (2R,3R,3aS,6S,6aR)-6-((2-amino-3-fluoroquinolin-7-yl)methyl)-2-(2,4-dimethyl-7H-pyrrolo[2,3-d] pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol, (2R,3R,3aS,6S,6aR)-6-((2-amino-3-chloroquinolin-7-yl)methyl)-2-(2,4-dimethyl-7H-pyrrolo[2,3-d] pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol, (2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(4-(methylamino)-7H-pyrrolo[2,3-d] pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol, (2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)oxy)-2-(4-(methylamino)-7H-pyrrolo[2,3-d] pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol, (2R,3R,3aS,6S,6aR)-6-((2-amino-3-fluoroquinolin-7-yl)methyl)-2-(4-(methylamino)-7H-pyrrolo[2,3-d] pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol, (2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(5-fluoro-4-(methylamino)-7H-pyrrolo[2, 3-d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol, (1S,2R,3aR,4S,6aR)-4-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(4-(methylamino)-7H-pyrrolo[2,3-d] pyrimidin-7-yl)hexahydropentalene-1,6a(1H)-diol, (2R,3R,3aS,6S,6aR)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-6-((2-aminoquinolin-7-yl)oxy) hexahydro-2H-cyclopenta[b]furan-3,3a-diol, (2R,3R,3aS,6S,6aR)-6-((2-aminoquinolin-7-yl)methyl)-2-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl) hexahydro-2H-cyclopenta[b]furan-3,3a-diol, (2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(4-amino-5-fluoro-7H-pyrrolo[2,3- d]pyrimidin-7-yl)hexahydro-2H-cyclopenta[b]furan-3,3a-diol, (1R,2S,3R,5R)-5-(((2-amino-3-bromoquinolin-7-yl)oxy)methyl)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidine -7-yl)-1,5-dimethylcyclopentane-1,2-diol, (2R,3R,3aS,6S,6aR)-6-((2-amino-3-chloroquinolin-7-yl)oxy)-2-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)hexahydro-2H-cyclopenta[b]furan-3,3a-diol, (2R,3R,3aS,6S,6aR)-6-((2-aminoquinolin-7-yl)oxy)-2-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl) hexahydro-2H-cyclopenta[b]furan-3,3a-diol, (2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)oxy)-2-(2-amino-4-methyl-7H-pyrrolo[2,3- d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol, (2R,3R,3aS,6S,6aR)-6-((2-amino-3-(difluoromethyl)quinolin-7-yl)oxy)-2-(4-methyl-7H-pyrrolo[2,3-d ]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol, (1S,2R,3aR,4S,6aR)-4-((2-amino-3-bromoquinolin-7-yl)oxy)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)hexahydropentalene-1,6a(1H)-diol, (2R,3R,3aS,6S,6aR)-6-((2-amino-3-fluoroquinolin-7-yl)amino)-2-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol, (2R,3R,3aS,6S,6aR)-6-((2-amino-3-fluoroquinolin-7-yl)methyl)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)-6a-methylhexahydro-3aH-cyclopenta[b]furan-3,3a-diol, (2R,3R,3aS,6S,6aR)-6-((2-amino-3-chloroquinolin-7-yl)methyl)-2-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol, (2R,3R,3aS,6S,6aR)-6-((2-amino-3-fluoroquinolin-7-yl)methyl)-2-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol, (2R,3R,3aS,6S,6aR)-6-((2-amino-3-fluoroquinolin-7-yl)methyl)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol, (2R,3R,3aS,6S,6aR)-6-((2-amino-3-methylquinolin-7-yl)methyl)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol, (2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(2-amino-4-methyl-7H-pyrrolo[2,3- d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol, (2R,3R,3aS,6S,6aR)-6-((2-amino-3-(difluoromethyl)quinolin-7-yl)oxy)-2-(4-amino-7H-pyrrolo[2,3-d ]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol, (2R,3R,3aS,6R,6aR)-6-((2-amino-3-bromoquinolin-7-yl)oxy)-2-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol, (2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)oxy)-2-(2-amino-5-fluoro-7H-pyrrolo[2,3- d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol, (2R,3R,3aS,6R,6aR)-6-((2-amino-3-chloroquinolin-7-yl)methyl)-2-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol, (3aS,4S,5R)-1-((2-amino-3-bromoquinolin-7-yl)methyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl) tetrahydro-1H-cyclopenta[c]furan-3a,4(3H)-diol, (2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)tetrahydrofuro[3,4-b]furan-3,3a(4H)-diol, (2R,3R,3aS,6R,6aR)-6-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)tetrahydrofuro[3,4-b]furan-3,3a(4H)-diol, (2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(4-amino-5-methyl-7H-pyrrolo[2,3- d]pyrimidin-7-yl)tetrahydrofuro[3,4-b]furan-3,3a(4H)-diol, (2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)tetrahydrofuro[3,4-b]furan-3,3a(4H)-diol or (2R,3R,3aS,6S,6aR)-6-((2-amino-3-(difluoromethyl)quinolin-7-yl)methyl)-2-(4-amino-7H-pyrrolo[2,3-d ]pyrimidin-7-yl)hexahydro-2H-cyclopenta[b]furan-3,3a-diol. 17. A compound or a pharmaceutically acceptable salt thereof, which is: (1R,2S,3R,5R)-5-(((2-amino-3-bromoquinolin-7-yl)oxy)methyl)-3-(4-chloro-7H-pyrrolo[2,3-d]pyrimidine -7-yl)-1-methylcyclopentane-1,2-diol, (1R,2S,3R,5R)-5-(((2-amino-3-bromoquinolin-7-yl)oxy)methyl)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidine -7-yl)-1-methylcyclopentane-1,2-diol, (2R,3S,4R,5R)-2-(((2-amino-3-bromoquinolin-7-yl)oxy)methyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidine -7-yl)-3-ethynyltetrahydrofuran-3,4-diol, (2R,3S,4R,5R)-2-(2-(2-amino-3-bromoquinolin-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)-2,3-dimethyltetrahydrofuran-3,4-diol, (2R,3S,4R,5R)-2-{[(2-amino-3-bromoquinolin-7-yl)oxy]methyl}-5-(4-chloro-7H-pyrrolo[2,3-d]pyrimidine -7-yl)-3-methyltetrahydrofuran-3,4-diol, (2R,3S,4R,5R)-2-(((2-amino-3-bromoquinolin-7-yl)oxy)methyl)-5-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidine -7-yl)-2-methyltetrahydrofuran-3,4-diol, (2R,3S,4R,5R)-2-(((2-amino-3-bromoquinolin-7-yl)oxy)methyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidine -7-yl)-2-methyltetrahydrofuran-3,4-diol, (1S,2R,3S,5R)-3-[2-(2-amino-3-bromo-7-quinolinyl)ethyl]-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)-3-methyl-1,2-cyclopentanediol, (1S,2R,3aR,4S,6aR)-4-((2-amino-3-fluoroquinolin-7-yl)methyl)-2-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)hexahydropentalene-1,6a(1H)-diol, (2R,3R,3aS,6S,6aR)-6-[(2-amino-3,8-difluoroquinolin-7-yl)methyl]-2-(4-amino-7H-pyrrolo[2,3-d] pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol, (2R,3R,3aS,6S,6aR)-6-[(2-amino-3-chloro-5-fluoroquinolin-7-yl)methyl]-2-(4-amino-7H-pyrrolo[2,3- d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol, (2R,3R,3aS,6S,6aR)-6-[(2-amino-3-chloro-8-fluoroquinolin-7-yl)methyl]-2-(4-methyl-7H-pyrrolo[2,3- d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol, (2R,3R,3aS,6S,6aR)-6-((2-amino-3,5-difluoroquinolin-7-yl)methyl)-2-(4-amino-5-fluoro-7H-pyrrolo[2, 3-d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol, (2R,3R,3aS,6S,6aR)-6-((6-amino-7-fluoro-1,5-naphthyridin-3-yl)methyl)-2-(4-methyl-7H-pyrrolo[2, 3-d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol, (2R,3R,3aS,6S,6aR)-6-((2-amino-3-chloro-8-fluoroquinolin-7-yl)methyl)-2-(4-amino-7H-pyrrolo[2,3- d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol, (2R,3R,3aS,6S,6aR)-6-[(2-amino-3,6-difluoroquinolin-7-yl)methyl]-2-(4-amino-7H-pyrrolo[2,3-d] pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol, (2R,3R,3aS,6S,6aR)-6-((7-amino-6-chloro-1,8-naphthyridin-2-yl)methyl)-2-(4-amino-7H-pyrrolo[2, 3-d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol, (2R,3R,3aS,6S,6aR)-6-[(2-amino-3,5-difluoroquinolin-7-yl)methyl]-2-(4-amino-7H-pyrrolo[2,3-d] pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol, (1S,2R,3aR,4S,6aR)-4-((2-amino-3-fluoroquinolin-7-yl)methyl)-2-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)hexahydropentalene-1,6a(1H)-diol, (1S,2R,3aR,4S,6aR)-4-[(2-amino-3,5-difluoroquinolin-7-yl)methyl]-2-(4-amino-5-methyl-7H-pyrrolo[2, 3-d]pyrimidin-7-yl)hexahydropentalene-1,6a(1H)-diol, (1S,2R,3aR,4S,6aR)-4-[(2-amino-3-chloro-5-fluoroquinolin-7-yl)methyl]-2-(4-amino-5-methyl-7H-pyrrolo[ 2,3-d]pyrimidin-7-yl)hexahydropentalene-1,6a(1H)-diol, (1R,2S,3R,5R)-5-(((2-amino-3-bromoquinolin-7-yl)oxy)methyl)-1-methyl-3-(4-(methylamino)-7H-pyrrolo[2 ,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol, (2R,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-methyl-2-((quinolin-7-yloxy)methyl) tetrahydrofuran-3,4-diol, (1S,2R,3R,5R)-3-(((2-amino-3-bromoquinolin-7-yl)oxy)methyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidine -7-yl)-3-methylcyclopentane-1,2-diol, (1S,2R,3R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-(((2-aminoquinolin-7-yl)oxy)methyl )-3-methylcyclopentane-1,2-diol, (1S,2R,5R)-3-(2-(2-amino-3-bromoquinolin-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7- yl)-3-(fluoromethyl)cyclopentane-1,2-diol, (1R,2S,3R,5S)-5-(2-(2-amino-3-bromoquinolin-7-yl)ethyl)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)-1-methylcyclopentane-1,2-diol, (1R,2S,3R,5R)-5-(((2-aminoquinolin-7-yl)oxy)methyl)-1-methyl-3-(7H-pyrrolo[2,3-d]pyrimidin-7-yl )cyclopentane-1,2-diol, (1R,2S,3R,5R)-5-(((2-amino-3-methylquinolin-7-yl)oxy)methyl)-1-methyl-3-(4-methyl-7H-pyrrolo[2,3 -d]pyrimidin-7-yl)cyclopentane-1,2-diol, (1S,2R,3S,5R)-3-(2-(2-amino-3-bromoquinolin-7-yl)ethyl)-3-methyl-5-(4-methyl-7H-pyrrolo[2,3- d]pyrimidin-7-yl)cyclopentan-1,2-diol, (1S,2R,3S,5R)-3-(2-(2,3-dihydro-1H-pyrrolo[2,3-b]quinolin-7-yl)ethyl)-3-methyl-5-(4- methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol, (1S,2R,3R,5R)-3-(2-(2-amino-3-fluoroquinolin-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)-3-methylcyclopentane-1,2-diol, (1R,2S,3R,5S)-5-(2-(2-amino-3-bromoquinolin-7-yl)ethyl)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)-1,5-dimethylcyclopentane-1,2-diol, (1R,2S,3S,4R)-1-(2-(2-amino-3-bromoquinolin-7-yl)ethyl)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)-2-methylcyclopentane-1,2,3-triol or (1S,2R,3S,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-(2-(2,3-dihydro-1H-pyrrolo[ 2,3-b]quinolin-7-yl)ethyl)-3-methylcyclopentane-1,2-diol. 18. A composition having PRMT5 inhibitory activity for the treatment of cancer, containing an effective amount of a compound according to any one of paragraphs. 1-17 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.