OA19125A - Substituted carbonucleoside derivatives useful as anticancer agents - Google Patents

Abstract

Compounds of the general formula : processes for the preparation of these compounds, compositions containing these compounds, and the compounds for use in treating cancer.

Description

Substituted Carbonucleoside Dérivatives Useful as Anticancer Agents

Field of the invention

This invention relates to novel carbonucleoside dérivatives useful in the treatment of abnormal cell growth, such cancer, in mammals. This invention also relates to a method of using such compounds in the treatment of abnormal cell growth in mammals, especially humans, and to phramaceutial compositions as anticancer agents.

Background of the invention

Post-translational modification of arginine residues by méthylation is important for many critical cellular processes including chromatin remodeling, gene transcription, protein translation, signal transduction, RNA splicing and cell prolifération. Arginine méthylation is catalyzed by protein arginine methyltransferase (PRMT) enzymes. There are nine PRMT members in ail, and eight hâve reported enzymatic activity on target substrates.

The protein arginine methyltransferase (PRMT) family of enzymes utilize S-adenosyl méthionine (SAM) to transfer methyl groups to arginine residues on target proteins. Type I PRMTs catalyze formation of mono-methyl arginine and asymmetric di-methyl arginines while Type II PRMTs catalyze mono-methyl arginine and symmetric di-methyl arginines. PRMT5 is a Type II enzyme, twice transferring a methyl group from SAM to the two ω-guanidino nitrogen atoms of arginine, leading to ω-NG, N’G di-symmetric méthylation of protein substrates.

PRMT5 protein is found in both the nucléus and cytoplasm, and has multiple protein substrates such as histones, transcription factors and spliceosome proteins. PRMT5 has a binding partner, Mep50 (methylosome protein 50) and functions in multiple protein complexes. PRMT5 is associated with chromatin remodeling complexes (SWI/SNF, NuRD) and epigenetically controls genes involved in development, cell prolifération, and différentiation, including tumor suppressors, through méthylation of histones (Karkhanis, V. et al., Versatility of PRMT5 Induced Méthylation in Growth Control and Development, Trends Biochem Sci 36(12) 633-641 (2011)). PRMT5 also controls gene expression through association with protein complexes that recruit PRMT5 to methylate several transcription factors p53 (Jansson, M. et al., Arginine Méthylation Régulâtes the p53 Response, Nat. Cell Biol. 10, 1431-1439 (2008)), E2F1 (Zheng, S. et al., Arginine Methylation-Dependent Reader-Writer Interplay Governs Growth Control by E2F-1, Mol Cell 52(1), 37-51 (2013)); HOXA9 (Bandyopadhyay, S. et al., HOXA9 Méthylation by PRMT5 is Essential for Endothélial Cell Expression of Leukocyte Adhesion Molécules, Mol. Cell. Biol. 32(7):1202-1213 (2012)); and NFkB (Wei, H. et al., PRMT5 dimethylates R30 of the p65 Subunit to Activate NFkB, PNAS 110(33), 13516-13521 (2013)). In the cytoplasm, PRMT5 has a diverse set of substrates involved in other cellular functions

-2 including RNA splicing (Sm proteins), golgi assembly (gm130), ribosome biogenesis (RPS10), piRNA mediated gene silencing (Piwi proteins) and EGFR signaling (Karkhanis, 2011).

Additional papers relating to PRMT5 include: Aggarwal, P. et al., (2010) Nuclear Cyclin D1/CDK4 Kinase Régulâtes CUL4B Expression and Triggers Neoplastic Growth via Activation 5 of the PRMT5 Methyltransferase, Cancer Cell 18: 329-340; Bao, X. et al., Overexpression of PRMT5 Promûtes Tumor Cell Growth and is Associated with Poor Disease Prognosis in Epithelial Ovarian Cancer, J Histochem Cytochem 61: 206-217 (2013); Cho E. et al., Arginine Méthylation Controls Growth Régulation by E2F1, EMBO J. 31(7) 1785-1797 (2012); Gu, Z. et al., Protein Arginine Methyltransferase 5 Functions in Opposite Ways in the Cytoplasm and 10 Nucléus of Prostate Cancer Cells, PLoS One 7(8) e44033 (2012); Gu, Z. et al., Protein Arginine Methyltransferase 5 is Essential for Growth of Lung Cancer Cells, Biochem J. 446: 235-241 (2012); Kim, J. et al., Identification of Gastric Cancer Related Genes Using a cDNA Microarray Containing Novel Expressed Sequence Tags Expressed in Gastric Cancer Cells, Clin Cancer Res. 11(2) 473-482 (2005); Nicholas, C. et al., PRMT5 is Upregulated in Malignant and 15 Metastatic Melanoma and Régulâtes Expression of MITF and p27(Kip1), PLoS One 8(9) e74710 (2012); Powers, M. et al., Protein Arginine Methyltransferase 5 Accélérâtes Tumor Growth by Arginine Méthylation of the Tumor Suppressor Programmed Cell Death 4, Cancer Res. 71(16) 5579-5587 (2011); Wang, L. et al., Protein Arginine Methyltransferase 5 Suppresses the Transcription of the RB Family of Tumor Suppressors in Leukemia and 20 Lymphoma Cells, Mol. Cell Biol. 28(20), 6262-6277 (2008).

PRMT5 is overexpressed in many cancers and has been observed in patient samples and cell lines including B-cell lymphoma and leukemia (Wang, 2008) and the following solid tumors: gastric (Kim 2005) esophageal (Aggarwal, 2010), breast (Powers, 2011), lung (Gu, 2012), prostate (Gu, 2012), melanoma (Nicholas 2012), colon (Cho, 2012) and ovarian (Bao, 25 2013). in many of these cancers, overexpression of PRMT5 correlated with poor prognosis.

Aberrant arginine méthylation of PRMT5 substrates has been linked to other indications in addition to cancer, such as metabolic disorders, inflammatory and autoimmune disease and hemaglobinopathies.

Summary of the Invention

Given its rôle in regulating various biological processes, PRMT5 is an attractive target for modulation with small molécule inhibitors. To date, few effective PRMT5 inhibitors hâve been developed, and no PRMT5 inhibitors hâve entered the clinic.

Each of the embodiments of the compounds of the présent invention described below can be combined with any other embodiment of the compounds of the présent invention 35 described herein not inconsistent with the embodiment with which it is combined. Furthermore, each of the embodiments below describing the invention envisions within its scope pharmaceutically acceptable salts of the compounds of the invention. Accordingly, the phrase “or a pharmaceutically acceptable sait thereof” is implicit in the description of ail compounds described herein.

The invention includes embodiments wherein there is provided a compound of formula (I):

Embodiments of the présent invention include compounds of formula (I):

or a pharmaceutically acceptable sait thereof, wherein:

R¹ is selected from the group consisting of (Ci-Ca)alkyl, (Ci-Cs)haloalkyl, hydroxy, (CiC8)alkoxy, (C5-Ci2)aryl, 5-12 membered heteroaryl, (C3-Ci0)cycloalkyl, 3-12 membered heterocyclyl, OR⁴, SR⁴ and N(R⁴)2, where each R⁴ is independently A-R¹⁴, where A is absent, 15 (CrC3)alkyl, -C(O)- or -SO2-, and R¹⁴ is hydrogen, (Ci-Cs)alkyl, (Cs-Ci2)aryl, 5-12 membered heteroaryl, (C₃-Ci₀)cycloalkyl or 3-12 membered heterocyclyl, or two R⁴ join to form a 4-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, O and S;

R² is hydrogen, halogen, (Ci-C8)alkyl, hydroxy, (Ci-Cs)alkoxy or N(R⁵)2, where each R⁵ is independently hydrogen or (Ci-C₈)alkyl, or two R⁵ join to form a 4-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, O and S;

each R³ is independently selected from hydrogen, hydroxy, NH2; (Ci-Cs)alkyl or heteroalkyl having 1-8 atoms, or when D is C(R³)2, R³ is additionally selected from fluorine, (CiC₈)alkylene or heteroalkylene bound to an atom on G to form a ring fused to G, where R³ is optionally substituted with 1-6 R⁸;

each R⁹ is independently hydrogen or fluorine;

D is C(R³)2, NR³, O, S or S(O)i_2;

G is a (C₅-Ci₂)aryl or a 5-12 membered heteroaryl ring System fused to (C₃-Ci₀)cycloalkyl or heterocyclyl ring System;

each R⁸ is absent or is independently selected from the group consisting of (Ci-C₈)alkyl, (Ci10 C₈)haloalkyl, hydroxy, (Ci-C₈)alkoxy, (C₅-Ci₂)aryl, 5-12 membered heteroaryl, (C₃-Ci₀)cycloalkyl,

3-12 membered heterocyclyl, OR⁴, SR⁴, N(R⁴)2, CN, halogen and CON(R⁴)2, where two R⁸ optionally join to form a 4-6 membered spiro-cycloalkyl ring, a cycloalkyl fused ring, or a alkyiene bridge spanning G, and where two R⁸ optionally join to form carbonyl;

where each R⁴ is independently A-R¹⁴, where A is absent, (Ci-C3)alkyl, -C(O)- or -SO2-, and R¹⁴ 15 is hydrogen, (Ci-C8)alkyl, (C₅-Ci₂)aryl, 5-12 membered heteroaryl, (C₃-Ci₀)cycloalkyl or 3-12 membered heterocyclyl, or two R⁴ join to form a 4-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, O and S;

Q is absent or is a divalent moiety selected from O, S, NH and (Ci-Cs)alkylene;

V is N or C if Z is présent, where if V forms a double bond V is carbon, or V is N or CH and 20 forms a double bond with W if Z is absent;

W is N or C, where if W forms a double bond if W is carbon;

X is N or C if Y is présent, where if X forms a double bond X is carbon, or X is O, NR¹⁶ or C(R¹⁶)₂ if Y is absent, where R¹⁶ is H or methyl;

Y is absent, CR¹⁰, N, NR¹⁰, O or S, or Y is absent, hydrogen or (Ci-C8)alkyl if Z is absent, where 25 each R¹⁰ is independently selected from hydrogen, (CrC₈)alkyl, hydroxy, (Ci-C₈)alkoxy, halogen, SH, S-(Ci-C₈)alkyl and N(R¹¹)2 if Y is CR¹⁰, where Y forms a double bond with an adjacent ring member when Y is CR¹⁰ or N, and where each R¹¹ is independently hydrogen, (C-iCsjalkyl, (C5-Ci₂)aryl or 5-12 membered heteroaryl or two R¹¹ join to form a 4-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, O and S, or Y is C(R¹⁰)₂ and the 30 two R¹⁰ and the carbon to which they are associated form a carbonyl or a thiocarbonyl;

Z is absent, CR¹², N, NR¹², O or S, or Z is absent, hydrogen or (Ci-Cs)alkyl if Y is absent, where each R¹² is independently selected from hydrogen, (Ci-Cs)alkyl, hydroxy, (Ci-Cs)alkoxy, fluoro, chloro, bromo, SH, S-(Ci-C8)alkyl and N(R¹³)2, where Z forms a double bond with an adjacent ring member if it is CR¹² or N, where each R¹³ is independently hydrogen, (Ci-C₈)alkyl, (Cs35 Ci₂)aryl or 5-12 membered heteroaryl, or two R¹³ join to form a 4-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, O and S, and where Z is not NR¹² if X is N, V is C,

-5W is C and Y is CR¹⁰, or Z is C(R¹²)₂ and the two R¹² and the carbon to which they are associated form a carbonyl or a thiocarbonyl; and each — is absent or an optional bond, where no more than two, non-adjacent — may be présent.

Embodiments of the présent invention also include compounds of formula (II):

or a pharmaceutically acceptable sait thereof, wherein:

R¹ is selected from the group consisting of (Ci-C8)alkyl, (Ci-C8)haloalkyl, hydroxy, (Cr C8)alkoxy, (C5-Ci2)aryl, 5-12 membered heteroaryl, (C3-Ci0)cycloalkyl, 3-12 membered heterocyclyl, OR⁴, SR⁴ and N(R⁴)2, where each R⁴ is independently A-R¹⁴, where A is absent, (Ci-C3)alkyl, -C(O)- or -SO2-, and R¹⁴ is hydrogen, (Ci-Cs)alkyl, (C8-Ci₂)aryl, 5-12 membered heteroaryl, (C₃-Cio)cycloalkyl or 3-12 membered heterocyclyl, or two R⁴ join to form a 4-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, O and S;

R² is hydrogen, halogen, (Ci-Cs)alkyl, hydroxy, (Ci-Cs)alkoxy or N(R⁵)₂, where each R⁵ is independently hydrogen or (Ci-Cs)alkyI, or two R⁵ join to form a 4-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, O and S;

each R³ is independently selected from hydrogen, hydroxy, NH₂; (Ci-Cs)aikyl or heteroalkyl having 1-8 atoms, or when D is C(R³)₂, R³ is additionally selected from fluorine, (Ci

C₈)alkylene or heteroalkylene bound to an atom on G to form a ring fused to G, where R³ is optionally substituted with 1-6 R⁸;

each R⁹ is independently hydrogen or fluorine;

D is C(R³)₂, O, or S(O)i-₂;

G is a (Cs-Ci₂)aryl, 5-12 membered heteroaryl ring System;

R¹⁵ is heteroalkyl having 1-8 atoms bound to an atom on G and optionally substituted with 1-6 R⁸, or R¹⁵ is heteroalkylene bound to an atom on G, optionally substituted with 1-6 R⁸, and bound to an adjacent atom on G (i.e., the two ends of R¹⁵ when R¹⁵ is heteroalkylene are bound to adjacent carbons on the G ring);

each R⁸ is absent or is independently selected from the group consisting of (Ci-Cs)alkyl, (CiC8)haloalkyl, hydroxy, (Ci-C8)alkoxy, (C5-Ci2)aryl, 5-12 membered heteroaryl, (C3-Ci0)cycloalkyl, 3-12 membered heterocyclyl, OR⁴, SR⁴, N(R⁴)2, CN, halogen and CON(R⁴)², where two R⁸ optionally join to form a 4-6 membered spiro-cycloalkyl ring, a cycloalkyl fused ring, or a alkylene bridge spanning G, and where two R⁸ optionally join to form carbonyl;

where each R⁴ is independently A-R¹⁴, where A is absent, (Ci-C3)alkyl, -C(O)- or -SO2-, and R¹⁴ is hydrogen, (Ci-Cs)alkyl, (Cs-Ci2)aryl, 5-12 membered heteroaryl, (C₃-Ci₀)cycloalkyl or 3-12 membered heterocyclyl, or two R⁴ join to form a 4-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, O and S;

Q is absent or is a divalent moiety selected from O, S, NH and (Ci-Cs)alkylene;

V is N or C, where if V forms a double bond V is carbon;

W is N or C, where if W forms a double bond W is carbon;

X is N or C, where if X forms a double bond X is carbon;

Y is CR¹⁰, N, NR¹⁰, O or S, where each R¹⁰ is independently selected from hydrogen, (CiC8)alkyl, hydroxy, (Ci-C8)alkoxy, or R¹⁰ is optionally selected from halogen, SH, S-(Ci-C8)alkyl 25 and N(R¹¹)₂ if Y is CR¹⁰, where Y forms a double with an adjacent ring member when Y is CR¹⁰ or N, and where each R¹¹ is independently hydrogen, (Ci-C8)alkyl, (C5-Ci2)aryl or 5-12 membered heteroaryl or two R¹¹ join to form a 4-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, O and S, or Y is C(R¹⁰)2 and the two R¹⁰ and the carbon to which they are associated form a carbonyl or a thiocarbonyl;

Z is CR¹², N, NR¹², O or S, where each R¹² is independently selected from hydrogen, (C-r C8)alkyl, hydroxy, (Ci-Cs)alkoxy, or R¹² is optionally selected from fluoro, chloro, bromo, iodo, SH, S-(Ci-C8)alkyl and N(R¹³)2 if Z is CR¹², where Z forms a double bond with an adjacent ring member if it is CR¹² or N, where each R¹³ is independently hydrogen, (Ci-Cs)alkyl, (Cs-Ci2)aryl or 5-12 membered heteroaryl, or two R¹³ join to form a 4-6 membered heterocyclic ring 35 containing 1-3 heteroatoms selected from N, O and S, and where Z is not NR¹² if X is N, V is C,

-7W is C and Y is CR¹⁰, or Z is C(R¹²)₂ and the two R¹² and the carbon to which they are associated form a carbonyl or a thiocarbonyl; and each — is an optional bond, where no more than two, non-adjacent — may be présent, provided that D is S(O)1-2 when G is Cioaryl or a 10-membered heteroaryl.

Additional embodiments of the présent invention include compounds of formula (III):

or a pharmaceutically acceptable sait thereof, wherein:

each R¹ is independently selected from the group consisting of (Ci-C8)alkyl, (Ci-C8)haloalkyl, hydroxy, (Ci-Cs)alkoxy, (C5-Ci2)aryl, 5-12 membered heteroaryl, (C3-Ci0)cycloalkyl, 3-12 membered heterocyclyl, OR⁴, SR⁴ and N(R⁴)2, where each R⁴ is independently A-R¹⁴, where A is absent, (Ci-C3)alkyl, -C(O)- or -SO2-, and R¹⁴ is hydrogen, (Ci-Cs)alkyl, (C5-Ci₂)aryl, 5-12 membered heteroaryl, (C₃-Ci₀)cycloalkyl or 3-12 membered heterocyclyl, or two R⁴ join to form a 4-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, O and S;

R² is hydrogen, halogen, (Ci-Cs)alkyl, hydroxy, (Ci-Cs)alkoxy or N(R⁵)₂, where each R⁵ is independently hydrogen or (Ci-Cs)alkyl, or two R⁵ join to form a 4-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, O and S;

-8each R³ is independently hydrogen, hydroxy or NH2; or when D is C(R³)2, R³ is additionally selected from fluorine;

each R⁹ is independently hydrogen or fluorine;

D is C(R³)₂, O, or S(O)i-₂;

E is NR¹, CH2, C(R¹)2, O or -S(O)₂;

each R⁸ is absent or is independently selected from the group consisting of (Ci-C8)alkyl, (CiC8)haloalkyl, hydroxy, (Ci-C8)alkoxy, (C5-Ci2)aryl, 5-12 membered heteroaryl, (C3-Cio)cycloalkyl, 3-12 membered heterocyclyl, OR⁴, SR⁴, N(R⁴)2, CN, halogen and CON(R⁴)², where two R⁸ optionally join to form a 4-6 membered spiro-cycloalkyl ring, a cycloalkyl fused ring, or a 10 alkylene bridge spanning G, and where two R⁸ optionally join to form carbonyl;

where each R⁴ is independently A-R¹⁴, where A is absent, (Ci-C3)alkyl, -C(O)- or -SO2-, and R¹⁴ is hydrogen, (Ci-Cs)alkyl, (C5-C₁₂)aryl, 5-12 membered heteroaryl, (C₃-Ci₀)cycloalkyl or 3-12 membered heterocyclyl, or two R⁴ join to form a 4-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, O and S;

Q is absent or is a divalent moiety selected from O, S, NH and (Ci-Cs)alkylene;

V is N or C, where if V forms a double bond V is carbon;

W is N or C, where if W forms a double bond W is carbon;

X is N or C, where if X forms a double bond X is carbon;

Y is CR¹⁰, N, NR¹⁰, O or S, where each R¹⁰ is independently selected from hydrogen, (Ci20 C8)alkyl, hydroxy, (Ci-Cs)alkoxy, halogen, SH, S-(Ci-C8)alkyl and N(R¹¹)2 if Y is CR¹⁰, where Y forms a double with an adjacent ring member when Y is CR¹⁰ or N, and where each R¹¹ is independently hydrogen, (Ci-C8)alkyl, (C5-Ci2)aryl or 5-12 membered heteroaryl or two R¹¹ join to form a 4-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, O and S, or Y is C(R¹⁰)2 and the two R¹⁰ and the carbon to which they are associated form a carbonyl or a 25 thiocarbonyl;

Z is CR¹², N, NR¹², O or S, where each R¹² is independently selected from hydrogen, (CiC8)alkyl, hydroxy, (CrC8)alkoxy, fluoro, chloro, bromo, SH, S-(Ci-C8)alkyl and N(R¹³)2, where Z forms a double bond with an adjacent ring member if it is CR¹² or N, where each R¹³ is independently hydrogen, (Ci-C₈)alkyl, (C₅-Ci₂)aryl or 5-12 membered heteroaryl, or two R¹³ join 30 to form a 4-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, O and S, and where Z is not NR¹² if X is N, V is C, W is C and Y is CR¹⁰, or Z is C(R¹²)₂ and the two R¹² and the carbon to which they are associated form a carbonyl or a thiocarbonyl; and each-----is an optional bond, where no more than two, non-adjacent-----may be présent.

Additional embodiments of the présent invention include compounds of formula (IV):

or a pharmaceutically acceptable sait thereof, wherein:

each R¹ is independently selected from the group consisting of (Ci-C₈)alkyl, (Ci-Cs)haloalkyl, hydroxy, (Ci-C₈)alkoxy, (C₅-Ci₂)aryl, 5-12 membered heteroaryl, (C₃-Ci₀)cycloalkyl, 3-12 membered heterocyclyl, OR⁴, SR⁴ and N(R⁴)₂, where each R⁴ is independently A-R¹⁴, where A is absent, (Ci-C3)alkyl, -C(O)- or -SO2-, and R¹⁴ is hydrogen, (Ci-Cs)alkyl, (C5-Ci₂)aryl, 5-12 membered heteroaryl, (C₃-Cio)cycloalkyl or 3-12 membered heterocyclyl, or two R⁴ join to form a 4-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, O and S;

R² is hydrogen, halogen, (Ci-Cs)alkyl, hydroxy, (Ci-Cs)alkoxy or N(R⁵)₂, where each R⁵ is independently hydrogen or (Ci-Cs)alkyl, or two R⁵ join to form a 4-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, O and S;

each R³ is independently hydrogen, hydroxy or NH2; or when D is C(R³)2, R³ is additionally selected from fluorine;

each R⁹ is independently hydrogen or fluorine;

B is N or C;

E is NR¹, CH2, C(R¹)2, O or-S(O)₂;

each R⁸ is absent or is independently selected from the group consisting of (Ci-C8)alkyl, (CiC8)haloalkyl, hydroxy, (Ci-Cs)alkoxy, (C5-Ci2)aryl, 5-12 membered heteroaryl, (C3-Ci0)cycloalkyl, 20 3-12 membered heterocyclyl, OR⁴, SR⁴, N(R⁴)2, CN, halogen and CON(R⁴)², where two R⁸

-10optionally join to form a 4-6 membered spiro-cycloalkyl ring, a cycloalkyl fused ring, or a alkylene bridge spanning G, and where two R⁸ optionaily join to form carbonyl;

where each R⁴ is independently A-R¹⁴, where A is absent, (Ci-C3)alkyl, -C(O)- or -SO2-, and R¹⁴ is hydrogen, (Ci-C8)alkyl, (C₅-Ci₂)aryl, 5-12 membered heteroaryl, (C₃-Ci₀)cycloalkyl or 3-12 membered heterocyclyl, or two R⁴ join to form a 4-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, O and S;

Q is absent or is a divalent moiety selected from O, S, NH and (Ci-Cs)alkylene;

V is N or C, where if V forms a double bond V is carbon;

W is N or C, where if W forms a double bond W is carbon;

X is N or C, where if X forms a double bond X is carbon;

Y is CR¹⁰, N, NR¹⁰, O or S, where each R¹⁰ is independently selected from hydrogen, (CiC8)aikyl, hydroxy, (Ci-C8)alkoxy, halogen, SH, S-(Ci-C8)alkyl and N(R¹¹)2 if Y is CR¹⁰, where Y forms a double with an adjacent ring member when Y is CR¹⁰ or N, and where each R¹¹ is independently hydrogen, (Ci-C₈)alkyl, (C₅-Ci₂)aryl or 5-12 membered heteroaryl or two R¹¹ join to form a 4-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, O and S, or Y is C(R¹⁰)₂ and the two R¹⁰ and the carbon to which they are associated form a carbonyl or a thiocarbonyl;

Z is CR¹², N, NR¹², O or S, where each R¹² is independently selected from hydrogen, (CiC8)alkyl, hydroxy, (Ci-Cs)alkoxy, fluoro, chloro, bromo, SH, S-(Ci-C8)alkyl and N(R¹³)2, where Z 20 forms a double bond with an adjacent ring member if it is CR¹² or N, where each R¹³ is independently hydrogen, (Ci-C₈)alkyl, (Cs-Ci₂)aryl or 5-12 membered heteroaryl, or two R¹³ join to form a 4-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, O and S, and where Z is not NR¹² if X is N, V is C, W is C and Y is CR¹⁰, or Z is C(R¹²)₂ and the two R¹² and the carbon to which they are associated form a carbonyl or a thiocarbonyl; and each-----is an optional bond, where no more than two, non-adjacent-----may be présent.

Further embodiments of the présent invention include compounds as described herein where

is selected from:

In certain embodiments:

is selected from:

Further embodiments of the présent invention include compounds as described herein where is selected from:

CF₃

In certain embodiments

- 16is:

Further embodiments of the présent invention include compounds selected from:

F

F

or a pharmaceutically acceptable sait thereof.

In certain embodiments of the présent invention the compound is selected from:

or a pharmaceuticaliy acceptable sait thereof.

Further embodiments of the présent invention include compounds selected from:

or a pharmaceutically acceptable sait thereof.

Also provided in the présent invention are pharmaceutical compositions comprising a compound as described herein and a pharmaceutically acceptable carrier.

Additionally, provided in the présent invention are methods of treating abnormal cell growth in a mammal comprising administering to the mammal a therapeutically effective amount of a compound as described herein. The abnormal cell growth is cancer. The cancer referred to herein may be lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal région, stomach cancer, colon cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine System, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the pénis, prostate cancer, chronic or acute leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, rénal cell carcinoma, carcinoma of the rénal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, spinal axis tumors, brain stem glioma, or pituitary adenoma.

Further still, the présent invention provides for the use of a compound as described herein for the préparation of a médicament useful in the treatment of abnormal cell growth in a mammal. The abnormal cell growth is cancer. The cancer referred to herein may be lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal région,

-49stomach cancer, colon cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine System, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the 5 adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the pénis, prostate cancer, chronic or acute leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, rénal cell carcinoma, carcinoma of the rénal pelvis, neoplasms of the central nervous System (CNS), primary CNS lymphoma, spinal axis tumors, brain stem glioma, or pituitary adenoma.

The invention further provides for embodiments wherein:

As found in formula I or formula II is selected from:

and

Additional embodiments of the invention include pharmaceutical composition comprising of a compound described herein or a pharmaceutically acceptable sait thereof, and a pharmaceutically acceptable carrier.

Additional embodiments of the invention include methods of treating abnormal cell growth in a mammal, the method comprising administering to the mammal a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable sait thereof, and a pharmaceutically acceptable carrier.

Additional embodiments of the invention include such methods of treatment as are described herein, wherein the abnormal cell growth is cancer. In particular, such methods wherein the cancer is lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal région, stomach cancer, colon cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, 15 carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine System, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the pénis, prostate cancer, chronic or acute leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, rénal cell carcinoma, 20 carcinoma of the rénal pelvis, neoplasms of the central nervous System (CNS), primary CNS lymphoma, spinal axis tumors, brain stem glioma, or pituitary adenoma.

There is also provided an embodiment of the invention which is the use of a compound described herein, or a pharmaceutically acceptable sait thereof for the préparation of a médicament useful in the treatment of abnormal cell growth in a mammal, particularly wherein 25 the abnormal cell growth is cancer, and more particularly wherein the cancer is lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal région, stomach cancer, colon cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of 30 the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine System, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the

-51 adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the pénis, prostate cancer, chronic or acute leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, rénal cell carcinoma, carcinoma of the rénal pelvis, neoplasms of the central nervous System (CNS), primary CNS lymphoma, spinal axis tumors, brain stem glioma, or 5 pituitary adenoma.

in another embodiment, the invention provides a pharmaceutical composition comprising a compound of the invention or a pharmaceutically acceptable sait thereof, and a pharmaceutically acceptable carrier.

In another embodiment, the invention provides a method of treating abnormal cell growth 10 in a mammal, including a human, the method comprising administering to the mammal a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable sait thereof. In another embodiment, the abnormal cell growth is cancer. In another embodiment, the cancer is lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal 15 cancer, cancer of the anal région, stomach cancer, colon cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin s Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of 20 the urethra, cancer of the pénis, prostate cancer, chronic or acute leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, rénal cell carcinoma, carcinoma of the rénal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, spinal axis tumors, brain stem glioma, or pituitary adenoma.

Définitions

Unless otherwise stated, the following terms used in the spécification and daims hâve the meanings discussed below. Variables defined in this section, such as R, X, n and the like, are for reference within this section only, and are not meant to hâve the same meaning as may be used outside of this définitions section. Further, many of the groups defined herein can be optionally substituted. The listing in this définitions section of typical substituents is exemplary 30 and is not intended to limit the substituents defined elsewhere within this spécification and daims.

Alkenyl refers to an alkyl group, as defined herein, consisting of at least two carbon atoms and at least one carbon-carbon double bond. Représentative examples include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, and the like. “Alkenylene” refers to a di35 valent form of alkenyl.

-52“Alkoxy” refers to -O-alkyl where alkyl is preferably Ci-C₈, C1-C7, Ci-C₈, C1-C5, C1-C4, C1-C3, C1C2 or Ci alkyl.

Alkyl refers to a saturated aliphatic hydrocarbon radical including straight chain and branched chain groups of 1 to 20 carbon atoms (“(Ci-C2o)alkyl”), preferably 1 to 12 carbon atoms (“(C15 Ci2)alkyl”), more preferably 1 to 8 carbon atoms (“(Ci-Cs)alkyl”), or 1 to 6 carbon atoms (“(CiC₆)alkyl”), or 1 to 4 carbon atoms (“(Ci-C₄)alkyl”). Examples of alkyl groups include methyl, ethyl, propyl, 2-propyl, n-butyl, /so-butyl, fert-butyl, pentyl, neopentyl, and the like. Alkyl may be substituted or unsubstituted. Typical substituent groups include cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, 10 thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, Ccarboxy, O-carboxy, nitro, silyl, amino and -NR^xR^y, where R^x and R^y are for example hydrogen, alkyl, cycloalkyl, aryl, carbonyl, acetyl, sulfonyl, trifluoromethanesulfonyl and, combined, a fiveor six-member heteroalicyclic ring. “Haloalkyl” for instance (Ci-C₈)haloalkyl, refers to an alkyl having one or more, halogen substituents. “Alkylene” refers to a di-valent form of alkyl.

Alkynyl refers to an alkyl group, as defined herein, consisting of at least two carbon atoms and at least one carbon-carbon triple bond. Représentative examples include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl, and the like. “Alkynylene” refers to a divalent form of alkynyl.

Amino refers to an -NR^xR^y group, wherein R^x and R^y are both hydrogen.

(C_s-Ci2)aryl refers to an all-carbon monocyclic or fused-ring polycyclic groups of 6 to 12 carbon atoms having a completely conjugated pi-electron System. Similarly, (Cs-Ci2)aryl refers to an all-carbon monocyclic or fused-ring polycyclic groups of 5 to 12 carbon atoms having a completely conjugated pi-electron System. Examples, without limitation, of aryl groups are phenyl, naphthalenyl and anthracenyl. The aryl group may be substituted or unsubstituted.

Typical substituents include halo, trihalomethyl, alkyl, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, nitro, carbonyl, thiocarbonyl, C-carboxy, O-carboxy, O-carbamyl, Ncarbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, sulfinyl, sulfonyl, amino and NR^xR^y, with R^x and R^y as defined above.

Cyano refers to a -C^N group. Cyano may be expressed as CN.

(C₃-C₁₀)cycloalkyl refers to a 3 to 10 member all-carbon monocyclic ring, a 3 to 10 member allcarbon bicyclic ring, an all-carbon 5-member/6-member or 6-member/6-member fused bicyclic ring, a multicyclic fused ring (a “fused” ring System means that each ring in the System shares an adjacent pair of carbon atoms with each other ring in the System) group wherein one or more of the rings may contain one or more double bonds but none of the rings has a completely 35 conjugated pi-electron System, and a bridged all-carbon ring system. Examples, without limitation, of cycloalkyl groups are cyclopropane, cyclobutane, cyclopentane, cyclopentene,

-53cyclohexane, cyclohexadiene, adamantane, cycloheptane, cycloheptatriene, and the like. A cycloalkyl group may be substituted or unsubstituted. Typical substituent groups include alkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, C-carboxy, O-carboxy, O-carbamyl, N-carbamyl, C-amido, N5 amido, nitro, amino and -NR^xR^y, with R^x and R^y as defined above.

“Halogen” or the prefix “halo” refers to fluoro, chloro, bromo and iodo. Preferably halogen refers to fluoro or chloro.

“Heteroalkyl refers to a straight chain or branched chain alkyl group of 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms, more preferably 1 to 8 carbon atoms, or 1 to 6 carbon atoms, 10 or 1 to 4 carbon atoms, wherein one, two or three of which carbon atoms are replaced by a heteroatom seiected from from NR^X, N, O, and S(O)_n (where n is 0, 1 or 2). Typically the heteroatoms, of there are more that one heteroatoms, are not adjacent to one another. Exemplary heteroalkyls include alkyl ethers, secondary and tertiary alkyl amines, amides, alkyl suifides, and the like. The group may be a terminal group or a bridging group. As used herein, 15 reference to the normal chain when used in the context of a bridging group refers to the direct chain of atoms linking the two terminal positions of the bridging group. As with “alkyl”, typical substituent groups on “heteroalkyl” include cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, Ocarbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, C-carboxy, O20 carboxy, nitro, silyl, amino and -NR^xR^y, where R^x and R^y are for example hydrogen, alkyl, cycloalkyl, aryl, carbonyl, acetyl, sulfonyl, trifluoromethanesulfonyl and, combined, a five- or sixmember heteroalicyclic ring. “Heteroalkenyl” refers to a heteroalkyl possessing one or more carbon-carbon double bonds. “Heteroalkylene” refers to a di-valent form of heteroalkyl. “Heteroalkenylene” refers to a di-valent form of heteroalkenyl.

Heteroaryl refers to a monocyclic or fused ring group of 5 to 12 carbon ring atoms containing one, two, three or four ring heteroatoms seiected from from NR^X, N, O, and S(O)_n (where n is 0, 1 or 2) and, in addition, having a completely conjugated pi-electron System. Preferred heteroaryl groups include (C₂-C₇)heteroaryl in accordance with the définition above. Examples, without limitation, of unsubstituted heteroaryl groups are pyrrole, furan, thiophene, imidazole, 30 oxazoie, thiazole, pyrazole, pyridine, pyrimidine, quinoline, isoquinoline, purine, tetrazole, triazine, and carbazole. The heteroaryl group may be substituted or unsubstituted. Typical substituents include alkyl, cycloalkyl, halo, trihalomethyl, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, nitro, carbonyl, thiocarbonyl, sulfonamido, C-carboxy, O-carboxy, sulfinyl, sulfonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, 35 amino and -NR^xR^y with R^x and R^y as defined above. A pharmaœutically acceptable heteroaryl is one that is sufficiently stable to be attached to a compound of the invention, formulated into a

-54pharmaceutical composition and subsequently administered to a patient in need thereof. Examples of typical monocyclic heteroaryl groups include, but are not limited to:

O	O	O	O	O '—N
pyrrole	furan	thiophene	pyrazole	imidazole
(pyrrolyl)	(furanyl)	(thiophenyl)	(pyrazolyl)	(imidazolyl)
A GN	ô V—n	û	ô N	N
isoxazole	oxazole	isothiazole	thiazolyl	1,2,3-triazole
(isoxazolyl)	(oxazolyl)	(isothiazolyl)	(thiazolyl)	(1,2,3-triazolyl)

N—N

1,3,4-triazole (1,3,4-triazolyl)

1-oxa-2,3-diazole (1-oxa-2,3-diazolyl)

1-oxa-2,4-diazole (1-oxa-2,4-diazolyl)

O

N ,Ν

Ό

1-oxa-2,5-diazole (1 -oxa-2,5-diazolyl)

1-oxa-3,4-diazole (1-oxa-3,4-diazolyl)

1-thia-2,3-diazole (1 -thia-2,3-diazolyl)

1-thia-2,4-diazole (1-thia-2,4-diazolyl)

1-thia-2,5-diazole (1 -thia-2,5-diazolyl)

1-thia-3,4-diazole tetrazole pyridine (1 -thia-3,4-diazoiyl) (tetrazolyl) (pyridinyl) pyridazine (pyridazinyl) pyrimidine (pyrimidinyl)

pyrazine (pyrazinyl)

-55Examples of suitable fused ring heteroaryl groups include, but are not limited to:

benzofuran (benzofuranyl) benzothiophene (benzothiophenyl)

(indolyl)

benzimidazole

(benzimidazolyl) indazole (indazolyl)

benzotriazole (benzotriazoiyl) pyrrolo[2,3-b]pyridine (pyrrolo[2,3-b]pyridinyl) pyrrolo[2,3-c]pyridine (pyrrolo[2,3-c]pyridinyl) pyrrolo[3,2-c]pyridine (pyrrolo[3,2-c]pyridinyl)

pyrrolo[3,2-b]pyridine (pyrrolo[3,2-b]pyridinyl) imidazo[4,5-b]pyridine (imidazo[4,5-b]pyridiny imidazo[4,5-c]pyridine (imidazo[4,5-c]pyridinyl) pyrazolo[4,3-d]pyridine (pyrazolo[4,3-d]pyidinyl)

pyrazolo[4,3-c]pyridine pyrazolo[3,4-c]pyridine pyrazolo[3,4-b]pyridine (pyrazolo[4,3-c]pyidinyl) (pyrazolo[3,4-c]pyidinyl) (pyrazolo[3,4-b]pyidinyl) isoindole (isoindolyl)

indazole (indazolyl) purine (purinyl) indolizine imidazo[1,2-a]pyridine imidazo[1,5-a]pyridine (indolininyI) (imidazo[1,2-a]pyridinyl) (imidazo[1,5-a]pyridinyl)

pyrazolo[1,5-a]pyridine (pyrazolo[1,5-a] py ridinyl) pyrrolo[1,2-b]pyridazine (py rrolo[1 -2, b]py ridazi nyl) imidazo[1,2-c]pyrimidine (imidazo[1,2-c]py rimidiny I)

5if-pyrrolo[3,2-&]pyrazine l//-pyrazolo[4,3-fe]pyrazine

177-pyrazoio[3,4-4]pyrimidine

7ff-pyrrolo[2,3-rf]pyrimidme

quinoline (quinolinyl) isoquinoline (isoquinolinyl) cinnoline quinazoline (cinnolinyl) (azaquinazoline)

quinoxaline (quinoxalinyl) phthalazine (phthalazinyl)

1,6-naphthyridine (1,6-naphthyridinyl)

1,7-naphthyridine (1,7-naphthyridinyl)

1,8-naphthyridine (1,8-naphthyridinyl)

1,5-naphthyridine (1,5-naphthyridinyl)

2,6-naphthyridine (2,6-naphthyridinyl)

2,7-naphthyridine (2,7-naphthyridinyl)

pyrido[3,2-d]pyrimidine (pyrido[3,2-d]pyrimidinyl) pyrido[4,3-d]pyrimidine (pyrido[4,3-d]pyrimidinyl) pyrido[3,4-d]pyrimidine (pyrido[3,4-d]pyrimidinyl)

pyrido[2,3-d]pyrimidine (pyrido[2,3-d]pyrimidinyl) pyrido[2,3-b]pyrazine (pyrido[2,3-b]pyrazinyl) pyrido[3,4-b]pyrazine (pyrido[3,4-b]pyrazinyl)

pyrimido[5,4-d]pyrimidine (pyrimido[5,4-d]pyrimidinyl) pyrazino[2,3-b]pyrazine (pyrazino[2,3-b]pyrazinyl) pyrimido[4,5-d]pyrimidine (pyrimido[4,5-d]pyrimidinyl)

Heterocyclyl” refers to a monocyclic or fused ring System having 3 to 12 ring atoms containing one, two, three or four ring heteroatoms selected from N, O, and S(O)_n (where n is 0, 1 or 2), 5 and 1-9 carbon atoms The rings may also hâve one or more double bonds. However, the rings do not hâve a completely conjugated pi-electron System. Preferred heterocycles include (C₂C₆)heterocycles in accordance with the définition above. Examples of suitable saturated heteroalicyclic groups include, but are not limited to:

oxirane thiarane aziridine (oxiranyl) (thiaranyl) (aziridinyl) oxetane thiatane (oxetanyl) (thiatanyl) azetidine (azetidinyl) tetrahydrofuran (tetrahydrofuranyl)

tetrahydrothiophene pyrrolidine (tetrahydrothiophenyl) (pyrrolidinyl) tetrahydropyran tetrahydrothiopyran (tetrahydropyranyl) (tetrahydrothiopyranyl)

piperidine (piperidinyl)

1,4-dioxane (1,4-dioxanyl)

1,4-oxathiane (1,4-oxathianyl) morpholine (morpholinyl)

1,4-dithiane (1,4-dithianyl)

piperazine 1,4-azathiane (piperazinyl) (1,4-azathianyl) oxepane thiepane (oxepanyl) (thiepanyl) azepane (azepanyl)

1,4-dioxepane (1,4-dioxepanyl)

1,4-oxathiepane (1,4-oxathiepanyl)

1,4-oxaazepane (1,4-oxaazepanyl)

1,4-dithiepane (1,4-dithiepanyl)

1,4-thieazepane (1,4-thieazepanyl)

1,4-diazepane (1,4-diazepanyl)

-58Exampies of suitable partially unsaturated heteroalicyclic groups include, but are not limited to:

3,4-dihydro-2H-pyran (3,4-dihydro-2H-pyranyl)

5,6-dihydro-2H-pyran (5,6-dihydro-2H-pyranyl)

2H-pyran (2H-pyranyl)

1,2,3,4-tetrahydropyridine (1,2,3,4-tetrahydropyridinyl)

1,2,5,6-tetrahydropyridine (1,2,5,6-tetrahydropyridinyl)

The heterocyclyl group is optionally substituted with one or two substituents independently selected from halo, lower alkyl, lower alkyl substituted with carboxy, ester hydroxy, or mono or dialkylamino. Moreover, the heterocycle may contain bridging, including bridging between nonadjacent carbons on the heterocycle, with the bridge containing 1-2 carbons and 0-1 heteroatoms selected from selected from NR^X, O, and S(O)_n (where n is 0, 1 or 2).

Hydroxy or “hydroxyl” refers to an -OH group.

In vitro refers to procedures performed in an artificial environment such as, e.g., without limitation, in a test tube or culture medium.

In vivo refers to procedures performed within a living organism such as, without limitation, a mouse, rat or rabbit.

Optional or optionally means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, heterocycle group optionally substituted with an alkyl group means that the alkyl may but need not be présent, and the description includes situations where the heterocycle group is substituted with an alkyl group and situations where the heterocycle group is not substituted with the alkyl group.

Organism refers to any living entity comprised of at least one cell. A living organism can be as simple as, for example, a single eukariotic cell or as complex as a mammal, including a human being.

A pharmaceutically acceptable excipient refers to an inert substance added to a pharmaceutical composition to further facilitate administration of a compound. Examples, without limitation, of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose dérivatives, gelatin, vegetable oils and polyethyiene glycols.

As used herein, the term “pharmaceutically acceptable sait” refers to those salts which retain the biological effectiveness and properties of the parent compound. Such salts include:

(i) acid addition salts, which can be obtained by reaction of the free base of the parent compound with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, sulfuric acid, and perchloric acid and the like, or with organic acids such as acetic acid, oxalic acid, (D) or (L) malic acid, maleic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, citric acid, succinic acid or malonic acid and the like; or (ii) salts formed when an acidic proton présent in the parent compound either is replaced by a métal ion, e.g., an alkali métal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N- methylglucamine, and the like.

A pharmaceutical composition refers to a mixture of one or more of the compounds described herein, or physiologically/pharmaceutically acceptable salts, solvatés, hydrates or prodrugs thereof, with other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate 15 administration of a compound to an organism.

As used herein, a physiologically/pharmaceutically acceptable carrier refers to a carrier or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.

Therapeutically effective amount refers to that amount of the compound being administered 20 which will relieve to some extent one or more of the symptoms of the disorder being treated. In reference to the treatment of cancer, a therapeutically effective amount refers to that amount which has at least one of the following effects:

reducing the size of the tumor;

inhibiting (that is, slowing to some extent, preferably stopping) tumor metastasis;

inhibiting to some extent (that is, slowing to some extent, preferably stopping) tumor growth, and relieving to some extent (or, preferably, eliminating) one or more symptoms associated with the cancer.

Treat, treating and treatment refer to a method of alleviating or abrogating a methyltransferase mediated cellular disorder and/or its attendant symptoms. With regard 30 particularly to cancer, these terms simply mean that the life expectancy of an individual affected with a cancer will be increased or that one or more of the symptoms of the disease will be reduced.

Detailed Description

General schemes for synthesizing the compounds of the invention can be found in the 35 Examples section herein.

-60Unless indicated otherwise, ail référencés herein to the inventive compounds include référencés to salts, solvatés, hydrates and complexes thereof, and to solvatés, hydrates and complexes of salts thereof, including polymorphs, stereoisomers, and isotopically labeled versions thereof.

Pharmaceutically acceptable salts include acid addition and base salts (including disaits). Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulfate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, 10 naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stéarate, succinate, tartrate, tosylate and trifluoroacetate salts.

Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, 15 magnésium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.For a review on suitable salts, see “Handbook of Pharmaceutical Salts: Properties, Sélection, and Use” by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002), the disclosure of which is incorporated herein by référencé in its entirety.

Tosylate, hydrochloride and mesylate salts are of interest.

A pharmaceutically acceptable sait of the inventive compounds can be readily prepared by mixing together solutions of the compound and the desired acid or base, as appropriate. The sait may precipitate from solution and be collected by filtration or may be recovered by évaporation of the solvent. The degree of ionization in the sait may vary from completely ionized to almost non-ionized.

The compounds of the invention may exist in both unsolvated and solvated forms. The term ‘solvaté’ is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molécules, for example, éthanol. The term ‘hydrate’ is employed when the solvent is water. Pharmaceutically acceptable solvatés in accordance with the invention include hydrates and solvatés wherein the 30 solvent of crystallization may be isotopically substituted, e.g. D₂O, d₆-acetone, de-DMSO.

Also included within the scope of the invention are complexes such as clathrates, drug-host inclusion complexes wherein, in contrast to the aforementioned solvatés, the drug and host are présent in stoichiometric or non-stoichiometric amounts. Also included are complexes of the drug containing two or more organic and/or inorganic components which may be in 35 stoichiometric or non-stoichiometric amounts. The resulting complexes may be ionized, partially ionized, or non-ionized. For a review of such complexes, see J Pharm Sci, 64 (8), 1269-1288 by

-61 Haleblian (August 1975), the disclosure of which is incorporated herein by reference in its entirety.

Also within the scope of the invention are polymorphs, prodrugs, and isomers (including optical, géométrie and tautomeric isomers) of the inventive compounds

Dérivatives of compounds of the invention which may hâve little or no pharmacological activity themselves but can, when administered to a patient, be converted into the inventive compounds, for example, by hydrolytic cleavage. Such dérivatives are referred to as ‘prodrugs’. Further information on the use of prodrugs may be found in ‘Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Sériés (T Higuchi and W Stella) and ‘Bioreversible Carriers 10 in Drug Design’, Pergamon Press, 1987 (ed. E B Roche, American Pharmaceutical Association), the disclosures of which are incorporated herein by référencé in their entireties. Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities présent in the inventive compounds with certain moieties known to those skilled in the art as ‘pro-moieties’ as described, for example, in Design of Prodrugs by H 15 Bundgaard (Elsevier, 1985), the disclosure of which is incorporated herein by référencé in its entirety.

Some examples of prodrugs in accordance with the invention include:

(i) where the compound contains a carboxylic acid functionality -(COOH), an ester thereof, for example, replacement of the hydrogen with (Ci-C₈)alkyl;

(ii) where the compound contains an alcohol functionality (-OH), an ether thereof, for example, replacement of the hydrogen with (Ci-C_s)alkanoyloxymethyl; and (iii) where the compound contains a primary or secondary amino functionality (-NH₂ or -NHR _Wh_ere R Ψ H), an amide thereof, for example, replacement of one or both hydrogens with (CiCio)alkanoyl.

Further examples of replacement groups in accordance with the foregoing examples and examples of other prodrug types may be found in the aforementioned référencés.

Finally, certain inventive compounds may themselves act as prodrugs of other of the inventive compounds.

Compounds of the invention containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. Where the compounds according to this invention hâve at least one chiral center, they may accordingly exist as enantiomers. Where the compounds possess two or more chiral centers, they may additionally exist as diastereomers. Similarly, where a compound of the invention contains a cyclopropyl group or other cyciic group where chirality exists, and alkenyl or alkenylene group, géométrie cisltrans (or Z/E) isomers are possible.

Where the compound contains, for example, a keto or oxime group or an aromatic moiety,

-62tautomeric isomerism (‘tautomerism’) can occur. A single compound may exhibit more than one type of isomerism.

Included within the scope of the invention are ail stereoisomers, géométrie isomers and tautomeric forms of the inventive compounds, including compounds exhibiting more than one 5 type of isomerism, and mixtures of one or more thereof. Also included are acid addition or base salts wherein the counterion is optically active, for example, D-lactate or L-lysine, or racemic, for example, DL-tartrate or DL-arginine.

Cisltrans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallization.

Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a sait or dérivative) using, for example, chiral high pressure liquid chromatography (HPLC) or supercritical fluid chromatography (SFC).

Alternative^, the racemate (or a racemic precursor) may be reacted with a suitable 15 optically active compound, for example, an alcohol, or, in the case where the compound contains an acidic or basic moiety, an acid or base such as tartaric acid or 1-phenylethylamine. The resuiting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to one skilled in the art.

Stereoisomeric conglomérâtes may be separated by conventional techniques known to those skilled in the art; see, for example, “Stereochemistry of Organic Compounds” by E L Eliel (Wiley, New York, 1994), the disclosure of which is incorporated herein by référencé in its entirety.

The invention also includes isotopically-labeled compounds of the invention, wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass 25 or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as ²H and ³H, carbon, such as ¹¹C, ¹³C and ¹⁴C, chlorine, such as ³⁶CI, fluorine, such as ¹⁸F, iodine, such as ¹²³l and ¹²⁵l, nitrogen, such as ¹³N and ¹⁵N, oxygen, such as ¹⁵O, ¹⁷O and ¹⁸O, phosphorus, such as ³²P, and sulfur, such as ³⁵S. Certain isotopically30 labeied compounds of the invention, for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, ³H, and carbon-14, ¹⁴C, are particularly useful forthis purpose in view of their ease of incorporation and ready means of détection. Substitution with heavier isotopes such as deuterium, ²H, may afford certain therapeutic advantages resuiting from greater metabolic stability, for example, 35 increased in vivo half-iife or reduced dosage requirements, and hence may be preferred in some circumstances. Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and ¹³N,

-63can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.

Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed.

Pharmaceutically acceptable solvatés in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D2O, de-acetone, deDMSO.

Compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products, or mixtures thereof. They may be obtained, for example, as solid plugs, powders, or films by methods such as précipitation, crystallization, freeze drying, spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose.

The compounds can be administered alone or in combination with one or more other compounds of the invention. Generally, they will be administered as a formulation in association with one or more pharmaceutically acceptable excipients. The term “excipient” is used herein to describe any ingrédient other than the compound(s) of the invention. The choice of excipient will to a large extent dépend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

Pharmaceutical compositions suitable for the delivery of compounds of the invention and methods for their préparation will be readily apparent to those skilled in the art. Such compositions and methods for their préparation can be found, for example, in ‘Remington’s Pharmaceutical Sciences’, 19th Edition (Mack Publishing Company, 1995), the disclosure of which is incorporated herein by reference in its entirety.

Oral Administration: The compounds of the invention may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth.

Formulations suitable for oral administration include solid formulations such as tablets, capsules containing particulates, liquids, or powders, lozenges (including liquid-filled), chews, multi- and nano-particulates, gels, solid solution, liposome, films (including muco-adhesive), ovules, sprays and liquid formulations.

Liquid formulations include suspensions, solutions, syrups and élixirs. Such formulations may be used as fillers in soft or hard capsules and typically include a carrier, for exampie, water,

-64éthanol, polyethylene glycol, propylene giycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.

The compounds of the invention may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, 11 (6), 981 986 by Liang and Chen (2001), the disclosure of which is incorporated herein by référencé in its entirety.

For tablet dosage forms, depending on dose, the drug may make up from 1 wt% to 80 wt% of the dosage form, more typically from 5 wt% to 60 wt% of the dosage form. In addition to 10 the drug, tablets generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinized starch and sodium aiginate. Generally, the disintegrant will comprise from 1 wt% to 25 wt%, preferably from 15 5 wt% to 20 wt% of the dosage form.

Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain diluents, such as lactose 20 (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.

Tablets may also optionally include surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When présent, surface active agents are typically in amounts of from 0.2 wt% to 5 wt% of the tablet, and glidants typically 25 from 0.2 wt% to 1 wt% of the tablet.

Tablets also generally contain lubricants such as magnésium stéarate, calcium stéarate, zinc stéarate, sodium stearyl fumarate, and mixtures of magnésium stéarate with sodium lauryl sulphate. Lubricants generally are présent in amounts from 0.25 wt% to 10 wt%, preferably from 0.5 wt% to 3 wt% of the tablet.

Other conventional ingrédients include anti-oxidants, colorants, flavoring agents, preservatives and taste-masking agents.

Exemplary tablets contain up to about 80 wt% drug, from about 10 wt% to about 90 wt% binder, from about 0 wt% to about 85 wt% diluent, from about 2 wt% to about 10 wt% disintegrant, and from about 0.25 wt% to about 10 wt% lubricant.

Tablet blends may be compressed directly or by relier to form tablets. Tablet blends or portions of blends may alternative^ be wet-, dry-, or melt-granulated, melt congealed, or

-65extruded before tableting. The final formulation may include one or more layers and may be coated or uncoated; or encapsulated.

The formulation of tablets is discussed in detail in “Pharmaceutical Dosage Forms:

Tablets, Vol. 1”, by H. Lieberman and L. Lachman, Marcel Dekker, N.Y., N.Y., 1980 (ISBN 05 8247-6918-X), the disclosure of which is incorporated herein by reference in its entirety.

Solid formulations for oral administration may be formulated to be immédiate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.

Suitable modified release formulations are described in U.S. Patent No. 6,106,864.

Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles can be found in Verma et al, Pharmaceutical Technology On-line, 25(2), 1-14 (2001). The use of chewing gum to achieve controlled release is described in WO 00/35298. The disclosures of these référencés are incorporated herein by reference in their entireties.

Parentéral Administration

The compounds of the invention may also be administered directly into the blood stream, into muscle, or into an internai organ. Suitable means for parentéral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous. Suitable devices for parentéral administration include needle (including micro needle) injectors, needle-free injectors and infusion techniques.

Parentéral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a stérile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as stérile, pyrogen-free water.

The préparation of parentéral formulations under stérile conditions, for example, by lyophilization, may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.

The solubility of compounds of the invention used in the préparation of parentéral solutions may be increased by the use of appropriate formulation techniques, such as the 30 incorporation of solubility-enhancing agents.Formulations for parentéral administration may be formulated to be immédiate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. Thus compounds of the invention may be formulated as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound. Examples of such 35 formulations include drug-coated stents and PGLA microspheres.

Topical Administration

-66The compounds of the invention may also be administered topically to the skin or mucosa, that is, dermally or transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. Liposomes may 5 also be used. Typical carriers include alcohol, water, minerai oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Pénétration enhancers may be incorporated; see, for example, J Pharm Sci, 88 (10), 955-958 by Finnin and Morgan (October 1999). Other means of topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and micro needle or needle-free (e.g. Powderject™, Bioject™, 10 etc.) injection. The disclosures of these references are incorporated herein by reference in their entireties.

Formulations for topical administration may be formulated to be immédiate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.

Inhaled/lntranasal Administration

The compounds of the invention can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aérosol spray from a pressurized 20 container, pump, spray, atomizer (preferably an atomizer using electrohydrodynamics to produce a fine mist), or nebulizer, with or without the use of a suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. For intranasal use, the powder may include a bioadhesive agent, for example, chitosan or cyclodextrin.

The pressurized container, pump, spray, atomizer, or nebulizer contains a solution or 25 suspension of the compound(s) of the invention comprising, for example, éthanol, aqueous éthanol, or a suitable alternative agent for dispersing, solubilizing, or extending release of the active, a propeliant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, oi an oligolactic acid.

Prior to use in a dry powder or suspension formulation, the drug product is micronized to 30 a size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying.

Capsules (made, for example, from gelatin or HPMC), blisters and cartridges for use in 35 an inhaler or insufflator may be formulated to contain a powder mix of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as

-67/-leucine, mannitol, or magnésium stéarate. The lactose may be anhydrous or in the form of the monohydrate, preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.

A suitable solution formulation for use in an atomizer using electrohydrodynamics to 5 produce a fine mist may contain from 1 pg to 20 mg of the compound of the invention per actuation and the actuation volume may vary from 1 pL to 100 pL. A typical formulation includes a compound of the invention, propylene glycol, stérile water, éthanol and sodium chloride. Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol.

1θ Suitable flavors, such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to those formulations of the invention intended for inhaled/intranasal administration.

Formulations for inhaled/intranasal administration may be formulated to be immédiate and/or modified release using, for example, poly(DL-lactic-coglycolic acid (PGLA). Modified 15 release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.

In the case of dry powder inhalers and aérosols, the dosage unit is determined by means of a valve which delivers a metered amount. Units in accordance with the invention are typically arranged to administer a metered dose or “puff” containing a desired mount of the 20 compound of the invention. The overall daily dose may be administered in a single dose or, more usually, as divided doses throughout the day.

Rectal/lntravaginal Administration: Compounds of the invention may be administered rectally or vaginally, for example, in the form of a suppository, pessary, or enema. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate. Formulations 25 for rectal/vaginal administration may be formulated to be immédiate and/or modified release.

Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.

Ocular Administration: Compounds of the invention may also be administered directly to the eye or ear, typically in the form of drops of a micronized suspension or solution in isotonie, pH30 adjusted, stérile saline. Other formulations suitable for ocular and aurai administration include ointments, biodégradable (e.g. absorbable gel sponges, collagen) and non-biodegradable (e.g. silicone) implants, wafers, lenses and particulate or vesicular Systems, such as niosomes or liposomes. A polymer such as crossed-linked polyacryiic acid, polyvinylalcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or 35 methyl cellulose, or a heteropolysaccharide polymer, for example, gelan gum, may be

-68incorporated together with a preservative, such as benzalkonium chloride. Such formulations may also be delivered by iontophoresis.

Formulations for ocular/aural administration may be formulated to be immédiate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, 5 controlled-, targeted, or programmed release.

Other Technologies

Compounds of the invention may be combined with soluble macromolecular entities, such as cyclodextrin and suitable dérivatives thereof or polyethylene glycol-containing polymers, in order to improve their solubility, dissolution rate, taste-masking, bioavailability and/or stability for use 10 in any of the aforementioned modes of administration.

Drug-cyclodextrin complexes, for example, are found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes may be used. As an alternative to direct complexation with the drug, the cyclodextrin may be used as an auxiliary additive, i.e. as a carrier, diluent, or solubilizer. Most commonly used for these purposes are 15 alpha-, beta- and gamma-cyclodextrins, examples of which may be found in PCT Publication

Nos. WO 91/11172, WO 94/02518 and WO 98/55148, the disclosures of which are incorporated herein by référencé in their entireties.

Dosage: The amount of the active compound administered will be dépendent on the subject being treated, the severity of the disorder or condition, the rate of administration, the disposition of the 20 compound and the discrétion of the prescribing physician. However, an effective dosage is typically in the range of about 0.001 to about 100 mg per kg body weight per day, preferably about 0.01 to about 35 mg/kg/day, in single or divided doses. For a 70 kg human, this would amount to about 0.07 to about 7000 mg/day, preferably about 0.7 to about 2500 mg/day. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adéquate, while in 25 other cases still larger doses may be used without causing any harmful side effect, with such larger doses typically divided into several smaller doses for administration throughout the day.

-69Kit-of-Parts: Inasmuch as it may désirable to administer a combination of active compounds, for example, for the purpose of treating a particular disease or condition, it is within the scope of the présent invention that two or more pharmaceutical compositions, at least one of which contains a compound in accordance with the invention, may conveniently be combined in the form of a kit 5 suitable for coadministration of the compositions. Thus the kit of the invention includes two or more separate pharmaceutical compositions, at least one of which contains a compound of the invention, and means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet. An example of such a kit is the familiar blister pack used for the packaging of tablets, capsules and the like.

The kit of the invention is particulariy suitable for administering different dosage forms, for example, oral and parentéral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another. To assist compliance, the kit typically includes directions for administration and may be provided with a memory aid.

EXAMPLES

For some of the steps described it may be necessary to protect potential reactive functions that are not wished to react, and to cleave said protecting groups in conséquence. In such a case, any compatible protecting radical may be used. In particular methods of protection 20 and deprotection such as those described by T.W. Greene (Protective Groups in Organic Synthesis, A. Wiley-lnterscience Publication, 1981) or by P. J. Kocienski (Protecting groups, Georg Thieme Verlag, 1994), may be used.

AH of the reactions herein and the préparations of novel starting materials used herein are conventional and appropriate reagents and reaction conditions for their performance or 25 préparation as weil as procedures for isolating the desired products will be well-known to those skilled in the art with référencé to literature precedents and the examples and préparations hereto.

The following abbreviations may be used herein:

Ac (acetyl); AcCI (acetyl chloride); AcOH or HOAc (acetic acid); Ac₂O (acetic anhydride);

aq. (aqueous); Boc or boc (tert-butoxycarbonyl); ca. (about or approximately); CDCI₃ (deuterated chloroform); CH₂CI₂ and/or DCM (dichloromethane); DAST (Diethylaminosulfur trifluoride); DCE (dichloroethane); DEA (diethylamine); DIBAL or DIBAL-H (diisobutylaluminum hydride); DIC (diisopropylcarbodiimide); DIPEA or Hunig’s base (A/,/\/-diisopropylethylamine); DMA (dimethylacetamide); DMF (dimethylformamide);DME (ethylene glycol); DMP (Dess-Martin 35 Periodinane); DMAP (4-dimethylaminopyridine); DMSO (dimethylsulfoxide); DMSO-d₆ (deuterated dimethylsulfoxide); EDC or EDCI (1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide);

-70Et (ethyl); Et₃N or TEA (triethylamine); EtOH (éthanol); EtOAc (ethyl acetate); Et₂O (diethyl ether); g or gm (gram or grams); HATU (2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3tetramethyluronium hexafluorophosphate); HBTU (o-(benzotriazole-1-yl)-1,1,3,3tetramethyluronium hexafluorophosphate); HMPT (Tris(dimethylamino)phosphine); HPLC (high5 performance liquid chromatography); HOBT (1-hydroxy benzotriazole); h or hr (hour or hours, as appropriate); iBu (isobutyl); IPA (/so-propyl alcohol); iPr (isopropyl); iPrOAc (isopropyl acetate); KHMDS (potassium bis(trimethylsilyl)amide); KOAc (potassium acetate); LCMS (liquid chromatography-mass spectrometry); LiHMDS (lithium bis(trimethylsilyl)amide); Me (methyi); MeOH (methanol); MeOD (deuterated methanol); MeCN (acetonitrile); m or min (minute or 10 minutes, as appropriate); mg (milligram or milligrams); Ms (methylsulfonyl); MsCI (methanesulfonyl chloride); N (normal); NBS (N-Bromosuccinimide); NFSI (ΛΑFluorodibenzenesulfonimide); NMR (nuclear magnetic résonance); nBu (n-butyl); nBuLi (n-butyl lithium); nPr (n-propyl); Pd/C (palladium on carbon); Pd₂(dba)₃ (tr/s(dibenzylideneacetone)dipalladium(0)); Pd(dppf)CI₂ ([1,1'15 b/s(diphenylphosphino)ferrocene]dichloropalladium(ll)); Ph (phenyl); PTSA or pTSA (p-Toluene sulfonic acid); Rt (rétention time); rt (room température); RuCI(p-cymene)[(R,R)-Ts-DPEN] ([ΛΑΚ 1 R,2A?)-2-(Amino-KA/)-1,2-diphenylethyl]-4-methylbenzenesulfonamidatoKA/]chloro[(1,2,3,4,5,6-q)-1-methyl-4-(1-methylethyl)benzene]-ruthenium); s or sec (second or seconds, as appropriate); Selectfluor (A/-Chloromethyl-A/'-fluorotriethyIenediammonium bis(tetrafluoroborate)); SEM (2-Trimethylsilylethoxymethoxy); SFC (supercritical fluid chromatography); Si-Thiol (silica 1-propanethiol); T3P (propylphosphonic anhydride); TBAF (tetrabutyl ammonium fluoride); TBDMSCI (t-butyl-dimethylsilyl chloride); TBME or MTBE (tertbutyl methyi ether); f-BuOH (2-methyl-2-propanol, feri-butanol or tert-butyl alcohol); TDA-1 (Tris[2-(2-methoxyethoxy)ethyl]amine or Tris(3,6-dioxaheptyl)amine); TEA, NEt₃ or Et₃N 25 (triethylamine); TFA (trifluoroacetic acid); THF (tetrahydrofuran); THP (tetrahydropyran); TLC (thin layer chromatography); TMS (trimethyisilyl); TMSCI (trimethylsilyl chloride); TMSCF₃ (Trimethyl(trifluoromethyl)silane); Tos or tosyl (4-toluenesulfonyl); TOSMIC (pToluenesulfonylmethyl isocyanide); UV (ultraviolet).

General Synthetic Scheme for Carbonucleoside compounds

Scheme 1:

RM

TsOH

M = Li, Mg, Sn, Zn, Si, Cu, Fe or other métal

réduction

deprotection

As exemplified in Scheme 1, a compound such as 1a can be purchased or synthesized (Chem. Rev., 2012, 112 (8), pp 4642-4686). Typically, methyl (1S,2R,3S,4R)-4-amino-2,3dihydroxycyclopentane-1-carboxylate can react with an appropriately functionalized pyrimidine 5 or other heterocycle to give compounds such as 1b. This reaction can be accomplished through standard nucleophilic aromatic substitution using conditions such as diisopropylethylamine or trimethylamine in DMSO, DMA or DMF or conditions using césium fluoride in DMSO. Alternative reaction condition may include métal coupling reactions such as palladium couplings. Cyclization of compounds such as 1b to compounds such as 1c can occur 10 under a variety of conditions including condensations or métal couplings depending on the atom type of A. Protection of the diol to produce 1d can be done using acetone or 2,2dimethoxypropane in mild acid. Esters such as 1d are converted into alkyl and aryl ketones such as 1e using alkyl and aryl métal reagents such as alkyl and aryl Grignards (M= Mg), alkyl and aryl lithium reagents, alkyl and aryl cuprates, alkyl and aryl zincates as well as other 15 organometal reagents. Typically these reactions are run in ethereal solvents such as THF,

MeTHF, dioxane or similar solvent at températures ranging from -78 °C to 60 °C. Alkyl and aryl ketones such as 1e can be converted to secondary alcohols such as 1f using reducing reagents such as NaBH4, LiBH4, LÎAIH4, DIBAL and others. Typically these reactions can be run in a variety of solvents such as DCM, THF, MeOH, EtOH or others at varying températures. Alkyl 20 and aryl ketones such as 1e can be preferentially converted to diastereomerically enriched secondary alcohols such as 1f using chiral reducing conditions such as RuCI(p-cymene)[(R,F?)Ts-DPEN] and sodium formate (J. Org. Chem, 2014, 79, 3238-3243). Typically, these reactions are done in EtOAc solvent and run at room température. Finally, compounds such as 1f can be

-72deprotected to reveal the triol compounds such as 1g by treatment with acid such as TFA or dilute HCl. Typically these reactions are done in the presence of water at 0 oC or rt. Compounds at every step may be purified by standard techniques such as column chromatography, crystallization, reverse phase HPLC or SFC. If necessary, séparation of the diastereomers of 1f 5 or 1g may be carried out under standard methods known in the art such as chiral SFC or HPLC to afford single diastereomers.

Scheme 2:

As exemplified in Scheme 2, compounds such as 1d can be hydrolyzed with base to give the acid 2a. Typically these reactions are run using some hydroxide source such as lithium hydroxide, sodium hydroxide or other. Compounds similar to the carboxylic acid 2a are converted to compounds such as the Weinreb amide 2b via treatment with N,ΟΙ 5 dimethylhydroxylamine HCl and standard amide coupling reagents such as HOBT and EDCI,

T3P or HATU with a base such as DIPEA or TEA. Typically, these reactions are done in solvents such as DMF or THFand run at températures ranging from 0 oC to 60 oC. Weinreb amides such as 2b are converted into alkyl and aryl ketones such as 1e using alkyi and aryl métal reagents such as alkyl and aryl Grignards (M= Mg), alkyl and aryl lithium reagents, alkyl 20 and aryl cuprates, alkyl and aryl zincates as well as other organometal reagents. Typically these reactions are run in ethereal solvents such as THF, MeTHF, dioxane or similar solvent at températures ranging from -78 °C to 60 °C.

Scheme 3:

As exemplified in Scheme 3, a compound such as 3a [(3aS,4R,7S,7aR)-2,2-dimethyltetrahydro4,7-methano[1,3]dioxolo[4,5-c]pyridin-6(3aH)-one] can be purchased or synthesized (Chem. Rev., 2012, 112 (8), 4642-4686) and can be protected as the carbamate using reagents such as Boc anhydride or benzoyl chloride resulting in lactams such as 3b. These activated lactams (3b) are converted into alkyl and aryl ketones such as 3c using alkyl and aryl meta! reagents such as alkyl and aryl Grignards (M= Mg), alkyl and aryl lithium reagents, alkyl and aryl cuprates, alkyl and aryl zincates as well as other organometal reagents. Typicaily these reactions are run in ethereal solvents such as THF, MeTHF, dioxane or similar solvent at 10 températures ranging from -78 °C to 60 °C. Alkyl and aryl ketones such as 3c can be converted to secondary alcohols such as 3d using reducing reagents such as NaBH4, LIBH4, LÎAIH4, DIBAL and others. Typicaily these reactions can be run in a variety of solvents such as DOM, THF, MeOH, EtOH or others at varying températures. Alkyl and aryl ketones such as 3c can be preferentially converted to diastereomerically enriched secondary alcohols such as 3d using 15 chiral reducing conditions such as RuCI(p-cymene)[(S,S)-Ts-DPEN] and sodium formate (J.

Org. Chem, 2014, 79, 3238-3243). Typicaily, these reactions are done in EtOAc solvent and run at room température. The resulting secondary alcohol such as 3d can be protected with a

-74variety of reagents that provide orthogonal deprotection strategies to the carbamate installed earlier in the route. Such reagents include TMSCI, TESCI, TBDMSCI, TIPSCI, as well as others. Compounds such as 3e can be deprotected to give compounds such as 3f through a variety of methods depending on what carbamate is installed. Examples include using dilute 5 trifluoroacetic acid solution in the case of Boc carbamate or hydrogenolysis with Pd catalyst and hydrogen gas in the case of benzoyl carbamate. Compounds such as 3f can react with appropriately substituted heterocycles in a nucleophilic aromatic substitution to yield compounds such as 3g. Such reactions are usually accomplished using organic bases such as diisopropylethylamine or trimethylamine in DMSO, DMA or DMF or conditions using césium 10 fluoride in DMSO. Alternative reaction condition may include métal coupling reactions such as palladium couplings. Cyclization of compounds such as 3g to compounds such as 3h can occur under a variety of conditions including condensations or métal couplings depending on the atom type of A. Finally, compounds such as 3h can be deprotected to reveal the triol compounds such as 3i by treatment with acid such as TFA or dilute HCl. Typically these reactions are done 15 in the presence of water at 0 °C or rt. Compounds at every step may be purified by standard techniques such as column chromatography, crystallization, reverse phase HPLC or SFC. If necessary, séparation of the diastereomers of 3d or any compound afterwards may be carried out under standard methods known in the art such as chiral SFC or HPLC to afford single diastereomers.

Scheme 4:

nucleophilic aromatic substitution

nucleophilic aromatic substitution

cyclization

As exemplified

deprotection

in Scheme 4, a compound such as 4a

[(3aR,4S,6R,6aS)-6-amino-2,2dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-ol] can be purchased or synthesizesd [J.

Perkin Trans. /, 1985, 1437; Tetrahedron Letters, 2000, (41) 9537-9530]. Compounds such as

- 75 4a can undergo nucleophilic aromatic substitution with the appropriately substituted heterocycle to yield compounds such as 4b. Cyclization of compounds such as 4b to compounds such as 4c can occur under a variety of conditions including condensations or métal couplings depending on the atom type of A. Compounds such as 4c can undergo nucleophilic aromatic 5 substitution with the appropriately substituted fluorobenzene to yield phénol ethers such as 4d.

Finally, compounds such as 4d can be deprotected to reveal the diol compounds such as 4e by treatment with acid such as TFA or dilute HCl. Typically these reactions are done in the presence of water at 0 °C or rt. Compounds at every step may be purified by standard techniques such as column chromatography, crystallization, reverse phase HPLC or SFC. If 10 necessary, séparation of the diastereomers of 4a or any compound afterwards may be carried out under standard methods known in the art such as chiral SFC or HPLC to afford single diastereomers.

Scheme 5:

ro₂co

oco₂r

Pd asymmetric allylic alkylation

Pd allylic alkylation

OsO₄ or

KMnO₄

As exemplified in Scheme 5, compounds such as 5a can be purchased or synthesized (Chemical Science, 2010, 1, p427; Journal of the American Chemical Society, 2000, 122, p5947; Organic Letters, 2012, 14(9), p2254). Compounds such as 5a can undergo asymmetric allylic alkylation with appropriately substituted heterocycles using a variety of palladium catalysts and chiral ligands to form compounds such as 5b. Compounds such as 5b can undergo allylic alkylation with appropriately substituted phénols or hydroxyheterocycles using a variety of palladium catalysts and ligands to form compounds such as 5c. Compounds such as

5c can be dihydroxylated to form diols such as 5d using reagents such as osmium tertroxide or potassium permanganate. Compounds at every step may be purified by standard

-76techniques such as column chromatography, crystallization, reverse phase HPLC or SFC. if necessary, séparation of the diastereomers of 5d may be carried out under standard methods known in the art such as chiral SFC or HPLC to afford single diastereomers.

Scheme 6:

oco₂r

Pd asymmetric allylic alkylation

OsO₄

or

KMnO₄

Pd allylic alkylation

As exemplified in Scheme 6, compounds such as 5a can undergo asymmetric allylic alkylation with appropriately substituted phénols or hydroxyheterocycles using a variety of palladium catalysts and chiral ligands to form compounds such as 6a. Compounds such as 6a can undergo allylic alkylation with appropriately substituted heterocycles using a variety of palladium 10 catalysts and ligands to form compounds such as 5c. Compounds such as 5c can be dihydroxylated to form diols such as 5d using reagents such as osmium tertroxide or potassium permanganate.

Scheme 7:

hydrolysis

OsO₄

or

KMnO₄ nucleophilic aromatic substitution

As exemplified in Scheme 7, compounds such as 5b can be hydrolyzed to compounds such as

7a using some hydroxide source such as lithium hydroxide, sodium hydroxide or other.

-77Compounds such as 7a can undergo nucleophilic aromatic substitution with the appropriately substituted heterocycle to yield compounds such as 7b. Compounds such as 7b can be dihydroxylated to form diols such as 7c using reagents such as osmium tertroxide or potassium permanganate. Compounds at every step may be purified by standard techniques such as 5 column chromatography, crystallization, reverse phase HPLC or SFC. If necessary, séparation of the diastereomers of 7c may be carried out under standard methods known in the art such as chiral SFC or HPLC to afford single diastereomers.

Scheme 8:

or

KMnO₄

OsO₄

nucleophilic aromatic substitution

As exemplified in Scheme 8; compounds such as 6a can be hydrolyzed to compounds such as

8a using some hydroxide source such as lithium hydroxide, sodium hydroxide or other.

Compounds such as 8a can undergo nucleophilic aromatic substitution with the appropriately substituted heterocycle to yield compounds such as 8b. Compounds such as 8b can be dihydroxylated to form diols such as 8c using reagents such as osmium tertroxide or potassium permanganate. Compounds at every step may be purified by standard techniques such as column chromatography, crystallization, reverse phase HPLC or SFC. If necessary, séparation of the diastereomers of 8c may be carried oui under standard methods known in the art such as chiral SFC or HPLC to afford single diastereomers.

Example 1 (Scheme A): Synthesis of (1S,2R,3R,5R)-3-((R)-1-hydroxyethyl)-5-(4-methyl-7Hpyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol (A-12)

Example 2 (Scheme A): Synthesis of (1S,2R,3R,5R)-3-((S)-1-hydroxyethyl)-5-(4-methyl-7H25 pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol (A-13)

Scheme A

Step 1: Synthesis of (1R,4S,5R,6S)-5,6-dihydroxy-2-azabicyclo[2.2.1]heptan-3-one (A-2)

To a light yellow bi-phasic mixture of (1 R,4S)-2-azabicyclo[2.2.1]hept-5-en-3-one A-1 (Chemical Reviews, 2012, 112 (8), pp 4642-4686) (100 g, 916 mmol) and NMO (118 g, 1.01 mol) in isoamyl alchol (500 mL) and water (500 mL) was added 2.5 % OsCU in t-BuOH (1.5 g, 5.9 mmol, 76 mL) at rt (15 °C). The mixture was heated at 70 °C for 2 hrs. The mixture was cooled to rt (15 °C). NaHSO₃ (12 g) was added and stirred at rt (15 °C) for 45 min. The mixture was 10 concentrated in vacuo to afford crude (150 g) as dark solid which was purified by silica gel chromatography eluted with MeOH in DCM = 10% to afford A-2 (90 g, 69 %) as a light pink solid. Ή NMR (400 MHz, DMSO-de) δ ppm 7.54 (br. s., 1H), 5.00 (dd, J=21.3, 22.6 Hz, 2H), 3.81 - 3.64 (m, 2H), 3.43 (s, 1 H), 2.25 (s, 1 H), 1.93 - 1.67 (m, 2H)

Step 2: Synthesis of methyl (1S,2R,3S,4R)-4-amino-2,3-dihydroxycyclopentane-1carboxylate-HCI (A-3)

Compound A-2 (33 g, 231 mmol) was added to 4N HCl in MeOH (500 mL) at rt (15 °C). The suspension was stirred at rt (15 °C) for 20 hrs. The mixture was concentrated in vacuo and the

-79residue was suspended in DCM and filtered. The solid was washed with DCM and dried in vacuo to afford A-3 (45 g, 92%) as a white solid. LCMS [M+1 ] 176; Ή NMR (400 MHz, D₂O) δ ppm 4.27 (t, J=5.1 Hz, 1H), 4.04 (t, J=6.4 Hz, 1H), 3.72 (s, 3H), 3.55 (q, J=8.4 Hz, 1H), 2.97 (dt, J=5.0, 8.8 Hz, 1H), 2.49 (td, J=8.5, 13.8 Hz, 1H), 1.83 (td, J=9.2, 13.7 Hz, 1H)

Step 3: Synthesis of methyl (1S,2R,3S,4R)-4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-

2,3-dihydroxycyclopentane-1-carboxylate (A-4)

To a white suspension compound A-3 (42 g, 200 mmol) and 2-(4,6-dichloropyrimidin-5yl)acetaldehyde (40 g, 209 mmol) in EtOH (400 mL) was added Et₃N (40.4 g, 400 mmol). The resulting yellow solution was stirred at reflux for 2 hrs. The mixture was concentrated in vacuo to about 100 mL. The residue was poured into NH₄CI aq (500 mL) and extracted with EtOAc (200 mL x 3). The extract was washed with brine (200 mL), dried over Na₂SO₄ and concentrated in vacuo to afford crude A-4 (60 g, >99%) as a red gum which was used in the next step directly. LCMS [M+1] 312

Step 4: Synthesis of methyl (3aR,4S,6R,6aS)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-

2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxole-4-carboxylate (A-5)

To a solution of crude compound A-4 (60 g, 192 mmol) in 2,2-dimethoxypropane (300 mL) and acetone (300 mL) was added TsOH.H₂O (40 g, 212 mmol). The mixture was stirred at rt (15 °C) for 1 hr. The mixture was poured into NaHCO₃ aq (1000 mL) and extracted with EtOAc (500 mL). The extract was washed with brine, concentrated in vacuo to afford crude material which was purified by silica gel chromatography eluted with EtOAc in petroleum ether from 0-100 % to afford A-5 (42 g, 62%) as a yellow gum which solidified upon standing. LCMS [M+1] 352; ¹H NMR (400 MHz, CDCI₃) δ ppm 8.63 (s, 1H), 7.29 (d, J=3.5 Hz, 1H), 6.64 (d, J=3.8 Hz, 1H), 5.15 - 5.04 (m, 2H), 5.03 - 4.98 (m, 1H), 3.76 (s, 3H), 3.12 (ddd, J=5.3, 7.6, 10.7 Hz, 1H), 2.75 - 2.59 (m, 2H), 1.59 (s, 3H), 1.33 (s, 3H)

Step 5: Synthesis of methyl (3aR,4S,6R,6aS)-2,2-dimethyl-6-(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxole-4-carboxylate (A-6)

To a solution of A-5 (15 g, 42.6 mmol) in dry THF (125 mL) was added Pd(PPh₃)₄ (1.97 g, 1.71 mmol). To the resulting yellow solution was added 1M solution of Zn(Me)₂(171 mL, 171 mmol). The mixture was degassed with N₂ four times. The yellow solution was heated at reflux for 3 hrs which changed to a dark solution. The mixture was poured into cooled NH₄CI aq (200 mL)

-80carefully and extracted with EtOAc (200 mL x 3). The extract was washed with brine (200 mL), dried over Na₂SO₄ and concentrated in vacuo to afford crude (18 g) as a yellow gum. The crude material was purified by silica gel chromatography eluted with EtOAc in petroleum ether from 0 to 100% to A-6 (13.5 g, 96%) as a yellow gum. [a]²⁰ _D -21.57° (c= 8.4 mg/mL, methanol). LCMS [M+1] 332; Ή NMR (400 MHz, DMSO-d₆) δ ppm 8.65 (s, 1H), 7.74 (d, J=3.5 Hz, 1H), 6.74 (d, J=3.8 Hz, 1H), 5.18 - 5.06 (m, 1H), 5.01 - 4.90 (m, 2H), 3.65 (s, 3H), 3.15 - 3.03 (m, 1 H), 2.64 (s, 3H), 2.46 - 2.40 (m, 1 H), 1.49 (s, 3H), 1.23 (s, 3H)

Step 6: Synthesis of (3aR,4S,6R,6aS)-2,2-dimethyl-6-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxole-4-carboxylic acid (A-7)

A mixture of A-6 (13 g, 33 mmol) and LiOH (2.8 g, 66.7 mmol) in THF (100 mL)/H₂O (100 mL) was stirred at rt (15 °C) for 4 hrs. TLC (DCM/MeOH=10/1) showed most of SM was consumed. The mixture was diluted with water (50 mL) and washed with EtOAc (100 mL x 2). To the aqueous layer was added H₃PO₄ (3.6 g, 37 mmol) and extracted with EtOAc/THF (50 mL/50 mL x 5). The extract was dried over Na₂SO₄ and concentrated in vacuo to afford A-7 (8.9 g, 84%) as a yellow solid. LCMS [M+1] 318; Ή NMR (400 MHz, CDCh) δ ppm 8.77 (s, 1H), 7.26 (br. s, 1H), 6.59 (d, J=3.8 Hz, 1H), 5.25 (t, J=5.3 Hz, 1H), 5.14 - 4.98 (m, 2H), 3.18 (ddd, J=4.8, 7.8, 10.0 Hz, 1H), 2.77 - 2.60 (m, 5H), 1.60 (s, 3H), 1.35 (s, 3H)

Step 7: Synthesis of (3aR,4S,6R,6aS)-N-methoxy-N,2,2-trimethyl-6-(4-methyl-7Hpyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxole-4-carboxamide (A-8)

To a suspension of crude A-7 (7 g , 22.1 mmol) and N,O-dimethylhydroxylamine-HCI (4.30 g, 44.1 mmol) in THF (140 mL) was added DIPEA (11.4 g, 88.2 mmol) and 50% T3P (28.1 g, 25.8 mL, 44.1 mmol) at rt (15 °C). The resulting red solution was stirred at rt (15 °C) for 20 hrs. LCMS showed the main peak was desired compound. The mixture was diluted with EtOAc and washed with NH₄CI aq, NaHCO₃ aq, brine, dried over Na₂SO₄and concentrated in vacuo to A8 (7.3 g, 91.8 %) as a yellow gum. [α]²% +27.30° (c= 2.82 mg/mL, methanol); LCMS [M+1] 361; Ή NMR (400 MHz, CDCI₃) δ ppm 8.77 (s, 1H), 7.31 (d, J=3.5 Hz, 1H), 6.60 (d, J=3.5 Hz, 1H), 5.36 - 5.27 (m, 1H), 5.11 - 5.03 (m, 1H), 4.91 (dd, J=5.6, 7.2 Hz, 1H), 3.77 (s, 3H), 3.61 - 3.51 (m, 1 H), 3.24 (s, 3H), 2.72 (s, 3H), 2.65 - 2.56 (m, 1 H), 2.54 - 2.42 (m, 1 H), 1.60 (s, 3H), 1.30 (s, 3H)

Step 8: Synthesis of 1-((3aR,4S,6R,6aS)-2,2-dimethyl-6-(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)ethan-1-one (A-9)

-81 To a light yellow solution of A-8 (130 mg, 0.361 mmol) in THF (5.39 mL) was added MeMgBr (3.0 M solution in diethyl ether, 0.144 mL, 0.433 mmol) at 0 °C. After the addition, the mixture was stirred at 0 °C for 40 min. The mixture was quenched with aq.NH₄CI (40 mL) in an ice bath 5 and extracted with EtOAc (30 mL x 2). The extract was washed with brine (20 mL), dried over

Na₂SO₄ and concentrated in vacuo to afford crude compound A-9 (110 mg, 97%) as a yellow oil and used as is in the next step.

Step 9: Synthesis of (R)-1-((3aR,4R,6R,6aS)-2,2-dimethyl-6-(4-methyl-7H-pyrrolo[2,310 d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)ethan-1-ol (A-10) and (S)-1((3aR,4R,6R,6aS)-2,2-dimethyl-6-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro-4Hcyclopenta[d][1,3]dioxol-4-yl)ethan-1 -ol (A-11 )

To a yellow solution of A-9 (110 mg, 0.349 mmol) in dry MeOH (6 mL) was added NaBH₄ (26 15 mg, 0.698 mmol) at 0 °C. After addition, the mixture was stirred at 0 °C for 60 min. Then the reaction mixture was concentrated in vacuum to give a white solid (150 mg) which was separated by chiral SFC to give A-10 (62 mg, 56%) and A-11 (61 mg, 55%) and used as is.

Step 10: Synthesis of (1S,2R,3R,5R)-3-((R)-1-hydroxyethyl)-5-(4-methyl-7H-pyrrolo[2,320 d]pyrimidin-7-yl)cyclopentane-1,2-diol (A-12) and (1S,2R,3R,5R)-3-((S)-1-hydroxyethyl)-5(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol (A-13)

To a yellow suspension of A-10 (74 mg, 0.02 mmol) in H₂O (1 mL) was added TFA (1 mL) at 0 °C. The mixture was stirred at room température (15 °C) for 2 hrs. Saturated aqueous K₂CO₃ 25 (10 mL) was added into the mixture (0 °C) slowly until the pH 7-8. Purify by prep HPLC to give compound A-12 (34 mg, 53%). LCMS [M+1] 278; ¹H NMR (400 MHz, MeOD-d₄) δ ppm 8.60 (s, 1H), 7.60 (d, J=3.8 Hz, 1H), 6.73 (d, J=3.5 Hz, 1H), 5.12 - 5.00 (m, 1H), 4.37 (dd, J=5.8, 9.3 Hz, 1H), 4.17 (dd, J=2.9, 5.6 Hz, 1H), 3.81 (quin, J=6.2 Hz, 1H), 2.71 (s, 3H), 2.31 (td, J=8.3, 12.7 Hz, 1H), 2.07 (ddt, J=2.8, 5.9, 9.0 Hz, 1H), 1.84 (ddd, J=9.3, 10.9, 12.7 Hz, 1H), 1.26 (d, J=6.3 30 Hz, 3H)

To a yellow suspension of A-11 (74 mg, 0.23 mmol) in H₂O (1.5 mL) was added TFA (1.5 mL) drop-wise at 0 °C. Then the reaction mixture was stirred at room température (20 °C) for 2hrs, then adjusted to pH=7 with 20% K₂CO₃. The aqueous phase was purified by prep HPLC to give 35 A-13 (45 mg, 70%). LCMS [M+1] 278; Ή NMR (400 MHz, MeOD-d₄) δ ppm 8.59 (s, 1 H), 7.61 (d, J=3.53 Hz, 1 H), 6.72 (d, J=3.53 Hz, 1 H), 5.03 - 5.12 (m, 1 H) , 3.92 - 4.30 (dd, J=8.60, 5.95

-82Hz, 1 H), 3.92 - 4.03 (m, 2 H) , 2.70 (s, 3 H), 2.28 (dt, J=12.57, 8.27 Hz, 1 H), 2.06 (tt, J=8.71,

4.30 Hz, 1 H), 1.88 - 1.99 (m, 1 H), 1.22 (d, J=6.62 Hz, 3 H)

Examples 3-16 were prepared in using similar chemistry in Scheme A using the appropriate Grignard reagent for step 8.

Example 3: 3,4- Difluorophenyl magnésium bromide	HO XX Α-Χ'χ-ΐΧ Α^χ vJ Γ If λ-λ HO OH F	375.90 [M+1]	(1S,2R,3R,5R)-3-[(S)-(3,4-difluorophenyl) (hydroxyl)methyl]-5-(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)cyclopentane-1,2-diol Ή NMR (700 MHz, DMSO-d6) δ ppm 8.61 (s, 1 H) 7.65 (d, J=3.74 Hz, 1 H) 7.39 - 7.45 (m, 1 H) 7.32 - 7.39 (m, 1 H) 7.19 - 7.28 (m, 1 H) 6.70 (d, J=3.52 Hz, 1 H) 5.69 (d, J=4.62 Hz, 1 H) 4.93 5.02 (m, 1 H) 4.80 (br. s., 1 H) 4.51 - 4.64 (m, 2 H) 4.23 - 4.35 (m, 1 H) 3.94 (d, J=4.18 Hz, 1 H) 2.63 (s, 3 H) 2.20 - 2.30 (m, 1 H) 2.00 (dt, J=12.93, 8.72 Hz, 1 H) 1.60 (ddd, J=12.87, 10.78, 8.25 Hz, 1 H)
Example 4: 3,4- Difluorophenyl magnésium bromide	HO χχ F HO OH	375.90 [M+1]	(1S,2R,3R,5R)-3-[(R)-(3,4-difluorophenyl) (hydroxy)methyl]-5-(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)cyclopentane-1,2-diol 1H NMR (700 MHz, DMSO-d6) δ ppm 8.62 (s, 1 H) 7.68 (d, J=3.74 Hz, 1 H) 7.32 - 7.41 (m, 2 H) 7.14 - 7.23 (m, 1 H) 6.73 (d, J=3.52 Hz, 1 H) 5.68 (d, J=4.40 Hz, 1 H) 4.90 - 4.98 (m, 1 H) 4.86 (br. s., 1 H) 4.80 (br. s., 1 H) 4.67 (br. s., 1 H) 4.23 (dd, J=8.14, 5.72 Hz, 1 H) 3.85 - 3.94 (m, 1 H) 2.65 (s, 3 H) 2.23 (tt, J=8.72, 4.37 Hz, 1 H) 1.85 (dt, J—12.98, 8.36 Hz, 1 H) 1.78 (dt, J=12.87, 9.74 Hz, 1 H)

Example 5:

3-chloro-4fluoropheny!

magnésium bromide

(1S,2R,3R,5R)-3-[(S)-(3-chloro-4-fluorophenyl) (hydroxy)methyl]-5-(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)cyclopentane-1,2-diol

Ή NMR (700 MHz, DMSO-d6) δ ppm 8.60 (s, 1 H) 7.64 (d, J=3.52 Hz, 1 H) 7.57 (dd, J=7.26, 1.76 Hz, 1 H) 7.37 - 7.42 (m, 1 H) 7.32 - 7.37 (m, 1 H) 6.69 (d, J=3.52 Hz, 1 H) 5.70 (d, J=4.62 Hz, 1 H) 4.93 - 5.02 (m, 1 H) 4.80 (d, J=6.82 Hz, 1 H)

			4.58 - 4.62 (m, 1 H) 4.57 (d, J=3.52 Hz, 1 H) 4.28 (dt, J=9.57, 6.00 Hz, 1 H) 3.94 (br. s., 1 H) 2.63 (s, 3 H) 2.22 - 2.28 (m, 1 H) 2.00 (dt, J=12.98, 8.80 Hz, 1 H) 1.60 (ddd, J=12.87, 10.78, 8.25 Hz, 1 H)
Example 6: 3-chloro-4fluorophenyl magnésium bromide	HO /=\ CI N jCj F HÔ OH	391.85 [M+1]	(1S,2R,3R,5R)-3-[(R)-(3-chloro-4-fluorophenyl) (hydroxy)methyl]-5-(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)cyclopentane-1,2-diol Ή NMR (700 MHz, DMSO-d6) δ ppm 8.60 (s, 1 H) 7.66 (d, J=3.52 Hz, 1 H) 7.52 (d, J=6.82 Hz, 1 H) 7.30 - 7.38 (m, 2 H) 6.71 (d, J=3.52 Hz, 1 H) 5.68 (d, J=4.62 Hz, 1 H) 4.90 - 4.98 (m, 1 H) 4.86 (br. s., 1 H) 4.80 (t, J=4.51 Hz, 1 H) 4.66 (br. s., 1 H) 4.23 (br. s., 1 H) 3.88 (br. s., 1 H) 2.64 (s, 3 H) 2.19 - 2.27 (m, 1 H) 1.86 (dt, J=12.82, 8.45 Hz, 1 H) 1.78 (dt, J=12.87, 9.74 Hz, 1 H)

Example 7: 3-chlorophenyl magnésium bromide	HO Ι.,Χ^Ν, Jk/ \\ J N^/N HO OH	373.90 [M+1]	(1S,2R,3R,5R)-3-[(S)-(3-chlorophenyl) (hydroxy)methyl]-5-(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)cyclopentane-1,2-diol 1H NMR (700 MHz, DMSO-d6) δ ppm 8.53 - 8.63 (m, 1 H) 7.59 - 7.68 (m, 1 H) 7.44 (s, 1 H) 7.31 7.39 (m, 2 H) 7.23 - 7.31 (m, 1 H) 6.66 - 6.73 (m, 1 H) 5.66 (d, J=4.62 Hz, 1 H) 4.93 - 5.03 (m, 1 H) 4.79 (d, J=6.60 Hz, 1 H) 4.57 - 4.62 (m, 1 H) 4.55 (br. s., 1 H) 4.30 (d, J=3.30 Hz, 1 H) 3.95 (br. s., 1 H) 2.58 - 2.67 (m, 3 H) 2.21 - 2.31 (m, 1 H) 1.96 - 2.05 (m, 1 H) 1.55 - 1.67 (m, 1 H)
Example 8: 3-chlorophenyl magnésium bromide	HO f=\ - ·- HO OH	373.80 [M+1]	(1S,2R,3R,5R)-3-[(R)-(3-chlorophenyl) (hydroxy)methyl]-5-(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)cyclopentane-1,2-diol 1H NMR (700 MHz, DMSO-d6) δ ppm 8.60 (s, 1 H) 7.67 (d, J=3.74 Hz, 1 H) 7.39 (s, 1 H) 7.32 7.37 (m, 1 H) 7.29 - 7.32 (m, 1 H) 7.27 (d, J=7.70 Hz, 1 H) 6.71 (d, J=3.52 Hz, 1 H) 5.65 (d, J=4.84 Hz, 1 H) 4.90 - 4.98 (m, 1 H) 4.85 (br. s., 1 H) 4.81 (t, J=4.40 Hz, 1 H) 4.67 (br. s., 1 H) 4.24 (br. s., 1 H) 3.91 (br. s., 1 H) 2.64 (s, 3 H) 2.24 (dt, J=8.47, 4.35 Hz, 1 H) 1.81 - 1.88 (m, 1 H)

			1.75-1.81 (m, 1 H)

Example 9: 3-fluorophenyl magnésium bromide	HO 7^7 HO OH F	357.85 [M+1]	(1S,2R,3R,5R)-3-[(S)-(4-fluorophenyl) (hydroxy)methyl]-5-(4-methyl-7H-pyrrolo[2,3- d]pyrimidin-7-yl)cyclopentane-1,2-diol 1H NMR (400 MHz, DMSO-d6) δ ppm 8.60 (s, 1 H) 7.62 (d, J=3.55 Hz, 1 H) 7.42 (dd, J=8.50, 5.81 Hz, 2 H) 7.13 (t, J=8.93 Hz, 2 H) 6.68 (d, J=3.55 Hz, 1 H) 5.51 (d, J=4.52 Hz, 1 H) 4.91 5.05 (m, 1 H) 4.76 (d, J=6.97 Hz, 1 H) 4.59 (dd, J=6.79, 4.71 Hz, 1 H) 4.53 (d, J=3.79 Hz, 1 H) 4.32 (dt, J=9.60, 6.08 Hz, 1 H) 3.99 (br. s., 1 H) 2.63 (s, 3 H) 2.26 (q, J=7.34 Hz, 1 H) 1.96 (dt, J=12.72, 8.80 Hz, 1 H) 1.49 - 1.64 (m, 1 H)
Example 10: 3-fluorophenyl magnésium bromide	HO /=\ XJw XJ F- HO OH	357.85 [M+1]	(1S,2R,3R,5R)-3-[(R)-(4-fluorophenyl) (hydroxy)methyl]-5-(4-methyl-7H-pyrrolo[2,3- d]pyrimidin-7-yl)cyclopentane-1,2-diol 1H NMR (700 MHz, DMSO-d6) δ ppm 8.57 (s, 1 H) 7.65 (d, J=3.52 Hz, 1 H) 7.36 (t, J=6.60 Hz, 2 H) 7.11 (t, J=8.36 Hz, 2 H) 6.73 (d, J=3.74 Hz, 1 H) 5.70 (br. s., 1 H) 4.93 (q, J=9.02 Hz, 2 H) 4.78 (d, J=4.40 Hz, 2 H) 4.19 - 4.26 (m, 2 H) 2.63 (s, 3 H) 2.18 - 2.28 (m, 1 H) 1.86 (dt, J=13.04, 8.45 Hz, 1 H) 1.71 - 1.82 (m, 1 H)

Exampie 11: 4-chlorophenyl magnésium bromide	ho /=\ HO OH Cl	373.90 [M+1]	(1S,2R,3R,5R)-3-[(S)-(4-chlorophenyl) (hydroxy)methyl]-5-(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)cyclopentane-1,2-diol 1H NMR (400 MHz, DMSO-d6) δ ppm 1.58 (ddd, J=12.90, 10.64, 8.13 Hz, 1 H) 1.98 (dt, J=12.93, 8.70 Hz, 1 H) 2.20 - 2.29 (m, 1 H) 2.58 - 2.66 (m, 3 H) 3.96 (d, J=3.79 Hz, 1 H) 4.25 - 4.35 (m, 1 H) 4.52 (br. s., 1 H) 4.58 (d, J=4.28 Hz, 1 H) 4.76 (br. s., 1 H) 4.91 - 5.04 (m, 1 H) 5.57 (br. s., 1 H) 6.70 (d, J=3.55 Hz, 1 H) 7.32 - 7.45 (m, 4 H) 7.64 (d, J=3.67 Hz, 1 H) 8.61 (s, 1 H)
Example 12: 4-chlorophenyl magnésium bromide	HO /=\ jXXX-X XX Cl HÔ OH	373.85 [M+1]	(1S,2R,3R,5R)-3-[(R)-(4-chlorophenyl) (hydroxy)methyl]-5-(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)cyclopentane-1,2-diol 1H NMR (400 MHz, DMSO-d6) δ ppm 1.73 - 1.92

(m, 2 H) 2.22 (tt, J=8.67, 4.23 Hz, 1 H) 2.67 (s, 3 H) 3.84 - 3.96 (m, 1 H) 4.24 (dd, J=8.44, 5.50 Hz, 1 H) 4.64 (br. s., 1 H) 4.73 - 4.89 (m, 2 H) 4.89 5.01 (m, 1 H) 5.56 (br. s., 1 H) 6.76 (d, J=3.55 Hz, 1 H) 7.33 - 7.40 (m, 4 H) 7.71 (d, J=3.55 Hz, 1 H) 8.65 (s, 1 H)

Example 13: 3,4,5trifluorophenyl magnésium bromide	HO vJ r t HO OH F \ F	393.90 [M+1]	(1S,2R,3R,5R)-3-[(S)-hydroxy(3,4,5trifluorophenyl)methyl]-5-(4-methyl-7Hpyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol 1H NMR (700 MHz, DMSO-d6) δ ppm 8.53 (s, 1 H) 7.59 (d, J=3.52 Hz, 1 H) 7.21 - 7.29 (m, 2 H) 6.63 (d, J=3.52 Hz, 1 H) 5.76 (d, J=4.40 Hz, 1 H) 4.88 - 4.95 (m, 1 H) 4.74 (d, J=6.82 Hz, 1 H) 4.48 - 4.56 (m, 2 H) 4.18 (dt, J=9.52, 6.02 Hz, 1 H) 3.84 (br. s., 1 H) 2.56 (s, 2 H) 2.15 - 2.23 (m, 1 H) 1.97 (dt, J=12.82, 8.67 Hz, 1 H) 1.57 (ddd, J=12.60, 10.95, 8.58 Hz, 1 H)
Exampie 14: 3,4,5trifluorophenyl magnésium bromide	HO Χη LJ v J \\ )> J L A/ HO OH F \ F	393.90 [M+1]	(1S,2R,3R,5R)-3-[(R)-hydroxy(3,4,5trifluorophenyl)methyl]-5-(4-methyl-7Hpyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol 1H NMR (700 MHz, DMSO-d6) δ ppm 8.53 (s, 1 H) 7.58 (d, J=3.52 Hz, 1 H) 7.21 (dd, J=8.69, 6.93 Hz, 2 H) 6.64 (d, J=3.52 Hz, 1 H) 5.75 (d, J=4.84 Hz, 1 H) 4.86 (dt, J=10.07, 8.39 Hz, 1 H) 4.81 (d, J=6.60 Hz, 1 H) 4.75 (t, J=4.62 Hz, 1 H) 4.61 (d, J=4.62 Hz, 1 H) 4.15 (dt, J=8.14, 6.16 Hz, 1 H) 3.85 (q, J=4.40 Hz, 1 H) 2.57 (s, 2 H) 2.17 (dq, J=8.80, 4.40 Hz, 1 H) 1.77 (dt, J=12.98, 8.36 Hz, 1 H) 1.69 (dt, J=12.87, 9.85 Hz, 1 H)

Synthesis of (3,4,5-trifluorophenyl)magnesium bromide (for Example 13 & 14)

Mg, THF

MgBr

To a mixture of magnésium (264 mg, 11.0 mmol) and THF (5 mL) was added iodine (5.0 mg) and a solution of 5-bromo-1,2,3-trifluorobenzene (211 mg, 1 mmol) in THF (0.5 mL). The mixture was heated to 60°C, and a solution of 5-bromo-1,2,3-trifluorobenzene (1.9 g, 9 mmol) in

-86THF (4.5 mL) was added by dropwise. The reaction was heated for two hours, the solution was cooled to room température and used directly in the next step.

Examples 15 & 16 (Scheme B) were prepared in using similar chemistry in Scheme A 5 using 2,6-dimethylpyridine and nBuLi in Step 8 in place of méthylmagnésium bromide.

Scheme B

nBuLi, THF

To a solution of 2.6-dimethyl pyridine (168 mg, 1.56 mmol) in dry THF (8 mL) at -75°C was added n-BuLi (125 mg, 1.96 mmol, 1.22 mL, 1.6 M) dropwise, the température was maintained at about -70°C. The resulting suspension was stirred at -75°C for 1 hr. A solution of A-8 (282 mg, 0.782 mmol) in dry THF (4 mL) was added at - 75°C dropwise. The resulting suspension 15 was stirred at -75°C and allowed to warm to r.t. and stirred overnight. THF was evaporated, the crude product was added H₂O and extracted with EtOAc, concentrated, purified by column chromatography with 5% MeOH/EtOAc to give 169 mg of B-1 (53% yield) as a yellow oil. LCMS

[M+1] 407.15.

Example 15	HO /= f 1 KaJ 1/ Λν \_/ 1 ,· -, N : ..N HO OH	368.90 [M+1]	(1S,2R,3R,5R)-3-[1-hydroxy-2-(6-methylpyridin2-yl)ethyl]-5-(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)cyclopentane-1,2-diol 1H NMR (700 MHz, DMSO-d6) δ ppm 8.55 (s, 1 H) 7.60 (d, J=3.52 Hz, 1 H) 7.52 (t, J=7.70 Hz, 1 H) 7.00 (d, J=7.70 Hz, 1 H) 7.01 (d, J=7.48 Hz, 1 H) 6.65 (d, J=3.30 Hz, 1 H) 4.98 - 5.02 (m, 1 H) 4.92 (q, J=8.80 Hz, 1 H) 4.73 (d, J=5.72 Hz, 1 H) 4.66 (d, J=3.08 Hz, 1 H) 4.06 - 4.12 (m, 1 H) 4.03 (dt, J=11.33, 5.56 Hz, 1 H) 3.83 (q, J=4.25 Hz, 1 H) 2.66 - 2.75 (m, 2 H) 2.58 (s, 3 H) 2.38 (s, 3 H) 2.09 (dt, J=12.27, 8.06 Hz, 1 H) 1.84 - 1.89 (m, 1 H) 1.79- 1.84 (m, 1 H)
Example 16	f X xXX /¼ \_/ 1 Y N«zN HO OH	368.90 [M+1]	(1S,2R,3R,5R)-3-[1-hydroxy-2-(6-methylpyridin- 2-yl)ethyl]-5-(4-methyl-7H-pyrrolo[2,3- d]pyrimidin-7-yl)cyclopentane-1,2-diol

1H NMR (700 MHz, DMSO-d6) δ ppm 8.59 (s, 1 H) 7.66 (d, J=3.52 Hz, 1 H) 7.58 (t, J=7.70 Hz, 1 H) 7.10 (d, J=7.48 Hz, 1 H) 7.07 (d, J=7.48 Hz, 1 H) 6.69 (d, J=3.74 Hz, 1 H) 5.11 (d, J=5.06 Hz, 1 H) 4.93 - 5.00 (m, 1 H) 4.79 (d, J=6.82 Hz, 1 H) 4.72 (d, J=3.08 Hz, 1 H) 4.20 (dt, J=9.19, 6.30 Hz, 1 H) 4.07 - 4.12 (m, 1 H) 3.85 - 3.90 (m, 1 H) 2.87 (dd, J=13.64, 4.40 Hz, 1 H) 2.80 (dd, J=13.86, 8.36 Hz, 1 H) 2.63 (s, 3 H) 2.43 (s, 3 H) 2.13 (dt, J=12.54, 8.36 Hz, 1 H) 1.95 - 2.03 (m, 1 H) 1.68- 1.76 (m, 1 H)

Example 17 (Scheme C): (1S,2R,3S,5R)-3-(1-hydroxycyclopropyl)-5-(4-methyl-7Hpyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol (C-2)

Scheme C

Step 1 :

Synthesis of 1 -((3aR,4S,6R,6aS)-2,2-dimethyl-6-(4-methyl-7H-pyrrolo[2,310 d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)cyclopropan-1-ol (C-1)

To a light yellow solution of A-6 (140 mg, 0.422 mmol) in dry THF (6.32 mL) was added Ti(OiPr)4 (168 mg, 0.591 mmol) and EtMgBr (3.0 M solution in diethyl ether, 0.845 mL, 2.53 mmol) at r.t (13 °C). After addition, the mixture was stirred at 13 °C for 10 min. The mixture was 15 quenched with H₂O (50 mL) in an ice bath and extracted with EtOAc (30 mL x 2). The extract was washed with brine (30 mL), dried over Na₂SO₄ and concentrated in vacuo to afford a crude residue which was purified by flash chromatography eluted with EtOAc/DCM 0-100% to give ΟΙ (90 mg, 65%) as a yellow solid. LCMS [M+1] 330; ¹H NMR (400 MHz, CDCh) δ ppm 8.72 (s,

H), 7.22 (d, J=3.5 Hz, 1 H), 6.55 (d, J=3.8 Hz, 1 H), 5.06 - 4.99 (m, 1 H), 4.94 (dd, J=3.3, 6.3 Hz, 20 1H), 4.86 (d, J=5.8 Hz, 1H), 2.74 (s, 3H), 2.68 - 2.57 (m, 2H), 2.11 (d, J=3.0 Hz, 1H), 1.59 (s,

3H), 1.34 (s, 3H), 1.25 (d, J=3.8 Hz, 1H), 0.93 (d, 1H), 0.88 - 0.78 (m, 1H), 0.77 - 0.67 (m, 1H),

0.60-0.51 (m, 1H)

-88Step 2: Synthesis of (1S,2R,3S,5R)-3-(1-hydroxycyclopropyl)-5-(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)cyclopentane-1,2-diol (C-2)

To a suspension of C-1 (65 mg, 0.20 mmol) in H₂O (3 mL) was added TFA (3 mL) at 0 °C. The 5 mixture was stirred at rt (13 °C) for 1.5 hrs. The mixture was poured into 20% K₂CO₃ aq (50 mL) and extracted with EtOAc (30 mL x 3). The extract was washed with brine (50 mL x 2), dried over Na₂SÜ4 and concentrated in vacuo to afford C-2 (50 mg, 88%) as a solid. LCMS [M+1] 290; Ή NMR (400 MHz, DMSO-d₆) δ ppm 8.60 (s, 1H), 7.66 (d, J=3.8 Hz, 1H), 6.70 (d, J=3.5

Hz, 1H), 5.32 (s, 1H), 5.03 - 4.93 (m, 1H), 4.77 (d, J=6.8 Hz, 1H), 4.61 (d, J=4.3 Hz, 1H), 4.19 (td, J=6.3, 8.9 Hz, 1H), 4.04 - 3.97 (m, 1H), 2.63 (s, 3H), 2.19 (td, J=8.5, 12.8 Hz, 1H), 1.93 1.82 (m, 1H), 1.63 (dt, J=3.0, 8.8 Hz, 1H), 0.67 - 0.60 (m, 1H), 0.57 - 0.48 (m, 2H), 0.46 - 0.39 (m, 1H)

Example 18 (Scheme D): (1S,2R,3S,5R)-3-(2-hydroxypropan-2-yl)-5-(4-methyl-7H15 pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol (D-2)

Scheme D

MeMgBr (>2 eq)

THF

Step 1: Synthesis of 2-((3aR,4S,6R,6aS)-2,2-dimethyl-6-(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)propan-2-ol (D-1 )

To a light yellow solution of A-6 (150 mg, 0.453 mmol) in dry THF (6.77 mL) was added

MeMgBr (3.0 M solution in diethyi ether, 0.905 mL, 2.72 mmol) at r.t (13 °C). After addition, the mixture was stirred at 13 °C for 10 min. The mixture was quenched with H₂O (50 mL) in a ice bath and extracted with EtOAc (30 mL x 2). The extract was washed with brine (30 mL), dried over Na₂SO₄and concentrated in vacuo to afford crude compound (160 mg) as yellow oil which was purified by flash chromatography eluted with EtOAc/DCM 0-100% to give D-1 (120 mg,

80%) as a white solid. LCMS [M+1] 332; Ή NMR (400 MHz, CDCh) δ ppm 8.76 (s, 1H), 7.26 (d, J=3.8 Hz, 1H), 6.57 (d, J=3.5 Hz, 1H), 5.03 (ddd, J=6.0, 8.3, 10.8 Hz, 1H), 4.96 - 4.88 (m,

-891H), 4.84 (dd, J=5.3, 7.3 Hz, 1H), 2.73 (s, 3H), 2.47 - 2.37 (m, 2H), 2.31 - 2.21 (m, 1H), 1.97 (s,

H), 1.59 (s, 3H), 1.40 (s, 3H), 1.32 (s, 3H), 1.27 (s, 3H)

Step 2: Synthesis of (1S,2R,3S,5R)-3-(2-hydroxypropan-2-yl)-5-(4-methyl-7H-pyrrolo[2,35 d]pyrimidin-7-yl)cyclopentane-1,2-diol (D-2)

To a suspension of D-1 (100 mg, 0.302 mmol) in H₂O (5 mL) was added TFA (5 mL) at 0 °C. The mixture was stirred at rt (13 °C) for 1.5 hrs. The mixture was poured into 20% K₂CO₃aq (50 mL) and extracted with EtOAc (30 mL x 3). The extract was washed with brine (50 mL x 2), 10 dried over Na₂SO₄ and concentrated in vacuo to afford D-2 (70mg, 80%) as a yellow solid.

LCMS [M+1] 292; ¹H NMR (400 MHz, DMSO-ds) δ ppm 8.60 (s, 1H), 7.65 (d, J=3.5 Hz, 1H),

6.69 (d, J=3.5 Hz, 1H), 4.92 (dt, J=7.3, 10.4 Hz, 1H), 4.73 (d, J=7.0 Hz, 1H), 4.53 (d, J=4.3 Hz,

1H), 4.32 (s, 1H), 4.08 (td, J=6.7, 9.7 Hz, 1H), 3.92 (t, J=6.3 Hz, 1H), 2.63 (s, 3H), 2.03 (td, J=7.8, 11.5 Hz, 1H), 1.88 (dt, J=2.3, 9.0 Hz, 1H), 1.84- 1.73 (m, 1H), 1.19 (s, 3H), 1.08 (s, 3H)

Example 19 (Scheme E): (1S,2R,3S,5R)-3-[(1S)-1-(4-fluorophenyl)-1-hydroxyethyl]-5-(4methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol (E-3)

Example 20 (Scheme E): (1S,2R,3S,5R)-3-[(1R)-1-(4-fluorophenyl)-1-hydroxyethyl]-5-(420 methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol (E-4)

Scheme E

Step 1: Synthesis of ((3aR,4S,6R,6aS)-2,2-dimethyl-6-(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)(4-fluorophenyl)methanone (E-1)

-90Following a similar procedure to Step 8 in Scheme A using (4-fluorophenyl)magnesium bromide gave E-1 (240 mg, 95%). LCMS [M+1] 395.80. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm

8.75 (s, 1 H) 8.12 (dd, J=8.86, 5.44 Hz, 2 H) 7.34 (dd, J=8.56, 5.50 Hz, 1 H) 7.15 - 7.22 (m, 2 H) 6.61 (d, J=3.67 Hz, 1 H) 5.28 - 5.37 (m, 1 H) 4.98 - 5.08 (m, 2 H) 3.71 (br. s., 1 H) 2.70 - 2.76 (m, 4 H) 2.60 - 2.70 (m, 1 H) 1.68 (s, 3 H) 1.33 (s, 3 H)

Step 2: Synthesis of 1-((3aR,4S,6R,6aS)-2,2-dimethyl-6-(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-1-(4-fluorophenyl)ethan-1-ol (E-2)

To a solution of E-1 (66 mg, 0.17 mmol) in dry THF (6.0 mL, c=0.106 M) at 50°C was added méthylmagnésium bromide (99.5 mg, 0.835 mmol, 0.278 mL, 3.0 M), the resulting solution was stirred at 50°C for 0.5 h. The mixture was added to std. NH₄CI (20 mL) slowly, the mixture was extracted with EtOAc (25 mLx3). The extract was washed with brine (25 mL), dried over Na₂SO₄ and concentrated in vacuum to give 70 mg of E-2 as a colorless oil. LCMS [M+1]

411.80.

Step 3: Synthesis of (1S,2R,3S,5R)-3-[(1S)-1-(4-fluorophenyl)-1-hydroxyethyl]-5-(4-methyl7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol (E-3) and (1S,2R,3S,5R)-3-[(1R)-1-(4fluorophenyl)-1-hydroxyethyl]-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane20 1,2-diol (E-4)

Following a similar procedure to Step 10 in Scheme A and subséquent séparation by chiral SFC gave E-3 (19 mg, 31%). LCMS [M+1] 371.90. Ή NMR (700 MHz, DMSO-d6) δ ppm 8.61 (s, 1 H) 7.61 (d, J=3.74 Hz, 1 H) 7.54 (dd, J=8.58, 5.72 Hz, 2 H) 7.13 (t, J=8.80 Hz, 2 H) 6.72 (d,

J-3.52 Hz, 1 H) 5.26 (s, 1 H) 4.97 - 5.06 (m, 1 H) 4.70 (d, J=5.94 Hz, 1 H) 4.17 (d, J=3.30 Hz, 1

H) 4.04 - 4.12 (m, 1 H) 3.54 (br. s., 1 H) 2.64 (s, 3 H) 2.39 (t, J=8.91 Hz, 1 H) 2.19 (dt, J=12.54, 8.58 Hz, 1 H) 1.95 (td, J=11.83, 8.91 Hz, 1 H) 1.35 (s, 3 H) and E-4 (12 mg, 19%). LCMS [M+1] 371.90. ¹H NMR (700 MHz, DMSO-d6) δ ppm 8.51 - 8.59 (m, 1 H) 7.52 - 7.59 (m, 1 H) 7.40 - 7.47 (m, 2 H) 7.02 - 7.10 (m, 2 H) 6.65 (dd, J=3.52, 1.54 Hz,

1 H) 5.24 (s, 1 H) 4.78 - 4.88 (m, 2 H) 4.67 - 4.74 (m, 1 H) 4.10 - 4.19 (m, 2 H) 2.57 - 2.65 (m, 3

H) 2.35 (t, J=9.35 Hz, 1 H) 1.54 (s, 3 H) 1.39 - 1.51 (m, 2 H)

Example 21 (Scheme F): (1S,2R,3S,5R)-3-[fluoro(4-fluorophenyl)methyl]-5-(4-methyl-7Hpyrrolo[2,3-d] pyrimidin-7-yl)cyclopentane-1,2-diol (F-3 Isomer A)

- 91 Example 22 (Scheme F): (1S,2R,3S,5R)-3-[fluoro(4-fluorophenyl)methyl]-5-(4-methyl-7Hpyrrolo[2,3-d] pyrimidin-7-yl)cyclopentane-1,2-diol (F-4 Isomer B)

Scheme F

Step 1 : Synthesis of ((SaR^R^R^aSi^^-dimethyl-S^-methyl-TH-pyrrolo^^d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)(4-fluorophenyl)methanol (F1)

Following a similar procedure to Step 8 in Scheme A gave F-1 (110 mg, 99%). LCMS [M+1]

398.15.

Step 2: Synthesis of 7-((3aS,4R,6S,6aR)-6-(fluoro(4-fluorophenyl)methyl)-2,2dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-4-methyl-7H-pyrrolo[2,3d]pyrimidine (F-2)

To a solution ofF-1 (110 mg, 0.277 mmol) in 5 mL DCM was added DAST (223 mg, 1.38 mmol), stirred at r.t. for 30 min. The reaction was quenched with std. NaHCO₃, the phases were separated and the aqueous phase was extracted with 3 portions of DCM. The organic phases were combined and washed with brine, concentrated to give crude F-2 which was used directly for next step. LCMS [M+1] 400.10.

Step 3: Synthesis of (1S,2R,3S,5R)-3-[fluoro(4-fluorophenyl)methyl]-5-(4-methyl-7Hpyrrolo[2,3-d] pyrimidin-7-yl)cyclopentane-1,2-diol

Following a similar procedure to Step 10 in Scheme A and subséquent séparation by chiral SFC gave

-92F-3 Isomer A (7.7 mg, 7.8% two steps)

LCMS [M+1] 360.10. ¹H NMR (700 MHz, DMSO-d6) δ ppm 1.40 - 1.49 (m, 1 H) 1.91 (dt, J=12.87, 8.64 Hz, 1 H) 2.55 (dd, J=17.39, 8.58 Hz, 1 H) 2.62 (s, 3 H) 4.07 (br. s., 1 H) 4.36 4.48 (m, 1 H) 4.91 - 5.02 (m, 3 H) 5.59 (dd, J=1.00 Hz, 1 H) 6.67 (d, J=3.30 Hz, 1 H) 7.22 (t, 5 J=8.58 Hz, 2 H) 7.45 - 7.56 (m, 2 H) 7.65 (d, J=3.30 Hz, 1 H) 8.60 (s, 1 H) and F-4 Isomer B (1.3 mg, 1.3% two steps)

LCMS [M+1] 360.15. Ή NMR (400 MHz, DMSO-d6) δ ppm 1.84 - 1.94 (m, 1 H) 2.09 - 2.16 (m, 1 H) 2.64 (s, 3 H) 3.83 (q, J=4.40 Hz, 1 H) 4.24 - 4.35 (m, 1 H) 4.80 (d, J=4.52 Hz, 1 H) 4.89 10 5.04 (m, 2 H) 5.72 - 5.83 (m, 1 H) 6.71 (d, J=3.55 Hz, 1 H) 7.20 - 7.30 (m, 2 H) 7.47 (dd, J=8.13,

5.81 Hz, 2 H) 7.66 (d, J=3.55 Hz, 1 H) 8.61 (s, 1 H)

Example 23 (Scheme G): (1R,2S,3R,5R)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((S)(4-chloro-3-fluorophenyl)(hydroxy)methyl)cyclopentane-1,2-diol (G-7)

Example 24 (Scheme G): (1R,2S,3R,5R)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)(4-chloro-3-fluorophenyl)(hydroxy)methyl)cyclopentane-1,2-diol (G-9)

Scheme G

G-9

-93Step 1: Synthesis of (3aR,4S,6R,6aS)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxole-4-carboxylic acid (G-1 )

A mixture of A-5 (200 mg, 0.48 mmol) and LiOH (40.6 mg, 0.966 mmol) in THF (2 mL)/H₂O (2 mL) was stirred at rt (25 °C) for 2 hrs. The mixture was diluted with water (5 mL) and adjusted with 1N HCl to pH=2 and extracted with EtOAc (10 mL x 2). The extract was dried over Na₂SO₄ and concentrated in vacuo to afford crude G-1 (200 mg) as yellow gum, used in the next step directly. LCMS [M+1] 338; Ή NMR (400MHz, DMSO-d_s) δ ppm 8.65 (s, 1 H), 7.97 (d, J=3.8 Hz, 1H), 6.72 (d, J=3.5 Hz, 1H), 5.17 - 5.07 (m, 1H), 5.01 -4.90 (m, 2H), 3.03 - 2.93 (m, 1H), 2.60 2.53 (m, 2H), 1.49 (s, 3H), 1.23 (s, 3H)

Step 2: Synthesis of (3aR,4S,6R,6aS)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-Nmethoxy-N,2,2-trimethyltetrahydro-4H-cyclopenta[d][1,3]dioxole-4-carboxamide (G-2)

To a suspension of crude G-1 (200 mg, 461 mmol) and Ν,Ο-dimethylhydroxylamine- HCl (70 mg, 0.72 mmol) in THF (4 mL) was added DIPEA (186 mg, 1.44 mmol) and 50% T3P (458 mg, 0.42 mL, 1.5 mmol) at rt (15 °C). The resulting red solution was stirred at rt (15 °C) for 20 hrs. Some solid was formed in the reaction mixture. The mixture was poured into NaHCOs aq (15 mL) and extracted with EtOAc (10 mL x 3). The extract was washed with brine (10 mL x 2), dried over Na₂SO4 and concentrated in vacuo to afford G-2 (150 mg, 82% in two steps) as yellow gum. LCMS [M+1] 381; Ή NMR (400 MHz, CDCI₃) δ ppm 8.66 (s, 1H), 7.42 (d, J=3.5 Hz, 1H), 6.67 (d, J=3.8 Hz, 1H), 5.27 (dd, J=5.1, 7.2 Hz, 1H), 5.06 (dd, J=5.0, 7.0 Hz, 1H), 4.92 (dd, J=5.5, 7.0 Hz, 1H), 3.78 (s, 3H), 3.64 - 3.51 (m, 1H), 3.25 (s, 3H), 2.70 - 2.42 (m, 2H), 1.61 (s, 3H), 1.32 (s, 3H)

Step 3: Synthesis of (4-chloro-3-fluorophenyl)((3aR,4S,6R,6aS)-6-(4-chloro-7Hpyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4yl)methanone (G-3)

To a solution of G-2 (150 mg, 0.394 mmol) in dry THF (3 mL) was added (4-chloro-3fluorophenyl)magnesium bromide (3.1 mL, 1.54 mmol) at 0 °C. The mixture was stirred at 0 °C for 3 hr. The mixture was quenched with NH₄CI aq (20 mL) and diluted with EtOAc (10 mL x 2). The organic layer was washed with brine (10 mL), dried over Na₂SÜ4 and concentrated in vacuo to afford crude G-3 (250 mg, >99%) as a yellow oil which was used in the next step directly. LCMS [M+1] 450

-94Step 4: Synthesis of (S)-(4-chloro-3-fluorophenyl)((3aR,4R,6R,6aS)-6-(4-chloro-7Hpyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4yl)methanol (G-4) and (R)-(4-chloro-3-fluorophenyl)((3aR,4R,6R,6aS)-6-(4-chloro-7H5 pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4yljmethanol (G-5)

To a solution of crude G-3 (150 mg, 0.4 mmol) in MeOH (5 mL) was added NaBH₄ (45 mg, 1.18 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 hr. The mixture was quenched with NH₄CI 10 aq (10 mL) and diluted with EtOAc (10 mL x 3). The organic layer was washed with brine (10 mL), dried over Na₂SO₄ and concentrated in vacuo then purified by silica gel chromatography eluting with EtOAc in petroleum ether from 0 to 60% to afford G-4 (30 mg, 17%) and G-5 (50 mg, 28%) as a light yellow solid.

G-4: LCMS [M+1] 452

G-5: LCMS [M+1] 452

Step 5: Synthesis of (S)-((3aR,4R,6R,6aS)-6-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,220 dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)(4-chloro-3-fluorophenyl)methanol (G-6)

A mixture of G-4 (30 mg, 0.0663 mmol) in dioxane/NH₃.H₂O (1 mL/1 mL) was heated at 120 °C under microwave for 2 h. LCMS showed most of SM was consumed and a good spot was 25 formed. The mixture was concentrated in vacuo to afford crude G-6 (50 mg, >100 %) as yellow solid, used in the next step directly. LCMS [M+1] 433

Step 6: Synthesis of (1R,2S,3R,5R)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((S)-(4chloro-3-fluorophenyl)(hydroxy)methyl)cyclopentane-1,2-diol (G-7)

A mixture of G-6 (30 mg, 0.0663mmol) in TFA/H₂O (1 mL/ 1 mL) was stirred at rt (25 °C) for 1 hr. LCMS showed most of SM was consumed and main peak was desired compound. The mixture was poured into 20% K₂CO₃ aq (10 mL) and extracted with EtOAc (10 mL x 2). The extract was washed with brine (10 mL x 2), dried over Na₂SO₄ and concentrated in vacuo to 35 afford crude material which was purified by prep-HPLC to afford G-7 (10 mg, 37 %) as a white solid. LCMS [M+1] 393; Ή NMR (400 MHz, DMSO-d₆) δ ppm 8.01 (s, 1H), 7.52 (t, J=8.0 Hz,

-951H), 7.35 (dd, J=1.6, 10.4 Hz, 1H), 7.27 - 7.18 (m, 2H), 6.92 (s, 2H), 6.55 (d, J=3.5 Hz, 1H),

5.74 (d, J=5.3 Hz, 1H), 4.85 (d, J=6.5 Hz, 1H), 4.84 - 4.73 (m, 2H), 4.62 (d, J=4.8 Hz, 1H), 4.24

-4.10(m, 1H), 3.91 (q, J=4.9 Hz, 1H), 2.21 (td, J=4.3, 8.5 Hz, 1H), 1.90 - 1.64 (m, 2H)

Compound G-9 was prepared from G-5 (10 mg, 37%) as a white solid in a similar method as G7 was prepared from G-4.

G-9: LCMS [M+1] 393; ¹H NMR (40 0MHz, DMSO-d₆) δ ppm 8.02 (s, 1H), 7.54 (t, J=8.0 Hz,

1H), 7.40 (dd, J=1.6, 10.7 Hz, 1H), 7.30 - 7.24 (m, 1H), 7.21 (d, J=3.5 Hz, 1H), 6.92 (s, 2H),

6.54 (d, J=3.5 Hz, 1H), 5.76 (d, J=4.5 Hz, 1H), 4.87 - 4.76 (m, 2H), 4.61 (t, J=5.5 Hz, 1H), 4.51 (d, J=3.8 Hz, 1H), 4.28 - 4.19 (m, 1H), 3.93 - 3.88 (m, 1H), 2.23 (d, J=8.5 Hz, 1H), 2.06 - 1.94 (m, 1H), 1.66- 1.52 (m, 1H)

Example 25 (Scheme H): (1R,2S,3R,5R)-3-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-715 yl)-5-[(S)-(4-fluorophenyl)(hydroxy)methyl]cyclopentane-1,2-dioi (H-5)

Example 26 (Scheme H): (1R,2S,3R,5R)-3-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7yl)-5-[(R)-(4-fluorophenyl)(hydroxy)methyl]cyclopentane-1,2-diol (H-6)

Scheme H

H-3 H-4

Step 1: Synthesis of (3aR,4S,6R,6aS)-6-(4-chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7y|)-N-methoxy-N,2,2-trimethyitetrahydro-4H-cyclopenta[d][1,3]dioxole-4-carboxamide (H25 1)

-96To a solution of G-2 (Scheme G) (400 mg, 1.05 mmol) in 20 ml_ anhydrous CH₃CN was added selectfluor (558 mg, 1.58 mmol) and AcOH (10 ml). The mixture was heated at 70°C for 6 hours in an atmosphère of N₂. The reaction mixture was concentrated, H₂O and EtOAc were added, the aqueous was extracted 3 times with EtOAc. The organic layer was washed with brine, dried 5 over Na₂SO₄, concentrated to give brown oil.

The above brown oil was added 2,2-dimethoxypropane (109 mg, 1.05 mmol, 3.50 ml_, 0.3 M) and toluenesulfonic acid monohydrate (599 mg, 3.15 mmol), the yellow brown suspension was stirred vigorously at r.t. for 15 min. The reaction mixture was diluted with 50 ml_ H₂O, neutralized with solid NaHCO₃, the volatiles were carefully removed in vacuo and the resulting 10 brown aqueous solution was extracted with EtOAc 3 x 20 ml_, the organic was combined and concentrated, purified by column chromatography with 60% EtOAc/heptane to give 100 mg of H-1 (24% yield) as a colorless gum.

LCMS [M+1] 398.80. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.63 (s, 1 H) 7.22 (d, 15 J=2.57 Hz, 1 H) 5.25 - 5.36 (m, 1 H) 5.01 (dd, J=7.03, 4.95 Hz, 1 H) 4.83 (dd, J=6.97, 5.50 Hz,

H) 3.77 (s, 3 H) 3.58 (d, J=7.34 Hz, 1 H) 3.25 (s, 3 H) 2.58 - 2.68 (m, 1 H) 2.38 - 2.52 (m, 1 H) 1.61 (s, 3 H) 1.31 (s, 3 H)

Step 2: Synthesis of ((3aR,4S,6R,6aS)-6-(4-chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-720 y|)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)(4-fluorophenyi)methanone (H-2)

Following a similar procedure to step 8 in Scheme A using 4-fluorophenylmagnesium bromide and H-1 to give H-2 (100 mg, 92%).

LCMS [M+1] 433.70. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.62 (s, 1 H) 8.07 - 8.16 (m,

H) 7.14 - 7.23 (m, 3 H) 5.25 - 5.37 (m, 1 H) 4.98 (dd, J=6.91,4.58 Hz, 1 H) 4.86 - 4.93 (m, 1 H) 4.03 (ddd, J=10.30, 7.79, 4.52 Hz, 1 H) 2.58 - 2.76 (m, 2 H) 1.67 (s, 3 H) 1.32 (s, 3 H)

Step 3: Synthesis of ((3aR,4R,6R,6aS)-6-(4-chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-730 yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)(4-fluorophenyl)methanol (H3)

Following a similar procedure to step 4 in Scheme G, H-2 was reduced to H-3 (88 mg, 88%).

LCMS [M+1] 435.70.

-97Step 4: Synthesis of ((3aR,4R,6R,6aS)-6-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)(4-fluorophenyl)methanol (H4)

Following a similar procedure to step 5 in Scheme G, H-3 was transformed to H-4 as crude for next step.

LCMS [M+1] 417.80.

Step 5: Synthesis of (1R,2S,3R,5R)-3-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5[(S)-(4-fluorophenyl)(hydroxy)methyl]cyclopentane-1,2-diol (H-5) and (1R,2S,3R,5R)-3-(4amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-[(R)-(4fluorophenyl)(hydroxy)methyl]cyclopentane-1,2-diol (H-6)

Following a similar procedure to step 6 in Scheme G and subséquent purification by chiral SFC, H-4 was deprotected and the isomers separated into H-5 and H-6 (26.5 mg, 35%).

H-5: LCMS [M+1] 376.90. ¹H NMR (700 MHz, DMSO-d6) δ ppm 8.01 (s, 1 H) 7.40 (dd, J=8.36,

5.72 Hz, 1 H) 7.19 (s, 1 H) 7.13 (t, J=8.80 Hz, 1 H) 6.85 (br. s., 1 H) 5.52 (d, J=4.62 Hz, 1 H)

4.87 (q, J=9.68 Hz, 1 H) 4.77 (d, J=6.82 Hz, 1 H) 4.53 (dd, J=7.04, 4.62 Hz, 1 H) 4.51 (d, J=3.52

Hz, 1 H) 4.16 (dt, J=9.63, 5.97 Hz, 1 H) 3.93 (br. s., 1 H) 2.16 - 2.22 (m, 1 H) 1.86 (dt, J=13.04,

8.78 Hz, 1 H) 1.42 (ddd, J=12.98, 10.56, 8.14 Hz, 1 H)

H-6: LCMS [M+1] 376.90. Ή NMR (700 MHz, DMSO-d6) δ ppm 8.01 (s, 1 H) 7.37 (dd, J=8.47,

5.61 Hz, 1 H) 7.23 (d, J=1.76 Hz, 1 H) 7.12 (t, J=8.80 Hz, 1 H) 6.87 (br. s., 1 H) 5.51 (d, J=4.84

Hz, 1 H) 4.82 - 4.88 (m, 1 H) 4.79 - 4.82 (m, 1 H) 4.76 (t, J=4.84 Hz, 1 H) 4.58 (d, J=4.62 Hz, 1 H) 4.10 (dt, J=8.36, 6.05 Hz, 1 H) 3.80 - 3.86 (m, 1 H) 2.17 (tt, J=8.64, 4.46 Hz, 1 H) 1.79 (dt, J=13.09, 8.53 Hz, 1 H) 1.68 (dt, J=12.93, 9.60 Hz, 1 H)

Example 27 (Scheme I) - (1S,2R,3R,5R)-3-[(S)-(3,4-difluorophenyl)(hydroxy)methyl]-5-(7Hpyrrolo[2,3-d]pyrimidin-4-ylamino)cyclopentane-1,2-diol (1-12)

Example 28 (Scheme I) - (1S,2R,3R,5R)-3-[(R)-(3,4-difluorophenyl)(hydroxy) methyl]-5-(7Hpyrrolo[2,3-d]pyrimidin-4-ylamino)cyclopentane-1,2-diol (1-13)

Scheme I

^19% |-8

Step 1: Synthesis of tert-butyl (3aS,4R,7S,7aR)-2,2-dimethyl-6-oxotetrahydro-4,7methano[1,3] dioxolo[4,5-c]pyridine-5(4H)-carboxylate (I-2)

To a solution of (3aS,4R,7S,7aR)-2,2-dimethyltetrahydro-4,7-methano[1 ,3]dioxolo[4,5-c]pyridin6(3aH)-one 1-1 (Chemical Reviews, 2012, 112 (8), pp 4642-4686) (5000 mg, 27.29 mmol) and Boc anhydride (7.15 g, 32.7 mmol) in THF (54.6 mL, c=0.5 M) was added triethylamine (3.31 g, 32.7 mmol, 4.56 mL) and DMAP (333 mg, 2.73 mmol). The reaction was stirred at r.t. for 3 hrs.

The mixture was concentrated to a tan solid which was purified by column chromatography with 10 30% EtOAc/Heptane to give 7.9 g of 1-2 (100% yield) as a white solid.

LCMS [M+1-tBu] 228. Ή NMR (400MHz, CHLOROFORM-d) δ ppm 4.60 (d, J=5.4 Hz, 1H), 4.49 (d, J=5.4 Hz, 1H), 4.44 (s, 1H), 2.90 (s, 1H), 2.16 - 2.07 (m, 1H), 2.05 - 1.96 (m, 1H), 1.53 (s, 9H), 1.50 (s, 3H), 1.37 (s, 3H).

-99Step 2: Synthesis of tert-butyl ((3aS,4R,6S,6aR)-6-(3,4-difluorobenzoyl)-2,2dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)carbamate (I-3)

To a solution of I-2 (1.42 g, 5.00 mmol) in THF (10.0 mL, c=0.5 M) cooled in an ice-water bath was added 4-fluorophenylmagnesium bromide (997 mg, 5 mmol, 5.00 mL, 1 M). The reaction mixture was stirred at ice bath for 10 min, quenched by adding 50 mL MeOH and 50 mL std. NH₄CI while cooling in ice bath. The aqueous layerwas extracted with EtOAc, the organic layer was concentrated, purified by column chromatography with 30% EtOAc/heptane to give 4.15 g 10 of I-3 (93% yield) as a white solid.

LCMS [M+1-Boc] 298. Ή NMR (400 MHz, CHLOROFORM-d) δ ppm 7.84 - 7.95 (m, 2 H) 7.29 7.35 (m, 1 H) 5.43 (br. s., 1 H) 4.77 (d, J=5.50 Hz, 1 H) 4.51 (d, J=5.62 Hz, 1 H) 4.18 (br. s., 1 H) 3.87 (d, J=8.68 Hz, 1 H) 2.53 (d, J=6.85 Hz, 1 H) 2.04 (d, J=13.94 Hz, 1 H) 1.55 (s, 3 H) 1.45 15 (s, 9 H) 1.31 (s, 3 H)

Step 3: Synthesis of tert-butyl ((3aS,4R,6R,6aR)-6-((3,4-difluorophenyl)(hydroxy)methyl)-

2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)carbamate (I-4)

To a solution of I-3 (4531 mg, 11.40 mmol) in EtOH (57.0 mL, c=0.2 M) was added NaBH₄ (2160 mg, 57.0 mmol), stirred at r.t. for 30 min. The reaction was quenched by adding std. NH4CI, extracted with EtOAc, the organic layers were concentrated, purified by column chromatography eluting with 50% EtOAc/heptane to give 4120 mg of I-4 (90% yield) as a white solid. LCMS [M+1-Boc] 300.

Step 4: Synthesis of tert-butyl ((3aS,4R,6S,6aR)-6-(((tert-butyldimethylsilyl)oxy)(3,4difluorophenyl)methyl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4yl)carbamate (I-5)

To a solution of I-4 (4300 mg, 10.77 mmol) and imidazole (2200 mg, 32.3 mmol) in DMF (53.8 mL, c=0.2 M) was added t-butyldimethylsilyl chloride (4870 mg, 32.3 mmol). The mixture was stirred at r.t. overnight. Additional TBSCI (1620 mg, 10.8 mmol) was added and stirred at r.t. overnight. The reaction mixture was quenched with H₂O and extracted with EtOAc (x3). The organic layer was dried over Na₂SO4, concentrated, purified by column chromatography with 1535 20% EtOAc/heptane to give 5.27 g of 1-5 (87% yield) as a colorless oil which solidified upon vacuum. LCMS [M+1-Boc] 414.

- 100Step 5: Synthesis of mixture of (3aS,4R,6S,6aR)-6-(((tert-butyldimethylsilyl)oxy)(3,4difluorophenyl)methyl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-amine (I-6) ^ar>d (1R,2S,3R,5S)-3-amino-5-(((tert-butyldimethylsilyl)oxy)(3,45 difluorophenyl)methyl)cyclopentane-1,2-diol (I-7)

I-5 (1250 mg, 2.433 mmol) in TFA (5.0 mL, c=0.5 M) was stirred at r.t. for 10-15 min. The reaction mixture was added EtOAc and neutralized with std. NaHCO₃ until pH about 7, the aqueous layer was extracted with EtOAc, the organic was combined and dried over Na₂SO₄, 10 concentrated to give 1 g (99% yield) as a light yellow oil as a mixture of the two compounds I-6 and I-7.

Step 6: Synthesis of mixture of N-((3aS,4R,6S,6aR)-6-(((tert-butyldimethylsilyl)oxy)(3,4difluorophenyl)methyl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-7H15 pyrrolo[2,3-d]pyrimidin-4-amine (I-8) and (1R,2S,3R,5S)-3-((7H-pyrrolo[2,3-d]pyrimidin-4yl)amino)-5-(((tert-butyldimethylsilyl)oxy)(3,4-difluorophenyl)methyl)cyclopentane-1,2diol (I-9)

To the above compounds i-6 and I-7 (154 mg, 0.372 mmol) in 4 mL nBuOH solution was added 20 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (85.8 mg, 0.559 mmol) and DIPEA (96.3 mg, 0.745 mmol,

0.123 mL), heated at 100°C for 2 days. The reaction mixture was cooled to r.t., EtOAc was added. The organic layer was washed with H₂O three times and then brine, dried over Na₂SO₄, concentrated, purified by column chromatography eluting from 80% EtOAc/heptane to 10% EtOAc/MeOH to give 35.3 mg (19% yield) of a mixture of two compounds i-8 and I-9 as a brown 25 oil.

Step 7: Synthesis of mixture of ((3aR,4R,6R,6aS)-6-((7H-pyrrolo[2,3-d]pyrimidin-4yl)amino)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)(3,4difluorophenyl)methanol (1-10) and (1R,2S,3R,5R)-3-((7H-pyrrolo[2,3-d]pyrimidin-430 yl)amino)-5-((3,4-difluorophenyl)(hydroxy)methyl) cyclopentane-1,2-diol (1-11)

To a mixture of the above compounds i-8 and i-9 (49 mg, 0.10 mmol) in 1 mL THF was added TBAF (39.2 mg, 0.150 mmol, 0.15 mL, 1.0 M) dropwise, stirred at r.t. for 0.5 h, concentrated and used crude for next step.

- 101 Step 8: Synthesis of (1S,2R,3R,5R)-3-[(S)-(3,4-difluorophenyl)(hydroxy)methyl]-5-(7Hpyrrolo[2,3-d]pyrimidin-4-ylamino)cyclopentane-1,2-diol (1-12) and (1S,2R,3R,5R)-3-[(R)(3,4-difluorophenyl) (hydroxy)methyl]-5-(7H-pyrrolo[2,3-d]pyrimidin-4ylamino)cyclopentane-1,2-dioi (1-13)

A mixture of above compounds 1-10 and 1-11 (42 mg, 0.10 mmol) was dissolved in TFA/H₂O (1 mL/1 mL) and stirred at rt for 2h. After completion, the mixture was concentrated to give crude oil, which was dissolved in H₂O, washed with EtOAc (1 mL x 2). The water layer was lyophilizated and the mixture separated by supercritical CO₂ fluid chromatography to give 10 (1S,2R,3R,5R)-3-[(S)-(3,4-difluorophenyl)(hydroxy)methyl]-5-(7H-pyrrolo[2,3-d]pyrimidin-4ylamino)cyclopentane-1,2-diol 1-12 (5.88 mg, 15%) and (1S,2R,3R,5R)-3-[(R)-(3,4difluorophenyl)(hydroxy)methyl]-5-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)cyclopentane-1,2-diol I13 (5.72 mg, 15%).

1-12: LCMS [M+1] 376.90. Ή NMR (700 MHz, DMSO-d6) δ ppm 1.06 - 1.12 (m, 1 H) 1.88 - 1.96 (m, 1 H) 2.15 - 2.21 (m, 1 H) 2.88 (q, J=6.83 Hz, 1 H) 3.77 (t, J=6.15 Hz, 1 H) 3.88 (br. s., 1 H)

4.24 - 4.32 (m, 1 H) 4.47 (d, J=5.98 Hz, 1 H) 6.53 (br. s., 1 H) 7.06 (br. s., 1 H) 7.15 (br. s., 1 H)

7.25 - 7.36 (m, 3 H) 7.99 (br. s., 1 H)

1-13: LCMS [M+1] 376.90. Ή NMR (700 MHz, DMSO-d6) δ ppm 1.32 - 1.40 (m, 1 H) 1.81 (dt,

J=12.55, 8.07 Hz, 1 H) 2.10 - 2.20 (m, 1 H) 2.88 (q, J=6.83 Hz, 1 H) 3.75 - 3.81 (m, 1 H) 3.83 (br. s., 1 H) 4.18 - 4.31 (m, 1 H) 4.73 (br. s., 1 H) 6.55 (br. s., 1 H) 7.07 (br. s., 1 H) 7.14 (br. s., 1 H) 7.24 - 7.41 (m, 3 H) 8.00 (br. s., 1 H)

Examples 29 and 30 were prepared in using similar chemistry in Scheme I using 425 chloroquinazoline-8-carbonitrile in step 6 in place of 4-chloro-7H-pyrrolo[2,3d]pyrimidine.

Example 29 Isomer A

H° H XûhI \\ /) Z ' N ' CN HO OH \^N F

LCMS [M+1] 412.85.

4-({(1 R;2S;3R;4R)-4-[(3;4difluorophenyl)(hydroxy)methyl]-2;3dihydroxycyclopentyl} amino)quinazoline-8-carbonitrile 1H NMR (700 MHz, DMSO-d6) δ ppm 1.40 (dt, J=13.11,8.82 Hz, 1 H) 1.85 (dt, J=13.15, 8.20 Hz, 1 H) 2.17 (dt, J=8.80, 4.31 Hz, 1 H) 3.86 (q, J=4.61 Hz, 1 H) 3.88 - 3.95 (m, 1 H) 4.43 (t, J=7.69 Hz, 1 H) 4.75 (t, J=4.10 Hz, 1 H) 7.09 - 7.16

-102 -

			(m, 1 H) 7.22 - 7.32 (m, 2 H) 7.58 (t, J=7.86 Hz, 1 H) 8.21 (d, J=7.34 Hz, 1 H) 8.38 (d, J=7.34 Hz, 1 H) 8.40 - 8.46 (m, 2 H)
Example 30 Isomer B	HO V H \\ /) ; N / CN HO OH \^N F	LCMS [M+1] 412.85.	4-({(1R;2S;3R;4R)-4-[(3;4difluorophenyl)(hydroxy)methyl]-2;3dihydroxycyclopentyl}amino)quinazoline8-carbonitrile 1H NMR (700 MHz, DMSO-d6) δ ppm 1.13 - 1.18 (m, 1 H) 1.92 - 1.99 (m, 1 H) 2.16 - 2.25 (m, 1 H) 3.92 (br. s., 2 H) 4.42 - 4.52 (m, 2 H) 7.11 - 7.15 (m, 1 H) 7.22 - 7.26 (m, 1 H) 7.26 - 7.30 (m, 1 H) 7.55 - 7.60 (m, 1 H) 8.21 (dd, J=7.34, 1.20 Hz, 1 H) 8.40-8.44 (m, 2 H)

Example 31 (Scheme J) - (1S,2R,3R,5R)-3-[(S)-(3,4-difluorophenyl)(hydroxy)methyl]-5[methyl(pyrimidin-4-yl) amino]cyclopentane-1,2-diol (J-5)

Example 32 (Scheme J) - (1S,2R,3R,5R)-3-[(R)-(3;4-difluorophenyl)(hydroxy)methyl]-5[methyl(pyrimidin-4-yl)amino]cyclopentane-1,2-diol (J-5)

Scheme J

Step 1: Synthesis of tert-butyl ((3aS,4R,6S,6aR)-6-(((tert-butyldimethylsilyl)oxy)(3,4difluorophenyl)methyl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-415 yl)(methyl)carbamate (J-1)

- 103Sodium hydride (304 mg, 7.59 mmol) was added in portions to a solution of I-5 (1300 mg, 2.531 mmol) in DMF (15 mL, 0.1 M) under an atmosphère of nitrogen, after 5 min, iodomethane (1080 mg, 7.59 mmol) was added, stirred at r.t. for 30 min. The reaction mixture was added H₂O, extracted with EtOAc, concentrated and purified by column chromatography with 20% EtOAc/heptane to give 1290 mg of J-1 (96% yield) as a colorless oil, LCMS [M+1-Boc] 428.1.

Step 2: Synthesis of (3aS,4R,6S,6aR)-6-(((tert-butyldimethylsilyl)oxy)(3,4difluorophenyl)methyl)-N,2,2-trimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-amine (J10 2)

J-1 (967 mg, 1.83 mmol) in TFA (5.0 mL, c=0.1 M) was stirred at r.t. for 10-15 min. The reaction mixture was added EtOAc and std. NaHCO₃ to neutralize to pH about 7, extracted with EtOAc, the organic layer was dried over Na₂SO₄, concentrated to give colorless oil.

The above oil was dissolved in acetone dimethyl acetal (10 mL, c=0.1 M), toluene-4-sulfonic acid (349 mg, 1.83 mmol) was added, stirred at r.t. for 15 min. The reaction mixture was added std NaHCO₃, extracted with EtOAc, the organic layer was washed with brine, dried over Na₂SO₄, concentrated to give 0.78 g of J-2 (99% yield) as a light yellow oil. LCMS [M+1] 428.15.

Step 3: Synthesis of N-((3aS,4R,6S,6aR)-6-(((tert-butyldimethylsilyl)oxy)(3,4difluorophenyl) methyl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-Nmethylpyrimidin-4-amine (J-3)

The mixture of J-2 (200 mg, 0.468 mmol), 4-chloropyrimidine (64.3 mg, 0.561 mmol) and DIPEA (121 mg, 0.935 mmol , 0.155 mL) in n-butanol (2.0 mL, c=0.2 M) was heated at 120°C overnight. The reaction mixture was cooied to r.t., the solvent was removed. The residue was added EtOAc, washed with H₂O 3 times and then brine, dried over Na₂SO₄ and concentrated, purified by column chromatography with 70% EtOAc/heptane to give 64 mg of J30 3 (27% yield) as a brown oil. LCMS [M+1] 506.20.

Step 4: Synthesis of (3,4-difluorophenyl)((3aR,4R,6R,6aS)-2,2-dimethyl-6(methyl(pyrimidin-4-yl) amino)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)methanol (J-4)

Followed similar procedure as step 7 in Scheme I, J-3 was deprotected to give J-4 as crude for the next step. LCMS [M+1] 392.15.

-104Step 5: Synthesis of (1S,2R,3R,5R)-3-[(S)-(3,4-difluorophenyl)(hydroxy)methyl]-5-[methyl (pyrimidin-4-yl)amino]cyclopentane-1,2-diol (J-5) and (1S,2R,3R,5R)-3-[(R)-(3;4difluorophenyl) (hydroxy)methyl]-5-[methyl(pyrimidin-4-yl)amino]cyclopentane-1,2-diol 5 (J-6)

Followed similar procedure as step 8 in Scheme I, J-4 (50 mg, 0.13 mmol) was deprotected to give J-5 (19.73 mg, 44%) and J-6 (3.14 mg, 7%).

J-5: LCMS [M+1] 351.90. ¹H NMR (700 MHz, DMSO-d6) δ ppm 1.18-1.31 (m, 1 H) 1.63 (d,

J=9.68 Hz, 1 H) 2.08 - 2.19 (m, 1 H) 2.90 (br. s., 3 H) 3.73 - 3.82 (m, 1 H) 3.90 (dd, J=9.35, 517

Hz, 1 H) 4.38 (br. s., 1 H) 4.49 (d, J=5.94 Hz, 1 H) 4.63 (br. s., 1 H) 5.60 (br. s., 1 H) 6.57 - 6.69 (m, 1 H) 7.21 (br. s., 1 H) 7.31 - 7.42 (m, 2 H) 8.02 - 8.14 (m, 1 H) 8.41 (br. s., 1 H)

J-6: LCMS [M+1] 351.90. ¹H NMR (700 MHz, DMSO-d6) δ ppm 1.42 (br. s., 2 H) 2.10 (br. s., 1

H) 2.90 (br. s., 3 H) 3.76 (br. s., 1 H) 3.86 - 3.97 (m, 1 H) 4.54 (br. s., 1 H) 4.65 (br. s., 1 H) 4.70

- 4.78 (m, 1 H) 5.58 (br. s., 1 H) 6.63 (br. s., 1 H) 7.17 (br. s., 1 H) 7.28 - 7.40 (m, 2 H) 8.09 (br. s., 1 H) 8.41 (br. s., 1 H)

Examples 33-36 were prepared in foilowing similar chemistry in Scheme J using the chloropyrimidine iisted in step 3.

Exampie 33

4-chloro-6methylpyrimidine

F

LCMS

[M+1] 366.1 (1S,2R,3R,5R)-3-[(S)-(3,4difluorophenyl)(hydroxy)methyl]5-[methyl(6-methyl pyrimidin-4yl)amino]cyclopentane-1,2-diol ¹H NMR (700 MHz, DMSO-d6) δ ppm 1.18 - 1.31 (m, 1 H) 1.61 (d, J=10.34 Hz, 1 H) 2.13 (d, J=7.04 Hz, 1 H) 2.22 (s, 3 H) 2.88 (br. s., 3 H) 3.77 (br. s., 1 H) 3.84 - 3.94 (m, 1 H) 4.32 4.41 (m, 1 H) 4.49 (t, J=5.06 Hz, 1 H) 4.61 (br. s., 1 H) 5.61 (d, J=4.40 Hz, 1 H) 6.49 (br. s., 1 H) 7.15 - 7.23 (m, 1 H) 7.32 7.43 (m, 2 H) 8.28 (s, 1 H)

-105-

Example 34 4-chloro-6methylpyrimidine	H W ZV HO OH V^N F	LCMS [M+1] 366.1	(1S,2R,3R,5R)-3-[(R)-(3,4difluorophenyl)(hydroxy)methyl]5-[methyl(6-methylpyrimidin-4yl)amino]cyclopentane-1,2-diol 1H NMR (700 MHz, DMSO-d6) δ ppm 1.40 (t, J=9.24 Hz, 2 H) 2.09 (dt, J=8.14, 4.29 Hz, 1 H) 2.22 (s, 3 H) 2.89 (br. s., 3 H) 3.71 - 3.78 (m, 1 H) 3.86 - 3.95 (m, 1 H) 4.46 - 4.54 (m, 1 H) 4.62 (br. s., 1 H) 4.73 (t, J=4.40 Hz, 1 H) 5.58 (d, J=4.62 Hz, 1 H) 6.50 (br. s., 1 H) 7.16 (br. s., 1 H) 7.29 - 7.39 (m, 2 H) 8.28 (s, 1 H)
Example 35 4-chloro-2methylpyrimidine	HV H F-Q H HO OH V^N F /	LCMS [M+1] 365.90	(1S,2R,3R,5R)-3-[(S)-(3,4difluorophenyl)(hydroxy)methyl]5-[methyl(2-methyl pyrimidin-4yl)amino]cyclopentane-1,2-diol 1H NMR (700 MHz, DMSO-d6) δ ppm 1.17 - 1.32 (m, 1 H) 1.57 - 1.68 (m, 1 H) 2.08 - 2.19 (m, 1 H) 2.31 (br. s., 3 H) 2.88 (br. s„ 3 H) 3.77 (br. s., 1 H) 3.84 3.94 (m, 1 H) 4.37 (br. s., 1 H) 4.49 (br. s„ 1 H) 4.63 (br. s., 1 H) 5.61 (br. s., 1 H) 6.43 (br. s., 1 H) 7.21 (br. s., 1 H) 7.37 (d, J=8.58 Hz, 2 H) 7.99 (br. s., 1 H)
Example 36 4-chloro-2methylpyrimidine	HQ' H FZj H Z> /^7 HO OH V=N F /	LCMS [M+1] 365.90	(1S,2R,3R,5R)-3-[(R)-(3,4difluorophenyl)(hydroxy)methyl]5-[methyl(2-methylpyrimidin-4yl)amino]cyclopentane-1,2-diol 1H NMR (700 MHz, DMSO-d6) δ ppm 1.35 - 1.48 (m, 2 H) 2.10 (tt, J=8.53, 4.24 Hz, 1 H) 2.31 (s, 3 H) 2.89 (br. s., 3 H) 3.71 3.79 (m, 1 H) 3.91 (dt, J=8.42,

-106-

6.02 Hz, 1 H) 4.52 (d, J=3.96 Hz, 1 H) 4.65 (br. s„ 1 H) 4.73 (t, J=4.51 Hz, 1 H) 5.59 (d, J=4.62 Hz, 1 H) 6.43 (d, J=5.06 Hz, 1 H) 7.12 - 7.19 (m, 1 H) 7.29 - 7.38 (m, 2 H) 7.99 (d, J=5.94 Hz, 1 H)

Example 37 (Scheme K) - (1R,2S,3R,5R)-3-[(4-amino-1,3,5-triazin-2-yl)(methyl)amino]-5[(S)-(3,4-difluorophenyl) (hydroxy)methyl]cyclopentane-1,2-diol (K-4)

Exampie 38 (Scheme K) - (1R,2S,3R,5R)-3-[(4-amino-1,3,5-triazin-2-yl)(methyl) amino]-5[(R)-(3,4-difluorophenyl)(hydroxy)methyl]cyclopentane-1,2-diol (K-5)

Scheme K

Step 1: Synthesis of N-((3aS,4R,6S,6aR)-6-(((tert-biityldimethylsilyl)oxy)(3,4difluorophenyl) methyl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-415 chloro-N-methyl-1,3,5-triazin-2-amine (K-1)

Following a similar procedure to step 3 in Scheme J using 2,4-dichloro-[1,3,5]triazine with J-2 generated K-1 (267 mg, 58%).

Step 2: Synthesis of N2-((3aS,4R,6S,6aR)-6-(((tert-butyldimethylsilyl)oxy)(3,4difluorophenyl) methyl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-N2methyl-1,3,5-triazine-2,4-diamine (K-2)

-107 Following a similar procedure to step 5 in Scheme G, K-1 was converted to K-2 (86 mg, 81%). LCMS [M+1] 522.

Step 3: Synthesis of ((3aR,4R,6R,6aS)-6-((4-amino-1,3,5-triazin-2-yl)(methyl)amino)-2,25 dimethyl tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)(3,4-difluorophenyl)methanol (K-3)

Following a similar procedure to step 4 in Scheme J, K-2 was deprotected with TBAF to give K3 as crude for the next step.

Step 4: Synthesis of (1 R,2S,3R,5R)-3-[(4-amino-1,3,5-triazin-2-yl)(methyl)amino]-5-[(S)(3,4-difluorophenyl)(hydroxy)methyl]cyclopentane-1,2-diol (K-4) and (1R,2S,3R,5R)-3-[(4amino-1,3,5-triazin-2-yl)(methyl)amino]-5-[(3R)-(3,4difluorophenyl)(hydroxy)methyl]cyclopentane-1,2-diol (K-5)

Following a similar procedure to step 5 in Scheme J with subséquent séparation with chiral

SFC, K-3 was converted to K-4 (12 mg, 20%) and K-5 (48 mg, 80%).

K-4: LCMS [M+1] 367.90. Ή NMR (400 MHz, DMSO-d6) δ ppm 1.12 - 1.23 (m, 1 H) 1.52 - 1.64 (m, 1 H) 2.08 (br. s., 1 H) 2.96 (d, J=9.78 Hz, 3 H) 3.78 (br. s., 1 H) 3.87 (br. s., 1 H) 4.48 (d, J=5.38 Hz, 1 H) 4.94 (br. s., 1 H) 5.55 (br. s., 1 H) 6.95 (s, 1 H) 7.08 (br. s, 2 H) 7.21 (br. s, 1 H) 20 7.30-7.45 (m, 2 H) 8.07 (br. s., 1 H)

K-5: LCMS [M+1] 367.90. ¹H NMR (700 MHz, DMSO-d6) δ ppm 1.31 - 1.45 (m, 2 H) 2.05 (br. s., 1 H) 2.93 (m, 3 H) 3.72 (br. s., 1 H) 3.90 (br. s., 1 H) 4.65 - 4.72 (m, 1 H) 4.86 (d, J=15.03 Hz, 1 H) 7.14 (br. s., 1 H) 7.25 - 7.35 (m, 2 H) 7.98 (br. s., 1 H) 8.30 (br. s., 2 H)

Examples 39-42 were prepared in following similar chemistry in Scheme K using 2,4dichloropyrimidine (Examples 39 & 40) or 2₎4-dichloro-6-methyl-1,3,5-triazine (Examples & 42) listed in step 1.

Example 39

2,4dichloropyrimidine

LCMS [M+1]

366.90 (1R,2S,3R,5R)-3-[(2aminopyrimidin-4yl)(methyl)amino]-5-[(S)-(3,4difluorophenyl) (hydroxy)methyl]cyclopentane1,2-diol ¹H NMR (700 MHz, DMSO-d6) δ ppm 1.17 - 1.22 (m, 1 H)

- 108-

			1.53 - 1.60 (m, 1 H) 2.06 2.11 (m, 1 H) 2.81 (br. s., 3 H) 3.75 (br. s., 1 H) 3.84 - 3.89 (m, 1 H) 4.32 (d, J=3.08 Hz, 1 H) 4.48 (t, J=5.28 Hz, 1 H) 4.60 (d, J=5.94 Hz, 1 H) 5.59 (d, J=4.62 Hz, 1 H) 5.81 (s, 2 H) 5.87 (d, J=5.94 Hz, 1 H) 7.20 (br. s., 1 H) 7.32 - 7.40 (m, 2 H) 7.67 (d, J-5.72 Hz, 1 H)
Example 40 2,4- dichloropyrimidine	HQ y A-Z HÔ OH N\=îN F / H2N	LCMS [M+1] 366.90	(1R,2S,3R,5R)-3-[(2aminopyrimidin-4yl)(methyl)amino]-5-[(R)(3,4difluorophenyl) (hydroxy)methyl]cyclopentane1,2-diol 1H NMR (700 MHz, DMSO-d6) δ ppm 1.30 - 1.44 (m, 2 H) 2.05 (dt, J=8.25, 4.24 Hz, 1 H) 2.82 (br. s., 3 H) 3.74 (br. s., 1 H) 3.88 (br. s., 1 H) 4.48 (br. s., 1 H) 4.62 (br. s., 1 H) 4.72 (br. s., 1 H) 5.57 (d, J=4.40 Hz, 1 H) 5.81 (br. s., 2 H) 5.87 (d, J=5.06 Hz, 1 H) 7.09 - 7.19 (m, 1 H) 7.28 - 7.38 (m, 2 H) 7.67 (br. s., 1 H)
Example 41 2,4-dichloro-6- methyl-1,3,5- triazine	HO i HO OH \^N F / h2n	LCMS [M+1] 381.90	(1R,2S,3R,5R)-3-[(4-amino-6methyl-1,3,5-triazin-2yl)(methyl)amino]-5-[(S)-(3,4difluorophenyl) (hydroxy)methyl]cyclopentane1,2-diol 1H NMR (700 MHz, DMSO-d6) δ ppm 1.18 (d, J=13.66 Hz, 1 H) 1.49 - 1.59 (m, 1 H) 2.12 (d, J=14.69 Hz, 4 H) 2.91 (d, J=19.81 Hz, 3 H) 3.79 (br. s.,

-109-

			1 H) 3.88 (br. s., 1 H) 4.46 (br. s., 1 H) 4.88 (br. s„ 1 H) 7.16 (br. s., 1 H) 7.23 - 7.36 (m, 2 H)
Example 42 2,4-dichloro-6methyl-1,3,5triazine	HQ / \ V y- \\ /) I N > HO OH \^N F / H2N	LCMS [M+1] 381.90	(1 R,2S,3R,5R)-3-[(4-amino-6methyl-1,3,5-triazin-2yl)(methyl)amino]-5-[(R)-(3,4difluorophenyl) (hydroxy)methyl]cyclopentane- 1,2-diol 1H NMR (700 MHz, DMSO-d6) δ ppm 1.31 - 1.45 (m, 2 H) 2.07 (d, J=18.62 Hz, 4 H) 2.82 - 2.96 (m, 3 H) 3.72 (br. s., 1 H) 3.87 (br. s., 1 H) 4.68 (br. s., 1 H) 4.94 - 4.78 (m, 1 H) 6.37 (br. s., 2 H) 7.13 (br. s., 1 H) 7.22 - 7.34 (m, 2 H)

Example 43 (Scheme L) - (1R,2S,3R,5R)-3-[(6-aminopyrimidin-4-yl)(methyl)amino]-5-[(S)(3,4-difluorophenyl) (hydroxy)methyl]cyclopentane-1,2-diol (L-4)

Example 44 (Scheme L) - (1R,2S,3R,5R)-3-[(6-aminopyrimidin-4-yl)(methyl)amino]-5-[(R)(3,4-difluorophenyl)(hydroxy)methyl]cyclopentane-1,2-diol (L-5)

Scheme L

L-3

L-4

L-5

-110-

Step 1: Synthesis of N-((3aS,4R,6S,6aR)-6-(((tert-butyldimethylsilyl)oxy)(3,4difluorophenyl)methyl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-6-chloroN-methylpyrimidin-4-amine (L-1)

Following a similar procedure to step 1 in Scheme K, J-2 was treated with 4,6dichloropyrimidine in n-butanol and DIPEAtogive L-1 (188 mg, 60%). LCMS [M+1] 540.20.

Step 2: Synthesis of N4-((3aS,4R,6S,6aR)-6-(((tert-butyldimethylsilyl)oxy)(3,4difluorophenyl) methyl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-N410 methylpyrimidine-4,6-diamine (L-2)

To a solution of L-1 (188 mg, 0.348 mmol) in THF (10 mL, c=0.035 M) was added tris(dibenzylideneacetone)dipalladium (41.4 mg, 0.045 mmol) and dicyclohexyl(2phenylphenyl)phosphane (33.7 mg, 0.092 mmol), capped and purged with nitrogen, 15 then LHMDS (153 mg, 0.905 mmol , 0.90 mL, 1.0 M) was added, heated at 75°C for 18 h. The reaction was cooled to r.t., diluted with water and EtOAc, the layers were separated. The organic phase was dried over Na2SC>4, filtered and concentrated. The product was purified by column chromatography with 80%-100% EtOAc/heptane to give 180 mg of L-2 (99% yield) as a light yellowoil. LCMS [M+1] 521.30.

Step 3: Synthesis of ((3aR,4R,6R,6aS)-6-((6-aminopyrimidin-4-yl)(methyl)amino)-2,2dimethyl tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)(3,4-difluorophenyl)methanol (L-3)

Following a similar procedure as step 3 in Scheme K, L-2 was treated with TBAF to give L-3 as 25 crude for the next step. LCMS [M+1] 407.20.

Step 4: Synthesis of (1R,2S,3R,5R)-3-[(6-aminopyrimidin-4-yl)(methyl)amino]-5-[(S)-(3,4difluoro phenyl)(hydroxy)methyl]cyclopentane-1,2-diol (L-4) and (1R,2S,3R,5R)-3-[(6aminopyrimidin-4-yl)(methyl) amino]-5-[(R)-(3,430 difluorophenyl)(hydroxy)methyl]cyclopentane-1,2-diol (L-5)

Following a similar procedure as step 4 in Scheme K, L-3 was treated with TFA in water. L-4 (31 mg, 25%) and L-5 (11 mg, 9%) were isolated after workup and purification by chiral SFC.

L-4: LCMS [M+1] 366.90. Ή NMR (700 MHz, DMSO-d6) δ ppm 1.13 - 1.26 (m, 1 H) 1.55 (dt,

3=12.60, 8.56 Hz, 1 H) 2.04 - 2.13 (m, 1 H) 2.77 (s, 2 H) 3.71 - 3.79 (m, 1 H) 3.81 - 3.88 (m, 1

H) 4.27 - 4.35 (m, 1 H) 4.47 (t, J=5.28 Hz, 1 H) 4.55 (d, J=5.72 Hz, 1 H) 5.47 (s, 1 H) 5.58 (d,

J=4.62 Hz, 1 H) 6.03 (br. s., 2 H) 7.15 - 7.23 (m, 1 H) 7.30 - 7.40 (m, 2 H) 7.86 (s, 1 H)

L-5: LCMS [M+1] 366.90. Ή NMR (700 MHz, DMSO-d6) δ ppm 1.29 - 1.42 (m, 2 H) 1.99 - 2.09 (m, 1 H) 2.78 (br. s., 3 H) 3.74 (br. s., 1 H) 3.86 (d, J=7.04 Hz, 1 H) 4.41 - 4.49 (m, 1 H) 4.52 4.60 (m, 1 H) 4.72 (br. s., 1 H) 5.47 (s, 1 H) 5.56 (d, J=3.96 Hz, 1 H) 6.03 (br. s., 1 H) 7.15 (br.

s., 1 H) 7.28 - 7.38 (m, 2 H) 7.86 (s, 1 H)

Example 46 (Scheme M) - (1S,2R,3R,5R)-3-[(S)-(3,4-difluorophenyl)(hydroxy)methyl]-510 [methyl(4-methyl-1,3,5-triazin-2-yl)amino]cyclopentane-1,2-diol (M-4)

Example 47 (Scheme M) - (1S,2R,3R,5R)-3-[(R)-(3,4-difluorophenyl)(hydroxy)methyl]-5[methyl(4-methyl-1,3,5-triazin-2-yl)amino]cyclopentane-1,2-diol (M-5)

Scheme M

Step 1: Synthesis of N-((3aS,4R,6S,6aR)-6-(((tert-butyldimethylsilyl)oxy)(3,4difluorophenyl) methyl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-4 chloro-N-methyl-1,3,5-triazin-2-amine (M-1)

The reaction mixture of J-2 (360 mg, 0.842 mmol), 2,4-dichloro-[1,3,5] triazine (152 mg, 1.01 mmol) and DIPEA (218 mg, 1.68 mmol, 0.279 mL) in DMA (5 mL, 0.16 M) was stirred at r.t. for 5 hrs. The rxn mixture was added EtOAc, washed with H₂O 3 times and then brine. The organic 25 layer was dried over Na₂SO₄ and concentrated, purified by column chromatography with 20%

EtOAc/heptane to give 267 mg of M-1 (58.6% yield) as a colorless oil. LCMS [M+1] 541.

-112 Step 2: Synthesis of N-((3aS,4R,6S,6aR)-6-(((tert-butyldimethylsilyl)oxy)(3,4difluorophenyl) methyl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-N,4dimethyl-1,3,5-triazin-2-amine (M-2)

M-2 (176 mg, 99%) was made from M-1 following a similar procedure to step 5 in Scheme A. LCMS [M+1] 521.

Step 3: Synthesis of (3,4-difluorophenyl)((3aR,4R,6R,6aS)-2,2-dimethyl-6-(methyl(4methyl-1,3,5-triazin-2-yl)amino)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)methanol (M3)

Following a similar procedure as step 3 in Scheme K, M-2 was treated with TBAF to give M-3 as crude for the next step. LCMS [M+1] 407.

Step 4: Synthesis of (1S,2R,3R,5R)-3-((S)-(3,4-difluorophenyl)(hydroxy)methyl)-5(methyl(4-methyl-1,3,5-triazin-2-yl)amino)cyclopentane-1,2-diol (M-4) and (1S,2R,3R,5R)-3((R)-(3,4-difluorophenyl) (hydroxy)methyl)-5-(methyl(4-methyl-1,3,5-triazin-2yl)amino)cyclopentane-1,2-diol (M-5)

Following a similar procedure as step 4 in Scheme K, M-3 was treated with TFA in water. M-4 (78.97 mg, 64%) and M-5 (24.48 mg, 20%) were isolated after subséquent workup and purification by chiral SFC.

M-4: LCMS [M+1] 366.90. Ή NMR (400 MHz, DMSO-d6) δ ppm 1.26 - 1.34 (m, 1 H) 1.56 - 1.69 (m, 1 H) 2.13 (br. s., 1 H) 2.24 - 2.32 (m, 3 H) 3.00 (s, 3 H) 3.78 (br. s., 1 H) 3.91 (br. s., 1 H) 4.33 (d, J=15.89 Hz, 1 H) 4.48 (br. s., 1 H) 4.60 (br. s., 1 H) 4.92 - 5.04 (m, 1 H) 5.56 (d, J=4.40 Hz, 1 H) 7.22 (d, J=4.52 Hz, 1 H) 7.30 - 7.43 (m, 2 H) 8.39 (d, J=14.67 Hz, 1 H)

M-5: LCMS [M+1] 366.90. Ή NMR (700 MHz, DMSO-d6) δ ppm 1.36 - 1.48 (m, 2 H) 2.09 (br. s., 1 H) 2.27 (d, J=23.74 Hz, 3 H) 2.98 (d, J=4.10 Hz, 3 H) 3.73 (br. s., 1 H) 3.90 (m, 1 H) 4.70 (br. s., 1 H) 4.93 (t, J=9.99 Hz, 1 H) 7.15 (br. s., 1 H) 7.31 (d, J=9.39 Hz, 2 H) 8.34 (d, J=33.65 Hz, 1 H)

Example 48 (Scheme N) - (1R,2S,3R,5R)-3-(2-amino-4-methyl-7H-pyrrolo[2,3-d]pyrimidin7-yl)-5-[(S)-(3,4-difluorophenyl)(hydroxy)methyl]cyclopentane-1,2-diol (N-5)

- 113 Example 49 (Scheme N) - (1R,2S,3R,5R)-3-(2-amino-4-methyl-7H-pyrrolo[2,3-d]pyrimidin7-yl)-5-[(R)-(3,4-difluorophenyl)(hydroxy)methyl]cyclopentane-1,2-diol (N-6)

Scheme N

cyclopenta[d][1,3] dioxol-4-yl)(3,4-difluorophenyl)methanol (N-1 )

I-5 (616 mg, 1.54 mmol) in TFA (3 mL, c=0.5 M) was stirred at r.t. for 10-15 min. The reaction mixture was added EtOAc and neutralized with std. NaHCOs to pH about 7, the aqueous layer was extracted with EtOAc 3 times, the organic was dried over Na₂SO4, concentrated to give 460 mg of N-1 (100% yield) as a white solid, used for next step. LCMS [M+1] 300.15.

Step 2: Synthesis of ((3aR,4R,6R,6aS)-6-((2-amino-6-chloro-5-(2,2diethoxyethyl)pyrimidin-4-yl) amino)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-

4-yl)(3,4-difluorophenyl)methanol (N-2)

The mixture of N-1 (214 mg, 0.714 mmol), 4,6-dichloro-5-(2,2-diethoxyethyl)pyrimidin-2-amine (200 mg, 0.714 mmol), and triethylamine (289 mg, 2.86 mmol) in 10 mL nBuOH was heated at 135°C in a sealed tube for 40 hrs. The reaction mixture was cooled to r.t., concentrated, H₂O was added, extracted with EtOAc, the product was purified by column chromatography with 5060% EtOAc/heptane to give 200 mg of N-2 (51% yield) as a yellow solid. LCMS [M+1] 543.20.

- 114 Step 3: Synthesis of ((3aR,4R,6R,6aS)-6-(2-amino-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)(3,4-difluorophenyl)methanol (N-3)

N-2 (200 mg, 0.368 mmol) was added to acetic acid (15 mL, c=0.025 M), the solution was heated at 100°C for 1 h. The volatiles were removed in vacuo, the residue was added EtOAc, neutralized with std. NaHCO₃, the layers were separated and the aqueous was extracted with EtOAc 3 times. The organic layer was concentrated, purified by column chromatography with 50% EtOAc/heptane to give 100 mg of N-3 (60% yield) as an off white solid. LCMS [M+1] 10 451.10.

Step 4: Synthesis of ((3aR,4R,6R,6aS)-6-(2-amino-4-methyî-7H-pyrrolo[2,3-d]pynmidin-7yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)(3,4-difluorophenyl)methanol (N-4)

Following a similar procedure to step 5 in Scheme A, N-3 was converted to N-4 (69 mg, 85%). LCMS [M+1] 431.15.

Step 5: Synthesis of (1R,2S,3R,5R)-3-(2-amino-4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)20 5-[(S)-(3,4-difluorophenyl)(hydroxy)methyl]cyclopentane-1,2-diol (N-5) and (1R,2S,3R,5R)-

3-(2-amino-4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-[(R)-(3,4difluorophenyl)(hydroxy)methyl]cyclopentane-1,2-diol (N-6)

Following a similar procedure as step 4 in Scheme K, N-4 was treated with TFA in water. N-5 25 (14.6 mg, 23%) and N-6 (6.6 mg, 11%) were isolated after subséquent workup and purification by chiral SFC.

N-5: LCMS [M+1] 390.85. Ή NMR (700 MHz, DMSO-d6) δ ppm 7.35 - 7.40 (m, 1 H) 7.29 - 7.35 (m, 1 H) 7.21 (br. s., 1 H) 7.07 (d, J=3.74 Hz, 1 H) 6.38 (d, J=3.52 Hz, 1 H) 5.90 (s, 2 H) 5.74 (d, 30 J=4.40 Hz, 1 H) 4.83 (d, J=6.60 Hz, 1 H) 4.71 - 4.79 (m, 1 H) 4.51 - 4.58 (m, 2 H) 4.15 - 4.21 (m, 1 H) 3.90 (br. s., 1 H) 2.38 (s, 3 H) 2.18 (d, J=7.92 Hz, 1 H) 1.83 - 1.93 (m, 1 H) 1.44 (d, J=10.34 Hz, 1 H)

N-6: LCMS [M+1] 390.90. ¹H NMR (700 MHz, DMSO-d6) δ ppm 7.29 - 7.36 (m, 2 H) 7.16 (br.

s., 1 H) 7.12 (d, J=3.52 Hz, 1 H) 6.40 (d, J=3.30 Hz, 1 H) 5.89 (s, 2 H) 5.76 (br. s., 1 H) 4.86 (d,

J=5.94 Hz, 1 H) 4.76 (t, J=4.62 Hz, 1 H) 4.73 (q, J=8.88 Hz, 1 H) 4.68 (br. s., 1 H) 4.08 - 4.12

-115(m, 1 H) 3.83 - 3.86 (m, 1 H) 2.39 (s, 3 H) 2.16 (dt, J=8.53, 4.21 Hz, 1 H) 1.76 (dt, J=12.98, 8.47 Hz, 1 H) 1.57- 1.64 (m, 1 H)

Example 50 (Scheme O) - (1S,2R,3S,5R)-3-[2-amino-1-fluoro-1-(4-fluorophenyl)ethyl]-5-(4methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol (0-5)

Example 51 (Scheme O) - (1S,2R,3R,5R)-3-[(1S)-2-amino-1-(4-fluorophenyl)ethyl]-5-(4methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol (0-6)

Example 52 (Scheme O) - (1S,2R,3R,5R)-3-[(1R)-2-amino-1-(4-fluorophenyl)ethyl]-5-(4methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol (0-7)

Scheme O

Step 1: Synthesis of 2-((3aR,4S_>6R,6aS)-2,2-dimethyl-6-(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-2-fluoro-2-(4fluorophenyl)acetonitrile (0-1)

To a mixture of E-1 (175 mg, 0.443 mmol) and zinc(ll) iodide (2.12 mg, 0.00664 mmol) in a sealable tube was added anhydrous 2 mL CH₂CI₂, followed by trimethylsilyl cyanide (0.25 mL) under nitrogen. The reaction was sealed and heated at 50°C for 2 days. The resulting mixture was cooled in an ice bath, DAST (78.5 mg, 0.487 mmol) was added dropwise, stirred at r.t. for 15 min. The reaction mixture was washed with H₂O, 0.5 N HCl, std. NaHCO₃, brine and

-116 concentrated. The product was purified by column chromatography with 50% EtOAc/heptane to give 80 mg of 0-1 (43% yield) as a yellow oil. LCMS [M+1] 425.10.

Step 2: Synthesis of 2-((3aR,4S,6R,6aS)-2,2-dimethyl-6-(4-methyl-7H-pyrrolo[2,35 d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-2-fluoro-2-(4fluorophenyl)ethan-1 -amine (0-2) and 2-((3aR,4R,6R,6aS)-2,2-dimethyl-6-(4-methyl-7Hpyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro-4H-cyc!openta[d][1,3]dioxol-4-yl)-2-(4fluorophenyl)ethan-1-amine (O-3)

O-1 (70 mg, 0.16 mmol) was dissolved in 0.5 mL MeOH. Cobalt (II) chloride hexahydrate (118 mg, 0.495 mmol) was added and the mixture was cooled in an ice bath. NaBH₄ (32.8 mg, 0.825 mmol) was added and the reaction stirred at 0°C for 0.5 h. The reaction mixture was quenched by std. NH₄CI, extracted with EtOAc, the organic layer was washed with brine, concentrated, purified by prep TLC plate with 5% MeOH/CH₂CI₂ to give 20 mg of O-2 (28% yield) as a yellow oil, (LCMS [M+1] 429.10) and 22 mg of O-3 (32% yield) as a yellow oil. (LCMS [M+1] 411.20)

Step 3: Synthesis of (1S,2R,3S,5R)-3-[2-amino-1-fluoro-1-(4-fluorophenyl)ethyl]-5-(4methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol (O-4)

Following a similar procedure as step 4 in Scheme K, 0-2 was treated with TFA in water. 0-4 (1.2 mg, 6.6%) was isolated after subséquent workup and purification by SFC.

LCMS [M+1] 388.90. Ή NMR (400 MHz, METHANOL-d4) δ ppm 1.62 - 1.73 (m, 1 H) 1.81 (s, 3 H) 2.54 - 2.73 (m, 4 H) 4.17 (br. s., 1 H) 4.76 - 4.94 (m, 2 H) 6.59 (d, J=3.42 Hz, 1 H) 7.04 (t, 25 J=8.68 Hz, 2 H) 7.29 - 7.42 (m, 3 H) 8.46 (s, 1 H)

Step 4: Synthesis of (1S,2R,3R,5R)-3-[(1S)-2-amino-1-(4-fluorophenyl)ethyl]-5-(4-methyl7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol (O-5) and (1S,2R,3R,5R)-3-[(1R)-2amino-1-(4-fluorophenyl)ethyl]-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-y!)cyclopentane30 1,2-diol (0-6)

Following a similar procedure as step 4 in Scheme K, 0-3 was treated with TFA in water. 0-5 (5.4 mg, 27%) and 0-6 (3.7 mg, 19%) were isolated after subséquent workup and purification by chiral SFC.

-1170-5: LCMS [M+1] 370.90. Ή NMR (400 MHz, METHANOL-d4) δ ppm 1.42 - 1.57 (m, 1 H) 1.65 - 1.79 (m, 1 H) 2.24 (br. s., 1 H) 2.49 - 2.68 (m, 3 H) 2.83 (br. s., 1 H) 2.96 - 3.10 (m, 1 H) 3.31 (d, J=13.20 Hz, 1 H) 4.02 (t, J=5.81 Hz, 1 H) 4.27 (t, J=6.79 Hz, 1 H) 4.75 (br. s., 1 H) 6.56 (d, J=3.18 Hz, 1 H) 6.98 (t, J=8.38 Hz, 2 H) 7.13 - 7.28 (m, 2 H) 7.31 (d, J=2.93 Hz, 1 H) 8.45 (s, 1

H)

0-6: LCMS [M+1] 370.90. Ή NMR (400 MHz, METHANOL-d4) δ ppm 1.78 (d, J=9.29 Hz, 1 H) 2.26 - 2.40 (m, 2 H) 2.53 - 2.67 (m, 4 H) 2.91 - 3.00 (m, 1 H) 3.24 - 3.25 (m, 1 H) 3.67 - 3.78 (m, 1 H) 4.19 - 4.32 (m, 1 H) 4.82 - 4.89 (m, 1 H) 6.60 (d, J=3.67 Hz, 1 H) 7.08 (t, J=8.68 Hz, 2 H)

7.27 - 7.40 (m, 3 H) 8.44 - 8.52 (m, 1 H)

Example 53 (Scheme P) - (1S,2R,3R,5R)-3-((SH2-(aminomethyl)-4chlorophenyl)(hydroxy)methyl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-

1,2-diol (P-8)

Example 54 (Scheme P) - (1S,2R,3R,5R)-3-((R)-(2-(aminomethyl)-4chlorophenyl)(hydroxy)methyl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-

1,2-diol (P-9)

Scheme P

- 118 Step 1: Synthesis of (1R,2S,3R,5R)-3-((6-chloro-5-(2,2-diethoxyethyl)pyrimidin-4yl)amino)-5-(hydroxymethyl)cyclopentane-1,2-diol (P-1) (1R,2S,3R,5R)-3-amino-5-(hydroxymethyl)cyclopentane-1,2-diol (4160 mg, 22.6 mmol) and 4,6dichloro-5-(2,2-diethoxyethyl)pyrimidine (J. Med. Chem. 10, 665, 1967) (5000 mg, 18.86 mmol) in 40 mL absolute éthanol in a sealed flask was treated with Et₃N (7630 mg, 75.4 mmol), heated at 80°C for 18 hrs. The reaction mixture was cooled in an ice bath, the solid was filtered and the mother liquor was concentrated to give P-1 as a brown slurry which was used directly for next step. LCMS [M+1] 375.80.

Step 2: Synthesis of (1R,2S,3R,5R)-3-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5(hydroxymethyl) cyclopentane-1,2-diol (P-2)

The suspension of P-1 (7088 mg, 18.86 mmol) in 30 mL dioxane, was treated with 10 mL 1 N HCl, heated at 80°C for 30 min. The reaction mixture was neutralized with NH₄OH to pH 7 and the volatiles were removed in vacuo to afford P-2 as a brown slurry which was used directly for next step. LCMS [M+1] 283.85.

Step 3: Synthesis of ((3aR,4R,6R,6aS)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)methanol (P-3)

P-2 (5350 mg, 18.86 mmol) and 2,2-dimethoxypropane (50 mL, c=0.38 M) was treated with ptoluenesulphonic acid monohydrate (7170 mg, 37.7 mmol) and the yellow brown suspension was adjusted to pH 4-5, stirred vigorously at r.t. for 15 min. The reaction mixture was diluted with 100 mL H₂O, neutralized with solid NaHCO₃. The volatiles were carefully removed in vacuo and the resulting brown aqueous solution was extracted with 20% isopropanol/DCM, the organic was combined, concentrated, purified by column chromatography with 50% EtOAc/DCM to 100% EtOAc to give 4.4 g of P-3 as a yellow gum (72% overall yield).

LCMS [M+1] 324.10. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.63 (s, 1 H) 7.33 (d, J=3.55 Hz, 1 H) 6.63 (d, J=3.67 Hz, 1 H) 4.94 - 5.06 (m, 2 H) 4.72 (dd, J=6.66, 4.46 Hz, 1 H) 3.85 - 3.92 (m, 1 H) 3.78 - 3.85 (m, 1 H) 2.43 - 2.56 (m, 2 H) 2.28 - 2.42 (m, 1 H) 2.09 (br. s., 1 H) 1.55- 1.64 (m, 3 H) 1.33 (s, 3 H)

Step 4: Synthesis of ((3aR,4R,6R,6aS)-2,2-dimethyl-6-(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)methanol (P-4)

-119Following a similar procedure to step 5 in Scheme A, P-3 was converted to P-4 (930 mg, 88%).

LCMS [M+1] 304.15. Ή NMR (400 MHz, CHLOROFORM-d) δ ppm 1.25 (s, 3 H) 1.53 (s, 3 H) 2.21 - 2.34 (m, 2 H) 2.38 - 2.47 (m, 2 H) 2.75 (s, 3 H) 3.75 (br. s., 1 H) 3.80 (br. s., 1 H) 4.65 (dd, J=6.66, 4.10 Hz, 1 H) 4.86 - 5.00 (m, 2 H) 6.57 (br. s., 1 H) 7.25 (br. s., 1 H) 8.71 (s, 1 H)

Step 5: Synthesis of (3aR,4S,6R,6aS)-2,2-dimethyl-6-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxole-4-carbaldehyde (P-5)

EDCHCI (3110 mg, 16.2 mmol) was added to a solution of P-4 (1230 mg, 4.055 mmol) in anhydrous dimethyl sulfoxide (22.5 mL, c=0.18 M). Pyridine (641 mg, 8.11 mmol) was added followed by TFA (462 mg, 4.05 mmol), stirred at r.t. for 1.5 h. The reaction mixture was diluted with H₂O, extracted with EtOAc twice, the combined organic was washed with H₂O 3 times, brine, dried over Na₂SO₄, filtered and concentrated to give P-5 (950 mg) as a brown oil (78% yield).

LCMS [M+1] 302.15. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.28 (s, 3 H) 1.53 (s, 3 H) 2.47 - 2.57 (m, 1 H) 2.58 - 2.69 (m, 1 H) 2.85 (s, 3 H) 3.13 (td, J=8.68, 4.28 Hz, 1 H) 4.94 (dd, J=6.60, 4.16 Hz, 1 H) 5.04 (td, J=8.04, 4.34 Hz, 1 H) 5.14 (dd, J=6.42, 4.22 Hz, 1 H) 6.66 (d, J=3.42 Hz, 1 H) 7.26 (br. s., 1 H) 8.73 (s, 1 H) 9.80 (s, 1 H)

Step 6: Synthesis of 5-chloro-2-(((3aR,4R,6R,6aS)-2,2-dimethyl-6-(4-methyl-7Hpyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4yl)(hydroxy)methyl)benzonitrile (P-6)

To a solution of 5-chloro-2-iodobenzonitrile (1570 mg, 5.97 mmol) in dry THF (29.9 mL, c=0.2 M) at -78°C was added isopropylmagnesium chioride (1080 mg, 7.47 mmol, 5.74 mL, 1.3 M). The resulting solution was stirred at -78°C for 15 min, P-5 (900 mg, 2.99 mmol) in THF (5.0 mL) was added dropwise. The reaction mixture was transferred to an ice bath, allowed to warm up to r.t. and stirred overnight. The reaction was then quenched with std. NH₄CI, extracted with EtOAc 3 times; the organic layers were combined, washed with brine, dried over Na₂SO₄, concentrated and purified by column chromatography with 5% MeOH/DCM to give P-6 (700 mg) as a yellow oil. LCMS [M+1] 439.10.

-120Step 7: Synthesis of (2-(aminomethyl)-4-chlorophenyl)((3aR,4R,6R,6aS)-2,2-dimethyl-6-(4methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4yl)methanol (P-7)

To a solution of P-6 (200 mg, 0.456 mmol) in MeOH (5 mL, c=0.09 M) was added cobalt(ll) chloride hexahydrate (545 mg, 2.28 mmol), and NaBH₄ (181 mg, 4.56 mmol). The reaction mixture was stirred at r.t. for 0.5 h, then quenched with std. NH₄CI. The aqueous was saturated with solid NaCI and extracted with 20% isopropyl alcohol/DCM multiple times. The organic layers were concentrated and purified by préparative HPLC to give 50 mg of P-7 as a colorless 10 oil (13% two steps). LCMS [M+1] 443.10.

Step 8: Synthesis of (1S,2R,3R,5R)-3-((S)-(2-(aminomethyl)-4chlorophenyl)(hydroxy)methyl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-

1,2-diol (P-8) and (1S,2R,3R,5R)-3-((R)-(2-(aminomethyl)-4-chlorophenyl)(hydroxy)methyl)-

5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol (P-9)

Following a similar procedure as step 4 in Scheme K, P-7 was treated with TFA in water. P-8 (5.5 mg, 12% yield) and P-9 (0.2 mg, 0.4% yield) were isolated after subséquent workup and purification by chiral SFC. LCMS [M+1] 403.00.

Example 55 (Scheme Q) - (1S,2R,3S,5R)-3-(2-(aminomethyl)-4-chlorobenzyl)-5-(4-methyl7H-pyrrolo[2,3-d] pyrimidin-7-yl)cyclopentane-1,2-diol (Q-4)

Step 1: Synthesis of 7-((3aS,4R,6S,6aR)-6-(iodomethyl)-2,2-dimethyltetrahydro-4Hcyclopenta[d] [1,3]dioxol-4-yl)-4-methyl-7H-pyrrolo[2,3-d]pyrimidine (Q-1)

The solution of triphenylphosphine (529 mg, 1.98 mmol) and imidazole (135 mg, 1.98 mmol) in methylene chloride (8.24 mL, c=0.2 M) was added l₂ (502 mg, 1.98 mmol) followed by dropwise

-121 addition of P-4 (500 mg, 1.65 mmol) in 2 mL methylene chloride. The resulting reaction mixture was stirred at r.t. overnight, and then diluted with water (20 mL), extracted with methylene chloride (3 x 20 mL). The combined organic layers were dried over Na₂SO₄, concentrated and purified by column chromatography with 60% EtOAc/heptane to give 280 mg of Q-1 as a yellow 5 oil (25% yield).

LCMS [M+1] 414.00. Ή NMR (400 MHz, CHLOROFORM-d) δ ppm 1.33 (s, 3 H) 1.60 (s, 3 H) 2.26 - 2.37 (m, 1 H) 2.40 (dd, J=11.55, 5.93 Hz, 1 H) 2.59 (dt, J=12.29, 6.08 Hz, 1 H) 2.80 (s, 3 H) 3.41 (dd, J=10.03, 6.72 Hz, 1 H) 3.50 (dd, J=10.09, 4.83 Hz, 1 H) 4.56 (t, J=6.11 Hz, 1 H) 10 5.02 - 5.13 (m, 2 H) 6.64 (d, J=3.55 Hz, 1 H) 7.28 (d, J=3.55 Hz, 1 H) 8.79 (s, 1 H)

Step 2: Synthesis of 5-chloro-2-(((3aR,4S,6R,6aS)-2,2-dimethyl-6-(4-methyl-7Hpyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4yl)methyl)benzonitrile (Q-2)

To a suspension ofzinc (318 mg, 4.87 mmol) in dry degased DMF (8.11 mL, c=0.1 M) was added 1,2-dibromoethane (33 mg, 0.17 mmol , 15 uL) under nitrogen. The mixture was heated with a heat gun for about 30 sec until the gas started to evolve from the solution indicating the activation ofzinc. The mixture was allowed to cool to r.t. TMSCI (19 mg, 0.18 mmol , 23 uL) was added and the reaction was stirred at r.t. for 15 min foilowed by the addition of a solution of Q-1 (335 mg, 0.811 mmol) in dry degassed DMF (1 mL). The resulting mixture was heated at 60°C for 5 min, then stirred at r.t. for 30 min. After allowing the zinc solids to settle, the reaction mixture was filtered through a syringe filter into a mixture of 5-chloro-2-iodobenzonitrile (214 mg, 0.812 mmol), Pd₂(dba)₃ (37.2 mg, 0.0406 mmol) and tri-o-tolylphosphine (49.4 mg, 0.162 mmol) in 1 mL dry degassed DMF. The reaction mixture was flushed with nitrogen, and stirred at 80°C for 2 h. After cooling to r.t., the reaction mixture was partitioned between H₂O (30 mL) and EtOAc (30 mL). The organic phase was separated, washed with H₂O (3 x 30mL) and brine (1 x 30mL), dried over Na₂SO₄, concentrated and purified by column chromatography with 70% EtOAc/heptane to give 25 mg of Q-2 (7.3% yield).

LCMS [M+1] 423.10. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.29 (s, 3 H) 1.56 (s, 3 H) 2.21 - 2.38 (m, 2 H) 2.48 - 2.60 (m, 1 H) 2.78 (s, 3 H) 2.95 - 3.04 (m, 1 H) 3.24 (dd, J=14.18, 6.72 Hz, 1 H) 4.62 (t, J=6.72 Hz, 1 H) 4.92 - 5.01 (m, 1 H) 5.04 (dd, J=7.09, 5.38 Hz, 1 H) 6.61 (d, J=3.67 Hz, 1 H) 7.25 (d, J=3.67 Hz, 1 H) 7.36 (d, J=8.31 Hz, 1 H) 7.52 (dd, J=8.44, 2.20 Hz, 35 1 H) 7.60 (d, J=2.20 Hz, 1 H) 8.76 (s, 1 H)

- 122 Step 3: Synthesis of (5-chloro-2-(((3aR,4S,6R,6aS)-2,2-dimethyl-6-(4-methyl-7Hpyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro-4H-cycIopenta[d][1,3]dioxol-4yl)methyl)phenyl)methanamine (Q-3)

Following a similar procedure as step 7 in Scheme P, Q-2 was reduced to Q-3 as crude for the next step. LCMS [M+1] 427.10.

Step 4: Synthesis of (1S,2R,3S,5R)-3-(2-(aminomethyl)-4-chlorobenzyl)-5-(4-methyl-7Hpyrrolo[2,3-d] pyrimidin-7-yl)cyclopentane-1,2-diol (Q-4)

Following a similar procedure as step 4 in Scheme K, Q-3 was treated with TFA in water. Q-4 (9.5 mg, 35%) was isolated after subséquent workup and purification by chiral SFC.

Q-4: LCMS [M+1] 386.85. ¹H NMR (700 MHz, DMSO-d6) δ ppm 1.48 - 1.56 (m, 1 H) 1.97 - 2.04 (m, 1 H) 2.11 (br. s., 1 H) 2.53 - 2.60 (m, 5 H) 2.91 (dd, J=14.09, 5.72 Hz, 1 H) 3.68 - 3.78 (m, 2 H) 4.29 (t, J=6.23 Hz, 1 H) 4.84 (q, J=8.37 Hz, 1 H) 6.63 (d, J=3.42 Hz, 1 H) 7.09 - 7.17 (m, 2 H) 7.41 (br. s., 1 H) 7.62 (d, J=2.22 Hz, 1 H) 8.53 (s, 1 H)

Example 56 (Scheme R) - (1S,2R,3R,5R)-3-((S)-hydroxy(1,2,3,4-tetrahydroisoquinolin-8yl)methyl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol (R-7) Example 57 (Scheme R) - (1S,2R,3R,5R)-3-((R)-hydroxy(1,2,3,4-tetrahydroisoquinolin-8yl)methyl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol (R-8)

Scheme R

- 123 -

Nal, Cul

B(Oi-Pr)₃ n-BuLi

THF

R-1 R-2 R-3

R-6

Step 1: Synthesis of tert-butyl 8-iodo-3,4-dihydroisoquinoline-2(1H)-carboxylate (R-2)

A mixture of tert-butyl 8-bromo-3,4-dihydroisoquinoline-2(1 H)-carboxylate (R-1) (1100 mg, 3.52 mmol), Nal (4.76 g, 31.8 mmol), Cul (402 mg, 2.12 mmol) and trans-N,N-dimethylcyclohexane (602 mg, 4.22 mmol) in dioxane (20 mL) was purged with N₂ for 10 min. The resulting yellow suspension was stirred at 110 °C in a sealed tube for 48 hrs. The reaction was diluted with petroleum ether (50 mL) and filtered. The filtrate was concentrated in vacuo and residue was 10 purified by silica gel chromatography eluted with EtOAC in petroleum ether from 0 to 20 % to afford R-2 (1200 mg, 94.8 %) as a light yellow gum. LCMS [M+1-tBu] 304; ¹H NMR (400 MHz, CDCb) δ ppm 7.70 (d, J=7.8 Hz, 1H), 7.45 - 7.39 (m, 1H), 7.12 (d, J=7.5 Hz, 1H), 6.88 (s, 1H), 4.44 (br. s., 2H), 3.62 (t, J=5.5 Hz, 2H), 2.81 (d, J=4.8 Hz, 2H), 1.50 (s, 9H)

Step 2: Synthesis of (2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)boronic acid (R-3)

To a solution of R-2 (250 mg, 0.696 mmol) and triisopropyl borate (262 mg, 0.321 mmol) in dry THF (8 mL) was added 2.5 M n-BuLi (0.418 mL, 1.04 mmol) at -60 °C.the mixture was stirred at 20 -60 0 °C for 30 min. The mixture was poured into NH₄CI aq (15 mL) and extracted with EtOAc (10 mL x 3). The extract was dried over Na₂SO₄ and concentrated in vacuo to afford crude. The crude was purified by silica gel chromatography eluted with MeOH in DCM from 0 to 10 % to afford R-3 (180 mg, 93 %) as a light yellow gum which was used in the next step directly.

- 124Step 3: Synthesis of S-(p-tolyl) (3aR,4S,6R,6aS)-2,2-dimethyl-6-(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxole-4-carbothioate (R-4)

To compound A-7 (270 mg, 0.851 mmol) in THF was added 4-methylbenzenethiol (211 mg, 1.7 mmol), DIPEA (440 mg, 3.4 mmol) and T3P (1.08 g, 1.7 mmol) at rt (15 °C). The mixture was stirred at rt 5-10 °C for 2 days. The mixture was poured into NaHCOs aq (20 mL) and extracted with EtOAc (10 mL x 2). The extract was washed with brine (15 mL) and concentrated in vacuo, then purified by silca gel chromatography eluted with EtOAc in petroleum ether from 0 to 100 % to afford R-4 (320 mg, 89% ) as a white solid. LCMS [M+1] 424

Step 4: Synthesis of tert-butyl 8-((3aR,4S,6R,6aS)-2,2-dimethyl-6-(4-methyl-7Hpyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxole-4-carbonyl)-3,4dihydroisoquinoline-2(1 H)-carboxylate (R-5) ¹⁵

A mixture of R-4 (125 mg, 0.3 mmol) and R-3 (180 mg, 0.32 mmol), CuTC (90 mg, 0.47 mmol), Pd₂(dba)₃.CHCI₃ (31 mg, 0.03 mmol) and TFP (20.6 mg, 0.0886 mmol) in dry THF (5 mL) was degassed with N₂ four times. The mixture was stirred at 50 °C in a sealed tube for 16 hours.

The mixture was diluted with EtOAc (10 mL) and filtered. The filtrate was concentrated in vacuo 20 to dryness. The residue was purified by silica gel chromatography eluted with EtOAc in petroleum ether from 0 to 100 % to afford R-5 (70 mg, 40%) as a white solid. LCMS [M+1] 533

Step 5: Synthesis of tert-butyl 8-(((3aR,4R,6R,6aS)-2,2-dimethyl-6-(4-methyl-7Hpyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-425 yl)(hydroxy)methyl)-3,4-dihydroisoquinoline-2(1 H)-carboxylate (R-6)

To a solution of R-5 (70 mg, 0.131 mmol) in MeOH (2 mL) was added NaBH₄ (86.9 mg, 2.30 mmol) at rt 15 °C. The mixture was stirred at rt 15 °C for 30 min. The mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 3). The extract was washed with brine (10 mL)^ dried over Na₂SO₄ and concentrated in vacuo to afford crude R-6 (60 mg, 85%) as a light yellow solid.

Step 6: Synthesis of (1S,2R,3R,5R)-3-((S)-hydroxy(1,2,3,4-tetrahydroisoquinolin-8y|)methyl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol (R-7) and 35 (1 S,2R,3R,5R)-3-((R)-hydroxy(1,2,3,4-tetrahydroisoquinolin-8-yl)methyl)-5-(4-methyl-7Hpyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol (R-8)

-125To compound R-6 (60 mg, 0.1 mmol) was added TFA/H2O (1 mL/ 1 mL, cooled to 0 °C previously). The mixture was stirred at rt (15 °C) for 3 hrs. The mixture was concentrated in vacuo to afford crude which was purified by SFC. After SFC, the products were re-purified by 5 prep TLC to obtain R-7 (4.5 mg, 13%) and R-8 (3.5 mg, 9%) as white solids.

R-7: LCMS [M+1] 395; ¹H NMR (400 MHz, MeOD-d₄) δ ppm 8.63 (s, 1H), 7.59 (d, J=3.8 Hz, 1H), 7.42 (d, J=7.5 Hz, 1H), 7.21 (t, J=7.5 Hz, 1H), 7.06 (d, J=7.3 Hz, 1H), 6.73 (d, J=3.8 Hz, 1H), 5.09 - 5.01 (m, 1H), 4.81 (d, J=7.0 Hz, 1H), 4.64 (dd, J=5.3, 9.5 Hz, 1H), 4.31 (dd, J=2.0, 10 5.5 Hz, 1H), 4.29 - 4.16 (m, 2H), 3.21 - 3.06 (m, 2H), 2.92 (d, J=4.0 Hz, 2H), 2.72 (s, 3H), 2.56 2.47 (m, 1H), 2.22 (td, J=8.8, 13.1 Hz, 1H), 1.83 (ddd, J=8.3, 10.7, 13.1 Hz, 1H)

R-8: LCMS [M+1] 395; Ή NMR (400 MHz, MeOD-d₄) δ ppm 8.63 (s, 1H), 7.72 (d, J=3.8 Hz, 1H), 7.42 (d, J=8.0 Hz, 1H), 7.23 - 7.17 (m, 1H), 7.07 (d, J=7.5 Hz, 1H), 6.77 (d, J=3.8 Hz, 1H),

5.12 - 5.04 (m, 2H), 4.48 - 4.42 (m, 1H), 4.30 - 4.15 (m, 2H), 4.14 - 4.10 (m, 1H), 3.24 - 3.18 (m,

2H), 3.00 - 2.94 (m, 2H), 2.74 (s, 3H), 2.45 - 2.36 (m, 1H), 2.20-2.14 (m, 1H) 2.09 - 1.99 (m, 1H)

Example 58 (Scheme S) - (1S,2R,3S,5R)-3-(4-fluorobenzyl)-5-(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)cyclopentane-1,2-diol (S-1 )

Scheme S

a) TFA, Et₃SiH 50 °C

b) LiOH,.H₂O, MeOH r.t

F

Example 10 S-1

A mixture of (1S,2R,3R,5R)-3-((R)-(4-fluorophenyl)(hydroxy)methyl)-5-(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)cyclopentane-1,2-diol (Example 10) (30 mg, 0.084 mmol), trifluoroacetic acid 25 (302 ul) and triethylsilane (268 ul, 1.68 mmol) was heated to 50 °C for 2 hours. The reaction mixture was concentrate to an oii then lithiumhydroxide monohydrate (20 mg, 0.48 mmol) and methanol (1 ml) were added and stirred at r.t. for 45 min. The reaction mixture was concentrated to remove methanol then partitioned between water and EtOAc. The EtOAc layer was washed with brine, dried with Na₂SO₄, filtered and concentrated to give S-1 as an oil in 52% yield.

LCMS-APCI(+): MH+=342, ¹H NMR (700MHz, DMSO-d6) δ ppm 8.58 (s, 1H), 7.64 (d, J=3.5 Hz, 1H), 7.25 (dd, J=5.9, 8.1 Hz, 2H), 7.08 (t, J=8.8 Hz, 2H), 6.68 (d, J=3.5 Hz, 1H), 4.98 - 4.84 (m, 2H), 4.77 (d, J=4.4 Hz, 1H), 4.44 - 4.23 (m, 1H), 3.82 - 3.75 (m, 1H), 2.92 (dd, J=6.6, 13.6

- 126Hz, 1H), 2.68 - 2.57 (m, 4H), 2.26 - 2.12 (m, 1H), 2.06 (td, J=8.3, 13.0 Hz, 1H), 1.60 - 1.41 (m, 1H)

Example 59 (Scheme T) - (+/-)-(1 S,2S,3S,5R)-3-methoxy-5-(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)cyclopentane-1,2-diol (T-5)

Example 60 (Scheme T) - (1S,2S,3S,5R)-3-methoxy-5-(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)cyclopentane-1,2-diol (T-6)

Example 61 (Scheme T) - (1R,2R,3R,5S)-3-methoxy-5-(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)cyclopentane-1,2-diol (T-7)

Scheme T

EtOH, TEA 80 °C

S-Phos pre catalyst, 1M Na₂CO3 dioxane 80 °C

Step 1 : (+/-)-(3aR,4S,6R,6aS)-6-((5-bromo-6-methylpyrimidin-4-yl)amino)-2,2dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-ol. (T-2)

A mixture of (+/-)-(3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-4Hcyclopenta[d][1,3]dioxol-4-ol (T-1) (786 mg, 4.54 mmol), 5-bromo-4-chloro-6-methylpyrimidine (1.04 g, 4.99 mmol) and trimethylamine (0.822 ml, 5.9 mmol) in éthanol (9.0 ml, 0.5 M) was heated to 80°C for 20 hours. The crude reaction mixture was concentrated to a solid then purified by silica gel chromatography with a gradient of 0% to 100% EtOAc in heptane to give T2 as white solid, 1.35 g (87% yield).

LCMS-ESI(+): MH+=344/346, Ή NMR (400MHz, METHANOL-d4) δ ppm 8.29 (s, 1H), 4.60 (d, J=6.4 Hz, 1H), 4.56 - 4.52 (m, 1H), 4.51 - 4.47 (m, 1H), 4.22 (d, J=3.9 Hz, 1H), 2.33 - 2.23 (m, 1H), 1.76 (d, J=14.2 Hz, 1H), 1.41 (s, 3H), 1.27 (s, 3H).

- 127 Step 2: Synthesis of (+/-)-(3aR,4S,6R,6aS)-6-((5-((E)-2-ethoxyvinyl)-6-methylpyrimidin-4yl)amino)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-ol. (T-3)

To a solution of T-2 (2.06 g, 5.98 mmol) and (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2dioxaborolane (1.19 g, 5.98 mmol) in dioxane (19.9 ml, 0.3 M) was vacuum flushed with nitrogen then 2N sodium carbonate (aq) (8.98 ml) was added followed by S-Phos pre-catalyst (136 mg, 0.180 mmol). The resulting mixture was heated to 80 °C for 23 hours. The reaction mixture was cooled to r.t. then diluted with EtOAc and water. The organic layer was washed with brine, dried with Na₂SO₄, filtered and concentrated to an oil then purified by silica gel chromatography eluting with a gradient of 0% to 100% EtOAc in heptane to give T-3 as a white solid, 1.21 g (60% yield).

LCMS-ESI(+): MH+=336, ¹H NMR (400MHz, DMSO-d6) δ ppm 8.23 (s, 1H), 6.66 (d, J=13.2 Hz, 1 H), 6.38 (d, J=8.6 Hz, 1 H), 5.63 (d, J=2.4 Hz, 1 H), 5.32 (d, J=13.2 Hz, 1 H), 4.50 - 4.33 (m, 3H), 4.07 (br. s., 1H), 3.87 (q, >6.9 Hz, 2H), 2.24 (s, 3H), 2.12 (td, >5.2, 13.6 Hz, 1H), 1.62 (d, >13.9 Hz, 1H), 1.34 (s, 3H), 1.25 (t, J=7.Q Hz, 3H), 1.18 (s, 3H)

Step 3: Synthesis of (+/-)-7-((3aS,4R,6S,6aR)-6-methoxy-2,2-dimethyltetrahydro-4Hcyclopenta[d][1,3]dioxol-4-yl)-4-methyl-7H-pyrrolo[2,3-d]pyrimidine. (T-4)

A mixture of (+/-)-(3aR,4S,6R,6aS)-6-((5-((E)-2-ethoxyvinyl)-6-methylpyrimidin-4-yl)amino)-2,2dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-ol (111 mg, 0.331 mmol) and trifluoroacetic acid (127 ul, 1.65 mmol) in acetone (3.31 ml, 0.1 M) was heated to 60 °C for 43 hours. The reaction mixture was concentrated to an oil then azeotroped with toluene. The crude oil was dissolved in acetone (3.31 ml) then DMP (81 ul, 0.662 mmol) and PTSA (3.1 mg, 0.016 mmol) was added. The mixture was stirred at r.t. for 48 hours. The reaction mixture was concentrated to an oil then re-dissolved in EtOAc. The EtOAc layer was washed with saturated NaHCO₃(aq), brine, dried with Na₂SO₄, filtered and concentrated to an oil. The crude mixture was purified by silica gel chromatography eluting a gradient of 0% to 100% EtOAc in heptane to give (3aR,4S,6R,6aS)-2,2-dimethyl-6-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro-4Hcyclopenta[d][1,3]dioxol-4-ol as a white solid, 76 mg (79% yield, 80% pure).

To a suspension of (3aR,4S,6R,6aS)-2,2-dimethyl-6-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-ol (76 mg, 80% pure) in 2-methyl-tetrahydrofuran (1ml) at r.t. was added 60% sodium hydride (26 mg). After 15 minutes methyl iodide (200 ul) was added. After 1 hour more methyl iodide (200 ul) was added and the mixture was stirred at r.t. for 3 more hours. The reaction mixture was quenched with saturated ammonium chloride ' -128(aq) then extracted with EtOAc. The EtOAc layer was washed with brine, dried with Na₂SO₄, filtered and concentrated to an oil. The crude oil was purified by silica gel chromatography eluting with a gradient of 0% to 100% EtOAc in heptane to give (+/-)-7-((3aS,4R,6S,6aR)-6methoxy-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-4-methyl-7H-pyrrolo[2,35 d]pyrimidine as a colorless oil, 39 mg (39% yield).

LCMS-ESI(+): MH+=304, Ή NMR (400MHz, CHLOROFORM-d) δ ppm 8.77 (s, 1H), 7.43 (d, >3.7 Hz, 1H), 6.53 (d, >3.7 Hz, 1H), 5.30 (ddd, >2.6, 5.3, 7.8 Hz, 1H), 4.84 (dd, >2.1,6.2 Hz, 1 H), 4.71 (d, >6.4 Hz, 1 H), 3.94 (t, >4.2 Hz, 1 H), 3.41 (s, 3H), 2.80 - 2.65 (m, 4H), 2.24 (td, >4.6, 14.5 Hz, 1 H), 1.54 (s, 3H), 1.30 (s, 3H).

Step 4: Synthesis of (+/-)-(1 S,2S,3S,5R)-3-methoxy-5-(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)cyclopentane-1,2-diol (T-5), (1 S^S^S.SRJ-S-methoxy-S^-methyl-THpyrrolo^^-dJpynmidin-T-ylJcyclopentane-l ,2-diol (T-6) and (1R,2R,3R,5S)-3-methoxy-5(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol (T-7).

A mixture of T-4 (39 mg, 0.13 mmol) and 50% aqueous TFA (800 ul) was heated to 60 °C for 2 hours. The reaction mixture was concentrated to an oil then purified by SFC (3HOP column) to give (+/-)-(1 S, 2S,3S, 5R)-3-methoxy-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-

1,2-diol (T-5) as a white solid, 25 mg (75% yield).

T-5: LCMS-APCI(+): MH+=264, Ή NMR (400MHz, CHLOROFORM-d) δ ppm 8.61 (s, 1H), 7.31 20 (d, >3.7 Hz, 1H), 6.59 (d, >3.4 Hz, 1H), 4.95 (q, >8.6 Hz, 1H), 4.54 - 4.39 (m, 1H), 4.23 (d, >4.9 Hz, 1H), 3.87 (t, >5.4 Hz, 1H), 3.47 (s, 3H), 2.98 - 2.81 (m, 1H), 2.71 (s, 3H), 2.09 (ddd, >5.1, 9.0, 13.8 Hz, 1H).

T-5 was resolved by chiral SFC (Lux Cellulose-4 4.6 x 100 mm 3u column, 30% MeOH/DEA @ 120 bar, 4 mL/min) to give (1S,2S,3S,5R)-3-methoxy-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-725 yl)cyclopentane-1,2-diol (T-6) as a white solid, 6 mg (19% yield).

T-6: LCMS-APCI(+): MH+=264, ¹H NMR (700MHz, DMSO-d6) δ ppm 8.61 (s, 1H), 7.60 (d, >3.5 Hz, 1H), 6.70 (d, >3.5 Hz, 1H), 5.11 - 4.83 (m, 3H), 4.40 - 4.26 (m, 1H), 3.91 (br. s., 1H), 3.61 (t, >4.8 Hz, 1H), 3.31 (s, 3H), 2.63 (s, 3H), 2.56 (td, >8.0, 14.0 Hz, 1H), 1.77 (ddd, >4.8, 9.1, 13.8 Hz, 1H) and (1 R,2R,3R,5S)-3-methoxy-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol (T-7) as a white solid, 6 mg (19% yield).

- 129T-7: LCMS-APCI(+): ΜΗ+=264, 1Η NMR (700MHz, DMSO-d6) δ ppm 8.61 (s, 1H), 7.60 (d, J=3.5 Hz, 1H), 6.70 (d, J=3.5 Hz, 1H), 5.07 -4.92 (m, 3H), 4.38 - 4.25 (m, 1H), 3.91 (br. s., 1H), 3.66-3.52 (m, 1H), 3.31 (s, 3H), 2.63 (s, 3H), 2.56 (td, J=8.1, 13.8 Hz, 1H), 1.76 (ddd, J=4.6, 8.9, 13.8 Hz, 1H)

Example 62: (Scheme U) - (1S,2S,3S,5R)-3-(2-(aminomethyl)phenoxy)-5-(4-methyl-7Hpyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol (U-6)

Example 63: (Scheme U) - (1R,2R,3R,5S)-3-(2-(aminomethyl)phenoxy)-5-(4-methyl-7Hpyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol (U-7)

Scheme U

TFA

DCM r.t.

Step 1: Synthesis of 2-(((3aR,4S,6R,6aS)-6-((5-((E)-2-ethoxyvinyl)-6-methylpyrimidin-4y|)amino)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)benzonitrile. (U-1 )

To a mixture of T-3 (181 mg, 0.54 mmol) and 2-fluorobenzonitrile (57.4 ul, 65.4 mg, 0.54 mmol) in THF (1.8 ml, 0.3 M) at r.t. was added 60% sodium hydride (45.3 mg, 1.13 mmol). After stirring for 5 minutes the reaction mixture was heated to 70°C for 6 hours. The reaction mixture was cooled to r.t. then quenched with saturated NH4CI(aq), diluted with water and extracted with EtOAc. The EtOAc layer was washed with brine, dried with MgSO4, filtered then concentrated to an oil. The crude oil was purified by silica gel chromatography eluting with 0-100% EtOAcHeptane to give U-1 as an amber oil, 210 mg (89% yield).

LCMS-ESI(+): MH+=437, Ή NMR (400MHz, CHLOROFORM-d) δ ppm 8.48 (s, 1H), 7.68 - 7.49 (m, 2H), 7.19 - 6.98 (m, 2H), 6.47 (d, J=13.2 Hz, 1H), 5.45 (d, J=7.6 Hz, 1H), 5.41 (d, J=13.2 ^w -130Hz, 1H), 4.82 - 4.69 (m, 4H), 3.86 (q, J=6.8 Hz, 2H), 2.70 (td, J=6.1, 15.0 Hz, 1H), 2.35 (s, 3H), 2.13 (d, J=15.2 Hz, 1H), 1.51 (s, 3H), 1.32 (s, 3H), 1.26 (t, J=7.0 Hz, 4H).

Step 2: 2-(((3aR,4S,6R,6aS)-2,2-dimethyl-6-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)benzonitrîle. (U-2)

A solution of U-1 (210 mg, 0.481 mmol in acetic acid (4.81 ml, 0.1 M) was heated to 110 °C for 19 hours. The reaction mixture was concentrated to an oil then purified by silica gel chromatography eluting with 0-100% EtOAc-Heptane to give U-2 as a dark amber glass, 166 mg (88% yield).

LCMS-ESI(+): MH+=391, ¹H NMR (400MHz, CHLOROFORM-d) δ ppm 8.79 (s, 1H), 7.69 (d, 10 J=3.4 Hz, 1H), 7.65 - 7.51 (m, 2H), 7.13 (d, J=8.6 Hz, 1H), 7.07 (t, J=7.6 Hz, 1H), 6.66 (d, J=3.7

Hz, 1H), 5.48 (dd, J=3.2, 6.8 Hz, 1H), 5.01 (d, J=4.6 Hz, 1H), 4.95 (dd, J=2.7, 6.1 Hz, 1H), 4.86 (d, J=5.9 Hz, 1H), 3.06 (td, J=7.6, 14.7 Hz, 1H), 2.74 (s, 3H), 2.57 (d, J=14.9 Hz, 1H), 1.62 (s, 4H), 1.34 (s, 4H).

Step 3: Synthesis of (2-(((3aR,4S,6R,6aS)-2,2-dimethyl-6-(4-methyI-7H-pyrrolo[2,315 d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)phenyl)methanamine (U3)

A mixture of U-2 (139 mg, 0.356 mmol) in éthanol (7.12 ml, 0.05 M) was added 28% NH₄OH (3 ml) and Raney Nickel (70 mg, 1.2 mmol). The mixture was hydrogenated at 50 psi in a stainless steel bomb for 24 hours. The reaction mixture was filtered through celite then the filtrate was 20 concentrated to an oil and purified by silica gel chromatography eluting with 0-100% MeOH in EtOAc to give U-3 as a colorless oil, 81 mg (58% yield).

LCMS-APCI(+): MH+=395, Ή NMR (400MHz, METHANOL-d4) δ ppm 8.64 (s, 1H), 7.62 (d, J=3.7 Hz, 1H), 7.34 - 7.23 (m, 2H), 7.12 (d, J=8.6 Hz, 1H), 6.96 (t, J=7.5 Hz, 1H), 6.75 (d, J=3.7 Hz, 1H), 5.28 (dt, J=3.5, 7.0 Hz, 1H), 5.19 (dd, J=3.4, 6.4 Hz, 1H), 4.94 (d, J=6.4 Hz, 1H), 4.87 25 (t, J=5.9 Hz, 1H), 3.72 (br. s., 2H), 2.95 (td, J=7.0, 14.1 Hz, 1H), 2.73 (s, 3H), 2.65 - 2.54 (m,

1H), 1.60 (s, 3H), 1.35 (s, 3H).

Step 4: Synthesis of tert-butyl (2-(((1 S,2S,3S,4R)-2,3-dihydroxy-4-(4-methyl-7Hpyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl)oxy)benzyl)carbamate (U-4) and tert-butyl (2(((1R,2R,3R,4S)-2,3-dihydroxy-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-730 yl)cyclopentyl)oxy)benzyl)carbamate (U-5)

- 131 A solution of the U-3 (81 mg, 0.21 mmol) in 50% TFA (aq) (600 ul) was stirred at r.t for 16 hours. The reaction mixture was then concentrated to an oil. A mixture of the crude oil and Boc₂O (30.8 mg, 1.41 mmol) in DCM 30.8 mg, 0.141 mmol) was stirred at r.t.for 6 hours. The reaction mixture was concentrated then purified by silica gel chromatography eluting with 40 to 100% EtOAc in heptane then 0-20% MeOH in EtOAc to give racemic mixture of U-4 and U-5 as a colorless oil, 73 mg. The enantiomers were separated by chiral SFC (Chiralpak IC-3 4.6 x 100 mm 3u column, 30% MeOH @ 120 bar, 4 mL/min) to give U-4 (25.4 mg, 40% yield) and U-5 (24.4 mg, 38% yield) as white solids.

U-4: LCMS-ESI(+): MH+=455, Ή NMR (400MHz, METHANOL-d4) δ ppm 8.52 (s, 1H), 7.51 (br. s., 1H), 7.23 - 7.09 (m, 2H), 6.92 (d, J=8.1 Hz, 1H), 6.84 (t, J=7.5 Hz, 1H), 6.64 (d, J=3.7 Hz, 1H), 5.15 (q, J=8.6 Hz, 1H), 4.67 -4.58 (m, 2H), 4.34-4.15 (m, 2H),4.11 (d, J=4.4 Hz, 1H), 2.90 (ddd, J=7.3, 9.4, 14.5 Hz, 1H), 2.61 (s, 3H), 2.24 - 2.08 (m, 1H), 1.33 (s, 9H). [a]D22= +61.3° (c=0.1, MeOH).

U-5: LCMS-ESI(+): MH+=455, Ή NMR (400MHz, METHANOL-d4) δ ppm 8.62 (s, 1H), 7.61 (br. s., 1H), 7.33 - 7.17 (m, 2H), 7.02 (d, J=8.1 Hz, 1H), 6.94 (t, J=7.3 Hz, 1H), 6.74 (d, J=3.7 Hz, 1H), 5.25 (q, J=9.0 Hz, 1H), 4.74 (d, J=7.1 Hz, 2H), 4.43 - 4.25 (m, 2H), 4.21 (d, J=4.4 Hz, 1H), 3.00 (ddd, J=7.3, 9.5, 14.7 Hz, 1H), 2.71 (s, 3H), 2.38 - 2.12 (m, 1H), 1.43 (s, 9H). [a]D22= 86.1° (c=0.1, MeOH)

Step 5: Synthesis of (1S,2S,3S,5R)-3-(2-(aminomethyl)phenoxy)-5-(4-methyl-7Hpyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol (U-6)

A mixture of U-4 (24 mg, 0.053 mmol) and trifluoroacetic acid (120 mg, 1.06 mmol) in DCM (0.176 ml, 0.3 M) was stirred at r.t. for 3 hours then concentrated to an oil and purified by SFC (ZymorSpher Pyridine Diol 150 x 21.2mm column with 20-40% MeOH @ 5%/min, 100 bar, 60 mL/min.) to give U-β as a white solid, 6.54 mg (35% yield).

LCMS-APCI(+): MH+=355, 1H NMR (700MHz, DMSO-d6) δ ppm 8.62 (s, 1H), 7.66 (d, J=2.2 Hz, 1H), 7.37 (d, J=7.0 Hz, 1H), 7.28 (t, J=7.5 Hz, 1H), 7.07 (d, J=7.9 Hz, 1H), 6.96 (t, J=7.0 Hz, 1H), 6.72 (d, J=2.6 Hz, 1H), 5.12 (q, J=8.8 Hz, 1H), 4.61 (d, J=3.1 Hz, 1H), 4.06 (br. s., 1H), 2.94 - 2.75 (m, 1H), 2.64 (s, 3H), 2.03 (t, J=9.7 Hz, 1H)

Step 6: Synthesis of (1R,2R,3R,5S)-3-(2-(aminomethyl)phenoxy)-5-(4-methyl-7Hpyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol (U-7)

- 132 U-7 was prepared in a similar manner to U-6 staring from U-5 to give a white sohd, 9 mg (50% yield).

LCMS-APCI(+): MH+=355, 1H NMR (700MHz, DMSO-d6) δ ppm 8.63 (s, 1H), 7.66 (d, J=3.5

Hz, 1H), 7.39 (d, J=7.5 Hz, 1H), 7.36 (t, J=7.7 Hz, 1H), 7.13 (d, J=8.4 Hz, 1H), 7.00 (t, J=7.5 Hz, 1H), 6.72 (d, J=3.5 Hz, 1H), 5.19 - 5.04 (m, 2H), 4.63 (d, J=4.4 Hz, 2H), 4.08 (d, J=4.4 Hz, 1H), 4.06 (s, 2H), 2.87 (td, J=8.3, 14.2 Hz, 1H), 2.64 (s, 3H), 2.06 (ddd, J=4.0, 9.5, 13.9 Hz, 1H)

Example 64 (Scheme V) - 2-(((1S,2S,3S,4R)-2,3-dihydroxy-4-(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)cyclopentyl)oxy)benzonitrile (V-1 )

Example 65 (Scheme V) - 2-(((1R,2R,3R,4S)-2,3-dihydroxy-4-(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)cyclopentyl)oxy)benzonitrile (V-2)

Scheme V

1N HCI(aq), dioxane r.t. TFA, 60 °C

Step 1: Synthesis of 2-(((1S,2S,3S,4R)-2,3-dihydroxy-4-(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)cyclopentyl)oxy)benzonitrile (V-1) and 2-(((1 R,2R,3R,4S)-2,3-dihydroxy-4(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl)oxy)benzonitrile (V-2)

V-1 (9.5 mg, 47% yield) and V-2 (9.4 mg, 47% yield) were prepared from U-2 in a similar manner to step 5 in Scheme U.

V-1: LCMS-ESI(+): MH+=351, Ή NMR (400MHz, METHANOL-d4) δ ppm 8.68 (br. s., 1H), 7.75 (d, J=3.7 Hz, 1H), 7.71 - 7.60 (m, 2H), 7.30 (d, J=8.6 Hz, 1H), 7.12 (t, J=7.6 Hz, 1H), 6.82 (d, J=3.7 Hz, 1H), 5.36 (q, J=8.5 Hz, 1H), 4.89 (d, J=6.1 Hz, 1H), 4.71 (dd, J=4.6, 8.3 Hz, 1H), 4.23 (d, J=4.2 Hz, 1H), 3.16-3.01 (m, 1H), 2.75 (s, 3H), 2.18 (ddd, J=2.4, 7.6, 14.7 Hz, 1H).

V-2: LCMS-ESI(+): MH+=351, Ή NMR (400MHz, METHANOL-d4) δ ppm 8.73 (br. s., 1H), 7.79 (d, J=3.7 Hz, 1H), 7.72 - 7.61 (m, 1H), 7.31 (d, J=8.6 Hz, 1H), 7.12 (t, J=7.6 Hz, 1H), 6.87(d,

J=3.7 Hz, 1H), 5.43 - 5.31 (m, 1H), 4.90 (d, J=5.9 Hz, 1H), 4.72 (dd, J=4.6, 8.6 Hz, 1H), 4.23(d,

J=4.4 Hz, 1H), 3.16 - 3.01 (m, 1H), 2.77 (s, 2H), 2.19 (ddd, J=2.3, 7.6, 14.8 Hz,1H)

-133Example 66 (Scheme W) - (1S,2S,3S,5R)-3-(2-(aminomethyl)-4-fluorophenoxy)-5-(4methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol (W-5)

Example 67 (Scheme W) - (1R,2R,3R,5S)-3-(2-(aminomethyl)-4-fluorophenoxy)-5-(4methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol. (W-6)

Scheme W

NaH, THF 70^eC

a) Ra-Ni, H₂ (50 psi) NH_dOH, EtOH r.t.

b) a) Boc₂0, DCM r.t. b) chiral SFC

Step 1: Synthesis of (3aR,4S,6R,6aS)-2,2-dimethyl-6-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-ol (W-1 )

A mixture of T-3 (111 mg, 0.331 mmol) and trifluoroacetic acid (127 ul, 1.65 mmol) in acetone (3.31 ml, 0.1 M) was heated to 60 °C for 43 hours. The reaction mixture was concentrated to an oil then dissolved in EtOAc. The EtOAc layer was washed with saturated NaHCO₃(aq), brine, dried with Na₂SO₄, filtered and concentrated to an oil. The crude mixture was purified by silica gel chromatography eluting a gradient of 0% to 100% EtOAc in heptane to give W-1 as a white solid, 76 mg (79% yieid, 80% pure).

Step 1: Synthesis of 2-(((3aR,4S,6R,6aS)-2,2-dimethyl-6-(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)-5-fluorobenzonitrile (W2)

To a mixture ofW-1 (67.1 mg, 0.2 mmol) and 2,5-difluorobenzonitrile (55.0 mg, 0.395 mmol , 55.0 uL) in THF (1.01 mL, c=0.3 M) at r.t. was added 60% sodium hydride (24.3 mg, 0.608 mmol). After stirring for 3 minutes the reaction mixture was heated to 70 °C for 6 hours then quenched with saturated NH₄CI(aq) then diluted wth EtOAc and water. The EtOAc layer was washed with brine, dried with Na₂SO₄ filtered then concentrated to an oil. The oil was purified by silica gel chromatography eluting with 0-100% EtOAc in heptane to give W-2 as a white foam, 101 mg (81% yieid).

- 134LCMS-ESI(+): MH+=409, 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.34 (s, 3 H) 1.61 (s, 3 H) 2.59 (d, >15.41 Hz, 1 H) 2.78 (s, 3 H) 3.05 (dt, >15.16, 7.34 Hz, 1 H) 4.84 (d, >6.36 Hz, 1 H) 4.86 - 4.92 (m, 1 H) 5.04 (d, >4.40 Hz, 1 H) 5.35 - 5.53 (m, 1 H) 6.68 (d, >3.18 Hz, 1 H) 7.11 (dd, >9.78, 3.67 Hz, 1 H) 7.32 (d, >7.58 Hz, 2 H) 7.66 (br. s., 1 H) 8.80 (s, 1 H).

Step 2: Synthesis of tert-butyl (2-(((1 S,2S,3S,4R)-2,3-dihydroxy-4-(4-methyl-7Hpyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl)oxy)-5-fluorobenzyl)carbamate (W-3) and tertbutyl (2-(((1 R,2R,3R,4S)-2,3-dihydroxy-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7yl)cyclopentyl)oxy)-5-fluorobenzyl)carbamate (W-4)

To a mixture ofW-2 (101 mg, 0.247 mmol) in éthanol (7.0 mL) was added 28% ammonium hydroxide (3.0 mL) and Raney Nickel (70 mg, 1.2 mmol).The mixture was hydrogenated at 50 psi in a stainless steel bomb for 24 hours. The reaction mixture was filtered through celite then concentrated to a foam.

To this crude amine was added boc anhydride (54 mg, 0.247 mmol) in DCM (3 ml, 0.3 M) and stirred at r.t. for 2 hours. This was concentrated to a foam and purified by silica gel chromatography to give a racemic mixture of W-3 and W-4 as a colorless oil, 104 mg 982% yield). The enantiomers were separated by chiral SFC (Chiralpak AS-3 4.6 x 100 mm 3u column, 8% MeOH + 10mM NH3 @ 120 bar, 4 mL/min) to give W-3 (34.2 mg, 27% yield) and W-4 (35.9 mg, 28% yield) as white solids.

W-3: LCMS-ESI(+): MH+=513, Ή NMR (400MHz, CHLOROFORM-d) δ ppm 8.86 - 8.76 (m, 1H), 7.45 (br. s., 1H), 7.02 (d, >8.6 Hz, 1H), 6.95 (d, J=5.1 Hz, 2H), 6.67 (d, >3.2 Hz, 1H), 5.35 (br. s., 1H), 5.07 (d, >3.7 Hz, 1H), 4.89 - 4.71 (m, 3H), 4.21 (br. s., 1H), 2.98 (td, >7.2, 14.7 Hz, 1H), 2.81 (s, 3H), 2.54 (d, J=15.2 Hz, 1H), 1.61 (s, 3H), 1.50 - 1.38 (m, 10H), 1.34 (s, 3H), [a]D22= +28.2° (c=0.1,MeOH)

W-4: LCMS-ESI(+): MH+=513 -80% pure.

Step 3: Synthesis of (1S,2S,3S,5R)-3-(2-(aminomethyl)-4-fluorophenoxy)-5-(4-methyl-7Hpyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol. (W-5)

A mixture of W-3 (34 mg, 0.066 mmol) in a mixture of 50% TFA(aq) (0.4 ml) was stirred at r.t. for 3 hours then concentrated and purified by SFC (ZymorSpher Pyridine Diol 150 x 21.2mm column with 20-40% MeOH @ 5%/min, 100 bar, 60 mL/min.) to give W-5 as a white solid, 16.5 mg (67% yield).

- 135 LCMS-ESI(+): MH+=373, ¹H NMR (400MHz, DMSO-d6) δ ppm 8.63 (s, 1H), 7.65 (d, J=3.7 Hz, 1H), 7.28 (dd, J=2.6, 9.2 Hz, 1H), 7.21 - 7.03 (m, 2H), 6.72 (d, J=3.4 Hz, 1H), 5.19 - 4.98 (m, 2H), 4.69 - 4.48 (m, 2H), 4.06 (d, J=4.6 Hz, 1H), 4.00 (s, 2H), 2.95 - 2.76 (m, 1H), 2.64 (s, 3H), 2.04 (ddd, J=4.0, 9.5, 13.8 Hz, 1H)

Step 4: Synthesis of (1R,2R,3R,5S)-3-(2-(aminomethyl)-4-fluorophenoxy)-5-(4-methyl-7Hpyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol. (W-6)

W-6 was prepared from W-4 in a similar manner to step 3 in Scheme W to give a white solid, 17.2 mg (70% yield).

LCMS-ESI(+): MH+=373, Ή NMR (400MHz, DMSO-d6) δ ppm 8.63 (s, 1H), 7.65 (d, J=3.7 Hz, 1H), 7.28 (dd, J=2.Q, 9.2 Hz, 1H), 7.21 - 7.07 (m, 2H), 6.72 (d, J=3.4 Hz, 1H), 5.18 - 5.02 (m, 2H), 4.69 - 4.54 (m, 2H), 4.06 (d, J=4.6 Hz, 1H), 4.01 (s, 2H), 2.94 - 2.74 (m, 1H), 2.64 (s, 3H), 2.04 (ddd, J=4.2, 9.5, 13.7 Hz, 1H).

Example 68 (Scheme X) - 2-(((1S,2S,3S,4R)-2,3-dihydroxy-4-(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)cyclopentyl)oxy)-5-fluorobenzonitrile (X-2)

Example 69 (Scheme X) - 2-(((1R,2R,3R,4S)-2,3-dihydroxy-4-(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)cyclopentyl)oxy)-5-fluorobenzonitrile (X-3)

Scheme X

F

Step 1: Synthesis of 2-(((3aR,4S,6R,6aS)-6-((5-((Z)-2-ethoxyvinyl)-6-methylpyrimidin-4yl)amino)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)-525 fluorobenzonitrile. (X-1)

A mixture of T-3 (67.1 mg, 0.2 mmol) and O-fluorobenzonitrile (25.5 ul, 0.240 mmol) in THF (0.67 ml, 0.3 M) at r.t. was added 60% sodium hydride (16.8 mg, 0.42 mmol). The mixture was then heated to 70°C in a microwave reactor for 30 minutes. The reaction mixture was quenched with saturated NH₄CI(aq) then diluted with water and extracted with EtOAc. The EtOAc was washed with brine, dried with Na₂SO₄, filtered and concentrated to an oii then purified by silica gel chromatography eluting with 0-100% EtOAc/Heptane to give X-1 as an amber oil, 58 mg (64% yield).

^w -136LCMS-ESI(+): MH+=455, ¹H NMR (400MHz, CHLOROFORM-d) δ ppm 8.47 (s, 1H), 7.35 - 7.28 (m, 2H), 7.16 - 7.06 (m, 1H), 6.47 (d, J=13.2 Hz, 1H), 5.43 (d, J=7.3 Hz, 1H), 5.39 (d, J=13.2 Hz, 1H), 4.81 - 4.65 (m, 4H), 3.87 (q, J=7.0 Hz, 2H), 2.69 (td, 0=6.1, 14.9 Hz, 1H), 2.34 (s, 3H), 2.11 (d, J=14.9 Hz, 1H), 1.50 (s, 3H), 1.31 (s, 2H), 1.27 (t, J=7.0 Hz, 3H).

Step 2: Synthesis of 2-(((1S,2S,3S,4R)-2,3-dihydroxy-4-(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yi)cyclopentyl)oxy)-5-fluorobenzonitrile (X-2) and 2-(((1R,2R,3R,4S)-2,3dihydroxy-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl)oxy)-5fluorobenzonitrile (X-3)

A mixture of the X-1 (58 mg, 0.13 mmol) and 1N HCI(aq) (255 ui, 0.255 mmol) in 1,4-dioxane 10 (0.382 ml, 0.15 M) was stirred at r.t.for 24 hours. Trifluoroacetic acid (200 ul) was added and the mixture was stirred at r.t for 48 hours then heated to 60 °C for 6 hours. The reaction mixture was concentrated to an oil then partitioned between EtOAc and and water. Saturated NaHCOs(aq) was added and the EtOAc layer was washed with brine, dried with Na₂SO₄, filtered then concentrated to a white solid, 44 mg. The enantiomers were separated by chiral SFC (Lux 15 Cellulose-2 4.6 x 100 mm 3u column, 30% MeOH @ 120 bar, 4 mL/min) to give X-2 (17 mg,

36% yield) and X-3 (16.2 mg, 35% yield) as white solids.

X-2: LCMS-ESI(+): MH+=369, Ή NMR (400MHz, DMSO-d6) δ ppm 8.64 (s, 1H), 7.79 (dd, J=3.1, 8.2 Hz, 1H), 7.70 (d, J=3.4 Hz, 1H), 7.65 - 7.51 (m, 2H), 7.40 (dd, J=4.2, 9.3 Hz, 1H), 6.76 (d, J=3.4 Hz, 1H), 5.41 (br. s., 1H), 5.15 (q, J=8.9 Hz, 1H), 4.77 (br. s., 1H), 4.53 (br. s., 20 1H), 4.05 (br. s., 1H), 2.97 - 2.75 (m, 1H), 2.65 (s, 3H), 2.11 - 1.93 (m, 1H), [a]D22= +47.3° (c=0.1, MeOH).

X-3: LCMS-ESI(+): MH+=369, Ή NMR (400MHz, METHANOL-d4) δ ppm 7.72 (d, J=3.4 Hz, 1H), 7.51 (dd, J=2.9, 7.6 Hz, 1H), 7.47 - 7.38 (m, 1H), 7.32 (dd, J=4.0, 9.2 Hz, 1H), 6.80 (d,

J=3.4 Hz, 1H), 5.33 (q, J=8.6 Hz, 1H), 4.85 (br. s., 1H), 4.71 (dd, J=4.8, 8.2 Hz, 1H), 4.22 (d,

J=3.9 Hz, 1H), 3.12 - 2.97 (m, 1H), 2.74 (br. s., 3H), 2.26 - 2.12 (m, 1H), [a]D22= -53.5° (c=0.1,

MeOH).

Example 70 (Scheme Y) - 2-(((1S,2S,3S,4R)-2,3-dihydroxy-4-(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)cyclopentyl)oxy)-5-fluorobenzamide (Y-3)

Scheme Y

- 137-

X-2 Y-1 Y-2 Y-3

Step 1 - Synthesis of 2-(((3aR,4S,6R,6aS)-2,2-dimethyl-6-(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)-5-fluorobenzonitrile (Y1)

To a suspension of X-2 (4 g, 9.8 mmol) in dimethoxypropane (60 mL)/DMF (20 mL) was added TsOH.H₂O (2990 mg, 15.75 mmol) at rt (20 °C). The resulting solution was stirred at rt (20 °C) for 24 hrs. The mixture was purified directly by silica gel chromatography eluted with EtOAc in petroleum ether from 0 to 100 % to afford Y-1 (2.2 g, 55%) as a white solid. LCMS 409 [M+1]; Ή NMR (400 MHz, CDCh) δ ppm 8.77 (s, 1H), 7.60 (d, J=3.8 Hz, 1H), 7.33 - 7.25 (m, 2H), 7.15 - 7.06 (m, 1H), 6.63 (d, J=3.5 Hz, 1H), 5.44 (ddd, J=2.5, 5.0, 7.8 Hz, 1H), 5.02 (dd, J=2.3, 6.0 Hz, 1H), 4.90-4.85 (m, 1H), 4.82 (d, J=6.3 Hz, 1H), 3.04 (ddd, J=6.8, 8.0, 15.1 Hz, 1H), 2.72 (s, 3H), 2.63-2.53 (m, 1H), 1.60 (s, 3H), 1.33 (s, 3H)

Step 2 - Synthesis of 2-(((3aR,4S,6R,6aS)-2,2-dimethyl-6-(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)-5-fiuorobenzamide (Y-2)

To a solution of Y-1 (50 mg, 0.12 mmol) in DMSO (0.25 mL) was added K2CO3 (20 mg, 0.15 mmol), followed by H₂O₂ (0.25 mL) drop-wise at ice-water, then the reaction can be warmed to room température for 2h, in which gas was observed. To the reaction mixture was added water and extracted with EtOAc two fîmes. The organic layer was dried over sodium sulfate, filtered, and the residue was purified by prep-TLC to give Y-2 (36 mg, 69%) and used as is in the next step.

Step 3 - Synthesis of 2-(((1S,2S,3S,4R)-2,3-dihydroxy-4-(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)cyclopentyl)oxy)-5-fluorobenzamide (Y-3)

To a suspension of Y-2 (42 mg, 0.1 mmol) in H₂O (0.3 mL) was added TFA (0.3 mL) drop-wise at 0 °C. Then the reaction mixture was stirred at room température (20 °C) for 16h. The reaction was then adjusted to pH 7 with 20% K₂CO₃ in which solid was formed, then filtered, and washed with water and MTBE. The solid was dried to give Y-3 (32 mg, 84%). LCMS 387 [M+1]; ¹H NMR (400 MHz, MeOD-d₄) δ ppm 8.63 (s, 1H), 7.62-7.65 (m, 1H), 7.60 (d, J=3.8 Hz, 1H), 7.24-7.30 (m, 2H), 6.75 (d, J=3.5 Hz, 1H), 5.16 (q, J=8.8 Hz, 1H), 4.82-4.87 (m, 2H), 4.27 (d, J=4.8 Hz, 1H), 3.02 (ddd, J=14.6, 9.6, 7.4 Hz, 1H), 2.73 (s, 3H), 2.42 ppm (ddd, J=13.7, 9.2, 4.3 Hz, 1H)

- 138 Example 71 (Scheme Z) - (1S,2S,3S,5R)-3-(2-((dimethylamino)methyl)-4-fluorophenoxy)-5(4-methyl-7H-pyrrolo[2,3-d]pyrïmidin-7-yl)cyclopentane-1,2-diol (8)

Scheme Z

Step 1 - Synthesis of (2-(((3aR,4S,6R,6aS)-2,2-dimethyi-6-(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)-5fluorophenyl)methanamine (Z-1)

A mixture of Y-1 (500 mg, 1.22 mmol) and Ra-Ni (100 mg) in EtOH (30 mL)/NH₃.H₂O (3 mL) was de-gassed with H₂ four times. The mixture was stirred at rt (20 °C) under H₂ balloon for 20 hrs then allowed to stand at rt for 20 hrs. The mixture was filtered and concentrated in vacuo to afford Z-1 (510 mg, >99%) as a light yellow gum. LCMS [M+1] 413; ¹H NMR (400 MHz, CDCI₃) δ ppm 8.79 (s, 1H), 7.37 (d, J=3.5 Hz, 1H), 7.05 (dd, J=2.4, 8.7 Hz, 1H), 6.99 - 6.88 (m, 2H), 6.58 (d, J=3.8 Hz, 1H), 5.33 (ddd, J=2.6, 5.5, 8.0 Hz, 1H), 5.05 (dd, J=2.9, 6.1 Hz, 1H), 4.88 4.80 (m, 1 H), 4.80 - 4.75 (m, 1 H), 3.76 (br. s., 2H), 3.06 - 2.89 (m, 1 H), 2.73 (s, 3H), 2.62 - 2.47 (m, 1H), 1.61 (s, 3H), 1.34 (s, 3H)

Step 2 - Synthesis of 1-(2-(((3aR,4S,6R,6aS)-2,2-dimethyl-6-(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)-5-fluorophenyl)-N,Ndimethylmethanamine (Z-2)

A mixture of Z-1 (100 mg, 0.24 mmol), 37% CH₂O (59 mg, 0.73 mmol) and NaBHOAc₃(206 mg, 0.970 mmol) in THF (2 mL) was stirred at rt for 2 hrs. The mixture was poured into NaHCO₃ aq (10 mL) and extracted with EtOAc (10 mL x 3). The extract was washed with brine (10 mL), dried over Na₂SO₄ and concentrated in vacuo to afford Z-2 (100 mg, 94%) as a colorless gum. LCMS 441 [M+1]; ¹H NMR (400 MHz, CDCI₃) δ ppm 8.79 (s, 1H), 7.49 (d, J=3.8 Hz, 1H), 7.14 7.08 (m, 1H), 7.01 - 6.86 (m, 2H), 6.55 (d, J=3.5 Hz, 1H), 5.37 (t, J=2.8 Hz, 1H), 5.02 (d, J=4.0

Hz, 1H), 4.83 (d, J=6.3 Hz, 1H), 4.77 (dd, J=3.3, 5.8 Hz, 1H), 3.33 (s, 2H), 2.97 (d, J=8.0 Hz, 1H), 2.73 (s, 3H), 2.54 (d, J=13.8 Hz, 1H), 2.23 (s, 6H), 1.60 (s, 3H), 1.33 (s, 3H)

Step 3 - Synthesis of (1S,2S,3S,5R)-3-(2-((dimethylamino)methyl)-4-fluorophenoxy)-5-(4methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol (Z-3)

To TFA/H2O (1 mL/2 mL) was added Z-2 (100 mg, 0.23 mmol) at rt. The mixture was stirred at rt for 1 hr. The mixture was poured into 20% K2CO3 (10 mL). The mixture was washed saturated with NaCI and extracted with EtOAc/THF (20 mL/ 20 mL) twice. The extract was washed with concentrated in vacuo. The residue was dissolved in CH3CN/H2O (10 mL/ 50 mL) and lyophilized to afford Z-3 (70 mg, 77%) as a white solid. LCMS 404 [M+1]; ¹H NMR (400

MHz, DMSO-d₆) δ ppm 8.61 (s, 1H), 7.69 (d, J=3.8 Hz, 1H), 7.13 (d, J=8.5 Hz, 1H), 7.05 (d, J=5.5 Hz, 2H), 6.72 (d, J=3.5 Hz, 1H), 5.36 (br. s., 1H), 5.16 - 5.09 (m, 2H), 4.60 - 4.49 (m, 2H), 4.01 (d, J=3.3 Hz, 1H), 3.57 - 3.48 (m, 1H), 3.44 (br. s., 1H), 2.90 - 2.78 (m, 1H), 2.63 (s, 3H), 2.23 (s, 6H), 1.96- 1.86 (m, 1H)

Example 72 (Scheme AA) - (1S,2S,3S,5R)-3-(4-fluoro-2-((methylamino)methyl)phenoxy)-5(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol (11)

Scheme AA

Step 1 - Synthesis of tert-butyl (2-(((3aR,4S,6R,6aS)-2,2-dimethyi-6-(4-methyl-7Hpyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)-5fluorobenzyl)carbamate (AA-1)

To a solution of Z-1 (140 mg, 0.34 mmol) and Et₃N (34 mg, 0.34 mmol) in DCM (5 mL) was added Boc₂O (74 mg, 0.34 mmol) at rt (20 °C). The mixture was stirred at rt (20 °C) for 1 hr.

The mixture was purified by silica gel chromatography eluted with EtOAC in petroleum ether from 0 to 100 % to afford AA-1 (140 mg, 81%) as a colorless oil. LCMS 513 [M+1]; ¹H NMR (400 MHz, CDCh) δ ppm 8.78 (s, 1H), 7.33 (s, 1H), 7.00 (d, J=8.8 Hz, 1H), 6.93 (d, J=5.2Hz, 2H), 6.58 (d, J=3.6Hz, 1H), 5.30-5.28 (m, 1H), 5.06-5.05 (m, 1H), 4.81 (d, J=6Hz, 2H), 4.76-4.75 (m, 1H), 4.18 (d, J=3.2Hz, 1H), 2.98-2.90 (m, 1H), 2.71 (s, 3H), 2.54-2.50 (m, 1H), 1.55 (s, 3H),

1.44 (s, 9H), 1.24 (s, 3H)

- 140Step 2 - Synthesis of tert-butyl (2-(((3aR,4S,6R,6aS)-2,2-dimethyl-6-(4-methyl-7Hpyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)-5fluorobenzyl)(methyl)carbamate (AA-2)

To a solution of AA-1 (140 mg, 0.27 mmol) in dry DMF (3 mL) was added 60 % NaH (16.4 mg,

0.41 mmol) at rt (0 °C). The mixture was stirred at rt (20 °C) for 1 hr. CH₃I (56 mg, 0.4 mmol) was added to the mixture and stirred at rt (20 °C) for 20 hrs. The mixture was poured into

NH4CI aq (10 mL) and extracted with EtOAc (5 mL x 3). The extract was washed with brine (5 mL), dried over Na₂SO₄and concentrated in vacuo to afford crude material (200 mg) as a brown oil which was purified by silica gel chromatography eluted with EtOAc in petroleum ether from 0 10 to 100 % to afford AA-2 (100 mg, 70%) as a colorless gum. LCMS 527 [M+1]

Step 3 - Synthesis of (1S,2S,3S,5R)-3-(4-fluoro-2-((methylamino)methyl)phenoxy)-5-(4methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol (AA-3)

To TFA/H₂O (1 mL/2 mL) was added AA-2 (89 mg, 0.169 mmol) at rt. The mixture was stirred at rt for 2 hrs, then poured into 20% K₂CO₃ aq (5 mL). The mixture was extracted with EtOAc (10 mL x 3). The extract was washed with brine (10 mL x 2), dried over Na₂SO₄, fiitered and concentrated in vacuo. The residue was dissolved in CH₃CN/H₂O (4 mL/10 mL) and lyophilized to afford AA-3 (55 mg, 84%) as a white solid. LCMS 387 [M+1]; ¹H NMR (400 MHz, DMSO-de) δ ppm 8.62 (s, 1H), 7.67 (d, J=3.8 Hz, 1H), 7.23 - 7.14 (m, 1H), 7.08 - 6.98 (m, 2H), 6.73 (d, J=3.8 Hz, 1H), 5.12 (q, J=9.1 Hz, 2H), 4.57 (br. s., 2H), 4.02 (d, J=4.8 Hz, 1H), 3.71 (s, 2H),

2.92 - 2.77 (m, 1 H), 2.65 (s, 3H), 2.34 (s, 3H), 2.03 - 1.93 (m, 1 H)

Example 73 (Scheme BB) - (1S,2S,3S,5R)-3-(4-fluorophenoxy)-5-(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)cyclopentane-1,2-diol (BB-4)

Scheme BB

BB-1

OBoc

Pd₂dba₃«CKCI₃ (2 mol%) (S.S)-DACH-Napthyl Trost Ligand (6 moi%) Cs₂CO₃, DCE, rt

BB-2 dppp (6 mol%) Cs₂CO₃, DCE, rt

Pd₂dba₃«CHCI₃ (2.5 moi%)

Step 1 : Synthesis of fert-butyl-((1S,4R)-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7yl)cyclopent-2-en-1 -yl)-carbonate (BB-2)

Vial A: To an oven dried reaction vial, equipped with a magnetic stirbar and cooled under a stream of argon, was added Tris(benzylideneacetone)dipalladium(0)chloroform adduct (78.7 mg, 0.0760 mmol) and (S,S)-DACH-Naphthyl Trost Ligand (MFCD02684552) (180 mg, 0.228

- 141 mmol). The vial was vacuum purged with argon under dynamic vacuum and DCE (7.5 mL), which had been sparged with argon for 30 minutes. The solution was stirred for 30 minutes at rt at which point a bright orange solution of ligated catalyst was obtained. At this stage Vial B was prepared.

Vial B: To an oven dried reaction vial, equipped with a magnetic stirbar and cooled under a stream of argon, was added 4-methyl-7H-pyrrolo[2,3-d]pyrimidine (HG-1) (506 mg, 3.8 mmol), di-tert-butyl-((1R,3S)-cyclopent-4-ene-1,3-diyl)-bis(carbonate) (BB-1) (prepared as reported in J. Am. Chem. Soc. 2006, 128, 6054-6055) (1.37 g, 4.56 mmol), and césium carbonate (1.36 g, 4.18 mmol). The vial was vacuum purged with argon under dynamic vacuum and DCE (7.5 mL), which had been sparged with argon for 30 minutes, was added followed by the addition of the contents of Vial A via airtight syringe. The reaction was stirred under argon at rt for 48 hours. The reaction was transferred to a separatory funnel with DCM. The solution was washed with 2 portions water and 1 portion brine. A small amount of 1M HCl was used to dissipate the émulsion in the last wash. The organic phase was dried (MgSO₄), filtered, and concentrated under vacuum. The crude residue was purified via flash column chromatography (40 g SiO₂, Isco, 100% Hept. to 100% EtOAc, 20 mL fractions) to afford the compound BB-2 (814 mg, 68%, >99% ee) as a brown gum which solidified upon standing. LCMS [M+H] = 316 observed; Chiral LCMS (Chiralcel OJ-3 4.6x100 mm 3μ column, 4% MeOH+10nM NH₃ @ 120 bar, 4 mL/min) peak 1 @ 0.63 min., peak 2 @ 0.77 min., observed major peak @ 0.65 min, 99.8:0.2% by MS area; Ή NMR (400MHz, CHLOROFORM-d) δ ppm 8.78 (s, 1H), 7.32 - 7.22 (m, 1H), 6.60 (d, J=3.7 Hz, 1H), 6.35 - 6.23 (m, 1 H), 6.10 (d, J=5.4 Hz, 1H), 6.00 (br. s., 1H), 5.66 - 5.57 (m, 1H), 3.21 - 3.07 (m, 1H), 2.75 (s, 3H), 1.89 (d, J=14.9 Hz, 1H), 1.57 - 1.46 (m, 9H).

Step 2: Synthesis of 7-((1R,4S)-4-(4-fluorophenoxy)cyclopent-2-en-1-yl)-4-methyl-7Hpyrrolo[2,3-d]pyrimidine (BB-3)

To a scintillation vial, equipped with a magnetic stirbar, was added BB-2 (56.8 mg, 0.180 mmol),

4-fluorophenol (22.2 mg, 0.198 mmol), diphenylphosphinopropane (dppp) (4.5 mg, 0.0108 mmol), tris(dibenzylideneacetone)dipalladium(0)chloroform adduct (4.7 mg, 0.0045 mmol), and césium carbonate (64.6 mg, 0.198 mmol). The vial was purged with argon under dynamic vacuum followed by the addition of DCE (0.9 mL) which had been sparged with argon for 30 minutes. The reaction was stirred at rt under argon for 2.5 hours. The reaction was taken up with DCM and loaded directly onto a pre-packed silica column. The crude residue was purified via flash column chromatography (12g SiO2, Isco, 100% Hept. to 100% EtOAc, 9 mL fractions) to afford the compound BB-3 (38.8 mg, 70% yield) as a colorless gum. LCMS [M+H] = 310 observed; Ή NMR (400 MHz, CHLOROFORM-d) δ ppm 8.77 (s, 1H), 7.34 (d, J=3.55 Hz, 1H),

- 1426.92-7.04 (m, 2H), 6.80-6.92 (m, 2H), 6.57 (d, J=3.55 Hz, 1H), 6.37 (d, J=5.38 Hz, 1H), 6.14 (d, J=4.03 Hz, 1H), 5.97-6.09 (m, 1H), 5.17-5.34 (m, 1H), 3.02-3.18 (m, 1H), 2.56-2.91 (m, 3H), 1.97 (td, J=3.35, 14.70 Hz, 1H).

Step 3: Synthesis of (1S,2S,3S,5R)-3-(4-fluorophenoxy)-5-(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)cyclopentane-1,2-diol (BB-4)

To a scintillation vial, equipped with a magnetic stirbar and containing BB-3 (38.8 mg, 0.125 mmol), was added DCM (0.73 ml_) and water (0.03 mL). To the solution was added 4Methylmorpholine-ZV-oxide (NMO) (44.1 mg, 0.376 mmol) followed by the dropwise addition of osmium tetraoxide (32 pL, 0.005 mmol) as a 4 wt% solution in water. The reaction was stirred at rt for 8 hours. The reaction was quenched with 1M NaHSOs aq., stirred for 30 minutes and transferred to a separatory funnel with DCM. The solution was further diluted with water and the product was extracted with 4 portions of a 3:1 mixture of CHCI₃//-PrOH. The combined organic extracts were dried (MgSO4), fiitered, and concentrated under vacuum to afford the crude product as a white solid. The crude residue was purified via préparative HPLC (Lux Cellulose-1 4.6x100 mm 3μ column, 15% MeOH @ 120 bar, 4 mL/min) to afford the compound BB-4 (30.4 mg, 71%, >99% de) as a white solid. LCMS [M+H] = 344 observed; [a]²²D = -36.0° (c=0.1, MeOH); Ή NMR (400 MHz, METHANOL-d4) δ ppm 8.61 (s, 1H), 7.58 (d, J=3.67 Hz, 1H), 6.947.09 (m, 4H), 6.75 (d, J=3.67 Hz, 1H), 5.27 (q, J=8.64 Hz, 1H), 4.58-4.68 (m, J=3.67 Hz, 2H), 4.17 (d, J=4.89 Hz, 1H), 2.96 (ddd, J=7.15, 9.32, 14.46 Hz, 1H), 2.71 (s, 3H), 2.09 (ddd, J=3.85, 8.53, 14.03 Hz, 1H). 19F NMR (377 MHz, METHANOL-d4) δ ppm = -125.65 (s, 1F).

Examples 74-77 were prepared using the chemistry depicted in Scheme BB and employing the appropriate commercial Phénol reagent for step 2.

Example 74: 2,6-difluorophenol	éCû-Ty fho oh	362 LCMS [M+1]	(1S,2S,3S,5R)-3-(2,6difluorophenoxy)-5-(4-methyl7H-pyrrolo[2,3-d]pyrimidin-7yl)cyclopentane-1,2-diol
			1H NMR (400 MHz, METHANOL-d4) δ ppm 8.64 (s, 1H), 7.70 (d, J=4.02 Hz, 1H), 7.18-7.02 (m, 3H), 6.82 (d, J=3.51 Hz, 1H), 5.39-5.31 (m, 1H), 4.75 (m, 1H), 4.68 (m, 1H), 4.23 (m, 1H), 3.03-

- 143 -

			2.94 (m, 1H), 2.75 (s, 3H), 2.19 (dd, J=14.8, 5.3 Hz, 1H).
Example 75: 4-fluoro-2methylphenol	N ΑΓ T il JL / 0H | OH	358 LCMS [M+1]	(1 S,2S,3S,5R)-3-(4-fluoro-2methylphenoxy)-5-(4-methyl7H-pyrrolo[2,3-d]pyrimidin-7yl)cyclopentane-1,2-diol 1H NMR (400 MHz, MeOD-d4) δ ppm 8.63 (s, 1H), 7.59 (d, J=3.8 Hz, 1H), 6.96 (td, J=9.5, 4.0 Hz, 2H), 6.85-6.91 (m, 1H), 6.78 (d, J=3.5 Hz, 1H), 5.29 (q, J=8.8 Hz, 1H), 4.644.73 (m, 2H), 4.21 (d, J=4.5 Hz, 1H), 3.01 (ddd, J=14.6, 9.5, 7.0 Hz, 1H), 2.73 (s, 3H), 2.31 (s, 3H), 2.16 ppm (ddd, J=14.5, 8.5, 3.4 Hz, 1H)
Example 76 8-hydroxy-3,4dihydroisoquinolin- 1(2H)-one	Γη »ν^ν jX/,!'°h O Il I OH H N jLj	395 LCMS [M+1]	8-(((1S,2S,3S,4R)-2,3dihydroxy-4-(4-methyl-7Hpyrrolo[2,3-d]pyrimidin-7yl)cyclopentyl)oxy)-3,4dihydroisoquinolin-1 (2H)-one 1H NMR (400 MHz, MeOD-d4) δ ppm 8.60 (s, 1H), 7.97 (d, J=4.0 Hz, 1H), 7.42 (t, J=8.0 Hz, 1H), 7.08 (d, J=8.8 Hz, 1H), 6.91 (d, J=7.3 Hz, 1H), 6.75 (d, J=3.8 Hz, 1H), 5.47 5.33 (m, 1H), 4.83 - 4.71 (m, 2H), 4.24 (d, J=3.8 Hz, 1H), 3.42 (t, J=6.5 Hz, 2H), 3.06 2.98 (m, 1H), 2.97 - 2.90 (m, 2H), 2.71 (S, 3H), 2.11 - 2.02 (m, 1H)

- 144Example 77 isoquinolin-8-ol

377

LCMS [M+1] (1 S,2S,3S,5R)-3-(isoquinolin8-yloxy)-5-(4-methyl-7Hpyrrolo[2,3-d]pyrimidin-7yl)cyclopentane-1,2-diol ¹H NMR (400 MHz, DMSO-ds) δ ppm 9.69 (br s, 1 H), 8.62 (s, 1H), 8.56 (br d, J=4.5 Hz,. 1H), 7.83 (br d, J=5.5 Hz, 1H), 7.79 (d, J=3.5 Hz, 1H), 7.72 (t, J=8.0 Hz, 1H), 7.53 (d, J=8.0 Hz, 1H), 7.24 (d, J=7.8 Hz, 1H), 6.76 (d, J=3.5 Hz, 1H), 5.50 (br s, 1H), 5.20 (q, J=1.0 Hz, 2H), 4.89 - 4.83 (m, 1H), 4.72 - 4.66 (m, 1H), 4.18 (br d, J=4.3 Hz, 1H), 3.02 - 2.91 (m, 1H), 2.66 (s, 3H), 2.24-2.14 (m, 1H)

Example 78 (Scheme CC) - (1S,2S,3S,5R)-3-((6-chloro-5-fluoro-1,2,3,4tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-

1,2-diol (CC-3)

Scheme CC

OH

OsO₄ (4% in t-BuOH soin) NMO, DCM, H₂O

Step 1 - Synthesis of tert-butyl 8-(((1 S,4R)-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-710 yl)cyclopent-2-en-1 -yl)oxy)-3,4-dihydroisoquinoline-2(1 H)-carboxylate (CC-1 )

-145 To a mixture of BB-2 (600 mg, 1.9 mmol) and tert-butyl 8-hydroxy-3,4-dihydroisoquinoline2(1 H)-carboxylate (474 mg, 1.9 mmol), Cs₂CO₃( 682 mg, 2.09 mmol) and DPPP (47.1 mg, 0.11 mmol) in DCE (15 mL) was sparged with N₂ for 40 min. To the mixture was added Pd₂(dba)₃.CHCI₃ (49 mg, 0.048 mmol) under N₂. The reaction was sparged with N₂ for 5 min then stirred at rt (20 °C) under N₂ for 40 min. The mixture was purified immediately (solution purified directly) by silica gel chromatography eluted with petroleum ether/EtOAc=8/1 to 1/1 then DCM/MeOH=12/1 to afford CC-1 (735 mg, 87%) as a yellow gum. LCMS [M+1] 447; ¹H NMR (400 MHz, CDCb) δ ppm 8.77 (s, 1H), 7.33 (d, J=3.5 Hz, 1H), 7.13 (t, J=7.9 Hz, 1H), 6.79 - 6.72 (m, 2H), 6.62 - 6.52 (m, 1H), 6.44 - 6.33 (m, 1H), 6.21 - 6.11 (m, 1H), 6.09 - 6.01 (m, 1H), 5.41 10 5.33 (m, 1H), 4.71 - 4.40 (m, 2H), 3.71 - 3.48 (m, 2H), 3.22 - 3.12 (m, 1H), 2.82 (br. s., 2H), 2.73 (s, 3H), 1.98 (d, J=15.1 Hz, 1H), 1.51 (s, 9H)

Step 2 - Synthesis of tert-butyl 8-(((1 S,2S,3S,4R)-2,3-dihydroxy-4-(4-methyl-7Hpyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl)oxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate (CC-2)

To a mixture of CC-1 (730 mg, 1.63 mmol) in DCM (15 mL)/H₂O (0.5 mL) was added NMO (575 mg, 4.9 mmol) and OsO₄(4 % in t-BuOH, 832 mg, 0.12 mmol). The mixture was stirred at rt (25 °C) for 3 hrs. Na₂SO₃ (500 mg) and water (20 mL) was added. The mixture was stirred at rt for 1 hr then the mixture was filtered. The fiitrate was diluted with water (50 mL) and extracted with EtOAc (50 mLx2). The extract washed with brine (50 mL), dried over Na₂SO₄ and concentrated in vacuo and purified with silica gel chromatography eluted with MeOH in DCM from 0 to 10 % to afford CC-2 (560 mg, 71%) as a white solid. LCMS [M+1] 481; ¹H NMR (400 MHz, CDCI₃) δ ppm 8.67 (s, 1H), 7.24 (d, J=3.8 Hz, 1H), 7.18 (t, J=7.9 Hz, 1H), 6.90 (d, J=8.0 Hz, 1H), 6.80 (d, J=7.8 Hz, 1H), 6.60 (d, J=3.3 Hz, 1H), 5.08 - 4.94 (m, 1H), 4.87 - 4.76 (m, 1H), 4.61 - 4.39 (m, 3H), 4.37 - 4.28 (m, 1H), 3.76 - 3.55 (m, 2H), 3.46 - 3.31 (m, 1H), 3.20 - 3.04 (m, 1H), 2.86 25 2.79 (m, 2H), 2.73 (s, 3H), 2.48 - 2.30 (m, 1 H), 1.48 (s, 9H)

Step 3 - Synthesis of (1S,2S,3R,5S)-3-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5((1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)cyclopentane-1,2-diol (CC-3)

To a solution of CC-2 (560 mg, 1.17 mmol) in DCM (15 mL) was added TFA (4.5 mL) at 0 °C.

The reaction mixture was stirred at 0 °C for 1 hour. The reaction mixture was evaporated and dissolved in water (30 mL) and K₂CO₃ (1 g) was added. The mixture was diluted with brine (30 mL) and extracted with EtOAc/THF (1/1, 30 mLx3). The extract was washed with brine (30 mLx2), dried over Na₂SO₄, filtered and concentrated in vacuo to afford CC-3 (400 mg, 90%) as a white solid. LCMS [M+1] 381; Ή NMR (400 MHz, DMSO-de) δ ppm 8.64 (s, 1H), 7.62 (d, J=3.8 Hz, 1H), 7.11 -7.02 (m, 1H), 6.81 (d, J=8.3 Hz, 1H), 6.73 (d, J=3.5 Hz, 1H), 6.68 (d, J=7.5

- 146Hz, 1H), 5.33 (br. s., 1H), 5.19 - 5.08 (m, 2H), 4.56 (br. s., 2H), 3.99 (br. s., 1H), 3.85 (s, 2H),

2.93 (t, J=5.8 Hz, 2H), 2.90-2.81 (m, 1H), 2.70-2.66 (m, 2H), 2.65 (s, 3H), 1.98- 1.86 (m, 1H)

Examples 79 & 80 were préparée! using the chemistry depicted in Scheme CC and employing the appropriate commercial NBoc-protected phénol reagent for step 1.

Exampie 79 tert-butyl 4hydroxyisoindoline-2carboxyiate	HN	-χ'Λ z \—/ O ° y)	367 LCMS [M+1]	(1 S,2S,3S,5R)-3-(2,3-dihydro-1 Hisoindol-4-yloxy)-5-(4-methyl-7Hpyrrolo[2;3-d]pyrimidin-7yl)cyclopentane-1,2-diol 1H NMR (400 MHz, MeOD-d4) δ ppm 8.63 (s, 1H), 8.43 - 8.33 (m, 1H), 7.59 (d, J=3.5 Hz, 1H), 7.45 7.36 (m, 1H), 7.13-7.08 (m, 1H), 7.07 - 7.01 (m, 1H), 6.77 (d, J=3.8 Hz, 1H), 5.28-5.19 (m, 1H), 4.824.78 (m, 1H), 4.76-4.71 (m, 1 H), 4.67 (d, J=4.8 Hz, 4H), 4.24 (d, J=3.8 Hz, 1H), 3.08- 2.94 (m, 1H), 2.73 (s, 3H), 2.28-2.15 (m, 1H)
Example 80 tert-butyl 5-hydroxy- 3,4- dihydroisoquinoline2(1H)-carboxylate	HN^,	/ °h ΐ OH	381 LCMS [M+1]	(1 S,2S,3R,5S)-3-(4-methyl-7Hpyrrolo[2,3-d]pyrimidin-7-yl)-5((1,2,3,4-tetrahydroisoquinolin-5yl)oxy)cyclopentane-1,2-diol 1H NMR (400 MHz, DMSO-de) δ ppm 8.64 (s, 1H), 7.64 (d, J=3.5 Hz, 1H), 7.26-7.18 (m, 1H),6.99 (d, J=8.0 Hz, 1H), 6.82 (d, J=7.8 Hz, 1H), 6.73 (d, J=3.5 Hz, 1H), 5.40 (br. s., 1H), 5.19 - 5.08 (m, 2H), 4.66-4.54 (m,2H), 4.22 (s, 2H), 4.02 (br. s., 1H), 2.96 - 2.83 (m, 3H), 2.65 (s, 3H), 2.01 - 1.90 (m, 1H)

Example 81 (Scheme DD) - (1S,2S,3R,5S)-3-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-50 [(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)oxy]cyclopentane-1,2-diol (DD-1 )

- 147 -

Scheme DD

NaBH(OAc)₃

37% CH₂O, THF

Example 80 DD-1

Step 1: Synthesis of (1S,2S,3R,5S)-3-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-[(2methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)oxy]cyclopentane-1,2-diol (DD-1 )

A mixture of compound Example 80 (42 mg, 0.11 mmol), 37 % CH₂O (26.9 mg, 0.331 mmol) and NaBHOAc₃ (93.6 mg, 0.442 mmol) in THF (1.2 mL) was stirred at rt for 2 hrs. The mixture was poured into NaHCO₃ aq (10 mL) and extracted with EtOAc (20 mL x 4). The extract was dried over Na₂SO₄ and concentrated in vacuo to afford the residue (50 mg) as a white solid which was purified by prep-TLC (DCM:MeOH=10:1 with NH₃.H₂O) to give DD-1 (35 mg, 80%) as a white solid. LCMS 395 [M+1]; ¹H NMR (400 MHz, DMSO-de) δ ppm 8.63 (s, 1H), 7.63 (d, J=3.5 Hz, 1H), 7.16 (t, J=8.0 Hz, 1H), 6.92 (d, J=8.5 Hz, 1H), 6.75 - 6.69 (m, 2H), 5.36 (d, J=3.8 Hz, 1H), 5.18 - 5.09 (m, 2H), 4.64 - 4.54 (m, 2H), 4.02 (br. s., 1H), 3.83 (br. s., 2H), 2.99 (br. s., 2H), 2.92 - 2.82 (m, 3H), 2.65 (s, 3H), 2.58 (br. s„ 3H), 1.95 (ddd, J=3.8, 9.5, 13.8 Hz, 1 H)

Example 82 & 83 was made in a similar fashion from Example 79 & 78 respectively

Example 82

381

[M+1] (1S,2S,3S,5R)-3-[(2-methyl-2,3-dihydro-1Hisoindol-4-yl)oxy]-5-(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)cyclopentane-1,2-diol ¹H NMR (400 MHz, MeOD-d₄) δ ppm 8.62 (s, 1H), 7.56 (d, J=3.8 Hz, 1H), 7.21 (t, J=7.9 Hz, 1H), 6.89 (dd, J=7.8, 14.1 Hz, 2H), 6.77 (d, J=3.8 Hz, 1H), 5.29 (q, J=8.7 Hz, 1H), 4.73 (ddd, J=1.8, 3.5, 7.0 Hz, 1H), 4.65 (dd, J=4.8, 8.8 Hz, 1H), 4.18 (d, J=4.5 Hz, 1H), 3.97 (d, J=12.5 Hz, 4H), 3.00 (ddd, J=7.0, 9.5, 14.6 Hz, 1H), 2.71 (s, 3H), 2.62 (s, 3H), 2.15-2.07 (m, 1H)

- 148 Example 83

395

[M+1] (1S,2S,3S,5R)-3-((2-methyl-1,2,3,4tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7Hpyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol ¹H NMR (400 MHz, MeOD-d₄) δ ppm 8.62 (s, 1H), 7.57 (d, J=3.8 Hz, 1H), 7.22 (t, J=8.0 Hz, 1H), 6.93 (d, J=7.8 Hz, 1H), 6.84 (d, J=7.5 Hz, 1H), 6.76 (d, J=3.8 Hz, 1H), 5.23 (q, J=8.9 Hz, 1H), 4.74 - 4.68 (m, 2H), 4.20 (d, J=5.5 Hz, 1H), 4.05 (s, 2H), 3.19 - 3.12 (m, 2H), 3.10 - 3.05 (m, 2H), 3.00 (ddd, J=7.0, 9.3, 14.3 Hz, 1H), 2.83 (s, 3H), 2.72 (s, 3H), 2.24 - 2.15 (m, 1H)

Synthesis of tert-butyl 6-fluoro-8-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (TP1)

Scheme EE

EE-4

TP-1

Step 1 - Synthesis of 5-fluoro-7-methoxy-2,3-dihydro-1H-inden-1-one (EE-2)

To a solution of 5-fluoro-7-hydroxy-2,3-dihydro-1 H-inden-1-one (prepared in a similar manner as

Bio. Med. Chem Letters, 20, 1004-1007, 2010) (1 g, 6.02 mmol) and K₂CO₃ (2.5 g, 18 mmol) in dry DMF (10 mL) was added Mel (1710 mg, 12.0 mmol) at 0 °C. After the addition, the reaction 10 was stirred at 25 °C for 4 hours. The reaction mixture was partitioned between EtOAc and H₂O.

The aqueous layer was extracted with EtOAc. The combined organic layers was washed with brine, dried over Na₂SO₄ and concentrated to afford EE-2 (1 g, 92%) as a yellow solid. LCMS

181 [M+1]; ¹H NMR (400 MHz, CDCb) δ ppm 6.73 - 6.69 (m, 1H), 6.51 (dd, J=2.0, 11.3 Hz, 1H), 3.94 (s, 3H), 3.13 - 3.03 (m, 2H), 2.73 - 2.65 (m, 2H)

Step 2 - Synthesis of 6-fluoro-8-methoxy-3,4-dihydroisoquinolin-1 (2H)-one (EE-3)

To a solution of EE-2 (950 mg, 5.27 mmol) in 1,2-DCE/MeSO₃H (38 mL/29 mL) at 0 °C was added portion-wise NaN₃ (1.4 mg, 21.1 mmol). After addition, the mixture was stirred at 70 °C

- 149for 16 hrs. The mixture was cooled to 0 °C, adjusted to pH 7-8 with addition of aqueous NaHCOs (sat). The mixture was extracted with DCM (15 mL x 2), dried over Na₂SO4, filtered and concentrated to give EE-3 (1.15 g, 74%) as a brown solid. LCMS 196 [M+1]; ¹H NMR (400 MHz, DMSO-de) δ ppm 7.70 (br. s., 1H), 6.85 (dd, J=2.4, 11.9 Hz, 1H), 6.73 (dd, J=2.4, 8.9 Hz,

1 H), 3.76 (s, 3H), 3.21 (dt, J=3.5, 6.3 Hz, 2H), 2.80 (t, J=6.3 Hz, 2H)

Step 3 - Synthesis of 6-fluoro-8-methoxy-1,2,3,4-tetrahydroisoquinoline (EE-4)

Compound EE-4 was prepared from EE-3 in a similar method as step 5 in Scheme FF to give crude EE-4 (455 mg, >99%) as a yellow oil and used directly in the next step. LCMS 182 [M+1]; Ή NMR (400 MHz, DMSO-d₆) δ ppm 6.63 (dd, J=2.3, 11.3 Hz, 1H), 6.48 (dd, J=2.3, 9.5 Hz, 10 1H), 3.75 (s, 3H), 3.67 - 3.61 (m, 2H), 2.85 (t, J=5.8 Hz, 2H), 2.61 (t, J=5.6 Hz, 2H)

Step 4 - Synthesis of 6-fluoro-1,2,3,4-tetrahydroisoquinolin-8-ol (EE-5)

Compound EE-5 was prepared from EE-4 in a similar method as step 6 in Scheme FF to give crude EE-5 (228 mg, 54%) as a yellow solid. LCMS 168 [M+1]; ¹H NMR (400 MHz, DMSO-de) δ ppm 6.39 - 6.28 (m, 2H), 3.63 (s, 2H), 2.85 (t, J=5.8 Hz, 2H), 2.63 - 2.57 (m, 2H)

Step 5 - Synthesis of tert-butyl 6-fluoro-8-hydroxy-3,4-dihydroisoquinoline-2(1 H)carboxylate (TP-1)

Compound TP-1 was prepared from EE-5 in a similar method as step 7 in Scheme FF to give TP-1 (182 mg, 50%) as a yellow solid. MS 212 [M-56+1]; ¹H NMR (400 MHz, DMSO-de) δ ppm 10.11 (s, 1H), 6.45 (d, J=10.5 Hz, 2H), 4.29 (s, 2H), 3.51 (m, J=5.8 Hz, 2H), 2.69 (m, J=5.6 20 Hz, 2H), 1.43 (s, 9H)

Synthesis of tert-butyl 5-fluoro-8-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (TP2)

Scheme FF

- 150-

Step 1 - Synthesis of tert-butyl (pivaloyloxy)carbamate (FF-2)

To a solution of compound FF-1 (20 g, 150 mmol) in CHCh (200 mL) was slowly added pivalic anhydride (34 g, 180 mmol) in an ice bath and then stirred at 70 °C for 16 h. The reaction 5 solution was diluted with DCM (200 mL) and washed with saturated NaHCOs (200 mL x 2) until pH~7. The organic layer was dried over Na₂SO₄, filtered and concentrated under reduced pressure to afford a light yellow oil. The crude product was crystallized with petroleum ether (20 mL) to afford FF-2 (18 g, 55%) as a white solid. ¹H NMR (400 MHz, CDCh) δ ppm 7.8 (br. s., 1H), 1.5 (s, 9H), 1.3 (s, 9H)

Step 2 - Synthesis of O-pivaloylhydroxylamine (FF-3)

To a solution of FF-2 (16 g, 70 mmol) in TBME (32 mL) was added CF3SO3H (10.6 g, 70.7 mmol) at 0 °C. The reaction solution was stirred at 15 °C for 2 h. The reaction mixture was evaporated to give the crude product FF-3 (20 g, >99%) as a white solid and used directly in the next reaction.

Step 3 - Synthesis of 5-fluoro-2-methoxy-N-(pivaloyloxy)benzamide (FF-4)

To a solution of 5-fluoro-2-methoxybenzoic acid (4.50 g, 26.4 mmol) in THF (90.0 mL) was added T3P (19 g, 29.1 mmol) at 0 °C. After the addition, the reaction mixture was stirred for 30 min at 25 °C. To the reaction mixture was added DIPEA (13.8 mL, 8.82 mmol) followed by FF-3 (7.28 g, 29.1 mmol). After the addition, the reaction mixture was stirred at 25 °C for 16 hours.

The reaction mixture was filtered and the filtrate was partitioned between EtOAc and H₂O. The organic layer was separated, dried over Na₂SO₄ and concentrated to afford the crude product which was purified via flash column chromatography (EtOAc: petroleum ether = 1-100%, then MeOH: DCM = 1%~10%) to afford FF-4 (9 g, >99%) as a white solid and used directly in the next reaction.

- 151 Step 4 - Synthesis of 5-fluoro-8-methoxy-3,4-dihydroisoquinolin-1(2H)-one (FF-5)

A suspension of FF-4 (8.00 g, 28.0 mmol), KOAc (6.06 g, 61.7 mmol) and [Cp*RhCI₂]₂ (867 mg, 1.40 mmol) in MeCN (100 mL) in a vessel was purged with N₂ for 5 min and then cooled to -40 °C with dry ice/acetone. Ethylene was purged into the vessel for 30 min then sealed and stirred at 25 °C for 16 h. The dark red suspension was filtered and the filtrate cake was washed with CH₃CN. The combined filtrate was concentrated to afford the crude product which was purified via flash column chromatography (EtOAc:Petroleum ether = 1%~100%, then MeOH:DCM = 1-8%) to afford FF-5 (4.62 g, 84%) as a yellow solid. Ή NMR (400 MHz, DMSO-d₆) δ ppm 7.85 (br. s., 1H), 7.32 (t, J=9.0 Hz, 1H), 6.99 (dd, J=4.3, 9.3 Hz, 1H), 3.76 (s, 3H), 3.31 - 3.22 (m, 2H), 2.79 (t, J=6.3 Hz, 2H)

Step 5 - Synthesis of 5-fluoro-8-methoxy-1,2,3,4-tetrahydroisoquinoline (FF-6)

To a solution of FF-5 (4.66 g, 23.9 mmol) in dry THF (240 mL) was added LÎAIH4 (3.62 g, 95.5 mmol) portion-wise. After the addition, the reaction mixture was heated at 65 °C (reflux) for 2 hours. The reaction mixture was quenched with 4 mL of H₂O. The mixture was distilled in EtOAc and filtered. The filtrate cake was washed with EtOAc. The filtrate was dried over Na₂SO₄ and concentrated to afford the crude product which was purified via flash column chromatography (MeOH: DCM = 1-8%) to afford FF-6 (2.9 g, 66%) as a yellow gum. Ή NMR (400 MHz, DMSO-d₆) δ ppm 6.92 (t, J=9.2 Hz, 1H), 6.73 (dd, J=4.4, 8.9 Hz, 1H), 3.73 (s, 3H), 3.69 (s, 2H), 2.88 (t, J=5.8 Hz, 2H), 2.55 (t, J=5.8 Hz, 2H)

Step 6 - Synthesis of 5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-ol (FF-7)

To a solution of FF-6 (2.86 g, 15.8 mmol) in DCM (28.6 mL) was added BBr₃ (2.86 mL, 30.3 mmol) at -10 °C drop-wise. After the addition, the reaction mixture was stirred at 0 °C for 2 hours. The reaction mixture was cooled to -10 °C and quenched with MeOH. The resulting mixture was diluted in H₂O, basified with sat. K₂CO₃to pH 9-10 and then extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine, dried over Na₂SO₄ and concentrated to afford the crude product which was purified via flash column chromatography (MeOH: DCM = 1:10) to afford FF-7 (1.0 g, 38%) as a yellow solid. ¹H NMR (400 MHz, DMSOd₆) δ ppm 9.24 (br. s., 1H), 6.76 (t, J=9.0 Hz, 1H), 6.55 (dd, J=4.6, 8.7 Hz, 1H), 3.69 (s, 2H), 2.90 (t, J=5.9 Hz, 2H), 2.54 (t, J=6.4 Hz, 2H)

Step 7 - Synthesis of tert-butyl 5-fluoro-8-hydroxy-3,4-dihydroisoquinoline-2(1H)carboxylate (TP-2)

- 152 To a solution of FF-7 (1.0 g, 6 mmol) in DCM (25.00 mL) and MeOH (5 mL) was added Boc₂O (1.4 g, 6.6 mmol) followed by Et₃N (2.08 mL, 15.0 mmol) at 0 °C. Afterthe addition, the reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was acidified with aq. citric acid to pH 3~4 and the resulting mixture was partitioned between DCM and H₂O. The organic layer was separated and the aqueous layer was extracted with DCM. The combined organic layers were washed with sat. NaHCO₃, brine, dried over Na₂SO₄ and concentrated to afford the crude product which was purified via flash column chromatography (MeOHOCM = 1:10) to afford the TP-2 (744 mg, 47%) as a white soiid. MS 212 [M-55+1]; Ή NMR (400 MHz, DMSO-d₆) δ ppm 9.55 (s, 1H), 6.83 (t, J=9.0 Hz, 1H), 6.62 (dd, J=4.6, 8.9 Hz, 1H), 4.32 (s, 2H), 3.52 (t, J=5.9 Hz,

2H), 2.63 (t, J=5.6 Hz, 2H), 1.41 (s, 9H)

The procedures above in Scheme FF were used to synthesis the hydroxytetrahydroisoquinoline intermediates TP-3 through TP-7.

TP-3	OH AV	228 LCMS [M-55+1]	tert-butyl 6-chloro-8-hydroxy-3,4dihydroisoquinoline-2(1H)-carboxylate 1H NMR (400 MHz, DMSO-de) δ ppm 10.13 (s, 1H), 6.68 (S, 2H), 4.29 (s, 2H), 3.53 - 3.45 (t, J=5.6 Hz, 2H), 2.74 - 2.64 (t, J=5.5 Hz, 2H), 1.42 (s, 9H)
TP-4	OH ApN-B“	262 LCMS [M-55+1]	tert-butyl 8-hydroxy-6-(trifluoromethyl)-3,4dihydroisoquinoline-2(1 H)-carboxylate ’H NMR (400 MHz, DMSO-de) δ ppm 10.36 (br. s., 1H), 7.00 - 6.96 (s, 1H), 6.95 - 6.91 (s, 1H), 4.40 (S, 2H), 3.55 (t, J=5.8 Hz, 2H), 2.79 (t, J=5.6 Hz, 2H), 1.44 (s, 9H)
TP-5	OH jÔOb°c	208 LCMS [M-55+1]	tert-butyl 8-hydroxy-6-methyl-3,4dihydroisoquinoline-2(1H)-carboxylate 1H NMR (400 MHz, CDCh) δ ppm 6.58 - 6.51 (m, 1H), 6.46 (s, 1H), 4.51 (br. s., 2H), 3.643.60 (m, 2H), 2.80-2.76 (m, 2H), 2.25 (s, 3H), 1.51 (s, 9H)
TP-6	OH Jx ,Boc Ia j F	230 LCMS [M-55+1]	tert-butyl 5,6-difluoro-8-hydroxy-3,4dihydroisoquinoline-2(1H)-carboxylate 1H NMR (400 MHz, DMSO-de) δ ppm 10.04 (s, 1H), 6.63 (dd, J=6.8, 12.3 Hz, 1H), 4.30 (s, 2H), 3.60 - 3.50 (t, J=5.8 Hz, 2H), 2.75 - 2.65 (t, J=5.9 Hz, 2H), 1.42 (s, 9H)

-153TP-7

320 tert-butyl 8-hydroxy-5-iodo-3,4LCMS - dihydroisoquinoline-2(1H)-carboxylate

[M-55+1 ] ¹H NMR (400 MHz, DMSO-ds) δ ppm 9.93 (s,

1H), 7.50 (d, J=8.3 Hz, 1H), 6.54 (d, J=8.5 Hz,

1H), 4.32 (s, 2H), 3.59 - 3.49 (m, 2H), 2.57 (t, J=5.8 Hz, 2H), 1.42 (s, 9H)

Synthesis of tert-butyl 8-hydroxy-6-(2-hydroxypropan-2-yl)-3,4-dihydroisoquinoline-2(1 H)carboxylate (TP-9)

Scheme GG

BnBr, K₂CO₃ n-BuNH₄Br THF, rt

GG-1

LiOH, MeOH water

GG-2

GG-3

T₃P, DIPEA THF

H₂NOPiv

N'°^PiV

H

GG-4

[Cp*RhCI₂]₂ (5 mol%)

KOAc, MeCN ethylene

BH₃«Me₂S THF

Then MeOH THF, microwave

(Boc)₂O, Et₃N DCM, THF

Pd(OAc)₂ dppp, Et₃N

CO gas DMF, MeOH

Step 1 : Synthesis of benzyl 2-(benzyloxy)-4-bromobenzoate (GG-2)

To a solution of the salicyclic acid GG-1 (50 g, 230 mmol) in THF (1000 mL) was added potassium carbonate (95.5 g, 691 mmol), tetrabutyl ammonium bromide (14.9 g, 46.1 mmol) 10 and benzyl bromide (95.8 g, 576 mmol). The reaction was stirred at 20°C for 16 hours. The solution was filtered and concentrated under vacuum to afford the desired product GG-2 as a crude brown solid (150 g). This material was used in the next step without further purification.

TLC (PE./EA=10:1, Rf~0.5)

Step 2: Synthesis of 2-(benzyloxy)-4-bromobenzoic acid (GG-3)

To a solution of GG-2 (140 g, 352 mmol, crude, -53% of purity) in MeOH/water/DCM (500 mL/500 mL/500 mL) was added lithium hydroxide (44.4 g, 1060 mmol) at 10 °C. The reaction was stirred at 70°C for 16 hours. The solution was concentrated under vaccum and a yellow solid precipitated from the solution. The solids were filtered and the filter cake was washed with

-154water (50 mL X 2). The yellow solid was acidified with 1N HCl to pH=2. Yellow solid was filtered and dried in an infrared oven to give compound GG-3 (43.3 g, 40%) as a yellow solid. ¹NMR (400MHz, DMSO-d6) δ ppm 12.76 (bs, 1H), 7.61 (d, J=8.3 Hz, 1H), 7.52 - 7.47 (m, 2H), 7.44 (d, J=1.8 Hz, 1H), 7.43 - 7.38 (m, 2H), 7.37 - 7.31 (m, 1H), 7.23 (dd, J=1.8, 8.3 Hz, 1H), 5.25 (s,

2H).

Step 3: Synthesis of 2-(benzyloxy)-4-bromo-N-(pivaloyloxy)-benzamide (GG-4)

To a solution of GG-3 (31.2 g, 101.58 mmol) in THF (630 mL) was added T₃P (71.1 g, 112 mmol) at 0°C. After the addition, the reaction mixture was stirred for 30 minutes at 25°C. To the above solution was added DIPEA (78.8 g, 609 mmol) followed by O-pivaloylhydroxylamine (28 10 g, 112 mmol). After the addition, the reaction mixture was stirred at 25°C for 2 hours. The solution was transferred to a separatory funnel with EtOAc (500 mL) and washed with 1 portion water (300 mL), 1 portion citric acid aq. (300 mL), 1 portion sat. NaHCO₃, and 1 portion brine (300 mL). The organic layer was dried over Na₂SO₄, filtered, and concentrated under vacuum. The crude residue was purified via flash column chromatography (silica gel, petroleum 15 ether:EtOAc=7:1) to afford compound GG-4 (30.4 g, 74%) as a yellow solid. ¹H NMR (400MHz,

DMSO-d6) δ ppm 10.74 (s, 1H), 8.06 (d, J=8.5 Hz, 1H), 7.52 - 7.35 (m, 5H), 7.28 (d, J=1.5 Hz, 1H), 7.26 (d, J=1.8 Hz, 1H), 7.23 (d, J=1.5 Hz, 1H), 5.27 (s, 2H), 1.34 (s, 9H)

Step 4: Synthesis of 8-(benzyloxy)-6-bromo-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl pivalate (GG-5)

A suspension of GG-4 (40.7 g, 100.18 mmol), KOAc (10.8 g, 110 mmol) and Cp₂RhCI₂ (3.1 g, 5.01 mmol) in MeCN (1300 mL) was cooled to 0°C and the solution was sparged with ethylene gas for 45 minutes. The vessel was sealed and stirred at 10°C for 16 hours. The reaction suspension was filtered and the cake was washed with 2 portions of a 5:1 mixture of DCM/MeOH (100 mL). The filtrate was concentrated under reduced pressure to give the crude 25 product (50 g) as a yellow solid. The crude residue was purified via flash column chromatography (silica gel, DCM:MeOH=40:1) to afford compound GG-5 (28 g, 84%) as a yellow solid. LCMS [M+H+Na] 356 observed; Ή NMR (400 MHz, DMSO-c/s) δ ppm 7.79 (t, J=3.1 Hz, 1H) 7.53-7.59 (m, 2H) 7.35 - 7.42 (m, 2H) 7.30 - 7.34 (m, 1 H) 7.26 (d, J=2.0 Hz, 1H) 7.15 (d, J=2.0 Hz, 1H) 5.20 (s, 2H) 3.25 (td, J=6.1,3.6 Hz, 2H) 2.83 (t, J=6.3 Hz, 2H).

Step 5: Synthesis of 8-(benzyloxy)-6-bromo-3,4-dihydroisoquinolin-1(2H)-one (GG-6)

To a mixture of GG-5 (36.5 g, 110 mmol) in anhydrous THF (700 mL) was added BH₃Me₂S (10M, 33 mL, 330 mmol) at 0°C dropwise under N₂. After the addition, the reaction was stirred at

- 155 5 °C for 12 hours. At this stage, the reaction mixture was heated at 78°C (reflux) for 3 hours to drive completion. The reaction was allowed to cool gradually to rt and carefully quenched with 70 mL of MeOH at 0°C. The solution was concentrated then taken up in THF (2 mL) and MeOH (10 mL) and transferred to a microwave vial. The solution was heated at 120°C in a microwave reactor for 1 hour. The solution was concentrated to afford a black solid. The crude residue was purified via flash column chromatography (120 g silica gel x 3, MeOH/DCM=10%~20%) to afford compound GG-6 (8.28 g, 24%) as a brown solid. LCMS [M+H] 319 observed; ¹H NMR (400 MHz, DMSO-de) δ ppm 8.99 (br. s, 1H) 7.37 - 7.50 (m, 5H) 7.23 (d, J=1.3 Hz, 1H) 7.11 (d, J=1.3 Hz, 1 H) 5.21 (s, 2H) 4.11 (s, 2H) 2.97 (t, J=5.9 Hz, 2H).

Step 6: Synthesis of tert-butyl 8-(benzyloxy)-6-bromo-3,4-dihydroisoquinoline-2(1H)carboxylate (GG-7)

To a mixture of GG-6 (10.99 g, 34.537 mmol) in DCM (110 mL) and THF (22 mL) were added Et₃N (10.5 g, 104 mmol) and (Boc)₂O (11.3 g, 51.8 mmol) at 10 °C. The reaction was stirred at 10°C for 16 hours. The mixture was concentrated under vacuum to give the crude product as black gum. The crude residue was purified by flash column chromatography (120 g of silica gel, EtOAc/Petroleum ether from 4% to 7%) to afford compound GG-7 (9.9 g, 68.5%) as yellow gum. LCMS [M+H-Boc] 319 observed; Ή NMR (400MHz, CHLOROFORM-d) δ ppm 7.48 7.30 (m, 5H), 6.98 - 6.88 (m, 2H), 5.15 - 4.96 (m, 2H), 4.60 - 4.44 (m, 2H), 3.71 - 3.54 (m, 2H), 2.88-2.71 (m, 2H), 1.50 (s, 9H).

Step 7: Synthesis of 2-(tert-butyl) 6-methyl 8-(benzyloxy)-3,4-dihydroisoquinoline-2,6(1H)dicarboxylate (GG-8)

A mixture of GG-7 (600 mg, 1.43 mmol), DPPP (296 mg, 0.717 mmol), TEA (435 mg, 4.30 mmol) and Pd(OAc)₂ (161 mg, 0.717 mmol) in MeOH (20 mL) and DMF (20 mL) was heated at 120 °C under 22 bar of carbon monoxide for 24 hours. The mixture was concentrated under vacuum and transferred to a separatory funnel with EtOAc. The solution was washed with 5 portions brine, dried over sodium sulfate, filtered, and concentrated under vacuum. The crude residue was purified via flash column chromatography (12 g, silica gel, 20% EtOAc/petroleum ether) to afford compound GG-8 (440 mg, 77% yield) as a white solid. ¹H NMR (400MHz, CHLOROFORM-d) δ ppm 7.54 - 7.28 (m, 7H), 5.22 - 5.08 (m, 2H), 4.67 - 4.54 (m, 2H), 3.91 (s, 3H), 3.70 - 3.57 (m, 2H), 2.93 - 2.77 (m, 2H), 1.50 (s, 9H).

Step 8: Synthesis of tert-butyl 8-(benzyloxy)-6-(2-hydroxypropan-2-yl)-3,4dihydroisoquinoline-2(1 H)-carboxylate (GG-9)

- 156To a colorless solution of GG-8 (327 mg, 0.823 mmol) in dry THF (15 mL) was added MeMgBr (3.0 M solution in diethyl ether, 1.65 mL, 4.94 mmol) dropwise at 0°C. The mixture was stirred at 17°C for 1.5 hours. The solution was cooled to 0°C and quenched with water (10 mL). The solution was transferred to a separatory funnel with EtOAc and the phases were separated. The 5 aqueous phase was extracted with 2 portions EtOAc (20 mL). the combined organic extracts were washed with 1 portion brine (30 mL), dried over sodium sulfate, filtered, and concentrated under vacuum. The crude residue was purified via flash column chromatography (silica gel, 12 g, petroleum ether:EA=3:1) to afford compound GG-9 (320 mg, 98%) as colorless gum. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.29 - 7.49 (m, 5H) 6.97 (s, 1H) 6.84 (s, 1H) 5.12 (br. s., 10 2H) 4.58 (s, 2H) 3.65 (br. s., 2H) 2.82 (br. s., 2H) 1.57 (s, 6H) 1.49 (s, 9H).

Step 9: Synthesis of tert-butyl 8-hydroxy-6-(2-hydroxypropan-2-yl)-3,4dihydroisoquinoline-2(1 H)-carboxylate (TP-9)

A mixture of GG-9 (290 mg, 0.73 mmol) and Pd/C (105 mg) in MeOH (10 mL) was stirred at 15°C for 5 hours under a balloon of hydrogen. The mixture was filtered through a pad of Celite 15 and the filtrate concentrated under vacuum. The crude residue was purified via flash column chromatography (4 g, silica gel, 60% EtOAc/petroleum ether) to afford compound TP-9 (144 mg, 64%) as a white solid. 1H NMR (400MHz, CHLOROFORM-d) δ ppm 6.91 (br. s., 1H), 6.76 (s, 1H), 4.53 (br. s., 2H), 3.63 (br. s., 2H), 2.80 (br. s., 2H), 1.55 (s, 6H), 1.50 (s, 9H).

A sequence consisting of Steps 1-6 & 9 from Scheme GG were used to synthesis the hydroxytetrahydroisoquinoiine intermediates TP-8 (Scheme III), TP-10 -12 from the appropriate salicyclic acid.

TP-8 (see Scheme iil) OBn /L/CO2 h F	OH jAjQn -B°C F	226 LCMS [M-55+1]	tert-butyl 5-fluoro-8-hydroxy-6-methyl-3,4dihydroisoquinoline-2(1H)-carboxylate 1H NMR (400 MHz, MeOD) δ ppm 6.45 (d, J=6.3 Hz, 1H), 4.40 (s, 2H), 3.66 - 3.50 (m, 2H), 2.70 (t, J=5.9 Hz, 2H), 2.14 (d, J=1.5 Hz, 3H), 1.50- 1.47 (m, 9H)
TP-10 OBn A^co2h F	OH ApN-Boc F	246 LCMS = [M-55+1]	tert-butyl 6-chloro-5-fluoro-8-hydroxy-3,4dihydroisoquinoline-2(1H)-carboxylate 1H NMR (400 MHz, DMSO-de) δ ppm 10.06 (s, 1H), 6.76 (d, J=6.3 Hz, 1H), 4.31 (s, 2H), 3.54 (t, J=5.8 Hz, 2H), 2.69 (t, J=5.8 Hz, 2H), 1.42 (s, 9H)

- 157-

TP-11 OBn A.CO2H IJ Br 'y F	OH ApN'Boc ΒΓψ'^'^ F		tert-butyl 6-bromo-5-fluoro-8-hydroxy-3,4dihydroisoquinoline-2(1H)-carboxylate 1H NMR (400 MHz, DMSO-de) δ ppm 10.04 (s, 1H), 6.88 (d, J=5.8 Hz, 1H), 4.30 (s, 2H), 3.54 (t, J=5.8 Hz, 2H), 2.69 (t, J=5.9 Hz, 2H), 1.42 (s, 9H)
TP-12 OBn J\,CQ2H Br '^	OH ^ΐΡ^'ΝΒοο	272 LCMS [M-55 +1]	tert-butyl 6-bromo-8-hydroxy-3,4dihydroisoquinoline-2(1H)-carboxylate ; 1H NMR (400 MHz, CDCI3) δ ppm 6.94 - 6.66 (m, 2H), 4.46 (m, 2H), 3.61 (t, J=5.6 Hz, 2H), 2.76 (m, 2H), 1.51 (s, 9H)

Synthesis of tert-butyl 6-ethyl-8-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (TP13)

Scheme HH

Pd(dppf)CI₂, K3PO4 3H₂O, dioxane

MeOH

Pd-C, H₂

OH

Step 1 - Synthesis of tert-butyl 8-(benzyloxy)-6-vinyl-3,4-dihydroisoquinoline-2(1H)carboxylate (HH-1)

A mixture of GG-7 (530 mg, 1.27 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane 10 (410 mg, 2.67 mmol), K₃PO₄.3H₂O (675 mg, 2.53 mmol), PdCI₂(dppf) (93 mg, 0.013 mmol) in dioxane (20 mL) and H₂O (5 mL) was degassed with N₂ heated at 100 °C for 2 hours. The mixture was purified by pre-TLC (Petroleum Ether/EtOAc=8/1) to afford HH-1 (370 mg, 80%) as a colorless gum. LCMS 266 [M-Boc+1]; Ή NMR (400 MHz, CDCI₃) δ ppm 7.51 - 7.28 (m, 5H), 6.83 (d, J=12.0 Hz, 2H), 6.65 (dd, J=10.9, 17.4 Hz, 1H), 5.69 (d, J=17.6 Hz, 1H), 5.22 (d, J=10.8

Hz, 1H), 5.12 (br. s., 2H), 4.58 (br. s., 2H), 3.73 - 3.56 (m, 2H), 2.90 - 2.73 (m, 2H), 1.50 (s, 9H)

Step 2 - Synthesis of tert-butyl 6-ethyl-8-hydroxy-3,4-dihydroisoquinoline-2(1H)carboxylate (TP-13)

- 158 A mixture of HH-1 (370 mg, 1.01 mmol) and Pd/C (370 mg) in MeOH (20 mL) was degassed with H₂ and stirred at 50 °C under H₂ (50 psi) for 24 hrs. The mixture was filtered and the filtrate was concentrated in vacuo to afford crude material which was purified by silica gel chromatography eiuted with EtOAc in petroleum ether from 0 to 20 % to afford TP-12 (210 mg,

75%) as a white solid. LCMS 222 [M-55+1]; ¹H NMR (400 MHz, CDCh) δ ppm 6.57 (br. s., 1 H),

6.48 (s, 1H), 4.51 (br. s., 2H), 3.63 (br. s., 2H), 2.78 (br. s, 2H), 2.62 - 2.45 (q, J=7.5 Hz, 2H), 1.50 (s, 9H), 1.20 (t, J=7.5 Hz, 3H)

Synthesis of tert-butyl 6-(difluoromethyl)-8-hydroxy-3,4-dihydroisoquinoline-2(1H)10 carboxylate (TP-14)

Scheme II

Step 1: Synthesis of tert-butyl 8-(benzyloxy)-6-formyl-3,4-dihydroisoquinoline-2(1H)carboxylate (11-1)

GG-7 (1000 mg, 2.390 mmol) in an oven dried two necked flask equipped with a thermometer 20 was dissolved in tetrahydrofuran (22.0 mL, c=0.109 M), cooled to -78°C, tert-butyllithium (459 mg, 7.17 mmol , 4.22 mL, 1.7 M) was added slowly under N₂ while maintaining the internai température around -70°C, stirred at -78°C for 30 min, Ν,Ν-dimethyl formamide (262 mg, 3.59 mmol) was added dropwise and stirred at -78°C for 1.5 h. The reaction was quenched by std.

NH₄CI at -78°C, extracted with EtOAc 3 times. The organic layers were combined, washed with 25 brine, dried over Na₂SO₄, concentrated and purified by column chromatography with 15% EtOAc/heptane to give 11-1 (300 mg, 34% yield) as a colorless oil.

LCMS [M+1-Boc] 268.10. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.51 (s, 9 H) 2.91 (t, J=5.38 Hz, 2 H) 3.68 (t, J=5.69 Hz, 2 H) 4.65 (s, 2 H) 5.17 (br. s., 2 H) 7.29 (d, J=9.05 Hz, 2 H) 30 7.31 - 7.37 (m, 1 H) 7.40 (t, J=7.27 Hz, 2 H) 7.43 - 7.48 (m, 2 H) 9.92 (s, 1 H)

-159Step 2: Synthesis of tert-butyl 8-(benzyloxy)-6-(difluoromethyl)-3,4-dihydroisoquinoline2(1H)-carboxylate (II-2)

To a solution of 11-1 (300 mg, 0.816 mmol) in DCM (16.3 mL, c=0.05 M) at 0°C was added (diethylamino)sulfur trifluoride (1320 mg, 8.16 mmol, 1070 uL). The reaction was removed from the ice bath and stirred at r.t. overnight. The reaction was diluted with DCM and quenched with std. NaHCO₃, stirred at r.t. until CO₂ évolution ceased. The layers were separated and the aqueous was extracted with DCM. The organic layer was dried over Na₂SC>4 and concentrated, purified by column chromatography with 15% EtOAc/heptane to give II-2 (240 10 mg, 75% yield) as a clear oil.

LCMS [M+1-Boc] 290.10. Ή NMR (400 MHz, CHLOROFORM-d) δ ppm 1.51 (s, 9 H) 2.86 (t, J=5.26 Hz, 2 H) 3.66 (t, J=5.62 Hz, 2 H) 4.61 (s, 2 H) 5.13 (br. s., 2 H) 6.58 (t, J=57.22 Hz, 1 H) 6.92 (d, J=8.31 Hz, 2 H) 7.31 - 7.48 (m, 5 H)

Step 3: Synthesis of tert-butyl 6-(difluoromethyl)-8-hydroxy-3,4-dihydroisoquinoline2(1H)-carboxylate (TP-14)

To a solution of II-2 (240 mg, 0616 mmol) in methanol (10 mL) was added palladium on carbon 20 (66 mg, 0.616 mmol). The reaction solution was degassed and back filled with hydrogen gas.

The mixture was fitted with a hydrogen balloon and stirred at rt overnight. The reaction was filtered, the solvents removed in vacuo and the material purified by column chromatography with 20% EtOAc/heptane to give TP-14 (175 mg, 95% yield) as a white solid.

LCMS [M+1-tBu] 242. Ή NMR (400 MHz, CHLOROFORM-d) δ ppm 1.52 (s, 9 H) 2.84 (br. s., 2 H) 3.66 (t, J=5.81 Hz, 2 H) 4.56 (br. s., 2 H) 6.53 (t, J=57.22 Hz, 1 H) 6.76 (s, 1 H) 6.84 (br. s., 1 H)

Synthesis of tert-butyl 6-(1,1-difluoroethyl)-8-hydroxy-3,4-dihydroisoquinoline-2(1H)30 carboxylate (TP-15)

Scheme JJ

-160 -

1) Pd₂dba₃ toluene, 90°C

2) 4N HCl

93% overall

Step 1: Synthesis of benzyl 4-acetyl-2-(benzyloxy)benzoate (JJ-1)

The mixture of GG-2 (8544 mg, 21.51 mmol), tributyl(1-ethoxyvinyl)tin (8160 mg, 22.6 mmol), Pd₂(dba)₃ (394 mg, 0.430 mmol) and 2,2'-bis(diphenylphosphino)-1,T-binaphthyl (536 mg, 0.860 mmol) in toluene (108 mL, c=0.2 M) was degassed and heated at 90°C for 18 h. Toluene was removed and the crude was carried to next step.

The crude was dissolved in THF (108 mL, c=0.20 M), hydrochloric acid (6670 mg, 183 mmol ,

45.7 mL, 4.0 M) was added, stirred at r.t. for 2 hrs. The organic solvent was removed; H₂O was added, extracted with EtOAc 3 times. The organic layers were combined, washed with brined, dried over Na₂SO₄, filtered and concentrated, purified with silica gel chromatography eluted with 15% EtOAc/heptane to give 7180 mg yellow oil.

LCMS [M+1] 361.10. Ή NMR (400 MHz, CHLOROFORM-d) δ ppm 2.60 (s, 3 H) 5.23 (s, 2 H)

5.37 (s, 2 H) 7.29 - 7.42 (m, 8 H) 7.45 (d, J=6.85 Hz, 2 H) 7.54 (dd, J=8.01, 1.28 Hz, 1 H) 7.62 7.65 (m, 1 H) 7.90 (d, J=7.95 Hz, 1 H)

Step 2: Synthesis of benzyl 2-(benzyloxy)-4-(1,1-difluoroethyl)benzoate (JJ-2)

JJ-1 (7.380 g, 20.48 mmol) was added deoxofluor (22.7 g, 102 mmol). The reaction mixture was heated to 80°C for 4.5 hrs, cooied to r.t., poured into std. NaHCOs, and after CO₂ évolution ceased, the aqueous was extracted with EtOAc 3 times. The organic layer was concentrated under vacuum, purified by column chromatography with 10% EtOAc/heptane to give JJ-2 (5.94 25 g, 76% yield) as a colorless oil which solidified upon vacuum.

- 161 Ή NMR (400 MHz, CHLOROFORM-d) δ ppm 1.89 (t, J=18.16 Hz, 3 H) 5.19 (s, 2 H) 5.36 (s, 2

H) 7.12 (d, J=8.07 Hz, 1 H) 7.17 (s, 1 H) 7.29 - 7.42 (m, 8 H) 7.45 (d, J=6.72 Hz, 2 H) 7.89 (d, J=8.07 Hz, 1 H)

Step 3: Synthesis of 2-(benzyloxy)-4-(1,1-difluoroethyl)benzoic acid (JJ-3)

Following a similar procedure as step 2 in Scheme GG, JJ-2 was hydrolyzed to JJ-3 (4.49 g, 99%) as white solid.

Ή NMR (400 MHz, DMSO-d6) δ ppm 1.97 (t, J=18.89 Hz, 3 H) 5.26 (s, 2 H) 7.19 (d, J=7.95 Hz, 1 H) 7.29 - 7.36 (m, 2 H) 7.40 (t, J=7.34 Hz, 2 H) 7.51 (d, J=7.21 Hz, 2 H) 7.71 (d, J=7.95 Hz, 1 H) 12.89 (br. s., 1 H)

Step 4-8: Synthesis of tert-butyl 6-(1,1-difluoroethyl)-8-hydroxy-3,4-dihydroisoquinoline15 2(1 H)-carboxylate (TP-15)

Following similar procedures as step 3 in Scheme GG (1.30 g, 70%), step 4 in Scheme GG (684 mg, 65%), steps 5 in Scheme FF and step 6 in Scheme GG (575 mg, 77%), step 9 in Scheme GG (400 mg, 90%), JJ-3 was converted to TP-15.

LCMS [M+1-Boc] 214.10. Ή NMR (400 MHz, CHLOROFORM-d) δ ppm 1.52 (s, 9 H) 1.87 (t, J=18.10 Hz, 3 H) 2.83 (br. s., 2 H) 3.65 (t, J=5.69 Hz, 2 H) 4.56 (br. s., 2 H) 6.76 (s, 1 H) 6.83 (br. s., 1 H)

Synthesis of tert-butyl 8-hydroxy-3,4-dihydro-2,6-naphthyridine-2(1H)-carboxylate (TP-16)

Scheme KK

HjNOPiv

57%

[Cp*RhCI₂]₂ (5 mol%)

CsOPiv, DCE ethylene 70%

LAH/THF

50%

48% HBr HOAc, reflux

100%

(Boc)₂O

Et₃N, DCM

51%

KK-4 KK-5 TP-¹6

Step 1-3: Synthesis of 8-methoxy-1,2,3,4-tetrahydro-2,6-naphthyridine (KK-4)

- 162 Following similar procedures as step 3 in Scheme GG (939 mg, 57%), step 4 in Scheme GG using césium pivolate and dichloroethane in place of potassium acetate and acetonitrile (290 mg, 70%), and steps 5 in Scheme FF (136 mg, 50%), KK-1 was converted to KK-4.

LCMS [M+1] 165.10. Ή NMR (400 MHz, CHLOROFORM-d) δ ppm 2.77 (t, J=5.81 Hz, 2 H)

3.11 (t, J=5.81 Hz, 2 H) 3.90 (s, 3 H) 3.94 (s, 2 H) 8.03 (d, J=2.93 Hz, 2 H)

Step 4: Synthesis of 5,6,7,8-tetrahydro-2,6-naphthyridin-4-ol (KK-5)

KK-4 (136.0 mg, 0.828 mmol) in 5 mL 48% HBr and 3 mL glacial acetic acid was sealed and refluxed at 120°C for 4 days. The reaction was cooled to RT, concentrated off the acetic acid by azeotroping from heptanes 3 times, neutralized by careful addition of 5 N NaOH until pH around 9. Rotavaporated to remove most H₂O, added MeOH, dried packed with silica gel. The product 15 was purified by column chromatography with 10% MeOH/DCM with 0.5%NH₄OH to give KK-5 (124 mg, 100%). LCMS [M+1] 151.10.

Step 5: Synthesis of tert-butyl 8-hydroxy-3,4-dihydro-2,6-naphthyridine-2(1H)-carboxylate (TP-16)

Following similar procedures as step 6 in Scheme GG, KK-5 was converted to TP-16 (106 mg, 51%).

LCMS [M-55+1] 228. Ή NMR (400 MHz, DMSO-d₆) δ ppm 10.13 (s, 1H), 6.68 (s, 2H), 4.29 (s, 25 2H), 3.53 - 3.45 (t, J=5.6 Hz, 2H), 2.74 - 2.64 (t, J=5.5 Hz, 2H), 1.42 (s, 9H)

Synthesis of tert-butyl 8-hydroxy-5-methyl-3,4-dihydro-2,6-naphthyridine-2(1H)carboxylate (TP-17)

Scheme LL

-163-

LAH/THF

T₃P, DIPEA THF

H₂NOPiv

68%

OBn

[Cp*RhCI₂]₂ (5 mol%)

CsOPiv, DCE ethylene 49%

64%

(Boc)₂O DIPEA, THF

96%

LL-7

Pd/C, H₂

MeOH

100%

OH

TP-17

Step 1 : Synthesis of (5-(benzyloxy)-2-methylpyridin-4-yl)(ethoxy)methanol (LL-2)

Ethyl 5-hydroxy-2-methylisonicotinate (LL-1) (synthesis described in WO10100475) (2190 mg,

17.22 mmol) and N-benzyl bromide (3540 mg, 20.7 mmol), K2CO3 (4810 mg, 34.4 mmol) in 20 5 mL DMF was heated at 80°C overnight. After the reaction mixture cooled to r.t., EtOAc was added, washed with H₂O 3 times. The organic layer was concentrated, purified by column chromatography with 30% EtOAc/heptane to give LL-2 (16 g, 48% yield) as a brown solid.

LCMS [M+1] 272.10. Ή NMR (400 MHz, CHLOROFORM-d) δ ppm 1.37 (t, J=7.15 Hz, 3 H)

2.54 (s, 3 H) 4.39 (q, J=7.13 Hz, 2 H) 5.23 (s, 2 H) 7.34 (d, J=7.09 Hz, 1 H) 7.36 - 7.43 (m, 2 H) 10 7.44- 7.51 (m, 3 H) 8.35 (s, 1 H)

Step 2: Synthesis of (5-(benzyloxy)-2-methylpyridin-4-yl)methanediol (LL-3)

To a solution of LL-2 (2160 mg, 7.961 mmol) in 20 mL MeOH was added sodium hydroxide (1590 mg, 39.8 mmol, 7.96 mL, 5.0 M), and the reaction was heated at 50°C for 4 hrs. The mixture was cooled to r.t., MeOH was evaporated, H₂O was added, neutralized with 1 N HCl to 15 pH about 4, the yellow solid crashed out which was filtered and rinsed with H₂O to give LL-3 (1.66 g, 86% yield).

LCMS [M+1] 244.10. Ή NMR (400 MHz, DMSO-d6) δ ppm 2.42 (s, 3 H) 5.27 (s, 2 H) 7.33 (d, J—7.21 Hz, 1 H) 7.35 - 7.43 (m, 3 H) 7.44 - 7.52 (m, 2 H) 8.41 (s, 1 H)

Step 3-7: - Synthesis of tert-butyl 8-hydroxy-5-methyl-3,4-dihydro-2,6-naphthyridine20 2(1 H)-carboxylate (TP-17)

Following similar procedures as step 3 in Scheme GG (1.60 g, 68%), step 4 in Scheme GG using césium pivolate and dichloroethane in place of potassium acetate and acetonitrile (620

- 164mg, 49%), steps 5 in Scheme FF (366 mg, 64%), step 6 in Scheme GG (483 mg, 96%), and step 9 in Scheme GG (386 mg, 100%), LL-3 was converted to TP-17.

Ή NMR (400 MHz, CHLOROFORM-d) δ ppm 1.51 (s, 9 H) 2.41 (s, 3 H) 2.71 (t, J=5.38 Hz, 2 H) 3.69 (t, J=5.75 Hz, 2 H) 4.59 (s, 2 H) 7.95 (s, 1 H)

Synthesis of tert-butyl 6-cyano-8-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (TP18)

Scheme MM

Zn(CN)₂, Pd₂(dba)₃

DMF, microwave

H₂, Pd-C

MeOH

TP-18

Step 1: Synthesis of tert-butyl 8-(benzyloxy)-6-cyano-3,4-dihydroisoquinoline-2(1H)carboxylate (MM-1)

Compound GG-7 (700 mg, 1.67 mmol) was dissolved in DMF (5.00 mL). Zn(CN)₂ (236 mg, 2.01 mmol) was added to the above solution. The reaction solution was degassed for 2 min. Pd(PPh₃)4 (580 mg, 0.502 mmol) was added to the above mixture. The reaction mixture was degassed with N₂ for 3 min. Then the reaction mixture was heated by microwave at 150 °C for 30 min. The reaction solution became black from yellow. The reaction solution was cooled and diluted with EtOAc/H₂O (8 mL/ 8mL), then the mixture was filtered, and the filtrate was extracted. The organic layer was separated, dried and evaporated to give the crude product which was purified by flash chromatography with petroleum ether/EtOAc from 0-25% to give MM-1 (350 mg, 57%) as a white solid. LCMS 265 [M-Boc]⁺; ¹H NMR (400MHz, DMSO-ds) δ ppm 7.52 - 7.32 (m, 6H), 7.29 (s, 1H), 5.22 (br. s., 2H), 4.53 - 4.40 (m, 2H), 3.54 (t, J=5.6 Hz, 2H), 2.79 (t, J=5.5 Hz, 2H), 1.41 (s, 9H)

Step 2: Synthesis of tert-butyl 6-cyano-8-hydroxy-3,4-dihydroisoquinoline-2(1H)carboxylate (TP-18)

Compound MM-1 (320 mg, 0.878 mmol) was dissolved in MeOH (3 mL). Pd/C (93 mg, 0.44 mmol) was added to the reaction solution and degassed by H₂ balloon three times, and stirred under H₂ balloon at 20 °C for 1 hour. DCM (5 mL) was added to the above mixture, the reaction mixture was filtered and concentrated to give the crude product, which was purified by flash

-165chromatography with petroleum ether/EtOAc from 0-50% to give TP-18 as a white solid (125 mg, 51.9%). LCMS [219-tBu]⁺; ¹H NMR (400 MHz, CDCh) δ ppm 7.45 - 7.28 (m, 1H), 7.10 6.95 (m, 1H), 6.87 (br. s., 1H), 4.57 (br. s., 2H), 3.66 (t, J=5.9 Hz, 2H), 2.82 (br. s., 2H), 1.53 (s, 9H)

Examples 84-98 were made in a similar fashion to Example 78 in Scheme CC using the appropriate NBoc-protected tetrahydroisoquinoline in step 1.

Example 84 TP-2 OH BocN^ F	H Ν''	0^ F	π ΐ N ν' YOH OH	399 [M+1]	(1 S,2S,3S,5R)-3-((5-fluoro-1,2,3,4tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7Hpyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol 1H NMR (400 MHz, DMSO-de) δ ppm 8.63 (s, 1H), 7.62 (d, J=3.5 Hz, 1H), 6.96 - 6.89 (m, 1H), 6.86 - 6.80 (m, 1H), 6.72 (d, J=3.5 Hz, 1H), 5.31 (d, J=3.8 Hz, 1H), 5.16 - 5.06 (m, 2H), 4.59 4.49 (m, 2H), 4.00 - 3.95 (m, 1H), 3.82 (s, 2H), 2.91 (t, J=5.8 Hz, 2H), 2.88 - 2.77 (m, 1H), 2.64 (s, 3H), 2.57 (t, J=5.8 Hz, 2H), 1.92 (ddd, J=3.8, 9.3, 13.6 Hz, 1H)
Example 85				399	(1 S,2S,3S,5R)-3-((6-fluoro-1,2,3,4-
TP-1				[M+1]	tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7H-
					pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol
OH			V'OH		1H NMR (400 MHz, MeOD-d4) δ ppm 8.61 (s,
EiocN		(T	OH		1H), 7.55 (d, J=3.5 Hz, 1H), 6.75 (d, J=3.8 Hz,
	H Ν'		f		1H), 6.68 (dd, J=2.3, 10.8 Hz, 1H), 6.49 (dd, J=2.1, 9.2 Hz, 1H), 5.24 (q, J=8.8 Hz, 1H), 4.74 4.63 (m, 2H), 4.17 (d, J=4.8 Hz, 1H), 3.93 (s, 2H), 3.06 (t, J=5.9 Hz, 2H), 3.03 - 2.94 (m, 1H), 2.80 (t, J=5.8 Hz, 2H), 2.22 - 2.10 (m, 1H)
Example 86				415	(1 S,2S,3S,5R)-3-((5-chloro-1,2,3,4-
TP-19			N	[M+1]	tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7H-
				pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol
OH			y-oh		1H NMR (400 MHz, MeOD-d4) δ ppm 8.64 (s,
BocN^^Jj^	H Ν''	o'	OH		1H), 7.57 (d, J=4.0 Hz, 1H), 7.25 (d, J=9.0 Hz, 1H), 6.92 (d, J=8.5 Hz, 1H), 6.77 (d, J=3.5 Hz,
Cl		Cl			1H), 5.25 (q, J=9.0 Hz, 1H), 4.72 (dd, J=4.8, 8.3 Hz, 2H), 4.20 (d, J=4.5 Hz, 1H), 4.03 (s, 2H), 3.16 (t, J=6.0 Hz, 2H), 3.07 - 2.91 (m, 1H), 2.83 _

- 166-

			(t, J=5.8 Hz, 2H), 2.74 (s, 3H), 2.27 - 2.05 (m, 1H)
Example 87 TP-3 OH BocN^X|Ji X/\X-Ci	CfS X/0H 0 - I OH	415 [M+1]	(1S,2S,3S,5R)-3-((6-chloro-1,2,3,4tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7Hpyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol 1H NMR (400MHz, DMSO-de) δ ppm 8.62 (s, 1H), 7.62 (d, J=3.8 Hz, 1H), 6.92 (s, 1H), 6.76 (s, 1H), 6.72 (d, J=3.5 Hz, 1H), 5.41 - 5.35 (m, 1H), 5.10 (d, J=9.3 Hz, 2H), 4.63 - 4.44 (m, 2H), 3.99 - 3.91 (m, 1H), 3.78 (s, 2H), 2.93 - 2.78 (m, 3H), 2.69 - 2.59 (m, 4H), 2.02 - 1.88 (m, 1H)
Example 88 TP-5 OH I	Γ>·οη O*^T 1 OH HN^'y	395 [M+1]	(1S,2S,3R,5S)-3-(4-methyl-7H-pyrrolo[2;3d]pyrimidin-7-yl)-5-[(6-methyl-1,2,3,4tetrahydroisoquinolin-8-yl)oxy]cyclopentane-1,2diol 1H NMR (400 MHz, MeOD-d4) δ ppm 8.64 (s, 1H), 7.56 (d, J=3.8 Hz, 1H), 6.77 (d, J=3.8 Hz, 1H), 6.70 - 6.66 (s, 1H), 6.61 - 6.55 (s, 1H), 5.34 - 5.23 (m, 1H), 4.73 - 4.66 (m, 2H), 4.22 - 4.16 (m, 1H), 3.96 (s, 2H), 3.07-3.06 (m, 3H), 2.84 2.76 (m, 2H), 2.73 (s, 3H), 2.30 (s, 3H), 2.18 2.07 (m, 1H)
Example 89 TP-12 OH BocN'^X^X	χΛ nV £ / oh OZ 7 ! OH hXX''	459 [M+1]	(1 S,2S,3S,5R)-3-((6-bromo-1,2,3,4tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7Hpyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol 1H NMR (400 MHz, MeOD-d4) δ ppm 8.63 (s, 1H), 7.57 (d, J=3.5 Hz, 1H), 7.13 (s, 1H), 7.05 6.94 (m, 1H), 6.76 (d, J=3.8 Hz, 1H), 5.22 (q, J=9.0 Hz, 1H), 4.76 - 4.67 (m, 2H), 4.24 - 4.14 (m, 1H), 4.09 (s, 2H), 3.23 (t, J=6.0 Hz, 2H), 3.00 (ddd, J=7.3, 9.3, 14.3 Hz, 1H), 2.95 - 2.86 (m, 2H), 2.73 (s, 3H), 2.32-2.15 (m, 1H)
Example 90 TP-4 OH	CO J YOH cr -, I OH ηΧΑ i Il f FC	449 [M+1]	(1S,2S,3R,5S)-3-(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)-5-((6-(trifluoromethyl)-1,2,3,4tetrahydroisoquinolin-8-yl)oxy)cyclopentane-1,2diol 1H NMR (400 MHz, MeOD-d4) δ ppm 8.62 (s, 1H), 7.57 (d, J=3.5 Hz, 1H), 7.13 (s, 1H), 7.07 (s, 1H), 6.75 (d, J=3.8 Hz, 1H), 5.23 (q, J=9.0 Hz,

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			1H), 4.76 (dd, >2.6, 4.6 Hz, 1H), 4.72 (dd, J=4.9, 8.9 Hz, 1H), 4.18 (d, J=5.0 Hz, 1H), 4.03 (s, 2H), 3.12 - 3.06 (m, 2H), 3.00 (ddd, >7.3, 9.3, 14.3 Hz, 1H), 2.88 (t, >5.6 Hz, 2H), 2.71 (s, 3H), 2.27-2.17 (m, 1H)
Example 91				428	8-(((1 S, 2S,3S,4R)-2,3-dihydroxy-4-(4-methyl-7H-
TP-18				(B	[M+23]	pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl)oxy)-
				N»		1,2,3,4-tetrahydroisoqiiinoline-6-carbonitrile
BocN^^	OH			\'OH		1H NMR (400 MHz, MeOD-d4) δ ppm 8.64 (s,
Ci		cr	OH		1H), 7.58 (d, >3.5 Hz, 1H), 7.24 (s, 1H), 7.17 (s,
		HN^''				1H), 6.77 (d, >3.8 Hz, 1H), 5.29 - 5.19 (m, 1H), 4.80 - 4.69 (m, 2H), 4.19 (d, J=4.5 Hz, 1H), 4.03 (s, 2H), 3.10 - 3.07 (m, 2H), 3.05 - 2.97 (m, 1H), 2.90-2.84 (m, 2H), 2.74 (s, 3H), 2.27 - 2.23 (m, 1H)
Example 92				417	(1 S,2S,3S,5R)-3-((5,6-difluoro-1,2,3,4-
TP-6				CO	[M+1]	tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7H-
			N- 'N-^		pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol
	OH			YOH		1H NMR (400 MHz, MeOD-d4) δ ppm 8.62 (s,
BocN'		HN^	or	OH		1H), 7.55 (d, >3.8 Hz, 1H), 7.02 (dd, >6.9, 12.2 Hz, 1H), 6.75 (d, >3.5 Hz, 1H), 5.21 - 5.11 (m,
	F		F	F		1H), 4.76 - 4.70 (m, 1H), 4.70 - 4.63 (m, 1H), 4.22 - 4.15 (m, 3H), 3.37 (t, >6.3 Hz, 2H), 3.03 - 2.90 (m, 3H), 2.72 (s, 3H), 2.31 - 2.21 (m, 1H)
Example 93				433	(1 S,2S,3S,5R)-3-((6-chloro-5-fluoro-1,2,3,4-
TP-10				CO	[M+1]	tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7H-
					pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol
	OH			YOH		1H NMR (400 MHz, DMSO-de) δ ppm 8.63 (s,
BocN		H Ν'	ex	OH		1H), 7.63 (d, >3.5 Hz, 1H), 7.14 (d, >6.3 Hz, 1H), 6.72 (d, >3.8 Hz, 1H), 5.41 (d, >3.0 Hz,
			F	ΌΙ		1H), 5.21 - 4.96 (m, 2H), 4.65 - 4.46 (m, 2H), 4.06 - 3.90 (m, 3H), 3.08 (t, >5.8 Hz, 2H), 2.91 2.78 (m, 1H), 2.77 - 2.69 (m, 2H), 2.64 (s, 3H), 2.04-1.90 (m, 1H)

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Example 94 TP-11	HN^	(y Λ F	N' OF Br	ό N ΌΗ	477 [M+1]	(1 S,2S,3S,5R)-3-((6-bromo-5-fluoro-1,2,3,4tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7Hpyrrolo[2,3-d]pyrimidin-7-yi)cyclopentane-1,2-diol 1H NMR (400 MHz, DMSO-de) δ ppm 8.63 (s, 1H), 7.63 (d, J=3.76 Hz, 1H), 7.22 (d, J=5.52 Hz, 1H), 6.72 (s, 1H), 5.40 (d, J=3.76 Hz, 1H), 5.01 5.17 (m, 2H), 4.51 - 4.62 (m, 2H), 3.88 - 4.01 (m, 3H), 3.06 (t, J=5.90 Hz, 2H), 2.78 - 2.87 (m, 1H), 2.71 (t, J=5.27 Hz, 2H), 2.64 (s, 3H), 2.00 - 1.95 (m, 1H)
BOOM''''	OH νχ F
Example 95					382.1	(1S,2S,3R,5S)-3-(4-methyl-7H-pyrrolo[2,3-
TP-16				Ν'		[M+1]	d]pyrimidin-7-yl)-5-((5,6,7,8-tetrahydro-2,6-
							naphthyridin-4-yl)oxy)cyclopentane-1,2-diol
	OH		ϋ''		OH		1H NMR (400MHz, DMSO-de) δ ppm 8.63 (s,
BocN^		HN'''	'y il	ÔH			1H), 8.19 (s, 1H), 8.03 (s, 1H), 7.64 (d, J=3.8 Hz,
			A^n				1H), 6.72 (d, J=3.5 Hz, 1H), 5.43 (d, J=4.3 Hz, 1H), 5.17 - 5.06 (m, 2H), 4.71 (br. s., 1H), 4.62 4.53 (m, 1H), 4.04 - 3.97 (m, 3H), 3.10 (br. s., 2H), 2.95 - 2.83 (m, 1H), 2.78 (br. s., 2H), 2.64 (s, 3H), 2.08- 1.94 (m, 1H)
Example 96					396.1	(1S,2S,3S,5R)-3-((1-methyl-5,6,7,8-tetrahydro-
TP-17					ό	[M+1]	2,6-naphthyridin-4-yl)oxy)-5-(4-methyl-7H-
					N		pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol
	OH		o**	/	OH		1H NMR (400MHz, METHANOL-d4) δ ppm 8.62
BocN^		H N'''	Γ il	OH			(s, 1H), 8.03 (s, 1H), 7.56 (d, J=3.8 Hz, 1H), 6.75 (d, J=3.5 Hz, 1H), 5.29 - 5.12 (m, 1H), 4.75 (ddd, J=4.8, 9.0, 13.6 Hz, 2H), 4.20 (d, J=4.3 Hz, 1H), 4.09 (s, 2H), 3.22 (t, J=6.0 Hz, 2H), 3.05 - 2.94 (m, 1H), 2.79 (t, J=5.8 Hz, 2H), 2.72 (s, 3H), 2.40 (s, 3H), 2.30-2.19 (m, 1H)
Example 97					439	(1S,2S,3S,5R)-3-((6-(2-hydroxypropan-2-yl)-
TP-9						observe	1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-
			N-		d
	methyl-7H-pyrrolo[2,3-d]pyrimidin-7-
BocN^^	OH		ζΓ		OH	[M+H]	yl)cyclopentane-1,2-diol
^OH	HN^		'OH
			OH			1H NMR (400 MHz, METHANOL-d4) δ ppm 8.64 (s, 1 H) 7.57 (d, J=3.5 Hz, 1 H) 7.00 (s, 1 H) 6.88 (s, 1 H) 6.77 (d, J=3.5 Hz, 1 H) 5.29 (q, J=8.8 Hz, 1 H) 4.73 (s, 2 H) 4.22 (d, J=4.8 Hz, 1 H) 4.02 (s,

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			2 H) 3.12 (t, 9=5.9 Hz, 2 H) 3.03 (ddd, 9=14.6, 9.5, 7.0 Hz, 1 H) 2.87 (t, 9=5.8 Hz, 2 H) 2.73 (s, 3 H) 2.17 (ddd, 9=14.3, 8.4, 3.6 Hz, 1 H) 1.53 (s, 6 H)
Example 98 TP-7 OH BocN'^V'v O I	CO L / 0H ? °H HN^Y|| I	507 M+1	(1 S,2S,3S,5R)-3-((5-iodo-1,2,3,4tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7Hpyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol 1H NMR (400 MHz, DMSO-de) δ ppm 8.64 (s, 1H), 7.71 (d, J=8.4 Hz, 1H), 7.62 (s, 1H), 6.80 (d, J=8.8 Hz, 1H), 6.71 (s, 1H), 5.38 (s, 1H), 5.19 5.02 (m, 2H), 4.60-4.55 (m, 2H), 4.08 - 3.93 (m, 3H), 3.18 (s, 2H), 2.91 - 2.78 (m, 1H), 2.64 (br. s., 4H), 2.00-1.96 (m, 1H)

Example 99 (Scheme NN) - (1S,2S,3R,5S)-3-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin7-yl)-5-(( 1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)cyclopentane-1,2-diol (NN-5)

Scheme NN

Step 1 - Synthesis of tert-butyl ((1S,4R)-4-(4-chioro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7yl)cyclopent-2-en-1-yl) carbonate (NN-1)

Vial A: To a dry round bottom flask (purged with N₂) was added (S,S)-DACH-Naphthyl Trost Ligand (1.13 g, 1.43 mmol) and Pd₂(dba)₃.CHCI₃ (493 mg, 0.48 mmol). The vial was purged 10 with N₂ four times and DCE (50 mL, sparged with N₂ for 30 min) was added. The black solution was stirred for 30 min at 12 °C at which point a red-brown solution was obtained.

Vial B: To a dry round bottom flask (purged with N₂) was added BB-1 (7155 mg, 23.82 mmol), 4-chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine (4.5 g, 26.23 mmol) and Cs₂CO₃ (8.54 g, 26.2 mmol). The vial was purged with N₂ five times and DCE (50 mL) was added, foliowed by the

-170addition of the contents of Vial A via syringe. The reaction stirred at 12 °C under N₂ for 24 hours.

The reaction mixture was filtered and concentrated to a brown gum. The crude residue was purified by flash biotage (120 g, silica gel, EtOAc/petroleum ether = 15%) to give NN-1 (6.4 g,

76%) as an off-white solid. LCMS [M+1] 354; ¹H NMR (400 MHz, CDCh) δ ppm 8.62 (s, 1H),

7.08 (d, J=2.5 Hz, 1H), 6.35 - 6.29 (m, 1H), 6.10 - 6.00 (m, 2H), 5.63 - 5.55 (m, 1H), 3.11 (td, J=7.8, 15.4 Hz, 1H), 1.87 (td, J=3.8, 15.0 Hz, 1H), 1.52 (s, 9H)

Step 2 - Synthesis of tert-butyl 8-(((1S,4R)-4-(4-chloro-5-fluoro-7H-pyrrolo[2,3d]pyrimidin-7-yl)cyclopent-2-en-1-yl)oxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate (NN10 2)

To a dry microwave vial (purged with N₂) was added NN-1 (200 mg, 0.57 mmol), tert-butyl 8hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate(141 mg, 0.57 mmol), Cs₂CO₃ (203 mg, 0.622 mmol), Pd₂(dba)₃.CHCI₃ (15 mg, 0.014 mmol) and DPPP (14 mg, 0.03 mmol). Then the vial was purged with N₂ three times and DCE (2.6 mL, sparged with N₂ for 30 mins) was added.

The black mixture was stirred at 20 °C for 1 hour. Then the reaction mixture was directly purified by prep-TLC (petroleum ether:EtOAc=4:1) to give NN-2 (260 mg, 95%) as a white foam.

LCMS [M+23] 507; Ή NMR (400 MHz, CDCh) δ ppm 8.63 (s, 1H), 7.16 (d, J=2.0 Hz, 1H), 7.14 - 7.09 (m, 1H), 6.79 (d, J=7.3 Hz, 1H), 6.74 (d, J=7.5 Hz, 1H), 6.46 - 6.40 (m, 1H), 6.15 - 6.06 (m, 2H), 5.37 - 5.31 (m, 1H), 4.74-4.42 (m, 2H), 3.75 - 3.54 (m, 2H), 3.19 - 3.10 (m, 1H), 2.87 20 2.79 (m, 2H), 1.97 (d, J=14.6 Hz, 1H), 1.51 (s, 9H)

Step 2 - Synthesis of tert-butyl 8-(((1S,2S,3S,4R)-4-(4-chloro-5-fluoro-7H-pyrrolo[2,3d]pyrimidin-7-yl)-2,3-dihydroxycyclopentyl)oxy)-3,4-dihydroisoquinoline-2(1H)carboxylate (NN-3)

To a mixture of NN-2 (260 mg, 0.536 mmol) in DCM (9 mL)/H₂O (0.3 mL) was added NMO (188 25 mg, 1.61 mmol) and OsO₄ (4 % in t-BuOH, 204 mg, 0.0322 mmol) at 20 °C. The black mixture was stirred at 20 °C for 2 hours. The mixture was diluted with DCM (10 mL) and quenched by sat. Na₂SO₃ (5 mL) and separated. The aqueous layer was extracted with DCM (10 mL). The combined organic layer was washed with brine (10 mL), dried over Na₂SO₄, filtered and concentrated and purified by ISCO (12 g, silica gel, EtOAc:petroleum ether=1:1) to yield NN30 3 (230 mg, 83%) as a colorless gum.

LCMS [M+23] 541; Ή NMR (400 MHz, CDCh) δ ppm 8.62 (s, 1H), 7.17 (t, J=8.0 Hz, 1H), 7.13 (d, J=2.5 Hz, 1H), 6.86 - 6.79 (m, 2H), 5.21 - 5.05 (m, 1H), 5.02 - 4.75 (m, 2H), 4.67 - 4.56 (m,

- 171 1H), 4.53 - 4.42 (m, 2H), 4.37 - 4.29 (m, 1H), 3.72 - 3.57 (m, 2H), 3.32 - 2.99 (m, 2H), 2.87 2.78 (m, 2H), 2.33 - 2.22 (m, 1 H), 1.50 - 1.44 (m, 9H)

Step 3 - Synthesis of tert-butyl 8-(((1S,2S,3S,4R)-4-(4-amino-5-fluoro-7H-pyrrolo[2,3d]pyrimidin-7-yl)-2,3-dihydroxycyclopentyl)oxy)-3,4-dihydroisoquinoline-2(1H)5 carboxylate (NN-4)

A solution of NN-3 (105 mg, 0.202 mmol) in NH3.H2O and dioxane (2.8 mL /2.8 mL) was sealed in a steel tube at 90 °C for 15 hours. The reaction was concentrated to give NN-4 (101 mg, >99%) as a yellow gum and used directly in the next step. LCMS [M+23] 522

Step 4 - Synthesis of (1S,2S,3R,5S)-3-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)10 5-((1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)cyclopentane-1,2-diol (NN-5)

To a light yellow solution of NN-4 (101 mg, 0.202 mmol) in DCM (5 mL) was added TFA (1 mL) dropwise at 0 °C. The yellow solution mixture was stirred at 20 °C for 2 hours. The mixture was concentrated MeOH (4 mL) was added to the residue and basified by solid K2CO3 to pH 7-8. The mixture was filtered and concentrated purified by prep-HPLC to give NN-5 (35 mg, 39%) as a 15 light yellow solid.

LCMS [M+1] 400; Ή NMR (400 MHz, MeOD) δ ppm 8.09 (s, 1H), 7.35 - 7.23 (m, 1H), 7.15 7.06 (m, 1H), 7.03 - 6.96 (m, 1H), 6.94 - 6.83 (m, 1H), 5.16 - 5.07 (m, 1H), 4.75 - 4.68 (m, 1H), 4.63 - 4.55 (m, 1H), 4.37 (s, 2H), 4.22 - 4.16 (m, 1H), 3.54 - 3.44 (m, 2H), 3.17 - 3.08 (m, 2H), 3.04 - 2.92 (m, 1H), 2.16 - 2.02 (m, 1H)

Examples 100-111 were made in a similar fashion to Example 99 in Scheme NN using the appropriate NBoc-protected tetrahydroisoquinoline in step 2.

Example 100

418 [M+1] (1S,2S,3R,5S)-3-(4-amino-5-fluoro-7Hpyrrolo[2,3-d]pyrimidin-7-yl)-5-((5-fluoro1,2,3,4-tetrahydroisoquinolin-8yl)oxy)cyclopentane-1,2-diol ¹H NMR (400 MHz, MeOD-d₄) δ ppm 8.09 (s, 1H), 7.08 (d, >2.0 Hz, 1H), 7.02 - 6.83 (m, 2H), 5.13 (q, >8.8 Hz, 1H), 4.68 4.62 (m, 1H), 4.55 (dd, >5.0, 8.8 Hz, 1H),

4.15 (d, >5.5 Hz, 1H), 4.13 (s, 2H), 3.26 (t, >6.0 Hz, 2H), 3.01 - 2.92 (m, 1H),

2.89 (t, >6.1 Hz, 2H), 2.04 (ddd, >4.3,

-172-

			9.1, 14.0 Hz, 1H)
Example 101				F nh2	478	(1S,2S,3R,5S)-3-(4-amino-5-fluoro-7H-
TP-12				J	[M+1]	pyrrolo[2,3-d]pyrimidin-7-yl)-5-((6-bromo-
						1,2,3,4-tetrahydroisoquinolin-8-
OH				\OH		yl)oxy)cyclopentane-1,2-diol
BocN'^x>|^i	'Br	H N''''	Ci Xj	OH		1H NMR (400 MHz, MeOD-d4) δ ppm 8.08 (s, 1H), 7.17 - 7.10 (m, 1H), 7.09 - 7.05
				Br		(m, 1H), 7.04 - 7.00 (m, 1H), 5.10 (q, J = 8.8 Hz, 1H), 4.69 - 4.63 (m, 1H), 4.57 4.51 (m, 1H), 4.16 - 4.06 (m, 3H), 3.29 3.24 (m, 2H), 2.99 - 2.89 (m, 3H), 2.13 2.02 (m, 1H)
Example 102				F NH2	434	(1S,2S,3R,5S)-3-(4-amino-5-fluoro-7H-
TP-3					[M+1]	pyrrolo[2,3-d]pyrimidin-7-yl)-5-((6-chloro-
						1,2,3,4-tetrahydroisoquinolin-8-
OH				\OH		yl)oxy)cyclopentane-1,2-diol
BocN	Cl	HN^'	cr X3	OH		1H NMR (400 MHz, MeOD-d4) δ ppm 8.08 (s, 1H), 7.07 (d, J=4.0 Hz, 2H), 6.93 (s,
			'''Cl		1H), 5.07 (q, J = 8.8 Hz, 1H), 4.72 - 4.63 (m, 1H), 4.60 - 4.53 (m, 1H), 4.28 (s, 2H), 4.16 - 4.12 (m, 1H), 3.44 (t, J=6.1 Hz, 2H), 3.06 (t, J=6.3 Hz, 2H), 2.99 - 2.88 (m, 1H), 2.19-2.04 (m, 1H)
Example 103				F NH2	436	(1S,2S,3R,5S)-3-(4-amino-5-fluoro-7H-
TP-6					[M+1]	pyrrolo[2,3-d]pyrimidin-7-yl)-5-((5,6-
			J		difluoro-1,2,3,4-tetrahydroisoquinolin-8-
OH				y OH		yl)oxy)cyclopentane-1,2-diol
BocN'^'Tj^		H N'	oz	OH		1H NMR (400 MHz, MeOD-d4) δ ppm 8.07 (s, 1H), 7.07 (d, J=2.0 Hz, 1H), 7.03 (dd,
F			Λ F	F		J=6.7, 12.2 Hz, 1H), 5.06 (q, J=9.0 Hz, 1H), 4.63 (td, J=2.6, 4.8 Hz, 1H), 4.55 (dd, J=5.3, 8.8 Hz, 1H), 4.20 (s, 2H), 4.13 (d, J=4.0 Hz, 1H), 3.40 (t, J=6.3 Hz, 2H), 3.01 (t, J=6.0 Hz, 2H), 2.93 (td, J=8.2, 14.3 Hz, 1H), 2.09 (ddd, J=4.8, 9.3, 14.1 Hz, 1H)

-173-

Example 104	F nh2 xx J N £ /OH	468 [M+1]	(1S,2S,3R,5S)-3-(4-amino-5-fluoro-7Hpyrrolo[2,3-d]pyrimidin-7-yl)-5-((6(trifluoromethyl)-l ,2,3,4- tetrahydroisoquinolin-8-
TP-4	OH
BocN^^'			0 I OH		yl)oxy)cyclopentane-1,2-diol
	^^cf3	H N'''	Ογί		1H NMR (400 MHz, MeOD-d4) δ ppm 8.08 (s, 1H), 7.12 (s, 1H), 7.08 (d, J=2.3 Hz,
			F		1H), 7.06 (s, 1H), 5.14 (q, J=9.3 Hz, 1H), 4.74 . 4.67 (m, 1H), 4.52 (dd, J=5.0, 8.8 Hz, 1H), 4.13 (d, J=5.5 Hz, 1H), 3.98 (s, 2H), 3.09 - 3.04 (m, 2H), 2.95 (ddd, J=7.3, 9.2, 14.4 Hz, 1H), 2.88 - 2.83 (m, 2H), 2.06 (ddd, J=4.1,9.0, 13.7 Hz, 1H)
Example 105		F NH2	414	(1S,2S,3R,5S)-3-(4-amino-5-fluoro-7H-
TP-5			èô	[M+1]	pyrrolo[2,3-d]pyrimidin-7-yl)-5-((6-methyl-
					1,2,3,4-tetrahydroisoquinolin-8-
	OH		JL ? ,ioh		yl)oxy)cyclopentane-1,2-diol
BocN^	XX	HN^'	I OH ÜL		1H NMR (400 MHz, DMSO-de) δ ppm 8.05 (s, 1H), 7.20 (s, 1H), 6.92 (br. s., 2H), 6.66 (s, 1H), 6.53 (s, 1H), 5.06 - 4.98 (m, 1H), 4.50 (br. s., 1H), 4.41 - 4.37 (m, 1H), 3.95 - 3.92 (m, 1H), 3.88 (br. s., 2H), 3.05 - 2.95 (m, 3H), 2.84 - 2.67 (m, 2H), 2.23 (s, 3H), 1.84 - 1.73 (m, 1H)
Example 106		H2N	428	(1S,2S,3R,5S)-3-(4-amino-5-fluoro-7H-
TP-13			XXN)	[M+1]	pyrrolo[2,3-d]pyrimidin-7-yl)-5-((6-ethyl-
			O- n		1,2,3,4-tetrahydroisoquinolin-8-
	OH		N		yl)oxy)cyclopentane-1,2-diol
BocN^'			jj / °H		1H NMR (400 MHz, MeOD-d4) δ ppm 8.14
	Et	HN^	crr OH XX		(s, 1H), 7.22 (d, J=2.0 Hz, 1H), 6.85 (s, 1H), 6.74 (s, 1H), 5.17 (q, J=9.0 Hz, 1H), 4.74 . 4.66 (m, 1H), 4.56 (dd, J=4.9, 8.9 Hz, 1H), 4.30 (S, 2H), 4.15 (d, J=5.0 Hz, 1H), 3.47 (t, J=6.4 Hz, 2H), 3.07 (t, J=6.1 Hz, 2H), 3.02 - 2.92 (m, 1H), 2.64 (q, J=7.4 Hz, 2H), 2.12 - 2.02 (m, 1H), 1.23 (t, J=7.7 Hz, 3H)

- 174 -

Example 107				c NH2 \ l	418	(1S,2S,3R,5S)-3-(4-amino-5-fluoro-7H-
TP-1				CT J	[M+1]	pyrrolo[2,3-d]pyrimidin-7-yl)-5-((6-fluoro-
OH						1,2,3,4-tetrahydroisoquinolin-8-
			YOH		yl)oxy)cyclopentane-1,2-diol
BocN^	''F	HN^	cr	OH		1H NMR (400 MHz, MeOD-d4) δ ppm 8.16 (s, 1H), 7.27 (d, J=2.0 Hz, 1H), 6.86 (dd,
				F		J=2.3, 10.8 Hz, 1H), 6.67 (d, J=9.3 Hz, 1H), 5.21 - 5.12 (m, 1H), 4.68 (t, J=5.3 Hz, 1H), 4.56 (dd, J=5.0, 9.0 Hz, 1H), 4.30 (s, 2H), 4.15 (d, J=4.8 Hz, 1H), 3.48 (t, J=6.3 Hz, 2H), 3.10 (t, J=6.0 Hz, 2H), 3.02 - 2.91 (m, 1H), 2.12 (ddd, J=4.6, 9.5, 14.0 Hz, 1H)
Example 108				F nh2	452	(1S,2S,3R,5S)-3-(4-amino-5-fluoro-7H-
TP-10				J*	[M+1]	pyrrolo[2,3-d]pyrimidin-7-yl)-5-((6-chloro-
OH						5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-
			2 OH		yl)oxy)cyclopentane-1,2-diol
BocN^'^'rj^	CI	HN^'		OH		1H NMR (400 MHz, MeOD-d4) δ ppm 8.08 (s, 1H), 7.08 (d, J=2.0 Hz, 1H), 7.01 (d,
F			F	~^CI		J=6.0 Hz, 1H), 5.16 - 5.09 (m, 1H), 4.63 4.58 (m, 1H), 4.53 - 4.47 (m, 1H), 4.14 4.08 (m, 1H), 3.92 (s, 2H), 3.07 (t, J=5.9 Hz, 2H), 2.98 - 2.88 (m, 1H), 2.82 - 2.73 (m, 2H), 2.07- 1.97 (m, 1H)
Example 109				F nh2	496	(1S,2S,3R,5S)-3-(4-amino-5-fluoro-7H-
TP-11					[M+1]	pyrrolo[2,3-d]pyrimidin-7-yl)-5-((6-bromo-
				y'V		5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-
OH			0^	OOH		yl)oxy)cyclopentane-1,2-diol
BocN'XXxT|^	Br	hn'		OH		1H NMR (400 MHz, MeOD) δ ppm 8.09 (s, 1 H), 7.04 - 7.20 (m, 2 H), 5.13 (m, J=9.00
F			F	'Br		Hz, 1 H), 4.59 - 4.68 (m, 1 H), 4.52 (m, J=8.80 Hz, 1 H), 4.13 (d, J-4.77 Hz, 1 H), 3.95 (s, 2 H), 3.11 (m, J=6.00 Hz, 2 H), 2.87 - 3.03 (m, 1 H), 2.81 (m, >5.80 Hz, 2H), 1.97-2.13(m, 1 H)

-175-

Example 110 tert-butyl 4hydroxyisoindoline- 2-carboxylate	F nh2 StS J N Xz,,OH 0 l·. I OH HN Z J	386 [M+1]	(1S,2S,3R,5S)-3-(4-amino-5-fluoro-7Hpyrrolo[2,3-d]pyrimidin-7-yl)-5-(2,3dihydro-1H-isoindol-4-yloxy)cyclopentane- 1,2-diol 1H NMR (400 MHz, MeOD-d4) δ ppm 8.09 (s, 1H), 7.45 - 7.38 (m, 1H), 7.14 - 7.07 (m, 2H), 7.07 - 7.01 (m, 1H), 5.18 - 5.08 (m, 1H), 4.78 - 4.72 (m, 1H), 4.66 (s, 4H), 4.58 - 4.52 (m, 1H), 4.20 - 4.15 (m, 1H), 3.03- 2.92 (m, 1H), 2.13 - 2.02 (m, 1H)
Example 111 tert-butyl 5hydroxy-3,4- dihydroisoquinoline -2(1H)-carboxylate	F nh2 <SrS Χ/'οη CF ï OH HN^XX	400 [M+1]	(1S,2S,3R,5S)-3-(4-amino-5-fluoro-7Hpyrrolo[2,3-d]pyrimidin-7-yl)-5-((1,2,3,4tetrahydroisoquinolin-5yl)oxy)cyclopentane-1,2-diol 1H NMR (400 MHz, MeOD-d4) δ ppm 8.09 (s, 1H), 7.29 (t, J=7.8 Hz, 1H), 7.08 (d, J=2.0 Hz, 1H), 7.04 (d, J=8.5 Hz, 1H), 6.86 (d, J=7.8 Hz, 1H), 5.22 - 5.09 (m, 2H), 4.74 - 4.68 (m, 1H), 4.57 (dd, J=5.0, 8.5 Hz, 1H), 4.37 (s, 2H), 4.18 (d, J=4.0 Hz, 1H), 3.56 (t, J=6.5 Hz, 2H), 3.10 (t, J=6.5 Hz, 2H), 3.04 - 2.93 (m, 1H), 2.11 1.98 (m, 1H)
Example 112 TP-15 OH BocN^^jj^ FF	F nh2 κΊι N L Χόη CFf I OH F F		(1S,2S,3R,5S)-3-(4-amino-5-fluoro-7Hpyrroio[2,3-d]pyrimidin-7-yl)-5-((6-(1,1 difluoroethyl)-1,2,3,4tetrahydroisoquinolin-8yl)oxy)cyclopentane-1,2-diol 1H NMR (400 MHz, MeOD) δ ppm 8.29 (s, 1H), 7.51 (d, J=2.3 Hz, 1H), 7.14 (s, 1H), 7.10 (s, 1H), 5.27 (q, J=9.0 Hz, 1H), 4.79 4.75 (m, 1H), 4.60 (dd, J=5.0, 9.0 Hz, 1H), 4.39 (s, 2H), 4.17 (d, J=4.8 Hz, 1H), 3.52 (t, J=6.3 Hz, 2H), 3.17 (t, J=6.0 Hz, 2H), 3.00 (ddd, J=7.7, 9.0, 14.2 Hz, 1H), 2.17 (ddd, J=4.1, 9.7, 14.1 Hz, 1H), 1.93 (t, J=18.3 Hz, 3H)

-176 Example 113

432 [M+1] (1S,2S,3R,5S)-3-(4-amino-5-fluoro-7Hpyrrolo[2,3-d]pyrimidin-7-yl)-5-((5-fluoro-6methyl-1,2,3,4-tetrahydroisoquinolin-8yl)oxy)cyclopentane-1,2-diol ¹H NMR with formic acid (400 MHz, MeOD-d₄) δ ppm 8.50 (br s, 1H), 8.07 (s, 1H), 7.07 (d, J=2.3 Hz, 1H), 6.88 (d, J=6.3 Hz, 1H), 5.07 (q, J=8.7 Hz, 1H), 4.67 4.61 (m, 1H), 4.55 (dd, J=5.0, 8.8 Hz, 1H), 4.28 (s, 2H), 4.16 - 4.11 (m, 1H), 3.49 3.41 (m, 2H), 3.01 (t, J=6.1 Hz, 2H), 2.96 - 2.87 (m, 1H), 2.27 (d, J=1.8 Hz, 3H), 2.10-2.01 (m, 1H)

Example 114 (Scheme OO) - (1S,2S,3R,5S)-3-(4-amino-5-fluoro-7H-pyrrolo[2,3d]pyrimidin-7-yl)-5-((2-methyl-1,2,3,4-tetrahydroisoquînolin-8-yl)oxy)cyclopentane-1,2-diol (00-1)

Scheme 00

37% H₂O

NaBH(OAc)₃

THF

00-1

Step 1 - Synthesis of (1S,2S,3R,5S)-3-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-

5-((2-methyl-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)cyclopentane-1,2-diol (00-1 )

A mixture of NN-5 (100 mg, 0.25 mmol), 37% CH₂O (31 mg, 0.38 mmol) and NaBH(OAc)₃ (212 mg, 1.0 mmol) in THF (6 mL) was stirred at 20 °C for 2 hrs. The mixture was filtered and sent to prep-HPLC to give 00-1 (65 mg, 53%) as a light yellow solid. LCMS 414 [M+1]; ¹H NMR (400 MHz, MeOD-d₄) δ ppm 8.10 (s, 1H), 7.34 - 7.27 (m, 1H), 7.16 - 7.10 (m, 1H), 7.03 - 6.97 (m,

1H), 6.94 - 6.88 (m, 1H), 5.18 - 5.09 (m, 1H), 4.75 - 4.68 (m, 1H), 4.59 - 4.53 (m, 1H), 4.42 15 4.34 (m, 2H), 4.21 - 4.16 (m, 1H), 3.55 - 3.46 (m, 2H), 3.23 - 3.16 (m, 2H), 3.08 (s, 3H), 3.04 2.92 (m, 1H), 2.16 - 2.03 (m, 1H)

-177Examples 115 & 116 were made using similar procedures to Scheme 00 from Examples

110 & 111 respectively.

Example 115	f nh2 Oj Γ YOH o^·- I OH -03	400 [M+1]	(1S,2S,3R,5S)-3-(4-amino-5-fluoro-7Hpyrrolo[2,3-d]pyrimidin-7-yl)-5-[(2-methyl-2,3dihydro-1 H-isoindol-4-yl)oxy]cyclopentane-1,2diol 1H NMR (400 MHz, MeOD-d4) δ ppm 8.09 (s, 1H), 7.41 (t, J=7.9 Hz, 1H), 7.15 - 7.06 (m, 2H), 7.02 (d, J=7.5 Hz, 1H), 5.21 - 5.10 (m, 1H), 4.77 - 4.70 (m, 1H), 4.66 (d, J=5.5 Hz, 4H), 4.53 (dd, J=5.1, 8.7 Hz, 1H), 4.18 (d, J=5.0 Hz, 1H), 3.11 (s, 3H), 2.98 (ddd, J=7.4, 9.0, 14.4 Hz, 1H), 2.05 (ddd, J=4.3, 9.3, 14.1 Hz, 1H)
Example 116	F NH2 Oj / n £ >0H O^ I OH /CO	414 [M+1]	(1S,2S,3R,5S)-3-(4-amino-5-fluoro-7Hpyrrolo[2,3-d]pyrimidin-7-yl)-5-((2-methyl-1,2,3,4tetrahydroisoquinolin-5-yl)oxy)cyclopentane-1,2diol 1H NMR (400 MHz, MeOD-d4) δ ppm 8.09 (s, 1H), 7.27 (t, J=8.0 Hz, 1H), 7.08 (d, J=2.0 Hz, 1H), 7.01 (d, J=8.3 Hz, 1H), 6.82 (d, J=7.8 Hz, 1H), 5.22 - 5.10 (m, 1H), 4.71 (br. s., 1H), 4.56 (dd, J=4.9, 8.7 Hz, 1H), 4.23 (br. s., 2H), 4.18 (d, J=4.5 Hz, 1H), 3.46 - 3.37 (m, 2H), 3.10 (t, J=6.1 Hz, 2H), 2.99 (ddd, J=7.5, 9.2, 14.4 Hz, 1H), 2.93 (s, 3H), 2.05 (s, 1H)

Synthesis of 5-fluoro-2-methyl-7H-pyrrolo[2,3-d]pyrimidine (HG-3)

Scheme PP

CH₃CN, HOAc

Selectfluor

PP-1

PP-2 HG-3

Step 1 - Synthesis of 2-chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine (PP-2)

To a solution of 2-chloro-7H-pyrrolo[2,3-d] pyrimidine (PP-1) (8.5 g, 55 mmol) and 10 selectfluor(29.4 g, 83.0 mmol) in CH₃CN (500 mL) was added AcOH (100 mL) under N₂. The mixture was stirred at 70 °C for 16 hours. The color of the reaction became orange from yellow.

The reaction concentrated and azeotroped with toluene (30 mL x 3). Then the solid was diluted

-178with CH₂CI₂/EtOAc (1/1, 200 mL) and stirred at room température (25oC) for 16 hrs and filtered. The filtrate was concentrated and washed with DCM to afford crude material as a brown solid. MBTE was added and stirred overnight and filtered to afford PP-2 (1.5 g, 15%) as a yellow solid. LCMS 172 [M+1]; Ή NMR (400 MHz, MeOD-d₄) δ ppm 8.89 (d, J=0.8 Hz, 1H), 7.31 (d, J=2.5 5 Hz, 1H)

Step 2 - Synthesis of 5-fluoro-2-methyl-7H-pyrrolo[2,3-d]pyrimidine (HG-3)

Pd(PPh₃)₄ (835 mg, 0.723 mmol) was added to a solution PP-2 (2.48 g , 14.46 mmol) in dry THF (36 mL) at 10 oC. The suspension was degassed with N₂. A solution of Me₃AI (2M, 14.5 mL, 28.9 mmol) was added to the above mixture at -10 °C slowly. After the addition, the mixture was heated at 70 °C for 16 hours. The reaction mixture was added to ice-water carefully. The mixture was diluted with EtOAc and filtered through celite. The filtrate was partitioned between EtOAc and H₂O. The organic layer was separated and washed with brine, dried over Na₂SO₄ and concentrated to afford the crude product and purified via flash column (MeOH: DCM =

1 %~7.5%) to afford the product HG-3 (1.2 g, 55%) as a yellow solid. LCMS 152 [M+1]; ¹H NMR (400 MHz, MeOD-d₄) δ ppm 11.76 (br. s., 1H), 8.96 (s, 1H), 7.44 (t, J=2.5 Hz, 1H), 2.63 (s, 3H)

Synthesis of 5-fluoro-4-methyl-7H-pyrrolo[2,3-d]pyrimidine (HG-4)

Scheme QQ

HG-2 HG-4

To Pd(PPh₃)₄ (2 g, 1.75 mmol) was added a solution of HG-2 (7.5 g, 43.7 mmol) in dry THF (75 mL). The suspension was degassed with N₂. A solution of AIMe₃ (43.7 mL, 87.5 mmol, 2M) was added to the above mixture at ice-water. After the addition, the yellow solution was heated at 80 °C for 16h. The reaction mixture was quenched with ice and aqueous Rochelle sait. The mixture was partitioned between EtOAc and H₂O. The mixture was filtered and the filtrate cake was washed with EtOAc (100 mL x 3). The organic layer was separated and dried over Na₂SO₄ and concentrated then purified via flash column (MeOHOCM = 1%~4%) to afford the product. The product was triturated in DCM and filtered. The filtrate cake was washed with TBME and 30 collected to afford the product HG-4 (2.00 g, 30%) as a yellow solid. The filtrate was concentrated purified via flash column (MeOH: DCM = 1%~5%) to afford the product. LCMS 152 [M+1]; Ή NMR (400 MHz, MeOD-d₄) δ ppm 11.89 (br. s., 1H), 8.62 (s, 1H), 7.48 (t, J=2.5 Hz, 1H), 2.70 (s, 3H)

-179 Synthesis of 4-chloro-5-fluoro-2-methyl-7H-pyrrolo[2,3-d]pyrimidine (HG-5)

Scheme RR

RR-1

Selectfluor

AcOH

Step 1 - Synthesis of 4-chloro-2-methyl-7H-pyrrolo[2,3-d]pyrimidine (RR-2)

A mixture of 2-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (RR-1) (2.7 g, 18.1 mmol) in

POCI₃ (35 mL) was heated at reflux for 4 hours. The mixture was cooled to 20 °C and concentrated. To the residue was added ice-water (20 mL) and basified by solid Na₂CO₃ to 10 pH~8. The mixture was extracted with EtOAc (60 mL X 2). The combined organic layers were washed with brine (100 mL), dried over Na₂SO₄, filtered and concentrated to yield RR-2 (2.4 g,

78%) as an off-white solid. LCMS 168 [M+1]; ¹H NMR (400 MHz, CDCI₃) δ ppm 10.70 - 10.41 (m, 1H), 7.36 - 7.29 (m, 1H), 6.67 - 6.56 (m, 1H), 2.81 (s, 3H)

Step 2 - Synthesis of 4-chloro-5-fluoro-2-methyl-7H-pyrrolo[2,3-d]pyrimidine (HG-5)

A mixture of RR-2 (2.35 g, 14 mmol) and Selectfluor (7.45 g, 21 mmol) in CH₃CN (110 mL) and

AcOH (22 mL) was stirred at 70 °C under N₂ for 16 hours in which the reaction became brown from pink. The mixture was concentrated and azeotroped toluene (50 ml x 2). The filtrate was concentrated and purified by prep-HPLC to give HG-5 (600 mg, 23%) as a yellow solid. LCMS 20 186 [M+1]; Ή NMR (400 MHz, MeOD-d₄) δ ppm 12.27 - 12.18 (m, 1H), 7.62 - 7.56 (m, 1H),

2.61 (s, 3H)

Examples 117-119 were made in a similar fashion to CC-3 (Example 78) using the appropriate pyrrolopyrimidine in step 1 of Scheme BB and the appropriate N-Boc 25 protected tetrahydroisoquinoline in step 1 of Scheme CC.

Example 117

399 [M+1] tert-butyl 8-hydroxy-3,4dihydroisoquinoline2(1H)-carboxylate (1S,2S,3R,5S)-3-(5-fluoro-4-methyl7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5((1,2,3,4-tetrahydroisoquinolin-8yl)oxy)cyclopentane-1,2-diol ¹H NMR (400 MHz, MeOD-d₄) δ ppm 8.62 (s, 1H), 8.50 (br. s., 1H), 7.44 (d, J=1.5 Hz, 1H), 7.27 (t, J=7.8 Hz, 1H), 6.97 (d, J=8.5 Hz,

-180-

OH			1H), 6.88 (d, J=7.5 Hz, 1H), 5.23 (q,
BocN^^j^^j			J=9.0 Hz, 1H), 4.74 - 4.69 (m, 1H), 4.69 - 4.62 (m, 1H), 4.36 (s, 2H), 4.18 (d, J=4.5 Hz, 1H), 3.47 (t, J=6.0 Hz, 2H), 3.10 (t, J=6.0 Hz, 2H), 3.04 - 2.90 (m, 1H), 2.78 (s, 3H), 2.21 -2.07 (m, 1H)
Example 118	CO	367	(1S,2S,3R,5S)-3-(7H-pyrrolo[2,3-
7H-pyrrolo[2,3-	[M+1]	d]pyrimidin-7-yl)-5-((1,2,3,4-
d]pyrimidine	JL /ioh		tetrahydroisoquinolin-8-
ΥΎρ-Ν	I OH		yl)oxy)cyclopentane-1,2-diol
H IN tert-butyl 8-hydroxy-3,4dihydroisoquinoline2(1H)-carboxylate OH			1H NMR (400 MHz, DMSO-de) δ ppm 9.00 (s, 1H), 8.79 (s, 1H), 7.70 (d, J=3.6 Hz, 1H), 7.12 - 7.03 (m, 1H), 6.87 - 6.78 (d, J = 8.0, 1H), 6.78 - 6.62 (m, 2H), 5.39 - 5.32 (m, 1H), 5.21 - 5.07 (m, 2H), 4.63 - 4.51 (m, 2H), 4.02 - 3.97 (m, 1H), 3.93 3.81 (m, 2H), 3.00 - 2.91 (m, 2H), 2.90 - 2.82 (m, 1H), 2.71 - 2.68 (m, 1H), 2.00- 1.89 (m, 1H)
Example 119	F	424	8-(((1 S,2S,3S,4R)-4-(5-fluoro-4-
HG-4		M+1	methyl-7H-pyrrolo[2,3-d]pyrimidin-7-
F I	N		yl)-2,3-dihydroxycyclopentyl)oxy)-
<1 ü1	J2 \’OH		1,2,3,4-tetrahydroisoquinoline-6-
νΛνζ	o^~- 1 OH		carbonitrile
H			1H NMR with formic acid (400 MHz,
TP-18 OH BocN/^r|::^ k^''^''CN	zn		DMSO-de) δ ppm 8.66 (s, 1H), 8.28 (S, 1H), 7.71 (S, 1H), 7.28 (s, 1H), 7.20 (s, 1H), 5.14 (q, J=9.6 Hz, 1H), 4.63 - 4.60 (m, 1H), 4.45 (dd, J=4.8, 9.0 Hz, 1H), 3.96 (d, J=4.8 Hz, 1H), 3.89 (S, 2H), 2.95 - 2.90 (m, 2H), 2.88 - 2.80 (m, 1H), 2.70 2.67 (m, 5H), 1.95 - 1.90 (m, 1 H)

Examples 120 was made in a similar fashion to NN-5 (Example 99) using the appropriate pyrrolopyrimidine in step 1 of Scheme BB and the appropriate N-Boc protected tetrahydroisoquinoline in step 1 of Scheme NN.

- 181 -

Example 120

5-bromo-4-chloro7H-pyrrolo[2,3djpyrimidine

485 [M+1]

8-(((1 S,2S,3S,4R)-4-(4-amino-5bromo-7H-pyrrolo[2,3-d]pyrimidin-7yl)-2,3-dihydroxycyclopentyl)oxy)1,2,3,4-tetrahydroisoquinoline-6carbonitrile ¹H NMR (400 MHz, MeOD-d₄) δ ppm 8.12 (s, 1H), 7.39 (s, 1H), 7.38 (s, 1H), 7.31 (s, 1H), 5.05 (q, J=9.2 Hz, 1H), 4.81 - 4.74 (m, 1H), 4.67 (dd, J=4.9, 8.9 Hz, 1H), 4.38 (s, 2H), 4.18 (br d, J=4.3 Hz, 1H), 3.48 (t, J=6.0 Hz, 2H), 3.13 (br t, J=5.9 Hz, 2H), 3.03 - 2.93 (m, 1H), 2.26 2.19 (m, 1H)

Example 121 (Scheme SS) - (1S,2S,3R,5S)-3-(4-amino-5-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)-5-((5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)cyclopentane-1,2-diol (SS-5)

Scheme SS

BocO

BB-1

Pd₂dba₃«CHCI₃ (2 mol%)

OBoc (R,/?)-DACH-Napthyl Trost Ligand (6 moi%) DCE, rt

SS-2

Pd₂dba₃*CHCI₃ (2 mol%) dppp (5 mol%) Cs₂CO₃, DCE, rt

OsO₄ (4 mol%)

NMO, DCM, rt

SS-3

NH₄OH aq.

Dioxane, MW, 120°C

HG-6

Step 1: Synthesis of tert-butyl 8-(((1 S,4R)-4-((tert-butoxycarbonyl)oxy)cyclopent-2-en-1 10 y|)oxy)-5-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate (SS-1)

Vial A: To an oven dried reaction vial, equipped with a magnetic stirbar and cooled under a stream of argon, was added Tris(benzylideneacetone)dipalladium(0)chloroform adduct (62 mg, 0.060 mmol) and MFCD02684551 (R,R)-DACH-Naphthyl Trost Ligand (142 mg, 0.180 mmol).

The vial was vacuum purged with argon under dynamic vacuum and DCE (5.0 mL), which had 15 been sparged with argon for 30 minutes, was added. The solution was stirred for 30 minutes at

- 182 rt at which point a bright orange solution of ligated catalyst was obtained. At this stage Vial B was prepared.

Vial B: To an oven dried reaction vial, equipped with a magnetic stirbar and cooied under a stream of argon, was added TP-2 (800 mg, 2.99 mmol), and di-tert-butyl-((1R,3S)-cyclopent-4ene-1,3-diyl)-bis(carbonate) (BB-1) (prepared as reported in J. Am. Chem. Soc. 2006, 128, 6054-6055) (1.08 g, 3.59 mmol). The vial was vacuum purged with argon under dynamic vacuum and DCE (5.0 mL), which had been sparged with argon for 30 minutes, was added followed by the addition of the contents of Vial A via airtight syringe. The reaction was stirred under argon at rt for 12 hours. The reaction was concentrated under vacuum and purified via flash column chromatography (24g SiO2, Isco, 100% Hept. to 100% EtOAc, 20 mL fractions) to afford SS-1 (1.33 g, >95%) as a pale yellow solid. LCMS [M+H-Boc-isobutylene] = 294 observed; 1H NMR (400MHz, CHLOROFORM-d) δ ppm 6.84 (t, J=8.8 Hz, 1H), 6.65 (dd, J=4.3, 8.9 Hz, 1H), 6.20 (td, J=1.5, 5.7 Hz, 1H), 6.17 - 6.11 (m, 1H), 5.46 (t, J=5.9 Hz, 1H), 5.09 (t, J=5.6 Hz, 1H), 4.57 - 4.40 (m, 2H), 3.72 - 3.54 (m, 2H), 3.02 (td, J=7.4, 14.5 Hz, 1H), 2.77 (t, J=5.7 Hz, 2H), 1.94 (td, J=4.5, 14.4 Hz, 1H), 1.50 (d, J=1.6 Hz, 18H).

Step 2: Synthesis of tert-butyl 8-(((1S,4R)-4-(4-chloro-5-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)cyclopent-2-en-1-yl)oxy)-5-fluoro-3,4-dihydroisoquinoline-2(1H)carboxylate (SS-2)

To a scintillation vial, equipped with a magnetic stirbar, was added HG-6 (113 mg, 0.674 mmol), SS-1 (303 mg, 0.674 mmol), diphenylphosphinopropane (dppp) (13.9 mg, 0.034 mmol), tris(dibenzylideneacetone)dipalladium(0)chloroform adduct (14 mg, 0.014 mmol) and césium carbonate (242 mg, 0.741 mmol). The vial was purged with argon under dynamic vacuum followed by the addition of DCE (2.25 mL) which had been sparged with argon for 30 minutes. The reaction was stirred at rt under argon for 1.5 hours. The reaction was transferred to a separatory funnel with DCM and diluted with water. The phases were separated and the aqueous phase was extracted with 2 portions DCM. The combined organic phases were dried (MgSO4), filtered, and concentrated under vacuum. The crude residue was purified via flash column chromatography (12g SiO2, Isco, 100% Hept. to 100% EtOAc, 9 mL fractions) to afford SS-2 (287.6 mg, 86%) as a colorless gum. LCMS [M+H] - 499 observed; 1H NMR (400MHz, CHLOROFORM-d) δ ppm 8.57 (s, 1H), 7.14 (s, 1H), 6.86 (t, J=8.8 Hz, 1H), 6.68 (dd, J=3.7, 8.4 Hz, 1H), 6.37 (d, J=5.4 Hz, 1H), 6.11 (d, J=4.4 Hz, 1H), 6.06 - 5.96 (m, 1H), 5.33 - 5.25 (m, 1H), 4.69 - 4.41 (m, 2H), 3.75 - 3.55 (m, 2H), 3.22 - 3.03 (m, 1H), 2.79 (t, J=5.4 Hz, 2H), 2.49 (s, 3H), 1.95 (td, J=3.6, 14.8 Hz, 1H), 1.51 (s, 9H).

-183 Step 3: Synthesis of tert-butyl 8-(((1S,2S,3S,4R)-4-(4-chloro-5-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)-2,3-dihydroxycyclopentyl)oxy)-5-fluoro-3,4-dihydroisoquinoline-2(1H)carboxylate (SS-3)

To a scintillation vial, equipped with a magnetic stirbar and containing SS-2 (278 mg, 0.557 mmol), was added DCM (2.79 mL). To the solution was added 4-Methylmorpholine-/\/-oxide (NMO) (0.13 mL, 0.613 mmol) as a 50 wt% solution in water followed by the dropwise addition of osmium tetraoxide (100 pL, 0.022 mmol) as a 4 wt% solution in water. The reaction was stirred at rt for 4 hours. The reaction was transferred to a separatory funnel with DCM, diluted with water and further diluted with 1M NaHSO3. The phases were separated and the aqueous phase was extracted with 3 portions of DCM. The combined organic extracts were dried (MgSO4), filtered, and concentrated under vacuum. The crude residue was purified via flash column chromatography (12g SiO2, Isco, 100% Hept. to 100% EtOAc, 9 mL fractions) to afford SS-3 (169 mg, 57%) as a white solid. LCMS [M+H] = 533 observed; 1H NMR (400MHz, CHLOROFORM-d) δ ppm 8.49 (s, 1H), 7.09 (br. s„ 1H), 6.89 (t, J=8.8 Hz, 1H), 6.81 (dd, J=4.2, 8.8 Hz, 1H), 5.03 (q, J=8.9 Hz, 1H), 4.73 (t, J=5.2 Hz, 1H), 4.55 (dd, J=5.2, 8.1 Hz, 1H), 4.53 4.40 (m, 2H), 4.30 (d, J=4.5 Hz, 1H), 3.73 - 3.54 (m, 2H), 3.13 - 2.97 (m, 1H), 2.79 (t, J=5.7 Hz, 2H), 2.49 (s, 3H), 2.31 (ddd, J=4.6, 9.4, 14.1 Hz, 1H), 1.48 (br. s., 9H).

Step 4: Synthesis of tert-butyl 8-(((1S,2S,3S,4R)-4-(4-amino-5-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)-2,3-dihydroxycyclopentyl)oxy)-5-fluoro-3,4-dihydroisoquinoline-2(1H)carboxylate (SS-4)

To a reaction vial, equipped with a magnetic stirbar, was added SS-3 (159 mg, 0.298 mmol) as a solution in dioxane (0.8 mL) and ammonium hydroxide (0.8 mL, 5.00 mmol). The reaction was placed in a microwave reactor and heated to 120°C for 6 hours. The solution was transferred to a separatory funnel with DCM and diluted with water. The phases were separated and the aqueous phase was extracted with 3 portions of a 3:1 mixture ofDCM:IPA. The combined organic extracts were dried (MgSO4), filtered, and concentrated under vacuum. The crude residue was purified via flash column chromatography (12g SiO2, Isco, 100% Hept. to 10% MeOH/EtOAc, 9 mL fractions) to afford SS-4 (98.4 mg, 64%) as a white solid. LCMS [M+H] = 514 observed; [a]²²D = -70.0° (C=0.1, MeOH); 1H NMR (400MHz, CHLOROFORM-d) δ ppm 8.13 (s, 1H), 6.98 - 6.81 (m, 2H), 6.76 (br. s., 1H), 5.32 (br. s., 2H), 4.93 - 4.80 (m, 1H), 4.73 (t, J=5.3 Hz, 1H), 4.54 (br. s., 1H), 4.44 (d, J=16.8 Hz, 2H), 4.25 (br. s., 1H), 3.75 - 3.51 (m, 2H), 3.11 -2.92 (m, 1H), 2.79 (t, J=5.5 Hz, 2H), 2.43 (s, 3H), 2.38-2.25 (m, 1H), 1.48 (br. s., 9H).

- 184Step 5: Synthesis of (1S,2S,3R,5S)-3-(4-amino-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-

5-((5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)cyclopentane-1,2-diol (SS-5)

To a scintillation vial, equipped with a magnetic stirbar and containing SS-4 (79.4 mg, 0.155 mmol), was added dioxane (0.4 mL). To the solution was added hydrochloric acid (0.4 mL) as a

4M solution in dioxane and the reaction was stirred at rt for 17 hours. The reaction was quenched with half saturated NaHCO₃ aqueous and transferred to a separatory funnel with DCM. The phases were separated and the aqueous phase was extracted with 3 portions of 3:1 mixture of DCM/IPA. The combined organic extracts were dried (MgSO4), filtered, and concentrated under vacuum. The isolated material was dissolved in a minimum amount of 10 methanol and diluted with water. The sample was frozen and lyophilized overnight to afford SS5 (51.3 mg, 80%) as a white solid. LCMS [M+H] 414 observed; 1H NMR (400MHz, METHANOL-d4) δ ppm 8.03 (s, 1H), 6.98 (d, J=1.0 Hz, 1H), 6.93 - 6.81 (m, 2H), 5.07 (q, J=8.7

Hz, 1H), 4.62 (ddd, J=1.8, 4.0, 7.0 Hz, 1H), 4.51 (dd, J=5.0, 8.5 Hz, 1H), 4.17 - 4.11 (m, 1H), 3.98 (s, 2H), 3.10 (t, J=6.0 Hz, 2H), 2.93 (ddd, J=7.3, 9.3, 14.5 Hz, 1H), 2.77 (t, J=5.9 Hz, 2H), 15 2.43 (d, J=1.1 Hz, 3H), 1.99 (ddd, J=4.0, 8.4, 13.8 Hz, 1H); 19F NMR (376MHz, METHANOLd4) d =-131.36 (s, 1F).

Examples 122-129 were made in a similar fashion to SS-5 (Example 121) using the appropriate N-Boc protected tetrahydroisoquinoline in step 1 S and the appropriate pyrrolopyrimidine in step 2 of Scheme SS.

Example 122

4-chloro-5-methyl-7Hpyrrolo[2,3-d]pyrimidine

410

M+1 (1 S,2S,3R,5S)-3-(4-amino-5methyl-7H-pyrrolo[2,3-d]pyrimidin7-yl)-5-((6-methyl-1,2,3,4tetrahydroisoquinolin-8yi)oxy)cyclopentane-1,2-diol ¹H NMR (400 MHz, MeOD-d₄) δ ppm 8.05 (s, 1 H), 6.99 (s, 1 H), 6.70 (S, 1 H), 6.61 (s, 1 H), 5.17 5.06 (m, 1 H), 4.71 -4.64 (m, 1 H), 4.53 (dd, J=8.53, 4.77 Hz, 1 H), 4.16 (d, JM.27 Hz, 1 H), 3.99 (s, 2 H), 3.12 (d, J=5.90 Hz, 2 H), 2.97 (dd, J=14.50, 9.50, 7.20 Hz, 1 H), 2.83 (t, J=5.77 Hz, 2 H), 2.45 (s, 3 H), 2.30 (s, 3 H), 2.04 - 1.93 (m, 1 H)

- 185-

Example 123	Μ Br d ___/	474	(1S,2S,3R,5S)-3-(4-amino-5-
TP-5	nh2	M+1	bromo-7H-pyrrolo[2,3-d]pyrimidin-
OH	\\ y) < N-i'./1’ ^7 HO OH		7-yl)-5-((6-methyl-1,2,3,4tetrahydroisoquinolin-8yl)oxy)cyclopentane-1,2-diol 1H NMR (400 MHz, MeOD-d4) δ
5-bromo-4-chloro-7Hpyrrolo[2,3-d]pyrimidine			ppm 8.12 (s, 1H), 7.35 (s, 1H),
Br θ'			6.77 (s, 1H), 6.67 (s, 1H), 5.11 (q,
			>9.0 Hz, 1H), 4.69 (ddd, J=1.6,
N^N^			4.0, 7.2 Hz, 1H), 4.62 (dd, >4.8,
H			8.8 Hz, 1H), 4.18 - 4.13 (m, 3H), 3.31 - 3.27 (m, 2H), 3.03 - 2.92 (m, 3H), 2.33 (s, 3H), 2.14 - 2.06 (m, 1H)
Example 124	F 1	413	(1 S,2S,3R,5S)-3-(5-fluoro-4-
TP-5	tu	M+1	methyl-7H-pyrrolo[2,3-d]pyrimidin-
OH	N^N		7-yl)-5-((6-methyl-1,2,3,4-
	f \OH		tetrahydroisoquinolin-8-
	ï ÔH		yl)oxy)cyclopentane-1,2-diol
			1H NMR (400 MHz, MeOD-d4) δ
HG-4 (step 4 is skipped)			ppm 8.65 (s, 1H), 7.43 (d, >2.0
F I			Hz, 1H), 6.81 (S, 1H), 6.70 (s, 1H),
			5.25 (q, >9.0 Hz, 1H), 4.71 (dt,
H			>2.3, 3.6 Hz, 1H), 4.69 - 4.64 (m, 1H), 4.26 (s, 2H), 4.17 (d, >4.8 Hz, 1H), 3.39 (t, >6.1 Hz, 2H), 3.04 - 2.95 (m, 3H), 2.80 (s, 3H), 2.34 (s, 3H), 2.20-2.11 (m, 1H)
Example 125	Br NH2	497	(1 S,2S,3R,5S)-3-(4-amino-5-
	U| N	[M+1]	bromo-7H-pyrrolo[2,3-d]pyrimidin-
TP-6	\ J J
OH			7-yl)-5-((5,6-difluoro-1,2,3,4-
BocN^^yi^	X/oh		tetrahydroisoquinolin-8-
	CfU ï OH		yl)oxy)cyclopentane-1,2-diol
F	HN^^r^ii		1H NMR (400 MHz, MeOD-d4) δ
			ppm 8.10 (s, 1H), 7.35 (s, 1H),
5-bromo-4-chloro-7H-	F		6.87 (dd, >6.8, 12.5 Hz, 1H), 5.09
pyrrolo[2,3-d]pyrimidine Br Cl			(q, >8.8 Hz, 1H), 4.58 - 4.51 (m,
			2H), 4.13 (d, >5.0 Hz, 1H), 3.90
O j			(s, 2H), 3.12 - 3.01 (m, 2H), 3.00 -
H

- 186 -

			2.90 (m, 1H), 2.78 (t, J=5.8 Hz, 2H), 2.13-2.00 (m, 1H)
Example 126			F NH2	432	(1 S,2S,3R,5S)-3-(4-amino-5-
TP-2			όι I	[M+1]	fluoro-2-methyl-7H-pyrrolo[2,3-
OH					d]pyrimidin-7-yl)-5-((5-fluoro-
BocN'^'^rf^			YOH		1,2,3,4-tetrahydroisoquinolin-8-
i II J		0	OH		yl)oxy)cyclopentane-1,2-diol
F	HN				1H NMR (400 MHz, DMSO-de) δ
HG-5		F			ppm 9.07 (br. s., 2H), 7.27 (br. s.,
F Cl					1H), 7.15 (t, J=9.2 Hz, 1H), 6.99
<7| j*					(dd, >4.1, 9.2 Hz, 1H), 5.38 (br.
					s., 1H), 5.18 (br. s., 1H), 5.08 (q,
H					J=9.0 Hz, 1H), 4.53 (br. s., 1H), 4.39 - 4.30 (m, 1H), 4.21 (br. s., 2H), 3.95 (br. s., 1H), 2.95 - 2.88 (m, 2H), 2.83 - 2.73 (m, 1H), 2.53 2.51 (m, 3H), 2.40 (s, 3H), 1.74 (ddd, J=4.4, 9.3, 13.7 Hz, 1H)
Example 127			F	413	(1 S,2S,3R,5S)-3-(5-fluoro-2-
TP-5			Ν^κΤ\	[M+1]	methyl-7H-pyrrolo[2,3-d]pyrimidin-
OH					7-yl)-5-((6-methyl-1,2,3,4-
	H Ν'	cr	y oh OH		tetrahydroisoquinolin-8yl)oxy)cyclopentane-1,2-diol 1H NMR (400 MHz, MeOD-d4) δ
HG-3 (step 4 is skipped)					ppm 8.90 (s, 1H), 7.39 (s, 1H),
F\ _					6.76 (s, 1H), 6.66 (s, 1H), 5.35 (q,
					J=9.2 Hz, 2H), 4.58 (dd, J=4.9, 8.7
H					Hz, 1H), 4.17 (d, J=4.3 Hz, 1H), 4.12 (s, 2H), 3.25 (t, J=6.0 Hz, 2H), 3.06 - 2.95 (m, 1H), 2.92 (t, J=5.9 Hz, 2H), 2.74 (s, 3H), 2.33 (s, 3H), 2.13-2.04 (m, 1H)
Example 128			Cl nh2	452	(1 S,2S,3R,5S)-3-(4-amino-5-
TP-6			Ojn	[M+1]	chloro-7H-pyrrolo[2,3-d]pyrimidin-
OH					7-yl)-5-((5,6-d ifl uoro-1,2,3,4-
BocN			O°h		tetrahydroisoquinolin-8-
		(/	OH		yl)oxy)cyclopentane-1,2-diol
F	H Ν'		1 F		1H NMR (400 MHz, MeOD-d4) δ ppm 8.09 (s, 1H), 7.29 (s, 1H),
4,5-dichloro-7H-		F

- 187 -

pyrrolo[2,3-d]pyrimidine			6.89 (dd, J=6.7, 12.4 Hz, 1H), 5.15
a ci				- 5.01 (m, 1H), 4.60 - 4.50 (m, 2H),
				4.16 - 4.07 (m, 1H), 3.94 (s, 2H),
				3.11 (t, J=6.0 Hz, 2H), 2.99 - 2.88
H				(m, 1H), 2.81 (t, J=5.8 Hz, 2H), 2.12-2.02 (m, 1H)
Example 129		Cl nh2	430	(1 S,2S,3R,5S)-3-(4-amino-5-
TP-5		Cu ?	M+1	chloro-7H-pyrrolo[2,3-d]pyrimidin-
OH				7-yl)-5-((6-methyl-1,2,3,4-
		r >-oH		tetrahydroisoquinolin-8-
H N''	0*^. i OH τι		yl)oxy)cyclopentane-1,2-diol 1H NMR (400 MHz, MeOD-d4) δ
4,5-dichloro-7Hpyrrolo[2,3-d]pyrimidîne				ppm 8.12 (s, 1H), 7.30 (s, 1H),
ci Çi				6.83 (S, 1H), 6.72 (S, 1H), 5.08 (q,
				J=9.0 Hz, 1H), 4.74 - 4.68 (m, 1H), 4.64 (dd, J=5.0, 8.8 Hz, 1H), 4.28
H				(s, 2H), 4.17 (d, J=4.8 Hz, 1H), 3.44 (t, J=6.1 Hz, 2H), 3.05 (t, J=6.1 Hz, 2H), 2.98 (ddd, J=7.4, 9.1, 14.4 Hz, 1H), 2.35 (s, 3H), 2.12 (ddd, J=4.0, 9.3, 14.0 Hz, 1H)

Examples 130 - 132 were prepared using the chemistry depicted in Scheme SS by employing the appropriate tetrahydroisoquinoline for step 1 and pyrrolopyrimidine for step 2. In a modification to step 5, trifluoroacetic acid (TFA) was used for the 5 deprotection.

Example 130 (Scheme TT) - (1S,2S,3R,5S)-3-(4-amino-5-chloro-7H-pyrrolo[2,3d]pyrimidin-7-yl)-5-((6-chloro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)cyclopentane-1,2-diol (TT-2)

Scheme TT

-188To a cooled solution of TT-1 (50.0 mg, 0.091 mmol) in DCM (2.0 mL) was added TFA (0.50 mL). The yellow solution was stirred at 15°C for 1 hour. The reaction was concentrated under vacuum to give the crude product and the pH of the solution was adjusted to 7~8 using saturated NaHCO₃ aq. (2 mL).Then FA (1%) aq. (2 mL) was added to the reaction solution. The 5 mixture was purified by prep-HPLC and the desired fractions were combined and lyophiiized to afford TT-2 (35.0 mg, 86%) as white solid.

Example 130	N L 1	450 observed	(1S,2S,3S,5R)-3-((6- chloro-1,2,3,4-
TP-3	WV riï 'LJ ii M T HO OH Cl	[M+H]	tetrahydroisoquinolin-8-
OH		yl)oxy)-5-(4,5-dichloro-7H-
BocN/^'T|i;ïj			pyrrolo[2,3-d]pyrimidin-7- yl)cyclopentane-1,2-diol
4,5-dichloro-7H-			1H NMR (400MHz,
pyrrolo[2,3-d]pyrimidine			DMSO-d6) δ ppm 8.04 (s,
Cl c.			1H), 7.38 (s, 1H), 7.01 -
			6.89 (m, 2H), 4.92 (q, J=9.0 Hz, 1H), 4.56 (d,
N tt
H			J=5.3 Hz, 1H), 4.47 (dd, J=4.9, 9.2 Hz, 1H), 4.13 (s, 2H), 3.95 (d, J=4.8 Hz, 1H), 3.29 (t, J=6.1 Hz, 2H), 2.94 (t, J=5.9 Hz, 2H), 2.86 - 2.76 (m, 1H), 1.89 (ddd, J=3.9, 9.5, 13.7 Hz, 1H)
Example 131	K Br	495	(1S,2S,3R,5S)-3-(5-
TP-3	L Ο nTY-V n H 2	observed	bromo-4-chloro-7H-
i -, N^N	[M+H]	pyrrolo[2,3-d]pyrimidin-7-
OH	Cl		yl)-5-((6-chloro-1,2,3,4-
BocN^^'ji^T			tetrahydroisoquinolin-8- yl)oxy)cyclopentane-1,2-
\^^CI			diol
5-bromo-4-chloro-7Hpyrrolo[2,3-d]pyrimidine			1H NMR (400MHz,
Br G1			DMSO-d6) δ ppm 8.10 (s,
ÔAÏ			1H), 7.53 (s, 1H), 6.92 (d, J=1.5 Hz, 1H), 6.85 - 6.57
N N H			(m, 2H), 5.36 (br. s., 1H),

- 189-

			5.16 (br. s., 1H), 4.99 (q, J=9.2 Hz, 1H), 4.58 - 4.51 (m, 1H), 4.50 - 4.42 (m, 1H), 3.93 (d, J=5.0 Hz, 1H), 3.79 (s, 2H), 2.91 (t, J=5.8 Hz, 2H), 2.84 - 2.73 (m, 1H), 2.70 - 2.62 (m, 2H), 1.96 - 1.84 (m, 1H)
Example 132	H N		F	417	(1 S,2S,3S,5R)-3-((5-
TP-2				observed	fluoro-1,2,3,4-
	J H. HÔ OH		[M+H]	tetrahydroisoquinolin-8-
OH					yl)oxy)-5-(5-fluoro-2-
BocN^^jj^					methyl-7H-pyrrolo[2,3- d]pyrimidin-7-
F					yl)cyclopentane-1,2-diol
HG-3 (Step 4 is skipped)					1H NMR (400MHz,
					METHANOL-d4) δ ppm
h					8.87 (d, J=0.8 Hz, 1H),
7.38 (d, J=2.3 Hz, 1H),
N					6.92 - 6.81 (m, 2H), 5.37 - 5.27 (m, 1H), 4.65 - 4.60 (m, 1H), 4.56 (t, J=8.9 Hz, 1H), 4.14 (d, J=5.0 Hz, 1H), 3.96 (s, 2H), 3.10 - 3.04 (m, J=6.0, 6.0 Hz, 2H), 3.01 - 2.91 (m, J=7.2, 9.4, 14.6 Hz, 1H), 2.79 - 2.73 (m, J=6.0, 6.0 Hz, 2H), 2.72 (S, 3H), 2.11 - 2.03 (m, 1H)

Examples 133 & 134 were prepared using the chemistry depicted in Scheme SS by empioying the appropriate tetrahydroisoquinoline for step 1 and pyrrolopyrimidine for step 2. In a modification to the general procedure for step 4, HOBt was employed as a 5 catalyst as described in Scheme UU.

-190Synthesis of tert-butyl 8-(((1S,2S,3S,4R)-4-(4-amino-5-chloro-7H-pyrrolo[2,3-d]pyrimidin7-yl)-2,3-dihydroxycyclopentyl)oxy)-5-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate (UU-2)

Scheme UU

HOBt (20 mol%) NH₄OH, DMA 100°C

To a reaction vial, equipped with a magnetic stirbar, was added UU-1 (147 mg, 0.266) as a solution in DMA (2.5 mL) followed by the addition of HOBt.hydrate (8.13 mg, 0.053 mmol). To the solution was added ammonium hydroxide (1.0 mL, 7.96 mmol). The vial was sealed with a teflon cap and placed in a heating block. The reaction was heated at 100°C for 19 hours. The 10 solution was transferred to a separatory funnel with DCM and diluted with water. The phases were separated and the aqueous phase was extracted with 3 portions of DCM. The combined organic extracts were dried (MgSO4), filtered, and concentrated under vacuum. The crude residue was purified via flash column chromatography (4g SiO2, Isco, 100% Hept. to 10%

MeOH/EtOAc, 9 mL fractions). Fractions containing product were collected and concentrated 15 under vacuum. The material was lyophilized to afford the product, containing minor impurities, as an off-white solid (140.7 mg, 99%). The material was used in step 5, employing TFA/DCM for the deprotection as depicted in scheme TT, without further purification.

Example 133

TP-2

4,5-dichloro-7Hpyrrolo[2,3djpyrimidine

434 observed

[M+H] (1 S,2S.3R,55)-3-(4amino-5-chloro-7Hpyrrolo[2,3-d]pyrimidin7-yl)-5-((5-fluoro1,2,3,4tetrahydroisoquinolin-8yl)oxy)cyclopentane1,2-diol

1H NMR (700MHz, DMSO-d6) δ ppm 8.08 (br. s., 1H), 7.44 (s, 1H), 6.97 - 6.89 (m, 1H), 6.82 (d, >4.6 Hz, 1H),

- 191 -

			5.26 (br. s., 1H), 5.11 (br. s., 1H), 4.99 (q, J=8.6 Hz, 1H), 4.55 - 4.39 (m, 2H), 3.94 (br. s., 1H), 3.83 (br. s., 2H), 2.93 (br. s., 2H), 2.84 - 2.70 (m, 2H), 2.58 (br. s., 2H), 1.92 - 1.82 (m, 1H).
Example 134	H χΝ	Br /	478 observed	(1 S,2S,3R,5S)-3-(4-
	Œ	/X -N ^nh2		amino-5-bromo-7H-
TP-2 OH BocN^^j^	X	HO OH	[M+H]	pyrrolo[2,3-d]pyrimidin- 7-yl)-5-((5-fluoro- 1,2,3,4- tetrahydroisoquinolin-8-
F				yl)oxy)cyclopentane- 1,2-diol
5-bromo-4-chloro- 7H-pyrrolo[2,3d]pyrimidine				1H NMR (700MHz, DMSO-d6) δ ppm (s,
Br C!				1H), 7.49 (S, 1H), 6.94 -
ôo1				6.88 (m, 1H), 6.84 -
H N				6.77 (m, 1H), 5.25 (br. s., 1H), 5.15 - 5.05 (m, 1H), 4.99 (d, J=9.0 Hz, 1H), 4.47 (d, J=3.3 Hz, 2H), 3.94 (br. s., 1H), 3.81 (br. s., 2H), 2.92 (br. s., 2H), 2.80 - 2.70 (m, 1H), 2.58 (br. s., 2H), 1.86 (br. s., 1H).

Example 135 (Scheme VV) - (1S,2S,3S,5R)-3-(4-fluoro-2-(hydroxymethyl)phenoxy)-5-(4methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol (2)

Scheme W

W-1

LiAIH₄

THF

VV-2

- 192 Compound VV-1 was prepared using procedures from steps 2 and 3 from Scheme BB starting from BB-2 and using commercially available methyl 5-fluoro-2-hydroxybenzoate. To a solution of VV-1 (90 mg, 0.22 mmol) in dry THF (5 mL) was added LÎAIH4 (30 mg, 0.79 mmol) at 0 °C for 2 hours. H₂O (30 mL) was added to the reaction mixture and the mixture was extracted with EtOAc (30 mL x 4). The organic layer was washed with brine, dried over Na₂SO₄ and concentrated in vacuo to a residue that was purified by prep-TLC giving W-2 (60 mg, 72%) as a white solid. LCMS 374 [M+1]; Ή NMR (400 MHz, DMSO-d₆) δ ppm 8.62 (s, 1H), 7.65 (d, J=3.8 Hz, 1H), 7.18 (d, J=9.0 Hz, 1H), 7.04 - 6.99 (m, 2H), 6.72 (d, J=3.5 Hz, 1H), 5.32 (d, J=3.8 Hz, 1H), 5.23 (t, J=5.6 Hz, 1H), 5.16 - 5.07 (m, 2H), 4.58 (d, J=5.8 Hz, 2H), 4.56 - 4.50 (m, 2H), 3.99 (br. s., 1 H), 2.88 - 2.78 (m, 1 H), 2.64 (s, 3H), 1.97 - 1.87 (m, 1 H)

Example 136 (Scheme WW) - (1S,2S,3S,5R)-3-(4-fluoro-2-hydroxyphenoxy)-5-(4-methyl7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol (WW-6)

Scheme WW

OH

I

HO. ,B.

B OH I

OH

O O

F₃C^x^O'^CF₃

WW-3 h₂o₂, dcm

□ MF

K₂CO₃

MeOH

WW-6

Step 1 - Synthesis of 1-(2-(((3aR,4S,6R,6aS)-2,2-dimethyl-6-(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)-5-fluorophenyl)ethan-1 one (WW-2)

Compound WW-1 was prepared using procedures from steps 2 and 3 from Scheme BB starting from BB-2 and using commercially available 1-(5-fluoro-2-hydroxyphenyl)ethan-1-one. To a stirred white suspension solution of WW-1 (1.06 g, 2.75 mmol) in acetone (6 mL) was added

2,2-dimethoxypropane (16 mL) and p-toluenesulfonic acid (523 mg, 2.75 mmol) at r.t (25 °C). The reaction was stirred at 25 °C for 15 hrs. Aqueous NaHCOs was added to the reaction mixture until the pH reached 8.0. Then the mixture was extracted with EtOAc (15 mL x 5). The organic layers were separated, dried and evaporated to give the crude product, which was purified by chromatography, eluted with MeOH/DCM 0-5% to give WW-2 (1.06 g, 91%) as a white solid. The material was used directly in the next step.

- 193Step 2 - Synthesis of 7-((3aS,4R,6S,6aR)-6-(2-acetyl-4-fluorophenoxy)-2,2dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-4-methyl-7H-pyrrolo[2,3d]pyrimidine 3-oxide (WW-3)

Compound WW-2 (1.03 g, 2.42 mmol) was dissolved in DCM (15 mL). Then m-CPBA (1.97 g, 9.68 mmol) was added to the above mixture. The reaction mixture was heated at 40 °C for 16 hours. The mixture was cooled to 25 °C .Then the mixture was diluted with DCM (15 mL) and then saturated sodium thiosulfate (15 mL) was added the organic layer was separated. The organic layer was washed with saturated NaHCO₃ (20 mL), dried over Na₂SO₄, filtered and purified by flash chromatography eluted with from 0-10% MeOH/DCM to give WW-3 (600 mg, 56%) as a yellow oil and used directly in the next step.

Step 3 - Synthesis of 7-((1R,2S,3S,4S)-4-(2-acetoxy-4-fluorophenoxy)-2,3dihydroxycyclopentyl)-4-methyl-7H-pyrrolo[2,3-d]pyrimidine 3-oxide (WW-4)

Trifluoroacetic anhydride (3.56 g, 16.9 mmol) was cooled to -10 °C for about 10-20 min and 30% H₂O₂ (457 mg, 3.13 mL) was added drop-wise and stirred for 10 min (maintaining the température between 0 and -10 °C). To this mixture was added compound WW-3 (570 mg, 1.29 mmol) in DCM (5 mL) drop-wise and stirred at 25 °C for 10-30 min. Saturated Na₂S2O₃/NaHCO₃ aq (15 mL) was added to the above mixture and stirred at 25 °C for 10 min. The reaction solution was extracted with DCM (10 mL x 2), dried and evaporated to give the crude WW-4 (540 mg, >99%) as a yellow oil. LCMS 418 [M+1]

Step 4 - Synthesis of 2-(((1S,2S,3S,4R)-2,3-dihydroxy-4-(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)cyclopentyl)oxy)-5-fluorophenyl acetate (WW-5)

Compound WW-4 (540 mg, 1.22 mmol) was dissolved in DMF (1 mL). Then hypodiboric acid (658 mg, 7.34 mmol) was added to the above mixture and stirred at 25 °C for 30 min. The reaction solution of WW-5 was used directly for the next step without further purification. LCMS 402 [M+1]

Step 5 - Synthesis of (1S,2S,3S,5R)-3-(4-fluoro-2-hydroxyphenoxy)-5-(4-methyl-7Hpyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol (WW-6)

A solution of compound WW-5 (490 mg, 1.11 mmol) in DMF was added MeOH (2 mL). K₂CO₃ (2.30 g, 16.6 mmol) was added to the above mixture. The reaction mixture was stirred at 25 °C for 2 hours. The solvent was evaporated and the crude product was purified by prep-HPLC to give WW-6 (62 mg, 16%) as a white solid. LCMS 360 [M+1]; ¹H NMR (400 MHz, DMSO-de) δ ppm 9.53 (s, 1H), 8.63 (s, 1H), 7.75 (d, J=3.5 Hz, 1H), 7.01 (dd, J=5.9, 8.9 Hz, 1H), 6.75 (d, J=3.8 Hz, 1H), 6.68 (d, J=3.0 Hz, 1H), 6.66 (d, J=3.0 Hz, 1H), 6.56 (dt, J=3.0, 8.7 Hz, 1H), 5.26

- 194(d, J=3.0 Hz, 1H), 5.16 (q, J=8.9 Hz, 1H), 5.07 (d, J=6.8 Hz, 1H), 4.54 (br. s., 2H), 4.00 (br. s.,

1H), 2.83-2.74 (m, 1H), 2.65 (s, 3H), 1.97- 1.90 (m, 1H)

Example 137 (Scheme XX) - (1S,2S,3S,5R)-3-(2-((R)-1-aminoethyl)-4-fluorophenoxy)-5-(4methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol (XX-3)

Example 138 (Scheme XX) - (1S,2S,3S,5R)-3-(2-((S)-1-aminoethyl)-4-fluorophenoxy)-5-(4methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol (XX-4)

Scheme XX

Step 1 - Synthesis of 1-(2-(((3aR,4S,6R,6aS)-2,2-dimethyl-6-(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)-5-fluorophenyl)ethan-1amine (XX-1)

Compound WW-2 (100 mg, 0.235 mmol) was dissolved in MeOH (1 mL). Then NH₄OAc (181 mg, 2.35 mmol) was added to the above mixture and stirred at 25 °C for 1 hour. Then NaBH₃CN (89 mg, 1.41 mmol) was added and heated to 80 °C for 16 hour. The mixture was cooled to 25 °C, then 1 mL saturated NaHCO₃ was added and stirred 25 °C for 10 min. The reaction mixture was extracted with DCM (5 mL x 3), separated, dried and evaporated to give crude material which was purified by prep-TLC (MeOH/DCM 0-10%) to afford XX-1 (35 mg, 35%) as a colorless oil and used directly in the next step.

Step 2 - Synthesis of (1S,2S,3S,5R)-3-(2-(1-aminoethyl)-4-fluorophenoxy)-5-(4-methyl-7Hpyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol (XX-2)

To compound XX-1 (100 mg, 0.234 mmol) in H₂O (0.5 mL) was added TFA (0.5 mL) at 0 °C. The mixture was stirred at 0 °C for 60 min. The pH of the reaction solution was adjusted to pH=9 by addition of saturated K₂CO₃ aq. The final solution was separated by prep-HPLC, to give 90 mg of the XX-2 (90 mg, 99%) as a white solid.

- 195Step 3 - Séparation of (1S,2S,3S,5R)-3-(2-((R)-1-aminoethyl)-4-fluorophenoxy)-5-(4methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol (XX-3) and (1S,2S,3S,5R)-3(2-((S)-1-aminoethyl)-4-fluorophenoxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7yl)cyclopentane-1,2-diol (XX-4)

Séparation of compound XX-2 by chiral SFC

XX-3: LCMS 370 [M-NH₂]; ¹H NMR (400 MHz, DMSO-ds) δ ppm 8.61 (s, 1H), 7.61 (d, J=3.7 Hz, 1H), 7.29 (dd, J=3.0, 10.0 Hz, 1H), 7.03 - 6.90 (m, 2H), 6.72 (d, >3.7 Hz, 1H), 5.34 (br. s., 1H), 5.18 - 5.01 (m, 2H), 4.61 - 4.49 (m, 2H), 4.33 (q, >6.4 Hz, 1H), 4.01 (d, >4.5 Hz, 1H), 2.94 - 2.79 (m, 1H), 2.64 (s, 3H), 2.00 (ddd, J=4.0, 9.4, 13.8 Hz, 2H), 1.25 (d, >6.5 Hz, 3H)

XX-4: LCMS 370 [M-NH₂]; Ή NMR (400 MHz, DMSO-d₆) δ ppm 8.62 (s, 1 H), 7.60 (d, J=3.7

Hz, 1H), 7.29 (dd, J=3.0, 10.0 Hz, 1H), 7.04 - 6.87 (m, 2H), 6.71 (d, J=3.5 Hz, 1H), 5.35 (br. s., 1H), 5.20 - 5.03 (m, 2H), 4.63 - 4.46 (m, 2H), 4.33 (q, J=6.6 Hz, 1H), 4.02 (d, >4.3 Hz, 1H), 2.91 - 2.78 (m, 1H), 2.64 (s, 3H), 2.04 - 1.91 (m, 2H), 1.26 (d, J=6.6 Hz, 3H)

Examples 139-142 were made in a similar fashion as XX-3 & XX-4 starting from BB-2 and the appropriate phenolic ketone. The sequence starts with steps 2 (allylic alkylation) & 3 (dihydroxylation) from Scheme BB followed by step 1 (acetonide formation) from Scheme WW and then steps 1 (reductive amination), 2 (deprotection) and 3 (chiral séparation) in Scheme XX.

Example 139	h2n-^Z /=\	421 [M+1]	(1S,2S,3S,5R)-3-(2-((S)-1- aminoethyl)-5-chloro-4-
1-(4-chloro-5-fluoro-2-	\\ /) z s N î- / N HO OH		fluorophenoxy)-5-(4-methyl-7H-
hydroxyphenyl)ethan-1-	F \ Cl
one			pyrrolo[2,3-d]pyrimidin-7-
			yl)cyclopentane-1,2-diol
ΌΗ J T			1H NMR (400 MHz, MeOD-d4) δ
		ppm 8.61 (s, 1H), 7.55 (d, >3.5 Hz,
F^'y			1H), 7.31 (d, >10.0 Hz, 1H), 7.20
Cl			(d, >6.3 Hz, 1H), 6.75 (d, >3.5 Hz, 1H), 5.16 (q, J=9.0 Hz, 1H), 4.80 - 4.73 (m, 1H), 4.72 - 4.64 (m, 1H), 4.49 - 4.39 (m, 1H), 4.22 (d, >5.0 Hz, 1H), 3.04 - 2.92 (m, 1H), 2.72 (s, 3H), 2.36 - 2.25 (m, 1H), 1.44 (d, >6.8 Hz, 3H)

-196-

Example 140 1-(4-chloro-5-fluoro-2hydroxyphenyl)ethan-1one \.O A.OH f 'y Cl	H2N-/ /=\ OaTyC t J - A/ HO OH Cl	421 [M+1]	(1 S,2S,3S,5R)-3-(2-((R)-1am inoethyl)-5-chloro-4fluorophenoxy)-5-(4-methyl-7Hpyrrolo[2,3-d]pyrimidin-7yl)cyclopentane-1,2-diol 1H NMR (400 MHz, MeOD-d4) δ ppm 8.62 (s, 1H), 7.56 (d, J=3.5 Hz, 1H), 7.31 (d, J=10.0 Hz, 1H), 7.19 (d, J=6.0 Hz, 1H), 6.75 (d, J=3.8 Hz, 1H), 5.17 (q, J=9.0 Hz, 1H), 4.79 (dd, J=5.0, 8.8 Hz, 1H), 4.69 (br. s., 1H), 4.42 (q, J=6.8 Hz, 1H), 4.20 (d, J=4.8 Hz, 1H), 3.06 - 2.93 (m, 1H), 2.72 (s, 3H), 2.41 - 2.28 (m, 1H), 1.45 (d, J=6.8 Hz, 3H)
Example 141 7-hydroxy-2,3-dihydro1H-inden-1-one O T vO	CO JL/ oh HCÔbH	364 [M-NH2]	(1S,2S,3S,5R)-3-(((S)-3-amino-2,3dihydro-1H-inden-4-yl)oxy)-5-(4methyl-7H-pyrrolo[2,3-d]pyrimidin-7yl)cyclopentane-1,2-diol 1H NMR (400 MHz, DMSO-de) δ ppm 8.63 (s, 1H), 7.67 (d, J=3.5 Hz, 1H), 7.21 - 7.06 (m, 1H), 6.86 - 6.77 (m, 2H), 6.71 (d, J=3.5 Hz, 1H), 5.40 (br. s., 1H), 5.15 - 5.04 (m, 2H), 4.65 - 4.57 (m, 2H), 4.51 - 4.45 (m, 1H), 4.04 (d, J=4.5 Hz, 1H), 3.03 - 2.93 (m, 1H), 2.90 - 2.79 (m, 1H), 2.70 (ddd, J=5.8, 9.1, 15.5 Hz, 1H), 2.64 (s, 3H), 2.34 - 2.22 (m, 1H), 2.15 - 1.81 (m, 2H), 1.76 - 1.65 (m, 1H)
Example 142 7-hydroxy-2,3-dihydro1H-inden-1-one	CO _n n [ \OH H-N θ - OH	364 [M-NH2]	(1S,2S,3S,5R)-3-(((R)-3-amino-2,3dihydro-1H-inden-4-yl)oxy)-5-(4methyl-7H-pyrrolo[2,3-d]pyrimidin-7yl)cyclopentane-1,2-diol 1H NMR (400 MHz, DMSO-de) δ ppm 8.60 (s, 1H), 7.70 (d, J=3.5 Hz, 1H), 7.12 (t, J=7.8 Hz, 1H), 6.86 6.75 (m, 2H), 6.69 (s, 1H), 5.37 (br.

- 197-

s., 1H), 5.23 - 5.03 (m, 2H), 4.66 4.55 (m, 2H), 4.48 (dd, J=4.5, 7.5 Hz, 1H), 4.02 (d, J=4.3 Hz, 1H), 3.02 - 2.93 (m, 1H), 2.90 - 2.80 (m, 1H), 2.76 - 2.66 (m, 1H), 2.66 - 2.59 (m, 3H), 2.28 (dt, J=8.2, 13.6 Hz, 1H), 2.06 - 1.97 (m, 1H), 1.77 - 1.64 (m, 1H)

Example 143 (Scheme YY) - (1S,2S,3S,5R)-3-(2-(aminomethyl)-4-chloro-3-fluorophenoxy)-

5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol (YY-6)

Scheme YY

NaBH₃CN, NH₄OAc

MeOH

HBr

H₂O

YY-2 YY-3 YY-4

Boc₂O

Et₃N, DCM

Follow procedures from Scheme BB

BB-2

YY-6

Step 1 - Synthesis of 3-chloro-2-fluoro-6-methoxybenzaldehyde (YY-2)

To a solution of 4-chloro-3-fluoroanisole (YY-1) (250 mg, 1.56 mmol) in anhydrous THF was added LDA (0.86 mL, 2M, 1.71 mmol) drop-wise under N₂, at -78 °C. and stirred at -78oC for 30 min under N₂. To the above solution was added DMF (125 mg, 1.71 mmol) at -78 °C under N₂ and the resuiting mixture was stirred at -78 °C for 20 min. The reaction was quenched by sat.

NH₄CI at -78 °C. The resuiting mixture was warmed to 25 °C. The mixture was partitioned between EtOAc and H₂O. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na₂SO₄ and concentrated to afford the crude product. The crude product was purified via flash column 15 (EtOAc:petroleum ether = 1%-12%) to afford YY-2 (178 mg, 61%) as a white solid. ¹H NMR (400 MHz, CDCI3) δ ppm 10.41 (d, J=1.3 Hz, 1H), 7.54 (dd, J=8.0, 9.0 Hz, 1H), 6.76 (dd, J=1.5, 9.0 Hz, 1H), 3.95 (s, 3H)

Step 2 - Synthesis of (3-chloro-2-fluoro-6-methoxyphenyl)methanamine (YY-3)

- 198 To a solution of YY-2 (400 mg, 2.12 mmol) in anhydrous MeOH (20.0 mL) was added NH₄OAc (1.63 g, 21.2 mmol). The mixture was stirred at 25 °C for 1 hour. To the above solution was added NaCNBH₃ (533 mg, 8.48 mmol) at 25 °C. The resulting mixture was stirred for 16 hours at 25 °C. The reaction mixture was partitioned between EtOAc and H₂O. The organic layer was separated, washed with brine, dried over Na₂SO₄ and concentrated to afford the crude product which was purified via flash column (MeOH: DCM = 1 %-15%) to afford YY-3 (270 mg, 67%) as a yellow gum. Ή NMR (400 MHz, DMSO-d_s) δ ppm 7.35 (t, J=8.8 Hz, 1H), 6.78 (d, J=9.0 Hz, 1H), 3.77 (s, 3H), 3.70 (s, 2H)

Step 3 - Synthesis of 2-(aminomethyl)-4-chloro-3-fluorophenol (YY-4)

To a solution of YY-3 (180 mg, 0.949 mmol) in H₂O (15.0 mL) was added aq.HBr (1.50 mL) drop-wise at 0 °C under N₂. After the addition, the reaction was heated at reflux (110 °C) and stirred for 6 hours. The reaction mixture was cooled to 0 °C, diluted in H₂O, and neutralized with sat. NaOH. The aqueous layer was extracted with EtOAc. The organic layer was washed with brine, dried over Na₂SO₄ and concentrated to afford the crude product which was purified via pre-TLC (MeOH: DCM = 1:10) to afford YY-4 (50 mg, 30%) as white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.18 (t, J=8.9 Hz, 1H), 6.52 (dd, J=1.5, 8.8 Hz, 1H), 3.92 (d, J=1.3 Hz, 2H)

Step 4 - Synthesis of tert-butyl (3-chloro-2-fluoro-6-hydroxybenzyl)carbamate (YY-5)

To a solution of YY-4 (50.0 mg, 0.285 mmol) in DCM (5.00 mL) and MeOH (1.0 mL) was added Boc₂O (68.4 mg, 0.313 mmol) followed by Et₃N (72 mg, 0.71 mmol) at 0 °C. After the addition, the reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was acidified by sat. citric acid to pH 5~6. The mixture was partitioned between DCM and H₂O. The organic layer was separated and the aqueous layer was extracted with DCM. The combined organic layer was washed with sat.NaHCO₃ and brine, dried over Na₂SO₄ and concentrated to afford the crude product which was purified via pre-TLC (EtOAc: Petroleum ether = 1:2) to afford YY-5 (45 mg, 57%) as a white solid. ¹H NMR (400 MHz, DMSO-ds) δ ppm 10.22 (s, 1H), 7.27 (t, J=8.4Hz), 7.02 (br. s, 1H), 6.67 (d, J=9.2 Hz), 4.14 (s, 2H), 1.37 (s, 9H)

Step 5 - Synthesis of (1S,2S,3S,5R)-3-(2-(aminomethyl)-4-chloro-3-fluorophenoxy)-5-(4methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol (YY-6)

Compound YY-6 was synthesized using YY-5 and BB-2 following procedures steps 2 & 3 in Scheme BB.

LCMS 407 [M+1]; Ή NMR (400 MHz, DMSO-d₆+D₂O) δ ppm 8.57 (s, 1H), 7.61 (d, J=3.5 Hz, 1H), 7.56 (t, J=8.7 Hz, 1H), 7.00 (d, J=9.0 Hz, 1H), 6.72 (br. s., 1H), 5.14 - 4.99 (m, 1H), 4.64

- 199(br. s., 1H), 4.59 (dd, J=4.6, 9.4 Hz, 1H), 4.08 (s, 3H), 2.90 - 2.78 (m, 1H), 2.62 (s, 3H), 2.06 (t, J=10.4 Hz, 1H)

Example 144- 146 were made in a similar fashion as YY-6 starting with the appropriate anisole reagent and following steps 3 & 4 in Scheme YY.

Example 144 2-methoxy-6(trifluoromethyl )phenyl)methan amine OMe Η2Ν^η F3C^^	H2N', /=\ F \ 2·./ vj r rt F \\ \ . ·. A HO OH	423 [M+1]	(1S,2S,3S,5R)-3-(2-(aminomethyl)-3(trifluoromethyl)phenoxy)-5-(4-methyl-7Hpyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol 1H NMR (400 MHz, DMSO-de) δ ppm = 8.60 (s, 1H), 7.71 (d, J=3.5 Hz, 1H), 7.56 - 7.48 (m, 1H), 7.47 - 7.40 (m, 1H), 7.33 (d, J=7.8 Hz, 1H), 6.71 (d, J=3.5 Hz, 1H), 5.11 (q, J=9.3 Hz, 1H), 4.71 (br. s., 1H), 4.65 (dd, J=4.9, 9.2 Hz, 1H), 4.13 (d, J=4.3 Hz, 1H), 4.02 (br. s., 2H), 2.97 - 2.82 (m, 1H), 2.64 (s, 3H), 2.11 (ddd, J=4.3, 9.7, 13.7 Hz, 1H)
Example 145 (2,3-difluoro-6methoxyphenyl Jmethanamine OMe HaN'^TjT F^y F	H2N- AT \ O^VN. X/ \\ 3 · ' HO OH F	391 [M+1]	(1S,2S,3S,5R)-3-(2-(aminomethyl)-3,4difluorophenoxy)-5-(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)cyclopentane-1,2-diol 1H NMR (400 MHz, DMSO-de) δ ppm 8.61 (s, 1H), 7.68 (s, 1H), 7.31 - 7.20 (m, 1H), 6.90 - 6.83 (m, 1H), 6.72 (d, J=3.5 Hz, 1H), 5.54 - 5.25 (m, 1H), 5.17 - 5.03 (m, 2H), 4.68 - 4.55 (m, 2H), 4.07 - 4.01 (m, 1H), 3.77 (d, J=1.3 Hz, 2H), 2.90 -2.79 (m, 1 H), 2.64 (s, 3H), 2.10 -1.99 (m, 1H)
Example 146 2-(5-ch!oro-2methoxyphenyl )ethan-1-amine OMe Cl	€(SN A N Γ\·ΌΗ 0 i oh TJ Cl	403 [M+1]	(1S,2S,3S,5R)-3-(2-(2-aminoethyl)-4chlorophenoxy)-5-(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)cyclopentane-1,2-diol 1H NMR (400 MHz, DMSO-d6+D2O) δ ppm 8.59 (s, 1H), 7.58 (d, J=3.8 Hz, 1H), 7.23 - 7.16 (m, 2H), 7.00 (d, J=8.5 Hz, 1H), 6.72 (d, J=3.8 Hz, 1H), 5.16 - 5.01 (m, 1H), 4.62 - 4.46 (m, 2H), 3.99 (d, J=5.3 Hz, 1H), 2.91 - 2.81 (m, 1H), 2.79 - 2.68 (m, 2H), 2.62 (s, 2H), 2.00 - 1.88 (m, 1H)

Example 147 (Scheme ZZ) - (1S,2S,3S,5R)-3-(2-(aminomethyl)-4,5-dichlorophenoxy)-5-(4methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol (ZZ-7)

Scheme ZZ

-200-

Step 1 - Synthesis of (4,5-dichloro-2-methoxyphenyl)methanol (ZZ-2)

To a solution of methoxybenznic acid (ZZ-1) (500 mg, 2.26 mmol) in anhydrous THF (23 mL) was added BH₃.THF (6.79 mL, 6.79 mmol) at 0 °C under N₂. After the addition, the reaction mixture was stirred at 30 °C under N₂ for 3 hours. The reaction mixture was cooled to -20 _OC and quenched with sat. NH₄CI. The reaction mixture was partitioned between EtOAc and H₂O.

The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na₂SO4and concentrated to afford the crude product which was purified via flash column chromatography (EtOAc: Petroleum ether 10 = 1 %-35%) to afford the ZZ-2 (383 mg, 81.8%) as a white solid. Ή NMR (400 MHz, DMSO-d₆) δ ppm 7.49 (s, 1H), 7.22 (s, 1H), 5.28 (t, J=5.6 Hz), 4.44 (d, J=6 Hz), 3.31 (s, 3H)

Step 2 - Synthesis of 2-(4,5-dichloro-2-methoxybenzyl)isoindoline-1,3-dione (ZZ-3)

To a solution of ZZ-2 (230 mg, 1.11 mmol) and phthalimide (163 mg, 1.11 mmol) in anhydrous

THF (12 mL) was added PPh₃ (291 mg, 2.30 mmol). The reaction mixture was stirred at -20 °C 15 under N₂ for 30 min. To the above solution was added DEAD (193 mg, 1.11 mmol) at -10 °C~20 °C. After the addition, the reaction mixture was became a yellow solution, which was warmed to 25 °C and stirred for 2 hours. The reaction mixture was concentrated and the residue was purified via flash column (12.0 g gel, EtOAc: petroleum Ether = 10%-35%) to afford the crude product and further purified via prep-TLC (EtOAc: petroleum = 1 %~15%) to afford the product

ZZ-3 (30 mg, 8%) as a white solid and used as is in the next step.

Step 3 - Synthesis of 2-(4,5-dichloro-2-hydroxybenzyl)isoindoline-1,3-dione (ZZ-4)

To a solution of ZZ-3 (50 mg, 0.15 mmol) in DCM (2.00 mL) was added BBr₃ (0.20 mL) dropwise at 0 °C. After the addition, the reaction was stirred at 0 °C for 2 hours. The reaction

-201 mixture was quenched with MeOH carefully. The resulting mixture was partitioned between DCM and sat. NaHCO₃. The organic layer was washed with brine, dried over Na₂SO₄ and concentrated to afford the crude product which was purified via prep-TLC (EtOAc: petroleum ether = 1:1) to afford ZZ-4 (43 mg, 90%) as a white solid. Ή NMR (400 MHz, DMSO-d₆) δ ppm 10.50 (s, 1H), 7.94 - 7.76 (m, 4H), 7.32 (s, 1H), 7.00 (s, 1H), 4.68 (s, 2H)

Step 4 - Synthesis of 2-(4,5-dichloro-2-(((1S,4R)-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7yl)cyclopent-2-en-1 -yl)oxy)benzyl)isoindoline-1,3-dione (ZZ-5)

To a stirred solution of ZZ-4 (43 mg, 0.13 mmol) and tert-butyl ((1S,4R)-4-(4-methyl-7Hpyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-2-en-1-yl) carbonate (42 mg, 0.13 mmol) in DCE (1.50 mL) was added Cs₂CO₃ (52 mg, 0.16 mmol), Pd₂(dba)₃.CHCI₃, (3.5 mg, 0.003 mmol) and dppp (3.3 mg, 0.008 mmol). The reaction mixture was degassed and purged with N₂ for 3 times. The resulting solution was stirred for 1.5 hrs at 25 °C. The reaction mixture was concentrated and purified via prep-TLC (EtOAc: petroleum ether = 1:1) to afford the product ZZ-5 (62 mg, 89%) as a yellow gum and used in the next step directly.

Step 5 - Synthesis of 2-(4,5-dichloro-2-(((1S,2S,3S,4R)-2,3-dihydroxy-4-(4-methyl-7Hpyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl)oxy)benzyl)isoindoline-1,3-dione (ZZ-6)

To a solution of ZZ-5 (62 mg, 0.12 mmol) in THF (2.50 mL) and H₂O (0.50 mL) was added NMO (29.4 mg, 0.251 mmol) followed by OsO₄ (136 mg, 0.02 mmol, 4% w/w in t-BuOH). After the addition, the reaction mixture was strirred at 28 °C for 4 hours. The reaction mixture was diluted in H₂O and quenched with sat. NaHSO₃. The dark solution was extracted with EtOAc, dried over Na₂SO₄ and concentrated to afford the crude product which was purified via prep-TLC (MeOH: DCM = 1:10, UV) to afford ZZ-6 (30 mg, 45%) as a yellow solid. Ή NMR (400 MHz, DMSO-de) δ ppm 8.61 (s, 1H), 7.95 - 7.77 (m, 4H), 7.60 (d, J=3.5 Hz, 1H), 7.56 (s, 1H), 7.36 (s, 1H), 6.73 (d, J=3.5 Hz, 1H), 5.43 (d, J=4.0 Hz, 1H), 5.18 - 5.05 (m, 2H), 4.81 (s, 2H), 4.70 - 4.61 (m, J=6.0 Hz, 1H), 4.52 - 4.41 (m, 1H), 3.99 - 3.94 (m, 1H), 2.91 - 2.78 (m, 1H), 2.65 (s, 3H), 1.98 - 1.86 (m, 1H)

Step 6 - Synthesis of (1S,2S,3S,5R)-3-(2-(aminomethyl)-4,5-dichlorophenoxy)-5-(4-methyl7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol (ZZ-7)

To a solution of ZZ-6 (30 mg, 0.05 mmol) in THF (2.5 mL) was added NH₂NH₂ (31 mg, 0.81 mmol) drop-wise. After the addition, the reaction solution was stirred at 28 °C for 16 hours. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified via prep-HPLC to afford ZZ-7 (11 mg, 46%) as a white solid. LCMS 423 [M+1]; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.62 (s, 1H), 7.66 (d, J=3.8 Hz, 1H), 7.60 (s, 1H), 7.31 (s, 1H), 6.72 (d, J=3.3

-202 Hz, 1H), 5.14 - 5.05 (m, 2H), 4.63 (m, 1H), 4.00 (m, 1H), 3.74 (s, 2H), 2.89 - 2.81 (m, 1H), 2.64 (s, 3H), 2.02 (m, 1H)

Example 148 (1S,2S,3S,5R)-3-(2-(aminomethyl)-4,5-difluorophenoxy)-5-(4-methyl-7Hpyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol was prepared in a similar fashion to 5 ZZ-7 starting with (4,5-difluoro-2-methoxyphenyl)methanol and following steps 2 through in Scheme ZZ.

Example 148 (4,5-difluoro-2methoxyphenyl )methanol

391 [M+1] (1S,2S,3S,5R)-3-(2-(aminomethyl)-4,5difluorophenoxy)-5-(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)cyclopentane-1,2-diol ¹H NMR (400 MHz, DMSO-de) δ ppm 8.62 (s, 1H), 7.75 - 7.57 (m, 1H), 7.51 - 7.32 (m, 1H), 7.25 - 7.05 (m, 1H), 6.72 (d, J=3.5 Hz, 1H), 5.39 (d, J=18.1 Hz, 1H), 5.20 - 4.98 (m, 2H), 4.57 (d, J=4.8 Hz, 2H), 4.01 (d, J=4.3 Hz, 1H), 3.72 (s, 2H), 2.95 - 2.72 (m, 1H), 2.62 (s, 3H), 2.00 (ddd, J=4.5, 9.1, 13.7 Hz, 1H)

Example 149 (Scheme AAA) - (1S,2S,3S,5R)-3-(2-(2-amino-1-hydroxyethyl)-410 chlorophenoxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol (AAA9)

Scheme AAA

Step 1 - Synthesis of 2-bromo-1-(5-chloro-2-hydroxyphenyl)ethan-1-one (AAA-2)

-203To a yellow solution of 1-(5-chloro-2-hydroxyphenyl)ethan-1-one (AAA-1) (2 g, 11.72 mmol) and in THF (60 mL) was added PhMe₃NBr₃ (4.85 g, 12.9 mmol) at rt (25 °C). The resulting red solution was stirred at rt for 12 hrs in which solid was formed, then the mixture was filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography eluted with EtOAc in petroleum ether from 0 to 10% to AAA-2 (2.4 g) as a yellow oil which was used in the next step directly.

Step 2 - Synthesis of 2-((3r,5r,7r)-114,3,5,7-tetraazaadamantan-1-yl)-1-(5-chloro-2hydroxyphenyl)ethan-1-one, bromide sait (AAA-3)

To a solution of 1,3,5,7-tetraazaadamantane (4.67 g, 33.3 mmol) in CHCI₃ (40 mL) was added to AAA-2 (2.6 g, 10 mmol) at rt (25 °C). The mixture was stirred at rt for 12 hrs in which solid was formed. The solid was collected by filtration and rinsed with DCM and dried in vacuo to afford crude AAA-3 (3 g, 74%) as a white solid, used in the next step directly.

Step 3 - Synthesis of 2-amino-1-(5-chloro-2-hydroxyphenyl)ethan-1-one (AAA-4)

To a suspension of SM1 (3 g, 8 mmol) in EtOH (15 mL) was added conc. HCl (3 mL) at rt (25 oC). The suspension was stirred at rt for 2 hrs. The reaction was evaporated to give AAA-4 (1.5 g, >100%) as yellow oil which was used directly without further purification. LCMS 186 [M+1]

Step 4 - Synthesis of tert-butyl (2-(5-chloro-2-hydroxyphenyl)-2-oxoethyl)carbamate (AAA-5)

To a solution of (Boc)₂O (2.29 g, 10.5 mmol) in dioxane (15 mL) was added the solution of AAA-4 (200 mg, solution, neutralized by NaHCO₃ aq.) at 0 °C. The reaction solution was stirred at 25 °C. The reaction solution was extracted with EtOAc (6 mL x 3). The organic layers were separated, dried and evaporated to give the crude product which was purified by flash chromatography with 0-25% EtOAc/petroleum ether, to give AAA-5 (600 mg, 22%) as a white solid and used as is in the next step.

Step 5 - Synthesis of tert-butyl (2-(5-chloro-2-(((1S,4R)-4-(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)cyclopent-2-en-1-yl)oxy)phenyl)-2-oxoethyl)carbamate (AAA-6)

- 204 Using BB-2 and following similar procedures as step 2 in Scheme BB, AAA-6 was obtained (288 mg, 31%) as a yellow gum and used in the next step directly.

Step 6 - Synthesis of tert-butyl (2-(5-chloro-2-(((1S,2S,3S,4R)-2,3-dihydroxy-4-(4-methyl7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl)oxy)phenyl)-2-oxoethyl)carbamate (AAA-7)

Starting with AAA-6 and following similar procedures as step 3 in Scheme BB, AAA-7 was obtained (70 mg, 33%) as a white solid. LCMS 517 [M+1]

Step 7 - Synthesis of tert-butyl (2-(5-chloro-2-(((1S,2S,3S,4R)-2,3-dihydroxy-4-(4-methyl7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl)oxy)phenyl)-2-hydroxyethyi)carbamate (AAA8)

To a mixture of AAA-7 (70 mg, 0.14 mmol) in MeOH (1 mL) was added NaBH₄ (15.4 mg, 0.406 mmol).The mixture was stirred at 25 °C for 2h. The mixture was quenched by 1N HCl aq. (5 mL).The mixture was evaporated to give the crude product AAA-8 (70 mg, >99%) as a white solid.

Step 8 - Synthesis of (1S,2S,3S,5R)-3-(2-(2-amino-1-hydroxyethyl)-4-chlorophenoxy)-5-(4methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol (AAA-9)

Compound AAA-8 (62 mg, 0.12 mmol) was dissolved in DCM (0.6 mL). The mixture was cooled to 0 °C in an ice bath. TFA (0.2 mL) was added to the above mixture drop-wise. The reaction mixture was stirred at 25 °C for 2 hours. The reaction solution was neutralized by saturated NaHCO₃ aq. (1 mL), filtered and the filtrate was purified by prep-HPLC directly to give AAA-9 (21 mg, 42%) as a white solid. LCMS 441 [M+23]; ¹H NMR (400 MHz, MeOD-d₄) δ ppm 8.62 (d, J=2.8 Hz, 1H), 7.58 (dd, J=3.3, 11.3 Hz, 1H), 7.48 (s, 1H), 7.26 - 7.22 (m, 1H), 7.03 (dd, J=2.1, 8.7 Hz, 1H), 6.75 (t, J=3.8 Hz, 1H), 5.20 (d, J=3.8 Hz, 1H), 5.10 (br. s., 1H), 4.70 (br. s., 2H), 4.22 (d, J=9.5 Hz, 1H), 3.04 - 2.94 (m, 2H), 2.77 (br. s., 1H), 2.71 (s, 3H), 2.26 (br. s., 1H)

Example 150 (Scheme BBB) - (1S,2S,3S,5R)-3-(2-(aminomethyl)-3,4-dichlorophenoxy)-5(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol (BBB-8)

Scheme BBB

-205 -

AICI3, anisole

DCM

BB-2

Pd₂(dba)₃-CHCI₃, DPPP

CS2CO3, DCE

Step 1 - Synthesis of 2,3-dichloro-6-fluorobenzaldehyde (BBB-2)

To a solution of 1,2-dichloro-4-fluorobenzene (BBB-1) (2 g, 12.12 mmol) in anhydrous THF (30 mL) was added LDA (6.67 mL, 2M, 13.3 mmol) drop-wise under N₂, at -65 °C. After the addition, the reaction mixture was stirred at -65 °C for 30 min under N₂. To the resulting red solution was added DMF (1.77 g, 24.2 mmol) at -65 °C under N₂and the resulting mixture was stirred at -65 °C for 20 min. The reaction was quenched with water (50 mL) and extracted with EtOAc (30 mL x 2). The extract was washed with 1 N HCl (30 mL), brine (30 mL), dried over Na₂SO₄ and concentrated to give the crude material which was extracted with petroleum ether (30 mL x 3). The extract was concentrated in vacuo to afford BBB-2 (2.2 g, 94%) as a yellow solid. Ή NMR (400 MHz, CDCI₃) δ ppm 10.44 (s, 1H), 7.66 (dd, J=5.3, 9.0 Hz, 1H), 7.10 (t, J=9.2 Hz, 1H)

Step 2 - Synthesis of 2,3-dichloro-6-hydroxybenzaldehyde (BBB-3)

To a yellow solution of crude BBB-2 (2.2 g, 11.4 mmol) in DMSO (10 mL) was added KOH (1280 mg, 22.8 mmol) slowly at 0 °C. After addition, the mixture was changed into red mixture and stirred at room température (20 °C) for 16 hrs. The mixture was diluted with MTBE (100 mL). The liquid was decanted out and residue was washed with MTBE (100 mL). The residue was then diluted with water (30 mL) and adjusted with 1 N HCl to pH 2 and extracted with EtOAc (20 mL x 2). The extract was washed with brine (20 mL), dried over Na₂SO₄ and concentrated in vacuo to afford crude BBB-3 (390 mg, 18%) as yellow solid. ¹H NMR (400 MHz, CDCI₃) δ ppm 11.98 (s, 1 H), 10.44 (s, 1 H), 7.56 (d, J=9.0 Hz, 1 H), 6.90 (d, J=9.3 Hz, 1 H)

Step 3 - Synthesis of (R,E)-N-(2,3-dichloro-6-hydroxybenzylidene)-2-methylpropane-2sulfinamide (4)

A mixture of crude BBB-3 (150 mg, 0.79 mmol), (R)-2-methylpropane-2-sulfinamide (143 mg,

1.2 mmol) and CuSO₄ (376 mg, 2.36 mmol) in CHCI₃ (3 mL) was stirred at rt (30 °C) for 5 days. The mixture was filtered and purified by silica gel chromatography eluted with EtOAc in

-206petroleum ether from 0 to 30 % to afford BBB-4 (70 mg, 30%) as a light yellow solid. ¹H NMR (400 MHz, CDCh) δ ppm 11.98 (s, 1H), 9.28 (s, 1H), 7.49 (d, J=8.8 Hz, 1H), 6.92 (d, J=9.3 Hz, 1H), 1.29 (s, 9H)

Step 4 - Synthesis of (R)-N-(2,3-dichloro-6-hydroxybenzyl)-2-methylpropane-2sulfinamide (BBB-5)

To a solution of BBB-4 (70 mg, 0.238 mmol) in MeOH (3 mL) was added NaBH₄ (27 mg, 0.714 mol) at rt (30 °C). The mixture was stirred at rt for 1 h. The mixture was concentrated in vacuo and dissolved in water (5 mL). To the mixture was added NH4CI aq (2 mL) in which some solid was formed. The mixture was extracted with EtOAc (5 mL x 3). The extract was washed with brine (5 mL), dried over Na₂SO₄ and concentrated in vacuo to afford BBB-5 (55 mg, 78%) as a yellow solid. Ή NMR (400 MHz, CDCh) δ ppm 9.31 (br. s., 1H), 7.17 (d, J=8.8 Hz, 1H), 6.69 (d, J=9.0 Hz, 1H), 4.58 - 4.40 (m, 2H), 4.09 - 3.97 (m, 1H), 1.27 (s, 9H)

Step 5 - Synthesis of (R)-N-(2,3-dichloro-6-(((1S,4R)-4-(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)cyclopent-2-en-1-yl)oxy)benzyl)-2-methylpropane-2-sulfinamide (BBB-6)

Compound BBB-6 (130 mg, 98%, containing 1 eq of DCM) was prepared as a yellow gum from BBB-5 and BB-2 using similar procedures to step 2 of Scheme BB. LCMS 493 [M+1]; ¹H NMR (400 MHz, CDCh) δ ppm 8.77 (s, 1H), 7.39 - 7.31 (m, 2H), 6.84 (d, J=9.0 Hz, 1H), 6.60 (d, J=3.5 Hz, 1H), 6.41 (d, J=5.5 Hz, 1H), 6.22 (d, J=4.8 Hz, 1H), 6.13 - 6.01 (m, 1H), 5.41 - 5.35 (m, 1H), 4.63 - 4.39 (m, 2H), 3.65 (t, J=6.7 Hz, 1H), 3.29 - 3.09 (m, 1H), 2.73 (s, 3H), 1.98 (td, J=3.8, 14.7 Hz, 1H), 1.18 (s, 9H)

Step 6 - Synthesis of N-(2,3-dichloro-6-(((1S,2S,3S,4R)-2,3-dihydroxy-4-(4-methyl-7Hpyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl)oxy)benzyl)-2-methylpropane-2-sulfonamide (BBB-7)

Compound BBB-6 was treated in a similar fashion to procedures of step 3 in scheme BB to afford BBB-7 (70 mg, 58%). LCMS 543 [M+16+1]; ¹H NMR (400 MHz, CDCh) δ ppm 8.62 (s, 1H), 7.56 (br. s., 1H), 7.19 (d, J=8.8 Hz, 1H), 6.77 (d, J=9.0 Hz, 1H), 6.54 (d, J=3.8 Hz, 1H), 5.64 (t, J=5.5 Hz, 1H), 5.14 (s, 1H), 5.13-5.04 (m, 1 H), 4.56 - 4.50 (m, 1H), 4.47 (dd, J=4.8, 8.5 Hz, 1H), 4.44 - 4.34 (m, 2H), 4.04 (d, J=4.8 Hz, 1H), 2.83 - 2.75 (m, 1H), 2.62 (s, 3H), 2.14 2.04 (m, 1H), 1.20 (s, 9H)

Step 7 - Synthesis of (1S,2S,3S,5R)-3-(2-(aminomethyl)-3,4-dichlorophenoxy)-5-(4-methyl7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol (BBB-8)

-207To a solution of BBB-7 (35 mg, 0.064 mmol) in dry DCM (5 mL) was added anisole (170 mg, 1.56 mmol) and AICI₃ (86 mg, 0.64 mmol) at rt (25 °C). The white suspension was stirred at rt for 3 h. The mixture was quenched with NaHCO₃ aq (3 mL), foilowed by potassium sodium tartrate aq (5 mL). The mixture was extracted with EtOAc (5 mL x 3). The extract was concentrated in vacuo and purified by TLC (DCM/MeOH=10/1) to afford BBB-8 (8 mg, 29%) as a white solid. LCMS 423 [M+1]; Ή NMR (400 MHz, DMSO-de) δ ppm 8.61 (s, 1H), 7.69 (d, J=3.5 Hz, 1H), 7.49 (d, J=8.8 Hz, 1H), 7.11 (d, J=9.0 Hz, 1H), 6.72 (d, J=3.8 Hz, 1H), 5.44 (br. s., 1H), 5.10 (q, J=9.0 Hz, 2H), 4.64 (d, J=5.3 Hz, 2H), 4.06 (d, J=4.8 Hz, 1H), 3.92 (s, 2H), 2.92 - 2.81 (m, 1H), 2.64 (s, 3H), 2.05 (ddd, J=4.1, 9.2, 13.8 Hz, 1H)

Example 151 (Scheme CCC) - (1S,2S,3S,5R)-3-(2-(2-aminoethoxy)-4,5-dichlorophenoxy)-5(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol (CCC-4)

Scheme CCC

Step 1 - Synthesis of 4,5-dichloro-2-(((1S,4R)-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7yl)cyclopent-2-en-1 -yl)oxy)phenol (CCC-1 )

Compound CCC-1 was prepared using similar procedures to step 2 in scheme BB with commercially available 4,5-dichlorobenzene-1,2-diol and BB-2

Step 2 - Synthesis of tert-butyl (2-(4,5-dichloro-2-(((1S,4R)-4-(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)cyclopent-2-en-1-yl)oxy)phenoxy)ethyl)carbamate (CCC-2)

To a stirred yellow solution of CCC-1 (78 mg, 0.21 mmol) in dry DMF (5 mL) was added K₂CO₃ (86 mg, 0.62 mmol) and tert-butyl (2-bromoethyl)carbamate (923 mg, 0.42 mmol) at 25 °C and stirred for 20 hours. Water (10 mL) was added to the reaction mixture and extracted with EtOAc

-208(2 x 20 mL). The combined organic layers were washed with brine (5 x 20 mL), dried over Na₂SO₄, filtered and concentrated in vacuum to give the residue which was purified by column chromatography (silica gel, eluted with EtOAc) to give CCC-2 (108 mg, >99%) as a colorless gum. LCMS [M+1] 519; Ή NMR (400 MHz, CDCI₃) δ ppm 8.77 (s, 1H), 7.42 (d, J=3.5 Hz, 1H), 7.04 (s, 1H), 6.98 (s, 1H), 6.60 (d, J=3.5 Hz, 1H), 6.39 (td, J=1.9, 5.5 Hz, 1H), 6.19 (dd, J=2.3,

5.3 Hz, 1H), 6.06 (dd, J=2.0, 4.8 Hz, 1H), 5.29 (d, J=7.0 Hz, 1H), 5.02 (br. s., 1H), 4.03 (t, J=5.0 Hz, 2H), 3.59 - 3.47 (m, 2H), 3.10 (td, J=7.7, 15.2 Hz, 1H), 2.73 (s, 3H), 2.07 (t, J=2.9 Hz, 1H), 1.42 (s, 9H)

Step 3 - Synthesis of tert-butyl (2-(4,5-dichloro-2-(((1 S,2S,3S,4R)-2,3-dihydroxy-4-(4methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl)oxy)phenoxy)ethyl)carbamate (CCC-3)

Compound CCC-2 was subjected to similar procedures as step 3 in Scheme BB to afford CCC3 (55 mg, 48%) as brown gum. LCMS [M+23] 575

Step 4 - Synthesis of (1S,2S,3S,5R)-3-(2-(2-aminoethoxy)-4,5-dichlorophenoxy)-5-(4methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol (CCC-4)

Compound CCC-3 was subjected to standard TFA/water deprotection methods similar to step 8 in scheme AAA followed by prep-HPLC to afford CCC-4 (35 mg, 75%). LCMS [M+23] 475, H NMR (400 MHz, MeOD-d₄) δ ppm 8.64 (s, 1H), 7.66 (d, J=3.8 Hz, 1H), 7.37 (s, 1H), 7.29 (s, 1H), 6.79 (d, J=3.5 Hz, 1H), 5.20 (q, J=8.9 Hz, 1H), 4.76 - 4.68 (m, 1H), 4.66 (dd, J=5.3, 8.0 Hz, 1H), 4.33 - 4.23 (m, 3H), 3.40 - 3.36 (m, 2H), 3.01 - 2.90 (m, 1H), 2.74 (s, 3H), 2.29 (ddd, J=5.0, 8.8, 14.3 Hz, 1H)

Example 152 (1 S,2S,3S,5R)-3-(2-(2-aminoethoxy)-4,5-difluorophenoxy)-5-(4-methyl-7Hpyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol was prepared in a similar fashion to

CCC-4 starting with 4,5-difluorobenzene-1,2-diol and following steps 1 through 4 in

Scheme CGC.

Example 152

4,5difluorobenzene1,2-diol

421 [M+1] (1S,2S,3S,5R)-3-(2-(2-aminoethoxy)-4,5difluorophenoxy)-5-(4-methyl-7Hpyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane1,2-diol ¹H NMR (400 MHz, MeOD-d₄) δ ppm 8.64 (s, 1H), 7.67 (d, >3.5 Hz, 1H), 7.26 - 7.07 (m, 2H), 6.80 (d, J=4.0 Hz, 1H), 5.19 (q,

-209-

J=8.9 Hz, 1H), 4.72 - 4.64 (m, 2H), 4.33 4.21 (m, 3H), 3.42 - 3.36 (m, 2H), 2.99 2.87 (m, 1H), 2.75 (s, 3H), 2.33 - 2.23 (m, 1H)

Example 153 (Scheme DDD) - (1S,2S,3S,5R)-3-(2-(2-aminoethoxy)-4-chlorophenoxy)-5-(4methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol (DDD-6)

Scheme DDD

DDD-1

DDD-6

Step 1 - Synthesis of 1-(5-chloro-2-(((1 S,2S,3S, 4R)-2,3-dihydroxy-4-(4-methyl-7Hpyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl)oxy)phenyl)ethan-1-one (DDD-1)

Compound DDD-1 was prepared using similar procedures to steps 2 & 3 in scheme BB with commercially available 1-(5-chloro-2-hydroxyphenyl)ethan-1-one and BB-2.

Step 2 - Synthesis of 5-chloro-2-(((1S,2S,3S,4R)-2,3-dihydroxy-4-(4-methyl-7Hpyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl)oxy)phenyl acetate (DDD-2)

Trifluoroacetic anhydride (1.46 g, 6.95mmol) cooled to -10 °C was added dropwise and 30% H2O2 (185 mg, 1.63 mmol) and the solution was stirred for 10 min. To this mixture was added DDD-1 (210 mg, 0.523 mmol) in DCM (3.5 mL) dropwise at 0 °C and stirred at 25 °C for 15 min. Then saturated sodium thiosulfate (2 mL) was added to the reaction solution. The reaction solution was basified by saturated NaHCO₃ to pH=7~8, extracted with DCM (30 mL x 2). The combined organic layers were washed with brine (40 mL), dried over Na₂SO₄, filtered and evaporated to give crude material, which was purified by ISCO (silica gel, 12 g, MeOH/DCM=10%~14%) to give desired product DDD-2 (160 mg, 73%) as a white solid. LCMS [M+1] 418; Ή NMR (400 MHz, CDCh) δ ppm 8.67 (s, 1H), 7.25 (m, 1H), 7.21 (dd, J=2.5, 8.8

- 210 Hz, 1H), 7.12 - 7.06 (m, 2H), 6.60 (d, J=3.8 Hz, 1H), 4.97 (q, J=8.5 Hz, 1H), 4.78 (t, J=6.0 Hz, 1H), 4.50 (dd, J=5.3, 8.3 Hz, 1H), 4.29 (d, J=5.5 Hz, 1H), 3.12 - 3.01 (m, 1H), 2.72 (s, 3H), 2.36 - 2.27 (m, 1 H), 2.24 (s, 3H)

Step 2 - Synthesis of 5-chloro-2-(((3aR,4S,6R,6aS)-2,2-dimethyl-6-(4-methyl-7Hpyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)phenyl acetate (DDD-3)

To a stirred colorless solution of DDD-2 (160 mg, 0.38 mmol) in acetone (0.64 mL) was added

2,2-dimethoxypropane (6.4 mL) and p-toluenesulfonic acid (73 mg, 0.38 mmol) at 25 °C. The reaction was stirred at 25 °C for 1 hour. Then aq.NaHCO3 (3 mL) was added to the reaction mixture until the pH 8.0. Then the mixture was extracted with EtOAc (15 mL x 2). The organic layers were separated, washed with brine (20 mL), dried over Na₂SO₄ and filtered. The organic layer was evaporated to give the crude product as a colorless gum, which was purified by column chromatography (ether:EtOAc=1:1, Rf~0.55) to give the DDD-3 (126 mg, 72%) as a white solid. LCMS [M+1] 458; Ή NMR (400 MHz, CDCh) δ ppm 8.79 (s, 1H), 7.43 (d, J=3.8 Hz, 1H), 7.25 - 7.20 (m, 1H), 7.14 - 7.07 (m, 2H), 6.58 (d, J=3.5 Hz, 1H), 5.46 - 5.38 (m, 1H), 4.93 (d, J=5.8 Hz, 1H), 4.83 - 4.74 (m, 2H), 3.06 - 2.89 (m, 1H), 2.74 (s, 3H), 2.52 - 2.37 (m, 1H),

2.21 (s, 3H), 1.60 (br. s., 3H), 1.32 (s, 3H)

Step 3 - Synthesis of 5-chloro-2-(((3aR,4S,6R,6aS)-2,2-dimethyl-6-(4-methyl-7Hpyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)phenol (DDD-4)

Compound DDD-3 (142 mg, 0.31 mmol) was dissolved in MeOH (3 mL) and H₂O (1 mL). K₂CO₃ (85.7 g, 0.62 mmol) was added to the above mixture. The reaction mixture was stirred at 25 °C for 1 hour. The mixture was neutralized with 10% citric acid to pH 6-7. The mixture was diluted with H₂O (10 mL), extracted by EtOAc (10 mL x 2). The combined organic layers were washed with brine (10 mL), dried over Na₂SO₄, filtered and evaporated to give DDD-4 (140 mg, >99%) as a colorless gum. LCMS [M+1] 416; Ή NMR (400 MHz, CDCh) δ ppm 8.79 (s, 1H), 7.22 (d, J=3.5 Hz, 1H), 6.96 - 6.90 (m, 2H), 6.87 - 6.81 (m, 1H), 6.61 (d, J=3.5 Hz, 1H), 5.95 - 5.74 (m, 1H), 5.27 - 5.19 (m, 2H), 4.87 - 4.78 (m, 2H), 2.99 - 2.87 (m, 1H), 2.74 (s, 3H), 2.61 - 2.50 (m, 1H), 1.59 (s, 3H), 1.34 (s, 3H)

-211 Step 4 - Synthesis of tert-butyl (2-(5-chloro-2-(((3aR,4S,6R,6aS)-2,2-dimethyl-6-(4-methyl7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4yl)oxy)phenoxy)ethyl)carbamate (DDD-5)

To a stirred solution of DDD-4 (140 mg, 0.34 mmol) in dry DMF (5 mL) was added K₂CO₃ (140 mg, 1.0 mmol) and tert-butyl (2-bromoethyl)carbamate (151 mg, 0.67 mmol) at 25 °C. The reaction was stirred at 25 °C for 15 hours. Water (10 mL) was added to the reaction mixture and the mixture was extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (20 mL x 5), dried over Na₂SO₄, filtered and concentrated to give crude material which was purified by ISCO (EtOAc/petroleum ether=60%) to give DDD-5 (170 mg, 90%) as a colorless gum. LCMS [M+23] 581; ¹H NMR (400 MHz, CDCI₃) δ ppm 8.80 (s, 1H), 7.77 (d, J=3.8 Hz, 1H), 6.96 - 6.84 (m, 3H), 6.59 (d, J=3.8 Hz, 1H), 5.50 (d, J=8.0 Hz, 1H), 5.18 (br. s., 1H), 4.92 - 4.86 (m, 1H), 4.85 - 4.81 (m, 2H), 4.08 - 3.98 (m, 2H), 3.65 - 3.54 (m, 2H), 3.08 - 2.98 (m, 1H), 2.74 (s, 3H), 2.47 (d, J=14.6 Hz, 1H), 1.59 (s, 3H), 1.42 (s, 9H), 1.31 (s, 3H)

Step 5 - Synthesis of (1S,2S,3S,5R)-3-(2-(2-aminoethoxy)-4-chlorophenoxy)-5-(4-methyl7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol (DDD-6)

Compound DDD-5 was subjected to standard TFA/water deprotection methods followed by prep-HPLC to afford DDD-6 (40 mg, 31%). LCMS [M+23] 441; Ή NMR (400 MHz, MeOD-d₄) δ ppm 8.64 (s, 1H), 7.78 (d, J=3.8 Hz, 1H), 7.14 - 7.05 (m, 2H), 6.96 (d, J=8.3 Hz, 1H), 6.82 (d, J=3.8 Hz, 1H), 5.41 - 5.27 (m, 1H), 4.74 - 4.70 (m, J=5.5 Hz, 1H), 4.67 (dd, J=4.6, 7.9 Hz, 1H),

4.21 (d, J=4.5 Hz, 1H), 4.15 - 4.07 (m, 2H), 3.18 - 3.08 (m, 2H), 3.06 - 2.94 (m, 1H), 2.74 (s, 3H), 2.14 (dd, J=6.8, 14.1 Hz, 1H) (Scheme EEE) - Synthesis of tert-butyl 5-chloro-8-hydroxy-3,4-dihydroisoquinoline-2(1H)carboxylate (TP-19)

Scheme EE

-212-

Step 1 - Synthesis of (2-chloro-5-methoxyphenyl)methanol (EEE-2)

To a solution of methyl 2-chloro-5-methoxybenzoate EEE-1 (4.55 g, 22.7 mmol) in anhydrous THF (200 mL) was added LiAIH₄ (1.72 g, 45.4 mmol) at -10 °C~-5 °C portion-wise. The température was raised to 0 °C. After the addition, the reaction was stirred at 0 °C for 2 hours. The reaction mixture was quenched by 5% NaOH. The reaction mixture was filtered through a pad of Celite. To the Celite cake was added THF (100 mL) and EtOAc (100 mL) and stirred sat 25 °C for 0.5 hour. The mixture was filtered and the combined organic layers were dried over Na₂SO₄ and concentrated to afford the crude EEE-2 (4.5 g) as a colorless oil and used directly in the next step. Ή NMR (400 MHz, CDCh) δ ppm 7.25 (d, J=9.5 Hz, 1H), 7.05 (d, J=2.8 Hz, 1 H), 6.78 (dd, J=2.9, 8.7 Hz, 1 H), 4.75 (d, J=3.8 Hz, 2H), 3.81 (s, 3H), 2.04 - 1.94 (m, 1 H)

Step 2 - Synthesis of 2-chloro-5-methoxybenzaldehyde (EEE-3)

To a solution of EEE-2 (3.63 g, 16.16 mmol) in CH₃CN (120 mL) was added IBX (17.7 g, 63.1 mmol) at 25 °C. The resulting mixture was heated at 80 °C for 2 hours. The reaction mixture was cooled to 25 °C, filtered, and washed with DCM (50 mL). The combined filtrate was concentrated to afford crude material which was purified by ISCO (silica gel, 80 g, EtOAc/petroleum ether=17%) to EEE-3 (1.76 g, 49%) as a white soiid. ¹H NMR (400 MHz, CDCh) δ ppm 10.45 (s, 1 H), 7.42 (d, J=3.0 Hz, 1 H), 7.36 (d, J=8.8 Hz, 1 H), 7.11 (dd, J=3.3, 8.8 Hz, 1H), 3.86 (s, 3H)

Step 3 - Synthesis of (E)-1-chloro-4-methoxy-2-(2-nitrovinyl)benzene (EEE-4)

To a solution of EEE-3 (1.76 g, 10.3 mmol) in AcOH (17.0 mL) was added NH₄OAc (0.795 g,

10.3 mmol) followed by MeNO₂ (3.15 g, 51.6 mmol). After the addition, the reaction mixture was heated at 85 °C for 10 hours, and then cooled to 28 °C. The reaction was diluted in DCM and concentrated to remove AcOH to afford the crude product which was purified via flash column (12 g gel, EtOAc: Petroleum ether = 1%~10%) to afford EEE-4 (1.78 g, 81%) as a

- -213yellow solid. ¹H NMR (400 MHz, CDCI₃) δ ppm 8.36 (d, J=13.8 Hz, 1H), 7.58 (d, J=13.8 Hz, 1H), 7.39 (d, J=9.0 Hz, 1H), 7.05 (d, J=3.0 Hz, 1H), 6.99 (dd, J=3.0, 9.0 Hz, 1H), 3.85 (s, 3H)

Step 4 - Synthesis of 2-(2-chloro-5-methoxyphenyl)ethan-1-amine (EEE-5)

To a solution of EEE-4 (862 mg, 4.04 mmol) in anhydrous THF (40 mL) was added LiAIH₄ (613 5 mg, 16.1 mmol) at -20 °C under N₂. After the addition, the reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was then heated at 50 °C and stirred for 2 hours. The reaction mixture was quenched with drops of water. The reaction mixture was diluted with EtOAx, filtered, and concentrated to afford the crude product which was purified via flash column chromatography (40 g gel, MeOH: DCM = 1 %~8.0%) to afford EEE-5 (290 mg, 38.7/o) as a 10 yellow oil. ¹H NMR (400 MHz, CDCI₃) δ ppm 7.27 - 7.24 (m, 1H), 6.79 (d, J=2.8 Hz, 1H), 6.72 (dd, J=3.0, 8.8 Hz, 1H), 3.79 (s, 3H), 3.02 - 2.95 (m, 2H), 2.90 - 2.80 (m, 2H)

Step 5 - Synthesis of 5-chloro-8-methoxy-1,2,3,4-tetrahydroisoquinoline (EEE-6)

To a solution of EEE-5 (195.0 mg, 0.679 mmol) in DCM (7.00 mL) was added TFA (0.70 mL), followed by aqueous HCHO (37%, 110 mg, 1.36 mmol). After the addition, the reaction mixture 15 was stirred at 25 °C for 3 hours. The reaction mixture was diluted in H₂O and neutralized by sat.

Na₂CO₃. The mixture was partitioned with EtOAc and H₂O. The organic layer was dried over Na₂SO₄ and concentrated to afford the crude product which was purified by prep-TLC (EtOAc:petroleum ether - 1:1) to afford the intermediate (170 mg) which was suspended in aq. HCl (24%, 2 mL) and heated at 110 °C for 3 hours. The reaction mixture was neutralized with 20 sat. Na₂CO₃ then partitioned between EtOAc and H₂O. The organic layer were evaporated to afford the crude product which was purified by prep-TLC thin layer chromatography (EtOAc:petroleum ether = 1:0) to afford the product EEE-6 (50.0 mg, 37%) as a yellow gum. ¹H NMR (400 MHz, DMSO-ds) δ ppm 7.22 (d, J=8.8 Hz, 1H), 6.81 (d, J=8.8 Hz, 1H), 3.76 (s, 3H), 3.70 (s, 2H), 2.91 (t, J=6.0 Hz, 2H), 2.57 (t, J=5.8 Hz, 2H)

Step 6 - Synthesis of 5-chloro-1,2,3,4-tetrahydroisoquinolin-8-ol (EEE-7)

To a solution of EEE-6 (50.0 mg, 0.253 mmol) in DCM (4.00 mL) was added BBr₃ (0.40 mL, 4.20 mmol) at 0 °C. After the addition, the reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was quenched with MeOH and basified by sat. K₂CO₃ to pH 11-12. The mixture was extracted with EtOAc. The organic layer was dried over Na₂SO₄ and concentrated 30 to afford the crude product which was purified by prep-TLC (MeOH: DCM = 1:10) to afford EEE- (50 mg, >99%) as a yellow gum and used directly in the next step. ¹H NMR (400 MHz, CDCI₃) δ ppm 7.05 (d, J=8.5 Hz, 1H), 6.51 (d, J=9.3 Hz, 1H), 4.00 (s, 2H), 3.16 (t, J=6.0 Hz, 2H), 2.79 (t, J=6.1 Hz, 2H)

-214Step 7 - Synthesis of tert-butyl 5-chloro-8-hydroxy-3,4-dihydroisoquinoline-2(1H)carboxylate (TP-19)

To a solution of EEE-7 (50 mg, 0.272 mmol) in DCM (5.00 mL) and MeOH (1.00 mL) was added Boc₂O (65 mg, 0.300 mmol) followed by Et₃N (68.9 mg, 0.681 mmol). After the addition, the 5 reaction mixture was stirred at 25 °C for 2.5 hours. The reaction mixture was neutralized by aq.

HCl (0.1 M) to pH 4-5 at 0 °C. The resulting mixture was partitioned between DCM and H₂O. The organic layer was separated, washed with brine, dried over Na₂SO₄ and concentrated to afford the crude product which was purified by prep-TLC (MeOH: DCM = 1:10) to afford TP19 (50 mg, 65%) as a white solid.

Examples 154 & 155 were made in a similar fashion to Example 78 in Scheme CC using the appropriate NBoc-protected tetrahydroisoquinoline in step 1.

Example 154 TP-14	HN^	T I OH Yjl '^''CHF	'N OH	431 [M+1]	(1 S,2S,3S,5R)-3-((6-(difluoromethyl)-1,2,3,4tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7Hpyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol 1H NMR (400MHz, D2O) δ ppm 8.85 (s, 1H), 7.81 (d, >3.8 Hz, 1H), 7.14 - 7.05 (m, 3H), 6.89 6.59 (m, 1H), 5.35 (q, >9.0 Hz, 1H), 4.86 - 4.82 (m, 1H), 4.70 - 4.67 (m, 1H), 4.37 (s, 2H), 4.32 (d, >4.8 Hz, 1H), 3.49 (t, >6.1 Hz, 2H), 3.15 3.02 (m, 3H), 2.90 (s, 3H), 2.26 - 2.15 (m, 1H)
EîocN^	OH F
Example 155				413	(1 S,2S,3S,5R)-3-((5-fluoro-6-methyl-1,2,3,4-
TP-8			//	ό	[M+1]	tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7H-
			N	N		pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol
	OH		>·'	OH
BocN^	JL	HN^'	Ό -, I OH Tl			1H NMR (400 MHz, MeOD-d4) δ ppm 8.62 (s, 1H), 7.54 (d, >3.8 Hz, 1H), 6.86 (d, >5.8 Hz,
	F					1H), 6.74 (d, >3.8 Hz, 1H), 5.18 (d, >8.8 Hz,
						1H), 4.73 (dd, >5.0, 8.8 Hz, 1H), 4.66 (br s, 1H), 4.24 (s, 2H), 4.17 (d, >4.5 Hz, 1H), 3.39 (t, >6.3 Hz, 2H), 3.00 - 2.93 (m, 3H), 2.72 (s, 3H), 2.26 (d, >1.8 Hz, 3H), 2.21 (ddd, >4.1, 9.3, 13.9 Hz, 1H)

Example 156 (Scheme FFF) - (1S,2S,3R,5S)-3-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-515 ((5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)cyclopentane-1,2-diol (FFF-4)

-215Scheme FFF

Step 1: Synthesis of (1S,4R)-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-2-en-1ol (FFF-1)

To a solution of BB-2 (650 mg, 2.06 mmol) in dioxane (0.3 mL) and H₂O (0.3 mL) was added lithium hydroxide (494 mg, 20.6 mmol). The reaction was heated at 90°C overnight. The reaction mixture was cooled to r.t., diluted with H₂O, extracted with 20% isopropyl alcohol/DCM, the organic layers were combined and purified by ISCO 4 g with 100% EtOAc to 10% MeOH/EtOAc to give 424 mg of FFF-1 (96% yield) as a colorless oil which solidified on standing.

LCMS [M+1] 216.15. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.22 (dt, J=15.16, 2.14 Hz, 1 H) 2.73 (s, 3 H) 3.00 (ddd, J=15.25, 9.20, 7.70 Hz, 1 H) 4.89 (br. s., 1 H) 5.37 (dq, J=9.23,

2.22 Hz, 1 H) 5.58 (br. s., 1 H) 5.85 (dd, J=5.50, 2.45 Hz, 1 H) 6.25 - 6.33 (m, 1 H) 6.54 (d, J=3.55 Hz, 1 H) 7.23 (d, J=3.55 Hz, 1 H) 8.69 (s, 1 H)

Step 2: Synthesis of tert-butyl 4-(((1 S,4R)-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7y|)cyclopent-2-en-1-yl)oxy)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (FFF-2)

To a solution of FFF-1 (100 mg, 0.465 mmol) in THF (3 mL, c=0.2 M) was added sodium hydride (27.9 mg, 0.697 mmol) in small batches. After stirring at r.t. for 10 min, tert-butyl 4chloro-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (TP-20) (125 mg, 0.465 mmol) was added. The resulting reaction mixture was stirred at r.t. for 3.5 hrs, and then quenched with H₂O, partitioned between EtOAc (20 mL) and H₂O (20 mL). The organic phase was separated, washed with brine, dried over Na₂SO4, concentrated, purified by column chromatography with 510% MeOH/EtOAc to afford 150 mg of FFF-2 (72% yield) as a light yellow foam solid.

LCMS [M+1] 449.15. Ή NMR (400 MHz, CHLOROFORM-d) δ ppm 1.44 (s, 9 H) 1.87 (d, J=15.04 Hz, 1 H) 2.66 (s, 3 H) 2.80 (t, J=4.77 Hz, 2 H) 3.15 (dt, J=15.31, 7.81 Hz, 1 H) 3.57

-2163.65 (m, 1 H) 3.65 - 3.75 (m, 1 H) 4.33 (d, J=17.61 Hz, 1 H) 4.44 (d, J=17.12 Hz, 1 H) 5.98 (dt, J=4.31, 1.94 Hz, 1 H) 6.01 - 6.07 (m, 1 H) 6.07 - 6.14 (m, 1 H) 6.33 (br. s., 1 H) 6.52 (d, J=3.18 Hz, 1 H) 7.20 (d, J=3.67 Hz, 1 H) 8.51 (s, 1 H) 8.70 (s, 1 H)

Step 3: Synthesis of tert-butyl 4-(((1S,2S,3S,4R)-2,3-dihydroxy-4-(4-methyl-7H-pyrrolo[2,3d] pyrimidin-7-yl)cyclopentyl)oxy)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (FFF-3)

Compound FFF-2 was treated in similar procedure as step 3 in Scheme BB to give FFF-3 (50 10 mg, 33%).

LCMS [M+1] 483.20. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.49 (s, 9 H) 2.36 - 2.50 (m,

H) 2.76 (s, 3 H) 2.91 (t, J=5.81 Hz, 2 H) 3.06 - 3.22 (m, 1 H) 3.62 - 3.84 (m, 2 H) 4.13 (s, 1 H)

4.36 - 4.50 (m, 2 H) 4.53 (d, J=6.24 Hz, 1 H) 4.93 - 5.05 (m, 1 H) 5.45 (td, J=7.12, 3.12 Hz, 1 H) 15 5.64 (br. s., 1 H) 6.61 (d, J=3.67 Hz, 1 H) 7.23 (d, J=3.67 Hz, 1 H) 8.64 (s, 1 H) 8.76 (s, 1 H)

Step 4: Synthesis of (1S,2S,3R,5S)-3-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((5,6,7,8tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)cyclopentane-1,2-diol (FFF-4)

Compound FFF-3 was treated to standard deprotection condition similar to step 3 in Scheme CC to yieid FFF-4 (24 mg, 100%).

LCMS [M+1] 383.10. Ή NMR (400 MHz, DMSO-d6) δ ppm 2.00 - 2.11 (m, 1 H) 2.92 (s, 3H)

2.94 - 3.02 (m, 1 H) 3.06 (br. s., 2 H) 3.48 (br. s., 2 H) 4.11 (d, J=3.42 Hz, 1 H) 4.25 (br. s., 2H)

4.66 (dd, J=8.86, 4.58 Hz, 1 H) 5.22 (q, J=8.93 Hz, 1 H) 5.28 - 5.37 (m, 1 H) 7.20 (br. s., 1H)

8.09 (br. s., 1 H) 8.69 (s, 1 H) 9.18 (br. s., 1 H) 9.71 (br. s., 1 H) 9.87 (br. s., 1 H)

Example 157 (Scheme GGG) - (1S,2S,3R,5S)-3-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-

5-((5,6,7,8-tetrahydro-2,7-naphthyridin-1 -yl)oxy)cyclopentane-1,2-diol (GGG-5)

Scheme GGG

-217Boc

GGG-4 GGG-5

Step 1: Synthesis of tert-butyl 8-chloro-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxylate (GGG-2)

To a solution of tert-butyl 8-hydroxy-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxylate (GGG-1) (250 mg, 0.999 mmol) in CH₃CN (2.5 mL) was added POCI₃ (2.5 mL) slowly, and heated at 90°C overnight. The reaction mixture was neutralized by std. NaHCO₃, the solvent was removed by rotavapor. The residue was added MeOH 10 mL, the slurry was added (BOC)₂ (337 mg, 1.50 10 mmol , 0.355 mL) and DIPEA (258 mg, 2.00 mmol , 0.331 mL), stirred at r.t. for 30 min. The organic solvent was rotavapored, EtOAc and H₂O were added, extracted with EtOAc, the organic layer was concentrated, purified by column chromatography with 30% EtOAc/heptane to give 240 mg of GGG-2 (89% yield) as a colorless oil.

LCMS [M+1] 269.10. Ή NMR (400 MHz, CHLOROFORM-d) δ ppm 1.51 (s, 9 H) 2.84 (t, J=5.69 Hz, 2 H) 3.66 (t, J=5.81 Hz, 2 H) 4.56 (s, 2 H) 7.03 (d, J=5.01 Hz, 1 H) 8.17 (d, J=5.01 Hz, 1 H)

Step 2: Synthesis of tert-butyl 8-(((1 S,4R)-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7yl)cyclopent-2-en-1 -yl)oxy)-3,4-dihydro-2,7-naphthyridine-2(1 H)-carboxylate (GGG-3)

To a solution of FFF-1 (92 mg, 0.43 mmol) and GGG-2 (115 mg, 0.427 mmol) in DMSO (4.27 mL, c=0.1 M) was treated with potassium butoxide (61.8 mg, 0.534 mmol , 0.534 mL, 1.0 M). The reaction was heated to 120°C for 15 min. The reaction was cooled to r.t., diluted with H₂O and EtOAc (10 mL each). The aqueous phase was extracted with EtOAc (10 mL). The 25 combined organics were washed with H₂O (2x15 mL), brine (15 mL), and dried over Na₂SO4.

The sample was concentrated and purified by préparative HPLC to give 40 mg of GGG-3 as a brown solid (21% yield).

-218LCMS [M+1] 448.20. Ή NMR (400 MHz, CHLOROFORM-d) δ ppm 1.45 - 1.56 (m, 9 H) 1.94 (d, J=14.92 Hz, 1 H) 2.63 (s, 3 H) 2.68 - 2.81 (m, 2 H) 3.20 (dt, J=15.13, 7.78 Hz, 1 H) 3.55 - 3.69 (m, 2 H) 4.33 - 4.45 (m, 1 H) 4.49 (br. s., 1 H) 6.06 (br. s., 2 H) 6.11 (d, J=4.03 Hz, 1 H) 6.45 (br.

s., 1 H) 6.62 (br. s., 1 H) 6.68 (d, J=5.01 Hz, 1 H) 7.39 (br. s., 1 H) 7.92 (d, J=5.14 Hz, 1 H) 8.84 5 (br. s., 1 H)

Step 3: Synthesis of tert-butyl 8-(((1S,2S,3S,4R)-2,3-dihydroxy-4-(4-methyl-7H-pyrrolo[2,3d] pyrimidin-7-yl)cyclopentyl)oxy)-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxylate (GGG4)

Compound GGG-3 was treated in similar procedure as step 3 in Scheme BB to give GGG-4 (7.3 mg, 17%).

LCMS [M+1] 481.90. Ή NMR (400 MHz, CHLOROFORM-d) δ ppm 1.49 (s, 10 H) 2.43 - 2.54 (m, 1 H) 2.75 (s, 3 H) 2.81 (t, J=5.75 Hz, 2 H) 3.03 (br. s., 1 H) 3.63 - 3.71 (m, 2 H) 4.38 (br. s., 15 1 H) 4.47 (br. s., 3 H) 4.66 (br. s., 1 H) 5.03 - 5.12 (m, 1 H) 5.25 - 5.32 (m, 1 H) 5.48 (s, 1 H)

6.60 (d, J=3.55 Hz, 1 H) 6.77 (d, J=5.26 Hz, 1 H) 7.29 (d, J=3.79 Hz, 1 H) 7.93 (d, J=5.14 Hz, 1 H) 8.77 (s, 1 H)

Step 4: Synthesis of (1S,2S,3R,5S)-3-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((5,6,7,820 tetrahydro-2,7-naphthyridin-1 -yl)oxy)cyclopentane-1,2-diol (GGG-5)

Compound GGG-4 was treated to standard deprotection condition similar to step 3 in Scheme CC to yield GGG-5 (6 mg, 90%).

LCMS [M+1] 382.20 Ή NMR (400 MHz, DMSO-d6) δ ppm 1.93 - 2.02 (m, 1 H) 2.86 - 2.92 (m, 3 25 H) 2.92 - 2.98 (m, 1 H) 3.01 (t, J=5.99 Hz, 2 H) 3.57 (s, 2 H) 4.08 (d, J=4.03 Hz, 1 H) 4.20 (br.

s., 2 H) 4.66 (dd, J=8.93, 4.52 Hz, 1 H) 5.15 - 5.23 (m, 1 H) 5.23 - 5.29 (m, 1 H) 6.91 (d, J=5.26 Hz, 1 H) 7.16 (d, J=3.30 Hz, 1 H) 7.99 - 8.06 (m, 2 H) 9.13 (s, 1 H) 9.52 (br. s., 1 H) 9.64 (br. s., 1 H)

Example 158 (Scheme HHH) - (1S,2R,3R,5S)-3-((2-methylpyrimidin-4-yl)oxy)-5-((1,2,3,4tetrahydroisoquinolin-8-yl)oxy)cyclopentane-1,2-diol (HHH-6)

Scheme HHH

-219-

BB-1

OsO₄ (4 mol%)

NMO, DCM, rt

HHH-2

NaH, DMF

115°C

Pd₂dba₃*CHCI₃ (2 mol%) (R,R)-DACH-Napthyl Trost Ligand (6 mol%) DCE, rt

HHH-5

Step 1: Synthesis of tert-butyl 8-(((1 S,4R)-4-((tert-butoxycarbonyl)oxy)cyclopent-2-en-1yl)oxy)-3,4-dihydroisoquinoline-2(1 H)-carboxylate (HHH-1 )

Vial A: To an oven dried reaction vial, equipped with a magnetic stirbar and cooled under a stream of argon, was added Tris(benzylideneacetone)dipalladium(0)chloroform adduct (44.7 mg, 0.043 mmol) and MFCD02684551 (R,R)-DACH-Naphthyl Trost Ligand (102 mg, 0.129 mmol). The vial was vacuum purged with argon under dynamic vacuum and DCE (3.6 mL), which had been sparged with argon for 30 minutes, was added. The solution was stirred for 30 minutes at rt at which point a bright orange solution of ligated catalyst was obtained. At this stage Vial B was prepared.

Vial B: To an oven dried reaction vial, equipped with a magnetic stirbar and cooled under a stream of argon, was added tert-butyl 8-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (538 mg, 2.16 mmol), and di-tert-butyl-((1R,3S)-cyclopent-4-ene-1,3-diyl)-bis(carbonate) (BB-1) (prepared as reported in J. Am. Chem. Soc. 2006, 128, 6054-6055) (778 mg, 2.59 mmol). The vial was vacuum purged with argon under dynamic vacuum and DCE (3.6 mL), which had been sparged with argon for 30 minutes, was added followed by the addition of the contents of Vial A via airtight syringe. The reaction was stirred under argon at rt for 14 hours. The reaction was concentrated under vacuum and purified via flash column chromatography (24g SiO2, Isco, 100% Hept. to 100% EtOAc, 20 mL fractions) to afford HHH-1 (973 mg, >95%) as a yellow foam. LCMS [M+H-Boc-isobutylene] = 276 observed; 1H NMR (400MHz, CHLOROFORM-d) δ ppm 7.12 (t, J=7.9 Hz, 1H), 6.75 (d, J=7.7 Hz, 1H), 6.72 (d, J=8.2 Hz, 1H), 6.22 (td, J=1.4, 5.7

-220Hz, 1H), 6.18-6.09 (m, 1H), 5.47 (t, J=5.8 Hz, 1H), 5.15 (t, J=5.7 Hz, 1H), 4.59 -4.40 (m, J=8.2 Hz, 2H), 3.74 - 3.54 (m, 2H), 3.05 (td, J=7.4, 14.5 Hz, 1H), 2.81 (t, J=5.7 Hz, 2H), 1.96 (td, J=4.5, 14.5 Hz, 1H), 1.52- 1.47 (m, 18H).

Step 2: Synthesis of tert-butyl 8-(((1S,2S,3R,4R)-4-((tert-butoxycarbonyl)oxy)-2,3dihydroxycyclopentyl)oxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate (HHH-2)

To a scintillation vial, equipped with a magnetic stirbar and containing HHH-1 (225 mg, 0.521 mmol), was added DCM (2.6 mL). To the solution was added 4-Methylmorpholine-A/-oxide (NMO) (0.32 mL, 1.50 mmol) as a 50 wt% solution in water followed by the dropwise addition of osmium tetraoxide (130 pL, 0.02 mmol) as a 4 wt% solution in water. The reaction was stirred at rt for 23 hours. The réaction was transferred to a separatory funnel with DCM, diluted with water and further diluted with 1M NaHSO3. The phases were separated and the aqueous phase was extracted with 3 portions of DCM. The combined organic extracts were dried (MgSO4), filtered, and concentrated under vacuum. The crude residue was purified via flash column chromatography (12g SiO2, Isco, 100% Hept. to 100% EtOAc, 9 mL fractions) to afford HHH-2 (211 mg, 87%) as a white solid. LCMS [M+H-Boc-isobutylene] = 310 observed; 1H NMR (400MHz, CHLOROFORM-d) δ ppm 7.12 (t, J=7.9 Hz, 1H), 6.76 (d, J=7.7 Hz, 1H), 6.71 (d, J=8.2 Hz, 1H), 4.90 (td, J=5.8, 9.0 Hz, 1H), 4.69 - 4.59 (m, 1H), 4.45 (s, 2H), 4.34 (s, 1H), 4.26 (br. s., 1H), 3.63 (d, J=5.7 Hz, 2H), 2.81 (t, J=5.7 Hz, 3H), 2.03 - 1.91 (m, J=5.7, 9.3 Hz, 1H), 1.53- 1.48 (m, 18H).

Step 3: Synthesis of tert-butyl 8-(((3aR,4S,6R,6aS)-6-((tert-butoxycarbonyI)oxy)-2,2dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)-3,4-dihydroisoquinoline-2(1H)carboxylate (HHH-3)

To a reaction vial, equipped with a magnetic stirbar and containing HHH-2 (211 mg, 0.453 mmol), was added acetone (0.29 mL), 4-toluenesulfonic acid monohydrate (172 mg, 0.906 mmol) and 2,2-dimethoxypropane (0,56 mL, 4.53 mmol). The reaction was stirred at rt for 1 hour. The reaction was transferred to a separatory funnel with EtOAc and water. The biphasic mixture was diluted with sat. NaHCO3 and the phases were separated. The organic phase was washed with 1 portion haif sat. NaHCO3 and the combined aqueous washed were back extracted with 1 portion EtOAc. The combined organic phases were dried (MgSO4), filtered, and concentrated under vacuum. The crude residue was purified via flash column chromatography (12g SiO2, Isco, 100% Hept to 100% EtOAc, 9 mL fractions) to afford HHH-3 (140.5 mg, 61%) as a white solid. LCMS [M+H-Boc-isobutylene] = 350 observed; 1H NMR (400MHz, CHLOROFORM-d) δ ppm 7.12 (s, 1H), 6.73 (t, J=8.1 Hz, 2H), 4.94 (d, J=4.6 Hz, 1H), 4.80

-221 4.66 (m, 3H), 4.61 - 4.43 (m, 2H), 3.63 (s, 2H), 2.80 (t, J=5.6 Hz, 2H), 2.47 (td, J=5.4, 15.4 Hz, 1 H), 2.25 (td, J=1.5, 15.4 Hz, 1 H), 1.49 (s, 12H), 1.45 (s, 9H), 1.31 (s, 3H).

Step 4: Synthesis of tert-butyl 8-(((3aR,4S,6R,6aS)-6-hydroxy-2,2-dimethyltetrahydro-4Hcyclopenta[d][1,3]dioxol-4-yl)oxy)-3,4-dihydroisoquinoline-2(1 H)-carboxylate (HHH-4)

To a microwave vial, equipped with a magnetic stirbar and containing HHH-3 (134.5 mg, 0.266 mmol) was added dioxane (1.3 mL) and water (1.3 mL). To the solution was added lithium hydroxide (63.7 mg, 2.66 mmol) and the vial was sealed with a Teflon cap. The vial was placed in a heating block and stirred at 100°C for 19 hours. The vial was removed from the heating block and alîowed to cool to rt. The solution was transferred to a separatory funnel with EtOAc and diluted with water. The phases were separated and the aqueous phase was extracted with 3 portions of EtOAc. The combined organic extracts were dried (MgSO4), filtered, and concentrated under vacuum. The crude residue was purified via flash column chromatography (4g SiO2, Isco, 100% Hept. to 100% EtOAc, 9 mL fractions) to afford HHH-4 (97.3 mg, 90%) as a white foam. LCMS [M+H-Boc] = 306 observed; 1H NMR (400MHz, CHLOROFORM-d) δ ppm 7.17 (t, J=7.9 Hz, 1H), 6.84 (d, J=8.3 Hz, 1H), 6.81 (d, J=7.7 Hz, 1H), 4.75 (dd, J=5.4, 7.8 Hz, 2H), 4.67 (dd, J=1.3, 5.6 Hz, 1H), 4.55 - 4.33 (m, 2H), 4.27 (d, J=4.6 Hz, 1H), 3.78 - 3.49 (m, 2H), 2.82 (t, J=5.7 Hz, 2H), 2.42 (td, J=5.0, 15.0 Hz, 1H), 2.10 (d, J=15.0 Hz, 1H), 1.49 (s, 9H), 1.46 (s, 3H), 1.31 (s, 3H).

Step 5: Synthesis of tert-butyl 8-(((3aR,4S,6R,6aS)-2,2-dimethyl-6-((2-methylpyrimidin-4yl)oxy)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)-3,4-dihydroisoquinoline-2(1H)carboxylate (HHH-5)

To an oven dried reaction vial, equipped with a magnetic stirbar and containing HHH-4 (43 mg, 0.110 mmol), was added DMF (0.53 mL) and sodium hydride (8.5 mg, 0.210 mmol) as a 60 wt% dispersion in minerai oil. The solution was stirred at rt for 1 hour to produce a dark brown solution of the sodium alkoxide. To the solution was added 4-chloro-2-methylpyrimidine (16.4 mg, 0.127 mmol) and the vial was placed in a heating block and heated at 115°C for 16 hours. The reaction was quenched carefully by the dropwise addition of water. The solution was further diluted with water and transferred to a separatory funnel with EtOAc. The phases were separated and the aqueous phase was extracted with 4 portions of a 3.1 mixture of DCM/IPA. The combined organic extracts were washed with 1 portion brine, dried (MgSO4), filtered, and concentrated under vacuum. The crude HHH-5 was used in the next step without further purification. LCMS [M+H-Boc] = 398 observed

- 222Step 6: Synthesis of (1S,2R,3R,5S)-3-((2-methylpyrimidin-4-yl)oxy)-5-((1,2,3,4tetrahydroisoquinolin-8-yl)oxy)cyclopentane-1,2-diol (HHH-6)

To a round bottom flask, equipped with a magnetic stirbar and containing HHH-5 (53 mg, 0.11 mmol, crude from step 5) was added water (1.0 mL) and TFA (0.5 mL). The solution was stirred at rt for 1 hour. The reaction was transferred to a separatory funnei with DCM and adjusted to basic pH with sat. NaHCO3 aq. The phases were separated and the aqueous phase was extracted with 4 portions of a 3:1 mixture of DCM/IPA. The combined organic extracts were washed with 1 portions sat. NaHCO3 aq., dried (MgSO4), filtered, and concentrated under vacuum. The crude residue was purified by prep-HPLC (Lux Cellulose-1 4.6 x 100 mm 3μ 10 column, 20% MeOH/DEA @ 120 bar, 4 mL/min) to afford HHH-6 (7.06 mg, 19% over 2 steps) as a white solid. LCMS [M+H] = 358 observed; [a]²²D= +3.7° (c=0.1, MeOH); 1H NMR (400MHz, METHANOL-d4) δ ppm 8.05 (d, J=6.4 Hz, 1H), 7.15 (t, J=7.9 Hz, 1H), 6.84 (d, J=8.1

Hz, 1H), 6.79 (d, J=7.6 Hz, 1H), 6.67 (d, J=6.5 Hz, 1H), 4.68 (br. s, 2H), 4.61 (td, J=4.2, 8.1 Hz, 1H), 4.26 (t, J=4.3 Hz, 1H), 4.12 (td, J=4.9, 7.4 Hz, 1H), 4.02 - 3.90 (m, 3H), 2.90 (t, J=5.7 Hz, 15 2H), 2.74 (td, J=7.7, 15.0 Hz, 1H), 2.47 (s, 3H), 1.62 (td, J=4.7, 14.6 Hz, 1H).

Synthesis of 2-(benzyloxy)-5-fluoro-4-methylbenzoic acid (III-4)

Scheme III

IH-1 III-2

ÎII-3

LiOH aq

MeOH

Step 1 - Synthesis of methyl 2-(benzyloxy)-4-bromo-5-fluorobenzoate (HI-2)

To a solution of methyl 4-bromo-5-fluoro-2-hydroxybenzoate 111-1 (1.62 g, 6.505 mmol) in DMF (20 mL) was added K₂CO₃ (2.7 g, 19.5 mmol) and BnBr (2.23 g, 13 mmol). The mixture was stirred at 16 °C for 3 hrs. The mixture was diluted with water (100 mL). Then the mixture was extracted with EtOAc (50 mL x 2). The organic layers were collected, dried and evaporated to give the crude product which was purified by flash chromatography, eluted with petroleum ether/EtOAc from 0-10% to give the III-2 (1.8 g, 82 %) as a white solid and used directly in the next step.

Step 2 - Synthesis of methyl 2-(benzyloxy)-5-fluoro-4-methylbenzoate (III-3)

- 223A mixture of III-2 (2 g, 5.87 mmol), Pd(Ph₃P)4 (339 mg, 0.293 mmol) in THF (2 OmL) was degassed with N₂ four times, then added AIMe₃ (7.87 mL, 15.7 mmol, 2M) at 0 ⁰ then reaction stirred at 80 °C for 24 hours. The reaction was then quenched with aq. potassium sodium tartrate tetrahydrate, extracted with EtOAc three times, the combined organic layers were dried 5 over Na₂SO4, removed the solvent in vacuum, the residue was purified by flash biotage (petroleum ether/EtOAc=0-5%) to give III-3 (660 mg, 41%) as a yellow oil. ¹H NMR (400 MHz,

CDCh) δ ppm 7.57 - 7.47 (m, 3H), 7.43 - 7.37 (m, 2H), 7.36 - 7.30 (m, 1H), 6.84 (d, J=6.0 Hz, 1H), 5.14 (s, 2H), 3.90 (s, 3H), 2.29 (d, J=2.0 Hz, 3H)

Step 3 - Synthesis of 2-(benzyloxy)-5-fluoro-4-methylbenzoic acid (III-4)

To a solution of III-3 (0.71 g, 2.59 mmol) in MeOH (4 mL) was added a solution of LiOH.H₂O (326 gm, 7.77 mmol) in H₂O (4 mL). The reaction mixture was stirred at 20 °C for 2 hours. The reaction solution was evaporated to remove most of the methanol, and then residue was adjusted to pH~2 with 1N HCl. White solids formed and extracted with EtOAc (20 mL x 2). The organic layers were dried and evaporated to give III-4 (670 mg, 99.5%) as a white solid. ¹H 15 NMR (400 MHz, CDCh) δ ppm 10.76 (br. s., 1H), 7.83 (d, J=9.5 Hz, 1H), 7.52 - 7.37 (m, 5H),

6.96 (d, J=6.0 Hz, 1H), 5.26 (s, 2H), 2.35 (s, 3H)

Example 159 (Scheme JJJ) - (1S,2S,3S,5R)-3-(2-(aminomethyl)-4-chlorophenoxy)-5-(4methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol (JJJ-3)

Pd₂(dba)₃-CHCI₃, DPPP

Cs₂CO₃, DCE

OsO₄ (4% H₂O solution)

NMO, DCM, H₂O

JJJ-3

JJJ-4

Step 1 - Synthesis of 5-chloro-2-(((1S,4R)-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7yl)cyclopent-2-en-1-yl)oxy)benzonitrile (JJJ-1)

To a dry microwave vial (purged with N₂) was added BB-2 (100 mg, 0.317 mmol), 5-chloro-2hydroxybenzonitrile (56 mg, 0.37 mmol), Cs₂CO₃ (114 mg, 0.35 mmol), Pd₂(dba)₃ (8.2 mg, 0.008 mmol) and DPPP (7.85 mg, 0.019 mmol). Then the vial was purged with N₂ three times 25 and DCE (1.5 mL, sparged with N₂ for 30 mins) was added. The black mixture was stirred at 20 °C for 1 hour. Then the reaction mixture was directly purified by prep-TLC (Petroleum ether.EtOAc= 1/4) to give JJJ-1 (83 mg, 75%, as a yellow gum. LCMS [M+1] 351; ¹H NMR (400

-224MHz, CDCI₃) δ ppm 8.77 (s, 1H), 7.56 (d, J=2.8 Hz, 1H), 7.50 (dd, J=2.6, 8.9 Hz, 1H), 7.41 (d, J=3.8 Hz, 1H), 7.00 (d, J=9.0 Hz, 1H), 6.63 (d, J=3.5 Hz, 1H), 6.40 (td, J=1.9, 5.5 Hz, 1H), 6.26 (dd, J=2.4, 5.6 Hz, 1 H), 6.14 - 6.08 (m, 1 H), 5.44 (d, J=7.0 Hz, 1 H), 3.21 - 3.11 (m, 1 H), 2.73 (s, 3H), 2.04 (td, J=3.2, 14.9 Hz, 1H)

Step 2 - Synthesis of 5-chloro-2-(((1S,2S,3S,4R)-2,3-dihydroxy-4-(4-methyl-7Hpyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl)oxy)benzonitrile (JJJ-2)

To a mixture of JJJ-1 (83 mg, 0.237 mmol) in DCM (6 mL)/H₂O (0.2 mL) was added NMO (96 mg, 0.71 mmol) and OsO₄ (4 % in t-BuOH, 80 mg, 0.013 mmol) at 20 °C. The brown mixture was stirred at 20 °C for 6 hours. The mixture was diluted with DCM (5 mL) and quenched by sat.Na₂SO₃ (2 mL) and separated. The organic layer was washed with brine (5 mL). The combined aqueous were extracted with DCM (5 mL X 2). The combined organic layers were dried over Na₂SO₄, filtered and concentrated to yield crude product (100 mg) as a light yellow solid, which was purified by prep-TLC (EtOAc:MeOH=10:1) to yield JJJ-2 (40 mg, 44%) as a white solid. LCMS [M+1] 385; Ή NMR (400 MHz, MeOD) δ ppm 8.60 (s, 1H), 7.73 (d, J=2.5 Hz, 1H), 7.66 (d, J=3.5 Hz, 1H), 7.63 (dd, J=2.6, 9.2 Hz, 1H), 7.30 (d, J=9.0 Hz, 1H), 6.76 (d, J=3.5 Hz, 1H), 5.35 - 5.26 (m, 1H), 4.69 (dd, J=4.9, 8.4 Hz, 1H), 4.21 (d, J=4.5 Hz, 1H), 3.04 (ddd, J=6.8, 9.8, 14.8 Hz, 1H), 2.71 (s, 3H), 2.17 (ddd, J=3.0, 7.7, 14.7 Hz, 1H)

Step 3 - Synthesis of (1S,2S,3S,5R)-3-(2-(aminomethyl)-4-chlorophenoxy)-5-(4-methyl-7Hpyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol (JJJ-3)

A mixture of JJJ-2 (40 mg, 0.104 mmol) and Raney-Ni (8 mg) in EtOH (7 mL)/NH₃.H₂O (0.5 mL) was degassed with H₂ four times. The mixture was stirred at 20 °C under H₂ balloon for 20 hrs. The mixture was filtered and the filtrate was concentrated in vacuo to afford a white solid, which was purified by prep-TLC (DCM:MeOH:NH₃.H₂O=10:1:0.1) to yield product (~20 mg) as yellow gum and lyophilized. The material was purified again by prep-HPLC to give JJJ-3 (9 mg, 22%). LCMS [M+1] 389; ¹H NMR (400 MHz, MeOD) δ ppm 8.60 (s, 1H), 7.56 (d, J=3.8 Hz, 1H), 7.42 (d, J=2.5 Hz, 2H), 7.21 (d, J=8.8 Hz, 1H), 6.74 (d, J=3.5 Hz, 1H), 5.11 (q, J=9.1 Hz, 1H), 4.82 4.76 (m, 2H), 4.29 (dd, J=2.1, 5.1 Hz, 1H), 4.26 - 4.15 (m, 2H), 3.06 - 2.92 (m, 1H), 2.72 (s, 3H), 2.37 (ddd, J=5.0, 9.7, 14.4 Hz, 1H)

Examples 160 & 161 were prepared in using similar chemistry in Scheme A using (4chloro-3-fluorophenyl)magnesium bromide for step 8.

Example 160

392

[M+1] (1S,2R,3R,5R)-3-((S)-(4-chloro-3fluorophenyl)(hydroxy)methyl)-5-(4-methyl-7Hpyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol

-225-

			1H NMR (400 MHz, DMSO-de) δ ppm 8.59 (s, 1H), 7.65 (d, >3.8 Hz, 1H), 7.53 (t, >8.0 Hz, 1H), 7.40 (dd, >1.8, 10.5 Hz, 1H), 7.27 (dd, >1.9, 8.2 Hz, 1H), 6.69 (d, >3.5 Hz, 1H), 5.73 (d, >4.8 Hz, 1H), 5.02 - 4.93 (m, 1H), 4.80 (d, >7.0 Hz, 1H), 4.64 - 4.58 (m, 1H), 4.56 (d, >3.8 Hz, 1H), 4.28 (td, >6.1, 9.9 Hz, 1H), 3.95 - 3.90 (m, 1H), 2.63 (s, 3H), 2.29 - 2.21 (m, 1H), 2.02 (td, >8.6, 12.9 Hz, 1H), 1.67 - 1.57 (m, 1H)
Example 161	HO XX y-ζ XJ· Cl HO OH	392 [M+1]	(1S,2R,3R,5R)-3-((R)-(4-chloro-3fluorophenyl)(hydroxy)methyl)-5-(4-methyl-7Hpyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol 1H NMR (400 MHz, DMSO-d6) δ ppm 8.59 (s, 1H), 7.65 (d, >3.5 Hz, 1H), 7.51 (t, >8.0 Hz, 1H), 7.35 (dd, >1.5, 10.5 Hz, 1H), 7.22 (dd, >1.9, 8.2 Hz, 1H ), 6.71 - 6.67 (m, 1H), 5.71 (d, >4.8 Hz, 1H), 4.97 - 4.88 (m, 1H), 4.86 (d, >6.5 Hz, 1H), 4.82 (t, >4.9 Hz, 1H), 4.67 (d, >4.5 Hz, 1H), 4.26 - 4.18 (m, 1H), 3.90 (q, >4.9 Hz, 1H), 2.63 (s, 3H), 2.27-2.18 (m, 1H), 1.89 - 1.71 (m, 2H)

Example 162 was made in a similar fashion to Example 99 in Scheme NN using isoquinolin-8-ol in step 2.

Example 162 isoquinolin-8-ol	F NH2 #Ί| n X X'OH o^X I OH	396 LCMS [M+1]	(1S,2S,3R,5S)-3-(4-amino-5fluoro-7H-pyrrolo[2,3d]pyrimîdin-7-yl)-5- (isoquinolin-8- yloxy)cyclopentane-1,2-diol
		1H NMR (400 MHz, MeOD-d4) δ ppm 9.62 (s, 1H), 8.46 (d, >5.8 Hz, 1H), 8.04 (s, 1H), 7.79 (d, >5.5 Hz, 1H), 7.72 (t, >8.0 Hz, 1H), 7.52 (d, >8.3 Hz, 1H), 7.21 (d, >8.0
1 II

-226-

Hz, 1H), 7.13 (d, J=2.0 Hz, 1H), 5.19 (q, J=9.0 Hz, 1H), 4.68 (br dd, J=4.9, 8.9 Hz, 2H), 4.33 (br d, J=4.8 Hz, 1H), 3.12 - 3.01 (m, 1H), 2.29 - 2.18 (m, 1H)

Synthesis of 6-hydroxy-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one (TP-21) and tert-butyl

6-hydroxy-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate (TP-22) (Scheme KKK)

Scheme KKK

O OH

KKK-1 ^ΒΓ'-^/''ΝΗΒοο

K₂CO₃, DMF

KKK-2

TFA, DCM

TP-21

1) BH₃Me₂S

2) HCl

OH

HN

KKK-4

Boc₂O

Et₃N, DCM

TP-22

Synthesis of

Step hydroxybenzoate (KKK-2) methyl 2-(2-( (tert-butoxycarbonyl)amino)ethoxy)-6A solution of methyl 2,6-dihydroxybenzoate (1.2 g, 7.14 mmol), tert-butyl (2bromoethyl)carbamate (2.33 g, 7.14 mmol) and K2CO3 (2.5 g, 17.8 mmol) in DMF(10 mL) was 10 stirred at 15 °C for 32 h. Water was added to the reaction mixture and extracted with EtOAc three times. The combined organic layers were dried over sodium sulfate, concentrated in vacuo, and the residue was purified by flash chromatography (petroleum ether/EtOAc= 10-20%) to give compound KKK-2 (900 mg, 41%) as a white solid and used in the next step directly.

Step 2 - Synthesis of methyl 2-(2-((tert-butoxycarbonyl)amino)ethoxy)-615 hydroxybenzoate (KKK-3)

To a solution of compound KKK-2 (900 mg, 2.89 mmol) in DCM (10 ml) was added TFA (2 mL) at 0-5 °C, then the reaction mixture was stirred at 15 °C for 2 h. The solvent was removed and the residue (700 mg, >99%) was used to next step directly.

Step 3 - Synthesis of 6-hydroxy-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one (TP-21)

-227 To a solution of compound KKK-3 (700 mg, 3.31 mmol) in i-PrOH (6 mL) was added TEA (3.35 g, 33.1 mmol) at 15 °C , then the reaction mixture was stirred at 95 °C for 6 h. The solvent was removed, and the residue was purified by flash chromatography (20 g, petroleum ether/EtOAc= 10-50%) to give compound TP-21 (480 mg, 81%) as a white solid. ¹H NMR (400 MHz, CDCh) δ ppm 12.61 (s, 1H), 7.33 - 7.29 (m, 1H), 6.70 (d, J=8.3 Hz, 1H), 6.57 (br. s., 1H), 6.53 (d, J=8.0 Hz, 1 H), 4.41 - 4.35 (m, 2H), 3.57 (q, J=4.8 Hz, 2H)

Step 4 - Synthesis of 2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-6-ol (KKK-4)

To a solution of compound TP-21 (100 mg, 0.56 mmol) in anhydrous THF (2 mL) was added BH₃-Me₂S (127 mg, 1.67 mmol) at 0 °C drop-wise under N₂. After the addition, the mixture was heated to 70 °C (reflux) for 3 hours. The reaction mixture was then quenched with 1 mL of MeOH carefully at -10-20 °C, then added another 6N HCl 10 mL , then refluxed for 3h, removed the most solvent under vacuum, then the residue was adjusted pH 8-9 with K₂CO₃, extracted with EtOAc three fîmes. The combined organic layers were dried over Na₂SO₄, filtered and concentrated to give the crude compound KKK-4 (0.5 g, >99%). LCMS [M+1] 166

Step 5 - Synthesis of tert-butyl 6-hydroxy-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)carboxylate (TP-22)

Crude compound KKK-4 (500 mg, 0.61 mmol) was dissolved in DCM (5 mL) and MeOH (5 mL). (Boc)₂O (132 mg, 0.605 mmol) and Et₃N (184 mg, 1.82 mmol) were added and the reaction mixture was stirred at 15 °C for 16 hours. DCM (10 mL) was added, then washed with acetic acid (5 mL) and saturated NaCI (5 mL). The organic layer was separated, dried and evaporated to give the residue. Then 10 mL MeOH was added to dissolve the residue, then K₂CO₃ (200 mg) was added to the mixture. The reaction mixture was stirred at 15 °C for 2 hours. DCM (25 mL x 2) was added to the solution, the solution was washed acetic acid (5 mL,pH <7) and saturated NaCI (5 mL). The organic layers were combined, dried and evaporate to give the crude product which was purified by prep-TLC to give compound TP-22 (13 mg, 8%) as a yellow solid. ¹H NMR (400 MHz, CDCI₃) δ ppm 7.62 (br s, 1H), 7.07 (t, J=8.2 Hz, 1H), 6.73 (d, J=7.5 Hz, 1H), 6.64 (d, J=7.8 Hz, 1H), 4.37 (s, 2H), 4.01 - 3.92 (m, 2H), 3.79 - 3.70 (m, 2H), 1.40 (s, 9H) LCMS [M-Boc+1] 210.

Synthesis of tert-butyl 6-(1-(tert-butoxycarbonyl)-1H-pyrazol-4-yl)-8-hydroxy-3,4dihydroisoquinoline-2(1H)-carboxylate (TP-23) (Scheme LLL)

Scheme LLL

-228-

Xphos-palladacycle, K₃PO₄, DMF

Under an N₂ atmosphère, TP-12 (50 mg, 0.15 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (67 mg, 0.23 mmol), K₃PO₄ (97 mg, 0.46 mmol) and XPhos-Palladacycle (13 mg, 0.015 mmol) was added to a vial. DMF (1.60 mL) was added 5 and the reaction solution was heated to 50 °C in a microwave for 16 hours. EtOAc and H₂O were added to dilute the reaction solution. The aqueous was extracted with EtOAc (3 mL x 2). The organic layers were separated, dried and evaporated to give the crude product, which was purified by prep-TLC (petroleum ether/EtOAc=1/1) to give the desired compound TP-23 (33 mg, 90%) as a colorless oil. LCMS [M-Boc+1] 316.

Synthesis of tert-butyl 6-( 1 -(tert-butoxycarbonyl)-l H-pyrazol-4-yl)-5-fluoro-8-hydroxy-3,4dihydroisoquinoline-2(1H)-carboxylate (TP-24) (Scheme MMM)

Scheme MMM

TP-11

Xphos-palladacycle, K₃PO₄, DMF

TP-24 was synthesized in a similar fashion to TP-23 (Scheme LLL) starting from TP-11. LCMS 15 [M-Boc+1]334.

Synthesis of tert-butyl 8-hydroxy-6-(1-methyl-1H-1,2,3-triazol-5-yi)-3,4dihydroisoquinoline-2(1H)-carboxylate (TP-25) (Scheme NNN)

Step 1 - Synthesis of tert-butyl 8-(benzyloxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-3,4-dihydroisoquinoline-2(1 H)-carboxylate (NNN-1 )

A mixture of GG-7 (3.00 g, 7.17 mmol), bis(pinacolato)diboron (2.73 g, 10.8 mmol), KOAc (1.4 g, 14.3 mmol) and PdCI₂(dppf).CH₂CI₂ (262 mg, 0.36 mmol) in dioxane (30.0 mL) was heated to 80 °C for 16 hours. Water (30 mL) was added to dilute the reaction solution then extracted with EtOAc (30 mL x 2). The organic layers were combined, dried and evaporated to give the crude product, which was purified by flash chromatography (120 g silica gel), eluted with petroleum ether/EtOAc 0-20%, to give NNN-1 (3 g, 90%) as a white solid. LCMS [M-Boc+1] 366; Ή NMR (400 MHz, DMSO-de) δ ppm 7.50 - 7.45 (m, 2H), 7.43 - 7.39 (m, 2H), 7.37 - 7.30 (m, 1H), 7.13 (d, J=2.5 Hz, 2H), 5.15 (br. s., 2H), 4.54 - 4.38 (m, 2H), 3.59 - 3.50 (m, 2H), 2.77 (t, J=5.5 Hz, 2H), 1.42 (s, 9H), 1.29 (s, 12H)

Step 2 - Synthesis of tert-butyl 8-(benzyloxy)-6-(1-methyl-1H-1,2,3-triazol-5-yl)-3,4dihydroisoquinoline-2(1 H)-carboxylate (NNN-2)

A vial under argon containing NNN-1 (800 mg, 1.72 mmol), 5-iodo-1-methyl-1H-1,2,3-triazole (467 mg, 2.23 mmol), PdCI₂(dppf)-DCM (126 mg, 0.172 mmol), K₂CO₃ (475 mg, 3.44 mmol), DME (10.0 mL) and water (1.00 mL) was capped and heated at 80°C for 16 hours. Water (10.0 mL) was added to the reaction and extracted with EtOAc (10 mL x 2). The organic layers were separated, dried and evaporated to give the crude product, which was purified by flash chromatography (80 g), eluted with petroleum ether/EtOAc (1:1) to give NNN-2 (640 mg, 89%) as a colorless oil. LCMS [M+1] 421.

Step 3 - Synthesis of tert-butyl 8-hydroxy-6-(1-methyl-1H-1,2,3-triazol-5-yl)-3,4dihydroisoquino!ine-2(1 H)-carboxylate (TP-25)

Compound NNN-2 (640 mg, 1.52 mmol) was dissolved in EtOAc (3 mL). Pd/C (162 mg, 1.52 mmol) was added to the above mixture, the reaction mixture was stirred at 25 °C for 48 hours. The solution was diluted with EtOAc (10 mL) and filtered. The filtrate was evaporated to give the crude product, which was purified by flash chromatography, eluted with petroleum ether/EtOAc from 0-30%, to give the desired product TP-25 (320 mg, 64%) as a white solid.

-230LCMS [M+1] 331; Ή NMR (400 MHz, DMSO-ds) δ ppm 10.04 (s, 1H), 7.82 (s, 1H), 6.91 - 6.77 (m, 2H), 4.40 (s, 2H), 4.04 (s, 3H), 3.56 (m, 2H), 2.78 (m, 2H), 1.45 (s, 9H)

Synthesis of tert-butyl 8-hydroxy-6-(thiazol-4-yl)-3,4-dihydroisoquinoline-2(1H)carboxylate (TP-26) (Scheme OOO)

Scheme OOO

Step 1 - Synthesis of tert-butyl 8-(benzyloxy)-6-(thiazol-4-yl)-3,4-dihydroisoquinoline2(1H)-carboxylate (OOO-1)

A vial under argon containing compound NNN-1 (800 mg, 1.72 mmol), 4-bromothiazole (367 mg, 2.23 mmol), Pd(PPh₃)₄ (278 mg, 0.241 mmol), K₂CO₃ (523 mg, 3.78 mmol), dioxane (10 mL) and water (1 mL) was capped and heated at 80 °C for 16 hours. Water (10 mL) was added to the reaction and extracted with EtOAc (10 mL x 2). The organic layers were separated, dried and evaporated to give the crude product, which was purified by flash chromatography, eluted with petroleum ether/EtOAc from 0-20%) to give OOO-1 (370 mg, 51%) as a colorless oil. LCMS [M+23] 445

Step 2 - Synthesis of 6-(thiazol-4-yl)-1,2,3,4-tetrahydroisoquinolin-8-ol (000-2)

Compound 000-1 (320 mg, 0.76 mmol) was dissolved in DCM (10 mL) and cooled to 0 °C in an ice bath. BBr₃ (1.14 g, 4.54 mmol) was added to the reaction solution and stirred at 25 °C for 16 hours. The reaction solution was cooled to 0 °C. Methanol (3.00 mL) was added to the reaction solution drop-wise followed by water (20 mL). The reaction solution was washed with DCM (10 mL x 2). The aqueous layer was separated. Na₂CO₃ solid was used to adjust the pH to 9. The final solution of compound OOO-2 was used for the next step directly. LCMS [M+1] 233.

Step 3 - Synthesis of tert-butyl 8-hydroxy-6-(thiazol-4-yl)-3,4-dihydroisoquinoline-2(1H)carboxylate (TP-26)

MeOH (5.00 mL) and dioxane (5.00 mL) were added to the solution of compound 000-2 (180 mg, reaction solution aqueous, 40.0 mL), then (Boc)₂O (335 mg, 1.55 mmol) was added to the reaction and stirred at 25 °C for 16 hours. DCM (20 mL) was added to dilute solution. The pH

-231 was adjusted to pH~3 by the addition of 1N HCl aq. The solution was separated and the aqueous layer was extracted with DCM (10 mL). The organic layers were combined and washed with saturated NaCI (20.0 mL). The organic layers were separated, dried and evaporated to give the crude product, which was purified by flash chromatography, eluted with petroleum ether/EtOAc 0-50% to give the TP-26 (180 mg, 70%) as a yellow solid. LCMS [M+1] 333; Ή NMR (400 MHz, DMSO-d_s) δ ppm 9.78 (s, 1H), 9.16 (d, J=2.0 Hz, 1H), 7.99 (d, J=2.0 Hz, 1H), 7.33 (d, J=1.3 Hz, 1H), 7.24 (s, 1H), 4.38 (s, 2H), 3.56 (m, 2H), 2.77 (m, 2H), 1.44 (s, 9H)

Synthesis of tert-butyl 8-hydroxy-3-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (TP-28) (Scheme PPP)

Scheme PPP

PtO₂, h₂ EtOH/AcOH

PPP-1

Step 1: Synthesis of 3-methyl-1,2,3,4-tetrahydroisoquinolin-8-ol (PPP-1)

A solution of 3-methylisoquinolin-8-ol (TP-27) [prepared from Tetrahedron Letters 49 (2008) 3725-3728] (100 mg, 0.628 mmol) in EtOH/AcOH (6mL/0.2mL) was added PtO₂ (80 mg, 0.35 mmol), hydrogenated under 45 psi H₂ at rt for 16h. The reaction mixture was filtered and washed with EtOH, the solvent was evaporated to give crude PPP-1 (103 mg, 100%) which was used to the next step without further purification. LCMS [M+1] 163.9.

Step 2: Synthesis of tert-butyl 8-hydroxy-3-methyl-3,4-dihydroisoquinoline-2(1H)carboxylate (TP-28)

To a solution of PPP-1 (103 mg, 0.628 mmol) in THF (6 mL, 0.1 M) was added Boc₂O (225 mg, 1.03 mmol) and K₂CO₃ (356 mg, 2.57 mmol) at 15 °C, stirred at rt for 15 hrs. The solvent was removed, the residue was dissolved in MeOH, added 0.1 g K₂CO₃, stirred for 2 hrs. The solid was filtered and washed with EtOAc, the filtrate was concentrated and purified by préparative TLC to give TP-28 (70 mg, 42%) as yellow solid.

LCMS [M+1-tBu] 207.9. Ή NMR (400MHz, CHLOROFORM-d) δ ppm 7.09 - 7.01 (m, 1H), 6.71 (d, J=7.8 Hz, 1H), 6.63 (d, J=8.0 Hz, 1H), 4.81 (br d, J=17.6 Hz, 1H), 4.63 (br s, 1H), 4.18 (d,

-232 J=17.6 Hz, 1H), 3.08 (brdd, J=5.5, 16.1 Hz, 1H), 2.55 (br ddd, J=1.8, 14.6, 16.3 Hz, 1H), 1.54 1.43 (s, 9H), 1.09 (d, J=6.8 Hz, 3H)

Synthesis of tert-butyl 8-hydroxy-6-(oxazol-5-yl)-3,4-dihydroisoquinoline-2(1H)carboxylate (TP-29) (Scheme QQQ)

Scheme QQQ

Step 1: Synthesis of tert-butyl 8-(benzyloxy)-6-(oxazol-5-yl)-3,4-dihydroisoquinoline2(1H)-carboxylate (QQQ-1)

To the solution of 11-1 (265 mg, 0.721 mmol) and p-toluenesulfonylmethyl isocyanide (465 mg, 2.38 mmol) in methanol (14.4 mL, c=0.05 M) was added K2CO3 (199 mg, 1.44 mmol), the resulting suspension was refluxed overnight. The reaction mixture was concentrated, EtOAc and H₂O were added. The layers were separated; the aqueous was extracted with EtOAc. The organic layers were concentrated, purified by column chromatography with 35% EtOAc/heptane to give QQQ-1 (100 mg, 34%) as colorless oil.

LCMS [M+1-Boc] 307.15. Ή NMR (400 MHz, CHLOROFORM-d) δ ppm 1.51 (s, 9 H) 2.86 (t, J=5.01 Hz, 2 H) 3.67 (t, J=5.62 Hz, 2 H) 4.62 (s, 2 H) 5.16 (br. s., 2 H) 7.06 (s, 1 H) 7.08 (s, 1 H) 7.31 (s, 1 H) 7.35 (d, J=7.21 Hz, 1 H) 7.41 (t, J=7.34 Hz, 2 H) 7.44 - 7.50 (m, 2 H) 7.90 (s, 1 H)

Step 2: Synthesis of tert-butyl 8-hydroxy-6-(oxazol-5-yl)-3,4-dihydroisoquinoline-2(1H)carboxylate (TP-29)

Compound TP-29 was prepared from QQQ-1 in a similar method as step 9 in Scheme GG (79 mg, 100%).

LCMS [M+1-Boc] 217.10. Ή NMR (400 MHz, CHLOROFORM-d) δ ppm 1.54 (s, 9 H) 2.83 (br. s., 2 H) 3.67 (t, J=5.69 Hz, 2 H) 4.60 (br. s., 2 H) 6.95 (br. s., 2 H) 7.27 (s, 1 H) 7.90 (s, 1 H)

Synthesis of tert-butyl 8-hydroxy-6-(1H-pyrazol-3-yl)-3,4-dihydroisoquinoline-2(1H)carboxylate (TP-30) (Scheme RRR)

-233 -

Scheme RRR

Boc.-

H2N NH2

GG-7

Boc..

TP-30

RRR-3 : Synthesis of

Step carboxylate (RRR-1) tert-butyl

6-acetyl-8-(benzyloxy)-3,4-dihydroisoquinoline-2(1H)Compound RRR-1 was prepared from GG-7 in a similar method as step 1 in Scheme JJ (360.0 10 mg, 80.2%).

Step 2: Synthesis of tert-butyl (E)-8-(benzyloxy)-6-(3-(dimethylamino)acryloyl)-3,4dihydroisoquinoline-2(1 H)-carboxylate (RRR-2)

RRR-1 (65 mg, 0.17 mmol) and Ν,Ν-dimethylformamide dimethylcetal (0.5 mL) were heated at 100°C overnight. The rxn mixture was concentrated, purified by column chromatography with 70% EtOAc/heptane to give RRR-2 70 mg (94% yield) as a yellow oil.

LCMS [M+1] 437.20. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.50 (s, 9 H) 2.77 - 2.92 (m, 20 2 H) 2.92 - 3.22 (m, 6 H) 3.66 (t, J=5.01 Hz, 2 H) 4.62 (s, 2 H) 5.17 (br. s., 2 H) 5.66 (d, J=12.35

Hz, 1 H) 7.28 (br. s„ 1 H) 7.32 (d, J=7.21 Hz, 1 H) 7.38 (t, J=7.27 Hz, 3 H) 7.43 - 7.49 (m, 2 H) 7.80 (d, J=12.35 Hz, 1 H)

Step 3: Synthesis of tert-butyl 8-(benzyloxy)-6-(1H-pyrazol-3-yl)-3,4-dihydroisoquinoline25 2(1 H)-carboxylate (RRR-3)

RRR-2 (70 mg, 0.16 mmol) and hydrazine monohydrate (183 mg, 1.28 mmol , 0.178 mL) in 2 mL EtOH was stirred at rt overnight. The reaction mixture was added EtOAc and H₂O, the layers were separated, the aqueous was extracted with EtOAc. The organic was combined and

-234washed with brine, dried over NazSCU, concentrated to give RRR-3 58.8 mg (90% yield) as a solid.

LCMS [M+1-tBu] 350.10. Ή NMR (400 MHz, CHLOROFORM-d) δ ppm 1.51 (s, 9 H) 2.76 - 2.93 (m, 2 H) 3.67 (t, J=5.50 Hz, 2 H) 4.62 (s, 2 H) 5.16 (br. s., 2 H) 6.59 (d, J=2.32 Hz, 1 H) 7.15 (s, 1 H) 7.23 (s, 1 H) 7.30 - 7.36 (m, 1 H) 7.39 (t, J=7.27 Hz, 2 H) 7.44 - 7.49 (m, 2 H) 7.62 (d, J=2.20 Hz, 1 H)

Step 4: Synthesis of tert-butyl 8-hydroxy-6-(1H-pyrazol-3-yl)-3,4-dihydroisoquinoline2(1H)-carboxylate (TP-30)

Compound TP-30 was prepared from RRR-3 in a similar method as step 9 in Scheme GG (32 mg, 70%).

LCMS [M+1-Boc] 216.10. Ή NMR (400 MHz, CHLOROFORM-d) δ ppm 1.51 (s, 9 H) 2.77 (t, J=5.26 Hz, 2 H) 3.62 (t, J=5.50 Hz, 2 H) 4.58 (br. s., 2 H) 6.46 (br. s., 1 H) 6.97 (s, 1 H) 7.12 (br. s., 1 H) 7.50-7.63 (m, 1 H)

Examples 163-171 were made in a similar fashion to Example 78 in Scheme CC using the appropriate NBoc-protected tetrahydroisoquinoline in step 1.

Example 163

TP-21

Skipped final deprotection step

411 LCMS

[M+1]

6-(((1 S, 2S,3S,4R)-2,3-dihydroxy-4(4-methyl-7H-pyrroio[2,3d]pyrimidin-7-yl)cyclopentyl)oxy)3,4-dihydrobenzo[f][1,4]oxazepin5(2H)-one ¹H NMR (400 MHz, DMSO-de) δ ppm 8.62 (s, 1H), 8.33 (t, J=6.1 Hz, 1H), 7.97 (d, J=3.8 Hz, 1H), 7.38 (t, J=8.3 Hz, 1H), 6.98 (d, J=8.3 Hz, 1H), 6.69 (dd, J=2.0, 5.8 Hz, 2H), 5.35 (d, J=3.5 Hz, 1H), 5.31 - 5.23 (m, 1H), 5.08 (d, J=6.8 Hz, 1H), 4.71 (br d, J=6.3 Hz, 1H), 4.63 4.56 (m, 1H), 4.11 (br d, J=4.8 Hz, 2H), 4.00 (br s, 1H), 3.25 - 3.16 (m, 2H), 2.90 - 2.80 (m, 1H), 2.64 (s, 3H), 1.72 (m, 1H)

-235-

Example 164		^NH		397	(1 S,2S,3R,5S)-3-(4-methyl-7H-
TP-22		T J \_	XnXXn J	LCMS [M+1]	pyrrolo[2,3-d]pyrimidin-7-yl)-5-
		ho'	OH		((2,3,4,5-
Bocx θΗ					tetrahydrobenzo[f][1,4]oxazepin-6-
Ν'^χΧ^					yl)oxy)cyclopentane-1,2-diol
					HCl sait 1H NMR (400 MHz, MeOD-d4) δ ppm = 9.12 - 8.97 (m, 1H), 8.15 7.95 (m, 1H), 7.36 - 7.26 (m, 1H), 7.25 - 7.12 (m, 1H), 7.00 - 6.88 (m, 1H), 6.75 (d, J=6.5 Hz, 1H), 5.46 5.33 (m, 1H), 4.81 - 4.73 (m, 2H), 4.68 - 4.52 (m, 2H), 4.36 - 4.14 (m, 3H), 3.67 - 3.56 (m, 2H), 3.12 - 3.04 (m, 1H), 3.00 (br. s., 3H), 2.40 - 2.25 (m, 1H)
Example 165		H		447	(1 S,2S,3S,5R)-3-((6-(1 H-pyrazol-4-
TP-23			/ Y H	LCMS [M+1]	yl)-1,2,3,4-tetrahydroisoquinolin-8-
		XX	OH ’		yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-
OH		X			d]pyrimidin-7-yl)cyclopentane-1,2-
Boc.Xa._		hn-n			diol
ι X X	A				HCl Sait
				1H NMR (400 MHz, D2O) δ ppm
	Boc				8.85 - 8.80 (m, 1H), 8.00 - 7.95 (m, 2H), 7.81 (br dd, J=1.4, 3.9 Hz, 1H), 7.14 - 7.07 (m, 2H), 7.05 (br d, J=3.3 Hz, 1H), 5.39 - 5.27 (m, 2H), 4.92 - 4.82 (m, 1H), 4.30 (br s, 3H), 3.50 - 3.39 (m, 2H), 3.11 - 2.99 (m, 3H), 2.88 (br s, 3H), 2.20 (br s, 1 H)
Example 166				465	(1 S,2S,3S,5R)-3-((5-fluoro-6-(1 H-
TP-24			oo 2 OH	LCMS [M+1]	pyrazol-4-yl)-1,2,3,4- tetrahydroisoquinolin-8-yl)oxy)-5-(4- methyl-7H-pyrrolo[2,3-d]pyrimidin-7-
OH
Β%χΛ		oz	OH		yl)cyclopentane-1,2-diol
i xx		HN' ''X ''
					HCl sait
	Ό Boc
F	F	X ,N NH		1H NMR (400 MHz, D2O) δ ppm

-236-

			8.57 (s, 1H), 8.42 (s, 1H), 8.08 (s, 1H), 7.51 (d, J=3.8 Hz, 1H), 7.12 (d, J=5.8 Hz, 1H), 6.80 (s, 1H), 5.22 5.13 (m, J=8.9, 8.9, 8.9 Hz, 2H), 4.89 - 4.84 (m, 1H), 4.66 - 4.61 (m, 1H), 4.39 - 4.27 (m, 3H), 3.54 - 3.49 (m, 2H), 3.11 - 3.04 (m, J=5.6, 5.6 Hz, 2H), 3.04 - 2.96 (m, 1H), 2.68 (s, 3H), 2.17-2.07 (m, 1H)
Example 167 TP-25 OH OuLx /N-N	CO νά £ / ”oh ο*Ά I OH ην^£|Ί N /N~N	462 LCMS [M+1]	(1S,2S,3S,5R)-3-((6-(1-methyl-1H- 1,2,3-triazol-5-yl)-1,2,3,4tetrahydroisoquinolin-8-yl)oxy)-5-(4methyl-7H-pyrrolo[2,3-d]pyrimidin-7yl)cyclopentane-1,2-diol HCl sait 1H NMR (400 MHz, D2O) δ ppm 8.93 - 8.91 (s, 1H), 7.93 - 7.90 (d, J=4.0 Hz, 1H), 7.88 (s, 1H), 7.19 (d, J=4.0 Hz, 1H), 7.14-7.11 (s, 1H), 7.08 (s, 1H), 5.42 (m, 1H), 4.94 - 4.86 (m, 2H), 4.46 (s, 2H), 4.40 (m, 1H), 4.10 (s, 3H), 3.61 - 3.54 (m, 2H), 3.24 - 3.16 (m, 2H), 3.17 - 3.07 (m, 1H), 2.98 (s, 3H), 2.37 - 2.26 (m, 1H)
Example 168 TP-26 OH BOC'M/XxJj OCV\ s N=/	Cu ? £ / 0H Ο*Ά I OH χ£τ££,-·Ν ~'S	464 LCMS [M+1]	(1 S,2S,3R,5S)-3-(4-methyl-7Hpyrrolo[2,3-d]pyrimidin-7-yl)-5-((6(thiazol-4-yl)-1,2,3,4tetrahydroisoquinolin-8yl)oxy)cyclopentane-1,2-diol HCI Sait 1H NMR (400 MHz, D2O) δ ppm 9.09 (d, J=1.8 Hz, 1H), 8.90 (s, 1H), 7.91 (d, J=2.0 Hz, 1H), 7.89 (d, J=4.0 Hz, 1H), 7.45 (s, 1H), 7.44 (s, 1H), 7.17 - 7.15 (m, 1H), 5.43 (m, 1H), 4.96 (m, 1H), 4.85 - 4.83 (m,

-237-

			1H), 4.43 (s, 2H), 4.41 (m, 1H), 3.59 - 3.54 (m, 2H), 3.23 - 3.18 (m, 2H), 3.18 - 3.11 (m, 1H), 2.96 (s, 3H), 2.35- 2.26 (m, 1H)
Example 169			\ N	391	(1 S,2S,3R,5S)-3-(4-methyl-7H-
TP-27			X N	LCMS [M+1]	pyrrolo[2,3-d]pyrimidin-7-yl)-5-((3- methylisoquinolin-8-
OH					yl)oxy)cyclopentane-1,2-diol
			Λ /OH		1H NMR (400MHz, METHANOL-d4)
ï II J			O*^
			J. °H		δ ppm 9.56 (s, 1H), 8.57 (s, 1H),
Skipped final deprotection step		N^	O		7.71 - 7.60 (m, 3H), 7.43 (d, J=8.3 Hz, 1H), 7.13 (d, J=7.3 Hz, 1H), 6.75 (d, J=3.8 Hz, 1H), 5.30 (q, J=8.9 Hz, 1H), 4.98 (m, 1H), 4.91 (m, 1H), 4.38 (d, J=5.0 Hz, 1H), 3.16 - 3.08 (m, 1H), 2.72 (s, 3H), 2.70 (s, 3H), 2.45-2.37 (m, 1H)
Example 170				448	(1 S,2S,3R,5S)-3-(4-methyl-7H-
TP-29			>=N	LCMS [M+1]	pyrrolo[2,3-d]pyrimidin-7-yl)-5-((6-
		H /-N		(oxazol-5-yl)-1,2,3,4-
OH					tetrahydroisoquinolin-8-
N			X/0H		yl)oxy)cyclopentane-1,2-diol
	£°>		Çy\ JL °H		1H NMR (400MHz, METHANOL-d4)
	HN/'·	θι°>		δ ppm 8.99 (s, 1H), 8.30 (s, 1H), 8.01 (d, J=3.8 Hz, 1H), 7.63 (s, 1H),
			-N		7.35 (d, J=16.6 Hz, 2H), 7.17 (d, J=3.8 Hz, 1H), 5.40 (q, J=9.3 Hz, 1H), 4.79 (dd, J=5.0, 9.0 Hz, 1H), 4.43 (s, 2H), 4.26 (d, J=4.5 Hz, 1H), 3.55 (t, J=6.3 Hz, 2H), 3.23 - 3.07 (m, 3H), 2.97 (s, 3H), 2.33 (ddd, J=4.1, 9.6, 13.9 Hz, 1H)

-238-

(1 S,2S,3S,5R)-3-((6-(1 H-pyrazol-3yl)-1,2,3,4-tetrahydroisoquinolin-8yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)cyclopentane-1,2diol

HCl sait ¹H NMR (400 MHz, D₂O) δ ppm = 8.88 (s, 1H), 7.86 (d, J=3.8 Hz, 1H), 7.79 (d, J=2.3 Hz, 1H), 7.34 (m, 2H), 7.14 (m, 1H), 6.77 (m, 1H), 5.41 (m, 1H), 4.93 (m, 1H), 4.75 4.70 (m, 1H), 4.44 - 4.36 (m, 3H), 3.58 - 3.50 (m, 2H), 3.25 - 3.07 (m, 3H), 2.93 (s, 3H), 2.31 (m, 1H)

Example 172 (Scheme SSS) - Synthesis of (1S,2S,3S,5R)-3-(isoquinolin-8-yloxy)-5-(4methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol (SSS-6)

Scheme SSS

OsO₄ (4% in H₂O soin)

NMO, DCM, H₂O

Dimethoxypropane pTsOH, rt

BB-2

Step 1: Synthesis of tert-butyl ((1S,2S,3S,4R)-2,3-dihydroxy-4-(4-methyl-7H-pyrrolo[2,310 d]pyrimidin-7-yl)cyclopentyl) carbonate (SSS-1 )

-239Compound SSS-1 was prepared from BB-2 in a similar method as step 2 in Scheme CC to give 274 mg (82% yield) as a colorless oil.

LCMS [M+1] 350.10. Ή NMR (400 MHz, CHLOROFORM-d) δ ppm 1.51 (s, 9 H) 2.18 (ddd, J=14.21, 9.14, 5.26 Hz, 1 H) 2.71 (s, 3 H) 3.02 (dt, 3=14.18, 8.07 Hz, 1 H) 3.95 - 4.02 (m, 1 H) 4.30 (dd, 3=5.38, 2.08 Hz, 1 H) 4.51 (dd, 3=7.82, 5.50 Hz, 1 H) 4.96 - 5.08 (m, 2 H) 6.61 (d, 3=3.67 Hz, 1 H) 7.29 (d, 3=3.67 Hz, 1 H) 8.66 (s, 1 H)

Step 2: Synthesis of tert-butyl ((3aR,4S,6R,6aS)-2,2-dimethyl-6-(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl) carbonate (SSS-2)

Compound SSS-2 was prepared from SSS-1 in a similar method as step 3 in Scheme P to give 181 mg (59% yield) as a colorless oil.

LCMS [M+1] 390.15. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.32 (s, 3 H) 1.50 (s, 9 H) 1.58 (s, 3 H) 2.38 - 2.48 (m, 1 H) 2.73 (s, 3 H) 2.84 - 2.95 (m, 1 H) 4.82 (d, J=6.11 Hz, 1 H) 4.99 (dd, 3=6.54, 3.12 Hz, 1 H) 5.06 - 5.13 (m, 1 H) 5.21 - 5.29 (m, 1 H) 6.57 (d, 3=3.67 Hz, 1 H) 7.31 (d, 3=3.67 Hz, 1 H) 8.78 (s, 1 H)

Step 3: Synthesis of (3aR,4S,6R,6aS)-2,2-dimethyl-6-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-

7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-ol (SSS-3)

Compound SSS-3 was prepared from SSS-2 in a similar method as step 1 in Scheme FFF to give 127 mg (94% yield) as a white solid.

LCMS [M+1] 290.15. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.33 (s, 3 H) 1.55 (s, 3 H) 2.20 (dd, 3=15.65, 1.34 Hz, 1 H) 2.75 (s, 3 H) 2.95 - 3.08 (m, 1 H) 4.44 - 4.50 (m, 1 H) 4.80 (d, 3=5.38 Hz, 1 H) 4.84 (dt, 3=10.58, 2.48 Hz, 1 H) 4.98 (d, 3=5.01 Hz, 1 H) 6.15 (d, 3=9.41 Hz, 1 H) 6.55 (d, 3=3.67 Hz, 1 H) 8.73 (s, 1 H)

Step 4: Synthesis of tert-butyl 8-(((3aR,4S,6R,6aS)-2,2-dimethyl-6-(4-methyl-7Hpyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)-3,4-dihydro-

2.7- naphthyridine-2(1H)-carboxylate (SSS-4) and 1-(((3aR,4S,6R,6aS)-2₎2-dimethyl-6-(4methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)-

2.7- naphthyridine (SSS-5)

- 240 To a solution ofSSS-3 (80.7 mg, 0.279 mmol) in DMF (5.58 mL, c=0.05 M) was added NaH (16.7 mg, 0.419 mmol, 60%). After stirring for 10 min, GGG-2 (75.0 mg, 0.279 mmol) was added. The resulting reaction mixture was heated at 100°C for 1.5 h. The reaction was quenched with diluted NaHCOs, and then partitioned between ethyl acetate (20 mL) and water (20 mL). The organic phase was separated, washed with brine, dried over sodium sulfate, concentrated and purified with column chromatography with 60% EtOAc/heptane to give SSS-4 (15 mg, 10%)

LCMS [M+1] 522.20. Ή NMR (400 MHz, CHLOROFORM-d) δ ppm 1.34 (s, 3 H) 1.50 (s, 9 H) 1.60 (s, 3 H) 2.45 (d, J=14.18 Hz, 1 H) 2.72 (s, 3 H) 2.76 (t, J=5.38 Hz, 2 H) 3.05 (dt, J=14.61, 7.12 Hz, 1 H) 3.60 (br. s., 1 H) 3.65 (br. s., 1 H) 4.39 (br. s., 2 H) 4.94 (d, J=6.24 Hz, 1 H) 5.05 (dd, J=6.17, 1.90 Hz, 1 H) 5.34 (ddd, J=7.70, 4.95, 2.38 Hz, 1 H) 5.60 (br. s., 1 H) 6.61 (br. s., 1 H) 6.69 (d, J=5.14 Hz, 1 H) 7.38 (d, J=3.67 Hz, 1 H) 7.95 (d, J=5.14 Hz, 1 H) 8.79 (m, 1 H) and eluted with 5% MeOH/EtOActo give SSS-5 (35 mg, 30%)

LCMS [M+1] 418.15. Ή NMR (400 MHz, CHLOROFORM-d) δ ppm 1.38 (s, 3 H) 1.63 (s, 3 H) 2.56 (dt, J=14.98, 3.82 Hz, 1 H) 2.72 (s, 3 H) 3.04 - 3.19 (m, 1 H) 5.11 (d, J=6.11 Hz, 1 H) 5.21 (d, J=6.11 Hz, 1 H) 5.35 - 5.46 (m, 1 H) 5.83 (dt, J=3.97, 2.05 Hz, 1 H) 6.61 (d, J=3.67 Hz, 1 H) 7.20 (d, J=5.87 Hz, 1 H) 7.39 (d, J=3.67 Hz, 1 H) 7.55 (d, J=5.62 Hz, 1 H) 8.22 (d, J=5.87 Hz, 1 H) 8.70 (br. s., 1 H) 8.77 (s, 1 H) 9.38 (br. s., 1 H)

Step 5: Synthesis of (1S,2S,3S,5R)-3-(isoquinolin-8-yloxy)-5-(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)cyclopentane-1,2-diol (SSS-6)

Compound SSS-6 was prepared from SSS-5 in a similar method as step 10 in Scheme A to give 11.6 mg (36% yieid) as a white solid.

LCMS [M+1] 378.10. Ή NMR (700 MHz, DMSO-d6) δ ppm 2.05 - 2.15 (m, 1 H) 2.64 - 2.72 (m, 3 H) 2.98 (ddd, J=14.75, 9.24, 7.48 Hz, 1 H) 4.25 (d, J=3.08 Hz, 1 H) 4.72 (dd, J=8.69, 4.73 Hz, 1 H) 5.21 (q, J=8.88 Hz, 1 H) 5.48 (dd, J=5.94, 3.30 Hz, 1 H) 6.80 (d, J=3.52 Hz, 1 H) 7.43 (d, J=5.94 Hz, 1 H) 7.78 - 7.89 (m, 2 H) 8.24 (d, J=5.72 Hz, 1 H) 8.64 (s, 1 H) 8.80 (br. s., 1 H) 9.72 (br. s., 1 H)

Example 173 was made in a similar fashion to CC-3 (Example 78) using the appropriate pyrrolopyrimidine in step 1 of Scheme BB and the appropriate N-Boc protected tetrahydroisoquinoline in step 1 of Scheme CC.

-241 Example 173

HG-3

TP-18

OH

8-(((1 S,2S,3S,4R)-4-(5-fluoro-2methyl-7H-pyrrolo[2,3-d]pyrim idin-7yl)-2,3-dihydroxycyclopentyl)oxy)1,2,3,4-tetrahydroisoquinoline-6carbonitrile ¹H NMR (400 MHz, MeOD-d4) δ ppm 9.09 (br. s., 1H), 7.66 (d, J=2.3 Hz, 1H), 7.40 (s, 1H), 7.33 (s, 1H), 5.38 (q, J=9.1 Hz, 1H), 4.79 (t, J=5.1 Hz, 1H), 4.60 (dd, J=5.3, 9.3 Hz, 1H), 4.44 (s, 2H), 4.19 (d, J=4.8 Hz, 1H), 3.60 - 3.50 (m, 2H), 3.21 3.13 (m, 2H), 3.02 (td, J=8.2, 14.5 Hz, 1 H), 2.83-2.79 (m, 3H),

2.19 (ddd, J=4.6, 9.6, 14.1 Hz, 1H)

Example 174 was made in a similar fashion to NN-5 (Example 99) using the appropriate pyrrolopyrimidine in step 1 of Scheme BB and the appropriate N-Boc protected tetrahydroisoquinoline in step 1 of Scheme NN.

Example 174 pyrrolo[2,3djpyrimidine

441 LCMS

[M+1]

8-(((1 S, 2S,3S, 4R)-4-(4-amino-5chloro-7H-pyrrolo[2,3-d]pyrimidin-7yl)-2,3-dihydroxycyclopentyl)oxy)1,2,3,4-tetrahydroisoquinoline-6carbonitrile

HCl sait ¹H NMR (400 MHz, MeOD-d4) δ ppm 8.30 (s, 1H), 7.68 (s, 1H), 7.46 (s, 1H), 7.30 (s, 1H), 5.29 - 5.21 (m, 1H), 4.78 (t, J=5.2 Hz, 1H), 4.62 (dd, J=5.2, 9.2 Hz, 1H), 4.43 (s, 2H), 4.19 (d, J=5.1 Hz, 1H), 3.57 3.51 (m, 2H), 3.18 (t, J=6.1 Hz, 2H), 3.09 - 2.96 (m, 1H), 2.20 (ddd, J=4.5, 9.7, 14.0 Hz, 1H)

Examples 175 - 179 were made in a similar fashion to SS-5 (Example 121) using the appropriate N-Boc protected tetrahydroisoquinoline in step 1 and the appropriate

-242pyrrolopyrimidine in step 2 of Scheme SS. Step 4 in Scheme SS was not required for these examples.

Example 175:	H ,N^	F	433	(1 S,2S,3S,5R)-3-((6chloro-1,2,3,4-
HG-3 (step 4 skipped)	is			/0^/		ΓΠ	LCMS	tetrahydroisoquinolin-8-
							[M+H]	yl)oxy)-5-(5-fluoro-2-
F				-7 HÔ	OH			methyl-7H-pyrrolo[2,3-
H TP-3				Cl				d]pyrimidin-7yl)cyclopentane-1,2-diol 1H NMR (400MHz, DEUTERIUM OXIDE) δ ppm 9.13 (s, 1H), 7.61 (d,
	Cl
J=2.3 Hz, 1H), 6.97 (d, >4.0 Hz, 2H), 5.40 (brd, J=8.5 Hz, 1H), 4.72 (brd, J=2.0 Hz, 1H), 4.58 (dd, >4.8, 9.0 Hz, 1H), 4.32 - 4.27 (m, 3H), 3.46 (t, >6.1 Hz, 2H), 3.09 - 3.05 (m, 2H), 3.01 (s, 1H), 2.83 (s, 3H), 2.17-2.07
	(m, 1H).
Example 176:		H				F	433	(1S,2S,3S,5R)-3-((6-
		,N-			Γ	=(		chloro-1,2,3,4-
HG-4 (step 4	is				s. su	JL /	LCMS
skipped)							tetrahydroisoquinolin-8-
						nU	[M+H]	yl)oxy)-5-(5-fluoro-4-
F I				7 HÔ	OH			methyl-7H-pyrrolo[2,3-
Ôô				Cl				d]pyrimidin-7-
H N								yl)cyclopentane-1,2-diol
TP-3								1H NMR (400MHz, DEUTERIUM OXIDE) δ
BocN	•ci							ppm 8.88 (s, 1H), 7.69 (d, >2.3 Hz, 1H), 7.01 (d, J=4.0 Hz, 2H), 5.43 (q, >9.0 Hz, 1H), 4.89-4.83 (m, 1H), 4.66 (dd, >4.8, 8.8 Hz, 1H),4.41 -4.30

-243-

			(m, 3H), 3.52 (t, J=6.3 Hz, 2H), 3.17-3.05 (m, 3H), 3.01 (s, 3H), 2.26-2.07 (m, 1H).
Example 177				λ	An	435 LCMS	(1S,2S,3S,5R)-3-((5,6- difluoro-1,2,3,4-
HG-4 (step 4	is					[M+1]
skipped)					'''N^	tetrahydroisoquinolin-8-
F I				\ I	OH		yl)oxy)-5-(5-fluoro-4-
\ 1 U			oz	OH			methyl-7H-pyrrolo[2,3-
N^%T H		HN”~				d]pyrimidin-7-
				F			yl)cyclopentane-1,2-diol
TP-6							HCl Sait
OH
							1H NMR (400 MHz, D2O) δ ppm = 8.77 (s, 1H),
F							7.58 (br s, 1H), 6.92 6.85 (m, 1H), 5.32 (br d, J=8.3 Hz, 1H), 4.78 - 4.77 (m, 1H, under D2O), 4.61 . 4.47 (m, 1H), 4.26 (br s, 3H), 3.46 (br s, 2H), 3.04 (br s, 2H), 2.98 (br d, J=7.5 Hz, 1H), 2.90 (s, 3H), 2.09 (brs, 1H)
Example 178				F		435	(1 S,2S,3S,5R)-3-((5,6-
			\ Γ	'N	LCMS	difluoro-1,2,3,4-
HG-4 (step 4	is			N^'		[M+1]	tetrahydroisoquinolin-8-
skipped)			0*^	. >iOH		yl)oxy)-5-(5-fluoro-2-
F				OH			methyl-7H-pyrrolo[2,3-
// N \ L y		H Ν'''	i				d]pyrimidin-7-
N^ H				'F			yl)cyclopentane-1,2-diol
			F				HCl Sait
TP-6
OH							1H NMR (400MHz, D2O) δ
	F						ppm = 9.09 (s, 1H), 7.59 (s, 1H), 6.87 (br dd,
F							J=6.5, 12.3 Hz, 1H), 5.39 - 5.30 (m, 1H), 4.58 - 4.57 (m, 1H), 4.24 (br s, 2H),

-244-

			3.63 (br d, J=5.0 Hz, 1H), 3.56 (s, 2H), 3.45 (br t, J=5.8 Hz, 1H), 3.03 (br s, 2H), 2.99 - 2.92 (m, 1H), 2.78 (s, 3H), 2.08 (br d, J=10.5 Hz, 1H)
Example 179		nh2	432	(1S,2S,3R,5S)-3-(4-
HG-6				LCMS	amino-5-methyl-7H-
	Cl			[M+1]	pyrrolo[2,3-d]pyrimidin-7- yl)-5-((5,6-difluoro-
// I**	N		I \OH
H	J] ΊΨ		ΐ OH		1,2,3,4- tetrahydroisoquinolin-8-
TP-6			F		yl)oxy)cyclopentane-1,2-
					diol
	OH		F		HCI Sait
BocN'					1H NMR (400 MHz,
	] Γ F				MeOD-d4) δ ppm = 8.27 (s, 1H), 7.37 (s, 1H), 7.15 - 7.00 (m, 1H), 5.29 - 5.11 (m, 1H), 4.73 - 4.57 (m, 2H), 4.35 (br s, 2H), 4.17 (br d, J=3.5 Hz, 1H), 3.61 - 3.49 (m, 2H), 3.13 (br s, 2H), 3.02 - 2.91 (m, 1H), 2.55 - 2.44 (m, 3H), 2.23 2.09 (m, 1H)

Example 180 (Scheme TTT) - (1S,2S,3R,5S)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5((5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)cyclopentane-1,2-diol (TTT-5)

Scheme TTT

-245-

ΤΤΤ-1 ΤΤΤ-2 ΤΤΤ-3

Pd(PPh₃)₄ (10 mol%) K₂CO₃ trimethylboroxine dioxane aq., 100°C

HCl, Dioxane

TTT-5

Step 1: Synthesis of tert-butyl 8-(((3aR,4S,6R,6aS)-6-(5-bromo-4-chloro-7H-pyrrolo[2,3d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)-5-fluoro-

3,4-dihydroisoquinoline-2(1 H)-carboxylate (TTT-2)

Intermediate TTT-1 was prepared by following the general procedures for steps 1-3 in Scheme SS employing TP-2 and 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine as the appropriate starting materials.

To a scintillation vial, equipped with a magnetic stirbar and containing intermediate TTT-2 (281 mg, 0.470 mmol), was added DCM (5.0 mL), 2,2-dimethoxypropane (0.58 mL, 4.70 mmol), and PPTS (11.8 mg, 0.047 mmol). The reaction was stirred at rt for 23 hours. The solution was transferred to a separatory funnel with DCM and washed with 2 portions half saturate brine. The organic phase was dried (MgSCU), filtered, and concentrated under vacuum to afford the title compound TTT-2 (266 mg, 89%) as a white solid. LCMS [M+H] = 637 observed. Ή NMR (400MHz, CHLOROFORM-d) δ ppm 8.68 (s, 1H), 7.49 (br. s., 1H), 6.97 - 6.86 (m, 1H), 6.84 6.71 (m, 1H), 5.35 (br. s., 1H), 4.95 (dd, J=2.1,6.1 Hz, 1H), 4.81 (d, J=6.1 Hz, 2H), 4.48 (br. s., 2H), 3.65 (br. s., 2H), 3.07 - 2.89 (m, 1H), 2.80 (br. s., 2H), 2.50 (d, J=15.3 Hz, 1H), 1.60 (s, 3H), 1.47 (br. s., 9H), 1.34 (s, 3H).

Step 2: Synthesis of tert-butyl 8-(((3aR,4S,6R,6aS)-6-(4-amino-5-bromo-7H-pyrrolo[2,3d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)-5-fluoro-

3,4-dihydroisoquinoline-2(1 H)-carboxylate (TTT-3)

To a microwave vial, equipped with a magnetic stirbar, was added TTT-2 (152 mg, 0.238 mmol) as a solution in dioxane (0.60 mL). To the solution was added ammonium hydroxide (0.6 mL, 5.00 mmol) and the vial was sealed with a Teflon cap. The vial was placed in a microwave reactor and heated to 120C for 6 hours then allowed to cool to rt overnight. The solution was transferred to a separatory funnel with DCM and diluted with water. The phases were separated and the aqueous phase was extracted with 3 portions of DCM. The combined organic extracts

-246were dried (MgSO₄), filtered, and concentrated under vacuum. The crude residue was purified via flash column chromatography (12g SiO₂, Isco, 100% Hept. to 100% EtOAc, 9 mL fractions) to afford the title compound TTT-3 (81 mg, 55%) as a white solid. LCMS [M+H] = 618 observed. Ή NMR (400MHz, CHLOROFORM-d) δ ppm 8.31 (s, 1H), 7.16 (s, 1H), 6.98 - 6.85 (m, 1H), 6.84 - 6.73 (m, 1H), 5.61 (br. s., 2H), 5.36 - 5.18 (m, 1H), 4.94 (dd, J=2.5, 6.1 Hz, 1H), 4.82 4.73 (m, 2H), 4.56 - 4.45 (m, 2H), 3.90 - 3.42 (m, 2H), 3.02 - 2.87 (m, 1H), 2.80 (t, J=4.9 Hz, 2H), 2.46 (td, J=4.4, 14.8 Hz, 1H), 1.59 (s, 3H), 1.53- 1.42 (m, 9H), 1.33 (s, 3H).

Step 3: Synthesis of tert-butyl 8-(((3aR,4S,6R,6aS)-6-(4-amino-7H-pyrrolo[2,3-d]pyrimidin7-yi)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)-5-fluoro-3,4dihydroisoquinoline-2(1 H)-carboxylate (TTT-4)

To a reaction vial, equipped with a magnetic stibar, was added TTT-3 (81.0 mg, 0.131 mmol), potassium carbonate (54.3 mg, 0.393 mmol), and Pd(PPh₃)4 (15.1 mg, 0.013 mmol). The vial was sealed with a teflon cap and purged with argon under dynamic vacuum. To the vial was added dioxane (0.58 mL) and water (0.07 mL). The vial was transferred to a heating block and heated at 100°C for 3.5 days. The vial was removed from the heating block and allowed to cool to rt. The reaction was diluted with water and transferred to a separatory funnel with DCM. The phases were separated and the aqueous phase was extracted with 3 portions of DCM. The combined organic extracts were dried (MgSO₄), filtered, and concentrated under vacuum. The crude residue was purified via préparative high performance liquid chromatography (Lux 5u Cellulose-2 30x250mm column, 33% MeOH w/ 0.05% DEA in CO₂, 100 bar, 80 mL/min) to afford the title compound TTT-4 (17.1 mg, 24%) as a white solid. LCMS [M+H] = 540 observed. [a]D22 = +2.2° (C=0.1, MeOH). ¹H NMR (400MHz, CHLOROFORM-d) δ ppm 8.35 (s, 1H), 7.19 (d, J=3.7 Hz, 1H), 6.94 -6.85 (m, 1 H), 6.84 - 6.75 (m, 1H), 6.44 (br. s., 1H), 5.34 - 5.26 (m, 1H), 5.19 (br. s., 2H), 5.01 (dd, J=2.6, 6.2 Hz, 1H), 4.79 (d, J=6.4 Hz, 1H), 4.75 (t, J=5.3 Hz, 1H), 4.44 (br. s., 2H), 3.65 (br. s., 2H), 3.07 - 2.86 (m, 1H), 2.78 (t, J=5.1 Hz, 2H), 2.59 - 2.42 (m, 1H), 1.60 (s, 3H), 1.49 (br. s., 9H), 1.33 (s, 3H).

Step 4: Synthesis of (1S,2S,3R,5S)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((5fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)cyclopentane-1,2-diol (TTT-5)

To a scintillation vial, equipped with a magnetic stirbar and containing TTT-4 (17.1 mg, 0.032 mmol), was added water (0.08 mL). To the solution was added hydrochloric acid (0.4 mL, 4.0 M in dioxane, 2 mmol) and the reaction was stirred at rt for 15 hours. The solution was transferred to a separatory funnel with DCM, diluted with water, and neutralized with sat. NaHCO3. The phases were separated and the aqueous phase was extracted with 3 portions of a 3.1 mixture of DCMJPA. The combined organic extracts were dried (MgSO4), filtered, and concentrated

-247under vacuum. The material thus obtained was freeze-dried to afford the title compound TTT-5 (12.5 mg, >95%) as a white solid. LCMS [M+H] = 400 observed. ¹H NMR (400MHz, METHANOL-d4) δ ppm 8.08 (s, 1H), 7.22 (d, J=3.7 Hz, 1H), 6.95 - 6.79 (m, 2H), 6.63 (d, J=3.7 Hz, 1H), 5.12 (q, J=8.6 Hz, 1 H), 4.69 - 4.61 (m, 1H), 4.57 (dd, J=4.8, 8.4 Hz, 1 H), 4.16 (d, J=4.3 Hz, 1H), 3.96 (br. s., 2H), 3.08 (t, J=5.1 Hz, 2H), 2.97 (ddd, J=7.3, 9.3, 14.6 Hz, 1H), 2.76 (t, J=5.9 Hz, 2H), 2.04 (ddd, J=3.9, 8.4, 14.1 Hz, 1H).

Example 181 - (1S,2S,3S,5R)-3-((3-methyl-5,6,7,8-tetrahydro-2,7-naphthyridin-1-yl)oxy)-5(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol

Scheme UUU

2) MeOH

3) Boc₂O

Step 1 - Synthesis of 2-benzyl-6-methyl-8-oxo-7,8-dihydro-2,7-naphthyridin-2-ium bromide (UUU-2)

To a mixture of 3-methyl-2,7-naphthyridin-1(2H)-one UUU-1 (prepared in a similar method in patent W02002068393) (3.9 g, 21.85 mmol) in CH₃CN (50 mL) was added BnBr (6.25 g, 36.5 mmol) at rt (25 °C). Then, the mixture was heated at refluxed (85 °C) for 16 hours. The precipitate was collected by filtration, washed with éthanol (30 mL) and dried in vacuo to obtain UUU-2 (4.8 g, 60%) as a yellow solid. LCMS [M-Br] 251; ¹H NMR (400 MHz, DMSO-de) δ ppm = 12.57 (br s, 1H), 9.77 (s, 1H), 8.88 (d, J=6.8 Hz, 1H), 8.08 (d, J=6.8 Hz, 1H), 7.55 (br d, J=6.8 Hz, 2H), 7.44 (brd, J=7.3 Hz, 3H), 6.70 (s, 1H), 5.86 (s, 2H), 2.40 (s, 3H)

Step 2 - Synthesis of 7-benzyl-3-methyl-5,6,7,8-tetrahydro-2,7-naphthyridin-1(2H)-one (UUU-3)

To a solution of compound UUU-2 (4.8 g, 14.49 mmol) in MeOH (50 mL) was added NaBH₄ (7.68 g, 203 mmol) in portions for 10 mins at 0 °C then stirred at rt (25 °C) for 4 hours. The mixture was concentrated in vacuo to remove the solvent. DCM (40 mL) was added and filtrated. The filtrate was concentrated in vacuo to get the crude product which was purified by

-248 silica gel chromatography (MeOH/DCM=0~10%) to obtain UUU-3 (2.65 g,72%) as a yellow solid. LCMS [M+1] 255; Ή NMR (400 MHz, DMSO-d₆) δ ppm = 11.33 (br s, 1H), 7.42 - 7.32 (m, 4H), 7.30 - 7.24 (m, 1H), 5.78 (s, 1H), 3.63 (s, 2H), 3.11 (s, 2H), 2.59 (br d, J=4.5 Hz, 2H), 2.56 (br d, J=3.5 Hz, 2H), 2.10 (s, 3H)

Step 3 - 2-benzyl-8-bromo-6-methyl-1,2,3,4-tetrahydro-2,7-naphthyridine (UUU-4)

To a solution of UUU-3 (2.15 g, 8.45 mmol) in CH₃CN (20 mL) and Ph₂O (40mL) at rt (25 °C). Then, POBr₃ (12.1 g, 42.3 mmol) was added portion-wise and heated at refluxed (85 °C) under N₂ for 4 hours in which an orange solid began to form after 20 min. The precipitate was collected by filtration, dissolved in water (20 mL), and neutralized with NaHCO₃ solution to pH 8. Then, the mixture was extracted with TBME (50mL x 2). The organic layer was washed with brine (25 mLx2), dried over Na₂SO₄, filtrated and concentrated in vacuo to get crude product which was purified by chromatography (silica gel EtOAc/Petroleum ether=0~40%) to obtain UUU-4 (1.55 g, 58%) as an orange solid. LCMS [M+1] 317; ¹H NMR (400 MHz, CDCI₃) δ ppm = 7.40 - 7.32 (m, 4H), 7.32 - 7.28 (m, 1H), 6.87 (s, 1H), 3.75 (s, 2H), 3.59 (s, 2H), 2.84 - 2.78 (m, 2H), 2.69 - 2.64 (m, 2H), 2.47 (s, 3H)

Step 4 - Synthesis of tert-butyl 8-bromo-6-methyl-3,4-dihydro-2,7-naphthyridine-2(1H)carboxylate (UUU-5) and tert-butyl 8-chloro-6-methyl-3,4-dihydro-2,7-naphthyridine-2(1H)carboxylate (UUU-6)

To a solution of compound UUU-4 (1.30 g, 4.1 mmol) in DCM (15 mL) was added drop-wise 1chloroethyl chloroformate (0.62 mL, 5.74 mmol) at rt (0 °C) for 1 min. Then, the mixture was warmed up to rt (20 °C) stirred for 10 mins and heated at refluxed (40 °C) for 2 hours. The mixture was concentrated in vacuo to remove the solvent. Then the solid was dissolved in MeOH (15 mL) and heated at refluxed (63 °C) for 1.5 hours. Then (Boc)₂O (1.07 g 4.92 mmol) and Et₃N (1.71 mL,12.3 mmol) were added. The mixture was heated at (63 °C) for 16 hours. The mixture was concentrated in vacuo to get crude product which was purified by chromatography (silica gel MeOH/DCM=0~10% ) to get product a mixture of compound UUU-5 and UUU-6 in a -1:1 ratio (872 mg) as a white solid and used directly in the next step. LCMS [M+1] 327 and 283.

Steps 5-7 were performed in a similar manner as steps 2-4 in Scheme GGG using FFF-1.

-249-

Example 181

396 (1S,2S,3S,5R)-3-((3-methyl-5,6,7,8tetrahydro-2,7-naphthyridin-1 yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)cyclopentane-1,2diol ¹H NMR (400 MHz, DMSO-de) δ ppm 8.64 (s, 1H), 7.61 (d, J=3.8 Hz, 1H), 6.72 (d, J=3.8 Hz, 1H), 6.63 (s, 1H), 5.26 - 5.21 (m, 1H), 5.12 (q, J=8.7 Hz, 1H), 4.56 (dd, J=4.9, 8.4 Hz, 1H), 4.05 (br d, J=2.3 Hz, 1H), 3.94 - 3.82 (m, 2H), 3.05 (br t, J=5.9 Hz, 2H), 2.86 (ddd, J=7.4, 9.6, 14.4 Hz, 1H), 2.722.66 (m, 2H), 2.64 (s, 3H), 2.31 (s, 3H), 1.92 - 1.78 (m, 1H)

Synthesis of tert-butyl-5-fluoro-8-hydroxy-4-methyl-3,4-dihydroisoquinoline-2(1 H)carboxylate (TP-31)

Scheme VW

VW-1

BnBr, K₂CO₃

AcMe, 65°C^

HONH2HCI, KOH MeOH, reflux

VW-2 (Boc)₂O, DMAP DIPEA, DMF

BH₃*Me₂S THF

PivCI, TEA THF, rt

[CptehCljfe (2.5 mol%)

CsOPIv, TFE, 45°C 4 bar propylene

Then MeOH THF, microwave

VW-7

Pd/C H₂, MeOH

TP-31

Step 1 : Synthesis of methyl 2-(benzyloxy)-5-fluorobenzoate (VW-2)

-250To a round bottom flask, equipped with a magnetic stirbar, was added methyl 5-fluoro-2hydroxybenzoate VVV-1 (3.68 g, 21.6 mmol), potassium carbonate (10.5 g, 75.7 mmol), and acetone (108 mL). To the solution was added benzyl bromide (2.70 mL, 22.7 mmol) and the flask was fitted with a Findenser™. The flask was placed in a heating mantle and heated at 65°C for 13 hours. The flask was removed from the heating block and allowed to cool to rt. The solids were filtered over a bed of celite and washed with several portions of acetone. The filtrate was concentrated under vacuum and transferred to a separatory funnel with EtOAc (-100 mL). The solution was washed with 2 portions of half sat. brine, dried (MgSO₄), filtered, and concentrated under vacuum to afford the title compound VVV-2 (5.64 g, >95% yield) as a white crystalline solid. This material was used in the next step without further purification. ¹H NMR (400MHz, CHLOROFORM-d) δ ppm 7.54 (dd, J=3.3, 8.7 Hz, 1H), 7.51 - 7.45 (m, 2H), 7.44 7.36 (m, 2H), 7.36 - 7.29 (m, 1H), 7.14 (ddd, J=3.2, 7.5, 9.1 Hz, 1H), 6.97 (dd, J=4.3, 9.0 Hz, 1H), 5.16 (s, 2H), 3.92 (s, 3H). ¹⁹F NMR (376MHz, CHLOROFORM-d) δ ppm -122.59 (s, 1F).

Step 2: Synthesis of 2-(benzyloxy)-5-fluoro-N-hydroxybenzamide (VVV-3)

To a round bottom flask, equipped with a magnetic stirbar and containing VVV-2 (5.64 g, 21.7 mmol), was added hydroxyi amine hydrochloride (4.52 g, 65.0 mmol), potassium hydroxide (7.29 g, 130 mmol), and methanol (108 mL). The flask was fitted with a Findenser™ and placed in a heating mantle. The reaction was heated at 75°C for 3.5 hours. The reaction was removed from the heating mantle and allowed to gradually cool to rt. The solution was neutralized with acetic acid and concentrated under vacuum. The residue was transferred to a separatory funnel with EtOAc and diluted with water. The phases were separated and the aqueous phase was extracted with 3 100 mL portions of EtOAc. The organic extracts were dried (MgSO₄), filtered, and concentrated under vacuum to afford the title compound VVV-3 (5.62 g, >95% yield) as a white solid. The material was used in the next step without further purification. LCMS [M+H] = 262 observed. Ή NMR (400MHz, DMSO-d6) δ ppm 10.71 (s, 1H), 9.18 (d, J=1.5 Hz, 1H), 7.47 (d, J=7.3 Hz, 2H), 7.39 (t, J=7.4 Hz, 2H), 7.35 - 7.27 (m, 2H), 7.25 (dd, J=3.2, 8.3 Hz, 1H), 7.19 -7.13 (m, 1H), 5.20 (s, 2H). ¹⁹F NMR (376MHz, DMSO-d6) δ ppm -123.18 (s, 1F).

Step 3: Synthesis of 2-(benzyloxy)-5-fluoro-A/-(pivaloyloxy)benzamide (VVV-4)

To a round bottom flask, equipped with a magnetic stir bar and containing VVV-3 (3.0 g, 11.5 mmol), was added THF (35 mL) and triethyl amine (1.60 mL, 11.5 mmol) followed by the dropwise addition of pivaloyl chloride (1.55 mL, 12.6 mmol). The reaction was stirred at rt for 30 minutes. The reaction was transferred to a separatory funnel with EtOAc. The solution was washed with 2 portions 1 M HCl aq., 1 portion half saturate NaHCO3, and 2 portions brine. The

-251 organic solution was then dried (MgSO₄), filtered, and concentrated under vacuum. The crude residue was purified via flash column chromatography (40 g SiO₂, Isco, 100% Hept. to 100% EtOAc, 20 mL fractions) to afford the title compound (3.83 g, >95%) as a colorless oil solvated with EtOAc. The oil was taken up in DCM and diluted with Heptane followed by concentration under vacuum. The material obtained was further dried under high vacuum overnight to afford the title compound VVV-4 (3.59 g, 90%) as a white solid. LCMS [M+H] = 346 observed. Ή NMR (400MHz, CHLOROFORM-d) δ ppm 10.95 (s, 1H), 7.89 (dd, J=3.2, 9.1 Hz, 1H), 7.53 - 7.33 (m, 5H), 7.16 (ddd, J=3.3, 7.2, 9.0 Hz, 1H), 7.00 (dd, J=4.1, 9.1 Hz, 1H), 5.27 (s, 2H), 1.35 (s, 9H).

Step 4: Synthesis of 8-(benzyloxy)-5-fluoro-4-methyl-3,4-dihydroisoquinolin-1(2H)-one (VVV-5)

To a scintillation vial, equipped with a magnetic stirbar, was added VVV-4 (500 mg, 1.45 mmol), césium pivalate (678 mg, 2.90 mmol), and [Cp^,RhCI₂]₂ (25.4 mg, 0.036 mmol). The contents of the vial were transferred to a high pressure reactor and TFE (7.0 mL) was added. The reactor was purged with nitrogen 3 times followed by 3 cycles of purging with propylene gas. The reaction was heated to 45°C under 4 bar pressure of propylene gas for 20 hours. The solution was transferred to a round bottom flask and concentrated under vacuum. The crude residue was purified via flash column chromatography (24 g SiO₂, Isco, 100% Hept. to 100% EtOAc, 9 mL fractions) to afford the title compound VVV-5 (270 mg, 65%, 93:7 r.r.) as a light pink solid. HSCQC and HOESY analyses are consistent with the assigned regioisomer. LCMS [M+H] = 286 observed. Ή NMR (400MHz, CHLOROFORM-d) δ ppm 7.55 (d, J=7.5 Hz, 2H), 7.43 - 7.34 (m, 2H), 7.30 (d, J=7.3 Hz, 1H), 7.10 (t, J=8.8 Hz, 1H), 6.87 (dd, J=4.3, 9.0 Hz, 1H), 5.98 (d, J=3.7 Hz, 1H), 5.29 - 5.21 (m, 1H), 5.18 - 5.11 (m, 1H), 3.70 (ddd, J=0.7, 4.0, 12.6 Hz, 1H), 3.38 - 3.28 (m, 1H), 3.23 (ddd, J=1.5, 6.0, 12.6 Hz, 1H), 1.35 (d, J=7.0 Hz, 3H). ¹⁹F NMR (376MHz, CHLOROFORM-d) δ ppm -129.24 (s, 1F).

Step 5: Synthesis of tert-butyl-8-(benzyloxy)-5-fluoro-4-methyl-1-oxo-3,4dihydroisoquinoline-2(1 H)-carboxylate (WV-6)

To a round bottom flask, equipped with a magnetic stirbar, was added VVV-5 (100 mg, 0.350 mmol) as a solution in DMF (4.0 mL). The solution was cooled to 10°C followed by the addition of (Boc)₂O (84.1 mg, 0.386 mmol), DIPEA (92 pL, 0.526 mmol) and DMAP (2.1 mg, 0.017 mmol). The reaction was allowed to stir at rt for 16 hours providing low conversion to desired product. The reaction was then heated at 50°C for 24 hours and then increased to 75°C for an additional 24 hours in order to achieve complété consumption of starting material. The reaction was diluted with water and transferred to a separatory funnel with EtOAc. The phases were

-252separated and the organic phase was washed with 1 portion brine, dried (NS2SO4), filtered, and concentrated under vacuum. The crude residue was purified via flash column chromatography (SiO₂, 1% EtOAc/Pet. Ether to 40% EtOAc/Pet. Ether) to afford the title compound VVV-6 (100 mg, 74%) as a colorless gum. LCMS [M+H-Boc] = 286 observed.

Step 6: Synthesis of tert-butyl-8-(benzyloxy)-5-fluoro-4-methyl-3,4-dihydroisoquinoline2(1H)-carboxylate (VVV-7)

To a round bottom flask, equipped with a magnetic stir bar, was added VVV-6 (100 mg, 0.259 mmol) as a solution in THF. The solution was cooled to 0°C followed by the dropwise addition of BH3 THF. Upon completion of the addition, the reaction was removed from the ice bath and heated to 60°C under nitrogen for 6 hours. At this stage the reaction was cooled to -10°C and quenched by the careful dropwise addition of MeOH. The reaction was allowed to stir at -10°C for 16 hours and then concentrated under vacuum. The crude residue was purified via préparative thin layer chomatography (SiO₂, 20% EtOAc/Pet. Ether) to afford the title compound VVV-7 (35.0 mg, 36%) as a colorless gum. LCMS [M+H-lsobutylene] = 316 observed.

Step 7: Synthesis of tert-butyl-5-fluoro-8-hydroxy-4-methyl-3,4-dihydroisoquinoline2(1H)-carboxylate (TP-31)

To a round bottom flask, equipped with a magnetic stirbar, was added VW-7 (70 mg, 0.190 mmol) as a solution in MeOH (4.5 mL). To the solution was added Pd/C (10.0 mg, 0.094 mmol) and the headspce of the flask was purged with hydrogen 5 times. The reaction was allowed to stir at rt under 1 atm hydrogen gas for 2.5 hours. The reaction was filtered and the solids were washed with DCM. The filtrate was concentrated under vacuum and the crude residue was purified via préparative thin layer chromatography (SiO₂, 20% EtOAc/Pet. Ether) to afford the title compound TP-31 (45 mg, 85%) as a colorless gum. LCMS [M+H-lsobutylene] = 226 observed. Ή NMR (400MHz, CHLOROFORM-d) δ ppm 6.76 (br t, J=8.8 Hz, 1H), 6.55 (dd, J=4.4, 8.7 Hz, 1H), 5.14 - 4.78 (m, 2H), 4.22 - 3.95 (m, 2H), 3.23 - 2.94 (m, 2H), 1.54 - 1.46 (s, 9H), 1.23 (d, J=7.3 Hz, 3H).

Synthesis of tert-butyl (8-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate (TP-32)

Scheme WWW

-253O NaCNBH₃ Ο ΝΗ_{2 0Η} ΝΗ₂ OH HN^°^C

NH₄OAc BBr₃ Boc₂O ch₃oh dcm ^EtsN’ ^dcm oC, 45 min

WWW-1 WWW-2 WWW-3 TP-32

Step 1 - Synthesis of 8-methoxy-1,2,3,4-tetrahydronaphthalen-1-amine (WWW-2)

To a stirred yellow suspension of 8-methoxy-3,4-dihydronaphthalen-1 (2H)-one WWW-1 (600 mg, 3.4 mmol) in MeOH (30 mL) was added CH3COONH4 (5.25 g, 68 mmol) at 15 °C. The mixture was stirred at 15 °C for 15 min and then, NaBH₃CN (1.5 g, 24 mmol) was added at 15 °C. The mixture was irradiated in a microwave reactor at 60 °C for 45 min. The mixture was quenched by sat.NaHCO₃ (15 mL) and H₂O (15 mL) and stirred at 15 °C for 5 min. The mixture was concentrated to remove MeOH. The residue was extracted with DCM (20 mL X 2). The combined organic layers were washed with brine (10 mL), dried over Na₂SO4, filtered and concentrated to give crude WWW-2 (580 mg, 96%) as a slight pink gum and used as is in the next step.

Step 2 - Synthesis of 8-amino-5,6,7,8-tetrahydronaphthalen-1-ol (WWW-3)

Compound WWW-2 (550 mg, 3.10 mmol) was dissolved in HCI/dioxane (5.00 mL), the solution was stirred at 15 °C for 10 min. Then the solution was evaporated to give a residue. The residue was dissolved in DCM and cooled to 0 °C on an ice bath. Then BBr₃ (7.77 mg, 31.0 mmol) was added to the reaction solution dropwise. The reaction solution was stirred at 20 °C for 5 hrs. The reaction solution was quenched with MeOH (8.00 mL), then the pH of the solution was adjusted to pH=7 by the addition of saturated aq NaHCO₃. The final solution of WWW-3 was used for the next step directly (100 mL).

Step 3 - Synthesis of tert-butyl (8-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate (TP-32)

To a solution of (Boc)₂O (730 mg, 3.34 mmol) in dioxane (5.00 mL) was added the solution of compound WWW-3 (solution in aq. sat. NaHCO₃, 15 mL ~3.3 mmol) at 0 °C in one portion. The reaction solution was stirred at 20 °C for 50 hours. The reaction was extracted with DCM (2x) and the organics combined and washed with sat. citric acid (2x15 mL), aq sat. Na₂CO₃ (2x15 mL), and brine (2x15 mL). The organics were dried and evaporated to give a residue which was purified by prep-TLC (Petroleum Ether/EtOAc=4/1 ) to give TP-32 (410 mg, 50%) as a white solid. LCMS [M-tBu+1] 207; Ή NMR (400 MHz, DMSO-d₆) δ ppm 9.20 (s, 1H), 6.96 (t, J=7.8 Hz, 1H), 6.78 (br d, J=7.5 Hz, 1H), 6.57 (d, J=7.7 Hz, 1H), 6.51 (d, J=7.4 Hz, 1H), 4.80 - 4.71

-254(m, 1H), 2.72 - 2.63 (m, 1H), 2.61 - 2.53 (m, 1H), 1.89 - 1.74 (m, 2H), 1.67 - 1.46 (m, 2H), 1.39 (s, 9H)

Synthesis of tert-butyl (5-hydroxychroman-3-yl)carbamate (TP-33)

Scheme XXX

PPh₃, DIAD, DPPA

DIEA, THF then, PPh₃, H₂O

Βοο₂0

MeOH/EA

Pd-C, H₂

MeOH/EtOA c

Step 1 - Synthesis of 5-(benzyloxy)chroman-3-amine (XXX-2)

Compound XXX-1 (700 mg, 2.73 mmol, prepared using exact procedures in literature J. Org. Chem, 2013, 78, 7859-7884) was introduced to similar Mitsunobu and Staudinger procedures in the same reference to give the product XXX-2 (520 mg, 75 %) as a colorless gum, used in the next step directly. LCMS [M+1] 266; ¹H NMR (400 MHz, CDCI3) δ ppm 7.48 - 7.36 (m, 4H), 7.36 - 7.30 (m, 1H), 7.07 (t, J=8.3 Hz, 1H), 6.52 (dd, J=2.5, 8.3 Hz, 2H), 5.07 (s, 2H), 4.18 - 4.07 (m, 1H), 3.80 (ddd, J=1.0, 7.3, 10.5 Hz, 1H), 3.43 - 3.29 (m, 1H), 3.07 (dd, J=5.0, 16.6 Hz, 1H), 2.50 (dd, J=7.3, 16.8 Hz, 1H)

Step 2 - Synthesis of tert-butyl (5-(benzyloxy)chroman-3-yl)carbamate (XXX-3)

To a solution of XXX-2 (520 mg, 2.04 mmol) in dry MeOH (20 mL) was added Boc₂O (889 mg, 4.07 mmol) at rt and stirred for 30 min (20 mL of EtOAc added for solubility). The mixture was concentrated in vacuo to afford crude material which was purified by silica gel chromatography eluted with EtOAc in petroleum ether from 0 to 50 % then EtOAc in DCM from 0 to 50 % to afford XXX-3 (620 mg, 76%) as white solid. LCMS [M-tBu+1] 300; ¹H NMR (400 MHz, CDCh) δ ppm 7.45 - 7.36 (m, 4H), 7.34 (br d, J=6.8 Hz, 1H), 7.12 - 7.05 (m, 1H), 6.53 (d, J=8.3 Hz, 2H), 5.06 (s, 2H), 4.91 - 4.79 (m, 1H), 4.26 - 4.15 (m, 1H), 4.08 (br s, 2H), 3.01 - 2.92 (m, 1H), 2.81 2.69 (m, 1H), 1.44 (s, 9H)

Step 3 - Synthesis of tert-butyl (5-hydroxychroman-3-yl)carbamate (TP-33)

A mixture of XXX-3 (620 mg, 2.43 mmol) and Pd/C (300 mg) in MeOH/EtOAc (10 mL/10 mL) was degassed with H₂ four times. The mixture was stirred at rt under an H₂ balloon for 16 hrs. The mixture was filtered and concentrated. (Excess Boc₂O from the previous step also Bocprotected the phénol, therefore MeOH (20 mL) and K2CO3 (2 g) were added and stirred for 2 h, then filtered). The mixture was filtered and concentrated. The crude material was diluted with

-255EtOAc and was washed with brine (15 mL), dried over Na₂SO₄ and concentrated in vacuo then lyophilized to afford TP-33 (420 mg, 91%) as a white solid. LCMS [M-tBu+1] 210; Ή NMR (400 MHz, CDCh) δ ppm 6.99 (t, J=8.2 Hz, 1H), 6.48 (d, J=8.3 Hz, 1H), 6.40 (d, J=8.0 Hz, 1H), 5.19 (br s, 1H), 4.96 - 4.89 (m, 1H), 4.22 (br s, 1H), 4.15 - 4.03 (m, 2H), 2.91 (dd, J=5.5, 16.8 Hz, 1H), 2.71 (brd, J=17.3 Hz, 1H), 1.45 (s, 9H)

Example 182 and Example 183 (Scheme YYY) - (1S,2S,3S,5R)-3-((-5-fluoro-4-methyl-

1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7- yl)cyclopentane-1,2-diol hydrochloride (YYY-3-isomer 1 and YYY-3-isomer 2)

Scheme YYY

SFC Séparation

TP-31

Pd₂(dba)₃’CHCI₃ (2.5 moi%) DPPP (6 mol%) Cs₂CO₃, DCE, rt

Boc

OsO₄ (4 mol%)

NMO, DCM, rt_w

YYY-2 isomer 1

H-HCI

YYY-3 isomer 1

YYY-2 isomer 2 YYY-3 isomer 2

Step 1: Synthesis of fert-butyl-5-fluoro-4-methyl-8-(((1S,4R)-4-(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)cyclopent-2-en-1-yl)oxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate (YYY-1)

To a microwave vial, equipped with a magnetic stirbar, was added TP-31 (45 mg, 0.160 mmol), BB-2 (50.4 mg, 0.160 mmol), Pd₂(dba)₃CHCI₃ (4.14 mg, 0.004 mmol), DPPP (3.96 mg, 0.010 mmol), and césium carbonate (57.3 mg, 0.176 mmol). The vial was purged with nitrogen under dynamic vacuum and freshly degassed DCE (1.0 mL) was added. The solution was stirred at rt under nitrogen for 1 hour. The solution was concentrated under vacuum and the crude residue was purified via préparative thin layer chromatography (SiO₂, 33% EtOAc/Pet. Ether) to afford the title compound YYY-1 (60 mg, 86%) as a gum. LCMS [M+H] = 579 observed. 1H NMR (400MHz, CHLOROFORM-d) δ ppm 8.76 (s, 1H), 7.35 - 7.28 (m, 1H), 6.84 (brt, J=8.7 Hz, 1H),

-256 6.73 - 6.51 (m, 2H), 6.37 (br s, 1H), 6.19 - 5.99 (m, 2H), 5.28 (br s, 1H), 4.24 - 3.95 (m, 2H), 3.22 - 3.05 (m, 3H), 2.73 (d, J=2.5 Hz, 3H), 1.96 (brd, J=14.6 Hz, 1H), 1.69 - 1.63 (m, 1H), 1.50 (s, 9H), 1.23 (t, J=7.0 Hz, 3H)

Step 2: Synthesis of fert-butyl-8-(((1S,2S,3S,4R)-2,3-dihydroxy-4-(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)cyclopentyl)oxy)-5-fluoro-4-methyl-3,4-dihydroisoquinoline-2(1H)carboxylate (YYY-2)

To a reaction vial, equipped with a magnetic stirbar, was added YYY-1 (60.0 mg, 0.130 mmol) as a solution in DCM (6.0 mL). To the solution was added water (0.2 mL), NMO (44.1 mg, 0.376 mmol) and OsO₄ (112 mg, 0.0176 mmol). The reaction was allowed to stir at rt for 5 hours. The reaction was quenched with sat. Na₂SO₃ (5 mL) and transferred to a separatory funnel with DCM. The phases were separated and the aqueous phase was extracted with 1 portion DCM. The combined organic extracts were dried (Na₂SO₄), filtered, and concentrated under vacuum. The crude residue was purified via préparative thin layer chromatography to afford the title compound YYY-2 (35 mg, 54%) as a colorless gum. LCMS [M+H] = 513 observed.

Step 3: Synthesis of tert-butyl-8-(((1S,2S,3S,4R)-2,3-dihydroxy-4-(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)cyclopentyl)oxy)-5-fluoro-4-methyl-3,4-dihydroisoquinoline-2(1H)carboxylate (YYY-2-isomer 1 & YYY-2-isomer 2)

YYY-2 (30 mg, 0.058 mmol) was further purified via préparative super-critical fluid chromatography (OD 250mmx30mmx5pm, 0.1% NH₄OH/IPA to 30% NH₄OH/IPA, 60 mL/min) to afford the separated diastereomers YYY-2-isomer 1 (15 mg, 50%) and YYY-2-isomer 2 (15 mg, 50%) as white solids. LCMS [M+H] = 513 observed.

Step 4 employing YYY-2-isomer 1: Synthesis of (1S,2S,3S,5R)-3-((-5-fluoro-4-methyl-

1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7yl)cyclopentane-1,2-diol hydrochloride (YYY-3-isomer 1)

To a reaction vial, equipped with a magnetic stirbar, was added YYY-2-isomer 1 (15 mg, 0.029 mmol) as a solution in EtOAc (1.0 mL). The solution was cooled to 0°C followed by the addition of HCl (4M EtOAc, 59 pL). The reaction was removed from the ice bath and stirred at rt for 16 hours. The solution was concentrated under vacuum followed by free-drying to afford the title compound YYY-3-isomer 1 (8.26 mg, 63%) as a white solid. LCMS [M+H] = 413 observed. Ή NMR (400MHz, METHANOL-d4) δ ppm 9.05 (d, J=3.3 Hz, 1H), 8.08 (d, J=2.4 Hz, 1H), 7.24 (d, J=3.7 Hz, 1H), 7.15 - 6.99 (m, 2H), 5.41 (q, J=9.3 Hz, 1H), 4.76 (brd, J=4.8 Hz, 2H), 4.52 - 4.41 (m, 1H), 4.36 - 4.27 (m, 1H), 4.23 (d, J=4.8 Hz, 1H), 3.57 - 3.40 (m, 3H), 3.12 - 2.99 (m, 4H), 2.27 (dt, J=5.1,9.5 Hz, 1H), 1.47 (d, >6.7 Hz, 3H).

-257Step 4 employing YYY-2-isomer 2: Synthesis of (1S,2S,3S,5R)-3-((-5-fluoro-4-methyl-

1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7yl)cyclopentane-1,2-diol hydrochloride (YYY-3-isomer 2))

To a reaction vial, equipped with a magnetic stirbar, was added YYY-2-isomer 2 (15 mg, 0.029 mmol) as a solution in EtOAc (1.0 mL). The solution was cooled to 0°C followed by the addition of HCl (4M EtOAc, 59 pL). The reaction was removed from the ice bath and stirred at rt for 16 hours. The solution was concentrated under vacuum followed by free-drying to afford the title compound YYY-2-isomer 2 (8.48 mg, 70%) as a white solid. LCMS [M+H] = 413 observed. ¹H 10 NMR (400MHz, METHANOL-d4) δ ppm 9.04 (d, J=3.0 Hz, 1H), 8.06 (d, J=3.2 Hz, 1H), 7.24 (d,

J=3.7 Hz, 1H), 7.16 - 7.01 (m, 2H), 5.42 (q, J=9.4 Hz, 1H), 4.77 - 4.70 (m, 2H), 4.48 - 4.39 (m, 1H), 4.36 - 4.27 (m, 1H), 4.21 (d, J=4.7 Hz, 1H), 3.55 - 3.40 (m, 3H), 3.17 - 2.96 (m, 4H), 2.33 2.18 (m, 1H), 1.46 (d, J=6.7 Hz, 3H).

Examples 184 -189 were made in a similar fashion as Examples 182 & 183 (Scheme YYY) starting with the appropriate racemic tetrahydroisoquinoline in step 1 and separating the diastereomers priorto the final deprotection.

Examples 184 & 185

(1S,2S,3S,5R)-3-((3-methyl-1,2,3,4tetrahydroisoquinolin-8-yl)oxy)-5-(4methyl-7H-pyrrolo[2,3-d]pyrimidin-7yl)cyclopentane-1,2-diol

Example 184 (Isomer 1) - Ή NMR (400MHz, METHANOL-d4) δ ppm 9.07 (s, 1H), 8.08 (d, J=3.8 Hz, 1H), 7.31 (t, J=8.0 Hz, 1H), 7.25 (d, J=3.8 Hz, 1H), 7.01 (d, J=8.3 Hz, 1H), 6.90 (d, J=7.8 Hz, 1H), 5.42 (q, J=9.2 Hz, 1H), 4.83 - 4.73 (m, 2H), 4.54 (d, J=16.3 Hz, 1H), 4.34 (d, J=16.6 Hz, 1H), 4.24 (d, J=4.5 Hz, 1H), 3.73 - 3.62 (m, 1H), 3.23 - 3.04 (m, 2H), 3.03 - 2.91 (m, 4H), 2.32 2.23 (m, 1H), 1.54 (d, J=6.5 Hz, 3H).

Example 185 (Isomer 2) - ¹H NMR (400MHz, METHANOL-d4) 9.08 (s, 1H), 8.06 (d, J=3.8 Hz, 1H), 7.31 (t,

-258-

			J=8.0 Hz, 1H), 7.24 (d, J=3.8 Hz, 1H), 7.01 (d, J=8.3 Hz, 1H), 6.90 (d, J=7.5 Hz, 1H), 5.41 (q, J=9.2 Hz, 1H), 4.84 - 4.73 (m, 2H), 4.59 - 4.50 (m, 1H), 4.34 (d, J=16.8 Hz, 1H), 4.22 (d, J=5.0 Hz, 1H), 3.70 - 3.60 (m, 1H), 3.21 - 3.05 (m, 2H), 3.04 - 2.92 (m, 4H), 2.34 - 2.25 (m, 1H), 1.55 (d, J=6.3 Hz, 3H)
Examples 186 & 187 TP-32 ,Boc	<VjN J /'OH nh2 cr/ °H OU	378 LCMS [M-16+1]	(1S,2S,3S,5R)-3-((8-amino-5,6,7,8tetrahydronaphthalen-1-yl)oxy)-5(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)cyclopentane-1,2diol Example 186 (Isomer 1) - 1H NMR (400 MHz, MeOD-d4) δ ppm 8.71 (s, 1H), 7.74 (d, J=3.8 Hz, 1H), 7.34 (t, J=8.0 Hz, 1H), 7.05 (d, J=8.3 Hz, 1H), 6.89 (d, J=7.8 Hz, 1H), 6.86 (d, J=3.5 Hz, 1H), 5.18 (q, J=9.4 Hz, 1H), 4.84 - 4.79 (m, 3H), 4.22 (d, J=5.3 Hz, 1H), 3.06 (td, J=8.4, 14.3 Hz, 1H), 2.98 - 2.88 (m, 1H), 2.88 2.81 (m, 1H), 2.80 (s, 3H), 2.50 (ddd, J=4.3, 10.0, 14.1 Hz, 1H), 2.25 - 2.10 (m, 2H), 1.98 - 1.89 (m, 2H) Example 187 (Isomer 2) - 1H NMR (400 MHz, MeOD-d4) δ ppm 8.63 (s, 1H), 7.53 (d, J=3.5 Hz, 1H), 7.15 (t, J=8.0 Hz, 1H), 6.89 (d, J=8.3 Hz, 1H), 6.78 - 6.72 (m, 2H), 5.18 (q, J=9.1 Hz, 1H), 4.82 (dd, J=5.0, 8.5 Hz, 1H), 4.78 - 4.72 (m, 1H), 4.40 4.29 (m, 2H), 3.04 - 2.93 (m, 1H), 2.89 - 2.74 (m, 2H), 2.73 (s, 3H), 2.36 - 2.23 (m, 1H), 2.02 - 1.86 (m,

-259-

			3H), 1.80 (d, >4.5 Hz, 1H)
Example 188 & 189 TP-33 I i OH Boc	\=N rO IL Z“N N i /OH O^i oh	397 LCMS [M+1]	(1S,2S,3S,5R)-3-((3aminochroman-5-yl)oxy)-5-(4methyl-7H-pyrrolo[2,3-d]pyrimidin-7yl)cyclopentane-1,2-diol Example 188 (Isomer 1) - 1H NMR (400 MHz, D2O) δ ppm 8.82 (s, 1H), 7.81 (d, >3.8 Hz, 1H), 7.15 (t, J=8.3 Hz, 1H), 7.08 (d, >4.0 Hz, 1H), 6.65 (d, >7.8 Hz, 1H), 6.56 (d, >8.3 Hz, 1H), 5.33 (q, >9.1 Hz, 1H), 4.77 - 4.73 (m, 1H), 4.62 (dd, >5.1, 8.7 Hz, 1H), 4.32 - 4.22 (m, 2H), 4.14 (d, J=11.3 Hz, 1H), 3.97 (br d, >1.8 Hz, 1H), 3.13 (dd, >6.3, 18.1 Hz, 1H), 3.02 (ddd, >7.0, 9.8, 15.1 Hz, 1H), 2.87 (m, 4H), 2.21 -2.12 (m, 1H) Example 189 (Isomer 2) - 1H NMR (400 MHz, D2O) δ ppm 8.84 (s, 1H), 7.80 (d, >4.0 Hz, 1H), 7.17 (t, >8.3 Hz, 1H), 7.10 (d, >3.8 Hz, 1H), 6.66 (d, >8.0 Hz, 1H), 6.58 (d, >8.5 Hz, 1H), 5.41 - 5.31 (m, 1H), 4.77 (br s, 2H), 4.36 - 4.28 (m, 2H), 4.17 (br d, >12.0 Hz, 1H), 4.01 (br d, >1.5 Hz, 1H), 3.20 - 3.10 (m, 1H), 3.09 - 2.99 (m, 1H), 2.94 (br s, 1H), 2.90 (s, 3H), 2.23 - 2.12 (m, 1H)

Example 190 (Scheme ZZZ) - (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-

1,2-diol (ZZZ-16)

Scheme ZZZ

-260-

Step 1 - Synthesis of methyl 4-bromo-5-fluoro-2-methoxybenzoate (ZZZ-2)

A solution of 4-bromo-2,5-difluorobenzoic acid ZZZ-1 (95 g, 400.85 mmol) in 4M HCI/MeOH (1500 mL) was heated at 65 °C for 3 hours. The mixture was concentrated in vacuum to gpt 777-9 (100 g, >99%) as a light yellow solid. ¹H NMR (400 MHz, DMSO-d_s) δ ppm 7.93 (dd, J=5.5, 9.8 Hz, 1H), 7.81 (dd, J=6.0, 8.5 Hz, 1H), 3.92 - 3.85 (m, 3H)

Step 2 - Synthesis of 4-bromo-5-fluoro-2-methoxybenzoic acid (ZZZ-3)

To a solution of 777-2 (80 g, 7.97 mmol) in dry DMF (1200 mL) was added a solution MeONa (~17.2 g, 319 mmol, 8 g Na dissolved in 80 mL MeOH obtained) at 0 °C. The mixture was stirred at 0 °C for 10 mins, then warmed up to rt (25 °C) and stirred for 1h. To the mixture was added TBME (1 L) then, poured into ice water (800 mL). The mixture was extracted with TBME (500 mL x 4). The organic layer was washed with brine (300 mL x 2) dried over Na₂SO₄, filtered and concentrated to get product the methyl ether, methyl ester (12.1 g) as light yellow gum.

The aqueous layer contained the carboxylic acid and was neutralized with HCl (1M) to pH=5 then, extracted with EtOAc (800 mL x 3). The organic layer was washed with brine (400mL x 2), dried over Na₂SO₄, filtered and concentrated to obtain ZZZ-3 (100g, >99% crude) as a yellow oil and used directly in the next step. NMR contained DMF. Ή NMR (400 MHz, DMSO-de) δ ppm 7.59 (d, J=8.8 Hz, 1H), 7.46 (d, J=5.8 Hz, 1H), 3.83 (s, 3H)

-261 Step 3 - Synthesis of 4-bromo-5-fluoro-2-hydroxybenzoic acid (ZZZ-4)

To a solution of ZZZ-3 (~60g crude, 240.93 mmol) in dry DCM (600 mL) was added BBr₃ (68.3 mL dissolved in DCM 600 mL, 723 mmol) at rt (20°C). The mixture was stirred at rt (20 °C) for 2 h. The mixture was poured water (500 mL) and extracted with DCM (800 mL x 3). The organic layer was washed with brine (300 mL x 2) dried over Na₂SO₄ filtered and concentrated to obtain 777-4 (35 g, 62%) as a yellow gum. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.62 (d, J=9.0 Hz, 1H), 7.33 (d, J=5.8 Hz, 1H)

Step 4 - Synthesis of benzyl 2-(benzyloxy)-4-bromo-5-fluorobenzoate (ZZZ-5)

To a solution of ZZZ-4 (35 g, 148.93 mmol) in dry DMF (300 mL) was added K₂CO₃ (41.2 g, 298 mmol) and BnBr (38.2 g, 223 mmol). The mixture was stirred at 25 °C for 16 hrs. The mixture was diluted with water (200 mL) and extracted with EtOAc (300 mL x 3). The organic layers were collected, dried and concentrated to give a crude light yellow oil which was purified by combi-flash (silica gel EtOAc/Petroleum ether = 0-8%) to obtain ZZZ-5 (22 g, 36%) as a light yellow solid. Ή NMR (400 MHz, CDCI₃) δ ppm 7.67 (d, J=8.6 Hz, 1H), 7.48 - 7.32 (m, 10H), 7.25 (d, J=5.5 Hz, 1H), 5.36 (s, 2H), 5.14 (s, 2H)

Step 5 - Synthesis of 2-(benzyloxy)-4-bromo-5-fluorobenzoic acid (ZZZ-6)

To a solution of ZZZ-5 (22 g, 52.98 mmol) in MeOH (200 mL) was added a solution of LiOH.H₂O (6.67 g, 159 mmol) in H₂O (200 mL).The reaction mixture was stirred at 20°C for 4 hours. The reaction mixture was extracted with EtOAc (150 mL x 2). The water layer was neutralized with 1 M aq. HCl at 0 °C to pH 4-5, then extracted with EtOAc (200 mL x 2). The organic layer was washed with brine (50mL x 2) dried over Na₂SO₄, filtered and concentrated to obtain ZZZ-6 (12.5 g, 73%) as a white solid. LCMS [M+1] 324.96; Ή NMR (400 MHz, DMSO-d₆) δ ppm 13.16 (br s, 1H), 7.66 - 7.56 (m, 2H), 7.53 - 7.46 (m, 2H), 7.45 - 7.37 (m, 1H), 7.45 - 7.37 (m, 1H), 7.37 - 7.30 (m, 1H), 5.22 (s, 2H)

Step 6 - Synthesis of 2-(benzyloxy)-4-bromo-5-fluoro-N-(pivaioyloxy)benzamide (ZZZ-7)

To a solution of 777-6 (23 g, 70.74 mmol) in THF (300 mL) was added O-pivaloylhydroxylamine (35.4 g, 141 mmol), DIPEA (54.9 g, 424 mmol) at rt (25°C). Then T3P (113 g, 177mmol) was added at 0°C. After addition the mixture was stirred 0 °C for 10 mins then, warmed up to rt (20 °C) and stirred for 16 hours. The mixture was concentrated to remove most of the solvent. The remaining mixture was diluted with EtOAc (80 mL), washed with sat. aq NaHCO₃ (50 mL) and extracted with EtOAc (100 mL x 2). The organic layer was washed with brine (50 mL x 2) dried over Na₂SO₄, filtered and concentrated to give the crude product (42 g) as a yellow gum which was purified by chromatography (silica gel, EtOAc/Petroleum ether = 0-25%) to afford ZZZ-7 (26 g, 87%) as a light yellow solid. LCMS [M+1] 424; ¹H NMR (400 MHz, CDCI₃) δ ppm 10.80 (br s, 1H), 7.93 (d, J=8.8 Hz, 1H), 7.51 -7.34 (m, 5H), 7.27-7.23 (m, 1H), 5.24 (s, 2H), 1.33 (s, 9H)

-262Step 7 - Synthesis of 8-(benzyloxy)-6-bromo-5-fluoro-3,4-dihydroisoquinolin-1(2H)-one (ZZZ-8)

To a suspension of ZZZ-7 (26g, 64 mmol) in MeCN (600 mL) was added KOAc (6.91g, 70.4 mmol) and [Cp*Rh₂CI₂]₂ (2.37 g, 3.84 mmol) in vessel was cooled to 0 °C in which ethyiene was purged into the vessel for 30 mins and sealed. The reaction was stirred at rt (20 °C) for 16 hours. The mixture was concentrated to give crude product (26 g) as a yellow solid which was purified by chromatography (silica gel petroleum ether:EtOAc = 0-100%) to obtain ZZZ-8 (12 g, 59%) as a yellow solid. LCMS [M+1] 351; Ή NMR (400 MHz, DMSO-d₆) δ ppm 7.92 (br s, 1H), 7.56 (d, J=7.0 Hz, 2H), 7.44 - 7.35 (m, 3H), 7.34 - 7.28 (m, 1H), 5.19 (s, 2H), 3.30 (dt, J=3.6, 6.2 10 Hz, 2H), 2.86 (t, J=6.1 Hz, 2H)

Step 8 - Synthesis of tert-butyl 8-(benzyloxy)-6-bromo-5-fluoro-1-oxo-3,4dihydroisoquinoline-2(1 H)-carboxylate (ZZZ-9)

To a solution of ZZZ-8 (11 g, 33.113 mmol) in THF (40 mL) and DCM (120mL) was added Boc₂0 (11.6 g, 53 mmol), DIPEA (15 g, 116 mmol) and DMAP (607 mg, 4.97 mmol). After the 15 addition, the mixture was stirred at rt (22 °C) for 16 hours. The reaction was concentrated to get the crude material (17.2 g,) as a yellow gum which was then purified by combi-flash (EtOAc/petroleum ether = 0-20%) to obtain ZZZ-9 (14.52 g, 97%) as a light yellow solid. LCMS [M+23] 472; ¹H NMR (400 MHz, DMSO-de) δ ppm 7.63 - 7.22 (m, 6H), 5.32 - 5.14 (m, 2H), 3.86 (t, J=6.0 Hz, 2H), 2.97 (t, J=5.9 Hz, 2H), 1.50 (s, 9H)

Step 9 - Synthesis of tert-butyl 8-(benzyloxy)-6-bromo-5-fluoro-3,4-dihydroisoquinoline2(1H)-carboxylate (ZZZ-10)

To a solution of ZZZ-9 (14.81 g, 32.9 mmol) in THF (150 mL) was added BH₃Me₂S (19.7 mL, 197 mmol) at rt (25 °C). The mixture was heated at 70°C for 1 hour. The reaction was quenched with MeOH (40 mL) slowly. The mixture was refluxed (65 °C) for 16 hs. The mixture 25 was concentrated to give the crude product (26 g) as a yellow gum in which water (60 mL) was added the product extracted with EtOAc (100mL x 2) .The organic layer was washed with brine (50 mL x 2) dried over Na₂SO₄ filtrated and concentrated to get crude material (17 g) which was purified by chromatography (silica gel, EtOAc/ petroleum ether = 0-25%) to afford ZZZ-10 (13.2 g) as a light yellow gum which was lyophilized to get ZZZ-10 (13.06 g, 91%) was obtained as a 30 white solid. LCMS [M-Boc+1] 337; Ή NMR (400 MHz, CDCI₃) δ ppm 7.44 - 7.31 (m, 5H), 6.92 (d, J=5.5 Hz, 1H), 5.04 (br s, 2H), 4.51 (s, 2H), 3.63 (br t, J=5.8 Hz, 2H), 2.88 - 2.72(m, 2H), 1.50 (s, 9H)

Step 10 - Synthesis of tert-butyl 8-(benzyloxy)-5-fluoro-6-formyl-3,4-dihydroisoquinoline2(1H)-carboxylate (ZZZ-11)

In an oven dried round bottom flask was added ZZZ-10 (285 mg, 0.653 mmol) and dry THF (4.35 mL, 0.15 M). A solution of DMF (0.98 mL, 0.98 mmol, 1M in THF) was added to and the

-263mixture was cooled to -78 °C with dry ice/acetone. nBuLi (0.92 mL, 1.47 mmol, 1.6M in hexanes) was added drop-wise and stirred at -78 °C for 30 min in which the reaction turned from clear to yellow. LCMS still showed -50% of ZZZ-10 and therefore another 0.5 eq of DMF (0.49 mL, 0.49 mmol, 1M in THF) and nBuLi (0.46 mL, 0.735 mmol, 1M in hexanes) were added and stirred for 25 min. The reaction was quenched with water and extracted with EtOAc. The aqueous layer was extracted with EtOAc 3x. The combined organics were washed with water and dried over Na₂SO₄, filtered and concentrated to a crude yellow oil (404 mg) which was purified by ISCO 25g 0-20% EtOAc/Heptanes to afford ZZZ-11 as a clear oil (215 mg, 60%).

LCMS [M+1] 286; ¹H NMR (400 MHz, CDCb) δ ppm 10.35 (s, 1H), 7.49 - 7.32 (m, 5H), 7.23 (d, 10 J=5.3 Hz, 1H), 5.13 (br. s., 2H), 4.64 (s, 2H), 3.69 (t, J=5.7 Hz, 2H), 2.86 (t, J=5.1 Hz, 2H), 1.52 (s, 9H)

Step 11 - Synthesis of tert-butyl 8-(benzyloxy)-6-(difluoromethyl)-5-fluoro-3,4dihydroisoquinoline-2(1H)-carboxylate (ZZZ-12)

To a solution of 777-11 (418 mg, 1.08 mmol) was added DCM (10.8 mL, 0.1 M). The solution was cooled to 0 °C then DAST (0.36 mL, 2.71 mmol) was added drop-wise and stirred for 4 h at r.t. LCMS shows -25% of product. The reaction was cooled down to 0 °C and DAST was readded drop-wise (0.36 mL, 2.71 mmol) and stirred at r.t. for 2 hours. The reaction was not complété and an additional 2 eq was added and stirred for 2h. The reaction was then neutralized with sat. aq. NaHCCb. The layers were separated and the aqueous layer was extracted with DCM 2x, dried over Na₂SO₄, filtered and concentrated then purified by ISCO 12g 0-15% EtOAc/Heptanes to afford ZZZ-12 as a white solid (322 mg, 73%). LCMS [M-Boc+1] 308; Ή NMR (400 MHz, CDCb) δ ppm 7.47 - 7.32 (m, 5H), 7.03 - 6.75 (m, 2H), 5.10 (br. s., 2H), 4.59 (br. s., 2H), 3.66 (t, J=5.6 Hz, 2H), 2.84 - 2.75 (m, 2H), 1.50 (s, 9H)

Step 12 - Synthesis of tert-butyl 6-(difluoromethyl)-5-fluoro-8-hydroxy-3,425 dihydroisoquinoline-2(1H)-carboxylate (ZZZ-13)

In round bottom flask was added ZZZ-12 (322 mg, 0.79 mmol) and MeOH (15.8 mL, 0.05 M). 10% Pd/C (30 mg) was added and a hydrogen balloon was added. The reaction was stirred at r.t. overnight. The reaction was filtered with a syringe and filter tip. The crude white material (252 mg) was dissolved in DCM:MeOH (-2:1) for complété solubility to added into an ISCO 12g 30 and purified with 0-25% EtOAc/heptanes to give ZZZ-13 as a white solid (239 mg, 95%). LCMS

[M-Boc+1] 218; Ή NMR (400 MHz, CDCb) δ ppm 6.99 - 6.62 (m, 2H), 4.55 (br. s., 2H), 3.66 (t, J=5.9 Hz, 2H), 2.79 (br. s., 2H), 1.52 (s, 9H)

Step 13 - Synthesis of tert-butyl 6-(difluoromethyl)-5-fluoro-8-(((1S,4R)-4-(4-methyl-7Hpyrrolo[2,3-d]pyrimidin-7-yl)cyclopent-2-en-1 -yl)oxy)-3,4-dihydroisoquinoline-2(1H)35 carboxylate (ZZZ-14)

- 264 To a microwave vial (which was dried with heat gun, then cooled under a stream of N₂) was added compound BB-2 (238 mg, 0.753 mmol), ZZZ-13 (239 mg, 0.753 mmol), Cs₂CO₃ (270 mg, 0.829 mmol), DPPP (18.7 mg, 0.0452 mmol) and Pd₂(dba)₃-CHCb (19.5 mg, 0.02 mmol), the vial was purged with N₂ for five and DCE (3 mL, sparged with N₂ for 30 mins) was added. The 5 vial was purged with N₂ three more times. The solution was stirred at 18 °C under N₂ for 55 min.

The reaction mixture was purified by prep-TLC (EtOAc/petroleum ether=1.5:1) to give product ZZZ-14 (330 mg, 85%) as a colorless gum. LCMS [M+1] 515; Ή NMR (400 MHz,

CDCb) δ ppm 8.78 (s, 1 H), 7.29 (br d, J=3.4 Hz, 1 H), 7.04 - 6.72 (m, 2H), 6.59 (br d, J=3.0 Hz, 1H), 6.39 (brd, J=5.3 Hz, 1H), 6.19 (br d, J=4.6 Hz, 1H), 6.08 (br dd, J=2.2, 4.3 Hz, 1H), 5.40 10 5.32 (m, 1H), 4.50 (br s, 2H), 3.73 - 3.57 (m, 2H), 3.26 - 3.16 (m, 1H), 2.80 (brt, J=5.4 Hz, 2H),

2.74 (s, 3H), 1.52 (s, 9H)

Step 14 - Synthesis of tert-butyl 6-(difluoromethyl)-8-(((1S,2S,3S,4R)-2,3-dihydroxy-4-(4methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl)oxy)-5-fluoro-3,4-dihydroisoquinoline2(1H)-carboxylate (ZZZ-15)

To a mixture of ZZZ-14 (330 mg, 0.641 mmol) in DCM (10 mL)/H₂O (0.4 mL) was added NMO (225 mg, 1.92 mmol) and OsO₄ (4% in t-BuOH, 285 mg, 0.045 mmol) at 15 °C. The black solution was stirred at 18 °C for 3 hours. The mixture was quenched with sat. aq. Na₂SO₃ (5 mL) and diluted with DCM (10 mL) and separated. The aqueous layer was extracted with DCM (5 mL). The combined organic layers were washed with brine (10 mL), dried over Na₂SO₄, filtered and concentrated to yieid crude product (450 mg) as a brown solid, which was purified by prepTLC (first, EtOAc/MeOH=20:1, second, EtOAc) to afford ZZZ-15 (210 mg, 60%) as a light yellow solid. LCMS [M+1] 549; Ή NMR (400 MHz, CDCb) δ ppm 8.69 (s, 1H), 7.22 (d, J=3.8 Hz, 1H), 7.10 (br d, J=5.3 Hz, 1H), 7.04 - 6.73 (m, 1H), 6.61 (d, J=3.8 Hz, 1H), 5.03- 4.88 (m, 1H), 4.80 (br s, 1H), 4.60 - 4.39 (m, 3H), 4.36 - 4.24 (m, 1H), 3.65 (br d, J=5.8 Hz, 2H), 3.46 - 3.29 (m,

1 H), 3.20 - 3.02 (m, 1 H), 2.80 (br t, J=5.4 Hz, 2H), 2.74 (s, 3H), 2.62 (s, 1 H), 2.39 (s, 1 H), 1.56 1.34 (m, 9H)

Step 15 - Synthesis of (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-

1,2-diol (ZZZ-16)

To a solution of ZZZ-15 (210 mg, 0.383 mmol) in DCM (2 mL) was added HCl (g) /dioxane (4 N, 0.766 mL, 3.06 mmol) at 0°C. The mixture was stirred at 23°C for 2 hours. Solid was precipitated. The solvent was decanted and the solid dried and lyophilized lyophilized to give 777-16 as 2HCI sait + 2 H₂O (165 mg, 83%) as a light yellow solid. LCMS [M+1] 449; ¹H NMR (400 MHz, D₂O) δ ppm 8.93 (s, 1H), 7.91 (d, J=3.8 Hz, 1H), 7.24 - 6.88 (m, 3H), 5.41 (q, J=9.0 35 Hz, 1H), 4.87 (br dd, J=2.4, 4.4 Hz, 1H), 4.75 (dd, J=5.0, 8.8 Hz, 1H), 4.45 (s, 2H), 4.39 (br d, J=5.0 Hz, 1H), 3.58 (t, J=6.3 Hz, 2H), 3.19 - 3.07 (m, 3H), 2.99 (s, 3H), 2.35 - 2.24 (m, 1H).

-265Exampie 191 (Scheme AAAA) - Synthesis of (1S,2S,3S,5R)-3-((4-fluoro-3-methoxy-5,6,7,8tetrahydro-2,7-naphthyridin-1-yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7yl)cyclopentane-1,2-diol (AAAA-6)

Scheme AAAA

Step 1: Synthesis of 2,6-dichloro-5-fluoro-N-(pivaloyloxy)nicotinamide (AAAA-1)

Compound AAAA-1 was prepared in a similar method as step 4 in Schème FF using 2,6dichloro-5-fluoronicotinic acid to give 5.85 g (80% yield) as a white solid. ¹H NMR (400 MHz, CHLOROFORM-d) â ppm 9.91 (br. s., 1 H) 8.02 (d, J=5.14 Hz, 1 H) 1.37 (s, 9 H)

Step 2: Synthesis of 6,8-dichloro-5-fluoro-3,4-dihydro-2,7-naphthyridin-1(2H)-one (AAAA2)

Compound AAAA-2 was prepared from AAAA-1 in a similar method as step 4 in Scheme GG using césium pivalate to give 1.47 g (33% yield) as a yellow solid. LCMS [M+1-2CI] 167.0. ¹H NMR (400 MHz, CHLOROFORM-d) à ppm 6.13 (br. s., 1 H) 3.59 (td, J=6.45, 3.48 Hz, 2 H) 3.09 (t, J=6.42 Hz, 2 H)

Step 3: Synthesis of 8-chloro-5-fluoro-6-methoxy-3,4-dihydro-2,7-naphthyridin-1(2H)-one (AAAA-3)

To a solution of AAAA-2 (200 mg, 0.85 mmol) in 20 mL MeOH was added sodium methoxide (161 mg, 2.98 mmol , 5.96 mL, 0.5 M), the solution was heated at 60C for 1 hr. The reaction was concentrated, redissolved in DCM, washed with H₂O twice, DCM was rotavapored,

-266the crude was purified by column chromatography with 100% EtOAc to give 100 mg of AAAA-3 (51% yield) as an off white solid. LCMS [M+1] 231.0. Ή NMR (400 MHz, CHLOROFORM-d) â ppm 5.96 (br. s., 1 H) 4.09 (s, 3 H) 3.52 (td, J=6.39, 3.48 Hz, 2 H) 3.03 (t, J=6.24 Hz, 2 H)

Step 4: Synthesis of tert-butyl 8-chloro-5-fluoro-6-methoxy-3,4-dihydro-2,7-naphthyridine2(1H)-carboxylate (AAAA-4)

Compound AAAA-4 was prepared from AAAA-3 in a similar method as step 5 in Scheme GG to give 105 mg (76% yield) as a colorless oil. LCMS [M+1-Boc] 217.0. ¹H NMR (400 MHz, CHLOROFORM-d) a ppm 4.48 (s, 2 H) 4.00 (s, 3 H) 3.63 (t, J=5.93 Hz, 2 H) 2.82 (t, J=5.69 Hz, 2 H) 1.50 (s, 9 H)

Step 5: Synthesis of tert-butyl 8-(((3aR,4S,6R,6aS)-2,2-dimethyl-6-(4-methyl-7Hpyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)-5-fluoro-6methoxy-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxylate (AAAA-5)

The mixture of (3aR,4S,6R,6aS)-2,2-dimethyl-6-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-ol (SSS-3) (98.0 mg, 0.34 mmol), AAAA-4 (107 mg, 0.339 mmol), césium carbonate (221 mg, 0.677 mmol), tris(dibenzylideneacetone)dipalladium (31.0 mg, 0.0339 mmol) and BINAP (42.2 mg, 0.0677 mmol) in toluene (6.77 mL, c=0.05 M) was degassed and purged with N₂ three times. The reaction mixture was heated at 100°C overnight, LCMS indicated the reaction didn’t complété. Césium carbonate (221 mg, 0.677 mmol), tris(dibenzylideneacetone)dipalladium (31.0 mg, 0.0339 mmol) and BINAP (42.2 mg, 0.0677 mmol) were added, degassed and continued to heat at 100°C for 2 days. The reaction mixture was cooled to rt, H₂O was added, extracted with EtOAc, the crude was concentrated and purified by column chromatography with 85% EtOAc/heptane to give 60 mg (31% yield) yellow oil. LCMS [M+1] 570.1. Ή NMR (400 MHz, CHLOROFORM-d) â ppm 8.79 (s, 1 H) 7.37 (d, J=3.67 Hz, 1 H) 6.61 (br. s., 1 H) 5.47 (br. s., 1 H) 5.35 (ddd, J=7.95, 5.26, 2.69 Hz, 1 H) 4.98 - 5.05 (m, 1 H) 4.89 (d, J=6.24 Hz, 1 H) 4.36 (br. s., 2 H) 3.99 (s, 3 H) 3.56 - 3.64 (m, 2 H) 3.01 (dt, J=14.55, 7.27 Hz, 1 H) 2.78 (t, J=5.26 Hz, 2 H) 2.73 (s, 3 H) 2.41 - 2.52 (m, 1 H) 1.60 (s, 3 H) 1.50 (s, 9 H) 1.33 (s, 3 H)

Step 6: Synthesis of (1S,2S,3S,5R)-3-((4-fluoro-3-methoxy-5,6,7,8-tetrahydro-2,7naphthyridin-1-yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol (AAAA-6)

-267Compound AAAA-6 was prepared from AAAA-5 in a similar method as step 10 in Scheme A to give 19.7 mg (33% yield). LCMS [M+1] 430.0. Ή NMR (400 MHz, DMSO-d6) a ppm 9.68 (br. s., 1 H) 9.56 (br. s., 1 H) 9.07 (s, 1 H) 7.99 (br. s., 1 H) 7.10 (br. s., 1 H) 5.11 - 5.26 (m, 2 H) 4.64 (dd, J=9.05, 4.65 Hz, 1 H) 4.15 (br. s., 2 H) 4.10 (d, J=4.03 Hz, 1 H) 3.94 (s, 3 H) 3.38 (br. s., 2 5 H) 2.91 - 3.03 (m, 3 H) 2.87 (s, 3 H) 1.95 - 2.05 (m, 1 H)

Examples 192 & 193 were prepared in a similar fashion to Example 191 except that sodium ethoxide in éthanol was used in step 3 of Scheme AAAA for Example 192 and sodium isopropoxide in isopropanol was used in step 3 of Scheme AAAA for Example 193.

Example 192	A Vï VJ N-7 L N c HO OH	444.05 [M+1]	(1S,2S,3S,5R)-3-((3-ethoxy-4-fluoro-5,6,7,8tetrahydro-2,7-naphthyridin-1-yl)oxy)-5-(4methyl-7H-pyrrolo[2,3-d]pyrimidin-7yl)cyclopentane-1,2-diol 1H NMR (400 MHz, DMSO-d6) â ppm 9.50 (br. s., 1 H) 9.40 (br. s., 1 H) 8.99 (br. s., 1 H) 7.93 (br. s., 1 H) 7.04 (br. s., 1 H) 5.19 (q, J=9.17 Hz, 1 H) 5.07 - 5.13 (m, 1 H) 4.63 (dd, J=9.05, 4.52 Hz, 1 H) 4.34 - 4.51 (m, 2 H) 4.15 (br. s., 2 H) 4.09 (d, J=4.16 Hz, 1 H) 3.39 (br. s., 2 H) 2.88 - 3.03 (m, 3 H) 2.83 (s, 3 H) 1.93 - 2.03 (m, 1 H) 1.33 (t, J=6.97 Hz, 3 H)
Example 193	Vï VJ V N ' ρΛ=γ HO OH ^,0	458.00 [M+1]	(1S,2S,3S,5R)-3-((4-fluoro-3-isopropoxy5,6,7,8-tetrahydro-2,7-naphthyridin-1yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)cyclopentane-1,2-diol Ή NMR (400 MHz, DMSO-d6) â ppm 9.98 (br. s., 1 H) 9.82 (br. s., 1 H) 9.21 (s, 1 H) 8.10 (d, J=3.67 Hz, 1 H) 7.22 (d, J=3.67 Hz, 1 H) 5.18 - 5.30 (m, 2 H) 5.10 (d, J=5.14 Hz, 1 H) 4.67 (dd, J=9.11,4.46 Hz, 1 H) 4.13 (d, J=4.52 Hz, 2 H) 4.09 (d, J=4.03 Hz, 1 H) 3.36 (br. s., 2 H) 2.96 - 3.03 (m, 2 H) 2.94 (m, 4 H) 1.96 - 2.08 (m, 1 H) 1.35 (d, J = 6.1

-268-

Hz, 3 H) 1.29 (d, J = 6.1 Hz, 3 H)

Scheme BBBB - Synthesis of 2-chloro-6-(difiuoromethyl)nicotinic acid (BBBB-4)

Scheme BBBB

POCI₃

Py, CHCI₃, rt

F 0 0

BBBB-1

NaOMe, MeOH reflux

NaOH

Step 1: Synthesis of (E)-4-butoxy-1,1-difluorobut-3-en-2-one (BBBB-1)

Compound BBBB-1 was prepared according to W020080269059. ¹H NMR (400 MHz, CHLOROFORM-d) â ppm 7.86 (d, J=12.47 Hz, 1 H) 5.90 (d, 1 H) 5.77 (t, J = 56 Hz, 1 H) 4.01 (t, J=6.48 Hz, 2 H) 1.68 - 1.80 (m, 2 H) 1.41 - 1.48 (m, 2 H) 0.97 (t, J=7.40 Hz, 3 H)

Step 2: Synthesis of methyl 6-(difluoromethyl)-2-oxo-1,2-dihydropyridine-3-carboxylate 15 (BBBB-2)

Compound BBBB-2 was prepared according to W020080269059. ¹H NMR (400 MHz, DMSOd6) â ppm 12.18 (br. s., 1 H) 8.20 (d, J=5.87 Hz, 1 H) 7.05 (br. s., 1 H) 6.86 (t, J = 52 Hz, 1 H) 3.81 (s, 3 H)

Step 3: Synthesis of methyl 2-chloro-6-(difluoromethyl)nicotinate (BBBB-3)

A mixture of BBBB-2 (3340 mg, 16.44 mmol) and phosphors oxychloride (10 mL) was heated at 110°C for 24 hrs, cooled to rt, ice water was added, neutralized by solid KOH. The reaction 25 mixture was extracted with EtOAc three fîmes, the organic layers were combined and concentrated, purified by column chromatography with 18% EtOAc/heptane to give 3.27 g (90% yield) of BBBB-3 as a white solid. Ή NMR (400 MHz, CHLOROFORM-d) â ppm 8.31 (d, J=7.83 Hz, 1 H) 7.67 (d, J=7.83 Hz, 1 H) 6.61 (t, J = 56 Hz, 1 H) 4.00 (s, 3 H); 19F NMR (376 MHz, CHLOROFORM-d) â ppm -116.82 (s, 1 F)

-269Step 4: Synthesis of 2-chloro-6-(difluoromethyl)nicotinic acid (BBBB-4)

To a solution of BBBB-3 (1160 mg, 5.235 mmol) in 20 mL MeOH was added sodium hydroxide (1050 mg, 26.2 mmol , 5.23 mL, 5 M), heated at 65°C for 4 hrs. The reaction mixture was 5 neutralized by 1 N HCl to pH 4, the solvent was removed, the solid was dried over vacuo and used for next step.

Example 194 was made in a similar fashion to Example 191 (Scheme AAAA) except that step is ommitted

Example 194	H / A LA vj L N ; 3 HO OH	432.05 [M+1]	(1S, 2S,3S,5R)-3-((3-(difluoromethyl)-5,6,7,8tetrahydro-2,7-naphthyridin-1-yl)oxy)-5-(4methyl-7H-pyrrolo[2,3-d]pyrimidin-7yl)cyclopentane-1,2-diol
			1H NMR (400 MHz, DMSO-d6) â ppm 10.27 (br. s., 1 H) 10.13 (br. s., 1 H) 9.22 (s, 1 H) 8.12 (d, J=3.67 Hz, 1 H) 7.15 - 7.28 (m, 2 H) 6.84 (t, J = 56 Hz, 1 H) 5.12 - 5.30 (m, 2 H) 4.69 (dd, J=8.93, 4.65 Hz, 1 H) 4.08 - 4.27 (m, 3 H) 3.38 (d, J=9.66 Hz, 2 H) 3.10 (br. s., 2 H) 2.86 - 3.00 (m, 4 H) 1.92 - 2.10 (m, 1 H)

Examples 195 & 196 were made in a similar fashion to Example 99 in Scheme NN using the appropriate NBoc-protected tetrahydroisoquinoline in step 2.

450.2

[M+1] (1S,2S,3R,5S)-3-(4-amino-5-fluoro7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((6(difluoromethyl)-l ,2,3,4tetrahydroisoquinolin-8yl)oxy)cyclopentane-1,2-diol

Ή NMR (400 MHz, D₂O, HCl sait) δ ppm 8.20 (s, 1H), 7.25 (d, J=2.0 Hz, 1H), 7.12 (s, 1H), 7.09 (s, 1H), 6.77 (t, J=56.0 Hz, 1H), 5.29 - 5.17 (m, 1H), 4.84 - 4.81 (m, 1H), 4.56 (dd, J=5.0, 8.8 Hz, 1H), 4.37 (s, 2H), 4.29 (d,

- 270-

J=4.3 Hz, 1H), 3.50 (t, J=6.3 Hz, 2H), 3.13 (t, J=6.3 Hz, 2H), 3.03 (ddd, J=7.2, 9.3, 14.9 Hz, 1H), 2.15 - 2.01 (m, 1H) (1S,2S,3R,5S)-3-(4-amino-5-fluoro7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((6(difluoromethyl)-5-fluoro-1,2,3,4tetrahydroisoquinolin-8yl)oxy)cyclopentane-1,2-diol

Ή NMR (400 MHz, DMSO-d6, HCl sait) δ ppm 9.84 (br s, 2H), 8.76 (br s, 1H), 8.43 (s, 1H), 7.70 (d, J=1.8 Hz, 1H), 7.38 - 7.02 (m, 2H), 5.07 (q, J=9.1 Hz, 1H), 4.71 - 4.56 (m, 1H), 4.47 (dd, J=4.9, 9.4 Hz, 1H), 4.23 (br s, 2H), 3.99 (br d, J=5.0 Hz, 1H), 3.37 (br s, 2H), 3.03 - 2.95 (m, 2H), 2.93 2.80 (m, 1H), 1.96 - 1.81 (m, 1H)

Scheme CCCC

Synthesis of tert-butyl

8-hydroxy-6-(isoxazol-4-yl)-3,4dihydroisoquinoline-2(1 H)-carboxylate (TP-34)

Scheme CCCC

Step 1 - Synthesis of tert-butyl 8-(benzyloxy)-6-(isoxazol-4-yl)-3,4-dihydroisoquinoline2(1H)-carboxylate (CCCC-1)

A solution of NNN-1 (600 mg, 1.29 mmol), 4-bromoisoxazole (286 mg, 1.93 mmol), K2CO3 (535 mg, 3.87 mmol) and PdCI₂(dppf)-DCM (94 mg, 0.129 mmol) in toluene (2.5 mL) and water (1.5 mL) was stirred under N₂ atmosphère at 75 °C for 16 h. The reaction mixture was then cooled to r.t. Water was added and the mixture was extracted with EtOAc (3x5 mL). The combined organic layers were washed with brine (5 mL), dried over Na₂SO4, filtered and concentrated.

-271 The crude product was purified by column chromatography with EtOAc/petroleum ether from 15-85% to give a colorless oil CCCC-1 (160 mg, 31%). LCMS [M-tBu+1] 350.9

Step 2 - Synthesis of 6-(isoxazol-4-yl)-1,2,3,4-tetrahydroisoquinolin-8-ol (CCCC-2)

Compound CCCC-1 (140 mg, 0.344 mmol) was dissolved in DCM (10 mL). The reaction solution was cooled to 0 °C in an ice bath. BBr₃ (518 mg, 2.07 mol) was added. The reaction became from a suspension to a clear yellow solution. The reaction mixture was stirred at 25 °C for 16 hours. The reaction was cooled to 0 °C and MeOH (2 mL) was added to the reaction drop-wise followed by water (20 mL). The reaction solution was washed with DCM (10 mL x 2). The aqueous layer was separated and pH which was adjusted to pH 9, using NaHCO₃ solid. The final solution of CCCC-2 was used for the next step directly without further purification (23 mL, aq soin crude, >99%).

Synthesis of tert-butyl 8-hydroxy-6-(isoxazol-4-yl)-3,4-dihydroisoquinoline-2(1H)carboxylate (TP-34)

MeOH (5 mL) and dioxane (5 mL) were added to the solution of CCCC-2 (23 mL aq), then Boc₂O (83 mg, 0.38 mmol) was added to the reaction solution, the solution was stirred at 25 °C for 16 hours. The pH of the reaction solution was adjusted to pH~3 by the addition of 1N HCl aq. The solution was separated, then aqueous layer was extracted with DCM (10 mL). The organic layers were combined and washed with saturated NaCI (20.0 mL). The organic layer was separated, dried and evaporated to give the crude product, which was purified by flash chromatography, eluted with petroleum ether/EtOAc from 0-50%, to give the desired product as white solid of TP-34 (84 mg, 77% yield over 2 steps). MS [M-Boc+1] 217.1; ¹H NMR (400 MHz, DMSO-d6) δ ppm 9.83 (s, 1H), 9.32 (s, 1H), 9.02 (s, 1H), 6.97 (s, 1H), 6.89 (s, 1H), 4.36 (s, 2H), 3.55 (m, 2H), 2.75 (m, 2H), 1.44 (s, 9H)

Example 197 was prepared using the chemistry depicted in Scheme CC and employing compound TP-34.

(1S,2S,3S,5R)-3-((6-(isoxazol-4-yl)-

1,2,3,4-tetrahydroisoquinolin-8yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)cyclopentane-1,2-diol

Ή NMR (400 MHz, D₂O) δ ppm 8.98 (s, 1H), 8.83 (s, 1H), 8.80 (s, 1H), 7.80 (d, J=3.8 Hz, 1H), 7.15 (s, 1H), 7.12 - 7.07 (m, 2H), 5.35 (q, J=9.0 Hz, 1H), 4.90 - 4.86 (m, 1H), 4.69 - 4.65 (m, 1H), 4.39 - 4.31 (m, 3H), 3.50 (t,

-272-

J=6.3 Hz, 2H), 3.17 - 3.01 (m, 3H), 2.89 (s, 3H), 2.28-2.16 (m, 1H)

Scheme DDDD - Synthesis of tert-butyl 5-fluoro-8-hydroxy-6-methoxy-3,4dihydroisoquinoline-2(1 H)-carboxylate (TP-35)

Scheme DDDD

Dioxane, r.t.

RockPhosPd3G (1% mol), t-BuBrettPhos (1 mol%), NaOtBu, MeOH

DDDD-1

MeOH

Pd-C, H₂

Step 1 - Synthesis of tert-butyl 8-(benzyloxy)-5-fluoro-6-methoxy-3,4dihydroisoquinoline-2(1 H)-carboxylate (DDDD-1 )

Vial A was charged with t-BuBrettPhos (49 mg, 0.10 mmol), NaOtBu (67.8 mg, 0.706 mmol) and ZZZ-10 (220 mg, 0.504 mmol) in dioxane (3 mL). The vial was degased with N₂ three times. Then MeOH (81 mg, 2.52 mmol) was added to the vial A. Vial B was charged with RockPhosPd3G (85 mg, 0.10 mmol) and degased with N₂ three times followed by addition of dioxane (2 mL) and stirred for 1 min. The precatalyst from vial B was transferred into vial A and the reaction solution was stirred at 25 °C for 16 hours. EtOAc (10 mL) was added to dilute the solution and washed with water (5 mL x 2). The organic layers were separated, dried and evaporated to give the crude product, which was purified by flash chromatography, eluted with EtOAc/petroleum ether from 0-15% to give the desired product as colorless oil DDDD-1 (110 mg, 56%). LCMS [M-Boc+1] 287.9; Ή NMR (400 MHz, DMSO-de) δ ppm 7.54 - 7.27 (m, 5H), 6.83 (d, J=7.5 Hz, 1H), 5.15 (s, 2H), 4.43 - 4.26 (m, 2H), 3.82 (s, 3H), 3.53 (t, J=5.8 Hz, 2H), 2.71 -2.66(m, 2H), 1.42 (s, 9H)

Step 2 - Synthesis of tert-butyl 5-fluoro-8-hydroxy-6-methoxy-3,4-dihydroisoquinoline2(1H)-carboxylate (TP-35)

Compound DDDD-1 (110 mg, 0.28 mmol) was dissolved in MeOH (3 mL) and EtOAc (1 mL) followed by addition of Pd/C (15 mg, 0.142 mmol). The solution was degased with H₂four times and stirred at 25 °C for 16 hours under an H₂ bailoon. The reaction was diluted with DCM (5 mL), filtered, and concentrated to give TP-35 as a white solid (70 mg, 83%). LCMS [M-tBu+1] 242.1; ¹H NMR (400 MHz, DMSO-de) δ ppm 9.58 (s, 1H), 6.46 (d, J=7.3 Hz, 1H), 4.28 (s, 2H), 3.74 (s, 3H), 3.55 - 3.50 (m, 2H), 2.65 (m, 2H), 1.43 (s, 9H)

-273Compound TP-36 was prepared using similar chemistry as Scheme DDDD using EtOH in Step

TP-36 OH Bocx Z'- zA. fïl F

256 [M-tBu+1]

tert-butyl 6-ethoxy-5-fluoro-8-hydroxy-3,4- dihydroisoquinoline-2(1H)-carboxylate 1H NMR (400 MHz, DMSO-d6) δ ppm 9.52 (s, 1H), 6.44 (d, J=7.0 Hz, 1H), 4.28 (s, 2H), 3.99 (q, J=6.9 Hz, 2H), 3.55 - 3.49 (m, 2H), 2.64 (br t, J=6.0 Hz, 2H), 1.43 (s, 9H), 1.32 (t, J=6.9 Hz, 3H)

Examples 198 & 199 were prepared using similar chemistry depicted in Scheme CC and employing compounds TP-35 & TP-36 respectively.

Example 198	<Πι T	428.9 [M+1]	(1 S,2S,3S,5R)-3-((5-fluoro-6methoxy-1,2,3,4-
TP-35					tetrahydroisoquinolin-8-yl)oxy)-5-(4-
			YOH		methyl-7H-pyrrolo[2,3-d]pyrimidin-7-
OH		cr	OH		yl)cyclopentane-1,2-diol
Boc-„ z\ zz. N X| X	HlY'				Ή NMR (400 MHz, MeOD, HCl sait) δ
XX^X^OMe			XMe		ppm 9.05 (s, 1H), 8.09 (d, J=3.7 Hz,
F		F			1H), 7.25 (d, J=3.7 Hz, 1H), 6.93 6.85 (m, 1H), 5.40 (q, J=9.3 Hz, 1H), 4.94-4.90 (m, 1H), 4.81 -4.66 (m, 1H), 4.33 (s, 2H), 4.21 (d, J=5.0 Hz, 1H), 3.93 (s, 3H), 3.57 - 3.47 (m, 2H), 3.14 - 3.05 (m, 3H), 3.02 (s, 3H), 2.37 2.24 (m, 1H)
Example 199				443.1	(1S,2S,3S,5R)-3-((6-ethoxy-5-fluoro-
			CO	[M+1]	1,2,3,4-tetrahydroisoquinolin-8-
TP-36					yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-
			Y'OH		d]pyrimidin-7-yi)cyclopentane-1,2-diol
OH			OH		1H NMR (400 MHz, D2O, HCl sait) δ
Boc.. zz. zA N YY	HN^				ppm 8.82 (s, 1H), 7.84 - 7.74 (m, 1H),
XXy<3Et			OEt		7.08 (d, J=3.8 Hz, 1H), 6.70 (d, J =
F		F			7.2 Hz, 1H), 5.28 (q, J=9.1 Hz, 1H), 4.76 - 4.73 (m, 1H), 4.66 - 4.58 (m, 1H), 4.36 - 4.20 (m, 3H), 4.18 - 4.05 (m, 2H), 3.45 (t, J-6.4 Hz, 2H), 3.08 -

-274-

2.93 (m, 3H), 2.87 (s, 3H), 2.23 - 2.09 (m, 1H), 1.31 (t, J=7.0 Hz, 3H)

Scheme EEEE - Synthesis of tert-butyl 6-(difluoromethoxy)-5-fluoro-8-hydroxy-3,4dihydroisoquinoline-2(1 H)-carboxylate (TP-37)

Scheme EEEE

777.1 η EEEE-1 EEEE-2 EEEE-3 TP-37

Step 1 - Synthesis of tert-butyl 8-(benzyloxy)-5-fluoro-6-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1 H)-carboxylate (EEEE-1 )

To a solution of ZZZ-10 (500 mg, 1.15 mmol) in dioxane (29 mL) was added bis(pinacolato)diboron (1.46 g, 5.73 mmol). The solution was degassed with N₂ for 10 min and cataCXium® A-Pd-G2 (76.6 mg, 0.12 mmol) and KOAc (337 mg, 1.79 mmol) were added to the reaction solution under N₂ atmosphère. The reaction was heated at 80 °C for 16 hours. Water (10 mL) was added and the reaction was extracted with EtOAc (10 mL x 2). The organic layers were separated, dried and evaporated to give the crude product, which was purified by flash chromatography, eluted with petroleum ether/EtOAc 0-20% to give EEEE-1 (78%, 443 mg) as a gray solid. LCMS [M-Boc+1] 384.0; Ή NMR (400 MHz, DMSO-ds) δ ppm 7.52 - 7.32 (m, 5H), 7.05 (d, J=4.3 Hz, 1H), 5.13 (s, 2H), 4.47 (br s, 2H), 3.57 (br t, J=5.8 Hz, 2H), 2.72 - 2.66 (m, 2H), 1.43 (s, 9H), 1.30 (s, 12H)

Step 2 - Synthesis of tert-butyl 8-(benzyloxy)-5-fluoro-6-hydroxy-3,4-dihydroisoquinoline2(1H)-carboxylate (EEEE-2)

To a solution of EEEE-1 (430 mg, 0.89 mmol) in THF (4 mL) and water (4 mL) was added sodium perborate (306 mg, 3.74 mmol) in one portion at RT under N₂. The reaction solution was stirred at room température for 8 hours. The mixture was diluted with EtOAc (10 mL) and water (5 mL). The organic layer was separated, dried and evaporated to give the crude product, which was purified by flash chromatography, eluted with petroleum ether/EtOAc 0-20% to give EEEE-2 (150 mg, 45%) as a white solid. LCMS [M+Na] 396.

Step 3 - Synthesis of tert-butyl 8-(benzyloxy)-6-(difluoromethoxy)-5-fluoro-3,4dihydroisoquinoline-2(1H)-carboxylate (EEEE-3)

KOH (165 mg, 2.95 mol) was suspended in a mixture of acetonitrile (1 mL) and water (1 mL) and cooled to -20 °C. Compound EEEE-2 (110 mg, 0.295 mmol) was added portion-wise, followed by diethyl (bromo-difluoromethyl)phosphonate (157 mg, 0.59 mmol) over 15 min. The

-275mixture was warmed to 25 °C for 2 days. Water was added to the reaction solution and extracted with EtOAc (10 mL x 3). The organic layers were separated, dried and concentrated to give the crude product, which was purified by flash chromatography, eluted with petroleum ether/EtOAc 0-10% , to give EEEE-3 (100 mg, 80%) as a white solid. LCMS [M-Boc+1] 324.

Step 4 - Synthesis of tert-butyl 6-(difluoromethoxy)-5-fluoro-8-hydroxy-3,4dihydroisoquinoline-2(1 H)-carboxylate (TP-37)

To a solution of EEEE-3 (100 mg, 0.23 mmol) in MeOH (5 mL) was added Pd/C (25 mg, 0.024 mmol). The mixture was degassed and purged with H₂ three times. The resulting mixture was stirred at r.t. (28 °C) for 16 hours. The reaction was diluted with DCM (20 mL) and filtered and concentrated to give TP-37 as a white solid (75 mg, 95%). LCMS [M-tBu+1] 278.0; ¹H NMR (400 MHz, DMSO-de) δ ppm 9.99 (bs, 1H), 7.31 (t, J=74 Hz, 1H), 6.62 (d, J=8 Hz, 1H), 4.33 (s, 2H), 3.55 (t, J=8 Hz, 2H), 2.69 (t, J = 8 Hz, 2H), 1.43 (s, 9H)

Example 200 was prepared using similar chemistry depicted in Scheme CC and employing compound TP-37.

Example 200
TP-37
			L / oh
Boc., N	OH H Ί		î ÔH χΐ x
	Il .1
	F /k F F		F

465.1 [M+1]

(1S,2S,3S,5R)-3-((6- (difluoromethoxy)-5-fluoro-1,2,3,4tetrahydroisoquinolin-8-yl)oxy)-5-(4methyl-7H-pyrrolo[2,3-d]pyrimidin-7yl)cyclopentane-1,2-diol 1H NMR (400 MHz, D2O, HCl sait) δ ppm 8.85 (s, 1H), 7.82 (d, J=3.8 Hz, 1H), 7.11 (d, J=3.8 Hz, 1H), 6.98 6.58 (m, 2H), 5.32 (q, J=9.0 Hz, 1H), 4.76 - 4.73 (m, 1H), 4.67 - 4.62 (m, 1H), 4.35 - 4.25 (m, 3H), 3.49 (t, J=6.3 Hz, 2H), 3.10 - 2.96 (m, 3H), 2.90 (s, 3H), 2.24 - 2.12 (m, 1H)

Scheme FFFF - Synthesis of tert-butyl 5-fluoro-8-hydroxy-6-isopropoxy-3,4dihydroisoquinoline-2(1 H)-carboxylate (TP-38)

Scheme FFFF

-276-

OBn		OBn		OH
Boc. N II Ί	DIAD, PPh3, i-PrOH	Boc.. N H Ί	Pd-C, H2	Boc. N j l
	THF	L A A^ V^^o	MeOH
F		F		F A\
EEEE-2		FFFF-1		TP-38
Step 1	Synthesis of	tert-butyl	8-(benzyloxy)-5-fluoro-6-isopropoxy-3,4-

dihydroisoquinoline-2(1H)-carboxylate (FFFF-1)

To a solution of EEEE-2 (170 mg, 0.455 mmol) in THF (3 mL) was cooled with an ice bath and 5 PPh₃ (478 mg, 1.82 mmol) was added under N₂. DIAD (368 mg, 1.82 mmol) was added dropwise and the reaction was stirred at 25 °C for 30 min which became a white suspension.

Then iPrOH (82.1 mg, 1.37 mmol) was added to the reaction solution in one portion and stirred at 15 °C for 16 hours. The mixture was diluted with EtOAc (50 mL) and H₂O (100 mL). The mixture was separated and the aqueous layer was extracted with EtOAc (50 mL). The combined 10 organic layers were washed with brine (50 mL), dried over Na₂SO₄, filtered and concentrated.

The crude product was purified by flash chromatography, eluted with petroleum ether/EtOAc 020% to give FFFF-1 (160 mg, 85%) as a colorless oil. LCMS [M-tBu+1] 270.1; ¹H NMR (400

MHz, DMSO-ds) δ ppm 7.50 - 7.29 (m, 5H), 6.78 (d, J=7.0 Hz, 1H), 5.15 (s, 2H), 4.65 - 4.53 (m, 1 H), 4.38 (br d, J=2.8 Hz, 2H), 3.54 (t, J=5.9 Hz, 2H), 2.74 - 2.62 (m, 2H), 1.43 (s, 9H), 1.23 (d, 15 J=6.0 Hz, 6H)

Step 2 - Synthesis of tert-butyl 5-fluoro-8-hydroxy-6-isopropoxy-3,4-dihydroisoquinoline2(1H)-carboxylate (TP-38)

To a solution of FFFF-1 (160 mg, 0.385 mmol) in MeOH (5 mL) was added Pd/C (41 mg, 0.039 mmol). The mixture was degassed and purged with H₂ three times using a H₂ balloon then 20 stirred at room température (28 °C) for 16 hours under a H₂ balloon. The reaction was diluted with DCM (20.0 mL) filtered and concentrated to give TP-38 as a yellow solid (118 mg, 94%). Ή NMR (400 MHz, DMSO-ds) δ ppm 9.50 (br d, J=2.5 Hz, 1H), 6.45 (d, J=7.3 Hz, 1H), 4.41 (td, J=6.0, 12.0 Hz, 1H), 4.28 (s, 2H), 3.52 (t, J=5.6 Hz, 2H), 2.64 (br t, J=5.8 Hz, 2H), 1.42 (s, 9H), 1.26 (d, J=6.0 Hz, 6H)

Example 201 was prepared using similar chemistry depicted in Scheme CC and employing compound TP-38.

-277 -

(1 S,2S,3S,5R)-3-((5-fluoro-6isopropoxy-1,2,3,4tetrahydroisoquinolin-8-yl)oxy)-5-(4methyl-7H-pyrrolo[2,3-d]pyrimidin-7yl)cyclopentane-1,2-diol

Ή NMR (400 MHz, D₂O, HCl sait) δ ppm 8.90 (s, 1H), 7.88 (d, J=3.8 Hz, 1H), 7.16 (d, J=3.8 Hz, 1H), 6.80 (d, J=6.8 Hz, 1H), 5.37 (q, J=9.0 Hz, 1H), 4.89-4.82 (m, 1H), 4.73 - 4.63 (m, 2H), 4.35-4.30 (m, 3H), 3.52 (t, J=6.3 Hz, 2H), 3.14 - 3.01 (m, 3H), 2.96 (s, 3H), 2.25 (ddd, J=4.0, 9.4, 13.9 Hz, 1H), 1.37-1.30 (m, 6H)

Scheme GGGG - Synthesis of tert-butyl 8-cyano-6-hydroxy-2,3dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate (TP-39)

Scheme GGGG

Zn(CN)₂

T3P DIPEA

THF

GGGG-2

BnOH

NaH, DMF

GGGG-3

DMAP DMF

Boc₂O

GGGG-5

Pd(PPh₃)₄ DMF

H₂O₂, K₂CO₃

DMSO

GGGG-6

GGGG-7

GGGG-8

Tf₂O pyridine

DCM

TP-39

Step 1 - Synthesis of 8-bromo-6-fluoro-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one (GGGG-2)

To a suspension of GGGG-1 (13.8 g, 43.87 mmol, prepared using reference patent US2015/64196) in dry THF (400 mL) was added DIPEA (28.3 g, 219 mmol) and T3P (50% in EtOAc, 41.9 g, 65.8 mmol) at 0 °C. The mixture was stirred at 0 °C for 10 h then at rt 25 °C for 6 h. The mixture was poured into water (400 mL) and extracted with EtOAc (400 mL x 2). The extract was washed with brine (300 mL), dried over Na₂SO₄ and concentrated to give GGGG-2 (9500 mg, 83%) as a light yellow solid. LCMS [M+1] 261.6; ¹H NMR (400 MHz, DMSO-d_s) δ

-278ppm 8.57 (br s, 1H), 7.44 (dd, J=1.8, 9.5 Hz, 1H), 7.22 (s, 1H), 4.22 (t, J=5.5 Hz, 2H), 3.27 (q, J=5.6 Hz, 2H)

Step 2 - Synthesis of 6-(benzyloxy)-8-bromo-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one (GGGG-3)

To a suspension 60% NaH (6 g, 150 mmol) in dry DMF (140 mL) was added a solution of GGGG-2 (6.5 g, 25 mmol) and BnOH (5.41 g, 50 mmol) in dry DMF (70 mL) at rt 25 °C under N₂, then was stirred at rt 25 °C under N₂ for 16 h. The mixture was poured into ice water (400 mL) in which solid was formed. The mixture was filtered. The solid was washed with water and dried in vacuo to afford GGGG-3 (9500 mg, >99%) as a white solid. LCMS [M+1] 347.7; ¹H NMR (400 MHz, DMSO-de) δ ppm 8.27 (brt, J=5.7 Hz, 1H), 7.47 (d, J=6.6 Hz, 2H), 7.42 - 7.36 (m, 2H), 7.35 - 7.29 (m, 1H), 7.26 - 7.15 (m, 1H), 6.93 (d, J=1.4 Hz, 1H), 5.19 (s, 2H), 4.12 (t, J=5.5 Hz, 2H), 3.18 (q, J=5.6 Hz, 2H).

Step 3 - Synthesis of tert-butyl 6-(benzyloxy)-8-bromo-5-oxo-2,3dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate (GGGG-4)

To a solution of GGGG-3 (7.3 g, 21 mmol) in DMF (150 mL) was added Boc₂O (6.86 g, 31.43 mmol), DIPEA (8.13 g, 62.9 mmol) and DMAP (256 mg, 2.1 mmol) at rt 25 °C for 2h. The mixture was poured into water. The solid was collected by filtration and washed with water. The solid was dissolved in EtOAc/THF (50 mL/ 50 mL) and dried over Na₂SO₄and concentrated in vacuo to afford crude GGGG-4 (10 g, >99%) as a yellow gum and used directly in the next step without further purification.

Step 4 - Synthesis of tert-butyl 6-(benzyloxy)-8-bromo-2,3-dihydrobenzo[f][1,4]oxazepine4(5H)-carboxylate (GGGG-5)

To a solution of GGGG-4 (10 g, 21 mmol) in THF (150 mL) was added BH₃.Me₂S (8.39 mL, 83.9 mmol) at rt 25 °C. The mixture was stirred at 60 °C under N₂ for 16 h then stand at rt for 2 days. The reaction was quenched with MeOH (70 mL) slowly. Then the mixture was refluxed for 16 h and concentrated. The crude product was purified by column chromatography (120 g silica column, EtOAc in petroleum ether from 0% to 50%) to afford GGGG-5 (3130 mg, 34%) as a white solid. LCMS [M+23] 456; Ή NMR (400 MHz, CDCI₃) δ ppm 7.52 - 7.31 (m, 5H), 6.84 (bs, 1H), 6.82 (bs, 1H), 5.06 (br s, 2H), 4.64 (br s, 2H), 4.15 - 4.10 (m, 2H), 3.80 (br s, 2H), 1.29 (br s, 9H)

Step 5 - Synthesis of tert-butyl 6-(benzyloxy)-8-cyano-2,3-dihydrobenzo[f][1,4]oxazepine4(5H)-carboxylate (GGGG-6)

Compound GGGG-5 (680 mg, 1.57 mmol), Zn(CN)₂ (368 mg, 3.13 mmol) and Pd(PPh₃)₄ (181 mg, 0.157 mmol) in DMF (10 ml) was sparged with N₂ for 10 min. The mixture was stirred at 120 °C for 3 h. The mixture was cooled, filtered, and concentrated. The residue was purified by

-279 silica gel chromatography eluted with EtOAc in petroleum ether from 0 to 50 % to afford GGGG6 (520 mg, 87%) as a white solid. LCMS [M-Boc+1] 280.9.

Step 6 - Synthesis of tert-butyl 6-(benzyloxy)-8-carbamoyl-2,3dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate (GGGG-7)

To a solution of GGGG-6 (520 mg, 1.37 mmol) and K₂CO₃ (189 mg, 1.37 mmol) in DMSO (5 mL) was added 30% H₂O₂ (465 mg, 4.1 mmol) at rt 25 °C slowly. Note: gas evolved and exothermic. The mixture was stirred at rt 25 °C for 1 h. The mixture was poured into water (10 mL) and filtered. The solid was washed with water. The solid was suspended in MeOH (30 mL) and concentrated in vacuo to afford GGGG-7 (520 mg, 96%) as a white solid. LCMS [M+Na] 421.

Step 7 - Synthesis of tert-butyl 8-carbamoyl-6-hydroxy-2,3dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate (GGGG-8)

A mixture of GGGG-7 (520 mg, 1.31 mmol) and Pd/C (125 mg) in MeOH/THF (15 mL/15 mL) was degassed with H₂ four times. The mixture was stirred at 25 °C under a H₂ balloon for 16 h. The mixture was filtered and concentrated in vacuo to afford GGGG-8 (400 mg, 99%) as a white solid. Ή NMR (400 MHz, DMSO-d₆, rotamers) δ ppm 9.85 (br s, 1 H), 7.80 (br s, 1 H), 7.22 (br s, 1H), 7.11 - 6.97 (m, 1H), 6.92 (br s, 1H), 4.57 (br s, 2H), 4.20 - 4.03 (m, 2H), 3.68 (br s, 2H), 1.42 - 1.13 (m, 9H)

Step 8 - Synthesis of tert-butyl 8-cyano-6-hydroxy-2,3-dihydrobenzo[f][1,4]oxazepine4(5H)-carboxylate (TP-39)

To a suspension of GGGG-8 (100 mg, 0.324 mol) and pyridine (128 mg, 1.62 mol) in anhydrous DCM (2 mL) was added Tf₂O (275 mg, 0.973 mol) at 0 °C and stirred for 0.5 h. The reaction mixture was warmed to 25 °C and stirred for 16 h. The mixture was concentrated in vacuo to dryness. The residue was dissolved in MeOH (3 mL), followed by K₂CO₃ (300 mg). The mixture was stirred at rt 25 °C for 16 h. The reaction was filtered and purified by prep-TLC (petroleum ether/EtOAc 1:1) to afford TP-39 (55 mg, 58%) as a white solid. LCMS [M-Boc+1] 190.8; ¹H NMR (400 MHz, DMSO-d₆, rotamers) δ ppm 10.47 (br s, 1H), 6.83 (br s, 2H), 4.70 4.51 (m, 2H), 4.22-4.18 (m,2H), 3.69 (br s, 2H), 1.46-1.21 (m, 9H)

Scheme HHHH - Synthesis of tert-butyl 8-fluoro-6-hydroxy-2,3dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate (TP -40)

Scheme HHHH

-280-

To a solution of HHHH-1 (prepared using similar method as steps 1-4 in Scheme GGGG using 2-(2-aminoethoxy)-4,6-difluorobenzoic acid, 1980 mg, 5.302 mmol) in MeOH (74 mL) was added 10% wet Pd/C (590 mg) at 25 °C. The mixture was stirred at 25 °C under a H₂ balloon for 1.2 hours. The reaction was filtered and concentrated to yield TP-40 (1420 mg, 95%) as a white solid. LCMS [M-Boc+1] 184.8 Ή NMR (400 MHz, DMSO-de,rotamers) δ ppm 10.60 - 9.69 (bs, 1H), 6.34-6.30 (m, 1H), 6.26 - 6.12 (m, 1H), 4.63 - 4.39 (m, 2H), 4.23 - 4.01 (m, 2H), 3.75 - 3.58 (m, 2H), 1.46 - 1.20 (m, 9H); Ή NMR (400 MHz, DMSO-de, Variable temp 80 °C) δ ppm 6.33 (br d, J=10.3 Hz, 1H), 6.19 (dd, J=2.3, 10.3 Hz, 1H), 4.53 (s, 2H), 4.19 - 4.06 (m, 2H), 3.69 (br t, J=4.4 Hz, 2H), 1.36 (s, 9H)

Scheme llll - Synthesis of tert-butyl 8-chloro-6-hydroxy-2,3dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate (TP-41)

Scheme llll

1111-1

BH₃.Me₂S then HCl

Boc₂O

illl-2 TP-41

Step 1 - Synthesis of 8-chloro-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-6-ol (IIII-2)

To a solution of IIII-1 (prepared using similar method as steps 1-3 in Scheme GGGG using 2(2-aminoethoxy)-4-chloro-6-fluorobenzoic acid, 1000 mg, 3.292 mmol) in dry THF (11 mL) was added BH₃.Me₂S (2.63 mL, 26.3 mmol) at rt 25°C under N₂. After addition, the mixture was heated at 70°C for 16 hours. The mixture was cooled to rt (25°C) and quenched with MeOH (3 mL).The mixture was concentrated as a white solid. The crude product was dissolved in conc HCl (13.7 mL) and heated at 110 °C for 16 hours. The mixture was concentrated to obtain illl-2 (860 mg, >99%) as a light yellow solid which was used in next step directly. LCMS [M+1] 199.7 Step 2 - Synthesis of tert-butyl 8-chloro-6-hydroxy-2,3-dihydrobenzo[f][1,4]oxazepine4(5H)-carboxylate (TP-41)

To a solution of IIII-2 (1171 mg, 3.3 mmol) in MeOH (21 mL) was added TEA (3.58 mL, 25.6 mmol) and Boc₂O (1.32 g, 6.02 mmol) then stirred at r.t. for 2 hours. The mixture was concentrated in vacuum to get crude product (1032 mg) as white solid. The crude product purified by combi-flash (EtOAc/ Petroleum ether=0~50%) to afford TP-41 (520 mg, 30%) as a

-281 white solid. LCMS [M-tBu+1] 243.6; Ή NMR (400 MHz, DMSO-de, rotamers) δ ppm 10.13 (s,

1H), 6.61 - 6.57 (m, 1H), 6.45 (bs, 1H), 4.61 - 4.46 (m, 2H), 4.25 - 4.05 (m, 2H), 3.66 (br s, 2H), 1.42- 1.27 (m, 9H)

Examples 202-204 were prepared using similar chemistry depicted in Scheme CC and employing compounds TP-39, TP-40 & TP-41 respectively

Example 202			422.2	6-(((1 S, 2S,3S,4R)-2,3-dihydroxy-4-(4-
		Ah?	[M+1]	methyl-7H-pyrrolo[2,3-d]pyrimidin-7-
TP-39				yl)cyclopentyl)oxy)-2,3,4,5-
		y OH		tetrahydrobenzo[f][1,4]oxazepine-8-
QH Boc	(T	OH		carbon itrile
ôon				1H NMR (400 MHz, D2O, HCl sait) δ
II J )		N		ppm 8.86 (s, 1H), 7.85 (d, J=3.8 Hz, 1H), 7.25 (d, J=1.0 Hz, 1H), 7.20 (d, J=1.3 Hz, 1H), 7.11 (d, J=3.8 Hz, 1H), 5.35 (q, J=9.2 Hz, 1H), 4.86 - 4.80 (m, 2H), 4.60 (q, J=14.8 Hz, 2H), 4.43 4.26 (m, 3H), 3.66 (t, J=4.9 Hz, 2H), 3.15 - 3.04 (m, 1H), 2.91 (s, 3H), 2.28 - 2.18 (m, 1H)
Example 203			414.9	(1S,2S,3S,5R)-3-((8-fluoro-2,3,4,5-
		CO	[M+1]	tetrahydrobenzo[f][1,4]oxazepin-6-
TP-40				yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-
Boc, ?H		V'OH		d]pyrimidin-7-yl)cyclopentane-1,2-diol
oz	OH		Ή NMR (400 MHz, MeOD, HCl sait) δ
			ppm = 9.07 (s, 1H), 8.12 (d, J=4.0 Hz,
		'F		1H), 7.25 (d, J=3.8 Hz, 1H), 6.86 (dd, J=2.5, 10.8 Hz, 1H), 6.59 (dd, J=2.4, 9.4 Hz, 1H), 5.40 (q, J=9.3 Hz, 1H), 4.77 (dd, J=5.0, 9.3 Hz, 2H), 4.62 4.50 (m, 2H), 4.34 (tdt, J=4.5, 9.3, 13.6 Hz, 2H), 4.25 (d, J=5.0 Hz, 1H), 3.65 (t, J=4.6 Hz, 2H), 3.13 - 3.04 (m, 1H), 3.02 (s, 3H), 2.36 (ddd, J=4.4, 9.7, 14.3 Hz, 1H)

-282 Example 204

431.1

[M+1] (1S,2S,3S,5R)-3-((8-chloro-2,3,4,5tetrahydrobenzo[f][1,4]oxazepin-6yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)cyclopentane-1,2-diol Ή NMR (400 MHz, MeOD) δ ppm 8.65 (s, 1H), 7.59 (d, J=3.7 Hz, 1H), 6.90 (d, J=1.9 Hz, 1H), 6.78 (d, J=3.6 Hz, 1H), 6.71 (d, J=1.9 Hz, 1H), 5.24 (q, J=9.0 Hz, 1H), 4.73 - 4.66 (m, 2H), 4.21 (d, J=5.1 Hz, 1H), 4.16-4.04 (m, 4H), 3.22 - 3.17 (m, 2H), 3.00 (ddd, J=7.5, 9.2, 14.4 Hz, 1H), 2.74 (s, 3H), 2.29-2.15 (m, 1H)

Scheme JJJJ - Synthesis of tert-butyl 8-(difluoromethyl)-6-hydroxy-2,3dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate (TP-42)

Scheme JJJJ

GGGG-5

G3-XantPhos, Et₃SiH, DIPEA, DMF, 75 °C

DAST

DCM

JJJJ-1

JJJJ-2

F

Step 1 - Synthesis of tert-butyl 6-(benzyloxy)-8-formyl-2,3-dihydrobenzo[f][1,4]oxazepine4(5H)-carboxylate (JJJJ-1)

Ref. Manabe, K. et al. Org. Lett., 2013, 5370-5373. A reaction vial was added a solution of 10 GGGG-5 (1.64 g, 3.62 mmol) in anhydrous DMF (18 mL) and N-formylsaccharin (1200 mg, 5.66 mmol), G3 Xantphos (107 mg, 0.113 mmol) and DIPEA (634 mg, 4.91 mmol). The mixture was sparged with N₂for 4 min. To the above solution was added Et₃SiH (571 mg, 4.91 mmol) at 0_oC.

After the addition, the resulting mixture was sparged with N₂ for 5 min and then heated at 75 °C for 16 hours. The reaction mixture was partitioned between EtOAc and water. The organic layer 15 was separated and the aqueous layer was extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried over Na₂SO₄ and concentrated to afford the crude product which was purified via flash column (20 g, gel, EtOAc: petroleum ether 1 %-14%) to afford JJJJ-1 (730 mg, 53%) as a white solid. ¹H NMR (400 MHz, CDCI₃, rotamers) δ ppm 9.87

-283(brs, 1 H), 7.59- 7.30 (m, 5H), 7.21 (bs, 1H), 7.14 (bs, 1H), 5.16 (br s, 2H), 4.75 (br s, 2H), 4.24 -4.17, (m, 2H), 3.85 (br s, 2H), 1.54 - 1.13 (m, 9H)

Step 2 - Synthesis of tert-butyl 6-(benzyloxy)-8-(difluoromethyl)-2,3dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate (JJJJ-2)

To a solution of (930 mg, 2.43 mmol) in anhydrous DCM (49 mL) was added DAST (3.91 g, 24.3 mmol) at 0°C under N₂. After the addition, the reaction mixture was warmed to room température (32 °C) and stirred at this température for 16 hours. The reaction solution was diluted in DCM (50 mL) and sat. aq NaHCO₃ and stirred until CO₂ évolution ceased. The reaction mixture was partitioned between DCM and H₂O. The organic layer was separated, washed with brine, dried over Na₂SO₄ and concentrated to afford the crude product which was purified via flash column (EtOAc: petroleum ether 1 %-15%) to afford JJJJ-2 (530 mg, 54%) as a white solid. ¹H NMR (400 MHz, CDCh, rotamers) δ ppm 7.58 - 7.29 (m, 5H), 6.82 (bs, 1H), 6.79 (bs, 1H), 6.54 (t, J = 54 Hz, 1H), 5.12 (br s, 2H), 4.72 (br s, 2H), 4.21 - 4.07 (m, 2H), 3.83 (brs, 2H), 1.54 - 1.13 (m, 9H)

Step 3 - Synthesis of tert-butyl 8-(difluoromethyl)-6-hydroxy-2,3dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate (TP-42)

To a solution of JJJJ-2 (530 mg, 1.31 mmol) in MeOH (13 mL) was added Pd/C (139 mg, 0.0163 mmol). The mixture was degassed and purged with H₂ three times, then stirred at rt (35 °C) for 16 hours. The reaction was filtered through celite and concentrated. The residue was lyophilized to remove the residual solvent to give TP-42 (360 mg, 87%) as a white solid. LCMS [M-tBu+1] 259.7; ¹H NMR (400 MHz, DMSO-de, rotamers) δ ppm 10.21 - 9.89 (m, 1H), 7.02 6.47 (m, 3H), 4.65 - 4.49 (m, 2H), 4.22 - 4.04 (m, 2H), 3.74 - 3.62 (m, 2H), 1.46 - 1.11 (m, 9H)

Example 205 was prepared using similar chemistry depicted in Scheme CC and employing compound TP-42.

(1S,2S,3S,5R)-3-((8-(difluoromethyl)-

2,3,4,5tetrahydrobenzo[f][1,4]oxazepin-6yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)cyclopentane-1,2-diol Ή NMR (400 MHz, D₂O, HCl sait) δ ppm 8.90 (s, 1H), 7.89 (d, J=3.9 Hz, 1H), 7.15 (d, J=3.7 Hz, 1H), 7.08 (s, 1H), 7.02 (s, 1H), 6.77 (t, J=55.8 Hz, 1H), 5.37 (q, J=9.0 Hz, 1H), 4.91 4.84 (m, 1 H), 4.73 - 4.68 (m, 1 H), 4.60

-284-

(dd, J=13.4, 30.7 Hz, 2H), 4.45 - 4.24 (m, 3H), 3.67 (t, J=4.8 Hz, 2H), 3.15 3.04 (m, 1H), 2.90 (s, 3H), 2.33 - 2.20 (m, 1H)

Scheme KKKK - Synthesis of tert-butyl 6-hydroxy-8-methyl-2,3dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate (TP-43)

Scheme KKKK

TP-43

6-(benzyloxy)-8-methyl-2,3-

dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate (KKKK-1 )

A solution of GGGG-5 (200 mg, 0.46 mmol) in dioxane (9.21 mL) was degassed with N₂ for 5 min. Then bis(tri-tert-butylphosphine)Pd(0) (23.5 mg, 0.05 mmol) and (Me)₂Zn (0.921 mL, 0.92 mmol) was then added to the réaction solution and heated at 90 °C for 16 hours. The reaction solution was poured into EtOAc and 1N HCl (20 mL:20 mL). The mixture was separated and the water layer was washed with EtOAc (20 mL x 2). The organic layers were separated, dried and evaporated to give the crude product, which was purified by flash chromatography, eluted with petroleum ether/EtOAc from 0-25%, to afford KKKK-1 (160 mg, 94%) as a yellow solid. LCMS [M+Na] 392.1; ¹H NMR (400 MHz, DMSO-d₆, rotamers) δ ppm 7.57 - 7.30 (m, 5H), 6.62 (bs, 1H), 6.39 (s, 1H), 5.09 (bs, 2H), 4.65-4.60 (m, 2H), 4.17 - 4.04 (m, 2H), 3.68 (br s, 2H), 2.22 (s, 3H), 1.42 - 1.15 (m, 9H)

Step 2 - Synthesis of tert-butyl 6-hydroxy-8-methyl-2,3-dihydrobenzo[f][1,4]oxazepine4(5H)-carboxylate (TP-43)

Compound KKKK-1 (160 mg, 0.433 mmol) was dissolved in MeOH (8.00 mL). Then Pd/C was added to the reaction solution, then was degassed with H₂ four times and stirred at 30 °C under H₂ (balloon) for 16 hours. DCM (20 mL) was added to dilute the reaction solution, then filtered and concentrated to give the crude product, which was purified by flash chromatography, eluted with petroleum ether/EtOAc from 0-25%, to give TP-43 (100 mg, 83%) as a white solid. LCMS [M-Boc+1] 179.9; Ή NMR (400 MHz, DMSO-d₆, rotamers) δ ppm 9.41 (s, 1H), 6.37-6.35 (m, 1H), 6.22-6.20 (m, 1H), 4.58 - 4.42 (m, 2H), 4.13 - 3.95 (m, 2H), 3.70 - 3.59 (m, 2H), 2.13 (s, 3H), 1.41 - 1.27 (m, 9H)

-285Example 206 was prepared using similar chemistry depicted in Scheme CC and employing compound TP-43

Example 206	CO	411.1 [M+1]	(1S, 2S,3S,5R)-3-((8-methyl-2,3,4,5- tetrahydrobenzo[f][1,4]oxazepin-6-
TP-43	,N N		yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-
	JL / OH		d]pyrimidin-7-yl)cyclopentane-1,2-diol
Bocx ?H	HN^X °H		Ή NMR (400 MHz, D2O, HCl sait) δ
N\A!1			ppm 8.89 (s, 1H), 7.87 (d, J=3.8 Hz,
			1H), 7.14 (d, J=3.8 Hz, 1H), 6.78 (s, 1H), 6.71 (s, 1H), 5.38 (q, J=9.0 Hz, 1H), 4.77 - 4.70 (m, 2H), 4.62 - 4.47 (m, 2H), 4.40 - 4.22 (m, 3H), 3.63 (t, J=4.8 Hz, 2H), 3.09 (ddd, J=7.3, 9.3, 14.7 Hz, 1H), 2.95 (s, 3H), 2.32 (s, 3H), 2.28-2.16 (m, 1H)

Scheme LLLL - Synthesis of tert-butyl (S)-6-hydroxy-3-methyl-2,35 dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate (TP-44)

Scheme LLLL

MeOH/H₂O

LiOH

T3P, DIPEA

THF

Step 1 - Synthesis of methyl (S)-2-(benzyloxy)-6-(2-((tert10 butoxycarbonyl)amino)propoxy)benzoate (LLLL-1)

To a solution of methyl 2-(benzyloxy)-6-hydroxybenzoate (2.80 mg, 10.8 mmol) in THF (40.0 mL) were added PPh₃ (7.11 g, 27.1 mmol) in an ice bath under N₂. DIAD (5.48 g, 27.1 mmol) was added to the above mixture drop-wise then stirred at 25 °C for 40 min. Then tert-butyl (S)(1 -hydroxypropan-2-yl)carbamate (5.70 g, 32.5 mmol) in dry THF (20.0 mL)was added and the 15 reaction stirred at 28 °C for 16 hours. The mixture was diluted with EtOAc (50 mL) and H₂O (100 mL). The mixture was separated and the aqueous layer was extracted with EtOAc (50 mL).

-286The combined organic layers were washed with brine (50 mL), dried over Na₂SO₄, filtered and concentrated to yield crude product which was purified by ISCO (120 g silica gel, petroleum ether:EtOAc=4:1) to yield LLLL-1 (3.50 g, 78%) as a coloriess gum. ¹H NMR (400 MHz, DMSO-ds) δ ppm 7.42 - 7.35 (m, 4H), 7.34 - 7.29 (m, 2H), 6.83 - 6.75 (m, 2H), 6.71 (d, J=8.5 Hz, 1H), 5.16 (s, 2H), 3.95-3.92 (m, 1H), 3.80 - 3.70 (m, 5H), 1.43 - 1.34 (m, 9H), 1.08 (d, J=6.5 Hz, 3H)

Step 2 - Synthesis of methyl (S)-2-(2-aminopropoxy)-6-(benzyloxy)benzoate (LLLL-2)

To a solution of LLLL-1 (4.30 g, 10.3 mmol) in DCM (10 mL) was added HCI(g)/dioxane (~4N, 20 mL) at 0 °C. The mixture was stirred 25 °C for 2 hours. The mixture was concentrated to yield LLLL-2 as the HCl sait (4.00 g, >99%) as a yellow solid, which was used in next step directly.

Step 3 - Synthesis of (S)-2-(2-aminopropoxy)-6-(benzyloxy)benzoic acid (LLLL-3)

To a suspension of LLLL-2 (4.0 g, 3.17 mmol) in MeOH (60 mL) and water (12 mL) was added LiOH.H₂O (3.46 g, 82.4 mmol) at 25 °C. The mixture was stirred 75 °C for 15 hours. The pH of the solution was adjusted to pH~3 with 1N. The solution was evaporated to give the crude product LLLL-3 (3.10 g, >99%) as a white solid which was used for the next step directly without further purification.

Step 4 - Synthesis of (S)-6-(benzyloxy)-3-methyl-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)one (LLLL-4)

To a suspension of LLLL-3 (4.00 g, 5.77 mmol) in dry THF (60 mL) was added DIPEA (3.73 g, 28.9 mmol) and T3P (50% in EtOAc, 7.35 g, 11.5 mmol) at 0 °C. The mixture was stirred 25 °C for 15 hours. The reaction was not complété and DIPEA (3.73 g, 28.9 mmol) and T3P (50% in EtOAc, 7.35 g, 11.5 mmol) was and stirred for another 16 hours. EtOAc (40.0 mL) was added to dilute the solution. The solution was washed with 1N HCl (30 mL), saturated aq NaHCO₃ (30 mL) and brine (30 mL). The organic layers were separated, dried and evaporated to give the crude product which was purified by flash chromatography, eluted with petroleum ether/EtOAc from 0-50% to give the desired product LLLL-4 (900 mg, 55%) as a white solid. LCMS [M+1] 283.9; Ή NMR (400 MHz, DMSO-d₆) δ ppm 8.09 (d, J=6.3 Hz, 1H), 7.51 - 7.44 (m, 2H), 7.41 7.25 (m, 4H), 6.99 - 6.91 (m, 1H), 6.68 (dd, J=0.9, 8.2 Hz, 1H), 5.15 (s, 2H), 3.97 (dd, J=4.3, 10.3 Hz, 1H), 3.86 - 3.77 (m, 1H), 3.46-3.44 (m, 1H), 1.05 (d, J=6.5 Hz, 3H)

Step 5 - Synthesis of tert-butyl (S)-6-(benzyloxy)-3-methyl-5-oxo-2,3dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate (LLLL-5)

To a solution of LLLL-4 (900 mg, 3.18 mmol) in DMF (20.0 mL) were added DIPEA (1.23 g, 9.53 mmol) and DMAP (38.8 mg, 0.318 mmol) at 25 °C. Boc₂O (1.04 mg, 4.76 mmol) and the reaction mixture was stirred at 25 °C for 16 hours. The mixture was diluted with ice-water (20 mL) and extracted with EtOAc (20 mL X 2). The combined organic layers were washed with

-287brine (30 mL X 5), dried over Na₂SO₄ and filtered, concentrated in vacuo to afford crude which was purified by ISCO (4 g silica gel, EtOAc:petroleum ether=18%-20%) to yield LLLL-5 (720 mg, 59%) as a white solid and used directly in the next step. LCMS [M-Boc+1] 238.9

Step 6 - Synthesis of tert-butyl (S)-6-(benzyloxy)-3-methyl-2,3dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate (LLLL-6)

To a solution of LLLL-5 (720 mg, 1.88 mmol) in THF (20 mL) was added BH₃.Me₂S (10 M, 0.751 mL, 7.51 mmol) at 0 °C. The mixture was stirred at 74 °C under N₂ for 2 hours. The reaction was quenched with MeOH (5 mL) slowly and heated at reflux for 16 hours. The mixture was concentrated to give the crude product which was purified by combi flash (40 g silica column, EtOAc in petroleum etherfrom 9-10% to afford LLLL-6 (530 mg, 76.4 %) as a colorless gum. LCMS [M-Boc+1] 270.0; ¹H NMR (400 MHz, DMSO-d₆, rotamers) δ ppm 7.54 - 7.32 (m, 5H), 7.06 (t, J=8.2 Hz, 1H), 6.70 (d, J=8.3 Hz, 1H), 6.46 (dd, J=0.8, 8.3 Hz, 1H), 5.35 - 4.97 (m, 3H), 4.54 - 4.30 (m, 1 H), 4.24 - 4.02 (m, 3H), 1.39-1.22 (m, 9H), 1.06 (m, 3H)

Step 7 - Synthesis of tert-butyl (S)-6-hydroxy-3-methyl-2,3-dihydrobenzo[f][1,4]oxazepine4(5H)-carboxylate (TP-44)

To a solution of LLLL-6 (530 mg, 1.43 mmol) in MeOH (10.0 mL) was added wet 10% Pd/C (100 mg). The reaction solution was stirred at 30 °C under a H₂ balloon for 16 h. Then the mixture was filtered through celite, washed with MeOH, and concentrated to give TP-44 (360 mg, 90%) as a white solid. ¹H NMR (400 MHz, DMSO-ds, rotamers) δ ppm 9.61 - 9.49 (m, 1H), 6.87 (t, J=8.2 Hz, 1 H), 6.44 (d, J=7.8 Hz, 1 H), 6.26 (dd, J=1.0, 8.0 Hz, 1 H), 5.23 - 4.94 (m, 1 H), 4.54 - 4.28 (m, 1 H), 4.15 - 4.00 (m, 3H), 1.39-1.25 (m, 9H), 1.06 (d, J=6.8 Hz, 3H)

Compound TP-45 was prepared using similar conditions as Scheme LLLL using tert-butyl (R)(1-hydroxypropan-2-yl)carbamate in step 1

TP-45

179.9

[M-Boc+1] tert-butyl (R)-6-hydroxy-3-methyl-2,3dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate ¹H NMR (400 MHz, CDCI₃, rotamers) δ ppm 8.15 7.57 (m, 1H), 6.81 (br t, J=7.9 Hz, 1H), 6.43 (br d, J=8.0 Hz, 1H), 6.39 - 6.20 (m, 1H), 4.96 (d, J=16.1 Hz, 1H), 4.71 - 4.31 (m, 1H), 4.17 - 4.03 (m, 2H), 3.87 (br dd, J=3.8, 12.5 Hz, 1H), 1.53 - 1.35 (m, 9H), 1.32 (brd, J=6.8 Hz, 3H)

Examples 207 & 208 were prepared using similar chemistry depicted in Scheme CC and employing compounds TP-44 & TP-45, respectively

-288Example 207

TP-44

Example 208

TP-45

410.9

[M+1]

(1 S,2S,3S,5R)-3-(((S)-3-methyl2,3,4,5tetrahydrobenzo[f][1,4]oxazepin-6yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)cyclopentane-1,2-diol 1H NMR (400 MHz, DMSO-d6) δ ppm

8.65 (s, 1H), 7.67 (d, J=3.6 Hz, 1H), 7.08 (t, J=8.1 Hz, 1H), 6.83 - 6.69 (m, 2H), 6.59 (d, J=8.0 Hz, 1H), 5.32 (d, J=4.0 Hz, 1H), 5.19 - 5.07 (m, 2H), 4.59 - 4.50 (m, 2H), 4.35 (d, J=14.9 Hz, 1H), 4.19 (dd, J=2.4, 11.8 Hz, 1H), 4.01 (br s, 1H), 3.59 (brd, J=14.7 Hz, 1H), 3.39 (br s, 1H), 3.15 (br d, J=6.5 Hz, 1H), 2.89 - 2.77 (m, 1H),

2.65 (s, 3H), 2.45-2.50 (m, 1H), 2.03 1.91 (m, 1H), 0.97 (d, J=6.5 Hz, 3H) (1 S,2S,3S,5R)-3-(((R)-3-methyl2,3,4,5tetrahydrobenzo[f][1,4]oxazepin-6yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)cyclopentane-1,2-diol Ή NMR (400 MHz, D₂O, HCl sali) δ ppm 8.81 (s, 1H), 7.77 (d, J=3.8 Hz, 1H), 7.32 (t, J=8.3 Hz, 1H), 7.07 (d, J=3.8 Hz, 1H), 6.86 (d, J=8.0 Hz, 1H), 6.77 (d, J=7.8 Hz, 1H), 5.31 (q, J=8.9 Hz, 1H), 4.84 - 4.73 (m, 3H), 4.42 (dd, J=2.5, 13.3 Hz, 1H), 4.34 (dd, J=1.4, 4.9 Hz, 1H), 4.21 (d, J=14.6 Hz, 1H), 3.93 - 3.72 (m, 2H), 3.11 - 2.94 (m, 1H), 2.88 (s, 3H), 2.24 - 2.11 (m, 1H), 1.28 (d, J=6.5 Hz, 3H)

Scheme MMMM - Synthesis of tert-butyl (R)-6-hydroxy-2-methyl-2,3dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate (TP-46)

-289Scheme MMMM

MMMM-1 MMMM-2 TP-46 step 1 - Synthesis of tert-butyl (R)-6-(benzyloxy)-2-methyl-2,3dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate (MMMM-1 )

To a compound MMMM-1 (prepared in a similar method as steps 1-5 in Scheme LLLL using tert-butyl (R)-(2-hydroxypropyl)carbamate), 500 mg, (1.5 mmol) in dry THF (10.0 mL) was added LAH (233 mg, 6.14 mmol) at 25 oC. The mixture was stirred at 75 °C for 2 h. The reaction was cooled to r.t., in which water (2.0 mL) was added to the reaction foilowed by Boc₂0 (670 mg, 3.07 mmol). The mixture was stirred for 2.5 h at r.t., then water was added and the reaction extracted with EtOAc (10 mL x3), dried with Na₂SO₄, concentrated to give the crude product which was purified by ISCO (20 g, silica gel, EtOAc/petroleum ether=15 %) to yield MMMM-2 (520 mg, 92%) as a colorless gum. LCMS [M-Boc+1] 269.9

Step 2 - Synthesis of tert-butyl (R)-6-hydroxy-2-methyl-2,3dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate (TP-46)

Compound MMMM-2 (520 mg, 1.3 mmol) dissolved in MeOH (10 mL) was added Pd/C (100 mg, 0.940 mmol). The reaction solution was stirred at 25 °C under H₂ for 2 h. Then the mixture was filtered through celite, washed with MeOH, and concentrated. The residue was purified by ISCO (20 g, silica gel, EtOAc/petroleum ether=25 %) to afford TP-46 (234 mg, 67%) as a white solid. LCMS [M-Boc+1] 179.7; Ή NMR (400 MHz, CDCI₃) δ ppm 7.55 (s, 1H), 7.06 (t, J=8.1 Hz, 1H), 6.73 (d, J=8.1 Hz, 1H), 6.67 - 6.55 (m, 1H), 4.64 (d, J=14.7 Hz, 1H), 4.15 - 4.07 (m, 1H), 3.90 (brd, J=14.4 Hz, 1H), 3.84- 3.76 (m, 1H), 3.29 (dd, J=8.9, 14.5 Hz, 1H), 1.41 (s, 9H), 1.29 (d, J=6.5 Hz, 3H)

Compound TP-47 was prepared in a similar method as Scheme MMMM using tert-butyl (S)-(2 hydroxypropyl)carbamate

TP-47

179.8

[M-Boc+1] tert-butyl (S)-6-hydroxy-2-methyl-2,3-

dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate

Ή NMR (400 MHz, CDCh) δ ppm 7.56 (s, 1H), 7.05 (t, J=8.2 Hz, 1H), 6.72 (d, J=8.0 Hz, 1H), 6.66 - 6.59 (m, 1H), 4.63 (d, J=14.3 Hz, 1H), 4.14 - 4.07 (m, 1H), 3.89 (br d, J=14.6 Hz, 1H), 3.85 - 3.76 (m, 1H), 3.29

-290-

(dd, J=8.8, 14.3 Hz, 1H), 1.40 (s, 9H), 1.29 (d, J=6.5 Hz, 3H)

Examples 209 & 210 were prepared using simiiar chemistry depicted in Scheme CC and employing compounds TP-46 & TP-47, respectively.

Example 209

TP-46

Exampîe 210

TP-47

411.2

[M+1] (1 S,2S,3S,5R)-3-(((R)-2-methyl2,3,4,5tetrahydrobenzo[f][1,4]oxazepin-6yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)cyclopentane-1,2-diol Ή NMR (400 MHz, D₂O, HCl sait) δ ppm 8.80 (s, 1H), 7.77 (d, J=3.8 Hz, 1H), 7.30 (t, J=8.4 Hz, 1H), 7.06 (d, J=3.8 Hz, 1H), 6.84 (d, J=8.3 Hz, 1H), 6.76 (d, J=8.0 Hz, 1H), 5.28 (q, J=9.0 Hz, 1H), 4.84 - 4.75 (m, 3H), 4.32 (dd, J=1.6, 4.9 Hz, 1H), 4.26 - 4.13 (m, 2H), 3.56 (br d, J=12.5 Hz, 1H), 3.34 (dd, J=10.5, 13.8 Hz, 1H), 3.06 - 2.94 (m, 1H), 2.87 (s, 3H), 2.23 - 2.09 (m, 1H), 1.38 (d, J=6.5 Hz, 3H)

410.9

[M+1] (1 S,2S,3S,5R)-3-(((S)-2-methyl2,3,4,5tetrahydrobenzo[f][1,4]oxazepin-6yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)cyclopentane-1,2-diol Ή NMR (400 MHz, MeOD, HCl sait) δ ppm 9.04 (s, 1H), 8.09 (d, J=3.8 Hz, 1H), 7.36 (t, J=8.2 Hz, 1H), 7.22 (d, J=3.8 Hz, 1H), 6.98 (d, J=8.3 Hz, 1H), 6.80 (d, J=8.3 Hz, 1H), 5.42 (q, J=9.2 Hz, 1H), 4.81- 4.72 (m, 3H), 4.33 (d, J=16 Hz, 1H), 4.29 - 4.22 (m, 2H), 3.63 - 3.60 (m, 1H), 3.42-3.39 (m, 1H), 3.14 - 3.05 (m, 1H), 3.01 (s, 3H), 2.33 (ddd, J=4.4, 9.8, 14.2 Hz, 1H),

- 291 -

1.48 (d, J=6.5 Hz, 3H)

Scheme NNNN - Synthesis of tert-butyl-6-(difluoromethyl)-5-fluoro-8-hydroxy-4-methyl3,4-dihydroisoquinoline-2(1 H)-carboxylate (TP-48)

Scheme NNNN

ί-BuOLi, BnOH DMSO, 80’C

PivONH₂*TfOH T₃P, DIPEA, THF 0°C - rt

[Cp‘RhCI₂]₂ (2.5 mol%) bar propene CsOPiv, TFE, 40’C

BH₃*SMe₂ THF, reflux

NNNN-3 n-BuLi, THF, -78’C Then DMF

NNNN-4

wt% Pd/C (10 mol%) atm H₂ MeOH, rt

TP-48

Step 1 : Synthesis of 2-(benzyloxy)-4-bromo-5-fluorobenzoic acid (ZZZ-6)

To a round bottom flask, equipped with a magnetic stirbar, was added lithium tert-butoxide (3.81 g, 47.6 mmol) and DMSO (119 mL, 0.2M). The flask was fitted with a fendenser and benzyl alcohol (4.95 mL, 47.6 mmol) was added. The flask was placed in a heating mantle and heated to 80°C for 5 minutes. The flask was removed and ZZZ-1 (5.64 g, 23.8 mmol) was added. The flask was returned to the heating mantle adn heated at 80°C for 17 hours. The reaction was removed from the heating mantle and ailowed to cool to rt. The solution was poured into 1.2 L of water and acidified with 48 mL of 1M HCl aq. resulting in a tan precipitate. The solids were filtered and washed with water. The solids were collected and dried in a vacuum oven for 3.5 hours at 80°C to afford the title compound ZZZ-6 (7.21 g, 93%) as a light tan solid. ¹H NMR (400MHz, DMSO-d6) δ ppm 13.10 (br. s., 1H), 7.61 (d, J=8.8 Hz, 1H), 7.57 (d, J=5.6 Hz, 1H), 7.48 (d, J=7.1 Hz, 2H), 7.44 - 7.36 (m, 2H), 7.35 - 7.28 (m, 1H), 5.22 (s, 2H).

Step 2: Synthesis of 2-(benzyloxy)-4-bromo-5-fluoro-N-(pivaloyloxy)benzamide (ZZZ-7)

To a round bottom flask, equipped with a magnetic stirbar, was added ZZZ-6 (5.73 g, 17.6 mmol) and THF (176 mL, 0.1M). The solution was cooled to 0°C and T3P (24.7 g, 38.8 mmol)

-292was added as a 50%wt. solution in EtOAc. Afterthe addition, the reaction mixture was stirred for 30 min at 25°C. To the above solution was added DIPEA (18.4 mL, 106 mmol) followed by FF-3 (5.18 g, 19.4 mmol). After the addition, the reaction mixture was stirred at 25°C for 1 hour. The reaction was quenched with water, diluted with EtOAc, and transferred to a separatory funnel. The phases were separated and the organic phase was washed with 1 portion 10% citric acid, 1 portion sat. NaHCO₃, and 1 portion brine. The organic extract was then dried (MgSO₄), filtered, and concentrated under vacuum. The crude residue was purified via flash column chromatography (12g SiO₂, Isco, 100% Hept. to 100% EtOAc, 9 mL fractions) to afford the title compound ZZZ-7 (6.24 g, 83%) as a white solid. Ή NMR (400MHz, CHLOROFORM-d) δ ppm 10.79 (s, 1H), 7.94 (d, J=8.9 Hz, 1 H), 7.52 - 7.35 (m, 5H), 7.27 - 7.23 (m, 1 H), 5.26 (s, 2H), 1.34 (s, 9H).

Step 3: Synthesis of 8-(benzyloxy)-6-bromo-5-fluoro-4-methyl-3,4-dihydroisoquinolin1(2H)-one (NNNN-1)

To a 80 mL steel reactor was added ZZZ-7 (4.00 g, 9.43 mmol), Césium pivalate (4.41 g, 18.9 mmol), [Cp‘RhCI₂]₂ (166 mg, 0.236 mmol) and trifluoroethanol (47 mL, 0.2M). The reactor was purged with nitrogen 3 times followed by 3 cycles of purging with propylene gas. The reaction was heated to 40°C under 4 bar of propylene gas for 3 days. The solution was quenched with NaHCO₃ aq. and transferred to a separatory funnel with DCM. The phases were separated and the aqueous phase was extracted with 2 portions DCM. The combined organic extracts were dried (MgSO₄), filtered, and concentrated under vacuum. The crude residue was purified via flash column chromatography (40g SiO₂, Isco, 100% Hept. to 10% MeOH/EtOAc, 25 mL fractions) to afford the title compound NNNN-1 (2.27 g, 66%, 9:1 r.r.) as a brown solid. LCMS [M+H] = 364 observed. Ή NMR (400MHz, CHLOROFORM-d) δ ppm 7.55 (d, J=7.5 Hz, 2H), 7.47 - 7.36 (m, 2H), 7.35 - 7.28 (m, 1H), 7.13 (d, J=5.5 Hz, 1H), 5.92 (d, J=3.8 Hz, 1H), 5.27 5.19 (m, 1H), 5.16 - 5.10 (m, 1H), 3.69 (dd, J=4.0, 12.7 Hz, 1H), 3.40 - 3.30 (m, 1H), 3.23 (ddd, J=1.3, 6.0, 12.6 Hz, 1H), 1.36 (d, J=7.1 Hz, 3H).

Step 4: Synthesis of tert-butyl-8-(benzyloxy)-6-bromo-5-fluoro-4-methyl-1-oxo-3,4dihydroisoquinoline-2(1 H)-carboxylate (NNNN-2)

To a round bottom flask, equipped with a magnetic stirbar and containing NNNN-1 (1.20 g, 3.29 mmol) was added DCM (11.0 mL, 0.3M), DIPEA (0.86 mL, 4.94 mmol), (Boc)₂O (1.08 g, 4.94 mmol), and DMAP (60.4 mg, 0.494 mmol). The flask was fitted with a findenser and placed in a heating block. The reaction was heated at 40°C for 16 hours. The flask was removed from the heating block and allowed to cool to rt. The reaction was quenched with water and transferred to a separatory funnel with DCM. The phases were separated and the aqueous phase was extracted with 2 portions DCM. The combined organic extracts were dried (MgSO₄), filtered, and concentrated under vacuum. The crude residue was purified via flash column chromatography

-293(40g SiO₂, Isco, 100% Hept to 100% EtOAc, 9 mL fractions) to afford the title compound NNNN2 (1.41 g, 92%) as a white foam. LCMS [M+H-Boc] = 364 observed. ¹H NMR (400MHz, CHLOROFORM-d) δ ppm 7.55 (d, J=7.5 Hz, 2H), 7.44 - 7.35 (m, 2H), 7.32 (d, J=7.3 Hz, 1H), 7.11 (d, J=5.6 Hz, 1H), 5.28 - 5.20 (m, 1H), 5.18 - 5.09 (m, 1H), 4.21 (dd, J=2.2, 13.2 Hz, 1H), 3.61 (dd, J=3.2, 13.1 Hz, 1H), 3.39 - 3.27 (m, 1H), 1.59 (s, 9H), 1.33 (d, J=7.1 Hz, 3H).

Step 5: Synthesis of fert-butyl-8-(benzyloxy)-6-bromo-5-fluoro-4-methyl-3,4dihydroisoquinoline-2(1H)-carboxylate (NNNN-3)

To a round bottom flask, equipped with a magnetic stirbar and containing NNNN-2 (1.41 g, 3.04 mmol), was added THF (15 mL, 0.2M) and borane dimethylsulfide complex (1.44 mL, 15.2 mmol). The flask was fitted with a findenser and transferred to a heating block. The reaction was heated at 70°C for 30 minutes. The flask was removed from the heating block and allowed to cool gradually to rt. The reaction was quenched by dropwise addition of methanol until the évolution of gas was complété, followed by dilution with heptane. The solution was concentrated under vacuum. The crude residue was purified via flash column chromatography (40g SiO₂, Isco, 100% Hept to 10% EtOAc/Hept. to 100% EtOAc, 9 mL fractions) to afford the title compound NNNN-3 (1.13 g, 82%) as a white foam. LCMS [M+H-Boc] = 350 observed. ¹H NMR (400MHz, CHLOROFORM-d) δ ppm 7.47 - 7.30 (m, 5H), 6.93 (d, J=5.5 Hz, 1H), 5.18 - 4.79 (m, 3H), 4.26 - 3.96 (m, 2H), 3.28 - 2.95 (m, 2H), 1.51 (s, 9H), 1.25 (d, J=6.8 Hz, 3H).

Step 6: Synthesis of tert-butyl-8-(benzyloxy)-5-fluoro-6-formyl-4-methyl-3,4dihydroisoquinoline-2(1 H)-carboxylate (NNNN-4)

Note: nBuLi was titrated, THF was dried over activated 4A molecular sieves, and syringe needles were oven dried @ 85C under vacuum prior to use.

A round bottom flask containing NNNN-3 (1.00 g, 2.22 mmol) was dried under high vacuum overnight, equipped with a magnetic stirbar, and purged with argon under dynamic vacuum. To the flask was added THF (11.0 mL, 0.2M) and the solution was cooled to -78°C with a AcMe/dry ice bath. To the cooled solution was added n-butyl lithium (1.7 mL, 2.30 mmol) dropwise to induce metal-halogen exchange. The reaction was stirred at -78°C under argon for 30 minutes. Note: The reaction turns bright orange upon dropwise addition of nBuLi.

To the solution was added DMF (0.26 mL, 3.4 mmol) dropwise at -78 C. At this stage, the ice bath was removed and the reaction was allowed to warm gradually to room température.

Note: The reaction turns pale yellow upon warming to room température.

The reaction was reverse quenched by addition of the reaction solution to sat. NH4CI aq. (10 mL). The aqueous phase was extracted with 4 portions DCM. The combined organic extracts were dried (MgSO₄), filtered, and concentrated under vacuum. The crude residue was purified via flash column chromatography (24 g S1O2, Isco, 100% Hept. to 100% EtOAc, 20 mL fractions) to afford the title compound NNNN-4 (885 mg, >95%) as a white waxy solid. LCMS

-294[M+H-Boc] = 300 observed. Ή NMR (400MHz, CHLOROFORM-d) δ ppm 10.34 (s, 1H), 7.48 7.31 (m, 5H), 7.21 (d, J=5.3 Hz, 1H), 5.29 - 4.87 (m, 3H), 4.32 - 4.03 (m, 2H), 3.35 - 3.18 (m, 1H), 3.17-3.00 (m, 1H), 1.52 (s, 9H), 1.29 (d, J=6.8 Hz, 3H).

Step 7: Synthesis of tert-butyl-8-(benzyloxy)-6-(difluoromethyl)-5-fluoro-4-methyl-3,4dihydroisoquinoline-2(1 H)-carboxylate (NNNN-5)

A scintillation vial, equipped with a magnetic stirbar and containing NNNN-4 (1.77 g, 4.43 mmol), was purged with argon under dynamic vacuum. The vial was charged with DCM (44 mL, 0.1 M) and the solution was cooled to 0°C followed by the dropwise addition of DAST (1.46 mL,

11.1 mmol). The ice bath was removed and the solution was allowed to gradually warm to rt. The reaction was stirred under argon for 24 hours. During the course of the reaction, 2 additional aliquots of DAST (1.46 mL, 11.1 mmol) were added at 12 and 17 hours respectively to drive conversion (7.5 équivalents of DAST total). The reaction was quenched via the dropwise addition of sat. NaHCO₃ aq. CAUTION. Rapid évolution of CO₂ gas occurs during quench. The contents of the vial were transferred to a separatory funnel with DCM and diluted with water. The phases were separated and the aqueous phase was extracted with 3 portions DCM. The combined organic extracts were dried (MgSCU), filtered, and concentrated under vacuum. The crude residue was purified via flash column chromatography (40g SiO₂, Isco, 100% Hept. to 100% EtOAc, 20 mL fractions) to afford the title compound NNNN-5 (1.59 g, 85%) as a pale yellow gum. LCMS [M+H-Boc] = 322 observed. ¹H NMR (400MHz, CHLOROFORM-d) δ ppm 7.49 - 7.29 (m, 5H), 6.95 (d, J=5.3 Hz, 1H), 6.89 (t, J=55.1 Hz, 1H),

5.22 - 4.90 (m, 3H), 4.27 - 4.02 (m, 2H), 3.28 - 2.96 (m, 2H), 1.51 (s, 9H), 1.26 (d, J=7.0 Hz, 3H).

Step 8: Synthesis of tert-butyl-6-(difluoromethyl)-5-fluoro-8-hydroxy-4-methyl-3,4dihydroisoquinoline-2(1 H)-carboxylate (TP-48)

To a 500 mL round bottom flask, equipped with a magnetic stirbar and containing NNNN-5 (1.65 g, 3.91 mmol), was added methanol (78 mL, 0.05M). To the solution was added Pd/C 10wt% (417 mg, 0.391 mmol) and the solution was purged with hydrogen gas under dynamic vacuum. The reaction was stirred vigorously under 1 atm of hydrogen for 1.5 hours. The reaction was filtered over celite, the solids washed with DCM, and the filtrate concentrated under vacuum. The crude residue was purified via flash column chromatography (24g SiO₂, Isco, 100% Hept. to 100% EtOAc, 20 mL fractions) to afford the title compound TP-48 (1.15 g, 88%) as a white foam. LCMS [M+H-Boc] = 232 observed. Ή NMR (400MHz, CHLOROFORM-d) δ ppm 7.00 6.65 (m, 2H), 5.22 - 4.79 (m, 1H), 4.29 - 3.94 (m, 2H), 3.28 - 2.95 (m, 2H), 1.58 - 1.51 (m, 9H),

1.23 (d, J=7.0 Hz, 3H).

-295 Scheme 0000 - Synthesis of fert-butyl-5-fluoro-8-hydroxy-1-methyl-3,4dihydroisoquinoline-2(1 H)-carboxylate (TP-49)

Scheme 0000

PhMe, 130’0 Microwave

OOOO-1

0000-2 (O)PCI₃, Et₃NBnCI

Me₂NPh

MeCN, 80°C

Pd(PPh₃)₄ (5 mol%)

ZnMe₂, THF reflux

[Cp*RhCI₂]₂ (0.5 mol%)

CsOPiv norbornadiene TFE, 45°C

PtO₂ (20 mol%) bar H₂ HCl, MeOH

(Boc)₂O, TEA

DCM, rt

0000-5

Step 1 :

Synthesis of 7-(benzyloxy)-1O-fluoro-1,4a,5,1 Ob-tetrahydro-1,4methanophenanthridin-6(4H)-one (0000-1 )

To a round bottom flask, equipped with a magnetic stirbar, was added VVV-4 (2.29 g, 6.63 mmol), césium pivalate (3.10 g, 13.3 mmol), [Cp*RhCl2]2 (20.5 mg, 0.0332 mmol), and trifluoroethanol (33 mL, 0.2M). The flask was capped with a rubber septum and norbornadiene (0.74 mL, 7.29 mmol) was added. The flask was placed in a heating mantle and the reaction was heated to 45°C for 40 minutes. The flask was removed from the heating block and allowed to cool to rt. The solution was diluted with water followed by DCM and the phases were separated. The organic phase was washed with 1 portion water, dried (MgSO₄), filtered, and concentrated under vacuum. The crude residue was further dried under high vacuum to afford the title compound 0000-1 as an orange solid which was used in the next step without further purification. LCMS [M+H] = 336 observed.

Step 2: Synthesis of 8-(benzyloxy)-5-fluoroisoquinolin-1(2H)-one (0000-2)

To a microwave vial, equipped with a magnetic stirbar, was added 0000-1 (~6.63 mmol) as a solution in toluene (15 mL, 0.44M). The vial was sealed with a tefion cap and placed in the microwave reactor. The reaction was heated to 130°C for 1 hour. The solution was transferred to a round bottom flask with DCM and concentrated under vacuum. The crude residue was further dried under high vacuum to afford the title compound 0000-2 (1.79 g, >95%) as a brown solid which was used in the next step without further purification. LCMS [M+H] = 270 observed. ¹H NMR (400MHz, DMS0-d6) δ ppm 11.07 (br. s., 1H), 7.62 (d, J=7.2 Hz, 2H), 7.46 (t, J=9.3 Hz, 1H), 7.39 (t, J=7.5 Hz, 2H), 7.33 - 7.27 (m, 1H), 7.24 - 7.19 (m, 1H), 7.00 (dd, J=4.2, 9.0 Hz, 1H), 6.45 (d, J=7.1 Hz, 1H), 5.20 (s, 2H).

-296Step 3: Synthesis of 8-(benzyloxy)-1-chloro-5-fluoroisoquinoline (OOOO-3)

To a reaction vial, equipped with a magnetic stirbar, was added benzyltriéthylammonium chloride (846 mg, 3.71 mmol) and 00 00-2 (500 mg, 1.86 mmol) as a solution in acetonitrile (19 mL, 0.1 M). The vial was sealed with a teflon cap and dimethylaniline (0.35 mL, 2.79 mmol) was added followed by the dropwise addition of phosphorous oxychloride (1.04 mL, 11.1 mmol). The vial was placed in a heating block and heated at 80°C for 10 minutes. The solution was concentrated and the crude residue was transferred to a separatory funnel with DCM and diluted with water. The phases were separated and the aqueous phase was extracted with 2 portions DCM. The combined organic extracts were dried (MgSCU), filtered, and concentrated under vacuum. The crude residue was purified via flash column chromatography (24g SiO₂, Isco, 100% Hept. to 100% EtOAc, 9 mL fractions) to afford the title compound OOOO-3 (465 mg, 87%) as a light orange solid. LCMS [M+H] = 288 observed. ¹H NMR (400MHz, CHLOROFORM-d) δ ppm 8.32 (d, J=5.6 Hz, 1H), 7.78 (d, J=5.6 Hz, 1H), 7.56 (d, J=7.2 Hz, 2H), 7.48 - 7.28 (m, 4H), 6.97 (dd, J=4.3, 8.7 Hz, 1H), 5.27 (s, 2H).

Step 4: Synthesis of 8-(benzyloxy)-5-fluoro-1-methylisoquinoline (OOOO-4)

To an oven dried reaction vial, equipped with a magnetic stirbar and cooled under a stream of argon, was added OOOO-3 (422 mg, 1.47 mmol) and Pd(PPh₃)₄ (84.7 mg, 0.0733 mmol). The vial was capped with a rubber septum and purged with argon under dynamic vacuum. To the vial was added THF (7.33 mL, 0.2M) followed by the dropwise addition of dimethyl zinc (2.20 mL, 4.40 mmol). The vial was sealed with a teflon cap and placed in a heating block. The reaction was refluxed at 75°C for 1 hour. The vial was removed from the heating block and allowed to cool to rt. The reaction was carefuliy quenched by the dropwise addition of sat. NH₄CI aq. The solution was transferred to a separatory funnel with DCM. The phases were separated and the aqueous phase was extracted with 3 portions DCM. The combined organic extracts were washed with 1 portion brine, dried (MgSCU), filtered, and concentrated under vacuum. The crude residue was purified via flash column chromatography (12g SiO₂, Isco, 100% Hept. to 100% EtOAc, 9 mL fractions) to afford (356 mg) of a light orange solid. The isolated material was re-subjected to flash column chromatography (12g SiO₂, Isco, 100% Hept. to 10% MeOH/EtOAc, 9 mL fractions) to afford the title compound 0000-4 (310 mg, 79%) as a white solid. The isolated solid was used in the next step with -80% purity based on ¹H NMR analysis. LCMS [M+H] = 268 observed. ¹H NMR (400MHz, CHLOROFORM-d) d = 8.43 (d, J=5.7 Hz, 1H), 7.68 (d, J=5.9 Hz, 1H), 7.50 (d, J=7.1 Hz, 2H), 7.47 - 7.39 (m, 3H), 7.22 (t, J=8.9 Hz, 1H), 6.86 (dd, J=4.3, 8.6 Hz, 1H), 5.22 (s, 2H), 3.10 (s, 3H).

Step 5: Synthesis of 5-fluoro-1-methyl-1,2,3,4-tetrahydroisoquinolin-8-ol (0000-5)

-297To a steel reactor was added 0000-4 (250 mg, 0.935 mmol), PtO₂ (42.5 mg, 0.187 mmol), éthanol (15 mL) and acetic acid (0.5 mL). The solution was hydrogenated under 45 psi of hydrogen gas at rt for 20 hours. The solution was filtered through celite and the solids washed with éthanol. The filtrate was concentrated under vacuum to give the title compound 0000-5 (178 mg, >95%) as slight yellow solid which was used in the next step without further purification. Ή NMR (400MHz, METHANOL-d4) δ ppm 6.92 - 6.85 (m, 1H), 6.71 - 6.65 (m, 1H), 4.69 (q, J=6.7 Hz, 1 H), 3.51 - 3.37 (m, 2H), 3.06 - 2.84 (m, 2H), 1.62 (d, J=6.8 Hz, 3H)

Step 6: Synthesis of tert-butyl 5-fluoro-8-hydroxy-1-methyl-3,4-dihydroisoquinoline-2(1H) carboxylate (TP-49)

To a round bottom flask, equipped with a magnetic stirbar and containing 0000-5 (130 mg, 0.717 mmol), was added methanol (10 mL, 0.07M), (Boc)₂O (157 mg, 0.717 mmol), and trimethylamine (145 mg, 1.43 mmol). The reaction was stirred at 25°C for 2.5 hours. The solution was concentrated under vacuum. The crude residue was purified via flash column chromatography (20g SiO₂, Isco, 25% EtOAc/pet ether) to afford the title compound TP-49 (158 mg, 78%) as a white solid. ^{* 1}H NMR (400MHz, CHLOROFORM-d) δ ppm 6.81 - 6,69 (m, 1H), 6.55 (dd, J=4.4, 8.7 Hz, 1H), 5.54 - 5.20 (m, 1H), 4.32 - 4.03 (m, 1H), 3.36-3.07 (m, 1H), 2.86 2.66 (m, 2H), 1.51 (s, 9H), 1.43 (d, J=6.6 Hz, 3H).

Examples 211 - 214 were made in a similar fashion as Examples 182 & 183 (Scheme YYY) starting with the appropriate racemic tetrahydroisoquinoline in step 1 and separating the diastereomers prior to the final deprotection.

463 observed [M+H] (1S,2S,3S,5R)-3-((6(difluoromethyl)-5fluoro-4-methyl-1,2,3,4tetrahydroisoquinolin-8yl)oxy)-5-(4-methyl-7Hpyrrolo[2,3-d]pyrimidin7-yl)cyclopentane-1,2diol

Example 211 (Isomer

1) - Ή NMR (400MHz, DEUTERIUM OXIDE) δ ppm 8.83 (s, 1H), 7.80

-298-

			(br s, 1H), 7.14 - 6.80 (m, 3H), 5.32 (q, J=9.0 Hz, 1H), 4.78 (br s, 2H), 4.48 - 4.37 (m, 1H), 4.32 - 4.18 (m, 2H), 3.50 - 3.32 (m, 3H), 3.10 - 2.98 (m, 1H), 2.89 (s, 3H), 2.24 2.13 (m, 1H), 1.33 (d, J=6.8 Hz, 3H).
			Example 212 (Isomer 2) - Ή NMR (400MHz, DEUTERIUM OXIDE) δ ppm 8.83 (s, 1H), 7.80 (d, J=3.7 Hz, 1H), 7.14 - 6.77 (m, 3H), 5.32 (q, J=9.1 Hz, 1H), 4.80 4.78 (m, 1H), 4.64 (br dd, J=5.0, 8.9 Hz, 1H), 4.47 - 4.35 (m, 1H), 4.30 - 4.20 (m, 2H), 3.51 - 3.30 (m, 3H), 3.09 - 2.95 (m, 1H), 2.88 (s, 3H), 2.26 2.10 (m, 1H), 1.32 (d, J=6.8 Hz, 3H).
Examples 213 &		413	(1S,2S,3S,5R)-3-((5-
214:		observed	fluoro-1-methyl-1,2,3,4-
TP-49		[M+H]	tetrahydroisoquinolin-8-
OH |	Γ/,,ιοη		yl)oxy)-5-(4-methyl-7H-
	IT OH		pyrrolo[2,3-d]pyrimidin-
	ΗνΧ|?Π		7-yl)cyclopentane-1,2-
F	F		diol

-299Examples 215 & 216 were made in a similar fashion as

Example 213 (Isomer

1) - ¹H NMR (400MHz, METHANOL-d4) δ ppm 9.04 (s, 1H), 8.03 (d, J=3.3 Hz, 1H), 7.23 (d, J=3.4 Hz, 1H), 7.14 6.96 (m, 2H), 5.39 (q, J=9.1 Hz, 1H), 4.79 (br dd, J=4.9, 9.3 Hz, 3H), 4.27 (br d, J=4.2 Hz, 1H), 3.67 - 3.48 (m, 2H), 3.19 - 2.95 (m, 6H), 2.29 (br t, J=10.1 Hz, 1H), 1.75 (d, J=6.5 Hz, 3H).

Example 214 (Isomer

2) - Ή NMR (400MHz, METHANOL-d4) ?= 9.03 (s, 1H), 8.08 (d, J=3.4 Hz, 1H), 7.25 (d, J=3.4 Hz, 1H), 7.14 7.01 (m, 2H), 5.37 (q, J=9.2 Hz, 1H), 4.82 4.73 (m, 3H), 4.22 (br d, J=4.5 Hz, 1H), 3.63 3.54 (m, 2H), 3.20 2.99 (m, 6H), 2.38 (ddd, J=3.9, 9.7, 13.8 Hz, 1H), 1.75 (d, J=6.6 Hz, 3H)

YYY) starting with the appropriate racemic tetrahydroisoquinoline in step 1, performing aminolysis in a similar fashion to step 4 (Scheme NN), and separating the diastereomers prior to the final deprotection.

-300482 observed [M+H]

(1S,2S,3R,5S)-3-(4amino-5-fluoro-7Hpyrrolo[2,3-d]pyrimidin7-yl)-5-((6(difluoromethyl)-5fluoro-4-methyl-1,2,3,4tetrahydroisoquinolin-8yl)oxy)cyclopentane-

1,2-diol

Example 215 (Isomer

1) - ¹H NMR (400MHz, DEUTERIUM OXIDE) δ

ppm 8.24 (s, 1H), 7.30 (s, 1H), 7.21 - 6.88 (m,
2H),	5.36 -	5.21	(m,
1H),	4.87 (br d, J	=1.8
Hz,	1H), 4.57 (br	dd,
J=5.1, 8.7	Hz,	1H),
4.51	- 4.42	(m,	1H),
4.36	- 4.23	(m,	2H),
3.58	- 3.43	(m,	3H),
3.14	- 2.99	(m,	1H),
2.17	- 2.06	(m,	1H),

1.41 (d, J=6.5 Hz, 3H).

Example 216 (Isomer 2) - Ή NMR (400MHz, DEUTERIUM OXIDE) δ ppm 8.22 (s, 1H), 7.28 (d, J=2.0 Hz, 1H), 7.21 - 6.85 (m, 2H), 5.30 5.16 (m, 1H), 4.86 (br d, J=1.5 Hz, 1H), 4.56 (dd, J=5.0, 9.0 Hz, 1H), 4.46 (br d, J=16.8 Hz,

-301 -

1H), 4.37 - 4.20 (m, 2H), 3.61 - 3.41 (m, 3H), 3.02 (ddd, J=7.5, 9.2, 14.9 Hz, 1H), 2.18 - 2.02 (m, 1H), 1.53 - 1.34 (m, 3_H).

Biological Examples

Biochemical Assay Methods

Compounds were solubilized in DMSO and serially diluted, using 3-fold dilutions, into 100% DMSO at a concentration 50-fold greater than the desired assay concentration. Following dilution, 1 ul was added to an empty 96-well microtiter plate. PRMT5/MEP50 protein complex was combined with H4(1-21) peptide (SGRGKGGKGLGKGGAKRHRKV) in PRMT5 assay buffer (50 mM Tris pH 8.5, 50 mM NaCI, 5 mM MgCI₂, 1 mM EDTA, 1 mM TCEP) and 44 ul was added to the microtiter plate containing compound. S-Adenosyl-L-methionine (SAM) was prepared by combining ³H labelled SAM with unlabelied SAM in PRMT5 assay buffer such that the final SAM concentration was 10 uM and the spécifie activity was 0.2 uCi/ul. The reaction was initiated by adding 5 ul of SAM stock to the microtiter plate. The final reaction conditions were 10 nM PRMT5/MEP50 complex, 200 nM peptide and 1 uM SAM. Following a 25 minute incubation at room température, the reaction was stopped with the addition of 100 uL of 20% TCA. The 3H-peptide product was captured using a 96-well filter plate (MSIPN4B, Millipore) and washed 5 times with PBS buffer. Scintillation fluid (100 ul) was added to the dried filter plate and counted in a liquid scintillation counter. IC50 values were determined by fitting the data to the standard 4-paramater dose response équation using Pfizer proprietary software.

Results for the biochemical assay of examples are summarized in Table 1, shown as IC₅₀ values in μΜ.

Table 1

PRNIT5 Enzyme Inhibition

Example	PRMT5 IC50 (uM)	Example	PRMT5 IC50 (uM)	Example	PRMT5 IC50 (uM)	Example	PRMT5 IC50 (uM)
1	0.510	56	0.002	111	0.028	166	0.003
2	8.382	57	0.048	112	0.004	167

-302-

3	0.032	58	0.289	113	0.001	168
4	0.681	59	5.743	114	0.004	169	0.037
5	0.025	60	>200	115	0.147	170	0.001
6	0.423	61	2.124	116	0.257	171	0.014
7	0.120	62	0.025	117	0.005	172	1.285
8	3.389	63	1.057	118	0.002	173	0.003
9	0.060	64	>200	119	0.001	174
10	0.941	65	>200	120	0.001	175	0.005
11	0.020	66	0.004	121	0.001	176	0.002
12	0.478	67	>200	122	0.003	177	0.004
13	0.016	68	>200	123	0.002	178	0.002
14	0.719	69	>200	124	0.002	179	0.001
15	>200	70	13.56	125	0.001	180	0.003
16	>200	71	0.069	126	0.001	181	0.001
17	2.767	72	0.022	127	0.009	182	0.002
18	3.701	73	6.885	128	0.001	183	0.001
19	0.064	74	63.29	129	0.001	184	0.001
20	17.09	75	37.85	130	0.001	185	0.006
21	0.217	76	143.59	131	0.001	186	0.012
22	0.003	77	0.065	132	0.002	187	0.971
23	0.572	78	0.001	133	0.001	188	0.004
24	0.071	79	0.083	134	0.001	189	0.604
25	0.056	80	0.130	135	10.22	190	0.001
26	0.704	. 81	1.666	136	11.11	191	0.001
27	0.449	82	0.991	137	0.123	192	0.055
28	5.769	83	0.020	138	0.002	193	0.180
29	>200	84	0.002	139	0.001	194	0.001
30	>200	85	0.002	140	0.017	195	0.001
31	0.466	86	0.004	141	3.931	196	0.001
32	15.69	87	0.002	142	0.011	197	0.001
33	3.580	88	0.001	143	0.006	198	0.001
34	59.47	89	0.001	144	0.077	199	0.091
35	0.150	90	0.002	145	0.011	200	0.001

-303-

36	2.697	91	0.001	146	0.027	201	0.310
37	0.266	92	0.001	147	0.024	202	0.001
38	15.71	93	0.001	148	0.002	203	0.001
39	0.114	94	0.001	149	0.069	204	0.002
40	2.045	95	0.006	150	0.071	205	0.001
41	0.046	96	0.019	151	0.078	206	0.002
42	1.387	97	0.065	152	0.008	207	0.024
43	0.879	98	0.011	153	0.005	208	0.008
44	16.97	99	0.002	154	0.001	209	0.005
45		100	0.001	155	0.002	210	0.001
46	0.297	101	0.001	156	0.107	211	0.001
47	29.47	102	0.001	157	0.004	212	0.001
48	0.005	103	0.001	158	>200	213	0.001
49	0.105	104	0.001	159	0.005	214	0.008
50	18.89	105	0.001	160	0.009	215	0.001
51	0.676	106	0.002	161	0.201	216	0.001
52	0.906	107	0.001	162	0.042
53	0.006	108	0.001	163	>200
54	0.126	109	0.001	164	0.004
55	0.002	110	0.008	165	0.002

A549 Prolifération Assay

A549 lung adenocarcinoma cells (Américain Type Culture Collection) were maintained in DMEM growth media (Life Technologies) supplemented with 10% v/v heat inactivated fêtai bovine sérum (Sigma) and cuitured at 37°C, 5% CO₂. Exponentially growing A549 cells were plated in 96-well black tissue culture treated plates (Corning) at a density of 2500 cells/ml in a volume of 10 100 pl culture media and allowed to adhéré overnight at 37°C, 5% CO₂. The following day, compound plates were prepared by making nine-point 3.3-fold dilutions in DMSO with a top concentration of 10 mM. Compounds were further diluted in culture media and 11 μΙ was added to the cells (final top assay concentration was 10 μΜ and DMSO was 0.2%). Cells were incubated with compound at 37°C, 5%CO₂ for 7 days with media and compound replacement 15 on day 4. Cell viability was assayed on Day 7 by adding 100 μΙ Cell Titer Glo (Promega)

-304reagent to the plate to measure the amount of ATP présent in the cells. Luminescence was read using the Envision 2104 Multilabel Reader (Perkin Elmer). The 50% inhibitory concentration (ICso) was determined using a 4-parameter fit model normalized to the DMSO control in dose response.

Results for the A549 prolifération assay of examples are summarized in Table 2, shown as IC50 values in μΜ.

- 305Table 2

A549 Cell Prolifération IC50

Example	A549 Cell IC50 (uM)	Example	A549 Cell IC50 (uM)	Example	A549 Cell IC50 (uM)	Example	A549 Cell IC50 (uM)
3	1.098	100	0.185	138	1.477	195	0.022
5	0.932	101	0.112	139	0.637	196	0.003
11	1.394	102	0.192	140	2.380	197	3.461
13	0.971	103	0.201	143	1.402	198	3.822
19	1.072	104	0.460	146	7.069	200	0.140
22	0.135	105	0.383	148	4.883	202	1.765
25	1.673	106	3.847	154	0.002	203	0.677
48	0.192	107	0.991	159	5.199	204	0.720
53	0.227	108	0.163	160	0.405	205	0.248
55	3.168	109	0.067	164	3.859	206	6.548
56	0.378	114	3.940	165	0.766	207	1.479
66	6.813	117	7.141	166	0.039	210	1.546
77	1.123	118	4.840	169	0.743	211	0.014
78	1.615	119	0.556	173	3.572	212	0.002
84	0.500	120	0.442	175	3.229	213	1.198
85	0.920	121	0.938	176	1.563	214	1.081
86	1.840	122	4.478	177	2.374	215	0.001
87	0.296	123	0.452	178	4.057	216	0.006
88	0.545	124	3.828	180	0.159
89	0.195	125	0.637	181	1.140
90	0.948	126	0.498	182	2.180
91	0.119	128	0.597	183	0.136
92	0.312	129	1.045	184	1.398
93	0.140	130	0.983	186	9.533
94	0.115	131	0.482	188	6.473
95	8.130	132	2.751	190	0.007
98	1.494	133	0.443	191	7.017
99	0728	134	0.640	194	0.111

-306Molecular Biology

Gene encoding full length PRMT5 open reading frame (ORF) was fused directly at Ala2 to MDYKDDDDKGRAT sequence encoding Flag tag (SEQ ID: 1) and full length untagged MEP50 (SEQ ID: 2) were codon optimized for mammalian expression and synthetized by GenScript, Piscataway, NJ. Synthetized genes were cloned into insect cell expression vector pFASTBac Dual (Life Technologies) using standard restriction enzyme based cloning procedures. In the final construct PRMT5 ORF was under control of polyhedrin promoter (polH) while MEP50 ORF was under control of p10 promoter. Additionally, MEP50 (SEQ ID: 2) was subcloned into pFASTBacl vector using standard restriction enzyme based cloning procedures.

Protein Expression

Viruses were generated using standard Bac-to-Bac viral génération protocols (Life Technologies) and amplified to high-titer passage two (P2) stocks. Protein over expression was conducted in exponentially growing Sf21 celis infected at 2x106 with P2 viral stock at MOI=1 of PRMT5-Mep50 dual construct virus and Mep50 construct virus at 1:1 ratio. The co-expression protocol was used to supplément additional Mep50 for FlagPRMT5-Mep50 heterodimer formation. Cells were harvested at 72h post infection by centrifugation and frozen pellet was stored at -80 0C.

Protein Purification

FlagPRMT5-Mep50 complex was purified from cell lysate using Flag affinity chromatrography. Cell were lyzed in 50mM Tris 7.5, 200mM NaCI, 10% glycerol, 0.25mM TCEP supplemented with EDTA-free protease inhibitor cocktail (Roche). 1.5 ml of lysis buffer was added per 1 g of frozen pellet. The clarified lysate was obtained by centrifugation of cell lysate at 10,000 g for 1 h at 4 C. 5 ml of Anti-FLAG M2 Agarose (Sigma) for 3h to isolate was added to the clarified lysate to isolate FlagPRMT5-Mep50. Following batch binding for 3 h at 4 C, Flag resin bound to FlagPRMT5-Mep50 washed with 20 column volumes (CV) of 50mM Tris 7.5, 200mM NaCI, 10% glycerol, 0.25mM TCEP followed by elution of FlagPRMT5-Mep50 complex using 3 CV of 50mM Tris 7.5, 200mM NaCI, 10% glycerol, 0.25mM TCEP supplemented with 200 ug/ml of FLAG Peptide (DYKDDDDK). FlagPRMT5-Mep50 was further purified using S300 26/600 column (GE Healthcare) pre-equilibrated with 2 CV of 25mM Tris pH7.5, 150mM NaCI, 5% glycerol, 0.5mM TCEP buffer. Peak fractions containing FlagPRMT5-Mep50 complex were concentrated to 1.6 mg/ml, flash frozen in small aliquots using liquid nitrogen and stored at -80 0C.

Sequences

SEQ ID: 1

MDYKDDDDKGRAT AAMAVGGAGGSRVSSGRDLNCVPEIADTLGAVAKQGFDFLCMPVFHP RFKREFIQEPAKNRPGPQTRSDLLLSGRDWNTLIVGKLSPWIRPDSKVEKIRRNSEAAML

- 307 QELNFGAYLGLPAFLLPLNQEDNTNLARVLTNHIHTGHHSSMFWMRVPLVAPEDLRDDll ENAPTTHTEEYSGEEKTWMWWHNFRTLCDYSKRIAVALEIGADLPSNHVIDRWLGEPIKA AILPTSIFLTNKKGFPVLSKMHQRLIFRLLKLEVQFIITGTNHHSEKEFCSYLQYLEYLS QNRPPPNAYELFAKGYEDYLQSPLQPLMDNLESQTYEVFEKDPIKYSQYQQAIYKCLLDR

VPEEEKDTNVQVLMVLGAGRGPLVNASLRAAKQADRRIKLYAVEKNPNAWTLENWQFEE

WGSQVTWSSDMREWVAPEKADIIVSELLGSFADNELSPECLDGAQHFLKDDGVSIPGEY TSFLAPISSSKLYNEVRACREKDRDPEAQFEMPYWRLHNFHQLSAPQPCFTFSHPNRDP

MIDNNRYCTLEFPVEVNTVLHGFAGYFETVLYQDITLSIRPETHSPGMFSWFPILFPIKQ PITVREGQTICVRFWRCSNSKKWVYEWAVTAPVCSAIHNPTGRSYTIGL*

SEQ ID: 2

MRKETPPPLVPPAAREWNLPPNAPACMERQLEAARYRSDGALLLGASSLSGRCWAGSLWL FKDPCAAPNEGFCSAGVQTEAGVADLTWVGERGILVASDSGAVELWELDENETLIVSKFC KYEHDDIVSTVSVLSSGTQAVSGSKDICIKVWDLAQQWLSSYRAHAAQVTCVAASPHKD SVFLSCSEDNRILLWDTRCPKPASQIGCSAPGYLPTSLAWHPQQSEVFVFGDENGTVSLV

DTKSTSCVLSSAVHSQCVTGLVFSPHSVPFLASLSEDCSLAVLDSSLSELFRSQAHRDFV

RDATWSPLNHSLLTTVGWDHQWHHWPTEPLPAPGPASVTE*

Claims (10)

1. We Claim:

   1. A compound of formula (II):

   or a pharmaceutically acceptable sait thereof, wherein:

   R¹ is seiected from the group consisting of (Ci-Cs)alkyl, (Ci-C8)haloalkyl, hydroxy, (C-iC8)alkoxy, (C5-Ci2)aryl, 5-12 membered heteroaryl, (C3-Cio)cycloalkyl, 3-12 membered heterocyclyl, OR⁴, SR⁴ and N(R⁴)2, where each R⁴ is independently A-R¹⁴, where A is absent, (Ci-C3)alkyl, -C(O)- or -SO2-, and R¹⁴ is hydrogen, (Ci-Cs)alkyl, (C5-C₁₂)aryl, 5-12 membered heteroaryl, (C₃-Ci₀)cycloalkyl or 3-12 membered heterocyclyl, or two R⁴ join to form a 4-6 membered heterocyclic ring containing 1-3 heteroatoms seiected from N, O and S;

   R² is hydrogen, halogen, (Ci-Cs)alkyl, hydroxy, (Ci-C8)alkoxy or N(R⁵)2, where each R⁵ is independently hydrogen or (Ci-C₈)alkyl, or two R⁵ join to form a 4-6 membered heterocyclic ring containing 1-3 heteroatoms seiected from N, O and S;

   each R³ is independently seiected from hydrogen, hydroxy, NH2; (CrCs)alkyl or heteroalkyl having 1-8 atoms, or when D is C(R³)2, R³ is additionally seiected from fluorine, (CiC₈)alkylene or heteroalkylene bound to an atom on G to form a ring fused to G, where R³ is optionally substituted with 1-6 R⁸;

   -309each R⁹ is independently hydrogen or fluorine;

   D is C(R³)₂, O, or S(O)i-₂;

   G is a (Cs-Ci₂)aryl, 5-12 membered heteroaryl ring System;

   R¹⁵ is heteroalkyl having 1-8 atoms bound to an atom on G and optionally substituted with 1-6 R⁸, or R¹⁵ is heteroalkylene bound to an atom on G, optionally substituted with 1-6 R⁸, and bound to an adjacent atom on G;

   each R⁸ is absent or is independently selected from the group consisting of (Ci-C8)alkyl, (C-iC8)haloalkyl, hydroxy, (Ci-Cs)alkoxy, (C5-Ci2)aryl, 5-12 membered heteroaryl, (C3-Cio)cycloalkyl, 3-12 membered heterocyclyl, OR⁴, SR⁴, N(R⁴)2, CN, halogen and CON(R⁴)², where two R⁸ optionally join to form a 4-6 membered spiro-cycloalkyl ring, a cycloalkyl fused ring, or a alkylene bridge spanning G, and where two R⁸ optionally join to form carbonyl;

   where each R⁴ is independently A-R¹⁴, where A is absent, (Ci-C3)alkyl, -C(O)- or -SO2-, and R¹⁴ is hydrogen, (Ci-C8)alkyl, (C₅-Ci₂)aryl, 5-12 membered heteroaryl, (C₃-Ci₀)cycloalkyl or 3-12 membered heterocyclyl, or two R⁴ join to form a 4-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, O and S;

   Q is absent or is a divalent moiety selected from O, S, NH and (C-i-Cs)alkylene;

   V is N or C, where if V forms a double bond V is carbon;

   W is N or C, where if W forms a double bond W is carbon;

   X is N or C , where if X forms a double bond X is carbon;

   Y is CR¹⁰, N, NR¹⁰, O or S, where each R¹⁰ is independently selected from hydrogen, (CiC8)alkyl, hydroxy, (CrC8)alkoxy, or R¹⁰ is optionally selected from halogen, SH, S-(Ci-C8)alkyl and N(R¹¹)2 if Y is CR¹⁰, where Y forms a double with an adjacent ring member when Y is CR¹⁰ or N, and where each R¹¹ is independently hydrogen, (CrCsjalkyl, (C5-Ci₂)aryl or 5-12 membered heteroaryl or two R¹¹ join to form a 4-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, O and S, or Y is C(R¹⁰)₂ and the two R¹⁰ and the carbon to which they are associated form a carbonyl or a thiocarbonyl;

   Z is CR¹², N, NR¹², O or S, where each R¹² is independently selected from hydrogen, (CiC8)alkyl, hydroxy, (Ci-C8)alkoxy, or R¹² is optionally selected from fluoro, chloro, bromo, iodo, SH, S-(Ci-C8)alkyl and N(R¹³)2 if Z is CR¹², where Z forms a double bond with an adjacent ring member if it is CR¹² or N, where each R¹³ is independently hydrogen, (Ci-Cs)alkyl, (C5-Ci₂)aryl or 5-12 membered heteroaryl, or two R¹³ join to form a 4-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, O and S, and where Z is not NR¹² if X is N, V is C, W is C and Y is CR¹⁰, or Z is C(R¹²)₂ and the two R¹² and the carbon to which they are associated form a carbonyl or a thiocarbonyl; and each-----is an optional bond, where no more than two, non-adjacent may be présent, provided that D is S(O)1-2 when G is Cioaryl or a 10-membered heteroaryl.

   -310-
2. 2. A compound of formula (III):

   or a pharmaceutically acceptable sait thereof, wherein:

   5 each R¹ is independently selected from the group consisting of (Ci-C8)alkyl, (Ci-Cs)haloalkyl, hydroxy, (Ci-C8)alkoxy, (C5-Ci2)aryl, 5-12 membered heteroaryl, (C3-Cio)cycloalkyl, 3-12 membered heterocyclyl, OR⁴, SR⁴ and N(R⁴)2, where each R⁴ is independently A-R¹⁴, where A is absent, (Ci-C3)alkyl, -C(O)- or -SO2-, and R¹⁴ is hydrogen, (Ci-Cs)alkyl, (C5-Ci₂)aryl, 5-12 membered heteroaryl, (C₃-Cio)cycloalkyl or 3-12 membered heterocyclyl, or two R⁴ join to form 10 a 4-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, O and S;

   R² is hydrogen, halogen, (CrC8)alkyl, hydroxy, (Ci-C8)aikoxy or N(R⁵)2, where each R⁵ is independently hydrogen or (Ci-Cs)alkyl, or two R⁵ join to form a 4-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, O and S;

   each R³ is independently hydrogen, hydroxy or NH2; or when D is C(R³)2, R³ is additionally 15 selected from fluorine;

   each R⁹ is independently hydrogen or fluorine;

   D is C(R³)₂, O, or S(O)i-₂;

   E is NR¹, CH2, C(R¹)2, O or-S(O)₂;

   - 311 each R⁸ is absent or is independently selected from the group consisting of (Ci-Cs)alkyl, (CiCs)haloalkyl, hydroxy, (Ci-Cs)alkoxy, (Cs-Ci2)aryl, 5-12 membered heteroaryl, (C3-Cio)cycloalkyl, 3-12 membered heterocyclyl, OR⁴, SR⁴, N(R⁴)2, CN, halogen and CON(R⁴)², where two R⁸ optionally join to form a 4-6 membered spiro-cycloalkyl ring, a cycloalkyl fused ring, or a alkylene bridge spanning G, and where two R⁸ optionally join to form carbonyl;

   where each R⁴ is independently A-R¹⁴, where A is absent, (Ci-C3)alkyl, -C(O)- or -SO2-, and R¹⁴ is hydrogen, (Ci-Cs)alkyl, (C5-Ci₂)aryl, 5-12 membered heteroaryl, (C₃-Ci₀)cycloalkyl or 3-12 membered heterocyclyl, or two R⁴ join to form a 4-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, O and S;

   Q is absent or is a divalent moiety selected from O, S, NH and (Ci-Cs)alkylene;

   V is N or C, where if V forms a double bond V is carbon;

   W is N or C, where if W forms a double bond W is carbon;

   X is N or C, where if X forms a double bond X is carbon;

   Y is CR¹⁰, N, NR¹⁰, O or S, where each R¹⁰ is independently selected from hydrogen, (CiCsjalkyl, hydroxy, (Ci-Cs)alkoxy, halogen, SH, S-(Ci-C8)alkyl and N(R¹¹)2 if Y is CR¹⁰, where Y forms a double with an adjacent ring member when Y is CR¹⁰ or N, and where each R¹¹ is independently hydrogen, (Ci-Ce)alkyl, (C5-Ci2)aryl or 5-12 membered heteroaryl or two R¹¹ join to form a 4-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, O and S, or Y is C(R'°)2 and the two R¹⁰ and the carbon to which they are associated form a carbonyl or a thiocarbonyl;

   Z is CR¹², N, NR¹², O or S, where each R¹² is independently selected from hydrogen, (CiCsjalkyl, hydroxy, (Ci-Cs)alkoxy, fluoro, chloro, bromo, SH, S-(Ci-C8)alkyl and N(R¹³)2, where Z forms a double bond with an adjacent ring member if it is CR¹² or N, where each R¹³ is independently hydrogen, (Ci-Cs)alkyl, (C5-C12)aryl or 5-12 membered heteroaryl, or two R¹³ join to form a 4-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, O and S, and where Z is not NR¹² if X is N, V is C, W is C and Y is CR¹⁰, or Z is C(R¹²)2 and the two R¹² and the carbon to which they are associated form a carbonyl or a thiocarbonyl; and each — is an optional bond, where no more than two, non-adjacent — may be présent.
3. 3. A compound of formula (IV):

   -312-

   or a pharmaceutically acceptable sait thereof, wherein:

   each R¹ is independently selected from the group consisting of (Ci-Cs)alkyl, (Ci-Cs)haloalkyl, hydroxy, (Ci-Cs)alkoxy, (C5-Ci2)aryl, 5-12 membered heteroaryl, (C3-Ci0)cycloalkyl, 3-12 membered heterocyclyl, OR⁴, SR⁴ and N(R⁴)2, where each R⁴ is independently A-R¹⁴, where A is absent, (Ci-C3)alkyl, -C(O)- or -SO2-, and R¹⁴ is hydrogen, (Ci-Cs)alkyl, (C5-C₁₂)aryl, 5-12 membered heteroaryl, (C₃-Cio)cycloalkyl or 3-12 membered heterocyclyl, or two R⁴ join to form a 4-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, O and S;

   R² is hydrogen, halogen, (Ci-C8)alkyl, hydroxy, (Ci-Cs)alkoxy or N(R⁵)2, where each R⁵ is independently hydrogen or (Ci-Cs)alkyI, or two R⁵ join to form a 4-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, O and S;

   each R³ is independently hydrogen, hydroxy or NH2; or when D is C(R³)2, R³ is additionally selected from fluorine;

   each R⁹ is independently hydrogen or fluorine;

   B is N or C;

   E is NR¹, CH2, C(R¹)2, O or -S(O)₂;

   each R⁸ is absent or is independently selected from the group consisting of (Ci-C8)alkyl, (CiC8)haloalkyl, hydroxy, (CrCsjalkoxy, (C5-Ci2)aryl, 5-12 membered heteroaryl, (C3-Ci0)cycloalkyl, 3-12 membered heterocyclyl, OR⁴, SR⁴, N(R⁴)2, CN, halogen and CON(R⁴)², where two R⁸

   -313optionally join to form a 4-6 membered spiro-cycloalkyl ring, a cycloalkyl fused ring, or a alkylene bridge spanning G, and where two R⁸ optionally join to form carbonyl;

   where each R⁴ is independently A-R¹⁴, where A is absent, (Ci-C3)alkyl, -C(O)- or -SO2-, and R¹⁴ is hydrogen, (Ci-C8)alkyl, (C₅-Ci₂)aryl, 5-12 membered heteroaryl, (C₃-Cio)cycloalkyl or 3-12 membered heterocyclyl, or two R⁴ join to form a 4-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, O and S;

   Q is absent or is a divalent moiety selected from O, S, NH and (Ci-C₈)alkylene;

   V is N or C, where if V forms a double bond V is carbon;

   W is N or C, where if W forms a double bond W is carbon;

   X is N or C, where if X forms a double bond X is carbon;

   Y is CR¹⁰, N, NR¹⁰, O or S, where each R¹⁰ is independently selected from hydrogen, (C1C8)alkyl, hydroxy, (Ci-C8)alkoxy, halogen, SH, S-(Ci-C8)alkyl and N(R¹¹)2 if Y is CR¹⁰, where Y forms a double with an adjacent ring member when Y is CR¹⁰ or N, and where each R¹¹ is independently hydrogen, (Ci-C8)alkyl, (C5-Ci2)aryl or 5-12 membered heteroaryl or two R¹¹ join to form a 4-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, O and S, or Y is C(R¹⁰)2 and the two R¹⁰ and the carbon to which they are associated form a carbonyl or a thiocarbonyl;

   Z is CR¹², N, NR¹², O or S, where each R¹² is independently selected from hydrogen, (C1C8)alkyl, hydroxy, (Ci-Cs)alkoxy, fluoro, chloro, bromo, SH, S-(C-i-C8)alkyl and N(R¹³)2, where Z forms a double bond with an adjacent ring member if it is CR¹² or N, where each R¹³ is independently hydrogen, (Ci-Cs)aikyl, (C5-Ci2)aryl or 5-12 membered heteroaryl, or two R¹³ join to form a 4-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, O and S, and where Z is not NR¹² if X is N, V is C, W is C and Y is CR¹⁰, or Z is C(R¹²)2 and the two R¹² and the carbon to which they are associated form a carbonyl or a thiocarbonyl; and each — is an optional bond, where no more than two, non-adjacent — may be présent.
4. 4. The compound or pharmaceutically acceptable sait of any one of daims 1-3, wherein

   is selected from:

   Λ/W

   -31510
5. 5. The compound or pharmaceutically acceptable sait of claim 4, wherein
6. 6. The compound or pharmaceutically acceptable sait of claim 2, wherein:

   -316-

   is selected from:

   CF₃

   -317-

   -318-

   -319-
7. 7. The compound or pharmaceutically acceptable sait of claim 6, wherein:

   is:

   I
8. 8. A compound selected from:

   F'

   NH;

   -324-

   -325-

   I

   -326-

   -327-

   -331 -

   -332-

   -334-

   Ο”

   -335-
9. 9. A compound selected from:

   -336-

   or a pharmaceutically acceptable sait thereof.

   -341 -

   -342-

   -348-

   -352or a pharmaceutically acceptable sait thereof.

   11. A compound of any of caims 1-9, wherein said sait is selected from acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulfate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stéarate, succinate, tartrate, tosylate, trifluoroacetate, aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnésium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.

   12. A compound of any of caims 1-10, wherein said sait is selected from hydrochloride, tosylate and mesolate salts.

   13. A pharmaceutical composition comprising a compound according to any one of daims 1-12 or a pharmaceutically acceptable sait thereof, and a pharmaceutically acceptable carrier.

   14. Use of a compound according to any one of daims 1-12 or a pharmaceutically acceptable sait thereof for the préparation of a médicament useful in the treatment of abnormal cell growth in a mammal.

   15. The use of daim 14, wherein the abnormal cell growth is cancer.

   16. The use of daim 15, wherein the cancer is lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal région, stomach cancer, colon cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vuîva, Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine System, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the pénis, prostate cancer, chronic or acute leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, rénal cell carcinoma, carcinoma of the rénal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, spinal axis tumors, brain stem glioma, or pituitary adenoma.

   17. A compound: (1S,2S,3S,5R)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol, having the structure:

   - 353 -

   or a pharmaceutically acceptable sait thereof.

   18. The compound of any of daims 17, wherein said sait is selected from acetate, aspartate, benzoate, besylate, bicarbonate, carbonate, bisulphate, sulfate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride, chloride, hydrobromide.bromide, hydroiodide, iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate, hydrogen phosphate, dihydrogen phosphate, saccharate, stéarate, succinate, tartrate, tosylate, trifluoroacetate, aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnésium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.

   19. The compound of daim 18, wherein said sait is selected from phosphate, hydrogen phosphate and dihydrogen phosphate.

   20. A pharmaceutical composition comprising the compound: (1S,2S,3S,5R)-3-((6(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yl)cyclopentane-1,2-diol, having the structure:

   or a pharmaceutically acceptable sait thereof, and a pharmaceutically acceptable carrier.

   -354-

   21. Use of the compound or sait according to claim 17, for the préparation of a médicament useful in the treatment of abnormal cell growth in a mammal.

   5 22. The use according to claim 21, wherein the abnormal cell growth is cancer.

   23. The use according to claim 22, wherein the cancer is lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal région, stomach cancer, colon cancer,
10. 10 breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the pénis, prostate cancer, chronic or acute 15 leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, rénal cell carcinoma, carcinoma of the rénal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, spinal axis tumors, brain stem glioma, or pituitary adenoma.

    24. The use according to claim 22, wherein the cancer is lung cancer, cancer of the head or 20 neck, breast cancer, carcinoma of the endometrium, carcinoma of the cervix, cancer of the esophagus or cancer of the bladder.

    25. The use according to claim 22, wherein the cancer is lung cancer.