EA042008B1 - SELECTIVE INHIBITORS OF PROTEIN ARGININE METHYLTRANSFERASE 5 (PRMT5) - Google Patents

Description

Cross references to related applications

This application claims priority over U.S. Provisional Application No. 62/742048, filed October 5, 2018; U.S. Provisional Application No. 62/666,726, filed May 4, 2018; and U.S. Provisional Application No. 62/642,727, filed March 14, 2018. Each of these applications is incorporated herein by reference in its entirety.

Technical field

The present disclosure relates to PRMT5 inhibitors and methods for their use.

State of the art

Protein arginine methylation is a common post-translational modification that regulates numerous cellular processes, including gene transcription, mRNA splicing, DNA repair, cellular protein localization, cell fate determination, and signaling. There are three types of methylarginine: ω NG monomethylarginine (MMA), ω NG, asymmetric NG dimethylarginine (ADMA), and ω NG, symmetrical N'G dimethylarginine (SDMA). The formation of methylated arginines is catalyzed by the arginine methyltransferase (PRMT) proteins of the methyltransferase protein family. Currently, nine PRMTs have been found in the human genome. Most of these enzymes are type I enzymes (PRMT1, -2, -3, -4, -6, -8) that are capable of mono- and asymmetric dimethylation of arginine with S-adenosylmethionine (SAM) as a methyl donor. PRMT-5, -7 and -9 are considered type II enzymes that catalyze the symmetrical dimethylation of arginines. Each PRMT species carries the characteristic motifs of seven beta-strand methyltransferases (Katz et al., 2003), as well as additional double E and THW sequence motifs characteristic of the PRMT subfamily.

PRMT5 is a general transcriptional repressor that functions with numerous transcription factors and repressor complexes, including BRG1 and hBRM, Blimp1 and Snail. This enzyme, once recruited to the promoter, symmetrically dimethylates H3R8 and H4R3. It is important to note that the H4R3 site is the main target for PRMT1 (ADMA) methylation and is generally regarded as a marker for transcriptional activation. Thus, both H4R3me2s (repressive; me2s indicates SDMA modification) and H4R3me2a (active; me2a indicates ADMA modification) marks are both formed in vivo. The specificity of PRMT5 for H3R8 and H4R3 may be altered by its interaction with COPR5, and this may play an important role in determining PRMT5 corepressor status.

The role of PRMT in cancer.

Aberrant PRMT expression has been identified in human cancers and PRMTs are considered therapeutic targets. A global analysis of histone modifications in prostate cancer showed that H4R3 histone dimethylation is positively correlated with an increase in cancer severity, and these changes predict clinical outcome.

PRMT5 levels have been shown to be elevated in a panel of lymphoid cancer cell lines as well as in clinical specimens of mantle cell lymphoma. PRMT5 interacts with a number of substrates that are involved in a variety of cellular processes, including RNA processing, signal transduction, and transcriptional regulation. PRMT5 can directly modify histones H3 and H4, resulting in downregulation of gene expression. Overexpression of PRMT5 can stimulate cell growth and induce transformation by directly repressing tumor suppressor genes. Pal et al., Mol. cell. Biol., 2003, 7475; Pal et al., Mol. cell. Biol., 2004, 9630; Wang et al., Mol. cell. Biol., 2008, 6262; Chung et al., J. Biol. Chem., 2013, 5534. In addition to its well-documented oncogenic functions in transcription and translation, transcription factor MYC also ensures proper messenger RNA splicing as an essential step in lymphomagenesis. Koh et al., Nature, 2015, 523, 7558; Hsu et al. Nature 2015, 525, 384.

The detection of cancer dependencies can provide information on therapeutic strategies and reveal putative drug targets. Summarizing data from complex genomic profiling of cancer cell lines and functional characterization of cancer cell dependencies, it was recently found that the loss of the enzyme methylthioadenosine phosphorylase (MTAP) leads to selective dependence on the protein arginine methyltransferase 5 (PRMT5) and its binding partner WDR77. MTAP is often lost due to its proximity to the commonly deleted tumor suppressor gene, CDKN2A. Cells carrying MTAP deletions have elevated intracellular concentrations of methylthioadenosine (MTA, a metabolite cleaved by MTAP). In addition, MTA specifically inhibits the enzymatic activity of PRMT5. Administration of either MTA or a small molecule inhibitor of PRMT5 shows a preferential decrease in the viability of MTAP-null cancer cell lines compared to isogenic counterparts expressing MTAP. Taken together, these data indicate that PRMT5 is a potential vulnerable target for multiple cancers, enhanced by a common passenger genomic change. Role of PRMT5 in hemoglobinopathies The switch in human globin gene subtype development from fetal to adult, which begins at birth, marks the onset of hemoglobinopathies, b-thalassemia, and sickle cell anemia (SCD). Observation

- 1 042008 that increased expression of the adult globin gene (under conditions of hereditary persistence of fetal hemoglobin [HPFH] mutations) significantly reduces the clinical severity of thalassemia and SCD has prompted the search for therapeutic strategies to reverse gammaglobin gene silencing. Central to gamma gene suppression is DNA methylation, which marks critical CpG dinucleotides flanking the gene transcription start site in adult bone marrow erythroid cells. These marks have been shown to be established by the recruitment of a DNA methyltransferase, DNMT3A, to the gamma promoter by the arginine methyltransferase protein PRMT5. Zhao et al., Nat. Struct. Mol. Biol., 2009, 16, 304. PRMT5-mediated H4R3 histone methylation recruits DNMT3 A by binding histone and DNA methylation in gene silencing.

PRMT5 induces the repressive histone mark H4R3me2s, which serves as a template for direct DNMT3A binding and subsequent DNA methylation. Loss of PRMT5 binding or enzymatic activity leads to demethylation of CpG dinucleotides and gene activation. In addition to the H4R3me2s tag and DNA methylation, PRMT5 binding to the gamma promoter and its enzymatic activity are important for the assembly of a multiprotein complex at the gamma promoter, which induces a number of coordinated repressive epigenetic marks. Violation of this complex leads to reactivation of gamma gene expression. These studies serve as the basis for the development of PRMT5 inhibitors as targeted treatments for thalassemia and SCD.

Brief description of the essence of the invention

This description relates to compounds of formula I

or a pharmaceutically acceptable salt or solvate thereof;

where And represents CR ³ ;

R ¹ is halogen, -C ₁ -C ₆ alkyl, -C 1 -C ₆ alkoxy, -C ₃ -C ₆ cycloalkyl, -C ₁ -C ₆ alk-O-C ₁ C 6 alkyl, - ^NR6R6 ';

R ² is H;

R ³ represents H, halogen or -C1-C ₆ -alkyl;

R ⁴ represents H or -C1-C ₆ -alkyl;

R ⁵ represents H or -C1-C ₆ -alkyl;

R ⁶ and R ⁶ are each independently H or C1-C ₆ alkyl; or

R ⁶ and R ⁶ together with the atom to which they are attached form a C1-C ₆ heterocycloalkyl ring containing one N heteroatom;

X represents O, S, NH or N(C ₁ -C ₆ -alkyl); And

Y is -(CR ⁹ R ⁹ ')n-, -CR ⁹ =CR ⁹ '-, C(=O), -C(=O)-(CR ⁹ R ⁹ )n-, -C(=O )-O-(CR ⁹ R ⁹ ') _n -, -CR9R ⁹ O-, -(CR ⁹ R ⁹ ')nO-(CR ⁹ R ⁹ ')m- or -(CR ⁹ R ⁹ ')n- ^NR10 ; or '

X is -SO ₂ - and Y is -(CR ⁹ R ⁹ ) _n -;

where n=1, 2 or 3;

m=1 or 2;

each R ⁹ or R ⁹ is independently H, D, C1-C ₆ alkyl, C1-C ₆ haloalkyl, halogen, -C1-C ₆ alkoxy or hydroxy;

R ¹⁰ is H;

Z is O or CH2; And

Ar is a phenyl ring which is optionally substituted with one or more substituents independently selected from halo, C1- _C6 haloalkyl, C1- _C6 haloalkoxy and C1- _C6 alkyl, a 6-membered heteroaryl ring containing one a N heteroatom, wherein said heteroaryl ring is optionally substituted with one or more substituents independently selected from halo, C1- _C6 haloalkyl, C1- _C6 haloalkoxy and C1- _C6 alkyl, or a 5-membered heteroaryl ring containing up to 4 heteroatoms independently selected from N and S, wherein said heteroaryl ring is optionally substituted with one or more substituents independently selected from halo, C1- _C6 haloalkyl, C1- _C6 haloalkoxy and C1- _C6 alkyl .

- 2 042008

Stereoisomers of the compounds of formula I and their pharmaceutical salts are also contemplated, described and covered in this document. Describes how to use compounds of formula I, as well as pharmaceutical compositions, including compounds of formula I.

Detailed Description of Exemplary Embodiments

The disclosure may be more fully appreciated with reference to the following description, including the following definitions and examples. Certain features of the disclosed compositions and methods that are described herein in the context of separate aspects may also be provided in combination in one aspect. Alternatively, various features of the disclosed compositions and methods, which for brevity are described in the context of one aspect, may also be provided separately or in any subcombination.

The term alkyl, when used alone or as part of a substituent group, refers to a straight or branched chain hydrocarbon group containing 1 to 12 carbon atoms (C1-C1 ₂ ), preferably 1 to 6 carbon atoms (C1-C6'' ) in Group. Examples of alkyl groups include methyl (Me, C ₁ -alkyl), ethyl (Et, C ₂ -alkyl), n-propyl (C ₃ -alkyl), isopropyl (C ₃ -alkyl), butyl (C ₄ -alkyl), isobutyl (C ₄ -alkyl), sec-butyl (C ₄ -alkyl), tert-butyl (C ₄ -alkyl), pentyl (C ₃ -alkyl), isopentyl (C ₅ -alkyl), tert-pentyl (C ₅ -alkyl), hexyl (C ₆ -alkyl), isohexyl (C ₆ -alkyl), and the like.

The term alkoxy, when used alone or as part of a substituent group, refers to an oxygen radical to which an alkyl group (ie, -O-alkyl) is attached. Examples of alkoxy groups include methoxy (-OMe, C ₁ alkoxy), ethoxy (-OEt, C ₂ alkoxy), n-propoxy (C ₃ alkoxy), isopropoxy (C ₃ alkoxy) and the like.

The term halogen, when used alone or as part of a substituent group, refers to chlorine, fluorine, bromine, or iodine.

The term haloalkyl, when used alone or as part of a substituent group, refers to an alkyl group in which one or more hydrogen atoms have been replaced by one or more halogen atoms. Halogen atoms include chlorine, fluorine, bromine and iodine. Examples of haloalkyl groups as used herein include, for example, trifluoromethyl (-CF ₃ ), chloromethyl (-CH ₂ Cl) and the like.

The term haloalkoxy, when used alone or as part of a substituent group, refers to an oxygen radical to which a haloalkyl group (ie, -O-haloalkyl) is attached. Examples of haloalkoxy groups include trifluoromethoxy (-OCF3, C ₁ haloalkoxy), difluoromethoxy (-OCHF2, C ₁ haloalkoxy), fluoromethoxy (-OCH2F, Cj-haloalkoxy), trifluoroethoxy (-OCH2CF3, C ₂ haloalkoxy) and the like.

The term cycloalkyl, when used alone or as part of a substituent group, refers to cyclic non-aromatic hydrocarbon groups having 3 to 10 carbon atoms (C ₃ -C ₁₀ ), preferably 3 to 6 carbon atoms (C ₃ -C ₆ ). Examples of cycloalkyl groups include, for example, cyclopropyl (C ₃ ), cyclobutyl (C ₄ ), cyclopropylmethyl (C ₄ ), cyclopentyl (C ₅ ), cyclohexyl (C ₆ ), 1-methylcyclopropyl (C ₄ ), 2-methylcyclopentyl (C ₄ ), adamantanyl (C ₁₀ ), etc.

The term halocycloalkyl, when used alone or as part of a substituent group, refers to cyclic non-aromatic hydrocarbon groups having 3 to 10 carbon atoms (C3-C10), preferably 3 to 6 carbon atoms (C ₃ -C ₆ ), where one or more hydrogen atoms are replaced by one or more halogen atoms. Halogen atoms include chlorine, fluorine, bromine and iodine. Examples of halocycloalkyl groups include, for example, halocyclopropyl (C ₃ ), halocyclobutyl (C ₄ ), halocyclopropylmethyl (C ₄ ), halocyclopentyl (C ₅ ), halocyclohexyl (C ₆ ), and the like.

The term heterocycloalkyl, when used alone or as part of a substituent group, refers to any three to ten membered monocyclic or bicyclic saturated ring structure containing at least one heteroatom selected from the group consisting of O, N and S. A heterocycloalkyl group may be attached to any heteroatom or carbon atom of the ring, so that the result is a stable structure. Examples of suitable heterocycloalkyl groups include, but are not limited to, azepanyl, aziridinyl, azetidinyl, pyrrolidinyl, dioxolanyl, imidazolidinyl, pyrazolidinyl, piperazinyl, piperidinyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl, oxazepanyl, oxiranyl, oxetanyl, quinuclidinyl, piperazinyl, tetrahydrofuranyl, tetrahydrofuranyl and so on.

The term alkenyl, when used alone or as part of a substituent group, refers to a straight or branched chain group containing 2 to 12 carbon atoms (C ₂ -C ₁₂ ), preferably 2 to 4 carbon atoms (C ₂ -C ₄ ) in a group, wherein the group includes at least one carbon-carbon double bond. Examples of alkenyl groups include vinyl (-CH=CH ₂ ; C ₂ -alkenyl) allyl (-CH ₂ -CH=CH ₂ ; C ₃ -alkenyl), propenyl (-CH=CHCH ₃ ; C ₃ -alkenyl), isopropenyl ( -C (CH ₃ ) \u003d CH ₂ ; C ₃ -alkenyl), butenyl (-CH \u003d CHCH ₂ CH ₃ ; C ₄ -alkenyl), sec-butenyl (-C (CH ₃ ) \u003d CHCH ₃ ; C ₄ -alkenyl ), isobutenyl (-CH=C(CH3)2; C4-alkenyl), 2-butenyl (-CH2CH=CHCH3; C4-alkyl), pentenyl (CH=CHCH2CH2CH3; _C5 -alkenyl), and the like.

The term alkynyl, when used alone or as part of a substituent group, refers to a straight or branched chain group containing 1 to 12 carbon atoms (C1-C12), preferably 1 to 4 carbon atoms (C ₂ -C ₄ ) in group, and in which the group includes at least

- 3 042008 one carbon-carbon triple bond. Examples of alkynyl groups include ethynyl (-C=CH; C ₂ alkynyl), propargyl (-CH ₂ -C=CH; C ₃ alkynyl), propynyl (-C=CCH ₃ ; C ₃ alkynyl), butynyl (- C=CCH ₂ CH ₃ ; C4 alkynyl), pentynyl (C=CCH ₂ CH ₂ CH ₃ ; C ₅ alkynyl) and the like.

The term aryl, when used alone or as part of a substituent group, refers to a mono- or bicyclic aromatic hydrocarbon ring structure having 6 or 10 ring carbon atoms, where one or more ring carbon atoms are optionally replaced. Examples of substituents include halogen atoms, -C ₁ -C ₃ alkyl groups, and C ₁ -C ₃ haloalkyl groups. Halogen atoms include chlorine, fluorine, bromine and iodine. C ₁ -C ₃ haloalkyl groups include, for example, -CF ₃ , -CH2CF3 and the like.

The term heteroaryl, when used alone or as part of a substituent group, refers to a mono- or bicyclic aromatic ring structure comprising carbon atoms as well as up to four heteroatoms selected from nitrogen, oxygen and sulfur. Heteroaryl rings may include as few as 5, 6, 9, or 10 ring atoms. The heteroaryl moiety may be optionally substituted. Examples of substituents include halogen atoms; -C ₁ -C ₃ -alkyl groups and C 1 -C ₃ haloalkyl groups. Halogen atoms include chlorine, fluorine, bromine and iodine.

When a range of carbon atoms is used herein, such as C1-C6, all ranges are covered, as well as the individual number of carbon atoms. For example, C1- _C3 includes C1- _C3 , C1-C2, C2-C3, C1, C2, and C3.

The term C1- _C6 -alk, whether used alone or as part of a substituent group, refers to an aliphatic linker having 1, 2, 3, 4, 5, or 6 carbon atoms and includes, for example, -CH2-, -CH( _CH3 )-, -CH(CH ₃ )-CH ₂ - and -C(CH ₃ ) ₂ -. The term -C ₀ -alk- refers to a bond. In some aspects, C1- _C6 -alk may be substituted with one or more substituents -OH, -NH2 or halo (eg -F, -Cl, -Br, preferably -F).

Pharmaceutically acceptable means approved or approved by a regulatory agency of the federal or state government, or an appropriate agency in countries other than the United States, or that is listed in the USP or other generally recognized pharmacopoeia for use in animals, such as humans.

A pharmaceutically acceptable salt refers to a salt of a compound of the present disclosure that is pharmaceutically acceptable and that has the desired pharmacological activity of the parent compound. In particular, such non-toxic salts may be inorganic or organic acid addition salts and base addition salts. In particular, such salts include (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2,2,2]-oct-2-en-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, laurylsulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound is either replaced by a metal ion, such as an alkali metal ion, an alkaline earth metal ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, and the like; salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functional group, salts of non-toxic organic or inorganic acids such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, and the like.

A pharmaceutically acceptable excipient refers to a substance that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to a subject, such as an inert substance added to a pharmacological composition or otherwise used as a carrier or diluent to facilitate administration of an agent compatible therewith. Examples of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.

Solvate refers to the physical association of a compound of formula I with one or more solvent molecules.

The subject includes people. The terms human, patient, and subject are used interchangeably herein.

- 4 042008

Treatment of any disease or disorder refers, in one embodiment, to alleviating the disease or disorder (ie, stopping or reducing the progression of the disease or at least one of its clinical symptoms). In another embodiment, the implementation of the treatment refers to the improvement of at least one physical parameter that may not be noticeable by the subject. In yet another embodiment, treatment refers to modulating a disease or disorder, either physically (eg, stabilization of a discernible symptom) or physiologically (eg, stabilization of a physical parameter) or both. In another embodiment, treatment refers to delaying the onset of a disease or disorder. In some embodiments, the treatment refers to prophylactic treatment, i. preventing the onset of a disease or disorder.

Compounds of the present disclosure and equivalent terms are intended to cover compounds of formula I as described herein, as well as their subgenera, the expression of which includes stereoisomers (for example, entanyomers, diastereomers) and structural isomers (for example, tautomers) of compounds of formula I, as well as pharmaceutically acceptable salts, if the context permits.

As used herein, the term isotopic variant refers to a compound that contains proportions of isotopes on one or more of the atoms constituting such a compound that are in excess of the natural abundance. For example, an isotopic variant of a compound may be labeled with a radioactive isotope, i. e. contain one or more radioactive isotopes or may be labeled with non-radioactive isotopes such as, for example, deuterium ( ² H or D), carbon-13 ( ¹³ C), nitrogen-15 ( ¹⁵ N), or the like. It should be understood that in a compound in which such isotopic substitution is carried out, the following atoms, if present, may vary, so that, for example, any hydrogen may be 2H/D, any carbon may be ¹³ C, or any nitrogen may be ¹⁵ N , and that the presence and arrangement of such atoms can be determined by those skilled in the art.

It should also be understood that compounds that have the same molecular formula, but differ in the nature or sequence of the binding of their atoms or the arrangement of their atoms in space, are called isomers. Isomers that differ in the arrangement of atoms in space are called stereoisomers, such as diastereomers, enantiomers, and atropisomers. The compounds of this disclosure may have one or more asymmetric centers; such compounds can therefore be obtained as individual (R)- or (S)-stereoisomers at each asymmetric center, or as mixtures thereof. Unless otherwise indicated, the description or name of a particular compound in the specification and claims is intended to include all stereoisomers and mixtures thereof, racemic or otherwise. If a single chiral center exists in a structure, but no specific stereochemistry is shown for that center, both enantiomers, individually or as a mixture of enantiomers, are covered by that structure. If more than one chiral center exists in a structure, but the specific stereochemistry of the centers is not shown, all enantiomers and diastereomers, individually or as a mixture, are covered by that structure. Methods for determining stereochemistry and separating stereoisomers are well known in the art.

In some aspects, the disclosure relates to compounds of formula I

^R1

According to the disclosure, R ¹ is a halogen, compounds of the formula alkyl, -C ₁ -C ₆ -alkoxy, -C ₃ -C ₆ -cycloalkyl, -C ₁ -C ₆ -alk-O-C ₁ -C ₆ -alkyl , -NR6R ⁶ .

In some embodiments, R ¹ is halo (eg, -F, -Cl, -Br, or -I), preferably -F.

In other embodiments, R ¹ is -C1-C ₆ -alkyl, for example -C1-alkyl, -C ₂ -alkyl, -C ₃ -alkyl, -C ₄ -alkyl, -C ₅ -alkyl, -C ₆ - alkyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, and the like. In some embodiments, R ¹ is methyl.

In some embodiments, when R ¹ is -C1 alkyl, R ¹ is -CD3.

In still other embodiments, R ¹ is -C ₁ -C ₆ -alkoxy, for example -C ₁ -alkoxy, -C ₂ -alkoxy, -C ₃ -alkoxy, -C ₄ -alkoxy, -C ₅ -alkoxy, - C ₆ -alkoxy, methoxy, ethoxy, propoxy, isopropoxy,

- 5 042008 butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, etc.

In other embodiments, R ¹ is —C ₃ —C ₆ cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R ¹ is cyclopropyl.

In other embodiments, R ¹ is -C ₁ -C _b -alk-O-C ₁ -C _b -alkyl, for example

-C ₁ -alk-O-C ₁ -alkyl, -C ₆ -alk-O-C ₁ -alkyl, -C ₅ -alk-O -C ₂ -alkyl, -C ₄ -alk-O -C ₃ - alkyl, -C ₃ -alk-O -C ₄ -alkyl, -C ₂ -alk-O -C ₅ -alkyl, -C ₁ -alk-O-C ₆ -alkyl,

-C ₂ -alk-O-C ₁ -alkyl, -C ₁ -alk-O-C ₂ -alkyl, -C _b -alk-O-C ₂ -alkyl, -C ₅ -alk-O-C ₃ - alkyl, -C4-alk-O-C4-alkyl, -C ₃ -alk-O-C ₅ -alkyl, -C2-alk-O-C6-alkyl,

-C ₃ -alk-O-C ₁ -alkyl, -C ₂ -alk-O-C ₂ -alkyl, -C 1 -alk-O-C ₃ -alkyl, -Cb-alk-O-C3-alkyl, -C ₅ -alk-O-C ₄ -alkyl, -C ₄ -alk-O-C ₅ -alkyl, -C ₃ -alk-O-C _b -alkyl,

-C ₄ -alk-O -C । -alkyl, -C ₃ -alk-O-C ₂ -alkyl, -C ₂ -alk-O-C ₃ -alkyl, -C1-alk-O -C ₄ -alkyl, -Cb-alk-O-C4- alkyl, -C ₅ -alk-O -C ₅ -alkyl, -C4-alk-O-C6-alkyl,

-C ₅ -alk-O-C 1 -alkyl, -C ₄ -alk-O-C ₂ -alkyl, -C ₃ -alk-O-C ₃ -alkyl, -C2-alk-O-C4-alkyl, -C 1 -alk-O-C ₆ -alkyl, -C ₆ -alk-O-C ₅ -alkyl, -C ₅ -alk-O-C ₆ -alkyl,

-C6-alk-O-C6-alkyl, -CHSSCHOMe, -C^OMe, -CHSSCHSSCHSSCH-CHSSCHSSCH, -CH2CH2CH2OCH3, etc.

In some embodiments, R ¹ is -NR ⁶ R ⁶ . Thus, in some embodiments where R ⁶ and R ⁶ are both H, R ¹ is -NH2. In some embodiments where R ⁶ and R ⁶ are both methyl, R ¹ is -N(CH3)2. In embodiments where R ⁶ is H and R ⁶ is methyl, R ¹ is -NH(CH3).

In embodiments of the present invention, each of R ⁶ and R ⁶ in formula I is independently H, C 1 -C ₆ -alkyl (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and so on.).

In some embodiments, R ⁶ is H or C1-C6-alkyl. In some embodiments, R ⁶ is H or C1-C6 alkyl.

In some embodiments, each of R ⁶ and R ⁶ is H.

In other embodiments, each of R ⁶ and R ⁶ is independently C1- _C6 alkyl. Thus, in some embodiments, R ⁶ is methyl and R ⁶ is methyl.

In some aspects, R ⁶ is C1-C ₆ alkyl and R ⁶ is H. Thus, in some embodiments, R ⁶ is methyl and R ⁶ is H.

In embodiments of the present invention, R ⁶ and R ⁶ together with the atom to which they are attached form a C ₂ -C ₆ -heterocycloalkyl containing one N heteroatom, for example, azepanyl, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, and the like.

According to the disclosure, R ² in formula I is H.

According to the disclosure, R ⁴ in formula I is H or -C ₁ -C _b -alkyl Thus, in some embodiments, R ⁴ is H.

In other embodiments, R ⁴ is -C ₁ -C ₆ alkyl, eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, and the like. Thus, in some embodiments, R ⁴ is methyl (Me).

According to the disclosure, R ⁵ in formula I is H or -C1-C6-alkyl. Thus, in some embodiments, R ⁵ is H. In other embodiments, R ⁵ is -C1-C ₆ alkyl, e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl , pentyl, etc. Thus, in some embodiments, R ⁵ is methyl (Me).

In certain aspects of the disclosure, X in formula I is O, S, NH, or N (C1- _C6 alkyl); and Y in formula I is -(CR ⁹ R ⁹ ')n-, -CR ⁹ =CR ⁹ '-, C(=O), -C(=O)-(CR ⁹ R ⁹ ')n, - C(=O)-O-(CR ⁹ R ⁹ ')n, -CR ⁹ R ⁹ -O-, -(CR ⁹ R ⁹ )nO-(CR ⁹ R ⁹ )m- or -(CR ⁹ R ⁹ )n-NR ¹⁰ where n=1 or 2, m=1 or 2 and each R ⁹ or R ⁹ independently represents H, D (i.e. deuterium), C1-C ₆ -alkyl, C1-C ₆ -haloalkyl, halogen, -C ₁ -C _b -alkoxy or hydroxy and where R ¹⁰ represents H.

In other aspects of the disclosure, X in formula I is -SO2- and Y in formula I is -(CR ⁹ R ⁹ )n, where n=1 or 2 and each R ⁹ or R ⁹ is independently H, D ( i.e. deuterium), _C1 -C6 alkyl, C1- _C6 haloalkyl, halogen, _-C1-6alkoxy or hydroxy.

In some embodiments, X is O. In other embodiments, X is S. In other embodiments, X is SO2. In still other embodiments, X is NH. In some embodiments, X is N(C ₁ -C ₆ alkyl), e.g., K(C 1 alkyl), K(C ₂ alkyl), K(C ₃ alkyl), K(C ₄ alkyl), K(C ₅ alkyl), K(C ₆ alkyl), N(CH ₃ ), N(CH2CH3) and the like. '

In some aspects, Y is -(CR ⁹ R ⁹ ) _n -. In some embodiments, n=1 and Y is -CR9R ⁹ -. In some embodiments, n=1, each of R ⁹ and R ⁹ is H and Y is -CH2-.

In other embodiments where Y is -(CR ⁹ R ⁹ ) _n -, n=1, each of R ⁹ and R ⁹ is F and Y is -CF2-.

In some embodiments where Y is -(CR ⁹ R ⁹ )n-, n=1, R ⁹ and R ⁹ are each C1-C6 alkyl and Y is -C(C ₁ -C ₆ -alkyl) ₂ -. In some variants

- 6 042008 max realization C1-C6-alkyl represents -CH ₃ and Y represents -C(CH ₃ ) ₂ -.

In some embodiments, where Y is -(CR ⁹ R ⁹ )n-, n=2 and Y is -CR9R ⁹ -CR9R ⁹ -. In some embodiments where Y is -(CR ⁹ R ⁹ )n- and n=2, R ⁹ and R ⁹ are each H and Y is -CH2CH2-.

In some embodiments where Y is -(CR ⁹ R ⁹ )n- and n=2, one R ⁹ is -C1-C6 alkoxy, the other R ⁹ is H, each R ⁹ is H and Y is -CH ₂ CH(C ₁ -C ₆ -alkoxy)-. In some embodiments, C1-C ₆ -alkoxy is -OCH ₃ and Y is -CH ₂ CH(OCH ₃ )-.

In some embodiments where Y is -(CR ⁹ R ⁹ )n- and n=2, one R ⁹ is hydroxy, the other R ⁹ is H, each R ⁹ is H, and Y is -CH2CH( HE)-. '

In some embodiments where Y is -(CR ⁹ R ⁹ )n- and n=2, one R ⁹ is -C1-C6 alkyl, the other R ⁹ is H, each R ⁹ is H and Y is -CH ₂ CH(C ₁ -C6 alkyl). In some embodiments, C1-C ₆ -alkyl is -CH ₃ and Y is -CH ₂ CH(CH ₃ )-.

In some embodiments where Y is -(CR ⁹ R ⁹ )n- and n=2, one R ⁹ is -C1-C ₆ alkyl, one R ⁹ is H, one R ⁹ is -C1 -C6-alkyl, one R ⁹ is H and Y is -CH2C(C1- _C6 alkyl) ₂ -. In some embodiments, C1-C ₆ -alkyl is -CH ₃ and Y is -CH ₂ C(CH ₃ ) ₂ -.

In some embodiments where Y is -(CR ⁹ R ⁹ )n- and n=2, one R ⁹ is -C1-C6 haloalkyl, the other R ⁹ is H, each R ⁹ is H and Y is -CH ₂ CH(C ₁ -C6-haloalkyl)-. In some embodiments, the C1- _C6 haloalkyl is -CF ₃ and Y is -CH2CH(CF ₃ )-.

In some embodiments where Y is -(CR ⁹ R ⁹ ) _n - and n=2, one R ⁹ is -F, the other R ⁹ is H, and each R ⁹ is H and Y is - CH2CHF-. '

In some embodiments where Y is -(CR ⁹ R ⁹ )n- and n=2, one R ⁹ is F, another R ⁹ is H, one R ⁹ is F, the other R ⁹ is H and Y is -CH2CF ₂ -.

In some embodiments where Y is -(CR ⁹ R ⁹ ) _n - and n=2, one R ⁹ is D, another R ⁹ is H, one R ⁹ is D, the other R ⁹ is H and Y is -CH2CD2-.

In some embodiments where Y is -(CR ⁹ R ⁹ )n- and n=1, R ⁹ and R ⁹ are each C1-C6 alkyl and Y is -C(C1-C ₆ -alkyl) ₂ -. In some embodiments, C1-C ₆ -alkyl is -CH ₃ and Y is -C(CH ₃ ) ₂ -.

In some embodiments, Y is -(CR ⁹ R ⁹ ) _n - and n=3. In some embodiments, n=3, R ⁹ and R ⁹ are each H and Y is -CH2CH2CH2-.

In some aspects, Y is -CR ⁹ =CR ⁹ -. In some embodiments where Y is -CR ⁹ ═CR ⁹ -, each of R ⁹ and R ⁹ is H and Y is -CH=CH-.

In other aspects, Y is C(=O).

In some aspects, Y is -C(=O)-(CR ⁹ R ⁹ )n-. In some embodiments, n=1, R ⁹ and R ⁹ are both H, and Y is -C(=O)-CH2-.

In some aspects, Y is -C(=O)-O-(CR ⁹ R ⁹ )n-. In some embodiments, n=1, R ⁹ and R ⁹ are both H, and Y is -C(=O)-O-CH2-. In other embodiments, n=2, R ⁹ and R ⁹ are both H and Y is -C(=O)-O-CH ₂ CH ₂ -.

In some aspects, Y is -CR ⁹ R ⁹ -O-. In some embodiments, R ⁹ and R ⁹ are both H and Y is -CH2-O-. In other embodiments, R ⁹ and R ⁹ are both F and Y is -CF ₂ -O-.

In some aspects, Y is -(CR ⁹ R ⁹ ) _n -O-(CR ⁹ R ⁹ )m-. In some embodiments, n=m=1, each R ⁹ and each R ⁹ is H and Y is -CH2-O-CH2-. In other embodiments, n=m=1 and one R ⁹ is H and one R ⁹ is F and one R ⁹ is H and one R ⁹ is F and Y is -CF2-O -CH2-. In other embodiments, n=1, m=2, each R ⁹ , each R ⁹ is H, and Y is -CH2-O-CH2CH2-. In other embodiments, n=1, m=2, one R ⁹ is F, another R ⁹ is H, one R ⁹ is F, the other R ⁹ is H, and Y is -CF2-O-CH2CH2- .

In some aspects, Y-(CR ⁹ R ⁹ ) _n -NR ¹⁰ -. In some embodiments, n=1, R ⁹ , R ⁹ and R ¹⁰ is H and Y is -CH2-NH-.

Those skilled in the art will appreciate that, in some embodiments, element Y is attached to element X of formula I via one atom and to the Ar group of formula I via another atom (i.e., when Y is -(CR ⁹ R ⁹ )n - with n=2, -CR ⁹ =CR ⁹ -, -C(=O)-(CR ⁹ R ⁹ )n-, -C(=O)-O-(CR ⁹ R ⁹ ) _n -,

- 7 042008

-CR ⁹ R ⁹ -O-, -(CR ⁹ R ⁹ )nO-(CR ⁹ R ⁹ )m- and -(CR ⁹ R ⁹ )n-NR ¹⁰ ). In such embodiments, when Y is attached to X and Ar only through non-carbonyl carbons (i.e., when Y is -(CR ⁹ R ⁹ )n- with n=2, -CR ⁹ =CR ⁹ - or -( CR ⁹ R ⁹ )nO-(CR ⁹ R ⁹ )m-, then Y can be attached to X or to Ar through any carbon atom For example, when Y is -CR ⁹ =CR ⁹ -, Y can be attached as to Ar -CR ⁹ ═CR ⁹ -X or to X-CR ⁹ ═CR ⁹ -Ar Similarly, when Y is -(CR ⁹ R ⁹ )nO(CR ⁹ R ⁹ )m-, Y can be attached either to Ar-(CR ⁹ R ⁹ )n-O-(CR ⁹ R ⁹ )mX or to X-(CR ⁹ R ⁹ )nO-(CR ⁹ R ⁹ ) _m -Ar.

In such embodiments, when Y is attached via a non-carbonyl carbon atom and a carbonyl carbon atom (ie, when Y is -C(=O)-(CR ⁹ R ⁹ )n- or -C(=O)-O- (CR ⁹ R ⁹ )n-), then the carbonyl carbon of Y is attached to X, and the non-carbonyl carbon of Y is attached to Ar. The following examples illustrate this. When Y is -C(=O)-(CR ⁹ R ⁹ ) _n - then

When, in embodiments, Y is attached to X and Ar via a carbon atom of Y and an oxygen or nitrogen atom of Y (i.e., when Y is -CR9R ⁹ -O- or -(CR ⁹ R ⁹ )n-NR ¹⁰ -), then Y is attached to Ar only through an oxygen or nitrogen atom, and Y is attached to X only through a carbon atom. Those. Y is attached as X-CR ⁹ R ⁹ -Q-Ar or X-(CR ⁹ R ⁹ )n-NR ¹⁰ -Ar. The following examples illustrate this. When Y is -CR ⁹ R ⁹ -Q- or -(CR ⁹ R ⁹ ) _n -NR ¹⁰ - then Y is attached as

In other embodiments, Y is CH-C ₁ -C ₄ -alk-NH ₂ , such as CH-C ₁ -alk-NH ₂ , CH-C ₂ -alk-NH ₂ , CH-C ₃ -alk-NH ₂ , CH-C ₄ -alk-NH ₂ , CH-CH ₂ -NH ₂ , CH-CH ₂ CH ₂ -NH ₂ etc.

According to the disclosure, Ar is a phenyl ring which is optionally substituted with one or more substituents independently selected from halogen, C ₁ -C 6 haloalkyl, C 1 -C ₆ haloalkoxy and C 1 -C ₆ alkyl, 6-membered heteroaryl ring, containing one N heteroatom, wherein said heteroaryl ring is optionally substituted with one or more substituents independently selected from halo, C1- _C6 haloalkyl, C1- _C6 haloalkoxy and C1- _C6 alkyl, or a 5-membered heteroaryl ring , containing up to 4 heteroatoms independently selected from N and S, where the specified heteroaryl ring is optionally substituted with one or more substituents independently selected from halogen, C ₁ -C ₆ -haloalkyl, C ₁ -C ₆ -haloalkoxy and C1- C ₆ -alkyl.

In some embodiments, Ar is an optionally substituted 6-membered heteroaryl ring. In some embodiments, the 6-membered heteroaryl ring is unsubstituted. In other embodiments, the 6-membered heteroaryl ring is substituted with one or more substituents independently selected from halo, C1- _C6 alkyl, C1- _C6 haloalkyl, and C1- _C6 haloalkoxy. In some preferred embodiments, the 6-membered heteroaryl ring is substituted with one or more -F, -Cl, -CH3, -CF3, or -OCF3 substituents.

In some embodiments, Ar is an optionally substituted 5-membered heteroaryl ring. In some embodiments, the 5-membered heteroaryl ring is unsubstituted. In other embodiments, the 5-membered heteroaryl ring is substituted with one or more substituents independently selected from halo, C1- _C6 alkyl, C1- _C6 haloalkyl, and C1- _C6 haloalkoxy. In some preferred embodiments, the 5-membered heteroaryl ring is substituted with one or more -F, -Cl, -CH ₃ , -CF ₃ or -OCF ₃ substituents.

According to the disclosure, A in formula I is CR ³ .

- 8 042008

In embodiments, A is CR ³ and compounds of formula I are of formula IC

In some embodiments of this invention, compounds are provided that are compounds of formula IC, R ³ is H, halogen, or -C ₁ -C ₆ -alkyl.

In some embodiments of compounds of formula IC, R ³ is H. In other embodiments of compounds of formula IC, R ³ is halo (i.e. -F, -Cl, -Br, or -I), preferably F. In others embodiments of compounds of formula IC, R ³ is -C 1 -C ₆ -alkyl, for example -C ₁ -alkyl, -C ₂ -alkyl, -C ₃ -alkyl, -C ₄ -alkyl, -C 5 -alkyl, -C ₆ -alkyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, and the like.

According to the disclosure, Z in formula I is O or CH2. In some embodiments, Z is O and compounds of formula I are of formula I-D

^R1

aX> r ² ^%^n /^ ^{0 HO} **\ Ξ R4|||X—'\ HO X NO R ⁵ / ^Y Ag ) ID is CH ₂ and compounds of formula I have R ⁵ / ^γ Ag ) ⁴ --' 1-E

- 9 042008

In some embodiments, Ar in compounds of formula I is an optionally substituted phenyl ring or an optionally substituted 6-membered heteroaryl ring and co-

R ⁸ is halo, C1- _C6 alkyl, C1- _C6 haloalkyl or C1- _C6 haloalkoxy.

Thus, in certain embodiments of compounds of formula IG, R ⁸ is halo (eg, -F, -Cl, -Br, -I), preferably -F or -Cl. In other embodiments of compounds of formula IG, R ⁸ is C ₁ -C ₆ -alkyl, for example -Q-alkyl, -C ₂ -alkyl, -C3-alkyl, -C ₄ -alkyl, -C6-alkyl, -C6 -alkyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, and the like.

In other embodiments of compounds of formula IG, R ⁸ is C 1 -C ₆ haloalkyl, for example -C ₁ haloalkyl, -C ₂ haloalkyl, -C 3 haloalkyl, -C ₄ haloalkyl, -C 5 haloalkyl, -C 6 -haloalkyl, fluoromethyl, fluoroethyl, fluoropropyl, fluorobutyl, fluoropentyl, chloromethyl, chloroethyl, chloropropyl, chlorobutyl, chloropentyl, bromomethyl, bromoethyl, bromopropyl, bromobutyl, bromopentyl, iodomethyl, iodoethyl, iodopropyl, iodobutyl, iodopentyl, etc.

In other embodiments of the compounds of formula IG, R ⁸ is -C ₁ -C ₆ -haloalkoxy, for example -Q-haloalkoxy, -C ₂ -haloalkoxy, -Q-haloalkoxy, -C ₄ -haloalkoxy, -C ₅ -haloalkoxy, -C ₆ haloalkoxy, halomethoxy, haloethoxy, halopropoxy, haloisopropoxy, halobutoxy, haloisobutoxy, halosec-butoxy, halotert-butoxy, halopentoxy, and the like.

In other embodiments, Ar is a 5-membered heteroaryl group and compounds of formula I are of formula I-H

^R1

^R2

IH where Q ⁵ and Q ⁶ are CH, CR ⁸ or N and Q ⁷ is NH, N (C ₁ -C ₆ alkyl), S, or when at least one of Q ⁵ and Q ⁶ is is N, Q ⁷ may be CH2 or CH-R ⁸ ; And

R ⁸ is halo, C1- _C6 alkyl, C1- _C6 haloalkyl or C1- _C6 haloalkoxy.

It will be appreciated that when Q ⁷ is NH, CH2 or CH-R ⁸ then the 5-membered heteroaryl group in the compounds of Formula IH may exist in tautomeric forms. All such tautomeric forms are covered by the present description.

Thus, in certain embodiments of compounds of formula IH, R ⁸ is halo (eg, -F, -Cl, -Br, -I), preferably -F or -Cl. In other embodiments of compounds of formula IH, R ⁸ is C 1 -C ₆ -alkyl, for example -C 1 -alkyl, -C ₂ -alkyl, -C 3 -alkyl, -C ₄ -alkyl, -C ₅ -alkyl, -C ₆ -alkyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, and the like.

In other embodiments of compounds of Formula IH, R ⁸ is

- 10 042008

C1-C6 haloalkyl, for example -C ₁ haloalkyl, -C ₂ haloalkyl, -C3 haloalkyl, -C ₄ haloalkyl, -C ₅ haloalkyl, -C6 haloalkyl, fluoromethyl, fluoroethyl, fluoropropyl, fluorobutyl, fluoropentyl , chloromethyl, chloroethyl, chloropropyl, chlorobutyl, chloropentyl, bromomethyl, bromoethyl, bromopropyl, bromobutyl, bromopentyl, iodomethyl, iodoethyl, iodopropyl, iodobutyl, iodopentyl, etc.

In other embodiments of the compounds of formula IH R ⁸ is -C1-C ₆ -haloalkoxy, for example -C ₁ -haloalkoxy, -C ₂ -haloalkoxy, -C 3 -haloalkoxy, -C ₄ -haloalkoxy, -C ₅ -haloalkoxy, - C ₆ haloalkoxy, halomethoxy, haloethoxy, halopropoxy, haloisopropoxy, halobutoxy, haloisobutoxy, halosec-butoxy, halotert-butoxy, halopentoxy, and the like.

In other embodiments, Ar is a 5-membered heteroaryl group and compounds of formula I are of formula I-I

where Q ⁸ and Q ¹⁰ are CH, CR ⁸ or N, and Q ⁹ is NH, N (C ₁ -C ₆ -alkyl), S, or when at least one of Q ⁸ and Q ¹⁰ is N, Q ⁹ may be CH2 or CH-R ⁸ ; And

R ⁸ is halogen, C ₁ -C ₆ alkyl, C 1 -C ₆ haloalkyl, C 1 -C ₆ alkoxy or C 1 -C ₆ haloalkoxy.

It will be apparent that when Q ⁹ is NH, CH2 or CH-R ⁸ then the 5-membered heteroaryl group in the compounds of formula II may exist in tautomeric forms. All such tautomeric forms are covered by the present description.

Thus, in certain embodiments of compounds of formula II, R ⁸ is halo (eg, -F, -Cl, -Br, -I), preferably -F or -Cl. In other embodiments of compounds of formula II, R ⁸ is C 1 -C ₆ -alkyl, for example -C 1 -alkyl, -C ₂ -alkyl, -C 3 -alkyl, -C ₄ -alkyl, -C ₅ -alkyl, -C ₆ -alkyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, and the like.

In other embodiments of the compounds of formula II, R ⁸ is C 1 -C ₆ -haloalkyl, for example -C ₁ -haloalkyl, -C ₂ -haloalkyl, -C ₃ -haloalkyl, -C ₄ -haloalkyl, -C ₅ -haloalkyl, - C6-haloalkyl, fluoromethyl, fluoroethyl, fluoropropyl, fluorobutyl, fluoropentyl, chloromethyl, chloroethyl, chloropropyl, chlorobutyl, chloropentyl, bromomethyl, bromoethyl, bromopropyl, bromobutyl, bromopentyl, iodomethyl, iodoethyl, iodopropyl, iodobutyl, iodopentyl, etc.

In other embodiments of compounds of Formula II _, R ⁸ is -C1- _C6 haloalkoxy, e.g. -C1 -haloalkoxy, _-C2 haloalkoxy, _-C3 haloalkoxy, -C4 haloalkoxy, -C5 haloalkoxy, -C6 haloalkoxy, halomethoxy, haloethoxy , halopropoxy, haloisopropoxy, halobutoxy, haloisobutoxy, halosec-butoxy, halotert-butoxy, halopentoxy, and the like.

- 11 042008

In yet other embodiments, Ar is a 5-membered heteroaryl group and compounds of formula I are of formula I-J

where Q ¹² and Q ¹³ are CH, CR ⁸ or N and Q ¹¹ is NH, N(C1-C6 alkyl), S, or when at least one of Q ¹² and Q ¹³ is N, Q ¹¹ may be CH2 or CH-R ⁸ ; And

R ⁸ is halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl or C ₁ -C ₆ haloalkoxy.

It will be apparent that when Q ¹¹ is NH, CH ₂ or CH-R ⁸ then the 5-membered heteroaryl group in the compounds of formula IJ may exist in tautomeric forms. All such tautomeric forms are covered by the present description.

Thus, in some embodiments of compounds of formula IJ, R ⁸ is halo (eg, -F, -Cl, -Br, -I), preferably -F or -Cl. In other embodiments of the compounds of formula IJ R ⁸ is C 1 -C ₆ -alkyl, for example -C ₁ -alkyl, -C ₂ -alkyl, -C ₃ -alkyl, -C ₄ -alkyl, -C ₅ -alkyl, - C ₆ -alkyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, and the like.

In other embodiments of the compounds of formula IJ R ⁸ is C 1 -C ₆ haloalkyl, for example -C ₁ haloalkyl, -C ₂ haloalkyl, -C ₃ haloalkyl, -C ₄ haloalkyl, -C ₅ haloalkyl, - C ₆ g-aloalkyl, fluoromethyl, fluoroethyl, fluoropropyl, fluorobutyl, fluoropentyl, chloromethyl, chloroethyl, chloropropyl, chlorobutyl, chloropentyl, bromomethyl, bromoethyl, bromopropyl, bromobutyl, bromopentyl, iodomethyl, iodoethyl, iodopropyl, iodobutyl, iodopentyl, etc.

In other embodiments of the compounds of formula IJ R ⁸ is -C ₁ -C ₆ -haloalkoxy, for example -O ₁ -haloalkoxy, -C ₂ -haloalkoxy, -C ₃ -haloalkoxy, -C ₄ -haloalkoxy, -C ₅ -haloalkoxy , -C ₆ haloalkoxy, halomethoxy, haloethoxy, halopropoxy, haloisopropoxy, halobutoxy, haloisobutoxy, halosec-butoxy, halo-tert-butoxy, halopentoxy, and the like.

In some embodiments, compounds of formula I-J are compounds in which

A is CH;

R ² is H;

R ³ is -CH3;

R^R ⁵ ^;

X=Z=O;

Y=-CH2CH2-;

Q ¹¹ is S, Q ¹³ is CH, and Q ¹² is CR ⁸ where R ⁸ is halogen.

- 12 042008

Some preferred embodiments of compounds of formula I are compounds of formula I-A

or a pharmaceutically acceptable salt or solvate thereof, wherein A is CR ³ ;

R ¹ is halogen, NH2, -C ₁ -C6 alkyl, -C ₁ -C6 alkoxy or -C ₁ -C ₆ alk-OC ₁ -C ₆ alkyl;

R ² is H;

R ³ represents H, halogen or -C ₁ -C ₆ -alkyl;

R ⁴ represents H or -C ₁ -C ₆ -alkyl;

R ⁵ represents H or -C ₁ -C ₆ -alkyl;

X represents O, S, NH or N(C ₁ -C ₆ -alkyl); And

Y represents CH2, -CH2CH2-, C(CH ₃ ) ₂ , CF2, C(=O) or CH-C ₁ -C ₄ -alk-NH ₂ ; or

X is SO2; And

Y is CH2, -CH2CH2-, C(CH ₃ ) ₂ or CF2; or

Z is O or CH2; And

Ar is an optionally substituted phenyl ring, an optionally substituted 6-membered heteroaryl ring, or an optionally substituted 5-membered heteroaryl ring.

Other preferred embodiments of compounds of formula I are compounds of formula IA, or a pharmaceutically acceptable salt or solvate thereof, wherein A is CR ³ ;

R ¹ is halogen, NH2, -C ₁ -C ₆ -alkyl, -C ₁ -C ₆ -alkoxy or -C ₁ -C ₆ -alk-OC ₁ -C ₆ -alkyl;

R ² is H;

R ³ represents H, halogen or -C ₁ -C ₆ -alkyl;

R ⁴ represents H or -C ₁ -C ₆ -alkyl;

R ⁵ represents H or -C ₁ -C ₆ -alkyl;

X represents O, S, NH or N(C ₁ -C ₆ -alkyl);

Y represents -C(=O)-(CR ⁹ R ⁹ )n-, where n=1 or 2, each R ⁹ and R ⁹ represents H;

Z is O or CH2; And

Ar is an optionally substituted phenyl ring, an optionally substituted 6-membered heteroaryl ring, or an optionally substituted 5-membered heteroaryl ring.

Other preferred embodiments of compounds of formula I are compounds of formula IA, or a pharmaceutically acceptable salt or solvate thereof, wherein A is CR ³ ;

R ¹ is halogen, NH2, -C ₁ -C ₆ -alkyl, -C ₁ -C ₆ -alkoxy or -C ₁ -C ₆ -alk-OC ₁ -C ₆ -alkyl;

R ² is H;

R ³ represents H, halogen or -C ₁ -C ₆ -alkyl;

R ⁴ represents H or -C ₁ -C ₆ -alkyl;

R ⁵ represents H or -C ₁ -C ₆ -alkyl;

X represents O, S, SO ₂ , NH or N(C ₁ -C ₆ -alkyl);

Y is -CR ⁹ ═CR ⁹ -, each R ⁹ and R ⁹ is H;

Z is O, CH2 or CF2; And

Ar is an optionally substituted phenyl ring, an optionally substituted 6-membered heteroaryl ring, or an optionally substituted 5-membered heteroaryl ring.

Other preferred embodiments of compounds of formula I are compounds of formula IA, or a pharmaceutically acceptable salt or solvate thereof, wherein A is CR ³ ;

R ¹ is halogen, NH2, -C ₁ -C ₆ -alkyl, -C ₁ -C ₆ -alkoxy or -C ₁ -C ₆ -alk-OC ₁ -C ₆ -alkyl;

R ² is H;

R ³ represents H, halogen or -C ₁ -C ₆ -alkyl;

- 13 042008

R ⁴ represents H or -C1-C ₆ -alkyl;

R ⁵ represents H or -C1-C ₆ -alkyl;

X is O, S, NH or ^C1- _C6 alkyl);

Y is -C(=O)-O-(CR ⁹ R ⁹ ) _n where n=1 or 2 and each R ⁹ and R ⁹ is H;

Z is O or CH2; And

Ar is an optionally substituted phenyl ring, an optionally substituted 6-membered heteroaryl ring, or an optionally substituted 5-membered heteroaryl ring.

Other preferred embodiments of compounds of formula I are compounds of formula I-A-1

or a pharmaceutically acceptable salt or solvate thereof, wherein A is CR ³ ;

^R1

^R2

^R3

^R4

R ⁵ is halo, NH2, -C1- _C6 alkyl, -C1- _C6 alkoxy or _-C1 - _C6 alk-OC1- _C6 alkyl;

is H;

represents H, halogen or -C1-C ₆ -alkyl;

represents H or -C1-C ₆ -alkyl;

represents H or -C1-C ₆ -alkyl;

X represents O, S, SO2, NH or N(C ₁ -C ₆ alkyl);

each R ⁹ is independently selected from H, D, F, OH, OCH ₃ , CH ₃ or CF ₃ ;

each R ⁹ is independently selected from H, D, F, OH, OCH ₃ , CH ₃ or CF ₃ ;

Z is O or CH2; And

Ar is an optionally substituted phenyl ring, an optionally substituted 6-membered heteroaryl ring, or an optionally substituted 5-membered heteroaryl ring. Other preferred embodiments of compounds of formula I are compounds of formula I-A-2

or a pharmaceutically acceptable salt or solvate thereof, wherein A is CR ³ ;

R ¹ is halogen, NH2, -C ₁ -C ₆ -alkyl, -C ₁ -C ₆ -alkoxy or -C ₁ -C ₆ -alk-OC ₁ -C ₆ -alkyl;

R ² is H;

R ³ represents H, halogen or -C ₁ -C ₆ -alkyl;

R ⁴ represents H or -C ₁ -C ₆ -alkyl;

R ⁵ represents H or -C ₁ -C ₆ -alkyl;

X represents O, S, SO ₂ , NH or N(C ₁ -C ₆ -alkyl);

each R ⁹ is independently selected from H, D or F;

each R ⁹ is independently selected from H, D or F;

Z is O or CH2; And

- 14 042008

Ar is an optionally substituted phenyl ring, an optionally substituted 6-membered heteroaryl ring, or an optionally substituted 5-membered heteroaryl ring.

In some preferred embodiments, compounds of formula I-A-2 are compounds in which

And represents CR ³ ;

R ¹ is -NH2 or -CH ₃ ;

R ² =R ³ =R ⁴ =R ⁵ =R ⁹ =R ⁹ =H;

Z is O;

X is O; And

Ar is a phenyl ring substituted with 1-2 halogen atoms.

Other preferred embodiments of formula I-A-3 compounds of formula I are compounds

or a pharmaceutically acceptable salt or solvate thereof, wherein A is CR ³ ;

R ¹ is halogen, NH2, -C ₁ -C ₆ -alkyl, -C ₁ -C ₆ -alkoxy or -C ₁ -C ₆ -alk-OC ₁ -C ₆ -alkyl;

R ² is H;

R ³ represents H, halogen or -C ₁ -C ₆ -alkyl;

R ⁴ represents H or -C ₁ -C ₆ -alkyl;

R ⁵ represents H or -C ₁ -C ₆ -alkyl;

X represents O, S, SO2, NH or N(C ₁ -C ₆ alkyl);

R ⁹ is selected from H, D or F;

R ⁹ is selected from H, D or F;

Z is O or CH2; And

Ar is an optionally substituted phenyl ring, an optionally substituted 6-membered heteroaryl ring, or an optionally substituted 5-membered heteroaryl ring.

In some preferred embodiments, the compounds of formula I-A-3 are compounds in which

And represents CR ³ ;

R ¹ is -NH2 or -CH ₃ ;

R ² =R ³ =R ⁴ =R ⁵ =R ⁹ =R ⁹ '=H;

Z is O;

X is O; And

Ar is a phenyl ring substituted with 1-2 halogen atoms.

Other preferred embodiments of formula I-A-4 compounds of formula I are compounds

or a pharmaceutically acceptable salt or solvate thereof,

- 15 042008 where And represents CR ³ ;

R ¹ is halogen, NH2, -C ₁ -C6 alkyl, -C ₁ -C6 alkoxy or -C ₁ -C ₆ alk-OC ₁ -C6 alkyl;

R ² is H;

R ³ represents H, halogen or -C ₁ -C ₆ -alkyl;

R ⁴ represents H or -C ₁ -C ₆ -alkyl;

R ⁵ represents H or -C ₁ -C ₆ -alkyl;

X represents O, S, SO2, NH or N(C ₁ -C ₆ alkyl);

R ⁹ is selected from H, D or F;

R ⁹ is selected from H, D or F;

Z is O or CH2; And

Ar is an optionally substituted phenyl ring, an optionally substituted 6-membered heteroaryl ring, or an optionally substituted 5-membered heteroaryl ring.

In other preferred embodiments of the invention, the compounds according to this description are compounds of formula I-G-1

R ³ is H or halogen; And

Q ¹ , Q ² , Q ³ and Q ⁴ are each independently selected from N, CH or CR ⁸ where R ⁸ is halogen, -C1-haloalkyl or C1-haloalkoxy.

In some preferred embodiments, the compounds of formula I-G-1 are compounds in which

R ¹ represents NH ₂ , -CH ₃ or -CH ₂ -O-CH ₂ CH ₃ ;

R ³ is H or F; And

Q ¹ , Q ² , Q ³ and Q ⁴ are each independently selected from N, CH or CR ⁸ where R ⁸ is -F, -Cl, -CF3 or -OCF3.

In other preferred embodiments, the compounds of formula I-G-1 are compounds in which

R ¹ is NH2;

R ³ is H; And

Q ¹ , Q ² , Q ³ and Q ⁴ are each independently selected from N, CH or CR ⁸ where R ⁸ is -F, -Cl, -CF3 or -OCF3.

In some preferred embodiments, the compounds of formula I-G-1 are compounds in which

R ¹ is NH2;

R ³ is H; And

Q ¹ , Q ² , Q ³ and Q ⁴ are each independently selected from N, CH or CR ⁸ where at least one of Q ¹ , Q ² , Q ³ and Q ⁴ is CR ⁸ and R ⁸ is -F , -Cl, -CF ₃ or -OCF ₃ .

In other preferred embodiments, the compounds of formula I-G-1 are compounds in which

R ¹ is -CH3;

R ³ is H; And

Q ¹ , Q ² , Q ³ and Q ⁴ are each independently selected from N, CH or CR ⁸ where R ⁸ is -F, -Cl, -CF3 or -OCF3.

In some preferred embodiments, the compounds of formula I-G-1 are compounds in which

R ¹ is -CH3;

R ³ is H; And

Q ¹ , Q ² , Q ³ and Q ⁴ are each independently selected from N, CH or CR ⁸ where at least one of Q ¹ , Q ² ,

- 16 042008

Q ³ and Q ⁴ is CR ⁸ and R ⁸ is -F, -Cl, -CF ₃ or -OCF ₃ .

In other preferred embodiments, the compounds of formula I-G-1 are compounds in which

R ¹ is -NH ₂ ;

R ³ is H; And

Q ¹ , Q ² , Q ³ and Q ⁴ are each independently selected from CH or CR ⁸ where R ⁸ is -F, -C1, -CF ₃ or -OCF ₃ .

In other preferred embodiments, the compounds of formula I-G-1 are compounds in which

R ¹ is -CH3;

R ³ is H; And

Q ¹ , Q ² , Q ³ and Q ⁴ are each independently selected from CH or CR ⁸ where R ⁸ is -F, -Cl, -CF ₃ or -OCF ₃ .

In other preferred embodiments, the compounds of formula I-G-1 are compounds in which

R ¹ is -NH2;

R ³ is H; And

Q ¹ , Q ² , Q ³ and Q ⁴ are each independently selected from N, CH or CR ⁸ where R ⁸ is -F or -Cl.

In some preferred embodiments, the compounds of formula I-G-1 are compounds in which

R ¹ is -NH2;

R ³ is H; And

Q ¹ , Q ² , Q ³ and Q ⁴ are each independently selected from N, CH or CR ⁸ where at least one of Q ¹ , Q ² , Q ³ and Q ⁴ is CR ⁸ and where R ⁸ is -F or -Cl.

In other preferred embodiments, the compounds of formula I-G-1 are compounds in which

R ¹ is -CH ₃ ;

R ³ is H; And

Q ¹ , Q ² , Q ³ and Q ⁴ are each independently selected from N, CH or CR ⁸ where R ⁸ is -F or -Cl.

In some preferred embodiments, the compounds of formula I-G-1 are compounds in which

R ¹ is -CH3;

R ³ is H; And

Q ¹ , Q ² , Q ³ and Q ⁴ are each independently selected from N, CH or CR ⁸ where at least one of Q ¹ , Q ² , Q ³ and Q ⁴ is CR ⁸ and where R ⁸ is -F or -Cl.

In other preferred embodiments, the compounds of formula I-G-1 are compounds in which

R ¹ is -NH2;

R ³ is H; And

Q ¹ , Q ² , Q ³ and Q ⁴ are each independently selected from CH or CR ⁸ where R ⁸ is -F or -Cl.

In other preferred embodiments, the compounds of formula I-G-1 are compounds in which

R ¹ is -CH ₃ ;

R ³ is H; And

Q ¹ , Q ² , Q ³ and Q ⁴ are each independently selected from CH or CR ⁸ where R ⁸ is -F or -C1.

In other preferred embodiments of the invention, the compounds according to this description are compounds of formula I-G-2

- 17 042008 where R ¹ represents NH2 or -C ₁ -C ₆ -alkyl;

R ³ is H or halogen; And

Q ¹ , Q2, Q ³ and Q ⁴ are each independently selected from CH or CR ⁸ where R ⁸ is halogen, -C1-haloalkyl or C1-haloalkoxy.

In some preferred embodiments, the compounds of formula I-G-2 are compounds in which

R ¹ is NH2 or -CH ₃ ;

R ³ is H or F; And

Q ¹ , Q ² , Q ³ and Q ⁴ are each independently selected from N, CH or CR ⁸ where R ⁸ is -F, -Cl, -CF ₃ or -OCF ₃ .

In other preferred embodiments, the compounds of formula I-G-2 are compounds in which

R ¹ is NH2;

R ³ is H; And

Q ¹ , Q ² , Q ³ and Q ⁴ are each independently selected from N, CH or CR ⁸ where R ⁸ is -F, -Cl, -CF ₃ or -OCF ₃ .

In some preferred embodiments, the compounds of formula I-G-2 are compounds in which

R ¹ is NH ₂ ;

R ³ is H; And

Q ¹ , Q2, Q ³ and Q ⁴ are each independently selected from N, CH or CR ⁸ where at least one of Q ¹ , Q ² , Q ³ and Q ⁴ is CR ⁸ and R ⁸ is -F, -Cl, -CF ₃ or -OCF ₃ .

In other preferred embodiments, the compounds of formula I-G-2 are compounds in which

R ¹ is -CH3;

R ³ is H; And

Q ¹ , Q ² , Q ³ and Q ⁴ are each independently selected from N, CH or CR ⁸ where R ⁸ is -F, -Cl, -CF ₃ or -OCF ₃ .

In some preferred embodiments, the compounds of formula I-G-2 are compounds in which

R ¹ is -CH ₃ ;

R ³ is H; And

Q ¹ , Q ² , Q ³ and Q ⁴ are each independently selected from N, CH or CR ⁸ where at least one of Q ¹ , Q ² , Q ³ and Q ⁴ is CR ⁸ and R ⁸ is -F , -Cl, -CF3 or -OCF3.

In other preferred embodiments, the compounds of formula I-G-2 are compounds in which

R ¹ is -NH2;

R ³ is H; And

Q ¹ , Q2, Q ³ and Q ⁴ are each independently selected from CH or CR ⁸ where R ⁸ is -F or -Cl.

In other preferred embodiments, the compounds of formula I-G-2 are compounds in which

R ¹ is -CH ₃ ;

R ³ is H; And

Q ¹ , Q ² , Q ³ and Q ⁴ are each independently selected from CH or CR ⁸ where R ⁸ is -F or -Cl.

In other preferred embodiments, the compounds of formula I-G-2 are compounds in which

R ¹ is -NH2;

R ³ is H; And

Q ¹ , Q ² , Q ³ and Q ⁴ are each independently selected from N, CH or CR ⁸ where R ⁸ is -F or -Cl.

In some preferred embodiments, the compounds of formula I-G-2 are compounds in which

R ¹ is -NH ₂ ;

R ³ is H; And

Q ¹ , Q ² , Q ³ and Q ⁴ are each independently selected from N, CH or CR ⁸ where at least one of Q ¹ , Q ² , Q ³ and Q ⁴ is CR ⁸ and R ⁸ is -F or -Cl.

In other preferred embodiments, the compounds of formula I-G-2 are compounds in which

R ¹ is -CH3;

R ³ is H; And

Q ¹ , Q2, Q ³ and Q ⁴ are each independently selected from N, CH or CR ⁸ where R ⁸ is -F or -Cl.

In some preferred embodiments, the compounds of formula I-G-2 are compounds in which

- 18 042008

R ¹ is -CH3;

R3 is H; And

Q ¹ , Q ² , Q3 and Q ⁴ are each independently selected from N, CH or CR ⁸ where at least one of Q ¹ , Q ² , Q3 and Q ⁴ is CR ⁸ and where R ⁸ is -F or -Cl.

In other preferred embodiments, the compounds of formula I-G-2 are compounds in which

R ¹ is -NH ₂ ;

R ³ is H; And

Q ¹ , Q ² , Q3 and Q ⁴ are each independently selected from CH or CR ⁸ where R ⁸ is -F or -Cl.

In other preferred embodiments, the compounds of formula I-G-2 are compounds in which

R ¹ is -CH3;

R ³ is H; And

Q ¹ , Q ² , Q3 and Q ⁴ are each independently selected from CH or CR ⁸ where R ⁸ is -F or -Cl.

In other preferred embodiments, the compounds of formula I-G-2 are compounds in which

R ¹ represents NH ₂ , -C ₁ -C ₆ -alkyl or -C ₁ -C ₆ -alk-OC ₁ -C ₆ -alkyl;

R ³ is H or halogen;

Y-(CR ⁹ R ⁹ ')n-, -CR ⁹ =CR ⁹ '-, C(=O), -C(=O)-(CR ⁹ R ⁹ ')n-, -C(=O) -O-(CR ⁹ R ⁹ ')n-, -CR ⁹ R ⁹ '-O, -(CR ⁹ R ⁹ ')nO-(CR ⁹ R ⁹ ')m-, -(CR ⁹ R ⁹ ') n-NR ¹⁰ -, -C(=O)NR ¹⁰ -;

n=1 or 2;

m=1 or 2;

each of R ⁹ and R ⁹ is independently H, D, CH3, CF3, OH, OCH3 or F;

R ¹⁰ represents H or C ₁ -C ₆ -alkyl;

each and Q ¹ , Q ² , Q3 and Q ⁴ are each independently selected from N, CH or CR ⁸ where R ⁸ is halogen, -C1-haloalkyl or C ₁ -haloalkoxy.

In some preferred embodiments, the compounds of formula I-G-2 are compounds in which

R ¹ is NH2 or -CH3;

R ³ is H or F;

Y represents -CH ₂ CH ₂ -, -CH ₂ CH (C ₁ -C ₆ -alkoxy) -, -CH ₂ CH (OCH 3) -, -CH (OH) CH ₂ -, -CH (C ₁ -C ₆ -alkyl) CH ₂ -, -CH (CH3) CH ₂ -, -CH ₂ C (C ₁ -C ₆ -alkyl) ₂ -, -CH ₂ C (CH3) ₂ -, -CH (C ₁ -C ₆ -haloalkyl)CH ₂ -, -CH2CH(CF3)-, -CH2CHF-, -CH2CF2-, -CH2CD2, -CH=CH-, -C(=O)-CH2-, -C(=O)-O -CH2-, -C(=O)-O-CH2CH2-, -CH2-O-, -CF2-O-, -CH2-O-CH2-, -CF2-O-CH2-, -CH2-O-CH2CH2 -, -CF2-O-CH2CH2-; And

Q ¹ , Q ² , Q3 and Q ⁴ are each independently selected from N, CH or CR ⁸ where R ⁸ is -F, -Cl, -CF3 or -OCF3.

In other preferred embodiments, the compounds of formula I-G-2 are compounds in which

R ¹ is NH ₂ or —CH ₃ ;

R ³ is H;

Y is -CH2CH2-, -CH(OCH3)CH2-, -CH(OH)CH2-, -CH2CH(CH3)-, -CH2C(C1-C6alkyl)2-, -CH2C(CH3)2-, -CH2CH(CF3)-, -CH2CHF-, -CH2CF2-, -CH2CD2-, -CH=CH-, -C(=O)CH2-, -C(=O)-O-CH2-, -C(= O)-O-CH2CH2-, -CH2-O-, -CF2-O-, -CH2-O-CH2-, -CF2-O-CH2-, -CH2-O-CH2CH2-, -CF2-O-CH2CH2 -; And

Q ¹ , Q ² , Q ³ and Q ⁴ are each independently selected from N, CH or CR ⁸ where R ⁸ is -F or -Cl.

In some preferred embodiments of the invention, the compounds according to the present description are compounds of formula I-G-3

where R ¹ represents NH ₂ , -C ₁ -C ₆ -alkyl or -C1-C6 - alk-OC ₁ -C ₆ -alkyl;

- 19 042008

R ³ is H or halogen;

Y represents -CH2CH2-, C(CH ₃ ) ₂ , CF2 or C(=O); And

Q ¹ , Q ² , Q3 and Q ⁴ are each independently selected from N, CH or CR ⁸ where R ⁸ is halo, -C ₁ haloalkyl or C ₁ haloalkoxy.

In some preferred embodiments, the compounds of formula I-G-3 are compounds in which

R ¹ is NH2, -CH ₃ or -CH ₂ -O-CH ₂ CH ₃ ;

R ³ is H or F;

Y represents -CH2CH2-, C(CH ₃ ) ₂ , CF2 or C(=O); And

Q ¹ , Q2, Q ³ and Q ⁴ are each independently selected from N, CH or CR ⁸ where R ⁸ is -F, -Cl, -CF3 or -OCF3.

In other preferred embodiments, the compounds of formula I-G-3 are compounds in which

R ¹ is NH2;

R ³ is H;

Y represents -CH2CH2-, C(CH ₃ ) ₂ , CF2 or C(=O); And

Q ¹ , Q2, Q ³ and Q ⁴ are each independently selected from N, CH or CR ⁸ where R ⁸ is -F, -Cl, -CF ₃ or -OCF ₃ .

In other preferred embodiments, the compounds of formula I-G-3 are compounds in which

R ¹ is -CH3;

R ³ is H;

Y represents -CH2CH2-, C(CH ₃ ) ₂ , CF2 or C(=O); And

Q ¹ , Q2, Q ³ and Q ⁴ are each independently selected from N, CH or CR ⁸ where R ⁸ is -F, -Cl, -CF3 or -OCF3.

In other preferred embodiments, the compounds of formula I-G-3 are compounds in which

R ¹ is -NH ₂ ;

R ³ is H;

Y represents -CH2CH2-, C(CH ₃ ) ₂ , CF2 or C(=O); And

Q ¹ , Q2, Q ³ and Q ⁴ are each independently selected from CH or CR ⁸ where R ⁸ is -F, -Cl, -CF ₃ or -OCF3.

In other preferred embodiments, the compounds of formula I-G-3 are compounds in which

R ¹ is -CH3;

R ³ is H; Y is -CH2CH2-, C(CH3)2, CF2 or C(=O); And

Q ¹ , Q2, Q ³ and Q ⁴ are each independently selected from CH or CR ⁸ where R ⁸ is -F, -Cl, -CF ₃ or -OCF ₃ .

In other preferred embodiments, the compounds of formula I-G-3 are compounds in which

R ¹ is -NH ₂ ;

R ³ is H;

Y represents -CH2CH2-, C(CH ₃ ) ₂ , CF2 or C(=O); And

Q ¹ , Q2, Q ³ and Q ⁴ are each independently selected from N, CH or CR ⁸ where R ⁸ is -F or -Cl.

In other preferred embodiments, the compounds of formula I-G-3 are compounds in which

R ¹ is -CH3;

R ³ is H;

Y represents -CH2CH2-, C(CH ₃ ) ₂ , CF2 or C(=O); And

Q ¹ , Q2, Q ³ and Q ⁴ are each independently selected from N, CH or CR ⁸ where R ⁸ is -F or -Cl.

In other preferred embodiments, the compounds of formula I-G-3 are compounds in which

R ¹ is -NH ₂ ;

R ³ is H;

Y is -CH2CH2-, C(CH3)2, CF2 or C(=O); And

Q ¹ , Q2, Q ³ and Q ⁴ are each independently selected from CH or CR ⁸ where R ⁸ is -F or -Cl.

In other preferred embodiments, the compounds of formula I-G-3 are compounds in which

R ¹ is -CH3;

R ³ is H;

Y represents -CH2CH2-, C(CH ₃ ) ₂ , CF2 or C(=O); And

Q ¹ , Q2, Q ³ and Q ⁴ are each independently selected from CH or CR ⁸ where R ⁸ is -F or -Cl.

- 20 042008

In other preferred embodiments, the compounds of formula I-G-3 are compounds in which

R ¹ is NH2, -C ₁ -C ₆ -alkyl or -C ₁ -C ₆ -alk-OC ₁ -C ₆ -alkyl;

R ³ is H or halogen;

Y is -(CR ⁹ R9')n, -CR ⁹ =CR ⁹ '-, -C(=O)-(CR ⁹ R ⁹ ')n-, -C(=O)-O-(CR ⁹ R ⁹ ')n-, -CR ⁹ R ⁹ '-O, -(CR ⁹ R ⁹ )nO-(CR ⁹ R ⁹ ')m-;

n=1 or 2;

R ⁹ and R ⁹ are each independently H, D, CH ₃ , CF3, OH, OCH3, from F;

each and Q ¹ , Q ² , Q ³ and Q ⁴ are each independently selected from N, CH or CR ⁸ where R ⁸ is halogen, -C1-haloalkyl or C ₁ -haloalkoxy.

In some preferred embodiments, the compounds of formula I-G-3 are compounds in which

R ¹ is NH2 or -CH3;

R ³ is H or F;

Y is -CH2CH2-, -CH ₂ CH(C ₁ -C ₆ alkoxy)-, -CH ₂ CH(OCH ₃ )-, -CH(OH)CH ₂ -, -CH(C ₁ -C ₆ - alkyl)CH ₂ -, -CH(CH ₃ )CH ₂ -, -CH ₂ C (C ₁ -C ₆ -alkyl) ₂ -, -CH ₂ C (CH ₃ ) ₂ -, -CH (C ₁ -C ₆ -haloalkyl)CH ₂ -, -CH2CH(CF3)-, -CH2CHF-, -CH2CF2-, -CH2CD2, -CH=CH-, -C(=O)-CH2-, -C(=O)-O -CH2-, -C(=O)-O-CH2CH2-, -CH2-O-, -CF2-O-, -CH2-O-CH2-, -CF2-O-CH2-, -CH2-O-CH2CH2 -, -CF ₂ -O-CH ₂ CH ₂ -; And

Q ¹ , Q ² , Q ³ and Q ⁴ are each independently selected from N, CH or CR ⁸ where R ⁸ is -F, -Cl, -CF ₃ or -OCF ₃ .

In other preferred embodiments, the compounds of formula I-G-3 are compounds in which

R ¹ is NH2 or -CH3;

R ³ is H;

Y is -CH2CH2-, -CH(OCH3)CH2-, -CH(OH)CH2-, -CH2CH( _CH3 )-, -CH2C(C1-C6-alkyl)2-, -CH2C(CH3)2- , -CH2CH(CF3)-, -CH2CHF-, -CH2CF2-, -CH2CD2-, -CH=CH-, -C(=O)CH2-, -C(=O)-O-CH2-, -C( \u003d O) -O-CH2CH2-, -CH2-O-, -CF2-O-, -CH2-O-CH2-, -CF2-O-CH2-, -CH2-O-CH2CH2-, -CF2-O- CH2CH2-; And

Q ¹ , Q2, Q3 and Q ⁴ are each independently selected from N, CH or CR ⁸ where R ⁸ is -F or -Cl.

In other preferred embodiments, the compounds of formula I-G-3 are compounds in which

R ¹ is NH ₂ , -CH ₃ or -CD ₃ ;

R ³ is H or F;

Y is -CH2CH2-, -CH2CH2CH2-, -C(=O) _CH2- or -CH2CHF-; And

Q ¹ , Q2, Q3 and Q ⁴ are each independently selected from N, CH or C-R ⁸ where R ⁸ is -F, -Cl or -CH3.

In other preferred embodiments, the compounds of formula I-G-3 are compounds in which

R ¹ is NH ₂ , -CH ₃ or -CD ₃ ;

R ³ is H or F;

Y is -CH2CH2-, -CH2CH2CH2-, -C(=O) _CH2- or -CH2CHF-; And

Q ¹ , Q ² and Q ⁴ are each independently selected from CH or CR ⁸ where R ⁸ is -F, -Cl or -CH ₃ ; And

Q ³ is CR ⁸ where R ⁸ is -Cl.

In other preferred embodiments, the compounds of formula I-G-3 are compounds in which

R ¹ is NH2 or -CH3;

R ³ is H;

Y is -CH2CH2-, -CH2CH2CH2-, -C(=O) _CH2- or -CH2CHF-; And

Q ¹ , Q ² and Q ⁴ are each independently selected from CH or CR ⁸ where R ⁸ is -F, -Cl or -CH3; And

Q ³ is CR ⁸ where R ⁸ is -Cl.

In other preferred embodiments, the compounds of formula I-G-3 are compounds in which

R ¹ is NH ₂ , -CH ₃ or -CD ₃ ;

R ³ is H or F;

Y is -CH2CH2-, -CH2CH2CH2-, -C(=O) _CH2- or -CH2CHF-; And

Q ¹ is CH;

Q ² and Q ⁴ are each independently selected from CH or CR ⁸ where R ⁸ is -F, -Cl or -CH3; And

Q ³ is CR ⁸ where R ⁸ is -Cl.

In other preferred embodiments, the compounds of formula I-G-3 are compounds in which

R ¹ is NH2 or -CH3;

R ³ is H;

Y is -CH2CH2-, -CH2CH2CH2-, -C(=O) _CH2- or -CH2CHF-; And

- 21 042008

Q ¹ is CH;

Q ² and Q ⁴ are each independently selected from CH or C-R ⁸ where R ⁸ is -F, -Cl or -CH3; And

Q3 is CR ⁸ where R ⁸ is -Cl.

In some preferred embodiments of the invention, the compounds according to the present description are compounds of formula I-G-4

where R ¹ represents NH ₂ , -C ₁ -C ₆ -alkyl or -C ₁ -C ₆ -alk-OC ₁ -C ₆ -alkyl;

R ³ is H or halogen;

X represents S, NH or N(C ₁ -C ₆ -alkyl);

Y represents CH ₂ or C(=O); And

Q ¹ , Q ² , Q3 and Q ⁴ are each independently selected from N, CH or CR ⁸ where R ⁸ is halo, -C _g haloalkyl or C ₁ haloalkoxy.

In some preferred embodiments, the compounds of formula I-G-4 are compounds in which

R ¹ represents NH ₂ , -CH ₃ or -CH ₂ -O-CH ₂ CH ₃ ;

R ³ is H or F;

X represents S, NH or N(C ₁ -C ₆ -alkyl);

Y represents CH ₂ or C(=O); And

Q ¹ , Q ² , Q3 and Q ⁴ are each independently selected from N, CH or CR ⁸ where R ⁸ is -F, -Cl, -CF3 or -OCF3.

In other preferred embodiments, the compounds of formula I-G-4 are compounds in which

R ¹ is NH2;

R ³ is H;

X represents S, SO ₂ , NH or N(C ₁ -C ₆ -alkyl);

Y represents CH ₂ or C(=O); And

Q ¹ , Q ² , Q3 and Q ⁴ are each independently selected from N, CH or CR ⁸ where R ⁸ is -F, -Cl, -CF3 or -OCF3.

In other preferred embodiments, the compounds of formula I-G-4 are compounds in which

R ¹ is -CH ₃ ;

R ³ is H;

X represents S, NH or N(C ₁ -C ₆ -alkyl);

Y represents CH ₂ or C(=O); And

Q ¹ , Q ² , Q3 and Q ⁴ are each independently selected from N, CH or CR ⁸ where R ⁸ is -F, -Cl, -CF3 or -OCF3.

In other preferred embodiments, the compounds of formula I-G-4 are compounds in which

R ¹ is -NH2;

R ³ is H;

X represents S, NH or N(C ₁ -C ₆ -alkyl);

Y represents CH ₂ or C(=O); And

Q ¹ , Q ² , Q3 and Q ⁴ are each independently selected from CH or CR ⁸ where R ⁸ is -F, -Cl, -CF3 or -OCF ₃ .

In other preferred embodiments, the compounds of formula I-G-4 are compounds in which

R ¹ is -CH3;

R ³ is H;

- 22 042008

X represents S, NH or N(C ₁ -C ₆ -alkyl);

Y is CH2 or C(=O); And

Q ¹ , Q ² , Q ³ and Q ⁴ are each independently selected from CH or CR ⁸ where R ⁸ is -F, -Cl, -CF ₃ or -OCF ₃ .

In other preferred embodiments, the compounds of formula I-G-4 are compounds in which

R ¹ is -NH ₂ ;

R ³ is H;

X represents S, NH or N(C ₁ -C ₆ -alkyl);

Y is CH2 or C(=O); And

Q ¹ , Q ² , Q ³ and Q ⁴ are each independently selected from N, CH or CR ⁸ where R ⁸ is -F or -Cl.

In other preferred embodiments, the compounds of formula I-G-4 are compounds in which

R ¹ is -CH3;

R ³ is H;

X represents S, NH or N(C ₁ -C ₆ -alkyl);

Y is CH2 or C(=O); And

Q ¹ , Q ² , Q ³ and Q ⁴ are each independently selected from N, CH or CR ⁸ where R ⁸ is -F or -Cl.

In other preferred embodiments, the compounds of formula I-G-4 are compounds in which

R ¹ is -NH2;

R ³ is H;

X represents S, NH or N(C ₁ -C ₆ -alkyl);

Y is CH2 or C(=O); And

Q ¹ , Q ² , Q ³ and Q ⁴ are each independently selected from CH or CR ⁸ where R ⁸ is -F or -Cl.

In other preferred embodiments, the compounds of formula I-G-4 are compounds in which

R ¹ is -CH3;

R ³ is H;

X represents S, NH or N(C ₁ -C ₆ -alkyl);

Y is CH2 or C(=O); And

Q ¹ , Q ² , Q ³ and Q ⁴ are each independently selected from CH or CR ⁸ where R ⁸ is -F or -Cl.

In some preferred embodiments, the compounds of formula I-G-4 are compounds in which

R ¹ is NH2 or CH3;

R ³ is H;

X is NH;

Y is -CH2CH2-; and each of Q ¹ , Q ² , Q ³ and Q ⁴ is independently selected from CH or CR ⁸ where R ⁸ is -F or -Cl.

In some preferred embodiments of the invention, the compounds according to the present description are compounds of formula I-G-5

^R1

where R ¹ represents NH2 or -C ₁ -C ₆ -alkyl, Y represents -CH2- or C(=O); And

Q ¹ , Q ² , Q ³ and Q ⁴ are each independently N, CH or CR ⁸ where R ⁸ is halogen.

In some preferred embodiments, the compounds of formula I-G-5 are compounds in which

R ¹ is NH ₂ ;

- 23 042008

Y is -CH2-; and each of Q ¹ , Q ² , Q ³ and Q ⁴ independently represents CH or CR ⁸ where R ⁸ represents -F or -Cl.

In other preferred embodiments, the compounds of formula I-G-5 are compounds in which

R ¹ is -CH3;

Y is -CH2-; And

Q ¹ , Q ² , Q ³ and Q ⁴ are each independently CH or CR ⁸ where R ⁸ is -F or -Cl.

In some preferred embodiments, the compounds of formula I-G-5 are compounds in which

R ¹ is NH2;

Y is C(=O); and each of Q ¹ , Q ² , Q ³ and Q ⁴ independently represents CH or CR ⁸ where R ⁸ represents -F or -Cl.

In other preferred embodiments, the compounds of formula I-G-5 are compounds in which

R ¹ is -CH3;

Y is C(=O); and each of Q ¹ , Q ² , Q ³ and Q ⁴ independently represents CH or CR ⁸ where R ⁸ represents -F or -Cl.

In some preferred embodiments of the invention, the compounds according to the present description are compounds of formula I-G-6

where R ¹ represents NH2 or -C ₁ -C ₆ -alkyl; And

Q ¹ , Q ² , Q ³ and Q ⁴ are each independently selected from N, CH or CR ⁸ where R ⁸ is halo, -C _g haloalkyl or C1 haloalkoxy.

In some preferred embodiments, the compounds of formula I-G-6 are compounds in which

R ¹ is NH2 or -CH ₃ ; And

Q ¹ , Q ² , Q ³ and Q ⁴ are each independently selected from N, CH or CR ⁸ where R ⁸ is -F, -Cl, -CF3 or -OCF3.

In other preferred embodiments, the compounds of formula I-G-6 are compounds in which

R ¹ is NH2; And

Q ¹ , Q ² , Q ³ and Q ⁴ are each independently selected from N, CH or CR ⁸ where R ⁸ is -F, -Cl, -CF3 or -OCF3.

In other preferred embodiments, the compounds of formula I-G-6 are compounds in which

R ¹ is -CH3; And

Q ¹ , Q ² , Q ³ and Q ⁴ are each independently selected from N, CH or CR ⁸ where R ⁸ is -F, -Cl, -CF3 or -OCF3.

In other preferred embodiments, the compounds of formula I-G-6 are compounds in which

R ¹ is -NH2; And

Q ¹ , Q ² , Q ³ and Q ⁴ are each independently selected from CH or CR ⁸ where R ⁸ is -F, -Cl, -CF ₃ or -OCF3.

In other preferred embodiments, the compounds of formula I-G-6 are

- 24 042008 connections in which

R ¹ is -CH3; And

Q ¹ , Q ² , Q3 and Q ⁴ are each independently selected from CH or CR ⁸ where R ⁸ is -F, -Cl, -CF3 or -OCF3.

In other preferred embodiments, the compounds of formula I-G-6 are compounds in which

R ¹ is NH ₂ ; And

Q ¹ , Q ² , Q3 and Q ⁴ are each independently selected from N, CH or CR ⁸ where R ⁸ is -F or -Cl.

In other preferred embodiments, the compounds of formula I-G-6 are compounds in which

R ¹ is -CH ₃ ; And

Q ¹ , Q ² , Q3 and Q ⁴ are each independently selected from N, CH or CR ⁸ where R ⁸ is -F or -Cl.

In other preferred embodiments, the compounds of formula I-G-6 are compounds in which

R ¹ is -NH ₂ ; And

Q ¹ , Q ² , Q3 and Q ⁴ are each independently selected from CH or CR ⁸ where R ⁸ is -F or -Cl.

In other preferred embodiments, the compounds of formula I-G-6 are compounds in which

R ¹ is -CH ₃ ;

R ³ is H; And

Q ¹ , Q ² , Q3 and Q ⁴ are each independently selected from CH or CR ⁸ where R ⁸ is -F or -Cl.

In other aspects, the invention is directed to compounds of formula I-H-1

where R ¹ represents NH ₂ or C ₁ -C ₆ -alkyl;

Q ⁵ and Q ⁶ are independently CH, CR ⁸ or N; And

Q ⁷ is NH or S; And

R ⁸ is halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy or C 1 -C ₆ haloalkoxy.

In preferred embodiments, compounds of formula I-H-1 are compounds in which

R ¹ is NH ₂ ;

Q ⁵ and Q ⁶ are independently CH, CR ⁸ or N;

Q ⁷ is NH or S; And

R ⁸ is -F or -Cl.

In other preferred embodiments, the compounds of formula I-H-1 are compounds in which

R ¹ is -CH ₃ ;

Q ⁵ and Q ⁶ are independently CH, CR ⁸ or N;

Q ⁷ is NH or S; And

R ⁸ is -F or -Cl.

- 25 042008

In other aspects, the invention is directed to compounds of formula I-I-1

where R ¹ represents NH2 or C ₁ -C ₆ -alkyl;

Q ⁸ and Q ¹⁰ are independently CH, CR ⁸ or N;

Q ⁹ represents N(C ₁ -C ₆ -alkyl); And

R ⁸ is halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy or C ₁ -C ₆ haloalkoxy.

In preferred embodiments, compounds of formula I-I-1 are compounds in which

R ¹ is NH2;

Q ⁸ and Q ¹⁰ are independently CH, CR ⁸ or N;

Q ⁹ is N(CH3); And

R ⁸ is -F or -C1.

In other preferred embodiments, the compounds of formula I-I-1 are compounds in which

R ¹ is -CH3;

Q ⁸ and Q ¹⁰ are independently CH, CR ⁸ or N;

Q ⁹ is N(CH ₃ ); And

R ⁸ is -F or -Cl.

References to compounds of formula I herein also refer to all subgenera described herein, including, for example, compounds of formula I-A, I-A-1, I-A-2, I-A-3, I-A-4, I-B, IC, I-D, I -E, I-F, I-G, I-G-1, I-G-2, I-G-3, I-G-4, I-G-5, I-G-6, I-H, I-H-1, I-1, I-I-1 and I-J.

It will be apparent that compounds of formula I, including all subgenera described herein, have multiple stereogenic centers. As a result, there are many stereoisomers (enantiomers and diastereomers) of the compounds of formula I (the subgenera described herein). The present disclosure contemplates and encompasses each stereoisomer of any compound of formula I (and the subgenera described herein), as well as mixtures of these stereoisomers.

Pharmaceutically acceptable salts and solvates of the compounds of formula I (including all subgenera described herein) are also within the scope of this disclosure.

Isotopic variants of compounds of formula I (including all subgenera described herein) are also contemplated in this disclosure.

Pharmaceutical compositions and methods of administration.

Contemplated pharmaceutical compositions are generally formulated to provide a therapeutically effective amount of a compound of this invention as an active ingredient or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof. If desired, the pharmaceutical compositions contain a pharmaceutically acceptable salt and/or coordination complex thereof, as well as one or more pharmaceutically acceptable excipients, carriers including inert solid diluents and excipients, diluents including a sterile aqueous solution and various organic solvents, penetration enhancers, solubilizers and adjuvants.

The subject pharmaceutical compositions may be administered alone or in combination with one or more other agents, which are also commonly administered in the form of pharmaceutical compositions. If desired, one or more of the compounds of the invention and the other agent(s) may be mixed in a formulation, or both components may be formulated into separate formulations for use in combination alone or at the same time.

In some embodiments, the concentration of one or more compounds provided in the pharmaceutical compositions of this invention is less than 100, 90, 80, 70, 60, 50, 40, 30, 20, 19, 18, 17, 16, 15, 14 , 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4 , 0.3, 0.2, 0.1,

- 26 042008

0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02, 0.01, 0.009, 0.008, 0.007, 0.006, 0.005, 0.004, 0.003, 0.002, 0.001, 0.0009, 0.0008, 0.0007, 0.0006, 0.0005, 0.0004, 0.0003, 0.0002, or 0.0001% (or a number within the range defined by any two of the above numbers inclusive) wt./wt., wt./about or about./about.

In some embodiments, the concentration of one or more compounds of the invention is greater than 90, 80, 70, 60, 50, 40, 30, 20, 19.75, 19.50, 19.25, 19, 18.75, 18.50, 18.25, 18, 17.75, 17.50, 17.25, 17, 16.75, 16.50, 16.25, 16, 15.75, 15.50, 15.25, 15, 14, 75, 14.50, 14.25, 14, 13.75, 13.50, 13.25, 13, 12.75, 12.50, 12.25, 12, 11.75, 11.50, 11, 25, 11, 10.75, 10.50, 10.25, 10, 9.75, 9.50, 9.25, 9, 8.75, 8.50, 8.25, 8, 7.75, 7.50, 7.25, 7, 6.75, 6.50, 6.25, 6, 5.75, 5.50, 5.25, 5, 4.75, 4.50, 4.25, 4, 3.75, 3.50, 3.25, 3, 2.75, 2.50, 2.25, 2, 1.75, 1.50, 1.25, 1, 0.9, 0, 8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.09, 0.08, 0.07, 0.06, 0.05, 0.04 0.03 0.02 0.01 0.009 0.008 0.007 0.006 0.005 0.004 0.003 0.002 0.001 0.0009 0.0008 0.0007 0.0006 0.0005, 0.0004, 0.0003, 0.0002, or 0.0001% (or a number in the range defined by and including any two of the above numbers) wt./wt., wt./about. or rev./rev.

In some embodiments, the concentration of one or more compounds of the invention is in the range from about 0.0001% to about 50%, from about 0.001% to about 40%, from about 0.01% to about 30%, from about 0.02 % to about 29%, from about 0.03% to about 28%, from about 0.04% to about 27%, from about 0.05% to about 26%, from about 0.06% to about 25%, about 0.07% to about 24%, about 0.08% to about 23%, about 0.09% to about 22%, about 0.1% to about 21%, from about 0.2% to about 20%, from about 0.3% to about 19%, from about 0.4% to about 18%, from about 0.5% to about 17%, from about 0.6% to about 16%, from about 0.7% to about 15%, about 0.8% to about 14%, about 0.9% to about 12%, about 1% to about 10% w/w, w/v . or rev./rev.

In some embodiments, the concentration of one or more compounds of the invention is in the range of about 0.001% to about 10%, about 0.01% to about 5%, about 0.02% to about 4.5%, about 0 03% to about 4%, about 0.04% to about 3.5%, about 0.05% to about 3%, about 0.06% to about 2.5%, from about 0.07 % to about 2%, from about 0.08% to about 1.5%, from about 0.09% to about 1%, from about 0.1% to about 0.9% wt./wt., wt. /about. or rev./rev.

In some embodiments, the amount of one or more compounds of the invention is equal to or less than 10, 9.5, 9.0, 8.5, 8.0, 7.5, 7.0, 6.5, 6.0, 5 .5, 5.0, 4.5, 4.0, 3.5, 3.0, 2.5, 2.0, 1.5, 1.0, 0.95, 0.9, 0.85 , 0.8, 0.75, 0.7, 0.65, 0.6, 0.55, 0.5, 0.45, 0.4, 0.35, 0.3, 0.25, 0 .2, 0.15, 0.1, 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02, 0.01, 0.009, 0.008 , 0.007, 0.006, 0.005, 0.004, 0.003, 0.002, 0.001, 0.0009, 0.0008, 0.0007, 0.0006, 0.0005, 0.0004, 0.0003, 0.0002 or 0.0001 g (or a number in the range defined by any two of the above numbers, inclusive).

In some embodiments, the amount of one or more compounds of this invention is greater than 0.0001, 0.0002, 0.0003, 0.0004, 0.0005, 0.0006, 0.0007, 0.0008, 0.0009, 0.001 0.0015 0.002 0.0025 0.003 0.0035 0.004 0.0045 0.005 0.0055 0.006 0.0065 0.007 0.0075 0.008 0.0085 0.009 0.0095, 0.01, 0.015, 0.02, 0.025, 0.03, 0.035, 0.04, 0.045, 0.05, 0.055, 0.06, 0.065, 0.07, 0.075, 0.08, 0.085, 0.09, 0.095, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0, 6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5 or 10 g (or a number in the range defined by any two of the above numbers, inclusive).

In some embodiments, the amount of one or more compounds of the invention is in the range of 0.0001-10, 0.0005-9, 0.001-8, 0.005-7, 0.01-6, 0.05-5, 0.1- 4, 0.5-4 or 1-3 g.

The compounds of the invention are effective over a wide dosage range. For example, in the treatment of adults, dosages of 0.01 to 1000 mg, 0.5 to 100 mg, 1 to 50 mg per day, and 5 to 40 mg per day are examples of dosages that can be used. The approximate dosage is from 10 to 30 mg per day. The exact dosage will depend on the route of administration, the form in which the compound is administered, the subject being treated, the body weight of the subject being treated, and the preference and experience of the attending physician.

A pharmaceutical composition of the invention typically contains an active ingredient (i.e., a compound of the disclosure) of the invention, or a pharmaceutically acceptable salt and/or coordination complex thereof, as well as one or more pharmaceutically acceptable excipients, carriers, including but not limited to inert solids. diluents and excipients, diluents, sterile aqueous solution and various organic solvents, penetration enhancers, solubilizers and adjuvants.

Non-limiting examples of pharmaceutical compositions and methods for their preparation are described below.

Pharmaceutical compositions for oral use.

In some embodiments, the invention provides an oral pharmaceutical composition comprising a compound of the invention and a pharmaceutical excipient suitable for oral administration.

In some embodiments, the invention provides a solid pharmaceutical composition for oral administration containing (i) an effective amount of a compound of the invention; optionally (ii) an effective amount of the second agent; And

- 27 042008 (iii) a pharmaceutical excipient suitable for oral administration.

In some embodiments, the composition further comprises (iv) an effective amount of a third agent.

In some embodiments, the pharmaceutical composition may be a liquid pharmaceutical composition suitable for oral administration. Pharmaceutical compositions of the invention suitable for oral administration may be presented as discrete dosage forms such as capsules, cachets or tablets, or liquids or aerosol sprays, each containing a predetermined amount of the active ingredient as a powder or granules, solution or suspension. in an aqueous or non-aqueous liquid, oil-in-water emulsion or water-in-oil emulsion. Such dosage forms may be prepared by any of the pharmaceutical methods, but all methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more of the required ingredients. In general, compositions are prepared by uniformly and intimately mixing the active ingredient with liquid carriers or finely divided solid carriers, or both, and then, if necessary, shaping the product into the desired form. For example, a tablet may be prepared by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable device the active ingredient in free flowing form such as powder or granules, optionally in admixture with an excipient such as, but not limited to, a binder, lubricant, inert diluent and/or a surfactant or dispersing agent. . Molded tablets can be made by molding in a suitable machine a mixture of a powdered compound wetted with an inert liquid diluent.

This invention also includes anhydrous pharmaceutical compositions and dosage forms containing the active ingredient, since water may promote the degradation of some compounds. For example, water can be added (eg 5%) in pharmaceuticals as a shelf life simulation to determine characteristics such as shelf life or formulation stability over time. Anhydrous pharmaceutical compositions and dosage forms of the invention may be prepared using anhydrous or low moisture ingredients and under low humidity conditions. Pharmaceutical compositions and dosage forms of the invention that contain lactose can be made anhydrous if significant contact with moisture and/or moisture is expected during manufacture, packaging and/or storage. The anhydrous pharmaceutical composition can be prepared and stored so as to retain its anhydrous nature. Accordingly, anhydrous compositions can be packaged using materials known to prevent exposure to water so that they can be included in suitable formulary sets. Examples of suitable packaging include, but are not limited to, sealed foil, plastic or the like, unit dose containers, blister packs, and strip packs.

The active ingredient may be combined in a homogeneous mixture with a pharmaceutical carrier in accordance with conventional pharmaceutical mixing techniques. The carrier may take a wide variety of forms depending on the form of the formulation desired for administration. When preparing compositions for oral dosage form, any of the usual pharmaceutical vehicles can be used as carriers, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like. in the case of oral liquid formulations (such as suspensions, solutions and elixirs) or aerosols; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders and disintegrants may be used in the case of oral solid formulations, in some embodiments lactose-free. For example, suitable carriers include powders, capsules and tablets for solid oral formulations. If desired, the tablets can be coated by standard aqueous or non-aqueous methods.

Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch or other starches, gelatin, natural and synthetic gums such as gum arabic, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (eg, ethylcellulose, cellulose acetate, calcium carboxymethylcellulose, sodium carboxymethylcellulose), polyvinylpyrrolidone, methylcellulose, pregelatinized starch, hydroxypropyl methylcellulose, microcrystalline cellulose, and mixtures thereof.

Examples of suitable excipients for use in the pharmaceutical compositions and dosage forms described herein include, but are not limited to, talc, calcium carbonate (eg, granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid , sorbitol, starch, pregelatinized starch and mixtures thereof.

Disintegrants can be used in the compositions of the invention to provide tablets that disintegrate when exposed to an aqueous environment. Too much baking powder can

- 28 042008 lead to the formation of tablets which may disintegrate in the vial. Too small an amount may not be sufficient for disintegration to occur and thus the rate and extent of release of the active ingredient(s) from the dosage form may change. Thus, a sufficient amount of disintegrant that is neither too small nor too large to adversely alter the release of the active ingredient(s) can be used to form dosage forms of the compounds disclosed herein. The amount of disintegrant used may vary depending on the type of formulation and route of administration and may be readily discernible to those skilled in the art. About 0.5% to about 15% by weight of disintegrant, or about 1% to about 5% by weight of disintegrant, may be used in the pharmaceutical composition. Disintegrants that can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, potassium polacrilin, sodium starch glycolate, potato or tapioic starch, other starches, pregelatinized starch, other starches, clays, other algins, other celluloses, gums, or mixtures thereof.

Lubricants that can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (eg, peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, or mixtures thereof. Additional lubricants include, for example, siloid silica gel, coagulated synthetic silica aerosol, or mixtures thereof. Optionally, a lubricant can be added in an amount of less than about 1% wt. pharmaceutical composition.

When aqueous suspensions and/or elixirs are desired for oral administration, the active ingredient may be combined with various sweetening or flavoring agents, coloring or coloring agents and, if desired, emulsifying and/or suspending agents, together with diluents such as water, ethanol. , propylene glycol, glycerin and various combinations thereof.

Tablets may be uncoated or coated by known methods to slow down disintegration and absorption in the gastrointestinal tract and thus provide sustained action over a longer period. For example, a release time delay material such as glyceryl monostearate or glyceryl distearate may be used. Oral formulations may also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oily medium. such as peanut butter, liquid paraffin or olive oil.

Surfactants that can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof. Those. a mixture of hydrophilic surfactants may be used, a mixture of lipophilic surfactants may be used, or a mixture of at least one hydrophilic surfactant and at least one lipophilic surfactant may be used.

A suitable hydrophilic surfactant may typically have an HLB value of at least 10, while suitable lipophilic surfactants may typically have an HLB value of about 10 or less. An empirical parameter used to characterize the relative hydrophilicity and hydrophobicity of non-ionic amphiphilic compounds is the hydrophilic-lipophilic balance (HLB value). Surfactants with lower HLB values are more lipophilic or hydrophobic and have greater solubility in oils, while surfactants with higher HLB values are more hydrophilic and have greater solubility in aqueous solutions.

Hydrophilic surfactants generally refer to compounds having an HLB value greater than about 10, as well as anionic, cationic, or zwitterionic compounds for which the HLB scale is not normally applicable. Similarly, lipophilic (i.e., hydrophobic) surfactants are compounds having an HLB value equal to or less than about 10. However, the HLB value of a surfactant is only a rough guideline commonly used to formulate industrial, pharmaceutical, and cosmetic emulsions. .

Hydrophilic surfactants may be ionic or non-ionic. Suitable ionic surfactants include, but are not limited to, alkyl ammonium salts; fusidic acid salts; fatty acid derivatives of amino acids, oligopeptides and polypeptides

- 29 042008 dov; glyceride derivatives of amino acids, oligopeptides and polypeptides; lecithins and hydrogenated lecithins; lysolecithins and hydrogenated lysolecithins; phospholipids and their derivatives; lysophospholipids and their derivatives; salts of esters of carnitine and fatty acids; alkyl sulfate salts; salts of fatty acids; docusate sodium; acyl lactylates; mono- and diacetylated esters of mono- and diglycerides of tartaric acid; succinylated mono- and diglycerides; esters of mono- and diglycerides of citric acid; and their mixtures.

In the above group, ionic surfactants include, for example: lecithins, lysolecithin, phospholipids, lysophospholipids and derivatives thereof; salts of esters of carnitine and fatty acids; alkyl sulfate salts; salts of fatty acids; docusate sodium; acylactylates; mono- and diacetylated esters of mono- and diglycerides of tartaric acid; succinylated mono- and diglycerides; esters of mono- and diglycerides of citric acid; and their mixtures.

Ionic surfactants can be ionized forms of lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP-ethanolamine c, lactic acid esters stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides, mono/diacetylated tartaric mono/diglyceride esters, citric acid mono/diglyceride esters, cholyl sarcosine, caproate, caprylate, caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate, linoleinate , stearate, lauryl sulfate, teracetyl sulfate, docusate, lauroyl carnitines, palmitoyl carnitines, myristoyl carnitines, as well as their salts and mixtures.

Hydrophilic non-ionic surfactants may include, but are not limited to, alkyl glucosides; alkyl maltosides; alkylthioglucosides; lauryl macrogol glycerides; polyoxyalkylene alkyl ethers such as polyethylene glycol alkyl ethers; polyoxyalkylene alkylphenols such as polyethylene glycol alkylphenol ethers; polyoxyalkylene alkylphenol fatty acid esters such as polyethylene glycol fatty acid monoesters and polyethylene glycol fatty acid diesters; esters of polyethylene glycol glycerol and fatty acids; esters of polyglycerol and fatty acids; polyoxyalkylene sorbitan fatty acid esters such as polyethylene glycol sorbitan fatty acid esters; hydrophilic transesterification products of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols; polyoxyethylene sterols, their derivatives and analogues; polyoxyethylated vitamins and their derivatives; block copolymers of polyoxyethylene and polyoxypropylene; and mixtures thereof; esters of polyethylene glycol sorbitan and fatty acids; and hydrophilic transesterification products of a polyol with at least one member of the group consisting of triglycerides, vegetable oils and hydrogenated vegetable oils. The polyol may be glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol or saccharide.

Other hydrophilic non-ionic surfactants include, without limitation, PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32 dilaurate, PEG-12 oleate, PEG-15 oleate, PEG oleate -20, PEG-20 Dioleate, PEG-32 Oleate, PEG-200 Oleate, PEG-400 Oleate, PEG-15 Stearate, PEG-32 Distearate, PEG-40 Stearate, PEG-100 Stearate, PEG-20 Dilaurate, PEG Glyceryl Trioleate -25, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate, PEG-30 glyceryl oleate, PEG-30 glyceryl laurate, PEG-40 glyceryl laurate, PEG-40 palm kernel oil, hydrogenated PEG-50 Castor Oil, PEG-40 Castor Oil, PEG-35 Castor Oil, PEG-60 Castor Oil, PEG-40 Hydrogenated Castor Oil, PEG-60 Hydrogenated Castor Oil, PEG-60 Corn Oil, Caprate/Caprylate PEG-Glycerides 6, PEG-8 Caprate/Caprylate Glycerides, PEG-8 Laurate, PEG-30 Cholesterol, PEG-25 Phytosterol, PEG-30 Soy Sterol, PEG-20 Trioleate, PEG-40 Sorbitanoleate, PEG-80 Sorbitan Laurate, Polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23 lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl ether, PEG-100 tocopheryl succinate, PEG-24 cholesterol, polyglyceryl oleate 10, Tween 40, Tween 60, sucrose monostearate, sucrose monolaurate, sucrose monopalmitate, PEG 10-100 nonylphenol range, PEG 15-100 octylphenol range and poloxamers.

Suitable lipophilic surfactants include, by way of example only: fatty alcohols; esters of glycerol and fatty acids; esters of acetylated glycerol and fatty acids; esters of lower alcohols and fatty acids; esters of propylene glycol and fatty acids; esters of sorbitan and fatty acids; esters of polyethylene glycol sorbitan and fatty acids; sterols and sterol derivatives; polyoxyethylated sterols and sterol derivatives; alkyl ethers of polyethylene glycol; esters of sugars; ethers of sugars; derivatives of mono- and diglycerides of lactic acid; hydrophobic interesterification products of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols; fat-soluble vitamins/vitamin derivatives; and their mixtures. In this group, the preferred lipophilic surfactants

- 30 042008 active substances include esters of glycerol and fatty acids, esters of propylene glycol and fatty acids and mixtures thereof or are products of hydrophobic transesterification of a polyol with at least one member of the group consisting of vegetable oils, hydrogenated vegetable oils and triglycerides.

In one embodiment, the composition may include a solubilizer to ensure good solubilization and/or dissolution of the compound of this invention and to minimize precipitation of the compound of this invention. This may be especially important for non-oral compositions, eg injectable compositions. A solubilizer may also be added to increase the solubility of the hydrophilic drug and/or other components such as surfactants or to maintain the composition as a stable or homogeneous solution or dispersion.

Examples of suitable solubilizers include, but are not limited to, the following: alcohols and polyols such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediols and their isomers, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinyl alcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives; ethers of polyethylene glycols with an average molecular weight of from about 200 to about 6000, such as PEG-ether of tetrahydrofurfuryl alcohol (glycofurol) or methoxy-PEG; amides and other nitrogen compounds such as 2-pyrrolidone, 2-piperidone, ε-caprolactam, N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam, dimethylacetamide and polyvinylpyrrolidone; esters such as ethyl propionate, tributyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, triethyl citrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, ε-caprolactone and its isomers, δ-valerolactone and its isomers, β-butyrolactone and its isomers; and other solubilizers known in the art such as dimethylacetamide, dimethylisosorbide, N-methylpyrrolidones, monooctanoin, diethylene glycol monoethyl ether and water.

Mixtures of solubilizers can also be used. Examples include, but are not limited to, triacetin, triethyl citrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropylcyclodextrins, glycol-propylene glycol 200-100, glucofurol, transcutol, propylene glycol, and dimethylisosorbide. Particularly preferred solubilizers include sorbitol, glycerol, triacetin, ethyl alcohol, PEG-400, glycofurol and propylene glycol.

The amount of the solubilizer that may be included is not particularly limited. The amount of this solubilizer may be limited to a biologically acceptable amount, which can be easily determined by a person skilled in the art. In some cases, it may be advantageous to include amounts of solubilizers far in excess of bioacceptable amounts, for example, to maximize drug concentration, with excess solubilizer removed prior to providing the composition to a subject using conventional methods such as distillation or evaporation. Thus, if present, the solubilizer may be in a weight ratio of 10%, 25%, 50%, 100%, or up to about more than 200% by weight, based on the total weight of the drug and other excipients. If desired, very small amounts of solubilizer may also be used, for example less than 5%, less than 2%, less than 1%, or even less. Typically, the solubilizer may be present in an amount of less than about 1% to about 100%, more typically less than about 5% to less than about 25% by weight.

The composition may further include one or more pharmaceutically acceptable additives and excipients. Such additives and excipients include, but are not limited to, tackifiers, antifoam agents, buffering agents, polymers, antioxidants, preservatives, chelating agents, visco-modulators, tonics, fragrances, colorants, odorants, opacifiers, suspending agents, binders, bulking agents, plasticizers, lubricating agents and mixtures thereof.

In addition, an acid or base may be included in the composition for ease of handling, stability, or other reasons. Examples of pharmaceutically acceptable bases include amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, synthetic aluminum silicate, synthetic hydrocalcite, magnesium aluminum hydroxide, diisopropylethylamine, ethanolamine, ethylenediamine , triethanolamine, triethylamine, triisopropanolamine, trimethylamine, tris(hydroxymethyl)aminomethane (TRIS) and the like. Also suitable are bases which are salts of a pharmaceutically acceptable acid such as acetic acid, acrylic acid, adipic acid, alginic acid, alkane sulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, sorrel

- 31 042008 oic acid, p-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid, and the like. It is also possible to use salts of polyprotic acids such as sodium phosphate, disodium hydrogen phosphate and sodium dihydrogen phosphate. When the base is a salt, the cation may be any suitable and pharmaceutically acceptable cation such as ammonium, alkali metal cation, alkaline earth metal cation, and the like. Examples may include, but are not limited to, sodium, potassium, lithium, magnesium, calcium, and ammonium.

Suitable acids are pharmaceutically acceptable organic or inorganic acids. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, and the like. Examples of suitable organic acids include acetic acid, acrylic acid, adipic acid, alginic acid, alkane sulfonic acids, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid , toluenesulfonic acid, uric acid, and the like.

Pharmaceutical compositions for injection.

In some embodiments, the invention provides an injectable pharmaceutical composition comprising a compound of the invention and a pharmaceutical excipient suitable for injection. The components and amounts of agents in the compositions are as described herein.

Forms in which the novel compositions of this invention may be incorporated for administration by injection include aqueous or oily suspensions or emulsions with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and the like. pharmaceutical carriers.

Aqueous solutions in saline are also commonly used for injection. Ethanol, glycerin, propylene glycol, liquid polyethylene glycol, and the like can also be used. (and suitable mixtures thereof), cyclodextrin derivatives and vegetable oils. Suitable fluidity can be maintained, for example, with a coating such as lecithin to maintain the required particle size in the case of a dispersion, and with the help of surfactants. Prevention of the action of microorganisms can be provided by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

Sterile injectable solutions are prepared by incorporating the compound of this invention in the required amount in an appropriate solvent with various other ingredients listed above, if necessary, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the other necessary ingredients listed above. In the case of sterile powders for the preparation of sterile injectable solutions, some desirable preparation methods are vacuum drying and freeze-drying methods which yield a powder of the active ingredient plus any additional desired ingredient from its pre-sterile filtered solution.

Pharmaceutical compositions for topical (eg, transdermal) delivery.

In some embodiments, the invention relates to a pharmaceutical composition for transdermal delivery comprising a compound of this invention and a pharmaceutical excipient suitable for transdermal delivery.

The compositions of this invention may be formulated in solid, semi-solid or liquid forms suitable for topical or topical application, such as gels, water-soluble jellies, creams, lotions, suspensions, foams, powders, suspensions, ointments, solutions, oils, pastes, suppositories, sprays, emulsions, physiological solutions, solutions based on dimethyl sulfoxide (DMSO). In general, higher density carriers are able to provide a zone of prolonged exposure to the active ingredients. On the contrary, the composition of the solution may provide a more rapid effect of the active ingredient on the selected area.

Pharmaceutical compositions may also contain suitable solid or gel carriers or excipients, which are compounds that enhance penetration or facilitate delivery of therapeutic molecules across the stratum corneum permeability barrier. Many of these penetration enhancing molecules are known to those skilled in the art of topical formulation.

Examples of such carriers and excipients include, but are not limited to,

- 32 042008 Antioxidants (eg urea), glycols (eg propylene glycol), alcohols (eg ethanol), fatty acids (eg oleic acid), surfactants (eg isopropyl myristate and sodium lauryl sulfate), pyrrolidones, glycerol monolaurate , sulfoxides, terpenes (eg menthol), amines, amides, alkanes, alkanols, water, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.

In another exemplary formulation for use in the methods of this invention, transdermal delivery devices (patches) are used. Such transdermal patches can be used to provide continuous or intermittent infusion of a compound of this invention in controlled amounts, either with or without another agent.

The design and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, for example, US Pat.

Pharmaceutical compositions for inhalation.

Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, and powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. Preferably, the compositions are administered by the oral or nasal respiratory route for local or systemic action. Compositions in preferably pharmaceutically acceptable solvents can be sprayed using inert gases. Nebulized solutions can be inhaled directly from a nebulization device, or the nebulization device can be attached to a tent with a face mask or intermittent positive pressure breathing apparatus. Solution, suspension or powder compositions can be administered, preferably orally or nasally, from devices that deliver the composition in an appropriate manner.

Other pharmaceutical compositions.

Pharmaceutical compositions may also be prepared from the compositions described herein and one or more pharmaceutically acceptable excipients suitable for sublingual, buccal, rectal, intraosseous, intraocular, intranasal, epidural, or intraspinal administration. The preparation of such pharmaceutical compositions is well known in the art. See, for example, Anderson, Philip O., Knoben, James E., Troutman, William G., eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Pratt and Taylor, eds., Principles of Drug Action, Third Edition, Churchill Livingston, New York, 1990; Katzung, ed., Basic and Clinical Pharmacology, Ninth Edition, McGraw Hill, 20037ybg; Goodman and Gilman, eds., The Pharmacological Basis of Therapeutics, Tenth Edition, McGraw Hill, 2001; Remingtons Pharmaceutical Sciences, 20th ed., Lippincott Williams & Wilkins., 2000; Martindale, The Extra Pharmacopoeia, Thirty-Second Edition (The Pharmaceutical Press, London, 1999); they are all incorporated herein by reference in their entirety.

The administration of the compounds or pharmaceutical composition of this invention may be by any method that delivers the compounds to the site of action. These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, intraarterial, subcutaneous, intramuscular, intravascular, intraperitoneal, or infusion), topical (e.g., transdermal application), rectal administration, via local delivery by a catheter or stent, or via inhalation. The compounds can also be administered intraadiposally or intrathecally.

The amount of compound administered will depend on the subject being treated, the severity of the disorder or condition, the rate of administration, the distribution of the compound, and the discretion of the attending physician. However, an effective dose is in the range of about 0.001 mg to about 100 mg per kg of body weight per day, preferably about 1 mg/kg/day to about 35 mg/kg/day, in a single or divided dose. For a 70 kg human, this would be from about 0.05 to 7 g/day, preferably from about 0.05 g/day to about 2.5 g/day. In some cases, dose levels below the lower end of the aforementioned range may be more than adequate, while in other cases even higher doses may be used without causing any harmful side effects, for example, by dividing such large doses into several small doses to administration throughout the day.

In some embodiments, a compound of the invention is administered as a single dose.

Typically, such administration will be by injection, eg intravenous injection, to rapidly administer the agent. However, other routes may be used if necessary. A single dose of a compound of this invention may also be used to treat an acute condition.

In some embodiments, a compound of the invention is administered in multiple doses. The dosage may be about one, two, three, four, five, six or more than six times a day. The dosage may be about once a month, once every two weeks, once a week, or once every other day. In another embodiment, a compound of the invention and another agent are administered together from about once a day to about 6 times a day. In another embodiment, the administration of the compound of the invention and the agent lasts less than about 7 days. In another embodiment, the introduction continues

- 33 042008 more than about 6, 10, 14, 28 days, two months, six months, or one year. In some cases, continuous dosing is achieved and maintained for as long as necessary.

The administration of the compounds of the invention may be continued for as long as necessary. In some embodiments, a compound of this invention is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, a compound of this invention is administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 days. In some embodiments, a compound of the invention is administered chronically on an ongoing basis, eg, to treat chronic effects.

An effective amount of a compound of this invention may be administered as a single or multiple dose by any of the accepted routes of administration for agents of similar use, including rectal, buccal, intranasal, and transdermal routes, intra-arterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral , topically or by inhalation.

The compositions of this invention can also be delivered through an impregnated or coated device such as, for example, a stent or a cylindrical polymer introduced into an artery. Such a route of administration may, for example, help prevent or reduce restenosis following procedures such as balloon angioplasty. Without being limited by theory, the compounds of this invention can slow down or inhibit the migration and proliferation of smooth muscle cells in the arterial wall that promote restenosis. The compound of the invention can be administered, for example, by local delivery from stent struts, from a stent graft, from grafts, or from a stent sheath or sheath. In some embodiments, a compound of this invention is mixed with a matrix. Such a matrix may be a polymeric matrix and may serve to bind the compound to the stent. Suitable polymer matrices for such use include, for example, lactone-based polyesters or copolyesters such as polylactide, polycaprolactone glycolide, polyorthoesters, polyanhydrides, polyamino acids, polysaccharides, polyphosphazenes, polyester-polyester copolymers (eg, PEO-PLLA); polydimethylsiloxane, poly(ethylene vinyl acetate), acrylate based polymers or copolymers (eg polyhydroxyethyl methyl methacrylate, polyvinyl pyrrolidinone), fluorinated polymers such as polytetrafluoroethylene and cellulose esters. Suitable matrices may not break down, or break down over time, releasing the compound or compounds. The compounds of the invention can be applied to the surface of the stent in a variety of ways, such as dip/spin coating, spray coating, dip coating, and/or brush coating. Compounds can be applied in a solvent and the solvent can be allowed to evaporate, thus forming a layer of the compound on the stent. Alternatively, the compound may be located in the body of the stent or graft, for example, in microchannels or micropores. During implantation, the compound diffuses out of the body of the stent and contacts the artery wall. Such stents can be made by immersing a stent that contains such micropores or microchannels in a solution of a compound of the invention in a suitable solvent, followed by evaporation of the solvent. Excess drug on the stent surface can be removed by additional short solvent flushing. In still other embodiments, the compounds of the invention may be covalently linked to a stent or graft. You can use a covalent linker that degrades in vivo, resulting in the release of the compounds of the invention. Any biolabile bond, such as ester, amide or anhydride bonds, can be used for this purpose. The compounds of the invention may additionally be administered intravascularly from a balloon used during angioplasty. Extravascular administration of compounds through the pericardium or additional use of the compositions of the invention can also be performed to reduce restenosis.

A variety of stent devices that can be used as described are disclosed, for example, in the following references, all of which are incorporated here by reference: US Pat. No. 5,451,233; US Pat. No. 5,040,548; US Pat. No. 5,061,273; No. US patent 5496346; No. US patent 5292331; US Pat. No. 5,674,278; US Pat. No. 3,657,744; No. US patent 4739762; US Pat. No. 5,195,984; No. US patent 5292331; US Pat. No. 5,674,278; US Pat. No. 5,879,382; U.S. Patent No. 6344053.

The compounds of this invention can be administered in doses. It is known in the art that, due to the intersubject variability in the pharmacokinetics of a compound, an individual adjustment of the dosing regimen is necessary for optimal therapy. The dosage of a compound of the invention can be found by routine experimentation in light of the present disclosure.

When a compound of the invention is administered in a composition that contains one or more agents and the agent has a shorter half-life than the compound of the invention, the unit dosage forms of the agent and the compound of the invention may be adjusted accordingly.

The pharmaceutical composition in question may, for example, be in a form suitable for oral administration as a tablet, capsule, pill, powder, sustained release formulation, solution, suspension, for parenteral injection as a sterile topical solution, suspension or emulsion, in in the form of an ointment or cream or for rectal administration in the form of suppositories. The pharmaceutical composition may be in the form of unit dosage forms,

- 34 042008 suitable for a single injection of precise doses. The pharmaceutical composition will include a conventional pharmaceutical carrier or excipient and a compound of the invention as an active ingredient. In addition, it may include other medicinal or pharmaceutical agents, carriers, adjuvants, and the like.

Examples of forms for parenteral administration include solutions or suspensions of the active compound in sterile aqueous solutions, for example, aqueous solutions of propylene glycol or dextrose. If desired, such dosage forms may be suitably buffered.

Ways to use.

The method generally comprises administering to a subject a therapeutically effective amount of a compound of the invention. A therapeutically effective amount of a contemplated combination of compounds may vary depending on the intended use (in vitro or in vivo) or the subject and disease state being treated, for example, the body weight and age of the subject, the severity of the disease state, the route of administration, and the like, which can be easily determined by a person skilled in the art. The term is also applied to a dose that will elicit a specific response in target cells, such as reduced proliferation or downregulated activity of the target protein. The specific dosage will vary depending on the specific compounds chosen, the dosage regimen to be followed, whether it is administered in combination with other compounds, the time of administration, the tissue into which it is administered, and the physical delivery system in which it is administered.

As used herein, the term IC ₅₀ refers to half the maximum inhibitory concentration of an inhibitor when inhibiting a biological or biochemical function. This quantitative measure indicates how much of a particular inhibitor is needed to inhibit a given biological process by half (or a component of the process, i.e., an enzyme, cell, cell receptor, or microorganism). In other words, it is half the maximum (50%) inhibitory concentration (IC ₅₀ ) of the substance (50% IC or IC ₅₀ ). EC ₅₀ refers to the plasma concentration required to obtain 50% of the maximum effect in vivo.

In some embodiments, the present methods use a PRMT5 inhibitor with an IC ₅₀ value of about or less than a predetermined value set in an in vitro assay. In some embodiments, the PRMT5 inhibitor inhibits PRMT5a with an IC ₅₀ value of about 1 nM or less, 2 nM or less, 5 nM or less, 7 nM or less, 10 nM or less, 20 nM or less, 30 nM or less, 40 nM or less, 50 nM or less, 60 nM or less, 70 nM or less, 80 nM or less, 90 nM or less, 100 nM or less, 120 nM or less, 140 nM or less, 150 nM or less, 160 nM or less, 170 nM or less, 180 nM or less, 190 nM or less, 200 nM or less, 225 nM or less, 250 nM or less, 275 nM or less, 300 nM or less, 325 nM or less, 350 nM or less, 375 nM or less, 400 nM or less, 425 nM or less, 450 nM or less, 475 nM or less, 500 nM or less, 550 nM or less, 600 nM or less, 650 nM or less, 700 nM or less, 750 nM or less, 800 nM or less, 850 nM or less, 900 nM or less, 950 nM or less, 1 μM or less, 1.1 μM or less, 1.2 μM or less, 1.3 µM or less, 1.4 µM or less, 1.5 µM or less, 1.6 µM or less, 1.7 µM or less, 1.8 µM or less, 1.9 µM or less, 2 µM or less , 5 µM or less, 10 µM or less, 15 µM or less, 20 µM or less, 25 µM or less, 30 µM or less, 40 µM or less, 50, 60, 70, 80, 90, 100, 200, 300, 400 or 500 µM or less (or a number in the range defined by any two numbers above, inclusive).

In some embodiments, the PRMT5 inhibitor selectively inhibits PRMT5a with an IC ₅₀ value that is at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45 , 50, 100, or 1000 times less (or a number in the range defined by any two of the above numbers, inclusive) than its IC50 value compared to one, two, or three other PRMTs.

In some embodiments, the PRMT5 inhibitor selectively inhibits PRMT5a with an IC50 value of less than about 1, 2, 5, 7, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 120, 140, 150, 160 , 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950 nM, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, or 500 μM (or the range defined by any two of the above numbers, inclusive), and a specified IC ₅₀ value of at least 2, 3 , 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 100, or 1000 times less (or a number in the range defined by any two of the above numbers, inclusive), than its IC ₅₀ value compared to one, two or three other PRMTs.

The contemplated methods are applicable to the treatment of a disease state associated with PRMT5. Any disease state that results directly or indirectly from an abnormal activity or expression level of PRMT5 may be a putative disease state.

Various disease states associated with PRMT5 have been reported. PRMT5 is involved, for example, in various human cancers, as well as in a number of hemoglobinopathies.

Non-limiting examples of such conditions include, but are not limited to, acanthoma, acinar cell carcinoma, acoustic neuroma, acral lentiginous melanoma, acrospiroma, acute eosinophilic leukemia, acute lymphoblastic leukemia, acute lymphocytic leukemia, acute megakaryoblastic leukemia, acute monocytic leukemia, acute myeloid leukemia with co

- 35 042008 maturation, acute myeloid dendritic cell leukemia, acute myeloid leukemia, acute myelogenous leukemia, acute promyelocytic leukemia, adamantine, adenocarcinoma, adenoid cystic carcinoma, adenoma, adenomatoid odontogenic tumor, adrenocortical carcinoma, adult T-cell leukemia, aggressive NK-cell leukemia , AIDS-related cancers, AIDS-related lymphoma, soft alveolar sarcoma, ameloblastic fibroma, anal cancer, anaplastic large cell lymphoma, anaplastic thyroid cancer, angioimmunoblastic T-cell lymphoma, angiomyolipoma, angiosarcoma, appendix cancer, astrocytoma, atypical teratoid rhabdoid tumor, basal cell carcinoma, basal-like carcinoma, B-cell leukemia, B-cell lymphoma, Bellini duct carcinoma, biliary tract cancer, bladder cancer, blastoma, bone cancer, bone tumor, brainstem glioma, brain tumor, breast cancer glands, Brenner's tumor, bronchial tumor, bronchial alveolar carcinoma, Brown's tumor, Burkitt's lymphoma, cancer of unknown primary site, carcinoid tumor, carcinoma, carcinoma in situ, carcinoma of the penis, carcinoma of unknown primary site, carcinosarcoma, Castleman's disease, embryonic tumor of the central nervous system , cerebellar astrocytoma, cerebral astrocytoma, cervical cancer, cholangiosarcoma, chondroma, chondrosarcoma, chordoma, choriocarcinoma, choroid plexus papilloma, chronic lymphocytic leukemia, chronic monocytic leukemia, chronic myelogenous leukemia, chronic myeloproliferative disease, chronic neutrophilic leukemia, colon cancer , craniopharynginoma, cutaneous T-cell lymphoma, Degos disease, protuberance dermatofibrosarcoma, dermoid cyst, desmoplastic small cell round tumor, diffuse larger B-cell lymphoma, dysembryoplastic neuroepithelial tumor, embryonic carcinoma, endodermal sinus tumor, endometrial cancer, endometrial uterine cancer, endometrioid tumor , enteropathy-associated T-cell lymphoma, ependymoblastoma, ependymoma, epidermoid carcinoma, epithelioid sarcoma, erythroleukemia, esophageal cancer, esthesioneuroblastoma, Ewing family tumor, Ewing family sarcoma, Ewing sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic bile cancer ducts, extramammary Paget's disease, fallopian tube cancer, embryonic embryo, fibroma, fibrosarcoma, follicular lymphoma, follicular thyroid cancer, gallbladder cancer, gallbladder cancer, ganglioglioma, ganglioneuroma, gastric cancer, gastric lymphoma, gastrointestinal cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor, gastrointestinal stromal tumor, germinocyte tumor, germinoma, gestational choriocarcinoma, gestational trophoblastic tumor, giant cell bone tumor, glioblastoma multiforme, glioma, cerebral gliomatosis, glomangioma, glucagonoma, gonadoblastoma , granulosa cell tumor, hairy cell leukemia, head and neck cancer, head and neck cancer, heart cancer, hemoglobinopathies such as b-thalassemia and sickle cell anemia (SCD), hemangioblastoma, hemangiopericytoma, hemangiosarcoma, hematological malignancies, hepatocellular carcinoma, hepatosplenic T-cell lymphoma, hereditary breast and ovarian cancer syndrome, Hodgkin's lymphoma, hypopharyngeal lymphoma, inflammatory breast cancer, intraocular melanoma, islet cell carcinoma, islet cell tumor, juvenile myelomonocytic leukemia, Kaposi's sarcoma, Kaposi's sarcoma, kidney cancer, Klatskin's tumor, Krukenberg's tumor , larynx cancer, laryngeal cancer, lentigo malignant melanoma, leukemia, lip and mouth cancer, liposarcoma, lung cancer, luteoma, lymphangioma, lymphangiosarcoma, lymphoepithelioma, lymphocytic leukemia, macroglobulinemia, malignant fibrous histiocytoma, malignant fibrous histiocytoma, malignant fibrous bone histiocytoma, malignant glioma, malignant mesothelioma, malignant peripheral nerve sheath tumor, malignant rhabdoid tumor, malignant newt tumor, MALT lymphoma, mantle cell lymphoma, mastocytosis cell leukemia, mastocytosis, mediastinal germ cell tumor, mediastinal tumor, medullary thyroid cancer, medulloblastoma, medulloblastoma, medulloepithelioma, melanoma, melanoma, meningioma, Merkel cell carcinoma, mesothelioma, mesothelioma, metastatic squamous cell carcinoma of the neck of unknown origin, metastatic urothelial carcinoma, mixed Muhler tumor, monocytic leukemia, oral cancer, mucosal carcinoma, multiple endocrine neoplasia syndrome, multiple myeloma, fungal mycosis, fungal mycosis, myelodysplastic disease, myelodysplasia syndromes, myeloid leukemia, myeloid sarcoma, myeloproliferative disease, myxoma, nasal cavity cancer, nasopharyngeal cancer, nasovarenal caricinoma, neoplasm, neuroma, neuroblastoma, neuroblastoma, neurofibroma, neuroma, nodular melanoma, non-Hodgkin's lymphoma, non-Hodgkin's lymphoma, non-melanoma skin cancer, non-small cell lung cancer, ocular oncology, oligoastrocytoma, oligodendroglioma, oncocytoma, optic nerve sheath meningioma, oral cavity cancer, oral cavity cancer, oropharyngeal cancer, osteosarcoma, osteosarcoma, ovarian cancer, ovarian cancer, epithelial ovarian cancer, ovarian germ cell tumor, low potential ovarian cancer, Paget's disease of the breast, Pancoast tumor, pancreatic cancer, pancreatic cancer, papillary thyroid cancer,

- 36 042008 papillomatosis, paraganglioma, cancer of the nasal sinuses, cancer of the parathyroid glands, cancer of the penis, perivascular epithelioid cell tumor, pharyngeal cancer of the pharynx, pheochromocytoma, parenchymal tumor of the pineal gland of intermediate differentiation, pineoblastoma, pitiucytoma, pityar adenoma, pityar neoplasmic cell tumor, plasma cell tumor tumor, pleuropulmonary blastoma, polyembryoma, progenitor T-cell lymphocytic lymphoma, primary central nervous system lymphoma, primary effusion lymphoma, primary hepatocellular carcinoma, primary liver cancer, primary peritoneal cancer, primitive neuroectodermal tumor, prostate cancer, peritoneal pseudomyxoma, rectal cancer, renal cell carcinoma, respiratory tract carcinoma involving the NUT gene on chromosome 15, retinoblastoma, rhabdomyoma, rhabdomyosarcoma, Richter's transformation, sacrococcygeal teratoma, salivary gland cancer, sarcoma, schwannomatosis, sebaceous carcinoma, secondary neoplasm, seminoma, serous tumor, Sertoli-Leydig cell tumor, sex cord stromal tumor, Cesari syndrome, ring cell carcinoma, skin cancer, small blue round cell tumor, small cell carcinoma, small cell lung cancer, small cell lymphoma, small bowel cancer, soft tissue sarcoma, somatostatinoma, sooty wart , tumor of the spinal cord, tumor of the spine, lymphoma of the marginal zone of the spleen, squamous cell carcinoma, gastric cancer, superficial spreading melanoma, supratent primitive neuroectodermal tumor, superficial epithelial-stromal tumor, synovial sarcoma, T-cell acute lymphoblastic leukemia, large granular T-cell leukemia lymphocytes, T-cell leukemia, T-cell lymphoma, T-cell prolymphocytic leukemia, teratoma, terminal lymphatic carcinoma, testicular cancer, tecoma, throat cancer, thymic carcinoma, thymoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, transitional cell carcinoma carcinoma, urachal cancer, urethral cancer, rogenital neoplasm, uterine sarcoma, uveal melanoma, vaginal cancer, Werner Morrison syndrome, verrucous carcinoma, optic pathway glioma, vulvar cancer, Waldenström's disease, Varsin's tumor, Wilms' tumor, or any combination thereof.

In some embodiments, said method is for the treatment of a disease selected from the group consisting of tumor angiogenesis, a chronic inflammatory disease such as rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases such as psoriasis, eczema and scleroderma, diabetes, diabetic retinopathy , retinopathy of prematurity, age-related macular degeneration, hemangiomas, gliomas, melanomas, Kaposi's sarcoma, and ovarian, breast, lung, pancreatic, prostate, colon, and epidermoid cancers.

In other embodiments, said method is for treating a disease selected from breast cancer, lung cancer, pancreatic cancer, prostate cancer, colon cancer, ovarian cancer, uterine cancer, or cervical cancer.

In other embodiments, said method is for the treatment of a disease selected from leukemia, such as acute myeloid leukemia (AML), acute lymphocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, myelodysplasia, myeloproliferative diseases, acute myelogenous leukemia (AML) , chronic myeloid leukemia (CML), mastocytosis, chronic lymphocytic leukemia (CLL), multiple myeloma (MM), myelodysplastic syndrome (MDS), epidermoid cancer, or hemoglobinopathies such as b-thalassemia and sickle cell anemia (SCA).

In yet other embodiments, said method is for the treatment of a disease selected from CDKN2A-deleted cancers; 9P deleted cancers; MTAP of deleted cancers; glioblastoma, NSCLC, head and neck cancer, bladder cancer, or hepatocellular carcinoma.

The compounds of the disclosure, as well as pharmaceutical compositions containing them, can be administered for the treatment of any of the diseases described, alone or in combination with drug therapy. Medical treatments include, for example, surgery and radiation therapy (eg, gamma radiation, neutron beam therapy, electron beam therapy, proton therapy, brachytherapy, systemic radioactive isotopes).

In other aspects, the compounds of the disclosure, as well as pharmaceutical compositions containing them, can be administered to treat any of the diseases described, alone or in combination with one or more other agents.

In other ways, the compounds of the disclosure, as well as pharmaceutical compositions containing them, can be administered in combination with nuclear receptor agonists.

In other ways, the compounds of the present disclosure, as well as pharmaceutical compositions containing them, can be administered in combination with nuclear receptor antagonists.

In other ways, the compounds of the disclosure, as well as pharmaceutical compositions containing them, can be administered in combination with an antiproliferative agent.

In other aspects, the compounds of the disclosure, as well as pharmaceutical compositions containing them, can be administered for the treatment of any of the diseases described, alone or in combination with one

- 37 042008 or more other chemotherapeutic agents. Examples of other chemotherapeutic agents include, for example, abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, all-trans retinoic acid, altretamine, anastrozole, arsenic trioxide, asparaginase, azacitidine, bendamustine, bevacizumab, bexarotene, bleomycin, bortezombi, bortezomib, intravenous busulfan, intravenous busulfan, intravenous busulfan, oral busulfan, calusterone, capecitabine, carboplatin, carmustine, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dalteparin sodium, dasatinib, daunorubicin, decitabine, denileukin, denileukin diphthitox, dexramostancinone, docetaxeloxane, docetaxonoxane propionate, eculizumab, epirubicin, erlotinib, estramustine, etoposide phosphate, etoposide, exemestane, fentanyl citrate, filgrastim, floxuridine, fludarabine, fluorouracil, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelin acetate, ibritumomab, tiuxamidine mesylate, interferon alfa 2a, irinotecan, lapatinib ditosylate, lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole, lomustine, meclorethamine, megestrol acetate, melphalan, mercaptopurine, methotrexate, methoxalene, mitomycin C, mitotpn, mitoxantrone, nandrolone, fenpropionabonate , oxaplatin, paclitaxel, pamidronate, panobinostat, panitumumab, pegaspargasa, pegfilgrastim, pemetrexed disodium, pentostatin, pipobroman, plicamycin, procarbazine, quinacrine, rasburicase, rituximab, ruxolitinib, sofatinib, streptozocin, sunitinib, sunitinib maleate, tammoxifen, temozolomide, tenopozide, lactone , thalidomide, thioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine, vorinstat and zoledronate, as well as any combination thereof.

In other aspects, the other agent is a therapeutic agent that targets an epigenetic regulator. Examples of epigenetic regulators include, for example, inhibitors of bromodomain, histone lysine methyltransferases, histone arginine methyltransferases, histone demethylases, histone deacetylases, histone acetylases, and DNA methyltransferases, and any combination thereof. Histone deacetylase inhibitors are preferred in some aspects and include, for example, vorinostat.

In other methods in which the disease being treated is cancer or other proliferative disease, the compounds of the disclosure, as well as pharmaceutical compositions containing them, can be administered in combination with targeted therapy agents. Targeted therapies include, for example, JAK kinase inhibitors (eg, Ruxolitinib), PI3 kinase inhibitors (including selective PI3K delta inhibitors and broad spectrum PI3K inhibitors), MEK inhibitors, cyclin-dependent kinase inhibitors (eg, CDK4/6 inhibitors), BRAF inhibitors , mTOR inhibitors, proteasome inhibitors (eg, bortezomib, carfilzomib), HDAC inhibitors (eg, panobinostat, vorinostat), DNA methyltransferase inhibitors, dexamethasone, bromo and extraterminal family member inhibitors, BTK inhibitors (eg, ibrutinib, acalabrutinib), BCL2 inhibitors (eg, venetoclax), MCL1 inhibitors, PARP inhibitors, FLT3 inhibitors, and LSD1 inhibitors, and any combination thereof.

In other methods in which the disease being treated is cancer or other proliferative disease, the compounds of the disclosure, as well as pharmaceutical compositions containing them, can be administered in combination with agents that inhibit immune checkpoints. Immune checkpoint inhibitors include, for example, PD-1 inhibitors, such as an anti-PD-1 monoclonal antibody. Examples of anti-PD-1 monoclonal antibodies include, for example, nivolumab, pembrolizumab (also known as MK-3475), pidilizumab, SHR-1210, PDR001 and AMP-224, and combinations thereof. In some aspects, the anti-PD1 antibody is nivolumab. In some aspects, the anti-PD1 antibody is pembrolizumab. In some aspects, the immune checkpoint inhibitor is a PD-L1 inhibitor, such as an anti-PD-L1 monoclonal antibody. In some aspects, the anti-PD-L1 monoclonal antibody is BMS-935559, MEDI4736, MPDL3280A (also known as RG7446), or MSB0010718C, or any combination thereof. In some aspects, the anti-PD-L1 monoclonal antibody is MPDL3280A or MEDI4736. In other aspects, the immune checkpoint inhibitor is a CTLA-4 inhibitor, for example, and an anti-CTLA-4 antibody. In some aspects, the anti-CTLA-4 antibody is ipilimumab.

In other methods in which the disease being treated is cancer or other proliferative disease, the compounds of the disclosure, as well as pharmaceutical compositions containing them, can be administered in combination with an alkylating agent (e.g., cyclophosphamide (CY), melphalan (MEL) and bendamustine), a proteasome inhibitor agent (eg, carfilzomib), a corticosteroid agent (eg, dexamethasone (DEX)) or an immunomodulatory agent (eg, lenalidomide (LEN) or pomalidomide (POM)) or any combination thereof.

In some embodiments, the disease to be treated is an autoimmune condition or an inflammatory condition. In these aspects, the compounds of the disclosure, as well as pharmaceutical compositions containing them, may be administered in combination with a corticosteroid agent such as, for example, triamcinolone, dexamethasone, fluocinolone, cortisone, prednisolone, or

- 38 042008 flumetholone or any combination thereof.

In other methods in which the disease being treated is an autoimmune condition or an inflammatory condition, the compounds of the disclosure, as well as pharmaceutical compositions containing them, can be administered in combination with an immunosuppressive agent such as, for example, fluocinolone acetonide (RETISERT™) , rimexolone (AL-2178, VEXOL™, ALCO™) or cyclosporine (RESTASIS™) or any combination thereof.

In some embodiments, the disease to be treated is beta thalassemia or sickle cell anemia. In these aspects, the compounds of the disclosure, as well as pharmaceutical compositions containing them, can be administered in combination with one or more agents such as, for example, HYDREA™ (hydroxyurea).

The examples and preparations below further illustrate the compounds of this invention and methods for preparing such compounds. It should be understood that the scope of the present invention is in no way limited by the scope of the following examples and formulations. In the following examples, molecules with a single chiral center, unless otherwise noted, exist as a racemic mixture. These molecules with two or more chiral centers, unless otherwise noted, exist as a racemic mixture of diastereomers. Individual enantiomers/diastereomers can be obtained by methods known to those skilled in the art.

Connection disclosure include, for example, the compounds listed in table. A.

Table A

Prime R structures Molecular mass chemical names 1A but 9Λ-. hh ₂ 388.81 (2R,3R,4 S, 5 8)-2-(4-amino7H-pyrrolo[2,3- d]pyrimidin-7-Ni)-5-((R)5-chloro-1,3dihydroisobenzofuran-1 yl)tetrahydrofuran-3,4diol 2A but gu-y nh ₂ 386.83 (lR,2S,3R,5S)-3-(4-aMHHO7Н-pyrrolo[2,3d]pyrimidin-7-nn)-5-((R)5-chloro-1,3dihydroisobenzofuran-1 yl)cyclopentan-1 ,2-diol BEHIND O ^H Q ".Αν- ⁰ nh ₂ 400.82 (S)-3-((lS,2R,3S,4R)-4-(4amino-7H-pyrrolo[2,3 d]pyrimidin-7-yl)-2,3dihydroxycyclopentyl)6-chloroisobenzofuran1(3H)-one SW Oh nh ₂ 400.82 (R)-3-((l S,2R,3S,4R)-4-(4amino-6H-714-pyrrolo[2,3 d]pyrimidin-7-yl)-2,3dihydroxycyclopentyl)6-chloroisobenzofuran- 1(ZN)-on

- 39 042008

IB but hh ₂ 388.81 (2R,3R,4S,5S)-2-(4-aMHHO7Н-pyrrolo[2,3d]pyrimidin-7-yl)-5-((8)5-chloro-1,3dihydroisobenzofuran-1 yl)tetrahydrofuran-3 ,4diol 2B but ho-<jQO^ ^ci nh ₂ 386.83 (lR,2S,3R,5S)-3-(4-aMHHO7H-pyrrolo[2,3d]pyrimidin-7-yl)-5-((8)5-chloro-1,3dihydroisobenzofuran-1yl)cyclopentan-1 ,2-diol 4 but, ^? Ύ. NO-LASA ¢0 nh ₂ 390, 34 (2R,3R,4S,5S)-2-(4-aMHHO7Н-pyrrolo[2,3d]pyrimidin-7-hh)-5-((R)5,6-difluoro-1,3dihydroisobenzofuran-1 yl)tetrahydrofuran -3,4- diol 5 ho, 9A-, ^ho, CQQ nh ₂ 388.8 (2R,3R,4S,5S)-2-(4-aMHHO7Н-pyrrolo[2,3d]pyrimidin-7-hh)-5-((R)6-chloro-1,3dihydroisobenzofuran-1 yl)tetrahydrofuran-3 ,4diol

-40042008

6 ^H Mb- _F ^H0 <I \=< ^F -OS? 389.3588 (2S,3S,4R,5R)-2-((R)-5,6difluoro-1,3dihydroisobenzofuran-1 yl)-5-(4-methyl-7Hpyrrolo[2,3-d]pyrimidin7-yl)tetrahydrofuran- 3,4diol 7 ^Η 100ν ^h o-OO ^f _N ' ^F oc? 431.4398 (2R,3R,4S,5S)-2-(4-6yran7H-pyrrolo[2,3d]pyrimidine-7-nn)-5-((R)5,6-difluoro-1,3dihydroisobenzofuran-1 yl)tetrahydrofuran -3,4- diol 8 Ooty ^H0 <J \^ ^F oc? 433.4118 (2S,3S,4R,5R)-2-((R)-5,6difluoro-1,3dihydroisobenzofuran-1 yl)-5-(4-(ethoxymethyl)-7Hpyrrolo[2,3-d]pyrimidin7-yl) tetrahydrofuran-3,4- diol 9 but 9'0—, .w % nh ₂ ^f 406.7984 (2R,3R,4S, 5 8)-2-(4-amino5-fluoro-7H-pyrrolo[2,3 d]pyrimidin-7-yl)-5-((s)5-chloro-1,3dihydroisobenzofuran- 1 yl)tetrahydrofuran-3,4diol

-41 042008

10 but ^but '<J ,ψο νη ₂ 388.808 (2R,3R,4S,5S)-2-(4-aMHHO7Н-pyrrolo[2,3d]pyrimidin-7-nn)-5-((R)4-chloro-1,3dihydroisobenzofuran-1 yl)tetrahydrofuran-3 ,4diol And but , λν^ΖΛ but< 1 }=/ Y ⁰ c/ -sro νη ₂ 388.808 (2R,3R,4S,5S)-2-(4-aMHHO7Н-pyrrolo[2,3d]pyrimidin-7-nn)-5-((R)7-chloro-1,3dihydroisobenzofuran-1 yl)tetrahydrofuran-3 ,4diol 12 but 9A—, 387.82 (2S,3S,4R,5R)-2-((R)-5chloro-1,3dihydroisobenzofuran-1 yl)-5-(4-methyl-7Hpyrrolo[2,3-d]pyrimidin7-yl)tetrahydrofuran-3, 4- diol 13 but ?A~U ^ΗΟ <2 OO 387.82 (2S,3S,4R,5R)-2-((R)-4chloro-1,3dihydroisobenzofuran-1 yl)-5-(4-methyl-7Hpyrrolo[2,3-d]pyrimidin7-yl)tetrahydrofuran-3, 4- diol

- 42 042008

14 but ΗΗ_^ ^Η0 '< J Cl 387.82 (2S,3S,4R,5R)-2-((R)-7chloro-1,3dihydroisobenzofuran-1 yl)-5-(4-methyl-7Hpyrrolo[2,3-d]pyrimidin7-yl)tetrahydrofuran-3, 4diol 15 HO 9A_^ ^ho \J O ,Ο ^ci co 387.82 (2S,3S,4R,5R)-2-((R)-6chloro-1,3dihydroisobenzofuran-1 yl)-5-(4-methyl-7Hpyrrolo[2,3-d]pyrimidin7-yl)tetrahydrofuran-3, 4- diol 16 but _r xAfy^ _F ^HO <J O'^N -ipo nh ₂ 422.3642 (2R,3R,4S,5S)-2-(4-aMHHO7Н-pyrrolo[2,3d]pyrimidin-7-yl)-5-((R)5 -(trifluoromethyl)-1,3dihydroisobenzofuran-1yl) tetrahydrofuran-3,4- diol 17 ho 9A-^ _c ^HO CI \=/ν o^rN OS 421.3762 (2R,3R,4S,5S)-2-(4-methyl7H-pyrrolo[2,3d]pyrimidin-7-yl)-5-((R)5 -(trifluoromethyl)-1,3dihydroisobenzofuran-1yl) tetrahydrofuran-3,4- diol

- 43 042008

18 οΛ /L \ Z~CI ^but y1 nh ₂ 402.835 (2R,3 S,4R,5R)-5-(4-amino7H-πirpolo[2,3d]pyrimidine-7-mi)-2-((R)5-chloro-1,3dihydroisobenzofuran-1 yl)-3methyltetrahydrofuran -3,4- diol 19 . 0^\ ^but <L>l /I \ /~C1 ^but <1 _N 'co 401.847 (2R,3S,4R,5R)-2-((R)-5chloro-1,3dihydroisobenzofuran-1 yl)-3 -methyl-5 -(4-methyl7H-pyrrolo[2,3d]pyrimidin-7 yl)tetrahydrofuran -3,4diol 20 CI ^but ^ -< Г ΓχΟ νη ₂ 402.835 (2R,3R,4S, 5 8)-2-(4-amino7H-pyrrolo[2,3- d]pyrimidin-7-yl)-5-((K)5-chloro-1-methyl-1,3dihydroisobenzofuran-1-yl)tetrahydrofuran-3,4- diol 21 Cl A ^ho GP co 401.847 (2S,3S,4R,5R)-2-((R)-5chloro-1 -methyl-1,3dihydroisobenzofuran-1 yl)-5-(4-methyl-7Hpyrrolo[2,3-d]pyrimidin7-yl) tetrahydrofuran-3,4- diol

-44042008

22 A 401.847 (2S,3S,4R,5R)-2-((R)-6chloroisochroman-1-yl)-5-(4methyl-7H-pyrrolo[2,3d]pyrimidin-7yl)tetrahydrofuran-3,4diol 23 io 9 LASUs! NOo/T \=/ OU 423.8008 (2S,3S,4R,5R)-2-((R)-5chloro-3,3-difluoro-1,3dihydroisobenzofuran-1 yl)-5-(4-methyl-7Hpyrrolo[2,3-d]pyrimidine7- yl)tetrahydrofuran-3,4diol 24 but 9 lasUs ^but <D with 415.874 (2S,3S,4R,5R)-2-((R)-5- chloro-3,3-dimethyl-1,3dihydroisobenzofuran-1 yl)-5-(4-methyl-7Hpyrrolo[2,3-d]pyrimidin7-yl)tetrahydrofuran-3,4diol 25 io f^S—. la<us| BUT<1 \=/ OU 403.881 (2S,3S,4R,5R)-2-((R)-5chloro-1,3d ihydrobenzo[c]thiophen-1 yl)-5-(4-methyl-7Hpyrrolo[2,3-d]pyrimidin7-yl )tetrahydrofuran-3,4diol

-45042008

26 _οχ 435.879 (I)-5-chloro-1- ((2S,3S,4R,5R)-3,4dihydroxy-5-(4-methyl-7Hpyrrolo[2,3-d]pyrimidin7-yl)tetrahydrofuran-2yl)-1,3dihydrobenzo[c]thiophene2,2-dioxide 27 ^Η °Ό co 437.3752 (2R,3R,4S,5S)-2-(4-methyl7H-pyrrolo[2,3d]pyrimidin-7-yl)-5-((K)5-(trifluoromethoxy)-1,3dihydroisobenzofuran-1yl) tetrahydrofuran-3,4diol 28 xAfy/ _F ^HO CJ ^=(7 ^F OS 439.3666 (2S,3S,4R,5R)-2-((R)-6fluoro-5-(trifluoromethyl)1,zdihydroisobenzofuran-1 yl)-5-(4-methyl-7Hpyrrolo[2,3-d]pyrimidin7-yl )tetrahydrofuran-3,4diol 29 but ?o>__ xA<yZ ^{F but,,} y1 ^F OS 455.3656 (2S,3S,4R,5R)-2-((R)-6fluoro-5-(trifluoromethoxy)1,3dihydroisobenzofuran-1 yl)-5-(4-methyl-7Hpyrrolo[2,3-d]pyrimidine7- yl)tetrahydrofuran-3,4diol

- 46 042008

thirty But 400.863 (2R,3S,4R,5R)-2-((R)-5chloro-2-methylisoindolin1-yl)-5-(4-methyl-7Нpyrrolo[2,3-d]pyrimidin7-yl)tetrahydrofuran-3,4 - diol 31 O ΟΟ 414.846 (R)-6-xlop-3- ((2R,3S,4R,5R)-3,4dihydroxy-5-(4-methyl-7Hpyrrolo[2,3-d]pyrimidin7-yl)tetrahydrofuran-2yl)-2-methylisoindoline-1 - He 32 but 9%χΑπ BUT< 1 \=/ g ° OO 354.366 (2S,3S,4R,5R)-2-((R)-l,3dihydrofuro[3,4c]pyridin-1-yl)-5-(4methyl-7H-pyrrolo[2,3d]πyrimidin-7yl)tetrahydrofuran -3,4diol 33 but XAH ^but <a Η ^Cl -OO 388.808 (2S,3S,4R,5R)-2-((R)-6chloro-1,3-dihydrofuro[3,4c]pyridin-1-yl)-5-(4methyl-7H-pyrrolo[2,34]pyrimidine -7yl)tetrahydrofuran-3,4- diol

- 47 042008

34 7 ⁵ ^ y. o /=4 ^x V/ 360.388 (2S,3S,4R,5R)-2-((R)-4,6dihydropoφypo[3,4-d]thiazol4-yl)-5-(4-methyl-7Нpyrrolo[2,3-d]pyrimidin7-yl )tetrahydrofuran-3,4- diol 35 ^but 1 ^ΗΟ γθ N^ _C| os 394.83 (2S,3S,4R,5R)-2-((R)-2chloro-4,6-dihydrofuro[3,40]thiazol-4-yl)-5-(4-methyl7H-pyrrolo[2,3d]pyrimidine -7 yl)tetrahydrofuran-3,4- diol 36 yO ^Η θ \ A r° co 359.4 (2S,3S,4R,5R)-2-((R)-4,6dihydrothieno[2,3-c]furan4-yl)-5-(4-methyl-7Hpyrrolo[2,3-d]pyrimidin7-yl )tetrahydrofuran-3,4- diol 37 ^but Ci OS 393.842 (2S,3S,4R,5R)-2-((R)-2chloro-4,6-dihydrothieno[2,3c]furan-4-yl)-5-(4-methyl7H-pyrrolo[2,3d]nnpHMHflHH -7yl)tetrahydrofuran-3,4- diol 38 Ο^Ο -a J< _V N OS 343.343 (2S,3S,4R,5R)-2-((R)-4,6dihydro-1H-furo[3,4c]pyrazol-4-yl)-5-(4methyl-7H-pyrrolo[2,3d]pyrimidine -7-

- 48 042008

yl)tetrahydrofuran-3,4- DIOL 39 ⁿ I JO GO 357.37 (2S,3S,4R,5R)-2-((R)-2methyl-2,6-d ihydro-4Нfuro[3,4-с] ^pirazol -4-yl)5-(4-methyl-7Нpyrrolo[ 2,3-d]pyrimidin7-yl)tetrahydrofuran-3,4diol 40 but ^HO <JOU 386.84 (2R,3S,4R,5R)-2-((R)-5chloroisoindolin-1-yl)-5(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7yl)tetrahydrofuran-3,4diol 41 О HO ₇ >с ^ΗΟ <Ϊ CO 400.82 (R)-6-xlop-3- ((2R,3S,4R,5R)-3,4dihydroxy-5-(4-methyl-7Hpyrrolo[2,3-d]pyrimidin7-yl)tetrahydrofuran-2yl)isoindolin-1-one 42 h ₂ n v5-N pH yj ^O UOH jOi I 432.86 (2R,3R,4S, 5 8)-2-(4-amino7H-pyrrolo[2,3- d] pyrimidin-7-yl)-5-((1 R)6-chloro-3-methoxyisochroman1-yl)tetrahydrofuran-3,4diol

- 49 042008

43 h ₂ n ⁿ /Xn ph ^N )—\ θγ^ΌΗ χχ X ci 418.83 (2R,3R,4S, 5 8)-2-(4-amino7H-pyrrolo[2,3- d] pyrimidin-7-yl)-5-((1 R)6-chloro-3hydroxyisochroman-1 yl)tetrahydrofuran-3,4-diol 44 .OH Ul °Hone Xl A 431.87 (2 S, 3 S,4R,5R)-2-((lR)-6-xnop3-methoxyisochroman-1-yl)5 -(4-methyl-7H-pyrrolo[2.3 0]pyrimidin-7- yl)tetrahydrofuran-3,4-diol 45 ~hx ph Ul °XOH jTO 399.83 (2S,3S,4R,5R)-2-((R)-6-xnop1Н-isochromen-1-yl)-5-(4methyl-7Н-pyrrolo[2,3d]pyrimidin-7yl)tetrahydrofuran-3, 4-diol 46 ^N vX-n pH ^N )—\ °XOH XXX Cl 415.83 (R)-6-xnop-l-((2S,3S,4R,5R)3,4-dihydroxy-5-(4-methyl7H-pyrrolo[2,3d]πyrimidin-7yl)tetrahydrofuran-2yl)isochroman-3 -He 47 ^CI \zxA. XjX° ΗΟ,.Αθ UCH ,Ν^ ^but 429.90 (2S,3S,4R,5R)-2-((R)-6-xnop- 4,4-dimethylisochroman-1yl)-5-(4-methyl-7Hpyrrolo[2,3-d]pyrimidin-7yl)tetrahydrofuran-3,4-diol

- 50 042008

48 but JZ ^but \1 zL VO ° \ od 407.87 (2S,3S,4R,5R)-2-((S)-2-xnop4,7-dihydro-5H-thieno[2,3c]pyran-7-yl)-5-(4-methyl7H-pyrrolo[2 ,3d] pyrimidin-7 yl )tetrahydrofuran-3,4-diol 49 No. pH % n °«UN from 366.38 (2R,3R,4S,5S)-2-(4-MeTHn-7Hpyrrolo[2,3-d]pyrimidin-7 yl)-5-((R)-1Н-pyrano[3.4с]pyr IDIN-1 - yl)tetrahydrofuran-3,4-diol 50 pH ^N /—\ ° * 3on 417.85 (2 S, 3 S,4R,5R)-2-((lR)-6-xnop3-hydroxyisochroman-l-yl)5 -(4-methyl-7H-pyrrolo[2,3 d]πyrimidin-7- yl)tetrahydrofuran-3,4-diol 51 pH ^N oO^en CO 368.39 (2S,3S,4R,5R)-2-((R)-3,4- e ihydro-1 H-pyrano[3,4c]pyridin-1-yl)-5-(4-methyl7H-pyrrolo[2,3d]pyrimidin-7 - yl)tetrahydrofuran-3,4-diol 52 F. F w/hyu no „.A _o lch ^no oh 437.83 (2S,3S,4R,5R)-2-((R)-6-xnop4,4-difluoroisochroman-1-yl)5-(4-methyl-7Н-pyrrolo[2,3 d]πyrimidin-7yl)tetrahydrofuran -3,4-diol

-51 042008

53 o^> ^z V o /—\ J )=\ c ''O W § O 403.82 (2S,3S,4R,5R)-2-((R)-7-chloro4H-benzo[<1] [1,3]dioxin-4yl)-5-(4-methyl-7Hpyrrolo[2,3 -d ]pyrimidin-7 yl )tetrahydrofuran-3,4-diol 54 o ZS A O, _z 7 \=/ 439.80 (2S,3S,4R,5R)-2-((R)-7-xlor- 2,2-difluoro-4Нbenzo[d][l,3]dioκsin-4-yl)5 -(4-methyl-7Н-pyrrolo[2,3 - d] pyrimidin-7 yl)tetrahydrofuran-3,4-diol 55 b $ \ Γ'^'Ό X 417.85 (2S,3S,4R,5R)-2-((R)-7-chloro1,5dihydrobenzo[e] [1,3] dioxep in-1-yl)-5-(4-methyl-7Hpyrrolo[2,3 -d] pyrimidin-7 yl)tetrahydrofuran-3,4-diol 56 ^Q , OS 453.83 (2S,3S,4R,5R)-2-((R)-7-chloro3,3-difluoro-1,5dihydrobenzo[e] [1,3] dioxepin-1-yl)-5-(4-methyl -7Hpyrrolo[2,3 -d] pyrimidin-7 yl)tetrahydrofuran-3,4-diol

-52042008

57 b V ί ° o 431.83 (R)-7-xnop-l-((2S,3S,4R,5R)3,4-dihydroxy-5-(4-methyl7H-pyrrolo[2,3d]pyrimidin-7yl)tetrahydrofuran-2-yl) 1,5dihydrobenzo[e] [ 1,3 ] dioxepin-3-one 58 O n / ° I / ό 431.87 (2S,3S,4R,5R)-2-((R)-8-xnop5,6-dihydro-1Hbenzo[e] [1,3]dioxocin-1yl)-5-(4-methyl-7Hpyrrolo[2 ,3 -d] pyrimidin-7 yl) tetrahydrofuran-3,4-diol 59 \ ^0H iV ^N SA N / T >OH \^N o fYV ^F A A o Cl^^x-/ 467.85 (2S,3S,4R,5R)-2-((R)-8-xnop3,3-difluoro-5,6-dihydro-1Hbenzo[e] [1,3] dioxocin-1 yl)-5-(4 -methyl-7Hpyrrolo[2,3-d]pyrimidin-7yl)tetrahydrofuran-3,4-diol 60 H Q oZ / y\/'O I / δ °4 ¹ o 445.86 (R)-8-xnop-l-((2S,3S,4R,5R)3,4-dihydroxy-5-(4-methyl7H-pyrrolo[2,3d]πyrimidin-7yl)tetrahydrofuran-2-yl)5 ,6-dihydro- 1Hbenzo[e] [ 1,3]dioxocin-3-one

- 53 042008

61 I 400.86 (2R,3 S,4R,5R)-2-((R)-6-xnop1,2,3,4tetrahydroisoquinolin-1 yl)-5-(4-methyl-7Нpyrrolo[2,3-d]pyrimidine-7 yl)tetrahydrofuran-3,4-diol 62 O 15 469.85 (2S,3 S,4R,5R)-2-((lR)-6-chloro4-(τpiφτopmethyl)isoxpomanl-yl)-5-(4-methyl-7Нpyrrolo[2,3-d]pyrimidin-7yl) tetrahydrofuran-3,4-diol 63 ,-ό /=\-\yj 2 O 419.84 (2S,3 S,4R,5R)-2-((lR)-6-chloro4-φτopisoxpoman-l-yl)-5-(4methyl-7H-pyrrolo[2,3d]pyrimidine-7- yl)tetrahydrofuran-3,4-diol 64 O 15 417.85 (2S,3 S,4R,5R)-2-((lR)-6-chloro4-hydroκciisooxpoman-l-yl)5 -(4-methyl-7Н-pyrrolo[2,3 d]pyrimidin-7 - yl)tetrahydrofuran-3,4-diol 65 rV ^Ηχ τ4 /=\ - Us o 415.87 (2 S, 3 S,4R,5R)-2-((lR)-6-xnop4-methylisochroman-1-yl)-5(4-methyl-7Н-pyrrolo[2,3 d]πyrimidin-7yl)tetrahydrofuran -3,4-diol

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66 ⁷ to I 415.87 (2S,3S,4R,5R)-2-((lR)-6-xnop3-methylisochroman-1-yl)-5(4-methyl-7H-pyrrolo[2,3<1]pyrimidin-7yl)tetrahydrofuran- 3,4-diol 67 DD ΗΟ,,.Αθ LCH ^H0 rO 403.86 (2S,3S,4R,5R)-2-((R)-6chloroisochroman-1-yl-4,4-d2)5 -(4-methyl-7Н-pyrrolo[2,3 d]pyrimidin-7yl) tetrahydrofuran-3,4-diol 68 nh ₂ NO.D5 <P cr 402.84 (2R,3R,4S, 5 8)-2-(4-amino7H-pyrrolo[2,3d]pyrimidin-7-yl)-5-((R)-6chloroisochroman-1 yl)tetrahydrofuran-3,4-diol 69 HN^^ otCh HO ^N---Q J /----f HO^X. >° jOO cr 416.86 (2S,3S,4R,5R)-2-((R)-6chloroisochroman-1-yl)-5-(4(methylamino)-7Hpyrrolo[2,3-d]pyrimidin-7yl)tetrahydrofuran-3,4 -diol

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70 BUT ---(AJ /-------no^^X.^ ⁰ Sk Y:, '° 401.85 (2S,3S,4R,5R)-2-((R)-7chloroisochroman-1-yl)-5-(4methyl-7H-pyrrolo[2,3d]pyrimidin-7yl)tetrahydrofuran-3,4-diol 71 nh ₂ BUT ----(A }/ /-------\ ^? but ^ X. X ° SK >: Όυ 402.84 (2R,3R,4S, 5 8)-2-(4-amino7H-pyrrolo[2,3d]pyrimidine-7-hh)-5-((R)-7chloroisochroman-1 yl)tetrahydrofuran-3,4-diol 72 Cl cX y>* ^{he he} η ₂ ν 402.84 (2R,3R,4S, 5 8)-2-(4-amino7H-pyrrolo[2,3d]pyrimidin-7-yl)-5-((R)-5chloroisochroman-1 yl)tetrahydrofuran-3,4-diol

- 56 042008

73 nh ₂ Gr4 HO. ---(AJ /-------- ηο^χ./' ⁰ 404.37 (2R,3R,4S, 5 8)-2-(4-amino7H-pyrrolo[2,3d]pyrimidine-7-nn)-5-((R)6,7-difluoroisochroman-1 yl)tetrahydrofuran-3, 4-diol 74 ^{o x} 403.39 (2S,3S,4R,5R)-2-((R)-6,7difluoroisochroman-1-yl)-5(4-methyl-7H-pyrrolo[2,3 d]πyrimidin-7yl)tetrahydrofuran-3,4 -diol 75 CI _O XX^ ^{OH he} 401.85 (2S,3S,4R,5R)-2-((R)-5chloroisochroman-1-yl)-5-(4methyl-7H-pyrrolo[2,3d]pyrimidin-7yl)tetrahydrofuran-3,4-diol

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76 FF 00 _O X\^ ^OH ° 403.39 (2S,3S,4R,5R)-2-((R)-4,4difluoroisochroman-1-yl)-5(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7yl)tetrahydrofuran-3, 4-diol 77 F схУ' ^he η ₂ ν 404.37 (2R,3R,4S,5S)-2-(4-aMHHO7Н-pyrrolo[2,3d]pyrimidin-7-yl)-5-((R)5,6-difluoroisochroman-1 yl)tetrahydrofuran-3,4 -diol 78 FF ₀ XX^ ^{0H OH} h ₂ n 404.37 (2R,3R,4S,5S)-2-(4-aMHHO7Н-pyrrolo[2,3d]pyrimidin-7-yl)-5-((R)4,4-difluoroisochroman-1 yl)tetrahydrofuran-3,4 -diol

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79 F \^ ^0H re ^4. 403.39 (2S,3S,4R,5R)-2-((R)-5,6difluoroisochroman-1-yl)-5(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7yl)tetrahydrofuran-3, 4-diol 80 .. dh /----U ΗΟ^\.Χ° Όυ cr--- 401.85 (2S,3S,4R,5R)-2-((S)-6chloroisochroman-1-yl)-5-(4methyl-7H-pyrrolo[2,3d]πyrimidin-7yl)tetrahydrofuran-3,4-diol 81 ^H 2 ^N Z\ ° ^h Ύ J/ ^N VC 1 /SH1OH °4./ ..) ΙΙΙΙ _Ο Cl 418.83 (2R,3R,4S,5S)-2-(4-aMHHO7Н-pyrrolo[2,3d]pyrimidin-7-yl)-5-((R)7-chloro-1,5dihydrobenzo[e] [ 1.3 ]dioxe pin-1yl)tetrahydrofuran-3,4diol

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82 nh ₂ OH HO ₄ N---(AJ /------- <P but*^ X/* Xxl 416.82 (R)-l-((2S,3S,4R,5R)-5-(4amino-7H-pyrrolo[2,3 d]pyrimidin-7-yl)-3,4dihydroxytetrahydrofura n-2-yl)-6- chloroisochroman3-one 83 F XX / ^cl <Χ y** ^OH pC" 419.84 (2S,3S,4R,5R)-2-((R)-6chloro-5-fluoroisochroman-1 yl)-5-(4-methyl-7Hpyrrolo[2,3-d]pyrimidin7-yl)tetrahydrofuran-3, 4diol 84 F /X /XX ¹ C ₀ Z'X^ ^0H h ₂ n 420.83 (2R,3R,4S, 5 8)-2-(4-amino7H-pyrrolo[2,3- d]pyrimidin-7-yl)-5-((K)6-chloro-5-fluoroisochroman-1 yl)tetrahydrofuran-3,4- diol

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85 F oh5 cr — — 419.84 (2S,3S,4R,5R)-2-((R)-6chloroisochroman-1-yl)-5-(5fluoro-4-methyl-7Hpyrrolo[2,3-d]pyrimidin7-yl)tetrahydrofuran-3,4diol 86 FI nh ₂ but*^. cr 420.83 (2R,3R,4S,5S)-2-(4-aMHHO5 -fluoro-7H-pyrrolo[2,3 d]pyrimidin-7-nn)-5-((R)6-chloroisochroman-1 yl)tetrahydrofuran- 3,4diol 87 to M HO^\ X° ck A, 300cr 436.29 (2S,3S,4R,5R)-2-((R)-6,7dichloroisochroman-1-yl)-5(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7yl)tetrahydrofuran-3,4diol 88 nh ₂ oZ HO ---(AJ /-------- ho*Zs. ^° Ck >:, 300 cr 437.28 (2R,3R,4S, 5 8)-2-(4-amino7H-pyrrolo[2,3- d]pyrimidin-7-yl)-5-((K)6,7-d ichloroisochroman-1 yl)tetrahydrofuran-3,4diol 89 Ό 1 ^h KZA hoi.......^^oZZy \J ^S -\ y ci 408.88 (2S,3S,4R,5R)-2-((S)-2- chloro-4,7-dihydro-5Hthieno[2,3-c]pyran-7-yl)-5(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7yl)tetrahydrofuran-3,4- diol 90 o ^X 1 il hoi.......^rZZv \J ^s -< .90 nh ₂ 409.87 (2R,3R,4S, 5 8)-2-(4-amino7H-pyrrolo[2,3d]pyrimidin-7-yl)-5-((8)2-chloro-4,\7-d ihydro-5Hthieno [2,3-c]pyran-7yl)tetrahydrofuran-3,4diol

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91 o ^x 1 Doch HOI....... \J -\ / Cl νη ₂ 409.87 (2R,3R,4 S, 5 8)-2-(4-amino7H-pyrrolo[2,3- d]pyrimidin-7-nn)-5-((R)2-chloro-4,7-d ihydro-5Hthieno[2,3-c]pyran-7yl)tetrahydrofuran-3,4- diol 92 lauo ..........ς L----ζ I F 419.84 (2 S, 3 S,4R,5R)-2-((lR,4S)-6chloro-4-fluoroisochroman-1 yl)-5-(4-methyl-7Hpyrrolo[2,3-d]pyrimidin7-yl) tetrahydrofuran-3,4diol 93 F Sk / x Ux. OO χΧ^ ^θΗ ° ⁿ η ₂ ν 420.83 (2R,3R,4S,5S)-2-(4aminopyrrolo[2,3d]pyrimidin-7-yl)-5[(lR,4S)-6-xnop-4fluoroisochroman-1yl]tetrahydrofuran-3,4diol

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94 F sk Г χχ^· ^{0Η 0H} 419.84 (2R,3R,4S,5S)-2-(4methylpyrrolo[2,3d]pyrimidin-7- yl)-5[(lR,4R)-6-xnop-4fluoroisochroman-1 yl]tetrahydrofuran-3,4- diol 95 F em o'' \^ ^0H o' ^m h ₂ n 420.83 (2R,3R,4S, 5 8)-2-(4-amino7H-pyrrolo[2,3d]pyrimidin-7-yl)-5((lR,4R)-6-xnop-4fluoroisochroman-1 yl)tetrahydrofuran- 3,4diol 97 . o I 405.36 (2S,3S,4R,5R)-2-((R)-7,8difluoro-4Нbenzo[d][l,3]dioκsyn-4-yl)5 -(4-methyl-7Н-pyrrolo[2,3 d] pyrimidin-7 yl)tetrahydrofuran-3,4-diol

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98 cr oA HO ---(A J 1--------\ ho^X. X° 400.86 (2R,3S,4R,5R)-2-[(lR)-6chloro-1,2,3,4- tetrahydroisoquinolin-1 yl] -5 -(4-methylpyrrolo[2,3 d]pyrimidin-7 yl)tetrahydrofuran-3,4- diol 99 415.87 (2S,3S,4R,5R)-2-((R)-6- A =O chloro-7-methyl isochroman-1 - To *° ^H yl)-5-(4-methyl-7H- pyrrolo[2,3-d]pyrimidine- °A'/OH 7-yl)tetrahydrofuran-3,4- A diol CI ^X 100 η ₂ ν 416.86 (2R,3R,4S, 5 8)-2-(4-amino- nV 7Н-pyrrolo[2,3- t )/— ^N << ^0H d]pyrimidin-7-yl)-5-((R)- 6-chloro-7-methylisochroman- °\/'won 1-yl)tetrahydrofuran-3,4- 2θό diol Cl ^x 101 415.87 (2S,3S,4R,5R)-2-((R)-7- AO» ?° ⁿ γν^-Ν. / chlorine-1,3,4,5- N A. —N'X 1 /ΉΙΙΙΟΗ / tetrahydrobenzo[c]oxepin -1-yl)-5-(4-methyl-7H- pyrrolo[2,3-d]pyrimidine- 7-yl)tetrahydrofuran-3,4- SG Χ_—/ diol 102 h ₂ n 416.86 (2R,3R,4S, 5 8)-2-(4-amino- nY G 6Н-714-pyrrolo[2,3- \ ^Ν 1 ^/ΙΙΙΙΟΗ d]pyrimidin-7-yl)-5-((R)- ο^. / 7-chloro-1,3,4,5- tetrahydrobenzo[c]oxepin -1-yl)tetrahydrofuran- cr 3,4-diol 103 D D 406.4 (2S,3S,4R,5R)-2-((R)-6,7- difluoroisochroman-1-yl)-5- A/ (4-(methyl-43)-7H- /— ^v < pyrrolo[2,3-d]pyrimidine- 7-yl)tetrahydrofuran-3,4- °wO'/he diol A

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experimental procedures.

Example 1A. Synthesis of (2R,3R,4S,5S)-2-(4-amino-7Н-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-5-chloro-1,3dihydroisobenzofuran- 1-yl)tetrahydrofuran-3,4-diol (example 1A).

1AI ^{Pr 1A}

Stage 1. Synthesis of (2-bromo-5-chlorophenyl)methoxy-tert-butyl-dimethylsilane (1AB).

To a solution of (2-bromo-5-chlorophenyl)methanol (1Aa, 5.0 g, 22.58 mmol) in DMF (10 ml) was added TBSCl (10.21 g, 67.73 mmol) and imidazole (3073.9 mg, 45.15 mmol). The reaction mixture was stirred at 25° C. for 16 hours. TLC (PE:EA=10:1, Rf=0.8) indicated that the reaction was complete. The reaction mixture was diluted with water (100 ml) and the mixture was extracted with EA (50 mlx3), then the organic layers were washed with saturated aqueous sodium chloride solution (100 mlx3), dried over Na ₂ SO ₄ and concentrated in vacuo to give the crude product, which was purified with chromatography on a silica gel column (100-200 mesh size, PE:EA=200:1 to 100:1) to give (2-bromo-5chlorophenyl)methoxy-tert-butyl-dimethylsilane (5.0 g, 14.9 mmol, 66% yield) as a colorless oil.

Step 2. Synthesis of [(3aR,4R,6S,6aS)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3а,4,6,6atetrahydrofuro[3 ,4-d][1,3]dioxol-6-yl]-[2-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-chlorophenyl]methanone (1Ae).

To a solution of (2-bromo-5-chlorophenyl)methoxy-tert-butyldimethylsilane (1Ab, 4.3 g, 12.80 mmol) in THF (50 ml) was added butyllithium (0.6 g, 9.10 mmol) at a temperature -78°C in N2 atmosphere. The mixture was stirred at -78°C for 10 min to give 1Ac. A solution of (3aR,4R,6S,6aS)-4-(4chloropyrrolo[2,3-d]pyrimidin-7-yl)-N-methoxy-N,2,2-trimethyl-3a,4 was added, 6.6a -tetrahydrofuro[3,4d][1,3]dioxol-6-carboxamide (1Ad, 1.4 g, 3.70 mmol) in THF (50 mL). The mixture was stirred at -78°C for 30 minutes. LC-MS showed that the reaction was complete. The reaction mixture was quenched with saturated NH4CI solution (50 ml). The mixture was extracted with ethyl acetate (100 mlx3). The combined organic layers were washed with saturated aqueous sodium chloride (40 mlx3), dried over Na ₂ SO ₄ and concentrated in vacuo to give a crude product which was purified by silica gel column chromatography (size 100-200 mesh, PE:EA=from 20: 1 to 10:1) to give [(3aR,4R,6S,6aS)-4-(4chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a -tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-[2[[tert-butyl(dimethyl)silyl]oxymethyl]-4-chlorophenyl]methanone (1Ae, 1.3 g, 2 , 20 mmol, 61.4% yield as a pale yellow oil.

LC-MS [M+H]: 578.2.

Stage 3. Synthesis of (R)-[(3aR,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-ul)-2,2-dimethyl-3а,4,6 ,6atetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-[2-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-chlorophenyl]methanol (1Af).

To a solution of [(3aR,4R,6S,6aS)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6atetrahydrofuro[3,4 -d][1,3]dioxol-6-yl]-[2-[[tert-butyl(dimethyl)silyl]hydroxymethyl]-4-chlorophenyl] methanone (1Ae, 50 mg, 0.11 mmol) in toluene ( 5 ml) diisobutylaluminum hydride (24.6 mg, 0.20 mmol) was added. The reaction mixture was stirred at -78°C for 0.5 h under N2 atmosphere. TLC (PE:EA=3:1, Rf=0.3) indicated that the reaction was complete. The reaction mixture was washed with water (10 mlx3) and saturated aqueous sodium chloride solution (10 mlx3). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated to give a crude product which was purified by silica gel column chromatography (size 100-200 mesh, PE:EA=10:1 to 5:1) to give (R)- [(3aR,4R,6R,6aR)-4-(4chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d ][1,3]dioxol-6-yl]-[2[[tert-butyl(dimethyl)silyl]oxymethyl]-4-chlorophenyl]methanol (1Af, 50 mg, 0.10 mmol, 99.7% yield) V

- 65 042008 as a pale yellow solid.

Step 4. Synthesis of (R)-[(3aR,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl3a,4,6,6a -tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-[4-chloro-2-(hydroxymethyl)phenyl]methanol (1Ag).

To a solution of (R)-[(3aR,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6atetrahydrofuro [3,4-d][1,3]dioxol-6-yl]-[2-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-chlorophenyl]methanol (1Af, 50 mg, 0.10 mmol ) in DMSO (12 ml) and methanol (0.2 ml), CsF (39.3 mg, 0.3 mmol) was added and the reaction mixture was stirred at 25°C for 0.5 h. LC-MS showed that the reaction has ended. The reaction mixture was filtered and purified by reverse phase combi-flash chromatography eluting CH3CN in H ₂ O (neutral conditions) from 10% to 55% to give (R)-[(3aR,4R,6R,6aR)-4-(4chloropyrrolo[2 ,3-d]pyrimidin-7-yl)-2,2-dimethyl-3а,4,6,6а-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-[4chloro-2 -(hydroxymethyl)phenyl]methanol (1Ag, 30 mg, 0.1 mmol, 71.7% yield) as a pale yellow oil.

LC-MS [M+H]: 466.1.

Stage 5. Synthesis of 7-[(3aR,4R,6R,6aR)-6-[(1R)-5-chloro-1,3-dihydroisobenzofuran-1-yl]-2,2-dimethyl3a,4,6,6a -tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-4-chloropyrrolo[2,3-d]pyrimidine (1Ah).

To a solution of (R)-[(3aR,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6atetrahydrofuro [3,4-d][1,3]dioxol-6-yl]-[4-chloro-2-(hydroxymethyl)phenyl]methanol (100.0 mg, 0.21 mmol) in THF (20 mL) was added pyridine (0.02 ml, 0.21 mmol) at 25°C, tributylphosphine (0.1 ml, 0.42 mmol) was added and then DIAD (0.1 ml, 0.52 mmol) at 25°C. The reaction mixture was stirred at 25° C. under N2 atmosphere for 4 h. TLC (PE:EA=1:1, Rf=0.4) indicated that the reaction was complete. The mixture was concentrated in vacuo to give a crude product which was purified by silica gel column chromatography (100-200 mesh, PE:EA=10:1 to 1:1) to give 7-[(3aR,4R,6R,6aR) -6-[(1R)-5chloro-1,3-dihydroisobenzofuran-1 -yl]-2,2-dimethyl-3а,4,6,6а-tetrahydrofuro[3,4-d] [1,3]dioxol- 4-yl]-4chloropyrrolo[2,3-d]pyrimidine (1Ah, 80.0 mg, 0.2 mmol, 83.2% yield) as a pale yellow oil.

Stage 6. Synthesis of 7-[(3aR,4R,6R,6aR)-6-[(1R)-5-chloro-1,3-dihydroisobenzofuran-1-yl]-2,2-dimethyl3a,4,6,6a -tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]pyrrolo[2,3-d]pyrimidin-4-amine (1Ai).

Solution 7-[(3aR,4R,6R,6aR)-6-[(1R)-5-chloro-1,3-dihydroisobenzofuran-1-yl]-2,2-dimethyl-3а,4,6,6atetrahydrofuro[ 3,4-d][1,3]dioxol-4-yl]-4-chloropyrrolo[2,3-d]pyrimidine (1Ah, 80.0 mg, 0.2 mmol) in 1,4-dioxane (3 ml) and NH3H2O (3 ml, 77.9 mmol) were stirred at 120°C for 16 hours in an autoclave. LC-MS showed that the reaction was complete. The mixture was concentrated in vacuo to give a crude product which was purified by reverse phase combi-flash chromatography eluting CH3CN in H2O (neutral) from 10% to 95% to give 7-[(3aR,4R,6R,6aR)-6-[( 1R)-5-chloro-1,3-dihydroisobenzofuran1-yl]-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]pyrrolo [2,3-d]pyrimidine-4-amine (1Ai, 45.0 mg, 0.11 mmol, 58.8% yield) as a pale yellow solid.

LC-MS [M+H]: 429.1.

Step 7 Synthesis (Example 1A)

Solution 7-[(3aR,4R,6R,6aR)-6-[(1R)-5-chloro-1,3-dihydroisobenzofuran-1-yl]-2,2-dimethyl-3а,4,6,6atetrahydrofuro[ 3,4-d][1,3]dioxol-4-yl]pyrrolo[2,3-d]pyrimidin-4-amine (1Ai, 45.0 mg, 0.10 mmol) in water (3 ml) and TFA (3 ml, 33.30 mmol) was stirred at 25° C. for 1 h. LC-MS indicated that the reaction was complete. The reaction mixture was concentrated and purified by preparative HPLC, (0.1% NH3-H2O), eluting CH3CN in _H2O from 10% to 95% to give (2R,3R,4S,5S)-2-(4-aminopyrrolo[ 2,3d]pyrimidin-7-yl)-5-[(1R)-5-chloro-1,3-dihydroisobenzofuran-1-yl]tetrahydrofuran-3,4-diol (Example 1A, 6.0 mg, 0. 02 mmol, 14.5% yield as a white solid.

LC-MS [M+H]: 389.1.

1H NMR (400 MHz, DMSO-d ₆ ): δ 8.06 (s, 1H), 7.42 (s, 1H), 7.34-7.35 (d, J=4, 0 Hz, 1H) , 7.29-7.32(m, 1H), 7.22-7.24(m, 1H), 7.03(s, 2H), 6.64(d, J=3, 6Hz, 1H ), 6.14-6.16 (d, J=7.6 Hz, 1H), 5.34-5.36 (m, 1H), 5.27-5.28 (d, J=6.4 Hz, 1H), 5.19-5.20 (d, J=4, 0 Hz, 1H), 5.04-5.12 (m, 2H), 4.51-4.56 (m, 1H) , 4.05-4.06 (m, 1H), 3.93-3.95 (m, 1H).

1H NMR (400 MHz, DMSO-d ₆ +D ₂ O): δ 8.07 (s, 1H), 7.43 (s, 1H), 7.34-7.35 (d, J=3.6 Hz, 1H), 7.30-7.33 (m, 1H), 7.23-7.25 (m, 1H), 6.65-6.66 (d, J=3.6 Hz, 1H) , 6.14-6.16 (d, J=7.6 Hz, 1H), 5.35-5.36 (m, 1H), 5.08-5.10 (m, 2H), 4.51 -4.54 (m, 1H), 4.07-4.09 (m, 1H), 3.93-3.94 (m, 1H).

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Example 1B. Synthesis of (2R,3R,4S,5S)-2-(4-amino-7Н-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((S)-5-chloro-1,3dihydroisobenzofuran- 1-yl)tetrahydrofuran-3,4-diol (example 1B).

1Ae 1Ba 1B

1Sun 1Bd Ave. 1B

Stage 1. Synthesis (1Ba).

To a solution of [(3 aR,4R,6S,6aS)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3 a,4,6,6atetrahydrofuro [3 ,4-d][1,3]dioxol-6-yl]-[2-[[tert-butyl(dimethyl)silyl]hydroxymethyl]-4-chlorophenyl] methanone (1Ae, 630 mg, 1.10 mmol) in methanol (5 ml) was added NaBH ₄ (82.4 mg, 2.20 mmol) and the mixture was stirred at 25°C for 1 h. TLC (PE:EA=1:1, Rf=0.4) showed that source material is used up. LC-MS showed that the reaction was complete. The reaction mixture was quenched with saturated NH4Cl solution (50 ml). The mixture was extracted with ethyl acetate (100 mlx3). The combined organic layers were washed with saturated aqueous sodium chloride (40 mlx3), dried over Na ₂ SO ₄ and concentrated in vacuo to give a crude product which was purified by chromatography on a silica gel column (size 100-200 mesh, PE:EA=from 10: 1 to 5:1) to give (R)-[(3aR,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a ,4,6,6atetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-[2-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-chlorophenyl]methanol (1Af 10, 0 mg, 0.02 mmol, 1.6% yield and (S)-[(3aR,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)- 2,2dimethyl-3 a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-[2-[[tert-butyl(dimethyl)silyl]oxymethyl]-4chlorophenyl ]methanol (1Ba), 520 mg, 0.9 mmol, 82.3% yield) as a pale yellow oil.

Stage 2. Synthesis of (S)-[(3aR,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl3a,4,6,6a -tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-[4-chloro-2-(hydroxymethyl)phenyl]methanol (1Bb).

To a solution of (S)-[(3aR,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6atetrahydrofuro [3,4-d][1,3]dioxol-6-yl]-[2-[[tert-butyl(dimethyl)silyl]hydroxymethyl]-4-chlorophenyl]methanol (1Ba, 520 mg, 0.90 mmol ) in DMSO (5 ml) and methanol (0.1 ml), CsF (408.2 mg, 2.70 mmol) was added and the reaction mixture was stirred at 25°C for 1 h. LC-MS indicated that the reaction was complete . The reaction mixture was filtered and purified by reverse phase combi-flash chromatography eluting CH3CN in H ₂ O (neutral) from 10% to 95% to give (S)-[(3aR,4R,6R,6aR)-4-(4chloropyrrolo[2 ,3-d]pyrimidin-7-yl)-2,2-dimethyl-3а,4,6,6а-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-[4chloro-2 -(hydroxymethyl)phenyl]methanol (1Bb, 300 mg, 0.64 mmol, 71.8% yield) as a white solid.

LC-MS [M+H]: 466.1.

Stage 3. Synthesis of 7-[(3aR,4R,6R,6aR)-6-[(1S)-5-chloro-1,3-dihydroisobenzofuran-1-yl]-2,2-dimethyl3a,4,6,6a -tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-4-chloropyrrolo[2,3-d]pyrimidine (1Bc).

To a solution of (S)-[(3aR,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6atetrahydrofuro [3,4-d][1,3]dioxol-6-yl]-[4-chloro-2-(hydroxymethyl)phenyl]methanol (1Bb, 250 mg, 0.5 mmol) in THF (5 mL) was added pyridine (0.04 ml, 0.50 mmol), tributylphosphine (0.3 ml, 1.10 mmol) and DIAD (0.2 ml, 1.10 mmol). The reaction mixture was stirred at 25°C for 16 hours. TLC (PE:EA=3:1, Rf=0.4) indicated that the reaction was complete. The mixture was concentrated in vacuo to give a crude product which was purified by silica gel column chromatography (size 100-200 mesh, PE:EA=50:1 to 20:1) to give 7-[(3aR,4R,6R,6aR) -6-[(1S)-5-chloro-1,3-dihydrousobenzofuran-1yl]-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d] [1,3]dioxol- 4-yl]-4-chloropyrrolo[2,3-d]pyrimidine (1Bc, 180.0 mg, 0.4 mmol, 74.9% yield) as a white solid.

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Stage 4. Synthesis of 7-[(3aR,4R,6R,6aR)-6-[(1S)-5-chloro-1,3-dihydroisobenzofuran-1-yl]-2,2-dimethyl3a,4,6,6a -tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]pyrrolo[2,3-d]pyrimidin-4-amine (1Bd).

To a solution of 7-[(3aR,4R,6R,6aR)-6-[(1S)-5-chloro-1,3-dihydroisobenzofuran-1-yl]-2,2-dimethyl3a,4,6,6a-tetrahydrofuro [3,4-d][1,3]dioxol-4-yl]-4-chloropyrrolo[2,3-d]pyrimidine (1Bc, 180 mg, 0.40 mmol) in 1,4-dioxane (5 ml ) was added NH3-H2O (5 mL, 129.81 mmol) and the reaction mixture was stirred at 25°C for 16 h in an autoclave. LC-MS showed that the reaction was complete. The mixture was concentrated in vacuo to give a crude product which was purified by reverse phase combi-flash chromatography eluting CH3CN in H2O (neutral) from 10% to 90% to give 7-[(3aR,4R,6R,6aR)-6-[( 1S)-5-chloro1,3-dihydroisobenzofuran-1-yl]-2,2-dimethyl-3 a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl] pyrrolo[2,3d]pyrimidin-4-amine (1Bd, 140 mg, 0.32 mmol, 81.3% yield) as a white solid.

LC-MS [M+H]: 429.1.

Stage 5. Synthesis of (2R,3R,4S,5S)-2-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-5-[(1S)-5-chloro-1,3dihydroisobenzofuran-1 -yl]tetrahydrofuran-3,4-diol hydrochloride (Example 1B).

Solution 7 - [(3 aR,4R,6R,6aR)-6-[( 1 S)-5-chloro-1,3-dihydroisobenzofuran-1 -yl] -2,2-dimethyl-3а,4,6, 6atetrahydrofuro[3,4-d][1,3]dioxol-4-yl]pyrrolo[2,3-d]pyrimidin-4-amine (1Bd, 180 mg, 0.40 mmol) in water (5 ml) and TFA (5 ml, 67.31 mmol) was stirred at 25°C for 1 h. LC-MS indicated that the reaction was complete. The reaction mixture was concentrated and purified by preparative HPLC, (0.1% NH3-H2O), eluting CH3CN in _H2O from 10 to 95%, 1 ml HCl (1 M) was added and lyophilized to give (2R,3R,4S ,5S)-2-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-5-[(1S)-5-chloro-1,3-dihydroisobenzofuran-1yl]tetrahydrofuran-3,4-diol hydrochloride (Ex. 1B, 45.1 mg, 0.10 mmol, 25.1% yield) as a pale yellow solid.

LC-MS [M+H]: 389.1.

1H NMR (400 MHz, DMSO-de): δ 13.89 (s, 1H), 9.45 (s, 1H), 8.50 (s, 1H), 8.36 (s, 1H), 7, 54-7.55 (d, J=3.6 Hz, 1H), 7.30-7.39 (m, 3 H), 7.01-7.02 (d, J=3.6 Hz, 1H ), 6.08-6.09 (d, J=4.8 Hz, 1H), 5.39 (s, 1H), 4.97-5.05 (m, 2H), 4.32-4 .38 (m, 3 N).

¹ H NMR (400 MHz, DMSO-d ₆ +D ₂ O): δ 8.37 (s, 1H), 7.55-7.56 (d, J=3.6 Hz, 1H), 7.37 -7.39 (m, 1H), 7.30-7.33 (m, 2H), 7.01-7.02 (d, J=3.6 Hz, 1H), 6.08-6.10 (d, J=7.2 Hz, 1H), 5.39 (s, 1H), 5.00-5.05 (m, 2H), 4.32-4.39 (m, 3H).

Example 2A. Synthesis of (1R,2S,3R,5S)-3-(4-amino-7Н-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-5-chloro-1,3dihydroisobenzofuran- 1-yl)cyclopentan-1,2-diol (Ex. 2A).

2Ab _2Ac 2Ad

Stage 1. Synthesis of [(3aS,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-4,5,6,6atetrahydro-3aH -cyclopenta[d][1,3]dioxol-6-yl]-[2-[[tert-butyl(dimethyl)silyl]oxymethyl]-4chlorophenyl]methanol (2Ab).

To a solution of (2-bromo-5-chlorophenyl)methoxy-tert-butyldimethylsilane (1Ab, 1826.0 mg, 5.44 mmol) in THF (20 ml) was added butyllithium (2.8 ml, 5.44 mmol) at - 78°C. The reaction mixture was stirred at -78°C for 0.5 h. Then (3aS,4R,6S,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin7-yl)-2,2 -dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-6-carbaldehyde (2Aa, 1750 mg, 5.44 mmol). The reaction mixture was stirred at -78°C for 1 h. LC-MS showed that the reaction was complete. The reaction mixture was quenched with H2O (30 ml) and extracted with ethyl acetate (60 ml). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (PE:EA=3:1) to give [(3aS,4R,6R,6aR)- 4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH

- 68 042008 cyclopenta[d][1,3]dioxol-6-yl]-[2-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-chlorophenyl]methanol (2Ab, 360.0 mg, 0, 62 mmol, 11.4% yield).

LC-MS [M+H]: 578.2.

Stage 2. Synthesis of (2Ac) and (2Ad).

To a solution of [(3aS,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-4,5,6,6atetrahydro-3aH-cyclopenta [d][1,3]dioxol-6-yl]-[2-[[tert-butyl(dimethyl)silyl]oxymethyl]-4chlorophenyl]methanol (2Ab, 360 mg, 0.62 mmol) in THF (5 ml ) was added TBAF (0.62 ml, 1N in THF, 0.62 mmol) at 0°C. The mixture was stirred at 0° C. for 1 hour. LC-MS indicated that the reaction was complete. Ethyl acetate (50 ml) was added to the mixture, which was washed with H2O (20 mlx3) and saturated aqueous sodium chloride solution (30 ml). The organic layer was dried over Na ₂ SO ₄ , concentrated in vacuo to give the crude product, which was purified by prep-TLC (PE:EA=3:1) to give (S)-[(3aS,4R,6R,6aR)- 4-(4-chloropyrrolo-[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-4,5,6,6a-tetrahydro3aH-cyclopenta[d][1,3]dioxol-6- yl]-[4-chloro-2-(hydroxymethyl)phenyl]methanol (2Ac, 42.0 mg, 0.09 mmol, 14.5% yield) and (R)-[(3aS,4R,6R,6aR) -4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-4,5,6,6atetrahydro-3aH-cyclopenta[d][1,3]dioxol-6- yl]-[4-chloro-2-(hydroxymethyl)phenyl]methanol (2Ad, 55.0 mg, 0.12 mmol, 19.0% yield).

LC-MS [M+H]: 464.1.

Stage 3. Synthesis of 7-[(3aS,4R,6R,6aR)-6-[(1R)-5-chloro-1,3-dihydroisobenzofuran-1-yl]-2,2-dimethyl4,5,6,6a -tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-4-chloropyrrolo[2,3-d]pyrimidine (2Ae).

To a solution of (R)-[(3aS,4R,6R,6aR)-4-(4-chloropyrro[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-4,5,6,6atetrahydro -3aH-cyclopenta[d][1,3]dioxol-6-yl]-[4-chloro-2-(hydroxymethyl)phenyl]methanol (2Ad, 100 mg, 0.22 mmol) in THF (5 mL) was added PPh ₃ (56.5 mg, 0.22 mmol) then DIAD (0.04 ml, 0.22 mmol) was added, the mixture was stirred at 25° C. for 16 h. The reaction mixture was concentrated in vacuo to give the crude product, which was purified by prep-TLC (PE:EA=3:1) to give 7-[(3aS,4R,6R,6aR)-6-[(1R)-5-chloro-1,3-dihydroisobenzofuran-1- yl]-2,2-dimethyl-4,5,6,6а-tetrahydro-3аНcyclopenta[d][1,3]dioxol-4-yl]-4-chloropyrrolo[2,3-d]pyrimidine (2Ae, 70 mg, 0.16 mmol, 72.8% yield).

LC-MS [M+H]: 446.2.

Stage 4. Synthesis of 7-[(3aS,4R,6R,6aR)-6-[(1R)-5-chloro-1,3-dihydroisobenzofuran-1-yl]-2,2-dimethyl4,5,6,6а -tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]pyrrolo[2,3-d]pyrimidin-4-amine (2Af).

To a solution of 7-[(3aS,4R,6R,6aR)-6-[(1 R)-5-chloro-1,3-dihydroisobenzofuran-1-yl]-2,2-dimethyl4,5,6,6a- tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-4-chloropyrrolo[2,3-d]pyrimidine (2Ae, 90 mg, 0.20 mmol) in 1,4-dioxane (3 ml) was added ammonium hydroxide (3 ml, 0.60 mmol), then the mixture was sealed and stirred at 120°C for 16 h. LC-MS showed that the reaction was complete. The reaction mixture was concentrated in vacuo, ethyl acetate (100 ml) was added and washed with saturated aqueous sodium chloride (60 ml). The organic layer was dried over Na2SO4, concentrated in vacuo to give 7-[(3aS,4R,6R,6aR)-6-[(1R)-5-chloro-1,3-dihydroisobenzofuran-1-yl]-2,2dimethyl- 4,5,6,6a-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]pyrrolo[2,3-d]pyrimidine-4-amine (2Af, 90 mg, 0.18 mmol , 92.0% yield).

LC-MS [M+H]: 427.1.

Stage 5. Synthesis of (1R,2S,3R,5S)-3-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-5-[(1R)-5-chloro-1,3dihydroisobenzofuran-1 -yl]cyclopentan-1,2-diol (Example 2A).

To a solution of 7-[(3aS,4R,6R,6aR)-6-[(1 R)-5-chloro-1,3-dihydroisobenzofuran-1-yl]-2,2-dimethyl4,5,6,6a- tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]pyrrolo[2,3-d]pyrimidin-4-amine (2Af, 70 mg, 0.16 mmol) in water (2 mL) was added TFA (0.9 ml, 11.45 mmol) and the reaction mixture was stirred at 30°C for 0.5 h. LC-MS showed that the reaction was complete. The mixture was purified by preparative HPLC eluting CH3CN in _H2O (0.1% NH4OH) from 5% to 95% to give (1R,2S,3R,5S)-3-(4aminopyrrolo[2,3-d]pyrimidine- 7-yl)-5-[(1R)-5-chloro-1,3-dihydroisobenzofuran-1-yl]cyclopentan-1,2diol (Ex. 2A, 30 mg, 0.08 mmol, 47% yield) as white solid.

LC-MS [M+H]: 387.3.

1H NMR (400 MHz, DMSO-d ₆ +D ₂ O): δ 8.00 (s, 1H), 7.31-7.37 (m, 3H), 7.15-7.16 (m, 1H ), 6.52-6.53 (m, 1H), 5.41-5.42 (m, 1H), 5.10-5.14 (m, 1H), 4.99-5.03 (m , 1H), 4.78-4.85 (m, 1H), 4.18-4.21 (m, 1H), 4.04-4.06 (m, 1H), 2.47-2.50 (m, 1H), 1.71-1.79 (m, 1H), 1.33-1.40 (m, 1H).

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Example 2B. Synthesis of (1R,2S,3R,5S)-3-(4-amino-7Н-pyrrolo[2,3-d]pyrimidin-7-ul)-5-((S)-5-chloro-1,3dihydroisobenzofuran- 1-yl)cyclopentan-1,2-diol (Example 2B).

Stage 1. Synthesis of 7-[(3aS,4R,6R,6aR)-6-[(1R)-5-chloro-1,3-dihydroisobenzofuran-1-yl]-2,2-dimethyl4,5,6,6а -tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-4-chloropyrrolo[2,3-d]pyrimidine (2Ba).

To a solution of (S)-[(3aS,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-ul)-2,2-dimethyl-4,5,6,6atetrahydro -3aH-cyclopenta[d][1,3]dioxol-6-yl]-[4-chloro-2-(hydroxymethyl)phenyl]methanol (2Ac, 90 mg, 0.19 mmol) in THF (4 mL) was added PPh ₃ (101.7 mg, 0.39 mmol) and DIAD (0.11 ml, 0.39 mmol). The mixture was stirred at 25° C. for 16 h under N2. TLC (PE:EA=3:1, Rf=0.4) indicated that the reaction was complete. The mixture was concentrated in vacuo to give the crude product, which was purified by prep-TLC (PE:EA=3:1) to give 7-[(3aS,4R,6R,6aR)-6-[(1R)-5-chloro -1,3dihydroisobenzofuran-1-yl]-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-ul]-4chloropyrrolo[2,3- d]pyrimidine (2Ba, 70 mg, 0.16 mmol, 80.9% yield).

LC-MS [M+H]: 446.2.

Stage 2. Synthesis of 7-[(3aS,4R,6R,6aR)-6-[(1S)-5-chloro-1,3-dihydroisobenzofuran-1-yl]-2,2-dimethyl4,5,6,6а -tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]pyrrolo[2,3-d]pyrimidin-4-amine (2Bb).

To a solution of 7-[(3aS,4R,6R,6aR)-6-[(1S)-5-chloro-1,3-dihydroisobenzofuran-1-yl]-2,2-dimethyl4,5,6,6a-tetrahydro -3aH-cyclopenta[d][1,3]dioxol-4-yl]-4-chloropyrrolo[2,3-d]pyrimidine (2Ba, 70 mg, 0.16 mmol) in 1,4-dioxane (3, 5 ml) was added ammonium hydroxide (3.5 ml, 0.47 mmol). The mixture was sealed and stirred at 120° C. for 16 hours. LC-MS indicated that the reaction was complete. The mixture was concentrated in vacuo to give 7-[(3aS,4R,6R,6aR)-6-[(1S)-5-chloro-1,3dihydroisobenzofuran-1-yl]-2,2-dimethyl-4,5,6 ,6a-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4yl]pyrrolo[2,3-d]pyrimidine-4-amine (2Bb, 60 mg, 0.09 mmol, 59.2% yield) .

LC-MS [M+H]: 427.1.

Stage 3. Synthesis of (1R,2S,3R,5S)-3-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-5-[(1S)-5-chloro-1,3dihydroisobenzofuran-1 -yl]cyclopentan-1,2-diol (Example 2B).

To a solution of 7-[(3aS,4R,6R,6aR)-6-[(1S)-5-chloro-1,3-dihydroisobenzofuran-1-yl]-2,2-dimethyl4,5,6,6a-tetrahydro -3aH-cyclopenta[d][1,3]dioxol-4-yl]pyrrolo[2,3-d]pyrimidin-4-amine (2Bb, 60 mg, 0.09 mmol) in water (2 ml) TFA was added (1 ml, 13.0 mmol). The reaction mixture was stirred at 30° C. for 0.5 h. LC-MS indicated that the reaction was complete. The reaction mixture was purified by preparative HPLC (0.1% NH3-H2O), eluting CH3CN in _H2O from 10% to 95% to give (1R,2S,3R,5S)-3-(4-aminopyrrolo[2,3 -d]pyrimidin-7-yl)-5-[(1S)-5-chloro-1,3-dihydroisobenzofuran-1yl]cyclopentan-1,2-diol (Ex. 2B, 27 mg, 0.07 mmol, 76 , 1% yield) as a white solid.

LC-MS [M+H]: 387.1.

¹ H NMR (400 MHz, DMSO-d6+D2O): δ 8.03 (s, 1H), 7.41-7.42 (m, 1H), 7.34-7.36 (m, 2H), 7.21-7.22(m, 1H), 6.57-6.58(m, 1H), 5.21-5.22(m, 1H), 4.97-5.07(m, 2H ), 4.86-4.91 (m, 1H), 4.16-4.191 (m, 1H), 3.65-3.66 (m, 1H), 2.38-2.43 (m, 1H ), 2.25-2.32 (m, 1H), 1.75-1.83 (m, 1H).

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Example 3A. Synthesis of (S)-3-((1S,2R,3S,4R)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,3dihydroxycyclopentyl)-6-chloroisobenzofuran -1(3H)-one (Ex. 3A).

D / ....

Etc. BEHIND

Stage 1. Synthesis of (3R)-3-[(3aS,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl4,5,6 ,6а-tetrahydro-3аН-cyclopenta[d] [1,3]dioxol-6-yl]-6-chloro-3Н-isobenzofuran-1 -one (3Ас) and (3S)-3[(3aS,4R,6R ,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-4,5,6,6а-tetrahydro-3аНcyclopenta[d][1,3]dioxol -6-yl]-6-chloro-3H-isobenzofuran-1-one (3Ad).

To a solution of methyl 5-chloro-2-iodobenzoate (3Ab, 829.3 mg, 2.80 mmol) in THF (15 ml) was added isopropyl magnesium chloride (2.2 ml, 2.80 mmol) at -20°C and the solution was stirred at -20°C for 2 h. ,5,6,6atetrahydro-3aH-cyclopenta[d][1,3]dioxol-6-carbaldehyde (3Aa, 900 mg, 2.80 mmol) in THF (10 ml) and stirred at 0°C for 2 h LC-MS indicated that the reaction was complete. H2O (30 ml) and ethyl acetate (60 ml) were added to the reaction mixture. The organic layer was washed with H2O (30 ml) and saturated aqueous sodium chloride (30 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (PE:EA= 6:1) to give (3R)-3-[(3aS,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7yl)-2,2-dimethyl-4,5 ,6,6a-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-6-yl]-6-chloro-3H-isobenzofuran-1one (3Ac, 330 mg, 0.72 mmol, 25.6% yield ) and (3S)-3-[(3aS,4R,6R,6aR)-4-(4-chloropyrrolo[2,3d]pyrimidin-7-yl)-2,2-dimethyl-4,5,6,6a -tetrahydro-3aH-cyclopenta[d][1,3]dioxol-6-yl]-6-chloro-3Nisobenzofuran-1-one (3Ad, 270.0 mg, 0.59 mmol, 21.0% yield).

LC-MS [M+H]: 460.0.

Stage 2. Synthesis of (3S)-3-[(3aS,4R,6R,6aR)-4-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl4,5,6 ,6a-Tetrahydro-3aH-cyclopenta[d][1,3]dioxol-6-yl]-6-chloro-3H-isobenzofuran-1-one (3Ae).

To a solution of (3S)-3-[(3aS,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-4,5,6 ,6ateΊhydro-3αH-cyclopenta[d][1,3]dioxol-6-yl]-6-chloro-3H-isobenzofuran-1-one (3Ad, 170 mg, 0.37 mmol) in 1,4-dioxane ( 5 ml) was added tert-butyl carbamate (86.5 mg, 0.74 mmol), Xantphos (32.1 mg, 0.06 mmol) and Pd ₂ (dba) ₃ (13.5 mg, 0.01 mmol). The mixture was stirred at 80° C. for 16 h under N2. LC-MS showed that the reaction was complete. The reaction mixture was filtered and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (DCM:CH ₃ OH=30:1) to give (3S)-3-[(3aS,4R,6R,6aR) -4-(4-aminopyrrolo[2,3-d]pyrimidin7-yl)-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-6- yl]-6-chloro-3H-isobenzofuran-1one (3Ae, 100 mg, 0.23 mmol, 61.4% yield).

LC-MS [M+H]: 441.2.

Stage 3. Synthesis of (3S)-3-[(1S,2R,3S,4R)-4-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-2,3dihydroxycyclopentyl]-6-chloro- 3H-isobenzofuran-1-one hydrochloride (Ex. 3A).

To a solution of (3S)-3-[(3aS,4R,6R,6aR)-4-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl4,5,6,6a -tetrahydro-3aH-cyclopenta[d][1,3]dioxol-6-yl]-6-chloro-3H-isobenzofuran-1-one (3Ae, 100 mg, 0.23 mmol) in water (3 ml) was added TFA (1.5 ml, 19.47 mmol). The reaction mixture was stirred at 30° C. for 0.5 h. LC-MS indicated that the reaction was complete. The mixture was purified by preparative HPLC eluting with CH3CN in H ₂ O (0.1% TFA) 5 to 9%, HCl (1 ml, 2N) was added and lyophilized to give (3 S)-3-[( 1S ,2R,3 S,4R)-4-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-2,3-dihydroxycyclopentyl] 6-chloro-3H-isobenzofuran-1-one hydrochloride (sp. 3A, 15 mg, 0.03 mmol, 15.1% yield) as a white solid.

LC-MS [M+H]: 401.1.

¹ H NMR (400 MHz, DMSO-d ₆ +D ₂ O): δ 8.35 (s, 1H), 7.94-7.95 (m, 1H), 7.86-7.88 (m, 1H), 7.74-7.76 (m,

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1H), 7.65-7.66 (m, 1H), 6.98-6.99 (m, 1H), 5.78-5.79 (m, 1H), 4.93-5.00 ( m, 1H), 4.14-4.18 (m, 1H), 3.54-3.56 (m, 1H), 2.68-2.69 (m, 1H), 2.38-2, 46 (m, 1H), 1.95-2.03 (m, 1H).

Example 3B. Synthesis of (R)-3-((1S,2R,3S,4R)-4-(4-amino-6H-714-pyrrolo[2,3-d]pyrimidin-7-yl)-2,3dihydroxycyclopentyl)-6 -chloroisobenzofuran-1(3H)-one (Ex. 3B).

_ZDE ZVA ZVZ Pr. SW

Stage 1. Synthesis of tert-butyl N-[7-[(3aS,4R,6R,6aR) -6-[(1R)-5-chloro-3-oxo-1H-isobenzofuran-1-yl]2,2- dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]pyrrolo[2,3-d]pyrimidin-4yl]carbamate (3Ba).

To a solution of (3R)-3-[(3aS,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-4,5,6 ,6atetrahydro-3aH-cyclopenta[d][1,3]dioxol-6-yl]-6-chloro-3H-isobenzofuran-1-one (3Ac, 230 mg, 0.50 mmol) in 1,4-dioxane ( 6 ml) was added tert-butylcarbamate (117.1 mg, 1.00 mmol), Xantphos (43.4 mg, 0.07 mmol) and Pd ₂ (dba) ₃ (18.3 mg, 0.02 mmol). The mixture was stirred at 80° C. for 16 hours under N2. LC-MS showed that the reaction was complete. The reaction mixture was filtered and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (DCM:CH ₃ OH=30:1) to give tert-butyl N-[7-[(3aS,4R,6R, 6aR)-6-[(1R)-5-chloro-3-oxo-1Nisobenzofuran-1-yl]-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopenta[d] [1, 3]dioxol-4-yl]pyrrolo[2,3d]pyrimidin-4-yl]carbamate (3Ba, 100 mg, 0.18 mmol, 37% yield).

LC-MS [M+H]: 541.2.

Stage 2. Synthesis of (3R)-3-[(3aS,4R,6R,6aR)-4-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl4,5,6 ,6а-tetrahydro-3аН-cyclopenta[d][1,3]dioxol-6-yl]-6-chloro-3Н-isobenzofuran-1-one (3Bb).

To a solution of tert-butyl N-[7-[(3aS,4R,6R,6aR)-6-[(1R)-5-chloro-3-oxo-1H-isobenzofuran-1-yl]-2,2dimethyl-4 ,5,6,6a-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]pyrrolo[2,3-d]pyrimidin-4yl]carbamate (3Ba, 100 mg, 0.18 mmol) in DCM (3 ml) was added TFA (3 ml, 38.94 mmol). The reaction mixture was stirred at 25° C. for 0.5 h. LC-MS indicated that the reaction was complete. The reaction mixture was concentrated in vacuo to give crude (3R)-3-[(3aS,4R,6R,6aR)-4-(4aminopyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-4 ,5,6,6а-tetrahydro-3аН-cyclopenta[d][1,3]dioxol6-yl]-6-chloro-3Н-isobenzofuran-1-one (3Bb), which was directly used in the next step.

LC-MS [M+H]: 441.1.

Stage 3. Synthesis of (3R)-3-[(1S,2R,3S,4R)-4-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-2,3dihydroxycyclopentyl]-6-chloro- 3H-isobenzofuran-1-one hydrochloride (Example 3B).

To a solution of (3R)-3-[(3aS,4R,6R,6aR)-4-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl4,5,6,6a -tetrahydro-3aH-cyclopenta[d][1,3]dioxol-6-yl]-6-chloro-3H-isobenzofuran-1-one (3Bb, 70 mg, 0.16 mmol) in water (3 ml) was added TFA (1.4 ml, 18.2 mmol). The reaction mixture was stirred at 30° C. for 0.5 hour. LC-MS showed that the reaction was complete. The mixture was purified by preparative HPLC eluting with CH3CN in H ₂ O (0.1% TFA) from 5% to 95%, HCl (1 ml, 2N) was added and lyophilized to give (3R)-3-[(1S ,2R,3S,4R)-4-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)2,3-dihydroxy-cyclopentyl]-6-chloro-3H-isobenzofuran-1-one (sp. 3B, 14.0 mg, 0.03 mmol, 19.0% yield) as a white solid.

LC-MS [M+H]: 401.3.

1H NMR (400 MHz, DMSO-d6+D2O): δ 8.30 (s, 1H), 7.80-7.90 (m, 3H), 7.48-7.49 (m, 1H), 6 .93-6.94 (m, 1H), 5.94-5.95 (m, 1H), 4.83-4.89 (m, 1H), 4.24-4.27 (m, 1H) , 4.15-4.18 (m, 1H), 2.68-2.76 (m, 1H), 1.73-1.80 (m, 1H), 1.18-1.26 (m, 1H).

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Example 5 Synthesis of (2R,3R,4S,5S)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-6-chloro-1 ,3dihydroisobenzofuran-1-yl)tetrahydrofuran-3,4-diol (Example 5).

5h Ave. 5

Stage 1. Synthesis of (2-bromo-4-chlorophenyl)methoxy-tert-butyldimethylsilane (5b).

TBSCl (5.10 g, 33.86 mmol) at 0°C. The mixture was stirred at room temperature for 2 hours. TLC (PE:EA=10:1, R _f =0.7) indicated that the reaction was complete. The reaction mixture was diluted with water (100 ml) and the mixture was extracted with ethyl acetate (50 mlx3), then the organic layers were washed with saturated aqueous sodium chloride solution (100 mlx3), dried over Na ₂ SO ₄ and concentrated in vacuo to give the crude product, which was purified using chromatography on a silica gel column (100-200 mesh size, PE:EA=200:1-100:1) to give (2-bromo-4chlorophenyl)methoxy-tert-butyldimethylsilane (5b, 6.80 g, 18.23 mmol , 80.7% yield) as a colorless oil.

¹ H NMR (400 MHz, DMSO-de): δ 7.70 (s, 1H), 7.49 (s, 2H), 4.66 (s, 2H), 0.91 (s, 9H), 0.10 (s, 6H).

Stage 2. Synthesis of [(3aR,4R,6S,6aS)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6atetrahydrofuro[3 ,4E][1,3]dioxol-6-yl]-[2-[[tert-butyl(dimethyl)silyl]oxymethyl]-5chlorophenyl]methanone (5d).

To a solution of (2-bromo-4-chlorophenyl)methoxy-tert-butyldimethylsilane (5b, 6.74 g, 20.06 mmol) in THF (50 ml) was added butyllithium (8.6 ml, 13.79 mmol) at - 78°C in an N2 atmosphere. The resulting solution 5c was stirred at -78°С for 10 min under N2 atmosphere. A solution of (3aR,4R,6S,6aS)-4-(4chloropyrrolo[2,3-d]pyrimidin-7-yl)-N-methoxy-N,2,2-trimethyl-3a,4,6,6a- tetrahydrofuro[3,4d][1,3]dioxol-6-carboxamide (1Ad, 2.4 g, 6.27 mmol) in THF (50 mL) and the mixture was stirred at -78°C for 30 min under N2 . LC-MS showed that the reaction was complete. The reaction mixture was quenched with saturated NH4Cl solution (50 ml). The mixture was extracted with ethyl acetate (100 mlx3). The combined organic layers were washed with saturated aqueous sodium chloride (40 mlx3), dried over Na ₂ SO ₄ , concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (100-200 mesh size, PE:EA=20 :1-10:1) to give [(3aR,4R,6S,6aS)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4, 6,6a-tetrahydrofuro[3,4d][1,3]dioxol-6-yl]-[2-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-chlorophenyl]methanone (5d, 3.36 g , 5.81 mmol, 92.6% yield) as a pale yellow oil.

LC-MS [M+H]: 578.1.

Stage 3. Synthesis of (R)-[(3aR,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl3a,4,6,6a -tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-[2-[[tert-butyl(dimethyl)silyl]oxymethyl]-5chlorophenyl]methanol (5e).

To a solution of [(3 aR,4R,6S,6aS)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6atetrahydrofuro[3, 4-d][1,3]dioxol-6-yl]-[2-[[tert-butyl(dimethyl)silyl]oxymethyl]-5chlorophenyl]methanone (5d, 3.3 g, 5.71 mmol) in toluene (100 ml) was added diisobutylaluminum hydride (9.5 ml, 14.26 mmol) at -78° C. under N2 atmosphere. The reaction mixture was stirred at -78°C for 0.5 h under N2 atmosphere. TLC (PE:EA=3:1, Rf=0.3) indicated that the reaction was complete. The reaction mixture was washed with water (10 ml x 3) and saturated aqueous sodium chloride solution (10 ml x 3). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated to give the crude product, which was purified by silica gel column chromatography (100-200 mesh size, PE:EA=10:1-8:1) to give (R) -[(3aR,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2dimethyl-3a,4,6,6a-tetrahydrofuro[3,4- d][1,3]dioxol-6-yl]-[2-[[tert-butyl(dimethyl)silyl]oxymethyl]-5chlorophenyl]methanol (5e, 1.8 g, 2.67 mmol, 46.7% yield) as a white solid.

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LC-MS [M+H]: 580.2.

Step 4. Synthesis of (R)-[(3aR,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl3a,4,6,6a -tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-[5-chloro-2-(hydroxymethyl)phenyl]methanol (5f).

To a solution of (R)-[(3aR,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6atetrahydrofuro [3,4-d][1,3]dioxol-6-yl]-[2-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-chlorophenyl]methanol (5e, 1.8 g, 3, 10 mmol) in DMSO (12 ml) and methanol (0.2 ml) was added CsF (1.2 g, 9.3 mmol). The reaction mixture was stirred at 25° C. for 4 hours. LC-MS indicated that the reaction was complete. The reaction mixture was filtered and purified by reverse phase combi-flash chromatography eluting CH ₃ CN in H2O (neutral) from 10 to 95% to give (R)-[(3aR,4R,6R,6aR)-4-(4 -chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4d][1,3]dioxol-6-yl]-[5 -chloro-2-(hydroxymethyl)phenyl]methanol (5f, 560 mg, 1.19 mmol, 38.3% yield) as a white solid.

LC-MS [M+H]: 466.1.

Stage 5. Synthesis of 7-[(3aR,4R,6R,6aR)-6-[(1R)-6-chloro-1,3-dihydroisobenzofuran-1-yl]-2,2-dimethyl3a,4,6,6a -tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-4-chloropyrrolo[2,3-d]pyrimidine (5g).

To a solution of (R)-[(3aR,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6atetrahydrofuro [3,4-d][1,3]dioxol-6-yl]-[5-chloro-2-(hydroxymethyl)phenyl]methanol (5f, 510 mg, 1.09 mmol) in THF (15.0 ml ) was added pyridine (0.1 ml, 1.09 mmol), tributylphosphine (0.6 ml, 2.19 mmol) and DIAD (0.2 ml, 2.3 mmol). The reaction mixture was stirred at 25° C. for 2 hours. TLC (PE:EA=3:1, Rf=0.4) indicated that the reaction was complete. The mixture was concentrated in vacuo to give a crude product which was purified by silica gel column chromatography (100-200 mesh size, PE:EA=20:1-10:1) to give 7-[(3aR,4R,6R,6aR )-6-[(1R)-6-chloro-1,3-dihydroisobenzofuran-1-yl]-2,2dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol -4-yl]-4-chloropyrrolo[2,3-d]pyrimidine (5g, 350 mg, 0.78 mmol, 71.4% yield) as a white solid.

LC-MS [M+H]: 448.1.

Stage 6. Synthesis of 7-[(3aR,4R,6R,6aR)-6-[(1R)-6-chloro-1,3-dihydroisobenzofuran-1-yl]-2,2-dimethyl3a,4,6,6a -tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-4-chloropyrrolo[2,3-d]pyrimidine (5h).

A mixture of 7-[(3aR,4R,6R,6aR)-6-[(1R)-6-chloro-1,3-dihydroisobenzofuran-1-yl]-2,2-dimethyl-3а,4,6,6atetrahydrofuro[ 3,4-d][1,3]dioxol-4-yl]-4-chloropyrrolo[2,3-d]pyrimidine (5g, 48.1 mg, 0.11 mmol), 1,4-dioxane (0 .5 ml) and NH3-H2O (0.5 ml, 12.98 mmol) were stirred at 120° C. for 16 hours in an autoclave. LC-MS showed that the reaction was complete. The mixture was concentrated in vacuo to give 7-[(3aR,4R,6R,6aR)-6-[(1R)-6-chloro-1,3-dihydroisobenzofuran-1-yl]-2,2-dimethyl-3a,4 ,6,6atetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-4-chloropyrrolo[2,3-d]pyrimidine (5h, 50 mg, 0.10 mmol, 94.6% yield ) as a white solid.

LC-MS [M+H]: 429.1.

Step 7. Synthesis of (2R, 3R, 4S, 5S)-2-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-5-[(1R)-6-chloro-1,3dihydroisobenzofuran-1 -yl]tetrahydrofuran-3,4-diol (Ex. 5).

A mixture of 7-[(3aR,4R,6R,6aR)-6-[(1R)-6-chloro-1,3-dihydroisobenzofuran-1-yl]-2,2-dimethyl-3а,4,6,6atetrahydrofuro[ 3,4-d][1,3]dioxol-4-yl]pyrrolo[2,3-d]pyrimidin-4-amine (5h, 50 mg, 0.12 mmol), water (0.5 ml), and TFA (0.8 ml, 9.06 mmol) was stirred at 40° C. for 16 hours. LC-MS indicated that the reaction was complete. The reaction mixture was concentrated and purified by preparative HPLC, (0.1% NH3-H2O), eluting CH3CN in _H2O from 10% to 95% to give (2R,3R,4S,5S)-2-(4aminopyrrolo[2, 3-d]pyrimidin-7-yl)-5-[(1R)-6-chloro-1,3-dihydroisobenzofuran-1-yl]tetrahydrofuran3,4-diol (Ex. 5, 19.5 mg, 0.05 mmol, 42.9% yield) as a white solid.

LC-MS [M+H]: 389.1.

¹ H NMR (400 MHz, DMSO-06): δ 8.07 (s, 1H), 7.37 (s, 3H), 7.30 (s, 1H), 7.03 (br, 2H), 6 .65 (d, J=3.6 Hz, 1H), 6.16 (d, J=7.6 Hz, 1H), 5.36 (d, J=2.0 Hz, 1H), 5.26 (d, J=7.2 Hz, 1H), 5.19 (d, J=4.0 Hz, 1H), 5.04-5.13 (m,

2H), 4.52 (dd, JJ=7.2 Hz, J2=5.2 Hz, 1H), 4.11 (d, J=4.8 Hz, 1H), 3.93 (t, J= 4.4 Hz, 1H).

1H NMR (400 MHz, DMSO-d6+D2O): δ 8.07 (s, 1H), 7.37 (s, 3H), 7.29 (s, 1H), 6.66 (d, J= 3.6Hz, 1H),

6.15 (d, J=3.6 Hz, 1H), 5.37 (br, 1H), 5.04-5.13 (m, 2H), 4.52 (dd, J=2.0 Hz , J2 = 5.2 Hz, 1H), 4.11 (d,

J=5.2 Hz, 1H), 3.93 (d, J=4.8 Hz, 1H).

Example 15 Synthesis of (2S,3S,4R,5R)-2-((R)-6-chloro-1,3-dihydroisobenzofuran-1-yl)-5-(4-methyl-7Hpyrrolo[2,3-d ]pyrimidin-7-yl)tetrahydrofuran-3,4-diol (Ex. 15).

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Stage 1. Synthesis of 7-[(3aR,4R,6R,6aR)-6-[(1R)-6-chloro-1,3-dihydroisobenzofuran-1-yl]-2,2-dimethyl3a,4,6,6a -tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-4-methylpyrrolo[2,3-d]pyrimidine (15a).

To a solution of 7-[(3aR,4R,6R,6aR)-6-[(1R)-6-chloro-1,3-dihydroisobenzofuran-1-yl]-2,2-dimethyl-3a,4,6,6atetrahydrofuro [3,4-d][1,3]dioxol-4-yl]-4-chloropyrrolo[2,3-d]pyrimidine (5g, 200.0 mg, 0.45 mmol) in THF (5 mL) was added dimethylzinc (4.5 ml, 4.46 mmol) at 25°C. The reaction mixture was stirred at 80° C. for 2 hours. LC-MS indicated that the reaction was complete. The mixture was cooled to room temperature and quenched with saturated NaHCO ₃ (aq) and extracted with ethyl acetate (100 mlx3). The organic layer was washed with saturated aqueous sodium chloride (50 mlx3), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give 7-[(3aR,4R,6R,6aR)6-[(1R)-6-chloro -1,3-dihydroisobenzofuran-1-yl]-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4d][1,3]dioxol-4-yl]-4-methylpyrrolo[2, 3-d]pyrimidine (15a, 206 mg, 0.40 mmol, 90.6% yield) as a brown solid.

LC-MS [M+H]: 428.1.

Stage 2. Synthesis of (2S,3S,4R,5R)-2-[(1R)-6-chloro-1,3-dihydroisobenzofuran-1-yl]-5-(4methylpyrrolo[2,3-d]pyrimidin-7 -yl)tetrahydrofuran-3,4-diol (Ex. 15).

A mixture of 7-[(3aR,4R,6R,6aR)-6-[(1R)-6-chloro-1,3-dihydroisobenzofuran-1-yl]-2,2-dimethyl-3a,4,6,6atetrahydrofuro[ 3,4-d][1,3]dioxol-4-yl]-4-methylpyrrolo[2,3-d]pyrimidine (15a, 106 mg, 0.25 mmol), water (0.5 ml) and TFA (0.8 ml, 8.33 mmol) was stirred at 40° C. for 2 hours. LC-MS indicated that the reaction was complete. The reaction mixture was filtered and purified by preparative HPLC (0.1% NH3-H2O) eluting CH3CN in _H2O from 10% to 95% to give (2S,3S,4R,5R)-2-[(1R)-6 -chloro-1,3dihydroisobenzofuran-1-yl]-5-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol (Ex. 15, 36.6 mg, 0, 09 mmol, 37.1% yield) as a white solid.

LC-MS [M+H]: 388.1.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.67 (s, 1H), 7.78 (d, J=3.6 Hz, 1H), 7.38 (s, 2H), 7. 31 (s, 1H), 6.83 (d, J=3.6 Hz, 1H), 6.29 (d, J=7.2 Hz, 1H), 5.33-5.40 (m, 3H ), 5.06-5.15 (m, 2H), 4.55-4.58 (m, 1H), 4.18 (d, J=4.8 Hz, 1H), 3.93 (d, J=4.8 Hz, 1H), 2.68 (s, 3H).

1H NMR (400 MHz, DMSO-d6+D ₂ O): δ 8.67 (s, 1H), 7.77 (d, J=4.0 Hz, 1H), 7.38 (s, 2H), 7.31 (s, 1H), 6.84 (d, J=4.0 Hz, 1H), 6.29 (d, J=3.2 Hz, 1H), 5.39 (br, 1H), 5.06-5.16 (m, 2H), 4.55-4.58 (m, 1H), 4.18 (d, J=4.0 Hz, 1H), 3.93 (d, J= 3.2 Hz, 1H), 2.68 (s, 3H).

Example 22 Synthesis of (2S,3S,4R,5R)-2-((R)-6-chloroisochroman-1-yl)-5-(4-methyl-7H-pyrrolo[2,3d]pyrimidin-7-yl )tetrahydrofuran-3,4-diol (Ex. 22).

22d Ave. 22

Step 1. Synthesis of 2-(2-bromo-5-chlorophenyl)ethanol (22a).

To a solution of 2-(2-bromo-5-chlorophenyl)acetic acid (20.0 g, 80.16 mmol) in THF (200 ml) was added borane in THF (240.49 ml, 240.49 mmol), and the mixture was stirred at 40°C for 8 hours. The mixture was quenched with MeOH at 0°C, concentrated and extracted with EA (400 mlx2). The combined organic layers were dried, concentrated and purified by combi-flash eluting with CH3CN/H2O (neutral) 5/95-95/5 to give 22b (18.1 g, 76.854 mmol, 95.9% yield) as a colorless oil.

LC-MS [M-18]: 217.0/219.0.

Stage 2. Synthesis of 2-(2-bromo-5-chlorophenyl)ethoxy-tert-butyldimethylsilane (22b).

To a solution of 22a (18.1 g, 76.85 mmol) in DMF (200 ml) was added imidazole (7.85 g, 115.28 mmol) and

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TBDMSCl (13.9 g, 92.23 mmol) and the mixture was stirred at 25°C for 8 hours. EA (800 ml) was added and the mixture was washed with saturated aqueous sodium chloride solution (400 mlx2). The organic layer was concentrated and purified by flash column chromatography (PE) to give 22b (26.7 g, 76.34 mmol, 99.3% yield) as a colorless oil.

Step 3. Synthesis of [2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-4-chlorophenyl]-[(3aR,4R,6S,6aS)-4-(4chloropyrrolo[2,3-d]pyrimidine -7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6yl]methanone (22c).

To a solution of 22b (8.91 g, 25.6 mmol) in dry THF (50 ml) was added n-BuLi (12.8 ml, 20.48 mmol) at -78° C. and the mixture was stirred for 10 minutes under atmosphere nitrogen. A solution of 1Ad (4.0 g, 10.24 mmol) in dry THF (20 ml) was added and the mixture was stirred for 5 min at -78°C. TLC (PE:EA=8:1) indicated that the reaction was complete. The reaction mixture was poured into dilute HCl (pH 6; maintained pH<8 during the quench process). The mixture was extracted with EA (200 ml x 2), the combined organic layers were dried, concentrated and purified with a combi-flash eluting with CH3CN/H2O (neutral) 5/95-95/5 to give 22c (5.1 g, 8.60 mmol, 84% yield) as a yellow solid.

Step 4. Synthesis of (R)-[(3aR,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl3a,4,6,6a -tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-[2-[[tert-butyl(dimethyl)silyl]oxymethyl]-5chlorophenyl]methanol (22d).

To a solution of 22c (5.0 g, 8.44 mmol) in THF (30 mL) at -78°C was added DIBAL-H (16.88 mL, 25.31 mmol) and the mixture was stirred at -78°C for within 30 min.

TLC (PE/EA=8/1) showed that the starting material Rf=0.5 was completely consumed with the main product Rf=0.4. The reaction mixture was poured into dilute HCl (pH=6, 400 ml, maintaining pH<8 during the quench process). The mixture was extracted with EA (300 ml x 2) and the combined organic layers were dried and concentrated to give crude 22d (5.0 g) as a yellow solid.

Stage 5. Synthesis of 2-[5-chloro-2-[(R)-hydroxy-[(3aR,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7yl)-2 ,2-dimethyl-3а,4,6,6а-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methyl]phenyl]ethanol (22f).

To a solution of 22d (3.0 g, 5.17 mmol) in THF (50 mL) was added tetrabutylammonium fluoride (5.17 mL, 5.17 mmol). The mixture was stirred at 25° C. for 40 minutes. The reaction mixture was poured into aqueous NH4Cl and extracted with EA (100 ml). The combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous Na ₂ SO ₄ and the solvent was evaporated under reduced pressure. The crude product was purified by flash column chromatography (PE:EA=15:1-3:1) to give 22e (2 g, 4.08 mmol, 79% yield) as a white solid.

LC-MS [M+H]: 480.1.

Stage 6. Synthesis of 4-chloro-7-[(3aR,4R,6R,6aR)-2,2-dimethyl-6-[(1R)-6-chloroisochroman-1-yl]-3a,4,6,6atetrahydrofuro [3,4-d][1,3]dioxol-4-yl]pyrrolo[2,3-d]pyrimidine (22f).

To a solution of 22e (2.0 g, 4.16 mmol) in THF (100 mL) was added tributylphosphine (2.1 mL, 8.33 mmol), isopropyl (NE)-N-isopropoxycarbonyliminocarbamate (1.72 mL, 8. 74 mmol) and pyridine (0.34 ml, 4.16 mmol) and the reaction mixture was stirred at 25°C for 16 hours.

TLC (PE/EA=3/1, Rf=0.4) indicated that the starting material had been consumed. The solvent was removed in vacuo and the crude product was purified by silica gel column chromatography using petroleum ether/EtOAc (10:1-5:1) as eluent to give 22f (1.7 g, 3.68 mmol, 88% yield) as a yellow oil.

LC-MS [M+H]: 462.1.

Stage 7. Synthesis of 4-methyl-7-[(3aR,4R,6R,6aR)-2,2-dimethyl-6-[(1R)-6-chloroisochroman-1-yl]-3a,4,6,6atetrahydrofuro [3,4-d][1,3]dioxol-4-yl]pyrrolo[2,3-d]pyrimidine (22g).

To a solution of iron acetylacetonate (0.13 g, 0.37 mmol) and 22f (1.7 g, 3.68 mmol) in THF (100 ml) was added bromomethylmagnesium (3.68 ml, 11.04 mmol) dropwise at 5°C in a nitrogen atmosphere. The reaction mixture was warmed to room temperature and stirred for 1 hour. TLC (EA:PE=1:1, Rf=0.3) indicated that the reaction was complete. Saturated NH ₄ Cl solution was added dropwise to quench the reaction, which was extracted with EA (200 mlx2), then dried over Na 2 SO 4 and concentrated. The residue was purified by flash column chromatography (PE:EA=10:1-1:1) to give 22g (900 mg, 1.93 mmol, 52.6% yield) as a white solid.

Step 8. Synthesis of (2R,3R,4S,5S)-2-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)-5-[(1R)-6chloroisochroman-1-yl]tetrahydrofuran-3 ,4-diol (Ex. 22).

To a solution of HCl (6.0 ml, 12 mmol) in methanol (10 ml) was added 22g (900 mg, 2.04 mmol) and the reaction mixture was stirred at 40°C for 2 h. The reaction mixture was concentrated and the residue was stirred with EA (50 ml) and filtered. The solid was purified by preparative HPLC eluting with CH3CN/H2O (0.1% NH4OH) 5/95-95/5. Product fractions were extracted with EA (100 mL x 2) and the extracts were concentrated to give Ex 22 (550 mg, 1.34 mmol, 66% yield) as a white solid.

LC-MS [M+H]: 402.3.

1H NMR (400 MHz, DMSO-d6): δ 8.67 (s, 1H), 7.76 (d, J=4.0 Hz, 1H), 7.22-7.31 (m, 3H), 6.81 (d,

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J=3.6Hz, 1H), 6.31(d, J=7.6Hz, 1H), 5.26(d, J=7.2Hz, 1H), 5.13(d, J= 4.0 Hz, 1H), 4.90 (d, J=3.6 Hz, 1H), 4.48-4.54 (m, 1H), 4.42-4.43 (m, 1H), 4.23-4.27(m, 1H), 3.84-3.86(m, 1H), 3.66-3.72(m, 1H), 2.91-2.99(m, 1H ), 2.70-2.74 (m, 1H), 2.67 (s, 3H).

1H NMR (400 MHz, DMSO-d6+D2O): δ 8.86 (s, 1H), 7.77 (d, J=4 Hz, 1H), 7.22-7.31 (m, 3H), 6.82 (d, J=3.6 Hz, 1H), 6.31 (d, J=7.6 Hz, 1H), 4.90 (d, J=3.6 Hz, 1H), 4, 49-4.53(m, 1H), 4.42-4.43(m, 1H), 4.24-4.28(m, 1H), 3.83-3.85(m, 1H), 3.66-3.72 (m, 1H), 2.91-2.99 (m, 1H), 2.70-2.75 (m, 1H), 2.69 (s, 3H).

Example 44 Synthesis of (2S,3S,4R,5R)-2-((1R)-6-chloro-3-methoxyisochroman-1-yl)-5-(4-methyl-7Hpyrrolo[2,3-d]pyrimidine -7-yl)tetrahydrofuran-3,4-diol (Ex. 44).

CI

1Ad

Stage 1. Synthesis of 1-bromo-4-chloro-2-(2-methoxyvinyl)benzene (44b).

To a solution of (methoxymethyl)triphenylphosphonium chloride (22.96 g, 66.98 mmol) in THF (100 ml) was added potassium tert-butoxide (7.16 g, 63.79 mmol) under N2 at -10°C. After 5 minutes, 2-bromo-5-chlorobenzaldehyde (44a; 7.0 g, 31.9 mmol) was added. The solution was stirred at -10° C. for 2 hours. TLC (PE=100%, Rf=0.8) indicated that the reaction was complete. The reaction mixture was poured into H2O (200 ml). The mixture was extracted with EA (200 ml), washed with water (60 ml) and saturated aqueous sodium chloride solution (60 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified by silica gel column chromatography eluting with PE (100%) to give 44b (7.2 g, 29.09 mmol, 91.2% yield, mixture of E and Z isomers) as a yellow oil.

1H NMR (400 MHz, DMSOCH): δ 7.99 (d, J=2.8 Hz, 1H), 7.61-7.56 (m, 2H), 7.43-7.40 (m, 1H ), 7.15-7.10 (m, 2H), 6.58 (d, J=6.8 Hz, 1H), 5.93 (d, J=12.8 Hz, 2H), 5, 44 (d, J=7.2 Hz), 3.84 (s, 3H), 3.71 (s, 3H).

Stage 2. Synthesis of 1-bromo-4-chloro-2-(2-methoxyvinyl)benzene (44c).

To a mixture of p-toluenesulfonic acid (537 mg, 2.83 mmol) in methanol (70 ml) was added 44b (7.0 g, 28.28 mmol). The mixture was stirred at 66° C. for 16 hours. TLC (PE=100%, Rf=0.4) indicated that the reaction was complete. The reaction mixture was poured into H ₂ O (200 ml). The mixture was extracted with EA (200 ml), washed with water (60 ml) and saturated aqueous sodium chloride solution (60 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified by silica gel column chromatography eluting with PE (100%) to give 44c (7.2 g, 25.7 mmol, 91% yield) as a yellow oil.

1H NMR (400 MHz, CDCl3): δ 7.62 (d, J=8.8 Hz, 1H), 7.43 (d, J=2.4 Hz, 1H), 7.25 (dd, J= 8.4, 2.8 Hz, 1H), 4.62 (t, J=5.2 Hz, 1H), 3.26 (s, 6H), 2.99 (d, J=5.6 Hz, 2H).

Stage 3. Synthesis of [4-chloro-2-(2,2-dimethoxyethyl)phenyl]-[(3aR,4R,6S,6aS)-4-(4-chloropyrrolo[2,3d]pyrimidin-7-ul)- 2,2-dimethyl-3а,4,6,6а-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanone (44f).

To a mixture of 44c (3.0 g, 10.73 mmol) in THF (30 ml) was added n-BuLi (2.04 g, 10.73 mmol) at -78°C. The resulting solution of 44d was stirred at -78°C for 1 min and 1Ad (3.24 g, 8.46 mmol) in THF (20 ml) was added at -78°C. The reaction mixture was stirred at -78°C for 30 min. TLC (PE:EA=5:1, Rf=0.5) indicated that the reaction was complete. The reaction mixture was quenched with NH4Cl (aq., 100 ml) and water (100 ml). The aqueous layer was extracted with EA (300 mlx3). The organic layers were concentrated to give the crude product which was purified by silica gel column chromatography eluting with PE:EA=10:1 to give 44e (3 g, 5.74 mmol, 53.5% yield) as a yellow oil.

LC-MS [M+H]: 522.3

Step 4. Synthesis of (S)-[4-chloro-2-(2,2-dimethoxyethyl)phenyl]-[(3aR,4R,6R,6aR)-4-(4-chloropyrrolo[2,3d]pyrimidine-7 -ul)-2,2-dimethyl-3а,4,6,6а-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanol (44f).

To a mixture of 44e (3.0 g, 5.74 mmol) in toluene (30 ml) was added DIBAL-H (1.33 ml, 11.49 mmol) at -78°C. The mixture was stirred at -78°C for 30 minutes. LC-MS showed that the reaction was complete.

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The reaction mixture was poured into H2O (100 ml) and extracted with DCM (200 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified by silica gel column chromatography eluting with DCM:MeOH=5:1 to give 44f (3 g, 5.72 mmol, 99.6% yield) as a yellow oil.

LC-MS [M+H]: 524.4

Stage 5. Synthesis of 4-chloro-7-[(3aR,4R,6R,6aR)-2,2-dimethyl-6-[(1R)-6-chloro-3-methoxy-isochroman-1yl]-3а,4 ,6,6а-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]pyrrolo[2,3-d]pyrimidine (44g).

To the mixture (S)-[4-chloro-2-(2,2-dimethoxyethyl)phenyl]-[(3aR,4R,6R,6aR)-4-(4-chloropyrrolo[2,3d]pyrimidin-7-yl )-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanol (2.0 g, 3.81 mmol) in methanol ( 20 ml) was added TsOH (0.03 ml, 5.72 mmol at 0°C. The mixture was stirred at 25°C for 2 h. TLC (PE:EA=5:1, Rf=0.5) showed that the reaction was completed The reaction mixture was poured into H2O (30 ml) and extracted with DCM (50 mlx3) The organic phase was washed with saturated NaCl solution (100 ml), dried over Na ₂ SO ₄ , filtered and concentrated The crude product was purified by column chromatography with silica gel eluting with PE:EA=10:1 to give 44g (1.36 g, 2.76 mmol, 72% yield) as a yellow oil.

LC-MS [M+H]: 492.2.

Stage 6. Synthesis of 4-methyl-7-[(3aR,4R,6R,6aR)-2,2-dimethyl-6-[(1R)-6-chloro-3-methoxy-isochroman-1yl]-3а,4 ,6,6a-Tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]pyrrolo[2,3-d]pyrimidine (44h).

To a mixture of 44g (200 mg, 0.41 mmol) and iron acetylacetonate (71.73 mg, 0.20 mmol) in THF (2 ml) was added MeMgBr (484 mg, 4.06 mmol) at -10°C. The reaction mixture was heated to 0°C and stirred for 1 h. TLC (PE:EA=5:1, R(=0.7) showed that the reaction was complete. The reaction mixture was poured into H2O (10 ml), extracted with DCM ( 10 mlx3), washed with saturated NaCl (20 ml), dried over Na ₂ SO ₄ , filtered and concentrated.The crude product was purified by silica gel column chromatography eluting with PE:EA=7:1 to give 44h (110 mg, 0. 23 mmol, 57.4% yield) as a yellow oil.

LC-MS [M+H]: 472.4.

Step 7. Synthesis of (2R,3R,4S,5S)-2-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)-5-[(1R)-6-chloro-3methoxyisochroman-1-yl ]tetrahydrofuran-3,4-diol (Ex. 44).

To a mixture of 44h (110 mg, 0.23 mmol) in methanol (2 ml) was added HCl (42 mg, 1.17 mmol). The mixture was stirred at 25° C. for 1 h. TLC (PE:EA=5:1, Rf=0.7) and LC-MS showed that the reaction was complete. The reaction mixture was poured into H2O (10 ml), extracted with DCM (10 mlx3), washed with saturated NaCl (20 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified by silica gel column chromatography eluting with PE:EA=7:1 to give a crude product which was further purified by preparative HPLC eluting with CH3CN in H ₂ O (0.1% NH3.H2O) from 10 to 95 %) to give Ex 44 (25 mg, 0.047 mmol, 20% yield) as a white solid.

LC-MS [M+H]: 432.4.

1H NMR (400 MHz, DMSO-d ₆ ): δ 8.67 (s, 1H), 7.79-7.81 (d, 1H), 7.22-7.32 (m, 3H), 6, 82-6.84 (m, 1H), 6.31-6.34 (m, 1H), 5.15-5.30 (m, 3H), 4.82 (d, 1H), 4.46- 4.58 (m, 2H), 3.89-3.91 (t, 1H), 3.38 (s, 3H), 3.08-3.13 (m, 1H), 2.77 (d, 1 H), 2.67 (s, 3H).

1H NMR (400 MHz, DMSO-d6+D ₂ O): δ 58.68 (s, 1H), 7.81 (d, 1H), 7.22-7.32 (m, 3H), 6.83 (d, 1H), 6.32 (d, 1H), 5.26 (d, 1H), 4.83 (d, 1H), 4.78-4.57 (m, 2H), 3.89 ( d, 1H), 3.08 (d, 1H), 2.77 (d, 1H), 2.67 (s, 3H).

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Example 46 Synthesis of (1R)-6-chloro-1-[(2S,3S,4R,5R)-3,4-dihydroxy-5-(4-methylpyrrolo[2,3d]pyrimidin-7-yl)tetrahydrofuran- 2-yl]isochroman-3-one (Ex. 46).

Etc. 46

Stage 1. Synthesis of 1-bromo-4-chloro-2-(2-methoxyvinyl)benzene (46b).

To a solution of (methoxymethyl)-triphenylphosphonium chloride (26.24 g, 76.55 mmol) in THF (70 ml) was added potassium tert-butoxide (4.65 ml, 72.91 mmol) at -25° C. under N2 atmosphere. After a few minutes, 2-bromo-5-chlorobenzaldehyde (46a, 8.0 g, 36.45 mmol) was added. The solution was stirred at -25° C. for 2 hours. The reaction was followed by TLC (petroleum ether=100%, Rf=0.8). The reaction mixture was poured into water (200 ml). Ethyl acetate (200 ml) was added and the organic phase was separated. The solution was washed with water (100 ml) and saturated aqueous sodium chloride (100 ml), dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give the crude product, which was purified by column chromatography on silica gel with petroleum ether (100% ) to give 1-bromo-4-chloro-2(2-methoxyvinyl)benzene (46b, 8.75 g, 35.351 mmol, 97% yield) as a yellow oil.

LC-MS [M+H]: 247.1.

Stage 2. Synthesis of 1-bromo-4-chloro-2-(2,2-dimethoxyethyl)benzene (46c).

To a mixture of TsOH (672 mg, 3.54 mmol) in methanol (70 mL) was added 1-bromo-4-chloro-2-(2methoxyvinyl)benzene (46b, 8.75 g, 35.35 mmol) and the mixture was stirred at 75°C for 16 hours. TLC (petroleum ether = 100%, R _f = 0.4) showed that the reaction was complete. The reaction mixture was poured into water (200 ml) and ethyl acetate (200 ml) was added. The organic layer was washed with saturated NaCl solution (100 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography eluting with petroleum ether (100%) to give 1-bromo- 4-Chloro-2-(2,2-dimethoxyethyl)benzene (46c, 5.5 g, 19.674 mmol, 56% yield) as a yellow oil.

LC-MS [M+H]: 279.1.

Stage 3. Synthesis of [4-chloro-2-(2,2-dimethoxyethyl)phenyl]-[(3aR,4R,6S,6aS)-4-(4-chloropyrrolo[2,3d]pyrimidin-7-yl)- 2,2-dimethyl-3а,4,6,6а-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanone (46d).

To a mixture of 1-bromo-4-chloro-2-(2,2-dimethoxyethyl)benzene (46c, 5.5 g, 19.7 mmol) in THF (30 ml) was added BuLi (3.74 g, 19. 7 mmol) at -78°C and stirred for 1 min. (3aR,4R,6S,6aS)-4(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-N-methoxy-N,2,2-trimethyl-3a,4,6,6a- tetrahydrofuro[3,4d][1,3]dioxol-6-carboxamide (1Ad, 5.94 g, 15.52 mmol) at -78°C and the reaction mixture was stirred for 30 minutes at -78°C. TLC (petroleum ether:ethyl acetate=5:1, Rf=0.5) indicated that the reaction was complete. The reaction mixture was quenched with NH ₄ Cl (100 ml) and water (100 ml).

The aqueous layer was extracted with ethyl acetate (300 mlx3), dried over Na ₂ SO ₄ and concentrated in vacuo. The crude product was purified by silica gel column chromatography eluting with petroleum ether:ethyl acetate (10:1) to give [4-chloro-2-(2,2-dimethoxyethyl)phenyl][(3aR,4R,6S,6aS)- 4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4d][1,3]dioxol-6-yl ]methanone (46d, 2.0 g, 3.8286 mmol, 19.5% yield) as a yellow oil.

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LC-MS [M+H]: 522.3.

Step 4. Synthesis of (S)-[4-chloro-2-(2,2-dimethoxyethyl)phenyl]-[(3aR,4R,6R,6aR)-4-(4-chloropyrrolo-[2,3d]pyrimidine- 7-yl)-2,2-dimethyl-3а,4,6,6а-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanol (46f).

To a mixture of [4-chloro-2-(2,2-dimethoxyethyl)phenyl]-[(3aR,4R,6S,6aS)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7yl)-2, 2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanone (46d, 2.0 g, 3.83 mmol) in toluene (30 ml ) was added DIBAL-H (0.89 ml, 7.66 mmol) at -78°C. The mixture was stirred at -78°C for 30 minutes. The reaction mixture was poured into water (100 ml) and extracted with DCM (200 ml). The aqueous layer was extracted with DCM (300 mlx3), dried over Na ₂ SO ₄ and concentrated in vacuo. The crude product was purified by silica gel column chromatography eluting with DCM:MeOH=5:1 to give (S)-[4-chloro-2-(2,2-dimethoxyethyl)phenyl]-[(3aR,4R,6R,6aR )-4-(4-chloropyrrolo-[2,3-d]pyrimidin-7-yl)-2,2dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol- 6-yl]methanol (46e, 2 g, 3.81 mmol, 100% yield) as a yellow oil.

LC-MS [M+H]: 524.3.

Stage 5. Synthesis of 4-chloro-7-[(3aR,4R,6R,6aR)-2,2-dimethyl-6-[(1R)-6-chloro-3-methoxy-isochroman-1yl]-3а,4 ,6,6а-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]pyrrolo[2,3-d]pyrimidine (46f).

To the mixture (S)-[4-chloro-2-(2,2-dimethoxyethyl)phenyl]-[(3aR,4R,6R,6aR)-4-(4-chloropyrrolo[2,3d]pyrimidin-7-yl )-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanol (46e, 2.0 g, 3.81 mmol) in methanol (20 ml) was added TsOH (0.03 ml, 5.72 mmol) at 0°C, then the mixture was stirred at 25°C for 2 h. TLC (petroleum ether: ethyl acetate=5:1, Rf=0, 5) and LC-MS showed that the reaction was complete. The reaction mixture was poured into water (30 ml) and extracted with DCM (50 mlx3). The organic layers were dried over Na ₂ SO ₄ and concentrated in vacuo. The crude product was purified by silica gel column chromatography eluting with petroleum ether:ethyl acetate=10:1 to give 4-chloro-7-[(3aR,4R,6R,6aR)-2,2-dimethyl-6-[(1R )-6-chloro-3-methoxyisochroman-1-yl]-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]pyrrolo[2,3-d] pyrimidine (46f, 1.6 g, 3.25 mmol, 85% yield) as a yellow oil.

LC-MS [M+H]: 492.0.

Stage 6. Synthesis of 4-methyl-7-[(3aR,4R,6R,6aR)-2,2-dimethyl-6-[(1R)-6-chloro-3-methoxy-isochroman-1yl]-3а,4 ,6,6а-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]pyrrolo[2,3-d]pyrimidine (46g).

To a mixture of 4-chloro-7-[(3aR,4R,6R,6aR)-2,2-dimethyl-6-[(1R)-6-chloro-3-methoxyisochroman-1-yl]-3а,4,6 ,6atetrahydrofuro[3,4-d][1,3]dioxol-4-yl]pyrrolo[2,3-d]pyrimidine (46f, 800 mg, 1.62 mmol) and iron acetylacetonate (287 mg, 0.81 mmol) in THF (10 ml), methylmagnesium bromide (1937.48 mg, 16.25 mmol) was added at -10°C. The mixture was heated to 0° C. and stirred for 1 hour. TLC (petroleum ether:ethyl acetate=5:1, Rf=0.7) indicated that the reaction was complete. The reaction mixture was poured into water (30 ml) and extracted with DCM (50 mlx3). The organic layers were dried over Na2SO4 and concentrated in vacuo. The crude product was purified by silica gel column chromatography eluting with petroleum ether:ethyl acetate=7:1 to give 4-methyl-7-[(3aR,4R,6R,6aR)-2,2-dimethyl-6[(1R) -6-chloro-3-methox-isochroman-1-yl]-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]pyrrolo[2,3d]pyrimidine (46g, 610 mg, 1.29 mmol, 80% yield) as a yellow oil.

LC-MS [M+H]: 472.1.

Step 7. Synthesis of (2R,3R,4S,5S)-2-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)-5-[(1R)-6-chloro-3hydroxyisochroman-1-yl ]tetrahydrofuran-3,4-diol (46h).

To a mixture of 4-methyl-7-[(3aR,4R,6R,6aR)-2,2-dimethyl-6-[(1R)-6-chloro-3-methoxyisochroman-1-yl]3а,4,6, 6a-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]pyrrolo[2,3-d]pyrimidine (46 g, 590 mg, 1.25 mmol) in water (6 ml) was added trifluoroacetic acid (228 mg, 2 mmol). The mixture was stirred at 25° C. for 1 h. TLC (petroleum ether: ethyl acetate=2:1, Rf=0.3) indicated that the reaction was complete. The reaction mixture was poured into water (30 ml) and extracted with ethyl acetate (50 mlx3). The organic layer was dried over Na ₂ SO ₄ and concentrated in vacuo to give a crude product which was purified by silica gel column chromatography eluting with petroleum ether:ethyl acetate=7:1 to give (2R,3R,4S,5S)-2- (4-methylpyrrolo[2,3-d]pyrimidin-7-yl)-5-[(1R)-6chloro-3-hydroxyisochroman-1-yl]tetrahydrofuran-3,4-diol (46h, 280 mg, 0, 54 mmol, 43% yield) as a yellow oil.

LC-MS [M+H]: 418.1.

Step 8. Synthesis of (1R)-6-chloro-1-[(3aR,4R,6R,6aR)-2,2-dimethyl-4-(4-methylpyrrolo[2,3-d]pyrimidin7-yl)-3a ,4,6,6а-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]isochroman-3-ol (46i).

To a mixture of (2R,3R,4S,5S)-2-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)-5-[(1R)-6-chloro-3-hydroxyisochroman1-yl]tetrahydrofuran -3,4-diol (46h, 50 mg, 0.12 mmol) in acetone (10 ml) TsOH (8.24 mg, 0.05 mmol) was added at 0°C. The mixture was stirred at 25°C for 3 hours. TLC (petroleum ether:ethyl acetate=5:1, Rf=0.3) showed that the reaction was complete. The reaction mixture was poured into water (30 ml) and extracted with DCM (50 mlx3). The organic layer was dried over Na2SO4, concentrated in vacuo to give a crude product which was purified by silica gel column chromatography eluting with petroleum ether:ethyl acetate=(7:1) to give (1R)-6-chloro-1

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[(3aR,4R,6R,6aR)-2,2-dimethyl-4-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)-3a,4,6,6a-tetrahydrofuro[3,4d ][1,3]dioxol-6-yl]isochroman-3-ol (46i, 76 mg, 0.13 mmol, 112% yield) as a white solid.

LC-MS [M+H]: 458.1.

Stage 9. Synthesis of 6-chloro-1-[(3aR,4R,6R,6aR)-2,2-dimethyl-4-(4-methylpyrrolo[2,3-d]pyrimidin-7yl)-3а,4,6 ,6а-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]isochroman-3-one (46J).

To a mixture of 6-chloro-1-[(3aR,4R,6R,6aR)-2,2-dimethyl-4-(4-methylpyrrolo-[2,3-d]pyrimidin-7-yl)3а,4,6 ,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]isochroman-3-ol (46i, 75 mg, 0.16 mmol) in DCM (3 mL) was added PCC (0.09 ml, 0.49 mmol) at 0°C and the mixture was stirred at 0°C for 30 min. Then the reaction mixture was heated to 25°C until the completion of the reaction. The reaction mixture was poured into water (30 ml) and extracted with DCM (3x50 ml). The organic layer was dried over Na ₂ SO ₄ and concentrated in vacuo to give 6-chloro-1-[(3aR,4R,6R,6aR)-2,2-dimethyl-4-(4-methylpyrrolo[2,3-d] pyrimidin-7yl)-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]isochroman-3-one (46j, 79 mg, 0.172 mmol, 100% yield) as a white solid, which was used without further purification in the next step.

LC-MS [M+H]: 456.3.

Step 10. Synthesis of (1R)-6-chloro-1-[(2S,3S,4R,5R)-3,4-dihydroxy-5-(4-methylpyrrolo[2,3-d]pyrimidin7-yl)tetrahydrofuran- 2-yl]isochroman-3-one (Ex. 46).

To a mixture of (1R)-6-chloro-1-[(3aR,4R,6R,6aR)-2,2-dimethyl-4-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)3а, 4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]isochroman-3-one (46j, 78 mg, 0.17 mmol) in water (2 ml), trifluoroacetic acid was added acid (31.19 mg, 0.27 mmol) and the mixture was stirred at 25° C. for 1 hour. LC-MS indicated that the reaction was complete. The reaction was neutralized with NaHCO ₃ and purified by preparative HPLC eluting CH3CN in water (0.1% TFA) from 10 to 95%) to give (1R)-6-chloro-1[(2S,3S,4R,5R)- 3,4-dihydroxy-5-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-2-yl]isochroman-3one (Ex. 46, 3.4 mg, 0.0078 mmol, 4 .6% yield) as an off-white solid.

LC-MS [M+H]: 416.0.

1H NMR (400 MHz, DMSO-d ₆ ): δ 8.74 (s, 1H), 7.58 (s, 1H), 7.30 (m, 3H), 6.86 (s, 1H), 6 .23 (d, J=5.6 Hz, 1H), 5.73 (d, J=4.8 Hz, 1H), 4.48 (m, 2H), 4.26 (s, 1H), 3 .77 (d, J=4.8 Hz, 2H), 2.72 (s, 3H).

1H NMR (400 MHz, DMSO-d6+D2O): δ 8.82 (s, 1H), 7.62 (d, J=3.2 Hz, 1H), 7.29 (m, 3H), 6, 93 (d, J=3.2 Hz, 1H), 6.24 (d, J=5.6 Hz, 1H), 5.73 (d, J=5.2 Hz, 1H), 4.49 ( m, 2H), 4.26 (s, 1H), 3.76 (s, 2H), 2.76 (s, 3H).

Example 50 Synthesis of (2R,3R,4S,5S)-2-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)-5-[(1R)-6-chloro-3hydroxyisochroman-1-yl ]tetrahydrofuran-3,4-diol (Ex. 50).

44h Ave. 50

To a mixture of 44h (100 mg, 0.21 mmol) in water (2 ml) was added trifluoroacetic acid (38.63 mg, 0.34 mmol). The mixture was stirred at 25° C. for 1 h. TLC (PE:EA=5:1, Rf=0.7) and LC-MS showed that the reaction was complete. The reaction mixture was poured into H2O (10 ml), extracted with DCM (10 mlx3), washed with saturated NaCl (20 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified by silica gel column chromatography eluting with PE:EA=7:1 to give a crude product which was further purified by preparative HPLC eluting with CH3CN in H ₂ O (0.1% NH3.H2O) from 10 to 95 %) to give Ex 50 as a mixture of diastereomers (10 mg, 0.019 mmol, 9% yield) as a white solid.

LC-MS [M+H]: 418.3.

1H NMR (400 MHz, DMSO-d ₆ ): δ 8.67 (s, 1H), 8.00 (d, 1H), 7.21-7.35 (m, 3H), 6.75-6, 82 (m, 1H), 6.30-6.36 (m, 1H), 5.05-5.25 (m, 2H), 4.98-5.04 (m, 2H), 4.45- 4.59(m, 2H), 3.74-3.87(m, 1H), 2.91-3.05(m, 1H), 2.72-2.81(m, 1H), 2. 50-2.51 (m, 3H).

1H NMR (400 MHz, DMSO-d ₆ +D2O): δ 8.66 (s, 1H), 7.81-8.00 (q, 1H), 7.22-7.34 (m, 3H), 6.79-6.81(t, 1H), 6.30-6.34(q, 1H), 4.98-5.05(q, 2H), 4.45-4.59(m, 2H ), 3.74-3.87 (m, 1H), 2.79-2.91 (m, 1H), 2.72 (s, 1H), 2.68 (s, 3H).

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Example 55 Synthesis of (2R,3R,4S,5S)-2-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)-5-[(1R)-7-chloro-1,5dihydro-2 ,4-benzodioxepin-1-yl]tetrahydrofuran-3,4-diol (Ex. 55).

Stage 1. Synthesis of (2-bromo-5-chlorophenyl)methoxy-tert-butyldimethylsilane (55b).

To a solution of (2-bromo-5-chlorophenyl)methanol (55a, 6.0 g, 27.09 mmol) and imidazole (3.69 g, 54.18 mmol) in DCM (50 mL) was slowly added tert-butylchlorodiphenylsilane ( 4.9 g, 32.51 mmol) at RT The mixture was stirred at 30° C. for 3 hours. TLC (petroleum ether, Rf=0.4) indicated that the reaction was complete.

The reaction mixture was concentrated in vacuo to give the crude product, which was purified by column chromatography on silica gel (petroleum ether) to give (2-bromo-5-chlorophenyl)methoxy-tert-butyldimethylsilane (55b, 9.0 g, 26.81 mmol , 99% yield) as a colorless oil.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 7.51 (d, J=8.4, 1H), 7.81 (d, J=2.8, 1H), 7.22-7, 19 (m, 1H), 4.57 (s, 1H), 0.83-0.81 (m, 9H), 0.02-0.01 (m, 6H).

Stage 2. Synthesis of [2-[[tert-butyl(dimethyl)-silyl]oxymethyl]-4-chlorophenyl]-[(3aR,4R,6S,6aS)-4-(4chloropyrrolo[2,3-d]pyrimidine- 7-yl)-2,2-dimethyl-3а,4,6,6а-tetrahydrofuro[3,4-d][1,3]dioxol-6yl]methanone (55c).

A solution of (2-bromo-5-chlorophenyl)methoxy-tert-butyldimethylsilane (55b, 9 g, 26.8 mmol) in dry THF (50 ml) with stirring at -78° C. under Ar. n-BuLi (12.02 mL, 30.04 mmol) was added and stirred at -78°C for 10 min. (3aR,4R,6S,6aS)-4-(4-chloropyrrolo-[2,3-d]pyrimidin-7-yl)-Nmethoxy-N,2,2-trimethyl-3a,4,6,6a- tetrahydrofuro[3,4-d][1,3]dioxol-6-carboxamide (1Ad, 4.6 g, 12.02 mmol) in anhydrous THF (50 ml), then the reaction mixture was stirred at -78°C for 30 min. TLC (petroleum ether:ethyl acetate=5:1) and LC-MS showed that the reaction was complete. The mixture was adjusted to pH 6 with HCl (1N). The reaction mixture was extracted with EtOAc (2x100 ml) and the organic layers were washed with water (100 mlx2) then saturated aqueous sodium chloride solution (50 mlx2). The organic layers were dried over MgSO ₄ , filtered and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=10:1 to 5:1) to give [2[[t-butyl(dimethyl)-silyl]oxymethyl]-4-chlorophenyl]-[(3aR ,4R,6S,6aS)-4-(4-chloropyrrolo[2,3d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1 ,3]dioxol-6-yl]methanone (55s, 4.03 g, 6.97 mmol, 58% yield).

LC-MS [M+H]: 578.2.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.67 (s, 1H), 7.68 (d, J=3.6, 1H), 7.62 (d, J=8.4, 1H), 7.47-7.46(m, 2H), 7.35(d, J=8.0, 1H), 7.26-7.20(m, 2H), 6.49(d, J=3.6, 1H), 6.42 (s, 1H), 5.53-5.51 (m, 2H), 5.42 (d, J=5.6, 1H), 5.27- 5.25(m, 1H), 4.54-4.44(m, 3H), 1.52(s, 3H), 1.31(s, 3H), 0.69(s, 9H), 0 .01--0.070 (m, 6H).

Step 3 Synthesis of (R)-[2-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-chlorophenyl]-[(3aR,6R,6aR)-2,2dimethyl-4-[(7S)-4 -chloropyrrolo[2,3-d]pyrimidin-7-yl]-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6yl]methanol (55d).

To a solution of [2-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-chlorophenyl]-[(3aR,4R,6S,6aS)-4-(4chloropyrrolo[2,3-d]pyrimidin-7-yl )-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6yl]methanone (55c, 4.39 g, 7.59 mmol) in toluene ( 10 ml) diisobutylaluminum hydride (3.23 g, 22.77 mmol, 1 M in toluene) was added dropwise at -78°C. The reaction mixture was stirred at -78°C for 30 minutes. The mixture was quenched with NH ₄ Cl (50 ml). The reaction mixture was concentrated in vacuo and extracted with ethyl acetate (2x100 ml). The combined organic layers were dried over MgSO ₄ . Solvent

- 82 042008 was removed in vacuo to give the crude (R)-[2-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-chlorophenyl][(3aR,6R,6aR)-2,2-dimethyl-4- [(7S)-4-chloropyrrolo[2,3-d]pyrimidin-7-yl]-3a,4,6,6a-tetrahydrofuro[3,4d][1,3]dioxol-6-yl]methanol (55d , 4.2 g), which was used in the next step without further purification.

LC-MS [M+H]: 580.2.

Step 4 Synthesis of (R)-[4-chloro-2-(hydroxymethyl)phenyl]-[(3aR,6R,6aR)-2,2-dimethyl-4-[(7S)-4chloropyrrolo[2,3-d ]pyrimidin-7-yl]-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanol (55e)

To a solution of (R)-[2-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-chlorophenyl]-[(3aR,6R,6aR)-2,2dimethyl-4-[^)-4-chloropyrrolo[ 2,3D]pyrimidin-7-yl]-3a,4,6,6a-tetrahydrofuro[3,4D][1,3]dioxol-6yl]methanol (55d, 4.2 g, 7.23 mmol) in THF (5 ml) TBAF (1M) (3.78 ml, 14.47 mmol) was added. The mixture was stirred at 25° C. for 2 hours under N2. The mixture was quenched with NH4C1 (50 ml). The reaction mixture was concentrated in vacuo and purified by silica gel column chromatography (petroleum ether:ethyl acetate=3:1) to give (R)-[4-chloro-2-(hydroxymethyl)phenyl]-[(3aR,6R,6aR) -2,2dimethyl-4-[(7S)-4-chloropyrrolo[2,3-d]pyrimidin-7-yl]-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3] dioxol-6yl]methanol (55e, 1.8 g, 3.78 mmol, 52% yield).

1H NMR (400 MHz, DMSO-d6): δ 8.69 (d, J=3.2, 1H), 8.03 (d, J=3.6, 1H), 7.53 (d, J= 8, 1H), 7.39-7.29 (m, 2H), 6.79 (d, J=3.6, 1H), 6.32 (d, J=3.6, 1H), 5, 96 (d, J=4.4, 1H), 5.27-5.17 (m, 3H), 4.94-4.91 (m, 1H), 4.46-4.41 (m, 1H ), 4.26-4.19 (m, 1H), 1.51 (s, 3H), 1.30 (s, 3H).

LC-MS [M+H]: 466.1.

Step 5. Synthesis of (R)-[4-chloro-2-(hydroxymethyl)phenyl]-[(6R)-2,2-dimethyl-4-(4-methylpyrrolo[2,3d]pyrimidin-7-yl)- 3а,4,6,6а-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanol (55f).

To a solution of iron acetylacetonate (22.72 mg, 0.06 mmol) and (R)-[4-chloro-2-(hydroxymethyl)phenyl][(6R)-4-(4-chloropyrrolo[2,3-d] pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol6-yl]methanol (55e, 300 mg, 0.64 mmol) in THF (5 ml) was added methylmagnesium bromide (721.9 mg, 6.43 mmol)) at 0° C. under N2 atmosphere. The reaction mixture was warmed to room temperature and stirred for 1 h. TLC (ethyl acetate:petroleum ether=5:1, Rf=0.6) indicated that the reaction was complete. Saturated NH4C1 was added dropwise to quench the reaction. The reaction mixture was extracted with ethyl acetate (2x50 ml), dried over Na ₂ SO ₄ and concentrated in vacuo. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=10:1-5:1) to give (R)-[4-chloro-2-(hydroxymethyl)phenyl]-[(6R)-2.2 -dimethyl-4-(4-methylpyrrolo[2,3d]pyrimidin-7-yl)-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanol ( 55f, 105 mg, 0.23 mmol, 37% yield) as a colorless oil.

1H NMR (400 MHz, DMSO-d6): δ 8.74 (s, 1H), 7.82 (d, 7 = 3.6, 1H), 7.53 (d, J=8, 1H), 7 .39-7.35 (m, 2H), 6.81 (d, J=3.6, 1H), 6.27 (d, J=4, 1H), 6.00 (d, J=4, 4, 1H), 5.25-5.15 (m, 3H), 4.92-4.90 (m, 1H), 4.47-4.41 (m, 1H), 4.24-4, 19 (m, 2H), 2.68-2.62 (m, 3H), 1.51 (s, 3H), 1.30 (s, 3H).

LC-MS [M+H]: 446.1.

Stage 6. Synthesis of 4-methyl-7-[(3aR,4R,6R,6aR)-2,2-dimethyl-6-[(1R)-7-chloro-1,5-dihydro-2,4benzodioxepin-1- yl]-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]pyrrolo[2,3-d]pyrimidine (55g).

To a solution of (R)-[4-chloro-2-(hydroxemithyl)phenyl]-[(3aR,4R,6R,6aR)-2,2-dimethyl-4-(4methylpyrrolo[2,3-d]pyrimidine-7 -yl)-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanol (55f, 150 mg, 0.34 mmol) in DCM (1.2 ml ) and DMF (2.5 ml) sodium hydride (80.74 mg, 3.36 mmol) was added. The mixture was stirred at 80° C. for 2 hours. LC-MS indicated that the reaction was complete. The reaction mixture was quenched with NH ₄ Cl (50 ml). The solvent was removed in vacuo to give the crude product, which was purified by silica gel column chromatography (DCM:MeOH=50:1) to give 4-methyl-7-[(3aR,4R,6R,6aR)-2,2-dimethyl -6-[(1R)-7-chloro-1,5-dihydro-2,4-benzodioxepin-1-yl]-3a,4,6,6atetrahydrofuro[3,4-d][1,3]dioxol- 4-yl]pyrrolo[2,3-d]pyrimidine (55g, 160 mg, 0.33 mmol, 97% yield) as a yellow oil.

1H NMR (400 MHz, DMSO-d ₆ ): δ 8.73 (s, 1H), 7.71 (d, J=3.6, 1H), 7.38 (d, J=1.6, 1H ), 73.31-7.30 (m, 2H), 6.80 (d, J=3.6, 1H), 6.48 (d, J=4, 1H), 5.33-5.31 (m, 1H), 5.20-5.14 (m, 2H), 5.05-5.01 (m, 2H), 4.83-4.78 (m, 3H), 2.68-2 .62 (m, 3H), 1.60 (s, 3H), 1.34 (s, 3H).

LC-MS [M+H]: 458.1.

Step 7. Synthesis of (2R,3R,4S,5S)-2-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)-5-[(1R)-7-chloro-1,5dihydro-2 ,4-benzodioxepin-1-yl]tetrahydrofuran-3,4-diol (Ex. 55).

To a solution of 4-methyl-7-[(3aR,4R,6R,6aR)-2,2-dimethyl-6-[(1R)-7-chloro-1,5-dihydro-2,4benzodioxepin-1-yl] -3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]pyrrolo[2,3-d]pyrimidine (55g, 160mg, 0.35mmol) in water (1 ml) 2,2,2-trifluoroacetic acid (2.0 ml, 2 mmol) was added and the mixture was stirred at 25° C. for 30 minutes. NH3 water was added to pH 7 and the mixture was concentrated in vacuo. The residue was purified by preparative HPLC eluting MeCN in water (0.1% NH ₃ water) from 10% to 90% to give (2R,3R,4S,5S)-2-(4-methylpyrrolo[2,3-d] pyrimidin-7-yl)-5-[(1R)-7-chloro-1,5dihydro-2,4-benzodioxepin-1-yl]tetrahydrofuran-3,4-diol (Ex. 55, 31 mg, 0.073 mmol, 21% yield) as a white solid.

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LC-MS [M+H]: 418.1.

1H NMR (400 MHz, DMSO^): δ 8.68 (s, 1H), 7.64 (d, J=4, 1H), 7.41 (s, 1H), 7.32 (d, J= 1.2, 2H), 6.78 (d, J=3.6, 1H), 6.32 (d, J=8.0, 1H), 5.51 (d, J=4.4, 1h ), 5.41 (d, J=7.2, 1H), 5.34-5.31 (m, 1H), 5.09 (d, J=4.8, 1H), 5.04 (d , J=6.4, 1H), 4.99-4.95 (m, 1H), 4.85-4.81 (m, 1H), 4.62-4.56 (m, 2H), 4 .19-4.17 (m, 1H), 2.66 (s, 3H).

Example 69 Synthesis of (2S,3S,4R,5R)-2-((R)-6-chloroisochroman-1-yl)-5-(4-(methylamino)-7H-pyrrolo[2,3d]pyrimidin-7 -yl)tetrahydrofuran-3,4-diol (Ex. 69).

^{ζζτ 69a} Prov. 69

Stage 1. Synthesis of N-methyl-7-[(3aR,4R,6R,6aR)-2,2-dimethyl-6-[(1R)-6-chloroisochroman-1-yl]-3a,4,6,6atetrahydrofuro [3,4-d][1,3]dioxol-4-yl]pyrrolo[2,3-d]pyrimidin-4-amine (69a).

To a solution of 22f (100 mg, 0.22 mmol) in 1,4-dioxane (2 ml) was added methylamine in water (2.0 ml, 0.09 mmol). The mixture was stirred at 120° C. for 16 hours. The mixture was purified by preparative HPLC eluting with CH ₃ CN/H ₂ O (neutral) 5/95 to 95/5. Product fractions were lyophilized to give 69a (75 mg, 0.16 mmol, 75% yield) as a yellow solid.

LC-MS [M+H]: 457.1.

Stage 2. Synthesis of (2S,3S,4R,5R)-2-((R)-6-chloroisochroman-1-yl)-5-(4-(methylamino)-7Н-pyrrolo[2,3d]pyrimidin-7 -yl)tetrahydrofuran-3,4-diol (Ex. 69).

To a solution of 69a (75 mg, 0.16 mmol) in MeCN (1 ml) was added TFA/H2O (0.97 ml, 0.39 mmol). The mixture was stirred at 40°C for 2 h. The mixture was purified by preparative HPLC eluting CH ₃ CN/H ₂ O (0.1% NH4OH) from 5/95 to 95/5 and lyophilized to obtain pr. 69 (36 .5 mg, 0.087 mmol, 53% yield) as a white solid.

LC-MS [M+H]: 417.3.

1H NMR (400 MHz, DMSO-d6): δ 8.15 (s, 1H), 7.48-7.49 (m, 1H), 7.36-7.37 (m, 1H), 7.28 -7.30 (m, 2H), 7.21-7.23 (m, 1H), 6.63 (d, J=3.2 Hz, 1H), 6.18 (d, J=7.6 Hz, 1H), 5.16 (d, J=7.6 Hz, 1H), 5.04 (d, J=4.0 Hz, 1H), 4.86-4.87 (m, 1H), 4.42-4.48(m, 1H), 4.35-4.36(m, 1H), 4.20-4.24(m, 1H), 3.83-3.86(m, 1H ), 3.65-3.71 (m, 1H), 2.96 (d, J=7.6 Hz, 3H), 2.89-2.94 (m, 1H), 2.69-2, 74 (m, 1H).

Example 76 Synthesis (Ex. 76)

CI

1Ad

76d OTBS OH

76e 76G

Stage 1. Synthesis of ethyl 2-(2-bromophenyl)-2,2-difluoroacetate (76a).

To a solution of copper (898.6 mg, 14.14 mmol) in DMSO (10 mL) was added ethyl 2-bromo-2,2-difluoroacetate (5739.98 mg, 28.28 mmol) and the mixture was stirred at room temperature under atmospheric nitrogen. Through

- 84042008 h 1-bromo-2-iodobenzene (2000 mg, 7.07 mmol) was added to the mixture. After 16 h, aqueous NH ₄ Cl (50 ml) was added to the mixture and extracted with EA (50.0 mlx3). The organic phases were combined, washed with water (100 ml) and saturated aqueous sodium chloride solution (100 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by flash column chromatography (PE:EA=40:1) to give 76a (750 mg, 2.66 mmol, 38% yield).

1H NMR (400 MHz, CDCl ₃ ): δ 7.75-7.73 (m, 1H), 7.65-7.62 (m, 1H), 7.46-7.42 (m, 1H), 7.38-7.34 (m, 1H), 4.36 (q, J=7.2 Hz, 2H), 1.32 (t, J=7.2 Hz, 3H).

Stage 2. Synthesis of 2-(2-bromophenyl)-2,2-difluoroethanol (76b).

To a solution of 76a (5.8 g, 20.78 mmol) in methanol (50 ml) was added NaBH ₄ (1.57 g, 41.57 mmol) at 0°C and the reaction mixture was stirred at room temperature for 30 min. TLC (PE:EA=10:1, Rf=0.1) indicated that the reaction was complete. The reaction mixture was concentrated and HCl (1 M) was added. The mixture was extracted with EA (30.0 mlx3). The organic phases were combined, washed with water (50 ml) and saturated aqueous sodium chloride solution (50 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (PE:EA=10:1) to give 76b (5.1 g, 19.36 mmol, 93% yield) as an oil.

1H NMR (400 MHz, CDCl ₃ ): δ 7.67-7.633 (m, 2H), 7.40 (t, J=7.6 Hz, 1H), 7.33-7.26 (m, 1H) , 4.21 (t, J=13.8 Hz, 2H).

Step 3. Synthesis of [2-(2-bromophenyl)-2,2-difluoroethoxy]-tert-butyldimethylsilane (76c).

To a solution of 76b (5.1 g, 21.52 mmol) and imidazole (2.93 g, 43.03 mmol) in DCM (20 ml) was slowly added tert-butylchlorodiphenylsilane (4.86 g, 32.27 mmol), and the reaction mixture was stirred for 2 h at RT. TLC (PE, Rf=0.7) showed a new spot and also that the starting material had been consumed. The solvent was removed in vacuo and the crude product was purified by silica gel (PE) column chromatography to give 76c (6.2 g, 15.88 mmol, 74% yield) as an off-white oil.

1H NMR (400 MHz, CDCl3): δ 7.67-7.633 (m, 2H), 7.39 (t, J=7.6 Hz, 1H), 7.32-7.29 (m, 1H), 4.23 (t, J=13.0 Hz, 2H), 0.82 (s, 9H), 0.0 (s, 6H).

Step 4. Synthesis of [2-[2-[tert-butyl(dimethyl)silyl]oxy-1,1-difluoroethyl]phenyl]-[(3aR,4R,6S,6aS)-4(4-chloropyrrolo[2,3 -d]pyrimidin-7-yl)-2,2-dimethyl-3а,4,6,6а-tetrahydrofuro[3,4-d][1,3]dioxol-6yl]methanone (76d).

To a solution of 76b (1.03 g, 2.95 mmol) in dry THF (10 mL) was added n-BuLi (1.5 mL, 2.4 mmol) at -78° C. and the mixture was stirred for 10 min under atmosphere nitrogen. Added 1Ad (720 mg, 1.84 mmol) in dry THF (5 ml) and the mixture was stirred for 30 min at -78°C. TLC (PE:EA=10:1, starting material Rf=0.3, product Rf=0.4) indicated that the reaction was complete. The reaction mixture was poured into dilute HCl (0.05 M) keeping the pH<8 during the quench process. The mixture was extracted with EA (200 ml x 2), the combined organic layers were dried, concentrated and purified on a silica gel column (PE:EA=100 to 10:1) to give 76d (610 mg, 1.02 mmol, 55% yield) as yellow oil.

LC-MS [M+H]: 594.3.

Step 5 Synthesis of (R)-[2-[2-[tert-butyl(dimethyl)silyl]oxy-1,1-difluoroethyl]phenyl]-[(3aR,6R,6aR)2,2-dimethyl-4- [(7S)-4-chloropyrrolo[2,3-d]pyrimidin-7-yl]-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol6-yl]methanol (76e ).

To a solution of 76d (610 mg, 1.03 mmol) in toluene (20 ml) was added diisobutylaluminum hydride (2.05 ml, 3.08 mmol) at -78°C under nitrogen atmosphere and the reaction mixture was stirred for 30 min at - 78°C. The reaction mixture was diluted with saturated NH ₄ Cl (aq.) and the mixture was extracted with EA, and washed with saturated aqueous sodium chloride. The organic layer was dried over anhydrous Na ₂ SO ₄ and the solvent was removed in vacuo to give 76e (600 mg, 0.93622 mmol, 91% yield) as the crude product, used without further purification.

Stage 6. Synthesis of 2,2-difluoro-2-[2-[(R)-hydroxy-[(3aR,4R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin7-yl)-2 ,2-dimethyl-3а,4,6,6а-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methyl]phenyl]tanol (76f).

To a solution of 76e (270 mg, 0.45 mmol) in THF (0.03 ml) was added TBAF (0.24 ml, 0.91 mmol) and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with saturated NH4Cl solution (100 ml), the mixture was extracted with EA (50 mlx3) and the combined organic layers were washed with saturated NaCl (100 ml). The organic layers were dried over anhydrous Na ₂ SO ₄ and the solvent was removed in vacuo. Residue by silica gel column chromatography (PE:EA=50:1-10:1) to give 76f (120 mg, 0.2291 mmol, 51% yield) as a solid.

LC-MS [M+H]: 482.3.

Stage 7. Synthesis of 4-chloro-7-[(3aR,4R,6aR)-2,2-dimethyl-6-[(1R)-4,4-difluoroisochroman-1-yl]-3a,4,6,6atetrahydrofuro [3,4-d][l,3]dioxol-4-yl]pyrrolo[2,3-d]pyrimidine (76g).

To a solution of 76f (100 mg, 0.21 mmol) in THF (4 mL) was added NaH (33.2 mg, 0.83 mmol) and stirred for 10 min. TSCl (39.56 mg, 0.21 mmol) was added and the reaction mixture was stirred for 1 h. The reaction mixture was poured into a saturated solution of NH4Cl, extracted with EA, the organic layers were washed with saturated NaCl. The organic phase was dried over anhydrous Na2SO4 and the solvent was concentrated under reduced pressure to give a crude product which was purified with

- 85 042008 by prep-TLC (PE:EA=5:1, Rf=0.3) to give 76g (50 mg, 0.10 mmol, 48% yield) as a white solid.

LC-MS [M+H]: 464.2.

Step 8. Synthesis of 4-methyl-7-[(3aR,4R,6R,6aR)-2,2-dimethyl-6-[(1R)-4,4-difluoroisochroman-1-yl]3а,4,6, 6а-Tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]pyrrolo[2,3-d]pyrimidine (76h).

To a solution of 76g (50 mg, 0.11 mmol) and ferrous acetylacetonate (3.81 mg, 0.01 mmol) in THF (6 mL) was added methylmagnesium bromide, 3.2 M in MeTHF (0.36 mL, 1.08 mmol ) at 0°C in a nitrogen atmosphere. The reaction mixture was stirred at rt. for 1 h. The mixture was poured into aqueous NH4C1 (30 ml) and extracted with EA (30.0 mlx3). The organic phases were combined, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by flash column chromatography (PE:EA=8:1-PE:EA=3:1) to give 76h (45 mg, 0.10148 mmol, 94% yield).

LC-MS [M+H]: 444.3.

Step 9. Synthesis of (2R,3R,4S,5S)-2-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)-5-[(1R)-4,4difluoroisochroman-1-yl]tetrahydrofuran -3,4-diol (Ex. 76).

To a solution of 76h (45 mg, 0.10 mmol) in water (1 ml) was added TFA (0.5 ml, 6.49 mmol) and the mixture was stirred at room temperature for 30 minutes. The residue was purified by prep-HPLC eluting with CH3CN in H2O (0.1% NH4OH) from 5.0 to 95.0% to give pr. 76 (8.58 mg, 0.021 mmol, 20.5% yield) as white solid.

LC-MS [M+H]: 404.3. 1H NMR (400 MHz, DMSOO): δ 8.68 (s, 1H), 7.75-7.72 (m, 2H), 7.57-7.48 (m, 3H), 6.81 (d , J=3.6 Hz, 1H), 6.34 (d, J=8 Hz, 1H), 5.35 (d, J=6.8 Hz, 1H), 5.20 (d, J=4 Hz, 1H), 5.09 (m, 1H), 4.61 (d, J=3.2 Hz, 1H), 4.56-4.46 (m, 2H), 4.16 -4.07 (m, 1H), 3.82 (t, J=4.4 Hz, 1H), 2.68 (s, 3H).

1H NMR (400 MHz, DMSO-dj+D2O) δ 8.66 (s, 1H), 7.74-7.71 (m, 2H), 7.55-7.46 (m, 3H), 6, 81 (d, J=3.6 Hz, 1H), 6.32 (d, J=8 Hz, 1H), 5.08 (m, 1H), 4.60 (d, J=3.2 Hz, 1H), 4.55 -4.46 (m, 2H), 4.14 -4.04 (m, 1H), 3.80 (d, J=5.2 Hz, 1H), 2.66 (s , 3H).

Example 81 Synthesis of (2R,3R,4S,5S)-2-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-5-[(1R)-7-chloro-1,5dihydro-2 ,4-benzodioxepin-1-yl]tetrahydrofuran-3,4-diol (Ex. 81).

Etc. S1

Step 1. Synthesis of (R)-[4-chloro-2-(hydroxymethyl)phenyl]-[(3aR,4R,6R,6aR)-4-[4-[bis[(4methoxyphenyl)methyl]amino]pyrrolo[2 ,3-d]pyrimidin-7-yl]-2,2-dimethyl-3а,4,6,6а-tetrahydrofuro[3,4d][1,3]dioxol-6-yl]methanol (81a).

K2CO3 mixture (292.98 mg, 2.12 mmol), (R)-[4-chloro-2-(hydroxymethyl)phenyl]-[(3aR,4R,6R,6aR)-4-(4chloropyrrolo[2,3 -d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6yl]methanol (55e, 300 mg, 0. 64 mmol) and bis-(4-methoxybenzyl)amine (331 mg, 1.29 mmol) in tert-butanol (5 ml) was stirred at 95°C for 2 h under N2 atmosphere. LC-MS showed that the reaction was complete. The reaction mixture was concentrated in vacuo to dryness and the residue was extracted with EtOAc (2x50 ml) and the organic layers were washed with water (2x10 ml) then saturated aqueous sodium chloride (2x10 ml). The organic layers were dried over MgSO ₄ , filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:1) to give (R)-[4-chloro-2-(hydroxymethyl)phenyl]-[(3aR,4R,6R,6aR)-4 -[4[bis[(4-methoxyphenyl)methyl]amino]pyrrolo[2,3-d]pyrimidin-7-yl]-2,2-dimethyl-3а,4,6,6atetrahydrofuro[3,4-d] [1,3]dioxol-6-yl]methanol (81a, 80 mg, 0.10 mmol, 16% yield) as a white solid.

LC-MS [M+H]: 687.2.

Stage 2. Synthesis of N,N-bis[(4-methoxyphenyl)methyl]-7-[(3aR,4R,6R,6aR)-2,2-dimethyl-6-[(1R)-7-chloro1,5- dihydro-2,4-benzodioxepin-1-yl]-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]pyrrolo[2,3d]pyrimidine-4- amine (81b).

To a solution of (R)-[4-chloro-2-(hydroxymethyl)phenyl]-[(3aR,4R,6R,6aR)-4-[4-[bis[(4

- 86 042008 methoxyphenyl)methyl]amino]pyrrolo[2,3-d]pyrimidin-7-yl]-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4d][1,3]dioxol -6-yl]methanol (81a, 80 mg, 0.12 mmol) in DCM (1.2 ml) and DMF (2.5 ml) sodium hydride (28 mg, 1.16 mmol) was added. The mixture was stirred at 80° C. for 2 hours. The reaction mixture was quenched with NH ₄ Cl (50 ml). The solvent was removed in vacuo to give N,N-bis[(4-methoxyphenyl)methyl]-7[(3aR,4R,6R,6aR)-2,2-dimethyl-6-[(1R)-7-chloro-1 ,5-dihydro-2,4-benzodioxepin-1-yl]-3а,4,6,6atetrahydrofuro[3,4-d][1,3]dioxol-4-yl]pyrrolo[2,3-d]pyrimidine -4-amine (81b, 90 mg, 0.10 mmol, 87% yield) as a yellow oil.

LC-MS [M+H]: 699.3.

Stage 3. Synthesis of (2R,3R,4S,5S)-2-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-5-[(1R)-7-chloro-1,5dihydro-2 ,4-benzodioxepin-1-yl]tetrahydrofuran-3,4-diol (Ex. 81).

To a solution of N,N-bis[(4-methoxyphenyl)methyl]-7-[(3aR,4R,6R,6aR)-2,2-dimethyl-6-[(1R)-7-chloro-1,5dihydro- 2,4-benzodioxepin-1-yl]-3а,4,6,6а-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]pyrrolo[2,3d]pyrimidin-4-amine ( 81b, 90 mg, 0.13 mmol) in water (1 ml) was added 2,2,2-trifluoroacetic acid (0.74 ml, 0.74 mmol). The reaction mixture was stirred at 25°C for 30 min. Added

NH3 water to pH 7 and the mixture was concentrated in vacuo. The residue was purified by preparative HPLC eluting MeCN in water (0.1% NH3·water) from 10% to 90% to give the crude product. The crude product was further purified by preparative HPLC eluting MeCN in water (0.1% TFA) from 10% to 90% to give (2R,3R,4S,5S)-2-(4-aminopyrrolo[2,3-d] pyrimidin-7-yl)-5[(1R)-7-chloro-1,5-dihydro-2,4-benzodioxepin-1-yl]tetrahydrofuran-3,4-diol (Ex. 81, 2.7 mg, 0.0063 mmol, 5% yield) as a white solid.

LC-MS [M+H]: 419.1.

¹ H NMR (400 MHz, DMSO-d ₆ +D ₂ O): δ 8.33 (s, 1H), 7.51 (d, J=3.6, 1H), 7.45 (s, 1H) , 7.42 (d, J=1.6, 2H), 6.94 (d, J=3.2, 1H), 6.32 (d, J=8.0, 1H), 5.33 ( d, J=6, 1H), 5.07-5.03 (m, 2H), 4.97 (d, J=1.2.1H), 4.83 (d, J=14.4, 1H ), 4.61 (d, J=4.8, 1H), 4.54-4.51 (m, 1H), 4.17 (d, J=4.8, 1H).

Example 82 Synthesis of 2,2,2-trifluoroacetate (1R)-6-chloro-1-[(2S,3S,4R,5R)-5-(4-aminopyrrolo[2,3d]pyrimidin-7-yl)- 3,4-dihydroxytetrahydrofuran-2-yl]isochroman-3-one (Ex. 82).

Stage 1. Synthesis of 7-[(3aR,4R,6R,6aR)-2,2-dimethyl-6-[(1R)-6-chloro-3-methoxy-isochroman-1-yl]3а,4,6, 6a-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]pyrrolo[2,3-d]pyrimidin-4-amine (82a).

To a mixture of 4-chloro-7-[(3aR,4R,6R,6aR)-2,2-dimethyl-6-[(1R)-6-chloro-3-methoxyisochroman-1-yl]-3а,4,6 ,6atetrahydrofuro[3,4-d][1,3]dioxol-4-yl]pyrrolo[2,3-d]pyrimidine (46f, 700 mg, 1.42 mmol) in 1,4-dioxane (8 mL) ammonium hydroxide (0.03 ml, 14.22 mmol) was added. The mixture was stirred at 120° C. overnight. TLC (petroleum ether:ethyl acetate=5:1, Rf=0.5) and LC-MS showed that the reaction was complete. The reaction mixture was poured into water (30 ml) and extracted with DCM (50 mlx3). The organic layers were washed with saturated NaCl (100 ml), dried over Na ₂ SO ₄ , filtered, concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography eluting with petroleum ether:ethyl acetate=7:1 to give 7- [(3aR,4R,6R,6aR)2,2-dimethyl-6-[(1 R)-6-chloro-3-methoxyisochroman-1-yl]-3 a,4,6,6a-tetrahydrofuro[3, 4-d] [ 1,3]dioxol-4yl]pyrrolo[2,3-d]pyrimidine-4-amine (82a, 460 mg, 0.97 mmol, 68% yield) as a yellow solid.

LC-MS [M+H]: 458.1.

Stage 2. Synthesis of (2R,3R,4S,5S)-2-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-5-[(1R)-6-chloro-3hydroxyisochroman-1-yl ]tetrahydrofuran-3,4-diol (82b).

To a mixture of 7-[(3aR,4R,6R,6aR)-2,2-dimethyl-6-[(1R)-6-chloro-3-methoxyisochroman-1-yl]-3a,4,6,6atetrahydrofuro [3,4-d][1,3]dioxol-4-yl]pyrrolo[2,3-d]pyrimidin-4-amine (82a, 460 mg, 0.97 mmol) in water (5 ml) was added trifluoroacetic acid (177 mg, 1.56 mmol). The reaction mixture was stirred at 25°C for 1 h. TLC (petroleum ether:ethyl acetate=3:1, Rf=0.3) and LC-MS showed that the reaction was complete. The reaction mixture was neutralized with NaHCO ₃ and purified by silica gel column chromatography eluting with petroleum ether:ethyl acetate=7:1 to give crude pro

- 87 042008 product, which was further purified by preparative HPLC eluting CH3CN in water (0.1% NH ₃ /water) from 10 to 95%) to give (2R,3R,4S,5S)-2-(4- aminopyrrolo[2,3-d]pyrimidin-7-yl)-5[(1R)-6-chloro-3-hydroxyisochroman-1-yl]tetrahydrofuran-3,4-diol (82b, 50 mg, 0.11 mmol , 12% yield) as an off-white solid.

LC-MS [M+H]: 419.1.

Stage 3. Synthesis of (1R)-6-chloro-1-[(3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-2,2dimethyl-3а ,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]isochroman-3-ol (82c).

To a mixture of (2R,3R,4S,5S)-2-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-5-[(1R)-6-chloro-3-hydroxyisochroman-1-yl ]tetrahydrofuran-3,4-diol (82b, 230.5 mg, 0.55 mmol) in acetone (10 ml) was added TsOH (38 mg, 0.22 mmol) at 0°C. The reaction mixture was stirred at 25°C for 3 hours. TLC (petroleum ether:ethyl acetate=5:1, Rf=0.3) and LC-MS showed that the reaction was complete. The reaction mixture was poured into water (10 ml) and extracted with DCM (10 mlx3). The organic layers were washed with saturated NaCl (100 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography eluting with petroleum ether:ethyl acetate=7:1) to give (1R)-6-chloro-1-[(3aR,4R,6R,6aR)-4-(4-aminopyrrolo[ 2,3-d]pyrimidin-7yl)-2,2-dimethyl-3а,4,6,6а-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]isochroman-3-ol ( 82c, 180 mg, 0.32 mmol, 58% yield) as a white solid.

LC-MS [M+H]: 458.1.

Stage 4. Synthesis of 6-chloro-1-[(3aR,4R,6R,6aR)-4-(4-aminopyrrolo-[2,3-d]pyrimidin-7-yl)-2,2dimethyl-3а,4, 6,6а-Tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]isochroman-3-one (82d).

To a mixture of 6-chloro-1-[(3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl3a,4,6,6a -tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]isochroman-3-ol (82c, 44 mg, 0.10 mmol) in DCM (10 ml) PCC (0.05 ml, 0.29 mmol) at 0°C. The mixture was stirred at 0°C for 30 min, then heated to 25°C to complete the reaction. The reaction mixture was poured into water (10 ml) and extracted with DCM (2x10 ml). The organic layers were concentrated in vacuo to give 6-chloro-1[(3aR,4R,6R,6aR)-4-(4-aminopyrrolo-[2,3-d]pyrimidin-7-yl)-2,2-dimethyl- 3a,4,6,6a-tetrahydrofuro[3,4d][1,3]dioxol-6-yl]isochroman-3-one (82d, 35 mg, 0.076 mmol, 79.5% yield) as white solid . The crude product was used in the next step without further purification.

LC-MS [M+H]: 457.1.

Stage 5. Synthesis of 2,2,2-trifluoroacetate (1R)-6-chloro-1-[(2S,3S,4R,5R)-5-(4-aminopyrrolo[2,3d]pyrimidin-7-yl)- 3,4-dihydroxytetrahydrofuran-2-yl]isochroman-3-one (Ex. 82).

To a mixture of (1R)-6-chloro-1-[(3aR,4R,6R,6aR)-4-(4-aminopyrrolo-[2,3-d]pyrimidin-7-yl)-2,2-dimethyl3a, 4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]isochroman-3-one (82d, 35 mg, 0.08 mmol) in water (2 ml) trifluoroacetic acid was added (14 mg, 0.12 mmol) and the mixture was stirred at 25°C for 1 h. TLC (petroleum ether:ethyl acetate=3:1, Rf=0.3) and LC-MS showed that the reaction was complete. The reaction mixture was neutralized with NaHCO ₃ and extracted with DCM (3x3 ml), the organic layers were washed with saturated NaCl (20 ml), dried over Na 2 SO 4 , filtered, concentrated in vacuo. The crude product was purified by silica gel column chromatography eluting with petroleum ether:ethyl acetate=7:1 and further purified by preparative HPLC eluting CH3CN in water (0.1% TFA) from 10% to 95% to give (1R)-6 -chloro-1-[(2S,3S,4R,5R)-5-(4-aminopyrrolo[2,3d]pyrimidin-7-yl)-3,4-dihydroxy-tetrahydrofuran-2-yl]isochroman-3- she; 2,2,2-trifluoroacetic acid (sp. 82, 3 mg, 0.0052 mmol, 7% yield) as a white solid.

LC-MS [M+H]: 417.1.

1H NMR (400 MHz, DMSO-d6): δ 8.50-8.64 (m, 2H), 8.30 (s, 1H), 7.30-7.44 (m, 4H), 6.91 (s, 1H), 6.10 (s, 1H), 5.83 (s, 1H), 5.55-5.67 (m, 2H), 4.37-4.41 (m, 3H), 3.74 (m, 2H).

1H NMR (400 MHz, DMSO-d6+D ₂ O): δ 8.30 (s, 1H), 7.31-7.42 (m, 4H), 6.93 (s, 1H), 6.10 (d, J=4 Hz, 1H), 5.83 (s, 1H), 4.38-4.43 (m, 3H), 3.74 (m, 2H).

- 88 042008

Example 83 Synthesis of (2R,3R,4S,5S)-2-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)-5-[(1R)-6-chloro-5fluoroisochroman-1-yl ]tetrahydrofuran-3,4-diol (Ex. 83).

Stage 1. Synthesis of 6-bromo-3-chloro-2-fluorobenzaldehyde (83b).

To a solution of 4-bromo-1-chloro-2-fluorobenzene (83a, 10 g, 47.75 mmol) in THF (60 ml) was added LDA (30 ml, 57.3 mmol) at -78°C. The reaction mixture was stirred at -78°C for 1 h, then DPMA (7.4 ml, 95.5 mmol) was added to the mixture, the reaction mixture was stirred at -78°C for 1 h. The reaction mixture was quenched with NH ₄ Cl (aq. ., 100 ml) and water (100 ml). The aqueous layer was extracted with ethyl acetate (3x300 ml). The organic layers were concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography eluting with petroleum ether:ethyl acetate=10:1 to give 6-bromo-3-chloro-2-fluorobenzaldehyde (83b, 6.1 g , 25.69 mmol, 54% yield) as a yellow oil.

¹ H NMR (400 MHz, CDCl3): δ 10.39 (s, 1H), 7.86 (s, 1H), 7.56 (dd, J=8Hz, 1H).

Stage 2. Synthesis of 1-bromo-4-chloro-3-fluoro-2-[(E)-2-methoxyvinyl]benzene (83c).

To a solution of (methoxymethyl)triphenylphosphonium chloride (83b, 18.2 g, 53.06 mmol) in THF (60 ml) was added potassium tert-butoxide 1.0 M in THF (5.67 g, 50.54 mmol) at -10 °C. The reaction mixture was stirred at -10°C for 10 min. The reaction mixture was diluted with water (150 ml) and extracted with ethyl acetate (150 ml). The organic layer was concentrated in vacuo and the residue was purified by silica gel column chromatography eluting with petroleum ether:ethyl acetate=10:1 to give 1-bromo-4-chloro-3-fluoro-2-[(E)-2-methoxyvinyl]benzene (83c, 4.50 g, 16.1 mmol, 64% yield) as a white solid.

1H NMR (400 MHz, DMSO-de): δ 7.64 (s, 1H), 7.51 (dd, J=10.8 Hz, 1H), 7.24 (dd, J=13.2 Hz, 1H), 5.73 (d, J=13.2 Hz, 1H), 3.71 (s, 3H).

Stage 3. Synthesis of 2-(6-bromo-3-chloro-2-fluorophenyl)acetaldehyde (83d).

HCl (1, 86 g, 50.85 mmol) and the mixture was stirred at 60° C. overnight. TLC (petroleum ether) indicated that the reaction was complete. The reaction mixture was concentrated in vacuo and extracted with ethyl acetate (50 ml). The organic layer was concentrated in vacuo to give 2-(6-bromo-3-chloro-2-fluorophenyl)acetaldehyde (83d, 4.0 g, 14.32 mmol, 84.5% yield) as a yellow solid.

1H NMR (400 MHz, DMSO-d ₆ ): δ 9.72 (s, 1H), 7.71 (s, 1H), 7.58 (d, J=11.2 Hz, 1H), 4.02 (d, J=8.4 Hz, 2H).

Stage 4. Synthesis of 2-(6-bromo-3-chloro-2-fluorophenyl)ethanol (83f).

To a solution of 2-(6-bromo-3-chloro-2-fluorophenyl)acetaldehyde (83d, 3.3 g, 13.12 mmol) in methanol (30 ml) was added sodium borohydride (1.5 g, 39.37 mmol ) at 0°С. The reaction mixture was stirred at rt. within 1 h. TLC (petroleum ether) showed that the reaction was complete. The mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (50 ml), washed with saturated aqueous sodium chloride (50 ml) and the organic layer was concentrated in vacuo to give 2-(6-bromo-3-chloro2-fluorophenyl)ethanol (83e, 3, 20 g, 11.99 mmol, 91% yield) as a yellow oil.

1H NMR (400 MHz, DMSO-d ₆ ): δ 7.62 (s, 1H), 7.48 (dd, J=9.2 Hz, 1H), 4.85 (t, J=5.6 Hz , 1H), 7.52 (dd, J=12.8 Hz, 2H), 2.88 (dd, J=7.2 Hz, 2H).

Step 5. Synthesis of tert-butyl-[2-(3-chloro-2,6-difluorophenyl)ethoxy]dimethylsilane (83f).

To a solution of 2-(3-chloro-2,6-difluorophenyl)ethanol (83e, 3.20 g, 16.62 mmol) in DCM (30 ml) was added tert-butyldimethylchlorosilane (3.01 g, 19.94 mmol) and imidazole (2.26 g, 33.23 mmol). The reaction mixture was stirred at 25° C. for 2 hours. The reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (3x50 ml) and washed with saturated aqueous sodium chloride solution (3x50 ml). The organic layers were concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography to give t-butyl-[2-(3-chloro-2,6

- 89 042008 difluorophenyl)ethoxy]-dimethylsilane (83f, 3.9 g, 12.07 mmol, 73% yield) as a colorless oil.

LC-MS [M+H]: 306.8.

Step 6. Synthesis of [2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-4-chloro-3-fluorophenyl]-[(3aR,4R,6S,6aS)4-(4-chloropyrrolo[2, 3-d]pyrimidin-7-yl)-2,2-dimethyl-3а,4,6,6а-tetrahydrofuro[3,4-d][1,3]dioxol-6yl]methanone (83g).

n-BuLi (535.5 mg, 8.36 mmol) in THF (20 ml) .36 mmol) at -78°C. The mixture was stirred for 10 min under N2. (3aR,4R,6S,6aS)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-N-methoxy-N,2,2trimethyl-3a,4,6,6a-tetrahydrofuro was added [3,4-d][1,3]dioxol-6-carboxamide (1Ad, 1.6 g, 4.18 mmol) in THF (10 mL). The mixture was stirred for 30 min at -78°C. TLC (petroleum ether:ethyl acetate=10:1) indicated that the reaction was complete. HCl (0.05 mol/l) was added to the reaction mixture keeping the pH<8 during the quenching process. The mixture was extracted with ethyl acetate (2x200 ml), the combined organic layers were dried, concentrated in vacuo and purified by silica gel column chromatography (petroleum ether:ethyl acetate=100% to 10:1) to give [2-[2-[t-butyl(dimethyl) silyl]oxyethyl]-4-chloro-3-fluoro-phenyl]-[(3aR,4R,6S,6aS)-4-(4-chloropyrrolo[2,3-d]pyrimidin7-yl)-2,2-dimethyl -3a,4,6,6a-Tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanone (83g, 1.2g, 1.87mmol, 45% yield) as yellow oil .

LC-MS [M+H]: 610.1.

Step 7 Synthesis of (R)-[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-4-chloro-3-fluorophenyl][(3aR,6R,6aR)-2,2-dimethyl -4-[(7S)-4-chloropyrrolo[2,3-d]pyrimidin-7-yl]-3a,4,6,6a-tetrahydrofuro[3,4d][1,3]dioxol-6-yl] methanol (83h).

To a solution of [2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-4-chloro-3-fluorophenyl]-[(3aR,6S,6aS)-2,2dimethyl-4-[(7S) -4-chloropyrrolo[2,3-d]pyrimidin-7-yl]-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6yl]methanone (83g, 1.1 g, 1.8 mmol) in toluene (15 ml) was added diisobutylaluminum hydride (3.6 ml, 5.4 mmol) at -78° C. under N2 atmosphere. The reaction mixture was stirred at -78°C for 30 min. Water (50 ml) was added and the mixture was extracted with ethyl acetate (100 ml) and washed with saturated NaCl (2x50 ml). The organic layers were dried over anhydrous Na ₂ SO ₄ and the solvent was removed in vacuo to give (R)-[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-4-chloro-3-fluorophenyl]-[(3aR ,6R,6aR)-2,2-dimethyl-4[(7S)-4-chloropyrrolo[2,3-d]pyrimidin-7-yl]-3a,4,6,6a-tetrahydrofuro[3,4-d ][1,3]dioxol-6-yl]methanol (83h, 1.0 g, 1.55 mmol, 86% yield), which was used directly in the next step.

LC-MS [M+H]: 612.2.

Step 8. Synthesis of 2-[3-chloro-2-fluoro-6-[(R)-hydroxy-[(3aR,4R,6R,6aR)-4-(4-chloropyrrolo[2,3d]pyrimidine-7- yl)-2,2-dimethyl-3а,4,6,6а-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methyl]phenyl]ethanol (83i).

To a solution of (R)-[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-4-chloro-3-fluorophenyl]-[(3aR,4R,6R,6aR)-4-(4chloropyrrolo [2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3а,4,6,6а-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanol (83h , 1.0 g, 1.63 mmol) in THF (3 ml) was added TBAF (0.85 ml, 3.26 mmol). The reaction mixture was stirred at room temperature for 1 hour. TLC (petroleum ether:ethyl acetate=10:1) indicated that the reaction was complete. The mixture was concentrated in vacuo and purified by silica gel column chromatography (petroleum ether:ethyl acetate=50:1-10:1) to give 2-[3-chloro-2-fluoro-6-[(R)-hydroxy[(3aR ,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4d][1 ,3]dioxol-6-yl]methyl]phenyl]ethanol (83i, 670 mg, 1.30 mmol, 80% yield) as a white solid.

LC-MS [M+H]: 498.1.

Stage 9. Synthesis of 4-chloro-7-[(3aR,4R,6R,6aR)-2,2-dimethyl-6-[(1R)-6-chloro-5-fluoro-isochroman-1-yl]3а, 4,6,6a-Tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]pyrrolo[2,3-d]pyrimidine (83j).

To a solution of 2-[3-chloro-2-fluoro-6-[(R)-hydroxy-[(3aR,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin7-yl) -2,2-dimethyl-3а,4,6,6а-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methyl]phenyl]ethanol (83i, 500 mg, 1 mmol) in THF (5 ml) was added PPh ₃ (526 mg, 2.01 mmol), DIAD (0.56 ml, 2.01 mmol) under Ar atmosphere. The reaction mixture was stirred at 25° C. for 1 hour. The mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography to give 4-chloro-7-[(3aR,4R,6R,6aR)2,2-dimethyl-6 -[(1R)-6-chloro-5-fluoroisochroman-1-yl]-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-4yl]pyrrolo[2,3- d]pyrimidine (83j, 390 mg, 0.77 mmol, 77% yield).

LC-MS [M+H]: 480.1.

Step 10. Synthesis of 4-methyl-7-[(3aR,4R,6R,6aR)-2,2-dimethyl-6-[(1R)-6-chloro-5-fluoroisochroman-1-yl]3а,4, 6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]pyrrolo[2,3-d]pyrimidine (83k).

To a solution of 4-chloro-7-[(3aR,4R,6R,6aR)-2,2-dimethyl-6-[(1R)-6-chloro-5-fluoroisochroman-1-yl]-3а,4,6 ,6atetrahydrofuro[3,4-d][1,3]dioxol-4-yl]pyrrolo[2,3-d]pyrimidine (83j, 100 mg, 0.21 mmol) in THF (2 ml) acetylacetonate was added dropwise iron (7.35 mg, 0.02 mmol) and methylmagnesium bromide (0.21 ml, 0.63 mmol) under N2. The reaction mixture was stirred at room temperature for 30 minutes. The mixture was extracted with ethyl acetate (3x10 ml) and washed with water (2x10 ml). The organic layer was concentrated in vacuo to give 4-methyl-7-[(3aR,4R,6R,6aR)-2,2-dimethyl-6-[(1R)-6-chloro-5

- 90 042008 fluoroisochroman-1-yl]-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]pyrrolo[2,3-d]pyrimidine (83k, 90 mg, 0.19 mmol, 89% yield) as a yellow oil.

LC-MS [M+H]: 460.2.

Step 11. Synthesis of (2R,3R,4S,5S)-2-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)-5-[(1R)-6-chloro-5-fluoroisochroman-1 -yl]tetrahydrofuran-3,4-diol (Ex. 83).

To a solution of 4-methyl-7-[(3aR,4R,6R,6aR)-2,2-dimethyl-6-[(1R)-6-chloro-5-fluoro-isochroman-1-yl]3а,4, 6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]pyrrolo[2,3-d]pyrimidine (83k, 100 mg, 0.22 mmol) in water (2 ml) was added TFA (1.1 ml, 12.34 mmol). The mixture was stirred at room temperature for 30 minutes. Residue The mixture was purified by prep-HPLC eluting CH3CN in water (0.1% NH ₄ OH) from 5% to 95% to give (2R,3R,4S,5S)-2-(4-methylpyrrolo[2,3- d]pyrimidin-7-yl)-5-[(1R)-6-chloro-5fluoro-isochroman-1-yl]tetrahydrofuran-3,4-diol (ex. 83, 18 mg, 0.042 mmol, 19% yield) as a white solid.

1H NMR (400 MHz, DMSO-de): δ 8.67 (s, 1H), 7.78 (d, J=4 Hz, 1H), 7.32-7.28 (m, 2H), 6, 82 (d, J=4 Hz, 1H), 6.31 (d, J=7.6 Hz, 1H), 5.31 (d, J=6.8 Hz, 1H), 5.20 (d, J=4Hz, 1H), 4.91(d, J=7.2Hz, 1H), 4.52-4.46(m, 2H), 4.32(s, 1H), 3.88( t, J=4 Hz, 1H), 3.69 (s, 1H), 2.73 (s, 2H), 2.67 (d, J=8 Hz, 3H).

1H NMR (400 MHz, DMSO-d6+D2O): δ 8.67 (s, 1H), 7.78 (d, J=4 Hz, 1H), 7.32-7.28 (m, 2H), 6.82 (d, J=4 Hz, 1H), 6.31 (d, J=7.6 Hz, 1H), 4.91 (d, J=7.2 Hz, 1H), 4.52- 4.46 (m, 2H), 4.32 (s, 1H), 3.88 (t, J=4 Hz, 1H), 3.69 (s, 1H), 2.73 (s, 2H), 2.67 (d, J=8 Hz, 3H).

Example 86 Synthesis of (2R,3R,4S,5S)-2-(4-amino-5-fluoro-pyrrolo[2,3-d]pyrimidin-7-yl)-5-[(1R)-6chloroisochroman-1 -yl]tetrahydrofuran-3,4-diol (Ex. 86).

Step 1. Synthesis of (R)-[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-4-chlorophenyl]-[(3aR,4R,6R,6aR)-4methoxy-2,2-dimethyl- 3а,4,6,6-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanol (86b).

To a solution of 2-(2-bromo-5-chlorophenyl)ethoxy-tert-butyldimethylsilane (22b, 23.6 g, 68 mmol) in dry THF (50 ml) was added n-BuLi (34 ml, 54.4 mmol) at -78°C. The reaction mixture was stirred at 78°C for 10 min under N2 atmosphere. (3aR,4R,6S,6aR)-4-methoxy-2,2-dimethyl3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-carbαaldehyde (86a, 5.5 g, 27.2 mmol) in dry THF (10 ml). The mixture was stirred for 5 min at -78°C. The reaction mixture was added to dilute HCl (300 mL, 0.6 M) maintaining pH 6. The mixture was concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography eluting with petroleum ether:ethyl acetate=5:1 to give (R)-[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-4-chlorophenyl][(3aR,4R,6R,6aR)-4-methoxy-2,2-dimethyl-3а,4 ,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanol (86b, 5.8 g, 11.6 mmol, 43% yield) as a yellow oil.

¹ H NMR (400 MHz, CDCl3): δ 7.54 (d, J=8.4 Hz, 1H), 7.22-7.29 (m, 2H), 5.36 (s, 2H), 4 .95 (d, J=6.0 Hz, 1H), 4.68 (d, J=5.6 Hz, 1H), 4.50 (s, 1H), 4.31 (s, 1H), 3 .83-3.90(m, 2H), 3.43(s, 3H), 2.78-2.99(m, 2H), 1.47(s, 3H), 1.30(s, 3H ), 0.87 (s, 9H), 0.02 (s, 6H).

Stage 2. Synthesis of 2-[5-chloro-2-[(R)-hydroxy-[(3aR,4R,6R,6aR)-4-methoxy-2,2-dimethyl-3a,4,6,6atetrahydrofuro[3 ,4-d][1,3]dioxol-6-yl]methyl]phenyl]ethanol (86c).

To a solution of (R)-[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-4-chlorophenyl]-[(3aR,4R,6R,6aR)-4-methoxy2,2-dimethyl-3а, 4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanol (86b, 4.8 g, 10.1 mmol) in THF (10 ml) was added tetrabutylammonium fluoride (10 .1 ml, 10.1 mmol) at r.t. The mixture was stirred at room temperature for 1 h. The mixture was poured into 50 ml of NH ₄ Cl (aq) and extracted with ethyl acetate (2x50 ml). The organic layers were concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography eluting with petroleum ether to petroleum ether:ethyl acetate=5:1) to give 2-[5-chloro-2-[(R)- hydroxy-[(3aR,4R,6R,6aR)-4methoxy-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methyl] phenyl]ethanol (86c, 3.8 g, 9.5 mmol, 94% yield) as a colorless oil.

1H NMR (400 MHz, CDCl3): δ 7.54 (d, J=8.4 Hz, 1H), 7.22-7.29 (m, 2H), 5.01 (s, 2H), 4, 95 (d, J=6.0 Hz, 1H), 4.65 (d, J=6.0 Hz, 1H), 4.55 (s, 1H), 4.33 (br, 1H), 3, 85-3.96(m, 2H), 3.41(s, 3H), 2.78-3.06(m, 2H), 1.47

- 91 042008 (s, 3H), 1.30 (s, 3H).

Stage 3. Synthesis of (1R)-6-chloro-1-[(3aR,4R,6R,6aR)-4-methoxy-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4d][ 1,3]dioxol-6-yl]isochroman (86d).

To a solution of 2-[5-chloro-2-[(R)-hydroxy-[(3aR,4R,6R,6aR)-4-methoxy-2,2-dimethyl-3а,4,6,6tetrahydrofuro[3,4 -d][1,3]dioxol-6-yl]methyl]phenyl]ethanol (86s, 2.3 g, 6.4 mmol) in THF (50 ml was added isopropyl(NE)-N-isopropoxycarbonyliminocarbamate (2.5 ml, 12.8 mmol) and triphenylphosphine (3.3 g, 12.8 mmol) and the reaction mixture was stirred at 25° C. for 16 h. The mixture was concentrated in vacuo to give the crude product, which was purified by column chromatography with silica gel, eluting with petroleum ether:ethyl acetate=20:1-5:1 to give (III)-6-chloro-1[(3aR,4R,6R,6aR)-4-methoxy-2,2-dimethyl-3a, 4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]isochroman (86d, 2.1 g, 6.1 mmol, 96% yield) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.58 (d, J=8.4 Hz, 1H), 7.12-7.17 (m, 2H), 5.09 (s, 2H), 4.56-4.62 (m, 2H), 4.14-4.28 (m, 2H), 3.71-3.77 (m, 1H), 3.70 (s, 3H), 2, 65-3.01 (m, 2H), 1.47 (s, 3H), 1.25 (s, 3H).

Step 4. Synthesis of (3R,4S,5S)-5-[(1R)-6-chloroisochroman-1-yl]tetrahydrofuran-2,3,4-triol (86e).

To a solution of (1R)-6-chloro-1-[(3aR,4R,6R,6aR)-4-methoxy-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4d][1, 3]dioxol-6-yl]isochroman (86d, 1.6 g, 4.7 mmol) in trifluoroacetic acid (16 mL, 215.4 mmol) water (10 mL) was added at rt. The mixture was stirred at 40° C. for 24 hours. The reaction mixture was concentrated in vacuo and purified by silica gel column chromatography eluting with petroleum ether:ethyl acetate=5:1 to 1:1 to give (3R,4S,5S)-5 -[(1R)-6-chloroisochroman-1yl]tetrahydrofuran-2,3,4-triol (86e, 700 mg, 2.4 mmol, 42% yield) as a colorless oil.

LC-MS [M+H]: 286.1.

Stage 5. Synthesis of (2R,3R,4S,5S)-2-(4-chloro-5-fluoro-pyrrolo[2,3-d]pyrimidin-7-yl)-5-[(1R)-6chloroisochroman-1 -yl]tetrahydrofuran-3,4-diol (86g).

To a solution of 4-chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine (86f, 461 mg, 2.7 mmol) and pyridine (0.8 ml, 9.8 mmol) in dry THF (10 ml) were added tributylphosphamide (1.2 ml, 4.9 mmol) and DIAD (1.0 ml, 5.1 mmol) under N2 atmosphere. (3R,4S,5S)-5-[(1R)-6-chloroisochroman-1-yl]tetrahydrofuran2,3,4-triol (86e, 700 mg, 2.4 mmol) and pyridine (0.8 ml , 9.8 mmol). The reaction mixture was stirred at 30° C. for 1.5 h under N2. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography eluting with petroleum ether:ethyl acetate=5:1 to 1:1) to give (2R,3R,4S,5S)-2-(4-chloro-5 -fluoropyrrolo[2,3-d]pyrimidin-7-yl)-5-[(1R)-6-chloroisochroman1-yl]tetrahydrofuran-3,4-diol (86g, 160 mg, 0.4 mmol, 15% yield ) as a yellow oil.

LC-MS [M+H]: 440.1.

Step 6. Synthesis of (2R,3R,4S,5S)-2-(4-amino-5-fluoro-pyrrolo[2,3-d]pyrimidin-7-yl)-5-[(1R)-6chloroisochroman-1 -yl]tetrahydrofuran-3,4-diol (Ex. 86).

(2R,3R,4S,5S)-2-(4-chloro-5-fluoro-pyrrolo[2,3-d]pyrimidin-7-yl)-5-[(1R)-6-chloroisochroman-1yl] mixture tetrahydrofuran-3,4-diol (86g, 156mg, 0.35mmol) in ammonium hydroxide (10mL, 260mmol) and 1,4dioxane (10mL) was stirred at 105°C in a closed tube overnight. The mixture was concentrated in vacuo and the residue was purified by preparative HPLC eluting with 5 to 95% CH3CN in water. The product fraction was extracted with ethyl acetate (2x50 ml) and concentrated in vacuo to give a yellow solid which was triturated with petroleum ether:ethyl acetate=100:1 (50 ml), filtered and dried in vacuo to give (2R,3R,4S, 5S)-2-(4-amino-5-fluoro-pyrrolo[2,3d]pyrimidin-7-yl)-5-[(1R)-6-chloroisochroman-1-yl]tetrahydrofuran-3,4-diol ( pr. 86, 74 mg, 0.17 mmol, 49% yield) as a white solid.

LC-MS [M+H]: 421.1.

1H NMR (400 MHz, DMSO-d6): δ 8.08 (s, 1H), 7.23-7.31 (m, 4H), 7.01 (s, 2H), 6.23 (d, J =7.6Hz, 1H), 5.23(d, J=6.8Hz, 1H), 5.08(s, 1H), 4.87(s, 1H), 4.35-4.39 (m, 2H), 4.23-4.26 (m, 1H), 3.79-3.82 (m, 1H), 3.66-3.71 (m, 1H), 2.89-2 .96 (m, 1H), 2.70-2.74 (m, 1H).

1H NMR (400 MHz, DMSO-d ₆ +D ₂ O): δ 8.08 (s, 1H), 7.23-7.30 (m, 4H), 6.23 (d, J=6.0 Hz, 1H), 4.87 (s, 1H), 4.35-4.39 (m, 2H), 4.23-4.26 (m, 1H), 3.79-3.81 (m, 1H), 3.65-3.71 (m, 1H), 2.89-2.96 (m, 1H), 2.70-2.74 (m, 1H).

¹⁹ F NMR (377 MHz, DMSO-d ₆ ): δ-166.8.

- 92 042008

Example 88 Synthesis of (2R,3R,4S,5S)-2-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-5-[(1R)-6,7dichloroisochroman-1-yl]tetrahydrofuran -3,4-diol (Ex. 88).

166 mmol) in H2SO4

Stage 1. Synthesis of 1-bromo-4,5-dichloro-2-iodobenzene (88b).

A solution of 4-bromo-1,2-dichlorobenzene (88a, 25 g, 110.67 mmol), I2 (42.13 g, (353.95 ml, 6640.1 mmol) was stirred at 140°C for 72 h in atmosphere of Ar. The reaction mixture was diluted with water (5000 ml), extracted with EtOAc (1500 ml), washed with Na ₂ SO ₃ (aq., 2x100 ml) and saturated aqueous sodium chloride solution (800 mlx1).The crude product was dried over MgSO ₄ , filtered and concentrated in vacuo to give the crude product which was then purified by silica gel column chromatography eluting with 2% EtOAc in petroleum ether to give 1-bromo-4,5-dichloro-2-iodobenzene (88b, 40 g, 113.7 mmol, 100% yield) as a white solid.

¹ H NMR (400 MHz, CDCl3): δ 7.84 (s, 1H), 7.62 (s, 1H).

Stage 2. Synthesis of 2-bromo-4,5-dichlorobenzaldehyde (88c).

A solution of 1-bromo-4,5-dichloro-2-iodobenzene (88b, 5 g, 14.21 mmol) in THF (20 ml) was stirred at 78° C. for 15 minutes under Ar. Isopropylmagnesium bromide [1M solution in THF] (15.6 mL, 15.63 mmol) was added slowly and stirred for 15 min. DMF (1.2 ml, 15.63 mmol) was added and stirred for 1 h at rt. The reaction mixture was extracted with EtOAc (80 ml), washed with Na ₂ SO ₃ (aq, 2x30 ml) and saturated aqueous sodium chloride solution (2x30 ml), dried over MgSO ₄ , filtered and concentrated in vacuo. The crude product was then purified by silica gel column chromatography eluting with 0.1% EtOAc in petroleum ether to give 2-bromo-4,5-dichlorobenzaldehyde (88s, 2.7 g, 10.6 mmol, 75% yield) as a white solid substances.

1H NMR (400 MHz, CDCl ₃ ): δ 10.16 (d, J=4.0 Hz, 1H), 7.89 (d, J=4.0 Hz, 1H), 7.10 (d, J =4.0 Hz, 1H).

Stage 3. Synthesis of 1-bromo-4,5-dichloro-2-[(E)-2-methoxyvinyl]benzene (88d).

A solution of (methoxymethyl)triphenylphosphonium chloride (7.29 g, 21.27 mmol) and tert-BuOK (2.39 g, 21.27 mmol) in THF (10 mL) was stirred at -25° C. under Ar for 15 min. . 2-Bromo-4,5-dichlorobenzaldehyde (88c, 2.7 g, 10.63 mmol) in THF was added and stirred at -25°C for 1.5 h. The reaction mixture was extracted with EtOAc (100 ml), washed with water (2x30 ml), then saturated aqueous sodium chloride solution (30 ml), dried over MgSO ₄ , filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography eluting with 0.1% EtOAc in petroleum ether to give 1-bromo-4,5-dichloro-2-[(E)-2-methoxyvinyl]benzene (88d, 1.1 g , 0.0039 mmol, 75% yield) as a white solid.

1H NMR (400 MHz, CDCl3): δ 7.54-7.53 (d, J=4.0 Hz, 1H), 7.37-7.35 (d, J=8.0 Hz, 1H), 6.94-6.89 (m, 1H), 5.88-5.85 (d, J=12.0 Hz, 1H), 3.66 (s, 3H).

Stage 4. Synthesis of 2-(2-bromo-4,5-dichlorophenyl)acetaldehyde (88e).

Solution of 1-bromo-4,5-dichloro-2-[(E)-2-methoxyvinyl]benzene (88d, 1.1 g, 3.9 mmol) and hydrochloric acid 2 N (aq.) (0.7 g , 19.51 mmol) in acetone (5 ml) was stirred at 70° C. for 2 hours under Ar atmosphere. The reaction mixture was concentrated in vacuo to give 2-(2-bromo-4,5-dichlorophenyl)acetaldehyde (88e, 830 mg, 3.09 mmol, 79% yield) as a colorless oil.

LC-MS [M+H]: 267.1.

Step 5. Synthesis of 2-(2-bromo-4,5-dichlorophenyl)ethanol (88f).

A solution of 2-(2-bromo-4,5-dichlorophenyl)acetaldehyde (88e, 830 mg, 3.1 mmol) in methanol (5 ml) was stirred at 0° C. for 15 min under Ar. NaBH ₄ (352 mg, 9.29 mmol) was added and stirred at 0° C. for 30 minutes.

The reaction mixture was extracted with EtOAc (50 ml), washed with water (2x20 ml) and saturated aqueous sodium chloride solution (10 ml), dried over MgSO 4 , filtered and concentrated in wa

- 93 042008 kuume to obtain 2-(2-bromo-4,5-dichlorophenyl)ethanol (88f, 800 mg, 3.0 mmol, 96% yield) as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.71 (s, 1H), 7.39 (s, 1H), 3.90-3.86 (m, 2H), 2.99-2.95 (m, 2H), 1.46-1.43 (m, 1H).

Stage 6. Synthesis of 2-(2-bromo-4,5-dichlorophenyl)ethoxy-tert-butyldimethylsilane (88g).

To a solution of 2-(2-bromo-4,5-dichlorophenyl)ethanol (88f, 810 mg, 3 mmol) in DCM (10 mL) was added imidazole (409 mg, 6.0 mmol) followed by tert-butylchlorodiphenylsilane (678 mg , 4.5 mmol) and the reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was diluted with EtOAc (50 ml), washed with water (2x20 ml) and saturated aqueous sodium chloride solution (10 ml), dried over MgSO ₄ . filtered, concentrated in vacuo. The crude product was purified by flash column chromatography eluting with 10% EtOAc in PE to give 2-(2-bromo-4,5-dichlorophenyl)ethoxy-tert-butyldimethylsilane (88g, 910 mg, 2.37 mmol, 79% yield) in the form of a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.66 (s, 1H), 7.40 (s, 1H), 3.83 (m, 2H), 2.93 (t, 2H), 7, 40 (s, 9H), 0.00 (s, 6H).

Step 7. Synthesis of [2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-4,5-dichlorophenyl]-[(3aR,4R,6S,6aS)-4(4-chloropyrrolo[2,3- d]pyrimidin-7-yl)-2,2-dimethyl-3а,4,6,6а-tetrahydrofuro[3,4-d][1,3]dioxol-6yl]methanone (88h).

Solution of [2-(2-bromo-4,5-dichlorophenyl)-2,2-difluoro-ethoxy]-tert-butyl-dimethylsilane (88g, 713.49 mg, 1.7 mmol in THF (6.5 ml) stirred at -78°C for 20 min under Ar atmosphere Added n-BuLi (83.67 mg, 1.31 mmol) and stirred at -78°C for 5 min Added (3aR,4R,6S,6aS )-4-(4chloropyrrolo[2,3-d]pyrimidin-7-yl)-N-methoxy-N,2,2-Ίrimetyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1 ,3]dioxol 6-carboxamide (1Ad, 250 mg, 0.65 mmol) in THF (3 ml) and stirred for 5 min. TLC showed the reaction was complete. The reaction mixture was quenched with ethyl acetate (25 ml.) The reaction mixture was extracted with EtOAc (25 ml), washed with water (2x10 ml) and saturated aqueous sodium chloride solution (10 ml), dried over MgSO ₄ , filtered and concentrated in vacuo The crude product was then purified using silica gel column chromatography eluting with 20% EtOAc in petroleum ether to give [2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-4,5-dichlorophenyl]-[(3aR,4R,6S,6aS)-4-(4-chloropyrrolo[2,3d] pyrimidin-7-yl)-2,2-dimethyl-3а,4,6,6а-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanone (88h, 210 mg, 0.33 mmol, 51% yield) as a yellow oil.

LC-MS [M+H]: 626.2.

Step 8 Synthesis of (R)-[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-4,5-dichlorophenyl]-[(3aR,4R,6R,6aR)4-(4-chloropyrrolo[ 2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3а,4,6,6а-tetrahydrofuro[3,4-d][1,3]dioxol-6yl]methanol (88i).

A solution of [2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-4,5-dichlorophenyl]-[(3aR,4R,6S,6aS)-4-(4chloropyrrolo[2,3-d]pyrimidine- 7-ul)-2,2-dimethyl-3а,4,6,6а-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanone (88h, 250 mg, 0.39 mmol) in toluene (5 ml) was stirred at -78°C for 5 min in an Ar atmosphere. DIBAL-H (0.13 mL, 1.1 mmol) was added and stirred for 2.5 h. The mixture was purified by preparative HPLC to give (R)-[2-[2-[t-butyl(dimethyl)silyl ]hydroxyethyl]-4,5-dichlorophenyl][(3aR,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3а,4 ,6,6a-Tetrahydrofuro[3,4d][1,3]dioxol-6-yl]methanol (88i, 195 mg, 0.31 mmol, 80% yield) as a white solid.

LC-MS [M+H]: 628.2.

Stage 9. Synthesis of 2-[4,5-dichloro-2-[(R)-hydroxy-[(3aR,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7yl) -2,2-dimethyl-3а,4,6,6а-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methyl]phenyl]ethanol (88j).

A solution of (R)-[2-[2-[tert-butyl(dimethyl)silyl]oxy-1,1-difluoro-ethyl]-4,5-dichlorophenyl][(3aR,4R,6R,6aR)-4- (4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4d][1,3]dioxol-6-yl]methanol (88i, 205 mg, 0.31 mmol) in THF (8 mL) was stirred at 25°C for 5 min under Ar. Tetrabutylammonium fluoride (0.17 mL, 0.62 mmol) was added and stirred for 2.5 h. The mixture was purified by preparative HPLC (MeCN in water, 10 to 90%) to give 2-[4,5-dichloro -2-[(R)-hydroxy-[(3aR,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl3а,4,6 ,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methyl]phenyl]ethanol (88j, 100 mg, 0.19 mmol, 63% yield) as a white solid.

LC-MS [M+H]: 514.2.

Step 10. Synthesis of 4-chloro-7-[(3aR,4R,6R,6aR)-2,2-dimethyl-6-[(1R)-6,7-dichloroisochroman-1-yl]3а,4,6, 6а-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]pyrrolo[2,3-d]pyrimidine (88k).

2-[4,5-Dichloro-2-[(R)-hydroxy-[(3aR,4R,6R,6aR)-4-(4-chloropyrrolo-[2,3-d]pyrimidin-7-yl)" solution 2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methyl]phenyl]ethanol (88j, 100 mg, 0.19 mmol) and PPh ₃ (101.9 mg, 0.39 mmol) in THF (3 ml) was stirred at 25° C. for 5 min under Ar atmosphere. DIAD (0.11 ml, 0.39 mmol) was added and stirred for 2 h. The reaction mixture was extracted with EtOAc (200 ml), washed with water (2x100 ml) and saturated aqueous sodium chloride solution (100 ml), dried over MgSO ₄ , filtered and concentrated in vacuo. The crude product was then purified by silica gel column chromatography eluting with 50% EtOAc in petroleum

- 94 042008 ether to give 4-chloro-7-[(3aR,4R,6R,6aR)-2,2-dimethyl-6-[(1R)-6,7-dichloroisochroman-1-yl]3a,4, 6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]pyrrolo[2,3-d]pyrimidine (88k, 70 mg, 0.14 mmol, 72.5% yield) in form of a white solid.

LC-MS [M+H]: 496.1.

Step 11. Synthesis of 7-[(3aR,4R,6R,6aR)-2,2-dimethyl-6-[(1R)-6,7-dichloroisochroman-1-yl]-3a,4,6,6atetrahydrofuro[3 ,4-d][1,3]dioxol-4-yl]pyrrolo[2,3-d]pyrimidin-4-amine (88I).

A solution of 4-chloro-7-[(3aR,4R,6R,6aR)-2,2-dimethyl-6-[(1R)-6,7-dichloroisochroman-1-yl]-3a,4,6,6atetrahydrofuro[ 3,4-d][1,3]dioxol-4-yl]pyrrolo[2,3-d]pyrimidine (88k, 70 mg, 0.14 mmol) and NH ₃ water (0.54 ml, 14 09 mmol) in 1,4-dioxane (2 ml) was stirred at 120°C for 16 h. The mixture was concentrated in vacuo to give 7-[(3aR,4R,6R,6aR)-2,2-dimethyl-6- [(1R)-6,7-dichloroisochroman-1-yl]3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]pyrrolo[2,3-d] pyrimidine-4-α-min (88i, 65 mg, 0.14 mmol, 97% yield) as a white solid.

LC-MS [M+H]: 477.2.

Step 12. Synthesis of (2R,3R,4S,5S)-2-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-5-[(1R)-6,7dichloroisochroman-1-yl]tetrahydrofuran -3,4-diol (Ex. 88).

A solution of 7-[(3aR,4R,6R,6aR)-2,2-dimethyl-6-[( 1 R)-6,7-dichloroisochroman-1 -yl]-3 a,4,6,6atetrahydrofuro[3, 4-d][1,3]dioxol-4-yl]pyrrolo[2,3-d]pyrimidin-4-amine (88i, 70 mg, 0.15 mmol) and TFA (502 mg, 4.4 mmol) in water (2 ml) was stirred at 25°C for 1.5 h. LC-MS showed that the reaction was complete. The mixture was concentrated in vacuo to give a crude product which was purified by preparative HPLC eluting with water:CH ₃ CN (0.l%NH4OH, 90:10 to 5:95) to give (2R,3R,4S,5S)- 2-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-5-[(1R)-6,7-dichloroisochroman-1yl]tetrahydrofuran-3,4-diol (Ex. 88, 5.1 mg, 0.011 mmol, 8% yield) as a white solid.

LC-MS [M+H]: 437.2.

¹ H NMR (400 MHz, DMSO^): δ 8.26 (s, 1H), 7.97-8.07 (m, 1.4H), 7.58 (m, 2H), 7.52 (s , 1H), 6.85 (s, 1H), 6.18-6.20 (d, J=8 Hz, 1H), 5.17-5.30 (m, 2H), 4.88-4, 89 (d, J=2.8 Hz, 1H), 4.43-4.47 (m, 2H), 4.23-4.24 (m,

1H), 3.84-3.85 (d, J=4 Hz, 1H), 3.64-3.65 (m, 1H), 2.88-2.95 (m, 1H), 2.67 -2.75 (m, 1H).

1H NMR (400 MHz, DMSO-d6+D2O): δ 8.25 (s, 1H), 7.59-7.60 (d, J=6.8 Hz, 1H), 7.54 (s, 1H ), 7.51 (s, 1H), 6.87-6.88 (d, J=3.2 Hz, 1H), 6.19-6.20 (d, J=7.6 Hz, 1H) , 4.90 (s, 1H), 4.47-4.50 (m, 1H), 4.42-4.43 (d,

J=4 Hz, 1H), 4.22-4.26 (m, 1H), 3.86-3.87 (d, J=5.2 Hz, 2H), 2.93-2.90 (m , 1H), 2.70-2.75 (m, 1H).

Example 89 Synthesis of 2,2,2-trifluoroacetate-(2R,3R,4S,5S)-2-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)5-[(7S)-2- chloro-5,7-dihydro-4H-thieno[2,3-c]pyran-7-yl]tetrahydrofuran-3,4-diol (Ex. 89).

Stage 1. Synthesis of morpholino-[(3aR,4R,6S,6aS)-2,2-dimethyl-4-(4-methylpyrrolo[2,3-d]pyrimidin-7ul)-3a,4,6,6a-tetrahydrofuro [3,4-d][1,3]dioxol-6-yl]methanone (89b).

To a solution of (3aR,4R,6S,6aS)-2,2-dimethyl-4-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)-3a,4,6,6atetrahydrofuro[3,4- d][1,3]dioxole-6-carboxylic acid (89a, 9.0 g, 28.19 mmol) in ethyl acetate (100 ml) was added morpholine (2.46 g, 28.19 mmol) and T3P (35 ml , 28.19 mmol) under an ice bath. The reaction mixture was then stirred at room temperature for 3 hours. NaHCO ₃ (aq) was added to the solution, adjusting the pH to 8. The mixture was extracted with EA (200 mlx3). The combined organic layers were concentrated and the residue was purified by flash column chromatography (PE:EA=5:1-1:1) to give morpholino-[(3aR,4R,6S,6aS)-2,2-dimethyl-4-( 4-methylpyrrolo[2,3-d]pyrimidin-7-yl)-3а,4,6,6atetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanone (89b, 9.5 g , 24.2 mmol, 86% yield) as a yellow oil.

LC-MS [M+H]: 389.3.

- 95 042008

Stage 2. Synthesis of 3-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-chloro-2-thienyl]-[(3aR,4R,6S,6aS)-4(4-chloropyrrolo[2,3 -d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6yl]methanone (89d).

Magnesium (123 mg, 5.06 mmol) in a 20 ml vial was etched with a spatula and stirred vigorously, then dried with a hair dryer under vacuum and filled with nitrogen while cooling. A solution of 2-(2-bromo-5-chloro-3-thienyl)ethoxy-tert-butyl-dimethylsilane (89c, 1.5 g, 4.22 mmol) in THF (1 ml) was added, then diisobutylaluminum hydride was added, 1 M in toluene (0.05 ml, 0.05 mmol). After 4 hours the solution turned dark and most of the magnesium was consumed and the solution was used as a 0.82 M solution of bromo-[3-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-chloro-2-thienyl] magnesium. Morpholino-[(3aR,4R,6S,6aS)-2,2-dimethyl-4-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)-3a,4,6,6a -tetrahydrofuro[3,4d][1,3]dioxol-6-yl]methanone (89b, 578.37 mg, 1.49 mmol) which was vacuum dried and 3 ml THF. The solution was cooled in an ice bath and bromine-[3-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-chloro-2-thienyl]magnesium (2.72 mL, 2.23 mmol) was added dropwise via syringe. The ice bath was removed and the reaction mixture was stirred for 1 h. An additional portion of bromo-[3-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-chloro-2-thienyl]magnesium (0.91 ml, 0. 75 mmol) and stirred 1 h before quenching with EtOAc. The reaction mixture was poured into NH ₄ Cl, the organic layers were separated and the aqueous layer was extracted with EtOAc. The organic layers were combined, washed with water then saturated aqueous sodium chloride and dried over Na ₂ SO ₄ . The solvent was removed in vacuo and the residue was purified by flash column chromatography to give [3-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5chloro-2-thienyl]-[(3aR,4R,6S,6aS) -2,2-dimethyl-4-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)-3a,4,6,6atetrahydrofuro[3,4-d][1,3]dioxol-6- yl]methanone (89d, 320 mg, 0.553 mmol, 37% yield).

Step 3 Synthesis of (R)-[3-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-chloro-2-thienyl][(3aR,4R,6R,6aR)-2,2-dimethyl -4-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)-3a,4,6,6a-tetrahydrofuro[3,4d][1,3]dioxol-6-yl]methanol (89e) .

Into a 50 ml round bottom flask containing a solution of [3-[2-[tert-butyl(dimethyl)silyl]oxyethyl]5-chloro-2-thienyl]-[(3aR,4R,6S,6aS)-2,2- dimethyl-4-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)-3a,4,6,6atetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanone (89d , 328 mg, 0.57 mmol) in toluene (6 ml) was sparged with nitrogen for 5 minutes, then cooled to -78°C, and diisobutylaluminum hydride, 1 M in toluene (1.18 ml, 1.42 mmol) for 5 min. The yellow solution was stirred at -78°C for 75 minutes. The reaction mixture was warmed to 0°C, water (80 µl), 15% sodium hydroxide (80 µl) and water (200 µl) were slowly added and stirred at room temperature for 15 min. The mixture was diluted with ether, dried over MgSO ₄ , stirred for 15 min and filtered. The filtrate was concentrated under reduced pressure and purified by flash column chromatography (0-45% EtOAc in hexane isomer mixture, wet loading in DCM/hexane isomer mixture) to give (S)-[3-[2-[tert-butyl( dimethyl)silyl]oxyethyl]-5-chloro-2-thienyl]-[(3aR,4R,6R,6aR)-2,2-dimethyl-4-(4methylpyrrolo[2,3-d]pyrimidin-7-yl) -3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanol (61 mg, 0.105 mmol, 18.5% yield) and (R)-[3- [2-[tert-Butyl(dimethyl)silyl]oxyethyl]-5-chloro-2-thienyl][(3aR,4R,6R,6aR)-2,2-dimethyl-4-(4-methylpyrrolo[2,3 -d]pyrimidin-7-yl)-3a,4,6,6a-tetrahydrofuro[3,4d][1,3]dioxol-6-yl]methanol (89e, 120 mg, 0.207 mmol, 36.5% yield ) as light white solid particles.

¹ H NMR (500 MHz, methanol^): δ 8.59 (d, J=5.0 Hz, 1H), 7.92 (d, J=3.8 Hz, 1H), 6.83 (d, J=0.8Hz, 1H), 6.70(dd, J=3.8, 6.2Hz, 1H), 6.50-6.25(m, 1H), 5.26-5.11 (m, 1H), 5.09 - 5.02 (m, 1H), 4.45 (ddd, J=2.5, 4.5, 15.6 Hz, 1H), 3.75 (kv, J =6.6 Hz, 2H), 2.72 (dt, J=6.5, 19.3 Hz, 2H), 2.01 (s, 2H), 1.61 (d, J=4.9 Hz , 3H), 1.35 (d, J=7.4 Hz, 3H), 0.83 (d, J=9.7 Hz, 8H), -0.06 (d, J=4.5 Hz, 5H).

Stage 4. Synthesis of 2-[5-chloro-2-[(R)-hydroxy-[(3aR,4R,6R,6aR)-2,2-dimethyl-4-(4-methylpyrrolo[2,3d]pyrimidine- 7-yl)-3а,4,6,6а-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methyl]-3-thienyl]ethanol (89f).

(R)-[3-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-chloro-2-thienyl][(3aR,4R,6R,6aR)-2,2-dimethyl -4-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)-3a,4,6,6a-tetrahydrofuro[3,4d][1,3]dioxol-6-yl]methanol (89e, 123 mg, 0.21 mmol), DMSO (5 ml) and cesium fluoride (98 mg, 0.64 mmol). The mixture was stirred for 1 hour, then directly purified by reverse phase chromatography (10-70% MeCN/water/0.1% TFA). Product fractions were lyophilized to give 2-[5-chloro-2-[(R)-hydroxy-[(3aR,4R,6R,6aR)-2,2-dimethyl-4-(4- methylpyrrolo[2,3d]pyrimidin-7-yl)-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methyl]-3-thienyl]ethanol (89f , 70 mg, 0.120 mmol, 56% yield).

1H NMR (500 MHz, methanol-d ₄ ): δ 8.96 (d, J=9.5 Hz, 1H), 8.33 (dd, J=3.9, 28.5 Hz, 1H), 7 .15 (dd, J=3.9, 8.6 Hz, 1H), 6.61 (dd, J=3.7, 18.7 Hz, 1H), 5.27 (d, J=3.4 Hz, 1H), 5.18 (ddd, J=3.0.5.9, 8.5 Hz, 1H), 5.12 (dd, J=1.9, 5.9 Hz, 1H), 4 .58-4.44 (m, 1H), 3.79-3.63 (m, 2H), 2.96 (d, J=4.9 Hz, 3H), 2.86-2.66 (m , 2H), 1.63 (s, 3H), 1.39 (s, 3H).

LC-MS [M+H]: 466.0.

- 96 042008

Stage 5. Synthesis of 4-methyl-7-[(3aR,4R,6S,6aR)-2,2-dimethyl-6-[(7S)-2-chloro-5,7-dihydro-4H-thieno[2, 3c]pyran-7-yl]-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]pyrrolo[2,3-d]pyrimidine (89g).

2-[5-Chloro-2-[(R)-hydroxy-[(3aR,4R,6R,6aR)-2,2-dimethyl-4-(4methylpyrrolo[2,3^]pyrimidine-7- yl)-3a,4,6,6a-tetrahydrofuro[3,4^][1,3]dioxol-6-yl]methyl]-3thienyl]ethanol (89f, 110 mg, 0.19 mmol) in THF (2 ml). Pyridine (0.03 ml, 0.38 mmol) was added and the mixture was stirred for 20 min, then triphenylphosphine (99.5 mg, 0.38 mmol) and diisopropyl azodicarboxylate (0.07 ml, 0.38 mmol) were added and stirred over 2.5 hours. Additional diisopropyl azodicarboxylate (0.07 ml, 0.38 mmol) and triphenylphosphine (99.5 mg, 0.38 mmol) were added. After 1 hour, the solvent was evaporated and the residue was purified by flash column chromatography (0-60% EtOAc/hexane) to give 4-methyl-7-[(3aR,4R,6S,6aR)-2,2-dimethyl-6 -[(7S)-2-chloro-5,7-dihydro-4Hthieno[2,3-c]pyran-7-yl]-3a,4,6,6a-tetrahydrofuro[3,4-d][1, 3]dioxol-4-yl]pyrrolo[2,3-d]pyrimidine (89g, 94.5mg, 0.21mmol, 111% yield).

LC-MS [M+H]: 448.1.

Stage 6. Synthesis of 2,2,2-trifluoroacetate (2R,3R,4S,5S)-2-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)-5[(7 S)-2- chloro-5,7-dihydro-4H-thieno[2,3-c]pyran-7-yl]tetrahydrofuran-3,4-diol (Ex. 89).

4-methyl-7-[(3aR,4R,6S,6aR)-2,2-dimethyl-6-[(7S)-2-chloro-5,7-dihydro-4Hthieno[2,3-c ]pyran-7-yl]-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]pyrrolo[2,3-d]pyrimidine (89g, 94.5 mg, 0.21 mmol) in water (0.50 ml) and 2,2,2-trifluoroacetic acid (0.16 ml, 2.11 mmol) was added. The reaction mixture was stirred for 3 h, then diluted with EtOAc and NaHCO ₃ . The organic layers were separated and washed with water and saturated aqueous sodium chloride. The solvent was evaporated in vacuo and the residue was purified by reverse phase chromatography (0-70% MeCN/water/0.1% TFA) to give 2,2,2-trifluoroacetate (2R,3R,4S,5S)-2-( 4-methylpyrrolo[2,3-d]pyrimidin-7-yl)-5-[(7S)2-chloro-5,7-dihydro-4H-thieno[2,3-c]pyran-7-yl]tetrahydrofuran -3,4-diol (sp. 89, 2.3 mg, 0.0042 mmol, 2% yield).

¹ H NMR (500 MHz, Methanol-d4): δ 8.78 (s, 1H), 7.92 (s, 1H), 6.97 (s, 1H), 6.76 (s, 1H), 6 .46 (d, J=7.5 Hz, 1H), 4.22 (dd, J=5.4, 12.1 Hz, 2H), 3.98-3.76 (m, 1H), 2, 84 (s, 5H).

LC-MS [M+H]: 408.0.

Example 90 Synthesis of 2,2,2-trifluoroacetate (2R,3R,4S,5S)-2-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)5-[(7S)-2-chloro -5,7-dihydro-4H-thieno[2,3-c]pyran-7-yl]tetrahydrofuran-3,4-diol (Ex. 90).

Stage 1. Synthesis of [3-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-chloro-2-thienyl]-[(3aR,4R,6S,6aS)-4(4-chloropyrrolo[2, 3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6yl]methanone (90a).

ml vial containing magnesium (43.52 mg, 1.79 mmol) and stirrer, dried with a hot air gun under vacuum and filled with nitrogen under cooling. A solution of 2-(2-bromo-5-chloro-3thienyl)ethoxy-tert-butyldimethylsilane (89c, 0.07 ml, 1.79 mmol) in 2 ml THF was added followed by diisobu hydride

- 97 042008 thylaluminium (0.02 ml, 0.02 mmol). The reaction mixture was stirred for 5 hours at room temperature until most of the magnesium was consumed. The solution was cooled to -78°C and (3aR,4R,6S,6aS)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-N-methoxy-N,2,2-trimethyl -3a,4,6,6atetrahydrofuro[3,4-d][1,3]dioxol-6-carboxamide (1Ad, 527 mg, 1.38 mmol) in THF (3 mL) and stirred cold 30 min before heating to room temperature. The reaction mixture was stirred at room temperature for 3 h, then cooled again to -78°C and extinguished EtOAc, and then NH ₄ Cl. The mixture was warmed to room temperature. The organic layers were separated, washed with water and saturated aqueous sodium chloride, and dried over Na ₂ SO ₄ . The residue was purified twice by flash column chromatography (0-70% EtOAc/hexane) to give [3-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-chloro-2-thienyl]-[(3aR, 4R,6S,6aS)-4-(4-chloropyrrolo[2,3-d]pyrimidin7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1, 3]dioxol-6-yl]methanone (90a, 104 mg, 0.17 mmol, 13% yield).

LC-MS [M+H]: 599.8.

Step 2. Synthesis of (R)-[3-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-chloro-2-thienyl]-[(3aR,4R,6R,6aR)-4(4- chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6yl]methanol (90b) .

[3-[2-[tert-Butyl(dimethyl)silyl]oxyethyl]-5-chloro-2-thienyl]-[(3aR,4R,6S,6aS)-4-(4chloropyrrolo[2,3-d]] solution pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6yl]methanone (90a, 104 mg, 0.17 mmol) in toluene (2 ml) was purged with Ar for 5 mi, cooled to -78°C and then diisobutylaluminum hydride 1 M in toluene (0.36 ml, 0.44 mmol) was added dropwise over 5 minutes. The yellow solution was stirred at -78°C for 75 minutes. The reaction mixture was warmed to 0°C, water (80 µl), 15% sodium hydroxide (80 µl) and water (200 µl) were slowly added and stirred at room temperature for 15 min. The mixture was then diluted with EtOAc, the organic layers were separated and the aqueous phase was back extracted with EtOAc. The organic layers were combined, washed with water and saturated aqueous sodium chloride, dried over MgSO ₄ and filtered. The filtrate was concentrated under reduced pressure and purified by flash column chromatography (0-45% EtOAc/hexane isomer mixture, wet loading in DCM+hexane isomer mixture) to give (R)-[3-[2-[tert-butyl( dimethyl)silyl]oxyethyl]-5-chloro-2-thienyl]-[(3aR,4R,6R,6aR)-4-(4-chloropyrrolo[2,3d]pyrimidin-7-yl)-2,2-dimethyl -3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanol (90b, 97 mg, 0.162 mmol, 93% yield) as light white solids.

¹ H NMR (500 MHz, methanol^): δ 8.59 (d, J=5.0 Hz, 1H), 7.92 (d, J=3.8 Hz, 1H), 6.83 (d, J=0.8Hz, 1H), 6.70(dd, J=3.8, 6.2Hz, 1H), 6.50-6.25(m, 1H), 5.26-5.11 (m, 1H), 5.09-5.02 (m, 1H), 4.45 (ddd, J=2.5, 4.5, 15.6 Hz, 1H), 3.75 (q, J =6.6 Hz, 2H), 2.72 (dt, J=6.5, 19.3 Hz, 2H), 1.61 (d, J=4.9 Hz, 3H), 1.35 (d , J=7.4 Hz, 3H), 0.83 (d, J=9.7 Hz, 9H), -0.06 (d, J=4.5 Hz, 6H).

Stage 3. Synthesis of 2-[5-chloro-2-[(R)-hydroxy-[(3aR,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7yl)-2 ,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methyl]-3-thienyl]ethanol (90c).

To a solution of (R)-[3-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-chloro-2-thienyl]-[(3aR,4R,6R,6aR)-4-(4chloropyrrolo[2 ,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6yl]methanol (90b, 202 mg, 0.34 mmol) in DMSO (5 ml), cesium fluoride (154 mg, 1.01 mmol) was added and the reaction mixture was stirred for 1 h. The mixture was purified directly by reverse phase chromatography (10-70% MeCN/water /0.1% TFA) to give 2-[5-chloro-2-[(R)-hydroxy[(3aR,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidine- 7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4d][1,3]dioxol-6-yl]methyl]-3-thienyl]ethanol; 2,2,2-trifluoroacetic acid (90s, 62 mg, 0.103 mmol, 31% yield).

LC-MS [M+H]: 487.5.

Stage 4. Synthesis of 4-chloro-7-[(3aR,4R,6S,6aR)-2,2-dimethyl-6-[(7R)-2-chloro-5,7-dihydro-4H-thieno[2, 3с]pyran-7-yl]-3а,4,6,6а-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]pyrrolo[2,3-d]pyrimidine (90d1) and ( 90d2).

To a solution of 2-[5-chloro-2-[(R)-hydroxy-[(3aR,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)2, 2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methyl]-3-thienyl]ethanol (90c, 58 mg, 0.12 mmol) in THF (2 ml), triphenylphosphine (61.86 mg, 0.24 mmol) and diisopropyl azodicarboxylate (0.05 ml, 0.24 mmol) were added. After 2.5 h, diisopropyl azodicarboxylate (0.05 ml, 0.24 mmol) and triphenylphosphine (61.86 mg, 0.24 mmol) were added. After 1 h the reaction mixture was cooled to room temperature and partitioned between EtOAc and water. The layers were separated and the aqueous layer was back extracted with EtOAc, the organic layers were combined, washed with water and saturated aqueous sodium chloride solution, dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was purified by flash column chromatography (0-80% EtOAc/DCM). Fractions containing the product were collected and a second set containing trifluoromethyl ether of the primary alcohol was also collected separately. The ester containing layers were combined and dissolved in THF, NaHCO ₃ was added and stirred for 2 h, after which they were diluted with EtOAc, the organic layers were washed with water, saturated aqueous sodium chloride solution and the solvent was evaporated to obtain 90s, 2-[5-chloro- 2-[(R)-hydroxy[(3aR,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3а,4,6 ,6a-tetrahydrofuro[3,4d][1,3]dioxol-6-yl]methyl]-3-thienyl]ethanol. It was then subjected to the initial reaction conditions for

- 98 042008 3 hours, treated and purified as described above and combined with the product obtained earlier to obtain 4-chloro-7-[(3aR,4R,6S,6aR)-2,2-dimethyl-6-[( 7S)-2-chloro-5,7-dihydro-4H-thieno[2,3-c]pyran-7yl]-3а,4,6,6а-tetrahydrofuro[3,4-d][1,3]dioxol -4-yl]pyrrolo[2,3-d]pyrimidine (90d1, 15 mg, 0.032 mmol, 27% yield), LC-MS (M+H): 468.1; and 4-chloro-7-((3aR,4R,6S,6aR)-6-((7R)-2-chloro-4,7-dihydro-5Hthieno[2,3-c]pyran-7-yl)- 2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-7H-pyrrolo[2,3d]pyrimidine (90d2, 6 mg, 12%).

Step 5. Synthesis of 7-[(3aR,4R,6S,6aR)-2,2-dimethyl-6-[(7S)-2-chloro-5,7-dihydro-4H-thieno[2,3-c] pyran7-yl]-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]pyrrolo[2,3-d]pyrimidin-4-amine (90e).

To a solution of 4-chloro-7-[(3aR,4R,6S,6aR)-2,2-dimethyl-6-[(7S)-2-chloro-5,7-dihydro-4H-thieno[2.3c] pyran-7-yl]-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]pyrrolo[2,3-d]pyrimidine (90d1, 15 mg, 0 03 mmol) in 1,4-dioxane (1 ml) was added ammonium hydroxide (0.1 ml, 2.4 mmol), the vial was closed and placed in a microwave oven for 14 hours at 120°C. The solvent was evaporated in vacuo, EtOAc (1 ml) was added and the mixture was evaporated twice in vacuo to give 7-[(3aR,4R,6S,6aR)-2,2-dimethyl-6[(7S)-2-chloro-5, 7-dihydro-4H-thieno[2,3-c]pyran-7-yl]-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-4yl]pyrrolo[2, 3-d]pyrimidine-4-amine (90e, 14 mg, 0.031 mmol, 97% yield).

LC-MS [M+H]: 449.0/450.9.

Stage 6. Synthesis of (2R,3R,4S,5S)-2-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-5-[(7S)-2-chloro-5,7dihydro-4H -thieno[2,3-c]pyran-7-yl]tetrahydrofuran-3,4-diol; 2,2,2-trifluoroacetic acid (Ex. 90).

7-[(3aR,4R,6S,6aR)-2,2-dimethyl-6-[(7S)-2-chloro-5,7-dihydro-4H-thieno[2,3-c]pyran-7 solution -yl]3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]pyrrolo[2,3-d]pyrimidin-4-amine (90e, 6.0 mg , 0.01 mmol) in water (1 ml) and 2,2,2-trifluoroacetic acid; TFA (0.0 ml, 0.01 mmol was stirred for 2 h and purified by reverse phase HPLC to give (2R,3R,4S,5S)-2-(4-aminopyrrolo[2,3d]pyrimidine-7 -yl)-5-[(7S)-2-chloro-5,7-dihydro-4H-thieno[2,3-c]pyran-7-yl]tetrahydrofuran-3,4-diol;2,2,2 -trifluoroacetic acid (sp. 90, 1.1 mg, 0.0021 mmol, 16% yield).

1H NMR (500 MHz, methanol D ₄ ): δ 8.26 (s, 1H), 7.80-7.56 (m, 1H), 6.96 (d, J=3.7 Hz, 1H), 6 .77 (s, 1H), 6.37 (d, J=7.6 Hz, 1H), 4.65 (dd, J=5.1, 7.5 Hz, 1H), 4.31 (dd, J=5.9, 11.1 Hz, 1H), 4.25-4.17 (m, 2H), 3.83 (td, J=3.6, 11.1 Hz, 1H), 2.91 -2.75 (m, 1H), 2.59 (d, J=16.2 Hz, 1H).

Peak water at 5 m.h. closes the multiplet.

LC-MS [M+H]: 409.1.

Example 91 Synthesis of 2,2,2-trifluoroacetate (2R,3R,4S,5S)-2-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)5-[(7R)-2-chloro -5,7-dihydro-4H-thieno[2,3-c]pyran-7-yl]tetrahydrofuran-3,4-diol (Ex. 91).

Starting from 4-chloro-7-((3aR,4R,6S,6aR)-6-((7R)-2-chloro-4,7-dihydro-5H-thieno[2,3-c]pyran-7- yl)-2,2dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine (90d2) and following the same procedures as for ex. 90 gave (2R,3R,4S,5S)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5((S)-2-chloro-4.7 -dihydro-5H-thieno[2,3-c]pyran-7-yl)tetrahydrofuran-3,4-diol (Ex. 91, 1.1 mg, 7% yield).

LC-MS [M+H]: 409.0.

1H NMR (500 MHz, methanol-d ₄ ): δ 8.22 (s, 1H), 7.70 (d, J=3.8 Hz, 1H), 6.90 (d, J=3.8 Hz , 1H), 6.71 (s, 1H), 6.31 (d, J=6.1 Hz, 1H), 4.98 (d, J=2.4 Hz, 1H), 4.50 (t , J=5.7 Hz, 1H), 4.41 (dd, J=3.1.5.2 Hz, 1H), 4.39-4.28 (m, 2H), 3.85 (td, J=3.5, 11.2 Hz, 1H), 2.78 (d, J=17.0 Hz, 1H), 2.55 (d, J=16.1 Hz, 1H).

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Example 94 Synthesis of 2,2,2-trifluoroacetate (2R,3R,4S,5S)-2-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)5-[(1R,4R)-6 -chloro-4-fluoroisochroman-1-yl]tetrahydrofuran-3,4-diol (Ex. 94).

Stage 1. Synthesis of 2-(2-bromo-5-chlorophenyl)-2-fluoroacetonitrile (94a).

To a solution of 2-bromo-5-chlorobenzaldehyde (44a, 8000 mg, 31.9 mmol) and zinc iodide (21 mg, 0.07 mmol) in DCM (100 ml) was added trimethylsilylformonitrile (3360 mg, 33.9 mmol) at 0°C. The mixture was stirred at 25°C for 18 hours Then DAST (5600 mg, 34.7 mmol) in DCM (80 ml) was added and the mixture was cooled to 0°C. The mixture was stirred at 25° C. for 18 hours. The mixture was washed with HCl (50 ml, 1 M), H2O (50 ml) and NaHCO ₃ (50 ml, aq.). The reaction mixture was dried over MgSO ₄ , filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography to give 2-(2-bromo-5-chlorophenyl)-2-fluoroacetonitrile (94a, 4670 mg, 16.10 mmol, 50.5% yield).

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 7.87-7.84 (m, 1H), 7.81 (s, 1H), 7.63-7.61 (m, 1H), 6 .55 (d, J=43.6, 1H).

Stage 2. Synthesis of 2-(2-bromo-5-chlorophenyl)-2-fluoroacetate (94b).

Sulfuric acid (10 ml, 187.6 mmol) was added dropwise to a solution of 2-(2-bromo-5-chlorophenyl)-2-fluoroacetonitrile (94a, 4.47 g, 17.99 mmol) in methanol (50 ml) at 75°C. The reaction mixture was stirred at 75° C. for 18 hours. TLC (PE, Rf=0.3) indicated that the reaction was complete. The mixture was quenched with NaHCO ₃ (aq.). The mixture was concentrated in vacuo and extracted with EA (2x100 ml). The combined organic layers were dried over MgSO ₄ . The solvent was removed in vacuo to give methyl 2-(2-bromo-5chlorophenyl)-2-fluoroacetate (94b, 4.8 g, 14.7 mmol, 73% yield).

1H NMR (400 MHz, DMSO-d ₆ ): δ 7.67 (d, J=8.8, 1H), 7.60 (d, J=2, 1H), 7.53-7.50 (m , 1H), 6.36 (d, J=45, 1H), 3.752 (s, 3H).

Stage 3. Synthesis of 2-(2-bromo-5-chlorophenyl)-2-fluoroethanol (94c).

To a solution of methyl 2-(2-bromo-5-chlorophenyl)-2-fluoroacetate (94b, 4.8 g, 17.05 mmol) in methanol (40 ml) was added NaBH ₄ (1.29 g, 34.1 mmol ). The reaction mixture was stirred at 25° C. for 2 hours. TLC (PE:EA=4:1, Rf=0.5) indicated that the reaction was complete. The mixture was quenched with HCl (1N). Then, the mixture was concentrated in vacuo and extracted with EA (2x100 ml). The combined organic layers were dried over MgSO ₄ . The solvent was removed in vacuo to give 2-(2-bromo-5-chlorophenyl)-2-fluoroethanol (94c, 3.8 g, 15 mmol, 80% yield).

1H NMR (400 MHz, DMSO-d ₆ ): δ 7.69 (d, J=8.4, 1H), 7.60 (d, J=2.8, 1H), 7.43-7.40 (m, 1H), 5.78-5.76 (m, 1H), 5.40-5.37 (m, 1H), 3.83-3.65 (m, 2H).

Step 4. Synthesis of [2-(2-bromo-5-chlorophenyl)-2-fluoroethoxy]-tert-butyldimethylsilane (94d).

To a solution of 2-(2-bromo-5-chlorophenyl)-2-fluoro-ethanol (94c, 3.8 g, 14.99 mmol) and imidazole (2.04 g, 29.98 mmol) in DCM (50 ml ) was slowly added tert-butylchlorodiphenylsilane (2.71 g, 17.99 mmol). The reaction mixture was stirred at 30° C. for 2 hours. TLC (PE, Rf=0.4) indicated that the reaction was complete. The solvent was removed in vacuo and the crude product was purified by silica gel (PE) column chromatography to give [2-(2-bromo-5-chlorophenyl)-2-fluoroethoxy]-tert-butyldimethyl-silane (94d, 5 g, 13.6 mmol , 91% yield) as a pale yellow oil.

1H NMR (400 MHz, DMSO-d ₆ ): δ 7.69 (d, J=8.4, 1H), 7.48-7.41 (m, 2H), 5.82-5.71 (m , 1H), 4.05-3.85 (m, 2H), 0.82 (s, 9H), 0.00-0.06 (m, 6H).

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Stage 5. Synthesis of [4-chloro-2-[(1R)-2-[tert-butyl(dimethyl)silyl]oxy-1-fluoro-ethyl]-phenyl][(3aR,4R,6S,6aS)-4 -(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4d][1,3]dioxol-6-yl] methanone (94е1) and [4-chloro-2-[(1S)-2-[tert-butyl(dimethyl)silyl]oxy-1-fluoroethyl]phenyl]-[(3aR,4R,6S,6aS)-4- (4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3а,4,6,6atetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanone (94е2).

A solution of [2-(2-bromo-5-chlorophenyl)-2-fluoro-ethoxy]-tert-butyl-dimethyl-silane (3.63 g, 9.87 mmol) in dry THF (8 ml) was stirred at -78 °C in an Ar atmosphere. n-BuLi (4.7 ml, 11.76 mmol) was added and the reaction mixture was stirred for 10 minutes. Then (3aR,4R,6S,6aS)-4-(4-chloropyrrolo2,3-d]pyrimidin-7-yl)-N-methoxy-N,2,2-trimethyl-3a,4,6,6a- tetrahydrofuro[3,4-d][1,3]dioxol-6carboxamide (1Ad, 1.8 g, 4.7 mmol) in anhydrous THF (2.00 mL). The mixture was stirred at -78°C for 30 minutes. TLC (PE:EA=5:1, Rf=0.5) indicated that the reaction was complete. The reaction mixture was quenched with CH3COOH. The mixture was combined with another batch for processing. The reaction mixture was extracted with EtOAc (100 mlx3) and the organic layers were washed with water (50 mlx3) then with saturated aqueous sodium chloride solution (50 mlx3). The organic layers were dried over MgSO ₄ , filtered, and concentrated in vacuo to give the crude product, which was further purified with SFC to give

[4-chloro-2-[(1S)-2-[tert-butyl(dimethyl)silyl]oxy-1-fluoroethyl]phenyl]-[(3aR,4R,6S,6aS)-4-(4chloropyrrolo[ 2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanone (94е2, 30o mg, 0.49 mmol, 10.5% yield),

LC-MS [M+H]: 610.2,

1H NMR (400 MHz, DMSO-d6): δ 8.59 (s, 1H), 8.09-8.02 (m, 2H), 7.85-7.75 (m, 2H), 6.84 (d, J=3.6, 1H), 6.69 (s, 1H), 5.62-5.54 (m, 2H), 5.50-5.37 (m, 1H), 3.97 -3.74 (m, 2H), 1.74 (s, 3H), 1.46 (s, 3H), 0.90 (s, 9H), -0.02 (d, J=13.6, 6H); And

[4-chloro-2-[(1R)-2-[tert-butyl(dimethyl)silyl]oxy-1-fluoroethyl]-phenyl]-[(3aR,4R,6S,6aS)-4-(4chloropyrrolo[2 ,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6yl]methanone (94e1, 800 mg, 1.31 mmol, 28% yield),

LC-MS [M+H]: 610.2,

1H NMR (400 MHz, DMSO-d ₆ ): δ 8.52 (s, 1H), 7.77 (d, J=9.2, 1H), 7.69 (d, J=3.6, 1H ), 7.28-7.26 (m, 1H), 6.48-6.46 (m, 2H), 5.77 (s, 1H), 5.71-5.51 (m, 2H), 5.44-5.31 (m, 1H), 3.97-3.33 (m, 2H), 1.59 (s, 3H), 1.42 (s, 3H), 0.83 (s, 9H), 0.01-0.01 (m, 6H).

Step 6 Synthesis of (R)-[4-chloro-2-[(1S)-2-[tert-butyl(dimethyl)silyl]oxy-1-fluoroethyl]phenyl][(3aR,4R,6R,6aR )-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3а,4,6,6а-tetrahydrofuro[3,4d] [1,3]dioxol-6 -yl]methanol (94f).

To a solution of [4-chloro-2-[(1S)-2-[tert-butyl(dimethyl)silyl]oxy-1-fluoro-ethyl]phenyl][(3aR,4R,6S,6aS)-4-(4 -chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4d][1,3]dioxol-6-yl]methanone (94е2 , 300 mg, 0.49 mmol) in toluene (7 ml) was added DIBAL-H (0.17 ml, 1.47 mmol). The mixture was stirred at -78°C for 30 min under N2. The solution was quenched with CH3COOH. The mixture was combined with another batch for processing. The mixture was extracted with EtOAc (15 mlx3) and the organic layers were washed with water (20 mlx3) then with saturated aqueous sodium chloride solution (20 mlx3). The organic layers were dried over MgSO ₄ , filtered and concentrated in vacuo. The crude product was purified by silica gel flash column chromatography (PE:EA=5:1) to give (R)-[4-chloro-2-[(1S)-2-[tert-butyl(dimethyl)silyl]oxy -1-fluoro-ethyl]phenyl]-[(3aR,4R,6R,6aR)-4(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4, 6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6yl]methanol (94f, 300 mg, 0.49 mmol).

LC-MS [M+H]: 612.2.

1H NMR (400 MHz, DMSO-d ₆ ): δ 8.75 (s, 1H), 7.70 (d, J=12.8, 1H), 7.49 (s, 1H), 7.73- 7.41 (m, 1H), 7.35-7.32 (m, 1H), 6.67-6.66 (m, 1H), 6.63 (d, J=1.6, 1H), 5.87-5.72 (s, 1H), 5.29-5.19 (m, 2H), 5.12-5.11 (m, 1H), 4.65 (s, 1H), 3, 97-3.81 (m, 2H), 1.59 (s, 3H), 1.24 (s, 3H), 0.87 (s, 9H), 0.02-0.00 (m, 6H) .

Step 7. Synthesis of (2S)-2-[5-chloro-2-[(R)-hydroxy-[(3aR,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidine- 7yl)-2,2-dimethyl-3а,4,6,6а-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methyl]phenyl]-2-fluoroethanol (94g).

To a solution of (R)-[4-chloro-2-[(1S)-2-[tert-butyl(dimethyl)silyl]oxy-1-fluoro-ethyl]phenyl]-[(3aR,4R,6R,6aR) 4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3а,4,6,6а-tetrahydrofuro[3,4-d][1,3]dioxol-6yl ]methanol (94f, 300 mg, 0.49 mmol) in THF (5 ml) was added TBAF (1 M) (0.26 ml, 0.98 mmol). The mixture was stirred at 25°C for 30 min under N2 atmosphere. The mixture was combined with another batch for processing. The reaction mixture was quenched with NH4C1, extracted with EA (10 mlx3). The combined organic extracts were washed with saturated aqueous sodium chloride, dried over MgSO ₄ , filtered, concentrated in vacuo and purified by silica gel column chromatography (PE:EA=1:1) to give (2S)-2-[5-chloro- 2-[(R)-hydroxy-[(3aR,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)2,2-dimethyl-3а,4,6 ,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methyl]phenyl]-2-fluoroethanol (94g, 200mg, 0.40mmol, 82% yield).

LC-MS [M+H]: 498.1.

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1H NMR (400 MHz, DMSO-d ₆ ): δ 8.67 (s, 1H), 7.65 (d, J=8, 1H), 7.52-7.50 (m, 1H), 7, 45-7.42 (m, 1H), 7.35-7.31 (m, 1H), 6.79 (s, 1H), 6.68 (d, J=3.6, 1H), 5, 31-5.14 (m, 4H), 4.69 (s, 1H), 4.15-3.85 (m, 2H), 1.62 (s, 3H), 1.33 (s, 3H) .

Step 8. Synthesis of (7S)-4-chloro-7-[(3aR,6R,6aR)-2,2-dimethyl-6-[(1R,4R)-6-chloro-4-fluoro-uzochroman-1yl] -3а,4,6,6а-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]pyrrolo[2,3-d]pyrimidine (94h1) and (7S)-4-chloro-7 [(3aR,6R,6aR)-2,2-dimethyl-6-[(1S,4R)-6-chloro-4-fluoro-isochroman-1-yl]-3a,4,6,6a-tetrahydrofuro[3 ,4d][1,3]dioxol-4-yl]pyrrolo[2,3-d]pyrimidine (94h2).

To a solution of 2-[5-chloro-2-[(R)-hydroxu-[(3aR,6R,6aR)-2,2-dimethyl-4-[(7S)-4-chloropyrrolo[2,3d]pyrimidine- 7-yl]-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methyl]phenyl]-2-fluoroethanol (94g, 200 mg, 0.40 mmol ) in THF (ml) was added NaH (19.26 mg, 0.80 mmol) at 25°C and stirred for 10 min. Tosyl chloride (76.52 mg, 0.40 mmol) was added and stirred for 1 hour. The reaction mixture was combined with another run for processing. The mixture was quenched with H2O and extracted with EA (10 mlx3). The combined organic layers were washed with saturated aqueous sodium chloride (10 ml), dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by prep HPLC eluting CH3CN in _H2O (0.1% NH4OH) from 5% to 95% to give (7S)-4-chloro-7-[(3aR,6R,6aR)-2.2 -dimethyl-6-[(1S,4R)-6-chloro-4-fluoroisochroman-1-yl]-3a,4,6,6atetrahydrofuro[3,4-d][1,3]dioxol-4-yl] pyrrolo[2,3-d]pyrimidine (94h2, 15 mg, 0.031 mmol, 8% yield),

LC-MS [M+H]: 480.1; and (7S)-4-chloro-7-[(3aR,6R,6aR)-2,2-dimethyl-6-[(1R,4R)-6-chloro-4-fluoroisochroman-1-yl]-3a, 4,6,6atetrahydrofuro[3,4-d][1,3]dioxol-4-yl]pyrrolo[2,3-d]pyrimidine (94h1, 34 mg, 0.071 mmol, 17.6% yield),

LC-MS [M+H]: 480.1.

1H NMR (400 MHz, DMSOO): δ 8.60 (s, 1H), 7.60 (d, J=4, 1H), 7.43-7.42 (m, 1H), 7.36-7 .33 (m, 1H), 7.15 (d, J=8.4, 1H), 6.60 (d, J=3.6, 1H), 6.55 (d, J=3.6, 1H), 5.25 (d, J=50.8, 1H), 4.99-4.97 (m, 1H), 4.86-4.84 (m, 1H), 4.78-4, 74 (m, 2H), 4.43-4.36 (m, 1H), 3.83-3.71 (m, 1H), 1.55 (s, 3H), 1.19 (s, 3H) .

Stage 9. Synthesis of 4-methyl-7-[(3aR,4R,6R,6aR)-2,2-dimethyl-6-[(1R,4R)-6-chloro-4-fluoro-isochroman-1yl]-3a ,4,6,6а-Tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]pyrrolo[2,3-d]pyrimudine (94i).

To a solution of tetrakis(triphenylphosphine)palladium (2.4 mg) and 4-chloro-7-[(3aR,4R,6R,6aR)-2,2-dimethyl-6[(1 R,4R)-6-chloro- 4-fluoro-isochroman-1-yl]-3 а,4,6,6а-tetrahydrofuro[3,4-d] [1,3]dioxol-4-yl]pyrrolo[2,3d]pyrimidine (94h1, 10 mg, 0.02 mmol) in THF (4 ml) was added dimethylzinc (20 mg, 0.21 mmol). The mixture was stirred at 70° C. for 3 hours. LC-MS showed 20% of the desired product. Another batch was combined with this reaction and concentrated in vacuo to give crude 4-methyl-7[(3aR,4R,6R,6aR)-2,2-dimethyl-6-[(1R,4R)-6-chloro-4 -fluoroisochroman-1-yl]-3a,4,6,6a-tetrahydrofuro[3,4-d] [1,3]dioxol-4-yl]pyrrolo[2,3-b]pyrimidine (94i), which was used directly to the next stage.

LC-MS [M+H]: 460.3.

Stage 10. Synthesis of 2,2,2-trifluoroacetate (2R,3R,4S,5S)-2-(4-methylpyrrolo [2,3-d]pyrimidin-7-yl)5-[(1R,4R)-6 -chloro-4-fluoro-uzochroman-1-yl]tetrahydrofuran-3,4-diol (Ex. 94).

To a solution of 4-methyl-7-[(3aR,4R,6R,6aR)-2,2-dimethyl-6-[(1R,4R)-6-chloro-4-fluoro-isochromαn-1-yl]3а, 4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]πpyrrolo[2,3-d]pyrimidine (94i, 30 mg, 0.07 mmol) in water (1 ml ) TFA (1.13 ml, 7.77 mmol) was added. The mixture was stirred at 25° C. for 2 hours. The residue was purified by preparative HPLC eluting with CH3CN in H ₂ O (0.1% TFA) from 5 to 95% to give a crude product which was further purified by preparative HPLC eluting CH3CN in H ₂ O (0.1% NH3/H2O) 5 to 95% to give 2,2,2-trifluoroacetate (2R,3R,4S,5S)-2-(4methylpyrrolo[2,3-d]nirumidine -7-yl)-5-[(1R,4R)-6-chloro-4-fluoro-isochroman-1-yl]tetrahydrofuran-3,4diol (Ex. 94, 3.5 mg, 0.0065 mmol, 10 % yield) as a white solid.

LC-MS [M+H]: 420.3.

1H NMR (400 MHz, DMSO-d ₆ +D2O): δ 8.83 (s, 1H), 7.87 (d, J=3.2, 1H), 7.67 (s, 1H), 7, 55-7.49 (m, 2H), 6.96 (s, 1H), 6.35 (d, J=8, 1H), 5.52 (d, J=50.4, 1H), 5, 02-5.00 (m, 1H), 4.94-4.91 (m, 1H), 4.61 (d, J=2.8, 1H), 4.53-4.46 (m, 2H ), 3.99-3.82 (m, 2H), 2.67 (s, 3H).

Example 95 Synthesis of (2R,3R,4S,5S)-2-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-5-[(1R,4R)-6-chloro-4fluoroisochroman-1 -yl]tetrahydrofuran-3,4-diol (Ex. 95).

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Stage 1. Synthesis of 7-[(3aR,4R,6R,6aR)-2,2-dimethyl-6-[(1R,4R)-6-chloro-4-fluoro-isochroman-1-yl]3а,4, 6,6a-Tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]pyrrolo[2,3-d]pyrimidin-4-amine (95a).

To a solution of 4-chloro-7-[(3aR,4R,6R,6aR)-2,2-dimethyl-6-[(1R,4R)-6-chloro-4-fluoro-isochroman-1-yl]3а, 4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]pyrrolo[2,3-d]pyrimidine (94h1, 35 mg, 0.07 mmol) in 1,4- dioxane (2.5 ml) was added ammonia (2.5 ml, 0.07 mmol). The mixture was sealed and stirred at 120° C. for 16 hours. The reaction mixture was concentrated in vacuo to give crude 7-[(3aR,4R,6R,6aR)-2,2-dimethyl-6-[(1R,4R)- 6-chloro-4-fluoroisochroman-1-yl]-3а,4,6,6а-tetrahydrofuro[3,4d][1,3]dioxol-4-yl]pyrrolo[2,3-d]pyrimidin-4- amine (95a), which was directly used in the next step.

LC-MS [M+H]: 461.2.

Stage 2. Synthesis of (2R,3R,4S,5S)-2-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-5-[(1R,4R)-6-chloro-4fluoroisochroman-1 -yl]tetrahydrofuran-3,4-diol (Ex. 95).

To a solution of 7-[(3aR,4R,6R,6aR)-2,2-dimethyl-6-[(1R,4R)-6-chloro-4-fluoroisochroman-1-yl]-3a,4,6,6atetrahydrofuro [3,4-d][1,3]dioxol-4-yl]pyrrolo[2,3-d]pyrimidin-4-amine (95a, 25 mg, 0.05 mmol) in water (1 ml) was added 2 ,2,2-trifluoroacetic acid (1.0 ml, 12.98 mmol). The mixture was stirred at 25° C. for 30 minutes. The residue was purified by preparative HPLC eluting CH ₃ CN in H ₂ O (0.1% NH ₄ OH) from 5 to 95% to give (2R,3R,4S,5S)-2-(4-aminopyrrolo[2, 3-d]pyrimidin-7-yl)-5[(1R,4R)-6-chloro-4-fluoro-isochroman-1-yl]tetrahydrofuran-3,4-diol (ex. 95, 6 mg, 0.014 mmol , 25% yield) as a white solid.

LC-MS [M+H]: 421.1.

¹ H NMR (400 MHz, DMSO-d6+D2O): δ 8.07 (s, 1H), 7.65 (s, 1H), 7.51 (s, 2H), 7.38 (d, J= 4, 1H), 6.67 (d, J=4.4, 1H), 6.21 (d, J=8, 1H), 5.59-5.46 (d, J=50, 1H), 4.88 (d, J=2.8, 1H), 4.52 (d, J=2.8, 1H), 4.46-4.34 (m, 2H), 3.96-3.87 (m, 1H), 3.81 (d, J=4.8, 1H).

Example 92 Synthesis of (2R,3R,4S,5S)-2-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)-5-[(1R,4S)-6-chloro-4fluoroisochroman-1 -yl]tetrahydrofuran-3,4-diol (Ex. 92).

34e1 92a 92b

92d Ir. 92

92s

Step 1. Synthesis of (R)-[4-chloro-2-[(1R)-2-[tert-butyl(dimethyl)silyl]oxy-1-fluoroethyl]phenyl][(3aR,4R,6R,6aR )-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3а,4,6,6а-tetrahydrofuro[3,4d] [1,3]dioxol-6 -yl]methanol (92a).

To a solution of [4-chloro-2-[(1R)-2-[tert-butyl(dimethyl)silyl]oxy-1-fluoro-ethyl]phenyl]-[(3aR,4R,6S,6aS)-4(4 -chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6yl]methanone (94е1 , 800 mg, 1.31 mmol) in toluene (7 ml) was added DIBAL (0.45 ml, 3.93 mmol). The mixture was stirred at -78°C for 30 min under N2. The solution was quenched with NH ₄ Cl. The mixture was combined with another batch for processing. The mixture was extracted with EtOAc (15 mlx3) and the organic layers were washed with water (20 mlx3) then with saturated aqueous sodium chloride solution (20 mlx3). The organic layers were dried over MgSO ₄ , filtered, concentrated in vacuo. The crude product was purified by silica gel flash column chromatography (PE:EA=5:1) to give (R)-[4-chloro-2-[(1R)-2[t-butyl(dimethyl)silyl]oxy- 1-fluoro-ethyl]phenyl]-[(3aR,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin7-yl)-2,2-dimethyl-3а,4,6, 6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanol (92a, 520 mg, 0.85 mmol, 65% yield).

LC-MS [M+H]: 612.2.

1H NMR (400 MHz, DMSO-d6): δ 8.68 (s, 1H), 7.69 (d, J=8, 1H), 7.40 (s, 1H), 7.34 (d, J =3.6, 1H), 6.67 (d, J=3.6, 1H), 6.46 (d, J=1.2, 1H), 5.86 (d, J=4.8, 1H), 5.83-5.68(m, 1H), 5.34(s, 1H), 5.27-5.16(m, 1H), 5.16-5.16(m, 1H) , 4.52 (s, 1H), 4.02-3.78 (m, 2H), 1.58 (s, 3H), 1.26 (s, 3H), 0.83 (s, 9H), 0.02-0.00 (m, 6H).

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Stage 2. Synthesis of (2R)-2-[5-chloro-2-[(R)-hydroxy-[(3aR,4R,6R,6aR)-4-(4-chloropyrrolo[2,3d]pyrimidine-7- yl)-2,2-dimethyl-3а,4,6,6а-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methyl]phenyl]-2fluoroethanol (92b).

To a solution of (R)-[4-chloro-2-[(1R)-2-[tert-butyl(dimethyl)silyl]oxy-1-fluoro-ethyl]phenyl][(3aR,4R,6R,6aR)- 4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4d][1,3]dioxol-6-yl ]methanol (92a, 520 mg, 0.85 mmol) in THF (5 ml) was added TBAF (1 M) (0.44 ml, 1.7 mmol). The mixture was stirred at 25°C for 30 min under N2 atmosphere. The mixture was combined with another batch for processing. The solution was quenched with NH ₄ Cl and washed with EA and the solvent was removed in vacuo. The crude product was purified by flash column chromatography (PE:EA=3:1) to give (2R)-2-[5-chloro-2-[(R)-hydroxy-[(3aR,4R,6R,6aR) -4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6- yl]methyl]phenyl]-2-fluoroethanol (92b, 330 mg, 0.66 mmol, 78% yield).

LC-MS [M+H]: 498.1.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.68 (s, 1H), 7.73 (d, J=8.4, 1H), 7.45-7.40 (m, 2H) , 7.33(d, J=4, 1H), 6.67(d, J=4, 1H), 6.39(d, J=1.6, 1H), 5.88-5.73( m, 2H), 5.33 (s, 1H), 5.28-5.25 (m, 1H), 5.17-5.15 (m, 1H), 4.48 (s, 1H), 3 .99-3.67 (m, 2H), 1.59 (s, 3H), 1.32 (s, 3H).

Stage 3. Synthesis of 4-chloro-7-[(3aR,4R,6R,6aR)-2,2-dimethyl-6-[(1R,4S)-6-chloro-4-fluoro-isochroman-1yl]-3a ,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]pyrrolo[2,3-d]pyrimidine (92c).

To a solution of (2R)-2-[5-chloro-2-[(R)-hydroxy-[(3aR,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7yl) -2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methyl]phenyl]-2-fluoroethanol (92b, 300 mg, 0, 60 mmol) in THF (ml) was added NaH (28.9 mg, 1.2 mmol) at 0°C and stirred for 10 min. Tosyl chloride (115 mg, 0.60 mmol) was added to the mixture and stirred for 1 hour. The mixture was combined with another batch for processing. The mixture was quenched with H ₂ O and extracted with EA (10 mlx3). The combined organic layers were washed with saturated aqueous sodium chloride (10 ml), dried over MgSO ₄ , filtered and concentrated in vacuo.

The crude product was purified by silica gel column chromatography (PE:EA=5:1) to give 4-chloro-7-[(3aR,4R,6R,6aR)-2,2-dimethyl-6-[(1R,4S )-6-chloro-4-fluoro-isochroman1-yl]-3а,4,6,6а-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]pyrrolo[2,3-d] pyrimidine (92c, 90 mg, 0.192 mmol).

LC-MS [M+H]: 480.1.

1H NMR (400 MHz, DMSO-d6): δ 8.61 (d, J=6, 1H), 7.46-7.43 (m, 2H), 7.19 (d, J=8, 1H) , 6.98 (d, J=8.4, 1H), 6.62 (d, J=3.6, 1H), 6.37 (d, J=3.2, 1H), 5.57- 5.41 (m, 1H), 5.08-5.05 (m, 1H), 4.89-4.85 (m, 2H), 4.53-4.51 (m, 1H), 4. 33-4.27(m, 1H), 3.79-3.72(m, 1H), 1.54(s, 3H), 1.25(s, 3H).

Stage 4. Synthesis of 4-methyl-7-[(3aR,4R,6R,6aR)-2,2-dimethyl-6-[(1R,4S)-6-chloro-4-fluoroisochroman-1yl]-3a,4 ,6,6а-Tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]pyrrolo[2,3-d]pyrimidine (92d).

To a solution of 4-chloro-7-[(3aR,4R,6R,6aR)-2,2-dimethyl-6-[(1R,4S)-6-chloro-4-fluoroisochroman-1-yl]3а,4, 6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]pyrrolo[2,3-d]pyrimidine (92c, 10 mg, 0.02 mmol) and iron acetylacetonate (0.74 mg, 0.002 mmol) in THF (4 ml) was slowly added methylmagnesium bromide (23 mg, 0.21 mmol) at -30°C. The mixture was stirred at 0° C. for 1 hour. The mixture was concentrated in vacuo to give crude 4-methyl-7-[(3aR,4R,6R,6aR)-2,2-dimethyl-6-[(1R,4S)- 6-Chloro-4fluoroisochroman-1-yl]-3а,4,6,6а-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]pyrrolo[2,3-d]pyrimidine (92d) , which was directly used in the next step.

LC-MS [M+H]: 460.2.

Stage 5. Synthesis of (2R,3R,4S,5S)-2-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)-5-[(1R,4S)-6-chloro-4fluoroisochroman-1 -yl]tetrahydrofuran-3,4-diol (Ex. 92).

To a solution of 4-methyl-7-[(3aR,4R,6R,6aR)-2,2-dimethyl-6-[(1R,4S)-6-chloro-4-fluoro-isochroman-1-yl]3a, 4,6,6a-Tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]pyrrolo[2,3-d]pyrimidine (92d, 10 mg, 0.02 mmol) in water (1 ml ) TFA (1.0 ml, 6.86 mmol) was added. The mixture was stirred at 25°C for 2 hours. The mixture was purified by preparative HPLC eluting CH3CN in _H2O (0.1% NH4OH) from 5% to 95% to give (2R,3R,4S,5S)-2- (4-methylpyrrolo[2,3-d]pyrimidin-7-yl)-5-[(1R,4S)-6-chloro-4-fluoro-isochroman-1yl]tetrahydrofuran-3,4-diol (Ex. 92 , 7 mg, 0.016 mmol, 75% yield) as a white solid.

LC-MS [M+H]: 420.2.

1H NMR (400 MHz, DMSO-d ₆ +D ₂ O): δ 8.67 (s, 1H), 7.75 (d, J=3.6, 1H), 7.55 (d, J=1 .6, 1H), 7.36 (d, J=8.8, 1H), 7.25 (d, J=8.4, 1H), 6.82 (d, J=4, 1H), 6 .25 (d, J=7.2, 1H), 5.67-5.52 (m, 1H).

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Example 93 Synthesis of (2R,3R,4S,5S)-2-(4-αminopyrrolo[2,3-d]pyrimidin-7-yl)-5-[(1R,4S)-6-chloro-4fluoroisochroman-1 -yl]tetrahydrofuran-3,4-diol (Ex. 93).

Stage 1. Synthesis of 7-[(3aR,4R,6R,6aR)-2,2-dimethyl-6-[(1R,4S)-6-chloro-4-fluoroisochromαn-1-yl]3а,4,6, 6a-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]pyrrolo[2,3-d]pyrimidin-4-amine (93a).

To a solution of 4-chloro-7-[(3aR,4R,6R,6aR)-2,2-dimethyl-6-[(1R,4S)-6-chloro-4-fluoroisochromαn-1-yl]3а,4, 6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]pyrrolo[2,3-d]pyrimidine (92c, 10 mg, 0.02 mmol) in 1,4-dioxane ( 2.5 ml) was added ammonia (2.5 ml, 0.02 mmol). The mixture was sealed and stirred at 120° C. for 16 hours. The mixture was concentrated in vacuo to give crude 7-[(3aR,4R,6R,6aR)-2,2-dimethyl-6-[(1R,4S)-6 -chloro-4-fluoroisochroman-1-yl]-3a,4,6,6a-tetrahydrofuro[3,4d][1,3]dioxol-4-yl]pyrrolo[2,3-d]pyrimidin-4-amine (93a), which was directly used in the next step.

LC-MS [M+H]: 461.2.

Stage 2. Synthesis of (2R,3R,4S,5S)-2-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-5-[(1R,4S)-6-chloro-4fluoro-isochroman -1-yl]tetrahydrofuran-3,4-diol (Ex. 93).

To a solution of 7-[(3aR,4R,6R,6aR)-2,2-dimethyl-6-[(1R,4S)-6-chloro-4-fluoro-isochroman-1-yl]-3а,4,6 ,6atetrahydrofuro[3,4-d][1,3]dioxol-4-yl]pyrrolo[2,3-d]pyrimidin-4-amine (93a, 10 mg, 0.02 mmol) in water (2 ml) 2,2,2-trifluoroacetic acid (1 ml, 13 mmol) was added. The mixture was stirred at 25°C for 60 minutes. The residue was purified by prep-HPLC eluting CH3CN in H ₂ O (0.1% NH4OH) from 5% to 95% to give (2R,3R,4S,5S)-2-(4-αminopyrrolo[2,3-d ]pyrimidin-7-yl)-5-[(1R,4S)-6-chloro-4fluoro-isochroman-1-yl]tetrahydrofuran-3,4-diol (5 mg, 0.011 mmol, 53% yield) as white solid.

LC-MS [M+H]: 421.1.

¹ H NMR (400 MHz, DMSO-d ₆ +D ₂ O): δ 8.06 (s, 1H), 7.55 (s, 1H), 7.39-7.32 (m, 1H), 7 .28 (d, J=19.2, 1H), 7.25 (d, J=8, 1H), 6.65 (d, J=3.6, 1H), 6.11 (d, J= 7.2, 1H), 5.64-5.51 (m, 1H), 4.99-4.98 (m, 1H), 4.53-4.50 (m, 1H), 4.40- 4.33(m, 1H), 4.31-4.25(m, 1H), 4.12-3.98(m, 1H), 3.95-3.91(m, 1H).

Example 97 Synthesis of (2R,3R,4S,5S)-2-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)-5-[(4R)-7,8-difluoro-4H1,3 -benzodioxin-4-yl]tetrahydrofuran-3,4-diol (Ex. 97).

Stage 1. Synthesis of 1,2-difluoro-3-(methoxymethoxy)benzene (97b).

To a clear colorless solution of 2,3-difluorophenol (97a, 3.08 g, 23.68 mmol) and N,N-diisopropylethylamine (4.95 ml, 28.41 mmol) under nitrogen at 0°C in an ice bath chloromethyl methyl ether (2.16 ml, 28.41 mmol) was added dropwise. The ice bath was removed and the clear orange reaction mixture was stirred at room temperature. After 35 minutes, TLC (2% EtOAc/hexane isomer mixture) showed a clear spot of product (rf=0.23) with no remaining phenol. The reaction mixture was concentrated and purified by flash column chromatography (0-3% EtOAc/mixture of hexane isomers, with a gradual increase to 30% to wash out the product due to the presence of blurred peaks). Product fractions were concentrated to give 1,2-difluoro-3(methoxymethoxy)benzene (97b, 2.79 g, 16.022 mmol, 68% yield) as a clear pale yellow oil.

LC-MS does not show good ionization.

Stage 2. Synthesis of [3,4-difluoro-2-(methoxymethoxy)phenyl]-[(3aR,4R,6S,6aS)-4-(4-chloropyrrolo[2,3d]pyrimidin-7-yl)-2, 2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanone (97c).

A solution of 1,2-difluoro-3-(methoxymethoxy)benzene (97b, 181.96 mg, 1.04 mmol) in diethyl ether (2 ml) was cooled in an ice bath. n-BuLi (0.67 mL, 1.07 mmol) was added dropwise, the solution was stirred cold for 3 min (to give a milk mixture) and the ice bath was removed. The reaction mixture turned into a pale yellow suspension. After 2 h the reaction mixture was returned to the ice bath and a solution of (3aR,4R,6S,6aS)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-N-methoxyN,2,2- trimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-carboxamide (1Ad, 150 mg, 0.39 mmol) in diethyl ether (1 ml). The bath was removed and the reaction mixture was stirred at room temperature to give an orange-red opaque mixture. After 2 h, LC-MS indicated that the reaction was complete. The reaction mixture was cooled in an ice bath and saturated NH ₄ Cl was added followed by EtOAc. The layers were separated and the aqueous layer was extracted with 2X EtOAc. The combined organic layers were washed with saturated aqueous sodium chloride, filtered through cotton wool, and concentrated to an orange oil which was purified by flash column chromatography, 5-40% EtOAc/hexane isomer mixture, to give [3,4-difluoro-2-( methoxymethoxy)phenyl]-[(3aR,4R,6S,6aS)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[ 3,4-d][1,3]dioxol-6-yl]methanone (97c, 77 mg, 0.15529 mmol, 40% yield).

LC-MS [M+H]: 496.0.

Step 3. Synthesis of (R)-[3,4-difluoro-2-(methoxymethoxy)phenyl]-[(3aR,4R,6R,6aR)-4-(4-chloropyrrolo[2,3d]pyrimidin-7-yl )-2,2-dimethyl-3а,4,6,6а-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanol (97d).

Amber solution [3,4-difluoro-2-(methoxymethoxy)phenyl]-[(3aR,4R,6S,6aS)-4-(4-chloropyrrolo[2,3d]pyrimidin-7-yl)-2,2 -dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanone (97c, 163 mg, 0.33 mmol) in toluene (5 ml) under atmosphere N ₂ was cooled to -78°C and diisobutylaluminum hydride (1 M in toluene; 0.66 ml, 0.66 mmol) was added slowly dropwise. The resulting clear yellow solution was stirred at -78° C. for 1 hour. LC-MS indicates the presence of a residual starting material. An additional portion of diisobutylaluminum hydride (1M in toluene; 0.2 ml, 0.2 mmol) was added. After 30 minutes, the reaction mixture was transferred to an ice bath, allowed to warm to 0° C., and quenched by the slow addition of a few milliliters of EtOAc, followed by the addition of several portions of saturated aqueous Rochelle's salt. The ice bath was removed, more EtOAc and saturated Rochelle's salt solution were added and the mixture was vigorously stirred. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with saturated aqueous sodium chloride, filtered through cotton wool, and concentrated to give (R)-[3,4-difluoro-2(methoxymethoxy)phenyl]-[(3aR,4R,6R,6aR)-4-( 4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6atetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanol ( 97d, 170 mg, 0.34145 mmol, 104% yield), which was used in the next reaction without further purification.

LC-MS [M+H]: 498.0.

Step 4 Synthesis of (R)-[3,4-difluoro-2-(methoxymethoxy)phenyl]-[(3aR,4R,6R,6aR)-2,2-dimethyl-4-(4methylpyrrolo[2,3-d ]pyrimidin-7-yl)-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanol (97e).

K (R)-[3,4-difluoro-2-(methoxymethoxy)phenyl]-[(3aR,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7yl)-2 ,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanol (97d, 170 mg, 0.34 mmol) and tetrakis(triphenylphosphine)palladium (0) (19.73 mg, 0.02 mmol) THF (10 ml) was added under nitrogen atmosphere in a closed 2 ml vial for microwave heating. The mixture was sparged with nitrogen for 10 minutes. Dimethylzinc (2M in a mixture of hexane isomers; 0.75 ml, 1.5 mmol) was carefully added via syringe (gas evolution) to give a light yellow solution which was heated to 70°C. The reaction mixture gradually turned dark orange. After 2 h, LC-MS indicated that the reaction was complete. The reaction mixture was cooled to room temperature, quenched with saturated NaHCO ₃ solution and extracted with 2X EtOAc. The combined organic layers were washed with saturated aqueous sodium chloride, filtered through cotton wool and concentrated. The crude product was purified by flash column chromatography, 14-100% EtOAc/mixture of hexane isomers to give (R)-[3,4-difluoro2-(methoxymethoxy)phenyl]-[(3aR,4R,6R,6aR)-2 ,2-dimethyl-4-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl ]methanol (97e, 111 mg, 0.23248 mmol, 68% yield).

LC-MS [M+H]: 478.1.

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Stage 5. Synthesis of 2,3-difluoro-6-[(R)-hydroxy-[(3aR,4R,6R,6aR)-2,2-dimethyl-4-(4-methylpyrrolo[2,3d]pyrimidine-7 -yl)-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methyl]phenol (97f).

To the mixture -7-yl)-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanol (97e, 85 mg, 0.18 mmol) and tetraethylammonium bromide (112 .24 mg, 0.53 mmol) was added with DCM (4 ml) and the resulting yellow solution was cooled in an ice bath. Chlorotrimethylsilane (0.07 mL, 0.53 mmol) was added and the reaction mixture was allowed to warm to room temperature in an ice bath and stirred at room temperature overnight. Additional tetraethylammonium bromide (112.24 mg, 0.53 mmol) and chlorotrimethylsilane (0.07 ml, 0.53 mmol) were added. After 4 h the reaction mixture was concentrated and purified by flash column chromatography (100% DCM-8% MeOH/DCM) to give 2,3-difluoro-6-[(R)-hydroxy-[(3aR,4R,6R, 6aR)-2,2-dimethyl-4-(4-methylpyrrolo[2,3-d]pyrimidin-7yl)-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol- 6-yl]methyl]phenol (97f, 43 mg, 0.01 mmol, 56% yield).

LC-MS [M+H]: 434.1.

Step 6. Synthesis of 4-methyl-7-[(3aR,4R,6R,6aR)-2,2-dimethyl-6-[(4R)-7,8-difluoro-4H-1,3-benzodioxin4-yl] -3а,4,6,6а-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]pyrrolo[2,3-d]pyrimidine (97g).

To an orange solution of 2,3-difluoro-6-[(R)-hydroxy-[(3aR,4R,6R,6aR)-2,2-dimethyl-4-(4methylpyrrolo[2,3-d]pyrimidine-7 -yl)-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methyl]phenol (97f, 56 mg, 0.13 mmol) in DMF (5 ml ) and DCM (2.5 ml) under nitrogen atmosphere was added sodium hydride (51.68 mg, 1.29 mmol) and the reaction mixture was heated to 80°C. After 5 hours, the reaction mixture was cooled in an ice bath, quenched with saturated aqueous NH ₄ Cl, diluted with saturated aqueous sodium chloride and extracted with 3X EtOAc. The combined organic layers were washed 3X with saturated aqueous sodium chloride, filtered through cotton wool, concentrated and dried under high vacuum. The crude product was purified by flash column chromatography, 13-100% EtOAc/hexane isomer mixture to give 4-methyl-7-[(3aR,4R,6R,6aR)-2,2-dimethyl-6-[(4R) 7,8-difluoro-4H-1,3-benzodioxin-4-yl]-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]pyrrolo[2, 3d]pyrimidine (97g, 31 mg, 0.0696 mmol, 54% yield).

LC-MS [M+H]: 446.0.

Step 7. Synthesis of (2R,3R,4S,5S)-2-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)-5-[(4R)-7,8-difluoro-4H1,3 -benzodioxin-4-yl]tetrahydrofuran-3,4-diol (Ex. 97).

Clear solution of 4-methyl-7-[(3aR,4R,6R,6aR)-2,2-dimethyl-6-[(4R)-7,8-difluoro-4H-1,3benzodioxin-4-yl]- 3a,4,6,6a-Tetrahydrofuro[3,4-d] [1,3]dioxol-4-yl]pyrrolo[2,3-d]pyrimidine (97g, 29 mg, 0.07 mmol) in methanol ( 2 ml) was briefly cooled in an ice bath, then hydrochloric acid (2 ml, 4 mmol) was added and the resulting slightly cloudy solution was stirred at room temperature. After 5 hours, the reaction mixture was cooled in an ice bath and carefully basified to pH ~ 8 with 1 N sodium hydroxide. NaOH, then extracted with 3X EtOAc. The combined extracts were washed with saturated aqueous sodium chloride, filtered through cotton wool and concentrated. The crude product was purified by flash column chromatography, 0-10% MeOH/DCM to give (2R,3R,4S,5S)-2-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)-5 -[(4R)-7,8-difluoro-4H-1,3-benzodioxin-4yl]tetrahydrofuran-3,4-diol (ex. 97, 20 mg, 0.0449 mmol, 69% yield).

LC-MS [M+H]: 406.1.

¹ H NMR (500 MHz, DMSO-06): δ 8.66 (s, 1H), 7.76 (d, J=3.8 Hz, 1H), 7.15 - 7.07 (m, 1H) , 7.00 (q, J=9.3 Hz, 1H), 6.80 (d, J=3.7 Hz, 1H), 6.31 (d, J=7.7 Hz, 1H), 5 .62 (d, J=5.7 Hz, 1H), 5.35 (d, J=6.9 Hz, 1H), 5.31 (d, J=5.7 Hz, 1H), 5.26 -5.22 (m, 2H), 4.56 (td, J=5.1, 7.3 Hz, 1H), 4.41 (dd, J=1.4, 4.5 Hz, 1H), 3.94 (t, J=4.9 Hz, 1H), 2.66 (s, 3H).

D ₂ O exchange: 1H NMR (500 MHz, DMSO-d ₆ ): δ 8.66 (s, 1H), 7.75 (d, J=3.8 Hz, 1H), 7.13-7.07 (m, 1H), 6.99 (td, J=7.2, 9.2, 9.6 Hz, 1H), 6.80 (d, J=3.8 Hz, 1H), 6.30 ( d, J=7.7 Hz, 1H), 5.61 (d, J=5.7 Hz, 1H), 5.30 (d, J=5.8 Hz, 1H), 5.23 (d, J=4.4Hz, 1H), 4.55(dd, J=5.1, 7.7Hz, 1H), 4.40(dd, J=1.4, 4.5Hz, 1H), 3.93 (dd, J=1.4.5.1 Hz, 1H), 2.66 (s, 3H).

- 107 042008

Example 98 Synthesis of 2,2,2-trifluoroacetate (2R,3S,4R,5R)-2-[(1R)-6-chloro-1,2,3,4-tetrahydroisoquinolin-1yl]-5-(4- methylpyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol (Ex. 98).

Step 1. (S)-[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-4-chlorophenyl]-[(3aR,4R,6R,6aR)-2,2-dimethyl-4(4 -methylpyrrolo[2,3-d]pyrimidin-7-yl)-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanol (98a).

Methyl magnesium bromide, 3.2 M in MeTHF (0.09 ml, 0.30 mmol) was added dropwise to the suspension of (S)-[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-4-chlorophenyl ]-[(3aR,4R,6R,6aR)-4-(4-chloropyrrolo[2,3d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4 -d][1,3]dioxol-6-yl]methanol (22d, 80 mg, 0.13 mmol) and iron (III) acetylacetonate (5 mg, 0.01 mmol) in THF (0.50 ml) at 0°C. The reaction mixture was stirred at 0°C for 40 min, then at room temperature overnight. The reaction mixture was quenched with EtOAc, then with saturated aqueous NH ₄ Cl, and the mixture was diluted with EtOAc. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over Na ₂ SO ₄ and concentrated. The crude product was purified by flash column chromatography (0-100% EtOAc/hexane) to give (S)-[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-4chlorophenyl]-[(3aR,4R,6R ,6aR)-2,2-dimethyl-4-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)-3a,4,6,6atetrahydrofuro[3,4-d][1,3]dioxol -6-yl]methanol (98a, 35 mg, 0.049 mmol, 36% yield) as a yellow oil.

LC-MS [M+H]: 574.16.

Step 2. 2-[(R)-[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-4-chlorophenyl]-[(3aR,4R,6R,6aR)-2,2dimethyl-4- (4-methylpyrrolo[2,3-d]pyrimidin-7-yl)-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6yl]methyl]isoindoline-1,3 -dione (98b).

Diisopropyl azodicarboxylate (0.02 mL, 0.12 mmol) was added dropwise to a solution of (S)-[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-4-chlorophenyl]-[(3aR,4R,6R, 6aR)-2,2-dimethyl-4-(4-methylpyrrolo[2,3d]pyrimidin-7-yl)-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol- 6-yl]methanol (98a, 35 mg, 0.06 mmol), triphenylphosphine (24 mg, 0.09 mmol) and phthalimide (13.45 mg, 0.09 mmol) in THF (0.50 ml). After 30 minutes, TLC (2:1 hexane/EA) indicated that the reaction was complete. The reaction mixture was concentrated and the crude product was purified by flash column chromatography (0-100% EtOAc/hexane) to give 2-[(R)-[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-4 -chlorophenyl]-[(3aR,4R,6R,6aR)-2,2-dimethyl-4-(4methylpyrrolo[2,3-d]pyrimidin-7-yl)-3a,4,6,6a-tetrahygrofuro[3 ,4-d][1,3]dioxol-6-yl]methyl]isoindoline 1,3-dione (98b, 37 mg, 0.042 mmol, 69% yield) as a yellow foamy solid.

LC-MS [M+H]: 703.2/705.2.

Step 3. (R)-[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-4-chlorophenyl]-[(3aR,4R,6R,6aR)-2,2dimethyl-4-(4- methylpyrrolo[2,3-d]pyrimidin-7-yl)-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6yl]methanamine (98c).

Hydrazine monohydrate (2.7 mg, 0.08 mmol) was added to a suspension of 2-[(R)-[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-4-chlorophenyl]-[(3aR,4R, 6R,6aR)-2,2-dimethyl-4-(4-methylpyrrolo[2,3d]pyrimidin-7-yl)-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3] dioxol-6-yl]methyl]isoindoline-1,3-dione (98b, 37 mg, 0.04 mmol) in EtOH (0.50 mL). The resulting mixture was stirred at room temperature overnight, then at 80° C. for 6 hours. The reaction mixture was concentrated to give the crude product, (R)-[2-[2-[t-butyl(dimethyl)silyl]oxyethyl]- 4-chlorophenyl]-[(3aR,4R,6R,6aR)-2,2-dimethyl-4-(4methylpyrrolo[2,3-d]pyrimidin-7-yl)-3a,4,6,6a-tetrahydrofuro[ 3,4-d][1,3]dioxol-6-yl]methanamine (98c, 40 mg, 0.042 mmol, 99.5% yield), which was used in the next step without purification.

LC-MS [M+H]: 574.2/576.1.

Step 4. tert-butyl N-[(R)-[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-4-chlorophenyl]-[(3aR,4R,6R,6aR)2,2- dimethyl 4-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6yl]methyl]carbamate (98d).

Triethylamine (0.01 ml, 0.08 mmol) was added dropwise to a suspension of (R)-[2-[2-[tert

- 108 042008 butyl(dimethyl)silyl]oxyethyl]-4-chlorophenyl]-[(3aR,4R,6R,6aR)-2,2-dimethyl-4-(4-methylpyrrolo[2,3d]pyrimidin-7-yl )-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanamine (98c, 40 mg, 0.04 mmol) and di-tert-butyl dicarbonate (18 mg , 0.08 mmol) in dry DCM (0.50 ml) at rt. and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and the residue was purified by flash column chromatography (0-8% MeOH/DCM) to give tert-butyl N[(R)-[2-[2- [tert-butyl(dimethyl)silyl]oxyethyl]-4-chlorophenyl]-[(3aR,4R,6R,6aR)-2,2-dimethyl-4-(4methylpyrrolo[2,3-d]pyrimidin-7-yl )-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methyl]carbamate (98d, 30 mg, 0.036 mmol, 85% yield).

LC-MS [M+H]: 673.1/675.3.

¹ H NMR (500 MHz, methanol-d4): δ 8.71 (s, 1H), 7.50 (d, J=3.7 Hz, 1H), 7.36 (d, J=8.4 Hz , 1H), 7.19-7.01 (m, 2H), 6.73 (d, J=3.7 Hz, 1H), 6.19 (d, J=2.5 Hz, 1H), 5 .33 (dd, J=2.4.6.6 Hz, 1H), 5.24 (dd, J=4.4.6.6 Hz, 1H), 5.16 (d, J=8.9 Hz, 1H), 4.32 (dd, J=4.4, 8.8 Hz, 1H), 3.62-3.52 (m, 1H), 3.46 (dt, J=5.6, 10.6 Hz, 1H), 2.72 (s, 3H), 2.50 (t, J=12.1 Hz, 2H), 1.63 (s, 2H), 1.60 (s, 3H) , 1.45 (d, J=10.3 Hz, 9H), 1.36 (s, 3H), 0.77 (s, 9H), -0.25 (d, J=15.6 Hz, 6H ).

Step 5. tert-butyl N-[(R)-[4-chloro-2-(2-hydroxyethyl)phenyl]-[(3aR,4R,6R,6aR)-2,2-dimethyl-4-(4methylpyrrolo[ 2,3-d]pyrimidin-7-yl)-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methyl]carbamate (98e).

A suspension of tert-butyl N-[(R)-[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-4-chlorophenyl][(3aR,4R,6R,6aR)-2,2-dimethyl- 4-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)-3a,4,6,6a-tetrahydrofuro[3,4d][1,3]dioxol-6-yl]methyl]carbamate (98d , 20 mg, 0.02 mmol), cesium fluoride (5.5 mg, 0.04 mmol) in DMSO (0.40 ml) was stirred at room temperature for 2 h. phase chromatography (10-100% MeCN/water) to give tert-butyl N-[(R)-[4-chloro-2-(2-hydroxyethyl)phenyl]-[(3aR,4R,6R,6aR)-2 ,2-dimethyl-4-(4methylpyrrolo[2,3-d]pyrimidin-7-yl)-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl] methyl]carbamate (98e, 10 mg, 0.018 mmol, 75% yield).

LC-MS [M+H]: 559.2/561.1.

Step 6 tert-butyl (1R)-6-chloro-1-[(3aR,4R,6R,6aR)-2,2-dimethyl-4-(4-methylpyrrolo[2,3d]pyrimidin-7-yl) -3а,4,6,6а-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-3,4-dihydro-1H-isoquinoline-2carboxylate (98f).

Diisopropyl azodicarboxylate (0.01 ml, 0.04 mmol) was added to a solution of triphenylphosphine (9.38 mg, 0.04 mmol) and tert-butyl N-[(S)-[4-chloro-2-(2-hydroxyethyl) phenyl]-[(3aR,4R,6R,6aR)-2,2dimethyl-4-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)-3a,4,6,6a-tetrahydrofuro[3, 4-d][1,3]dioxol-6yl]methyl]carbamate (98e, 10 mg, 0.02 mmol) in dry THF (0.50 mL). The reaction mixture was stirred at room temperature for 1 h. Diisopropyl azodicarboxylate (0.01 ml, 0.04 mmol) and triphenylphosphine (9.38 mg, 0.04 mmol) were added and the reaction mixture was stirred for an additional 1 h. The reaction mixture was concentrated and purified by flash column chromatography (0-12% MeOH in DCM) to give tert-butyl (1R)-6-chloro-1-[(3aR,4R,6R,6aR)-2,2-dimethyl-4 -(4methylpyrrolo[2,3-d]pyrimidin-7-yl)-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-3,4-dihydro -1Hisoquinoline-2-carboxylate (98f, 10 mg, 0.009 mmol, 52% yield).

LC-MS [M+H]: 541.1/543.3.

Step 7. 2,2,2-trifluoroacetate (2R,3S,4R,5R)-2-[(1R)-6-chloro-1,2,3,4-tetrahydroisoquinolin-1-yl]-5(4- methylpyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol (Ex. 98).

A mixture of tert-butyl (1R)-6-chloro-1-[(3aR,4R,6R,6aR)-2,2-dimethyl-4-(4-methylpyrrolo[2,3d]pyrimidin-7-yl)-3а ,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]-3,4-dihydro-1H-isoquinoline-2carboxylate (98f, 10 mg, 0.02 mmol), HCl (0.67 mg, 0.02 mmol) and methanol (0.50 ml) were stirred at room temperature overnight. LC-MS showed that acetonide was cleaved, but not Boc. The reaction mixture was concentrated and lyophilized to a white solid, which was dissolved in DCM (0.50 ml) and TFA (0.26 ml, 2.89 mmol) and stirred at room temperature for 1 h. The reaction mixture was concentrated and the residue was purified by reverse phase chromatography (0-70% MeCN/water/0.1% TFA) to give 2,2,2-trifluoroacetate(2R,3S,4R,5R)-2-[(1R)-6-chloro -1,2,3,4tetrahydroisoquinolin-1-yl]-5-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol (Ex. 98, 3 mg, 0.006 mmol , 30% yield) as a white solid.

LC-MS [M+H]: 401.1.

¹ H NMR (500 MHz, DMSO-d6): δ 8.74 (s, 1H), 7.37-7.15 (m, 3H), 7.00 (d, J=3.8 Hz, 1H) , 6.75 (d, J=3.8 Hz, 1H), 6.08 (d, J=4.0 Hz, 1H), 4.83 (d, J=3.2 Hz, 1H), 4 .50 (dd, J=3.3.5.5 Hz, 1H), 4.39 - 4.26 (m, 2H), 3.49 (dd, J=6.8, 13.3 Hz, 1H ), 3.33 (dt, J=6.0, 12.3 Hz, 1H), 3.00-2.82 (m, 2H), 2.69 (s, 3H).

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Example 102 Synthesis of (2R,3R,4S,5S)-2-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-5[(1R)-7-chloro-1,3,4 hydrochloride ,5-tetrahydro-2-benzoxepin-1-yl]tetrahydrofuran-3,4-diol (Ex. 102).

Etc. 102

Stage 1. Synthesis of ethyl 3-(2-bromo-5-chlorophenyl)prop-2-enoate (102b).

Ethyl 2-(diethoxyphosphoryl)acetate (102a, 12.258 g, 54.68 mmol) was slowly added to a solution of NaH (0.01 ml, 54.68 mmol) in dry THF (50 ml) at 0°C and stirred for 10 min. 2-bromo-5-chloro-benzaldehyde (46a, 10 g, 45.57 mmol) was added to the reaction mixture and stirred at room temperature for 1 h. TLC (petroleum ether, R _f = 0.2) and LC-MS showed that the reaction was complete. The reaction mixture was poured into ice water (100 ml), extracted with ethyl acetate (200 ml) and washed with water (50 ml) and saturated aqueous sodium chloride solution (50 ml). The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give a crude product which was purified by silica gel column chromatography (petroleum ether:ethyl acetate=100:1-50:1) to give ethyl 3-(2- bromo-5-chlorophenyl)prop-2-enoate (102b, 11.6 g, 36.58 mmol, 80% yield) as an off-white oil.

LC-MS [M+H]: 291.0.

¹ H NMR (400 MHz, CDCl3): δ 7.92-7.97 (m, 1H), 7.53-7.57 (m, 2H), 7.19-7.21 (m, 1H), 6.37-6.40 (m, 1H), 4.26-4.31 (m, 2H), 1.33-1.37 (m, 3H).

Stage 2. Synthesis of ethyl 3-(2-bromo-5-chlorophenyl)propanoate (102c).

Mixture of ethyl 3-(2-bromo-5-chlorophenyl)prop-2-enoate (102b, 5.0 g, 17.27 mmol), p-toluenesulfonyl hydrazide (32.15 g, 172.68 mmol) and sodium acetate trihydrate (35.24 g, 259.02 mmol) in THF (58 ml)/water (58 ml) was stirred and refluxed for 20 h. Water (50 ml) was added, then extracted with ethyl acetate (100 ml), washed water (2x300 ml) and saturated aqueous sodium chloride solution (100 ml). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product which was purified by silica gel column chromatography (petroleum ether:ethyl acetate=100:1-20:1) to give ethyl 3-(2-bromo-5 -chlorophenyl)propanoate (102c, 4.6 g, 13.8 mmol, 80% yield) as an off-white oil.

LC-MS [M+H]: 293.0.

1H NMR (400 MHz, CDCl3): δ 7.44-7.46 (m, 1H), 7.25-7.26 (m, 1H), 7.05-7.08 (m, 1H), 4 .12-4.18 (m, H), 3.01-3.05 (m, 2H), 2.61-2.65 (m, 2H).

Stage 3. Synthesis of 3-(2-bromo-5-chlorophenyl)propan-1-ol (102d).

To a solution of ethyl 3-(2-bromo-5-chlorophenyl)propanoate (102s, 4.6 g, 15.78 mmol) in toluene (50 ml) was added diisobutylaluminum hydride (31.55 ml, 47.33 mmol) at -78 °C under N2 atmosphere and the reaction mixture was stirred for 60 min at -78°C. TLC (petroleum ether:ethyl acetate=40:1, Rf=0.1, petroleum ether:ethyl acetate=10:1, Rf=0.3) indicated that the reaction was complete. To the mixture was added a saturated solution of NH ₄ Cl (100 ml), the mixture was extracted with ethyl acetate (100 ml) and washed with a saturated aqueous sodium chloride solution (50 ml). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed in vacuo to give crude 3-(2-bromo-5-chlorophenyl)propan-1-ol (102d) which was used in the next step without further purification.

Stage 4. Synthesis of 3-(2-bromo-5-chlorophenyl)-propoxy-tert-butyldimethylsilane (102e).

To a solution of 3-(2-bromo-5-chlorophenyl)propan-1-ol (102d, 5.1 g, 20.44 mmol) and imidazole (2.78 g,

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40.88 mmol) in DCM (20 ml) was added slowly tert-butylchlorodiphenylsilane (3.7 g, 24.53 mmol). The reaction mixture was stirred for 2 h at rt. TLC (petroleum ether, Rf=0.7) indicated that the reaction was complete. The solvent was removed in vacuo to give the crude product, which was purified by column chromatography on silica gel (petroleum ether) to give 3-(2bromo-5-chlorophenyl)-propoxy-tert-butyldimethylsilane (102e, 1.7 g, 4.67 mmol , 23% yield) as an almost white oil.

¹ H NMR (400 MHz, DMSO-d6): δ 7.56 (d, 0.83 s, J=7.6 Hz, 1H), 7.37 (d, J=2.8 Hz, 1H), 7.20 (d, J=2.8 Hz, 1H), 3.56-3.59 (m, 2H), 2.68-2.71 (m, 2H), 1.69-1.72 ( m, 2H), 0.83 (s, 9H), 0.00 (s, 6H).

Stage 5. Synthesis of [2-[3-[tert-butyl(dimethyl)silyl]oxypropyl]-4-chlorophenyl]-[4-(4chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2- dimethyl-3а,4,6,6а-tetrahydrofuro[3,4-d][1,3]dioxol-6yl]methanone (102f).

To a solution of 3-(2-bromo-5-chlorophenyl)propoxy-tert-butyldimethylsilane (102e, 1130.9 mg, 3.11 mmol) in THF (15 ml) was added n-butyllithium (175.71 mg, 2.74 mmol) at -78°C. The reaction mixture was stirred at -78°C for 10 min. 4-(4-Chloropyrrolo[2,3-d]pyrimidin-7-yl)-N-methoxyN,2,2-trimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1, 3]dioxol-6-carboxamide (1Ad, 700 mg, 1.83 mmol) and the reaction mixture was stirred for 1 h at -78°C. The reaction mixture was poured into water (20 ml), extracted with ethyl acetate (30 ml). The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate=1:7) to give [2-[3-[t-butyl( dimethyl)silyl]oxypropyl]-4-chlorophenyl]-[4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl3a,4,6,6a-tetrahydrofuro[3,4 -d][1,3]dioxol-6-yl]methanone (102f, 600 mg, 0.99 mmol, 54% yield) as a yellow oil.

LC-MS [M+H]: 606.2.

Step 6 Synthesis of (R)-[2-[3-[tert-butyl(dimethyl)silyl]oxypropyl]-4-chlorophenyl]-[(3aR,4R,6R,6aR)2,2-dimethyl-4-( 4-methylpyrrolo[2,3-d]pyrimidin-7-yl)-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6yl]methanol (102g).

To the mixture -d]pyrimidin-7-yl)-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanone (102f, 600 mg, 1.02 mmol) in toluene (3 ml) was added DIBAL-H (0.24 ml, 2.05 mmol) at -78°C. The mixture was stirred at -78°C for 30 minutes. The reaction mixture was poured into ethyl acetate (50 ml), concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate=8:1) to give (R)-[2-[3-[t-butyl (dimethyl)silyl]oxypropyl]-4-chlorophenyl]-[(3aR,4R,6R,6aR)-2,2-dimethyl-4-(4-methylpyrrolo[2,3d]pyrimidin-7-yl)-3a, 4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanol (102g, 320mg, 0.54mmol, 53% yield) as a yellow oil.

LC-MS [M+H]: 608.2.

Stage 7. Synthesis of 3-[5-chloro-2-[(R)-hydroxy-[(3aR,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7yl)-2 ,2-dimethyl-3а,4,6,6а-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methyl]phenyl]propan-1-ol (102h).

To a mixture of (S)-[2-[3-[tert-butyl(dimethyl)silyl]oxypropyl]-4-chlorophenyl]-[(3aR,4R,6R,6aR)-4-(4chloropyrrolo[2,3-d ]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6yl]methanol (102g, 550 mg, 0.90 mmol ) in THF (3 ml) was added tetrabutylammonium fluoride (0.03 ml, 1.08 mmol) at 25°C. The mixture was stirred at 25° C. for 30 minutes. The reaction mixture was poured into water (10 ml), extracted with ethyl acetate (20 ml). The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (ethyl acetate) to give 3-[5-chloro-2-[(R)-hydroxy[( 3aR,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4d][ 1,3]dioxol-6-yl]methyl]phenyl]propan-1-ol (102h, 410 mg, 0.83 mmol, 91.8% yield) as a yellow oil.

LC-MS [M+H]: 494.2.

Step 8. Synthesis of 4-chloro-7-[(3aR,4R,6R,6aR)-2,2-dimethyl-6-[(1R)-7-chloro-1,3,4,5-tetrahydro-2benzoxepin- 1-yl]-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]pyrrolo[2,3-d]pyrimidine (102i).

To a mixture of 3-[5-chloro-2-[(R)-hydroxy-[(3aR,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2 ,2dimethyl-3а,4,6,6а-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methyl]phenyl]propan-1-ol (102h, 100 mg, 0.20 mmol) in THF (4 ml) was added sodium hydride (0.06 ml, 0.40 mmol) at -5°C. The reaction mixture was stirred at -5°C for 10 min. Tosyl chloride (38.56 mg, 0.20 mmol) was added at -5°C, then stirred at -5°C for 30 min. The reaction mixture was poured into water (10 ml) and extracted with ethyl acetate (20 ml). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give crude 102i which was used in the next step without further purification.

LC-MS [M+H]: 476.3.

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Step 9. Synthesis of 7-[(3aR,4R,6R,6aR)-2,2-dimethyl-6-[(1R)-7-chloro-1,3,4,5-tetrahydro-2-benzoxepin1-yl] -3а,4,6,6а-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]pyrrolo[2,3-d]pyrimidin-4-amine (102j).

To a mixture of 4-chloro-7-[(3aR,4R,6R,6aR)-2,2-dimethyl-6-[(1R)-7-chloro-1,3,4,5-tetrahydro-2-benzoxepin- 1yl]-3a,4,6,6a-tetrahydrofuro[3,4-d] [1,3]dioxol-4-yl]pyrrolo[2,3-d]pyrimidine (102i, 84 mg, 0.18 mmol) in 1,4-dioxane (3 ml) was added ammonium hydroxide (61.81 mg, 1.76 mmol). The mixture was stirred at 110° C. for 16 hours. LC-MS showed the detection of 10% of the product. The reaction mixture was poured into water (10 ml) and extracted with ethyl acetate (20 ml). The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give a crude product which was purified by preparative HPLC eluting MeCN in water (0.1% NH ₃ . water) from 10% to 95% to give 7- [(3aR,4R,6R,6aR)-2,2-dimethyl-6-[(1R)-7-chloro-1,3,4,5-tetrahydro-2-benzoxepin-1-yl]-3а,4 ,6,6atetrahydrofuro[3,4-d][1,3]dioxol-4-yl]pyrrolo[2,3-d]pyrimidin-4-amine (102j, 10 mg, 0.022 mmol, 12% yield).

LC-MS [M+H]: 457.3.

Step 10. Synthesis of (2R,3R,4S,5S)-2-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-5-[(1R)-7chloro-1,3,4, hydrochloride, 5-tetrahydro-2-benzoxepin-1-yl]tetrahydrofuran-3,4-diol (Ex. 102).

To a mixture of 7-[(3aR,4R,6R,6aR)-2,2-dimethyl-6-[(1R)-7-chloro-1,3,4,5-tetrahydro-2-benzoxepin-1-yl] 3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]pyrrolo[2,3-d]pyrimidine-4-amine (102j, 10 mg, 0.02 mmol ) in methanol (2 ml) was added HCl (1.6 mg, 0.04 mmol). The mixture was stirred at 25° C. for 1 hour. The mixture was purified by preparative HPLC eluting MeCN in water:CH ₃ CN (0.1% HCl) 10 to 95% to give (2R,3R,4S,5S)- 2-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-5-[(1R)-7-chloro-1,3,4,5-tetrahydro2-benzoxepin-1-yl]tetrahydrofuran-3 ,4-diol; hydrochloride (sp. 102, 1.46 mg, 0.0031 mmol, 14% yield) as a white solid.

LC-MS [M+H]: 417.3.

1H NMR (400 MHz, DMSO-d ₆ ): δ 8.44-8.45 (m, 1H), 8.20 (d, J=5.6 Hz, 1H), 7.08-7.10 ( m, 3H), 6.82 (d, J=4 Hz, 1H), 6.66-6.69 (m, 1H), 6.22 (d, J=3.6 Hz, 1H), 5, 69 (m, 2H), 5.26 (d, J=2 Hz 1H), 5.16 (d, J=4 Hz 2H), 3.94-3.97 (m, 1H), 3.45- 3.59 (m, 1H), 2.73-2.77 (m, 2H), 1.96-2.03 (m, 2H), 1.58-1.62 (m, 2H).

1H NMR (400 MHz, DMSO-d ₆ +D2O): δ 8.42-8.43 (m, 1H), 8.20-8.22 (m, 1H), 7.07-7.11 (m , 3H), 6.83 (d, J=4 Hz, 1H), 6.24 (d, J=3.6 Hz, 1H), 5.67-5.71 (m, 2H), 4.84 -4.87(m, 1H), 3.95-3.98(m, 1H), 2.74-2.77(m, 2H), 1.98-2.01(m, 2H), 1 .54-1.60 (m, 2H).

Example 101 Synthesis of (2R,3R,4S,5S)-2-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)-5-[(1R)-7-chloro1,3,4,5 -tetrahydro-2-benzoxepin-1-yl]tetrahydrofuran-3,4-diol (Ex. 101).

1O2i 101a 1O1b Ex. 101

Stage 1. Synthesis of 3-[5-chloro-2-[(R)-hydroxy-[(3aR,4R,6R,6aR)-2,2-dimethyl-4-(4-methylpyrrolo[2,3d]pyrimidine- 7-yl)-3a,4,6,6a-tetrahydrofuro[3,4-d] [1,3]dioxol-6-yl]methyl]phenyl]propan-1-ol (101a).

To a mixture of 3-[5-chloro-2-[(R)-hydroxy-[(3aR,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]-pyrimidin-7-yl)- 2,2dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methyl]phenyl]propan-1-ol (102i, 20 mg, 0.04 mmol ) and iron acetylacetonate (7.14 mg, 0.02 mmol) in THF (2 ml) was added methylmagnesium bromide (48.24 mg, 0.40 mmol) at -10°C. The mixture was heated to 0° C. and stirred for 1 hour. TLC (petroleum ether:ethyl acetate=5:1, Rf=0.7) indicated that the reaction was complete. The reaction mixture was poured into water (5 ml), extracted with DCM (3x5 ml). The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=7:1) to give 3-[5-chloro-2-[(R)-hydroxy[(3aR,4R,6R,6aR)-2.2 -dimethyl-4-(4-methylpyrrolo[2,3-d]pyrimidin-7-yl)-3a,4,6,6a-tetrahydrofuro[3,4d][1,3]dioxol-6-yl]methyl] phenyl]propan-1-ol (101a, 10 mg, 0.0211 mmol, 52% yield) as a yellow oil.

LC-MS [M+H]: 474.2.

Stage 2. Synthesis of 4-methyl-7-[(3aR,4R,6R,6aR)-2,2-dimethyl-6-[(1R)-7-chloro-1,3,4,5-tetrahydro-2benzoxepin- 1-yl]-3а,4,6,6а-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]pyrrolo[2,3-d]pyrimidine (101b).

To a mixture of 3-[5-chloro-2-[(R)-hydroxy-[(3aR,4R,6R,6aR)-2,2-dimethyl-4-(4-methylpyrrolo[2,3-d]pyrimidine7- yl)-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methyl]phenyl]propan-1-ol (101a, 20 mg, 0.04 mmol) in THF (2 ml) was added sodium hydride (0.06 ml, 0.08 mmol) at -5°C and the reaction mixture was stirred for 10 min at -5°C. Tosyl chloride (8.05 mg, 0.04 mmol) was added and the mixture was stirred at -5° C. for 30 minutes. LC-MS showed that the reaction was complete. The reaction mixture was poured into NH ₄ Cl (10 ml) and extracted with ethyl acetate (10 ml). The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=7:1) to give 4-methyl-7-[(3aR,4R,6R,6aR)-2,2dimethyl-6-[(1R)-7 -chloro-1,3,4,5-tetrahydro-2-benzoxepin-1-yl]-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol

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4-yl]pyrrolo[2,3-d]pyrimidine (101b, 4 mg, 0.0088 mmol, 21% yield) as a white solid.

LC-MS [M+H]: 456.3.

Stage 3. Synthesis of (2R,3R,4S,5S)-2-(4-methylpyrrolo[2,3-d]n-yrimidin-7-yl)-5-[(1R)-7-chloro-1,3,4 ,5tetrahydro-2-benzoxepin-1-yl]tetrahydrofuran-3,4-diol (Ex. 101).

To a mixture of 4-methyl-7-[(3aR,4R,6R,6aR)-2,2-dimethyl-6-[(1R)-7-chloro-1,3,4,5-tetrahydro-2-benzoxepin1- yl]-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]pyrrolo[2,3-d]pyrimidine (101b, 4 mg, 0.01 mmol) in methanol (2 ml) was added HCl (0.64 mg, 0.02 mmol). The mixture was stirred at 25° C. for 1 hour. The reaction mixture was purified by preparative HPLC eluting MeCN in water (0.1% TFA) from 10 to 95% to give (2R,3R,4S,5S)-2-( 4-methylpyrrolo[2,3-d]pyrimidin-7-yl)-5-[(1R)-7-chloro-1,3,4,5tetrahydro-2-benzoxepin-1-yl]tetrahydrofuran-3,4- diol (pr. 101, 1 mg, 0.0024 mmol, 27% yield) as a white solid.

LC-MS [M+H]: 416.3.

1H NMR (400 MHz, DMSO-d ₆ ): δ 8.66 (s, 1H), 8.44 (s, 2H), 7.62 (d, J=3.6 Hz, 1H), 7.30 (d, J=1.6 Hz, 1H), 7.18-7.25 (m, 2H), 6.77 (d, J=3.6 Hz, 1H), 6.29 (d, J= 7.6 Hz, 1H), 5.44-5.53 (m, 1H), 4.78 (d, J=4.2 Hz, 1H), 4.61-4.64 (m, 1H), 4.39 (d, J=4.8 Hz, 1H), 4.25-4.30 (m, 2H), 3.10-3.16 (m, 1H), 2.89-2.94 ( m, 1H), 2.65-2.67 (m, 3H), 1.68-1.77 (m, 2H).

1H NMR (400 MHz, DMSO-d ₆ +D ₂ O): δ 8.67 (s, 1H), 8.43 (s, 4H), 7.62 (d, J=4 Hz, 1H), 7 .30 (d, J=1.6 Hz, 1H), 7.18-7.25 (m, 2H), 6.78 (d, J=3.6 Hz, 1H), 6.29 (d, J=8Hz, 1H), 4.7 8(d, J=4.2Hz, 1H), 4.62-4.65(m, 1H), 4.39(d, J=4.2Hz , 1H), 4.25-4.30 (m, 2H), 3.10-3.12 (m, 1H), 2.89-2.94 (m, 1H), 2.65-2.69 (m, 3H), 1.68-1.81 (m, 2H).

Table 1

Examples were prepared according to the above procedures.

Etc name no. Structure Obtained in accordance with Rev. No. Spectral Data 4 but 9%—, ^F nh ₂ 1A HC1 salt: Ή NMR (400 MHz, DMSOάβγ. δ 8.40 (s, 1H), 7.72 (d, J= 3.2 Hz, 1H), 7.45-7.49 (m, 1H), 7.32-7.36 (m, 1H), 7.06 (s, 1H), 6.19 (d, J = 7.2 Hz, 1H), 5.36 (s, 1H), 5.04 -5.13(m, 2H), 4.48(t, J=6.0Hz, 1H), 4.21(d, J=4.4Hz, 1H), 3.89(d, J = 4.4 Hz, 1H). 12 but _h 15 Ή NMR (400 MHz, DMSOJ6+D ₂ O): 68.66 (s, 1H), 7.74 (d, J= 3.2 Hz, 1H), 7.44 (s, 1H), 7.32 (d, J= 8.4 Hz, 1H), 7.25 (d, J= 8.0 Hz, 1H), 6.84 (d, J= 3.2 Hz, 1H), 6.29 (d , J= 7.2 Hz, 1H), 5.38 (br, 1H), 5.07-5.15 (m, 2 H), 4.56-4.59 (m, 1H), 4.16 (d, J = 4.4 Hz, 1H), 3.95 (d, J = 4.8 Hz, 1H), 2.68 (s, 3 n). 16 but ^but <J nh ₂ 1A Ή NMR (DMSO + O2O, 400 MHz) δ 8.07 (s, 1H), 7.74 (s, 1H), 7.63-7.65 (d, J = 8.0 Hz, 1H), 7 .45-7.47 (d, J= 8.0 Hz, 1H), 7.32-7.33 (d, J= 3.6 Hz, 1H), 6.66 (d, J= 3.6 Hz, 1H), 6.15-6.17

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(d, J= Ίβ Hz, 1H), 5.47 (m, IH), 5.165.18 (m, 2 H), 4.52-4.55 (m, IH), 4.134.14 (m, IH ), 3.97-3.98 (m, IH). 17 but ^but <1 co 15 Ή NMR (DMSO-D6+O ₂ O, 400 MHz) δ 8.67 (s, 1H), 7.74-7.76 (m, 2H), 7.627.64 (d, J= 7.6 Hz , 1H), 7.44-7.46 (d, J= 8.0 Hz, 1H), 6.82-6.83 (d, J= 3.6 Hz, 1H), 6.28-6, 30 (d, J= 7.6 Hz, 1H), 5.49 (m, 1H), 5.17-5.20 (m, 2H), 4.59-4.62 (m, 1H), 4.17-4.19 (m, 1H), 3.98-3.99 (m, 1H), 2.68 (s, 3H) 42 h ₂ n V^-N PH Ul °K/0N PS ϊ 44, ΙΑ LCMS [M+H]: 433.1 Ή NMR (400 MHz, DMSO-s/6) δ 8.39 (s, 1H), 7.71 (s, 1H), 7.23-7.32 (m, 3H) 7.05 (s, 1H ), 6.22 (d, 1H), 5.27 (d, 1H), 4.82 (d, 1H), 4.48-4.51 (m, 2H), 3.87 (d, 1H) , 3.07-3.12 (q, 2H), 2.78 (d, 1H). Ή NMR (400 MHz, DMSO-D6+ D2O) δ 8.37 (d, 1H), 7.73 (s, 1H) 7.25-7.32 (m, 3H), 7.02 (s, 1H) , 6.23 (d, 1H), 5.28 (s, 1H), 4.84 (s, 1H), 4.50-4.52 (m, 2H), 3.86 (d, 1H), 3.09 (d, 1H), 2.78 (d, 1H). The CH3 peak is below the water peak.

- 114042008

43 h ₂ n N PH 5-g °UOH XXI 50, IA LCMS [M+H]: 419.0 SNMR (400 MHz, DMSO pure) δ 8.05 (s, 1H), 7.58 (s, 1H), 7.06 (s, 1H) 7.227.41 (m, 3H), 7.10 (s, 2H ), 6.61-6.64 (m, 2H), 6.16-6.23 (m, 1H), δ 5.56 (s, 1H), 5.15-5.18 (m, 1H) , 4.95-5.06 (m, ZN) 4.38-4.52 (m, ZN), 3.85 (s, 1H), 3.72-3.74 (m, 1H), 2, 76-2.90 (m, 1H), δ 2.49-2.51 (m, 1H). Ή NMR (400 MHz, DMSO-s/6+ D2O) δ 8.06 (s, 1H), 7.61 (s, 1H), 7.22-7.34 (m, 3H) 6.65 (s , 1H), 6.16-6.23(m, 1H), 5.56(s, 1H), 4.95-5.02(m, 2H), δ 4.39-4.53(m, 2H), 3.71-3.85 (d, 1H), 2.90-3.00 (m, 1H), 2.67-2.80 (m, 1H). 68 nh ₂ yC NOD/ xx cr 22, IA LCMS [M+H]: 403.2. 1HNMR (400 MHz, DMSO-άό): δ 8.06 (s, 1H), 7.37 (d, J=3.6 Hz, 1H), 7.28-7.31 (m, 2H), 7.21-7.24 (m, 1H), 7.01 (s, 2H), 6.64 (d, J = 4.0 Hz, 1H), 6.17 (d, J = 7.6 Hz, 1H), 5.13(br, 2H), 4.86-4.88(m, 1H), 4.43-4.47( _m , 1H), 4.35-4.36(m , 1H), 4.21-4.24 (m, 1H), 3.83-3.85 (m, 1H), 3.64-3.71 (m, 1H), 2.89-2.94 (m, 1H), 2.69-2.74 (m, 1H). 1HNMR (400 MHz, DMSO-06 + O2O): δ 8.07 (s, 1H), 7.38 (d, J = 4.0 Hz, 1H), 7.27 -7.29 (m, 2H ), 7.22-7.25 (m, 1H),

- 115 042008

6.66 (d, J = 3.6 Hz, 1H), 6.18 (d, J = 7.6 Hz, 1H), 4.87-4.88 (m, 1H), 4.444.48 (m , 1H), 4.37-4.39 (m, 1H), 4.214.25 (m, 1H), 3.83-3.85 (m, 1H), 3.643.70 (m, 1H), 2, 91-2.99(m, 1H), 2.702.74(m, 1H). 70 4^5 /---\ N-^ x\0 \ ,/ Ck Wv '° 22 LCMS [M+H]: 402.2. 1HNMR (400 MHz, DMSO-06 + O2O) 58.95 (s, 1H), 8.07 (d, 7=2.1 Hz, 1H), 7.29-7.15 (m, 4H), 6 .34 (d, 7=7.5 Hz, 1H), 4.90 (br.s., 1H), 4.55-4.49 (m, 2H), 4.284.24 (m, 1H), 3.83-3.82 (m, 1H), 3.663.61 (m, 1H), 2.93-2.86 (m, 4H), 2.692.65 (m, 1H). 71 nh ₂ NO**Y ,Z° Ck A '° 22.1A LCMS [M+H]: 403.3. 1HNMR (400 MHz, DMSO-06 + O2O) 58.32 (s, 1H), 7.71 (d, 7=3.1 Hz, 1H), 7.26-7.21 (m, 3H), 6 .98 (s, 1H), 6.18 (d, 7=7.4 Hz, 1H), 4.86 (br.s., 1H), 4.49-4.44 (m, 2H), 4.23-4.21(m, 1H), 3.81-3.80(m, 1H), 3.64-3.59(m, 1H), 2.90-2.85(m, 1H ), 2.68-2.63 (m, 1H). 72 Cl i rJ h ₂ n 22.1A LCMS [M+H]: 403.2. 1HNMR (400 MHz, DMSO-ab) 58.06 (s, 1H), 7.37 (d, J = 4 Hz, 2 H), 7.29 (d, J = 7.6 Hz, 1H), 7 .24 -7.20 (t, J = 7.6 Hz, 1H), 7.01 (s, 2 H), 6.64 (d, J = 3.6 Hz, 1H), 6.17 (d , J = 7.6 Hz, 1H), 5.17 (d, J = 7.2 Hz, 1H), 5.04 (d, J = 4 Hz, 1H),

- 116 042008

4.90 (br, 1N), 4.47 -4.40 (m, 2N), 4.33 -4.28 (m, 1N), 3.83 (t, J = 7.6 Hz, 1N ), 3.76 -3.69 (m, 1H), 2.87 -2.76 (m, 2H). 1HNMR (400 MHz, DMSO-6O2O) 58.08 (s, 1H), 7.40 -7.37 (m, 2H), 7.29 -7.22 (m, 2H), 6.67 ( d, J = 3.6 Hz, 1H), 6.18 (d, J = 7.6 Hz, 1H), 4.91 (br, 1H), 4D8 -4.42 (m, 2 H), 4 .33 -4.30 (m, 1H), 3.83 -3.78 (m, 2H), 2.81 (br., 2H). 73 νη _ξ 22.1A LCMS [M+H]: 405.3. 1HNMR (400 MHz, DMSO-D6 + O2O): 5 8.08 (s, 1H), 7.35 -7.31 (m, 3H), 7.01 -7.04 (m, 2H), 6, 63 -6.65 (m, 1H), 6.17 (d, J= 8.0, 1H) 5.17 -5.19 (d, J= 8.8 Hz, 1H), 5.07 (d , J= 4.0 Hz, 1H), 4.83 (d, J= 3.6 Hz, 1H), 4.44 -4.49 (m, 1H), 4.35 4.38 (m, 1H ), 4.20 -4.24 (m, 1H), 3.84 3.87 (m, 1H), 3.64 -3.72 (m, 1H), 2.85 2.93 (m, 1H ), 2.76 -2.71 (m, 1H). 74 H r=7iS \ r* N - but^\^° 22 LCMS [M+H]: 404.4. 1HNMR (400 MHz, DMSO-06 + O2O): 5 8.87 (s, 1H), 7.95 (d, J=3.6 Hz, 1H), 7.28 7.41 (m, 2H), 7.02 (d, J = 3.6 Hz, 1H), 6.3 (d, J = 8.0 Hz, 1H), 4.88 (s, 1H), 4D7 .4.54 (m, 2H ), 4.24 -4.28 (m, 1H), 3.85 (m, 1H), 3.48 -3.72 (m, 1H), 2.88 (m, 1H), 2.79 ( s, ZN), 2.68 -2.72 (m, 1H).

- 117042008

75 Cl rl ⁴ 22 LCMS [M+H]: 402.2. 1HNMR (400 MHz, DMSO-C16) δ 8.67 (s, 1H), 7.77 (d, J = 3.6 Hz, 1H), 7.37 (d, J = 8 Hz, 1H), 7 .37 (d, J = 7.6 Hz, 1H), 7.22 (t, J = 7.6 Hz, 1H), 6.81 (d, J = 3.6 Hz, 1H), 6.30 (d, J = 7.6 Hz, 1H), 5.26 (d, J = 7.2 Hz, 1H), 5.5.13 (d, J = 4 Hz, 1H), 4.92 (br .1H), 4.53 -4.46 (m, 2H), 4.34 -4.3o ( _m , 1H), 3.84 (t, J = 4.4 Hz, 1H), 3.77 -3.70 (m, 1H), 2.87 -2.76 (m, 2H), 2.67 (s, 3H). 1HNMR (400 MHz, DMSO-06 + O2O) δ 8.67 (s, 1H), 7.77 (d, J = 4 Hz, 1H), 7.40 -7.36 (m, 1H), 7, 30 -7.23 (m, 2H), 6.84 (d, J = 4 Hz, 1H), 6.31 (d, J = 7.6 Hz, 1H), 4.93 (br, 1H) , 4.54 -4.48 (m, 2H), 4.36 -4.32 (m, 1H), 3.82 (d, J = 5.6 Hz, 1H), 3.79 (s, 1H), 2.84 -2.81 (br, 2H), 2.68 (s, 3N). 77 F o ⁴ *'\<* ^he *---X /(V/ \ _H h ₂ n 22.1A LCMS [M+H]: 405.2. 1HNMR (400 MHz, DMSO-ab) δ 8.06 (s, 1H), 7.38 7.37 (d, J = 4 Hz, 1H), 7.27 -7.22 (m, 1H), 7 .17-7.13 (m, 1H), 7.02 (s, 2H), 6.65-6.64 (d, J = 4 Hz, 1H), 6.18-6.17 (d, J = 4 Hz, 1H), 5.21 -5.20 (d, J = 4 Hz, 1H), 5.08 -5.07 (d, J = 4 Hz, 1H), 4.87 -4, 86 (d, J = 4 Hz, 1H), 4.46 -4.45 (m, 1H), 4.39 -4.38(d, J = 4 Hz, 1H), 4.29 -4.25 (m, 1H), 3.89-3.88 (m, 1H), 3.75-3.67 (m, 1H), 2.84-2.80 (m, 2H).

-118042008

1HNMR (400 MHz, DMSO-ab + O2O) δ 8.07 (s, 1H), 7.38 -7.37 (d, J = 4 Hz, 1H), 7.26 -7.24 (m, IH ), 7.17 -7.14 (m, 1H), 6.65 -6.64 (d, J = 4 Hz, IH), 6.18 6.17 (d, J = 4 Hz, IH), 4.87 -4.86 (d, J = 4 Hz, IH), 4.46 -4.45 (m, IH), 4.39 4.38 (d, J = 4 Hz, IH), 4, 29 -4.25 (m, IH), 3.89 -3.88 (m, IH), 3.75 -3.67 (m, IH), 2.81 (s, 2 H). 78 FF h ₂ n 76.1A LCMS [M+H]: 405.1. 1HNMR (400 MHz, DMSO-c16) δ 8.08 (s, 1H), 7.73 (d, J=8 Hz, 1H), 7.57-7.48 (m, 3H), 7.34 (d, J = 3.6 Hz, 1H), 7.05 (s, 2 H), 6.66 (d, J = 3.6 Hz, 1H), 6.20 (d, J = 7.6 Hz, 1H), 5.26 (d, J = 7.2 Hz, 1H), 5.11 (d, J = 4.4 Hz, 1H), 5.06 (m, 1H), 4.56 - 4.40 (m, 3 H), 4.15 -4.05 (m, 1 H), 3.80 (t, J = 4.2 Hz, 1 H). 1HNMR (400 MHz, DMSO-ab, +D2O) δ 8.08 (s, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.57 -7.47 (m, 3H ), 7.34 (d, J = 3.6 Hz, 1H), 6.67 (d, J = 3.6 Hz, 1H), 6.20 (d, J = 8 Hz, 1H), 5, 07 (m, 1H), 4.56-4.41 (m, 3H), 4.13-4.04 (m, 1H), 3.81-3.796 (m, 1H).

- 119 042008

79 F w ^h 22 LCMS [M+H]: 404.2. 1HNMR (400 MHz, DMSO-C16): δ 8.67 (s, 1H), 7.77-7.76 (d, J = 4 Hz, 1H), 7.27-7.25 (m, 1H) , 7.17 -7.14 (m, 1H), 6.81 -6.80 (d, J = 4 Hz, 1H), 6.31 -6.29 (d, J = 8 Hz, 1H), 5.29 -5.28 (d, J = 4 Hz, 1H), 5.15 -5.14 (d, J = 4 Hz, 1H), 4.90 -4.89 (d, J = 4 Hz , 1H), 4.53 -4.51 (m, 1H), 4.45 -4.44 (m, 1H), 4.32 -4.29 (m, 1H), 3.90 -3.88 (m, 1H), 3.73 -3.70 (m, 1H), 2.84 -2.82 (m, 2H), 2.67 (s, 3H). 1HNMR (400 MHz, DMSO-06 + O2O): δ 8.66 (s, 1H), 7.79 -7.78 (d, J = 4 Hz, 1H), 7.25 -7.20 (m, 1H), 7.14 -7.11 (m, 1H), 6.88 -6.87 (d, J = 4 Hz, 1H), 6.33 6.31 (d, J = 8 Hz, 1H) , 4.90 (s, 1H), 4.59 -4.57 (m, 1H), 4.55 -4.50 (m, 1H), 4.35 -4.31 (m, 1H), 3 .90 -3.89 (m, 1H), 3.70 -3.68 (m, 1H), 2.87 -2.85 (m, 2H), 2.70 (s, 3H). 80 h de no*su° 22.1V LCMS [M+H]: 402.2. 1HNMR (400 MHz, DMSOH + O2O): δ 8.62 (s, 1H), 7.66 (d, J = 3.6 Hz, 1H), 7.27 (d, J = 8.4 Hz, 1H ), 7.21 -7.15 (m, 2H), 6.76 (d, J= 4 Hz, 1H), 6.20 (d, J= 6.4 Hz, 1H), 4.93 ( s, 1H), 4.49 (s, 1H), 4.46 4.44 (m, 1H), 4.36 -4.33 (m, 1H), 4.26 4.22 (m, 1H) , 3.76-3.69 (m, 1H), 2.87-2.78 (m, 1H), 2.68-2.63 (m, 4H).

- 120042008

84 F Cl O/, „ _t cXx. ^oh o ⁴ pQi h ₂ n 83, ΙΑ LCMS [M+H]: 421.1 Ή NMR (400 MHz, DMSO-de) 8.06 (s, 1H), 7.39 (d, 7=3.6 Hz, 1H), 7.327.27 (m , 2H), 7.03(s, 2H), 6.65(d, 7=3.6Hz, 1H), 6.18(d, 7=7.6Hz, 1H), 5.23(d , 7=7.2 Hz, 1H), 5.13(d, 7=4.4 Hz, 1H), 4.88 (d, 7=3.6 Hz, 1H), 4.62 (dd, 7 =6.8 Hz, 1H), 4.40 (d, 7=3.2 Hz, 1H), 4.27(s, 1H), 3.87 (t, 7=4 Hz, 1H), 3, 69(s, 1H), 2.76(s, 2H). Ή NMR (400 MHz, DMSOD ₆ +O ₂ O) 8.07 (s, 1H), 7.40 (d, 7=3.2 Hz, 1H), 7.30-7.24 (m, 2H) , 6.67 (d, 7=4Hz, 1H), 6.18 (d, 7=8Hz, 1H), 4.89 (d, 7=3.6Hz, 1H), 4.78 (dd, 7 =6.8 Hz, 1H), 4.39 (d, 7=3.2 Hz, 1H), 4.26 (s, 1H), 3.88 (d, 7=5.2 Hz, 1H), 3.70 (s, 1H), 2.76 (s, 2H). 85 F \\-//( Λ N HO. .N^—(A )1 \ / /----( ^N - cP \ l'' ^x '° ar 87.15 LCMS [M+H]: 420.1 Ή NMR (400 MHz, DMSO-de) δ 8.71 (s, 1H), 7.69 (s, 1H), 7.23-7.31 (m, 3H), 6.36 (m, 1H ), 5.18-5.30 (m, 2H), 4.89 (s, 1H), 4.41-4.45 (m, 2H), 4.264.29 (m, 1H), 3, 81-3.83 (m, 1H), 3.663.72 (m, 1H), 2.90-2.97 (m, 1H), 2.702.74 (m, 4H).

- 121 042008

Ή NMR (400 MHz, DMSO-a ₆ + B ₂ O) δ 8.71 (s, 1H), 7.69 (s, 1H), 7.23-7.31 (m, 3 H), 6, 36 (m, 1H), 4.89 (s, 1H), 4.414.45 (m, 2H), 4.26-4.29 (m, 1H), 3.813.83 (m, 1H), 3. 66-3.72 (m, 1H), 2.902.97 (m, 1H), 2.70-2.74 (m, 4H). 87 4.^-2 —\ CT \ /X — x\ ¹ \ // Vk 0 (( ) > t \A // o o 89, 22 LCMS [M+H]: 436.1 Ή NMR (400 MHz, DMSO-de) δ 8.80 (s, 1H), 7.88 (s, 1H), 7.59 (s, 1H), 7, 52 (s, 1H), 6.94 (s, 1H), 6.33-6.31 (d, 7=8 Hz, 1H), 5.43-5.11 (m, 2H), 4, 91-4.90 (d, 7=4 Hz, 1H), 4.52-4.51 (m, 1H), 4.46-4.45 (m, 1H), 3.87-3.86 ( d, 7=4 Hz, 1H), 3.69-3.65(m, 1H), 3.302.96(m, 1H), 2.92-2.90(m, 1H), 2.74(s , 3H), 2.71 (s, 1H). Ή NMR (400 MHz, DMSOOb+O ₂ O) 68.84 (s, 1H), 7.93-7.92 (d, 7=4 Hz, 1H), 7.56 (s, 1H), 7, 52 (s, 1H), 7.017.00 (d, 7=4 Hz, 1H), 6.34-6.32 (d, 7=8 Hz, 1H), 4.91 (s, 1H), 4. 55-4.52 (m, 1H), 4.48-4.47 (d, 7=4 Hz, 1H), 4.284.24 (m, 1H), 3.88-3.87 (d, 7= 4 Hz, 1H), 2.93-2.90(m, 1H), 2.77(s, 3H), 2.76(s, 1H).

- 122 042008

99 "But \\ )/--- ^N < + ^he Λ--/ Chu/ 'ON TOO cr — — 100, 22 LCMS [M+H]: 416.2 Ή NMR (400 MHz, DMSO-a ₆ + B ₂ O) 59.02 (s, 1H), 8.08-8.10 (m, 1H), 7.267.28 (m, 2H), 7.20-7.21 (d, 7=4 Hz, 1H), 6.37-6.41 (m, 1H), 4.91 (s, 1H), 4.53 -4.55(m, 2H), 4.27-4.31(m, 1H), 3.78-3.83(m, 1H), 3.63-3.68(m, 1H), 2.90-2.93 (m, 4H), 2.67-2.71 (d, 7=16Hz, 1H), 2.25 (s, 3H). 100 η ₂ ν Λ )/--- ^Ν < + ^he Y--/ Chu/'on C|/ 88 using 2Br-6-Cl-4methylbenzal code LCMS [M+H]: 417.2 Ή NMR (400 MHz, DMSO-a ₆ + H ₂ O) 58.40 (s, 1H), 7.72-7.73 (d, 7=3.6 Hz , 1H), 7.27-7.28 (m, 2H), 7.04-7.05 (d, 7=4 Hz, 1H), 6.20-6.22 (d, 7=7, 6 Hz, 1H), 4.87(s, 1H), 4.44-4.51(m, 2H), 4.25-4.27(m, 1H), 3.77-3.78( e, 7=4.8 Hz, 1H), 3.61-3.68(m, 1H), 2.66-2.91(m, 2H), 2.28(s, 3H). 103 ^D \ Z ^D \ /--- ^N < Y--/ °\L''''on XXj 22 using CD ₃ MgI LCMS (ESI): m/z calculated for C ₂ oHi ₇ D ₃ F ₂ N ₃ 0 ₄ [M+H] ⁺ : 407.15; found: 406.99. 'H NMR (600 MHz, DMSO-ab) 5 8.69 (s, 1H), 7.79 (d, J = 3.8 Hz, 1H), 7.42 7.34 (m, 1H), 7 .34 - 7.25 (m, 1H), 6.82 (d, J = 3.7 Hz, 1H), 6.32 (d, J = 7.7 Hz, 1H), 5.26 (d, J = 6.7 Hz, 1H), 5.15 (s, 1H), 4.88 (d, J = 3.5 Hz, 1H), 4.52 (d, J = 5.8 Hz, 1H) , 4.44 (d, J = 3.2 Hz, 1H), 4.30-4.19 (m, 1H), 3.88 (d, J = 4.9 Hz, 1H), 3.70 ( etc., J = 11.0, 3.2 Hz, 1H), 2.97 - 2.85 (m, 1H), 2.70 (d, J = 16.4 Hz, 1H).

Protocol for biochemical analysis.

Compounds were dissolved and diluted 3 times in 100% DMSO. These diluted compounds were further diluted in assay buffer (20 mM Tris-HCl, pH 8.0.50 mM NaCl, 0.002% Tween 20, 1 mM TCEP, 1% DMSO) for a 10-dose IC ₅₀ regimen at a concentration of 10 times the desired concentration for analysis. Standard reactions were performed in a total volume of 30 μl in assay buffer with 300 nM histone H4 based on AcH4-23 (Anaspec: AS-65002) as substrate. To this was added a PRMT5/MEP50 complex diluted to a final assay concentration of 2.5 nM and the compounds were pre-incubated for 20 min at 37°C. The reaction was initiated by adding S-^Hmethyl]adenosyl-L-methionine (PerkinElmer: NET155001MC) to a final concentration of 1 μM. After a 30 minute incubation at 37° C., the reaction was stopped by adding 25 μl of 8 M guanidine HCl. YSI SPA streptavidin beads (Perkinelmer: RPNQ0012) were prepared at a concentration of 0.3 mg/ml in assay buffer. To each reaction mixture, 150 μl of SPA bead suspension was added and incubated with shaking at room temperature for 30 min. The plate was centrifuged at 100xg for 30 seconds before being read with a scintillation counter. IC ₅₀ values were determined by fitting data to standard 4 parameters using Hill Slope using GraphPad Prism software. See table. 2 below (PRMT5 IC ₅₀ ).

Protocol for cell analysis.

Cell processing and Western blotting for the detection of symmetrical dimethylarginine (SDMA) labels.

Titration with compounds and cell culture: Compounds were dissolved in DMSO to obtain a 10 mM stock solution, and an additional 3-fold dilution series was performed to bring

- 123 042008 working stock solution up to 1 mM. Granta-519 cells were maintained in PRMI 1640 (Corning Cellgro, catalog # 10-040-CV) supplemented with 10% v/v. FBS (GE Healthcare, cat. no. SH30910.03) and U-87 MG cells were maintained in DMEM (Corning Cellgro, cat. no. 10-013-CV) with 10% FBS and 2 mM glutamine (Corning Cellgro, cat. no. 25005CV).

Determination of IC ₅₀ values of enzyme inhibition in Granta-519 and U-87 MG cells by Western blotting. The day before the experiment, Granta-519 cells were passaged to a density of 0.5x106 cells/ml. U-87 MG cells were trypsinized and 4x105 cells were plated in 6-well plates and allowed to grow overnight. The next day, Granta-519 cells were centrifuged at 1500 rpm for 4 min, resuspended in fresh medium at 0.5x106 cells/ml and 3 ml of culture (1.5x106 cells) were plated in a 6-well plate. Eight-point 3-fold serial dilutions of compound working solutions (3 µl, dilution 1:1000, DMSO concentration was 0.1%; final maximum concentration 1 µM) were added to the cells and incubated for 3 days. Cells incubated with DMSO were used as vehicle controls.

Cells were harvested after 3 days, resuspended in 15 μl PBS, lysed in 4% SDS and homogenized by passing through a homogenizer column (Omega Biotek, catalog # HCR003). Total protein concentrations were determined using a BCA assay (ThermoFisher Scientific, cat. no. 23225). The lysates were mixed with 5x Laemmli's buffer and boiled for 5 min. Forty µg of total protein was separated on SDS-PAGE gels (Bio-Rad, catalog number: 4568083, 4568043), transferred to a PVDF membrane, blocked with 5% milk powder (Bio-Rad, catalog number: 1706404) in TBS with 0, 1% v/v Tween 20 (TBST) for 1 h at room temperature (rt) and incubated with primary antibodies (sDMA: Cell signaling, cat. no. 13222, 1:3000; β-Actin: sigma, cat. no. 1:5000 ) in 5% dry milk in TBST at 4°C overnight. The next day, the membranes were washed with TBST, 5x5 min and incubated with a horseradish peroxidase conjugated secondary antibody (GE Healthcare; Cat # NA934-1ML, NA931-1ML; 1:5000) for 2 h at room temperature followed by a 5x5 min wash TBST and incubated with ECL substrates (Bio-Rad, cat# 1705061, 1705062). The chemiluminescent signal was recorded using a Fluochem HD2 thermal imager (Proteinsimple). SmD3me2s bands were quantified using ImageJ. Signals were normalized to control β-actin and DMSO. IC50 values were calculated using Graphpad Prism ([Inhibitor] versus normalized response - variable slope. See Table 2 below (sDMA IC ₅₀ ).

Cell proliferation assay to determine IC ₅₀ in Granta-519 and U-87 MG cells.

The day before the experiment, Granta-519 cells were passaged to a density of 0.5x106 cells/ml. U-87 MG cells were trypsinized, 2000 cells were plated in 96-well plates and allowed to grow overnight. On the day of the experiment (Day 0), Granta-519 cells were centrifuged at 1500 rpm for 4 min, resuspended in fresh medium to 0.5x106 cells/ml, and 190 μl of cells were added to 96-well plates. For U-87 MG cells, the previous medium was removed and replaced with 190 μl of fresh medium. Initial working solutions were first diluted 1:50 with fresh medium in a 96-well plate, 10 μl of diluted drugs were added to 96-well plates containing cells and incubated for 3 days. DMSO was used as a control vehicle.

On day 3, 50 µl of Granta-519 cells were transferred to a new 96-well plate and 140 µl of fresh medium was added. For U-87 MG cells, the previous medium was removed and replaced with 190 μl of fresh medium. The initial working solutions were re-diluted 1:50 with the medium, 10 μl of diluted drugs were added to the cells and grown for another 3 days. The same process was repeated on the 6th day. The cells were allowed to grow for an additional 4 days.

On day 10, 100 µl of Granta-519 cells were transferred to a new 96-well plate and 10 µl of Cell Counting Kit-8 solution (CCK-8, Jojindo, CK04-13) was added. For U-87 MG cells, the previous medium was removed and replaced with 100 µl of fresh medium, and 10 µl of CCK-8 solution was added. The plates were incubated in a CO ₂ incubator for 2 h (Granta-519 cells) or 30 min (U-87 MG cells) and OD450 values were measured using a microplate reader (iMark microplate reader, Bio-Rad). Percentage of viable cells relative to DMSO vehicle control was calculated and plotted in Graphpad Prism ([inhibitor] versus normalized response - variable slope) to determine proliferation IC ₅₀ values at day 10. See table. 2 below (prof. IC50).

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table 2

Biochemical and cellular activity in the U-87 MG cell line [Granta-519 cell line]

No. example PRMT5 1С ₅ o µM PRMT5 ic _{50_n} sDMA IC50 µM sDMA ic _{50_n} Profile IC50 µM Profile _{IC50_N} 1A 0.0038 1 0.12 [0.027] 1[1] 0.142 2 2A 0.68 1 BEHIND 0.021 1 [1.62] [1] SW 1.02 1 1B 0.27 1 2B 0.031 1 0.563 1 >1 2 4 0.0015 1 0.031 1 0.095 2 5 0.001 1 0.025 1 15 0.001 1 22 0.0048 2 0.0176 2 0.054 3 42 0.428 43 0.019 44 0.606 50 0.059 55 0.0117 1 4.58 2 10 2 68 0.0012 2 0.00258 3 0.0091 2 69 0.0149 2 0.109 1 0.181 2 70 0.303 1 0.382 1 0.458 1 71 0.0062 1 0.0297 1 0.073 2 72 0.00298 1 0.078 2 73 0.00145 1 0.0091 2 74 0.00728 1 0.066 1 75 0.0151 1 0.339 1 76 0.081 1 77 0.00282 1 78 0.0067 1

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79 0.0084 1 80 1.01 1 81 0.0415 1 82 0.585 1 83 0.0132 1 0.199 2 0.377 2 84 0.0044 1 0.0276 2 0.094 2 85 0.0147 2 0.173 1 0.304 1 86 0.002 2 0.0054 2 0.013 1 87 0.0077 1 0.12 2 0.509 1 88 0.0016 2 0.0185 2 0.06 2 89 0.0157 1 0.0844 2 0.179 2 90 0.0022 1 0.0114 2 0.0333 2 91 0.554 1 92 0.02 1 93 0.014 1 94 0.0032 1 95 0.0016 3 0.0111 1 0.0185 1 97 0.0047 2 0.0517 2 0.117 2 98 0.0119 2 0.579 1 0.662 1 99 0.0396 1 100 0.0056 1 101 1.58 1 102 6.28 1

Additional data.

Cell culture and compound treatment.

Compounds were dissolved in DMSO to give 10 mM stock solutions and further diluted to give 1 and 0.1 mM stock solutions.

K562 cells were purchased from ATCC and stored in DMEM Iscove (Corning Cellgro, Cat # 15-016-CVR) supplemented with 10% v/v. FBS (GE Healthcare, p/n SH30910.03) in CO ₂ incubator (5% CO ₂ ) at 37°C. Cells were seeded at a density of 5x105 cells/ml and treated with compound at final concentrations of 0.1 and 1 μM. Media and compound in culture were renewed after 3 days and cells harvested for RNA isolation after 6 days of treatment.

Human erythroid progenitors were derived from purified CD34+ cells from mobilized peripheral blood purchased from AllCells. CD34+ cells were cultured in StemSpan SFEM II (StemCell Technologies, cat. no. 09605) supplemented with 100 ng/ml FLT3 ligand (R&D systems, cat. no. 308-FK), 100 ng/ml SCF (R&D systems, cat. no. 255 -SC), 20 ng/ml IL-3 (R&D systems, catalog # 203-IL), 20 ng/ml IL-6 (R&D systems, catalog # 206-IL) for 6 days, then repeated seeded in the same medium supplemented with 20 ng/ml SCF, 5 ng/ml IL-3, 1 U/ml EPO (R&D systems, cat. no. 287-TC), 2 μM dexamethasone (Sigma-Aldrich, cat. no. D4902 ), 1 μM β-estradiol (Sigma-Aldrich, cat. no. E2758). Cells were treated with 0.1 and 1 μM compound from the 8th day of differentiation. Medium and compound were renewed every 3 days and cells were harvested for RNA isolation after 9 days of treatment.

Evaluation of γ-globin induction by quantitative PCR.

RNA was isolated using a Quick-RNA Microprep kit (Zymo Research, cat. no. Z1050), cDNA was synthesized using qScript cDNA SuperMix (Quantabio, cat. no. 95048). Quantitative PCR for γ-globin was performed using PerfeCTa SYBR Green FastMix (Quantabio, catalog # 95071) on a Bio-Rad CFX Connect real-time PCR analyzer. Gene expression analysis was performed using CFX Manager software.

Treatment of K562 cells with 0.1 and 1 μM solution of the compound of example 5 resulted in a dose-dependent increase in γ-globin expression (3 and 8 times, respectively, N=1).

Treatment of erythrocyte precursors with 0.1 and 1 μM solution of the compound of example 5 resulted in a dose-dependent increase in γ-globin expression (1.5 and 2-fold, respectively, N=1).

Estimation of % F-cells by flow cytometry.

Human erythroid cells were harvested on day 7 of compound treatment. Cells were fixed in

- 126 042008

0.05% glutaraldehyde (Electron Microscopy Sciences, cat. no. 16019), permeabilized with 0.1% Triton-X, and stained with fluorescein labeled antibodies directed to hemoglobin F (ThermoFisher, cat. no. MHFH01). Analysis of erythroid cells expressing hemoglobin F (% F cells) was performed on an Attune Nxt flow cytometer (ThermoFisher).

Treatment of erythrocyte progenitors with 0.1 and 1 μM solution of the compound of example 5 resulted in a dose-dependent increase in % F-cells compared to the DMSO-treated control (1.3 and 3 times, respectively, N=1).

Evaluation of γ-globin induction by quantitative PCR in K562 cells.

Compounds were dissolved in DMSO to give 10 mM stock solutions and further diluted to give 1 and 0.1 mM stock solutions. K562 cells were purchased from ATCC and stored in DMEM Iscove (Corning Cellgro, Cat # 15-016-CVR) supplemented with 10% v/v. FBS (GE Healthcare, p/n SH30910.03) in CO2 incubator (5% CO2) at 37°C. Cells were seeded at a density of 5x105 cells/ml and treated with compound at final concentrations of 0.1 and 1 μM. Medium and compound were renewed after 3 days in culture and cells were harvested for RNA isolation after 6 days of treatment.

Treatment of K562 cells with 0.1 and 1 μM solution of the compound of example 5 resulted in a dose-dependent increase in γ-globin expression (3 and 8 times, respectively, N=1).

Compound Titration and Cell Culture: Compounds were dissolved in DMSO to prepare 10 mM stock solutions. Human peripheral blood mononuclear cells (PBMCs) from healthy donors were purchased from AllCells (Emeryville, CA), stored in RPMI 1640 (Corning Cellgro, Cat # 10-040-CV) supplemented with 10% v/v. heat-inactivated FBS (GE Healthcare, cat. no. SH30910.03), 2 mM L-glutamine (Corning Cellgro, cat. no. 25005CV), and 1X penicillin-streptomycin (Sigma-Aldrich, cat. no. P4333) in a CO ₂ incubator (5 % CO ₂ ) at 37°C.

To determine the IC ₅₀ values of enzyme inhibition in human PBMC: freshly thawed cells were seeded at a density of 25x105 cells/ml in 2 ml of medium in a 12-well plate. Cells were activated by adding 5 μg/ml PHA-L (Sigma-Aldrich, catalog # L4144) for 3 days. A series of 8-point 3-fold dilutions of the compound was dispensed into wells from 1 mM stock solution using a TECAN digital dispenser (D300e) and the DMSO concentration was normalized to 0.1%. Cells incubated with 0.1% DMSO were used as controls only.

Cells were harvested after 3 days, resuspended in 15 μl PBS, lysed in 4% SDS and homogenized by passing through a homogenizer column (Omega Biotek, catalog # HCR003). Total protein concentration was determined using a BCA assay (ThermoFisher Scientific, cat. no. 23225). The lysates were mixed with 5x Laemmli's buffer and boiled for 5 min. 30 μg total protein was separated on SDS-PAGE gels (Bio-Rad, cat. no. 4568083, 4568043), transferred to a PVDF membrane, blocked with 5% milk powder (Bio-Rad, cat. no.: 1706404) in TBS with 0.1 % v/v Tween 20 (TBST) for 1 hour at room temperature (RT) and incubated with primary antibodies (sDMA: Cell signaling, cat. no. 13222, 1:2000; β-Actin: sigma, cat. no. 1:5000 ) in 5% dry milk in TBST at 4°C overnight. The next day, membranes were washed with TBST, 5x5 min and incubated with horseradish peroxidase conjugated secondary antibodies (GE Healthcare; Cat # NA934-1ML, NA931-1ML; 1:5000) for 2 h at room temperature followed by 5x5 min washes TBST and incubated with ECL substrates (Bio-Rad, cat# 1705061, 1705062). The chemiluminescent signal was recorded using a Fluochem HD2 thermal imager (Proteinsimple). SmD3me2s bands were quantified using ImageJ. Signals were normalized to control β-actin and DMSO. IC ₅₀ values were calculated using Graphpad Prism ([Inhibitor] versus normalized response - variable slope. See Table 3 below.

Table 3

Cellular activity in human PBMC

Example No. sDMA ICso µM SDMA IC50 N 5 0.016 3

- 127 042008

This invention is also directed to the following aspects.

Aspect 1 Compound of Formula I

or a pharmaceutically acceptable salt or solvate thereof, wherein A is CR ³ ;

R ¹ is halogen, -C ₁ -C ₆ -alkyl, -C ₁ -C ₆ -alkoxy, -C ₃ -C ₆ -cycloalkyl, -C ₁ -C ₆ -alk-O-C ₁ C ₆ -alkyl or -NR ⁶ R ⁶ ;

R ² is H;

R ³ represents H, halogen or -C1-C ₆ -alkyl;

R ⁴ represents H or -C1-C ₆ -alkyl;

R ⁵ represents H or -C1-C ₆ -alkyl;

R ⁶ and R ⁶ are each independently H or C1-C ₆ alkyl; or

R ⁶ and R ⁶ together with the atom to which they are attached form a C ₂ -C ₆ heterocycloalkyl ring containing one N heteroatom;

X represents O, S, NH or N(C ₁ -C ₆ -alkyl); And

Y is -(CR ⁹ R ⁹ ')n-, -CR ⁹ CR ⁹ -, C(=O), -C(=O)-(CR ⁹ R ⁹ ')n-, -C(=O) -O-(CR ⁹ R ⁹ ')n-, -CR ⁹ R ⁹ '-O-, -(CR ⁹ R ⁹ ')nO-(CR ⁹ R ⁹ ')m- or -(CR ⁹ R ⁹ ' )n-NR ¹⁰ ; or

X is -SO ₂ -; And

Y is -(CR ⁹ R ⁹ ) _n - where n=1 or 2;

m=1 or 2;

each of R ⁹ or R ⁹ independently represents H, D, C ₁ -C ₆ -αkyl, C ₁ -C ₆ -haloalkyl, halogen, -C1-C ₆ -alkoxy or hydroxy;

R ¹⁰ is H or C1-C ₆ alkyl;

Z is O or CH ₂ ; And

Ar is a phenyl ring which is optionally substituted with one or more substituents independently selected from halo, C1- _C6 haloalkyl, C1- _C6 haloalkoxy and C1- _C6 alkyl, a 6-membered heteroaryl ring containing one a N heteroatom, wherein said heteroaryl ring is optionally substituted with one or more substituents independently selected from halo, C1- _C6 haloalkyl, _C1 - _C6 haloalkoxy and C1- _C6 alkyl, or a 5-membered heteroaryl ring, containing up to 4 heteroatoms independently selected from N and S, wherein said heteroaryl ring is optionally substituted with one or more substituents independently selected from halogen, C ₁ -C ₆ haloalkyl, C 1 -C ₆ haloalkoxy and C 1 -C ₆ -alkyl.

Aspect 2. The compound according to aspect 1, where R ¹ represents halogen, -NR ⁶ R ⁶ , -C1-C ₆ -alkyl, -C1C ₆ -alkoxy or -C ₁ -C ₆ -alk-O-C ₁ -C ₆ -alkyl.

Aspect 3 A compound according to aspect 2 wherein R ¹ is halogen, preferably -F or -Cl.

Aspect 4 A compound according to aspect 2 wherein R ¹ is -NR ⁶ R ^6' , preferably -NH ₂ .

Aspect 5 A compound according to aspect 2 wherein R ¹ is -C1-C ₆ alkyl, preferably -CH ₃ .

Aspect 6 A compound according to aspect 2 wherein R ¹ is -C ₁ -C ₆ -alk-O-C ₁ -C ₆ -alkyl, preferably -CH ₂ -O-CH ₂ CH ₃ .

Aspect 7 A compound according to any one of aspects 1-6 wherein R ² is H.

Aspect 8 A compound according to any one of aspects 1-7 wherein R ⁴ is H or -C ₁ -C ₆ alkyl.

Aspect 9 The compound of Aspect 8 wherein R ⁴ is H.

Aspect 10 A compound according to aspect 8 wherein R ⁴ is -C ₁ -C ₆ alkyl, preferably methyl.

Aspect 11 A compound according to any one of aspects 1-10 wherein R ⁵ is H.

Aspect 12 A compound according to any one of aspects 1-10 wherein R ⁵ is -C ₁ -C ₆ alkyl, preferably -CH ₃ .

Aspect 13 A compound according to any one of aspects 1-12 wherein Ar is an optionally substituted phenyl ring.

- 128 042008

Aspect 14 A compound according to aspect 13 wherein the phenyl ring is substituted with one or more halogen atoms, preferably -F or -Cl.

Aspect 15 A compound according to Aspect 13 or 14 wherein the phenyl ring is substituted with one or more -CH ₃ , CF3 or -OCF3 groups.

Aspect 16 A compound according to any one of aspects 1-12 wherein Ar is an optionally substituted 6-membered heteroaryl ring.

Aspect 17 A compound according to aspect 16 wherein the 6-membered heteroaryl ring is substituted with one or more halogen atoms, preferably -F or -Cl.

Aspect 18 A compound according to Aspect 16 or 17 wherein the 6-membered heteroaryl ring is substituted with one or more -CH ₃ , CF3 or -OCF3 groups.

Aspect 19 A compound according to any one of aspects 1-12 wherein Ar is an optionally substituted 5-membered heteroaryl ring.

Aspect 20 A compound according to aspect 19 wherein the 5-membered heteroaryl ring is substituted with one or more halogen atoms, preferably -F or -Cl.

Aspect 21 A compound according to aspect 19 or 20 wherein the 5-membered heteroaryl ring is substituted with one or more -CH ₃ , CF ₃ or -OCF ₃ groups.

Aspect 22 A compound according to any one of aspects 1-21 wherein X is O.

Aspect 23 A compound according to any one of aspects 1-21 wherein X is S.

Aspect 24 A compound according to any one of aspects 1-21 wherein X is SO ₂ .

Aspect 25 A compound according to any one of Aspects 1-21 wherein X is NH.

Aspect 26 A compound according to any one of aspects 1-21 wherein X is N(C ₁ -C ₆ alkyl), preferably N(CH ₃ ).

Aspect 27 A compound according to any one of aspects 1-26 wherein Y is -(CR9R9) _n

Aspect 28 A compound according to aspect 27 wherein -(CR9R9) _n is -CH2-, -CH2CH2-, -C(CH ₃ ) ₂ or -CF2-.

Aspect 29 A compound according to any one of Aspects 1-26 wherein Y is -CR9= ^CR9 -.

Aspect 30 A compound according to any one of aspects 1-23 and 25-26 wherein Y is -C(=O)-(CR ⁹ R ⁹ V Aspect 31 A compound according to any one of aspects 1-23 and 25-26 wherein Y is -C(=O)-O-(CR9R9')n-.'

Aspect 32 A compound according to any one of aspects 1-26 wherein Y is -CR9R ⁹ -O.

Aspect 33 A compound according to any one of aspects 1-26 wherein Y is -(CR ⁹ R ⁹ )nO-(CR ⁹ R ⁹ ') _m -.

Aspect 34 A compound according to any one of aspects 1-23 and 25-26 wherein Y is C(=O).

Aspect 35 A compound according to any one of aspects 1-26 wherein Y is CH-C ₁ -C 4 -alk-NH ₂ .

Aspect 36 A compound according to any one of aspects 1-26 wherein Y is -(CR9R9) _n -NR ¹⁰ .

Aspect 37 A compound according to any one of aspects 27, 29-33, or 36, wherein each R ⁹ and each R ⁹ is independently H, D, —CH ₃ , OH, —OCH ₃ , F, or CF3.

Aspect 38 A compound according to any one of aspects 27, 30, 31, 33, 36, or 37, wherein n=1.

Aspect 39 A compound according to any one of aspects 27, 30, 31, 33, 36, or 37, wherein n=2.

Aspect 40 A compound according to aspect 33 wherein m=1.

Aspect 41 The compound of Aspect 33 wherein m=2.

Aspect 42 A compound according to any one of aspects 1-41 wherein Z is O.

Aspect 43 A compound according to any one of Aspects 1-41 wherein Z is CH2.

Aspect 44 A compound according to any one of Aspects 1-43 wherein A is CR ³ .

Aspect 45 The compound of Aspect 44 wherein R ³ is H.

Aspect 46 The compound of Aspect 44 wherein R ³ is halogen, preferably -F.

Aspect 47 A pharmaceutical composition comprising a compound according to any one of aspects 1-46 and a pharmaceutically acceptable excipient.

Aspect 48 A method of inhibiting the arginine methyltransferase 5 (PRMT5) enzyme, comprising contacting the PRMT5 enzyme with an effective amount of a compound according to any one of aspects 1-46.

Aspect 49. A method of treating a disease or disorder associated with aberrant PRMT5 activity in a subject, comprising administering to the subject a compound of any one of aspects 1-46.

Aspect 50. The method of aspect 49 wherein the disease or disorder associated with aberrant PRMT5 activity is breast cancer, lung cancer, pancreatic cancer, prostate cancer, colon cancer, ovarian cancer, uterine cancer, cervical cancer, leukemia such as acute myeloid leukemia (AML), acute lymphocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, myelodysplasia, myeloproliferative disorders, acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), mastocytosis, chronic lymphocytic leukemia ( CLL), multiple myeloma (MM), myelodysplastic syndrome (MDS), epidermoid cancer, hemoglobinopathies such as b-thalassemia and sickle cell anemia (SCA),

- 129 042008 malignant tumors with delegated CDKN2A; 9P deleted cancers; MTAP deleted cancers; glioblastoma, NSCLC, head and neck cancer, bladder cancer, or hepatocellular carcinoma.

Claims (31)

CLAIM 1. Compound of formula I ^R1 or a pharmaceutically acceptable salt thereof, wherein A is CR ³ ; R1 is halogen, -C1- _C6 alkyl, -C1- _C6 alkoxy, _-C3 - _C6 cycloalkyl, -C1 _{- C6} alk-O- _C1C6 alkyl, -NR6R6; R ² is H; R ³ represents H, halogen or -C1-C ₆ -alkyl; R ⁴ represents H or -C1-C ₆ -alkyl; R ⁵ represents H or -C1-C ₆ -alkyl; R6 and R6 are each independently H or C1-C6 alkyl; or R6 and R6 together with the atom to which they are attached form a C ₂ -C6 heterocycloalkyl ring containing one N heteroatom; X represents O, S, NH or N(C ₁ -C ₆ -alkyl); And Y is -(CR ⁹ R ⁹ ')n-, -CR ⁹ =CR ⁹ '-, C(=O), -C(=O)-(CR ⁹ R ⁹ ')n-, -C(= O)-O-(CR ⁹ R ⁹ ')n-, -CR ⁹ R ⁹ '-O-, -(CR ⁹ R ⁹ ')nO-(CR ⁹ R ⁹ ')m- or -(CR ⁹ R ⁹ ')n-NR ¹⁰ ; or X is -SO ₂ -; And Y is -(CR ⁹ R ^9' ) _n - where n=1, 2 or 3; m=1 or 2; each R ⁹ or R ⁹ is independently H, D, C1-C ₆ alkyl, C ₁ -C ₆ haloalkyl, halogen, -C ₁ -C ₆ alkoxy or hydroxy; R ¹⁰ is H; Z is O or CH2; And Ar is a phenyl ring which is optionally substituted with one or more substituents independently selected from halogen, C ₁ -C ₆ haloalkyl, C 1 -C ₆ haloalkoxy and C 1 -C ₆ alkyl, a 6-membered heteroaryl ring containing one N heteroatom, wherein said heteroaryl ring is optionally substituted with one or more substituents independently selected from halogen, C1- _C6 haloalkyl, C1- _C6 haloalkoxy and C1- _C6 alkyl, or a 5-membered heteroaryl ring, containing up to 4 heteroatoms independently selected from N and S, wherein said heteroaryl ring is optionally substituted with one or more substituents independently selected from halo, C1- _C6 haloalkyl, C1- _C6 haloalkoxy and C1- _C6 - alkyl. 2. Connection according to claim 1, where R ¹ is halogen, preferably -F or -Cl; or R ¹ is -NR ⁶ R ^6' , preferably -NH ₂ ; or R ¹ is -C1-C ₆ alkyl, preferably -CH ₃ ; or R ¹ is -C ₁ -C ₆ -alk-O-C ₁ -C ₆ -alkyl, preferably -CH ₂ -O-CH ₂ CH ₃ . 3. A compound according to claim 1 or 2, wherein R ⁴ is H or methyl. 4. A compound according to any one of claims 1 to 3, wherein R ⁵ is H or -CH ₃ . 5. Connection according to any one of claims 1-4, where Ar is an optionally substituted phenyl ring; or Ar is a phenyl ring substituted with one or more halogen atoms, preferably -F or -Cl; or Ar is a phenyl ring substituted with one or more -CH ₃ , CF ₃ or -OCF ₃ groups. - 130 042008 6. A compound according to any one of claims 1 to 4, wherein Ar is an optionally substituted 6-membered heteroaryl ring containing one heteroatom N, or characterized in that said 6-membered heteroaryl ring is substituted with one or more halogen atoms, preferably -F or -Cl, or characterized in that the 6-membered heteroaryl ring is substituted with one or more -CH ₃ , CF ₃ or -OCF ₃ groups. 7. A compound according to any one of claims 1 to 4, wherein Ar is an optionally substituted 5-membered heteroaryl ring containing up to 4 heteroatoms independently selected from N and S. 8. The compound according to claim 7, characterized in that the 5-membered heteroaryl ring is substituted with one or more halogen atoms, preferably -F or -Cl, or characterized in that the 5-membered heteroaryl ring is substituted with one or more -CH3, CF3 or -OCF3 groups. 9. A compound according to any one of claims 1 to 8, wherein X is O. 10. Connection according to any one of claims 1-8, where X is S; or X is SO2; or X is NH; X is N(C ₁ -C ₆ alkyl), preferably N(CH ₃ ). 11. A compound according to any one of claims 1-10, wherein Y is -(CR9R9) _n . 12. Connection according to any one of claims 1-10, where Y is -CR9=CR ⁹ -; or Y is -C(=O)-(CR ⁹ R ⁹ ) _p -; or Y represents -C(=O)-O-(CR ⁹ R ⁹ ) _n -; or Y is -CR ⁹ R ⁹ -O; or Y is -(CR ⁹ R ⁹ ) _n -O-(CR ⁹ R ⁹ )m-; or Y is C(=O); or Y is -(CR9R9) _n -NR ¹⁰ 13. A compound according to any one of claims 11 or 12, wherein each R ⁹ and each R ⁹ is independently H, D, -CH ₃ , OH, -OCH ₃ , F or CF ₃ . 14. Connection according to any one of paragraphs. 11 or 12, characterized in that n=1, or characterized in that n=2, or characterized in that n=3. 15. The compound according to claim 12, characterized in that m=1, or characterized in that m=2. 16. A compound according to any one of claims 1 to 15, wherein A is CR ³ , where R ³ is H or halogen, preferably -F. 17. A pharmaceutical composition containing a compound according to any one of claims 1 to 16 and a pharmaceutically acceptable excipient. 18. A method for inhibiting the enzyme arginine methyltransferase 5 (PRMT5), comprising contacting the PRMT5 enzyme with an effective amount of a compound according to any one of claims 1-16. 19. A method of treating a disease or disorder associated with aberrant PRMT5 activity in a subject, comprising administering to the subject a compound according to any one of claims 1-16. 20. The method of claim 19, wherein the disease or disorder associated with aberrant PRMT5 activity is breast cancer, lung cancer, pancreatic cancer, prostate cancer, colon cancer, ovarian cancer, uterine cancer, cervical cancer , leukemia such as acute myeloid leukemia (AML), acute lymphocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, myelodysplasia, myeloproliferative diseases, acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), mastocytosis, chronic lymphocytic leukemia (CLL), multiple myeloma (MM), myelodysplastic syndrome (MDS), epidermoid cancer, hemoglobinopathies such as b-thalassemia and sickle cell anemia (SCA), malignant tumors with deleted CDKN2A, 9P deleted cancers, MTAP deleted cancers, glioblastoma, NSCLC, head and neck cancer, bladder cancer, or hepatocellular carcinoma. 21. The method of claim 19, wherein the disease or disorder associated with aberrant PRMT5 activity is adenoid cystic carcinoma (ACC), primary central nervous system lymphoma, fallopian tube cancer, or non-Hodgkin's lymphoma. 22. A compound according to claim 1, wherein said compound is (2S,3S,4R,5R)-2-((R)-6chloroisochroman-1-yl)-5-(4-methyl-7H-pyrrolo[2, 3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol or a pharmaceutically acceptable salt thereof. 23. The pharmaceutical composition according to claim 17, wherein the compound is (2S,3S,4R,5R)-2((R)-6-chloroisochroman-1-yl)-5-(4-methyl-7H-pyrrolo[2 ,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol or a pharmaceutically acceptable salt thereof. 24. The method according to any one of claims 19, 20 or 21, wherein the compound is (2S,3S,4R,5R)-2-((R)6-chloroisochroman-1-yl)-5-(4-methyl- 7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol or a pharmaceutically acceptable salt thereof. 25. A compound according to claim 1, wherein said compound is (2R,3R,4S,5S)-2-(4-amino-7H - 131 042008 pyrrolo[2,3-4]pyrimidin-7-yl)-5-((R)-b-chloro-1,3-dihydroisobenzofuran-1-yl)tetrahydrofuran-3,4diol or a pharmaceutically acceptable salt thereof. 26. Pharmaceutical composition according to i. )-6-chloro-l,3-dihydroisobenzoφyran-lyl)tetrahydrofuran-3,4-diol or a pharmaceutically acceptable salt thereof. 27. Method according to any of pi. 19, 20 or 21, where the compound is (2R,3R,4S,5S)-2-(4amino-7H-pyrpolo[2,3-d]pyrimidin-7-yl)-5-((R)-6 -chloro-l,3-dihydroisobenzoφyran-lyl)tetrahydrofuran-3,4-diol or a pharmaceutically acceptable salt thereof. 28. The compound of claim 1, wherein said compound is (2R,3R,4S,5S)-2-(4-aMHHo-7Hπirpolo[2,3-d]πyrimidin-7-yl)-5-((R )-6-chloroisoxpoman-l-yl)tetrahydropyran-3,4-diol or a pharmaceutically acceptable salt thereof. 29. Pharmaceutical composition according to i. )-6-chloroisoxpoman-l-yl)tetrahydropyran-3,4-diol or a pharmaceutically acceptable salt thereof. 30. Method according to any of pi. 19, 20 or 21, where the compound is (2R,3R,4S,5S)-2-(4amino-7H-pyrpolo[2,3-d]pyrimidin-7-yl)-5-((R)-6 -chloroisoxpoman-l-yl)tetrahydroxpoφyran-3,4-diol or a pharmaceutically acceptable salt thereof. 31. Connection by and. 11, where Y is -CH ₂ -, -CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ -, -C(CH ₃ ) ₂ - or -CF ₂ -.