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Title:
SELECTIVE INHIBITORS OF PROTEIN ARGININE METHYL TRANSFERASE 5 (PRMT5)
Document Type and Number:
WIPO Patent Application WO/2018/085833
Kind Code:
A2
Abstract:
The disclosure is directed to compounds of Formula I, Formula II, and Formula III [Formulas should be inserted here]. Methods of their use and preparation are also described.

Inventors:
LUENGO JUAN (US)
LEAL RAUL (US)
LIN HONG (US)
SHETTY RUPA (US)
Application Number:
US2017/060396
Publication Date:
May 11, 2018
Filing Date:
November 07, 2017
Export Citation:
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Assignee:
PRELUDE THERAPEUTICS INCORPORATED (US)
International Classes:
C07D487/04; A61K31/70; C07H19/14; C07H19/167
Foreign References:
US5023252A1991-06-11
US4992445A1991-02-12
US5001139A1991-03-19
US5451233A1995-09-19
US5040548A1991-08-20
US5061273A1991-10-29
US5496346A1996-03-05
US5292331A1994-03-08
US5674278A1997-10-07
US3657744A1972-04-25
US4739762A1988-04-26
US5195984A1993-03-23
US5879382A1999-03-09
US6344053B12002-02-05
Other References:
PAL ET AL., MOL. CELL. BIOL., 2003, pages 7475
PAL ET AL., MOL. CELL. BIOL., 2004, pages 9630
WANG ET AL., MOL. CELL. BIOL., 2008, pages 6262
CHUNG ET AL., J BIOL CHEM, 2013, pages 5534
KOH ET AL., NATURE, vol. 523, 2015, pages 7558
HSU ET AL., NATURE, vol. 525, 2015, pages 384
ZHAO ET AL., NAT STRUCT MOL BIOL., vol. 16, 2009, pages 304
"Handbook of Clinical Drug Data", 2002, MCGRAW-HILL
"Principles of Drug Action", 1990, CHURCHILL LIVINGSTON
"Basic and Clinical Pharmacology", MCGRAW HILL
"The Pharmacological Basis of Therapeutics", 2001, MCGRAW HILL
"Remingtons Pharmaceutical Sciences", 2000, LIPPINCOTT WILLIAMS & WILKINS
MARTINDALE: "The Extra Pharmacopoeia", 1999, PHARMACEUTICAL PRESS
Attorney, Agent or Firm:
DOYLE, Timothy, J. et al. (2929 Arch StreetCira Centre, 12th Floo, Philadelphia PA, US)
Download PDF:
Claims:
What is claimed:

1. A compound of Formula I, Formula II, or Formula III:

wherein

A is CH or N;

n is 0 or 1 ;

R1 is -Ci-Cealkyi, -CH(OH)-Ci-C6aikyL -Ci-Cehaioalkyl, -CH(OH)-Ci-C6haloalkyl, -Co- C6alk-C3-C6cycloalkyL -Co-C6alk-C3-C6halocycloalk 'l; -C2-Cealkenyl, -C2- Ohaloalkenyl, -Ci-Gsalkynyl, -OfcS-Ci-Cealkyl, -Ci¾S-Ci~C6haloalkyi, -CH2S- Cj-Cecycloalkyl; -CHiS-C -Cehalocycloalkyi: -CHjOG-Cealkyl, -CH2O-C3- Cecycloalkyi, -CH(OH)-aiyl, -CH(F)-aryi, -CH(NH2 aryi, -C(Me)(OH)-aryl, - CHiSCHi-aryl, or -CI !•('{0}N! ί-an I:

R2 is H, halo, -Ci-Cealkyl, -Ci-Cehaloalkyl, -Co-Cealk-Cs-Cecycloalkyl, -Co-Cealk-OH, -Co-Cealk-O-Ci-Cealkyl, -Co-Cealk-NHi, -Co-Cealk-NH-Ci-Cealkyl, -Co-C6alk-N(Ci-C6alkyi)-Ci-C6alkyl, -Co-Cealk-NH-C -Cecycloalkyl, -Co-C6alk-N(Ci-C6alkyI)-C3-C6cycloalkyI, -Co-Cealk-heterocycloalkyl, heteroaryl, or -CN; R3 is H, halo, -Ci-Cealkyl, -Ci-Cehaloalkyl, -Co-Cealk-Cs-Cecydoalkyl, -Co-Cealk-OH, -Co-Cealk-Q-Ci-Cealkyl, -Co-Ceaik-NH , -Co-Cealk-NH-Ci-Ceaikyl, -Co-Cealk- N(Ci-C&alkyl)-Ci-C6alkyl, -Co-Cealk-NH-Cs-Cecycloalkyl, -Co~Cealk-N(Ci- C6alkyl)-C3-C6Cycloalkyl -Co-Cealk-heterocycloalkyl, heteroaryi, or -CN;

R4 is H, halo, -Ci-Cealkyl, -Ci-Cehaloalkyl, -Co-Cealk-Cs-Cecycloalkyl, -Co-Cealk-OH, -Co-Cealk-O-Ci-Cealkyl, -CVCeaik-NJi, -Co-Cealk-NH-Ci-Ceaikyl, -Co-Cealk- N(Ci~Cealkyl Ci-Cealkyl, -Co-Cealk-NH-Cs-CecycloalkyL -Co-Cealk-N(Ci- CealkylJ-Cs-CecycJoalkyl -Co-Cealk-heterocycloalkyl, heteroan'l, or -CN;

or R2 and R3, together with the atoms to which they are attached, form a

Cs-Cecycioalkenyl ring;

or R2 and R3, together form a triple bond;

or R3 and R4, together with the atom to which they are attached, form a Cn-Cecycloalkyl rmg or a heterocycioalkyi ring;

R3 is H, Ci-Cealkyl, or Co-Cealk-CVCeeycloalkyl;

Rb and R7 are each independently H, Me, NH2, or CH2F;

R8a and R8b are each independently H, Ci-Cealkyl, or -Co-Cealk-OCi-Cealkyl, or R8a and R8b, together with the atom to which they are attached, form a Ci-Cecycloalkyi ring;

R8 and R8 are each independently H, Ci -Cealkyl, or -Co-Cealk-OCi-Cealkyi;

or R8 and R8 , together with the atom to which they are attached, form a Ci-Cecycloalkyl ring;

R9 is -C2-C4alkenyl, -C2-C4haloalkenyl, -Ci-Gcyanoalkenyl, -Ci-Cialkynyl, -Ci~

C-thaloalkyi, -C^-Ceheterocycloalkyl, oxo-substituted-Cz-Ceheterocycloalkyl, -C3- Cecycloalkyl, -CHO, -C(0)R10, ·( R"RK ( N. -CH2NR8R8', -Co-Cealk-OH, - NR8R8', -NH-CN, -N(R10)CN, -O-C1-C4 alkyl, -NR5CONR8R8', -OCO NR8R8', or -NR5C(O)OR]0;

R10 is -Ci-Cealkyl or Co-Cealk-Cs-Cecycioaikyl; and

R10a is H, -Ci-Cealkyl, or Co-C&alk-C3-C6cycloalkyl.

2. The compound of claim 1 wherein A is CH.

The compound of claim 1 wherein

4. The compound of any one of claims 1, 2, or 3 wherein R1 is -CH(OH)-aryl, -CthS-Ci- Cealkyi, -Ci-Cehaloalkyl, -Co-Cealk-Cs-Cec cloalkyl, -CFhSCFh-aryl, or -Π K i<))\! 1-· aryl.

5. The compound of any one of claims I to 4 wherein R5 is H or -Ci-C6aikyl.

6. The compound of any one of claims 1 to 5 wherein R6 is H, Nth, or Me.

7. The compound of any one of the preceding claims where R7 is H.

8. The compound of any one of the preceding claims, which is a compound of Formula I.

9. The compound of claim 8 wherein at least one of R2, R3, and R4 is H.

10. The compound claim 8 wherein R2, RJ, and R4 are each H.

11. The compound of any one of claims 8 to 10, wherein R5 is H.

12. The compound of any one of claims 1 to 7, which is a compound of Formula II.

13. The compound of claim 12 wherein n is 0.

14. The compound of claim 12 wherein n is 1.

15. The compound of claim 14 wherein R!0a is H.

16. The compound of any one of claims 12 to 15 wherein R8a is H or Ci-C6alkyl.

17. The compound of claim any one of clams 12 to 16 wherein R8b is H or Ci-Cealkyl.

18. The compound of claim 12, 13, 14, or 15 wherein R8a and R8b, together with the atoms to which they are attached, form a C3-Cecycloalkyl ring.

19. The compound of any one of claims 12 to 18 wherein R5 is H or Ci-Cealkyl.

20. The compound of any one of claims 1 to 7, which is a compound of Formula III.

21. The compound of claim 20 wherein R9 is -C2-C4alkenyl.

22. The compound of claim 20 wherein R is -C2-C4haloalkenyl.

23. The compound of claim 20 wherein is Ci-C-tcyanoalkenyl.

24. The compound of claim 20 wherein R9 is -C2~C4alkynyl.

25. The compound of claim 20 wherein R9 is -Ci-Ceheterocycloalkyl.

26. The compound of claim 20 wherein R9 is oxo-suhstituted-Ci-Ceheterocycloalkyl.

27. The compound of claim 20 wherein R9 is -G-Cecycloalkyl.

28. The compound of claim 20 wherein R9 is -C(0)R10.

29. The compound of claim 20 wherein R9 is -CR8R8' CN.

30. The compound of claim 20 wherein R is ~CH2NR8R8'.

31. The compound of claim 20 wherein R9 is -Co-Cealk-OH.

32. The compound of claim 20 wherein R9 is -NR8R8'.

33. The compound of claim 20 wherein R9 is -NH-CN.

34. The compound of claim 20 wherein R9 is -N(R!0)CN.

35. The compound of claim 20 wherein R is -NR5CONR8R8'.

36. The compound of claim 20 wherein R9 is -NR3C(0)OR10.

37. The compound of any one of claims 28 and 36 wherem Ri0 is -Ci-Cealkyl.

38. The compound of any one of claims 35 and 36 wherein R5 is H.

39. The compound of any one of claims 29, 30, 32 and 35 wherein R8 is H or Ci-Cealkyl.

40. The compound of any one of claims 29, 30, 32 and 35 wherein R8 is H or Ci-Ceaikyi.

41. The compound of claim 29 wherein R8 and R8 , together with the atom to which they are attached, form a CVCeeycloalky! ring.

42. A pharmaceutical composition comprising a compound according to any one of the preceding claims and a pharmaceutically acceptable excipient.

43. A method of inhibiting a protein arginine methyltransferase 5 (PRMT5) enzyme, comprising: contacting the PRJVITS enzyme with an effecti ve amount of a compound of any one of any one of claims 1 to 41 ,

44. A method of treating a disease or disorder associated with aberrant PRJVITS activity in a subject comprising administering to the subject, a compound of any one of claims 1 to 41.

45. The method of claim 44, 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, ham' cell leukemia, myelodysplasia, myeloproliferative disorders, acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), mastocytosis, chronic lymphocytic leukemia (CLL), multiple myeloma (MM), myelodysplasia syndrome (MDS), epidermoid cancer, or hemoglobinopathies such as b-thalassemia and sickle cell disease (SCD).

Description:
SELECTIVE INHIBITORS OF PROTEIN ARGININE METHYLTRANSFERASE 5 (PRMT5)

CROSS REFERENCE TO RELATED APPLICATION

[00011 This application claims priority to U.S. Provisional Application No. 62/418,541, filed November 7, 2016, which is incorporated by reference herein in its entirety.

TECHNICAL FIELD

[0002] The disclosure is directed to PRMT5 inhibitors and methods of their use.

BACKGROUND

[0003] Protein arginine methylation is a common post-translational modification that regulates numerous cellular processes, including gene transcription, mRNA splicing, DNA repair, protein cellular localization, cell fate determination, and signaling. Three types of methyl- arginine species exist: co NG monomethylarginine (MMA), ω G, NG asymmetric

dimethylarginine (ADMA) and o NG,N'G symmetric dimethylarginine (SDMA). The formation of methylated arginines is catalyzed by the protein arginine methyl transferases (PRMTs) family of methyltransferases. Currently, there are nine PRMTs annotated in the human genome The majority of these enzymes are Type I enzymes (PRMT ' l , -2,-3,-4,-6,-8) that are capable of mono- and asymmetric dimethyiation of arginine, with S-adenosylmethionine (SAM) as the methyl donor. PRMT-5, -7 and -9 are considered to be Type II enzymes that catalyze symmetric dimethyiation of arginines. Each PRMT species harbors the characteristic motifs of seven beta strand methyltransferases (Katz et al., 2003), as well as additional "double E" and "THW" sequence motifs particular to the PRMT subfamily.

[0004] PRMTS is as a general transcriptional repressor that functions with numerous transcription factors and repressor complexes, including BRG1 and hBRM, Blimp 1, and Snail. Tins enzyme, once recruited to a promoter, symmetrically dimethylates H3R8 and H4R3.

Importantly, the H4R3 site is a major target for PRMTl methylation (ADMA) and is generally regarded as a transcriptional activating mark. Thus, both H4R3me2s (repressive; me2s indicates SDMA modification) and H4R3me2a (active; me2a indicates ADMA modification) marks are produced in vivo. The specificity of PRMTS for H3R8 and H4R3 can be altered by its interaction with COPR5 and this could perhaps play an important role in determining PRMTS corepressor status. Role of PRMTs in Cancer

[0005] Aberrant expression of PRMTs has been identified in human cancers, and PRMTs are considered to be therapeutic targets. Global analysis of histone modifications in prostate cancer has shown that the dimethylation of histone H4R3 is positively correlated with increasing grade, and these changes are predictive of clinical outcome,

[0006] PRMTS levels have been shown to be elevated in a panel of lymphoid cancer cell lines as well as mantle cell lymphoma clinical samples. PRMTS interacts with a number of substrates that are involved in a variety of cellular processes, including RNA processing, signal transduction, and transcriptional regulation. PRMTS can directly modify histone H3 and H4, resulting in the repression of gene expression , PRMTS overexpression 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. Ceil. Biol. 2008, 6262; Chung et al. J Biol Chem 2013, 5534. In addition to its well-documented oncogenic functions in transcription and translation, the transcription factor MYC also safeguards proper pre- messenger-RNA splicing as an essential step in lymphomagenesis. Koh et al. Nature 2015, 523 7558; Hsu et al. Nature 2015 525, 384.

[0007] The discovery of cancer dependencies has the potential to inform therapeutic strategies and to identify putative drug targets. Integrating data from comprehensive genomic profiling of cancer cell lines and from functional characterization of cancer cell dependencies, it has been recently discovered that loss of the enzyme methylthioadenosine phosphorylase (MTAP) confers a selective dependence on protein arginine methyl transferase 5 (PRMTS) and its binding partner WDR77. MTAP is frequently lost due to its proximity to the commonly deleted tumor suppressor gene, CDKN2A. Cells harboring MTAP deletions possess increased intracellular concentrations of methylthioadenosine (MTA, the metabolite cleaved by MTAP). Furthermore, MTA specifically inhibits PRMTS enzymatic activity. Administration of either MTA or a small-molecule PRMTS inhibitor shows a preferential impairment of cell viability for MTAP -null cancer cell lines compared to isogenic MTAP-expressing counterparts. Together, these findings reveal PRMTS as a potential vulnerability across multiple cancer lineages augmented by a common "passenger" genomic alteration.

Role of PRMTS in Hemoglobinopathies

[0008] The developmental switch in human globin gene subtype from fetal to adult that begins at birth heralds the onset of the hemoglobinopathies, b-thalassemia and sickle cell disease (SCD). The observation that increased adult globin gene expression (in the setting of hereditary persistence of fetal hemoglobin [HPFH] mutations) significantly ameliorates the clinical severity of thalassemia and SCD has prompted the search for therapeutic strategies to re v erse gamma- globin gene silencing. Central to silencing of the gamma-genes is DNA methyiation, which marks critical CpG dmucleotides flanking the gene transcriptional start site in adult bone marrow erythroid cells. t has been shown that these marks are established as a consequence of recruitment of the DNA methyltransferase, DNMT3A to the gamma-promoter by the protein arginine methyltransferase PRMT5. Zhao et al. Nat Struct Mol Biol. 2009 16, 304. PRMT ' 5- mediated methyiation of histone H4R3 recraits DNMT3A, coupling histone and DNA methyiation in gene silencing.

[0009] PRMT5 induces the repressive histone mark, H4R3me2s, which serves as a template for direct binding of DNMT3A, and subsequent DNA methyiation. Loss of PRMT5 binding or its enzymatic activity leads to dernethyiation of the CpG dinucleotides and gene activation. In addition to the H4R3me2s mark and DNA metliylation, PRMT5 binding to the gamma-promoter, and its enzymatic activity are essential for assembly of a multiprotein complex on the gamma-promoter, which induces a range of coordinated repressive epigenetic marks. Disruption of this complex leads to reactivation of gamma gene expression. These studies provide the basis for developing PRMT5 inhibitors as targeted therapies for thalassemia and SCD.

SUMMARY

[0010] The disclosure is directed to compounds of Formula I, Formula II, and Formula

III:

- .5 -

wherein

A is CH or N;

n is 0 or 1;

is -Ci-Cealkyl, -CH(QH)Ci-C6alkyi, -Ci -Cehaloalkyl, -( ' ! l)( ' : -( ' : .ha!oa!kyi . ~Cc- Cealk-Cs-Cecycloalkyl, -Co-C6alk-C3-C6halocycloalkyl; -Ci-Cealkenyl, -Ci- Cehaloalkenyl, -Ci-Ceaikynyl, -CHjS-Ci-Cealkyl, -CHiS-Ci-Cehaloalkyl, -CH2S- C3-C6cycloalkyl; -CH2S-C3-C6halocycloalkyl; -CHiOCi-Cealkyl, -CH2O-C3- Cecycloalkyl, -CH(QH)-aryi, -CH(F)-aryl, -CH( H 2 )-aiyi, -C(Me)(GH)-aryl, - CHiSCHb-aryl, or -( ! ! ·( (O iN H-nrv!:

R 2 is H, halo, -Ci-Cealkyl, -Ci-Cehaloalkyl, -Co-C6alk-C3-C6cycloalkyl, -Co-Cealk-OH, -Cc-Cealk-O-Ci-Cealkyl, -Co-Cealk-NH , -Co-Cealk-NH-Ci-Cealkyl, -Cc-Cealk-NiCi-Cealky -Ci-Cealkyi, -Co-Cealk-NH-Cs-Cecycloalkyl, -Co-C6alk-N(Ci-C6alkyl)-C:i-C6CycloaIkyl, -Co-Cealk-heterocycloalkyl, heteroaryl, or -CN;

R 3 is H, halo, -Ci-Cealkyl, -Ci-Cehaloalkyl, -Co-Cealk-Cs-Cecycloalkyl, -Co-Cealk-OH, -Co-Cealk-O-Ci-CealkyL -Co-Cealk- H 2 , -Co-Cealk-NH-Ci-Cealkyl, -Co-Cealk- N(Ci-C6alkyl)-Ci-C 6 aIkyl, -Co-Cealk-NH-Cs-Cecycloalkyl, -Co-Cealk-N(Ci- Cealkyl)-C3-CecycloalkyI, -Co-Cealk-heterocycloalkyl, heteroaryl, or -CN: R 4 is H, halo, -Ci-Cealkyl, -Ci-Cehaloalkyi, -Co-Cealk-Cs-CoCycloalkyl, -Co-Cealk-OH, -Co-Cealk-Q-Ci-Cealkyl, -Co-Ceaik-NH?., -Co-Cealk-NH-Ci-Ceaikyl, -Co-Cealk- N(Ci-C&alkyl)-Ci-C6alkyl, -Co-Cealk-NH-Cs-Cecycloalkyl, -Co-C6alk-N(Ci- C6alkyl)-C3-C6Cycloalkyl, -Co-Cealk-heterocycloalkyl, heteroary], or -CN;

or R 2 and R 3 , together with the atoms to which they are attached, form a

C3 -Cecycloalkenyi ring ;

or R 2 and R 3 , together form a triple bond;

or R 3 and R 4 , together with the atom to which they are attached, form a Cj-Cecycloalkyl ring or a heterocycloalkyl ring;

R 5 is H, Ci-Cealkyl, or Ci)-C&alk-C3~Cecyeloalkyl;

R 6 and R 7 are each independently H, Me, NH2, or CH2F;

R 8a and R 8b are each independently H, Ci-Cealkyl, or -Co-Cealk-OCi-Cealkyl, or R 8a and R 8b , together with the atom to which they are attached, form a CB-Cecycloalkyi ring;

R 8 and R 8' are each independently H, Ci-Cealkyl, or -Co-Cealk-OCi-Cealkyl;

or R 8 and R 8 , together with the atom to which they are attached, form a C -Cecycioalkyl ring;

R 9 is -Ci-C alkenyl, -Ci-CAaioaikenyl, C2-C4cyanoalkenyl, -C2-C4alkynyl, -Ci-

C/jhaloalkyl, -Ci-Ceheterocycloalkyl, oxo-substituted-Ci-Ceheterocycloalkyl, -Cs- Cecycloalkyi, -CHO, -C(O)R i0 , ~CR 8 R 8' CN, -CH2NR 8 R 8' , -Co-Cealk-OH, - NR 8 R 8' , -NH-CN, -N(R !0 )CN, -0-Ci-C 4 alkyl, ~NR 5 CONR 8 R 8' , -OCONR 8 R 8' , or - NR ' ( ' (()}( ) ! ' ':

R 10 is -Ci-Cealkyl, or Co-Coalk-CB-Cecycloalkyl; and

R 10a is H, -Ci-Cealkyl, or Co-Ceaik-Cs-Cecycloalkyi.

[0011] Stereoisomers of the compounds of Formula I, Formula Π, and Formula III, and the pharmaceutical salts thereof, are also described. Methods of using compounds of Formula I, Formula 11, or Formula III are described, as well as pharmaceutical compositions including the compounds of Formula I, Formula II, or Formula III.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

[0012] The disclosure may be more fully appreciated by reference to the following description, including the following definitions and examples. Certain features of the disclosed compositions and methods which are described herein in the context of separate aspects, may also be provided in combination in a single aspect. Alternatively, various features of the disclosed compositions and methods that are, for brevity, described in the context of a single aspect, may also be provided separately or in any subcombination,

[0013] The term "alkyl," when used alone or as part of a substituent group, refers to a straight- or branched-chain hydrocarbon group having from 1 to 12 carbon atoms ("C1-C12"), preferably 1 to 6 carbons atoms ("Ci-Ce"), in the group. Examples of alkyl groups include methyl (Me, Cialkyl), ethyl (Et, Chalky!), n-propyl (Cialkyl), isopropyl (Csalkyi), butyl (C'-ialky]), isobutyl (C alkyl), sec-butyl (Cialkyl), tert-butyl (C-mlkyl), pentyl (Csalkyl), isopentyl (Csalkyl), tert-pentyl (Csalkyl), hexyl (Cealkyl), isohexyl (Ceaikyl), and the like.

[0014] The term "halo" when used alone or as part of a substituent group refers to chloro, fluoro, bromo, or iodo.

[0015] The term "haloalkyl" when used alone or as part of a substituent group refers to an alkyl group wherein one or more of the hydrogen atoms has been replaced with one or more halogen atoms. Halogen atoms include chlorine, fluorine, bromine, and iodine. Examples of haloalkyl groups of the disclosure include, for example, trifluoromethyl (-CF3), chloromethyl (- CH 2 Cl), and the like.

[0016] The term "cycloalkyi" when used alone or as part of a substituent group refers to cyclic, non-aromatic hydrocarbon groups having from 3 to 10 carbon atoms ("C3-C10"), preferably from 3 to 6 carbon atoms ("Cs-Ce")- Examples of cycloalkyi groups include, for example, cyclopropyl (Ci), cyciobutyl (C 4 ), cyclopentyl (C5), cyclohexyi (Ce), 1- methylcyclopropyi (C 4 ), 2-methylcyclopentyl (C 4 ), adamantanyl (Cio), and the like.

1001 7| The term "halocycloalkyl" when used alone or as part of a substituent group refers to a cycloalkyi group wherein one or more of the hydrogen atoms has been replaced with one or more halogen atoms. Halogen atoms include chlorine, fluorine, bromine, and iodine. Examples of halocycloalkyl groups include, for example, chlorocyclopropyl (C3),

fluorocyclobutyl (C 4 ), bromocyclopenty] (Cs), iodocyclohexy] (Ce), and the like.

[0018] 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 stractuxe containing at least one heteroatom selected from the group consisting of O, N and S. The heterocycloalkyl group may be attached at any heteroatom or carbon atom of the ring such 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, piperazinyi, piperidinyl, dioxanyl, moipholinyl, dithianyl, thiomorpholinyl, oxazepanyl, oxiranyl, oxetanyl, quinuclidinyl, tetrahyofuranyl, tetrahydropyranyl, piperazinyi, and the like.

[0019] The term "oxo-substituted-heterocycloalkyl" when used alone or as part of a substituent group refers to a heterocycloalkyl group wherein at least one of the carbon atoms in the ring is substituted with an oxo group. Examples of oxo-substiiuted heterocycloalkyl groups include, but are not limited to, 2-aziridinonyl, 2-azetidinonyi, pyrrolidinonyl, dioxolanonyl, imidazolidinonyl, pyrazolidinonyl, piperazinonyl, piperidinonyl, dioxanonyl, dithianonyl, thiomorpholinonyl, oxazepanonyl, oxiranonyl, oxetanonyl, quinuclidinonyl, tetrahyofuranonyl, tetrahydropyranonyl, piperazinonyl, and the like.

[0020] The term "alkenyl" when used alone or as part of a substituent group refers to a straight- or branched-chain group having from 2 to 12 carbon atoms ("C2-C12"), preferably 2 to 4 carbons atoms ("C2-C4"), in the group, wherein the group includes at least one carbon-carbon double bond. Examples of alkenyl groups include vinyl (-CH=CH2; C alkenyl) ailyl (-CH2- CH=CH 2 ; C alkenyl), propenyl (-CH=CHCH3; Csalkenyl); isopropenyl {~C(Cft)=CH 2 ;

Csalkenyl), butenyl (-( 1 1 Π Κ H i l l :; Gtalkenyl), sec-butenyl (-C(CH3)=CHCH 3 ; Cialkenyl), iso-butenyl { ··( ! 1 ( ' ( ( I I ··) ·: Oaikenyl), 2-butenyl C4alkyl), pentenyl !-CH ( ' ! ICS !.·( ' ! I. i 1 1 Csaikenyl), and the like.

[0021] The term "haloalkenyl" when used alone or as part of a substituent group refers to an alkenyl group wherein at least one carbon atom in the group is substituted by one or more halogen atoms. Halogen atoms include chlorine, fluorine, bromine, and iodine.

[0022] The term "cyanoalkenyl" when used alone or as part of a substituent group refers to an alkenyl group wherein at least one carbon atom in the group is substituted by one or more cyano groups.

[0023] The term ' " cycloalkenyl," when used alone or as part of a substituent group refers to cyclic, non-aromatic hydrocarbon groups having from 3 to 10 carbon atoms ("C3-C10"), preferably from 3 to 6 carbon atoms ("Ci-Ce") and containing at least one carbon-carbon double bond. For example, cycloalkenyl groups include, but are not limited to cyclopropenyl, cyclobutenyl, and the like.

[0024] The term "alkynyl" when used alone or as part of a substituent group refers to a straight- or branched-chain group having from 1 to 12 carbon atoms ("Ci-Ci j")- preferably 1 to 4 carbons atoms ("C2-C4 " '), in the group, and wherein the group includes at least one carbon- carbon triple bond. Examples of alkynyl groups include ethynyl (-O H; C2alkynyl); propargyi ·;-Π ί.-(· (Ί Ι: Csalkynyl), propynyl ( ··( " C * i i h; Csalkynyl); butynyl (-G CH2CH3; C/ialkynyl), pentynyl (-OCCH2CH2CH3; Csalkynyl), and the like.

[0025] 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 carbon atoms in the ring, wherein one or more of the carbon atoms in the ring is optionally substituted with a halogen atom or with a -C1-C3 alkyl group. Halogen atoms include chlorine, fluorine, bromine, and iodine. Examples of aryl groups (substituted and unsubstituted) include phenyl, naphtyl, fluorophenyl, difluorophenyl, chlorophenyl, 4-chlorophenyl, 3,4-difluoropheny], 3-fluoro-4- chlorophenyl, 3-methyl-4-chlorophenyl, 3,4-dichlorophenyl, bromophenyl, iodophenyl, fluoronaphthyl, difluoronaphthyl, chloronaphthyi, bromonaphthyl, iodonaphthyl, methylphenyl, ethylphenyl, and the like.

[0026] The term "heieroaryF when used alone or as pari of a substituent group refers to a mono- or bicyclic- aromatic ring structure including carbon atoms as well as up to four heteroatoms selected from, nitrogen, oxygen, and sulfur. Heteroaryl rings can include a total of 5, 6, 9, or 10 ring atoms ("C5-C10"). The heteroaryl moiety can be unsubstituted or one or more of the carbon atoms in the ring can be substituted with a halogen atom or with a -G-C.3 alkyl group. Halogen atoms include chlorine, fluorine, bromine, and iodine. Examples of heteroaryl groups include but are not limited to, pyrrolyl, furyl, thiophenyl (thienyl), oxazolyl, imidazolyl, purazolyl, isoxazolyl, isothiazolyl, iriazolyl, thiadiazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, furazanyl, indolizinyl, indolyl, isomdolinyl, indazolyl, benzofuranyl, benzothiophenyl, benzimidazolvl, benzthiazolyl, purinyl, quinolizinyl, quinolinyl, isoquinoliny], isothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, and the like.

[0027] When a range of carbon atoms is used herein, for example, Ci-Ce, all ranges, as well as individual numbers of carbon atoms are encompassed. For example, "C1-C3" includes Ci- C3 , C 1-C2, C2-C3, Ci, C2, and C3.

[0028] The term "Ci-Cealk" when 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(CH3)-CH2-, and -CiCTT i-. The term "-Coalk-" refers to a bond.

[0029] ''Pharmaceutically acceptable" means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, e.g., in humans. [0030] ''Pharmaceutically acceptable salt" refers to a salt of a compound of the disclosure that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1 ) acid addition salts, formed with inorganic acids such as hydrochloric acid, hvdrobromic 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-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4- toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-l-carboxylic acid, glucoheptomc acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric 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 either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth 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 functionality, salts of non-toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.

[0031] A "pharmaceutically acceptable excipient" refers to a substance that is nontoxic, 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 vehicle, carrier, or diluent to facilitate administration of an agent and that is compatible therewith. Examples of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.

[0032] "Subject" includes humans. The terms "human," "patient," and "subject" are used interchangeably herein.

[0033] "Treating" or "treatment" of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e., arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment "treating" or

"treatment" refers to ameliorating at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, 'treating" or "treatment" refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom),

physiologically, (e.g., stabilization of a physical parameter), or both. In yet another embodiment, "treating" or "treatment" refers to delaying the onset of the disease or disorder.

[0034] "Compounds of the present disclosure," and equivalent expressions, are meant to embrace compounds of Formula I, Formula II, and/ or Formula III as described herein, as well as their subgenera, which expression includes the stereoisomers of compounds of Formula I, Formula II, and/ or Formula III, as well as the pharmaceutically acceptable salts or isotopic variants, where the context so permits.

[0035] As used herein, the term "isotopic variant" refers to a compound that contains proportions of isotopes at one or more of the atoms that constitute such compound that is greater than natural abundance. For example, an "isotopic variant" of a compound can be radiolabeled, that is, contain one or more radioactive isotopes, or can 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 will be understood that, in a compound where such isotopic substitution is made, the following atoms, where present, may vary, so that for example, any hydrogen may be H/D, any carbon may be !3 C, or any nitrogen may be !fr N, and that the presence and placement of such atoms may be determined within the skill of the art. It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed "isomers." Isomers that differ in the arrangement of their atoms in space are termed "stereoisom ers," for example, diastereomers, enantiomers, and atropisomers. The compounds of this disclosure may possess one or more asymmetric centers; such compounds can therefore be produced as individual (i?)-or (^-stereoisomers or as mixtures thereof. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. Where a 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 encompassed by that structure. The methods for the determination of stereochemistr - and the separation of stereoisomers are well-known in the art.

100361 The disclosure is directed to compounds of Formula I, Formula II, and Formula III. In some aspects, the disclosure is directed to compounds of Formula I:

[0037] In other aspects, the disclosure is directed to compounds of Formula IT:

100381 In other as nds of FormuJ

100391 According to the disclosure, A in Formula I, Fonnula II and/or Fonnula III is N or CH. In some aspects, A i s N and the compounds of Formula I are of Formula IA :

- I I -

[0040] In some aspects, A is N and the compounds of Formula II are of Formula

10041 1 In some aspect of Formula III are of Fomrula III A:

[0042] In other aspects, A is CH and the compounds of Formula I are of Formula IB:

[0043] In some aspects, A is CH and the compounds of Formula II are of Formula ΠΒ: s

p5 R , <:

116

100441 In some aspects, A is CH and the compounds Formula III are of Formula

100451 According to the di sclosure, in compounds of Formula Π, including all subformulas, n is 0 (zero) or 1 . Thus, in some aspects, when n=0 the compounds of Formula are of Formula IIC:

[0046] In some aspects, when n ; =l the compounds of Formula II are of Formula IID:

IID [0047] In those aspects wherein the compounds of Formula II are of Formula IID, !0a is H, Ci-Cealkyl, or Co-Ceaik-G-CecycloalkyL Thus, in some aspects, R i0a is H. In other aspects, R 10a is Ci-C&alkyi, for example, methyl, ethyl, propyl, isopropyi, butyl, isobutyl, s-butyl, t-butyl, pentyl, and the like. In other aspects, R !(¾ is Co-C6alk-C3-C6cycloalkyl, for example, Co- alk-Cj-CbCycloalkyl, Ci-Cbalk-Cn-Cecycloalkyl, Ci-Csalk-Cs-Cecycioalkyl, Ci-Gtalk-Cj- Cecycloalkyl, Ci-C3aik-C3-C6cycloalkyi, Ci-C alk-Cs-C&cycloalkyl, Cialk-Cs-Cbcycioalkyl, Coalk~C3cyeloalkyL Coalk-C cycloalkyl, Coalk-Cscycloalkyl, Coalk-Cecycloalkyi, Ci-Cealk- C'3cycloalkyl, Ci-Cealk-C-cycloalkyl, Ci-Cealk-Cscycloalkyl, or Ci-Cealk-Cbcycloalkyl.

[0048] According to the disclosure, R 1 in Formula I, Formula II and/or Formula III is - Ci-Cealkyl, -CH(OH)Ci-C6alkyl, -Ci-Cchaloalkyl, ~CH(OH)Ci-C6haloalkyl, -Co-Cealk-CV Cecycloalkyl, -Cc-Cealk-C^-Cehalocycloalky]; -Ci-Cealkeny], -Ci-Cehaloalkenyl, -Ci-Cealkyny], -CFfcS-Ci-Cealkyl, -CHiS-Ci-Cehaloalkyl, -CHjS-Cs-Cecycloalkyl; -CHjS-Cs-Cehaiocycloalkyl; •CI ! ·()( ' :··( aii-A i. -CFbQ^-Cecycloalkyl, -CH(QH)-aryl, -CH(F)-ar l, -CH(NH 2 )-aryl, - C(Me)iOH)-aryl, -( H -S( H -ar> i. or -CH 2 C(0)NH-aryl.

[0049] In some aspects, R ! is -Ci-Cehaloalkyl, -Co-Cealk-C^-CecycJoalkyl, -CFfcS-Ci- Cealkyl, -CH(OH)-aryl, -Π ! SC! \:- v 1. or ~Ci K (O)NH-aiyl .

100501 In some aspects, R ! is -Ci-Cealkyl, for example, methyl, ethyl, propyl, isopropyi, butyl, isobutyl, s-butyl, t-butyl, pentyl, and the like.

10051 1 In other aspects, R ] is -CH({)H)Ci-C 6 alkyl, for example, -CH(OH)-methyl, - CH(OH)-ethyi, -CH(OH)-propyl, -CH(GH)-isopropyl, -CH(OH)-pentyl, -CH(OH)-butyl, and the like. In some embodiments, R 1 is -CH(OH)Ci-C4alkyl.

[0052] In some aspects, R ! is Ci-Cehaloalkyl, for example, fluoromethyl, fluoroethyl, fluoropropyl, fluorobutyl, fluoropentyl, chloromeihyl, chloroeihyl, chloropropyl, chlorobutvl, chloropentyl, bromomethvl, bromoethvl, bromopropyl, bromobutyl, bromopeniyl, lodomeiiiyl, iodoethy], iodopropyl, iodobutyl, iodopenty] and the like. Thus, in some aspects, R 1 is chloromeihyl (i.e. , -CH2-CI.)

100531 In other aspects, R 1 is -CH(OH)Ci-C6haloalkyl, for example, -CH(OH)- fluoromethyl, -CH(OH)-fluoroethyl, -CH(OH)-fluoropropyl, -CH(OH)-fluoroisopropyl, - CH(OFT) -fluoropentyl, -CH(OFf)-fluorobutyl, and the like. In some embodiments, R 1 is - CH(OH)Ci-C4haloalkyl.

[0054] In other aspects, R 1 is -Co-Cealk-Cj-Cecycioaikyl, for example, -Coalk-C.3- C&cyeloalkyl, -Ci-Cealk-Cs-Cecyc oalkyi, -Ci -Csalk-Cs-Cecycloalkyl, -Ci-C4alk-C3- Cecycloalkyl, -Ci-C3alk-C3-C6cycloalkyl, -Ci-Cialk-Cs-Cecycloalkyl, -Cialk-Cn-Cecycloalkyl, - Coalk-Cncycloalkyl, -Coalk-Ctcycloalkyk -Coalk-Cscycloalkyl, -Coalk-Cecycloalkyl, -Ci-Cealk- Cicycloalkyl, -Ci -C6alk-C cycioaikyl, -Ci-Cealk-Cjcycloalkyl, or ---Ci-Cbaik-Cecycioaikyl. Thus, in some aspects, R 1 is -CH2~cyclopropyl,

[0055] In some aspects, R 1 is -Co-Cealk-Cs-Cehalocycloalkyl, for example, Coalk-Cs- Cehalocycloalkyl, -Ci-Cealk-Ca-Cehalocycloalkyl, -Ci-Cjalk-C-s-Cehalocycloalkyl, -Ci-C4alk-C-3- Cehalocycloalkyl, -Ci-Csalk-Cs-Cehalocycloalkyi, -Ci-Cialk-Cs-Cehalocycloalkyl, -Cialk-CV Cehalocycloalkyl, -CoaSk-Cshalocyeloaikyl, -Coalk-CAalocycloalkyl, -Coalk-Cshalocycloalkyl, - Coalk-Cehalocycloalkyl, -Ci-Cealk-Cihalocycloalkyi, -C i-Cealk-C4halocycloalkyl, -Ci-Cealk- Cshalocycloalkyl, or -Ci -Cealk-Cehalocy cloalkyl .

[0056] In some aspects, R is -( ' .'-( ' Valkenvi. for example, vinyl, allyl, and the like.

[0057] In some aspects, R 1 is -C2-Cehaloalkenyl, for example, -C(F)=CHMe, - and the like.

100581 In some aspects, R 1 is -Ci-Cealkynyl, for example, ethynyl, propargyl, and the like.

100591 in some aspects, R ! is -CftS-Ci-Cealkyl, for example -CH2S-Cialkyl, -CH2S- C2alkyl, -CH 2 S-C3alkyl, -CifcS-C alkyl, -CTfcS-CsalkyL and -CI-LS-Cealkyl. Thus, in some aspects R 1 is -CH-S-Cialkyl. In some aspects, R 1 is -CH2-S-CH3.

[0060] In some aspects, R is -CftS-Ci-Cehaloalkyl, for example -CH2S-Ciha3oa3kyi, - CftS-Cihaloalkyl, -CHjS-Cshaloalkyl, -CH 2 S-C4haloalkyl, -Cl-fcS-Cshaloalkyl, and -CH2S- Cehaloalkyi.

100611 In some aspects, R 1 is -CH2S-C3-C6cycloalkyl, for example -CH2S- C'3Cycloalkyl, -CH2S-C4cycloalkyl, -CTbS-Cscycloalkyl, -CthS-Cecycloalkyl, and the like.

[0062] In some aspects, R 1 is -Cl^S-Cn-Cehalocycloalkyl, for example -CH2S- Cshalocycloalkyi, -CH2S-C4halocycloalkyl, -CHaS-Cshalocycloalkyl, -CHaS-Cehalocycloalkyl, and the like.

[0063] In some aspects, R 1 is for example, -CFhOCialky], - ( 1 !.·()( •aiky! . -CHbOCsalkyl, ·( ' ! ! ·()( ' ialk> I. -Ci )Oaik> I. -CHzOCealkyl, and the like.

[0064] In some aspects, R 1 is -CH20-C3-C6cycloalkyl, for example, -CH2O- Cecycloalkyl, -CFfcO-Cscycloalkyl, -CH20-C4cycloalkyl, -CftO-Cscycloalkyl, and the like.

10065| In some aspects, R ! is -CH(OH)-aryl, for example, -CH(OH)-phenyl, -CH(OH)- naphthyl, -CH(QH)-fluorophenyl, -CH(OH)-difluorophenyl, -CH(OH)-3,4-difluorophenyl, - CH(OH}-fluoronaphthyl, -CH(OH)-cli3oroplienyl, -CH(OH)-4-chlorophenyl, -CH(OH)-3-fluoro- 4-chlorophenyl, -CH(OH)-dichlorophenyl, -CH(OH)-3,4-dichlorophenyl, -CH(OH)- bromophenyl, -CH(OH)-iodopheny 1, -CH(OH)-methylpheny 1 , -CH(OH)-3 -methyl-4- chlorophenyl, and the like. In some aspects R 1 is -CH(OH)-difluorophenyl. Thus, in some aspects R 1 is ~CH(QH)~3,4~difluorophenyl. In other aspects, R 1 is -CH(OH)-4~chlorophenyl. In other aspects, R 1 is -CH(OH)-3-fluoro-4-chlorophenyl. In other aspects, R 1 is -CH(OH)- dichlorophenyl. In other aspects, R 1 is -CH(OH)-3,4-dichlorophenyl. In other aspects, R 1 is - CH(OH) -3 -methy 1-4-chloropheny 1.

[0066] In some aspects, R ! is -CH(F)-aiyl, for example, -CH(F)-phenyl, -CH(F)- naphthyl, -CH(F)-fluoropheny], -CH(F)-difluorophenyl, -CH(F)-fluoronaphthyl, -CH(F)- chlorophenyl, -CH(F)-bromophenyl, -CH(F)-iodophenyl, -CH(F)-methylphenyl, and the like.

[0067] In some aspects, R ! is -CH(NFb)-aryl, for example, -CH(NH2)-phenyl, - CH(NH2)-naphthyl, -CH(NH 2 ) -phenyl, -CH(NH 2 )-naphthyl, ~CH(M¾)~f]uorophenyl, - CH(NH2)-difluorophenyl, -CH(NH2)-fluoronaphihyl, -CH(NH 2 )-chlorophenyl, -(Ή(ΝΗ 2 )- bromophenyl, -CH(NH2)-iodophenyl, -CH( H2)-methyIphenyl, and the like.

[0068] In some aspects, R ! is ~C(Me)(OH)~aryl, for example, -C(Me)(OH)-phenyl, - C(Me)(OH)-naphthyl, -C(Me)(OH)-fiuorophenyl, -C(Me)(OH)-difiuorophenyl, -C(Me)(OH)~ fluoronaphthyl, -C(Me)(OH)-chlorophenyl, -C(Me)(OH)-bromophenyl, -C(Me)(OH)- iodophenyl, -C(Me)(OH)-methylphenyl, -C(Me)(OH)-3 ,4-difluorophenyl, -C(Me)(OH)-4- chlorophenyl, -C(Me)(OH)-3-fluoro-4-chlorophenyl, -C(Me)(OH)-dichlorophenyi, -C(Me)(OH)- 3,4-dichlorophenyl, -C(Me)(OH)-3-methyl-4-chlorophenyl, and the like. In some aspects R 1 is - C(Me)(OH)-difluorophenyl. Thus, in some aspects R 1 is -C(Me)(OH)-3,4-difluorophenyl. In other aspects, R 1 is -C(Me)(OH)-4-chloropheny3. In other aspects, R 1 is -C(Me)(OH)-3-fluoro-4- chlorophenyl. In other aspects, R ! is -C(Me)(OH)-dichlorophenyl. In other aspects, R ! is - C(Me)(OH)-3,4-dichlorophenyl. In other aspects, R 1 is -C(Me)(OH)-3 -methyl -4-chlorophenyl.

[0069] In some aspects, R is ·ί.Ί I 'Si I l ' -ar 1. for example --U i.'SO I -phcn> i. ·· CH SCtfc-naphthyi, -CH2SCH2-fiuorophenyl, -CH2 SCFfc-difluorophenyl, -CH2SCH2- fluoronaphthyl, -CHjSCHj-chlorophenyl, -CH2SCH2-bromophenyl, -CH2SCH2-iodophenyl, - CH2SCH2-methylphenyl, and the like. r I ius, in some aspects R 1 is -CH SCHj-phenyl.

[0070] In some aspects, R ! is -CH2C(0)NH-aryl, for example -CH2C(0)NH-phenyl, - CH2C(0) H-naphthyl, -CH 2 C(0)NH-fluoropbenyl, -CH 2 C(0)NH-difiuorophenyl, -CH 2 C(0)NH -fluoronaphthyl, -CH 2 C(0)NH-chIorophenyl, -CH 2 C(0)NH-bromophenyl 5 -CH 2 C(0)NH- iodophenyl, -CH 2 C(0)NH-methylphenvl, and the like. Thus, in some aspects R 1 is - CH2C(0)NH-phenyL 100711 n embodiments of the disclosure wherein the compounds are of Formula I, Formula Π, and/or Formula 111, R 5 is H, -Ci-Cealkyl, or Co-Cealk-Ci-Cecycloalkyl.

[0072] In some aspects, R 3 is H or -Ci-C&alkyl.

[0073] In some aspects, R 5 is H.

[0074] In other aspects, 5 is -Ci-Cealkyl, for example, methyl, ethyl, propyl,

isopropyl, butyl, isobutyl, s-butyl, t-butyi, pentyl, and the like. Thus, in some aspects, R 5 is methyl,

[0075] In other aspects, R 5 is Co-Cealk-Cn-Cecycloalkyl, for example, Co-alk-Ci- Cocycloalkyl, Ci-Cealk-CB-Cecycloalkyl, Ci -Csalk-C -Cecycloalkyl, Ci-C 4 alk-C3-C6cycloalkyl, Ci-C3alk-C3-C6cycloalkyl, Ci-Cialk-Cs-Cecycloalkyl, Cialk-C3-C6cycloalkyl, Coalk- Cscycloalkyl, Coalk-C4cycloalkyl, Coalk-Cscycloalky], Coalk-Cecycloalkyl, Ci-Cealk- Cicycloalkyl, Ci-C6alk-C4cycloalkyl, Ci-Cealk-Cscycloalkyl, or Ci -Coalk-Cecycloalkyl.

[0076] In embodiments of the disclosure wherein the compounds are of Formula I, Formula II, and/or Formula I I I . R 6 and R " are each independently H, Me, Nth, or CthF.

[0077] In some embodiments, R 6 is H, Me, or NH2. Thus, in some embodiments, R 6 is H. In other embodiments, R 6 is Me. In yet other embodiments, R b is NH2.

[0078] In some embodiments, R 7 is H, Me, or NH2. Preferably, R 7 is H.

[0079] In some aspects, R 6 and R 7 are each H. In some aspects, R 6 is Nth, methyl or CthF, and R 7 is H. In other aspects, R 6 is H and R 7 is NH2, methyl, or CH2F.

100801 In embodiments of the disclosure wherein the compounds are of Formula I, R 2 is H, halo, -Ci-C&alkyl, -Ci-Cehaloalkyl, -Cc-Cealk-Cs-Cecycloalkyi, -Co-C&alk-OH, -Co-Cealk- O-d-Cealkyl, -Co-C 6 alk-NH 2 , -Co-Cealk-NH-Ci-Cealkyl, -Co-Cealk-NiCi-CealkyO-d-Cealkyl, - Co-Cealk-NH-CB-Cecycloalkyl, -Co-C6alk-N(Ci-C6alkyi)-C3-C6Cycloalkyi, -Co-Cealk- heterocycloalkyl, heteroaryl, or -CN .

[0081] In some aspects, R 2 is H.

[0082] In some aspects, R 2 is halo, for example, F, CI, Br, or I, with F, CI, and Br being preferred and F and CI being more preferred.

[0083] In some aspects, R 2 is -Ci-Cealkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, and the like.

[0084] In some aspects, R 2 is -Ci-Cehaloalkyl, for example, -CF3 or -CHF2.

[0085] In some aspects, R 2 is -Co-C6alk-C3-C6cycloalkyl, for example, -Coalk-C3- C&cycloalky3, -Ci-Cealk-Cs-Cecycloalkyi, -Ci -Csalk-Cs-Cecycloalkyl, -Ci-C4alk-C3- Cecycloalkyl, -Ci-C3alk-C3-C6cycloalkyl, -Ci-Caalk-Cs-Cecycloalkyl, -Cialk-Cn-Cecycloalkyl, - Coalk-Cncycloalkyl, -Coalk-Ctcycloalkyl, -Coalk-Cscycloalkyl, -Coalk-Cecycloalkyl -Ci-Cealk- Cicycloalkyl, -Ci -C6alk-C cycioaikyl, -Ci-Cealk-Cjcycloalkyl, or -Ci-Cbalk-Cecycloalkyl. In some aspects wherein R 2 is -Co-Cbalk-Cs-Ceeycloalkyl, the cycloalkyl is un substituted. In other aspects wherein R 2 is -Co-Cealk-Cs-Cecycloalkyl, the eycioalky] is substituted with one, two, or three R substituents independently selected from Ci-Cealkyl, (e.g., methyl, ethyl, propyl, isopropyl, butyl), -OCi-Cealkyl (e.g., -Omethyl, -Oethyl, -Opropyl, -Oisopropyl, -Obutyl), and halo (e.g., F or CI).

100861 in some aspects, R 2 is -Co-Cealk-OH, for example, -Coalk-OH, -Ci-Cealk-OH, - Ci-Csalk-OH, -Ci-C4alk-OH 5 -Ci-Csalk-OH, -Ci-Cialk-OH, or -Cialk-OH.

[0087] In some aspects, R 2 is -Co-Cealk-O-Ci-Cealkyl, for example, -Coalk-O-Ci- Cealkyl, -Ci-Cealk-O-Ci-Cealkyl, -Ci-Csalk-O-Ci-Cealkyl, -Ci-Calk-O-Ci-Cealky], -Ci-Csalk- O-Ci-Cealkyl, -d-Cialk-O-Ci-Cealkyl, -Cialk-O-Ci-Cealkyl, -Coalk-O-Ci-Csalkyl, -Coalk-O-Ci- Ctalkyl, -Coalk-O-Ci-Csalkyl.-Coalk-O-Ci-Caalkyl, -Coalk-O-Cialkyl, -Ci-Ceaik-Q-Ci-Cjalkyl, - Ci-C6alk-0-Ci-C4alkyl, -Ci-C6alk-0-Ci-C3alkyl,-Ci-C6alk-0-Ci-C2alkyl, or -Ci-Cealk-O- Cialky] ,

10088| In some aspects, R 2 is Ci-Qalk-NFfc, for example, -Coalk-NHz, -Ci-Cealk-NH?., - Ci-Csalk-NFfc, -Ci-Cwlk-NHi, -Ci-Csalk-NlHb, ··( : ·(· ·αΓ ·\ 1 1 . or -Cialk-NFfc.

[0089] In some aspects, R 2 is -Co-Cealk-NH-Ci-Cealkyl, for example, -Coalk-NH-Ci- Ceaikyl, -G-Cealk-NH-Ci-Cealkyl, -Ci- alk-NH-Ci-Cealkyl, -Ci- Csalk-NH-Ci-Cealkyl, -C•( •• •aik-NI i-( ' :-( ' ..a!k s 1. -CiaJk-NH-Ci-Cealkyl, -Coaik-NH-Ci-Csalkyl, -Coalk-NH-Ci-C4alkyl, -CoaSk-NH-Ci-Cialkyl, -Coalk-NH-Ci -Chalky], -Coalk-NH-Cialkyl, -Ci- Cealk-NH-Ci-Csalkyl, -C :-( ^lk-N H-C -Galkvl. -Ci-Cealk-NH-Ci-Csalkyl, -Ci-Cealk-NH-Ci- Cialkyl, or -C L-Cealk-NH-Cialkyl.

[0090] In some aspects, R 2 is -CVC6alk-N(Ci-C&alkyl)-Ci-C6alkyl, for example, -Coalk- N(Ci-C6a3kyl)-Ci-C 6 alkyl, -Ci-C6alk-N(Ci-C 6 aIkyl)~Ci-C6a3kyl, -Ci-Csalk-N(Ci-C6alkyl)-Ci- Cealkyl, -Ci-aalk-NiCi-CealkylJ-Ci-Cealkyl, -Ci-Cialk-NiCi-CealkylJ-Ci-Cealkyl, -Ci-Cialk- N(Ci-C6alkyl)-Ci-C6alkyl, -Cialk-N(C!-C6aikyl)-Ci-C6alkyl, -Coalk-N(Ci-C6alkyl)-Ci-C5aikyl, - Coalk~N(Ci-C6alkyl)-Ci-C4alky3, -Coalk-N(Ci-C6alkyl)-Ci-C 3 alkyl, ~CoaIk-N(Ci-C6alky3)-Ci- C2alky], -CGalk-N(Ci-C6alk y r)-Cialkyl, -Ci-C6alk-N(Ci-C6alky])-Ci-C 5 alkyl, -Ci-Ceaik- iCi- C6alkyl)-Ci-C4alkyi, -Ci-Cealk-NiCi-Cealky -Ci-Cialkyl, -Ci-C6alk-N(Ci-C6alkyl)-Ci-C2aIk>'l, -Ci-C6alk-N(Ci-C6alkyl)-Cialkyl, -Coa3k-N(C;-Cjalkyl)"Ci-C6alkyl, -Coalk-N(Ci-C4alkyl)-Ci- C&alkyl, -Coalk-N(Ci-C3alkyl)-Ci-C6alkyl, -Coalk-N(Ci-C2alkyl)-Ci-C6alkyl, -Coalk-N(Cialkyl)- Ci-Cealkyl, -Ci-Cealk-NiCi-Csalk^'D-Ci-Cealkyl, -Ci-C6alk-N(Ci-C4alkyl)-Ci-C6alky], -Ci- C6alk-N(Ci-C 3 alkyl)-Ci-C6alkyl, -Ci-C 6 alk-N(C i-C 2 alkyl)-Ci-C6alkyl, or -Co-C6alk-N(Cialkyl)- Ci-Cealkyi.

10091 1 In some aspects, R 2 is -Co-Cealk- H-Cs-Cecycloalkyl, for example, -Coalk-NH- C3-C6cycloalkyl, -Ci-Ceaik- H-Cs-Cecycloalkyl, -Ci-Csalk-NH-Cs-Cecycloalkyl, -Ci-C.alk-NH- C3-C6CV cloalkyl, -Ci-Csalk-NH-Cs-Cecycioalkyl, -Ci-Cialk-NH-Cs-Cecycloalkyl, -Cialk- H-Cs- Cecycloalkyl, -Coalk-NH-C cycloalkyl, -Coalk-NH-C4cycloalkyl, -Coalk-NH-Cscycioaikyl, - Coalk-NH-Cecyeloalkyl, -Ci-Cealk- H-Cscycloalkyl, -( " -G.aikA H-C ;evcioaik U. -Ci-Cealk- NH-Cjcycloalkyl, or -Ci-Cealk-NH-Cecycloalkyl. In some aspects wherein R 2 is -Co-Cealk-NH- Ci-Cecy cloalkyl, the cycloalkyl is unsubstituted. In other aspects wherein R 2 is -Co-Cealk-NH- C3-C6C}' cloalkyl, the cycloalkyl is substituted with one, two, or three R substituents

independently selected from Ci-Cealkyl, (e.g., methyl, ethyl, propyl, isopropyl, butyl), -OCi- Cealkyl (e.g., -Omethyl, -Oethyi, -Opropyl, -Oisopropyl, -Obutyl), and halo (e.g., F or CI).

[0092] In some aspects, R 2 is -Co-C¾alk-N(C!-C6alkyI)-C3-C6cycloalkyl, for example, - Coalk~N(Ci-C6alkyl)-C3-C6cycloalkyl, -Ci-C6alk-N(Ci-C6alkyl)-C3-C6cycloalkyl, -Ci-Csalk- Nid-Cealky -Cs-Cecycloalkyl, -Ci-C4alk-N(Ci-C6alky3)-C3-C6Cycloalkyl, -Ci-C 3 alk-N(Ci- C6alkyl)-C3-C6cycloalkyl, -Ci-C2alk-N(Ci-C6alkyl)-C3-C6cycloalkyl, -Cialk-N(C;-C6alkyl)-C3- C&cycloalkyl, -Coalk-N(Ci-C6alkyl)-C3cycloalkyl, -Coalk-N(Ci-C6alkyl)-C4cycloalkyl, -Coalk- N(Ci-C6alkyl)-C5cycloaIkyl, -Coalk-N(Ci-Cealkyl)-C6cycloalkyl, -Ci-Cealk-NCCi-Cealkyl)- Cicycloalkyl, -Ci-C6alk-N(C i-C6alkyl)-C4cycloalkyl, -Ci-C6aIk-N(Ci-C6alkyl)-C5cycloalkj'l, - Ci -C6alk-N(Ci-C6alkyl)-C6cycloalkyl, -Coalk-N(Ci-Csalkyl)-C3-C6cycloalkyl, -Coalk-N(Ci- C4alkyl)-C3~C6cycloalkyl, -Coalk-N(Ci-C3alkyi)-C3-C6cycloalkyi, -Coalk-N(C i-C2alkyl)-C3- Cecycloalkyl,

Ci-C6alk-N(Ci- alkyl)-C 3 -C6cycloalkyl, -Ci-Cealk-NiCi-CsalkylJ-Cs-Cec cloalkyl. -Ci-Cealk- N(Ci-C2alkyl)-C3-Cecy cloalkyl, or -Ci-C6alk-N(Cialkyl)-C3-C6cycloalkyl. In some aspects wherein R 2 is -Co-C6aik-N(Ci-C6alkyl)-C3-C6cycloalkyl, the cycloalkyl is unsubstituted. In other aspects wherein R 2 is -Co-Cealk-NiCi-Cealkylj-Ci-Cecycloalkyl, the cycloalkyl is substituted with one, two, or three R substituents independently selected from Ci-Cealkyi, (e.g., methyl, ethyl, propyl, isopropyl, butyl), -OCi-Cealkyl (e.g., -Omethyl, -Oethyi, -Opropyl, -Oisopropyl, - Obutyl), and halo (e.g., F or CI).

[0093] In some aspects, R 2 is -Co-Cealk -lieterocycloalkyl, for example, -Coalk- heterocycloalkyl, -Ci-Ceaik-heterocycioaikyl, -Ci-Csaik-heterocycloalkyl, -Ci-Gialk- heterocycloalkyl, -Ci-Csalk-heteroeycloalkyl, -Ci-C2alk~heteroeycloalkyl, or -Cialk- heterocy cloalkyl. Preferred lieterocyloalkyi moieties include, for example piperidinyl, piperazinyl, morpholinyl, aziridinyl, dioxanyl, pyrroiidinyl, tetrahydrofuranyl, tetrahydropyranyl, and oxetanyl. In some aspects wherein R 2 is -Co-Cealk-heterocycloalkyi, the heterocycloalkyl is unsubstituted. In other aspects wherein R 2 is -Co-Ceaik-heterocyeloalkyl, the heterocycloalkyl is substituted with one, two, or three R substituents independently selected from Ci-Cealkyl, (e.g., methyl, ethyl, propyl, isopropyl, butyl), -OCi-Cealkyl (e.g., -Omethyl, -Oethyl, -Opropyl, - Oisopropyl, -Obutyi), and halo (e.g., F or Ci).

100941 In some aspects, R 2 is heteroaryl, for example furanyl, imidazolyl, and pyrazolyl. In some aspects wherein R 2 is heteroaryl, the heteroaryl is unsubstituted. In other aspects wherein R 2 is heteroaryl, the heteroaryl is substituted with one, two, or three R substituents independently selected from Ci-Cealkyl, (e.g., methyl, ethyl, propyl, isopropyl, butyl), -OCi-Cealkyl (e.g., -Omethyl, -Oethyl, -Opropyl, -Oisopropyl, -Obutyi), and halo (e.g., F or CI).

[0095] In some aspects, R 2 is -CN.

100961 In embodiments of the disclosure wherein the compounds are of Formula I, R 3 is H, halo, -Ci-Oalkyl, -Ci-Cehaloalkyl, -Co-Cealk-C^-Cecycioaikyl, -Co-Cealk-OH, -Co-Cealk- O-C i-Cealkyl, -Co-Cealk-NFfc, -Co-Cealk-NH-Ci-Cealkyl, -Co-Cealk-NiCi-CealkylJ-Ci-Cealkyl. - Co-C6alk-NH-C3-C6cycloalkyl, -Co-C&alk-N(Ci-C6alkyl)-C3-C6cycloalkyl, -Co-Cealk- lieterocycloaikyl, heteroaryl, or -CN.

[0097] In some aspects, R 3 is I I .

100981 In some aspects, R 3 is halo, for example, F, CI, Br, or I, with F, CI, and Br being preferred and F and CI being more preferred.

[0099] In some aspects, R 3 is -Ci-Cealkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, and the like.

[0100] In some aspects, R J is -Ci-Cehaloalkyl, for example, -CF3 or --CHF2.

[0101] In some aspects, R 3 is -Co-Cealk-Cs-Ceeycioaikyl, for example, -Coalk-C3- Cecycloalkyl, -Ci-Cealk-Ci-Cecycloalkyl, -Ci-Csalk-Cj-Cecycloalkyl, -Ci-C-ialk-Cs- Cecycloalkyl, -Ci-Cjalk-Ci-Cecycioaikyl, -Ci-Czaik-CB-Cecycloalkyi, -Cialk-C3-C6cycloalkyl, - Coalk-Cicycloalkyi, -Coalk-C cycloalkyl, -Coalk-Cscycloalkyl, -Coalk-Cecycloalkyl -Ci-Cealk- C'3Cycloalkyl, -Ci-Cealk-Cscycloalkyl, or -Ci-Cealk-Cecycloalkyl. In some aspects wherein R 3 is -Co-Cealk-Cs-Cecycloalkyl, the cycloalkyl is unsubstituted. In other aspects wherein R 3 is -Co-Cealk-Cs-Cecycloalkyl, the cycloalkyl is substituted with one, two, or three R substituents independently selected from Ci-Cealkyl, (e.g., methyl, ethyl, propyl, isopropyl, butyl), -OCi-Cealkyl (e.g., -Omethyl, -Oethyl, -Opropyl, -Oisopropyl, -Obutyl), and halo (e.g., F or CI).

[0102] In some aspects, R J is -Co-Cealk-OH, for example, -Coalk-OH, -Ci-Cealk-OH, - Ci-Csalk-OH, -Ci-Cialk-OH, -Ci-Csalk-OH, -Ci-Cialk-OH, or -Cialk-OH.

[0103] In some aspects, R 3 is -Co-Cealk-O-Ci -Cealkyl, for example, -Coalk-O-Ci- Ceaikyl, -Ci-Cealk-O-Ci-Cealkyl, -Ci-Csalk-O-Ci-Cealkyl, -Ci-C4alk-0-Ci-C6alkyl, -Ci-Csalk- O-Ci-Cealkyl, ~Ci-C2a3k-0-Ci-C6alkyl, -Cialk-O-Ci-Cealkyl, -Coalk-O-C i-Csalkyl, -Coalk-O-Ci- C4aikyl, -Coalk-O-Ci-Csalkyl.-Coalk-O-Ci-Czalkyl, -Coalk-O-Ciaikyl, -Ci-Cealk-O-Ci-Csalkyl, - Ci-Cealk-O-Ci-Cialkyl, -Ci-Ceaik-O-Ci-Caalkyl.-Ci-Cealk-O-Ci-Czaikyl, or -Ci -Cealk-O- Ciaikyl.

[0104) In some aspects, R 3 is Ci-Cealk-Nth, for example, -Coalk-NT-fc, -Ci-Cealk-NHb, - G -Csalk-NHz, -( ' :-< ' m!k A S S.:. ·· ( - ulk-N I I ·. -G-C^alk-NI-b, or -Cialk- H_.

[0105] In some aspects, R 3 is -Co-Cealk-NH-Ci-Ceaikyl, for example, -Coalk-NH-Ci - Cealkyl, -Ci-Cealk-NH-Ci-Cealkyl, -Ci-Cs k-NH-Ci-Cealkyl, -( ' ' : -( ' ml k i i-( ' : -( ' a!ky 1. -Ci- Csalk-NH-Ci-Cealkyl, -Ci-Cialk-NH-Ci-Oaikyl, -Cialk-NH-Ci-Cealkyl, -Coalk-NH-Ci-Csalkyl, -Coalk-NH-Ci-Csalkyl, -Coalk-NH-Ci-Csalkyl. -Coalk-NH-Ci-C2alkyl, -Coalk-NH-Cialkyl 5 -Ci - C&aik-NH-Ci-Csalkyl, -Ci-C6alk-NH-Ci-C4alkyl, -Ci-Cealk-NH-Ci-Csaikyl, -Ci-C&alk-NH-Ci- Cialkyl, or -Ci-CeaSk-NH-Cialkyl.

[0106] In some aspects, R 3 is -Co-C6alk-N(Ci-C6aikyl)-Ci-C6alkyl, for example, -Coalk- N(Ci-C6alkyl)-Ci-C6alkyl, -d -Cealk-NCCi-CeaikyD-Ci-Cealkyl, -Ci-C 5 alk-N(Ci-C6alkyl)-Ci- Cealkyl, -Ci-C4aIkA Ci-C6alky3)-Ci-C6alk l, -Ci-Csalk-NiCi-CealkylJ-Ci-Cealkyl, -Ci-C2alk- N(Ci-C 6 alkyl)-Ci-C6a]kyl, -Cialk-NCCi-Cealky -Ci-Cealkyl, -Coalk-NiCi-CealkylJ-Ci-Csalkyl, - Coalk-N(Ci-C6alkyl)-Ci- alkyl, -C«alk-N(Ci-C6alk3'I)-Ci-C3alkyl, -Coalk-N(Ci-C6alkyl)-Ci- C2aikyl,••( ' :dk -N(C :-(Vaik> i )-C:alk> I.••( :-(V-a!k A((\--( ,alk> IH ' : -( ¾ikyl. -Ci-Ceaik-NCCi- Ci.alkyl)-Ci-C4a3kyl, -Ci-Cealk- CCi-Cealky -Ci-Csalkyl, -( ' : -( \.ai k A (( ' -(. ' .-.a! k> i )-(. ' : -(•niky I . -Ci-C6alk-N(Ci-C6a1kyl)-C!a1kyl, -Coalk-NCCi-Csalkylj-Ci-Cealkyl, -Coalk-N(Ci-C4a1kyl)-Ci- Ceaikyl, -Coalk-N(Ci-C3alkyl)-Ci-C6alkyl 5 -Coalk-N(Ci-C2alkyl)-Ci-C6alkyl, -Coalk-N(Ci alkyl)- Ci-Cealkyl, -Ci-C6alk-N(Ci-C5alkyl)-Ci-C6alkyi, -Ci-C6alk-N(Ci-C4alkyl)-Ci-C6alkyl, -Ci- aalk-N(Ci-C 3 alkyl)-Ci-C6alkyl, -Ci-aalk-N(C 1 -C2alkyl)-Ci-C6a]kyl 5 or -Co-Ceaik- iCialky!)- Ci-Cealkyl.

[0107] In some aspects, R 3 is -Co-Cealk-NH-Ci-Cecycioaikyl, for example, -Coalk-NH- Cs-Ceeycloalkyl, -Ci-Cealk-NH-Cs-Cecycloalkyl, -C i-Csalk-NH-Cs-Cecycloalkyi , -Ci-C4alk-NH- Ci-Cecycloalkyl, -Ci-Csalk-NH-Cs-Cecycloalkyl, -Γ· -(\ιΙΚ-\Ή-(ν( ^ycioaikyl . -Cialk-NH-Cs- CbCycloalkyl, -Coalk-NH-Cscycloalkyl, -Coalk-NH-C4cycioalkyl, -Coalk-NH-Cjcycloalkyl, - Coalk-NH-Cecycloalkyl, -Ci-Cealk-NH-Cjcycloalkyl, -Ci-Cealk-NH-C cycioaikyl, -Ci-Cealk- NH-Cjcyeloalkyl, or -Ci-Coalk-NH-C&cyeloalkyl, In some aspects wherein R 3 is -Co-Cealk-NH- Cs-Cecycloalkyl, the cycloalkyl is unsubstituted. In other aspects wherein R 3 is -Co-Cealk-NH- Ci-Cecycloalkyl, the cycloalkyl is substituted with one, two, or three R substituents

independently selected from Ci-Cealkyl, (e.g., methyl, ethyl, propyl, isopropyl, butyl), -OCi- Cealkyl (e.g., -Omethyl, -Oethyl, -Opropyl, -Oisopropyl, -Obutyl), and halo (e.g., F or CI).

[0108] In some aspects, R 3 is -Co-Cealk-NiCi-Cealkylj-Ci-Cecycloalkyl, for example, - Coalk-N(Ci-C6alkyl)-C3-C6cycloalkyl, -Ci-C6alk-N(Ci-C6alkyl)-C3-C6cycloalkyl, -Ci-Csaik- N(Ci-C6alkyl)-C 3 -C6cycloalkyl, -Ci-C4alk-N(Ci-C6alkyl)-C3-C6cycloalkyl, -Ci-C 3 aik-N(Ci- Cealkylj-Cs-Cecycloalkyl, -Ci-Ciaik- rCi-CealkylJ-C^-CecycJoalkyl, -Cialk~N(Ci-C6alkyl)-C3- Cecycloalkyl, -G>alk-N(Ci-C6alkyl)-C3cycloalkyl, -Coalk-N(Ci-C6alkyl)-C4Cycloalkyl, -Coalk- N(Ci -C6alkyl)-C5cycloalkyi, -Coalk-N(Ci-C6alkyl)-C6cycloalkyl, -Ci-Cealk-NiCi-Cealkyl)- Cscycioalkyl, -Ci-C6alk-N(Ci-C6alkyl)-C4cycloalkyl, -Ci-C6alk-N(Ci-C6alkyl)-Cscycloalkyl, - Ci-C6alk-N(Ci-C6alkyl)-C6Cyc]oa]kyl, -Coalk-NiCi-CsalkylJ-Cs-Cecycloalkyl, -Coa]k-N(G- C4alkyl)-C 3 -C6cycloalkyl, -Coalk-N(Ci-C3alkyi)-C3-C6cycloalkyi, -Coalk-N(Ci-C2alkyi)-C 3 - C&cycloalkyl, -Coaik-N(Ciaik l)-C3-C6cycioaikyl, -Ci-C6alk-N(Ci-C5alkyl)-C3-C6cycloalkyl, - Ci-C6a3k~N(Ci-C4aIkyl)-C3-C6cycioaIkyi, -Ci-C6alk-N(Ci-C3alkyl)-C3-C6cycloalkyl, -Ci-Cealk- N(Ci-C2alkyi)-C3-C6cycloalkyi, or -Ci-C6alk-N(Cialkyl)-C3-C6cycloalkyl. In some aspects wherein R 3 is -Co-C6alk-N(Ci-C6alkyl)-C3-C6cycloalkyl, the cycloalkyl is unsubstituted. In other aspects wherein R 3 is -Co-Cealk-N(Ci-C6alkyl)-C3-C6cycloalkyl, the cycloalkyl is substituted with one, two, or three R substituents independently selected from Ci-Cealkyl, (e.g., methyl, ethyl, propyl, isopropyl, butyl), -OCi-Cealkyl (e.g., -Omethyl, -Oethyl, -Opropyl, -Oisopropyl, - Obutyl), and halo (e.g., F or CI).

[01 9] In some aspects, R 3 is -Co-Cealk-heteroeycloalkyl, for example, -Coalk- heterocycioaikyl, -Ci-Cealk-heterocycloalkyl, -Ci-Csalk-heterocycloalkyl, -Ci-C4alk- heterocycloalkyl, -Ci-C alk-heterocycloalkyl, -Ci-Ciaik-heterocycloalkyl, or -Cialk- heterocycloalkyl. Preferred heterocyloalkyl moieties include, for example piperidinyl, piperazinyl, morpholinyl, aziridinyl, dioxanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, and oxetanyl. In some aspects wherein R 3 is -Co-Cealk-heterocycloalkyl, the heterocycloalkyl is unsubstituted. In other aspects wherein R 3 is -Co-Cealk-heterocycloalkyl, the heterocycloalkyl is substituted with one, two, or three R substituents independently selected from Ci-Cealkyl, (e.g., methyl, ethyl, propyl, isopropyl, butyl), -OCi-Cealkyl (e.g., -Omethyl, -Oethyl, -Opropyl, - Oisopropyi, -Obutyl), and halo (e.g., F or CI).

[0110] In some aspects, R J is heteroaryl, for example furanyl, imidazolyl, and pyrazolyl. In some aspects wherein R 3 is heteroaryl, the heteroaryl is unsubstituted. In other aspects wherein R 3 is heteroaryl, the heteroaryl is substituted with one, two, or three R substituents independently selected from Ci-Ceaikyi, (e.g., methyl, ethyl, propyl, isopropyl, butyl), -OCi-Cealkyl (e.g., -Omethyl, -Oethyl, -Opropyl, -Oisopropyi, -Obutyl), and halo (e.g., F or CI).

[0111] In some aspects, R 3 is -CN.

[ 112] In embodiments of the disclosure wherein the compounds are of Formula I, R 4 is H, halo, -Ci-Cealkyl, -Ci-Cehaloalkyl, -Co-Cealk-Cs-Cecycloalkyl, -Co-Cealk-OH, -Co-Cealk- O-Ci-Cealkyl, -Co-Cealk-Ntt, -Co-Cealk-NH-C i-Cealkyl, -Co-Cealk-NiCi-Ceaiky^-Ci-Cealkyl, - Co-Cealk-NH-Ci-Cecycloalkyl, -Co-C6alk-N(Ci-C6alkyl)-C3-C6cycloalkyl, -Co-Cealk- heterocycloalkyl, heteroaryl, or -CN.

[0113] In some aspects, R 4 is H.

[0114] In some aspects, R 4 is halo, for example, F, CI, Br, or I, with F, CI, and Br being preferred and F and CI being more preferred.

[01 5] In some aspects, R 4 is -Ci-Cealkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, and the like.

[0! 16] In some aspects, R 4 is -Ci-Cehaloalkyl, for example, -CF3 or -CHF2.

[0117] In some aspects, R 4 is ~Co-C6alk-C3-C6cycloalkyl, for example, -Coalk-Cs- Cecycloalkyl, -Ci-Cealk-Cs-Cecycloalkyl, -Ci-C5alk-C3-C6cycloalkyl, -Ci-C4alk-C3- CbCycloalkyl, -Ci-C3alk-C3-C6CycloaIkyi, -Ci-Cialk-Cn-Cecycloalkyl, -Ciaik-Cs-Cecycloalkyi, - Coaik-C3cycioaikyl, -Coalk-C4cycloalkyl, -Coalk-Cscycloalkyl, -Coalk-Cecycloalkyl -Ci-Cealk- Cscycloalkyl, -Ci-C6aIk-C4cycioaIkyl, -Ci-Cealk-Cscycloalkyl, or -Ci-Cealk-Cecycloalkyl. In some aspects wherein R 4 is -Co-Cealk-CB-CbCycloalkyl, the cycloalkyl is unsubstituted. In other aspects wherein R 4 is -Co-C6alk-C3-C6cycloalkyl, the cycloalkyl is substituted with one, two, or three R substituents independently selected from Ci-Ceaikyl, (e.g., methyl, ethyl, propyl, isopropyl, butyl), -OCi-Cealkyl (e.g., -Omethyl, -Oethyl, -Opropyl, -Oisopropyi, -Obutyl), and halo (e.g., F or CI).

[0118] In some aspects, R 4 is -Co-Cealk-OH, for example, -Coalk-OH, -Ci-Cealk-OH, -Ci-Csalk-OH, -( " : -C ialk-OH. -Ci-C 3 aIk-OH, -Ci-Cialk-OH, or ~CiaIk-OH. [0119] In some aspects, R 4 is -Co-Cealk-O-Ci-Cealkyl, for example, -Coalk-O-Ci- Cealkyl, -Ci-Cealk-O-Ci-Cealkyl, -Ci-Csalk-O-Ci-Cealkyl, -d-C alk-Q-CVCealkyl, -Ci-Csalk- O-Ci-Cealkyl, -Ci-Cialk-O-Ci-Cealkyl, -Galk-G-Ci-Cealkyl, -Coalk-O-Ci-Csalkyl, -Coalk-O-Ci- Ctalkyl, -Coalk-O-Ci-Csalkyi .-Coalk-O-Ci-Cialkyl, -Coalk-O-Cialkyl, -Ci-Cealk-O-Ci-Csalkyl, - d-Cealk-O-Ci-Ctalkyl, -Ci-C 6 alk-0-Ci-C 3 alkyl > -Ci-C6alk-0-Ci-C2alk>4,--Ci- alk-0-C4alkyl.

[0120] In some aspects, R 4 is CVCealk-Nfb, for example, -Coalk-NHa, -Ci-Cealk-NHj., - Ci-Csalk- Hi, -Ci-C4alk- H2, -Ci-C 3 alk-NH2, -Ci-Cialk- Hi, or -Cialk-NHi.

[0121] In some aspects, R 4 is -Co-Cealk-NH-Ci-Cealkyl, for example, -Coalk-NH-Ci- Cealkyl, -Ci-Cealk-NH-Ci-Ceaikyl, -Ci-Csalk-NH-Ci-Ceaikyl, -Ci-Qalk-NH-Ci-Cealkyl, -Ci- Caalk-NH-Ci-Cealkyl, -Ci-Ciaik-NH-Ci-Cealkyl, -Cialk-NH-Ci-Cealkyl, -Coalk-NH-Ci-Csalkyl, -Coalk-NH-Ci-C4alkyl, -Coalk-NH-Ci-Csalkyl, -Coalk-NH-Ci-Cialkyl, or -Coalk-NH-Cialkyl, - Ci-Cealk-NH-Ci-Csalkyi, -Ci-Cealk-NH-Ci-Ctalkyl, -Ci-Cealk-NH-Ci-Caalkyl, -Ci-Cealk-NH- Ci-Cialkyi, or -Ci-Cealk-NH-Cialkyl.

[0122] In some aspects, R 4 is -Co-Cealk-NiCi-CealkyiJ-Ci-Cealkyl, for example, -Coalk- Nid-Cealky -Ci-Cealkyl, -d-Cealk-NiCi-Cealky^-d-Cealkyl, -Ci-Csalk-NCCi-CealkylVCi- Cealkyl, -Ci-C4aIk-N(Ci-C6alkyl)-Ci-C6alkyl, -Ci-Csalk-NiCi-CealkylJ-Ci-Cealkyl, -Ci-Cialk- N(Ci-C6alkyl)-Ci-C6alkyl, -Cialk-N(Ci-C6alkyl)-Ci-C6alkyl, -Coaik-N(Ci-C6alkyl)-Ci-C5alkyl, - Coalk-N(Ci-C6alkyl)-Ci-C4alkyl, -Coalk-N(Ci-C6alkyl)-Ci-C3alkyl, -Coalk-N(Ci-C6alkyl)-Ci- Czalkyl, -Coalk-N(C i-C 6 alkyl)-Cialkyl, -Ci-Cealk-NtCi-CealkylJ-Ci-Csalkyl, -Ci-C 6 aIk-N(Ci- CealkyiVCi-C alkyl, -Ci-C6alk-N(C;-C6aikyl)-Ci-C 3 aIkyi, -Ci-Cealk-NCCi-Cealkyi -Ci-Ciaikyl, -Ci-C6alk-N(Ci-C6alky3)-Cialky3, -Coalk- (Ci-C5alkyl)-Ci-C6alkyl, -Coalk-N(Ci-C4alkyl)-Ci- Cealkyl, -Coalk-N(Ci-C3alkyl)-Ci-C6alkyl, -Coalk-N(Ci-C2alkyl)-C 1 -C 6 alkyl, -Coalk-N(Cialkyl)- Ci-Cealkyl, -Ci-Cealk-NiCi-Csalky^-Ci-Cealkyl, -Ci-C6alk-N(Ci-C4alkyl)-Ci-C6alk>'l, -Ci- C6alk-N(Ci-C3alkyl)-Ci-C6alkyl, -Ci-Cealk-NCCi-Caalky -Ci-Cealkyl, or -Co-C&alk-N(Cialkyi)- Ci-Cealkyl.

[0123] In some aspects, R 4 is -Co-Cealk-NH-Ci-Cecycloalkyl, for example, -Coalk-NH- Cs-Cbcycloalkyl, -Ci-Cealk-NH-Cs-Cecydoalkyl, -Ci-Csalk-NH-Cs-Cecycloalkjd, -Ci-C4alk-NH- C -Cecycloalkyl, -Ci-Csalk-NH-Cs-Cecycloalkyl, -Ci-dalk-NH-Cs-Cecycloalkyl, -Cialk-NH-Cs- Cecycloalkyl, -Coalk-NH-CjCycloalkyl, -Coalk-NH-C4cycloalkyl, -Coalk-NH-Cscycloalkyl, - Coalk-NH-Cecycloalkyl, -C i-Cealk-NH-Cicycloalkyl, -Ci-C6alk-NH-G.cycloalkyl, -Ci-Cealk- NH-Cscycloalkyl, or -Ci-Cealk-NH-Cecycloalkyl. In some aspects wherein R 4 is -Co-Cealk-NH- Cs-Ceeycloalkyl, the cycloalkyl is uiisubstituted. In other aspects wherein R 4 is -Co-Cealk-NH- Cj-Cecycloalkyl, the cycloalkyl is substituted with one, two, or three R suhstituents independently selected from Ci-Cealkyl, (e.g., methyl, ethyl, propyl, isopropyl, butyl), -OCi- Cealkyl (e.g., -Omethyl, -Oethyl, -Opropyl, -Oisopropyl, -Obutyl), and halo (e.g., F or CI).

[0124] In some aspects, R 4 is -Co-C6alk-N(Ci-C6alkyl)-C3-C6cycloalkyl, for example, - -Ci-Csalk- N(Ci-C6alkyl)-C3-C6cycloalkyl, -C i-C4alk-N(Ci-C6alkyl)-C3-C6cycloalkyl, -Ci-C3aIk-N(C i- CealkyD-Cj-CbCycloalkyl, -Ci -C2alk-N(Ci -C6alkyl)-C3-C6cycloalkyl, -Cialk-NiCi-CealkyD-Cs- Ceeycloalkyl, -Coalk-N(Ci-C6alkyl)-C3cycloalkyl, -Coalk-N(Ci-C6alkyl)-C4cycloalkyl, -Coalk- N(C i-C6alkyl)-Cscycloalkyl, -Coaik-N(Ci-C6alkyl)-C6cycloalkyl, -Ci-Ceaik- iCi-Cealkyl)- Cicycloalkyl, -Ci -C6alk-N(Ci -G>alkyl)-C cycloalkyi, -Ci-C6alk-N(Ci-C6alkyl)-Cjcycloalkyl, - Ci-C6alk-N(Ci-C6aikyl)-C6cycloalkyl, -Coalk-N(Ci-C5alkyl)-C3-C6cycloalkyl, -Coaik-N(Ci- Gtalkylj-Cs-Cecycloalkyl, -Coalk-NiCi-CsalkylJ-Cs-Cecycloalkyl, -Coalk-N(Ci-C2alkyl)-C 3 - Cecycloalky 1 , -Coalk-N(C i alkyl)-C3 -Cecycloalkyl, -C i -Coalk-N(C l-CjalkyD-Cs-Cecycloalkyi, - Ci -C6alk-N(Ci-C4a kyl)-C3-C6cycloalkyl, -Ci-C6aik-N(Ci-C3alkyl)-C3-C6cycloalk>d, -Ci-Cealk- N(Ci-C2alkyl)-C3-C6cycloalkyl, or -Ci-C6alk-N(Cialkyl)-C3-C6cycloalkyl. In some aspects wherein R 4 is -Co-C6alk-N(Ci-C6alkyl)-C3-C6Cycloalkyl, the cycloalkyl is unsubstituted. In other aspects wherein R 4 is -Co-C6alk-N(Ci-C6alkyl)-C3-C6Cycloalkyl, the cycloalkyl is substituted with one, two, or three R substituents independently selected from Ci-Ceaikyi, (e.g., methyl, ethyl, propyl, isopropyl, butyl), -OCi-CeaSkyl (e.g., -Omethyl, -Oethyl, -Opropyl, -Oisopropyl, - Obutyl), and halo (e.g., F or Ci).

[0125| In some aspects, R 4 is -Co-Cealk-heterocycloalkyi, for example, -Coalk- heterocycloalkyl, -Ci-C&alk-heterocycloalkyl, -Ci-Csalk-heterocycloalkyl, -Ci~C4alk- heterocycloalky], -Ci-Csalk-heterocycloalkyl, -Ci-Cialk-heterocycloalkyl, or -Cialk- heterocycloalkyl. Preferred heterocyioaikyl moieties include, for example, piperidinyl, piperazmvl, morpholinyi, aziridmyl, dioxanyL pvrrolidinvl, tetrahydrofuranyl, tetrahydropyranyi, or oxetanyl. In some aspects wherein R 4 is -Co-Cealk-heterocycloalkyl, the heterocycloalkyl is unsubstituted. In other aspects wherein R 4 is -Cc-Cealk -heterocycloalkyl, the heterocycloalkyl is substituted with one, two, or three R substituents independently selected from Ci-Cealkyl, (e.g., methyl, ethyl, propyl, isopropyl, butyl), -OCi-C&alkyl (e.g., -Omethyl, -Oethyl, -Opropyl, - Oisopropyl, -Obutyl), and halo (e.g., F or CI).

[00100] In some aspects, R 4 is heteroaryl, for example furanyl, imidazolyl, and pyrazolyl. In some aspects wherein R 4 is heteroaryl, the heteroaryl is unsubstituted. In other aspects wherein R 4 is heteroaryl, the heteroaryl is substituted with one, two, or three R substituents independently selected from Ci-Cealkyl, (e.g., methyl, ethyl, propyl, isopropyl. butyl), -OCi-Cealkyl (e.g., -Omethyl, -Oethyl, -Opropyl, -Oisopropyi, -Obutyl), and halo (e.g., F or CI).

[0126] In some aspects, R 4 is -CN,

[0127] In some aspects, at least one of R 2 , R 3 , and R 4 is H. In some aspects, R 2 , R 3 , and R 4 are each H.

[0128] In some aspects, R 2 and R 3 are each H and R 4 is halo, -Ci-Cealkyl, -Ci- CehaloalkyL -Cc-Cealk-CB-Cecycloalkyi, -Co-Cealk-OH, -Co-Cealk-Q-Ci-Cealkyi, -Co-Cealk- ΝΙ-Ϊ2, -Co-Cealk-NH-Ci-Cealkyl -Co-Cealk-NiCi-Cealky -Ci-Cealkyl, -Co-Cealk-NH-Cs- Cocycloalkyl, -Co-C6alk-N(C] -C6alkyl)-C3-C6cycloalkyl, -Co-Cealk-heterocycloalkyl, heteroaryl, or -CN.

[0 9] In some aspects, R 2 and R 4 are each H and R 3 is halo, -Ci-Cealkyl, -Ci- Cehaloalkyl, -Co-Cealk-Ci-Cecycioaikyl, -Co-Cealk-OH, -Co-Cealk-O-Ci-Ceaikyl, -Co-Ceaik- Ntb, -Co-Cealk-NH-Ci-Cealkyl, -Co-Ceaik-NCC] -CealkyD-Ci-Cealkyl, -Co-Cealk-NH-Cs- Ceeycloalkyl, -Co-C6alk-N(Ci-C6alkyl)-C3-C6cycloalkyl, -Co-Cealk-heterocycloalkyl, heteroaryl, or -CN.

[0130] In some aspects, R J and R 4 are each H and R 2 is halo, -Ci-Cealkyl, -Ci- C&haloalkyl, -Co-Cealk-Cs-Cecycloalkyl, -Co-Cealk-OH, -Co-Cealk-O-Ci-Cealkyl, -Co-C&alk- NHi, -Co-Cealk-NH-Ci-Cealkyi, -Co-Cealk-NXCi-Cealky -Ci-Cealkyl, -Cc-C6alk-NH-C3- Cecycloalkyl, -Co-C6alk-N(Ci-C6alkyl)-C:i-C6Cycloalkyl, -Co-Cealk-heterocycloalkyl, heteroaryl, or -CN.

[0131] In some embodiments of the disclosure wherein the compounds are of Formula I, R 2 and R 3 , together with the atoms to which they are attached, form a C3-Ci,cycloalkenyl ring, for example, cyclopropenyl, cyclobutenyl, cyclopentenyi, or cyclohexenyl.

[0132] In some embodiments of the disclosure wherein the compounds are of Formula I, R 2 and R 3 together form a triple bond.

[0133] In some embodiments of the disclosure wherein the compounds are of Formula I, R 3 and R 4 , together with the atom to which they are attached, form a CVCecycIoalkyl ring or a heterocycloalkyi ring. In some aspects, R 3 and R 4 , together with the atom to which they are attached, form a C3-Cecycloalkyl ring, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In other aspects, R 3 and R 4 , together with the atom to which they are attached, form a heterocycloalkyi ring, for example, piperidinyl, piperazinyl, morpholmyl, aziridinyl, dioxanyi, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, or oxetanyi. [0134] Tn embodiments of the disclosure wherein the compounds are of Formula Π, R 8a and R 8b are each independently H, Ci-Ceaikyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, and the like), or -Co-Cealk-QCi-Cealkyl (e.g., Coaik-OCi- Cealkyl, Ci-Cealk-OCi-Cealkyl, Ci-Csalk-OCi-Cealkyl, Ci-Csalk-OCi- Ceaikyl, Ci-Cialk-OCi-Ceaikyl, Cialk-OCi-Cealkyl, Co-Cealk-OCi-Csalkyl, Co-Cealk-OCi- C4aikyl, Co-Cealk-OCi-Cjaikyl, Co-Cealk-OCi-C aikyl, or Co-Cealk-QCiaikyl). In some embodiments, R 8a is Ci-Cealkyl or -Co-Cealk-GCi-CeaTkyl and R 8b is H, Ci-Cealkyl, or -Co- Qalk-OCi-Cealkyl.

[0135] In some embodiments, R 8a is H or Ci-Cealkyi. In some embodiments, R 8b is H or Ci-C6alkyl.

10136] In some embodiments, R 8a and R 8b are each H.

[0137] In other embodiments, R 8a and R 8b are each independently C i-Cealkyl. T ms, in some embodiments R 8a is methyl and R 8b is methyl.

[0138] In some aspects, R a is Ci-Cealkyl and R b is H. Thus, in some embodiments, R 8a is methyl and R 8b is 1 1.

[0139] In other aspects, R 8a and R 8b are each independently -Co-Cealk-OCi-Cealkyi.

10140] In other aspects, R 8a is -Co-Cealk-OCi-C&alkyl and R 8 is H.

101 1 ] In some embodim ents of the disclosure wherein the compounds are of Formula II, R a and R b , together with the atom to which they are attached, form a Cj-Cecycloalkyl ring, for example, cyciopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. Thus, in some embodiments, R 8a and R 8b , together with the carbon atom to which they are attached, form a cyciopropyl ring.

[0142] In embodiments of the disclosure wherein the compounds are of Fonnula ITT, R 10 is -Ci-Cealkyl, or -Co-Cealk-Cs-Cocycloalkyi. In some embodiments, R 10 is Ci-Ceaikyl, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, and the like. Thus, in some embodiments, R i0 is methyl .

[0143] In other aspects, R !u is Cc-Cealk-Ci-Cecycloalkyl, for example, Co-alk-Cs- Cecycloalkyl, Ci-Ceaik-CB-Cecycloalkyi, Ci-Csalk-Ci-Cecycloalkyl, Ci-C aik-CB-Cecycloalkyl, Ci -C3alk-C3-C6cycloalkyl, Ci-Cialk-Cs-Cecycloalkyl, Cialk-C3-C6cycloalkyl, Coalk- C3cycloalkyl, Coalk-C4cycloalkyl, Coalk-Cscycloalkyl, Coalk-Cecycloalkyl, Ci-Cealk- C3cycloalkyl, Ci-Cealk-C cycloalkyl, Ci-Cealk-Cjcycloalkyl, or Ci-Cealk-Cbcycloalkyl.

[0144] In embodiments of the disclosure wherein the compounds are of Formula III, R 8 and R 8 are each independently H, Ci-Cealkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, and the like), or -Co-Coaik-OCi-Cealkyl (e.g., Coalk-OCi- Cealkyl, Ci-Cealk-OCi-Cealkyl, Ci-Csalk-OCi-Cealkyl, Ci-Cialk-OCi-Cealkyl, Ci-Csalk-OCi- Ceaikyl, Cialk-OCi-Cealkyl, Co-Cealk-OCi-Csalkyl, Co-Cealk-OCi- C alkyl, Co-Cealk-OCi-Csalkyi, Co-CeaSk-OCi-Cialkyi, or Co-Cealk-OCialkyl). In some embodiments, R 8 is Ci-Cealkyl or -Co-Cealk-OCi-Cealkyl and R 8' is H, Ci-Cealkyl, or -Co-Cealk- OCi-Cealkyl.

0145| In some embodiments, R 8 is H or Ci-Cealkyl. In some embodiments, R 8 is H or Ci-Cealkyl.

[0146] In some embodiments, R 8 and R 8 are each H.

j0147j In other embodiments, R 8 and R 8 are each independently Ci-Cealkyl . Thus, in some embodiments R 8 is methyl and R 8' is methyl.

101 8] In some aspects, R 8 is Ci-Cealkyl and R 8 is H. Thus, in some embodiments, R 8 is methyl and R 8' is H.

[0149] In other aspects, R 8 and R 8' are each independently -Co-Cealk-QCi-Cealkyl.

[0150] In other aspects, R 8 is -Co-Cealk-QCi-Cealkyl and R 8' is H.

[015.IJ In some embodiments of the disclosure wherein the compounds are of Formula III, R 8 and R 8' , together with the atom to which they are attached, form a Cj-Cecycloalkyi ring, for example, cyciopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0152] In embodiments of the disclosure wherein the compounds are of Formula III, R 9 is -Ci-C-talkenyl, -C?-C4haloalkenyl, C2-C4Cyanoalkenyi, -Ci-C alkynyl, -Ci-C ' 4haloalkyl, -C2- Ceheterocycloalkyl, oxo-substituted-Ci-Ceheterocycioalkyl, -Cj-Cecycloalkyl, -CHO, -C(0)R 10 , - CR 8 R 8' CN, -CH 2 NR 8 R 8' , -Co-Cealk-OH, -NR 8 R 8' , -NH-CN, -N(R 10 )CN, -O-C1-C4 alkyl, - NR 5 C(0) R 8 R 8' , -OC(0)NR R 8' , or -NR 5 C(O)OR ] 0 ;

[0153] In some aspects, R v is -C2-C4alkenyl, for example, vinyl, allyl, and the like. Thus, in some embodiments, R 9 is vinyl (-CH CH2).

[0154] In some aspects, R 9 is -C2-C4haloalkenyl, for example, -C(F)=CH 2 ,

and the like. Thus, in some embodiments, R 9 is -C(F)=CH2.

[0155] In other aspects, R 9 is -C2-C4cyanoalkenyl, for example, -C(CN)~CH2, - CH=CHCN, and the like. Thus, in some embodiments, R 9 is -C(CN)=CH 2 .

[0156] In other embodiments, R 9 is -C2-C4alkyny], for example, ethynyl, propargyl, and the like. Thus, in some embodiments, R 9 is ethynyl (-C≡CH).

[0157] In some embodiments, R 9 is -Ci-C4haloalkyl, for example, -CF3 or -CHF2.

[0158] In some embodiments, 9 is -C2-C6heterocycloalkyl, for example

C2heterocycloalkyl, Csheterocycloalkyl, C4 heterocycloalkyl, Cs heterocycloalkyl, and Ce heterocycloalkyl, including azepanyl, aziridinyl, azetidinyl, pyrrolidinyl, dioxolanyl, imidazolidinyl, pyrazoiidmyl, piperazinyl, piperidinyi, dioxanyl, morpholinyl, dithianyi, thiomorpholinyl, oxazepanyi, oxiranyl, oxetanyl, tetrahvofuranyl, tetrahydropyranyl, piperazinyl, and the like. Thus, in some embodiments, R 9 is 2-oxiranyl . in other embodiments, R 9 is 1 - azetidinyl.

[0159] In some embodiments, R 9 is oxo-substituted-Cz-Ceheterocydoalkyl, for example, oxo-substituted-C2heterocycloalkyl, oxo-substituted-Ciheterocycloalkyl, oxo- substituted-CAeterocycloalkyl, oxo-substituted-Csheterocycloalkyl, oxo-substituted- Coheterocycloalkyl, including aziridinonyi, azetidinonyl, pyrrolidinonyl, dioxolanonyi, imidazolidinonyl, pyrazolidinonyl, piperazinonyl, piperidinonyl, dioxanonyl, dithianonyl, thiomorpholinonyl, oxazepanonyl, oxiranonyl, oxetanonyl, quinuclidinonyl, tetrahyofuranonyl, tetrahydropyranonyl, piperazinonyl, and the like. Thus, in some embodiments, R 9 is azetidin-2- one-l-yi.

[0160] In some embodiments, R 9 is -C -Cecycloalkyl, for example -Cscycloalkyl, - C4cycloalkyl, -Cscycloalkyl, -Cecycloalkyl, and the like. In some embodiments, R 9 is - Cicycloalkyl. Thus, in some embodiments, R 9 is cyclopropyl.

1 . 0161] In some embodiments, R 9 is -CHO.

[0162] In other embodiments, R 9 is -C(O)R i0 . In some embodiments wherein R 10 is Ci- Ceaikyl, R 9 is -C(0)Ci-Cea]kyl. Thus, in some embodiments wherein R !0 is methyl, R v is acetyl (i.e., -C(0)CH3). In some embodiments wherein R i0 is Co-Cealk-Cs-Cecycloalkyl, R 9 is - C(0)Co-C6alk-C3-C6cycloalkyl.

[0163] In some embodiments, R 9 is -CR 8 R 8' CN. Thus, in some embodiments wherein R 8 and R 8' are both H, R 9 is cyanomethyl (i.e., -CH2CN). In some embodiments wherein R 8 is - Ci-Ceaikyi and R 8' is H, R 9 is -CH(-Ci-C6alkyl)CN. In some embodiments wherein R 8 and R 8' are both -Ci-Cealkyi, R 9 is -C(Ci-C6alkyl)(Ci-C6alkyl)CN. In some embodiments wherein R 8 is -Co-Cealk-OCi-Cealkyl and R 8' is H, R 9 is -CH(-Co-C6alk-OCi-C6alkyl)CN. In some embodiments wherein R 8 and R 8' are both -Co-Cealk-OCi-Cealkyi, R 9 is -Ci-Co-Cealk-OCi- Cealkyl -Co-Cealk-OCi-Cealky CN,

[0164] In some embodiments, R 9 is CH2NR 8 R 8' . Thus, i some embodiments wherein R 8 and R 8' are both H, R 9 is aminomethyl (i.e., -CH2NH2). In some embodiments wherein R 8 is - Ci-Cealkyl and R 8' is H, R 9 is -CHiNHiCi-Ceaikyl). In some embodiments wherein R 8 and R 8' are both -Ci-Cealkyl, R 9 is -CH2N (Ci-C6alkyl)(Ci-C6alkyl). In some embodiments wherein R 8 is -Co-Cealk-OCi-Cealkyl and R 8' is H, R 9 is -CHi HC-Cc-Cealk-OCi-Cealkyl). In some embodiments wherein R s and R 8 are both -Co-Cealk-OCi-Cealkyl, R 9 is -CH2N (-Co-Cealk-OC 1- CeaikylX-Co-Cealk-QCi-Cealkyl).

[0165] In some embodiments, R 9 is -Co-Cealk-QH, for example, -Coalk~OH, -Cialk- OH, -Cialk-OH, -Cjalk-OH, -Cialk-OH, -Csalk-OH, -Cealk-OH, and the like. In some embodiments R 9 is -C ialk-OH. In some embodiments, R 9 is hydroxymethyl (i.e., -CH2OH).

[0166] In some embodiments, R 9 is -NR 8 R 8' . Thus, in some embodiments wherein R 8 and R 8 are both H, R 9 is amino (i.e., - H2). In some embodiments wherein R 8 is -Ci-Cealkyl and R 8 is H, R v is -NH(Ci-C6alkyl). Thus, in some embodiments wherein R 8 is methyl and R 8 is H, R 9 is methylamino (i.e., -NHCTI3). In some embodiments wherein R 8 and R 8 are both -Ci- C&aikyl, R 9 is -N(-Ci-C&alkyl)( -Ci-Cealkyl). In some embodiments wherein R 8 is -Co-Cealk- OC i-Cealkyl and R 8' is H, R 9 is -NHi-Co-Cealk-OCi-Cealkyl) . In some embodiments wherein R 8 and R 8' are both -Co-Cealk-OCi-Cealkyl, R 9 is -Nt-Co-Cealk-OCi-CealkylX-Co-Cealk-OCi- Ceaikyl).

[0167] In some embodiments, R 9 is -NH-CN.

[®168j In some embodiments, R 9 is -N(R l0 )CN. In some embodimenst wherein R 1 " is - Ci-Cealkyl, R 9 is -N(Ci-C6alkyl)CN. Tims, in some embodiments wherein R 10 is methyl, R 9 is - N(CH_)CN. In some embodiments wherein R i0 is -Co-Ceaik-Cs-Cecycloalkyi, R 9 is -N(-Co- C6alk-C3-C6cycloalkyl)CN.

[0169] In some embodiments, R 9 is -O-C1-C4 alkyl, for example -O-Cialkyl, -O- C aikyl, -O-Csalkyl, -O-Cialkyl.

[0170] In some embodiments, R 9 is -NR 5 C(0)NR 8 R 8' . In some embodiments wherein R 5 is H, R v is - HC(0) R 8 R 8' . In some embodiments wherein R 5 is -Ci-Cealkyl, R 9 is -N(-Ci- Cbalkyl)C(0)NR 8 R 8 . In some embodiments wherein R 5 is Co-Cealk-Cs-CoCycloalkyl, R 9 is - N(Co-C6alk-C3-C6cycloalkyl)C(0)NR 8 R 8' . In some embodiments wherein R 8 is H, R 9 is - NR 5 C(0)NHR 8' . In some embodiments \s herein R 8 is H and R 8' is H, R 9 is -NR 5 C(0)NH2. Thus, in some embodiments wherein R 3 is H and R 8 and R 8' are both H, R 9 is urea-l-yl (i.e. , - NHC(0)NH2.). In some embodiments wherein R 8 is -Ci-Cealkyl and R 8' is H, R 9 is - NR 5 C(Q)NH(C!-C&alkyl). In some embodiments wherein R 8 and R 8' are both -Ci-Cealkyl, R 9 is -NR 5 C(0)N(Ci-Cealkyl)(Ci-C6alkyl). In some embodiments wherein R 8 is -Co-Cealk-OCi- Cealkyl and R 8' is H, R 9 is -NR 3 C(0)NH(-Co-C6alk-OCi-C6alkyl). In some embodiments wherein R 8 and R 8' are both -Co-Cealk-OC; -Ceaikyl, R 9 is -NR 5 C(0)N(-Co-C6alk-OC;-Cealkyl)(- Co-Cealk-OCi-Cealkyl). [0171] In some embodiments, R 9 is -OC(0)NR 8 R 8' . In some embodiments wherein R 8 is H, R 9 is -OC(0)NHR 8' . In some embodiments wherein R 8 is H and R 8 is H, R 9 is - OC(0)NH2. In some embodiments wherein R 8 is -Ci-C&alkyl and R 8' is H, R 9 is -0( {())\H(C:- Cealkyl). In some embodiments wherein R 8 and R 8' are both -Ci-Cealkyl, R y is -OC(0)N(Ci- CeaikylXCi-Cealkyl). In some embodiments wherein R 8 is (-Co-Cbalk-OCi-Cealkyl and R 8' is H, R 9 is -OC(0)NH(-Co-C6alk-OCi-C6alkyl). In some embodiments wherein R 8 and R 8' are both - Co-Cealk-GCi-Cealkyl, R 9 is -OC(0)N(-Co-C6alk-OCi-C6a3kyI)(-Co-C6aIk-OCi-C6alkyl) ,

[0172] In some embodiments, R 9 is -NR 3 C(0)OR 10 . In some embodiments wherein R 3 is H, R 9 is -NHC(0)OR 10 . In some embodiments wherein R 3 is -Ci -Cealkyl, R v is -N(-Ci- C&aikyl)C(Q)QR 10 . In some embodiments wherein R 3 is Co-C6alk-C3-C6cycloalkyl, R 9 is -N Co- CeaIk-C3-C6cycloa]kyl)C(0)OR 10 . In some embodiments wherein R 10 is -Ci-Cealkyl, R 9 is - NR 5 C(0)0-Ci-C6alkyl. In some embodiments wherein R 10 is -Co-Cealk-Cj-Cecycloalkyl, R v is - NR 5 C(0)0-Co-C6alk-C3-C6cycloalkyl. In some embodiments wherein R 5 is H and R !0 is -Ci- Cealkyl, R 9 is - HC(0)0-Ci-C6alkyl. Thus, in some embodiments wherein R 5 is H and R 10 is methyl, R 9 is -NHC(0)OCH 3 ,

[0173] Stereoisomers of compounds of Formula I, Formula II and/or Formula III are also contemplated.

[0174] Pharmaceutically acceptable salts, and isotopic variants, of the compounds of Formula I, Formula II, and/or Foimuia III are also within the scope of the disclosure.

[00101] In some aspects, the present disclosure is directed to compounds of the formula

I!IA-1 :

wherein R ! is -CH(OH)-aryl, -or -C(Me)(OH)-aryl; R 7 is H or NH 2 ; and R 9 -C2- C4aikenyl, -C 2 -C4alkynyl, -C(0)R 10 , or -Co-Cealk-OH; and R i0 is -Ci-Cealkyl.

[0175] In some embodiments of the compound of formula IIlA- 1, R : is -CH(OH)~aryl. Tlius, in some embodiments of the compound of formula III A- 1 , R ! is ~CH(OH)-3,4~ dif!uorophenyl, ~CH(OH)~4-chlorophenyl, -CH(OH)-3-fluoro~4~chlorophenyi, -CH(OH)- dichlorophenyl, -CH(OH)-3,4-dichlorophenyl, or -CH(OH)-3-methyl-4-chlorophenyl.

[0176] In other embodiments of the compound of formula III A- 1 , R 1 is -C(Me)(OH)- aryl. Thus, in some embodiments of the compound of formula IITA-1, R 1 is -C(Me)(OH)-3,4- difluorophenyl, -C(Me)(OH)-4-chlorophenyl, -C(Me)(OH)-3-fluoro-4-chlorophenyl, - C(Me)(OH)-dichlorophenyi, -C(Me)(OH)-3,4-dichlorophenyl, -C(Me)(OH)-3-methyl-4- chlorophenyl.

[0177] In some embodiments of the compound of formula IIIA-1, R 7 is H. In other embodiments of the compound of formula IIIA-1, R 7 is NHz.

[0178] In some embodiments of the compound of formula IIIA-1, R 9 is -C2-C4alkenyl. Thus, in some embodiments, R 9 is vinyl (-CH=CH2).

[0179] In other embodiments of the compound of formula IIIA-1, R 9 is -Ci-Cialkynyl. r riius, in some embodiments, R 9 is is ethyny l (-C≡CH). In otlier embodiments, R 9 is prop-l-yn-

[0180[ In other embodiments of the compound of formula IIIA-1 , R 9 is -C(O)R !0 where R 10 is methyl. That is, in some embodiments, R 9 is acetyl (i.e. , -C(O)CHj).

[ 0181] In some embodiments of the compound of formula IIIA-1, R 9 is -Co-Cealk-OH. Thus, in some embodiments, R 9 is hydroxymethyl (i.e. , -CH2OH). In other embodiments, R 9 is 1 -hydroxyethyl (i.e., -CH(OH)-CH3). In yet other embodiments, R 9 is 2-hydroxyethyl (i.e., -

[0182] In some aspects, the present disclosure is directed to compounds of the formula

ΠΤΑ-2

wherein R 1 is -CH(OH)-aryl, -or -C(Me)(OH)-aryl; and R 7 is H or NH2.

[0183] In some embodiments of the compound of formula IIIA-2, R : is ~CH(QH)~aryi. Thus, in some embodiments of the compound of formula IIIA-2, R ! is -CH(OH)-3,4- dif!uorophenyl, ~CH(OH)~4-chlorophenyl, -CH(OH)-3-fluoro-4-chlorophenyl, -CH(OH)- dichlorophenyl, -CH(OH)-3,4-dichlorophenyl, or -CH(OH)-3-methyl-4-chlorophenyl.

[0184] In other embodiments of the compound of formula ΙΠΑ-2, R 1 is -C(Me)(OH)- aryl. Thus, in some embodiments of the compound of formula ΙΠΑ-2, R 1 is -C(Me)(OH)-3,4- difluorophenyl, -C(Me)(OH)-4-chlorophenyl, -C(Me)(OH)-3-fluoro-4-chlorophenyl, - C(Me)(OH)-dichlorophenyl, -C(Me)(OH)-3,4-dichlorophenyl, or -C(Me)(OH)-3-methyl-4- chlorophenyl.

[0185] In some embodiments of the compound of formula ΠΙΑ-2, R 7 is H. in other embodiments of the compound of formula ΠΙΑ-2, R 7 is NHJ.

[0186] In some aspects, the present disclosure is directed to compounds of the formula

IIIA-3

wherein R 1 is -CH(QH)-aryl, -or -C(Me)(GH)-aryl; and R 7 is H or NH 2 .

[0187] In some embodiments of the compound of formula IIIA-3, R 1 is -CH(OH)-aryl. Thus, in some embodiments of the compound of formula ΙΠΑ-3, R 1 is -CH(OH)-3,4- difluorophenyl, -CH(OH)-4-chlorophenyl, -CH(OH)-3-fluoro-4-chlorophenyl, -CH(OH)- dichlorophenyl, -CH(OH)-3,4-dichlorophenyl, or -CH(OH)-3-methyl-4-chlorophenyl.

[0188J In other embodiments of the compound of formula ΙΠΑ-3, R 1 is -C(Me)(OH)- aryl. Thus, in some embodiments of the compound of formula IIIA-3, R ! is -C(Me)(OH)-3,4- difluorophenyl, -C(Me)(OH)-4-chlorophenyi, -C(Me)(OH)-3-fluoro-4-chlorophenyl, - C(Me)(OH)-dichlorophenyl, -C(Me)(OH)-3,4-diehlorophenyl, or -C(Me)(OH)-3-methyl-4- chlorophenyl.

[0189] In some embodiments of the compound of formula IIIA-3, R 7 is H. in other embodiments of the compound of formula IIIA-3, R 7 is Ntb.

[0190] In some aspects, the present disclosure is directed to compounds of the formula

ΠΙΑ-4

wherein R 9 is -C...-C ialkem l. - ' .!-C saik> n> i. -Cs-Cecycloalkyl, -C(0)R 10 , or -NR 8 R 8' ; R 7 is H or NH 2 ; R 6 is H or Nth, R 8 and R 8' are both H, and R i0 is -Ci-Cealkyl.

[0191] in some embodiments of the compound of formula IIIA-4, R 9 is -d-Ctalkenyl , Tims, in some embodiments, R is vinyl (-CH=Cth).

[0192] In other embodiments of the compound of formula IIIA-4, R 9 is -Cj-C alkynyl. Thus, in some embodiments, R 9 is is ethynyl (-C≡CH).

[01 3] In other embodiments of the compound of formula ΠΙΑ-4, R 9 is -C(O)R i0 where R 10 is methyl. TTiai is, in some embodiments, R 9 is acetyl (i.e. , -C(0)CH:i).

[0194] In some embodiments of the compound of formula IIIA-4, R 9 is -C3- Cecycloalkyl. Thus, in some embodiments, R 9 is cyclopropyl.

[0195] In other embodiments of the compound of formula IIIA-4, R 9 is -NR 8 R 8' and R 8 and R 8 are both H. That is, in some embodiments, R 9 is amino (-Nth).

In some embodiments of the compound of formula IIIA-4, R 6 is H. In other embodiments of the compound of formula IIIA-4, R 6 is Nth.

[0196] In some embodiments of the compound of formula IIIA-4, R 7 is H. In other embodiments of the compound of formula IIIA-4, R 7 is Nth.

[0197] In some aspects, the present disclosure is directed to compounds of the formula

IIIB-1

wherein R ; is -CH(OH)-aryl, -or -C(Me)(QH)-aryl; R 7 is H or NH2; and R" -C2-

C alkenyl, -Cz-C aikynyl, -C(G)R 10 , or -Co-Cealk-OH; and R !0 is -Ci-Cealkyl.

[0198] In some embodiments of the compound of fonnula ΠΙ Β- 1. R 1 is -CH(OH)-a!yl. Thus, in some embodiments of the compound of fonnula ITIB-1 , R ! is -CH(OH)-3,4- difluorophenyl, -CH(OH)-4-chlorophenyl, -CH(OH)-3-fluoro-4-chlorophenyl, -CH(OH)- dichlorophenyl, -CH(OH)-3,4-dichlorophenyl, or -CH(OH)-3-methyl-4-chlorophenyl.

[0199] In other embodiments of the compound of formula IIIB-1 , R 1 is -C(Me)(OH)- aryl. Thus, in some embodiments of the compound of formula IIIB-I , R 1 is -C(Me)(OH)-3,4- difluorophenyl, -C(Me)(OH)-4-chlorophenyl, -C(Me)(OH)-3-fluoro-4-chlorophenyl, - C(Me)(QH)-dichlorophenyi, -C(Me)(OH)-3,4-dichlorophenyl, -C(Me)(OH)-3-methyl-4- chlorophenyl.

10200 J In some embodiments of the compound of fonnula IIIB-1, R 7 is H. In other embodiments of the compound of formula IIIB-1, R 7 is Nth.

[0201] In some embodiments of the compound of formula IIIB-1 , R 9 is -C2-C4alkenyl. Thus, in some embodiments, R is vinyl (-CH=Cth).

[ 2G2J In other embodiments of the compound of formula IIIB-1, R 9 is -C2-C ' 4alkynyl. Thus, in some embodiments, R 9 is is ethynyl (-C≡CH). In other embodiments, R 9 is prop-l-yn- 1 -yl (-( ( -CH :).

[0203] In other embodiments of the compound of formula IIIB-1, R 9 is -C(0)R 10 where R 10 is methyl. That is, in some embodiments, R 9 is acetyl (i.e. , -C(O)Cth).

[0204] In some embodiments of the compound of formula IIIB-1 , R 9 is -Co-Cealk-OH. Thus, in some embodiments, R is hydroxymethyl (i.e., -CH2OH). In other embodiments, R 9 is 1 -hydroxy ethyl (i.e., -CH(OH)-CH3). In yet other embodiments, R 9 is 2-hydroxyethyl (i.e., -

[0205] In some aspects, the present disclosure is directed to compounds of the formula IHB- l-a

wherein R ; is -CH(OH)-aryl, -or -C(Me)(QH)-aryl; R 7 is H or NH2; and R" -C2- C alkenyl, -Cz-t alkynyl, -C(0)R : ". or -Co-Cealk-OH; R 10 is -Ci-Cealkyl; and R 6 is 1 1 or Me (i.e., methyl).

[0206] In some embodiments of the compound of fomiula IIIB- l-a, R l is -CH(OH)- aryl. Thus, in some embodiments of the compound of formula IIIB-l-a, R 1 is -CH(OH)-3,4- difluorophenyl, -CH(OH)-4-chlorophenyl, -CH(OH)-3-fluoro-4-chlorophenyl, -CH(OH)- dichlorophenyl, -CH(GH)-3,4-diehlorophenyl, or -CH(OH)-3-methyl-4-chlorophenyl.

[0207] In other embodiments of the compound of formula TUB- 1 -a, R 1 is -C(Me)(OH)- aryl. Thus, in some embodiments of the compound of formula IIIB-l -a, R 1 is -C(Me)(OH)-3,4- difluorophenyl, -C(Me)(OH)-4-chlorophenyl, -C(Me)(OH)-3-fluoro-4-chlorophenyl, - C(Me)(OH)~dichlorophenyl, -C(Me)(OH)-3,4-dichlorophenyl, -C(Me)(OH)-3-methyl-4- chlorophenyl.

[02081 In some embodiments of the compound of formula IIIB-l-a, R 7 is H. In other embodiments of the compound of formula IIIB-l -a, R " is NH2.

[0209] In some embodiments of the compound of formula ΠΙΒ- 1 -a, R 9 is -C2- C4alkenyl. Thus, in some embodiments, R 9 is vinyl (-CH=CH2).

[0210] In other embodiments of the compound of formula IIIB- l-a, R 9 is -C2- CUalkynyl. Thus, in some embodiments, R 9 is is ethynyl (-C=CH).

[0211] In other embodiments of the compound of formula IIIB- l-a, R 9 is -C(0)R 10 where R i0 is methyl. That is, in some embodiments, R 9 is acetyl (i. e. , -C(0)CH3).

[0212] In some embodiments of the compound of formula IIIB-l -a, R 9 is -Co-Cealk- OH. Thus, in some embodiments, R 9 is 1 -hydroxy ethyl (i.e. , ~€Η(0Η)~Ο¾).

[0213 J In some aspects, the present disclosure is directed to compounds of the formula

ΙΠΒ-2

wherein R 1 is -CH(OH)-atyl, -or -C(Me)(OH)-atyl; and R 7 is H or NHJ. [0214j In some embodiments of the compound of formula ΠΙΒ-2, R ! is -CH(OH)-aryl. Thus, in some embodiments of the compound of formula ΙΠΒ-2, R 1 is -CH(OH)-3,4- difluorophenyl, -CH(OH)-4-chlorophenyl, -CH(OH)-3-fluoro-4-chlorophenyl, -CH(OH)- dichloropheny], -CH(OH)-3,4-dichlorophenyl, or -CH(OH)-3-methyl-4-chlorophenyl.

[0215] In other embodiments of the compound of formula IIIB-2, R 1 is -C(Me)(OH)- aryl. Thus, in some embodiments of the compound of formula IIIB-2, R 1 is -C(Me)(OH)-3,4- difluorophenyl, -C(Me)(OH)-4-chlorophenyl, -C(Me)(OH)-3-fluoro-4-chlorophenyl, - C(Me)(OH)-dichlorophenyl, -C(Me)(OH)-3,4-dichlorophenyl, or -C(Me)(OH)-3-methyl-4- chlorophenyl.

[0216] In some embodiments of the compound of formula IIIB-2, R ' is H. in other embodiments of the compound of formula IIIB-2, R 7 is NHi.

[0217] In some aspects, the present disclosure is directed to compounds of the formula

ΠΙΒ-3

wherein R ! is ~CH(OH)~aryl, -or -C(Me)(OH)~aryl; and R 7 is H or NH 2 .

[0218] In some embodiments of the compound of formula IIIB-3, R 1 is -CH(OH)-aryl. Thus, in some embodiments of the compound of formula ΙΠΒ-3, R 1 is -CH(OH)-3,4- difluorophenyl, -CH(OH)-4-chlorophenyl, -CH(OH)-3-fluoro-4-chlorophenyl, -CH(OH)- dichlorophenyl, -CH(OH)-3,4-dichlorophenyl, or -CH(OH)-3-methyl-4-chlorophenyl.

[0219] In other embodiments of the compound of formula IIIB-3, R 1 is -C(Me)(OH)- aryl. 1 bus. in some embodiments of the compound of formula IIIB-3, R 1 is -C(Me)(OH)-3,4- difluorophenyl, -C(Me)(OH)-4-chlorophenyl, -C(Me)(OH)-3-fluoro-4-chlorophenyl, - C(Me)(OH)-dichlorophenyi, -C(Me)(OH)-3,4-dichlorophenyl, or -C(Me)(OH)-3-methyl-4- chlorophenyl.

[0220] In some embodiments of the compound of formula IIIB-3, R' is H. in other embodiments of the compound of formula ΠΙΒ-3, R' is NPh. [022ij In some aspects, the present disclosure is directed to compounds of the formula ΙΠΒ-3-a

wherein R 1 is -CH S-Ci-Cealkyl; and R 7 is H orNHz

[0222] In some embodiments of the compound of formula ΙΠΒ-3-a, R 1 is -CH2S-CH3. | 223{ In some embodiments of the compound of formula ΙΠΒ-3-a, R 7 is H. in other embodiments of the compound of formula IIIB-3-a, R 7 is Nth.

[0224] In some aspects, the present disclosure is directed to compounds of the formula

IIIB-4

wherein R ! is ~CH(OH)~aryl, -or -C(Me)(OH)-aiyl; and R 7 is H or NH2.

[0225] In some embodiments of the compound of formula IIIB-4, R 1 is -CH(OH)-aryl. Thus, in some embodiments of the compound of formula IIIB-4, R 1 is -CH(OH)-3,4- difluorophenyl, -CH(OH)-4-chlorophenyl, -CH(OH)-3-fluoro-4-chlorophenyl, -CH(OH)- dichlorophenyl, -CH(OH)-3,4-dichlorophenyl, or -CH(OH)-3-methyl-4-chlorophenyl.

|0226J In other embodiments of the compound of formula IIIB-4, R 1 is -C(Me)(OH)- aryl. Thus, in some embodiments of the compound of formula IIIB-4, R 1 is -C(Me)(OH)-3,4- difluorophenyl, -C(Me)(OH)-4-chlorophenyl, -C(Me)(OH)-3-fluoro-4-chlorophenyl, - C(Me)(OH)-dichlorophenyi, -C(Me)(OH)-3,4-dichlorophenyl, or -C(Me)(OH)-3-mefliyl-4- chlorophenyl. [0227j In some embodiments of the compound of formula ΠΙΒ-4, R' is H. in other embodiments of the compound of formula 1IIB-4, R 7 is NH2.

[0228] In some aspects, the present disclosure is directed to compounds of the formula

IIIB-5

wherein R 1 is -CH(OH)-aryl, -or -C(Me)(GH)-aryl; and R 7 is H or NH 2 .

[4)229] In some embodiments of the compound of fonnula IIIB-5, R 1 is -CH(OH)-a!yl. Thus, in some embodiments of the compound of fonnula ΠΙΒ-5, R ! is -CH(OH)-3,4- difluorophenyl, -CH(OH)-4-chlorophenyl, -CH(OH)-3-fluoro-4-chlorophenyl, -CH(OH)- dichlorophenyl, -CH(OH)-3,4-dichlorophenyl, or -CH(OH)-3-methyl-4-chlorophenyl.

[0230] In other embodiments of the compound of formula ΠΙΒ-5, R 1 is ~C(Me)(OH)~ aryl. Thus, in some embodiments of the compound of formula ΙΠΒ-5, R 1 is -C(Me)(OH)-3,4- difluorophenyl, -C(Me)(OH)-4-chlorophenyl, -C(Me)(OH)-3-fluoro-4-chlorophenyl, - C(Me)(OH)-dichlorophenyl, -C(Me)(OH)-3,4-dichlorophenyl, or -C(Me)(OH)-3-methyl-4- chlorophenyl.

[0231] In some embodiments of the compound of fonnula IIIB-5, R 7 is H. in other embodiments of the compound of formula IIIB-5, R 7 is Nth.

[0232J In some aspects, the present disclosure is directed to compounds of the formula

IIIB-6

wherein R 1 is -CH(OH)-aryl, -or -C(Me)(OH)-ar}'l; and R " is H or NH2. [0233j In some embodiments of the compound of formula ΠΙΒ-6, R ! is -CH(OH)-aryl. Thus, in some embodiments of the compound of formula 1IIB-6, R 1 is -CH(OH)-3,4- difluorophenyl, -CH(OH)-4-chlorophenyl, -CH(OH)-3-fluoro-4-chlorophenyl, -CH(OH)- dichloropheny], -CH(OH)-3,4-dichlorophenyl, or -CH(OH)-3-methyl-4-chlorophenyl.

[0234] In other embodiments of the compound of formula IIIB-6, R 1 is -C(Me)(OH)- aryl. Thus, in some embodiments of the compound of formula IIIB-6, R 1 is -C(Me)(OH)-3,4- difluorophenyl, -C(Me)(OH)-4-chlorophenyl, -C(Me)(OH)-3-fluoro-4-chlorophenyl, - C(Me)(OH)-dichlorophenyl, -C(Me)(OH)-3,4-dichlorophenyl, or -C(Me)(OH)-3-methyl-4- chlorophenyl.

[0235] In some embodiments of the compound of formula IIIB-6, R ' is H. in other embodiments of the compound of formula IIIB-6, R 7 is NHi.

[0236] In some aspects, the present disclosure is directed to compounds of the formula

ΠΙΒ-7

wherein R 7 is H or NH ; and R 9 -Ci-Cialkenyl, -Ci-C alkynyl, -C(0)R 10 , or -Co-Cealk- ( ) ! !. and R 10 is -Ci-Cealkyl.

[0237] In some embodiments of the compound of fonnula IIIB-7, aryl is -3,4- difluorophenyl, -4-chlorophenyl, -3-fluoro-4-chlorophenyl, -dichlorophenyl, -3,4- dichlorophenyl, or - 3-methyl -4-chlorophenyl.

[0238] In some embodiments of the compound of formula IIIB-7, R 7 is H. In other embodiments of the compound of formula IIIB-7, R is NH2.

[0239] In some embodiments of the compound of formula IIIB-7, R 9 is -C2-C4alkenyl. Thus, in some embodiments, R 9 is vinyl (-CH=CH2).

[ 0240] In other em bodiments of the compound of formula IIIB-7, R 9 is -C2-C4alkynyl. Thus, in some embodiments, R 9 is is ethynyl (-C≡CH). In other embodiments, R 9 is prop-l-yn- 1 -yl (··(· ( ·( ' ! ! .). [0241] In other embodiments of the compound of formula IIIB-7, R 9 is -C(0)R 10 where R 10 is methyl. That is, in some embodiments, R 9 is acetyl (i.e. , -C(0)CH3).

[0242] In some embodiments of the compound of formula IIIB-7, R 9 is -Co-Cealk-OH. Thus, in some embodiments, R 9 is hydroxymethy] (i.e., -CH2OH). In other embodiments, R 9 is 1 -hydroxyethyl (i.e., -CH(OH)-CH3). In yet other embodiments, R 9 is 2-hydroxyethyl (i.e., -

[0243] In some aspects, the present disclosure is directed to compounds of the formula

ΠΙΒ-8

wherein R 7 is H or Nth; and R 9 ~C2-C4a3kenyl, ~C2-C4a3kyny3, -C(O)R ! 0 , or -Co-Cealk- OH; and R 10 is -Ci-Cealkyl.

[0244] In some embodiments of the compound of formula IIIB-8, aryl is -3,4- difluorophenyl, -4-chlorophenyl, -3-fluoro-4-chlorophenyl, -dichlorophenyl, -3,4- dichlorophenyl, or - 3-methyl-4-chlorophenyl.

[0245] In some embodiments of the compound of formula IIIB-8, R 7 is H. In other embodiments of the compound of formula IIIB-8, R 7 is Nth.

[0246] In some embodiments of the compound of formula IIIB-8, R 9 is -C2-C4alkenyi. Thus, in some embodiments, R 9 is vinyl (-CH=Cth).

[0247] In other embodiments of the compound of formula IIIB-8, R 9 is -C2-C4alkynyl. Thus, in some embodiments, R 9 is is ethynyl (-C≡CH). In other embodiments, R? is prop-l-yn-

[0248] In other embodiments of the compound of formula IIIB-8, R 9 is -C(0)R l ° where R 10 is methyl. That is, in some embodiments, R 9 is acetyl (i.e. , -C(O)Cth).

[0249] In some embodiments of the compound of fonnula IIIB-8, R 9 is -Co-Cealk-OH. Thus, in some embodiments, R 9 is hydroxymethy] (i.e., -CH2OH). In other embodiments, R 9 is 1 -hydroxyethyl (i.e., -CH(OH)-CH3). In yet other embodiments, R 9 is 2-hydroxyethyl (i.e., - CH2CH2OH). [0250] in some aspects, the present disclosure is directed to a compound that is

(2R,3R,4S,5S)-2-(4-amino-3-ethynyl-lH-pyrazolo[3,4-d]pyri midin-l-yl)-5-

((methylthio)methyl)tetrahydrofuraii-3,4-diol;

(2S,3S,4R,5R)-2-((methyl1hio)methyl)-5-(3-vinyl-lH-pyrazolo[ 3,4-d]pyrim

yl)tetrahydrofuran-3 ,4-diol;

(2R,3R,4S,5S)-2-(4-amino-3-vin}'l-lH-pyrazolo[3,4-d]pyrimidi n-l-yl)-5- ((fflethylthio)methyl)tetrahydrofliran-3,4-diol:

(2R,3R,4S,5S)-2-(3-arnino-lH-pyrazolo[3,4-d]pyrimidin-l-y l)-5- ((methylthio)methyl)tetrahydrofuran-3,4-diol;

(2R,3R,4S,5S)-2-(4-amino-5-vinyl-7H-pyrrolo[2,3-dJpyrimidin- 7-yl)-5- ((methylthio)methy])tetrahydrofuran-3,4-diol;

(2R,3S,4R,5R)-2-((R)-(3,4-difluorophenyl)(hy(kox} methyl)-5-(5-eth3'nyl-7H- py rrolo [2,3 -d]pyrmiidin-7-yl)tetraliydrofuran-3 ,4-diol;

(2R,3S,4R,5R)-2-i(RH3,4-difluoropheny

pyrro]o[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3 ,4-diol;

(2R,3R,4S,5R)-2-(4-aniino -e ny

chlorophenyl)(hydroxy)methyl)tetfahydfofiiran-3,4-diol;

(2R,3R,4S,5R)-2-(4-amino-3-ethyTiyl-lH-p\Tazo]o[3,4-d]pyrimi din-l-yl)-5-((R)-(4- chlorophenyl)(liydroxy)methyl)tetrahydrofuran-3,4-diol;

(2R,3R,4S,5R)-2-(4-amino-3-vinyl-lH-pyrazolo[3,4-d]pyrimidin -l-yl)-5-(

chlorophenyl)(hydroxy)methy3)tetrahydrofiiran-3,4-diol;

(2R,3R,4S,5R)-2-(4-amino-3-vinyl-lH-pyrazolo[3,4-d]pyrimidin -l-yl)-5-((4- chlorophenyl)(hy(koxy methyl)tetrahydrofuran-3,4-diol;

l-(7-((2R,3R,4S,5R)-5-((R)-(3,4-difluorophenyl)(hydroxy)m ethyl)-3,4- dihydroxytetrahydrofuran~2-yl)~7H^

(2R,3S,4R,5R)-2-((R)-(3,4-difluorophenyl)(hy(kox> me l)-5-(5-(l-hydroxyethyl)-7H- py rrolo [2,3 -d]pyrimidin-7-y l)tetraliydrofuran~3 ,4-diol;

l-(7-((2R,3R,4S,5R)-5-((R)-(3,4-difluorophenyl)(liydroxy) inethy^

(2R,3R,4S,5R)-2-(4-ammo-5-vinyl-7H-pyrroki[2,3-d;|pyrimidra- 7-yl)- chlorophenyl)(hydroxy)methyl)tetraliydrofiiran-3,4-diol;

(2R,3R,4S,5R)~2-(4-am.mo-5-ethym

ch loroph eny 1) (hydroxy )m eth yl)tetrahy drofuran -3 ,4-diol ; (2R,3R,4S,5R)-2-(4-ammo-5-(2-hydroxyethyl)-7H-pym^

(4-chlorophenyl)(hydroxy)methyl)tetrahydrofuran-3,4-diol;

(2R,3R,4S,5R)-2-(4-amino-5-vinyl-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)-5-((R)-(4-chloro-3- fluorophenyl)(hydroxy)methyl)tetrahydrofuran-3,4-diol ;

(2R,3R,4S,5R)-2-(4-amino-5-e nyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-(4-chloro-

3-metliyIphenyl)(hydroxy)methyl)tetrahydrofufari"3,4"diol ;

(2R,3R lS,5R)-2-(4~amino-5~ethynyl~7H~pyrrolo[23-d]pyrim

3-fluorophenyl)(hydroxy)me1hyl)tetra ydrofuran-3,4-diol;

(2R,3R,4S,5R)-2-(4-amino-5-vinyl-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)-5-((R)-(3,4- dichlorophenyl)(hydrox} nielhyl)tetrahydrofuran-3,4-cliol;

(2R,3R,4S,5R)~2~(4-ammo-5-vmy1~7H~py^

me1i ylphenyl)(hydroxy)methyl)tetrahydrofuran-3,4-diol;

(2R,3R,4S,5R)-2-(4-amino-5-e nyl-7H-pyrro^^

dichlorophenyl)(liydroxy)methyl)tetrahydrofuran-3,4-diol;

(2R,3R,4S,5R)-2-(4¾mmo-5-elhynyl-7H-pyiTOlo[2,3-d]pyrimidin

difluorophemd)(hydroxy)methyl)tetrah}'drofuran-3,4-diol;

(2R,3R,4S,5S)-2-(4-amino-5-e nyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((S)-l-(4- chloro-3-methylphenyiH^

l-(4-amino-7-((2R,3R,4S,5S)-5-((S)-l-(4^oro^-me1hylphenyl )-l-hydroxye dihydroxytetrahydrofi.iran-2-yl)-7H-pyrrolo 12,3 -dJpyrimidin-5 -yl)ethan- 1 -one ;

(2R,3R,4S,5R)-2-(4-amino-5-(hyckoxymethyl)-7H-pyrrolo[2,3 -d]pyrimidin-7-yl)-5-((R)- (3,4-dichlorophenyl)(liydroxy)me1hyl)tetrahydrofuran-3,4-dio l;

(2R,3R,4S,5R)-2-(2,4-diamino-5-ethynyl-7H-pyrrolof2,3-d]p yrimidin-7-yl)-5-((R)-(3 difluoropheny l)(liydroxy)methyi)tetrahy drofuran-3 ,4-diol;

(2R,3R,4S,5R)-2-(4-amino-5-(prop-l-yn-l-yl)-7H-pyrrolo[2,3-d ]pyrimidin-7-yl)-5-((R)-

(3,4-diclilorophenyl)(hydroxy)nieihyl)teirahydrofuran-3 ,4-diol;

(2R,3R,4S,5R)-2-(2,4-diammo-5-(prop-l-_^^

((R)-(3,4-dichlorophenyl)(hydroxy)methyl)tetrahydrofuran-3,4 -diol;

(2R,3R,4S,5R)-2-(2,4-dian ino-5-(prop-l -yn-l-yl)-7H-p\Trolo[2,3-d]pyriniidin-7-y])-5- ((R)-(3,4-difluorophenyl)(hydroxy)methyl)tetrahydrofurati-3, 4-diol; or

(2R,3R,4S,5R)-2-(2,4-diamino-5-ethy^

dichlorophenyl)(hydroxy)me1 yl)tetrahydrofuran-3 ,4-diol .

[0251] In some aspects, the present disclosure is directed to a compound of formula

[0252] In other aspects, the present disclosure is directed to a compound of formula

[0253 J References to Formula I herein also refer to subgeneric formulae IA, IB.

References to Formula II herein also refer to subgeneric formulae IIA, IIB, IIC, and IID, References to Formula III herein also refer to subgeneric formulae I11A, IIIA-l, IIJA-2, IIIA-3, ΠΙΑ-4, IlIB, ΙΠΒ-1, ΠίΒ-1-a, ΙΠΒ-2, ΠΙΒ-3, ΙΠΒ-3-a, ΠΙΒ-4, ! U B-5. ΠΙΒ-6, ΙΠΒ-7, and IIIB-8.

[0254] Stereoisomers of compounds of Formula I, Formula Π, and Formula III are also contemplated by the present disclosure. Thus, the disclosure encompasses all stereoisomers and constitutional isomers of any compound disclosed or claimed herein, including all enantiomers and diastereomers.

[0255] Pharmaceutically acceptable salts and solvates of the compounds of Formula I, Formula Π, and Fonnula III are also within the scope of the disclosure.

[0256] Isotopic variants of the compounds of Formula I, Formula Π, and Formula III are also contemplated by the present disclosure.

Pharmaceutical compositions and methods of administration

[0257] The subject pharmaceutical compositions are typically formulated to provide a therapeutically effective amount of a compound of the present disclosure as the active ingredient, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof. Where desired, the pharmaceutical compositions contain pharmaceutically acceptable salt and/or coordination complex thereof, and one or more pharmaceutically acceptable excspients, earners, including inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants.

[0258] The subject pharmaceutical compositions can be administered alone or in combination with one or more other agents, which are also typically administered in the form of pharmaceutical compositions. Where desired, the one or more compounds of the invention and other agent(s) may be mixed into a preparation or both components may be formulated into separate preparations to use them, in combination separately or at the same time.

[0259] in some embodiments, the concentration of one or more compounds provided in the pharmaceutical compositions of the present 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%, 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 numbers above) w/w, w/v or v/v.

f 260 J 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 numbers above) w/w, w/v, or v/v.

[0261] In some embodiments, the concentration of one or more compounds of the invention is in the range from approximately 0.0001 % to approximately 50%, approximately 0.001% to approximately 40%, approximately 0.01% to approximately 30%, approximately 0.02% to approximately 29%, approximately 0.03% to approximately 28%, approximately 0.04% to approximately 27%, approximately 0.05% to approximately 26%, approximately 0.06% to approximately 25%, approximately 0.07% to approximately 24%, approximately 0,08% to approximately 23%, approximately 0.09% to approximately 22%, approximately 0.1% to approximately 21%, approximately 0.2% to approximately 20%, approximately 0.3% to approximately 19%, approximately 0.4% to approximately 18%, approximately 0.5% to approximately 17%, approximately 0.6%J to approximately 16%, approximately 0.7% to approximately 15%, approximately 0.8% to approximately 14%, approximately 0.9% to approximately 12%, approximately l% to approximately 10% w/w, w/v or v/V.

[0262] In some embodiments, the concentration of one or more compounds of the invention is in the range from approximately 0.001 % io approximately 10%, approximately 0.01% to approximately 5%, approximately 0.02% to approximately 4.5%, approximately 0.03% to approximately 4%, approximately 0.04% to approximately 3.5%, approximately 0.05% to approximately 3%, approximately 0.06% to approximately 2.5%, approximately 0.07% to approximately 2%, approximately 0.08% to approximately 1.5%, approximately 0.09% to approximately 1%, approximately 0.1% to approximately 0.9% w/w, w/v orv/v.

[0263] In some embodiments, the amount of one or more compounds of the invention is equal to or less than 10 g, 9.5 g, 9.0 g, 8.5 g, 8,0 g, 7.5 g, 7.0 g, 6,5 g, 6.0 g, 5.5 g, 5.0 g, 4,5 g, 4,0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g, 0.15 g, 0.1 g, 0.09 g, 0.08 g, 0.07 g, 0.06 g, 0.05 g, 0.04 g, 0.03 g, 0,02 g, 0.01 g, 0.009 g, 0.008 g, 0.007 g, 0.006 g, 0.005 g, 0.004 g, 0.003 g, 0.002 g, 0.001 g, 0.0009 g, 0.0008 g, 0.0007 g, 0.0006 g, 0.0005 g, 0.0004 g, 0.0003 g, 0.0002 g, or 0.0001 g (or a number in the range defined by and including any two numbers above).

[0264] In some embodiments, the amount of one or more compounds of the invention is more than 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005 g, 0.0006 g, 0.0007 g, 0.0008 g, 0.0009 g, 0.0 1 g, 0.0 15 g, 0.002 g, 0.0025 g, 0.003 g, 0.0035 g, 0.004 g, 0.0045 g, 0.005 g, 0.0055 g, 0.006 g, 0.0065 g, 0.007 g, 0.0075 g, 0,008 g, 0,0085 g, 0,009 g, 0,0095 g, 0.01 g, 0.015 g, 0.02 g, 0.025 g, 0.03 g, 0.035 g, 0.04 g, 0.045 g, 0.05 g, 0.055 g, 0.06 g, 0.065 g, 0.07 g, 0.075 g, 0.08 g, 0.085 g, 0.09 g, 0.095 g, 0.1 g, , 0.15 g, 0.2 g, , 0.25 g, 0.3 g, , 0.35 g, 0.4 g, , 0,45 g, 0,5 g, 0.55 g, 0.6 g, , 0.65 g, 0.7 g, 0,75 g, 0.8 g, 0.85 g, 0.9 g, 0,95 g, 1 g, 1.5 g, 2 g, 2.5, 3 g, 3,5, 4 g, 4,5 g, 5 g, 5.5 g, 6 g, 6.5g, 7 g, 7.5g, 8 g, 8.5 g, 9 g, 9.5 g, or 10 g (or a number in the range defined by and including any two numbers above).

[0265] In some embodiments, the amount of one or more compounds of the invention is in the range of 0.0001-10 g, 0,0005-9 g, 0.001-8 g, 0.005-7 g, 0,01-6 g, 0,05-5 g, 0,1-4 g, 0,5-4 [0266] The compounds according to the invention are effective over a wide dosage range. For example, in the treatment of adult humans, dosages from 0.01 to 1000 mg, from 0.5 to 100 mg, from 1 to 50 mg per day, and from 5 to 40 mg per day are examples of dosages that may be used. An exemplar - dosage is 10 to 30 mg per day. The exact dosage will depend upon the route of administration, the form in which the compound is administered, the subject to be treated, the body weight of the subject to be treated, and the preference and experience of the attending physician.

[0267] A pharmaceutical composition of the invention typically contains an active ingredient (i.e., a compound of the disclosure) of the present invention or a pharmaceutically acceptable salt and/or coordination complex thereof, and one or more pharmaceutically acceptable excipients, carriers, including but not limited to inert solid diluents and fillers, diluents, sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants.

[0268] Described below? are non- limiting exemplary pharmaceutical compositions and methods for preparing the same.

Pharmaceutical compositions for oral administration.

26 ] In some embodiments, the invention provides a pharmaceutical composition for oral administration containing a compound of the invention, and a pharmaceutical excipient suitable for oral administration.

[0270] 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 a second agent; and (iii) a pharmaceutical excipient suitable for oral administration. In some embodiments, the composition further contains: (iv) an effective amount of a third agent.

10271 J In some embodiments, the pharmaceutical composition may be a liquid pharmaceutical composition suitable for oral consumption. Pharmaceutical compositions of the invention suitable for oral administration can be presented as discrete dosage forms, such as capsules, cachets, or tablets, or liquids or aerosol sprays each containing a predetermined amount of an active ingredient as a powder or in granules, a solution, or a suspension in an aqueous or non-aqueous liquid, an oil-in- water emulsion, or a water-in-oil liquid emulsion. Such dosage forms can be prepared by any of the methods of pharmacy, but all methods include the step of bringing the active ingredient into association with the earner, which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately- admixing the acti ve ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation. For example, a tablet can be prepared by compression or molding, optionally with one or more accessory ingredients.

Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free- flowing form such as powder or granules, optionally mixed with an excipient such as, but not limited to, a binder, a lubricant, an inert diluent, and/or a surface active or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0272] This invention further encompasses anhydrous pharmace tical compositions and dosage forms comprising an active ingredient, since water can facilitate the degradation of some compounds. For example, water may be added (e.g., 5%) in the pharmaceutical arts as a means of simulating long-term storage in order to determine characteristics such as shelf- life or the stability of formulations over time. Anhydrous pharmaceutical compositions and dosage forms of the invention can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. Pharmaceutical compositions and dosage forms of the invention which contain lactose can be made anhydrous if substantial contact with moisture and/or humidity during manufacturing, packaging, and/or storage is expected. An anhydrous pharmaceutical composition may be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions may be packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastic or the like, unit dose containers, blister packs, and strip packs.

[0273] An active ingredient can be combined in an intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take a wide variety of forms depending on the form of preparation desired for administration. In preparing the compositions for an oral dosage form, any of the usual pharmaceutical media can be employed as carriers, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like in the case of oral liquid preparations (such as suspensions, solutions, and elixirs) or aerosols; or carriers such as starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents can be used in the case of oral solid preparations, in some embodiments without employing the use of lactose. For example, suitable earners include powders, capsules, and tablets, with the solid oral preparations. If desired, tablets can be coated by standard aqueous or nonaqueous techniques.

[0274] 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 acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidine, methyl cellulose, pre-gelatinized starch, hydroxy-propyl methyl cellulose, microcrystalline cellulose, and mixtures thereof.

[0275] Examples of suitable fillers for use in the pharmaceutical compositions and dosage fonns disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, manmtol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.

[0276] Disintegrants may be used in the compositions of the invention to provide tablets that disintegrate when exposed to an aqueous environment. Too much of a disintegrant may produce tablets which may disintegrate in the bottle. Too little may be insufficient for disintegration to occur and may thus alter the rate and extent of release of the active ingredient(s) from the dosage form. Thus, a sufficient amount of disintegrant that is neither too little nor too much to detrimentally alter the release of the active ingredient(s) may be used to form the dosage forms of the compounds disclosed herein. The amount of disintegrant used may vary based upon the type of formulation and mode of administration, and may be readily discernible to those of ordinary skill in the art. About 0.5 to about 15 weight percent of disintegrant, or about 1 to about 5 weight percent 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, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, other starches, clays, other algms, other celluloses, gums or mixtures thereof.

[0277J Lubricants which can be used to form pharmaceutical compositions and dosage fonns 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 (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, com oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, or mixtures thereof. Additional lubricants include, for example, a syloid silica gel, a coagulated aerosol of synthetic silica, or mixtures thereof. A lubricant can optionally be added, in an amount of less than about 1 weight percent of the pharmaceutical composition.

[0278] When aqueous suspensions and/or elixirs are desired for oral administration, the active ingredient therein may be combined with various sweetening or flavoring agents, coloring matter or dyes and, if so desired, emulsifying and/or suspending agents, together with such diluents as water, ethanol, propylene glycol, glycerin and various combinations thereof.

[0279] The tablets can be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as gly ceryl monostearate or glyceryl distearate can be employed. Formulations for oral use can also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil .

[0280] Surfactant which 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. That is, a m ixture of hydrophilic surfactants may be employed, a mixture of lipophilic surfactants may be employed, or a mixture of at least one hydrophilic surfactant and at least one lipophilic surfactant may be employed.

[0281] A suitable hydrophilic surfactant may generally have an HLB value of at least 10, while suitable lipophilic surfactants may generally have an HLB value of or less than about 10. An empirical parameter used to characterize the relative hydrophiiicity and hydrophobicity of non-ionic amphiphilic compounds is the hydrophilic-iipophilic 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.

[0282] Hydrophilic surfactants are generally considered to be those compounds having an HLB value greater than about 10, as well as anionic, cationic, or zwitterionic compounds for which the HLB scale is not generally applicable. Similarly, lipophilic (i.e., hydrophobic) surfactants are compounds having an HLB value equal to or less than about 10. However, HLB value of a surfactant is merely a rough guide generally used to enable formulation of industrial, pharmaceutical and cosmetic emulsions. [0283j Hydrophilic surfactants may be either ionic or non-ionic. Suitable ionic- surfactants include, but are not limited to, alkylammonium salts; fusidic acid salts; fatty acid derivatives of amino acids, oligopeptides, and polypeptides; glyceride derivatives of amino acids, oligopeptides, and polypeptides; lecithins and hydrogenated lecithins; lysolecithins andivdrogenated lysolecithins; phospholipids and derivatives thereof; iysophosphohpids and derivatives thereof; carnitine fatty acid ester salts; salts of alkylsulfates; fatty acid salts; sodium docusate; acyl iactylates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citric acid esters of mono- and di-glycerides; and mixtures thereof.

[0284] Within the aforementioned group, ionic surfactants include, by way of example: lecithins, lysolecithin, phospholipids, lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkylsulfates; fatty acid salts; sodium docusate; acylactylates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di- glycerides; citric acid esters of mono- and di-glycerides; and m ixtures thereof.

|0285| Tonic surfactants may be the ionized forms of lecithin, lysolecithin,

phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, ^©phosphatidylcholine, lysophosphatidylethanolamine,

lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG- phosphatidylethanolamine, PVP -phosphatidylethanolamine, lactylic esters of fatty acids, stearoyl-2-iaciylate, stearoyl lactylate, succinylated monoglycerides, mono/diacetyiated tartaric acid esters of mono/diglycerides, citric acid esters of mono/digiycerides, cholylsarcosine, caproate, caprylate, caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate, linolenate, stearate, lauryl sulfate, teracecyl sulfate, docusate, lauroyl carnitines, palmitoyl carnitines, myristoyl carnitines, and salts and mixtures thereof.

[0286] Hydrophilic non-ionic surfactants may include, but are not limited to,

alkylglucosides; alkylmaltosides; alkylthioglucosides; lauryl macrogolglycerides;

poiyoxyalkviene alkyl ethers such as polyethylene glycol alkyl ethers; poiyoxyalkyiene alkylphenols such as polyethylene glycol alkyl phenols; poiyoxyalkyiene alkyl phenol fatty ac d esters such as polyethylene glycol fatty acids monoesters and polyethylene glycol fatty acids diesters; polyethylene glycol glycerol fatty acid esters; polyglycerol fatty acid esters;

poiyoxyalkyiene sorbitan fatty acid esters such as polyethylene glycol sorbitan fatty acid esters; hydrophilic transesterification products of a poly oi with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols; polyoxyethylene sterols, derivatives, and analogues thereof; polyoxyethylated vitamins and derivatives thereof; polyoxyethylene-polyoxypropylene block copolymers; and mixtures thereof; polyethylene glycol sorbitan fatty acid esters and hydrophilic transesterification products of a poiyol with at least one member of the group consisting of triglycerides, vegetable oils, and hydrogenated vegetable oils. The poiyol may be glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, or a saccharide.

[0287] 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-20 oleate, 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-25 glyceryl trioleate, 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, PEG-50 hydrogenated 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 com oil, PEG-6 caprate/caprylate glycerides, PEG-8 caprate/caprylate glycerides, polygly eery 1-10 laurate, PEG-30 cholesterol, PEG-25 phyto sterol, PEG-30 soya sterol, PEG-20 trioleate, PEG-40 sorbitan oleate, PEG-80 sorbitan laurate, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23 lauiyl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl ether, tocopherol PEG- 100 succinate, PEG-24 cholesterol, polyglyceryl-lOoleate, Tween 40, Tween 60, sucrose monostearate, sucrose mono laurate, sucrose monopalmitate, PEG 10-100 nonyl phenol series, PEG 15-100 octyl phenol series, and poloxamers.

[0288] Suitable lipophilic surfactants include, by way of example only: fatty alcohols; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lower alcohol fatty acids esters; propylene glycol fatty acid esters; sorbitan fatty acid esters; polyethylene glycol sorbitan fatty acid esters; sterols and sterol derivatives; polyoxyethylated sterols and sterol derivatives;

polyethylene glycol aikyl ethers; sugar esters; sugar ethers; lactic acid derivatives of mono- and di-giyeerides; hydrophobic transesterification products of a poiyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols; oil-soluble vitamins/vitamin derivatives; and mixtures thereof. Within this group, preferred lipophilic surfactants include glycerol fatty acid esters, propylene glycol fatty acid esters, and mixtures thereof, or are hydrophobic transesterification products of a poiyol with at least one member of the group consisting of vegetable oils, hydrogenated vegetable oils, and triglycerides.

[0289] In one embodiment, the composition may include a solubilizer to ensure good solubilization and/or dissolution of the compound of the present invention and to minimize precipitation of the compound of the present invention. This can be especially important for compositions for non-oral use, e.g., compositions for injection. 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.

[0290] Examples of suitable solubilizers include, but are not limited to, the following: alcohols and poiyois, such as ethanoi, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediols and isomers thereof, glycerol, pentaeiythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinylalcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives; ethers of polyethylene glycols having an average molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether (glycofurol) or methoxy PEG ; amides and other nitrogen -containing compounds such as 2-pyrrolidone, 2-piperidone, ε-caprolactam, N- alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkyicaprolactam, dimethylacetamide and polyvinylpyrrolidone; esters such as ethyl propionate, tributylcitrate, acetyl triethylcitrate, acetyl tributyl citrate, triethylcitrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, ε-caprolactone and isomers thereof, δ-valerolactone and isomers thereof, β-butyrolactone and isomers thereof; and other solubilizers known in the art, such as dimethyl acetamide, dimethyl isosorbide, N-methyl pyrrolidones, monooctanoin, diethylene glycol monoethyl ether, and water.

[0291] Mixtures of solubilizers may also be used. Examples include, but not limited to, triacetin, triethylcitrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose,

hydroxypropyl cyclodextrins, ethanoi, polyethylene glycol 200-100, glycofurol, transcutol, propylene glycol, and dimethyl isosorbide. Particularly preferred solubilizers include sorbitol, glycerol, triacetin, ethyl alcohol, PEG-400, glycofurol and propylene glycol.

[0292] The amount of solubilizer that can be included is not particularly limited. The amount of a given solubilizer may be limited to a bioacceptable amount, which may be readily determined by one of skill in the art. In some circumstances, it may be advantageous to include amounts of solubilizers far in excess of bioacceptable amounts, for example to maximize the concentration of the drug, with excess solubilizer removed prior to providing the composition to a subject using conventional techniques, such as distillation or evaporation. Thus, if present, the solubilizer can be in a weight ratio of 10%, 25%o, 50%), 100%o, or up to about 200%> by weight, based on the combined weight of the drag, and other excipients. If desired, very small amounts of solubilizer may also be used, such as 5%>, 2%>, ! %) or even less. Typically, the solubilizer may be present in an amount of about 1%> to about 100%, more typically about 5%> to about 25 %> by weight.

[0293] The composition can further include one or more pharmaceutically acceptable additives and excipients. Such additives and excipients include, without limitation, detackifiers, anti-foaming agents, buffering agents, polymers, antioxidants, preservatives, chelating agents, viscomodulators, tonicifiers, flavorants, colorants, odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.

[0294] In addition, an acid or a base may be incorporated into the composition to facilitate processing, to enhance stability, or for 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 that are salts of a pharmaceutically acceptable acid, such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic 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, oxalic acid, para-bromophenyisulfonic 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. Salts of polyprotic acids, such as sodium phosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate can also be used. When the base is a salt, the cation can be any convenient and pharmaceutically acceptable cation, such as ammonium, alkali metals, alkaline earth metals, and the like. Example may include, but not limited to, sodium, potassium, lithium, magnesium, calcium and ammonium.

[0295] Suitable acids are pharmaceutically acceptable organic or inorganic acids. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydriodic 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, alkanesulfonic acids, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbsc acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thiogiycolic acid, toluene sulfonic acid, uric acid and the like.

Pharmaceutical compositions for injection.

|0296j In some embodiments, the invention provides a pharmaceutical composition for injection containing a compound of the present invention and a pharmaceutical excipient suitable for injection. Components and amounts of agents in the compositions are as described herein,

[0297] The forms in which the novel compositions of the present invention may be incorporated for administration by injection include aqueous or oil suspensions, or emulsions, with sesame oil, com oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles.

| 298J Aqueous solutions in saline are also conventionally used for injection. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be employed. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, for the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

[0299] Sterile injectable solutions are prepared by incorporating the compound of the present invention in the required amount in the appropriate solvent with various other ingredients as enumerated above, as required, 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 required oilier ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, certain desirable methods of preparation are vacuum-drying and freeze- drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile- filtered solution thereof.

Pharmaceutical compositions for topical (e.g. transdermal) delivery- [0300] ΐη some embodiments, the invention provides a pharmaceutical composition for transdermal delivery containing a compound of the present in vention and a pharmaceutical excipient suitable for transdermal delivery.

[0301] Compositions of the present invention can be formulated into preparations in solid, semisolid, or liquid forms suitable for local or topical administration, such as gels, water soluble jellies, creams, lotions, suspensions, foams, powders, slurries, ointments, solutions, oils, pastes, suppositories, sprays, emulsions, saline solutions, dimethyl sulfoxide (DMSO)-based solutions. In general, carriers with higher densities are capable of providing an area with a prolonged exposure to the active ingredients. In contrast, a solution formulation may provide more immediate exposure of the active ingredient to the chosen area,

10302] The pharmaceutical compositions also may comprise suitable solid or gel phase carriers or excipients, which are compounds that allow increased penetration of, or assist in the delivery of, tlierapeuiic molecules across the stratum corneum permeability barrier of the skin. There are many of these penetration- enhancing molecules known to those trained in the art of topical formulation .

[0303] Examples of such carriers and excipients include, but are not limited to, humectants (e.g., urea), glycols (e.g., propylene glycol), alcohols (e.g., ethanol), fatty acids (e.g., oleic acid), surfactants (e.g., isopropyl myristate and sodium lauryl sulfate), pyrrolidones, glycerol monolaurate, sulfoxides, terpenes (e.g., menthol), amines, amides, alkanes, alkanols, water, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.

[0304] Another exemplar ' formulation for use in the methods of the present invention employs transdermal delivery devices ("patches"). Such transdermal patches may be used to provide continuous or discontinuous infusion of a compound of the present in v ention in controlled amounts, either with or without another agent.

[0305] The construction and use of transdermal patches for the delivery of

pharmaceutical agents is well known in the art. See, e.g., U .S. Pat. Nos. 5,023,252, 4,992,445 and 5,001, 139. Such patches may be constructed for continuous, pulsatile, or on demand deliver}' of pharmaceutical agents.

Pharmaceutical compositions for inhalation.

[0306] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. Preferably the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a face mask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner.

Other pharmaceutical compositions.

10307] Pharmaceutical compositions may also be prepared from compositions described herein and one or more pharmaceutically acceptable excipients suitable for sublingual, buccal, rectal, intraosseous, intraocular, intranasal, epidural, or intraspinal administration.

Preparations for such pharmaceutical compositions are well-known in the art. See, e.g.,

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 Oilman, eds., The Pharmacological Basis of Therapeutics, Tenth Edition, McGraw Hill, 2001 ; Remingtons Pharmaceutical Sciences, 20th Ed., Lippincott Williams & Wiikins., 2000; Martindale, The Extra Pharmacopoeia, Thirty-Second Edition (The Pharmaceutical Press, London, 1999); all of which are incorporated by reference herein in their entirety.

[0308 J Administration of the compounds or pharmaceutical composition of the present invention can be effected by any method that enables deli very of 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 catheter or stent or through inhalation. Compounds can also be administered intraadiposally or intrathecally.

[0309] The amount of the compound administered will be dependent on the subject being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound and the discretion of the prescribing physician. However, an effective dosage is in the range of about 0.001 to about 100 mg per kg body weight per day, preferably about 1 to about 35 mg/kg/day, in single or divided doses. For a 70 kg human, this would amount to about 0,05 to 7 g/day, preferably about 0,05 to about 2.5 g/day. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, e.g. by dividing such larger doses into several small doses for administration throughout the day.

[0310] In some embodiments, a compound of the invention is administered in a single dose .

[0311] Typically, such administration will be by injection, e.g., intravenous injection, in order to introduce the agent quickly. However, other routes may be used as appropriate. A single dose of a compound of the invention may also be used for treatment of an acute condition.

[031 ] In some embodiments, a compound of the invention is administered in multiple doses. Dosing may be about once, twice, three times, four times, five times, six times, or more than six times per day. Dosing 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 about once per day to about 6 times per day. In another embodiment the administration of a compound of the invention and an agent continues for less than about 7 days. In yet another embodiment the administration continues for more than about 6, 10, 14, 28 days, two months, six months, or one year. In some cases, continuous dosing is achieved and maintained as long as necessary.

[0313] Administration of the compounds of the invention may continue as long as necessary. In some embodiments, a compound of the invention is administered for more than I, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, a compound of the invention is administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, a compound of the invention is administered chronically on an ongoing basis, e.g., for the treatment of chronic effects.

[0314] An effective amount of a compound of the invention may be administered in either single or multiple doses by any of the accepted modes of administration of agents having similar utilities, including rectal, buccal, intranasal and transdermal routes, by intra-arterial injection, intravenously, intraperitoneal ly, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.

[0315] The compositions of the invention may also be delivered via an impregnated or coated device such as a stent, for example, or an artery-inserted cylindrical polymer. Such a method of administration may, for example, aid in the prevention or amelioration of restenosis following procedures such as balloon angioplasty. Without being bound by theory, compounds of the invention may slow or inhibit the migration and proliferation of smooth muscle cells in the arterial wall which contribute to restenosis. A compound of the invention may be administered, for example, by local delivery from the stmts of a stent, from a stent graft, from grafts, or from the cover or sheath of a stent. In some embodiments, a compound of the invention is admixed with a matrix. Such a matrix may be a polymeric matrix, and may serve to bond the compound to the stent. Polymeric matrices suitable for such use, include, for example, lactone-based polyesters or copolyesters such as polylactide, polycaprolactonglycolide, polyorthoesters, polyanhydrides, polyaminoacids, polysaccharides, polyphosphazenes, poly (ether-ester) copolymers (e.g. PEO-PLLA); polydimethylsiloxane, poly(ethylene-vinylacetate), acrylate-based polymers or copolymers (e.g. poiyhydroxyethyl methylmethacrylate, polyvinyl pyrrolidinone), fluorinated polymers such as polytetrafluoroethylene and cellulose esters. Suitable matrices may be nondegrading or may degrade with time, releasing the compound or compounds. Compounds of the invention may be applied to the surface of the stent by various methods such as dip/spin coating, spray coating, dip-coating, and/or brash -coating. The compounds may be applied in a solvent and the solvent may be allowed to evaporate, thus forming a layer of compound onto the stent. Alternatively, the compound may be located in the body of the stent or graft, for example in microchannels or micropores. When implanted, the compound diffuses out of the body of the stent to contact the arterial wall. Such stents may be prepared by dipping a stent manufactured to contain such micropores or microchannels into a solution of the compound of the invention in a suitable solvent, followed by evaporation of the solvent. Excess drag on the surface of the stent may be removed via an additional brief solvent wash. In yet other embodiments, compounds of the invention may be covalently linked to a stent or graft. A covalent linker may be used which degrades in vivo, leading to the release of the compound of the invention. Any bio-labile linkage may be used for such a purpose, such as ester, amide or anhydride linkages. Compounds of the invention may additionally be administered intravascularly from a balloon used during angioplasty. Extravascular administration of the compounds via the pericard or via advential application of formulations of the invention may also be performed to decrease restenosis.

[0316] A variety of stent devices which may be used as described are disclosed, for example, in the following references, all of which are hereby incorporated by reference: U.S. Pat. No. 5451233; U.S. Pat. No. 5040548: U.S. Pat. No. 5061273; U.S. Pat. No. 5496346; U.S. Pat. No. 5292331; U.S. Pat. No. 5674278; U.S. Pat. No. 3657744; U.S. Pat. No. 4739762; U.S. Pat. No. 5195984; U.S. Pat. No. 5292331 ; U.S. Pat. No. 5674278; U.S. Pat. No. 5879382; U.S. Pat. No. 6344053. [03.17] The compounds of the invention may be administered in dosages. It is known in the art that due to intersubject variability in compound pharmacokinetics, individualization of dosing regimen is necessary for optimal therapy. Dosing for a compound of the invention may be found by routine experimentation in light of the instant disclosure.

[0318] When a compound of the invention is administered in a composition that comprises one or more agents, and the agent has a shorter half- life than the compound of the invention unit dose forms of the agent and the compound of the invention may be adjusted accordingly.

[0319] The subject pharmaceutical composition may, for example, be in a form suitable for oral administration as a tablet, capsule, pill, powder, sustained release formulations, solution, suspension, for parenteral injection as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository. The pharmaceutical composition may be in unit dosage forms suitable for single administration of precise dosages. The pharmaceutical composition will include a conventional pharmaceutical carrier or excipient and a compound according to the invention as an active ingredient. In addition, it may include other medicinal or pharmaceutical agents, carriers, adjuvants, etc.

[0320] Exemplary parenteral administration forms include solutions or suspensions of active compound in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms can be suitably buffered, if desired.

Methods of Use

[0321] The method typically comprises administering to a subject a therapeutically effective amount of a compound of the invention. The therapeutically effective amount of the subject combination of compounds may vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated, e.g., the weight and age of the subject the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. The term also applies to a dose that will induce a particular response in target cells, e.g., reduction of proliferation or downreguiation of activity of a target protein. The specific dose will vary depending on the particular compounds chosen, the dosing regimen to be followed, whether it is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried.

[0322] As used herein, the term "IC50" refers to the half maximal inhibitory concentration of an inhibitor in inhibiting biological or biochemical function. This quantitative measure indicates how much of a particular inhibitor is needed to inhibit a given biological process (or component of a process, i.e. an enzyme, cell, cell receptor or microorganism) by half. In other words, it is the half maximal (50%) inhibitory concentration (IC) of a substance (50% IC, or IC50). EC50 refers to the plasma concentration required for obtaining 50%> of a maximum effect in vivo.

[03231 In some embodiments, the subject methods utilize a PRMT5 inhibitor with an IC50 value of about or less than a predetermined value, as ascertained in an in vitro assay. In some embodiments, the PRMT5 inhibitor inhibits PRMT5 a with an IC50 value of about 1 nM or less, 2 nM or less, 5 n : 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 μΜ or less, 1.1 μΜ or less, 1.2 μΜ or less, 1.3 μΜ or less, 1.4 μΜ or less, 1.5 μΜ or less, 1.6 μΜ or less, 1.7 μΜ or less, 1.8 μΜ or less, 1.9 μΜ or less, 2 μΜ or less, 5 μΜ or less, 10 μΜ or less, 15 μΜ or less, 20 μΜ or less, 25 μΜ or less, 30 μΜ or less, 40 μΜ or less, 50 μΜ, 60 μΜ, 70 μΜ, 80 μΜ, 90 μΜ, 100 μΜ, 200 μΜ, 300 μΜ, 400 μΜ, or 500 μΜ, or less, (or a number in the range defined by and including any two numbers above).

[0324] In some embodiments, the PRMT5 inhibitor selectively inhibits PRMT5 a with an IC50 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 and including any two numbers above)than its IC50 value against one, two, or three other PRMTs.

[0325] In some embodiments, the PRMTS inhibitor selectively inhibits PRMT5 a with an IC50 value that is less than about 1 nM, 2 nM, 5 nM, 7 nM, 10 nM, 20 nM, 30 nM, 40 nM, 50 nM, 60 nM, 70 nM, 80 nM, 90 nM, 100 nM, 120 nM, 140 nM, 150 nM, 160 nM, 170 nM, 180 nM, 190 nM, 200 nM, 225 nM, 250 nM, 275 nM, 300 nM, 325 nM, 350 nM, 375 nM, 400 nM, 425 nM, 450 nM, 475 nM, 500 nM, 550 nM, 600 nM, 650 nM, 700 nM, 750 nM, 800 nM, 850 nM, 900 nM, 950 nM, 1 μΜ, 1.1 μΜ, 1.2 μΜ, 1.3 μΜ, 1.4 μΜ, 1.5 μΜ, 1.6 μΜ, 1.7 μΜ, 1.8 μΜ, 1.9 μΜ, 2 μΜ, 5 μΜ, 10 μΜ, 15 μΜ, 20 μΜ, 25 μΜ, 30 μΜ, 40 μΜ, 50 μΜ, 60 μΜ, 70 μΜ, 80 μΜ, 90 μΜ, 100 μΜ, 200 μΜ, 300 μΜ, 400 μΜ, or 500 μΜ (or in the range defined by and including any two numbers above), and said IC50 value 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 and including any two numbers above) than its 1C50 value against one, two or three other PRMTs.

[0326] The subject methods are useful for treating a disease condition associated with PRMTS, Any disease condition that results directly or indirectly from an abnormal activity or expression level of PRMT5 can be an intended disease condition.

[0327] Different disease conditions associated with PRMTS have been reported.

PRMTS has been implicated, for example, in a variety of human cancers as well as a number of hemoglobinopathies.

[0328] Non- limiting examples of such conditions include but are not limited to Acanthoma, Acinic cell carcinoma, Acoustic neuroma, Acral lentigmous melanoma,

Acrospiroma, Acute eosinophilic leukemia, Acute lymphoblastic leukemia, Acute lymphocytic leukemia, Acute megakaryoblastic leukemia. Acute monocytic leukemia, Acute myeloblasts leukemia with maturation, Acute myeloid dendritic cell leukemia, Acute myeloid leukemia, Acute myelogenous leukemia, Acute promyelocytic leukemia, Adamantinoma, Adenocarcinoma, Adenoid cystic carcinoma, Adenoma, Adenomatoid odontogenic tumor, Adrenocortical carcinoma, Adult T-cell leukemia, Aggressive N -cell leukemia, AIDS-Related Cancers, AIDS- related lymphoma, Alveolar soft part 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, Biastoma, Bone Cancer, Bone tumor, Brain Stem Glioma, Brain Tumor, Breast Cancer, Brenner tumor, Bronchial Tumor,

Bronchioloalveolar carcinoma, Brown 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, Central Nervous System

Embryonal Tumor, Cerebellar Astrocytoma, Cerebral Astrocytoma, Cervical Cancer,

Cholangiocarcmoma, Chondroma, Chondrosarcoma, Chordoma, Choriocarcinoma, Choroid plexus papilloma. Chronic Lymphocytic Leukemia, Chronic monocytic leukemia, Chronic myelogenous leukemia, Chronic Myeloproliferative Disorder, Chronic neutrophilic leukemia, Clear-cell tumor, Colon Cancer, Colorectal cancer, Craniopharyngioma, Cutaneous T-cell lymphoma, Degos disease, Dermatofrbrosarcoma protuberans, Dermoid cyst, Desmopiastic small round cell tumor, Diffuse large B cell lymphoma, Dysembryoplastic neuroepithelial tumor, Embryonal carcinoma, Endodermal sinus tumor, Endometrial cancer, Endometrial Uterine Cancer, Endometrioid tumor, Enteropathy-associated T-cell lymphoma, Ependymoblastoma, Ependymoma, Epidermoid cancer, Epithelioid sarcoma, Erythroleukemia, Esophageal cancer, Esthesioneuroblastoma, Ewing Family of Tumor, Ewing Family Sarcoma, Ewing's sarcoma, Extracranial Germ Cell Tumor, Extragonadal Germ Cell Tumor, Extrahepatic Bile Duct Cancer, Extramammary Paget' s disease, Fallopian tube cancer, Fetus in fetu, 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, Germ cell tumor, Germinoma, Gestational choriocarcinoma, Gestational Trophoblastic Tumor, Giant cell tumor of bone. Glioblastoma multiforme, Glioma, Gliomatosis cerebri, Glomus tumor, 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 disease (SCD), Hemangioblastoma, Hemangiopericytoma,

Hemangiosarcoma, Hematological malignancy, Hepatocellular carcinoma, Hepatosplenic T-cell lymphoma, Hereditary breast-ovarian cancer syndrome, Hodgkin Lymphoma, Hodgkin's lymphoma, Hypopharyngeal Cancer, Hypothalamic Glioma, Inflammatory breast cancer, Intraocular Melanoma, Islet cell carcinoma, Islet Cell Tumor, juvenile myelomonocytic leukemia, Kaposi Sarcoma, Kaposi's sarcoma, Kidney Cancer, Klatskin tumor, Krukenberg tumor. Laryngeal Cancer, Laryngeal cancer. Lentigo maligna melanoma, Leukemia, Lip and Oral Cavity Cancer, Liposarcoma, Lung cancer, Luteoma, Lymphangioma,

Lymphangiosarcoma, Lymphoepithelioma, Lymphoid leukemia, Lymphoma,

Macroglobulinemia, Malignant Fibrous Histiocytoma, Malignant fibrous histiocytoma, Malignant Fibrous Histiocytoma of Bone, Malignant Glioma, Malignant Mesothelioma, Malignant peripheral nerve sheath tumor, Malignant rhabdoid tumor, Malignant tnton tumor, MALT lymphoma, Mantle cell lymphoma, Mast cell leukemia, Mastocytosis, Mediastinal germ cell tumor, Mediastinal tumor, Meduilaiy thyroid cancer, Medulloblastoma, Medulloblastoma, Meduiloepithelioiria, Melanoma, Melanoma, Meningioma, Merkel Ceil Carcinoma,

Mesothelioma, Mesothelioma, Metastatic Squamous Neck Cancer with occult Primary,

Metastatic urothelial carcinoma, Mixed Mullerian tumor, Monocytic leukemia, Mouth Cancer, Mucinous tumor, Multiple Endocrine Neoplasia Syndrome, Multiple Myeloma, Multiple myeloma, Mycosis Fungoides, Mycosis fungoides, Myelodysplasia Disease, Myelodysplasia Syndromes, Myeloid leukemia. Myeloid sarcoma, Myeloproliferative Disease, Myxoma, Nasal Cavit 7 Cancer, Nasopharyngeal Cancer, Nasopharyngeal carcinoma, Neoplasm, Neurinoma, Neuroblastoma, Neuroblastoma, Neurofibroma, Neuroma, Nodular melanoma, Non-Hodgkin Lymphoma, Non-Hodgkin lymphoma, Nonmelanoma Skin Cancer, Non-Small Cell Lung Cancer, ocular oncology, Oligoastrocytoma, Oligodendroglioma, Oncocytoma, Optic nerve sheath meningioma. Oral Cancer, Oral cancer. Oropharyngeal Cancer, Osteosarcoma,

Osteosarcoma, Ovarian Cancer, Ovarian cancer, Ovarian Epithelial Cancer, Ovarian Germ Cell Tumor, Ovarian Low Malignant Potential Tumor, Paget's disease of the breast, Pancoast tumor. Pancreatic Cancer, Pancreatic cancer, Papillary thyroid cancer, Papillomatosis, Paraganglioma, Paranasal Sinus Cancer, Parathyroid Cancer, Penile Cancer, Perivascular epithelioid cell tumor, Pharyngeal Cancer, Pheochromocytoma, Pineal Parenchymal Tumor of Intermediate

Differentiation, Pineoblastoma, Pituicytoma, Pituitary adenoma, Pituitary tumor, Plasma Ceil Neoplasm, Pleuropulmonary blastoma, Polyembryoma, Precursor T-lymphoblastic lymphoma, Primary central nervous system lymphoma, Primary effusion lymphoma, Primary Hepatocellular Cancer, Primary Liver Cancer, Primary peritoneal cancer, Primitive neuroectodermal tumor, Prostate cancer, Pseudomyxoma peritonei, Rectal Cancer, Renal cell carcinoma, Respiratory Tract Carcinoma Involving the NUT Gene onChromosome 15, Retinoblastoma, Rhabdomyoma, Rhabdomyosarcoma, Richter's transformation, Sacrococcygeal teratoma. Salivary Gland Cancer, Sarcoma, Schwannomatosis, Sebaceous gland carcinoma, Secondary neoplasm, Seminoma, Serous tumor, Sertoli-Leydig cell tumor. Sex cord-stromal tumor, Sezary Syndrome, Signet ring cell carcinoma, Skin Cancer, Small blue round cell tumor, Small cell carcinoma, Small Cell Lung Cancer, Small cell lymphoma, Small intestine cancer, Soft tissue sarcoma,

Somatostatinoma, Soot wart, Spinal Cord Tumor, Spinal tumor, Splenic marginal zone lymphoma, Squamous cell carcinoma. Stomach cancer, Superficial spreading melanoma,

Supratentorial Primitive Neuroectodermal Tumor, Surface epithelial-stromal tumor, Synovial sarcoma, T-ceil acute lymphoblastic leukemia, T-cell large granular lymphocyte leukemia, T-ceii leukemia, T-cell lymphoma, T-cell prolymphocyte leukemia, Teratoma, Terminal lymphatic cancer, Testicular cancer, Thecoma, Throat Cancer, Thymic Carcinoma, Thymoma, Thyroid cancer, Transitional Cell Cancer of Renal Pelvis and Ureter, Transitional cell carcinoma, Urachal cancer, Urethral cancer. Urogenital neoplasm, Uterine sarcoma, Uveal melanoma, Vaginal Cancer, Verner Morrison syndrome, Verrucous carcinoma, Visual Pathway Glioma, Vulvar Cancer, Waldenstrom's macroglobulinemia, Warthin's tumor, Wilms' tumor, or any combination thereof.

10329] In some embodiments, said method is for treating a disease selected from the group consisting of tumor angiogenesis, 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, hemangioma, glioma, melanoma, Kaposi's sarcoma and ovarian, breast, lung, pancreatic, prostate, colon and epidermoid cancer,

[0330] The examples and preparations provided below further illustrate and exemplify the compounds of the present invention and methods of preparing such compounds. It is to be understood that the scope of the present invention is not limited in any way by the scope of the following examples and preparations. In the following examples molecules with a single chiral center, unless otherwise noted, exist as a racemic mixture. Those molecules with two or more chiral centers, unless otherwise noted, exist as a racemic mixture of diastereomers. Single enantiomers/diastereomers may be obtained by methods known to those skilled in the art.

[0331] Compounds of the disclosure can be prepared, for example, by reference to the following schemes.

Scheme 1

S1-S S1-S Ex-Sg

Scheme 3

S3-2 S3~3

Scheme 4

Scheme 5

S2~5 S5-1

1)

2)

3}

Schemt

S6-7

[0332] Compounds of the disclosure can be tested for inhibition of PRMT5 -mediated H4R3 methylation using the following protocol.

f 333j Hi stone methylation is performed in the presence of DMSO, and 1 -40 μ.Μ inhibitor compounds. The first assay that is carried out explored activity on PRMT5 alone in order to calculate an ICso by using 2 ug of HeLa S3 core histones and 500 ng of recombinant PRMT1, 500 ng of recombinant PRMT4, 5 uL of affinity-purified hSWI/SNF associated PRMT5, or 15 μΛ of affinity- purified hSWI/SNF associated F1 -PRMT7 in a 25 uL reaction mixture containing 15 niM HEPES (pH 7.9), 100 mM KC1, 5 mM MgC12, 20% glycerol, 1 mM EDTA, 0.25 mM dithiothreitol, 0.5 mM phenylmethylsulfonyl fluoride, and 2.75 Ci of S~

[3H]adenosylmethionine (SAM) (Amersham Pharmacia Biotech., Inc.). After 1.5 h incubation at 30°C, reaction mixtures are spotted on Whatman P-81 filter paper, washed five times with 10 mL of 0.1 mM sodium carbonate buffer (pH 9.0) to remove unincorporated [3H]SAM, and methylated peptides are detected by scintillation counting. Compounds of the disclosure include, for example, the compounds identified '

Table A.

- 1 - o [ 3 , 4 - 1 -

- d ro xy )m ,4 - )-2 - 1 - 1 H- dro fur

- ri mi di n-5 - -

- S, 5 S)- - hy d ro xy)m

drofuran-3,4-dioi Ex. No. Structu re MW Name

(2R,3S,4R,5R)-2-((R)-(3,4- di fluo top en 1) { hy d no xy )m

392.3628 ethyl)-5-(5-(methylainino)-

110 064 7H-pyrrolo[2,3- d]pyrimidin-7- yl)tetrahydrofuran-3,4-diol

(2R,3R,4S,5R)-2-(4-amino-3- ethynyl-lH-pyrazolo[3,4-

401.8 d]pyrimidin-l-yl)-5-((S)-(4-

111

chlorophenyl)(hydroxy)met hyl)tetrahydrofuran-3,4-diol

(2R,3R,4S,5R)-2-(4-amino-3- ethynyl-lH-pyrazolo[3,4-

401.8 d]pyrimidin-l-yl)-5-((R)-(4-

112

chlorophenyl)(hydroxy)met

AH, hyl)tetrahydrofuran-3,4-diol

(2R,3R,4S,5R)-2-(4-amino-3- vinyl-lH-pyrazolo[3,4-

403.82 d]pyrimidin-l-yl)-5-((4-

113

chlorophenyl)(hydroxy)met

NH 2 hyl)tetrahydrofuran-3,4-diol

HQ I O (2R,3R,4S,5R)-2-(4-amino-3- vinyl-lH-pyrazolo[3,4-

403.82 d]pyrimidin-l-yl)-5-((4-

114

chlorophenyl)(hydroxy)met hyl)tetrahydrofuran-3,4-diol

1- (7-((2R,3R,4S,5R)-5-((R)- (3,4- difluorophenyl)(hydroxy)me thyl)-3,4-

405.35

115 dihydroxytetrahydrofuran-

2- yl)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)ethan-l- one

(2R,3S,4R,5R)-2-((R)-(3,4- H9 F dif!uoropheny!jjhydroxySme thyl)-5-(5-(l-hydroxyethyl)-

407.37

1 16 7H-pyrrolo[2,3-d]pyrirnidin-

7-yl Jtetra hyd rof u ra n-3,4- diol Ex. No. Structu re MW Name

1- (7-((2R,3R,4S,5R)-5-((R)- (3,4- difluorophenyl)(hydroxy)me thyl)-3,4-

419.38

117 d i hyd roxytetrahyd rof u ran-

2- yl)-4-methyl-7H- pyrrolo[2,3-d]pyrimidin-5- yl)ethan-l-one i 9

(2R,3R.4S,5R)-2-(4-amino-5- vinyl-7H-pyrrolo[2,3-

402.83 d]pyrimidin-7-yl)-5-((R)-(4-

118

chlorophenyl)(hydroxy)met hyl)tetrahydrofuran-3,4-diol

(2R,3R,4S,5R)-2-(4-amino-5- ethynyl-7H-pyrrolo[2,3-

400.82 d]pyrimidin-7-yl)-5-((R)-(4-

119

chlorophenyl)(hydroxy)met hyl)tetrahydrofuran-3,4-diol H9

(2R,3R,4S,5R)-2-(4-amino-5- (2-hydroxyethyl)-7H- pyrrolo[2,3-d]pyrimidin-7-

420.85

120 yl)-5-((R)-(4- chlorophenyl)(hydroxy)met hyl)tetrahydrofuran-3,4-diol H9 (2R,3R,4S,5R)-2-(4-amino-5- vinyl-7H-pyrrolo[2,3-

•• °- - pf X c d]pyrimidin-7-yl)-5-((R)-(4-

420.82

121 chioro-3- fluorophenyl)(hydroxy)met hyl)tetrahydrofuran-3,4-diol

io

diol Ex. No. Structu re MW Name

(2R,3R,4S,5R)-2-(2,4- diamino-5-(prop-l-yn-l-yl)-

7H-pyrrolo[2,3-d]pyrirnidin-

431.39

134 7-yl)-5-((R)-(3,4- difluorophenyl)(hydroxy)me thyl)tetrahydrofuran-3,4- diol

~gftx (2R,3R,4S,5R)-2-(2,4- diamino-5-eth nyl-7H-

""VV pyrrolo[2,3-d]pYrimidin-7-

450.28

135 i, yl)-5-((R)-(3,4- '

TV dichlo ropheny l)(hy droxy )m ethy Ijteirahy dro furan-3.4- diol

Experimental Procedures

Example 2. (2R,3R,4S,5S)-2-(3-ethynyl-lH-pyrazolo[3,4-d]p\Timidin-l-yl) -5- ((methylthio)methyl)tetrah}'drofuran-3,4-diol (2)

Step 1, Synthesis of (2R,3R,4R,5R)-2-(4-amino-3-iodo-lH-pyrazolo[3,4-d]pyrimidin- l -yl)-5-

((benzoyloxy)metliyI)tetrahydiOfuraii-3,4-diyl dibenzoate (2a)

[0335| A solution of 3-iodo-lH-pyrazolof3,4-dlpyrimidin-4-amine (1, 14.6 g, 56 mmol, 1 eq) and (2S,3R 4R,5R)-2~acetoxy-5-((benzoyloxy)inethyl)tetrahydrofjjran~3 dibenzoate (2, 42 g, 84 mmol, 1.5 eq) in CH3NO2 (350 mL) was heated to reflux and BFs -EtaO (15 mL) was added in one portion. During the reflux, the suspension became clear immediately and the color of the reaction mixture became dark slowly. After two hours, the reaction was completed (monitored by LC-MS). The mixture was then cooled to r.t. and concentrated to dryness under vacuo. The residue was purified by silica gel column chromatography (DCM: MeOH = 50: 1 , v:v) to afford (2R,3R,4R,5R)-2-(4-amino-3-iodo-l H-pyrazolo|3,4-d]pyrimidin-l -yl)-5- ((benzoyloxy)methyl)tetrahydrofuran~3,4~diyl dibenzoate (2a) (3.30 g, 76.1% yield) as brown solid, LCMS (M+FT): m/z calculated 706.1, found 706, 'H NMR (400 MHz, CDCb): δ 8.33 (s, 2H) , 8.1 1 (d, 2 H), 7.96 (t, 4H), 7.55 (t, 3 H), 7.44 (t, 3 H ), 7.40-7.34 (rn, 4 H), 6.78 (d, 1 H), 6.43-6.41 (m, 1 H), 6.25 (t, 1 H), 5.29 (s, 1 H) , 4.82 (d, 2 H).

Step 2, Synthesis of (2R,3R,4R,5R)-2-((benzoyloxy)methyl)-5-(3-iodo-lH-pyrazolo[3 ,4- d]pynmidin-l-yl)tetraliydrofuran-3,4-diyl dibenzoate (2b)

| 336J To a solution of (2R,3R,4R,5R)-2-(4-amino-3-iodo-lH-pyrazolo[3,4- d]pyrimidin~l-yl)-5~((benzoyloxy)methyl)tetrahydrofiiran-3,4 -diyl dibenzoate (2a) (3.30 g, 42 rnmol) in THF (200 ml) was added isoamyl nitrite (200 ml). The reaction mixture was heated to 100 °C and stirred for 12 hrs. LCMS showed the reaction was completed. The reaction mixture was cooled to r.t. and the solvent was removed under vacuo. The residue was purified by silica gel column chromatography (PE: EA=1 : 1 , v: v) to afford the product (2R,3R,4R,5R)-2- ((benzoyloxy)memyl)-5-(3-iodo-l H-pyrazolo[3,4-d]pyrim

dibenzoate (2b) (4, 13 g, 29.4% yield) as off-white solid. LCMS ( M l ! :· m/z calculated 690, found 690, 1 H NMR (400 MHz, CDCb): 5 9.07 (s, 1 H), 8,95 (s, 1 H), 8.10 (d, 2 H), 7.98-7.96 (m, 3H), 7.56 (t, 3H), 7.46 (t, 2 H), 7.41-7.26 (m, 5 H), 6.89 (d, 1 H), 6.47-6.44 (m, 1 H), 6.26 (t, 1 H), 4.86 (t, 1 H).4.79 (t, 1H), 4.66-4.62 (m, 1H)

Step 3. Synthesis of (2R,3S,4R,5R)-2-(hydroxymethyl)-5-(3-iodo-l H-pyrazolo[3,4-d]pyrimidin- l-yl)tetrahydrofiiran-3,4-diol (2c) [0337] To a solution of (2R,3R,4R,5R)-2-((benzoyloxy)methyl)-5-(3-iodo- 1H- pyrazolo-[3,4-d]pyrimidin-l-yl) tetrahydrofuran-3,4-diyl dibenzoate (2b) (4.9 g, 1.3 mmol) in CHsOH (50 mL) was added sodium metlioxide until pH = 1 1. Then the reaction mixture was heated to 50 °C and stirred for 2 hrs. LCMS showed the reaction was completed. The reaction mixture was cooled to r.i. and HC1 (6 M) was added to adjust pH = 7. The solvent was removed under vacuo and the residue was purified by silica gel column chromatography (DCM:MeOH :=: 20: 1) to afford

yl)tetrahydrofuran-3,4-diol (2c) (5.28 g, 56.8% yield) as white solid. LCMS (M+LT) m/z calculated 379.0, found 378.7. 'HNM (400 MHz, DMSO-c ): δ 9.12 (d, 2H), 6.22 (d, 1H), 5.45 (d, 1H), 5.21 (d, 1H), 4.75 (t, IH), 4.66 (q, 1H), 4.22 (q, 1H), 3.94 (q, 1H), 3.60-3.54 (m, 1H), 3.47-3,41 (m, H).

Step 4. Synthesis of ((3aR,4R,6R,6aR)-6-(3-iodo-lH-pyrazolo[3,4-d]pyrimidin-l -yl)-2,2- dimethyitetrahydrofuiO|3,4-d][ l,3]dioxol-4-yl)methanol (2d)

[0338] To a solution of (2R,3S,4R,5R)-2-(hydroxymethyl)-5-(3-iodo-l H-pyrazolo[3,4- d] pyrimidin-l-yl)tetrahydrofuran-3,4-diol (2c) (5,28 g, 0.74 mmol) and Amberiyst resm (280 nig) in DMF (4 mL) was added 2,2-dimethoxypropane (0.84 mL) at r.t. The reaction mixture was heated to 60 °C and stirred for 2 hrs. LCMS showed the reaction completed. The mixture was filtered through the celite and the mixture was concentrated under vacuo to give crude product which was purified by silica gel column chromatography (PE:EA=10: 1 to PE:EA=3: 1) to afford ((3aR,4R,6R,6aR)-6-(3~iodo~lH~pyrazolo[3,4~d]pyrimidin-l~y3) -2,2-dimethyh

d][l,3]dioxol-4-yl)methano1 (2d) (6.215 g, 69.4% yield) as white solid. LCMS (M+FT) m/z calculated 419.0, found 418.8. 'H NMR (400 MHz, DMSO-i/<5): δ 9.10 (s, IH), 8.98 (s, I H), 6.60 (d, IH), 5.25 (q, IH), 5 ,09 (q, IH), 4,55 (s, IH), 3 ,93 (q, IH), 3,77 (q, IH), 1.66 (s, 3H), 1.39 (s, 3H).

Step 5. Synthesis of S-(((3aS,4S,6R,6aR)-6-(3 odo~lH~pyrazolo[3,4~d]pyri^

dimethyltetrahydrofuro[3,4-d]| T,3]dioxol-4-yl)methyl) ethanethioate (2e)

[0339] To a solution of PPh 3 ( 1 .516 g, 5.78 mmol) in dry THF (20 mL) was added DIAD (0.9 g, 4.4 rnmol) at 0 °C and stirred for 20 min. ((3aR,4R,6R,6aR)-6-(3-iodo-lH- pyrazolo[3,4-dj pyrimidin-l-yl)-2,2-dimethyltetrahydrofuro[3,4-d][l,3]dioxol -4-yl)methanol (2d) (L i g, 2.63 mmol) was added and stirred for 30mm at 0 °C. Ethanethioic acid (0.22 g, 2.89 mmol) was added and stirred for 2hrs at 0 °C . LCMS showed the reaction was completed. The solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to afford crude S-(((3aS,4S,6R,6aR)-6-(3-iodo-lH-pyrazolo[3,4- d]pyrimidin-l-yl)-2,2-dimethyltetrahydrofuro[3,4-d] [l,3]dioxol-4-yl)methyl) ethanethioate (2e) (2.2 g) as yellow solid. LCMS ( M · Π } m/z calculated 477.0, found 477.0. ! H NMR (400 MHz, DMSO /6): δ 9.15 (s, 1H), 8.87 (s, 1H), 6.45 (s, 1H), 5.43 (d, 1H), 4.96 (d, 1H), 4.21 (t, i l l). 3.19 (q, U i).. 2.99 (q. 1H), 2.30 (s, 3H), 1.51 (s, .·■! !). 1.33 (s, 3H).

Step 6. Synthesis of l-((3aR,4R,6S,6aS)-2,2-dime1hyl-6-((methyltliio)me1hyl)telTa liy(kofuro[3,4- d][l,3]dioxol-4-yl)-3-iodo-lH-pyrazolo[3,4-d]pyrimidine (2f)

[0340] To a solution of S-(((3aS,4S,6R,6aR)-6-(3-iodo-lH-pyrazolo[3,4-d]pyrimidin-l- yl)-2,2-dimethyltetrahydrofuro[3,4-d][l,3]dioxol-4-yl)methyl ) ethanethioate (2e) (500 mg, 1.05 mmol) in CH3OH (15 mL) was added MeONa (139 mg, 2.6 mmol) at 0 °C. After the mixture was stirred for 0.5 h, Mel (372 mg, 2.6 mmol) was added, then the mixture was warmed up to 20 °C and stirred for 2 hrs. TLC (PE:EA=3: 1) showed 2e was consumed completed and a new desired product spot was detected. The reaction was adjusted to pH = 7-8 by aqueous HQ ( IN) solution, and the solution was concentrated in vacuo. ' The residue was diluted with EA (50 mL), and the solution was washed with H2O, NaCl sat. solution. The organic layer was dried over Na2S04 and concentrated in vacuo. The residue was purified by silica gel column

chromatography (PE:EA=5: 1 to 3: 1, v:v) to afford l-((3aR,4R,6S,6aS)-2,2-dimethyl-6- ((methylthio)methyl)teti^ydrof u'o[3,4-d][l ,3]dioxol-4-yl)-3-iodo-lH-pyrazolo[3,4- d]pyrimidme (2f) (300 mg , 63,8% yield) as yellow solid. LCMS (M+H+) m/z calculated 449.0, found 449.0. ! H NMR (400 MHz, CDCI3): δ 9.09(s, I I I ). 8.94 (s, 1 H), 6.69 (s, 1 H), 5.45 (d, 1 1 1). 5.04 (dd, 1H), 4.43 (m, 1 H), 2.77-2.61 (m, 2 H), 2,07 (s, 3 ! !),. 1.62 (s, 3 H), 1.41 (s, 3 H).

Step 7. Synthesis of l-((3aR,4R,0S,6aS)-2,2-dimetiiyl-6-((methyitiiiQ)m

d][l,3]dioxol-4-yl)-3-((trimethylsilyl)ethynyl)-lH-pyrazo lo[3,4-d]pyrimidine (2g)

[03411 To a solution of 1 ~((3aR,4R,6S,6aS)-2,2-dim.ethyl-6- ((methylthio)methyl)tetrahydrofuro [3 ,4-d] [ 1 ,3] dioxol-4-yl)-3 -lodo- 1 H-pyrazolo [3,4- djpyrimidine (2f) (300 mg, 0.67 mmol) and Ethynyltrimetliylsilane (331 mg, 3.34 rnmol) in DMF (10 mL) was added Pd(PPh.3)2.Ci2 (47mg, 0.067 mmol), Cul (25.6 mg, 0.134 mmol), Et 3 N (203 mg, 2.01 mmol) at 20 °C. Then the mixture was stirred at 20 °C overnight under N2 atmosphere. The reaction was monitored by LCMS, and desired product was detected. TLC (PE:EA=10: 1) showed 21 " was consumed completed and a new desired product spot was detected. The reaction was concentrated in vacuo directly and purified by silica gel column

chromatography (PE; EA=20: 1 to 10: 1 , v:v) to afford l-((3aR,4R,6S,6aS)-2,2-dimethyl-6- ((methylthio)meihyl)teirahydrofuro[3,4-d] j 1 ,3]dioxol-4-yl)-3-((trimethylsilyl)ethynyl)-lH- pyrazolo[3,4-d]pyrimidine (2g) (247 mg , 88.5% yield) as yellow solid. LCMS (M+H + ) m/z calculated 419.1, found 419.1. Π N .M R (400 MHz, CDCb): δ 9.22 (s, 1H), 9.09 (s, 1 I I). 6.71 (s, 1 H), 5,48 (d, 1 H), 5.04 (dd, 1H), 4,43 (q, 1 H), 2.79-2,59 (tn, 2 H), 2,06 (s, 3 H), 1 .61 (s, 3 H), 1 ,40 (s, 3 H), 0.34 (s, 9 H).

Step 8. Synthesis of l-((3aR,4R,6S,6aS)-2,2-dimemyl-6-((meihylto

d][l,3]dioxol-4-yl)-3-ethynyl-lH-pyrazolo[3,4-d]pyrimidin e (2h)

[0342] To a solution of l-((3aR,4R,6S,6aS)-2,2-dimethyl-6- ((methylthio)methyl)tetr^ydrofuro[3,4-d][l ,3]dioxol-4-yl)-3-((trimethylsi

pyrazoloj 3,4-d]pyrirnidine (2g) (247 mg, 0.59 mmol) in THF ( 10 mL) was added TBAF solution (1M m THF, 2.9 mL, 2.9 mmol). Then the mixture was stirred at 20 °C for 0.5 h. LCMS detected the desired product and TLC (PE:EA=3: 1) showed 2g was consumed completed and a new desired product spot was detected. The reaction was concentrated in vacuo directly and purified by silica gel column chromatography (PE: EA=20: 1 to 10: 1, v:v) to afford l-((3aR,4R,6S,6aS)- 2,2~dimemyi-6~((methylthio)methyi)tetrahydroforo 3,4~d][ l,3]dw

pyrazolo[3,4-d]pyrimidine (2h) (200 mg , 88.5% yield) as yellow oil. LCMS (M+H + ) m/z calculated 347.1, found 347.1 .

Step 9. Synthesis of (2R,3R,4S,5S)-2-(3-ethynyl-lH-pyrazolo[3,4-d]pyrimidin-l -yl)-5- ((rnethylthio)methyl)tetrahydrofuran-3,4-diol (2)

[0343 . 1 To a solution of H(3aR,4R,6S,6aS)-2,2-dimethyl-6- ((methylthio)methyl)tetrahydroforo

d]pyrimidine (2h) (200 mg, 0.59 mmol) in H2O (5 mL) was added TFA (2.0 mL), then the mixture was stirred at 20 °C overnight. LCMS detected the desired product as the major product and the reaction was adjusted to PH = 7-8 and purified by prep-HPLC (NH4HCO3 condition) to afford (2R,3R,4S,5 S)-2-(3 -ethynyl- IH-pyrazoio [3 ,4-djpyrimidin- 1 -yl)-5 -

((methylthio)methyl)tetrahydrofuran-3,4-diol (Ex, 2) (56.8 mg, 32% yield) as white solid. LCMS (Μ+Ι-Γ) m/z calculated 307. 1. found 307.1 , Ή NMR (400 MHz, ί IX i < ): δ 9.23 is. I I I). 9.09 (s, 1 H), 6.56 (s, 1 H), 4.83 (q, 1 H), 4.70 (q, 1H), 4.25 (q, 1 H), 3.47(s, 1 H), 2.86-2.79 (m, 2 H), 2.15 (s, 3 H).

Example 4. (2R,3R,4S,5S)-2-(4-aniino-3-etliynyl-lH-pyrazolo[3,4-d]pyrim idin-l-yl)-5- ((methylthio)methyl)tetrahydrofuran-3,4-diol (4)

4a 4ta 4c Ex. 4

Step 1. Synthesis of l-((3aR,4R,6S,6aS)-2,2 -dimet yl-6 -

((methylthio)methyl)tetraliydrofuro [3 ,4-d] [ , 3] dioxol-4-yl)-3 -((triisopropylsilyl)ethynyl) - 1 H- pyrazolo[3,4-d]pyrimidin-4-amine (4b)

10344] To a solution of l-((3aR,4R,6S,6aS)-2,2-dimethyl-6- ((methylthio)methyl)tetrahydrofuro [3,4-d] [l,3]dioxol-4-yl)-3-iodo-lH-pyrazolo[3,4- d]pyrimidin-4-amine (4a) (420.0 mg , 0.90 mmol, 1.0 eq) in DMF (5.0 mL) was added ethynyltriisopropylsilane (494.0 mg, 2.7 mmol, 3.0 eq), Pdi PPh .:t h (63.0 mg, 0.09 mmol, 0.1 eq), triethylamine (364.0 mg, 3.6 mmol, 4.0 eq) and cuprous iodide (17.1 mg, 0.09 mmol, 0.1 eq). The reaction mixture was stirred at 25 °C for 2 h under N?. The reaction mixture was diluted with EA (100.0 mL) and washed with H2O (25.0 mL X 2), dried over Na2S04, filtered and concentrated in vacuum, to give crude product which was purified by silica gel column chromatography, eluted with PE ; EA from 3 : 1 to 1 : 1 to give I ~((3aR,4R,6S,6aS)-2,2 - dimethyl-6 -((methyllMo)meth}d)tetrahydrofurof3,4-d][l,3]dioxol-4-yl)-3 - ((triisopropylsilyl)ethynyl)-lH-pyrazolo[3,4-d]pyrimidin-4-a rnine (4b) (240.0 mg, 0.46 mmol, 64.0% yield) as a colorless oil. LCMS [M+H]: 518.2.

Step 2. Synthesis of l~((3aR,4R,6S,6aS)-2,2-dimethyl-6-((metliylthio)m.ethyl) tetrahydrofuro f3,4-d] f l,3]dioxol-4-yl)-3-ethynyl-l H-pyrazolof3,4-d]pyrirnidin-4-amine (4c) [0345] To a solution of l-((3aR,4R,6S,6aS)-2,2 -dimethy]-6-((methylthio)methy]) tetrahydrofuro [3,4-d] [l,3]dioxol-4-yl)-3-((triisopropyls l)ethynyl)-lH-pyrazolo[3,4- d]pyrimidin-4-aniine (4b) (120.0 mg, 0.23, 1.0 eq) in THE (10 mL) was added TBAF (0.69 niL, 1 M, 3.0 eq). The mixture was stirred at 25 °C for 30 min. The mixture was diluted with H2O (20 mL), extracted with EA (3x 50 mL) and washed with H2O (2x 20 mL), dried over Na2S()4, filtered and concentrated in vacuum to give crude product winch was purified by silica gel column chromatography, eluted with Pe : EA from. 4 : 1 to 1 : 1 to afford l -((3aR,4R,6S,6aS)~2,2~ dimethyl-6-((methylthio)methyl) tetrahydrofuro [3,4-d] [l,3]dioxol-4-yl)-3-ethynyl-lH- pyrazolo[3,4-d|pyrimidin-4-arnine (4c) (30.0 mg, 0.08 mmol, 38.3% yield) as a white solid. LCMS [M+H] : 362.1.

Step 3. Synthesis of (2R,3R,4S,5S)-2-(4-aniino-3-ethyByl-lH-pyrazolo[3,4-d]pyrimi

((methylthio)methyl)tetrahydrofuran-3 ,4-diol (4)

[0346] To a solution of l-((3aR,4R,6S,6aS)-2,2-dimemyl-6-((memylthio)methyl) tetraliydrofuroj 3,4-d] [1,3] dioxol-4-yi)-3-ethynyl-lH-pyrazolo[3,4-d]pyrimidin-4-aniine (4c) (30.0 mg, 0.08 mmol, 1.0 eq) in Water (1.5 mL) was added TFA (1.5 mL). The mixture was stirred at 25 °C for 4.5 h. The mixture was concentrated in vacuum to give cmde, which was purified by pre-HPLC, eluted with MeCN in water (0.1 % ΝΗ3Ή2Ο) from 10.0% to 95.0% to afford (2R,3 R,4S,5 S)-2-(4-amino-3-ethynyl- lH-pyrazolo [3,4-d]pyrimidin- 1 -yl)-5- ((methylthio)methyi)tetrahydrofuraii-3,4-diol (Ex, 4) (9.1 mg, 0.03 mmol, 34% yield) as a white solid. LCMS [M+H]: 322.1. T NMR (400 M Hz, DMSC e): δ 8.26 (s, U i).. 6 ! I (d, J= 3.6 Hz, 1H), 5.41 -5.43 (m, 2H), 4.71 (s, 1H), 4.58-4.60 (m, IH), 4, 19-4.22 (m, 1H), 4.02-4.03 (m, 1H), 2.74-2.80 (m, 1H), 2.61-2.66 (m, 1H), 2.02 (s, 3H).

Example 14. (25,35,4i?,5 ?)-2-((methylmio)methyl)-5-(3-vinyl-lH-pyrazolo[3,4-ii]py yl)tetrahydrofuran-3,4-diol (14)

2f 1 a Ex. 14 Step 1. Synthesis of l -((3aR,4R,6S,6aS)~2,2~dimethyl-6~((methyl^^

dj [ 1,3] dioxol-4-yl)-3-vinyl-lH-pyrazolo[3,4-d]pyrimidine (14a)

[03471 To a solution of l-((3aR,4R,6S,6aS)-2,2-dimethyl-6-

((niethylthio)!nethyi)tetrahydrofuro [3 ,4-d] [ 1,3] dioxol-4-yl)-3 -iodo- 1 H-py razolo [3 ,4- d]pyrimidine (2f) (50,0 mg, 0.1 1 mmol) in 1 ,4-dioxane (5 ,0 mL) and water (0.2 mL) was added 4,4,5,5-tetramethyl-2-vinyl-l,3,2-dioxaborolane (25.7 mg, 0.17 mmol), NazCOs and Pd(dppf)Ch. (36.0 mg, 0.04 mmol). The reaction mixture was stirred at 100 °C for 18 h. The mixture was poured into water (20.0 mL) and extracted with EA (3x 50 mL), the combined organic layers were washed with brine, dried over anhydrous Na2S04, concentrated in vacuum to give 1 - ((3aR,4R,6S,6aS)-2,2-dime l-6-((me lmio)memyl)tetrahydrofuro[3,4-d] [1,3] dioxol-4-yl)- 3-vinyl-lH-pyrazolo[3,4-d]pyrimidine (14a) (30,0 mg, crude) which was used for the next step directly. LCMS [M+H] :349.1 ,

Step 2. Synthesis of (2 i S 3 i S',4i?,5i?)-2-((m.ethyithio)methyl 5-(3~vinyi- lH-pyrazolo[3,4- i/]pyrimidin- l-yl)tetrahydrofuran-3,4-diol (14)

|0348| A mixture of 1 -((3aR,4R,6S,6aS)-2,2-dimethyl-6- ((methylmio)methyl)tetrahydrofuro[3,4-d] [l,3]dioxol-4-yl)-3-vinyl-lH-pyrazolo[3,4- djpyrimidme (14a) (30.0 mg, crude), water (5.0 mL) and TFA (0.5 mL) was stirred at 25 °C for 1 .5 h. The mixture was purified by prep-HPLC, eluted with CHsCN in I K) (0.1% \ H > 1 1 :0) from 10.0% to 95.0% to afford Ex. 14 (10.0 mg, 0.033 mmol) as a white solid. LCMS [M+H] : 309.1. R NMR (400 MHz, DMSG-<:/ 6 ) o 9.68 i s. 1 H), 9.09 (s, 1 H), 6.99-7.06 (m, 1 l i s. 6.40 (d, ./ = 18.4 Hz, 1 H), 6.27 (d . J = 4.4 Hz, 1 H), 5.76 (d, J = 1 1.6 Hz, 1 H), 5.52 (d, J= 5 ,6 Hz, 1 H), 5 ,33 (d, J = 5.6 Hz, 1 H), 4.68-4.72 (m, 1 H), 4.25-4.29 (m, 1 H), 4.05-4.09 (m, 1 H), 2,77-2,82 (m, 1 H),2.64-2.69 (m, 1 H), 2.00 (s, 3 H).

Example 15. (2i?,3i?,46 1 ,5^y2-(4-amino-3-vmyl-lH-pyrazolo[3,4- ]pyrimidin-l-yl)-5-

((methylthio)methyl)tetraliydrofuran-3,4-diol (15)

Step 1. Synthesis of I -((3aR,4R,6S,6aS)-2,2-dimethyl-6-((methylthio)m

d I [ 1,3 J dioxol-4-yl)-3 -vinyl - lH-pyrazolo [3 ,4-d jpy rirnidin-4-amine (15a)

[03491 To a solution of l-((3aR,4R,6S,6aS)-2,2-dimet yl-6- ((methyl1hio)methyl)tetraliydrofuro[3,4-d] [l,3]dioxol-4-yl)-3-iodo-lH-pyrazolo[3,4- d]pyrimidin-4-amine (4a) (300.0 mg, 0.65 mmol) in 1 ,4-dioxane (5.0 mL) and water (0.2 niL) was added 4,4,5,5-tetramethyl-2-vinyl- 1,3,2-dioxaborolane (49.9 mg, 1.94 mmol), NaiCCb (137.0 mg, 1.29 mmol) and Pd(dppf)Ch (52.8 mg, 0.064 mmol). The reaction mixture was stirred at 100 °C for 4 h under N2. The mixture was poured into water (20 mL) and extracted with EA (3x 50 mL), the combined organic layers were washed with brine, dried over anhydrous Na2S04, concentrated in vacuum to give l-((3aR,4R,6S,6aS)-2,2-dimethyl-6- ((methyl1hio)methyl)tetraliydrofuro[3,4-d][l,3]dioxol-4-yl)- 3-viiiyl -lH-pyrazolo[3,4- d]pyrimidin-4-amine (15a) (200. mg, crude) which was used for the next step directly. LCMS | \i H i. 64.2.

Step 2. Synthesis of (2i?,3 ?,45,5S)-2-(4-amino-3-vinyl-lH-pyrazolo[3,4^pyrimidi^

((methylthio)methy4)tetraliydrofuran-3,4~diol (15)

10350] To a solution of l-((3aR,4R,6S,6aS)-2,2-dimethyl-6- ((methylthio)methyl)tetrahydrofuro[3,4-d] [l,3]dioxol-4-yl)-3-vinyl-lH-pyrazolo[3,4- d]pyrimidin-4-aniine (15a) (200.0 mg, erode) in water (10.0 mL) was added T ' FA (1.0 mL). The reaction mixture was stirred at 25 °C for 1.5 h. The reaction mixture was purified by prep-HPLC, eluted with CH3CN m H2O (0.1% NH3.H2O) from 10.0% to 95.0% to give Ex. 15 (7.1 mg, 4.0% yield) as a white solid. LCMS [M+H] :324.1. 1 1 NMR (400 MHz, DMSQ-J&+D2Q) δ 8,20 (s, 1 H), 7.22-7.30 (m, 1 H), 6.14 (d, J= 4.0 Hz, 1 H), 6.07 (d, J = 17.6 Hz, 1 H), 5.49 (d, J= 10.8 Hz, 1 H), 4.62-4.64 (m, 1 H), 4.28-4.30 (m, 1 H), 4.02-4.06 (m, 1 H), 2.77-2.82(m, 1 H), 2.65- 2.70 (m, 1 H), 2.01 (s, 3 H).

Example 25. {2R.2RAS, 5,S)-2-(3 -amino- lH-py razoio [3 ,4-a pyrimidin- 1 -y l)-5 - ((methylthio)methyl)tetrahydrofuran~3,4-diol (25)

Step 1. Synthesis of l -((3aR,4R,6S,6aS)~2,2~dimethyl -6- ((methylthio)rnethyl)tetrahydrofuro|3,4-d][ l,3 dioxol-4-yl)-N- pyrazolo [3 ,4~d ipyrimidm-3 -amine (25a)

[0351] To a solution of l-((3aR,4R,6S,6aS)-2,2-dimethyl-6- ((methylthio)methyl)tetrahydrofuro [3 ,4-d] [1,3] dioxol-4-yl)-3 -iodo- 1 H-py razolo [3 ,4- d]pyrimidine (50,0 mg, O i l mmol) in 1,4-dioxane (2,0 mL) was added diphenylmethanimine (21) (24.2 mg, 0.13 mmol), Xantphos (7.75 mg, 0,013 mmol), CszCO? (101.8 mg, 0.31 mmol) and Pd(OAc)j. (2.5 mg, 0.011 mmol). The reaction mixture was stirred at 100 °C for 18 h under N2. The mixture was poured into water (10.0 mL) and extracted with DCM (50.0 mL X 3). The mixture was concentrated in vacuum to give l-((3aR,4R,6S,6aS)-2,2-dimetliyl -6- ((methylmio)methyl)tetrahydrofur

pyrazolo[3,4-d]pyrimidin-3-amine (25a) (45.0 mg, crude) which was used for the next step directly. LCMS [M+H]:502.2.

Step 2. Synthesis of (2i?,3iR,45,55)-2-(3-animo-lH-pyrazolo[3,4^pyrimidin-l-yl)-5 - ((methylthio)metliyl)tetrahydrofuran-3,4-diol (25)

[0352] A mixture of 1 -((3aR,4R,6S,6aS)-2,2-dimethy!-6- ((methylthio)methyl)tetrahydrofuro[3,4-d][ l,3] dioxol-4-yl)-N-(diphenylmethylene)-lH- pyrazolo[3,4~d|pyrimidm-3~amine (25a) (45.0 mg, crude) in water (10.0 mL) and TFA (1.0 mL) was stirred at 25 °C for 1 ,5 h. The mixture was purified by prep-HPLC, eluted with CH3CN in H2O (0.1% ΝΗ3.Η2θ) from 10.0% to 95.0% to give Ex. 25 (10.0 mg, 0,033 mmol) as an off- white solid. LCMS [M+H] : 298.1. I I N MR (400 MHz, DMSO- e) 6 9.12 (s, 1 l i s. 8.84 (s, 1 H), 6,34 (s, 2 H), 6.07 (d, J= 4.0 Hz, 1 H), 5.37 (d, J= 5,6 Hz, 1 H), 5.20 (d, J= 5 ,6 Hz, 1 H), 4.52- 4,56(m, 1 H), 4.15-4.18 (m, 1 H), 3 ,55-3,99 (m, 1 H), 2,72-2,76 (m, 1 H),2,50-2,64 (m, 1 H), 2,02 (s, 3 H). Example 56. (2/?,3i?,45',5<S)-2-(4-amino-5-vinyl-7H-pyrrolo[2,3-d]pyr imidin-7-yl)-5-

((methylthio)metliyI)tetrahydrofuraii-3,4-diol (56)

56s 58f 58g Ex, Sfs

Step 1. Synthesis of 5-bromo-4-chloro-7H-pyrrolo[2,3-<^pyrimidine (56b)

| 353J A solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (56a) (50 g, 0.32 mol) in DMF (300 mL) was charged with N-bromosuccinimide (64.0 g, 0.35 mol) and stirred at RT for 15 h. The reaction mixture was quenched with ice-cold water (1 L), filtered, rinsed with ice-cold water (200 mL), and dried on high vacuum. The crude compound was redissolved in 20% MeOH in DCM (2 L), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 56b as light brown solid (73 g, 0.31 mol, 95% yield), ¾ NMR (400 MHz, DMSO-d6): 5 12,97 (s, 1H), 8,62 (s, I I I). 7,95 (s, 11 1). LCMS Purity: 98,7%; I .R.MS (ESI) m/z calcd for | \i I I . 231.93/233.93. Found: 231.92/233.92.

Step 2. Synthesis of (2i 3/?,4A 5i?)-2-((benzoyloxy)me1liyl)-5-(5-bromo-4-chloro-7H- pyrro3o 2,3~rf]pyiimidin-7~yl)tetraliydrofuran~3,4~diyl dibenzoate (56d)

(0354] A solution of 56b (20 g, 86 mmoi) in dry ACN (300 mL) under nitrogen was charged with N 0-Bis(trimethvlsilyl)acetamide (19.3 g, 95 mmoi) then stirred at RT for 30 min. The mixture was then charged with 1 -0-acetyl-2,3,5-tri-0-benzoyl-P-d-ribofuxanose (56c) (48.1 g, 78 mmoi) and TMSOTf (21 g, 78 mmoi) and stirred at RT for 30 min. The mixture was then heated and stirred at 80 °C for 5 h. The reaction mixture was cooled to RT, diluted with EtOAc (1 L) washed with sat. sodium, bicarbonate (1 L), brine (1 L), dried over Na2S04, and filtered. The filtrate was concentrated under reduced pressure and purified by FCC (SiCh, 15% EtOAc in hexanes) to afford 56d (31.4 g, 40.1 mmol, 51% yield) as a white solid foam. LCMS purity: 86.5%; LRMS (ESI) m/z calcd for [M+Hf: 676.05/678,05. Found: 676.05/678.05.

Step 3. Synthesis of (2i?,3i?,4S,51?)-2-(4-ammo-5-brom

(hydroxyn ethyl)tetrahydrofuran-3,4-diol (56e)

10355] A solution of 56d (20. g, 29 mmol) in methanol and THF (2: 1 , 180 mL) at 0 °C in a pressure tube was purged with ammonia gas for 30 minutes. After sealing the tube, the mixture was heated at 120 °C for 5 h. The mixture was cooled to RT, concentrated under reduced pressure, and purified by FCC (SiCh, 5→15% MeOH in DCM) to afford 56e (6.81 g, 19 mmol, 67% yield) as a light brown solid, ¾ NMR (400 MHz, DMSO~d6): δ 8.09 (s, IH), 7.65 (s, 1H), 7.00-6.60 (br, 2Π). 6.05 (d, J ------- 6.16 Hz, 1H), 5.33 (d,■/ 6.36 Hz, I I I ). 5.16-5.1 l(m, 2H), 4.33

(m, 1H), 4.06 (m, 1H), 3.88 (m, 1H), 3.62 (m, IH), 3.53 (m, 1H). LCMS purity: 97.6%; LRMS (ESI) m/z calcd for [M+Hf: 345.02/347.02. Found: 345.02/347.02.

Step 4. Synthesis of (2i?,3i?,4S,5.S)-2-(4-ammo-5-brom

(chl orom ethy l)tetrahy drofuran -3 ,4-diol (56f)

[0356] A solution of 56e (3 ,51 g, 10 mmol) in LIMP A ( 15 mL) under nitrogen atmosphere at 0 °C was charged with thionyi chloride (7.3 g, 61 mmol, 4.5 mL) dropwise over 10 min, then stirred at RT for 18 h. The reaction mixture was cooled to 0 °C, carefuliy quenched with water (15 mL), and treated with 1 M NaOH until an alkaline pH was obtained. The aqueous mixture was extracted with EtOAc (3x 250 mL). The organic fractions were combined and washed with ice cold water (500 mL), brine (500 mL), dried over Na2S()4, and filtered. The filtrate was concentrated under reduced pressure and purified by FCC (SiCh, 5→10% MeOH in DCM) to afford 56f (1.0 g, 2.4 mmol, 24% yield) as white solid. LCMS purity: 88%; LRMS (ESI) m/z calcd for [M+H]H: 362.99/364.98. Found: 363.06/365.05.

Step 5. Synthesis of (2i?,3/?,45 ' ,5<S)-2-(4-amino-5-bromo-7H-pyrrolof2,3-i/]pyrimidi n-7-yl)-5-

((methylthio)methyi)tetrahydrofuraii-3,4-diol (56g)

[0357] A solution of 56f (800. mg, 2.2 mmol) in DMF (15 mL) was charged with sodium thiomethoxide (462 mg, 6.6 mmol) and stirred vigorously at 80 °C for 12 h. The reaction mixture was cooled to RT and concentrated under reduced pressure. The crude material was diluted with sat. ammonium acetate (30 mL) and extracted with EtOAc (2x 150 niL). The organic fractions were combined, dried over Na2S04, filtered, and concentrated under reduced pressure. The crade mixture was purified by prep-HPLC to afford 56g (95 mg, 0.24 mmol, 1 1% yield) as white solid. ¾ NMR (400 MHz, DMSO-d6); δ 8.1 1 (s, 1 H), 7.64 (s, 1 H), 6.79 (bs, 21 1 ). 6.08 (d, J= 5.60 Hz, i l l). 5.37 (d, J ----- 5.60 Hz, 1H), 5.24 (d,■/ 4.4 Hz, 1H), 4.44 (m, 1H), 4.03 (m, 1H), 3.97 (m, IH), 2.83 (m, 1H), 2.72 (m, 1H), 2.07 (s, 3H). LCMS purity: 96.4%; LRMS (ESI) ni/x calcd for [M+H] + : 375.01/377.01. Found: 374,99/376.98.

Step 6. Synthesis of (2i?,3 ?,4S,55)-2-(4~amino~5-vinyl-7H-pyrro3o[2,3-d]pynmidin-7- ((methylthio)methyl)tetrahydrofuran-3,4-diol (56)

[0358] A solution of 56g (312 mg, 0.832 mmol) in DMF (10 mL) under nitrogen was charged with trihutyl(vinyl)tin (795 mg, 2.5 mmol) and sparged with nitrogen for 10 min. The reaction mixture was charged with Pd(PPh3 }4 (46 mg, 0.04 mmol) and then microwaved at 1 10 °C for 5 h. The reaction mixture was cooled to RT, filtered through a Ceiite plug, and rinsed with DMF (10 mi). The filtrate was concentrated under reduced pressure and purified by FCC (SiC , 10→15% MeOH in DCM) to afford impure Ex. 56 (210 mg) which was further purified by prep- HPLC to obtain Ex. 56 (75 mg, 0.22 mmol, 26% yield) as a white solid, ¾ N .M R (400 MHz, DMSO-d6): 5 8 , 10 (s, IH), 7.65 (s, H), 7.15-7.08 (m, IH), 6.72 (bs, 2H), 6.10 (d, J= 5.96 Hz, i l l). 5.62 (d, ./ 16.28 Hz, IH), 5.37 (d,■/ 6.28 Hz, IH), 5.25 id. ./ 5.08 Hz, IH), 5.14 (d, ./ 1 1 Hz, IH), 4.47 (m, IH), 4.05 (m, IH), 3.96 (m, IH), 2.85 (in. IH), 2.74 (m, IH), 2.07 (s, 3H). LCMS punt}- : 94,2%; LRMS (ESI) m/z calcd for [M+Hf: 323.12. Found: 323.09.

Example 65. (2R,3 S,4R,5R)~2- [(R)-(3 ,4 -difluorophenyl)-hydroxy-methyl] -5 -(5 - ethynylpyrrolo[2,3~d]pyrimidin-7~yl)tetrahydrofuran-3,4-diol (65)

Step 1. Synthesis of (2i^3/^4A 5i?)-2-((benzoyloxy)Tneft^

yl)tetrahydfofiiran~3,4-diyl dibenzoate (65a)

|0359j A solution of ((2 i,3ii,4i?,5i?)-2-((benzoyloxy)methyl)-5-(4-chloro-7H- pyrrolo[23-</jpyrimidin-7-yl)tetrahydrofijran-3,4-diy3 dibenzoate (30.0 g, 50.2 mmol) in MeOH (500 mL), was charged with 10% palladium on carbon (50% wet, 8.0 g) and stirred at RT for 16 h under hydrogen (hydrogen balloon). The reaction mixture was filtered through a Celite plug and the Celite plug was washed with MeOH and THF (1: 1, 2x 300 mL). The filtrate was concentrated under reduced pressure and the resulting crude material was purified by FCC (SiCte, 50% EtOAc in hexanes) to afford 65a (12.0 g, 20.5 mmol, 41 % yield) as white solid. LCMS punty: 96.4%; LRMS (ESI) m/z caicd for i .M ! ! | 564.18. Found: 564.35.

Step 2. Synthesis of (2R,3R,4R,5R)-2-((benzoyloxy)methyi)-5-(5-bromo-7H-pyrrolo[2 ,3- d]pynmidin-7-yl)tetraliydrofuran-3,4-diyl dibenzoate (65b)

[0360] To a solution of 65a (12.0 g, 21.3 mmol) in DMF (200 mL) under nitrogen atmosphere at 0 °C, was added NBS (3.8 g, 21 ,3 mmol). The reaction mixture was stirred at RT for 1 h. Tire reaction mixture was cooled to 0 °C, basified with aqueous sat. NaHCC solution (500 mL) and extracted with EtOAc (2x 300 mL). The combined organic fractions were combined, washed with water (2x 500 mL), brine (500 mL), dried over Na2S04, and filtered. The filtrate was concentrated under reduced pressure and purified by FCC (SiOi, 30% EtOAc in hexanes) to afford 65b as a white solid (6.6 g, 9.4 rnrriol, 44% yield). LCMS purity: 91.7%; LRMS (ESI) m/z calcd for j . l i | . 642.09/644.08. Found: 642.36/644.36.

Step 3. Synthesis of (2R,3R,4S,5R)-2-(5-bromo-7H-pyirolo[2,3-djpyrimidin-7-yl)-5- (hydroxymethyl)tetrahydrofuran~3,4-diol (65c)

[0361] To a solution of 65b (7.0 g, 1 1 mmo! ) in MeOH and THF ( 1 : 1, 100 mL) under nitrogen atmosphere, was added K2CO3 (3.7 g, 27 mmol). The reaction mixture was stirred at RT for 30 min. The reaction mixture was filtered through a Celite plug and rinsed with MeOH and THF (1 : 1, 2x 100 mL). The filtrate was concentrated under reduced pressure and purified by FCC (S1O2, 16% MeOH in DCM) to afford 65c as off-white solid (3.32 g, 9.74 mmol, 89% yield). l H NMR (DMSO-de, 400 MFIz): δ 8.96 (s, 1H), 8.91 (s, i l l). 8.14 (s, i l l ). 6.23 (d. J 6.08 Hz, 1H), 5.43 (d. ./ 5.96 Hz, 1H), 5.21 (d, J = 4.24 Hz, 1H), 5.08 (t, J = 5.20 Hz, 1H), 4.43 (m, I I I ) . 4.1 1 (m, 1H), 3.93 (m, 1H), 3.64 (m, 1H), 3 ,56 (m, 1H); LCMS purity 96.9%; LRMS (ESI) m z calcd for | i ! | · 330.01 /332.01. Found: 329,95/331.93.

Step 4. Synthesis of [(3aR,4R,6R,6aR)-4-(5-bromopyn lo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl- 3a,4,6,6a-tetrahydrofuro[ 3,4-d] [ 1 ,3]dioxol-6-yl]methanol (65d)

[0362] A mixture of (2R,3R,4S,5R)-2-(5-bromopyrrolo[2,3-d]pyrimidin-7-yl)-5-

(hydroxymethyl)tetrahydrofuran-3,4-diol (65c) (2,00g, 6.06 mmol), 4-methylbenzenesulfonic acidJiydrate ( 1 152.39mg, 6.06 mmol), and 2,2-Dimethoxypropane (2.23mL, 18.17 mmol) in DMF (15 mL) was stirred at RT overnight. TLC (4: 1 DCM/MeOH) showed 20-30% starting material and other by products. Another 0.25 mL of Dimethoxypropane was added. The reaction mixture was taken into EtOAc, which was washed with water, sat. aq. NaHCCb, brine, dried over Na2S04, and filtered. The filtrates were concentrated and the residue was purified on a 24 g column, eluted with 0-100% EA/hexane to give [(3aR,4R,6R,6aR)-4-(5-bromopyrrolo[2,3- d|pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4- d] [ l,^ (65d) (1.60 g, 4.32 mmol, 71.3% yield) as a white solid. LCMS showed the right mass peaks. Step 5. Synthesis of (3a ,4R,6S,6aS)-4-(5-bromopyrrolo[2,3-d]pyrjmidin-7-yl)-N-methox y- N,2,2-trimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d] [ 1,3 jdioxole-6-carboxamide (65e)

[0363| A mixture of [(3aR,4R,6R,6aR)-4-(5-bromopyrrolof2,3-d]pyrimidin-7-yl)-2,2 - dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d] [l ,3]dioxol-6-yl]methanol (65d) (1.60 g, 4.32 mmol), TEMPO (339.8 mg, 2.16 mmol), and (Diacetoxyiodo)benzene (3.48 g, 10.8 mmol) in MeCN (10 mL) and Water (10 mL) was stirred at RT overnight, and cooled with ice. A few crystals of sodium thiosuifate pentahydrate were added. The aqueous layer was separated and extracted with EtOAc twice. The combined organic layers were dried over Na2S0 4 , filtered and concentrated to give (3aR,4R,6S,6aS)-4-(5-bromopyTTolo[2,3-d]pyrimidin-7-yl)-2,2- dimethy]-3a,4,6,6a- tetrahydrofuro[3,4-d][l,3]dioxole-6-carboxylic acid a light yellow solid.

[0364] N-emyl-N-isopropyl-propan-2 -amine (1.5 lmL, 8.64 mmol) was added to a suspension of the crude acid, N-methoxymethanan ine;hydrochloride (632.35mg, 6.48 mmol). Propylphosphonic Acid Anhydride (5.5rnL, 8.64 mmol) in Ethyl acetate (20 mL) at 0 °C. The reaction mixture became clear and was stirred at RT. A few minutes later, the precipitate was formed again. TLC showed the completion of the reaction. The reaction mixture was poured on ice, which was extracted by EtOAc 2X. The combined organic layers was washed with water, sat. aq. NaHCC , brine, dried, and filtered. The filtrates were concentrated and the residue was purified on a 24 g column, which was eluted with 0-70% EA/hexane to give (3aR,4R,6S,6aS)-4- (5~bromopyrrolo[2,3-d]pyrimidin~7-yl)~N~inethoxy~N,2,2-trime thyi^

tetrahydrofuro[3,4-d] [ l ,3]dioxole-6-carboxamide (65e) (1.39 g, 3.25 mmol, 75.2% yield)

Step 6. (R)-((3aR,4R,6R,6aR)-6-(5-bromo-7H-pyrrolo[2,3-d]

dimethyltetrahydrofiiro[3,4-d]jT,3]dioxo (65f)

[0365] (3,4-Difluorophenyl)magnesium(l ) bromide (9.75mL, 4.87 mmol) was added a solution of (3aR,4R,6S,6aS)-4-(5-bromop} 7 rrolo[2,3-d]pyrimi(iin-7-yl)-N-methoxy-N,2,2- trimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][l,3]dioxole-6-carb oxainide (65e) (1.39 g, 3.25 mmol) in THF (20 mL) at -78 °C. The resulting mixture was stirred at RT for 1 hr. TLC showed one clean product peak (3: 1 hexane/EA). The reaction mixture was poured onto ice-cold sat. aq. NH4C1, the aq. layer was back extracted with EtOAc 2X. The combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated to give the crude ketone as a foamy solid. [0366] A mixture of the crude ketone, sodium formate (5.2mL, 12,99 mmol), and Ethyl acetate (10 niL) was purged with N 2 for 1 hr. RuCl(p-cymeneO{R,R)-Ts-DPEN] (20.7mg, 0.030 mmol) was added and the resulting mixture was purged with N2 for another 5 min, stirred under N2 over night. TLC showed a little hit remaining starting ketone. Two more polar spots about 3 : 1 ratio, minor was more polar. Major was closely eluted with unreaeted ketone on TLC

[0367] The aqueous layer was separated, back extracted with EtOAc 2X. The combined organic layers were washed with brine, dried over Na2S04, filtered, concentrated and the residue was purified on a 40 g column which was eluted with 0-50% EA/hexane to give (R)- [(3aR,4R6R,6aR)-4-(5-bromop}'rrolo[2,3-d]pyrimidm-7-}d)-2,2- dimethyl-3a,4,6,6a- tetrahydiOfuro[3,4~di [L3 |dioxoi-6"yl]-(3,4-difluorophenyl)methaiioi (65f) (774 mg, 1.6049 mmol, 49.4% yield) as a light yellow solid and (S)-[(3aR,4R,6R,6aR)-4-(5-bromopyrrolo[2,3- dlpyrimidin-7-yl)-2,2-dimemyl-3a,4,6,6a-tetrahydrofuro[3,4-d ] |T,3]di

difluorophenyl)methanol (450 mg, 0.9331 mmol, 28.7% yield) as a brown solid

[0368] HNMR for 65f : ! H NMR (DMSO-d.6, 400 MHz): δ 8.91 (s, IH), 8.86 (s, I I I ) . 8,29 (m, I H), 7.1 1 (m, 2H), 6.66 (d, .1 = 2 Hz), 5.70 (d, .1 = 8 Hz), 5.13 (m, IH), 4.98 (s, IH), 4.90 (m, IH), 4.45 (m, IH), 1.47 (s, 3H), 1.29 (s, 3H).

Step 7. Synthesis of (R)-[(3aR 5 4R,6R 5 6aR)-2,2-dimet yl-4-[5-(2- trimethylsilylethynyl)pyrrolo[2,3-d]p} 7 rimidin-7-yl]-3a,4,6,6a-tetrah

6-yl]-(3,4-difiuorophenyl)methanol (65g)

[0369] A 10 mL microwave vial with septum containing 65 f (R)-[(3aR,4R,6R,6aR)~4~ (5-bromopyn-o]o[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a -tetrahydrofiiro[3,4-d]

6-yl]-(3,4-difluorophenyl)methanol (65f) (370. mg, 0.767 mmol), cuprous iodide ( 15.6 mg, 0.080 mmol), Pd(PPli3)4 (45 mg, 0.040 mmol), and triethylamine (0.7 mL, 5 mmol) under Ar was charged with DMF (3 mL) and sparged with Ar for 2 min. The mixture was charged with ethynyl(trimethyl)silane (0.32 mL, 2.3 rnmol) dropwise over 1 min while still sparging, and then stirred at 80 °C for 5 h. The mixture was concentrated under reduced pressure and heat (50 °C), and purified by flash chromatography ( 0g column, 0→3% MeOH in DCM, wet-loaded in DCM). The desired fractions were combined and concentrated under reduced pressure to yield 65g (339 mg, 0.61 1 mmol, 80% yield) as a light brown glass. ! H NMR (400 MHz, DMSO- e) δ 8.94 (s, IH), 8.28 (s, IH), 7.67 - 7.55 (m, IH), 7.37 - 7.19 (m, 2H), 7.08 - 7.00 (m, IH), 6.35 (d, ./ = 3.1 Hz, IH), 6.16 (d, J = 4 ,8 Hz, IH), 5 ,24 (dd, «/ = 6.3, 3.1 Hz, IH), 5.05 (dd, J = 6,3, 2,7 Hz, 1 H), 4.69 (d, J= 5.2 Hz, IH), 4.23 (dd, J= 5.6, 2.8 Hz, IH), 1 ,49 (s, 3H), 1.28 (s, 3H), 0.27 (s, 9H); I . RMS (ESI) m/z calcd for | M ! ! | C2.JH2SF2N3O4S1: 500.18. Found: 500.1.

Step 8. Synthesis of (R)-|X3aR,4R,6R,6aR)-4-(5-ediynylpyrrolo| 2,3-dlpyrirnidin-7-yl)-2,2- di!nethyl-3a,4,6,6a-tetrahydrofiiro[3,4-d] [l ,3]dioxol-6-yl]-(3,4-di^ (65h).

[0370] A 100 mL RBF containing 65g (339 mg, 0.610 mmol) under Ar was charged with Methanol ( 12 mL) followed by potassium carbonate (126 mg, 0.920 mmol). The mixture was sparged with Ar for 3 rnin and stirred at RT for 13 h. The reaction mixture was quenched by addition of Ammonium chloride (82 mg, 1.5 mmol). The mixture was concentrated under reduced pressure to remove a majority of the methanol, then purified by FCC (24g S1O2, 1→5% Me OH in DCM, wet-loaded in DCM with filtration). Fractions containing product were combined, concentrated, and repurified by FCC (24g S1O2, 20%—>5()% EtOAc in hexanes) to yield 65h (110 mg, 0.24 mmol, 40% yield) as a tan oil. LRMS (ESI) m/z calcd for [M+H] + C22H20F2N3O4: 428.14, Found: 428 , 1.

Step 9. Synthesis of (2R,3S,4R,5R)~2-[(R)-(3,4-difiuorophenyl)-hydroxy-methyl]-5- (5~ ethynylpyrrolo[2,3~d]pyrimidin-7~y3)tetrahydrofuran-3,4-diol (65)

[0371] A 100 mL RBF containing 65h ( 1 10. mg, 0.260 mmol) was charged with a RT mixture of 2,2,2-trifluoroacetic acid (5 mL, 65 mmol) and Water (5 mL). The vessel was purged with Ar and stirred at RT for 2 h. The reaction mixture was concentrated under reduced pressure and purified by FCC (C 18, 20g, 0→50% MeCN in H2O, 0.1% TFA, wet-loaded in DM SO) Fractions containing desired product were combined, concentrated, and neutralized with Amberlite IRA-67 in MeOH. The filtrate was concentrated under reduced pressure and purified by FCC (S1O2, 24 g, 1→5% MeOH in DCM, wet-loaded in DCM with minimal MeOH) , Fractions containing pure product were concentrated under reduced pressure with heat (50 °C) to yield Ex. 65 (82.5 mg, 0.21 1 mmol, 82% yield) as a white foam.

[0372] Rf = 0.5 (10% MeOH m DCM): H NMR (400 MHz, DMSO-ifc + D20) 6 9.04 (s, IH), 8.89 (s, I I I). 8.20 (s, 1H), 7.43 - 7.31 (m, 2H), 7,2,3 { . J 5 -1 Hz, H), 6.17 (d, J= 7.4 Hz, I H), 4.80 (d, J= 5.0 Hz, IH), 4.53 (dd, J= 7.4, 5.0 Hz, IH), 4.31 (s, I H), 4.10 (dd, J= 5.0, 1.7 Hz, IH), 4.01 (dd, ./ 5.0, 1.7 Hz, I H): LRMS (ESI) m/z calcd for [M+Hf C19H16F2N3O4: 388.1 1. Found: 388.1. Example 66. (R)-((3aR,4R,6R,6aR)-6-(5-bromo-7H-pyrrolo[2,3-d]pyrimidin-7 -y])-2,2- dimethyltettahydrofuro[3,4-d][ l,3]dioxo (66)

Step 1. Synthesis of (3aR,4R,6S,6aS)-4-(5-bromo-4-me1hyl-pyrrolo[2,3-d]p} 7 rimidin-7-yl)-N- methoxy-N,2,2-trimethyl-3a,4,6,6a-tetrahydro (66a)

[0373] Intermediate 66a was prepared following the similar procedures of 6Se except for substituting 65d with ((3aR,4R,6R,6aR)-6-(5-bromo-4-methyl-7H-pyrrolo[2,3-d]pyrimi din-7- yl)-2,2-dimethyltetrahydrofuro[3,4-d][ l,3]dioxol-4-yl)methanol in step 5 of synthesis of Example 65.

Step 2. Synthesis of j 3aR_4R,6S,6aS)-4-(5-bromo-4-methyl-pyrrolo[2,3-d]pyrimidin-7 -yl)-2,2- dimethyl-3a,4,6,6a-tetraliydrofuro[3,4-d][l,3]dioxol-6-yl]-( 3,4-difluorophenyl)methaiione (66b)

[0374] (3,4-Difluorophenyl)magnesium(l ) bromide (6.46mL, 3.23 mmol) ΓΜ in 2- Me-THF was added to a solution of (3aR,4R,6S,6aS)-4-(5-bromo-4-methyl-pyrrolo[2,3- dlpyrimidin-7-yl)-N-methoxy-N,2,2-trimethy

carboxamide (66a) (0.95g, 2.15 mmol) in dry THF (10 mL) at -60 °C. The resulting mixture was warmed up at RT and stirred for 1 hr. TLC showed the completion of the reaction (3: 1 hexane/EA). The reaction mixture was poured onto ice-cold sat. aq. NH4C1. The aq. layer was extracted with EtOAc and the combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated to give crude [(3aR,4R,6S,6aS)-4-(5-bromo-4-methyl- pyiTolo [2,3 -d]pyrimidin-7-yl)-^ ^

(3,4-difluorophenyl)methanone (66b) ( 100 rag, 2.23 mmol, 100% yield) as a light yellow solid. LCMS showed the desired mass peaks: 494/496

Step 3. Synthesis of (R)-[(3aR,4R,6R,6aR)-4-(5-bromo-4Hnethyl-pymilo[2,3-d]pyrimi din-7-yl)^ 2,2-dimethyl-3a,4,6,6a-tetrahydrofiiro[3,4-d][l ^

(66c) and (S)-[(3aR,4R,6R,6aR)-4-(5-bromo-4-methyl-pyrrolo[2,3-dJpyrim idin-7-yl)-2,2- dimethyl-3a,4,6,6a-tetraliydrofuro[3,4-d][l,3]dioxol-6-yl]-( 3,4-difluorophenyl)methaiiol (66d)

[0375] A mixture of [(3aR,4R,6S,6aS)-4-(5-bromo-4-methyl-pyrrolo[2,3-d]pyrimidin - 7-yl)-2,2-dime1hyl-3a,4,6,6a-tetrahydrofuro[3,4-d][l ,3]dioxol-6-yl]-(3,4- difluorophenyl)methanone (66b) (l . lg, 2.23 mmol), sodium formate (3.56mL, 8.9 rnmol) and Ethyl acetate (10 mL) was purged with N2 for 1 hr. RuCl(p-cymeneO{R,R)-Ts-DPEN]

(14.16mg, 0.0200 mmol) was added, and the resulting mixture was purged with N2 for additional 10 min, stirred at RT over weekend, TLC (4: 1, hexane/EA) showed the reaction was completed. The aq. layer was separated and the organic layer was washed with brine, dried over N2S04, filtered and concentrated. The residue was purified on a 24 g column eluted with 0-30%

EA/hexane to give (R)-[(3a ,4R,6 ,6aR)-4-(5-bromo-4-methyl-pyxrolo[2,3-d]pyrimidin^ 2,2-dimethyl-3a,4,6,6a-tetrahydrofliro^

(66c) (645 mg, 1.3 mmol, 58%> yield) as an off-white foamy solid and(S)-[(3aR,4R,6R,6aR)-4- (5-bromo~4~m.ethyi~pyrrolo[2,3-d]pyriin ^

d][l,3]dioxol-6-yl]-(3,4-difluorophenyl)methanol (66d) (310 mg, 0.62 mmol, 28% yield) as a brown solid. LCMS showed correct mass peaks:496/498 for both isomers.

Step 4. Synthesis of j (R)-[(3aR,4R,6R,6aR)-4-(5-bromo-4-memyl-py roio[2,3-d]pyrimidin-7- yi)-2,2~dimemyl-3a,4,6,6a-tetrahydroforo[3,4~d][ l,3]dioxol-6-yl]-(3,4-diiluoroph

benzoate (66e)

[0376] Isopropyi (NE)-N-isopropoxycarbonylimmocarbamate (0.15mL, 0.7500 mmol) was added drop wise to a mixture of (S)-[(3aR,4R,6R,6aR)-4-(5-bromo-4-metiiyl-pyrrolo[2,3- d|pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4- d][ l,^

difluorophenyl)methanol (66d) (310.mg, 0.62 mmol), tnphenylphosphane (246 mg, 0.94 mmol),Benzoic acid (91 ,5 mg, 0.75 mmol) in THF (5 mL). The reaction mixture became warm , The solution was stirred over weekend, TLC showed completion of the reaction (3 : 1 hexane/EA). The reaction was concentrated and purified on a 20 g column which was eluted with 10-40% EA/hexane to give[(R)-[(3aR,4R,6R,6aR)-4-(5-bromo-4-methyl-pyrrolo[2,3- d]pyrimidin-7-yl)-2,2-dimethy]-3a,4,6,6a-t^

difluorophenyl)methyl] benzoate (66e) (350 mg, 0.58 mmol, 93% yield) as a white foamy solid. LCMS showed clean 600/602 peaks.

Step 5. Synthesis of (R)-((3aR,4R,6R,6aR)-6-(5-bromo-7H-pyrrolo[2,3-d]pyrimidin-7 -yl)-2,2- dimethyltetrahydroftiro[3,4-d][l ,3]dioxol-4-yl)(3,4-difluorophenyl)methanol (66)

[0377] A mixture of [(R)-[(3aR,4R,6R,6aR)-4-(5-bromo-4-methyl-pyrrolo[2,3- d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4- d][l,3]dioxol-6-yl]- difluorophenyl)methyl] benzoate (66e) (189.mg, 0.31 mmol), palladium;triphenylphosphane (18 mg, 0.020 mmol),cuprous:iodide (6.4 mg, 0.034 mmol), ethynyl(trimethyl)siiane (0.13 mL, 0.95 mmol), and N,N-diethylethanamine (0.29 mL, 2.06 mmol) in DMF (2 mL) was purged with N2, sealed and heated at 100 °C overnight. The reaction mixture was concentrated under vaccum and the residue was purified on a 20 g column which was eluted with 0-25% DMF to give -100 mg of product aThiss a brown solid.

11378] This product was dissolved in TFA (0.5mL, 0,3100 mmol), cooled to 0 °C. Water (0.0500 rnL) was added. The resulting mixture was stirred at RT for 30 rnin, concentrated and the residue was purified on a 20 g C18 column on 1SCO (0.1% TFA, 0-50% ACN in water) to give -50 mg of brown solid.

[03791 The brown solid was dissolved in Methanol (1 mi .).k.-C ()■ (43.44mg, 0.3100 mmol) was added and the reaction mixture was stirred at RT overnight. The reaction mixture was taken into EtOAc, which was washed with water, brine, dried, filtered and concentrated. The residue was purified on prep-TLC (95:5 DCM/MeOH) to give[(R)-[(3aR,4R,6R,6aR)-2,2- dimethyl-4-[4-me1hyl-5-(2-trimethylsilylemynyl)pyrrolo[2,3-d ]pyrimidin-7-yll-3a,4,6,6a- tetrahydiOfuro[3,4-di[L3 |dioxoi-6-y3]-(3,4-difiuoi phenyl)methyl| benzoate (Ex. 66) (26 mg, 0.063 mmol, 20% yield) as a light yellow solid, ! H NMR (CHsQF Li, 400 MHz): δ 8,68 (s, 1H), 7.96 (s, 1H), 7.39 (m, III), 7,26 (m, 2H), 6.22 (d, J = 6, 1H), 4.98 (m, 1H), 4.71 (m, 1H), 4,26 (m, 2H), 3.75 (s, 1H), 2.97 (s, 3H).

Example 111. (2R,3R,4S,5R)-2-(4-amino-3-emynyl-lH-pyrazolo[3,4-d]pyrimidi n-l-}4)-5-((S)-

(4-chlorophenyi)(hydroxy)methy3)tetrahydrofuraii-3,4-diol (111)

111a 111b

111d me Ex. 111

Step 1. (3aS,4S,6R,6a )-6-(4~amino~3 -((tnisopropyisi3yl)etliynyi)-lH-pyrazolo[3,4- d]pyrimidin-l-yl)-N-methoxy-N,2,2-trimeto^ ^

(111b)

[0380] To a solution of (3aS,4S,6R,6aR)-6-(4-amino-3-iodo-l H-pyrazolo[3,4- djpyrimidin- 1 -y 1)- - methoxy-N,2,24rimethyltetrahydrofuro [3 ,4-d] [ 1 , 3] dioxole-4-carboxamide (111a) (1.0 g , 2.04 mmol, 1.0 eq) in DMF (12.0 mL) was added ethynyltriisopropylsilane (1.49 g, 8.16 mmol, 4.0 eq), PdiPPhs Ch (143.0 mg, 0,2 mmol, 0.1 eq), triethylamme (1.03 g, 10.21 mmol, 5.0 eq) and cuprous iodide (78.0 mg, 0.41 mmol, 0.2 eq). The reaction mixture was stirred at 25 °C for 18 h under N 2 . The reaction mixture was diluted with EA (100.0 mL) and washed with H2O (25.0 mL X 2), dried over Na2S04, filtered and concentrated in vacuum to give crude product which was purified by silica gel column chromatography, eluted with PE : EA from 3 : 1 to 1 : 1 to give (3aS,4S,6R,6aR)-6-(4-amino-3 -((tiiisopropylsilyl)etliynyi)-lH-pyrazolo| 3,4- d]pyrimidin-l-yl)-N-methoxy-N,2,2-trimethyk^

(111b) (0.71 g, 1.30 mmol, 51 .5% yield) as a colorless oil. LCMS [M+ITj: 545.3.

Step 2. Synthesis of ((3aS,4S,6R,6aR)-6-(4-amino-3-((triisopropylsilyl) ethynyl)- 1H- py razolo 13 ,4-d]pyrimidin- 1 -y l)-2,2-dimethyltetrahydrofuro [3 ,4-d] [1,3] dioxol-4-yl)(4- chlorophenyDmethanone (111 c)

|038IJ To a solution of (3aS,4S,6R,6aR)-6-(4-amino-3-((triisopropyls l)ethynyl)-lH- pyrazolo[3,4-d]pyrimidin-l-yl)-N-methoxy-N,2,2-trimethyltetr ahydrofuro[3,^ carboxamide (111 b) (675.0 mg, 1.24 mmol, 1.0 eq) in THF (10.0 mL) was added (4- chloi phenyl)magnesium bromide (7.5 mL, 1 M, 6.0 eq) at 0 °C. The mixture was stirred at 0 °C for 1 h. The reaction mixture was added H 4 C1 aqueous (20.0 mL), extracted with EA (30.0 mL X 2), dried over Na2S04, filtered and concentrated in vacuum to give crude product which was purified by silica gel column chromatography, eluted with PE : EA from 7 : 1 to 5 : 1 to give ((3aS,4S,6R,6aR)-6-(4-amino-3-((triisopropylsilyl) ethynyl)- lH-pyrazolo[3,4-d]p} 7 rimidin-l-yl)- 2,2-dimethyltetrahydrofuro[3,4-d] [l,3]dioxol-4-yl)(4-chlorophenyl)methanone (111c) (0.51 g, 0,80 mmol, 69.0% yield) as a colorless oil. LCMS [M+H]: 596.3.

Step 3. Synthesis of (S)-((3aR,4R,6R,6aR)-6-(4-amino -3-((triisopropylsilyl)ethynyl)-lH- py razolo 13 ,4-d]pyrimidin- 1 -y l)-2,2-dimethyltetrahydrofuro [3 ,4-d] [1,3] dioxol-4-yl)(4- chlorophenyl)methanol (111 d)

[0382] To a solution of ((3aS,4S,6R,6aR)-6-(4-amino-3-((triisopropylsilyl)ethynyl)-l H- py razolo [3 ,4-d]pyrimidin- 1 -yl)-2,2-dimethyltetrahydrofuro [3 ,4-d] [ 1 ,3] dioxol-4-yl)(4- chlorophenyl)methanone (111c) (510.0 mg, 0.85 mmol, 1.0 eq) in CILOH (9.0 mL) was added Sodium borohydride (32.4 mg, 0.85 mmol, 1.0 eq). The mixture was stirred at 25 °C for 1 h. The reaction mixture was added H2O (10.0 mL) and concentrated in vacuum. The residue was extracted with EA (30.0 mL X 2), dried over Na2S04, filtered and concentrated in vacuum to give crude product which was purified by silica gel column chromatography, eluted with PE : EA === 5 : 1 to afford (S)-((3aR,4R,6R,6aR)-6-(4-amino -3-((triisopropylsilyl)ethynyl)-lH- py razolo [3 ,4-d]pyrimidin- 1 -yl)-2,2-dimethyltetrahydrofuro [3 ,4-d] [ 1 ,3] dioxol-4-yl)(4- chlorophenyl)methanol (llld) (0.51 g, 0.85 mmol, 99.0% yield) as a colorless oil. LCMS

[M+H]: 598.3.

Step 4. Synthesis of (S)-((3aR,4R,6R,6aR)-6-(4-amino-3-ethynyl-l H-pyrazolo[3,4-d] - pyrimidin-l-yl)-2,2-dimemyltetrahydro

(l l le)

[0383] To a solution of ί ;)-((. ' ·¾Κ .4 .6!¾ .onR )-«>-( i -am u

((triisopropylsilyl)ethynyl)- lH-pyrazolo[3,4-d]pyrimidin- 1 -yl)-2,2-dimethyltetrahydrofuro[3,4- d][l,3]dioxol-4-yl)(4-chlorophenyl)methanol (llld) (113.0 mg, 0.21 rnmol, 1.0 eq) in THF (3.0 mL) was added TBAF (0.37 mL, 1 M, 2.0 eq). The mixture was stirred at 25 °C for 20 min. The mixture was diluted with H2O (20.0 mL), extracted with EA (50.0 mL X 3) and washed with H2O (20.0 rtiL X 2), dried with Na2S04, filtered and concentrated in vacuum to give crude product which was purified by silica chromatography, eiuted witli DCM : CH3OH = 30 : 1 to afford (S)-((3aR,4R,6R,6aR)-6-(4-ainiiio-3-ethyiiyl-lH-pyrazolo[3,4 -d] -pyrimidin-l-yl)-2,2-

rnmol, 35.0% yield) as a white solid. LCMS [M+H] : 442.1.

Step 5. Synthesis of (2R,3R,4S,5R)-2- (4-amino-3-ethynyl-lH-pyrazolo[3,4-d]pyrimidin- l -yl)-

5-((S)-(4-chloropheny3)(hydi xy)methyl)tetrahydrofuraii-3,4-dioi (111)

[0384] To a solution of (S)-((3aR,4R,6R,6aR)-6-(4-amino-3-ethynyl- IH-pyrazolo j 3,4- d]pyrimidin- l-yl)-2,2-(nmethyltetrahydrofc

(30.0 mg, 0.07 rnmol) in Water (2.0 niL) was added TFA (0.50 ml, 6.73 rnmol). The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated in vacuum to give crude product which was purified by pre-HPLC, eiuted with MeCN in water (0.1% ΝΗ3Ή2Ο) from 10.0% to 80.0% to afford (2R,3R,4S,5R)-2- (4-amino-3-ethynyl-lH-pyrazolo[3,4-d]pyrimidin-l- yl)-5-((S)-(4-chlorophenyl)(hydroxy)methyl)tetraliydrofuran- 3,4-diol (Ex. Ill) ( 17.0 mg, 0.04 mmoi, 62.3% yield) as a white solid. LCMS j . R | : 402.1. ¾ NMR (400 M Hz, DMSO-afe ): δ 8.27 (s, 1H), 7.31-7.42 (m, 4H), 6.01-6.02 (d, J = 5.6 Hz, I I I ) . 5.70-5.71 (d, J = 6.4 Hz, 1H), 5 ,37-5.38 (d, J = 6.4 Hz, 1 H), 5.07-5.08 (d, J = 5 ,2 Hz, 1H), 4.73 (s, 1H), 4.69-4.71 (m, 1 H), 4.48-4.52 (in. I I I ). 4.14-4.16 (m, i l l). 4.04-4.06 (m, I I I ).

Example 112. (2R,3R,4S,5R)-2-(4-amino-3-ethynyl-l H-pyrazolo[3,4-d]pyrimidin-l -yl)-5-((R)-

(4-chlorophenyi)(hydiOxy)methyl)tetraiiydrofuran-3,4-diol (112)

Step 1. Synthesis of (R)-((3aR,4R,6R,6aR) -6-(4-amino-3-((triisopropylsilyl)ethynyl)-lH- py razolo [3 ,4-d]pyrimidin- 1 -yl)-2,2-dimethyltetrahydrofuro [3 ,4-d] [ 1 ,3] dioxol-4-yl)(4- chlorophenyl)methanol (112a) [0385] To a solution of ((3aS,4S,6R,6aR)-6-(4-amino-3-((triisopropy pyrazolo [3 ,4-d jpy rimidm- 1

chlorophenyl)methanone (600.0 mg, 1.00 mmoi, 1.0 eq) in THF (7.0 mL) was added lithium, aluminium hydride (38.0 mg, 1.00 mmoi, 1.0 eq). The mixture was stirred at 25 °C for 1 h. The reaction mixture was added NLLCl aq (20.0 mL). The mixture was filtered and the filtrate was extracted with EA (2x 30 mL), dried over Na2S04, filtered and concentrated in vacuum to give erode product which was purified by silica gel column chromatography, eluted with PE : EA from 6 : 1 to 3 : 1) to give (R)-((3aR,4R,6R,6aR) -6-(4-amino-3-((triisopropylsilyl)ethyny pyrazoki[3,4-d|pyrimidin-l-yl)-2,2-dimethyltetraliydrofuro[3 ,4-^

chlorophenyl)methanoi (112a) (0.19 g, 0.31 mmoi, 32% yield) as a colorless oil. LCMS [M+H]: 598.3.

Step 2. Synthesis of (R)-((3aR,4R6R,6aR)-6-(4-amino-3-eth>Tiyl-lH-pyrazo]o[3,4 -d]pyrimidin- 1 -yl)-2,2-dimethyltetrahydrofuro| 3,4-d] f 1 ,3 ]dioxol-4-yl)(4-chlorophenyl)methanol (112b)

[0386] To a solution of (R)-((3aR,4R,6R,6aR)-6-(4-amino-3-

((tnisopiOpylsiiyi)ethynyi)-lH-pyr^

d][l,3]dioxol-4-yl)(4-cli3oroplienyl)methanol (190.0 mg, 0.32 mmoi, 1.0 eq) in THF (3.0 mL) was added TBAF (0.64 mL, 1 M, 2.0 eq). The mixture was stirred at 25 °C for 20 min. The mixture was diluted with H2O (20.0 mL), then extracted with EA (50.0 mL X 3), separated the organic phases, washed with H2O (20.0 mL X 2), dried over Na2S04, filtered and concentrated in vacuum to give crude product which was purified by silica gel column chromatography, eluted with DCM : CH3OH = 30 : 1 to afford (R)-((3aR,4R,6R,6aR)-6-(4-amino-3-ethynyl-lH- py razolo j 3 ,4-d]pyrimidin- 1 -y l)-2,2-dimethyltetrahydrofuro [3 ,4-d] [1,3] dioxol-4-yl)(4- chlorophenyl)methanol (112b) (140.0 mg, 0.31 mmoi, 99.0% yield) as a white solid. LCMS [M+H]; 442,2.

Step 3. Synthesis of (2R,3R,4S,5R)-2~(4-aniino~3-etliynyi-lH-pyra^

((R)-(4-chlorophenyl)(hydroxy)methyi)tetrahydroiuran-3,4- diol (112)

[0387] To a solution of (R)-((3aR,4R,6R,6aR)-6-(4-ammo-3-ethynyl- lH-pyrazolo[3,4- d]pyrimidin-l-yl)-2,2-dimethyltetrahydrofuro[3,4-d] [T,3]dioxol-4-yl)(

(140.0 mg, 0.32mol, 1.0 eq) in Water (2.0 mL) was added TFA (1.0 mL) and THF (1.5 mL). The mixture was stirred at 25 °C for 16 h. The mixture was concentrated in vacuum to give crude product which was purified by pre-HPLC, eluted with MeCN in water (0.1% ΝΗ3Ή2Ο) from 10.0% to 80.0% to afford (2R,3R,4S,5R)-2-(4-ammo-3-e nyl-lH-pyrazolo^

yl)-5-((R)-(4-chlorophenyl)(hydroxy)methyl)tetrahydrofura n-3,4-diol (Ex. 112) (60.0 rag, 0.15 mmol, 46.7% yield) as a white solid, LCMS [M+H] : 402.1 , ¾ NMR (400 M Hz, DMSO-cfc ): δ 8.25 (s, i l l). 7.26-7.31 (m, 4! ! }. 6.02-6.04 (d,■/ 6.4 Hz, I I I ). 5.93-5.94 (d, J= 4.4 Hz, i l l). 5.37-5.39 (d, J = 6.8 Hz, 1H), 5.17-5.19 (d, J = 4.8 Hz, IH), 4.78-4.82 (m, 1H), 4.73 (s, 1H), 4,67-4.69 (m, lH),4.22-4.23 (m, IH), 3 ,97-3,99 (m, I H).

Example 113 and Example 114. (2 ?,3 ?,4>?>,5 ?)-2-(4-amiiio-3-vinyl-lH-pyrazolo[3,4- d]pyrimidm~ i~yl)~S~((i?)~(4-chlorophenyiX^ (113) and

(2A\3i?,45 5i?)-2-(4-ammo-3-v^

chlorophenyl)(hydroxy)methyl)tetrahydrofuran-3,4-diol (114)

25 °C

111a 113a 113b

Step 1. Synthesis of (3aS,4S,6R,6aR)-6 -(4-amino-3 -vinyl -lH-pyrazolo[3,4-d|pyrimidin-l-yi)- N-methoxy-A^2,2-trimethyitetrahydrofuro|3,4- ][ l,3]dioxole-4-carboxainide (113a)

| 388J To a solution of (3aS,4S,6R,6aR)-6-(4-amino-3-iodo-lH-pyrazolo[3,4- d]pyrimidin-l-yl)-N- methoxy-N,2,2-trimethyltetrahydrofuro[3,4-d][l,3]dioxole-4-c arboxam.ide (111a) (0.85 g , 1 .73 mmol, 1.0 eq) in 1 , 4-dioxane (10.0 mL) and H2O (1.0 mL) was added fl,l'-Bis(diphenylphosphino) -ferrocene]dichloropalladium(II) (142.0 mg, 0.17 mmol, 0.1 eq), 4,4,5, 5-tetramethyl-2- vinyl -1,3,2-dioxaborolane (0.53 g, 3.47 mmol, 2.0 eq) and sodium carbonate (368.0 mg, 3,47 mmol, 2.0 eq). The reaction mixture was stirred at 80 °C for 16 h under N2. The reaction mixture was concentrated in vacuum to give crude product which was purified by silica gel column chromatography, eluted with DCM : CH3OH = 30 : 1 to give (3aS,4S,6R,6aR)~6 -(4-amino-3-vinyl - lH-pyra∞lo [3 ,4-d]pyrimidin- 1 -yl)-N-methoxy-N,2,2- trimethyltetrahydrofiiro[3,4- ] [l,3]dioxole-4-carboxamide (113a) (0.25 g, 0.64 mmol, 37.0% yield) as a white solid. I . ( MS [Μ+Η]: 391.2.

Step 2. Synthesis of ((3aS,4S,6R,6aR)-6-(4-amino-3-vinyl-lH-pyrazolo[3,4-d] pyrimidin-I -yl)- 2,2 -dimethyltetrahydrofuro[3,4-d] [ 1 ,3]dioxol-4-yl)(4-chlorophenyl)methanone (113b)

[0389] To a solution of (3aS,4S,6R,6aR)-6-(4-amino-3-vinyl- lH-pyrazolo[3,4- d]pyrimidin-l-y -N-methoxy-N,2,2-tri^

(113a) (235.0 mg, 0.6 mmol, 1.0 eq) in THF (8.0 ml.) was added (4-chlorophenyl)magnesium bromide (3.0 mL, 1 M, 3.0 eq) at 0 °C. The mixture was stirred at 0 °C for 1 h. The reaction mixture was added NH4CI aqueous (20.0 mL), extracted with EA (30.0 mL X 2), dried over Na2SQ4, filtered and concentrated in vacuum to give crude product which was purified by silica gel column chromatography, eluted with DCM : CH3OH = 60 : 1 to give ((3aS,4S,6R,6aR)-6-(4~ amino-3-vinyl-lH-pyrazolo[3,4-d] pyrimidin-l-yl)-2,2 -dimethyltetrahydrofuro[3,4- d][l,3]dioxol-4-yl)(4-chlorophenyl)methanone (113b) (0.20 g, 0.45 mmol, 75.6% yield) as a colorless oil. LCMS [M+H]: 442.2

Step 3. Synthesis of (R)~((3aR,4R }R,6aR)-6-(4~ammo~3~viny

yl)-2,2-dimethyitetrahydroruro[3,4-d][l,3]dioxol-4-yl)(4- chloropheny (113c) and (S)-

((3aR,4R,6R,6aR)-6-(4-ammo-3-vimd-lH-pyrazolo[3,4-dlpyrim idin-l-yl)-2,2- dimethyitetrahydrofuro [3 ,4-d] [ 1 , 3] dioxol-4-yl)(4-chloropheny l)methanol (114a)

\ W] To a solution of ((3aS 5 4S.6R,6aR)-6-(4-amino-3-vinyl- 1 H-pyrazolo[3,4- d]pyrimidin~l~yl)-2,2-dimethyitetrahydroruro[3,4-d] [l,3]dioxol-4

(113b) (180.0 mg, 0.41 mmol, 1.0 eq) in THF (7.0 mL) was added lithium aluminium hydride (18.0 mg, 0.41 mmol, 1.0 eq). The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was added NH4CI aq (20.0 mL). The mixture was filtered and the filtrate was extracted with EA (30.0 mL X 2), dried over Na2S04, filtered and concentrated in vacuum to give erode product which was purified by pre-TLC (DCM : CH3OH = 30 : 1 ) to give 113c (60.0 mg) as a colorless oil and 114a (80.0 mg) as a colorless oil. LCMS [M+H]: 444.2.

Step 4a. Synthesis of (2i?,3i?,45',5i?)-2-(4-amino-3-vinyl-lH-pyrazolo[3,4-d]pyrim idin-l-yl)-5-

((i?)-(4~chloropheny3)(hydi xy)methyl)tetrahydrofuraii-3,4-dioi (113) [0391] To a solution of 113c (60.0 mg, 0.13 mmol) in Water (2.0 mL) was added TFA (1.0 mL). The mixture was stirred at 25 °C for 24 h. The mixture was concentrated in vacuum to give crude which was purified by pre-HPLC, eluted with MeCN in water (0.1% ΝΗ3Ή2Ο) from 10.0% to 80.0% to afford Ex. 113 (28.0 mg, 0,07 mmol, 53% yield) as a white solid. LCMS [M+H]: 404.1. TT NMR (400 MHz, DMSO- e ): δ 8.18 (s, i l l). 7.41-7.74 (b, 2Π). 7.25-7.40 (m, 5H), 6.04-6.09 (m, 2H), 5.98-6.02 (b, i l l). 5.46-5.50 (d. ./ 16.4 Hz, 1H), 5.32-5.38 (b, i l l). 5, 12-5.15 (b, IH), 4.82-4.85 (m, 1H), 4,73-4.74 (d, ./ 6 Hz, 1H), 4 ,24-4,23 (d, ,/ 5.6 Hz, 1H), 3,97-3.99 (m, IH).

Step 4b. Synthesis of (2i?,3 ?,45,5 ?)-2-(4-amino-3-viny]-lH-pyrazolo[3,4-£¾pyrimidin-l-y^ ((5)-(4-chlorophenyl)(hydroxy)methyl)tetrahydrofuran-3,4-dio l (114)

[0392J To a solution of 114a (60.0 mg, 0.13 mmol) in Water (2.0 mL) was added TFA (1.0 mL). The mixture was stirred at 25 °C for 24 h. The mixture was concentrated in vacuum to give crude product which was purified by pre-HPLC, eluted with MeCN in water (0.1%

ΝΗ3Ή2Ο) from 10.0% to 80.0% to afford Ex. 114 (38.0 mg, 0.09 mmol, 72% yield) as a white solid. LCMS | \Ι · Η |: 404.1. I I N .MR (4U0 MHz, DMSO-ifc+D 2 0): δ 8.22 (s, IH), 7.26-7.34 (m, 5H), 6.04-6.11 (m, 2H), 5,51-5.54 (m, IH), 4.74-4.75 (d, ./ 6 Hz, IH), 4.46-4.48 (t, IH), 4.22- 4,25 (t, IH), 4.08-4.10 (t, I I I).

Example 115. l-(7-((2i?,3i?,4i 5i?)-5-((/?)-(3,4-dif!uoropheny1)(hydroxy)methy

dihy(koxytetrahydro:fiuran-2-yl)-7

|0393] A 20 mL vial containing Ex. 65 (39.5 mg, 0.100 mmol) was charged with a RT mixture of 2,2,2-trifluoroacetic acid;TFA (0.9 mL, 12 mmol) and water (0.1 mL), and stirred at RT for 24 h. The reaction mixture was concentrated under reduced pressure to remove a majority of the TFA. The reaction was diluted with MeCN (15 mL) and treated with Amberlite 67-IRA basic resin until a neutral pH was obtained. The mixture was filtered through a cotton plug and rinsed with MeOH. The filtrate was concentrated under reduced pressure and purified by FCC (12g S1O2, 2→6% MeOH m DCM, wet-loaded in DCM + MeOH) to yield Ex. 115 (24 mg, 0.054 mmol, 91% purity, 53% yield) as a white solid. Ri = 0.44 (10% MeOH m DCM): ¾ NMR (400 MHz, DMSO-ife) δ 9.41 (s, 1H), 8.95 (s, 1H), 8,78 (s, 1H), 7,46-7,31 (m, 2H), 7.29 - 7,20 (m, I I I ). 6.22 (d. ./ 7.3 Hz, 1H), 6.17 (bs, 1H), 5.51 (bs, 1H), 5.29 (bs, 1H), 4.88 (d. -/ 5.4 Hz, 1H), 4.67 (dd, ./ 7.3, 5.0 Hz, 1H), 4.16 (d, J = 4.7 Hz, 1H), 4.06 (dd,■/ 5.4, 1.7 Hz, 1H), 2.56 (s, 3H); LRMS (ESI) mlz calcd for [M+H]+ Ci9Hi 8 F 2 3 05: 406.12. Found: 406.0,

Example 116. (2R,3S,4R,5R)-2-((R)-(3,4-difluorophenyl)(hydroxy)methyl)-5- (5-(l- hydroxyethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofkra ii-3,4-diol (116)

Step 1. Synthesis of [(R)-[(3aR,4R,6R,6aR)-4-(5-brornopyrrolo[2,3-d]pyririiidin-7 -yl)-2,2- dirnethyl-3a,4,6,6a-tetrahydrofiiro[3,4-d|[l ,3]dioxol-6-yl]-(3,4-difluoro^ benzoate i)

[0394] Intermediate 116a was prepared following the same procedure for making 66e except for substituting 66d with (S)-[(3aR,4R,6R,6aR)-4-(5-bromopyrrolo[2,3-d]pyrimidin-7- yl)-2,2-dimethyl~3a,4,6,6a-tetra

Step 2. Synthesis of [(R)-[(3aR,4R,6R,6aR)-4-(5-acety]pyrro]o[2,3-d]pynmidin-7-yl )-2,2- dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d] fl,3]dioxol-6-yl]-(3,4-difluorophenyl)methyl] benzoate (116b)

| 395J A mixture of [(R)-[(3aR,4R,6R,6aR)-4-(5-bromopyrrolo[2,3-d]pyrimidin-7-yl )-

2,2-dimethyl-3a,4,6,6a-tetraliydrofuro[3,4-d][l,3]dioxol- 6-yl]-(3,4-difluorophenyl)methyl] benzoate (116a) ( 170.mg, 0,29 mmol), dichloromethane;dichloropalladium;(r~

diphenylphosphanylferrocen-l-yl)-diphenyl-phosphane (1 1.84mg, 0.0100 mmol), and 1 -

Ethoxyvmyltri-n-butyltin (0.15mL, 0,4300 mmol) in dry 1,4-Dioxane (2 mL) was purged with

N2, sealed and heated at 90 °C overnight. LCMS showed product peak of 550. TLC: 1 : 1 EA/hexane product Rf -0.3. The reaction mixture was loaded direactly on a 20 g column, eluted with 0-50% EA/hexane to give [(R)-[(3aR,4R,6R,6aR)-4-(5-acetylpyrrolo[2,3^

2,2-dimemyl-3a,4,6,6a-tetrahydrofuro[3,4-d][l,3]d^

benzoate (116b) (78 mg, 0.141 mmol, 48.96% yield) as an off-whrte foamy solid.

Step 3. Synthesis of [(R)-[(3aR,4R,6R,6aR)-4-[5-(l-hydroxyethyl)pyrro]o[2,3-d]pyr imidin-7- yl]-2,2-dimethyl-3a,4,6,6a-tetrahydro

benzoate (116c)

[0396] NaBH4 (lO.mg, 0.2600 mmol) was added to a solution of[(R)- [(3aR,4R,6R,6aR)-4-(5-acetylpyrrolo[2,3-d]pyrimidin-7-yl)-2, 2-dimethyl-3a,4,6,6a- tetrahydrofuro[3,4-d][l ,3]dioxol-6-yl]-(3,4-difluorophenyl)methyl] benzoate (11.6b) (55.mg, 0.10 mmol) in Methanol (1 rnL) at RT. The resulting solution was stirred at RT for 1 hr. TLC showed completion of the reaction (1 : 1 EA/hexane, product Rf 0.1). The reaction was taken into EtOAc, which was washed with sat. aq NH Cl, brine, dried over Na2S04, filtered and concentrated. The residue was purified on a 4 g column, eluted by 50-100% EA/hexane to give [(R)-[(3aR,4R,6R,6aR)-4-[5-(l-hydrox} 7 ethyl)pyrrolo[2,3-d]pyrimidin-7-}'l]-2,2-dimethyl- 3a,4,6,6a-tetrahydrofuro[3,4-d][l,3]dioxol-6-yl]-(3,4-difluo rophenyl)methyl] benzoate (116c) (43 mg, 0,078 mmol, 78% yield) as a light yellow oil , LCMS | M I 1 ! : 552.

Step 4. Synthesis of (2R,3S,4R,5R)-2-((R)-(3,4-difluoroplienyl)(hydroxy)metliy

hydrox>'elhyl)-7H-pyrrolof2,3-d]pyrimidin-7-yl)tetrahy drofuran-3,4-diol (116)

[0397] A mixture of [(R)~[(3a.R,4R,6R,6aR)-4-[5~(l -hydroxyethyl)pyrrolo[2,3- dlpyrimidin-7-yl]-2,2-dimethyl-3a,4,6,6a-tetrahy(kofuro[3,4- d][ l,3]dioxol-6-yl]-(3,4^ difluorophenyl)methyl] benzoate (116c) (43.mg, 0.0800 mmol) in trifluoric acid (0.3mL, 0.0800 mmol) and Water (0,3000 mL) was stirred at RT for 2 hr. LCMS showed >80% of hydrolysis based on LTV trace. The reaction was concentrated, taken into MeOH at 0 C. NLLOH (cone.) was added drop wise until pH=8. The resulting mixture was concentrated under vacuum. The residue was dissolve in Methanol (1 mL), sodium methoxide (0.2mL, 0.20 mmol) was added. The reaction mixture was stirred at RT for 1 hr, LCMS showed complete hydrolysis of the Bz group (M+l 408). The reaction mixture was diluted with EtOAc, which was washed with sat. aq. NH4CI, brine, dried over Na2S04, filtered and concentrated. The residue was purified on a 4 g column, eluted with 0-14% MeOH in DCM to gvie (2R,3S,4R,5R)-2-[(R)-(3,4-difluoroplieny])- hydroxy-methyl] -5 - [5 -( 1 -hydroxyethyl)pyrrolo [2,3 -d]pyrimidin-7-yl]tetrahydrofuran-3,4-diol (Ex, 116) (13 mg, 0.030 mmol, 39% yield) as an off-white foamy solid. . ¾ NMR (DMSO-de, + D O. 400 MHz, mixture of diastereomers): δ 9.083 (s, 0.5H), 9.077 (s, 0.5H), 8.75 (s, IH), 7,552 (s, 0.5Η), 7.548 (s, 0.5H), 7.33 (m, 2Η), 7.21 (m, H), 6.13 (d, J = 4,8, IH), 5.02 (m, IH), 4,77 (m, IH), 4.52 (m, i l l ). 4.10 (m, IH), 4.01 (m, IH), 1.51 (d, J = 4.0, 1.5H), 1.50 (d, J = 4.0 Hz, 1.5H).

Example 117. l-(7-((2R,3R,4S,5R)-5-((R)-(3,4-difluoropheny

dihydroxytetrahydrofuran-2-yl)-4-methyl-7H^ (117)

[0398] A mixture of (R)-[(3aR,4R,6R,6aR)-4-(5-bromo-4-methyl-pyrrolo[2,3- d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4- d][l,3]dioxol-6-y

difluorophenyl)methanol (66c) ( lOO.mg, 0.20 mmol), 1-Ethoxyvinyltri-n-butyltin (O. lmL, 0.3000 mmol), and dichioromethaiieidichioropalladiimi^l'-diphenylphosphanyifer i cen-l-yl)- diphenyl-phosphane (8.2mg, 0.010 mmol) in dry 1 ,4-Dioxane (2 mL) was purged with N2, sealed and heated at 95 °C overnight. The reaction was concentrated and the residue was purified on a 12 g column, which was eiuted with 10-70% EA/hexane to give l-[7-[(3aR,4R,6R,6aR)-6-[(R)- (3 ,4 ~difIuoropheny3)~hydroxy~m.ethy

4-yl]-4-methyl-pyrrolo[2,3-d]pyrimidin-5-yl]ethanone (30 mg, 0.065 mmol, 32% yield) as an off-white foamy solid. TLC: 1 : 1 EA/hexane product Rf -0.3.

10399] l-[7-[(3aR,4R,6R,6aR)-6-[(R)-(3,4-dif ^

dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d] [l,3]dioxo

yljethanone (30 mg, 0,065 mmol) was dissolved in a mixed solvent: TFA (0.25mL, 3 mmol) and Water (0.25 mL) . The resulting mixture was stirred at RT for 2hr, cooled to 0 °C, cone. aq. NH4OH was added and pH was ~8. The resulting mixture was concentrated and inorganic salt was filter. The filtrates were concentrated and the residue was purified on a 4 g column, which was eiuted with 0-15% of DCM/MeOH to give l-[7-[(2R,3R,4S,5R)-5-[(R)-(3,4- difluoropheny l)-hydroxy-methyl] -3 ,4-dihydroxy-te trahydrofuran-2-yl] -4-methy 1-pyrroio [2,3 - d]pyrimidin-5-yl]ethanone (11 mg, 0.026 mmol, 13% yield) as an off-white solid. . 'H NMR (DMSO-de, 400 MHz, mixture of diastereomers): δ 8.76 (s, H), 7.40 (m, 2H), 7.25 (m, IH), 6.22 (m, 2H), 5.46 (d, J - 6.8 Hz, IH), 5.25 (d, J = 4.4 Hz, I H), 4.89 (m, IH), 4.67 (m, IH), 4.16 (m, IH), 4.05 (m, IH), 2.94 (s, 3H), 2.58 (s, 3H). Example 118. (2 ?,3i?,45,5i?)-2-(4-amino-5-vinyl-7H-pyrro]o[2,3-c ]pyrimidin-7-yl)-5-((R)-(4- chlorophenyl)(3iydroxy)methyl)tetraliydrofuran-3,4-diol (118)

Step 1. Synthesis of ( lR)-(4-chlorophenyl)((3aR,4R,6aR)-6-hydroxy-2,2- dinieihylieirahydiOfuro[3,4-d]| T,3]dioxol-4-yl)methyl benzoate (118b)

[0400] A 100 mL RBF with septum containing l ,2,3-trihydroxy-5-(benzoyloxy)(4- chloi phenyl)-ribose (118a) (1.68 g, 4.61 mmol) and 4-methylbenzenesulfonic acid;hydrate (49 mg, 0.26 mmol) was charged with Acetone (2 mL), purged with Ar, and heated at 40 °C for 5 h. The reaction mixture was charged with 4-methylbenzenesulfonic acid;hydrate (80. mg, 0.42 mmol), heated at 50 °C for 3 h, and then at RT for 12 h. The reaction was stirred with solid sodium bicarbonate for 5 min then filtered and rinsed with DCM (20 mL) and EtOAc (20 mL). The filtrate was concentrated under reduced pressure to form white solids and was purified by- FCC (80 g SiC , ()→35% EtOAc in hexanes, wet-loaded in DCM+hexanes) to yield 118a (1.31 g, 3.17 mmol, 69% yield) as a white solid (-3:2 ratio of anomers). R f 0.49 (1 :2 EtOAc: Hex).

Step 2. Synthesis of (R)-((3aR,4R,6R,6aR)-6-(4-cUoro-5-iodo-7H-pyrrolo[2,3-d]pyri midin-7- yl)-2,2-dimemyltetrahydrofnro[3,4-d][l,3]dioxol-4-yl)(4-chlo rophenyl)methyl benzoate (118c)

[0401] A 25 mL RBF with septum containing a solution of 118b (503 mg, 1.24 mmol), 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (347 mg, 1 .24 mmol), Tributylphosphine (0.4 mL, 1 ,6 mmol), and pyridine (0.1 mL, 1 ,24 mmol) in THF (5 mL) at 30 °C under Ar was charged with isopropyl (NE)-N-isopropoxycarbonyliminocarbamate (0.3 mL, 1.5 mmol) dropwise over 3 min. The solution was stirred at 30 °C for 1 h, then RT overnight. The reaction mixture was quenched with water (100 μΐ,), concentrated under reduced pressure, and purified by FCC (40 g SiCh, ()--→30% EtOAc in hexanes, wet-loaded in DCM). Mixed fractions were combined and repurified by FCC (12 g Gold Redisep SiO?., 0→30% EtOAc in hexanes, wet-loaded in DCM). Fractions containing pure desired product from both purifications were combined and concentrated under reduced pressure to yield 1.18c (277 mg, 0.395 mmol, 32% yield) as a white foam. Rf = 0.56 ( 1 :2 Et()Ac:hexanes); 1 H NMR (400 MHz, Oiloroform-ί δ 8.56 (s, 1H), 7.98 - 7.90 (m, 2H), 7.56 (tt, J = 1.3, 7.5 Hz, i l l). 7.43 - 7.35 (m, 2H), 7.34 - 7.28 (m, 2H), 7.27 - 7.23 (m, 3H), 6.27 (d, J= 4,8 FIz, 1H), 6, 18 (d, J= 2.5 Hz, I FI), 5.44 (dd, J= 2,5, 6,4 FIz, lH), 5.12 (dd,■/ 3.1, 6.4 Hz, 1FI), 4.69 (dd, J= 3.0, 4.8 Hz, I I I). 1.61 (s, 3H), 1.39 (s, 3H); LRMS (ESI) m/z calcd for [M+H] + : 666.01/668.00. Foimd:665.9/668.0.

Step 3. Synthesis of (R)-((3aR,4R,6R,6aR)-6-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyri midin-7- y3)-2,2-dimethyitetrahydrofuro[3,4-d][l,3]dioxol-4-yl)(4-chl oropheny (118d)

[0402] A 5 mL microwave vial containing a mixture of 118c (276 mg, 0. 10 mmol) in 1,4-dioxane (3 mL) was sparged with Ar for 5 min, charged with ammonium hydroxide ( 1.1 mL, 28 mmol), and heated in a microwave reactor at 120 °C for 3 h. The reaction mixture was charged with hydrazine solution, 1.0 M in THF (2 mL, 2 mmol) and heated in a microwave reactor at 120 °C for 8 h. The reaction mixture was diluted with EtOAc (60 mL), washed with sat. sodium bicarbonate (2 mL) + water (58 mL), water (60 mL), and brine (30 mL). The organic fraction was dried over Na2S04, filtered, concentrated under reduced pressure, and purified by- FCC (20 g SiOi, 0→6% MeOH in DCM, dry-loaded on Celite using DCM/EtOAc/MeOH) to yield 118d (195 mg, 0,356 mmol, 86% yield) as a white solid. Rf = 0.56 (6% MeOH in DCM);

1 NMR (400 MFIz, DMSO- fc) δ 8, 13 (s, 1H), 7.70 (s, 11 1). 7.38 - 7.31 (m, 2H), 7.30 - 7.23 (rn, 2H), 6.77 (s, 2H), 6.19 (d, ./ 4.3 Hz, 1H), 6.14 (d. ./ 3.6 Hz, 1H), 5.16 (dd, ./ 3.6, 6.4 Hz, i l l). 4.99 (dd, J = 2.5, 6.4 Hz, 1H), 4.72 (t, ./ 4.9 Hz, 1 1 1}. 4.16 (dd, ./ 2.5, 5.5 Hz, i l l). 1.47 (s, 3H), 1.25 (s, 3H). LRMS (ESI) m/z calcd for [M+Hf: . Found: 542.9/544.9,

Step 4. Synthesis of (R)-((3a-^,4i?,6i?,6ai?)-6-(4-amino-5-vmyl-7H-pyrrolo[2,3-^p yrimidin-7- yl)-2,2-dimethyltetrahydrofuro[3,4-d]| " l,3]dioxol-4-yl)(4-chlorophenyl)methanol (118e) [0403j A 20 mL vial with septum containing 118d (1 87 mg, 0.340 mmol), sodium carbonate (73 mg, 0.69 mmol), and dichloro l,r-bisdiphenylphosphino)ferrocene Palladium (II) dichloromethane (28 mg, 0.030 mmol) was evacuated and backfilled with Ni (2x). The flask was charged with 1 ,4-dioxane (900 uL) and Water (90 uL), purged with for 2 min, then charged with 4,4,5,5-tetramethyl-2-vinyl- l,3,2-dioxaborolane (1 15 uL, 0.680 mmol) and heated at 60 °C for 3 h. The reaction mixture was diluted with EtOAc (80 mL), washed with water (2x 80 mL), brine (40 mL), and dried over Na2S04. The mixture was filtered, and the filtrate purified by FCC (40 g S1O2, 0-→6% MeOH in DCM, wet-loaded in DCM) to yield 1 18e (86 mg, -90% punt}', 0.175 mmol, 57% yield) as a brown solid. ¾ NMR (400 MHz, Chloroform-rf) δ 8.28 (s, 1H), 7.47 - 7.36 (m, 4H), 7.17 (s, 1H), 6.83 (dd, ./ 10.8, 17.5 Hz, IH), 6.64 (s, i l l ). 6.40 i s. 1 H), 5.82 (d, J = 4.9 Hz, 1H), 5.58 (d, J= 17.3 Hz, 1H), 5 ,46 (d, J= 10.8 Hz, IH), 5.20 (t, J = 5.6 Hz, IH), 5.10 (s, IH), 4.94 - 4.87 (m, IH), 4.55 (s, IH), 3.71 (s, IH), 1.56 (s, 3H), 1.28 - 1.26 (m, 3H); LRMS (ESI) m/z calcd for [M+H] + : 443.15/445.15. Found: 443.1/445.0.

Step 5. Synthesis of (2i¾,3i?,4S,5i?)-2-(4-ammo

((R)-(4-chlorophenyl)(hydroxy)methyl)tetrahydrofuran-3,4- diol (118)

[0404] A 4 mL vial containing 118e ( 120. mg, 0.2700 mmol) under Ar was charged with a RT mixture of TFA (2.7mL, 35.05 mmol) and Water (0.3000 mL), and stirred at RT for 40 min. The reaction mixture was concentrated under reduced pressure and co-evaporated with water to remove a majority of the TFA. The residue was then purified by FCC (30 g C18,

5→35% MeCN in H2O, wet-loaded in DMSO) . Fractions containing pure desired product were concentrated under reduced pressure, dissolved in MeOH, neutralized with Amberlite 67-IRA resin, and filtered through a cotton plug. The filtrate was concentrated under reduced pressure and heat (50 °C) to yield Ex. 118 (46 mg, 0. 1 mmol, 41% yield) as an off-white solid. ! H NMR of 5- 1 (400 MHz, DMSO-ifc) δ 8.05 (s, IH), 7.61 (s, IH), 7.46 - 7.35 (m, 4H), 7. 13 (dd, J= 10,9, 17.2 Hz, IH), 6.81 (s, 2H), 6.49 (d, ,/ 3.8 Hz, IH), 5.97 (d. ./ 7.8 Hz, IH), 5.58 (dd, ,/ 1 .7, 17.2 Hz, IH), 5.26 (d, J = 7.0 Hz, IH), 5.15 (dd, ./ 1.8, 10.9 Hz, IH), 5.05 (d. ./ 3.8 Hz, IH), 4.82 (t, J = 4.1 Hz, IH), 4.57 (q, J = 6.2 Hz, IH), 4.04 - 3 ,98 (m, II I): LRMS (ESI) m/z calcd for | .\1 · Η Γ : 403.12/405 , 1 1 , Found: 403.1 /405.1 ,

Example 119. (2R,3R,4S,5R)-2-(4-amino-5-e1h^

(4-chlorophenyl)(hydroxy)methyl)tetrahydrofuran-3,4-diol (119)

Step 1. Synthesis of (2R,3R,4S,5R)-2-(4-amino-5-iodo-p}'rrolo[2,3-d]pyrimidin-7-} 'l)-5-[(R)-(4- chlorophen}4)-hydrox\'-methyl]tetrahydrofuran-3,4-diol (119b)

[0405] To a solution of [(R)-[(2S,3S,4R,5R)-5-(4-chloro-5-iodo-pyrrolo[2,3- d]pynniidin-7~yl)-3,4-di4iydroxy~tetrahydroft 4- phenylbenzoate (119a) (1.6 g, 2.05 mmol) in 1,4-dioxane (3 mL) was added ΝΗ3 Ή2Ο (2.91 mL, 74.77 mmol). The mixture was stirred at 120 °C in an autoclave for 16 hrs. After the reaction was complete, the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography on (PE: EtOAc 1 : 1 to EtOAc) to afford (2R,3R,4S,5R)-2-(4-amino- 5-iodo-pyrrolo[2,3-d]pyrimidin-7-yl)-5-[(R)-(4-cM

3,4-diol (119b) (800 mg, 1.25 mmol, 61.3% yield) as white solid. LCMS [M+HJ: 502.3.

Step 2. Synthesis of (2R,3R,4S,5R)-2-[4-amino-5-(2-triisopropylsilyl^

d]pyrimidin~7-y3]-5~[(R.)-(4~chlorophenyl)~liydroxy~methy l]tetraliy (119c)

[0406] To a solution of (2R,3R,4S,5R)-2-(4-aniino-5-iodo-pyrrolo[2,3-d]pyrimidin-7- yl)-5-[(R)-(4-ch]oro-phenyl)-hydroxy-memyl]tetrahydrofuran-3 ,4-diol (119b) (310,0 mg, 0.49 mmol) in DMF (2 mL) was added Cul (19mg, 0.1 mmol), (Triisopropylsilyl)acetylene (0.56 mL, 2.47 mmol), Et N (0.79 mL, 5.7 mmol) and Pd(PPh3) 4 (57 mg, 0.05 mmol). The mixture was degassed by N2 and stirred at 25 °Cfor 16 hrs. After the reaction was complete, it was diluted by EtOAc and water, the organic layer was washed with brine, dried over NaiSO/j and filtered. The filtrate was concentrated in vacuo. The residue was purified by prep-TLC (PE: EtOAc 2: 1 ) to afford (2R,3R,4S,5R)-2-[4-amino-5-(2-triisopropylsilylemynyl)pyrrol o[2,3-d]pyrimidin-7-yl]-5- [(R)-(4-chlorophenyl)-hydroxy-methyl]tetrahydrofuran-3,4-dio l (119c) (85 mg, 0.1 1 mmol, 22% yield) as colorless oil. LCMS [M+H] : 557.4.

Step 3. Synthesis of (2R,3R,4S,5R)-2-(4-amino-5-et ynyl-pyrrolof2,3-d]pyrimidin-7-yl)-5-f(R)-

(4-chlorophenyl)-hydroxy -methyl ]tetrahydrofuran-3,4-diol (119) [0407] To a solution of (2R,3R,4S,5R)-2-[4~amino~5~(2- triisopropylsilylethynyl)pyrroloj 2,3-d]pyrimidin-7-yi ]-5-| (R)-(4-chiorophenyl)-hydroxy- methyl]tetrahydrofuran-3,4-diol (80.0 mg, 0.12 mmol) in DMSO (2 mL) and methanol (0.05 mL) was added CsF (0.08 mL, 0.53 mmol). The mixture was stirred at 25 °C for 3 hrs. After the reaction was complete, the mixture was filtered. The filtrate was purified by prep-HPLC (0.1% NH3 H2O, elutmg with I ! ·():( ' ! I CS from 90: 10 to 5:95) to afford (2R,3R,4S,5R)-2-(4-amino-5- ethynyl-pyrrolo[2,3-d]pynmidin-7-yl)-5-[(R)-(4-cli3orophenyl )-hy

3,4-dio! (Ex, 119) (15.9 mg, 0,040 mmol, 32% yield) as white solid. Ή NMR (400 MHz,

DMSO-£¾) δ 8.13 (s, 1 H), 7.79 (s, 1 H), 7.36-7.47 (m, 4 H), 6.73 (bs, 2H), 6.35-6.36 (m, 1H), 5.95-5.97 (m, 1H), 5.27-5.28 (m, 1 H), 5.03-5.04 (m, 1 H), 4.80-4.82 (m, 1 H), 4,53-4,58 (m, 1 H), 4.30 is. I I I). 3.99-4.04 (m, 2 H). LCMS | M l l i : 401.1.

Example 120. (2R,3R,4S,5R)-2-(4-ainino-5-(2-hydroxyethy])-7H-pyrrolo[2,3- d]pyrimidin-7-yl)-

5-((R)-(4-chlorophenyl)(hydroxy)methyl)tetraliydrofuran-3 ,4-diol (120)

Step 1. Synthesis of tert-butyl-[2-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)etho xy]-dimethyl- silane (120a)

[0408] To a solution of 5-bromo-4-chloiO-7H-pyrroio[2,3-d]pyrimidine (6.1 g, 26.24 mmol) in THF (100 mL) was added n-BuLi (1.6M in THF, 66 mL, 105,60 mmol) slowly at - 76°C under N2. The reaction mixture was stirred at -76 °C for 1 h. Then 2-Bromoethoxy-tert- butyldimethylsilane (22.52 mL, 104.96 mmol) was added to the reaction mixture at -76 °C under N2. The mixture was stirred at 20 °C for 2 hrs. LCMS showed the reaction was complete. The mixture was diluted with NH4CI aqueous solution, extracted with EA, dried over Na2S04, concentrated. The residue was purified by reversed phase Chem-flash elating (neutral condition, H 2 O/ACN=80/20-5/95) to give tert-butyl-[2-(4-cMoro-7H-py^

dimethyl -silane (120a) (1.5 g, 4.81 mmol, 18.33% yield) as gray solid. LCMS [M+H]: 312.3. Step 2. Synthesis of [(R)-[(2S,3S,4R,5R)-5-[5-[2-[tert-b^^

pyrrolo[2,3-d]pyrimidm-7-yl]-3,4-dihydroxy-tetrah^ 4- phenylbenzoate (120b)

[0409] To a solution of (lR)-(4-chlorophenyl)((2S,3S,4R)-3,4,5- trihydroxytetrahydrofuran~2-yl)ro.ethyl [1, l'-biphenyl]-4-carboxylate (2.1g,4.80mmol) and tert- butyl-[2-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)ethoxy]-d imethy (120a) (1.5 g, 4.81 mmol in THF (25 mL) was added PBu3 (1.45 g,7.2mmol), pyridine (380 mg, 4.8 mmol) and D1AD (1.45 g, 7.2 mmol) under N2. The mixture was stirred at 20 °C for 2 hrs. LCMS showed the reaction was complete. The solvent was removed and the residue was purified by reversed phase Chem-flash elutmg with H2O/ACN = 30/70-5/95 to give [(R)-[(2S,3S,4R,5R)-5-[5-[2- jtert-butyl(dimemyl)silyl]oxyethy

tetrahydrofuran-2-yl]-(4-chlorophenyl)methyl] 4-phenylbenzoate (120b) (2.2 g, 2.99 mmol, 62 % yield) as gray solid, LCMS [M+H]: 734.2.

Step 3. Synthesis of [(R)-(4-ch1orophenyl)-[(2R,3R,4R,5R)-3,4-diacetoxy-5-[5-[2-[ tert- butyl(dimemyl)silyl]oxyethyl]-4-chloro^

yljmethyl j 4-phenylbenzoate (120c)

[0410] To a solution of [(R)-[(2S,3S,4R,5R)-5-[5-[2-[tert- butyl(diinethyl)silyi]oxyethy

tetrahydrofuran-2-yl]-(4-chlorophenyl)methyl] 4-phenylbenzoate (120b) (2.2 g, 2.99 mmol) in DCM ( 15 mL) was added DMAP (36.53 mg, 0.30 mmol) and Ac?.() (1.53 g, 14.97 mmol). The mixture was stirred at 20 °C for 1 h. TLC showed the reaction was complete. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography with PE:EA = 50: 1-20: 1 to give [(R)-(4-ch3orophenyl)-[(2R,3R,4R,5R)-3,4-diacetoxy-5-[5-[2-[ tert- butyl(dimemyl)silyijoxyethyl j-4-chloro^

yljjniethyl] 4-phenylbenzoate (120c) (2.2 g, 2.69 mmol, 89.73% yield) as colorless solid. LCMS [M+H]: 818.3. Step 4. Synthesis of [(R)-(4-chlorophenyl) (2R,3R,4R,5R)-3,4-diacetoxy-5-[4-chloro-5-(2- hydroxyethyl)pyrrolQ 2,3-d]pyiim 4-phenylbenzQate (120d)

[0411] To a solution of [(R)-(4-cMorophenyl)-[(2R,3R,4R,5R)-3,4-diacetDxy-5-[5-[2- [tert-bu (dime1hyl)sily]]oxye1hy]]-4-chloro-pyrro]o[2,3-d]pyrimidm

yljmethyl] 4-phenylbenzoate (120c) (2.2 g, 2.69 mmol) in THF (10 mL) was added TBAF (2.1 1 mL, 8.06 mmol). The mixture was stirred at 20 °C for 16 hrs. LCMS showed the reaction was complete. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography with PE:EA =10: 1-5: 1 to give [(R)-(4-chlorophenyl)-[(2R,3R,4R,5R)-3,4- diacetoxy-5-|4-chkiro-5-(2-hydroxyethyl)pyrrolo 2,3-d]pyrimidin-7

yl] methyl] 4-phenylbenzoate (120d) (1.5 g, 2.13 mmol, 79.24% yield) as gray solid. LCMS [M+H]: 704,3.

Step 5. Synthesis of (2R,3R,4S,5R)-2-[4~amino~5-(2-hydroxyethyl)pyrrolo[2,3-d]pyr imidi yi]-5-| (R)-(4-chlorophenyl) iydroxy-methyi]tetrahydrofuran-3,4-diol (12Θ)

[0412J To a solution of [(R)-(4-chlorophenyl)-[(2R 5 3R,4R,5R)-3 5 4-diacetoxy-5-[4- chloro-5-(2-hydroxyemyl)pyrrolo[2,3-d]pyrim^ 4- phenylbenzoate (120d) (100.0 mg, 0.14 mmol) in 1,4-dioxane (1 mL) was added NHsOH (2487.4 mg, 70.97 mmol). The reaction mixture was stirred at 100 °C for 16 hrs. LCMS showed the reaction was complete. The solvent was removed in vacuum .The residue was purified by prep-HPLC(H 2 O/ACN(0.1% M ! - ! ! ·()) 90/ 10- 20/80) to give (2R,3R,4S,5R)-2-[4-amino-5-(2- hydroxyethyl)pyrrolo[2,3-d]pyrimidin-7-yl]-5-[(R)-(4-chlorop henyl)-hydroxy- memyl]tetrahydrofuran-3,4-dio] (Ex, 120) 7.3 mg, 0.0392 mmol, 27.61% yield) as white solid. LCMS [M+H] : 421.1. : H NMR (400 MHz, DMSO- 6+D 2 0) δ 8.00 (s, i l l). 7.34 - 7.41 (m, 4 H), 7.03 (s, 1 H), 5.88 (d, J = 7.8 Hz, 1H ), 4.76 (d, J == 4.2 Hz, 1H), 4.49 - 4.52 (m, 1 H), 3.99 ·· 4.01 (m, 2 H), 3.64 (t, J= 6.2 Hz, 2 H), 2.86 (t, J= 6.2 Hz, 2 H).

Example 121. (2R,3R,4S,5R)~2-(4-amino-5-vinyl-7H 3yrrolo[2,3-d]pyrimidm

chloro-3-fiuorophenyl)(hydroxy)methyl)tetrahydroiuran-3,4 -diol (121)

Step 1. Synthesis of [( )-(4-chloro-3-fluoro-phenyl)-f(2S,3S,4R,5R)-5-(4-chloro-5-io do- pyrrolo[2,3-d]pyrimidm-7-yl)-3,4-dihydroxy-tetrahydrofuraii- 2-yl]methyl] 4-phenylbenzoate (121b)

[0413] To a solution of [(R)-(4-chloro-3-fluoro-phenyl)-[(2S 5 3S,4R,5R)-5-(4- chloropyrrolo[2,3-d]pyrimidin -7-yl)-3,4-dihydroxy etraliydrofuran-2-yl]niethyi| 4- phenylbenzoate (121a) (310 mg, 0.39 mmol) in DMF (15 mL) was added NIS (173.65 mg, 0.77 mmol). The reaction mixture was heated to 80 °C and stirred for 3 hrs. LCMS showed the reaction was completed. The solution was purified by reversed-phase combi-ffash (neutral condition) eiuting with tfcOiCHsCN from 90: 10 to 5:95 to give [(R)-(4-chloro-3-fluoro-phenyl)- [(2S,3S,4R,5R)-5-(4-chloro-5-iodo-pyrrolo[2,3-dJpyrimidin-7- yl)-3,4-dihydroxy- tetrahydrofuran-2-yl]methyl] 4-phenyibenzoate (121b) (292, mg, 0.37 mmol, 94.54% yield) as pale yellow solid, LCMS [M+H]:720.2.

Step 2. Synthesis of (2R,3R,4S,5R)-2-(4-animo-5-Kido-pyrro3o[2,3-d]pyrimidin-7-yl )-5-[(R) chloro-3-fluoro-phenyl)-hydiOxy-methyl |tetrahydrofuran-3,4-diol (121c)

[0414] To a solution of [(R)-(4-chloro-3-fluoro-phenyl)-[(2S 5 3S,4R,5R)-5-(4-chloK)-5- iodo-pyrrolo[2,3-d] pyrimidin-7-yl)-3,4-dihydroxy-tetrahydrofuraii-2-yl]memy3] 4- phenylbenzoate (121b) (292, mg, 0.36 mmol) in 1,4 -dioxane (5 mL) was added ammonium hydroxide (5 mL, 129.81 mmol). The reaction mixture was heated to 120 °C and stirred for 18 hrs in a sealed tube. LCMS showed the reaction was completed. The solvent was concentrated under reduced pressure, and the residue was purified by reversed-phase combi-flash (neutral condition) eiuting with H 2 0:CH_CN from 90: 10 to 5:95 to give (2R,3R,4S,5R)-2-(4-amino-5- iodo-pyrrolo[2,3-d]pyrimidin-7-yl)-5-[(R)-(4-chloro-3-fluoro -phenyl)-hydroxy- methyi|tetraliydrofuran-3,4-diol (121c) ( 105 mg, 0.20 mmol, 55.54% yield) as white solid. LCMS [M+H] :521 , l . Step 3. Synthesis of (2 ,3R,4S,5R)-2-(4-amino-5-vinyl- pyrrolo[2,3-d]pyrimidin-7-yl)-5-[(R)- (4-cUoro-3-fluoro-phenyl)-hydroxy-methyl]tetrahydfofi.iran-3 ,4-diol hydrochloride (121)

[0415] To a solution of (2R,3R,4S,5R)-2-(4-amino-5-iodo-pyrrolo[2,3-d]pyrimidin-7- yl)-5-[(R)-(4-chloro- 3-fluoro~plienyl)-hydroxy-metliy3]tetrahydrofijxan-3,4-dioi (100 mg, 0.18 mmol), pinacol vinylboronate (42.15 mg, 0.27 mmol) and aiCOs (38.68 mg, 0.36 mmol) in 1,4- dioxane (10 mL) and water (0.10 mL) was added Pd(dppf)Ck (13.35 mg, 0.02 rnmol) under N?„ The reaction mixture was heated to 120 °C and stirred for 18 hrs. LCMS showed the reaction was completed. The solution was filtered and the filtrate was purified by prep-HPLC (0.1% TFA) eluting with EbC CPfcCN from 90: 10 to 5:95 to give crude TFA salt which was dissolved in 0.1% HQ aqueous and lyophilized to give (2R,3R,4S,5R)-2-(4-amino-5-vinyl- pyrrolo[2,3- d]pyrimidin-7-yl)-5-[(R)-(4-chloro-3-fluoro-pheny

hydrochloride (Ex.121) (11.7 mg, 0.0243 mmol, 13.34% yield) as white solid. LCMS

|\i Hi.421.3.

1 161 R MR (400 MHz, DMSG-ί/ό) o 8.37 (br, 3 H), 7.97 (s, 1 H), 7.52 (t, J = 8.0 Hz, 1 H), 7,40 (d, J= 10.4 Hz, 1 H), 7.27 (d,./= 8.4 Hz, 1 H), 7.13-7.19 (m, 1 H), 6.11 (d, J= 7.2 Hz, 1 H), 5.75 (d, J= 17.2 Hz, 1 H), 5.32 (d,J= 12,0 Hz, 1 H ), 4,84 (d, J= 3.2 Hz, 1 H), 4.48-4.50 (ni.1 H), 4.10 (d, J= 4.8 Hz, 1 H), 4.02 (d, ./ 5.2 Hz, 1 H). i! NMR (400 MHz, DMSO-i:/6- D 2 0) δ 8.37 (s, 1 H), 7.95 (s, 1 H), 7.52 (t, ./ 8.0 Hz, 1 H), 7.39 (dd, Ji =11.6 Hz, Ji =1.6 Hz, 1 H), 7.27 (dd../: =8.0 Hz, Ji =1.2 Hz, 1 H), 7,13-7,19 (m, 1 H), 6.11 (d, J=7.6Hz, 1 H), 5,75 (d, J= 17.2 Hz, 1 H), 5.34 (d, J= 12.4 Hz, 1 H), 4.84 (d, J= 6,4 Hz, 1 H), 4.48-4.50 (m, 1 H),4.11 (dd, Ji = 4.8 Hz, Ji =1.2 Hz, 1 H), 4.03 (dd,Ji = 5.2 Hz, Ji =1.6 Hz, 1 H). !9 FNMR (376 MHz, DMSO- '6) δ -116.886 (s, 1 F),

Example 122, (2R,3R,4S,5R)~2-(4-amino-5~e nyl~7H~py^

(4-cUoro-3-methylphenyl)(hydroxy)methyl)tetrahydro&ra n-3,4-diol (122)

Step 1. Synthesis of [(R)-[(2S,3S,4R,5R)-5-(4-cUoro-5-iodo-pyrrolo[2,3-d]pyrimidi n-7-yl)-3,4- dihydroxy-te1rahydrofufan-2-ylJ-(4-chloro-3-methyl-phenyl)me thyl] 4-phenylbenzoate (122b)

[0417| To a solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (309 rng, 1.1 mmol) in dry THF (15 mL) was added pyridine (0.09 mL, 1.1 mmol), then tributylphosphane (0.55 mL, 2,2 mmol) and DIAD (0.45 mL, 2.31 mmol) at 30 °C, then [(R)-(4-chloro-3-methyl- phenyl)-j(2S,3S,4R)-3,4,5-trihydroxytetrahy (122a) (555 mg, 1.1 mmol) was added at once. The reaction mixture was stirred at 30 °C for 1.5 h. After the reaction was complete, the solution was concentrated in vacuo, and the residue was purified by silica gel column chromatography (PE: EtOAc 1: 1 to EtOAc) to give [(R)-[(2S,3S,4R,5R)~5-(4- chloro-5-iodo-pyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxy-te trahydrofuran-^

methyl -phenyl)methyl] 4-phenylbenzoate (122b) (400 mg, 0.50 mmol, 45.7% yield) as white solid, LCMS [M+H]: 716.0.

Step 2. Synthesis of (3R,4S,5R)-2-(4-aniino~5-iodo-pyrrolo[2,3-d]pyri.midin-7-yl) - chloro-3-meu¾yl-phenyl)-hydroxy-methyl |tetrahydrofuran-3,4-diol (122c)

|04I8j To a solution of [(R)-[(2S,3S,4R)-5-(4-ch]oro-5-iodo-pyrrolo[2,3-d]pyrimidin-

7-yl)-3,4-dihydroxy-tetrahydrofuran-2-yl]-^ 4-phenylbenzoate (122b) (400.0 mg, 0.50 mmol) in 1,4-dioxane (5 mL) was added Ni L ! N) (3.0 mL, 77.89 mmol). The mixture was stirred at 115 °C for 16 hrs. The solvent was removed in reduced pressure. The residue was purified by silica gel column chromatography (PE: EtOAc 1 : 1 to EtOAc) to afford (3R,4S,5R)-2-(4-amino-5-iodo-pyrrolo[2,3-d]p} 7 rimidin-7-yl)-5-[(R)-(4-chloro- 3-methyl-phenyl)-hydroxy'-methyl]tetrahydrofuran-3,4-diol (122c) (250 mg, 0.411 mmol, 81.8 % yield) as white solid. LCMS [M+H]: 517, 1.

Step 3. Synthesis of (2R,3R,4S,5R)-2-[4-an ino-5-(2-triisopropylsi]yleth Tiyl)pyrrolo[2,3- dJpyrimidin-7-yTj-5-j (R)-(4-chloro-3-methy

(122d)

[0419] To a solution of (2R,3R,4S,5R)-2-(4-amino-5-iodo-pyrrolo[2,3-dJpyrimidin-7- yl)-5-[(R)-(4-chloro-3-methyl-phenyl)-hydroxy-methyl]tetrahy drofuran-3,4-diol (122c) (294 mg,

0.48 mmol) in DMF (6 mL) was added Cul (18.3 mg, 0.10 mmol), (Triisopropylsi]yl)acetylene

(0.84 mL, 3.71 mmol), Et 3 N (1.5 mL, 11 mmol) and Pd(PPh 3 i (55.0 mg, 0.05 mmol). The mixture was degassed by N2 and stirred at 25 °C for 16 hrs. EtOAc and water were added to quench the reaction and the organic layer was washed with brine, dried over NaaSC and filtered. The filtrate was concentrated in vacuo. The residue was purified by prep-TLC (PE: EtOAc 2: 1) to afford (2R,3R,4S,5R)-2-[4-amino-5-(2-triisopropylsilylethynyl)pyrro lo[2,3-d]pyriniidin 5-[(R)-(4-chloro-3-methyl-phenyl)-hydroxy-methyl]tetrahydrof uran-3,4-diol (122d) ( 180 mg, 0.312 mrnol, 64.48% yield) as colorless oil. LCMS | M - H j: 571.2.

Step 4. Synthesis of (2R,3R,4S,5R)-2-(4-amino-5-ethynyl-pyrrolo[2,3-d]pyrimidin-7 -}'l)-5-[(R)-

(4-chloro-3 -methyi-pheiiyl)-hydroxy -methyl jteirahydrofuran-3, 4-diol (122)

[0420] To a solution of (2R,3R,4S,5R)-2-[4-amino-5-(2- triisopropylsilyletiiynyl)pyrrolo[2,3-d]pyrimidin-7-yl]-5-[( R)-(4-chloro-3-me1hyl-phenyl)- hydroxy-methyl]tetrahydrofuran-3,4-diol (122d) (182 mg, 0.32 mmol) in DMSO (4 mL) and methanol (0.1 mL) was added CsF (180 rng, 1.18 mrnol). The mixture was stirred at 25 °C for 3 h. The mixture was filtered. The filtrate was purified by prep-HPLC (0.1% ΝΗ3 Ή2Ο, eiutmg with ! ! ·():( H ^CN from. 90: 10 to 5:95) to afford (2R,3R,4S,5R.)-2~(4-am.mo-5-ethynyl- pyrrolof2,3-d]pyrimidin-7-yl)-5-f(R)-(4-chloro-3-methyl-phen yl)-hydroxy- methyl]tetrahydrofuran-3,4-diol (Ex, 122) (92.9 mg, 0.22 mrnol, 70% yield) as white solid. 'H NMR (400 MHz, DMSO-Je) δ 8.13 (s, 1 H), 7.76 (s, 1 H), 7.37-7.23 (m, 3 H), 6.73 (s, 2H), 6.35- 6,36 (m, 1H), 5.94-5.96 (m, IH), 5.27-5.28 (m, 1 H), 5.03-5.04 (m, 1 H), 4,80-4,82 (m, 1 H), 4.53-4.58 (in. 1 H), 4.29 (s, IH), 4.01-4.04 (m, 2 H), 2.30 (s, 3 H). LCMS | M I I I. 415.4.

Example 123. (2R,3R,4S,5R)-2-(4-amino-5-ethynyl-7H-pyrrolor2,3-d]pyrimidi n-7-yl)-5-((R)-

(4-chloro-3-fluorophenyl)(hydroxy)methyl)tetraliydrofuran -3,4-dioi (123)

Step 1. Synthesis of (2R,3R,4S,5R)-2-[4-amino-5- (2-triisopropylsilylethynyl)pyriOlo[2,3- d]pyrimidin-7-yl]-5-[(R)-(4-chloro-3-fluoro-phenyl)-hydroxy -methyl] tetrahydrofuran~3,4~diol (123a) [0421] To a solution of (2R,3R,4S,5R)-2-(4-amir)o-5-iodo-pyrrolo[2,3-d]pyrimidin-7- yl)-5-[(R)-(4-chloro- 3-fluoro-phenyl)-hydroxy-methyl]tetrahydrofiirati-3,4-diol (121c) (600.0 mg, 1.03 mmol) , Cul (19.5 nig, 0.1000 mmol) and Pd(Pl¾3)4 (59.26mg, 0.05 mmol) in DMF (10.0 niL) was added (Triisopropylsilyl)acetylene (0.35 mL, 1.54 mmol) and TEA (0.43 ml, 3.08 mmol). The reaction mixture was stirred at 25 °C for 18 h under N2. The mixture was poured into water (20.0 mL), extracted with EA (100.0 mL X 3), the combined organic layers were washed with brine, dried over anhydrous a2S04, filtered and concentrated in vacuum, to give (2R,3R,4S,5R)-2-[4-amino-5- (2-triisopropylsilyleth Tiyl)pyrrolo[2,3-d]pyrimidin-7-yl]-5- [(R)-(4-chloro-3-fluoro-phenyl)-hydroxy -methyl] tetrahydrofuran-3,4-diol (123a) (600.0 mg, 0.83 mmol, 81.4% yield) which was used in the next step without further purification. LCMS [M+H] :575 ,3.

Step 2. Synthesis of (2R,3R,4S,5R)-2-(4-amino-5-ethynyl-pyixolo[2,3-d]pyrimidin-7

(4-cUoro-3-fluoro-phenyl)-hydroxy-methyl]tetrahydrofuran- 3,4-diol (123)

[0422] To a solution of (2R,3R,4S 5 5R)-2-[4-amino-5-(2- triisopropylsilylethynyl)pyriOlo[2,3"d|pyrimidin~ 7-yl]-5-[(R)-(4-chloro-3-fluoro-phenyl)- hydroxy-methyl]tetrahydrofuran-3,4-diol (123a) (280.0 mg, 0.46 mmol) in DMSO (5.0 mL) and methanol (0.1 mL) was added CsF (70.3 mg, 0,46 mmol) under N2. The reaction mixture was stirred at 25 °C for 1.5 h. The solution was filtered and the filtrate was purified by prep-HPLC, eluted with CH3CN i n H O (0.1% M l : .! ! ·{)) from 10.0% to 95.0% to give ( 2 Η.3 Η .48.-· Κ :···2··ί 4 · animo-5-emynyl-pyrrolo[2,3-d]pyrimidm-7-yl)-5-[(R)-(4-chloro -3-fluoro-phenyl)-hydroxy- methyl]tetrahydrofuran-3,4-diol (Ex, 123) (63.3 mg, 0.15 mmol, 32.5% yield) as a white solid. LCMS [M+H] : 419.3. TT NMR (400 MHz, DMSO-fife) δ 8.13 (s, 1 H), 7.80 (s, 1 H), 7.53 U. ./ 8,0 Hz, 1 H), 7.41 (d, ./ 10.4 Hz, 1 H), 7,28 (d, J =8.4 Hz, 1 H), 6.77 (b, 2 H), 6.46 (d, «/ = 4.0 Hz, 1 H), 5.97 (d, J = 7.6 Hz, 1 H), 5.29 (d, J= 6.4 Hz, 1 H ), 5 ,07 (d, ,/= 4.0 Hz, 1 H), 4,82-4.86 (m, 1 H), 4.52-4.57 (m, 1 H), 4.30 (s, 1 H), 4.01-4.04 (m, 2 H); Ή NMR (400 MHz, DMSO- ck+ΏιΟ) 6 8.13 (s, 1 H), 7.79 (s, 1 H), 7.53 it. ./ 8.0 Hz, 1 H), 7.40 (d. ./ 10.4 Hz, 1 H), 7.28 (d, J = 8.0 Hz, 1 H), 5 ,97 (d, J = 7.6 Hz, 1H), 4.83 (d, J= 4,4 Hz, 1H), 4,52-4,55 (m, i l l). 4.27 (s, 1 H), 4.01-4.04 (m, 2 H); 19 FNMR (376 MHz, DMSO- e) δ -1 16.835 (s, 1 F).

Example 124. (2R,3R,4S,5R)-2-(4-amino-5-viny -7H-pyrro3o[2,3-d]pyrimidin- dichlorophenyl)(hydroxy)methyi)tetrahydrofuran-3,4-diol (124)

Step 1. Synthesis of [(S)-[(2S,3S,4R,5R)-5-(4-ch!oro-5-iodo-^^

dihydro -xy-tetra y-drofuran-2-yl]-(3,4-dichlorophenyl)methyl]4-phenylbenzoate (124b)

[0423] To a solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (1 .06 g, 3.79 mmol) in THF (20.0 mL) was added Pyridine (0.3 mL, 3.79 mmol), DIAD (1 .61 g, 7.95 mmol) and Tributylphosphine ( 1.9 mL, 7.57 mmol) at 25 °C. [(S)-(3,4-dichlorophenyl)- | (2S,3S,4R)- 3,4,5-trihydroxytetrahydrofuran -2-yl]methyl] -4-phenylbenzoate (124a) (1.8 g, 3,79 mmol) was added all at once. The reaction mixture was stirred at 25 °C for 18 h under N?.. The reaction mixture was concentrated in vacuum to give crude product which was purified by re versed-phase combi-falsh, eluted with MeCN in H2O from. 10.0% to 86.0% to afford [(S)~[(2S,3S,4R,5R)-5- (4-ch]oro-5-iodo-pyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydro -xy-tetrahy-drofuran-2-yl]-(3,4- dichlorophenyl)methyl]4-phenylbenzoate (124b) (920.0 mg, 1.25 mmol, 33.0% yield) as a pale yellow solid. LCMS [M+H] : 736.2.

Step 2. Synthesis of (2R,3R,4S,5R)-2-(4-amino-5-iodo-p} rolo[2,3-d]pyrimidin-7-} )-5-[(R)-

(3,4 -dichiorophenyl)-hydroxy-methyi]tetrahydrofuran~3,4~diol (124c)

[0424] To a solution of (R)-[(2S,3S,4R,5R)-5-(4-chloro-5-iodo-pyrrolo[2,3- d]pyrimidin-7-yl)-3,4-dihydroxy -tetrahydrofuran-2-yl]-(3,4-dichlorophenyl)methyl]-4- phenylbenzoate (124b) (917.5 rng, 1.25 mmol) in 1,4-Dioxane (5.0 mL) was added NH3.H2O (5.0 mL, 129.8 mmol). The reaction mixture was stirred at 120 °C for 18 h in sealed tube. The reaction mixture was concentrated in vacuum to give cmde product w h ich was purified by reversed-phase combi-ffash eluied with MeCN in H2O from 10.0% to 35.0% to afford

(2R,3R,4S,5R)-2-(4-amino-5-iodo-pyrrolo[2,3-d]pyrimidin-7 -}'l)-5-[(R)-(3,4 -dichlorophenyl)- hydroxy-methyl]tetrahydrofuran-3,4-diol (124c) (559.0 mg, 0.31 mmol . 25.1% yield) as a pale yellow solid. LCMS [M+H] : 537.1 , Step 3. Synthesis of (2R,3R,4S,5R)-2-(4-amino-5-vinyl^

(3,4-dichlorophenyl) -hydroxy-methyl]tetrahydrofuran-3,4-diol hydrochloride (Ex. 124)

[0425| To a solution of (2R,3R,4S,5R)-2-(4-amino-5-iodo-pyrrolo[2,3-d]pyrimidin-7- yl)-5-[(R)-(3,4- dichlorophenyl)-hydroxy-methyl]tetrahydrofuran-3,4~diol (124ε) (559.0 mg, 0.31 mmol) in 1,4-Dioxane (5.0 mL) and Water (1 .0 mL) was added 4,4,5,5-tetramethyl-2-vinyl- 1,3,2 -dioxaborolane (72.1 mg, 0.47 mmol), NaiCOs (66.2 mg, 0.62 mmol) and Pd(dppf)Ch (22.8 mg, 0.03 mmol). The reaction mixture was stirred at 120 °C for 18 h under Ni. The reaction mixture was filtered and concentrated in vacuum, to give crude product which was purified by prep-HPLC , eluted with MeCN in H 2 0 (0.1% TFA) from 10.0% to 95.0%, added 1 .0 mL of HC1 (1 M) and lyophilized to obtain (2R,3R,4S,5R)-2-(4-amino-5-vinyl-pyrrolo[2,3-d]pyrimidin-7- yl)-5-[(R)-(3,4-dichlorophenyl) -hydroxy-methy1]tetrahydrofuran-3,4~diol hydrochloride (Ex. 124) ( 16.0 mg, 0.03 mmol, 10.4% yield) as a white solid. LCMS [M+H] : 437,3. l H NMR (400 MHz, DMSO- 6+D2O) δ 8.35 (s, 1 H), 7.92 (s, 1 H), 7.61-7.62 (d, J ----- 1.6 Hz 1 H), 7.56-7.58 (d, ./ 8.4 Hz, 1 H), 7.38-7.40 (m, 1 H), 7.10-7.17 (m, 1 l i s. 6.10-6.12 id. ./ 7.2 Hz 1 H), 5.73-5.78 (m, 1 I !}. 5.32-5.35 (m, 1 H), 4.82-4.84 (d, J= 5,6 Hz, 1 H), 4.48-4.52 (m, 1 H), 4 , 10-4 , 12 (d, J = 5.2 Hz, 1 H), 4.02-4.04 (m, 1 H).

Example 125. of (2R,3R,4S,5R)-2-(4-amino-5 -vinyl-pyrro]o[2,3-d]pyrimidin-7-yl)-5-[(R)-(4- chloro-3-metliyl-phenyl)-hydroxy-methyl]tetrahydro-furaii-3, 4-diol (125)

122c Ex. 125

\M26] To a solution of (2R,3R,4S,5R)-2-(4-amino-5-iodo-pyrrolo[2,3-dJpyrimidin-7- y3)-5~[(R) -(4-chloro~3 -methyl-phenyl)-hydroxy-metliyl]tetrahydrofuran-3,4-diol (122c) (300.0 mg, 0.49 mmol) in 1 ,4-Dioxane (10.0 mL) and Water (0,3 mL) was added Pinacol vinylboronate (170.0 mg, 1.09 mmol), Na?.C03 (120.0 mg, 1.13 mmol) and Pd(dppf)Ch (36.0 mg, 0.05 mmol The reaction mixture was stirred at 100 °C for 18 h under Ni. The mixture was filtered and the filtrate was purified by prep-HPLC eluted with CftCN in thO (0.1% NH3.H2O) from 10.0% to 95.0% to give Ex. 125 (14.4 mg, 0.0345 mmol, 7.0% yield) as a white solid. 5 (MS [M+ffJ: 417.1 . T-I MR (400 MHz, DMSO-ifc): δ 8.05 (s,lH), 7.58 (sJH), 7.33-7.28 (m, 2H), 7.24-7.26 (m, 1H), 7.08-7.15 (m, 1H), 6.76 (brs,2H), 6.42-6.43 (rn,lH), 5.95-5.97 (m, lH), 5.55-5.59 (m, lH), 5.20-5.22 (m, lH), 5.13-5.16 (m, lH), 4.98-4.99 (m, 1 H), 4.77-4.79 (m, 2 H), 4.54-4.59 (m, I I I). 4.01-4.03(m, 2 H), 2.29 (s, 3 H). ¾ NMR (400 MHz, DMSCW6+D2O): δ 8.07 (s,lH), 7,52 (s,lH), 7.33-7.36 (m, 2H), 7,24-7.26 (m, 1H), 7.04-7.15 (m, 1H), 5.96-5.98 (m, ! H), 5.55- 5.60 (m, lH), 5.19-5.22 (m,lH), 4.78-4.79 (m, 1H), 4.53-4.56 (m, 1H), 4.04-4.05 (m, 2H), 2.30 (s, 3H).

Example 126. (2R,3R,4S,5R)~2-(4-amino-5~e nyl~7H~py^

(3,4-dichlorophenyl)(hydroxy)methyl)tetrahydrofuran-3,4-d iol (126)

124c 26a Ex, 126

Step 1. Synthesis of (2R,3R,4S,5R)- 2-[4-amino-5-(2-trimethylsilyiethyny3)pyrroio[2,3- d]pyrimidin-7-yl]-5-[(R)-(3,4-dichlorophenyl)-hydroxy-m (126a)

[0427] To a solution of (2R,3R,4S,5R)-2-(4-amino-5-iodo-pyrrolo[2,3-d]pyrimidin-7- yl)-5-[(R)-(3,4- dichlorophenyl)-hydroxy-methyl]tetrahydrofuran-3,4-diol (124c) (210.0 mg, 0.39 mmol) in DMT (5 ,0 mL) was added Cul (14.9 mg, 0.08 mmol), TEA (0.07 mL, 1 ,95 mmol), (Trimethylsilyl)acetyl-ene (0.22 mL, 1.56 mmol), pd(pph3)2C . (27.4 mg, 0.04 mmol). The reaction mixture was stirred at 25 °C for 1.5 h under N2. The reaction mixture was concentrated in vacuum to give crude product which was purified by silica chromatography, eluted with PE : EA from 50 : 1 to 20 : 1 to give (2R,3R,4S,5R)- 2-[4-amino-5-(2- trimemylsilylem}'nyl)p}Trolo[2,3-d]pyrimidm-7-yl]-5-[(R)-(3, 4-dichlorophenyl)-hydroxy- methyl|tetraliydrofuran-3,4-diol (126a) (198.0 mg, 0.39 mmol, 99.8% yield) as a pale yellow solid. LCMS [M+HJ: 507.3. Step 2. Synthesis of (2R,3R,4S,5R)~2-(4-amino-5-e†hynyl-7FI-py

((R)-(3,4-dichlorophenyl)(hydroxy)methyl)tetrahydrofuran- 3,4-diol (126)

[04281 To a solution of (2R,3R,4S 5 5R)-2-[4-amino-5-(2- trimethy3siiylethyny3)pyn lo[2,3~d]pyrimidin- 7-yl]-5-[(R)-(3,4-dichlorophenyl)-hydroxy- methyl]tetrahydrofuran-3,4-diol ( 26a) (200.0 mg, 0.39 mmol) in DMSO (5.0 mL) and Methanol (0.20 mL) was added CsF (59.87 mg, 0.39 rnmol). The reaction was stirred at 25 °C for 1.5 h under Ni. The reaction mixture was filtered and concentrated in vacuum to give erode product which was purified by prep-HPLC, eluted with CH 3 CN in H2O (0.1% NH3.H2O) from 10.0% to 95.0% to obtain (2R,3R,4S,5R)-2-(4-amino-5-ethynyl-pyrrolo[2,3-d] pyrimidin-7-yl)-5-[(R)- (3,4- dichlorophenyl)-hydroxy-metliyl]tetrahydiOfuraii-3,4-diol (Ex. 126) (12.5 mg, 0.03 mmol, 7.3% yield) as a white solid. LCMS [M+H] : 435.3. H-.WIR (400 MHz, DMSO-fl¾5+D 2 0) δ 8.13 (s, 1 H), 7,78 (s, 1 H), 7.62-7.63 (d, J= 1.6 Hz, 1 H), 7.57-7.59 (d, J= 8,4 Hz, 1 H), 7.38-7.41 (m, 1 H), 5.96-5.98 (d, J= 7.6 Hz, 1 1 1). 4.82-4.84 (d, ./ 4.8 Hz, 1 H), 4.53-4.56 (m, 1 H), 4.27 (s, 1 H), 4.03-4.05 (m, 1 H), 4.01-4.02 (m, l H).

Example 127. (2R,3R,4S,5R)-2-(4-amino-5-et ynyl-7H-pyrroloL2,3-d]pyrimidin-7-yl)-5-((R)-

(3,4-difiiiorophenyl)(hydroxy)m.ethyl)tetrahydrofLiran-3, 4-diol (127)

Step 1. Synthesis of | (R)-[(2S,3S,4R,5R) -5-(4-chloro-5-iodo-pyrrolo[2,3-d]pyrimidin-7' dihydroxy-tetrahydrofuran-2-yl] -(3 ,4-difluorophenyl)methyl] 4-phenylbenzoate (127b)

To a solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyriniidine (1.9 g, 6.65 mmol) in dry- THF (150.0 mL) was added pyridine (0,6 mL, 6.65 mmol), tributylphosphane (3.3 mL, 13.3 mmol) and DIAD (2.75mL, 14.0 mmol at 25 °C. [(R)-(3,4-difluorophenyl)- [(2S,3S,4R)-3,4,5- trihydroxy tetra -hydrofiirati-2-yl]methyl] 4-phenylbenzoate (127a) (3.0 g, 6.65 mmol) in dry THF was added at once. The reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was purified by reversed -phase combi-f!ash, eluted with CHbCN in H2O from 30.0% to 95.0% to give [(R)-[(2S,3S,4R,5R) -5-(4H*loro-5-iodo-pyi olo[2,3-d]pyriinidin-7-yl)- 3,4-dihydroxv'-tetrahy(kofuran-2-yl]-(3,4-difluorophenyl)met liylJ 4-phenylbenzoate (127b) (3.26 g, 3.70 mmol, 55 ,8% yield) as a yellow solid. LCMS [M+H] : 704.0.

Step 2. Synthesis of (2R,3R,4S,5R)-2-(4-amino-5-iodo-pyrrolo[2,3-d] pyrimidin -7-yl)-5-[(R) -

(3,4-difluoropheny3)-hydroxy-methy]]tetrahydrofiiran-3,4- diol (127c)

[0430] To a solution of [(R)-[(2S,3S,4R,5R)-5-(4-chloro-5-iodo-pyrrolo[2,3- d|pyrimidin-7-yl)-3,4- dihydroxy-tetrahydrofuraii-2-yi|-(3,4-difluorophenyl)methyi] 4- phenylbenzoate (127b) ( 1.6 g, 1.82 mmol) in 1,4-Dioxane (16.0 mL) was added ammonium hydroxide (16.0 mL, 415.41 mmol). The reaction mixture was heated to 120 °C and stirred for 18 h in sealed tube. The solvent was concentrated in vacuum to give crude product which was purified by silica gel column chromatography, eluted with DCM : CH3OH from 20 : 10 : 1 to give (2R,3R,4S,5R)-2-(4-amino-5-iodo-pyrrolo[2,3-d] pyrimidin -7-yl)-5-[(R) -(3,4- difluorophenyl)-hydroxy-methyl]tetrahydrofuran-3,4-diol (127c) (816.0 mg, 1.54 mmol, 71 .2 % yield) as a solid. LCMS [M+H] :505.0.

Step 3. Synthesis of (2R,3R,4S,5R)-2-[4-amino-5-(2-triisopropylsilyleth}Tiyl)pyrr olo| 2,3 - d]pyrimidin-7-yl] -5-[(R)- (3,4-difluorophenyl)-hydroxy-methyl]tetrahydrofuran-3,4-diol (127d)

104-31 j To a solution of (2R,3R,4S,5R)-2-(4-amino-5-iodo-pyrrolo[2,3-d]pyrimidin-7- yl)-5-[(R)- (3,4-difluorophenyl)-hydroxy-metliyl]tetrahydrofuraii-3,4-di ol (127c) (816.0 mg, 1.54 mmol) in DMF ( 10.0 mL) was added Pd(PPh 3 )4 (88.8 mg, 0.08 mmol), Cul (29,28 mg, 0.15 rnmol), (triisopropylsilyl)acetylene (0.52 mL, 2.31 mmol) and TEA (0.64 mL, 4.61 mmol). The reaction mixture was stirred at 25 °C for 18 h under N 2. The solution was filtered and the filtrate was washed with water , extracted with EA, the combined organic layers were washed with brine, dried over anhydrous NazSOs, the solvent was concentrated in vacuum to give crude product which was purified by silica gel column chromatography, eluted with PE : EA from 10 : 1 to PE : EA = 3 : 1 to give (2R,3R,4S,5R)-2-[4-ammo-5-(2-triisopropylsilylethynyl)pyrrol o[2,3 - d]pyrimidin-7-yl] -5-[(R)- (3,4-difluorophenyl)-hydroxy-methyl]tetrahydrofuran-3,4-diol (127d)

(600.0 mg, 1.02 mmol, 66.4% yield) as a white solid. LCMS [M+H]:559.2.

Step 4. Synthesis of (2R,3R,4S,5R)-2-(4-amino-5-et ynyl-pyrrolof2,3-d]pyrimidin-7-yl)-5-f(R)- (3,4-difluorophenyl) -hydroxy -methyl]tetrahydrofuran-3,4-diol (127)

10432] To a solution of (2R,3R,4S,5R)-2-[4-amino-5-(2- triisopropyisilylethynyi)pyrrolo[2,3^]pyrimidin- 7-yl]-5-[(R)-(3,4-difluorophenyl)-hydrox '- methyl]tetrahydrofuran-3,4-diol (127d) (500.0 mg, 0.85 mmol) in DMSO (10.0 mL) and Methanol (0.10 mL) was added CsF (129.2 mg, 0.85 mmol) under N2. The reaction mixture was stirred at 25 °C for 1.5 h. The mixture was filtered and the filtrate was purified by prep-HPLC, eluted with CTI3C in H2O (0.1% H3.H2O) from 10.0% to 95.0% to give (2R,3R,4S,5R)-2~(4- amino-5 -ethynyl-pyrrolo [2 ,3 -d]pyrimidin-7-yl)-5 - [(R)-(3 ,4-difluorophenyl) -hydroxy - methyi|tetraliydrofuran-3,4~diol (Ex. 127) (300.0 mg, 0.74 mmol, 87.5% yield) as an off-white solid. LCMS [M+H]:403, l . i ! W! (400 MHz, DMSO-rfe) δ 8, 13 (s, 1 H), 7.80 (s, 1 H), 7.34- 7.44 (m, 2 H), 7.20-7.26 (m, 1 H), 6.74 (br, 2 H), 6.41 (d, ./ 4.0 Hz, 1 H), 5.97 (d, J ==7.6 Hz, 1 H), 5.30 (d, ./ 6.8 Hz, 1 H), 5.07 id. ./ 4.0 Hz, 1 H), 4.82 (t, J -4.0 Hz, 1 H), 4.52-4.57 (m, 1 I !}. 4.30 (s, 1 H), 4.04(1./ 4.4 Hz, 1 H), 4.00 (d, ./ 4.8 Hz, 1 H).¾ NMR (400 MHz, DMSO- de+ O) δ 8.14 (s, 1 H), 7,76 (s, 1 H), 7.34-7.43 (m, 2 H), 7.21 -7.25 (m, 1 H), 5.97 (d, J= 7.6 Hz, 1 H), 4.82 (d, ./ 4.4 Hz, 1 H), 4.52-4.55 (in, 1 H), 4.26 (s, 1 H), 4.02-4.06 (m, 2 H).

! 9 FNMR(376 MHz, DMSO-iie) δ -139.22 (d, 1 F), -141.28 (d, 1 F).

Examples 128 and 129. (2R,3R,4S,5S)-2-(4-amino-5-emynyl-7H-pyn-o3o|2,3-d]pyiimidin - yl)-5-((S)-l-(4-chloro-3-methylphenyl)-l-hydroxyethyl)tetrah ydrof raii-3,4-di (128) and l-(4~ amino-7-((2R,3R,4S,5S)-5-((S)- i-(4-chloro-3-mefty3phenyl)-l-hydroxyethy])-3,4^

dihydrox}1:etrahydrofuran-2-yl)-7Ii-pyiTolo[2,3-d]pyrimid in-5-yl)ethan-l-one (129)

Step 1. Synthesis of (R)-[(3aR,41^6R,6aR)-4-(4-ch]oro-5-iodo-pyrrolo[2,3-d]pyrimi din-7-yl)- 2,2-dimethyl-3a,4,6,6a-tetrahydrofiiro[3,4-d][l ,3] -dioxol-6-yl]-(4-chloro-3-methyl- phenyDmethanol (128a)

[0433] A mixture of (2R,3R,4S,5R)-2-(4-chloro-5-iodo-pyrrolo[2,3-dJpyrimidin-7-y l)-

5- [(R)- (4-chloro-3-methyl-phenyl)-hydroxy-me1hyl]tetraliy(kofuran-3 ,4-diol (122c) (280.0 mg, 0,52 mmoi), 2,2-Dimethoxy-propane (0.84 mL, 6.83 mmoi), Amberlyst- 15 resin (280, Omg ) and DMF (5.0 mL) was stirred at 60 °C for 12 h under NJ.. The mixture was filtered and concentrated in vacuum to give cmde product which was purified by silica gel column chromatography, eluted with PE : EA = 10 : 1 to give (R)-[(3aR,4R,6R,6aR)-4-(4-chloro-5-iodo-pyrrolo[2,3- d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrah}'drofuro[3,4 -d][l,3] -dioxol-6-yl]-(4-chloro-3- methyl-phenyl)methanol (128a) (220.0 mg, 0.38 mrnol, 73.1% yield) as a yellow solid. LCMS [M+H]: 557,0.

Step 2. Synthesis of (R)-[(3aR,4R,6R, 6aR ) -4-[4-amino-5 -(2-triisopropylsilyl - ethynyl)pyrrolo[2,3-d] pyrimidin-7-yl]-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d] [l ,3]dioxol-

6- y!j -(4-chloro-3-methyl-phenyl)methanol (128b)

|0434j To a solution of (R)-[(3aR,4R,6R,6aR)-4-(4-amino-5-iodo-pyrrolo[2,3- d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydro

methyl-phenyl)methanol (128a) (170.0 mg, 0.31 mmoi) in DMF (10.0 mL) was added ethynyl(triisopropyl)silane (222.7 mg, 1.22 mmoi), Cul (1 1 .6 mg, 0.06mmol), Pd(PPh3) (3.2 rng, 0.01 mrnol) and TEA (0.2 ImL, 1.53 mrnol). The reaction mixture was stirred at 25 °C for 18 h under N2. The reaction mixture was concentrated in vacuum to give crude product which was purified by silica gel column chromatography, eluted with PE : EA from 10 : 1 to 1 : 1 to give (R)-[(3aR,4R,6R, 6aR ) -4-[4-amino-5 -(2-triisopropylsilyl -ethynyl)pyrrolo[2,3-d] pyrimidin-7- yl]-2,2-dimethyl-3a,4,6,6a-tetrahy(kofuro[3,4-d][ l,3]dioxol-6-yl] ~(4-chloro-3 -methyl - phenyl)methanol (128b) (157.0 nig, 0,24 mmol, 80.7% yield) as a yellow solid, 5 (MS [M+H] : 61 1.0.

Step 3. Synthesis of [(3aR,4R,6S,6aS)-4-[4-amino-5 -(2-triisopropyl-silylethyny])Pyrrolo-[2,3- dlpyrimidin-7-yl]-2,2-dimemyl-3a,4,6,6a-tetrahydrofurof3,4-d ][ l,3] -dioxol-6-yl]-(4-chloro-3- methyl-phenyl)methanone (128c)

[0435] To a solution of (R)-L(3aR,4R,6R,6aR)-4-[4-amino-5-(2- triisopropylsilylethynyl)pyrrolo[2,3-d] pyrimidin-7-yl]-2,2-dimethyl-3a,4,6,6a- tetrahydrofuro[3,4-d] [1 ,3]dioxol-6-yl]-(4-chloro-3-methyl-phenyl)methanol (128b) (157.0 mg, 0.26 mmol) in DCM (10.0 mL) was added Dess-Martin periodinane (326.8 mg, 0.77 mmol). The mixture was stirred at 25 °C for 2 h. The mixture was filtered and the filtrate was concentrated in vacuum to give crude product which was purified by silica gel column chromatography, eluted with PE : EA from 5: 1 to 1 : 1 to give [(3aR,4R,6S,6aS)-4-|4-amino-5 -(2-triisopropyl- siiyiethynyl)Pyrrolo-|2,3 i]pyrimidin-7-yli-2,2-dimemy - dioxol-6-yl]-(4-chloro-3-methyl-phenyl)methanone (128c) (1 10.0 mg, 0.17 mmol, 66.8% yield) as a yellow solid. I .C.MS [M+H]: 609,0.

Step 4. Synthesis of ( lS)-l-[(3aR,4R,6S,6aR)-4-[4-amino -5-(2-triisopropylsilylethynyl) py rrolo 12,3 -d]pyrimidin-7-yl] -2,2-dimethy l-3a,4,6,6a-tetrahy drofuro 13 ,4-d] [ 1 ,3 ]dioxol-6-y 1] - 1 -

(4-chloro-3-methyi-phenyi)ethanol (128d)

|0436] To a solution of [(3aR,4R,6S,6aS)-4-[4-amino-5-(2- triisopropylsilylethynyl)pyrrolo[2,3-d]pyrimidin -7-yl]-2,2-dimethyl-3a,4,6,6a- tetrahydrofuro[3,4-d] [l,3]dioxol-6-yl]-(4-chloro-3-me1hyl-phenyl)methanone (128c) (1 10.0 mg, 0.18 mmol) in THF (5.0 mL) was added Methyl magnesium bromide (0.09 mL, 3.0 M/L, 0.27 mmol) at 0 °C. The mixture was quenched by aq NJTsCl (2.0ml) and water (2.0ml). The mixture was extracted with EA (50,0 ml X 2). The organic layer was concentrated in vacuum to give crude product which was purified by silica gel column chromatography, eluted with PE : EA from 5 : 1 to 1 : 1) to give (l S)-l-[(3aR,4R,6S,6aR)-4-[4-amino -5-(2-triisopropylsilylethynyl) pyrrolo[2,3-d]pyrimidm-7-yl]-2,2-dimethyl-3a,4,6,6a^ (4-chloro-3-methyl-phenyl)ethano] (128d) (70,0 mg, 0.11 mmol, 61. 4% yield) as a yellow solid. LCMS [M+H] : 625.2.

Step 5. Synthesis of (lS)-l-[(3aR,4R,6S,6aR)-4-(4-amino-^

yl)-2,2-dimetiiyl-3a,4,6,6a-tetraIiydrofuro[3,4-d][l,3]di oxol-6

phenyl)ethanol (128e)

104371 To a solution of (l S)-l-[(3aR,4R,6S,6aR)-4-[4-amino-5-(2- triisopropylsilylethynyl) pyrrolo[2,3-d] pyrimidin-7-yl]-2,2-dimeth}d-3a,4,6,6a- tetrahydrofuro[3,4-d][l,3]dioxol-6-yl]-l-(4-chloro-3-melh}4- phenyl)ethanol (128d) (70.0 mg, 0, 11 mmol) in DMSO (3.0 mL) and Methanol (0.03 mL) was added CsF (17.0 mg, 0.11 mmol). Tlie mixture was stirred at 25 °C for 18 h. Tlie mixture was purified by pre-HPLC, eluted with OfcCN in HzO (0.1% TFA) from 10.0% to 95.0% to obtain (lS)-l-[(3aR,4R,6S,6aR)-4-(4- ammo-5-eftynyl-pyrrolo[2,3-d]pyrimidm

d][l,3]dioxol-6~y3]-l~(4-chloro-3-methyl-phenyl)ethanol (128e) (50,0 mg, 0.10 mmol, 94.3% yield) as a yellow solid. LCMS ] Μ · Π |: 469.2.

Step 6. Synthesis of (2R,3R,4S,5S)-2-(4-amino-5-emynyl-7H-pyrrolo[2,3-d]pyrimidin -7-yl)-5- ((S)-l-(4-chloro-3-met ylphenyl)-l-hydrox}'ethyl)tetrahydrofuran-3,4-diol (128) and l-(4- ammo-7-((2R,3R,4S,5S)-5-((S)-l-(4-chloro-3-me lphenyl)-l-hydroxyethyl)-3,4- dihydroxytetrahydrofuran~2-yl)~7H-pyrrolo[2,3-d]pyrimidin-5- y (129)

[0438] To a mixture of (lS)-l-[(3aR,4R,6S,6aR)-4-(4-amino-5-ethynyl-pyrrolo[2,3- d]pyrimidin -7-yl)-2,2 -dime1hyl-3a,4,6,6a-tetrahydrofuro[3,4-d][l ,3]dioxol-6-yl]-l-(4-chloro-3- methyl-phenyl)ethanol (128e) (50.0 mg, 0.11 mmol) in Water (3.0 mL) was added TFA (3.2 mL, 42.65 mmol). The reaction mixture was stirred at 40 °C for 1 h. Tlie reaction mixture was adjusted to pH = 7-8 with sodium bicarbonate (aq), filtered, the filtrate was purified by pre- HPLC, eluted with CftCN in i I O <0. l °.,\l hOH) from 10.0% to 95.0% to obtain i -j 7- [(2R,3R,4S,5S)-5-[(lS)-l-(4-chloro- 3-meth} 7 l-phenyl)-l-hydroxy-ethyl]-3,4-dihydroxy- tetrahydroforan-2-yl]-4-imino-lH-pyrrolo[23 (Ex. 129) (1.6 mg,

0.01 mmol, 3.3% yield) as a white solid, and (2R,3R,4S,5S)-2-(4-amino-5-ethyny]-pyrrolo-[2,3- dlpyrimidin-7-yl)-5-[(lS)-l-(4-chloro-3 -methyl -phenyl)- 1-hydroxy-ethy l]tetrahydrofnran-3, 4- dioi (Ex. 128) (2.6 mg, 0.01 mmol, 5.5% yield) as a white solid. 1 HNMR for Ex. 128, ¾ NMR (400 MHz, DMSO-ae+DiO) δ 8,21 (s, 1 H), 7.86 (s, 1 H), 7,52 (s, 1 H), 7.38 (s, 2 H), 5.93 (d, J = 8.0 Hz, 1 H), 4.48-4.51 (m, 1 H), 4.32 (s, I H), 4.12 (s, 1 H), 3.67-3.70 (m, 1 H), 2.35 (s, 3 H), 1.41 (s, 3 H). LCMS j M · 1 11 : 429.4

10439] H N .MR for Ex. 129, H NMR (400 MHz, DMSO-afc) δ 8.77 (s, 1H), 8,61 (s, 1H), 8.29 (s, 1H), 8.05 (s, ! H), 7.53 (s, 1H), 7.38 (s, 1H), 6.00 (d, J= 8.0 Hz, 1H), 4.58-4.61 (m, 1 H), 4.18 (s, 1H), 3.73-3.74 (m, 1H) , 2.56 (s, 3H), 2.35 (s, 3H) , 1.43 (s, 3H). Ή NMR (400 MHz, D SO /r. · ΙΗ)) δ 8.60 (s, i l l). 8.30 is. 1H), 7.51 (s, 1H), 7.37 (s, 2H), 6.01 (d, ./ 8.0 Hz, 1H), 4.55-4 ,59 (m, 1H), 4.17 (s, 1H), 3.73-3.75 (m, 1H), 2,56 (s, 3H), 2,33 (s, 3H), 1.43 (s, 3H). LCMS [M+H]; 447.3

Example 130. (2R,3R,4S,5R)-2-(4-an ino-5-(hydroxyme1hyl)-7H-pyrrolo[2,3-d]pyrimidin-7-y])- 5-((R)-(3,4-dichlorophemd)(hydroxy)methyl)tetrah}drofuran-3, 4-diol hydrochloride (13Θ)

Step 1. Synthesis of [(R)-[(2S,3S,4R,5R)-5-[5-[[tert-birtyl(dimethyl)silyl]oxymet hy]] -4-chloro- pyrrolo-[2,3-d]-pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofura n-2-yl]-(3,4- dichlorophenyl)methyl] 4-phenylbenzoate (130a)

[0440] To a solution of tert-butyl-[(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5- yl)methoxy]-dimethyl-silane (2, lg, 7.05 mmol) in dry THF (20,0 mL) was added Pyridine (0.6 mL, 7.05 mmol), DIAD (2,9 mL, 14.81 mmol), Tributylphosphane (3.5mL, 14, 10 mmol) under N;2. [(R)-(3,4-dichlorophenyl)-[(2S,3S,4R)-3,4,5-trihydroxytetrah ydroforan-2-yr]methyi| 4- phenylbenzoate (124a) (3.4 g, 7.05 mmol) was added all at once. The reaction mixture was stirred at 25 °C for 1 h. The mixture was concentrated in vacuum to give crude product which was purified by silica gel column chromatography, eluted with PE : EA from 50 : 1 to 10 : 1 to give [(R)-[(2S,3S,4R,5R)-5-[5-[[tert-buty'l(dimethyl)silyl]oxymet hyl] -4-chloro-pyrrolo-[2,3-d]- pyrimidin-7-yl]-3,4-dihydroxy-te1iahydro^ 4- phenylbenzoate (130a) (2.5 g, 3.31 mmol, 46.9% yield) as a yellow solid. LCMS [M+H]: 754.0. Step 2. Synthesis of (R)-[(3aR,4R,6R,6aR)~4-[4-ammo-5- [[tert-butyl- (dimeth}4)silyl]ox melhyl]pyrrolo[2,3-d]pyrimidin -7-yl]-2,2-dimethyl-3a,4,6,6a- te1xaliydrofuro[3,4-d][l,3]dioxol-6-yl]-(3,4-dichlorophenyl) methanol (130b) 0441] To a solution of [(R)~[(3aR,4R,6R,6aR)-4-[5~[[tert- butyl(dimethyl)silyl]oxymethy]]-4-chloro-pyrro]o [2,3-d]pyrimidin-7-yl]-2,2-dimethyl-3a,4,6,6a- tetrahydrofiiro[3,4-d][l,3]dioxol-6-yl]-(3,4-dichlorophenyl) methyl] 4-phenylbenzoate (130a) (2.5 g, 3.14 mmol) in 1,4-Dioxane (10.0 mL) was added ammonium hydroxide (10.0 mL, 259.63 mmol). The reaction mixture was stirred at 120 °C for 18 h in sealed tube. The mixture was concentrated in vacuum to give crude product which was purified by silica gel column chromatography, eluied with PE : EA from 5 : 1 to 100% of EA to obtain (R)-[(3aR,4R,6R,6aR)-

4- [4-amino-5- [[tert-but> -(dm emyl)silyl]oxymethyl]pyrrolo[2,3-d]pyrimidin -7-yl]-2,2- dimethyl-3a,4,6,6a-tetrahydrofaro[3,4-d][l ,^ (130b) (254.0 mg, 0.40 mmol, 12.8% yield) as a yellow solid. LCMS f M+H] : 555.0.

Step 3. Synthesis of (2R,3R,4S,5R)-2-[4-amino-5-(hydroxymeth}'l)pyrrolo[2,3-dlpyr imidin-7- yl]-5-[(R)-(3,4-dichlorophenyl)-hydroxy-methylJtetrahydrofi. iran-3,4-diol hydrochloride (130)

|0442j To a solution of (2R,3R,4S,5R)-2-[4-amino-5-[[tert- butyl(dimethyl)silyl]oxymetliyljpyiTolo[2,3-d] pyrimidin-7-yl]-5-[(R)-(3,4-dichloi phenyl)- liydroxy~methyl]tetrahydrofuran-3,4-diol (130b) (120.0 mg, 0.22 mmol) in DMSO (5.0 mL) and Methanol (0.05 mL) was added CsF (32.8 mg, 0.22 rnmol). The mixture was stirred at 25 °C for 18 h. The mixture was purified by pre-HPLC, eluted with MeCN in water (0.1%TFA) from 10.0% to 95.0%, added HC1 (1 M, 0.5 ml,) and lyophilized to obtain (2R,3R,4S,5R)-2-[4-amino-

5 - (hydroxym ethyl)pyrrolo [2,3 -d]pyrimidin-7-yl] -5 -[(R)-(3 ,4-di chlorophenyl)-hydroxy- methyT|teirahydrofuran-3,4-diol hydrochloride (Ex, 130) (2.6 mg, 0.005 mmol, 2.5% yield). LCMS [M+H] : 441.3. ¾ NMR (400 MHz, DMSQ-ae+DiQ) δ 8.64 (s, 2 H), 8.40 (s, 1 H), 7.60 (s, 2 H), 7.56 (d, ./ 8 Hz, 1 H), 7.38 (d, ./ 8,0 Hz, 1 H), 6.08 (d, ,/ 8.0 Hz, 1 H), 4 ,79 (s, 1 H), 4.70 (s, 2 H), 4.41-4.44 (m, 1 I I) , 4.09 (s, 1 H), 4.01 (s, 1 H).

Example 131. (2R3R4S,5R)-2-(2,4-diammo-5-eAynyl-7H-pyrrolo[2,3-d]pyrimidi n-7-yl)-5- ((R)-(3,4-difluorophenyl)(hydroxy)methyl)tetrahydrofiiran-3, 4-diol (131)

Step 1. Synthesis of 2,4-dichloro-5-iodo-7H-pyrro]o[2,3-d]pyrimidine (Ola)

[0443] To a suspension of 2,4-dichloro-7H-pyrro]o[2,3-d]pyrimidine (7,2 g, 38 mmol) in DCM (120 mL) was added N-Iodosuccinimide (12.0 g, 53.3 mmol) in portions over 30 min. The mixture was stirred at 25 °C for 16 h. The mixture was filtered, the filtered cake was washed with DCM to give 2,4-dichloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (131a) (7.6 g, 24 mmol, 64% yield) as a white solid. LCMS | M I I I. 313.9.

Step 2. Synthesis of [(R)-[(2S,3S,4R,5R) -5-(2,4-dichloro-5-iodo-pyrrolo[2,3-d]pyrimidin-7- yl)3,4-dihydroxy-tetrahydrofuran-2-yll-(3,4-difluorophenyl) -methyl] 4-phenylbenzoate (131c)

[0444] To a solution of 2,4-dichloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (131a) (7.2 g, 23 mmol) in dry THF (200.0 mL) was added Pyridine (1.9 mL, 22.94 mmol), Tributylphosphane (1 1.5 mL, 45.87 mmol) and DIAD (9.5 mL, 48, 17 mmol) under Ni. [(R)-(3,4-difluoro phenyl)- [(2S,3S,4R,5R)-3,4,5 rihydroxytetrahydrofuran-2-yi]metiiyl] 4-phenylbenzoate (131b) (10.1 g, 22,94 mmol) in dry THF (100.0 mL) was added to the reaction mixture at once. The reaction mixture was stirred at 25 °C for 2 h under N2. The mixture was concentrated in vacuum to give crude product which was purified by combi-flash eluted with CHsCN in H2O from 10,0% to 90.0% to afford [(R)-[(2S,3S,4R,5R) -5-(2,4 Iic oro-5 odo-pyrrolo[2,3~dipyrimidm~7--y3)3,4- dihydroxy-tetrahydrofuran-2-yl]-(3,4-difluorophenyl) -methyl] 4-phenylbenzoate (131ε) (6.6 g, 8.9 mmol, 39 % yield) as a yellow solid. LCMS [M+H]: 738.0,

Step 3. Synthesis of (2R,3R,4S,5R)-2-(4-amino-2-chloro-5- >do-pyrrolo[2,3Kl]pynniidin-7-yl) - 5-[(R) -(3,4-difluorophen yl)-hydroxy-methyl]tetraliydrofuran-3,4-diol (131d) and

(2R,3R,4S,5R)-2-(2,4-diamino -5-iodo-pyrrolo[2,3-d]pyrimidin-7-yl)-5-[(R)-(3,4- difluorophenyl)-hydroxy-methyl]tetrahydrofuran-3,4-diol (131e)

[0445] To a solution of [(R)-[(2S,3S,4R,5R)-5-(2,4-dichloro-5-iodo-pynOlo[2,3~ d]pyrimidin-7-yl)-3,4-di hydroxy-tetrahydrofuran-2-yl]-(3,4-difluoropheriyl)methyl] 4- phenylbenzoate (131c) (2.0 g, 2.71 mmol) in 1,4-Dioxane (5.0 mL) was added Ammonium hydroxide (5.0 mL, 129.81 mmol). The mixture was stirred at 120 °C for 16 h in sealed tube. The mixture was concentrated in vacuum to give crude product which was purified by reversed phase combi-flash eluted with CHsCN in H2O from 10.0% to 90.0% to give (2R,3R,4S,5R)-2-(4- amino-2-chioro-5-iodo-pyrrolo[2,3-d]pyrimidin-7-yl) -5-[(R) -(3,4-difluorophen yi)-hydroxy- methyl]tetrahydrofuran-3,4-diol (131d) (1.4 g, 2.22 mmol, 82.0 % yield, purity 82.0 %, LCMS [M+H]: 538,9) as an off white solid and (2R,3R,4S,5R)-2~(2,4~diammo -5-iodo-pyrrolo[2,3- d]pyrimidin-7-yl)-5-[(R)-(3,4-difluorophenyl)-hydroxy-m (131e) (100.0 mg, 0.17 mmol, 6.3 % yield, purity 88.0 %, LCMS | .M H i . 520.0.) as an οίϊ-white solid.

Step 4. Synthesis of (2R3R4S,5R)-2-[2,4-diamino-5-(2-triisopropy3silyiethynyl)pyr roio [2,3- d]pyrimidin-7 -yl]-5-[(R)-(3,4-difluorophenyl)-hydroxy-methyl]tetraliy(kof uran-3,4-diol (131f)

[0446] To a solution of (2R3R,4S,5R)-2-(2,4-diamiiio-5-iodo-pyrrolo[2,3-d]pyrimidin- 7-yl)-5-[(R)-(3,4-di fluorophenyl)-hydroxy-methyl]tetrahydrofuran-3,4-diol (131e) (80.0 mg, 0.15 mmol) in DMF (2.0 mL) was added Cul (1.5 mg, 0.01 rnmol), (triisopropylsilyl)acetylene (0.2 mL, 0.77 mmol), Pd(PPli3)4 (17.8 mg, 0.02 mmol) and triethylamine (0.1 mL, 0.46 mmol). The reaction mixture was stirred at 25 °C for 4 li under N2. The reaction mixture was filtered and washed with EA (10.0 mL), the filtrate was washed with brine (2x 10.0 mL), the organic layer was concentrated in vacuum to give cmde product which was purified by silica gel column chromatography, eluted with PE : EA from 10 : 1 to 1 : 1 to give (2R,3R,4S,5R)-2-[2,4- diamino-5-(2-triisopropylsily]ethynyl)pyrrolo [2,3-d]pyrimidin-7 -yl]-5-[(R)-(3,4- difluorophenyl)-hydroxy-methyl]tetrahydrofuran-3,4-diol (131f) (85.0 mg, 0.15 mmol, 96,2 % yield) as an off-white solid. LCMS [M+H] : 574.2.

Step 5. Synthesis of (2R,3R,4S,5R)-2-(2,4-diamino-5-ethynyl-7H-pyrrolo[2,3-dlpyri midin-7-}'l)- 5 -((R)-(3 ,4-difluorophenyl)(hydroxy)metliyl)tetrahydrofuran-3 ,4-diol (131)

10447] To a solution of (2R,3R,4S,5R)-2-[2,4-diamino-5-(2- triisopropyisilylethynyi)pyrrolo[2,3-d]pyri midin-7-yl]-5-[(R)-(3,4-difluorophenyl)-hydrox '- methyl]tetrahydrofuran-3,4-diol (131f) (85.0 mg, 0.15 mmol) in DMSO (2.0 mL) and Methanol

(0.02 mL) was added Caesium fluoride (67.5 mg, 0.44 mmol). The mixture was stirred at 25 °C for 2 h. The mixture was filtered and the filtrate was purified by prep-HPLC eluted with CftCN m i-fcO (0.1 % NH 4 OH) from 10.0% to 90.0% to give (2R,3R,4S,5R)-2~(2,4~diammo-5-ethynyl- pyrrolo[2,3-d]pyrimidm-7-yl)-5-[(R)-(3,4-difiuoro^

dioi (Ex. 131) (16.3 mg, 0.04 mmol, 25.5 % yield) as an off-white solid. LCMS [M+H]: 418.1. H NMR (400 M Hz, DMSO-ife): δ 7.79-7.87 (m. 3 H), 7.65-7,68 (m, 1 H), 6,64-6.79 (m, 3 H), 6.22-6.27 (m, 3 H), 5.65 (brs, 1 H), 5.43 (brs, 1 H), 5.20 (d,■/ 4.8 Hz, 1 H), 4.87-4.90 (m, 1 H), 4.64 (s, 1 H), 4.44 (d, ./ 4.8 Hz, 1 H), 4.35 (d, ./ 4.8 Hz, 1 H). i l NMR (400 M Hz, DMSO- de+ O) δ 7.33-7.41 (m, 2 H), 7.28 (s, 1 H), 7.23-7.26 (m, 1 H), 5.80 (d, J= 7.2 Hz, 1 H), 4,80 (d, J= 4.4 Hz, 1 H), 4.46-4.49 (m, 1 H), 4.12 (s, 1 H), 4.04 (d, J= 5.2 Hz, 1 H), 3.99 (m, 1 H). '•" 'I- ' NMR (376 M Hz, DMSO-cfe): δ -138.97 (d, J ----- 22.5 Hz, 1 F), -140.84 (d, ./ 22.5 Hz, 1 F).

Example 132. (2R,3R,4S,5R)-2-(4-amino-5-(prop- 1-yn- l-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)- 5-((R)-(3,4-dichlorophenyl)(hydfoxy)methyl)tetrahydrofi.iran -3 ,4-diol (132)

124c Ex. 132

[0448] To a solution of (2R,3R,4S,5R)-2-(4-amino-5-iodo-pyrrolo[2,3-d]pyrimidin-7- yl)-5-[(R)- (3,4-dichloropheny3)-hydroxy-methy]]tetrahydrofiiran-3,4-dio l (124c) (100.0 mg, 0.19 mmol) in DMF (20.0 mL) was added TEA (94.0 mg, 0.93 mmol), Cul (5.3 mg, 0.03 rnmol), Pd(PPh.3)4 (21.5 mg, 0.02 mmol) and Prop-l-yne (0.93 mL, 1 M, 0.93 mmol). The reaction mixture was stirred at 30 °C for 18 h under Ni. The reaction mixture was filtered and the filtrate was purified by prep-HPLC, eluted with MeC in H 2 0 (0.1% TFA) from 10.0% to 95.0% to give the product which was added saturated H3HCO3 (aq, 2.0 mL) before freeze -drying. The product was further purified by prep-HPLC, eluted with CH3CN in H2O (0.1% NH3.H2O) from 5.0% to 90.0% to obtain (2R,3R,4S,5R)-2-(4-amino-5-prop-l-ynyl-pyrroki[2,3-d |pyrimidin-7- yl)-5-[(R)-(3,4-dichlorophenyl) -hydroxy-methyl]tetrahydrofuran-3,4-diol (Ex. 132) (2.5 mg, 0,0053 mmol, 2.9% yield) as a white solid. LCMS [M+H] : 451.8. ¾ NMR (400 M Hz, DMSO- d6+OiQ ): δ 8.10 (s, 1 I s ). 7,62 (d, ./ 1 ,6 Hz, 1 H), 7,58-7,60 (m, 2 H), 7,38-7,41 (m, I H), 5.94-5.96 (d,■/ 7.6 Hz, 1 H), 4.81-4.82 (d, ,/ 4.4 Hz, 1 H), 4.51-4.54 (m, 2 H), 4.00-4.03 (m, 1 H), 2.10 (s, 3 H).

Example 133. (2R,3R,4S,5R)-2-(2,4-diamino-5-(prop-l-yn-l-yl)-7H-pyrrolo[2 ,3-d]pyrimidin-7- y3)-5-((R)-(3,4-dichlorophenyl)(hydroxy)methyl)tetrahydrofur an-3,4-diol (133)

Step 1. Synthesis of [(R)-[(2S,3S,4R, 5R)-5- (2,4-dichloro-5-iodo-pyrrolo[2,3-d]pyrimidin-7-yl)- 3,4-dihydroxy-tetrahydrofuran-2-yl]-(3,4-dichlorophenyl)meth yl] 4-phenylbenzoate (133a)

[0449J To a solution of 2,4-dichloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (131a) (2.6 g, 8.42 mmol) in dry THF ( 100.0 mL) was added Pyridine (0.7 mL, 8.42 mmol), Tributylphosphane (4.2 ml,, 16,83 mmol) and DIAD (3.5 mL, 17.67 mmol) at 2.5 °C under N 2 . [(R)-(3,4- dichlorophenyl)-[(2S,3S,4R,5R)-3,4, 5-trihydrox\ :etrahydrofuran-2-yl]methy]] 4- phenylbenzoate (124a) (4.0 g, 8.42 mmol) in dry THF(50.0 mL) was added the reaction mixture at once. The reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated in vacuum to give cmde product which was purified by combi-flash eiuted with CH3CN in H2O from 10.0% to 90.0% to give [(R)~[(2S,3S,4R, 5R)-5- (2,4-dichloro-5-iodo-pyrrolo[2,3- d]pyrimidin-7-yl)-3,4-dihydroxy-tetrahydrofe 4- phenylbenzoate (133a) (4.0 g, 4.25 mmol, 50.5 % yield) as a yellow solid. LCMS [M+H] : 769.9.

Step 2. Synthesis of (2R,3R,4S,5R)-2-(4-amino-2-chloro-5-iodo-pyrrolo | 2,3-d]pyrimidin-7-yl) - 5-[(R)-(3,4-dichlorophenyl)-hydroxy-met yl]tetra ydroftiran-3,4-diol (133b) f0450 ' j To a solution of [(R)-[(2S,3S,4R,5R)-5-(2,4-dichloro-5-iodo-pyrrolo[2,3- d]pyrimidin-7-yl)-3,4-di hydroxy-tetrahydrofuran-2-yl]-(3,4-dichlorophenyl)methyl] 4- phenylbenzoate (133a) (4.0 g, 5.19 mmol) in 1,4-Dioxane (8.0 mL) was added Ammonium hydroxide (8.0 mL, 198.84 mmol). The reaction mixture was stirred at 140 °C for 60 h in sealed tube. The mixture was concentrated in vacuum to give crude product which was purified by reversed phase combi-flash eiuted with CH3CN in H2O from 10.0% to 90.0% to give the product (1.76 g, 1.85 mmol, yield 35.6 %), (a mixture of [Ι, Γ-biphenyl] -4-carboxamide and

(2R,3R,4S,5R)-2-(4-amino-2-chloro-5-iodo-pyrrolo [2,3-d]pyrimidin-7-yl) -5-[(R)-(3,4- dichlorophenyl)-hydroxy-methyl]tetrahydrofuran-3,4-diol (133b)) as a yellow solid. LCMS [M+H] : 552.0.

Step 3. Synthesis of (2R,3R,4S,5R)-2-(2,4-diamino-5-prop-l -ynyl- pyrrolo[2,3-d]pyrimidin-7- yl)-5- [(R)-(3,4-dichloro phenyl)-hydroxy-memyl]tetJuhydrofuran-3,4-diol dihydrochioride (133)

[0451] To a solution of (2R,3R,4S,5R)-2-(2,4-diamino-5-iodo-pyrrolo[2,3-d]pyrimidin-

7-yl)~5-[(R)~(3,4~di chlorophenyl)~liydroxy~methy4]tetrahydrofuran~3,4-diol (133b) (500.0 mg, 0.54 mmol) in DMF (5 ,0 mL) was added Cul (10,4 mg, 0.05 mmol),

Tetrakis(triphenylphosphine)palladium (62.8 mg, 0.05 mmol), Triethylamine (0.3 mL, 2.17 mmol) and Propyne (5.4 mL, 1.0 M, 5.43 mmol). The mixture was stirred at 25 °C for 6 h under N2, The mixture was filtered and the filtrate was purified by prep-HPLC eiuted with CH3CN in H2O (0.1 % TFA) from 10.0% to 90.0% to give the solution of TFA salt of the desired product which was added 2 M HQ aq . (4.0 mL) and lyophilized to give (2R,3R,4S,5R)-2-(2,4-diamino- 5-prop-l-ynyl- pyrroio[2,3-d]pyrimidin-7-yl)-5- [(R)-(3,4-dichloro phenyl)-hydroxy- methyl]tetrahydrofuran-3,4-diol dihydrochioride (Ex, 133) (33.2 mg, 0.06 mmol, 1 1 .1 % yield) as an off-white solid. LCMS [M+H]: 484.1. Ή NM (400 M Hz, DMSO- 6): δ 12.02 (brs, 1 H), 7.91 (brs, 2 H), 7.57-7.61 (m, 2 H), 7.46-7.55 (m, 3 H), 7.35-7.38 (m, 1 H), 6.06 (brs, 1 H), 5.86 (d, ,/ 7.6 Hz, 1 H), 5,35 (brs, 1 1 I). 5.13 (brs, 1 H), 4.76 (d, ./ 4.8 Hz, 1 H), 4.35-4.38 (m, 1 H), 4.05 (d, J= 4,4 Hz, 1 H), 3.92 (d, .1= 5,6 Hz, 1 H), 2.09 (s, 3 H), Ή MR (400 M Hz, DMSO- 6+D2O): δ 7.57-7.59 (m, 2 H), 7.46 (s, 1 H), 7.36-7.38 (m, 1 H), 5.86 (d, ./ 7.6 Hz, 1 H), 4.75 (d, ./ 5.2 Hz, 1 H), 4.35-4.38 (m, 1 H), 4.06 (d, ./ 4.0 Hz, 1 H), 3.92 (d, ./ 4.8 Hz, 1 I !}. 2,09 (s, 3 H).

Example 134. (2R,3R,4S,5R)-2-(2,4~diamino-5-(prop-l-yn-l~y3)-7H~pyrrolo[2 ,3-d]pyri yl)-5-((R)-(3,4-dif!uorophenyl)(hydroxy)methyl)tetrahydrofur an-3,4-di (134)

1318 Ex. 134

| 452) To a solution of (2R,3R,4S,5R)-2-(2,4-diamino-5-iodo-pyiTolo[2,3-d]pyrimidin- 7-yl)-5-j(R)-(3,4-di fluorophenyl)-hydroxy-niethyi|tetraliydrofuran-3,4-diol (131e) (100.0 nig, 0.19 mmol) in DMF (3.0 mL) was added Cul (3.7 mg, 0.02 mmoi),

Tetrakis(triphenyiphosphine)paliadium (22.2 mg, 0.02 mmoi), Triethylamine (0.1 mL, 0.77 mmol) and Propvne (1.9 mL, 1 M, 1.93 mmol). The reaction mixture was stirred at 25 °C for 6 h under N2. The mixture was filtered and the filtrate was purified by prep-HPLC eluted with CftCN in H2O (0, 1 % NH4OH) from 10.0% to 90,0% to give the erode product (30.0 mg, purity 69.18 %) which was further punfied by prep-HPLC eluted with CHbCN in H2O (0.1 % TFA) from 10.0% to 90.0% to afford the solution of TFA salt of the desired product. The solution was added 2.0 M HC1 aq. (4.0 mL) and lyophilized to give the (2R,3R,4S,5R)-2 -(2,4-diamino-5- prop-l-ynyl-pyirolo[2,3-d]pyrimidin-7-yl)-5-[(R)-(3,4-difluo rophenyl)-hydroxy- metiiyl]tetrahydrofuran-3,4-diol dihydrochloride (Ex. 134) (11 .0 mg, 0.02 mmol, 11.1 % yield) as an off-white solid. LCMS [M+H]: 432.2. Ή NMR (400 M Hz, DMSO- 6): δ 12.38 (brs, 1 H), 8.02 (brs, 2 H), 7.48-7.52 (m, 3 H), 7.34-7.42 (m, 2 H), 7.20-7.26 (m, 1 H), 6.07 (brs, 1 H), 5.86 (d, ,/= 7.6 Hz, 1 H), 5,35 (brs, 1 H), 5.15 (brs, 1 H), 4.75 (d, J= 5.2 Hz, 1 H), 4.35-4.38 (m, 1 H), 4.06 (d. ./ 4.8 Hz, 1 H), 3.92 id. ./ 5.2 Hz, 1 H), 2.09 (s, 3 H). : I I NMR (400 M Hz, DMSO-c¾+D 2 0 ): δ 7,44 (s, 1 H), 7.34-7.39 (m, 2 H), 7.18-7,24 (tn, 1 H), 5,84 (d, J= 7.6 Hz, 1 H), 4.73 (d, J = 5.2 Hz, 1 H), 4.33-4.36 (m, 1 H), 4.05 (d, J = 4.4 Hz, 1 H), 3.92 (d, J = 5.2 Hz, 1 H), 2.07 (s, 3 H). i9 F NMR (376 M Hz, DMSO- 6): δ -139.25 (d, J= 22,5 Hz, 1 F), -141 ,24 (d, J = 22,5 Hz, 1 F).

Example 135. (2R,3R,4S,5R)-2-(2,4-diamino-5-ethynyl-7H-pyrrolo[2,3-d]pyri midin-7-yl)-5-

((R)-(3,4-dichlorophenyl)(hydroxy)methyl)tetraliydrofuran -3,4-diol (135)

Step 1. Synthesis of (2R,3R,4S,5R)-2~[2,4~diamino-5-(2~tnisopro

djpyrirnidin -7-yl]-5-[(R) -(3,4-dichlorophenyl)-hydroxy-methyl]tetrahydrofuran-3,4-dio l (135a)

|0453J To a solution of (2R,3R,4S,5R)-2-(2,4-diamino-5-iodo-pyrrolo[2,3-d]pyrimidin- 7-yl)-5-[(R)-(3,4-di chlorophenyl)-hydroxy-methyl]tetra }'drofurati-3,4-diol (133b) (500.0 mg, 0.54 mmol) in DMF (5.0 mL) was added Cul (10.4 mg, 0.05 mmol),

Tetrakis(triphenylphosphine)palladium (62.8 mg, 0,05 mmol), Triethylamine (0.3 mL, 2.17 rnmol) and (Triisopropylsilyl)acetylene (495.5 mg, 2.72 mmol). The reaction mixture was stirred at 25 °C for 6 h under N2. The mixture was filtered and the filtrate was diluted with water (20.0 mL) and extracted with EA (30.0 mi , ?. }. The combined organic layers were washed with brine (10.0 mL), dried over Na2S04 , filtered and concentrated in vacuum to give crude product which was purified by silica gel column chromatography, eluted with PE : EA from 40 : 1 to 10 : 1 to give (2R,3R,4S,5R)-2~[2,4~diamino-5-(2~triisopropy -7-yl]- 5-[(R) -(3,4-dichlorophenyl)-hydrox '-methyl]tetrahydrofuran-3,4-diol (135a) (280.0 mg, 0,46 mmol, 85.0 % yield) as an off-white solid. LCMS ! M 606.2.

Step 2. Synthesis of (2R,3R,4S,5R)-2-(2,4-diamino-5-em>nnyl-7H-pyrrolo[2,3-d]p yrimidin-7-yl)- 5-((R)-(3,4-dichlorophenyl)(hydroxy)methyl)tetrahydrofuran-3 ,4-diol (135) [0454] To a solution of (2R,3R,4S,5R)-2-[2,4-diamino-5-(2- triisopropylsilylethynyl)pyrrolo[2,3-d]pyri midin~7-yl]~5-[(R)-(3,4-dichlorop3ienyl)-liydroxy- methyl]tetraliydrofuran-3,4-diol (135a) (250. mg, 0.41 mmol) in DMSO (4.0 mL) and Methanol (0.04 mL) was added Caesium fluoride (187,8 mg, 1.24 mmol). The mixture was stirred at 25 °C for 2 h. The mixture was filtered and the filtrate was purified by prep-HPLC, elated with CI-fcCN in H2O (0.1 % NH4OH) from 10.0% to 90.0% to give (2R,3R,4S,5R)-2-(2,4-diamino-5- ethynyl- pyrrolo[2,3-d]pyrimidin-7-yl)-5-[(R)-(3,4-dichlorophenyl) -hydroxy-methyl]tetrahydrofuran-3,4- diol (Ex. 135) (44.5 mg, 0.10 mmol, 23.78 % yield) as an white solid. LCMS [M+H]: 450,0. ! H NMR (400 M Hz, DMSi //. - !).·.<) ): δ 7.63 (d. ./ 1.6 Hz, 1 H), 7.58 (d. ./ 8,4 Hz, 1 H), 7.39 (dd, ./: = 8.4 Hz, ./ = 1.6 Hz, 1 H), 7.36 (s, 1 H), 5.83 (d. ./ 7.6 Hz, 1 H), 4.80 (d. ./ 4.8 Hz, 1 H), 4.45-4.48 (m, 1 H), 4.19 (s, 1 H), 4.00 (d, J= 4.8 Hz, 1 H), 3.94 (d, J= 4.8 Hz, 1 H).

Biochemical Assay Protocol

[0455] Compounds were solubilized and 3-fold diluted in 100% DMSO. These diluted compounds were further diluted in the assay buffer (50 mM Tris-HCl, pH 8,5, 50 mM NaCl, 5 mM MgCh, 0,01% Bnj35, 1 mM DTT, 1% DMSO) for 10-dose IC50 mode at a concentration 10-fold greater than the desired assay concentration. Standard reactions were performed in a total volume of 50 μΐ in assay buffer, with hi stone H2A (5 μΜ final) as substrate. To this was added the PRJVIT5/MEP50 complex diluted to provide a final assay concentration of 5 11M and the compounds were allowed to preincubate for 15 to 20 mmutes at room temperature. The reaction was initiated by adding S-[3 H-methyl]-adenosyl-L-methionine (PerkinElmer) to final concentration of 1 μΜ. Following a 60 minutes incubation at 30 °C, the reaction was stopped by- adding 100 uL of 20% TCA. Each reaction was spotted onto filter plate (MultiScreen FB Filter Plate, Millipore), and washed 5 times with PBS buffer, Scintillation fluid was added to the filter plate and read in a scintillation counter. IC50 values were determined by fitting the data to the standard 4 parameters with Hill Slope using GraphPad Prism software Cellular Assay Protocol

Cell treatment and Western Blotting for detecting Symmetric Di-Methyl Arginine (sDMA) and Histone H3R8 Dimethyl Symmetric (H3R8me2s) marks

[0456] Initial compounds screening in A549 cells: Compounds were dissolved in DMSO to make 10 mM stock and further diluted to 0.1, and 1 mM. A549 cells were maintained in PRMI 1640 (Corning Celigro, Catalog #: 10-040-CV) medium supplemented with 10% v/v FBS (GE Healthcare, Catalog #: SH30910.03). One day before experiment, 1.25 x HP cells were seeded in 6 well plate in 3 mL medium and incubated overnight. The next day, medium was changed and 3 uL of compound solution was added (1: 1 ,000 dilution, 0.1 and 1 uM final concentration; DMSO concentration: 0.1 %), and incubated for 3 days. Cells incubated with DMSO was used as a vehicle control. Cells were washed once with PBS, trypsinized in 150 uL 0.25% Trypsin (Corning, Catalog #: 25-053-CT), neutralized with 1 mL complete medium, transferred to microcentrifuge tubes and collected. Cell pellet was then resuspended in 15 uL PBS, lysed in 4% SDS, and homogenized by passing through homogenizer column (Omega Biotek, Catalog #: HCR003). Total protein concentrations were determined by BCA assay (ThermoFisher Scientific, Catalog #: 23225). Lysates were mixed with 5x Laemmli buffer and boiled for 5 min. Forty ug of total protein was separated on SDS-PAGE gels (Bio-Rad, catalog #: 4568083, 4568043), transferred to PVDF membrane, blocked with 5% diy milk (Bio-Rad, Catalog #: 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, Catalog #: 13222, 1 :3,000; H3R8me2s: Epigentek, Catalog #: A-3706-100, 1 :2,000; β-Actm: Abeam, Catalog #: ab8227, 1 : 10,000) in 5% dry milk in TBST at 4 °C for overnight. The next day, membranes were washed with TBST, x 5 min, and incubated with HRP conjugated seconded antibody (GE Healthcare; Catalog #: NA934-1ML; 1 :5,000) for 2 hours at RT, followed by 5 x 5 mm washes with TBST, and incubation with ECL substrates (Bio-Rad, Catalog #: 1705061, 1705062). Chemilumine scent signal was captured with Fiuochem HD2 imager (Proteinsimpie) and analyzed by Image J.

[0457] To determine enzyme inhibition ICso values using Western Blot analysis,

Granta cells were seeded at density of 5 x 10 5 cells/mL in 3 mL medium (PRMI +10% v/v FBS).

Nine-point 3-fold serial dilutions of compound were added to cells (3 ul, 1: 1,000 dilution,

DMSO concentration was 0.1%; final top concentration was 10 or 1 uM, depending on compounds potency) and incubated for 3 days. Cells incubated with DMSO was used as a vehicle control . Cells were harvested and subjected to western blot analysis as described above. SmD3me2s and H3R8me2s bands were quantified by Image J. Signals were normalized to β- Actin and DMSO control. ICso values were calculated using Graphpad Prism.

Cell proliferation assay to determine ICso on Granta-519 cells

[0458] Granta-519 cells were maintained in PRMI 1640 (Corning Cellgro, Catalog #: 10-040-CV) medium supplemented with 10% v/v FBS (GE Healthcare, Catalog #: SH30910.03). Compounds were dissolved in DMSO to make 10 mM stocks and stored at -20 °C. Nine-point, 3 -fold serial dilutions were made with DMSO with top concentration at 1 mM (working stocks).

[0459] On day of experiment, compound working stocks were further diluted at 1 :50 with fresh medium in 96 well plate, and 10 μΕ of diluted drags were added to a new 96 well plate for proliferation assay. Ceils growing at exponential phase were spun down at 1500 rpm for 4 min and resuspend in fresh medium to reach a density of 0.5xl0 6 cells/ml. 200 ul of cells were added to 96 well plate containing diluted drugs and incubated for 3 days. DMSO was used a vehicle control.

[0460] On day 3, 10 fiL of Cell Counting Kit-8 (CCK-8, Jojindo, CK04-13) solution was added to a new 96 well plate. Cells incubated with drags for 3 days were resuspended by pipetting up and down, and 1 0 μί, of cells were transferred to 96 well plate containing CCK-8 reagent to measure viable cells. Plates were incubated in C02 incubator for 2 hours and OD450 values were measured with a microplate reader (iMark microplate reader, Bio-Rad).

[0461] For re-plating, compound working stocks were diluted at 1 :50 with fresh medium and 10 μΙ_, of diluted drags were added to a new 96 well plate. Cells from Day 3 plate (50 ul) were added to 96 well plate containing fresh drag and additional 150 uL of fresh medium was added to reach 200 μΐ, volume. Plate was returned to COi incubator and incubated for 3 more days. Viable cells measurement and re-plating were repeated on day 6, and the final viable cells measurement was taken on day 10.

[0462] Percentage of viable cells, relative to DMSO vehicle control, were calculated and plotted in Graphpad Prism ([Inhibitor] vs. normalized response - Variable slope) to determine proliferation ICso values on day 10.

Table 2 Biochemical and cellular potency (in Granta cell line)

19 300

24 300

25 64

56 0.0237

65 0.07

66 0.01 4

111 9.2

112 0.116

113 0.159

114 5.21

115 0.108

116 4.14

117 0.0248

118 0.002 0.031 1 0,053 0.239

119 0.0015 0.0173 0,038 0.131

120 0.011 0.087 0.097

121 0.0047 0.0347 0.087

122 0.0017 0.0058 0.16 0.138

123 0.001 1 0.0085 0.0667

124 0.0018 0.0063

125 0.001 0.0059

126 0.0007 0.0013 0.019 0.033

127 0.0013 0.003 0.0558

128 0.0012 0.0123 0.352

129 0.0022 0.0273 0,355

130 0.0132 0.137

131 0.0079 0.0355 0.235

132 0.0039 0.0083

133 0.0013 0.0111

134 0.0101 0.08 9

135 0.0063

|0463] The disclosure encompasses the following aspects:

Aspect 1. A compound of Formula I, Formula II, or Formula III:

wherein

A is CH or N;

n is 0 or 1 ;

R 1 is -Ci-Cealkyl, -CH(OH)-Ci-C 6 alkyL -Ci-Cehaloalkyl, -CH(OH)-Ci-C6haloalkyl. -Co- C6alk-C3-C6cyeloalkyL ~Co-C&aik-C3~C6haiocyeloalkyl; -Ci-Cealkenyl, -C2- Cehaloalkenyl, -Ci-Cealkynyl, -OfcS-Ci-Cealkyl, -CftS-C.-Cehaloalkyl, -CH2S- C3-C6cyeloalkyl; -CHiS-CB-Cehalocycloalkyl: -CHjOG-Cealkyl, -CH2O-C3- Cecycioalkyl, -CH(OH)-aiyl, -CH(F)-aiyl, -CH(NH2 aryi, -C(Me)(OH)-aiyl, - OfcSOfc-aiyl, or -CI 1 C(0}\! i-aiyl:

R 2 is H, halo, -Ci-Cealkyl, -Ci-Cehaloalkyl, -Co-C6alk-C3-C6cycloalkyl, -Cc-Cealk-OH, -Co-Cealk-O-Ci-Cealkyl. -Co-Qalk-NH., -Co-Cealk-NH-Ci-Cealkyl.

-Co-C6alk-N(Ci-C6alkyi)-Ci-C6alkyl, -Co-Cealk-NH-Cs-Cecycloalkyl,

-Co-C6alk-N(Ci-C6alkyl)-Cj-C6cycloalkyl, -Co-Cealk-heterocyeloalkyi, heteroaryi, or -CN;

R 3 is H, halo, -Ci-Cealkyl, -Ci-Cehaloalkyi, -Co-Cealk-Cs-Cecycloalkyl, -Co-Cealk-OH, -Cc-Cealk-O-Ci-Cealkyl, -Co-Cealk-Nfb, -Co-Cealk-NH-Ci-Cealkyl, -Co-Cealk- NCCi-Cealkylj-Ci-CealkyL -Co-Cealk-NH-Cs-Cecycloalkyl, -Co-Cealk-N(Ci- Cealkyl)-C3-C6cycloalkyl -Co-Cealk-heterocycloalkyl, heteroarvl, or -CN; R 4 is H, halo, -Ci-Cealkyl, -Ci-Cehaloalkyi, -Co-Cealk-Cs-CoCycloalkyl, -Co-Cealk-OH, -Co-Cealk-Q-Ci-Cealkyl, -Co-Ceaik-NH , -Co-Cealk-NH-Ci-Ceaikyl, -Co-Cealk- N(Ci-Cealkyl)-Ci-Cealkyl, -Co-Cealk-NH-Gi-Cecycloalkyl, -Co-Cealk-N(Ci- C6alkyl)-C3-C6Cycloalkyl -Co-Cealk-heterocycloalkyl, heteroaryl, or -CN;

or R 2 and R 3 , together with the atoms to which they are attached, form a

C3 -Cecy cloalkenyi ring ;

or R 2 and R 3 , together form a triple bond;

or R 3 and R 4 , together with the atom to which they are attached, form a Cj-Cecycloalkyl ring or a heterocycloalkyl ring;

R 5 is H, Ci-Cealkyl, or Co-Cealk-C3-Cecycloalkyl;

R 6 and R 7 are each independently H, Me, NH2, or CH2F;

R 8a and R 8b are each independently H, Ci-Cealkyl, or -Co-Cealk-OCi-Cealkyl, or R 8a and R 8b , togetlier with the atom to which they are attached, form a C3-Cecyc3oaikyi ring;

R 8 and R 8' are each independently H, Ci-Cealkyl, o -Cc-Cealk-OCi-Cealkyl;

or R 8 and R 8 , together with the atom to which they are attached, form a C -Cecycioalkyl ring;

R 9 is -Ci-C alkenyl, -Ci-Gihaloalkenyl, -C2-C4cyanoalkenyl, -C2-C4alkynyl, -Ci-

C/ihaloalkyl, -Ci-Ceheterocycloalkyl, oxo-substituted-Ci-Ceheterocycloalkyl, -Cs- Cecycloalkyi, -CHO, -C(O)R i0 , -CR 8 R 8' CN, -CH2NR 8 R 8' , -Co-Cealk-OH, - NR 8 R 8' , -NH-CN, -N(R !0 )CN, -O-C1-C4 alkyi, -NR 5 CONR 8 R 8' , -OCO NR 8 R 8' , or -NR 5 C(0)OR 10 ;

R 10 is -Ci-Cealkyl or Co-Cealk-C3-Cecycloalkyl; and

R 10a is H, -Ci-Cealkyi, or Co-Ceaik-C3-Cecycloalkyi.

Aspect 2. The compound of aspect 1 wherein A is CH. Aspect 3. The compound of aspect 1 wherein A is N.

Aspect 4. The compound of any one of aspects 1 , 2, or 3 wherein R 1 is -CH(OH)-aryl, - CifcS-Ci-Cealkyi, -Ci-Cehaioaikyl, -Co-Cealk-C3-Cecycloalkyl, -CFbSCFb-aryl, or -

Aspect 5. The compound of any one of aspects 1 to 4 wherein R 5 is H or -Ci-Cealkyl. Aspect 6. The compound of any one of aspects 1 to 5 wherein R b is H, NFfe, or Me.

Aspect 7. The compound of any one of the preceding aspects where R 7 is H.

Aspect 8. The compound of any one of the preceding aspects, which is a compound of Formula I.

Aspect 9. The compound of aspect 8 wherein at least one of R 2 , R 3 , and R 4 is H.

Aspect 10. The compound aspect 8 wherein R 2 , R 1 , and R 4 are each H.

Aspect 11. The compound of any one of aspects 8 to 10, wherein R 5 is H.

Aspect 12. The compound of any one of aspects 1 to 7, which is a compound of Formula II.

Aspect 13. The compound of aspect 12 wherein n is 0.

Aspect 14. The compound of aspect 12 wherein n is 1.

Aspect 15. The compound of aspect 14 wherein 10a is H.

Aspect 16. The compound of any one of aspects 12 to 15 wherein R 8a is H or Ci-Cealkyl .

Aspect 17. The compound of aspect any one of clams 12 to 16 wherein R 8b is H or Ci- Cealkyl.

Aspect 18. The compound of aspect 12, 13, 14, or 15 wherein R 8a and R 8B , together with the atoms to which they are attached, form a Cj-Cecycloalkyl ring.

Aspect 19. The compound of any one of aspects 12 to 18 wherein R 5 is H or Ci-Cealkyl.

Aspect 20. The compound of any one of aspects 1 to 7, which is a compound of Formula III.

Aspect 21. The compound of aspect 20 wherein R 9 is -C2-C4a!kenyl.

Aspect 22. The compound of aspect 20 wherein R 9 is -Ci-Cdialoalkenyi.

Aspect 23. The compound of aspect 20 wherein R 9 is C ' 2-C4cyanoalkenyl.

Aspect 24. The compound of aspect 20 wherein R 9 is -Cj-C'-ialkynyl. Aspect 25. The compound of aspect 20 wherein R 9 is -Ci-Cbheterocycloalkyl.

Aspect 26. The compound of aspect 20 wherein R 9 is oxo-substituted-C2-Ceheterocycloalkyl.

Aspect 27. The compound of aspect 20 wherein R 9 is -Cs-Cecycioaikyl.

Aspect 28. The compound of aspect 20 wherein R 9 is -C(0)R 10 .

Aspect 29. The compound of aspect 20 wherein R 9 is -CR 8 R 8 'CN .

Aspect 30. The compound of aspect 20 wherein R 9 is -CH2NR 8 R 8' .

Aspect 31. The compound of aspect 20 wherein R 9 is -Co-Ceaik-OH.

Aspect 32. The compound of aspect 20 wherein R 9 is -NR 8 R 8 .

Aspect 33. The compound of aspect 20 wherein R 9 is -NH-CN.

Aspect 34. The compound of aspect 20 wherein R 9 is -N(R i0 )CN.

Aspect 35. The compound of aspect 20 wherein R 9 is -NR 5 CONR 8 R 8' .

Aspect 36. The compound of aspect 20 wherein R 9 is -NR 5 C(0)OR 10 .

Aspect 37. The compound of any one of aspects 28 and 36 wherein R 10 is -Ci-Ceaikyl.

Aspect 38. The compound of any one of aspects 35 and 36 wherein is H.

Aspect 39. The compound of any one of aspects 29, 30, 32 and 35 wherein R 8 is H or Ci- Cealkyi.

Aspect 40. The compound of any one of aspects 29, 30, 32 and 35 wherein R 8' is H or Ci- Cealkyl.

Aspect 41. The compound of aspect 29 wherein R 8 and R 8' , together with the atom to which they are attached, form a Ci-Cecycloalkyi ring.

Aspect 42. A phaimaceutical composition comprising a compound according to any one of the preceding aspects and a pharmaceutically acceptable excipient. Aspect 43. A method of inhibiting a protein arginine methyltransferase 5 (PRMT5) enzyme, comprising: contacting the PRMT5 enzyme with an effecti ve amount of a compound of any one of any one of aspects 1 to 41.

Aspect 44. 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 to 41.

Aspect 45. The method of aspect 44, 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), myelodysplasia syndrome (MDS), epidermoid cancer, or hemoglobinopathies such as b- thalassemia and sickle cell disease (SCD).