1,2-DITHfOLANE COMPOUNDS USEFUL IN NEUROPROTECTION, AUTOIMMUNE AM) CANCER DISEASES AND CONDITIONS

FIELD OF INVENTION

The present invention is directed towards novel 1 ,2-dithiolanes and related compounds and pharmaceutical compositions comprising the compounds, which are useful for the treatment of tyrosine kin ses-- mediated diseases or conditions, such as neurodegeneration. neuroprotection, cancer, autoimmune as well as other diseases and conditions associated with the modulation of tyrosine kinases. The present invention is further useful for the treatrnentof niitogen-aetivate protein kinase (MAPK) and PI3K AKT/mTor signaling pathways mediated diseases and conditions. The present invention is further directed towards methods of treatment of diseases or conditions associated with tyrosine kinases, MAPK and P13K/AKT/mTor signaling pathways activity and provide processes for the preparation of novel 1 ,2-dithiolanes.

BACKGROUND OF THE INVENTION

The human genome encodes for 5 i 8 protein kinases of which 30 distinct targets have been developed in the clinic primarily for the treatment of cancer. However, deregulation of kinase functions has also been implicated in immunological diseases and disorders, neurological diseases and disorders, metabolic diseases and disorders, and infectious disease. The utility of kinases as drug targets is driven by several factors, which include their involvement in signal transduction pathways that are dependent on a phosphotransfer cascade to elicit a real physiological response (Zhang, J. et a!.. Nature, 2009, 9, 28-39). Approximately 100 are tyrosine kinases, which are either receptor (RTK) or non-receptor tyrosine t ^' NRTK) kinases. These kinases regulate several physiological mechanisms including, but not limited to, cell proliferation, cell differentiation, ceil migration, and cellular metabolism by transferring the ATP terminal phosphate to one or more tyrosine or serine residues of the protein substrates (Carmi, C. et al, Biochem. Ph mcol. 2012, 84, 1388- 1399). Inhibition of kinases affect signaling pathways associated with that kinase and therefore can have profound effects on cancer, autoimmune diseases and central nervous system (CNS) diseases. Many kinases are involved in oncogenesis resulting from a point mutation or deletion of an amino acid sequence, chromosome translocation or over-expression, in every case, the outcome is a hyperactive kinase that confers non-regulated growth stimulus in cells. Receptor tyrosine kinases function in. transmembrane signaling, whereas non-receptor tyrosine kinases exert their activities within the cell function and nucleus affecting signal transduction, cell cycle and transcription factors.

Cancer is a major global problem. Every year, there are about 1.7 million new cancer cases and about 580,000 deaths from cancer in the United States, amounting to one in deaths is due to cancer. Cancer can impact all organs and systems in the body including, but not limited to, the genital system, which includes the prostate; the digestive system that includes the colon and the pancreas; the respiratory system thai includes the lung and bronchus; the breast; the urinary system that includes bladder renal and kidney; the skin; blood such as (lymphoma, leukemia, myeloma); endocrine; oral cavity and pharynx; brain; soft tissue; hones; joints; and eye (Siegel, . et al., CA Cancer ./. Clin. 201 , 63, ] i -30).

The mammalian non-receptor tyrosine kinases (NRT s) are divided into ten families: ABL, ACK, CSK, FA , FES, FRK, JA , SRC, SYK and TEC. In addition to their tyrosine kinase catalytic domains, they all contain non-cataiytie domains that are important in enzyme regulation and substrate recognition. The SRC f mily kinases (SPKs) members include SRC, YES, FYN, PGR, BLK, HCK, LCK, and LY . SFKs play key roles in regulating signal transduction by a diverse set of ceil surface receptors. For example, SRC is a major activator of proteins by phosphorylation and is linked to cancer progression. Inhibitors of SRC such as bosutinib and dasatinib have demonstrated anticancer acti vities in humans, particularly in chronic myelogenous leukemia and acute lymphoblastic leukemia. LYN is considered a .key enzyme in cell activation, while FOR is a positive regulator of mast cells which are critical for various allergic disorders (Lee, J ^' .H. et al. J. Immunol. 201 1, 187, i 807- 1815). LCK is expressed in T-eeiis and is responsible for signaling through T-celi receptors, BL plays a key role in B-ccll receptor signaling, .HCK. plays a role in neutrophil migration, and YES is implicated in melanomas, basal-like and ER breast cancers, and rhabdomyosarcomas

FYN is a 59 KDa protein which has three isofornis: FynB that is mainly expressed in the brain, FynT expressed in. hematopoietic cells (T-cells), and FynDcita? identified in peripheral blood mononuclear celts (Goldsmith, IF. et al. Bi chem. Biophys. Res. Comm n. 2002, 298, 501 -504). ^' Through its interactions with almost 300 proteins, FYN plays key roles in physiological and pathological conditions associated with the centra! nervous system (CNS), cancer, the immune system and T-eeSI development (Kopec, A. et al. Arch. Immunol, ^' flier. Exp. 2006, 54, 393-401 ). In the CNS, FYN is implied in tnyeli nation and morphological differentiation associated with neurite formation (Sehenone, S. et at Can. Med. Chem. 200 L 18, 2921-2942), Alteration of the Tau protein in the CNS is associated with Alzheimer's disease (AD) and in this disease state, the protein Tau is phosphor lated at Ty l S by FYN. A set of FYN inhibitors in a cellular model of AD inhibited Ty l 8- Tau phosphorylation (Tintori, C. et al. J. Med Chem. 2015, 58, 4590-4609). In a transgenic AD mouse FYN overexpression accelerates synapse loss and the onset of cognitive impairment while inhibition of FYN expression rescues synapse loss (Chin, J. et al. ./. Neu sci, 2005 , 25, 9694-9703). The S.RC/PYN dual inhibitor saracatinib rescues memory deficits, restores synapse density and reduces microglial activation and Tau aggregation {Kaufman, A.C. el al. Ann. Neurol, 2015, 77, 953-971 ) in a transgenic AD mouse model, it is currently undergoing clinical evaluation in AD patients {Nygaard, H.B. et al. Alzheimer's Res. Ther. 2015, 7, 35-46). FYN and SRC knockdown contribute to cell apoptosis resulting from brain ischemia and A.B neurotoxicity suggesting FYN as a promising target

7 for neuroprotective therapy in ischemic stroke and AD (Du, C-P. et al CNS Neuro.Tfiemp. 2012, 18, 754-761). in oncology, overexpression of FYN is found in many cancers including glioblastoma mulliformae, squamous cell carcinoma of the head and neck, melanoma, breast, ovarian, prostate and pancreatic cancer (Saito, Y.D. et al. Cancer 201.0, 1 1.6, 3629- 1637). FYN is highly expressed in the testis and appears to have a role in spermatogenesis (Lao, J. et al. Biol. Reprotl. 2012, 86, 1 -8). FYN displays strong association with FLT3 as well as mutant FL3-1TD oncogene and cooperates with the hitter by selective activation of the STAT5 pathway suggesting that FYN in combination with FLT3 inhibition wit! be beneficial in AMI. patients (Chougule, .A. et al. Oncotarget 2016, ?, 9964-9974),

The oncogene BCR-ABL1 is responsible for the human Philadelphia chromosome positive chronic myeloid ieiikemia (CML) and B eel! acute lymphocytic leukemia (ALL). In vitro and in vivo studies have demonstrated that Bcr-Ael activates FGR, LYN and HCK kinases in lymphoid cells (Hit, Y. et al. Nature Genetics 2004, 36, 453-461) and thus, inhibitors of FGR, LYN and HCK have utility in CML and ALL cancers. YES kinase- activity has been shown to be unregulated in melanoma, head and neck, renal, lung and stomach cancers (Patel, P. . et al Bioorg, Med Chem. Lett. 2013, 23, 4398- 4403). YES ), was singled out. amongst SFK as functionally involved in malignant brain-metasiatie melanoma (Marchetti, D. et al. Oncogene 1 98. J.6. 3253-3260) and was shown to be a central mediator of cell growth in malignant mesothelioma cells (Sato, A. et al Oncol, Rep. 201.2, 28. 1889- 1893). A ioss-of --function screen by knock down, of expression, in rhabdomyosarcoma cell lines significantly inhibited ceil growth in vitro suggesting YES1 as a potential target for this cancer (Ycung, C..L. et al Oncogene 2 13, 32, 5429-5438). Similar studies demonstrated significant effects on cell survival and growth for basal-like and HER2 -positive breast cancers (Bilai, E. et al. Genes Cancer 201 1 , I , 1063-1067}.

Breast tumor kinase (BRK) is a member of the FRK family of NRTs. it is a soluble tyrosine kinase expressed in the epithelial cells of the skin and gastrointestinal tract and aberrantly expressed in melanoma, lymphoma, ovarian, prostate, colon and up to 86% of breast tumors (Ostrancier, J.H. et al Curr, Opiit. Pharmacol. 2010, 1 , 662-669), BRK was recently shown to be a key regulator of hypoxia-induced breast cancer progression (Regan-Anderson, T.M. et al Cancer Res. 2053, 73, 5810- 5820), thus targeting BRK expression activity may provide an effective method to block the progression of aggressive breast cancers.

The TEC famil of non-receptor tyrosine kinases constitutes BTK, BMX, ITK, TEC and TXK kinases and is involved in the intracellular signaling mechanisms of cytokine receptors, lymphocyte surface antigens, heterotrimeric G-protein-coapied receptors and integsin molecules, Loss-of-function mutations in the BTK gene were reported as the cause of X-linked agammaglobulinemia. Ibmtinib, an inhibitor of BTK, has utility in patients with chronic lymphocytic leukemia and mantle cell lymphoma.

FMS-iike tyrosine kinase (FLT3) is a type III receptor tyrosine kinase that plays key roles in differentiation, and survival of hematopoietic stem cells in bone marrow and has been observed overe osed in acute myeloid leukemia (Smith, C,C. et al Nature 201.2. 485. 260-263) and acute lymphocytic leukemia (Markovic, A , hit. J. B cliem. Cell. Biol. 2005, 37, Ϊ 168- ! 172). Specific gain- of- functi n mutations such as FLT3-ITD, FLT3-D835Y have been identified in AML patients thus suggesting that FLT3 targeted therapy addresses an unmet medical need for FLT3 mutant positi ve AML patients {Li, X. et l j. Med. Chem. 2015, 58, 9625-9638).

RET (Rearranged during Transfection.) is a single-pass transmembrane receptor tyrosine kinase that is mainly expressed in both the peripheral nervous system and the CNS. Deregulation of RET signaling can lead to thyroid cancers including medullary thyroid carcinoma (MTC) and its inherited forms which are characterized by misseose mutations in RET involving cysteine (Mulligan, L.M. et al. Nature 1993, 363, 458-460) or methionine residues ⁽ Mulligan, L.M. et al. J. tiuern. Med. 1998, 238, 343-346) and papillary thyroid carcinoma (PTC) associated with specific chromosomal rearrangements of RET. Chimeric RET proteins have been identified in lung adenocarcinoma of NSCLC (Song, M. /. Med. Chem. 2015, 58, 3672-368 l).and are being investigated in the clinic with cahozantirtib and vandefanih which are approved for treatment of MTC patients, inhibitors of RET gatekeeper mutants V804L and V804M .have been reported recently (Li, X. et al J. Med. Chem. 2015, 58, 625-9638) potentially for MTC therapeutics.

The ROS 1 kinase is a receptor tyrosine kinase first discovered in Sung adenocarcinoma and has been shown to have a role in glioblastoma (Birchmeter, C. et al. Proa Natl. Acad, Sci. USA 1987, 84, 9270-9274). Like SET, ROSi is involved in rearrangements resulting in fusion of its .kinase domain to different partners (Bos, M. et al. Tmti-sl. Lung Cancer Rex. 2013, 2, 1 12-· 121 ), which play a role in NSCLC. Activation of ROS I causes downstream signaling pathways activation including STATS, PI3K/AKT, RAS/MAPK MEK pathways. There are no selective inhibitors of ROSI described to date.

The ErbB family of receptor tyrosine kinases and their ligands are important regulators of tumor cell proliferation, tumor angiogenesis and metastasis. (Gschwind, A. et al., Nat. Rev. Cancer, 2004, 4. 361 ). There are four receptors in the ErbB family, EGFR (endothelial growth factor receptor), HER2, HER3 and HER4, EG R plays a key role in si nal transduction pathways controlling proliferation and apoptosis (Zhou, B-B S. et. al. Cancer Cell.. 2006, 10, 39-50). Activation of the EGER pathway results in downstream events stimulating five of the six hallmarks of cancer: 5 ) independence of growth signals 2) insensitivity to growth-inhibitory signals 3) resistance to apoptosis, 4) angiogenesis, and 5) metastasis. Thus, inhibition of EGFR signaling presents multiple opportunities for identifying novel therapeutic agents,

A number of non-tyrosine kinases are also important in cancer therapy. Mitogert-aetivated protein kinase (M.APK) pathways link extracellular signals to the cellular machinery that controls fundamental processes such as growth, proliferation, differentiation, migration and apoptosis. Abnormalities in MARK signaling play a critical role in the development and progression of cancer. To date six distinct, groups of MAPKs have been characterized in mammals; extracellular signal- regulated kinase ER )l 2, ER 3/4, ER 5, ER 7/8, km N-terimna! kinase (JN.K):i/2/3 and the p38 isoforms *?β/ΎφΜΚ6) and in the E /MAP module. ERK (ERR ! and ERK2) is activated upon phosiphoryiation by MEK. (MEK i and MEK2), which h itself activated when phosphorylaied by RAF (RAF- 1 , B-RA.F and .A-RAF). The B-RAF gene is found mutated in 66% of malignant melanomas, and at a lower frequency in many other human malignancies, including colon cancer, papillary thyroid cancer and serious ovarian cancer {Dimes, H. el al Nature 2002, 417, 949-954). ERK signaling also plays, a role in disrupting the anti-proiiferative effects of Itgands such as transforming growth factor beta ( GF?) and is deregulated in about one-third of all human cancers iDhiS Son, A.S, et al Oncogene 2007, 26. 3279-3290). A number of agents are used to treat melanoma including sorafenib, vemurafenib (B-RAF), trametinib and eobimet b as two specific and potent MEK 1/2 and ME l inhibitors, respectively, approved for the treatment of patients with -unresectable or metastatic melanoma with BRAF V600E or Y600K ^' mutation as dete ed by an FDA-approved test (Yamaguchi T, et el Int Oncol. 201 1, 39, 23-31 ). BiX02 i89 is a selective inhibitor of MEK5 and ERK5.

Serine/threonine protein kinases play a central role in regulating cellular metabolism, growth and survival in response to hormones, growth factors, nutrients, energy and stress signals. Mammalian target of rapa ycin. (mTOR) directly or indirectly regulates the phosphorylation of at least 800 proteins and functions as part of two structurally and fuiKtionally distinct signaling complexes mTORC I and mTORC2 (mTOR complex I and 2). Smg! is another example <sf a .kinase in this pathway. MTOR inhibitors have found utility in treating a variety of cancers such as advance renal cell-carcinoma (temsirolimus) and everolimus indicated it! patients with progressive neuroendocrine tumors pf pancreatic origin. Cyciio dependent kinases (CDKs.! are sexine/lhreoninc k n se whose activity depends on a regulatory ubmits - a cyclin for enzymatic activity. CDKs, proteins belonging to this family have been recently renamed as CDK! throug to CDK20. CDKs re a major enksryotk: protein kinase family Involved in the integration of extracellular and intracellular signals to modulate gene transcription rid eel! division (Makenbres. M. Genonie BioL 2014, /5, S 22 - 132).

SUMMARY OF THE INVENTION

The present invention is directed to novel 1 ,2-dithioSane compounds and related compounds, pharmaceutical compositions comprising the compounds, processe for making the compounds, and methods of using the compounds and pharmaceutical compositions for the treatment and/or prevention of tyrosine , MARK and R13K/A T/ii¾Tor signaling pathways kinases-medialed diseases or conditions such as neurodegeneration, neuroprotection, autoimmune and cancer. Accordingly, one embodiment of the invention is directed to compounds of formula (I):

wherein:

W ^f is selected from a group consisting of hydrogen, C¾-o aifcy!.€?.-? cyeloa!kyi, cycloalkylalkyl, aryi, ai-ylalJkyl, hetefoeych heteroeyeycMkyl, hetefoarvi heteroarylalkyl, alkoxyheteroarylalkyL C(0) ', C(0)R\ C(0)OR \ C(0)OR ² , trial.kyisi.iyi and diaryialkyisiiyi;

X ^s and X ² are at each independenily selected from the group consisting of S, SO and SC

Y' and Y ¹ are each independently seiected from the group consisting of hydrogen, Q-s alky], C(0) .', C{0)R\ Cf O)OR\ and C(O)0 " ;

Z is selected from the group consisting of hydrogen, Ct.« alkyl, G.* aikenyl, Q^s alkynyl, arylalkynyl, .halogen, C(0)R'. C(0)R\ C(0)OR ⁱ , CiO)0R ^: \

R' is selected from the group of hydrogen, alkyl, CV?cycJoalkyl and CM> aikenyl;

R ^* is selected from die grou of hydrogen, , heteroaryl, arylalkyl, heteroarylalkyl;

R- ^* is selected from die group of hydrogen, alkyl. CM eycioaikyl, cycloalkylalkyl and halogen; ' ^k \ R* and R ^¾ are each independently selected from the group of hydrogen, CSJ, alkyl . Ct.* haioalkyi,

Ci-6 alkoxy, heieroeyelyl, heteroeyciyialkyi, aryi, arylalkyl, aryloxy, heteroaryl, heteroarylalkyl and alkoxybetefoaryiaik.yl ;

R ^->a" R ^3h , 8 : , R ⁱ⁴ and R" ^!ii are each independently selected from the group of hydrogen, Q-s alkyl, Ci^ alkenyl, CMS alkynyl, Cj.* haloalkyl, Cs.;, alkoxy, C.*.? eycioaikyl, cycloalkylalkyl, heterocyclyl, heteroeyciyialkyi, aryi, arylalkyl. aryloxy, arylalkynyl, heteroaryl, heteraaryialkyl and alkoxybetefoaryialfcyl or enantiomers. dtastereomers, hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof.

in another embodiment of the invention, preferred groups of compounds of formula (J), which include eiiarti.ion.ers, diasiereomers, hydrates, solvates, pharmaeeuticaliy acceptable salts, prodrugs and complexes thereof, include those compounds in the subgroups below, wherein the other variables of formula (Ϊ) in the subgroups are defined as follows:

a) Z is the moiety

or a enafttiorner, diastereoroer, hydrate, solvate, a pharmaceutically acceptable salt, prodrug and complexes thereof;

b) Z is the moiety or a enantiomer, diastereomer, hydrate, solvate, a pharniaceiitiealiy acceptable salt, prodrug and compl exe s thereof;

c) Z is the moiety

or an enantiomer, diastereomer, hydrate, solvate, a pharmaeeuticaliy acceptable salt, prodrug and comple es thereof;

d) X ^! and X ³ are S, and Y ^! and Y ^* are H, or a enantiomer, diastereomer, hydrate, solvate, a pharmaceutically acceptable salt, prodrug and complexes thereof;

e) Z i the moiety

^s and X ² are S, and Y ^! and Y ^'2 are H; Γ) Z is the moiet

X ^! and X ^J are S, and Y ¹ and Y* are H, or an enantioraer, diastereorner, hydrate, solvate, a pharmaceutically acceptable sail:, prodrug and complexes thereof;

g) Z is arylalkynyi, X ¹ and X" are S, and Y' and Y ¹ are H, or an enantioraer, diastereorner, hydrate, sol ate, a pharmaceutically acceptable salt, prodrug and complexes thereof.

Additional preferred compounds of the invention include those selected from the following group:

trans 3-(( 4-aniino-3-phenyi-l/i-pyrazolo[3,4-t/]pyrimidi n-1 -yl jmethyl}- 1 ,2-dithiolan-4-yl benzoate); trans 3-i(4-aoiifto-3-phejwM / ) ra^^

tram 3-iX4-amin«v3-( h oropheny! -lH-pyra¾oloi3,4-rfjpyrimidin- 1 -yJ)roethyl> 1.2-dlthiolan-4-y! benzoate:

tram 3-iX4-amin«v3-( h oropheny! -lH-pyra¾oloi3,4-rfjpyrimidin- 1 -yJ)roethyl> 1.2-dithiolan-4-o!; tram 3 (4-araino-3 4-nie{lioxyplK;nyl)-lH-pyra«»1o(3 _> 4-iflpyrin}idin- i -y].)methyl>- 1 ,2-dithiolan-4~yi benzoate;

tram 3 (4-araino-3 4-nie{lioxyplK;n> )-lH-pyra«»1o(3 _> 4-iflpyrin}idin- i -y].)methyl>- 1 ,2-dithiolan-4- ol;

(3S,4/Q-3-((4-ammo-3-(4-metho

4-oi;

(3/?,4S)-3-((4-amino-3-(4-methoxy^^

4-oi;

ch 3H (4-amim M4- ^ffl eihox

benzoate;

cix 3H (4-amim M4- ^ffl eihox

(3 \45)-3-((4-aroino-3-(4-niethoxyp

4-oi; (3?,4/? -3-{( -a«Hno-3-{4-«}ethox :phenyl)- 1 ^- yra7 lo[3,4-fi]p im!d!n-l- )ii^tby! -l ,2-ditb an-

4-oi;

trans i-ii^methox -l^-dfthiol n-S- ^m^

4 -amine;

cis i'-{(4--methoxy-4,2-ditbio.ia^^^^

amine;

ifms M(4--( enzy1ox l,2^

i/jpyrimidin-4-amine;

cs 1 -«4-(benzyloxy J ^2-dit k>lan-3-yl)mei yi)-3-(4-p enoxyp enyl )- ί //-pyrazol i3,4-./|pyriOTidin-

4-amine;

trans 3-i(4-amino-3-(4-phenoxyphenyl)- 1 //-pyrazolof3,4-«0pyrimjdjn-i-yl)methy]}- 1 ,2-dit ioian-4-yi enzoai ;

trans 3-(( 4-aniino-3-(4-phenoxyphenyi)- 1 //-pyrazolof3,4-«0pyrimjdjn-i-yl)methy]}- 1 ,2-dit ioian-4- ok

(3S W -3-((4-aJttino-3-(4-ph«n^

4-oi;

(3SA¾-3-((4-awino-3-(4-phfinoxy^

4-ol;

ck 3-{{4-amino-3-{4-phenoxyphe-iyi)- i-pyi ok![3,4^]pTitriidiii-l--yl)methy] :i .2-dit iolan-4-yl beazoaie;

ck 3-{{4-amino-3-{4-phenoxyphe-iyi)- i-pyi ok![3,4^]pTitriidiii-l--yl)methy] :i .2-dit iolan-4-ol; {35,45 >-3-( (4-amino-3-(4-phenoxypheny1 }- 1 H -pyrazoSo| 3,4-rf j pyri tnidin- 1 -yl)methyi)- 1 ,2-dithiolan-4- oh

0R .4R }- ( 4 -amino- 4-p enoxy p en i } - 1 W-pyfaTOlo[3,4-^]pyrimidm-l-y{)methyi)-l _I 2-dithioian- 4-oi;

trans- 1 -Ci4 (im-butyldimetliykilyl )oxy)-i ,2-dit iolan-3-yl)methyJ)-3-(4-phenoxy phenyl)- 1 - IH- pyrazoio[3,4-(flpyriiTii(jii)-4-canine;

trans- 1 -Ci4 (im-butyldimetliykilyl )oxy)-i ,2-dit iolan-3-yl)methyJ)-3-(4-phenoxy phenyl)- 1 - IH- pyrazoH>[3,4-i]pryiffiidin-4-aniine ; and

tmns 34(4-amino-344-pht;noxyp t;ny ^' i)-l /-i-pyrti2oio[3,4-ii]pyrimidin- 1 -yl)methyi)- 1 ,2-dithit>]an-4- oi;

ίΓΰίίΛ 3-i(4-ai«ino-3-ipheny1et ¾y!)-l^^

benzoate,

trans 3-(4-amHio-3^ henyleth n i)-i#- ra«oto^ _^ ^

trans 3'-(f4»an)ioa--3'-(piie]:iyiethynyl)-l W-pyrazoio| 3,4-¾/|pyrinikSin- ].«y.i)»:iethy - -axido« i ,2- diihiolan-4-yl betizoate. trans 3-((4-ai«ino-3-(2-ain oben7^^ ,2- difhioIan-4-yI benzoate,

trans 3'-ii4~ar nO" -i2-amiM}fa ,2- dithiolaii--4-ol .

trans 3'-ii4~ar nO" -i2-amiM}fa - oxkio- 1 ,2-dithiotan-4-yt benzoate,

if ms 3-((4-amino-3-(2-a:minobenro^

hydroxy-! ,2-dfthiol ne 1 -oxide,

if ms 3-((4-amino-3-(4"{2 luorc^^^^

di thi lan-4-yl benzoate,

trans 3-(( 4-aniino-3-(4-(2-fktor phenoxy phenyl)- l //-pyraz ]oi3,4-t/3pyrimi<lin-l-yf)methyl}-i ,2- dithioian-4-oi,

trans 3-(( 4-amino-3-(3-(3-fktor -4-phenoxypheny!)- 1 / -pyrazolof 3,4-t ]p rimidin- i-yi jmethyl}- 1 ,2- ditbi.o!an-4-y! benzoate and,

trans 3-i(4-aoi!no-3-i3H3 ¾oro-4-phenoxyphenY.IH ,2- ditbi.o!an-4-o!;oi' an ensntiomer. dsasiereomer, hydrate, solvate, a pharmaceutically acceptable salt prodrug and complexes thereof.

In another embodinsenf of the invention, additional preferred groups of compounds of Formula (I ), which include enantiomeric diasiereorners, hydrates, solvates, pharmaceutically acceptable sails, prodrugs and complexes thereof, include those compounds in the subgroups below, wherein the other variables of formula (I ) iii the subgroups are defined as follows:

Z is the moiety

Y ^! is H; ^3a , R-*, R ^¾ , R ^¾ , and R ⁵ * are H, and X\ X ² , Y\ J * and W ' are selected as a single group from one of the following groups:

Hi or an enaiitiomer, diastereomer, hydrate, scsi vate, prodrug, complex, or pharmaceutically acceptable sail form thereof; b> Z is the moietv

Y ^! is H, and X ^! . X' ^' , Y' R ^" and W ¹ are selected are selected as a single group from one of the fallowing groups:

i .i Group X ¹ X ² Y ^"2 R ³ w

umber

3 s so H CH ₂ Phenyi Cl

4 so s H CHaPhenyl Cti

5 s so COi-i-Butyl <: -prop) i H,

6 so s CXV/-.Bufyl c-propyl H,

7 s so COi-i-Butyl <: -prop) i ah

8 so s COi-i-Butyi c-propyl (.11..

9 s so COCHj c-propyl c-pentyi.

10 so s COC¾ <: -prop) i !. -pcnt l.

1 1 s so H c-butyl (.11..

12 so s H Ϊ -htuyl C¾,

13 s so H Br (.11..

1 so s H Br C¾,

15 s so H i-propyi H and

16 so s H i-propyi H or an etiantiomer, diastereoriier, hydrate, scsivate, prodrug, complex, or pharmaceutically acceptable sail form thereof; ) Z is the moiety

Y ^s is H, and X' , X ² , Y\ R ^',s> and W ¹ are sele ted as a single group from one of the following groups:

or an etiantiomer, diastereoriier, hydrate, scsi vate, prodrug, complex, or pharmaceutically acceptable sail form thereof; and d) Z. is ethynyibenxene, ¥ ^! is H, and X ¹ , X ² , Y ¹ and W ^! are selected as a single group from one of the following groups:

or an enantiomer. diastereomer, hydrate, solvate, prodrug, complex, or pharmaceutically acceptable salt form thereof.

The present invention further provides a pharmaceutical composition which comprises an effective amount of one or more compounds according to the present invention or an enantiomer, diastereomer, hydrate, solvate, pharmaceutically acceptable salt, prodrug and complexes thereof, and an exeipieiit or a pharmaceutically acceptable carrier.

The present invention further provides; a method of modulating the activity of tyrosine kinases, MAPK pathway kinases, and PI3 /A. T/m ^' Tor pathway kinases in a mammal, wherein the tyrosine kinases are selected from PYN, ΡΎΝ Y531 P, FLT3, PLT3TTD, BRK. ITK, FRK, BTK, BMX, SRC. PGR, YES i , LCK, HOC, RET, CS , LYN, ROS i ; MAPK pathway kinases are selected from ARAP, BRAE CRAP, ERK1 2, ME I , MEK2, MEK3, MFK4, ME 5. MEK6, ME 7; and Pi3K AKT/mTbr pathway kinase* are selected from mTor, PBK α, ΡΪ3Κ β, PI3 γ, PI3 δ, comprisin administering to the mamma! compound of formula (1) or an enantiomer, diastereomer, hydrate, solvate, pharmaceutically acceptable salt, prodrug and complexes thereof.

The present invention further provides methods of ameliorating, treating or preventing diseases that involve modulation of tyrosine, MAPK and PB A T/niTor pathway kinases including RTKs such as SRFs and TEC, and RTK ^' s such as FLT3, RET, and FRK families. These diseases include, for example, neurodegenerafion, neuroprotection, Alzheimer's disease, ischemic stroke, autoimmune diseases. T-ceSI. disorders, cancer such as, melanoma, adenocarcinoma, carcinoma, leukemia, chronic lymphoblastic Seu.ke.nria, acute myeloid leukemia, adenocarcinoma, thyroid cancer, papillary thyroid carcinoma, medullary thyroid carcinoma, non-small cell lung cancer, small cell, lung cancer, glioblastoma multiforme, colon, breast, prostate, testicular cancer malignant peripheral nerve sheath tumors. The method comprises administering to a subject an effecti ve amount of a compound or a pharmaceutically acceptable salt thereof or composition according to the present invention and an excipient. Particular embodiments of the present invention provide methods for ameliorating, treating or preventing diseases that involve modulation of tyrosine kinases including NRTKs such as SRFs and Tec, RTKs such as FLT RET, FRK families, MARK and PBK/AKT/mTor pathway kinases. Embodiments of the present invention further relate to a method for treating or preventing diseases that involve modulation of tyrosine kinases including FYN. FY ^' .N ¥53 I F, PLT3, FLT3-1TD, BRK, Π'Κ, FRK, BT RMX, SRC, EGR, YES ! , LCK, HCK, RET, CSK, LYN, ROS ! ; MAPK pathway kinases ARAF, BRAP, CRAF, BRK 1/2, MEK I , ME 2, MEK3, MEK4, MEK5, MEK6, ME 7 and PBK/AKT/mTor pathway kinases: raTor, P13K a, P13K β, ΡΪ3Κ γ, ΡΪ3Κ 5.

The present invention further provides processes for preparing the compounds of the present invention. In one embodiment, a process is provided for the preparation of i ,2-dithioiane compounds of formula (i)

or enantiomers. diastereomers, hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof, wherein:

W ^f is hydrogen;

X ^! and X ^* are each independently selected from the group consisting of S, SO and SO2;

Y ^! and Y' ^; are each independently seieeted from the group consisting of hydrogen, alk l . C(0)R ^l ,

C{0)R", CfO)OR\ and C(O)0R";

Z is selected from the group consistin of hydrogen, O-s alkyl, G.* alkenyl, ^s aikynyl, arylalkynyl, halogen,€(0)R\ CiO)R\ C(0}GR', C( Q)OR ^: \

R ^! is selected from the group of hydrogen, Cj alkyl, C cydoalkyl and alkenyl;

R ² is selected from the group of hydrogen, aryl, heteroaryl arylalkyi, heteroary kyl:

.R ⁱ⁽ is selected from the group of hydrogen, Ci. _<¾ alkyl, Gs _? eyeioalkyi, cycloaikylalkyi and halogen;

R* R*>, and R ^",<: are each independently selected front the group of hydrogen, C s alky], Ci.fi haioa!kyj, Ci.« atkoxy. heterocycty!, heterocyciySalkyl . aryl, arylalkyi, aryloxy, heteroaryl, he ternary laiky S and aifcoxyhe ter ary lalkyi;

*- R ^'h , R , R ^5d and R ^5'" are each independently selected from the group of hydrogen. CY<; alkyl, C« alkenyl, alkyny!, haloaikyl, Ct. _& alkoxy, CY? eyeioalkyi, cyetoalky!atkyl, heterocyciyi, heterocyciylaifcyl, aryi, arySaikyl. aryloxy, ar lalkynyl, heteroaryl, heteraaryialkyi and alko xy heteroaryl al k ! ; which process comprises the steps of:

a. reacting a 3-sijbstj.tuted-li -pymzx>lo 3,4-i |pyrimidiB-4-sijbstj.tuted amine having the formul

with an inorganic base such as cesium carbonate in a polar aprotic sol vent such as N,N dimethyl formamide followed b addition of a substituted L ^' 2~diihi.ane compound having the formula

optionally with microwave irradiation to produce a substituted product of the formula

b. further reacting the substituted product with art inorganic base in a polar protic or aptotic solvent, optionally with to produce a product of the formula

la another embodiment a process is provided for the preparation of a tnixfitre of sulfoxides of formula A and of sulfoxides of formula B

wherein:

Y' and ~ are each independently seiected from the group consisting of hydrogen. Q-s aikyl, C(0) ', C{0)R\ C(0)OR\ and C(O)0 "; Z is selected from, the group consisting of hydrogen, Ο-* alkyl, CVe, alkenyi. CM alkynyl, arylalkynyl, halogen, C(0)R', ² , C(0)OR\ C(0)OR ² ,

R ^! is selected from the groap of hydrogen, Ct* alkyl, C3.7 eycloalkyS and CYs alkenyi;

R ^J is selected from the group of hydrogen, aryi, heteroaryl, ar iaikyl, heteroaryiaikyi:

R ³ is selected from the group of hydrogen, Cw alkyl,€¾.-,· cyeloalkyi, cycloaJkylalkyl and halogen;

R \ R ^S \ and R ^¾ are each independently selected from the group of hydrogen. Cw alkyl, Cn> haloaikyl. CM alkoxy, heierocyclyi, beteroeycly1.al.kyi, aryi, arylalkyL aryloxy, heteroaryl, heteroaiylalkyl and alkoxyheteroarylalkyl;

R ^: "" R' ^'! '. R' ¹¹ , R ^! and R** are each independently selected from the group of .hydrogen, Co alkyl, C>.* alkenyi, 0·«. alkynyl, Cw; haloaikyl, Ci^ alkoxy, C.-,. : cycloaikyl, cyeloalkylalkyl, heierocyclyi, heterocyclyiaikyl, aryi, aryiaikyl, aryloxy. arylalkynyl, .heteroaryl, heteroarylalkyi and alkoxy heteroary I alkyl ; which process comprises the steps of:

a. contacting a compound of the formula

with an oxidizing agent in a polar orotic or aprotic solvent with heating and optional microwave irradiation and isolating the mixture of sulfoxides A and sulfoxides B.

In another emixidiment, a process is provided for the preparation of 1,2-dithiolaiie compounds of formula (Ϊ :

wherein:

W ⁽ is seiected from a group consisting of hydrogen,€Υ<> ai ^' kyi. CM cycloalkyl, cycloaikylalkyl, aryl, aryialkyl, heteroeycl, hettjrocycyciaikyL heteroaryl, heteroarylalkyl, alfcoxyhete-roaryl alkyl, C(0)R', C(0)R\ C(O R ^! , C(0)OR% trialkylsilyl and diarylaikylsilyi;

X ^s and X ^* are at each independently selected from the group consisting of S, SO and SO2;

Y' and Y ² ace each independently selected from the group consisting of hydrogen. Q-s alkyl, C(0)R',

C(0)R\ C(0)OR ' . and C(0 _, )OR ² ;

Z is selected from file group consisting of hydrogen. O-* alkyl, Ci-* alkenyl. CM alkynyl, arylalkynyl, .halogen, C(0).R\ ² , C(0)QR\ CtO)0R ² ,

' ^! is selected front the group of hydrogen, C alkyl, C3.7 cycloalkyl and C alkenyl;

R" is selected from the group of hydrogen, aryl, heteroaryl, aryialkyl, heteroarylalkyl;

R ³ is selected from the group of hydrogen, C alkyl, C3.7 cycloalkyl, cycloaikylalkyl and halogen;

R ^' -\ R ^' *°, and R ^!C are each independently selected from the grou of hydrogen, Cw alkyl, CM, ha!oalky!, C alkoxy, heterocyciyl, heterocyeiylalky], aryl, aryialkyl, aryloxy, heteroaryl, heteroarylalkyl and alkoxyheteroaryJalkyl;

R ^: " ^S - R ^Sb , R ^& , R ^{' ll} and R ^' " ^! are- each independently seiected from the group of hydrogen, CM alkyi. CM, alkenyl, Cs„e alkynyl, C baloalkyi. CM aikoxy, C3.7 cycloalkyl. cycloaikylalkyl, betefoeyelyl, heterocyciyialkyl, aryl, aryialkyl, aryloxy, arylalkynyl, heteroaryl, heteroarylalkyl and alk xy heteroary lalkyi ; which process comprises the steps of : a, reacti ng a 3-substituted- 1 ^-pyrazt>lo[3,4-</]p 5rimidin-4-substituted amine having the formula

with an inorganic base such as cesium carbonate in a polar aprotic solvent such as N,N dimethyl foroiaruide followed by addition of a substituted L ^' 2~diihi.aiie compound having ilie formula

optionally with microwave irradiation to produce a substituted product of the formula

where W ^! is OR\ or enantioiriers, diasiereomers, hydrates, solvates, phamiiiceutieaily acceptable salts, prodrugs and complexes thereof.

In another embodiment, a process is provided for the preparation of i„2-di thiol ane compounds of formula (I):

(I)

w herein:

W ⁽ is selected from the group consisting of hydrogen, C;.<¾ alkyl, C.vj eycioaikyl, cycloalkyiaikyl, ar l, arylalkyl, heterocvc ^' i, heterocyxyciaikyL heteroaryi, heteroarylalkyl, aikx>xyheteroarylalkyl, C(0)R', C(0)R\ C(O R ^! , C(0)OR% trialkylsilyl and diary laikylsilyi;

X ^s and - are each independently selected from the group consisting of S, SO and Si¾:

Y' and ~ are each independently seiected from die group consisting of hydrogen. Q-s alkyl, C(0)R', C{0)R\ C(0)OR ' . and C(0 _, )OR ² ;

Z is selected from the group consisting of hydrogen, alkyl, Ci-* alkenyl. CM ai.kyiiyl, arylalkynyl, halogen, C(0).R\ C(0)R ² , C(0)OR\ CtO)0R ² ,

R ^! is selected from the grou of hydrogen, Ct* alkyl, C3.7 eycioaikyl and CYs alkenyl;

R ^J is selected from the groap of hydrogen, aryl, heteroaryi, aryialkyl, heteroarylaikyi;

R ' is selected from the groap of hydrogen, Ct* alkyl, C3.7 eycioaikyl, cycloalkyiaikyl and halogen;

R-\ R ^4I> , and R* ^: are each independently selected from, the group of hydrogen. Cw alkyl, Cn> haioa!kyi, alkoxy, heterocyc!y betefocyeiyJalkyl, aryl, aryialkyl, aryioxy, heteroaryi, heteroarylaikyi and aikoxyheteroarylalkyi;

R ^3¾ R* R ^¾ . R- ^'a and R- ^¾ are each, i ndependently seiected from the group of hydrogen, C > alkyl, alkenyl, alkynyl, C«> haloalkyl, Ct-e alkoxy. C3-7 eycioaikyl, cycloalkyiaikyl, heierocyciyi, hete oe clyiaikyl . aryl, aryialkyl, aryioxy. arylalkynyl, heteroaryi, heteroarylalkyl and alk.oxyheteroary lalkyi ; which process comprise* the steps of:

2.1 a. reacti ng a 3-substituted W-pyrazolo[3,4-</]p 5rimidin-4-substituted amine having the formula

with an. inorganic base in a polar apro!ie solvent followed by reaction with a substituted 1 ,2-dimiane compound having the formula

optionally with microwave irradiation to produce a substituted product of the formula

or enantiomeric diastereomers, hydrates, solvates, pharmaceutically acceptable salts, prodrugs and comple es thereof.

The process further comprises reacting the substituted product of the formula

or enant!oroers. diastereomers, hydrates, solvates, pharmaceutically acceptable salts, psrocfrugs and complexes thereof with an acid in a polar protic or aprotic solvent, optionally with microwave irradiation to produce a product of the formula

or enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, prodrugs and comple es thereof.

In another embodiment, a process is provided for the preparation of ! .2-dithio!ane compounds of formula (I);

wherein:

W ¹ is hydrogen;

X ^! and X' ^* ' are at each independently selected from the group consisting of S. SO and SO.;

Y ^! and Y' ^; are each independently selected from the group consisting of hydrogen, alky], C(0)R ^l ,

Z is selected from the group consisting of hydrogen, Ct.« ikyt, Ci.<, alkenyl, ^s aikynyl, aryialkynyl, halogen,€(0)R\ QO)R ² , C<0)O ', Cc ^' OPR ² ,

R ^s is selected from the group of hydrogen, Cs-e alkyl, Cj.?cycloalkyl and Cs-« alkenyl;

R ^* is selected from the grou of hydrogen, aryi, heteroaryl, arylalkyl, heteroarylalkyl;

J is selected from the group of hydrogen, Ct* alkyl, (¾■? eycloalkyl, cycloalkylaikyi and halogen:

haloalkyl, aikoxy, heteroeyciyl, heteroeyciyl alk i, aryl, arylalkyl, arylosy, heteroaryl, heteroaryial.ky! and aikoxyhetefoarylaikyi :

R ^¾ - R ^¾ , R ^& , R ^5<J and R ⁵ * are each independently selected from the group of hydrogen, Q-s alkyl, C _f -, alkenyl, C« alkynyl, Cj* haloaiky!. C>^ alkoxy, C ; cyc!oalkyi, cycloalkylaikyi heteroeyciyl, heterocyclylalfcyl, aryl, arylalkyl, aryloxy, arylalkyiiyL heteroaryl, hetexoaryialkyl and alkoxyheieroar ! alkyl ; which process comprises the steps of:

<t. reacting a 3-subsf.itiited i / -pyrazoSo| 3,4--rf]pyTioitdtn-4--sijbstituted amine having the formula

with a siiy.l compound having the formula

in the presence of an azodicarboxyiate and triaryiphosphine in a polar aprotic solvent, optionally with microwave irradiation to produce a substituted product of the formula

or enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, prodrugs and compl exe s thereof.

The process further comprises reacting the substituted product of the formula

or enantiomeric diastereomers, hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof with an acid in a polar protic or aprotic solvent, optionally with microwave irradiation to produce a product of the formula

or enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof,

^' These and other objects, features, and advantages will become apparent to those of ordinary skill in the ait from a reading of the following detailed description and the appended claim**. All percentages, ratios and proportions herein are by weight, unless otherwise specified. All temperatures are in degrees Celsius P C) unless otherwise specified. All documents cited are in. relevant part, Incorporated herein by reference; the citation of any document is not. to be construed as an. admission that it is prior art with respect to the present invention.

DETAILED DESCRIPTION OF THE INVENTION

The tyrosine kinases, MAPK pathway kinases and the PBK AKT/mTor pathway kinases inhibitors of the present invention are capable of treating and preventing disease* associated with .modulating tyrosine kinases including NRTKs such as S Fs and TEC family, RTKs such as EET3, RET, and FRK family, MAPK pathway kinases such as RAF. MEK and ERK kinases, and Pi3K/AKT/mTor pathwa kinases such as mTor, P13 a, P13K β, PI3K γ, ΡΪ3Κ 8, These diseases include, for example, neurodegeneration, neuroprotection, Alzheimer's disease, ischemic stroke, autoimmune diseases, T-cell disorders, cancer such as, melanoma, adenocarcinoma, carcinoma, leukemia, chronic lymphoblastic leukemia, acute myeloid leukemia, adenocarcinoma, thyroid cancer, papillary thyroid carcinoma, medullary thyroid carcinoma, non-small cell lung cancer, small cell lung cancer, glioblastoma multiforme, colon, breast, prostate, testicular cancer malignant peripheral nerve sheath tumors. The tyrosine kinases inhibitors of the present invention are capable of treating and preventing diseases associated with modulating tyrosine kinase activity. It has been discovered that inhibition of tyrosine kinases acti vity will prevent neurodegeneration, neuroprotection, T-cell disorders, tumor ceil proliferation, tumor angiogenesis, and metastasis. Without, wishing to be limited by theory, if. is believed that tyrosine kinases inhibitors of the present invention can ameliorate, abate, otherwise cause to be controlled, diseases associated with tyrosine kinases.

Throughout the description, where compositions are described as having, including, or comprising specific components, or where processes are described as having, including, or comprising specific process steps, it is contemplated that compositions of the present teachings also consist essentially of, or consist of, the recited components, and that the processes of the present teachings also consist essentially of, or consist of, the recited processing steps.

In the application, where an element or component is said to be included in and/or selected from a list of recited elements or components, it should be understood that the element or component can be any one of the recited elements or components and can be selected from a rou consisting of tw or more of the recited elements or components.

The use of th singular herein includes the plural (and vice versa) unless specifically stated othen.vi.se. In addition, where the use of the term "about" is before a quantitative value, the present teachings also include the specific quantitative value itself, unless specifically stated otherwise.

If. shouid be understood that the order of steps or order for performing certain actions is immaterial so long as the present teachings remain operable. Moreover, two or more steps or actions can be conducted simultaneously.

As used herein, flie term "halogen" shall mean chlorine, bromine, fluorine and iodine.

As used herein, unless otherwise noted ^" , "alky!' ^* and/or "aliphatic" whether used alone or as part of a subsiiiuent group refers to straight and branched carbon chains having i to 20 carbon atoms or any number within this range, for example, 1 to 6 carbon atoms or i to 4 carbon atoms. Designated numbers of carbon atoms (e.g., Ci. ) shall refer independently to the number of carbon toms in an alkyl. moiety or to the alky! portion of a larger aikyl -containing substituent. Non-limiting examples of alkyl groups include methyl, ethyl, »-propyl, tw-propyl, H-buiyi, see-butyl, tw- tuyl, ten -butyl, and the like. Alkyl groups can be optionally substituted. Non-limiting examples of substituted alkyl groups include hydroxymethyf chloromethyl, trifluoromethyl, aminomethyi, i-cbloroeihyl, 2- hydroxyeihyl, 1,2-dilluoroethyl, 3-cafboxypropyi, and the like. In substituent groups with multiple alkyl groups such as (Ci aikyl)jamino, the alkyl groups may be the same or different.

As used herein, the terms "alkenyl" and "alkynyl" groups, whether used alone or as part of a subsiiiuent group, refer to straight and branched carbon chains having 2 or more carbon atoms, preferabl 2 t 20, wherein an alkenyl chain has at least one double bond in the chain and an aJkynyl chain has at least one triple bond in the chain, Alkenyl and aikynyl groups can be optionally substituted. NonJirniting examples of alkenyl groups include ethenyi, 3-propenyl, i-propenyl (also 2- mefhyiethenyl), isopropenyl (also 2-metbylethen-2--y.i), buten-4-yl, and the like. Nonlitrtiting examples of substituted alken l groups include 2-eMoroeiheny.i (aha 2-chJorovmy ), 4- hydrosybuten- ].~yi, 7-hydroxy-7-:nietltyiocf-4-en-2-yl, 74iydroxy-7-methyloet-3,5-dien-2-yk and the like. Nonlimiting examples of aikynyi groups include ethynyl. prop-2-yn- l -yl (also propargyl). propyn- i - yl, and 2-methyl-hex-4-yB- ! -yL Nonlimiting examples of substituted a!kynyl groups include, 5- hydfosy-5-meth.ylhex-3-yn.yl, 6- ydroxy-6-met ylbept-3-yn-2-y , 3-b.ydi\>xy-5-ethyltej>t-3-yoyi, and the like.

As used herein, "cycloalkyl," whether used alone or as pari of another group, refers to a non- arooiatic carbon-containing ring including eyelized alkyl, alkertyi, and alkynyl groups, e.g., having from 3 to 14 ring carbon atoms, preferably from 3 to 7 or 3 to 6 ring carbon atoms, or even 3 to 4 ring carbon atoms, and optionally containing one or more (e.g. , I , 2, or 3) double or triple bond. Cycloalkyl groups can be monocyclic (e.g. , cyclohexyl.) or polycyciic (e.g., containing fused, bridged, and/or spiro ring systems), wherein the carbon atoms are located inside or outside of the ring system. Any suitable ring position of the cycloalkyl group can be covalently linked to the defined chemical structure. Cycloalkyl rings can be optionall substituted. Nonlimiting examples of cycloalkyl groups include: eyclopropyl, 2-methyi-cyclopropyi, eyelopropenyl, eyelobutyl, 2,3-dihydroxycyclobutyl, cyclobutenyl, cyclopentyi, cyciopentenyl, cyclopentadienyJ, cyclohexyl, cyclohexenyi, cycloheptyl, cyclooctanyl. decal.inyi, 2,5-dimethylcye.lopentyi, 3,5-dichlorocyc ohe.xyl, 4-hydiOxycyelohexyi. 3,3, -trii«etbyScyclobes- 1 -yl, octatrydropentalenyl, octatrydro- 1 W-indenyl, 3a,4,3,6,7 Ja-hexabydro- 3i/-inden-4-yl, decahydroaz.uienyi: bicyclo{ ^' 6.2,0]decanyl, decahydronaphthalenyi, and dodecahydro- l i/-t1uoi¾nyl. The tenia "cycloalkyl" also includes carhocyel.ic rings which are bie clic hydrocarbon rings, not! -limiting examples of which include, bicyclo-|2. 1..1 Jhexanyl, bicyclo|2.2. 1 Jheptanyl, bicyclo|3. 1 . 1 ]heptanyl. 1 ,3-di.mcmyl[2.2.1]hq>tan-2-yl, bieycio[2.2.2]oetanyi, and b i cy elo [ 3. . ] u ndecanyl .

"Haloalkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups havin the specified number of carbon atoms, substituted with 1 or more halogen. Haloalkyl groups include perhaloaikyl groups, wherein all hydrogens of an alkyl group have been replaced with halogens (e.g. -CPs, -CFjCI¾). Haloalkyl groups can optionally be substituted with one or more substttuents in addition to halogen. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, dichioroethyl, trill uoromethyl, trichJoromethyi, pentafluoroethyi, and pe ntachlor oethyi groups.

The term "alkoxy" refers to the group -O-alkyl, wherein the alkyl group is as define above. Aikoxy groups optionally may be substituted. Examples of alkoxy groups include but are not li mited to, ethoxy, isopropoxy arid trifiuoromethoxy groups.

The term "ary ^' l, ^" wherein used alon or as part of another group, is defined herein as an unsaturated, aromatic monocyclic ring of 6 carbon members or an unsaturated, aromatic polycyciic ring of from 1.0 to 14 c rbon members, Aryl rings can be. for example, phenyl or naphthyl ring each optionally substituted with one or more moieties capable of replacing one or more hydrogen atoms. on-liiiiitiiig examples of aryl groups include: phenyl, naphihyien-I -yl, naphthylen-2--y.l, 4- iluorophenyi, 2-hydroxyph.eiiyl, 3-methylphenyl, 2-ainiiio-4-fl uorophenyk 2-(A?,A ^? - dieihyiamin.o)phenyi, 2-cyaoopheny.l, 2,6-dt-tm-hulylpheiiyl, 3-inethoxyphenyl, 8- .hydxoxynap.hthYlen-2-yJ 4,5-dim.eihoxynaphlhyien-l -y!, and o-cyano-naphthykn- 1 -yL Aryl groups also include, for example, phenyl or naphthyl rings fused with one or more saturated or partially saturated carbon rings {e.g., bicyck! 4.2.0Jocte- 1 ,3,5-trienyl, indanyl), wiiich can be substituted at one or more carbon, atoms of the aromatic and/or saturated or partially .saturated rings.

The term "aryioxy" refers to the group -O-aryi, wherein the aryl group is as defined above. Ary.Soxy groups optionally may be substituted. Examples of aryloxy groups include but are not limited to phenoxy, m-ehlorophenoxy and 4-phenyiphenoxy.

The term "aryialkyi" or "araikyS" refers to the group ~alky1-aryi, where the alkyl and aryl groups are as defined herein. Aryialkyi groups of the present invention are optionally substituted. Examples of aryialkyi groups include, for example, benzyl, 1-phenylethyl, 2-phenylethyS, 3- phenylprapyl, 2-phenylpropyl, and iluorenylmethyl.

The term "arylalkynyl" or "araikynyr refers to the group -alkynyl-aryl, where the alkynyi and aryl groups are as defined herein. Arylalkynyl groups of the present invention are optionally substituted. Examples of arylalkynyl groups include, for example, ethynyibenzeoe, i -methoxy-3- (prop- ! -yn- i -y!)henzene. 1 -eh!oro-4-{prop- ! -yu- 1 -yifhenzene, 2-chloro-l-phe:noxy-4-{prop- l-ya-I- y! .(benzene 1 -ethynylnaphthalene, prop-2-yn-:i -ylbenzene (aha propargyibenzene).

As used herein., iriaiky!silyi whether used alone or as part of another group, refers to three alkyl. groups attached to a silicon atom. The alkyl groups could be eyeloalkyl. substituted or us!.-. (instituted, branched or straight chains each containing i - i o carbon atoms prederabit 1 -6 carbon atoms. Noniimiting examples of triaikyisiiyi include /-butyl-dimethylsilyl. tri nethyisflyi. d i isop rop y 1 ethy i si i y 1.

As used herein, diaryialky!si!yl whether used alone or as part of another group, refers to two aryl groups and an alkyl. group attached to a silicon atom. The aryl groups as defined here refer ski unsaturated aromatic rings substituted or unsubstituted. The alkyl groups could be eyeloalkyl, substituted or unsubstituted, branched or straight chains each containing 1 -10 carbon atoms preferably 1-6 carbon atoms. Noniimiting examples of diarylalkyisiiyi include diphenylmethylsilyl, fiuorenyimethy 1 silyl ,

The terms "heterocyclic" and/or "heierocyele" and/or "heteroc el l, ^" whether used alone or as part of another group, are defined herein as one or mor ring having from 3 to 20 atoms wherein at least one atom in at least one ring is a heteroatom selected from nitrogen (N ), oxygen (Q), or sulfur (S), and wherein further the ring that includes th heteroatom is non-aromatic, in heierocyele groups that include 2 or more fused rings, the non -heteroatom bearing ring may be aryl (e.g.. indo!iny!, tetrahydroquinofmyJ., ehrornanyl). Exemplary heierocyele groups have front 3 to 14 ring atoms of which from 1 to 5 are heteroatoms independently selected from nitrogen (N), oxygen (O), or sulfur i ^' S ). One or more N or S atoms in a heierocyele group can be oxidized. Heteroeyele groups can be optionally substituted. Non-lim ng xamples of heterocyclic units having a single ring include; diazulnyl, aziridinyi, urazolyl, azetsdinyi, pyrazolidinyi, sniidazolidinyL oxa lidinyi, Lsoxazolmyl, isoxazolyl, thiamlidinyi, ¾w»thia¾olyl, isothiazolinyl oxathiazoliditionyl, oxazolidinonyl, hydantoinyl, tetrahydrofirranyl, p iT ilidiiiyl. morpholinyi, piperazinyl, piperidinyl . dihydr pyranyl, tetrahydr pyranyl, piperidm-2-onyl {vaierolact m). 2,3,4,5-ietrahydro- i//-azepinyl, 2.3-dihydj:o- l W- indo!e. and 1 ,2,3,4-{etrahydro-cjuinoline, Non-limiting examples of heterocyclic unite having 2 or more rings include: ^' hexahydro-lW-p>Troii¾jnyi, 3a 5,6,7 7a-hexahya o-l / -benzo(d]imida£oiyi, 3a,4,5,0,7,7a-hexahydro- i/i-indoiyi, I ehromanyl isochroraanyl, indolinyl, isoindoimy and de thydro-l/jf-cyclooctaib)p>Troiyl.

The term "heteroaryl " whether used alone or as part of another group, is defined herein as one or more rings having from 5 to 20 atoms wherein at least one atom in at least one ring is a heteroatom chosen from nitrogen (N), oxygen (O), or sulfur (S), and wherein further at least one of the rings that includes a heteroatom is aromatic. In heteroaryl groups that include 2 or more- fused rings, the non-heieroatorn. bearing ring ma be a carhocycte (e.g., 6,7-dibydro-5i - cyclopentapyrimicfine) or aryl (eg,, beuzofunmyl, benzothiophenyl, i.ndo.ly.1). Exemplary heteroaryl groups have from 5 to 14 rin atoms and contain from ! to ring heteroatoms independently selected from nitrogen ( ), oxygen (O), or sulfur (S), One or more N or S atoms in a heteroaryl group can be oxidized. Heteroaryl groups can be substituted. Non-limiting examples of heteroaryl rings containing a single ring include: 1. , 2, 3 ,4--iet razes I y 3 , { }.,2,3]tria2olyl, { L2.4]£i'iazolyl. triaziiryl, tbiazolyl. 1H- inifdazcslyl . oxazcjlyl, furanyl, thiopheneyl, pyrimidinyl. 2-phenylpyrimidinyl, pyridinyL 3- methylpyndinyl, and 4-diinethylamiiK»pyridi.nyl. Non-limiting examples of heteroaryl rings containing 2 or more fused rings include: benzofuranyl, benzothiopheny!, benzoxazoiyl, 2- a:miiioben¾o[(:f|oxazolyl, beriztbiazolyl, benztriazolyl, cmnolinyl. naph.thyridi.nyl, phenanfhridinyi, 7H- purinyi, 9//-pnrinyl, 6-atnino- /-/-parinyl, 5W-pym>lo|.3,2-rfjpyrifnidinyl, 7 -/-pyrroio|2,3- ii]pyriniidinyS, pyrido(2,3-i/jpyrinridinyl , 2-phenylbenzo{d]thiazolyl, 1 W-indolyl, 4,5,6,7-tetrahydro-l - /i-indolyl, quinoxalinyl, 5- ethyiquinoxalinyl, quin&tolinyl, quinoiinyl, 8-hydroxy-quinoiinyl, and isoquinolinyl.

One non-limiting example of a heteroaryl grou as described above is Ct-C$ heteroaryl, which has ! to 5 carbon ring atoms and at least one additional ring atom that is a heteroatom (preferably 1 to 4 additional ring atoms that are heteroatoms) independently selected from nitrogen (N , oxygen (O), or sulfur {$), Examples of C1-C5 heteroaryl include, but are not limited to, triazinyl, thia2ol-2-yl, thiazo.l-4-yl, i.niidazoi- i -yS, l¾midazol-2-yt i.W-imidazo.l-4-yi, isoxazolin-5-yl. furan-2-yl, furan-3- yl, thiophen-2-yl, thiophen-4-yi, pyrimidin-2-yl, pyxiroidin-4-yl, pyrimMra-5-yl, pyridra-2-yl. pyridin- 3-yi, and pyridhi-4-yl.

The tenn "cycloalkylalkyl" refers to the group -alkyi-cycioaifcyl, where the aifcyl and cydoalkyl groups are as defined herein. Cycloalkylalkyl groups of die present invention are optionally substituted. Ndn-Jim!fiiig examples of cycloalkylalkyl groups include, for example, 1 - cylcohexykthyl, 2-eyc.lohexyiethyJ., i.-cyclo exyipropyl, cyelopropyltnethyi. 2-cycJ.opentylpropyi, and the like.

The terra "heterocyelylalkyl" refers to the group -al.kyi ^» beiercseyclyl, where the alky] and heterocyclyl groups are defined as herein. Heterocyclylalkyi groups of the present invention, are optionally substituted. Non-limiting examples of heterocyelylalkyl group include, for example, 3-(4- piperidinyD-propyl , 2-{ -roorp olinyi)ethyl, 3-{l-pym>iicImyi)propyl, 4-{oxiranyi)butyl, 4-(2- u iridiny! jlmtyi. and the like.

The term "heieroaryiaikyl" refers to the group -alkyl-heteroaryt, where the aikyl and heteroaryl groups are defined as herein. Heteroaryiaifc l groups of the present invention are optionally substituted. Non-limiting examples of heteroaryiaifcyl groups include, for example, 3-(4- pyridy 1 jpropyi , 3-( 2-pyridyl jpropyl, 2-{2-i midazol y l)e thyi, 4-{ 1 -imidazolyl)butyl , 2-(2-pyrrolyl }ethyi, 5-(2-ftiranyi)pentyi, and the like. The term "alkoxyheteroarylalkyT refers to the group -alkyl- heteroaryl-aikoxy, where the aikyl, heteroary and alkoxy groups are defined herein. Aikoxybetefoaryiaiky! groups of the present invention are optionally substituted. Non-limiting examples of aikoxyhetefoaryiatky! include, for example, 3-i3- .efjioxy-4-pyr!dyi)propyl, 4-(2- methoxy-4-pyrimidiny!)buty 4-{4-ethoxythiopheney! )btityJ., ; {f -propoxy-3-pyridiny.l)propyi, and the like.

For flie purposed of the present invention fused ring writs, as well as spirocyelie rings, bieyelie rings and the like, which comprise a single beteroatorn will be considered to belong to the cyclic family corresponding to the heteroatom containing ring.

Whenever a term or either of their prefix roots appears in a name of a substituent, flie name is to be interpreted as including those limitations provided herein. For example, whenever the term "alkyl" or "aryl" or either of their prefix roots appear in a name of a substitueirt (e.g., aryi aikyl, alky!amtno) the name is to be interpreted as including those limitations given above for "alkyl" and "aryi."

The term "substituted ^" is used throughout the specification. The term "substituted" is defined herein as a moiety, whether acyclic or cyclic, which has one or more hydrogen atoms replaced by a substituent or several (e.g. , 1 to 50} siib istuents as defined herein below. The substituents are capable of replacing one or two hydrogen atoms of a singl moiet at a time. In addition, these substituents can replace two hydrogen atoms on two adjacent carbons to form said substituent, new moiety or unit. For example, a substituted unit that requires a single hydrogen atom replacement includes halogen, hydrox !, and the like. A two hydrogen atom replacement includes carhonyl, oxiroino, and the like. A two hydrogen atom replacement from, adjacent carbon, atoms includes epoxv, and the like. The term, "substituted" is used throughout the present specification to indicate that a moiety can have one or more of the hydrogen atoms replaced by a substituent. When a moiety is described as "substituted" any number of the hydrogen atoms may be replaced. For example, di iuoromethyl is a substituted Ci _. alkyl; trifluoromefhyl is a substituted C> alkyl: 4-hydroxyphenyl is a substituted aromatic ring; (N.N- dimethyl-5-amino _, )octanyl is a substituted C* aikyi; 3-gtt3ntdi nopropyl is a substituted€ ^■ aikyi; and 2- earboxypyrititnyi is a substituted heteroaryi.

The variable groups defined herein, e.g., aikyi, aikeiiyl, alkynyl, cycloalkyl, alkoxy, aryloxy, aryl, heterocycle and heteroaryi groups defined herein, whether used alone or as part of another group, can be optionally substituted. Optionally substituted groups will be so indicated

The following are non-limiting examples of substituents which can substitute for hydrogen atoms cm a moiety: halogen (chlorine (CI ), bromine (Br), fluorine iP) and iodtneil)}, -CN, - O2, oxo ~SQ>N(R*h, ~C(0)R ^fi , ~C(0}OR*. ~ C(0)N(R¾, Ci -6 aikyi, C|. ₍ , haioalkyh Ci-* alkoxy, C¾.& alkeny!, C>.« alkynyl, C n cycloalkyl, aryi, heterocycle, or heteroaryi, wherein each of the alky!, haloalfcyl, alfcenyt, alkynyl, alkoxy, cycloalkyl, aryl, heterocycle, and heteroaryi groups is optionally substituted with 1-10 {e.g., 1 -6 or 1 -4) groups selected independently from halogen, ~C , -NO., oxo, and R"; wherein R°, at each occurrence, independently is hydrogen, -OR ⁷ , -SR ⁷ ,™C(0)R ⁷ , -C(OK>R ^? , -C(0)N(R ⁷ fe, -S .R ⁷ , -SfOfcOR ⁷ , - (R ^? ) ₂ , -NR ^? C(0)R\ CM aikyi, C _Kl h&loaikyl, C ₂ .. _s aikenyl. C24 alkynyl, cycloalkyl (e.g., C3* cycloalkyl), aryi, heterocycle, or heteroaryi, or two ^E units taken together with the atomfs) to which they are bound form an optionally substituted carbocyc!e or heterocycle wherein said car ocycle or heterocycle has 3 to 7 ring atoms; wherein R ⁷ , at each occurrence, independently is hydrogen, d-* aikyi, Cj-6 haloalkyl, Q-s alkenyi. C2-* alkynyl, cycloalkyl {e.g., Cs-s cycloalkyl), aryl, heterocycle, or heteroaryi, or two R* units taken together with the atoin(s) to which they are hound form at! optionally substituted carbocycle or heferocycle wherein said carbocycle or heterocycle preferably has 3 to 7 ring atoms.

In some embodiments, the substiuiems are selected from where is R^

i) -OR ; for example, -OH, ~OCH. _5> -OCH ₂ C¾, -OCH ₂ C¾C¾;

Si) ~C(0)R ^K ; for example, -COCH3, -€OC¾C¾, -COCHaCHaOHh;

iii ) ~-C(Q}OR ^s ; for example, -CQjCHj, -COiCHjCHj, -COjCHjCHjCHj;

iv) ~CiO)N{R ^s h; for example, ~CONf¾, -CONHCH3, -CONCCFbte

V) -NiR¾ for example, -NHj, -NHCH3, -N(CH ₃ ) ₂ , ~NH(CH ₂ C¾);

vi) halogen: ~F, -CI, -Br, and -Ϊ;

vii) ~CM ₀ X _S ; wherein X is halogen,; for example, ~€H ₂ F, -CHI¾, -CF ₃ , -CC¾, or™CBr¾; viii) -S .R ⁸ : for example, ~S0 ₂ H; -SQ2CH3: ~S0 ₂ Q¾;

ix) Ci -C& linear, bra ched, or eye! ί c alkyl ;

x > Cyano;

xi) Nitro;

xii) N(R ⁸ )C(0)R ^s ;

xiii) Oxo (=0);

xiv) Heferocycle; and

V ) Heteroaryi: wherein each .R ^a is independently hydrogen, optionally substituted O-Ce linear or branched alkyl (e.g., optionally substituted C* linear or branched alkyl ), or optionally substituted C ₆ -€*cye!oalky! (e.g., optionally substituted C?-G> cycksalkyl ): or two R ^a units can be taken together Us form a ring comprising 3- 7 ring atoms, in certain aspects, each 8 ^s is independently hydrogen. C _: -·( ,· linear or branched alkyl optionally substituted with halogen or C _: $-C _> cycloalkyl.

At various places in the present specification, subsrituents of compounds, are disclosed in groups or in ranges. It is specifically intended that the description include each and every individual sub-combi nation of the members of such groups and ranges. For example, the term "Cj.« alkyl" is specifically intended to individually disclose C¾, {¾, C C*, C¾, Q CpC{„ G-C$ _» Ci-C , Cs-Cj, C pC;, C:;-Q _; CrCj, Cj-Cf, C»-C _3; (¾-<¼. C ₅ -C ₆ , Cj-C*. -C¾, C _r C>, and Cs-Q,, alkyl.

For the purposes of the present invention, the terms "compound," "analog," and "composition of matter" stand equally well for the kinase inhibitors described herein, including all enantiomeric forms, diastereomeric forms, salts, and the like, and the terms "compound," "analog," and "composition of matter ^" are used interchangeably throughout the present specification.

Compounds described herein can contain an asymmetric atom, (also referred as a chirai center), and some of the compounds can contain one or more asymmetric atoms or centers, which can thus give rise to optica! isomers (enantiomers) and dsasiereomers. The present teachings and compounds disclosed herein include such enantiomers and diastexeoiners. as well as the racemic and resolved, enantioirteriealiy pure R and S stereoisomers, as well as other mixtures of the and S stereoisomers and pharmaceutically acceptable saifs thereof. Optica! isomers can be obtained in pure font) by standard procedures known to those skilled in the art, which include, but are not limited to, diastereomeric salt formation, kinetic resolution, chirai separation by HPLC, simulated moving bed chromatography i ^' SMB), and asymmetric synthesis. The present teachings also encompass cts and trans isomers (Z and E) of compounds containing alkeny! moieties (e.g. , a!kenes and immes). It is als understood that the present teachings encompass all possible regiotsomers, and mixtures thereof, which can be obtained in pure form by standard separation procedures known to those skilled in the art, and include, but are not limited to, column chromatography , thin-layer chromatography, and high- performance li uid chromatography.

Pharmaceuticall acceptable salts of compounds of the present teachings, which can have an acidic moiety, can be formed using organic and inorganic bases. Both mono and poiyaniotuc salts are contemplated, depending on the number of acidic hydrogens available for deprotonatton. Suitable salts formed with bases include metal salts, such as alkali, metal or alkaline earth, metal salts, for example sodium, potassium, or magnesium salts; ammonia salts and organic amine salts, such as those formed with morpholine, thiomorpholine, piperidine, pyrrolidine, a mono-, di- or hi- lower alkyiainine {e.g., ethyl -tcrt-butyl-, diethyl-, diisopropyl-, tnetbyl-, tiibutyl- or dimethy iprcspylamine), or a mono-, di-, or frihydrox lower alkyiainine (e.g., mono-, di- or triethaooiaminc). Specific non- limiting examples of inorganic bases include aHCOj, Na _^ OO;;, KHCO3, K2CO.;, CsiCO.i, UGH, NaOH, OH, Na¾K¾, Na>RPO, _t , and Na _; iPO. ₍ . internal salts also can be formed. Similarly, when, a compound disclosed herein contains a basic moiety, salts can be formed using organic and inorganic acids. For example, sails can be formed from the following acids: acetic, propionic, lactic, benzenesulfonie, benzoic, camphorsitifoiiic, citric, tartaric, succinic, dichloroacetic, ethenesulfonie, formic, fumarie, gluconic, glutamic, hippisric, hydrobromic, hydrochloric, iscthioiiic, lactic, rnaieie, malic, ma!onic, raande!ic, methanesulfomc, mocic, napthalenesulfonic, nitric, oxalic, patnoic, pantothenic, phosphoric, phthaiic, propionic, succinic, sulfuric, tartaric, toluenesulfonic, and camphorsulfonic as well as other known pharmaceutically acceptable acids.

When any variable occurs more than one nine in any constituent or in any formula, its definition in each occurrence is independent of its definition at every other occurrence {e.g., in N(R j¾ each R ⁴ may be the same or different than the other). Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

As used herein, th term "polar protie solvent" refers to a solvent which has O-H or N-H bonds that can. participate in. hydrogen bonding intermolecularly. These solvents can serve as a source of proton and have high dielectric constants and high dipole moments. Examples of polar protie solvents include ammonia, water, methanol, ethanoi, «-propanol. /-butanol, and acetic acid.

As used herein, the term "polar aprotic solvent. ^" refers to a solvent, which is a polar solvent with high dielectric and dipole moments hut it does not participate in hydrogen bonding. .Examples of polar aprotic solvents include tetrahydrofisran, ethyl acetate, dichloroinethane, acetone, N.N~ dirnethyifortrtarnidc, acetonit ile, and dimethyl sulfoxide.

As used herein, the term "oxidizing agent" refers to a substance that oxidizes other substances. An oxidizing agent, gives oxygen to another substance. An oxidizing agent takes electrons from other substances and by doing so, it gains electrons. Examples of oxidizing agents include ?.«·- ehioroperoxybenzoic acid, monoperphthaiic acid, peracetie acid, perpropionic acid, pertrifhioroaeetie acid, potassium periodate, sodium tnetaperiodate, sodium perborate, potassium peroxymonosuifat.e (Oxone(s>), potassium peroxydisulfate, dimethyldioxirane, dipheny) sulfoxide, dimethyl sulfoxide, urea hydrogen peroxide complex in the presence of a rhenium catalyst such as ReOCHi i, an oxidoreduetase such as Baeyer-Villiger monooxygenase, cytochrome P450 2C , cytochrome P450 2C1 , and cytochrome P450 3A4 hydrogen peroxide in the presence titanium (IV) isopropoxide- diethyitartarate. An oxidizing agent could also oxidize substances electrochemical! y or photochemical!) ¹ .

As used herei n the term "modulation" refer to modification, alteration, inhibition, regulation, activation or stimulation of the activity of a kinase protein.

As used herein the term "organic bases" refers to an organic compound which acts as base by accepting a proton. Typically, organic bases contain nitrogen atoms such as alkylamirtes or aromatic amines that can. donate electrons. .Examples of organic bases include, ammonia, ammonium .hydroxide. meth !aroine, trtmetbylamioe, dtisopropylethylamme, trioieth !amine, 2-methylpico ine, 4-dtmetbylami:nopyrtdine, dimethyiani.ii.ne.

As used herein, the term "inorganic bases" refers to a compound that contains a metal and cat! accept a proton or alternatively donate a negative species such as a pair of electrons or oxide ion. .Examples of inorganic bases include potassium carbonate, cesium carbonate, lithium carbonate, sodium carbonate, sodium hydroxide, magnesium hydroxide, lithium hydroxide, cesium hydroxide, rubidium hydroxide, sodium amide, lithium amide, potassium amide, magnesium oxide, calcium oxide, stronthium oxide, barium oxide, scandium oxide.

As used herein, the terms "treat ^*' and "treating" and 'treatment" refer to partially or completely alleviating, inhibiting, ameliorating and/or relieving a condition from which a patient is suspected to suffer.

As used herein, "therapeutically effective" and "effective dose" refer to a substance or an amount that elicits a desirable biological activity or effect.

Except when noted, the terms "subject" or "patient" are used interchangeably and refer to mammals such as .human patients and non.-b.uman. primates, as well as experimental animals such as rabbits, rats, and mice, and other animals. Accordingly, the term "subject" or "patient" as used herein means any mammalian patient or subject, to which the compounds of the invention can be administered. In an exemplary embodiment of the present invention, to identify subject patients for treatment according to the methods of the invention, accepted screening methods are employed its determine risk factors associated with a targeted or suspected disease or condition or to determine the .status of an existing disease or condition in a subject. These screening methods include, for example, conventional work-ups to determine risk factors that, may be associated with the targeted or suspected disease or condition. These and other routine methods ailow the clinician to select patients in need of therapy using the methods and compounds of the present invention,

EMBODIMENTS OF THE INVENTION

The kinase inhibitors of the present invention include all enantiomeric arid diastereomeric forms and pharmaceutically accepted salts thereof having the formula (I):

wherein:

W is selected from a group consisting of hydrogen, C¾ aifcy!. C?-? cycloalkyl., cyeloalfcyl alkyl, aryi, aryJ.al.kyl, heterocycl . heteroeyeycMkyl, hetefoarvl, heteroaryJ.al.ky!, aJkoxyheteroarylalkyl, C(0) ', C(0)R\ C(0)OR \ C(0)OR ² , triaiky.lsily.1 and diarylaikyisilyi.

X' and X ^" are at each occurrence selected from the group consisting of S, SO and SO>.

Y' and Y ² are at each occurrence selected from the group consisting of hydrogen, C« alkyl, C(0)R', C{0)R", C(0)OR\ and C(O)0 %

Z is seieeted from the group consisting of hydrogen, Cu, alkyl Cu _> alkcnyL Cwt alkynyl, arylalkynyl, .halogen, '. C(0)R\ C(0)OR ⁱ _? CiO)0R ^: \

R ^! is selected from the group of hydrogen, Ct-s alkyl and Ci-* aikenyl.

R ² is selected from the group of hydrogen, aryi, heteroaryl, ar ialkyl, heteroafyiaiky!,

R ³ is selected from the group of hydrogen, CM> alkyl. Cw cycloalkyl, cyeloalkyialky!, aryi, aryialkyl, heteroaryl and halogen,

R ^a , R*\ and R * are each independently selected from the group of hydrogen, C^, alk l, Ci-s halo alkyl.,

Cs.i, alkoxy, heterocyclyl , heteroeycly1.al.kyi, aryi, aryialkyl, aryloxy, heteroaryl, heteroarylalkyl and alkoxy hef.er oary i alkyl ,

R ^'a , R' ^h , R ^w , R'* and R ^' are each independently selected from the group of hydrogen, C ; alkyl, C>.* alkenyl, Ct.* alkynyl, i haSoaikyl, CYs alkoxy, C3.7 cycloalkyl, cycloalkylalkyl, heterocyclyl, he terocyciyl alkyl, aryl, arylaikyi, aryJoxy, arylalkyrsyl, heteroafyl, heteroaryialkyl and alkoxyhetefoaryiaikvl ,

including enantioiners, diastereomers, hydrates, sol vates, pharmaceutically acceptable salts, prodrugs and complexes thereof.

The compounds of the present invention include compounds where X ^s and X ^} are at each occurrence selected to be S, and Y ^l and Y" are H, including enamknners, diastereomers, hydrates, sol ates, pharmaceutically acceptable salts, prodrugs and complexes thereof.

The compounds of the present invention include compounds where X ¹ and X ² are at each occurrence selected to be S, and Y ^l and Y ^J are H, and Z is the moiety phenyl with R ^3a , R ^'!1 , R ^' „ R " , R- ^¾' , including enantiotners, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, prodrugs arid complexes thereof.

In some embodiments W ^! is hydrogen.

In some embodiments W ^! is optionally substituted Cr« alkyl.

In some embodiments W ^! is optionally substituted CM eyc!oalkyl.

In some embodiments W ^! is optionally substituted cycloaikyialkyL

In some embodiments W ^! is optionally substituted aryl.

In some embodiments W ^! is optionally substituted as-yiaikyl.

In some embodiments W ^! is optionally substituted heferocycl.

In some embodiments W ^! is optionally substituted heferocyclalkyl.

In some embodiments W ^s is optionally substituted heferoaryi.

In some embodiments VV ^S is optionally substituted heferaaryiaik.yi.

In some embodiments W ^s is optionally substituted alkoxyheteroarylalfcyl.

In some embodiments VV ^S is C(0) ^! .

In some embodiments W' is C(0)R ² .

In some embodiments W' is C(0)OR ^l .

In some embodiments W ¹ is CiOOR".

In some embodiments W ^! is iriaikylsilyl.

In some embodiments W' is diar laikyl sil J .

In some embodiments X ^s is S.

In some embodiments X ^s is SO.

In some embodiments X ^s is SO2.

In some embodiments X" is S.

In some embodiments X" is SO,

In some embodiments X ¹ is S(¾.

In some embodiments Y ^; is hydrogen.

In some embodiments Y ^! is optionally substituted Cw, alkyl.

In some embodiments Y ^; is C(0)R' . In some embodiments Y ^! is C(0)R ² .

In some embodiments Y ^! is C(0)OR ^] .

In some embodiments Y ^! is C(0)OR~.

In some embodiments Y" is hydrogen.

In some embodiments Y" is optionally substituted C -, alkyl.

In some embodiments Y ² is C(0.)R'.

In some embodiment}; Y ² is C(0.)R ² .

In some embodimenti; Y ² is C(0 _. )OR' ,

In some embodimenti; Y ² is C(0)OR ^: ,

In some embodimenti; 2 is hydrogen.

In some embodiments Z is optionally substituted C M _> alkyl. in some embodiments Z is optionally substituted Cs^aikenyl.

In some embodiments Z is optionally substituted Cs^aikynyl.

In some embodiments Z is optionally substituted arylaJkyn !.

In some embodiments Z is halogen.

In some embodiments Z is C(( ^" »R '.

In some embodiments Z is C( ^' 0)R ² .

In some embodiments Z is CiO}OR\

In some embodiments Z is C(0)QR ² .

In preferred embodiment* Z is

In preferred embodiments Z is

In preferred embodiments Z is

In s me embodiments R ^! is hydrogen.

In some embodiments R ^! is optionally substituted Ci alkyl.

In some embodiments R ^! is optionaiiy substituted CM _> alkenyl.

In some embodiments R* is hydrogen.

In some embodiments R ^J is optionaiiy substituted aryi.

In some embodiments R ^J is optionaiiy substituted heteroaryt

In some embodiments R ² is optionaiiy substituted aryialkyi.

In some embodiments R ² is optionaiiy substituted heieroary!a!kyi.

In ome embodiments R ^¾ is hydrogen.

In some embodiments R* is optionaiiy substituted CM. alkyl.

In some embodiments ^J is optionaiiy substituted C _¾ .? eycioalkyi.

In some embodiments ^J is optionaiiy substituted eyeloalkylalkyl.

In some embodiments R ' is optionaiiy substituted aryi.

In some embodiments R ' is optionaiiy substituted aryialkyi.

In some embodiments R ' is optionaiiy substituted heteroary.

In some embodiments R ' is halogen.

In some embodiments R ^'M is hydrogen.

In some embodiments R ^'M is optionaiiy substituted . alkyl.

In some embodiments R** is optionaiiy substituted C)-<, haioaikyS.

In some embodiments R**is optionaiiy substituted Cs.« aikoxy.

In some embodiments R** is optionaiiy substituted beterocyciyi.

1B some embodiments R**is optionaiiy substituted heterocyelylaikyi

1B some embodiments R ^s is optionaiiy substituted aryi,

1B some embodiments R^ is optionaiiy substituted aryialkyi,

1B some embodiments R ⁴ * is optionaiiy substituted aryioxy.

1B some embodiments R ^s is optionaiiy substituted heteroaryi.

In some embodiments R** is optionaiiy substituted heferaaryialkyi.

In some embodiments R' ⁵ * is optionaiiy substituted alkoxyheteroEuylaikyl.

In some embodiments ^" "' is hydrogen.

In some embodiments R ^'5t ' is optionaiiy substituted C;.& alkyl.

In some embodiments R ^'5t ' is optionaiiy substituted CM, haSoaifcyt. In some embodiments R ^! ¾ optionally substituted Cw aikoxy.

In some embodiments R ^4h is optionally substituted heterocyciyl .

In some embodiments R* ^h is optionally substituted heteroeyclylalkyl .

In some embodiments * is optionaiiy substituted aryl.

In some embodiments R* is optionally substituted arylaikyl.

In some embodiments R* ^b is optionally substituted aryloxy.

In some embodiments R* ^b is optionaiiy substituted heteroaryl.

In some embodiments R* ^b is optionaiiy substituted heteroarylaikyS.

In some embodiments R* ^b is optionaiiy substituted aikoxyheteroarylalkyi.

In some embodiments R ^' " ^: is hydrogen.

In some embodiments R ^' " ^: is optionaiiy substituted CM alkyl.

In some embodiments R ^'H' is optionaiiy substituted CM _> haloalkyl.

In some embodiments R ^'H' is optionally substituted C M* aikoxy.

In some embodiments R ^'k' is optionally substituted heterocyciyl

In some embodiments R ^'k' i.s optionally substituted heteroeyclylalkyl

1B some embodiments R " is optionaiiy substituted aryl,

1B some embodiments R ⁴ " i.s optionally substituted arylaikyl.

Iii some embodiments R ^i; is optionally substituted aryloxy.

In some embodiments . * is optionally substituted heferoaryi.

In some embodiments R* ^<: is optionally substituted heferoaryialkyl.

In some embodiments ^' "' is optionally substituted alkoxyheteroaryl alkyl.

In some embodiments R"* is hydrogen.

In some embodiments ™ is optionally substituted Ci.«, alkyl.

In some embodiments R ^"14 is optionally substituted CM, aikeny!.

In some embodiments R ^"14 is optionally substituted CM, alkynyl.

In some embodiments R ^"14 is optionaiiy substituted CM, haioalkyi.

In some embodiments R ^"14 is optionaiiy substituted CMS aikoxy.

In some embodiments R ³ * is optionaiiy substituted CV? cycloalkyl.

In some embodiments R ³ * is optionaiiy substituted cyeSoaikyialkyL

In some embodiments R ³ * is optionaiiy substituted heterocyciyl.

In some embodiments R ³ * is optionaiiy substituted heteroeyclylalkyl.

In some embodiments R ³ * is optionaiiy substi tuted aryl.

In some embodiments R ^3a is optionaiiy substituted arylaikyl.

In some embodiments R ^3a is optionally substituted aryloxy.

In some embodiments R' ^a is optionally substituted aryl.alkynyl.

In some embodiments R' ^a is optionally subsiiiuied heteroaryl.

In some embodiments R' ^a is optionally subsiiiuied heteroaryl.alkyi. In some embodiments ^' R ^3a optionally substituted alkoxyheteroaryi alkyl.

In some embodiments R: ^¾ is hydrogen.

In ome embodiments R ^1h is optionally substituted C-.-t, al.kyl.

In some embodiments R* is optionaiiy substituted€·* alkenyi.

In some embodiments R* is optionally substituted€·* alkynyl.

In some embodiments R* is optionaiiy substituted Cs-ghaloalkyl.

In some embodiments R* is optionaiiy substituted CYs alkoxy.

In some embodiments R* is optionaiiy substituted Cj.? eyc!oalkyi.

In some embodiments R* is optionaiiy substituted cycioalkylalfcyl.

In some embodiments R* is optionaiiy substituted hetenxyety!.

In some embodiments R* is optionaiiy substituted heterocyciyiaiky ^' i.

In some embodiments R ° is optionaiiy substituted aryl.

In some embodiments R ° is optionaiiy substituted arylalkyl.

In some embodiments .R ^i> is optionaiiy substituted aryioxy.

In some embodiments .R ^i> is optionaiiy substituted aryiaikynyl.

In some embodiments R* is optionaiiy substituted heleroaryl

In some embodiments R ^s ' is optionaiiy substituted heleroaryiaikyl

In some embodiments R' ' optionally substituted alkoxy.lieteroaryla1.kyl.

In some emboditnents R' is hydrogen.

In some embodiments .R™ is optionally substituted Ci.«, alkyl.

In some embodiments .R™ is optionally substituted Ci.«, alkenyl.

In some embodiments ™ is optionally substituted Ci.«, alkynyl.

In some embodiments is optionally substituted Ci.«, haloalkyl.

In some embodiments R* is optionally substituted Ci-*. alkoxy.

In some embodiments R* is optionaiiy substituted C t cyeloalkyl.

In some embodiments R ^1c is optionaiiy substituted cyeioaikyiaikyL

In some embodiments R ^¾ is optionaiiy substituted beteroeyeiyl.

In some embodiments R ^: " is optionaiiy substituted beteroeyeiylaikyi.

In some embodiments R ^: " is optionaiiy substituted aryl.

In some embodiments R ^: " is optionaiiy substituted arylalkyl

In some embodiments R ^: " is optionaiiy substituted aryloxy.

In some embodiments R" is optionaiiy substituted aryk!kyny!.

In some embodiments R ^3c is optionaiiy substi tuted heteroaryl

In some embodiments R ^1C is optionally substituted heteroarylalkyl.

In some embodiments R* optionaiiy substituted alkoxyhcteroarylalkyl.

In some embodiments R ^l is hydrogen.

In some embodiments R ^l is optionaiiy substituted CYs alkyl.

4.1 In some embodiments : ^)d is optionally substituted Vs alkenyt

In some embodiments R: ^)d is optionally substituted Vs alkynyl .

In some embodiments R ^1d is optioiiiilly substituted Ci-fjhaloalkyl.

In sotne embodiments R ^l is optioiiiilly substituted d al.koxy.

In sotne embodiments R ^l is optioiiiilly substititfed€ _? ■·; cycioaikyl.

In some embodiments R ^" is optionally substituted cycioalkylalfcyl.

In some erabodimenti; R ^" is optionally substituted heterocyety!.

In some erabodimenti; R ^" is optionally substituted heterocyciylalfcyl.

In some embodiments R ^" is optionally substituted aryl.

In some embodiments R ^" is optionally substituted arylalkyl.

In some embodiments R ^" is optionally substituted aryioxy.

In some embodiments R ^5d is optionally substituted arylalkynyl.

In some embodiments R ^5d is optionally substituted heteroaryl.

1B some embodiments R ^5d is optionally substituted heteroaryiaikyL

1B some embodiments R ^5d optionally substituted a!koxyhetero t-yialkyi,

1B some embodiments .R- ^¾ is hydrogen.

1B some embodiments .R- ^¾ is optionally substituted C^. alkyl.

In some embodiments R' ^>5 is optionally substituted Cj-$ alkenyl.

In some embodiments ' ^>5 is optionally substituted Ci.«, alkynyl.

In some emboditnents R^ ^' is optionally substituted Ci.«, haloalkyl.

In some emboditnents .R ^w is optionally substituted Ci.«, alkoxy.

In some embodiments R is optionally substituted C?>. ? cyeloalfcyl.

In some emboditnents R is optionally substituted cycloalkylalkyl.

In some embodiments R ^"¾' is optionally substituted eteraeyelyl.

In some embodiments R ^"¾' is optionally substituted eteraeyel laikyi.

In some embodiments R ^¾ is optionally substituted aryl.

In some embodiments R ^¾ is optionally substituted arylalkyl.

In some embodiments ^' R ^3C is optionally substituted aryioxy.

In some embodiments ^' R ^3C is optionally substituted arylalkynyl.

In some embodiments ^' R ^3C is optionally substituted heteroaryl.

In some embodiments ^' R ^3C is optionally substituted heteroarylalkyi.

In some embodiments ^' R ^3C optionally substituted alkoxyheteroarylalkyk

Exemplary embodiments include compounds having the formula 0) or an enantiomer, diastereomer, hydrate, solvate, prodrug, complex., or pharmaceutically acceptable salt form, thereof wherein Y ^s is H, and Z is

wherein R ^a , R ³¹ ', R ^¾3 , and R ³ * are ail H, and wherein non-limiting examples of X ^! , X ² , \ R^ ^' and W ^! are defined herein below in Table 1 ,

Table 1 : Exemplary compounds of the formula (1)

Exemplary embodiment* include compounds havin formula (I) or an enantioiner, diastereomer, hydrate, solvate, prodrug, complex, or pharniaceuticaiiy acceptable sail: form thereof: wherein Y* is H, and Z is

and wherein non-limiting examples of X ¹ , X ² , Y ² , ³ and W' are defined herein, below in Table 2.

Table 2: Exemplary compounds of the formula (I)

Exemplary embodiments include compounds aving formula (I ) or an cnantiomer, diastereomer, hydrate, solvate, prodrug, complex, or pharmaceutically acceptable salt form thereof: wherein R ^a and R ^c are H, and wherein non-limiting examples where X ^s , X ² , Y ² , R* or W' are defined herein below in Table 3.

Table 3: Exemplary compounds of the formula (Ϊ)

Exemplary embodiments include compounds having the formula (I) or an enamkwner, diastereomer, hydrate, solvate, prodrug, complex, or pharmaceutically acceptable salt form thereof wherein Y ^l is H, and Z is ethynyibenzene, and wherein non-iirniling examples of X \ X" , Y ^~ \ and W ^! are defined herein below i Table 4,

Table 4: Exemplary compounds of the formula (1)

Group X ¹ X ² Y ² W

Number

3 S so H CH,

4 SO s H CH?

5 s so COw-Buiyi H

6 so s COri-Botyl H

7 s so COw-Buiyi CH _}

o s COj-i-Buiyl Oh

9 s so coc¾ CQz- CH?

10 so s coce. CO- CH _} i ! so H c-pentvl

12 so s H e-pentyi

13 so H opropyl

14 so s H cNpropyi

15 s so H CHjPhenyi

16 so s H CH .Phe.m i

For the purposes of demonstrating the manner in which the compounds of the present invention are named and referred fo herein, bonds between two different sishstii.ueni.s one of which being in a heterocycie are represented by plain !ines {— - ) to denote above the plane as a mixture of both enandoroers and a dashed Sine {—— - ) to denote bonds pointing downward as a mixture of enandoroers. Bonds to atoms above the plane of the drawing denoting absolute stereochemistry are represented by {— ^■ " ^■ * ). Bonds below the plane of the drawing denoting absolute stereochemistry are represented by ( · ^» Ι»ΗΗ|). A wavy line denotes situations where the stereochemistry is unknown

For the purposes of demonstrating the manner in which the compounds of th present invention are named and referred to herein, the compound having the formula:

has the chemical name trans 3-((4-aroino-3-phenyl-lH-pyi¾zolo[3,4-rfjpyrimidin-:i -yl imethyl)- ! ,2- di.thiolan~4 -yl henzoate) .

For the purposes of demonstratin the manner in which the compounds of the present, tnvetitioii are named and referred to herein, the compound having the formula:

has the chemical nam /nww 3-{(4-amino-3-pheny ^' i - 1 /-pyrazoio [3 ,4- jpyrimidin- 5 -yi)methyl )- 1 ,2- dit i.oian-4-ol

For the purposes of demonstrating the manner in which the compounds of the present invention are named and referred to herein, the compound having the formula:

has the chemical name trans

yl )met yJ )- Ϊ ;2-ditbio.ian-4- y i benzoate.

For the purposes of demonstrating the manner in which the compounds of the present invention are named and referred to herein, ihe compound having the formula: has the chemical name trans 3-((4-aoiioo-3-(4-cMor ¾>henyl)- 1 W-pyrazolo[3, -«?]pyfim!din-l- yl)methy 1 >- Ϊ .2 -di tbi .ii«:i-4 ^« i .

For the purposes of demonstrating the manner in which the compounds of the present invention are named and referred to herein, ihe compound having the formula:

has the chemical name trans 3-{{4"amin ^-{4-medm y^

yl)methyi 1 ,2-dfthk>lan-4-yI benz ate.

has the chemical name imns 3-((4-amim 3-(4-methoxyphenyl)- f W-pyfazo.io 3,4^ |pyri.m:id;in.- 1 yi).oiethyiy J. ,2-dirhiol an-4-oL

For the purposes of demonstratin the manner in which the compounds of the invention are named and referred to herein, the compound having the formula:

has the chemical name i35,4/ -3-i(4-atnsno-3 4-meifroxypto^

yi)m £hyi)- 5 ,2-dithiolan-4-oi.

For the purposes of demonstrating the manner in which the compounds of the present. invention are named and r ferred to herein, the compound having the formula:

has the chemical name (3AASj -((4-&nran^

yi )methy1 )- Ϊ ,2-di thio.lan-4-oi ,

For t!ie purposes of demonstrating the manner in which the compounds of the present invention are named arid referred to herein, the compound having the formula:

has the chemical name civ 3-((4-mnjno-3-(4-methoxphe«> )-iH-pTazoJo|3 _J 4^/jp rini}<iin- 1 - yl)methyl>- S. ,2-dithiol an-4-y 1 beozoaie.

For the urposes of demonstrating the manner in which the compounds of the present invention are named and referred to herein, the compound having the formula:

has the chemical name eh 3^{^ fnim>-3^4-fneeioxy henyi)-l /- yra^lo3,4-^ yrimjdjn-J- y] jmethy])- ! ,2-dilhio!an-4-oi.

For the purposes oi demonstrating the manner in which the compounds of the present invention are named and referred to herein, the compound having the formula:

has the chemical name (3.V,4S)-3-((4-amiai 3-(4-me^)oxyj>henyi)- f i/-pyrazolo{ ^' 3.4-< Jpyri«Hdin- 1 - yl).m.ethy.i)- J. ,2-dithiol an-4-oL

For the purpose* of demonstrating the manner in which the compounds of the present invention are named and referred to herein, the compound having the formula:

has the chemical name (3 4jR)-3-( ^' (4-am!no^-(4-methox

yl )methyJ )- Ϊ ,2-dithiolaa-4-ol

For the purposes of demonstrating the manner in which the compounds of the present invention are named and referred to herein, the compound having the formula:

has the chemical name trans I -C(4-methoxy- 1 ,2-dithjoIan-3-yl}meihyl)-3-(4-phenoxy phenyl)- 1 H- pyrazoio[ ^' 3,4-rf]pjTimidin-4-amine.

For th purposes of demonstrating the manner in which the compounds of the present i vention are- named and referred to herein, the compound having the formula:

5.1 has the chemical name cis l-((4-n^thoxy-i,2-d!^iolan-3-yl)me<¾yl)-3-( -pheooxypheoy!)-ljW- py ra zo i o [ ^' 3,4-</ ] pyxi ro idi fl -4- ami ne .

For the purposes of demonstrating the manner in which the compounds of the tnvetitioii are named and referred to herein, the compound having the formula:

has the chemical name trans H(4-(be zy!oxyH,2-dtthi.oian-3-yft

py ra zo i o [ ^' 3,4-</ ] pyxi m idi xi -4 - ami ne .

For the purposes of demonstrating the manner in which the compounds of the present invention are named and referred to herein, the compound having the formula:

has the chemical name ds I -((4-{beiu;yloxy)- 1 ,2-dithiolan-3-yl)n}ethylK^-<4-phenoxyphenyl)- 1 H- pyraa)lo 3,4-i/|{>yriiiiidii):-4-aii:ti:oe.

For the purposes of demonstrating the manner in which the compounds of the present invention are named and referred to herein, the compound having the formula: has the chemical name- trans 3-ii4-amino -i4-phenoxyphenyi)-i #-pyra^

yl )meth l )- i ,2-di tb:iolan-4- i benzoate.

For the purposes of demonstrating the manner in which the compounds of the present invention are named and referred to herein, the compound having the formula:

has the chemical name tratis 3-f{4-aniino-3-i4-phenoxyphenyi)- ! f/-pyrazo!oS 3,4-iijpyrim!din-i- yl )methyJ )- J ;2-ditb:iolan-4-oi ,

For the purposes of demonstrating the manner in which the compounds of the present invention are named and referred to herein, the compound having the formula:

has the chemical name

yDmethvD- J ^-dithiolan-4-ol. For. the purposes of demonstrating the manner in which the compounds of the present invention are named and r ferred to herein, the compound having the formula:

h

has the chemical name (3/f,4« )-3-((4-amino-3-(4-phenoxyphenyi)- 1 //-pyrazolo[3,4^jpyrimidin- 1- yi)methyl)- 5 ,2-dit iolan-4-oi.

For the purposes of demonstrating the manner in which the compounds of the present invention are named and referred to herein, the compound having the formula:

h

has the chemical name cis 3-({4-amino-3-(4-phenoxyphenyi)-! /-j)yraz l i3 4-t/3pyi'i«iidin-l- yl jmethyl}- ! ,2-diihiolan-4-yi benzoate.

For the purposes of d monstrating the manner in which the compounds of the present invention are named and referred to herein, the compound having the formula:

has the chemical name cis 3-((4-amino-H^pbenosypheny! -iH-pyra¾olol3,4-rfjpyrio)idio-f - yl) eihyl)- S. ,2-dithiol an-4-oL

For the purposes of demonstratin the manner in which the compounds of the present, invention are named and referred to herein, the compound having the formula:

h

has the chemical name 3S,45)--3-{{4-a:mit)o--3-{4-phet)oxyphen l }- l/jf-pyrazoloj 3,4-f jpyriraidin- ! - yi)m t yl ^' )- 5 ,2-dit iolan-4-oi.

For the urp ses of demonstrating the manner in which the compound?! of the present invention are named and r ferred to herein, the compound having the formula:

h

has the chemical name (3^ _? 4i?)-3-((4-aniino-3-(4-p enoxyp eny.l)- Iff- yraioioiS^-ffl Timiciin-l-- yi )methy 1 )- 12-di thio.lart-4-oi ,

For the purposes of demonstrating the manner in which the compounds of the present invention are named and referred to herein, fhe compound having the formula:

has the chemical name fram- 3-(i4-ammo-3-(phenylemynyi)-lH-pyt^^

yl )methy]-l ,2-dithiolan-4-yI benzoate.

For the purposes of demonstrating the manner in which the compounds of the present invention are named and referred to herein, the compound having the formula:

has the chemical name trans 3-(4-amiiK»-3-{{Aenyle ynyl)- 1 W-pyras«>lol ^' 3,4-< jpyrimjdjn-i- y limetliyl" i ,2-di thiolan-4-oi.

For the purposes of demonstrating the manner in which the compounds of the present invention are named and referred to herein, the compound having the formula:

has the chemical name trans 3-{{4-_mimo-3-{pheny]eihynyi)- -if -pyi¾zo]o[3 _» 4-<ii]py itnidm- vDmethvl- t-oxido- ί ,2-dfthiolan-4-vi benzoate. For. the purposes of demonstrating the manner in which the compounds of the present invention are named and r ferred to herein, the compound having the formula:

has the chemical name trans 3-(i4-am»no-3-(2-ammobenzo[ii]oxazo^

^ ^' ipyrimidin-i -yl imethyl}-- 1 ,2-dithioian-4-yi benzoate.

For the purposes of demonstrating the manner in which the compounds of the present iiivention are named and referred to herein, die compound having the formula:

has the chemical name trans 3HX4-aoitno-3H ^' 2-aminobe:nzo[ii]oxa^

<ijpyrimidin-l-y!)methyl)- f 2-ditmolan-4-ol.

For the purposes of demonstrating the manner in which the compounds of the present invention are named and referred to herein, die compound having the formula:

has the chemical name mj/i,v 3-((4-aiiiino-3-(2-an«noben.?:o (: joxazol-5-yi)- 1 W-pyrazolo[3,4- t/jpyrimidin- 1 -yl)mcihyi)- 1-oxido- i. ,2 ^» didiiolan -4- l benzoate. For. the purposes of demonstrating the manner in which the compounds of the present invention are named and r ferred to herein, the compound having the formula:

has the chemical name irons 3-((4-amino-3-(2-an«BOben.?:o (: joxazol-5-y!)- 1 W-pyrazolo[3,4- rfjpyrijtmdm- 1 -y!)tnethyi)-4-hydroxy-- 1 ,2-dithioiane 1 -oxide.

For the purposes; of demonstrating the manner in which the compounds of the present tnvetitioii are named and referred to herein, the compound having the formula:

has the chemical name trans 3-{{4-_miino-3-{4-(241uorophenoxyphenylV i if-pyrazoioj 3,4- <i]pyrimidin-l -yl )metir } - i ,2-dithioian-4-yi henzoate.

For the purposes of demonstrating the manner in which the compounds of the present iiivention are named and referred to herein, flie im ound having the formula:

has the chemical name irons 3-((4-amir ^3-(4-(2-t1«oxt)p.hejnoxyp.heflyl)-l /-pyraz;oloi3 _> 4- rf]pv ijmidjn-l -yl)n5!ethy )-l,2-dithiolan-4-oL

For the purposes of demonstrating the manner in which the compounds of the present, invention are named and referred to herein, the compound having the formula:

has the chemical name trans LV({4-ainin« LV(3-(3-f}ittm!^-p.heiioxyp.hen> )-lH-pyra2c»1.o(3 _> 4- t/jpymnidin- l.-yl)nx:myl)-i,2-d ik»kn-4-y1. benzoate.

For the purposes of demon.strati.ng the manner in which fhe compounds of the present invention are named and referred to herein the compound having the formula:

has the chemical name trans 3-{{4-arnino-3-{3-(3-fiu<»n 4-phenoxyphenyl)- 1 f -pyrazolo|3,4-

<i]pyrimidi.n-:i -yl )nietbyl - i ,2-dithiolan-4-oi

in. all of fhe embodiments provided herein, examples of suitable optional substituents are not intended to limit the scope of the claimed invention. The compounds of fhe invention may contain any of the substituents, or combinations of subsiiiuems, provided herein.

it will also be appreciated by those of skilled in the art, may be administered to a mammal and thereafter metabolized in the body to form compounds of the invention which are pharmacologically active. Such derivatives may therefore be described as "prodrugs". All prodrugs of compounds of formula (1) are included within the scope of this invention.

It is understood that one skilled in the art would be able to make compounds of the invention by similar methods as shown below, or by methods known to one skilled in the art. It is also understood that one skilled in the art would be able to make in a similar manner as described below other compounds of formula (I) not specifically illustrated below by using appropriate starting components and modifying the parameters of the synthesis as needed, fa general, starting materials may be obtained from sources such as Sigma Aklrieh, TCI and the like, or synthesized according to sources known to those of skill in the art (see Smith, M.B. and J. March. Advanced Organic Chemistry: Reactions, Mechanisms and Slnurture, 5* edition (Wiley, December 2000).

COMBINATION THERAPY

in another embodiment of the invention, compound of the disclosure may be combined with one or more additional compounds of the disclosure for the treatment of tyrosine kinases-mediated disease and conditions. The compound of the disclosure may be administered simultaneously, sequentially or separately with the one or more additional compounds of the disclosure for the treatment of tyrosine kinases-mediated disease and conditions. In a further embodiment of the invention, a compound of the disclosure ma be combined with one or more additional compounds of the disclosure and an excipient for the treatment of tyrosine kinases-mediated disease and conditions.

In another embodiment of the invention, a compound of the disclosure may be combined with an ant! -cancer agent for the treatment of tyrosine kinases-mediated disease and conditions. The compound of the disclosure may he administered simultaneously, sequentially or separately with for the treatment of tyrosine -mediated disease and conditions. Anti-cancer agents include receptor tyrosine kinase inhibitors such as erioti.mb, neratiiii.b, daeoioiiiiiib. afatinib, peliiinib, gefitinib, crizoti nib, roeileiinih, osimertinib, HM617I 3, AST- 1.306, WZ4002, and the like. Said anti-cancer agents also ineiude non receptor tyrosine kinase inhibitors such as ibrutinib, paeriiinib, iideghssib, RVX-20S, B MS -536924, MNS, quizartinib, dovitimh, tanduiinih, KW-2449, ENMD-2076, UNC- 2025, AMG925, AZD2932, cabozantimb, R406, ruxolitinib, tofaci tinib, A2D1480, fedratinib, AT9283, it !Hteiotinib, gandotinib, barieitinib, AZ960, CEP-33779, XL019, ruxolitinib. deeemoiinib, cerdulatinib, fi!gotinib, saracatinib, dasatimb, bosutinib, RX2-3 I , PP2, SU6656, WH-4-023, OSI 923, raf inhibitors, AZ 628, SGX-523, Dabrafenib, R05126766, CEP- 2496. ERK inhibitors SCM772984, VX-I l e, idxettinib, GDC-0994, ME inhibitors including selametinib, PD0325903 , trametinib, U0! 26, PD 184352, BIX 02189, pimasertib, AZD833 , binimetinib, GDC-0623, refametinib phosphatidylinositol 3-kinase (PI3K) inhibitors such as wortmannin, demethoxyviridin, LY294002, perifosme, idelalisib, PX-866, IPi-145, BAY 80-6946, BEZ235, RP6530, TGR 1202, SF1 126, INK1 1 17, GDC-09 1 , BKM120, XL147, XL765, Palomid 529, GSK 1059615, ZST 474, PWT33597, rC87114, TG 100-1 35, CAL263, RP6503, PI- 103, GNE-477, CUDC-907, AEZS-136, and the like, A T inhibitors such as M 2206, M C- 1 , GSK 690693, FPA 1.24, AT7867, GDC- 0068, ALM3G 1. AZD5363, KP372-1 and the like, mTor inhibitors such as rapamycin, evero!imus, temsirolirnus, ridaforolinsus, sirolimus, AZD80S5, XL38S, KU-0063794, GDC--0349, WYE-354, GSK 1059615, PP242, Palomid 529. OSI -027, PF-05212384 , WAY-600, WYE-125132, WYE-687, AZD20I.4, INK 1.28, Torin 1 , Torin 2 and the iike, e-Me£ inhibitors such as SU1. 1274. K252a, PHA- 665752, PHA-66752, PF- 2341.066, BMS-777607, JNJ-38877605, PF-042I 7903, M -2461 , GSK 1.363089, AMG-458, tivantinib, INCB28060, cabozantinih, forettntb, and the like, vascular endothelial growth factor fVEGF) monoclonal antibodies such as bevaetzumab, rantbizumab, and the like, PD- 1 immunotherapy such as r nbroiizumab, epidermal growth factor receptor i ^' EGFR) inhibitor such as gefiti.nib, erlotinib, and tlie like, epidermal growth factor receptor i ^' EGFR) monoclonal antibodies such as cetuximah, panitumuirtab and the like, Wnt pathway inhibitors such as XAV939 and the like, bioactive flavo!ignans such as siiibinin and the like, DNA rnethylation inhibitors such as 5-aza-2 ^* -deoxyeyudine and the like, platinum based anticancer agents such as carboplatin, cispiariri, and the like. Anti-cancer agents also include pac!itaxeS, genicitabine, docetaxel, vinore!bine, irinotecan, pemetrexed, and the like, dual anti-cancer therapies such as carhop tat in/pa itaxel, carboplatin gemcitabine, earboplatin docetaxel, carboplatin vinoreSbine, carboplatin/ irinotecan, carboplatin/ penietxexed, cispiatin/paelitaxel, eispiatiiVgemcitabine, cispiatin/docetaxel, cisplatin/vinorelbine, cispiatsn/ irinotecan, eisplatin penw-trexed, and the like. Anti-cancer agents also includes autophagy inducing agents such as imatinib and the like, Rexinoids or retinoid x receptor selective iigands such as baroxetene and the like, Cye.!ooxygenase-2 inhibitor such as rofecoxib and the like, Src family kinases and .Bcr-Abl inhibitor such as hosu!if and the like, and Recombinant adenovi ral vector TRAIL protein.

In another embodiment of the invention, a compound of the disclosure may be combined with radiation therapy for the treatment of tyrosine kinase -mediated disease and conditions.

K ITS

The present invention also provides kits that contain a pharmaceutical composition which includes one or more compounds of the invention. The kit also includes instructions for the use of the pharmaceutical composition for modulating the activity of RTK. for the treatment, of cancer, as well as other utilities as disclosed herein. Preferably, a commercial package will contain one or more unit doses of the pharmaceutical composition.

PREPARATION OF THE COMPOUNDS OF THE INVENTION

The present invention further relates to processes for preparing the compounds of the disclosure.

Compounds of the present teachings can be prepared in accordance with the procedures outlined herein, from commerciall available starting materials, compounds known in the literature, or readily prepared intermediates, by employing standard synthetic methods and procedures known to those skilled in the art. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be readily obtained from the relevant scientific l iterature or from standard textbooks in the field. It wi.il be appreciated that where typical or preferred process conditions {i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum

6.1 reaction conditions can vary with the particular reaetants or solvent, used, but such conditions can be determined by one skilled in the art by routine opti mization procedures. Those skilled in the art of organic synthesis will recognize that the nature and order of the synthetic steps presented can be varied for the purpose of optimizing the formation of the compounds described herein.

The processes described .herein can be monitored according to any suitable method known in the an. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., Ή or ^{: !} C), infrared spectroscopy, spectrophotometry (e.g., yV-visibie}, mass spectrometry, or by chromatography such as high pressure liquid chromatograpy (HPLC), gas chromatography (GC), gel-permeation chromatography (GPC), or thin layer chromatography (TLC). Preparation of the compounds can involve protection and deprotection of various chemical groups. The need for protection and deprotection and the selection of appropriate protecting groups can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in Greene et ah. Protective Groups in Organic Synthesis, 2d. Ed. (Wiley & Sons, 1991 ), the entire disclosure of which is incorporated by reference herein for all purposes.

The reactions or the processes described herein can be carried out in suitable solvents which can be readily selected by one skilled in the art of organic synthesis. Suitable solvents typically are substantial ly nonreaetive with the reaetants, intermediates, and/or products at die teinperatures at which the reactions are carried out, i.e., temperatures tiiat can range from the solvent's freezing temperature to die solvent's boiling temperature. A given reaction can be carried out in one solvent or a mixture of more t han one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected.

GENERAL SYNTHETIC SCHEMES FOR PREPARATION OE COMPOUNDS

The reagents used in the preparation of the compounds of this invention can be either commercially obtained or can be prepared by standard procedures described in the literature. In accordance with this invention, compounds in the genus may be produced by one of the following reaction schemes.

Scheme 5

A compound of the formula (1 ), a known compound or compound prepared by known methods, is reacted with dtmethylsulfoxk!e or potassium ferrieyanide in a solvent such as water in. the presence of a base uch as potassium hydroxide, sodium, hydroxide, lithium hydroxide and the like, optionally with heating, optionally with, microwave irradiation to provide a compound of the formula (2).

Scheme 2

(3) (5) (7)

A. compound of the formuia (3), a known compound or compound prepared by known methods, is reacted with a known compound of formula (4) or compound prepared by known methods such as benzoyl chloride, p-nitrobenzoyi chioride and the like in the presence of a base such as, trimethylamine, pyridine, pieolme, lutidine, dmopropylethylaraine and the like in a solvent such as methylene chloride, 1 ,2-dichloroethane, acetonitriie, N,N dimethylfonnamide, N,N dimethylacetamide, dioxane, tetrahydrofuran optionally with heating, optionally with microwave irradiation to provid a compound of the formuia (5).

A compound of the formuia (5), a known compound or compound prepared by known methods, is reacted with a ^' known compound of formula (6) or compound prepared by known methods such as methanesulfonyl chloride, trifl uoromethanesuifonyi chloride, and the like in die presence of a base such as, trimethylamine, diisopropyiethyiamine, pyridine, picoline, lutidine, and the like in a solvent such as methylene chloride. 1,2-dichloroethane. acetonitriie, toluene, dioxane. tetrahydfofuran optionally with beating, optionally with microwave irradiation to provide a compound of the formula <7>-

Scheme 3

A compound of the formula <8), a known compound or compound prepared by known methods, is reacted with a known compound of formul (9) or compound prepared by known methods such as benzoyl chloride, -nitrobenxoyl chioride and the like in the presence of a base such as, trimethylamine, pyridine, pieoline, lutidine, diisopropyiethyiamine and the like in a solvent such as methylene chioride, 1 ,2-dichloroethane, acetonitriie, N,N dimethylfonriamide, NJi dioietoylacetamide, dioxane, tetfahydrofuran optionally with heating, optionally with microwave irradiation to provide a compound of the formula ( S O),

Scheme

A compound of the formula (1 1 ), a known compound or compound prepared by known methods, is reacted with a known compound of formula (12) or compound prepared b known methods such as methyl iodide, ethyl iodide, benzyl bromide and the like in the presence of a base such as, sodium hydride, potassium hydride, trimethyiamine, pyridine, picoline, mtidine, diisopropylethylamine and the like in a solvent such as tetrahycfrofuran. ether, dioxane, methylene chloride, 1 ,2-dichloroefhane, acetoriitrile, N,N dimeihyliormamide, N,N dimethyl acetami.de, optionally with beating, optionally with microwave irradiation to provide a compound of the formula (13 ).

A compound of the formula ( 13), a known compound or compound prepared by known methods, is reacted with a known compound of formula { i 4) or compound prepared by known methods such as meth nesidfonyi chloride, trifluoromethariesulfonyl chloride, and flie like i:o the presence of a base such as, trirnethylami.iie. diisopropyle yiamine, pyridine, picoline, lutidine, and the like in a solvent such as methylene chloride, 1 ,2-diehioroethane, acetomtriie, toluene, dioxane, tcirahydrof uraii optionally with heating, optionally with microwave irradiation to provide a compound of the formula { ί 5).

Scheme

A compound of the formula ( 1 ), a known compound or compound prepared by known methods, is reacted with a known compound of formula { i 7) or compound prepared by known methods such as irimefhyisiiyi ch.iori.de, i-butyidiiiiethylsilyl chloride, and the like in the presence of a base such as, imidazole, trimethyiamine, pyridine, picoline, luddine, dii sopropylethylaraine and the like in a solvent such as tetrahydrofuran, ether, dioxane, methylene chloride, 1 ,2-dichioroethaiie, N.N dimethylformamkie, ,<V, ;V di ethyiacetarmde, optionally with heating, optionally with microwave irradiation to provide a compound of the formula ( 18),

A. compound <»f the formula (18), a known compound <»r compound prepared by known methods, is reacted with a known compound of formula (19) or compound prepared by known methods such as rnethanesuiforiyi chloride, trifiuoronieihanesuifonyi chloride, and the like, in the presence of a base such as, trimemylamine, du»>propyleth larmne, pyridine, picoline, lutidine, and the like in a solvent: such as methylene chloride, 1 ,2-dichloroethane, aeetoimriie, toluene, dioxane, tetrahydrofuran optionally with heating, optionally with microwave irradiation to provide a compound of the formula (20).

Schem 6

A compound of the formula (21 ), a known compound or compound prepared by known methods, is reacted with a known compound of formula (22) such as A'-iodosuceinimde or N- bromosuceinimide or compound prepared by known methods and the like in a solvent such as tetrahydrofuran, ether, dioxane, aeetonitriie, N.N dimethyll ^' ormamide, N,N dimethylacetamide, optionally with heating, optionally with microwave irradiation to provide a compound of the formula

A compound of the formula (24). a known compound or compound prepared by known methods, is reacted with a known compound of formula (25) or compound prepared by known methods such as phenylhoronie acid, p-methoxyphenylfa¾ronic acid, -chlorophenylhoronic acid and the like, in the presence of a phosphate salt such as potassium phosphate, sodium phosphate, and the like in the presence of a palladium catalyst (26) such as palladium acetate, tetrafcis(iriphen.y1:phosphi]:ie)pallaiurn(0), bis(£riphe:oylphosphine)pallaiuiri(Il) diciiioiide, ( }., }.'- his(diphe!iylphosphino)femx'e!ie)palladfum(ll) diciiiori.de and the like solvent such as N,N dimemyltbrmamide, N.N dimeth a etaroide, aeetonitri!e, tetrahydrofuran, 1 ,4-dioxane, water, and the like, optionally with, heating, optionally with microwave irradiation to provide a compound of the formula i ^' 27).

Scheme 8

A compound of the formula (28), a known compound or compound prepared by known methods, is reacted with an inorganic base seel) as potassium carbonate, sodium carbonate, cesium carbonate, sodium hydride, potassium hydride, and the like in a polar aprotic solvent such as N.N dimethyiformamide, N,N dim thylaeetamide, aceionitriie, tetrahydrofiiran, dioxane and the like, followed by reaction with a known compound of formula (29) or compound prepared by known methods such as 5-((m«¾hylsuliOnyl)oxy)- 1 ,2-dithian-4-yl benzoate, and the like, in a in a polar aprotic solvent such as such as N.N ditnethyiformamid , N.N dimethylaceiamide, acetoni tri ^' l , tetrahydrofuran, dioxane and the hke optionally with heating, optionally with microwave irradiation to produce a compound of formula (30),

Scheme 9

A compound of the formula (31 ), is reacted with a base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium carbonate, cesium carbonate and th like, in a solvent such as methanol, ethanol, N,N dimethyltbrmamide, N,N dimethyiacetaniide, acetonitrile, tetrahydrofuran, dioxane and the like, optionally with beating, optionally with microwave irradiation to provide a compound of formula (32), Scheme S O

A. compound of the formula (33), a kiiowii compound or compound prepared by known methods, is reacted with an inorganic base such as potassium carbonate, sodium carbonate, cesium carbonate, sodium hydride, potassium hydride, and the like in a polar aprotic solvent such as A'JV ciimethyiformanikie, N,N dimethylacetamide, acetonitrile, tetrahydrofuran, dioxane and the like, followed by further reaction with a compound of formula (34) or compound prepared by known methods such as 5-methoxy-l ,2-dithian-4-yl methanesalfonale, 5-(benzyloxy)-l ,2-dkhian-4-yl methanesu!fonate and the like, optionally with heating, optionally with microwave irradiation to produce a compound of formula (35),

Scheme 1 1.

A compound of the formula (36), a known compound or compound prepared by known methods, is reacted with an inorganic base such as potassium carbonate, sodium carbonate, cesium carbonate, sodium hydride, potassium hydride, and the like in a polar aprotic solvent such as A'JV difnemylfoiroamide, N,N dimethylacetamide, acetonitrile, tetrahydrofuran, dioxane and the like, followed by reaction with a compound of formula (37) or compound prepared by known methods suc as 5-ten- butyldimethylsilyloxy- 1 ,2-dithian- -yi methanesullbn te and the like, optionally with heating, optionally with microwave irradiation to provide a compound of formula ( 38), Scheme V,

{39} ( ⁴ °)

A compound of the formula {39} is, reacted with a tetra-w-butylaramomiim fluoride, hydrofluoric acid in pyridine, atmplwrsulfonic acid and die like, in a solvent such as A'JV dimethyiformamide, M,N dimeth lacetainide, acetonitrile, tetrahydrofuran, dioxane and the like optionally with heating, optionally with microwave irradiation to provide a compound of formula (40Ί.

Scheme

A compound of the formula (41 ), a known compound or compound prepared by known methods, is reacted with, a compound of formula (42) such as 5-t rt- bufykiimefhylsilyioxy-1,2- dithiane-4-ol and the like, in the presence of fiipheiiylphosphiiie or resin-bound triphenylphospbine and an azodicarboxyiate such as diethyl azodiearboxyiate, diisopropyl azodiearboxyiate, di-i- butyiazodiearboxylate, di-(4-chlorober-zyl)a2<ritearboxy]ate in the presence of a solvent such as tetrahydrofuran, diethyl ether, dioxane and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (43).

Scheme 14

( ⁴⁴ > {45} {46} A compound of the formula (44) is reacted with an oxidizi ng agent such as m- ehiorojXTOxybenzoic acid, monoperp tthalie acid, peracetie acid, perpropionie acid, pertri itioroaeettc acid, potassium periodate, sodium rnetaperioda e, sodium perborate, potassium peroxyrnonosul.fate i ^' Oxone©), potassium peroxydisulfate, dimet yldi xiraoe, and the like, in the presence of a solvent such as tetraliydrofurao, ether, 1,4-dioxaiie, acetone, acetonitrile, methanol, ethaocsl, isopropanoi, water, and the like, optionally with heating, optionally with microwave irradiation to provide compounds of the formula (45} and (46). Alternatively, a formula of the compound (44) is reacted with a sulfoxide such as di henyl sulfoxide, dimethyl sulfoxide, and the like, in die presence of a rhenium catalyst such as ReOCljiPPhjh, and the like, in a solvent such as methylene chloride, 1 ,2- dichloroethane, chloroform, tetrahydrofuran, ether, 1 ,4-dioxane, acetone, acetonitrile, and the like, optionally with heating, optionally with microwave irradiation to provide compounds of the formula (45} and (46). Alternatively, a formula of the compound (44) is reacted with a urea hydrogen peroxide complex in the presenc of a rhenium catalyst such as ReQCljtPPhih, and the like, in a solvent such as methylene chloride, 1,2-dichloroemane, chloroform, tetrahydrofuran, ether, 1.,4-dioxarte, acetone, acetonitrile, Α',Λ'-dtmetnyi.f ormami.de, and the like, optionally with heating, optionally with microwave irradiation to provide compound* of the formula (45) and (46). Alternatively, a formula of the compound (44) is reacted with art oxidoreductase such as Baeyer-V ^' iUiger nionooxygenase, cytochrome P450 2C9, cytochrome P450 2C19, cytochrome P450 A4 and, in a solvent such as water, methanol, eihanol, isopropanoi, acetonitrile, acetone, and the like, optionally with heating, optionally with microwave irradiation to provide compounds of the formula (45) and (46). Alternatively, a compound of the formula (44) is reacted ish hydrogen peroxide in ihe presence titanium (IV) isopropoxide-diethyltartarate, optionally in the presence of an amino alcohol such as 2- a:mii).o ^« 3-pheii} lpro an ^» l -ol, 2-ami.no-4-methy1pentan- 1 -<»!., 2-aimiio-4-{methy1thio)butan-l -ol, 2- aminopropan- i -ol, and the like, in a solvent such as methylene chloride, 1 ,2-dichioroethane, chloroform, tetrahydrofuran, ether, 1 ,4-dioxane, acetone, acetonitrile. (V V-diroethylformaroide, and the like optionally with heating, optionally with microwave irradiation to provide compounds of the formula (45) and (46), Alternati ely, a compound of the formula of the compound (44) is electrochemically oxidized optionall in the presence of a buffer solution such as a sodium phosphate solution, a potassium phosphate solution, and the like to provide compounds of the formula (45) and (46). Alternatively, a compound of the formula of the compound (44) is photochemical! y oxidized in a solvent such as methylene chloride, 1 ,2-dichloroethane, chloroform, tetrahydrofuran, ether, 1 ,4- dioxane, acetone, acetonitrile. A ^' -dmieth lformaoude, water, methanol, ethartoi, isopropanoi, and the like, optionally with heating, optionally with microwave irradiation to provide compounds of the formula (45) and (46). It is understood that one skilled it! the art would readily understand thai the ratio of products (45) through (46) will be controlled by the amount of oxidant added and would adjust the amount of oxidant accordingly to produce the desired ration of products. Scheme L5

A compound of the formula (47 ) is reacted with an oxidizing agent such as m- chloroperoxybenzoic acid, monoperphthalic acid, peracetic acid, perpRpionic acid, pertriftuoroacetie acid, potassium periodate, sodium metaperiodate, sodium perborate, potassium peroxyraonosulfate iOxone®), potassium peroxydisuSfate, dtmethyldfoxirane, and the tike, in the presence of a solvent such as tetrahydroftiran, ether, 1 ,4-dioxane, acetone, acetonttrile, methanol, ethanoi, isopropanol, water, and the like, optionally with heating, optionally with microwave irradiation to provide compounds of the formula (48) and (49). Alternatively, a forma la of the compound (47) is reacted with a sulfoxide such as di phenyl sulfoxide, dimethyl sulfoxide, and the like, in the presence of a rhenium catalyst such as ReOCi?(PPh?)¾ and the like, in a solvent such, as methylene chloride, 1,2- dieMoroeffiane, chloroform, tetm ydrofuraii, ether, 1 .4-dioxane, acetone, acetordtriie, and the like, optionally with heating, optionally with microwave irradiation to provide compounds of the formula (48 ) and (49). Alternatively, a formula of the compound (47) is reacted with a urea hydrogen peroxide complex in the presence of a rhenium catalyst such as ReOCi?(PPh¾):>, and the like, in a solvent such as methylene chloride, 1,2-dichksroethane, chloroform, tetrahydrofurati, ether, 1,4-dioxane, acetone, aeetonitrile, and the like, optionally with heating, optionally with microwave irradiation to provide compounds of the formula (48) and (49). Alternatively, a formula of the compound (47) is reacted with an oxidoreduetase such as Baeyer-Vi Sliger monooxygenase, cytochrome P450 2€9, cytochrome P450 2C 19, cytochrome P450 3A4 and, in a solvent such as water, methanol, ethanoi, isopropanol, aceionitrile, acetone, and the like, optionally with heating, optionally with microwave irradiation to provide compounds of the formula (48) and (49). Alternatively, a compound of the formula (47) is reacted with hydrogen peroxide in the presence titanium (IV) isopropoxide-diet yltartarate, optionall in the presence of an amino alcohol such as 2- amino-3-phenylpropan- 1 -ol, 2-anisno-4-meihylpentan- l-ol, 2-arnino-4-(methyHhio}butan- 1 -ol, 2- aminopropan-l -ol, and the like, in a solvent such as methylene chloride, L2-dicMoroethane, chloroform, tetrahydroftiran, ether, 1,4-dioxane, acetone, aeetoniuile, N.A'-diraethylformamide, and the like optionally with heating, optionally with microwave irradiation to provide compounds of the formula (48) and (49), Alternatively, a compound of the formula of the compound (47) is clectToehemicaily oxidized optionally in the presence of a buffer solution such as a sodium phosphate solution, a potassiu.ni. phosphate solution, and toe like to provide conipotinds of the formula (48) and (49), Alternati vely, a compound of the formula of the compound (47) is pbotocheniically oxidized in a solvent such as methylene chloride, l.,2-diehloroethane, chloroform, ietrahydrofuran, ether, 1 ,4- dioxane, acetone, acetonitriie, #,A ^? -dimeihYlformainide, water, methanol, ethanoi, isopropanol, and the like, optionally with heating, optionally with microwave irradiation io provide com oun s of the formula (48) and (49 ), It is understood that one skilled in the art would readily understand that the ratio of products (48) through (49) will be controlled by the amount of oxidant added and would adjust the amount of oxidant accordingly to produce the desired ration of products.

A compound of the formula (50) is reacted with an oxidizing agent such as ?.«-- chloroperoxybenzoic acid, monoperphthaiic cid, peracetie acid, perproptonic acid, pertrifhtoroaeetic acid, potassium periodate, sodium metaperiodate, sodium perborate, potassium peroxymonosuifate (Oxone®), potassium peroxydisuSfate, dimethyldioxirane, and the like, in the presence of a solvent such as tetrahydroiuran, ether, 1 ,4-dioxane, acetone, acetonitriie, methanol, ethanoi, isopropanol . water, and the like, optionally with heating, optionally with microwave irradiation to provide compounds of the formula (51 ) and (52), Alternatively, a formula of the compound (50) is reacted with a sulfoxide such as diphenyl sulfoxide, dimethyl sulfoxide, and the like, in the presence- of a rhenium catalyst sach as ReOCMPPhj).* and the like, in a solvent such as methylene chloride, 1 ,2- dichloroethane, chloroform, tetrahydrofuran, ether, 1 ,4-dioxane, acetone, acetonitriie, and the like, optionally with heating, optionally with microwave irradiation to provide compounds of the formula (51 ) and (52). Alternati vely, a formula of the compound (50) is reacted with a urea hydrogen peroxide complex in the presence of a rhenium catalyst such as ReOC¾(PPh:ib. and the like, in a solvent such as methylene chloride, i ,2-diehloroe£hane. chloroform, tetrahydrofuran, ether, 1 ,4-diox.ane, acetone, acetonitriie, ALV-clitnethyiformatnide, and the like, optionally with heating, optionally with microwave irradiation to provide compounds of the formula (51.) and (52). Alternatively, a formula of the compound (50) is reacted with an oxidoredisctase such as Baeyer--Vil.Si.ger monooxygenase, cytochrome P450 2C9, cytochrome P450 2C 19, cytochrome P450 3A4 and, in a. solvent such as water, methanol, ethanoi, isopropanol, acetonitriie, acetone, and the like, optionally with hearing,

7.1 optionally with microwave irradiation, to provide compounds of the formula (51.) and (52), Alternatively, a compound of the formula (50) is reacted with, hydrogen peroxide in the presence titanium i ^' lV) isopropoxide-diethyltartarate, optionally in the presence of an amino alcohcsi such as 2- amiiio-3-phenylpropan- 1 -ol, 2-ammo-4-nieihy1pentan-l-ol, 2-amiiio-4-(m&hylthio)butan- 1 -ol, 2- antiiiopropan- 1 -ol, and the like, in a solvent such as methylene chloride, 1,2-dichioroeihane, chloroform, tetnihydrofuran, ether, 1 ,4-dioxane, acetone, acetoni trile, ΛζΛ'-dimefhylfonnamitde, and the like optionally with heating, optionally with microwave irradiation to provide compounds of the formula (51.) and (52), Alternatively, a compound of the formula of the compound (50} is e!ectrochemiea! Sy oxidized optionally in the presence of a buffer solution such as a sodium phosphate solution, a potassium phosphate solution, and the like to provide compounds of the formula (51 ) and (52), Aiternative ^' i , a compound of the formula of the compound (50) is photochemical !y oxidized in a solvent such as methylen chloride, i ,2-dichioroethane, chloroform, tetrafiydrofuran, ether, 1 ,4- dioxane, acetone, acetoniinie, iV.iV-dimethylforniamide, water, methanol, ethanoi, isopropanol, and the like, optionally with heating, optionally with microwave irradiation to provide compounds of the formula (51 ) and (52), It is understood that one skilled in the art would readily understand that the ratio of products (51 ) through (52) will be controlled by the amount of oxidant added and would adjust the mount of oxidant accordingly to produce the desired ration of products.

Scheme 7

A compound of the formula (53), is reacted with a base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium carbonate, cesium carbonate and the like, in a solvent such as methanol, ethanoi, N,N dimethylformamide, N,N dimethylacetaniide, acetoni tri!e, tctraliydrofuran, dioxane and the like optionally with healing, optionally with microwave irradiation to provide a compound of formula (54), Scheme S.8

(55) (56)

A compound of the formula (55), is reacted with a base such as lithium hydroxide, sodium hydroxid , potassium hydroxide, potassium carbonate, cesium carbonate and the like, in a solvent such as methanol ethanoi, N,N diroethylformarflide, N.N dimethyiacetarosde, acetonitille, tetranydroftiran, dioxane and the like optionally with heating, optionally with microwave irradiation to provide a compound of formula (56),

Scheme I V

(57)

(58)

A compound of the formula (57), is reacted with a base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium carbonate, cesium carbonate and the like, in a solvent such as methanol, ethanoi, Λ',ΛΓ dimethyl formamide, N.N dimethyiac tamide, acetoni tri ^' ie, tetnthydrofuran, dioxane and the like optionally with heating, optionally with microwave irradiation to provide a compound of formula (58). Scheme 20

A compound of the formula (59), is reacte with a base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium carbonate, c sium carbonate and the like, i a solvent such as methanol, etbanol, N,N dimethylforaramkSe, N,N dimethylacetaniide, aeetonitrile, tetrahydrofuran, dioxane and the like optionally with heating, optionally with microwave irradiation to provide a compound of formula (60),

The following examples further illustrate the present invention. It should be understood, however, that the invention is not limited solely to the particular examples given below.

EXAMPLE i

(4S, 55)- i,2-Diihiane-4,5-dio]

Th compound (25,35)- i ,4-dimercaptobiitane-2,3-(iioi (4 g, 25,9 mmoi) was dissolved in diniethylsnlfoxkfe (2,3 g, 28.5 mmoi) in an open beaker and heated to 1 ) ⁽ C with stirrin for 3 hours. The reaction mixture was then cooled and dimethylsiiii ^' oxide was removed under vacuum to give a residual oil which was kept at room temperature for 20 minutes after which a white semi-solid was formed. About 25 mi, of diethyl ether were added and the mixture was stirred for ! 0 minutes, then filtered. The solid was dried under vacuum to give a white solid (3,5 g, yield 90%). ^S H NM 400 MHz (DMSC s): δ 5.23 (d, ./ = 4.0 Hz, 2H.), 3.39 (ra, 2H), 3.06-3.02 (m, 2H), 2.54-2.50 (m, 2H}; LCMS n/e: 135 [M + H - I 8f.

EXAMPLE 2

{45, 5R 1 ,2-Dithiane-4,5-diol OH

The compound (2i .S L4-dtmereaptobutane-2.3Klioi (2,5 g, 16,2 mmol ) was dissolved in ciimethylsulfoxide (1.4 g, 17.9 mmol) and in an open beaker was heated to E 10 '"C with vigorous stirring. After 3 hours, dimethyl sulfoxide was removed under reduced pressure and the residua! reaction mixture was allowed to stand at room temperature for 20 minutes. A while semi solid was formed to which was added diethyl ether (25 mL) and stirred for 1.0 mi nutes, then filtered. The resultant solid was dried under vacuum to give a white solid (2.3 g, yield 92%). *H NMR 400 MHz (DMSO-cfc): § 4.94 (m. 2H), 3.71 {m, 2H), 2.99-2.96 (m, 4H); LCMS m/e: Ϊ35 \M + H. - 18] ' ^" .

EXAMPLE 3

ci$- 5 ,2-Dithiane- ,5-dioi

A solution of dUhioe-rythritol (DTE, 22,0 g, 0, 1 mol) in 537 mL of water was treated with potassium ferricyanide (0.8 M) solution (0,29 mol in 358 mL of water) until the yellow color persisted while maintai ning pH 7 b addition of 2 OH (0.29 mol i n 143.2 mL of water). The solution was evaporated to dryness and 200 mL f ethanol was added to the crude product. After filtration, the clear filtrate was evaporated to dryness and crystallized from ethyl acetate hexanes (2: i). The product was isolated by filtration s a white crystalline solid: rap. 130-132 °C; ^! H NMR (DMSO-ffe, 300 MHz) δ 2.70-3.00 (br s, 2H), 2.99 (dd, J - 8.0, 13.2 Hz, 2H), 3.60-3.80 (br s, 2H), 4.80-5.00 (br s, 2H).

EXAMPLE 4

trans 5 -H droxy- 1 ,2-dilhian--4-yl be zoate

To a solution of trans- 1 ,2-dithiane-4,5-dsol ( 30,0 g, 0,065 moi), pyridine (15,9 mL, 0,20 mol) and methylene chloride ( 125 mL) at 0 °C was added benzoyl chloride (8.08 mL, 0,072 moi) over a period of 5 minutes. The reaction was then stirred for 15 hours at room temperature. The reaction mixture was then Quenched with methanol (5,0 mL), washed with saturated aqueous sodium bicarbonate ( i x 50 mL), brine (i x 50 mL), I N HCI ( i s 50 mL), dried over sodium sulfate and concentrated to yield 19.2 g of crude product. The crude product was purified by column chromatography e!uting with a gradient solvent of 5% to 20% ethyl aeetate;fiexanes to yield 10,85 g (65%) of the desired product as a white crystalline solid: m.p. 1 17-1 19 °C: ^' ¾ NMR (CDi¾, 300 MHz) S 2,62 (bd, 7 * 5.8 Hz, IH), 3.07 idd, 7■ 9,4. 3.5 Hz, 2H), 3.26-3.38 Cm, 2H), 3.97-4.06 (m, IH), 7.48 (L J 7.9 Hz, 2H), 7.58-7.62 (in, IHj, 8.06 (d, J «= 7.0 Hz, 2H).

EXAMPLE 5

t m 5 -( ( Meth l su If on i )o y ) - ! ,2-di t i an -4 -y I be n zo a te

To a solution of mww 5-hydroxy-i,2-dithiati-4-yl benzoate (0.55 g. 2.1.4 mmoi) and triethylaniine (0.96 mL, 6.86 mmol) in dichloromethane was added metbaBesulfon l chloride (0.41 mL, 5.14 mmol ) at 0 °C and the reaction mixture was stirred at room, temperature for 2 hours. The mixture was then poured into water. The aqueous mixture extracted with ethyl acetate (3 x 300 m ^' L) and the organic exfracis were washed wiftt water, dried over anhydrous a^SG* and concentrated at reduced pressure to give ihe title compound as a colorless solid {0.61g, yield 90%). ^! H .NMR. (CDCU, 400 MHz) δ 8.07 (d, 8,0 Hz, 2H), 7,62-7,58 (m, I H). 7.49-7.45 to, 2H), 5.32-5.26 (m, i.H). 5.02- 4.96 (m, I H), 3.46-3.42 im, 2H), 3.36-3.32 (ra, 2H), 2.91 s, 3H); LCMS ra e: 135 [M + H ~ 32f.

EXAMPLE 6

trans 5-fBenzoyioxy)- 1 ,2-difltian-4-yl-4-nitroben2oate

To a slurry of m¾fii-l,2-dithiane-4-benzoate-5-ol (441 nig. 1.72 mmoi), / -oi.trobenzoic acid (1.44 g, 8,61 mmol), triphenyl phosphine (2.26 g, 8,61. mmol ) in benzene (30 mL) at 0 °C was added dietiiylazodicarboxylatc (DEAD, 1.36 mL, 1.50 g, 8.61 mmol) dropwise. The resulting clear yellow solution was then stirred overnight, at room, temperature. Thin layer chromatography TLC) indicated that the starting materia), was consumed. The reaction mixture was adsorbed on silica gel (2.0 g) and purified by column chromatography (eluent 5% ethyl acetate/he s nes.). The less polar compound gave 51 org (8%) of the desired product ; 'H NMR (CDCh, 400 MHz) 6 3.35 (m, 4H), 5.48 (m, 2H), 7.37 (t. / = 7,8 Hz, 2H), 7.52 (t, 7 » 7.3 Hz. IH), 7,93 (d, 7 = 7.3 Hz, 2H), 8.1 (dd, 7 » 8.8 and 6.8 Hz, 4H).

EXAMPLE 7

irons 1 ,2-Dithiane-4,5-diy Ldibenzoate

OBz To a solution of imm-\ ,2-ditbiane- ,5-dio! (10.0 g, 0,065 mol l, pyridine (15.9 mL, 15,57 g, 0,20 moi l and methylene chloride (125 mL) at 0 °C was added benzoyl chloride (8, S mL, 0.072 mol) over a period of 5 rain. The reaction was stirred for ! 5 hours at room leinperature. he reaction mixture was; then quenched with methanol i ^' 5 mL), washed wi th saturated aqueous sodium bicarbonate ϊ 1 x 50 mL), brine ( 1 x 50 mL), I N HQ (J x 50 mL), dried over anhydrous and concentrated to yield 19,2 g of the crude product. The crude product comprising tnms 5-hydroxy- I ,2- dithian-4-yi benzoaie and tram 1 ,2-dithiane-4,5-diyi-d¾enzoate was purified by column chromatography eliiting with a gradient solvent of 5% to 20% ethyl acetate/hexanes to yield 2.86 g ( 12%) of the desired product as a white crystalline solid: m.p. 139- 141 ^e C; Ή NMR {CDC , 300 MHz) 8 2.62 {fed, ./ = 5.8 Hi;, I H), 3.07 (dd, . = 4. 13.5 Hz. 2H), 3.26-3.38 (m, 2H), 3.97-4.06 (m, IH), 7,48 (t, zz 7.9 Hz, 2H), 7.58-7.62 (m, IH), 7.58-7.62 (m, I ^' M), 8.06 id, /= 7,0 Hz, 2H).

EXAMPLE 8

inmsS-tert- Butyidi ethyisiiyioxy- ! ,2-dithtane-4-oi

To a solution of tnms- 1 ,2-dithaine-4,5-diol (5.0 g, 0,033 mol , imidazole (3, 54 g, 0.046 mol) and Λ ¥ dimethyl formamide (DMF, 25 mL) at 0 ^! C was added a solution of ierf-butyldimethylsilyl chloride (5.96 g, 0,040 mol) in N,N dimethyl formamide (15 mL) over a period of 5 minutes. The reaction mixture was stirred for 20 hours at room temperature. The reaction mixture was then concentrated in vacuo, and the resulting residue dissolved in methylene chloride/ methanol, then adsorbed on silica gel (3,0 g) and purified by column chromatography elutiog with a gradient solvent of 2% to 5% ethyl acetate/hex an es to yield 7,77 g (99%) of the desired product as a clear, colorless oil; ¾ NMR (CDC! j, 300 MHz) δ 0.12 (d, / =- 3.8 Hz, 6H), 0,92 (s, 914), 2,78 (bs, I H), 2.82-3.70 (m, 4H). 3.58-3.70 (in, 2H).

EXAMPLE 9

ms-5-tert- Butyidimethyisiiyioxy- 1 ,2-di ihian-4-yi tnethanesuiibnaie

Methanesulfonyl chloride (0.93 mL, 137 mg, 1.2 mmol) as added to a solution of xrans-5~ m~ batyldimethylsilyloxy- 1 ,2-dithtane-4-ol (266 mg, 1.0 mmol) and methylene chloride ⁽ 15 mL) at 0°C. The reaction was stirred for 2 hoars at room temperature at which time 5 drops of methanol were added. The reaction mixture was concentrated in vacuo, and the resulting residue dissolved in methylene chloride/ methanol then adsorbed on silica gel ( 1 ,0 g) and purified by column chromatography eiuting with a gradient solvent of 10% to 15% ethyl acetate hexaoes to yield 341 mg (99%) of the desired product as a clear, colorless oil which solidified on. standing: ^! H NMR (CD€1.¾ , 300 MHz) 5 0.12 (d, J - 1.5 Hz, 6H). 0.92 (s, 9H), 3.05 (b s, 5H), 3.16 (t, J - 1 1.0 Hz, ! H) 3,44 (d. ./ ^ 13.? Hz, I H), 3.81 -3.83 On, 1H ), 4.44-4,50 {m, 1 H).

EXAMPLE 10

trans 5-Methoxy- 1 ,2-<Hihian- -ol

To a solution of {45, 5.S)-l ,2-dithiane-4 _> 5-diol (0.8 g, 5.26 mmol) in dry te rah cirofiiran (150 nil.) was added sodium hydride (NaH, 60%, 0.32 g, 7.9 mmol ) at 0 ^C C, stirred the reaction mixture for 15 minutes. Methyl iodide (0.49 mL, 7.9 mmol) was then added dropwise and the reaction mixture was stirred at room temperature for 12 hours. The reaction mixture- was then quenched with dilute hydrochloric acid, poured into cold water and extracted with ethyl acetate (3 x 200 mL). The organic extracts were washed with water, dried over anhydrous Na>5<¾, filtered and concentrated at reduced pressure to give the crude compound was purified by column chromatography on. silica gel (100-200 mesh) eiuting with 20%- (v/v) ethyl acetate in hexanes. The title racemic compound was obtained as a white solid (0-6 g, yield 68% ) and separated from the diniethyiated compound, 4.5-dtmethoxy-l,2- dithiane (150 mg). ^! H NMR (DMSQ-&, 400 MHz): S 5.32 (m, br, 1H), 3.49 (m, 3M) 3.47-3.40 (m, 1H). 3.33-3.29 (in, 1 H>, 3.09-3.04 (m, 2H), 2.78-2.70 (tn. 2H); LCMS m/e: 135 }M - H - 32f .

EXAMPLE 1 i

tra ns 5 -Methox - 1 ,2- di thi an -4-yl met h an e s ui f nate

To a solution of irons 5-methoxy- ! ,2-dithian-4-o! (0.6 g, 3.61 mmol) arid triethyl amine (0,65 mL, 4.69 mmol) in dichloromethaiie was added fnethanestilfonyl chloride (0.28 m ^' L, 3,61 mmol) at 0 °C and the reaction was stirred for 2 hours. The mixture was then poured into water and was extracted with ethyl acetate (3 x 200 mL). The combined extracts were washed with water, dried over anhydrous Na^SCk filtered and concentrated at reduced pressure to produce the title racemic compound as a white solid (0.48 g, yield 55%). Ή NMR (DMSO-ifc 400 MHz): S 4,58-4,52 (m, 5 H), 3.52-3.41 Oil, 2H), 3.37 {s, 3H). 3.35-3.30 (in, 2H>, 3. 1. {s, 3H), 2.92-2.86 (m, 1 H). EXAMPLE i 2

trans 5-i.Benz.y!oxyH 2-d»thian-4-ol

To a solution of (4S ^' .55)- ! ,2--dii iat!e- -diol (0.7 g„ 4.6 mmol) in dry N,N dimethylformamide (25 oiL) was added sodium hydride (60%, 0.24 g. 5.9 mmol ) at 0 *C. The reactioii mixture was stirred for 20 minutes followed by addition of benzyl bromide (0.66 laL 5.6 mmol) dr pwise and then left to stir at room temperature for 12 hours. The reaction mixture was then quenched with dilute hydrochloric acid and poured into water. The aqueous mixture was extracted with ethyl acetate (3 x 300 washed with water, dried over anhydrous asSOt. filtered and concentrated at reduced pressure. The crude compound was purified by column chromatography on silica gel { 100-200 mesh) during with 20% (v/v) ethyl acetate in hexanes to give the title compound as white solid (500 mg, yield 46%) separated from 4,5-dibenzyl- 1 ,2-dithiane compound ⁽ 180 mg). Ή

NMR {DMSCMs, 400 MHz): § 7.38-7.31 (ra, 4I¾ 7.28 (d, / = 6.9 Hz, i.H), 5.37 (d, / = 4.9 Hz, ill). 4,68-4,59 (m, 2H), 3-56-3.54 (m, i.H). 3.35-3.32 ( , 2H), 3.1.4-3, 1.0 (m. IH), 2.80-2.74 (tn, 2H); LCMS m e: 243 [ M+ If.

EXAMPLE 1

tram 5-{Ben7,y methanesulfonate

To a solution of trans 5-ibenzyloxyH,2-«fithian-4-ol f 0.5 g, 2,07 mmol) and triethylamioe (0.37 mi,, 2.68 mmol) in diehloromethane was added methanesiiifonyl chloride (0, 1 ixtL, 2.07 mmol) ai. 0 'C. The reaction mixture was stirred for 3 hours at room temperature and then carefully poured into water. The aqueous mixture was extracted with ethyl acetate (3 x 200 mL) and the combined organic extracts were washed with water, dried over anhydrous Ν¼8(¾, filtered and concentrated at reduced pressure to furnish the title compound as a white solid (220 mg, yield 75%). Ή .NMR. {DMSO-t 400 MHz): 8 7.38-7.29 (m, 5H), 4.71,4.60 (m, 2H), 3.68-3.65 (ra, ! H), 3.64-3.60 (m, 1H), 3,59-3,52 (m, IH), 3.49-3.40 (m, 2H), 3.5 1 (s, 3H), 2.99-2.96 (m, I H): LCMS m/e: 321 iM+I f. EXAMPLE 14

ck-5-iim- Butyidimethylsilyloxy-l ,2-d!thiane-4-ol

To a solution, of m-l 2-djthiane-4,5-diol (5,0 g, 0.03 moi). imidazole (3.14 g, 0.05 moi) and N,N dimethylfcraiamide (25 nil.) at 0 °C was added a solution of feri-butyldimetbylsilyl chloride (5,96 g, 0.040 moi) in N,N duxtethyJfonnamkle (15 mL) over a period of 5 minutes. The reaction was then stirred for 20 hours at room temperature. The reaction mixture was concentrated in vacuo and the resulting mixture was dissolved in methylene eMoride/ ethano!, adsorbed on silica gel (3,0 g) and purified by column chromatography eiuting with a gradient solvent of 2% to 5% ethyl, acefate/hexanes to yield 7,7? g (99%) of the desired product as a clear, colorless oil ; Ή NMR iCDC , 300 MHz) δ 0.12 (d. 3.8 Hz, 6H), 0.92 is, 9H), 2.78 (br s, I H), 2.82-3.70 (m, 4H), 3.58-3.70 (ra,2H).

EXAMPLE 15

cis 5-Hydroxy- 1 ,2-dithian-4-yl benzoate

To solution of (4S',5/?)-l ,2-dithiane-4,5-diol ( ! g, 6.57 mmoi), and benzoyl chloride (0,84 mL, 7,23 mmoi) in mixture of dtchloromethane (15 niL) and NJN dimethyltorassimide (15 mL) were added trtetliylami.ne ( 1 mL, 7.23 mmo! ) and 4-dimethyiaromopyridine (250 mg, 1.64 mmoi) at 0 °C and stirred for S. hour. The mixture was then poured into water and was extracted with ethyl acetate (3 s 400 mL). The combined extracts were washed with wafer, dried over anhydrous Κ¾·_>8ί\ filtered and concentrated at reduced pressure to give the crude compound which was purified by column chromatography on silica gel (1.00-200 mesh.) eiuting with 20% (v/v) efhyl acetate in hexanes to gi ve the title compound as colorless solid { I . I g, yield 65%) separated from the dihertzoyiated. compound 4,5-dibenzoate 1,2-dii ane (300 mg). Ή-NMR (CDCL, 400 MHz): S 8,07 (d. J = 8.0 Hz, 2H), 7.69- 7.66 (si, I H), 7,57-7.52 (m, 2H), 5.53-5.52 (m, I H), 5.25 (m, I H). 3.94 (ra, Hi), 3.37-3.27 im, 3H), 3.15 (s, 1 H); LCMS m e; 135 [M + H - 32] \

EXAMPLE 1

cis -4-im-Batyldimethylsilyl)oxy)-l,2-dithian-4-yl methane-suifonate To a solution of dx-ian- utyldinieth lsil loxy- - ydroxy- i.,2-dit iane {858 rog, 3,22 mmoi), 2,6-lufcidine (0.63 irtg, 5,41 mmol ), diisopropylethylamine (1.43 mL, 8.19 mmol) and methylene chloride (20 mL) at 0 °C was slowly added methanesitlf nyl chloride {0.42 mL, 5.46 mmol). The reaction mixture was stirred at 0 "C for 30 minutes at which time 5 drops of methanol were added to quench (he reaction, ^' i he reaction mixture was diluted with 15 niL of methylene chloride, washed with 1 N HQ (3X) and brine ί 1 X). dried over MgSO and then concentrated in vacuo. The resulting residue as co-evaporated with toluene (2X> and dried under vacuum to yield 1.18 g ( 100%) of the desired product as a clear, colorless oil; ^] .H NMR (CDCh, 300 MHz) § 0.12 id, J « 7 Hz, 6H), 0.92 (s, 9H), 2.5-4.3 (br m, 5H), 3.07 (br s, 3H), 4.80- 5.00 (br s, 1H).

EXAMPLE 17

cis 5-((Methylsulft)nyl)oxyh 1 ,2-dithian-4-yl beiizoate

To a solution of vis 5 -hydroxy- l.,2-dithian-4-yl benzoaie i ^' 2 g, 7.81 mmol) and triethyi amine (1.6 mL, 11 .71 mmol) in dichloromethane was added methartesulfonyl chloride (0,66 mL, 8.6 mmol} at 0 °C. The reaction mixture was srirred for 2 hours at room temperature and then was poured into water. The mixture was extracted with ethyl acetate (3 x 300 mL) and the combined extracts were washed with water, dried over anhydrous Na¾SQ*. filtered and concentrated at reduced pressure to prodace the title compound as colorless solid ( 1.8 g, yield 70%). ^! H- MR (CDOb, 400 MHz): δ S.0? (d, 7 = 8.0 Hz, 2H), 7.71-7.66 (m, ! H), 7,58-7.53 (ni, 2H), 5,28-5.22 (m, 1H), 3.92-3.98 (m, 2H), 3.36-3.32 (m, 3H), 2.93 (s, 3H): LCMS m/e: 135 j ^' M + H - 32]".

EXAMPLE 18

cis 5-Methoxy- 1 ,2-ditbian-4-oi

To a soiution of (45,5i?H ,2-dithiane-4,5-dsol (0.5 g, 3.29 mmol) in dry teirahydrofuran (20 nil.) was added sodium hydride (60%, 0, 1.9 g, 4,94 mmol ) at 0 ° and the reaction mixture was stirred for 15 minutes. Methyl iodide (0.3 mL) was then added dropwise and the reaction mixture was stirred at room temperature for 12 hours. The reaction, mixture was then quenched with dilute hydrochloric acid and poured info cold wafer. The aqueous layer was extracted with ethyl acetate (3 x 300 mL) and the organic extracts were washed with water, dried over anhydrous Na^SO^. filtered and concentrated at reduced pressure io give a crude oily compound which was purified by column chromatography on silica gel (100-200 mesh) eluting with 20% (v/v) ethyl acetate in Itexanes to gi ve

8.1 the title compound as a white solid ( 160 mg, yield 30%) separated from the diniethyia!ed compound. 4,5 dmwthoxy-L2-dithiane (50 mg). Ή MR ⁽ DMSO-<¾, 400 MHz) § 5.03 im, br, I H), 3.80 (m, br, IH), 3.38 (m, 2M), 3.33 (s, 3H), 3.29 fro. IH), 2.98-2.95 (ra, 2H); LCMS ra/e: 135 |M + H ~ 32J ⁺ .

EXAMPLE 19

as 5-Methoxy- 1 ,2-dithian-4-yl methanesuifonate

To a solution of 5-methoxy- 1 ,2-dithian-4-ol (0.16 g, 0.96 mmol) and triethylamme (0.17 mL, 1.26 mmol) in dieWorornethane was add d methanesulfonyl chloride (0.082 mL, 1.06 mmoi) at 0 °C, The reaction nii.xtu.fe was allowed to warm up to room temperature and stirred for 2 hours. The mixture was then poured into water and extracted with ethyl acetate (3 s 300 mL). The combined extracts were washed with water, dried over anhydrous Na^SO*. filtered and concentrated at reduced pressure to furnish the title compound a (90 mg, yield 40%) as a colorless solid, Ή NMR (DMSO-i 400 MHz): 5 4.56-4.53 (m, I H), 3.50-3,41 (m, 2H), 3.37 is, 3H), 3.36-3.32 (m, 2H), 3, 19 is, 3M), 2.92-2.86 ( 1», :i H).

EXAMPLE 20

c is 5 -i Ben zyiox ) - 1 , 2-d i th i an -4 -oS

To a solution of (4&5jR)-L2-dithiaiie-4,5-diol (1.0 g. 6.57 mmol) in dry N,N dimethyltamianitde (30 mL) was added NaH (60%, 0.34 g, S.55 mmoi ) at 0 °C, and the reaction mixture was stirred for 20 minutes before the addition of benzyl bromide (0.93 mL,?,89 mmol ) ciropwise. The reaction mixture was then stirred at room teniperattire for 12 hours and quenched, with dilate hydrochloric acid and poured into water. The aqueous solution was extracted with ethyl acetate (3 X 300 mL) and the combined extracts were washed with water, dried over anhydrous a-j.SQi. filtered and concentrated at reduced pressure. The crude compound was purified b column chromatography on silica gel ( 100-200 mesh) eluting with 20% (v v) ethyl acetate in hexanes to give the title compound as colorless solid (650 mg, yield 44%) separated from 4,5-dibenzyl- i ,2-dithiane (200 mg). ^f H NMR (DMSO-A, 400 MHz}: δ 7.39-7.30 m, 5H), 5.16 is. I H), 4.64-4.54 (m, 2H), 3.86-3.66 (m, 2H), 3.22-3. 19 do, I H), 3.06-3.10 (m, 3H); LCMS /c: 243 j l ]\ EXAMPLE 2 i

as 5-{Bertz.yJoxy}- i ,2-ciith.ian-4-yi methanesulfortate

To a solution of cix 5-(benz.yloxyV l,2--diiiiiaii-4-ol (0.65 g. 2.68 mtnol) and triethylai ne (0.78 HtL, 3.49 liiiiiol) in dichloro methane was added ntethanesulibnyl chloride (0.22 nsL, 2.68 inmol) iif 0 '"C. Tiie reaction mixture was mined for 3 hours at room temperature and then poured info water. The aqueous mixture was exiraeted mill ethyl acetate {3 x 200 HtL) and the combined extracts were washed with wafer, dried over anhydrous NibSO . filtered and concentrated at reduced pressure to produce the title compound as a colorless solid (360 rag, yield 43%). ^S H NMR c ^' DMSO-<¾, 400 MHz): S 7.36-7.28 fm, 5H), 4.70-4.60 {in, 2H), 3.60-3.62 <m, 1H). 3.50-3.48 (ra, I H), 3.42-338 (m, 2H), 3.32-3.25 (m, IH), 3.10 (s, 3H), 2.97-2.95 fm, IH); LCMS m/e: 321 [M+lf.

EXAMPLE 22

3 -lodo- 1 if- y razol o [ ,4-a py ri m ί di n -4-a mi ne

To a mixture of lff-pyrazole[3,4-r/]pyrfniidit!e-4-an!i.iie (5 g, 37.03 nimol) in N.N dimethylformamide (40 ml.) was added ;V-iodo nccinimide (12.5 g, 55.6 tnmol) and the reaction mixture was heated at SO ^i:' C for 12 hours under argon atmosphere. The resultant solid was filtered, rinsed with cold ethanol and dried in vacuuni overnight to gi e the product as a pale brown solid (9 g, yield 93.7 %). Ή-NMR (DMSO~i 400 MHz): δ 1 .80 (s, I H), 8.17 (s, 1 H ), 7.00 (s, 2H); MS (ES) m/e 262 ΓΜ + I f .

EXAMPLE 23

3-P eny.l-ii/-pyrazok)[3,4-d ⁱ ]pyt iir¾)diri-4-anitne

To a stirred suspension of 3-iodo--Iff-pyni2olo[3,4--ri]pyiimkli.t!-4-aniine (2 g. 7.66 nimol), phenyl oronic acid ( 1.12 g, 9.18 tntnol) and K.tPO* (2,4 g, 1 1.3 raraol) in degassed N,N diniet|]ySlbnnaniide:water (3:2, 20 mL), was added 1 , 1 " (bisdiphenylphosphino)fefr<^enepa11adi«m(Ii) dscbioride (PdidppftCl;: ( 1 ,3 g, 1 , 15 niniol). The reaction mixture was purged with argon and heated at 120 ^W C for 18 hours. After cooling, the reaction mixture was filtered through celite and washed with ethyl acetate. The organic layer was poured into water {100 inL). extracted with ethyl acetate {3 x 400 raL) and the combined extracts were washed again with water. The combined organic layer was dried over anhydrous Na?Sf¾ filtered and evaporated to dryness to furnish the desired crude prtxluct which was purified by column chrotnatogntp ^' hy over ilica gel ( 100-200 mesh size) as a stationary phase and 5% (v/v) methanol in dichloromethane as einent to give the title compound as a colorless solid i0.S5 g, yield 53%}. Ή NMR (DMSCMs, 400 MHz) 8 3.59 (*. 1 H), 8.22 (s, 1 H>, (d, . = 7.2 Hz, 2H), 7.55-7.46 (rn, 3H), 6,50 (br s, 2H); MS (ES) /n <? 212 [M + 5

EXAMPLE 24

3-(4-Chlorophenyl)- ! H -pyraz«>loP,4-ij!]pyrijm.jdjrA-4-amtne

To a stirred suspension of 3-t«xlo-lH-pyra2o3<»[3 <' jpyriHtidin-4-aniine (2 g. 7.662 rnrnol), 4- chiorophenylboronic acid (1.44 g, 9. IS rnrnol ) and 3PO4 (2.4 g, 1 1.3 mmol) in degassed N,N diniethySfomvanikie: water (3:2, 20 mL), was added ί ,

(bi^jphe«ylpk)sphim))femx:enepaHadlura(Ii) dtc oride (Pd(dppf}C¾ ( 1.3 g, 1 , 15 mmol). The reaction mixture- was flashed with argon and heated at 120 "C for 18 hoars. After cooling, the reaction mixture was filtered through celite- and washed with excess ethyl acetate. The organic layer was poured into water ( 100 mL), extracted with ethyl acetate (3 x 400 niL) and washed with water. The combined organic layer was dried over anhydrous a2S<¼ filtered and solvents were evaporated to furnish the desired crade product. The pure- product was obtained by column chromatography over silica gel ( ! 00-200 mesh) as a stationary phase and 5% (v/v) methanol in dichloromethane as e ^' luent to give tiie title compound as a colorless solid (0.49 g. yield 27%), ^! H NMR (QMSO- , 400 MHz) 5 53.64 (s, 1 H). 8.22 {», 1H), 7.68 (d. J = 8,4 Hz. 2H), 7.59 (d, » 8.4 Hz, 2H), 6,8 (br s, 2H); MS i ^' ES) mi. 246 }M + If. EXAMPLE 25

3-i4-Meth.oxyph.enyl)- 1 #-pyrazolo[3 A^]py*imldm-4-amine

To a stirred suspension of 3-iodo- 1 W-pyraz ioP,4-^jpyrifnitdin- -ainine (2 g, 7.66 mtnol), 4- methoxyphenylboronic acid ( 1.4-4 g, 9. I S mmol) and ¾PO< (2.0 §, 7.66 raniol) in degassed N,N dimethylibrmamide:water (3:2, 20 mL), was added

f isdip enyipi)osp ino)i ^: errc>cenepai!adiuiii(Ii) dichloride t ^' Pd(dppf) ¾ (1.3 g, 1.15 mmol). The reaction mixture was Hushed with argon and heated at Ϊ20 ¾ for I S hours. After cooling, the reaction mixture was filtered through ce!ite and washed with excess ethyl acetate. The organic layer was poured into water (100 mL), extracted with ethyl acetate (3 x 400 mL) washed with water. The combined organic layer was then dried over anhydrous Na^SO* filtered and evaporated to dryness to furnish the desired crude product. The title compound was obtained by column chromatography over silica gei (100-200 mesh size) as a stationary phase and 5% (v/v) methanol in tfich!orornethane as eluent as a colorless solid (0.75 g, yield 42%). ¾ NMR (DMSOi i. 400 MHz); 5 13.58 is, 1H), 8.22 (s, Ϊ H), 7,48-7,44 ( m, 1JH), 7.25-7.19 ( m, 2H), 7.06-7.03 ( m, 1 H), 3.83 (s, 3H): MS (ES) m/ 242

EXAMPLE 26

3-( 4-P henox y pheny Ϊ )- 1 //- pyra zol of 3 ,4-<¾>y ri m i d in -4-ami ne

To a stirred suspension of 3-iix}o-l W-pyntzolo[3,4-< pyTiniidjn-4-arnine (0.1 g, 0.3S mmol), (4-phenoxyphenyl ^' )boronic acid (0.09 g, 0.42 mmol) and K?PQt (0. ! 2 g, 0.56 mmol) in degassed N,N dimethyiformamide:water (3:2, 2 mL), was added L i ' (bisdirA<my)phosphino)ferrocenepalladioni(lI) dichloride Pd(dppf)Cl2 (0.09 g, 0. 12 mmol). The reaction mixture was flushed with argon and heated at 120 °C for 5 hours. After cooling, the reaction mixture was filtered through celite and washed with excess ethyl acetate. The organic layer was poured into water ( 100 mL), extracted with ethyl acetate (3 x 200 mL) and washed with water. The organic layer was dried over anhydrous Na>S<¾ filtered and evaporated to dryness to furnish toe crude product. The title compound was obtained by column chromatography over silica gel (100-200 mesh size) as a stationary phase and 5% (v/v) methanol in dichlorornethane as elucnt to give the product as a colorless solid {0.03 g. yield 25.8%). ^! H NM . ( SO-i 400 MHz) δ 3.54 (s, 1H), 8.21 (s, 1H). 7,66 (d, J - 8,0 Hz, 2H), 7,43 (t ./ - 8,0 Hz, 2H), 7.20-7.12 fro, 5H); 1XMS m/e: 304 |M + If.

EXAMPLE 27

?«mv 3-{(4-Arai!K>-3-phenyl-l //-pyrazolo 1 -yl )rnethyl)-l ,2Klithiolan-4-yi benzoate)

To a solution of .^iKai l-l f- yra^lolS.^i jp rjmidiB^-amjiie (0.3 g, 1.42 mints! ) in dry N,N dimethyifonnamide was added CsjO¾ (0.7 g, 2.14 ininol) stirred for 10 minutes followed by slo addition of tnms 5-((raethylsulfonyl)oxy 1 ,2-dithian-4-yl benzoate (0.94 g, 2.81 mrnol) at room temperature. The reaction mixture was stirred and heated at. 80 ^,:' C for 2.5 hours. After cooling, the mixture was carefully poured into cold water and extracted with ethyl acetate (3 x 200 ml). The combined extracts were washed with water, dried over anhydrous zSO*. filtered and concentrated at reduced pressure. The pure product was obtained by coiamn chromatography on silica gel (100-200 mesh) elating with 1 -2% (v/v) methanol in diehioromethane as a pale brown solid (190 mg, yield 30%). MS (ES) /e 450 fM +l f.

EXAMPLE 28

trans 3-((4-Amino-3-phenyl-lH-pyi¾zolo[3 _> 4 /jpyrimldln-:i -y! methyl)- 1 ,2-dithiolan-4-ol

3~-t

^- ^" ^ OH

To a solution of irons 3-((4-amino-3-(4-phenox phenyl l/f-p Ta2olo|3,4-./jpyrimidin- 1 - yl)methyl - J ,2-dithiolan-4-yi benzoate (0, 18 g, 0.40 mrnol) in tetrahydrofuran ( 15 mL) was added 10% LiOH (5 mL) and was stirred for 4 hours at room temperature. The reaction mixture was then poured into water, acidified with saturated citric acid and extracted with ethyl acetate ⁽ 3 x 200 mL),

The combined organic extracts were dried over anhydrous NiteSO filtered and concentrated at. reduced pressure. The pure product was obtained by column chromatography on. silica gel ⁽ 100-200 mesh) ektting with 0.5% (v/vi methanol in dichlosroroethane to give the title compound as a pale btxnvn solid (70 mg, yield 50%). ^S H NMR (DM5C ¾, 400 MHz) 5 8.27 (s. 1 H), 7.69 ( 7.6 Hz. 2H), 7.58-7,43 <m, 3H), 5.52 (4 4,4 Hz, 1 H), 4.63-4.49 n, 3H), 3.99 (be, ! H), 3.45-3.37 (m, 1H), 3.08 idd, Ji « 1 1.6 Hz, ./.? ^ 3.6 Hz, i H); MS (ES) m e 346 (M + If.

EXAMPLE 29

tnims 3-({4-Ammo-3-{4-ehiorophen>1}-l/^

ben :zo ate

To a solution of 3-(4-ch.lotx)phenyl 1Η-ρ^τ8ζοΙο| , ^ί]ρ>'ηΓηί<ϋίη-4-αιηίη« (0.4 g, 5 ,63 mmol) in dry N,N dimeihyltormamide was added C¾C<¼ 0.0 g, 3.26 mmol) stirred for 10 minutes, followed by the addition of trans 5-((roeti)yls«lfonyl)oxy)-l,2-dithian-4-yl beozoate (1 ,0 g, 3.26 mmol). The reaction mixture was heated at SO *C for 2.5 hours and was poured info cold water after cooling. The aqueous mixture extracted with ethyl acetate (3 x 200 roL). was washed with water, dried over anhydrous Na^SO^ filtered and concentrated at reduced pressure. The pure product was obtained by column chromatography on silica gel (100-200 mesh) elating with 1-2% (v/v) titethano] in diehlorotnetliane to produce as a pale brown solid (230 nig, yield 29%). ^f H NMR (DMSO--/*, 400 MHz) δ 8.27 (s, l.H), 7,86 id, = 7.6 Hz, 2H), 7.65-7,57 (ni, 5H), 7-55-7.47 (m, 2H), 6. (s hr, 2H), 5.81-5.78 (m, 1H), 4.75-4.72 (m, 2H), 4.45-4.42 (m, 1H), 3.72-3.68 (m, 1H), 3.46-3.42 (m, ! H); MS (ES) ffi i? 485 [M + I f.

EXAMPLE 30

trans 3-((4^mino-.3-(4-chJorophenyl)-l //-pyra^

To a solution of imm 3-((4-atninc~3-(4-chlorophenyl l/f-p Tazolo|3 _J 4-./jpyrimidin- 1 - yl)jmethyl l,2-dithiolan-4-yl benzoate (0.2 g, 0.41 mmol) in tetrahydxtrfuran 05 roL) was added 10% Li OH. (6 m ^' L) at room temperature. After stifriag for 4 hours, the reaction mixture was poured into water, acidified with saturated citric acid and extracted with ethyl acetate (3 x 200 roL) and the combined organic extracts were dried over anhydrous N&2SO4 concentrated at reduced pressure. The pure product was obtained by column chromatography on silica gel { i 0-200 mesh) eluting with 0.5% i ^' v v) methanol in diebloromethane to give the title compound as pale brown solid {90 tng, yield 57%). ^! H NMR (D SO~i 400 MHz) S 8.27 {s, 1H), 7.70 {d, . = 8.4 Hz, 2H), 7.61 id, ./= S.4 Hz, 2H), 5.53 {d. J= 4.8 Hz, 2H), 4.59-4,52 {m, 3H), 4.05 -3,92 (m, I H >, 3.44-3.40 im, iH >, 3.09-3.05 im, 1H); MS (ES) m e 380 [M

EXAMPLE 1

trans 3-({4-£tmtno-3-(4-m ihoxyphenyi)-5 //-pyrazoH>[3,4-< jpyrimidin-l -yl jmethyl)- 1 ,2-dithtolan-4-yl

benzoate

To a solution of 3-(4-methoxyphcnyl l W-pyrai;olo{3,4^ yriimdtn-4-ainHie {0.4 g, 1.65 mmol) in dry N.N dirnetliylfonnarnide was added Cs?,COj (0.81 g. 2.48 minol.) and was stirred for 10 minutes followed by the addition of trans 5-({metbylsuifonyl)oxy )-1.2-dithian-4-yl henzoate (1 .1 g, 3.29 mmol). The reaction mixture was healed with stirring at SO °C for 2.5 hours, cooled and then quenched with coid water. The aqueous mixture was extracted with ethyl acetate (3 x 300 mL) and the combined extracts were washed with water, dried over anhydrous Na.SQ<, filtered and concentrated at reduced pressure. The pure product was obtained by column chromatography on silica gel (100-200 mesh) eluting with 1 -2% (v/y) methanol in dichJoromethane to produce as a pale brown solid (240 rog, yield 31 ). MS (ES.) m/ 480 (M + i f.

EXAMPLE 32

trans 3-((4^Ammo-3-(4-mefho.xyphei^

oi

To a solution of tram 3-((4-mnjno-3-(4-methox phen>^ i/f-p TazoJo|3 _J 4^/jpyrimi<iin- 1 - yl)mefhylM,2-dithiolan-4-yi benzoate (0.22 g, 0,45 mmoi i in tetrabydrof ^' uran (20 mL) was added 10% UOH (8 ml,) at room temperature and the mixture was stirred for 4 hours. The reaction mixture was then poured into water, acidified with saturated citric acid and extracted with ethyl acetate (3 x 200 mi,). The combined organic extracts were dried over anhydrous Na>S<¾, filtered and concentrated at reduced pressure to gi ve the crude product which was purified by cofumn chromatography on silica gel (100-200 mesh) eluting with 0.5% (v/v) methanol in diehloroiiietha e to give the title compound as pale brown sol id (SO trig, yield 47%). ^S H NM 400 MHz (DMS0-r 400 MHz) δ 8.27 (s, 1H), 7.47 (d, J - 7.6 Hz, 2H), 7.26-7,20 im„ 3H), 7.07-7,05 fro, I B), 5.53 (d, J - 4.8 ϊ¾ 2H), 4.63-4.48 (m, 3H), 4.01-3.96 (m, 1HL 3.83 is, 3H), 3.45-3,40 I ^' m, 1 H), 3.09-3.06 (m, I Hj; MS (ES) m e 376 [M +| .

EXAMPLE 33

(3«V,4/i)-3-((4-Amino-. ^: )-(4-methoxyphenyl)- 1 /i-pyra2olo ,4-rf|pyrimidin-l-yl)methyl )- 1 ,2-dithiolan- 4-ol and (3jf?,4S .H(^-Amino-3-(4-methoxyphenyl )- i /-pyrazoio 3,4-a ^r jpyrtnadiii- 1 -yl)methyl)- 1 ,2- dithioJan-4-o!

The two ertarttioniers of /ram 3-((4-anii:no-3-(4-iitetboxypbetiyi)-l/f--pyra7.oioi3.4- d|pyri.m:iditi- ! -yl)t)iethyi)-i,2-dithiolaB-4-ol were separated by c tiral HPLC techniques as peak 1 retention time 11.7 minutes (5 rog) and peak. 2 retention time 19,7 minutes (7 nig) by following chins! HPLC conditions. Column: C!iiralpak-J.A(250*4.6*5.()p); mobile pliase-A: 0.1% diethyl amine in n- hexanes; mobile phase-B:efltartol; mobile phase C:isopropariol:diehioroirte£hane (90:10); method- isocratic::: 10:80: 10 (A:R:C); flow rate: 15.0 mL/min; Column temp: ambient; diluent: mobile phase; sample loading: 30 rag/injection; run time 35 minutes. A. Peak I Data

4~oi

^! H NMR 400 MHz (DMSO-, 400 MHz) § 8.27 (s, I.H).7.47 (it . = 7.6 Hi;, 2H), 7.26-7.20 (ra, 3H). 7,07-7,05 ( , !H).5,53 (d, 4.8 Hz, 2H).4,63-4.48 (m, 3H).4,01-3,96 (m.1H), 3.83 (s, 3H).3,45- 3,40 (ro, 1.H), 3.09-3.06 (jtn, !H); MS (ES) w/¾ 376 j ^' M

B, Peak 2 ^' Data

(3A ^> ,4; -3-(i4-.A«ij.no-3-{4-«ieth.oxyp en.yi)- ! i/-p ra7,oio ,4^]pyriniid!n-i-yl)methyl)-l,2-dithiolaii-

4-oi

^! H NMR (DMSO-ifi.400 MHz) S 8.27 <s, 1 H >, 7.47 (d, J~ 7.6 Hz, 2H), 7.26-7.20 do, 3H), 7.07-7.05 (m, IHX 5,53 (d, /= 4.8 Hz, 2H), 4.63-4.48 (m, 3H), 4,01-3,96 Cm, H), 3,83 (s 3H), 3,45-3,40 (m, m 3,09-3,06 (ra, !H); MS (ES) /«/* ^■ : 376 [M +1 . EXAMPLE 34

as 3-{(4-Am!n0-3^4-methoxyphertyl K^

hertzoate

To a solution of 3-(4-methoxyphenyl )- i//-pyrazoloi3,4-£/|p rirojdin-4-ararae {0.5 g, 2.0? ratnol) in dry M,N dinieihylforniamide was added C jCOi { LOI g, 3, 12 mmol ) and the resultant solution was stirred for 10 initiates followed by the slow addition of cix 5-((methylsul fonyJ)oxy)-l ,2- dithian-4-yi benzoate (2.07 g, 6.22 mmol). The reaction mixture was heated to 80 °C for 2.5 hoots and then after cooling was poured carefully into water. The aqueous mixture was extracted with ethyl acetate (3 x 300 tn ^' L) and th combined extracts were washed with water, dried over anhydrous Na>SO¾ filtered and concentrated at reduced pressure. The pure product was obtained by column chromatography on silica gel ( 100-200 mesh) elutirtg with 1-2% (v/v) methanol in diehloromethaoe to furnish the title compound as a pale brown solid (600 trig, yield 60%). MS (ES) w' 480 M +1 ] ⁺ ,

EXAMPLE 35

cix 3-{{4-Amiiio-3-{4-rnethoxyphe!iyi)- l W^yTamio{ 3,4^ |pyrimidin-i-yl}methyl)-i,2-dtfliioia!i-4-oi

To a solution of cix .3-((4-aniino-.3-(4-nie^oxyphenyl)-l/i-py«i-x)lo ,4-d)pyrimidin-l^ yS )iiiethyi}- ! .2-dithioian-4-yi benzoate (0.6 g, 1 ,25 mmol) in tetrahydrofuran (20 niL) was added 1 % LiOH ( 10 niL) at room temperature and the reaction mixture was stirred for 4 hours followed by addition of cold water. The reaction mixture was then acidified with saturated citric acid and extracted with ethyl acetate (3 x 200 ml.). The combined organic extracts were dried over anhydrous filtered and concentrated at reduced pressure. The pure product was obtained by column

9.1 chromatography on si lica gel (100-200 mesh) eiutirtg with 0,3% (v/v) methanol in diehioromethane to give the title compound as a pale brown solid (100 nig crude).

EXAMPLE 36

(3S,45')-3 -({ -Annno-3-i4-fiie£hox.y phenyl )- :i-¥-pyra7.oio[3.4-_/]pyrirniciiii-- l --yi)itieihyl)- 1.,2-dit iolan- 4-Cil and {3 f,4 ?)- ^' 3--((4-amiiio-3-(4-methoxyphe!iyl)- l W^yTazoioj -i,4-ij!jpyrit}iidin--} -yl)t}iethy})-i _* 2- dithiolan-4-ol

The two enantioraers were separated as peak 1 retention time 7.6 minutes (10 tag) and peak 2 retention time 9.1 minutes (8 rag) by following ehint! HPLC conditions.

Column: Clitralpak-IA( 250 - ⁱ 4.6*5.0p); mobile phase- A: 0. 1 % diethyiamine in n-hexanes; mobile phase B: isopropanol: dichSoromet ane (80:20); method-is cratie: 70:30 (A:B ); flow rate: 15,0 mL/min; column temp: ambient; diluent: mobile phase; sample loading; 20 mg/injection; runtime: 45 minutes.

A. Peak Ϊ Data

.2-dithiolan-

^! H NMR 400 MHz (DMSO-dW): δ 8.27 (s, IH), 7.60 (d, J S.4 H¾, 2H), 7. i i (d, J- 8.4 Hz, 2H), 5.66 id, / = 4.8 Hz, 2H), 4.81,4.61 ini, 3H), 4. 12-4.07 (m, 1H), 3.83 (s, 3H), 3.43-3.39 fin, i.H), 3.12 (dd, J.t = Ϊ 1 .6 Hz, J ₂ * 3.2 Hz, I H); MS (ES) m/ 376 \M + i.f .

B. Peak 2 Data

{3.R,4/?)-3-((4-Amt!io-3-{4-iiieihoxyphenyi)- 4. i-pyi¾zok![3 _» 4^]p Titriidiii-l--yl)methy] )-l ,2-dithiolan-

4-ol

'Η NMR 400 MHz (DMSO-iftS): δ 8.27 (s, IH), 7,60 ./= 8.4 Hz, 2H), 7.1 1 (d, 8.4 Hz, 2H), 5.66 {d, 7 = 4.8 .Hz, 2H), 4.8 14.61 (m, 3H), 4.12-4.07 (rn, I H), 3.83 (s, 3H), 3.43-3.39 (m, J H), 3.12 (dd, , = 1 1.6 Jj = 3.2 Hz, IH); MS (ES) m/r 376 (M +1 )*.

EXAMPLE 37

trans H{4-Methoxy ,2--difh^

4- amine

h

To a solution of 3-(4-pher»>xyphenylH#-pyra^ (0.50 g, 0. 16 mmol) in dry AW dimethylforroamide was added Cs >C(¾ (96 mg, 0.83 rorool i and stirred for 10 minutes followed by the addition of /ram 5-methoxy-i,2-djthlan4-yl--jmethanesult oate (0.2 g, 0,3 mmol). The reaction mixture was heated for 2 hours at 80 ^W C then, cooieci and poured into cold water. The aqueous solution was extracted wit ethyl acetate (3 x 150 rnL) and the combined extracts were washed with water, dried over anhydrous N -iSO,,, filtered and concentrated at reduced pressure. The pare product was obtained by column chromatography on silica gel (100-200 mesh) etuting with 1- 2% (v/v) methanol in dichioromethane to furnish the title compound as a pale brown solid ( 15 rag, yield 18%). Ή NMR iDMSO 400 MHz): 8 8.27 (s, H), 7.67 (d, / = 8.0 Hz, 2H), 7.45 -7.42 (nr. 2H), 7.22-7,12 (m, 5H), 4,604.57 (m, 2M), 4.24 (m, I H), 4.1 (m, I H), 3.49-3.45 (m, IH), 3.23-3.20 (m, I H), 3.12 (s, 3H); LCMS m/e: 452 [M EXAMPLE 38

as l-((4-Methoxy-i,2-dilMola!^

amine

h

To a solution of 3-(4-phenoxy phenyl)- 1 //-pyra2olo[3,4-djpyrimidin-4-amine (30 mg. 0.099 mmol) i dry dim thyiformamide was added (48 mg, 0.149 mmol) and was stirred for 15 minutes followed by the addition of m 5-methoxy- i.,2-dith!an-4-yl methatiesuifonate ( 0.12 g. 0,49 mmol). The reaction mixture was heated for 2 hours at 80 *C, cooled and poured into water. The aqueous solution was extracted with ethyl acetate (3 x 150 mL) and the combined extracts were washed with water, dried over anhydrous Na^SO^ filtered and concentrated at reduced pressure. The pure product was obtained by column chromatography on silica gel ( 100-200 mesh) elating with I.~ 2% (v/v) methanol in dichloromethane to furnish the title compound as a pale brown sol id i ^' S mg, yield 19%). Ή MR ( SO-ii, 400 MHz) δ 8.26 (s. I E)., 7.68 (d, J = 8,8 Hz, 2H), 7.45-7.4! fm, 2H), 7.20-7, i i (m, 5H), 4.80-4,76 (ra, I H), 4.68-4,62 (ra, I H), 4.46-4.44 (m, I H), 4,28-4,23 (m, Hi), 3,50-3, 1 (m, 2H), 3.36 is, 3H); LCMS m/e: 452 (M +1 )

EXAMPLE 39

tmns 14 (4-(Benzy loxy )- 1,2-di thiolan-3-yl)methyl )-3-(4~phenoxyphenyl )- 1 /-/-pyrazoiol 3,4- d jpyri midin-4-ami tie

To solution of 3-(4-phenoxyphenyl)-l//-pyrazolo(3,4-^pyrimidin-4-afnitne (40 mg, 0, 132 mmol} in dry N,N diraethy!fonnamtde ( 10 mL) was added CSJ.COJ (65 mg, 0, 19 mmol.) and was stirred for 10 minutes followed by the addition of trans 5-((methylsalfonyl)oxy)-l,2-dithian-4-yl benzoai (0.21 g, 0,66 mmol). The reaction mixture was heated 1Ό2 hours at 80 °C, then cooled, and poured into water. The aqueous solution was extracted with ethyl, acetate (3 x .200 oil..) and the combined extracts were washed with water, dried over anhydrous Na?J50 ₄ , filtered and concentrated at reduced pressure. The pure product was obtained by- column chromatography on silica gel () 00- 200 mesh) eluting with i-2% (v/v) methanol in diehioromethane to produce as a pale brown solid (10 rng, yield 15%), ^! H NMR (DMSC 400 MHz) δ 8.24 (s, IH), 7.65 (d, J ~ 8.8 Hz, 2H), 7.46-7.42 (m, 2H), 7.22-7.08 (m, iOH), 4.58-4.55 (m, 2M), 4.38 (m, I H), 4,33 {s, IH), 4,24-4.20 (m, IH), 3,53-3.49 (m, I H), 3.29-3.26 fro. 1H); LCMS ro/e: 528 (M +lf.

EXAMPLE 40

M(4-(Benzyiox} - 5

To a solution of 3-(4-phenoxyphenyl}-lW-p>TaTOlo|.3,4^jpyrifnidin-4-amine (40 rag, 0.132 mmo ) in dry N,N ditnethylformanride (10 was added CSJCOJ (65 nig, 0. 19 mmol) and was stirre for 10 minutes followed by the addition of cis 5-i (methykulfonyl)oxy)- 1 ,2-dithian-4-yl benzoate (0,21 g, 0,66 mmol). The reaction mixture was heated for 2 hours 80 X-, cooled and poured into water. The aqueous solution was extracted with ethyl acetate ( 3 x 200 mL) and the combined extracts were washed with water, dried over anhydrous NaaSQ*, iiitered and concentrated at reduced pressure. The pure product was obtained by column chromatography on silica gel 000-200 mesh) e!ufin with I -2% (v/v) methanol in diehioromethane to furnish the title compound as a pale brown solid (20 mg, yield 30%). Ή NMR (DMSO-<& 400 MHz) 5 8.25 is, I H), 7,65 id, 7,8 Hz, 2H), 7.45-7.40 On, 7H), 7.18-7.08 (m, 5.H), 4.85-4.80 (m, iH), 4.72-4.68 (m 3H), 4.57-4.54 fm, I H), 4.34- 4.29 iin, i H), 3.45-3.41 (m, 2H); LCMS fe: 528 \M EXAMPLE 4 i

trans

yi be izoate

To a solution of 3-(4-ohenoxyotenylH#-py (0.55 g, 1 ,8 mmol) in dry N,N dinieihylforrnatnide was added Cs^COn {0.9 g, 2.7 mmol) and was stirred for 10 minutes followed by flie addition of 5--f(niethyli.idfo]:iy oxy)"L ^' 2-d!tbian-4 ^« y1 hetizoate (0.77 g, 2.3 mmol). The reaction mixture heated for 2 hours at 80 °C and then cooled and poured into water. The aqueous so!utiori was extracted wit ethyl acetate (3 x 200 mL) and ihe combined extracts were washed with water, dried over anhydrous N _>SO filtered and concentrated at reduced pressure. The pare product as obtained by column chromatography on silica gel (100-200 mesh) during with 1- 2% (v/v) methanol in dichiorotnethane to furnish the title compound as pale brown solid (160 rag. yield 17%). Ή-NMR iDMSO^, 400 MHz) δ 8.26 (s, 7.83 id, / = 7.2 i-k, 2H), 7.65-7.63 (m, 2H), 7.62 (d, / == 8.8 Hz, 2H), 7.51-7.41 (m, 5H), 7.18-7.1 1 (m, 5H), 5.80 (m, 1H), 4.73 (d, J « 7.2 Hz, 2H), 4.63-4.52 (m. 1H), 3.73 (dd, J, - Ϊ 2. Hz, = 5.6 Hz, 1H). 3.47 idd, Jt - 1.2.8 Hz, - 2.8 Hz, 1 H); LCMS m/e: 542 M ÷ ! ] ^* ,

EXAMPLE 42

irons 3- i4-Ajtmno-3-(4-phenoxyphenyl> 1 i/-pyrazolo! ^' 3,4-«i!]pyrinsd!ri- l-yl)methyl)-l,2-diti iolan-4- oi

To a solution of tram 3 (4-amtno-3-(4-p.hejnosyp.heny!)-lH-pyra¾oloi3,4-rfjpyrimtdi n- 1 - yl)jmethyl l,2-dithiolan-4-yl henzoate (0.8 g, ί .478 rorooi i in tetrahydrofuran (60 mL) was added 1.0% Li OH (30 mL) and was stirred for 4 hours at room temperature and then was poured info water, acidified with saturated citric acid and extracted with ethyl acetate (3 s 300 mL), The combined extracts were dried over anhydrous N;¾SO.t, filtered and concentrated at reduced pressure. The pure product was obtained by column chromatography on silica gel (100-200 mesh) eiuting with 0,5 ¾ i ^' v v) methanol in diehloromethatie to give the title compound as a pale brown solid (310 nig, yield 47%), %), 'H-NMR (DMSO-afe. 400 MHz) δ 8.26 (s, IH), 7,67 (d, 7 - 8.8 Hz, 2H), 7.45-7,42 (m, 2H), 7.19-7.12 iro, 5H), 5,33 <d, J- 4.8 Hz, I H), 4,62-4,4? (tn, 3H), 4.01-4.00 (m, IH), 3.73 (dd, 7/ - 12.8 Hz, h « 5.6 Hz, 1 H), 3.47 (dd, J, ^ 12,8 Hz, 7; = 2.8 Hz, IH); LCMS mfe 438 I ^' M +1) ^* .

EXAMPLE 43

(35,4/i)-3-((4-Amin0-3-(4-phen0xypfe

4-oi and (3i?,45)-3-((4-ammo-3-(4-pheno)t:yphenyi)- 5 /f-pyrazolof 3,4-t ]pyrimidin-i-yi jmethyl)- I ,2- dithiolan-4-ol

^' The two en ant t ilers of treats 3-((4-aiiiino-3-(4-phenoxypheny ^' i)- ! /7-pyrcffioio 3,4- d|pyr!.m:iditi- l -yi)niethyi)-l,2-ditO! laB-4-ol were separated as peak i , retention time 8.4 minutes (20 nig) and peak 2 retention time 10,4 minutes (1 nig) by the following corral HPLC conditions:

Column: Chiralpak A(250*4.6*5.(ty): mobile phase-A;n-hexanes (0.1 % trifluoroacetic acid) ; mobile phase-C: isopropanoi:dichiofometli;ine (90: 10) isocratic: S0;50(A:C); flow rate: 1.5.0 m ^' L/min; column temp: ambient; diluent: mobile phase + dichloroincihane; sample loading: 25 mg/injeetkm; runtime: 20 minutes.

A. Peak 1 Data

(3S,4i?)-3^(4~Amino-3-(4-phenoxyphenylM

4-oS h

^! H NMR 400 MHz (DMSC 400 MHz) S 8.26 (s, IH), 7.67 (d, - 8.4 Hz, 2H), 7.43 (t, - 8.0 Hz, 2H), 7.21 - 7.1 1 (m, 5 H), 5.53 (d, ,/ » 4.8 Hz, IH), 4,62-4,47 (tn, 3 H), 4.01 -3.98 (m, 1 H), 3,42 (dd, J, = ! 1,6 Hz, J? « 4.8 Hz, I H), 3.07 (dd, J, « 12,0 Hz, 7> = 4,0 Hz, I H): MS (ES) m'e 438 | ^' M + 1 . B, Peak 2 ^' Data

(3.$, 4S)-3-i(4-Aroino-3-(4^henoxyphe:nylH#^

4~oi

Ή NMR 400 MHz (DMSO- 4 0 MHz) 3 8,26 {», 1H), 7,67 (d, J = 8,4 Hz, 2H), 7.43 (t, /= 8.0 Hz, 2H), 7.2 !- 7.11 im, 5 H), 5.53 id, ,/ = 4.8 Hz, 1H), 4.62-4,47 <m, 3 H), 4.01-3.98 <ra, 1 H), 3.42 {dd„ J> « 1 1.6 Hz, _^ 4.8 H¾, 1H), 3.07 (dd, . i = 12.0 Hz, h = 4.0 Hz, 1H); MS (ES) >« ,? 438 [M + \\

EXAMPLE 44

cis i ~ nmm~i ^~ -{^

benzoate

h

To a solution of 3- 4-ph nox> henyl)-l WHp>Taz-otoP,4^jpyrimidin-4-aniii^ (0.2 g, 0.66 mmol) in dry N,N dimethylformamide was added Cs CO¾ {0.32 g, 0.99 mmol). The solution was stirred for 10 minutes, followed by the addition of m S-((methy5suli ^' onyl}oxy)- 1 ,2-dithian-4-yl benzoate ( i . i g, 3.29 mmoi) and was heated for 2 hours at 80 °C. After cooling, it was poured into water and extracted with ethyl acetat (3 x 300 niL). The combined extracts were washed with water, dried over anhydrous a^SO* filtered and concentrated at reduced pressure. The pare product was obtained by column chromatography on silica gel ( 100-200 mesh) eluting with i -2 (v/v) methanol in dicMoromethane to furnish the title compound as a pale brown solid (70 nig. yield 20%) and proceeded next step, LCMS m/e: 542 [M +1 ] ⁺ , EXAMPLE 45

cis 3-((4-Amino-3-(4-phem»xyp^

h

To a solution of cis 3 (4-amlno-H^pbeflosypheny!)-lH-pyra¾oloi3,4-rfjpyrimidio- f - yi)mefhyl)- i,2-dirhiolan-4-yi benzoate (900 mg, S..4 mmol) in tetrahydrofuran (80 ml,) was added 10% aqueous LiOH (40 niL) at room temperature and was stirred lor 4 hours. The reaction mixture was then poured into water, acidified with saturated citric acid and extracted with ethyl acetate (3 x 300 rnL) and the combined extracts were dried over anhydrous NioS filtered and concentrated at reduced pressure. The pure product was obtained by coiamn chromatography on silic gel (100-200 mesh) eiuting with 0.5% (v/v) methanol in dichloromethane to give the title compound as a pale brown solid (360 nig, yield 50 %>. 'H-NMR (DMSO-- , 400 MHz): δ 8.26 (s, 1H), 7.9 i. (d, J = 7.6 Hz, 2H), 7.42 (d, J » 7.6 Hz, 2H), 7.19-7.5 1 (m, SH), 5.66 (bs„ 1H), 4,81-4,76 (m, 2H), 4.68-4.62 (m, 1H), 4.12-4.08 (m, I H), 3.40 (dd, // « 1 1.6 Hz, » 4,8 Hz, 5 H), 3.10 (dd, Ji = 1 .6 Hz, i _: = 3.2 Hz, 1H); LCMS m e: 438 [M +5 Γ.

EXAMPLE 46

(35, 4.S -3-((4-Amino-3-(4-pheno.xypheny^ ,2-dithiolan- 4-ol and QR, 4 ? 3-((4-amino-3-(4-phet»>xypheny S. H-py razolo[3,4-<./]pyrimtdin- 1 -yl )methyl )- Ϊ ,2- di.t ioian-4-ol

The two enantiomers of cis 3-((4-aiiiin.o»3-(4-phe oxyphen.yi)- i ff-pyrazo.io[3,4--i/ipyrinitdtn- l-yl)raethyl)-l,2-dithiolan-4-ol were separated as peak 1 retention lime 6.5 minutes (20 trig) and peak 2 retention time 9 A minutes (26 mg) by the following c iral HPLC conditions:

Column: Oiiralpak-IA ϊ 250*4.6*5.0μ); mobile phase- A.: n-hexanes; mobile phase- B:0.3 trifluoroacetic acid in ethanol: dic ^' hloromethane (85: 15); isocratic: 40:60iA:B); flow rate: 15.0 mL min; column temp: ambient; diluent: mobile phase; sample loading: 25 mg/inj; run time: 25 minutes. A. Peak I Data

(35, 4S)-3-((4-A mo-3-(4-phenoxyphenyi)-l W~pyfazolo| ,4^]pvTimidin-l-yi)nK*> )-l 2-dithioian~

4~oi

h

Ή NMR 400 MHz (DMSO- ): δ 8.26 (s, IH), 7.67 (d, = 8.4 Hz, 2H), 7.45-7.413 (m, 2H), 7.1 - 7. i Ϊ (ra, 5 H), 5.53 (d, / = 4.8 Hz, IH), 4.62-4.47 fin, 3 H), 4.01-3.96 (m, 1 H).3.44 (dd, J, ~ 11.6

H¾, «= 4.8 Hz, Hi), 3.07 (dd, Ji ^ !2.0 Hz, J ₂ 4.0 Hz, IH); MS (ES) 438 (M +if.

B. Peak 2 Data

{3R, 4/i)--3-((4--Aniom-3"(4~p e^

4-ol

h

'H NMR (DMSO-< 400 ΜΗζ}: δ 8.26 (s, i H), 7.67 (d, /« 8.4 Hz, 2H>, 7.45-7.4 ! (m, 2H), 7.1.9- 7.1 Ϊ (m, 5 H), 5,53 (d, 7 » 4.8 Hz, IH), 4,62-4.47 (m, 3H), 4.01-3.96 Cm, ! H), 3.44 (dd, ) » ! 1.6 Hz, Λ « 4.8 Hz, IH), 3.07 (dd,./, « 12,0 Hz, 7> = 4,0 Hz, IH): MS (ES) m/e 438 |M + lf .

EXAMPLE 47

trans l-((4-{(i ^' i:r/-BufykSime

py raz< ύο{ 3. -d] pi: i m ic!i.n-4 - am i ne

To a slurry of frmy^-i^rt-buiyld na ylsHyloxy-S-h df oxy- 1 ,2-dithiane (200 rag, 0.75 ratnol), of 3-(4-phenoxyphenyl)-l//-pyrazolo(3,4^pyrimjdin-4-amin (342 mg, 1 ,13 ramo!), and triphenyiphospiiine (296 mg, 1.13 mmoi) in NN dimethyll ^' ormamide (1 niL) at 0 °C tinder argon atmosphere was added diethyl azodicarboxylate {0.18 raL, 1.13 mmoi ) dropwise and the mixture w s stirred at room temperature for 16 hours. The reaction mixture- was then quenched with one drop of acetic acid and methanol, diluted and filtered through celite pad. The filtrate was concentrated in vacuo to give a residue which was diluted with methanol and adsorbed into silica gel (5 g) and then purified by flash chromatography using ethyl aeetate hexanes (3/7) as an eluent. to give the desired product ( 174 mg, 43%) as a colorless oil: Ή NMR (DMSOcfe 400 MHz): δ 8.27 is, IH), 7,51 (d, J = 8.4 Hz, 2H), 7.41 (in, 2H>, 7.25- 7.08 (m, 5 H), 5.53 {d, / = 4.8 Hz, ΪΗ), 4.62-4.47 {in, 3H), 4.01 -3.96 On, ΪΗ), 3.07 (dd, J, ~ 1 1.6 Hz, = 4.8 Hz, I H>, 2.82 (dd, J _t - 1 1.0 Hz, . = 4.0 Hz, 1.H), 2,62 Οίΐ,ΪΗ), 0.98 (s. 9H), 0.21 is,6H).

EXAMPLE 48

m»s- l-{(4-((/ii'i<-Butyldirne{hylsilyl)oxy)- 1 ,2-dithiolan- ^' 3-yl)rrtethyl )-3-(4-phenoxyphenyl)- /jf- pyni¾okij ^' 3,4-ii)pryiraidin--4-;itnine

To a solution of 3-(4-phenoxyphenyl ^' )- 1 //-pyrazolof 3,4-«0py rimidin-4-aniine (0,46 g, 1 ,5 mmoi}

in dry N.N dimethyl formamide wa added Csj.CQj (0,7 g, 2, 1 mmoi) and was stirred for 10 minutes followed by the addition of tmns-5-terf- butyldimethylsilyloxy- 1 ,2-di thian-4-yl methanesuifonate (0.70 g, 2.1 mmoi). Th reaction mixture heated for 2 hours at 8 "C and then cooled and poured into water. Th aqueous solution was extracted with ethyl acetate (3 x 200 mL) and the combined extracts were washed with water, dried over anhydrous Na>SO- , filtered and concentrated at reduced pressure. The pure product was obtained by column chromatography on silica gel ( ! 00-200 mesh) during with ethyl acetaie/hexanes (3/7) methanol in. dichloromethane to furnish the title compound as pale brown solid ( 120 mg, yield 17%). ^! H NMR (DMSQ-<¾, 400 MHz): 5 8.27 (s, 1H), 7.5 Ϊ (d, J » 8.4 Hz, 2H), 7.41 On, 2H). 7.25-- 7.08 (in, 5 H), 5.53 (d, J = 4.8 Hz, 1 H , 4.62-4.47 {in, 3H >, 4.01-3.96 {in, I H ), 3,07 (dd, ./ _/ - I J .6 Hz, h - 4.8 Hz, i H), 2.82 (dd, ./,· - 1 1.0 Hz, ./, - 4.0 Hz, i H). 2.62 (m, i H), 0.98 (s, 9H), 0,2 i (s,6H),

EXAMPLE 9

trans H^4-^A:min.o--3-( ^iten.o ypiten. ^^^^ J.-yl)fne{liyl)-i,2-d iiolari.-4- oi

A solution of /raws l-((4-{(/m-buiy]dHneihylsilyl)oxyH ^

phenoxyphenyl)- 1 -1Η^Γ3«»1.ο(3 _» 4-< |ρ^·ϊπ».ϋίη-4-40ΐϊηβ (70 mg, 0.17 mrnol), glacial iicetic acid ( 1 7 uL, 0.3 niniol), tefra-H- buiylaniinonium fluoride in tetrahydrofuran ( 1 .0 M, 0.19 inL, 0.1.9 mmol.) and tetrahydrofuran i ^' 2.0 mL was stirred under argon atmosphere for 1.5 hours. The reaction mixture was quenched with i drop of acetic acid, dissolved in methanol and concentrated to produce a crude mixture which as dissolved in methanol, adsorbed on silica gel and purified by flash chrornatognip ^' hy (eluent ethyl acetate). Concentration of the fractions gave the product as a tight yellow powder (29.5 nig, 59%). Ή NMR 400 MHz (DMSO-c 400 MHz) 8 8.26 (s. 111). 7.67 (d, . = 8,4 Hz, 2H), 7.43 (t, J - 8.0 Hz, 2H), 7.21 - 7. 1 1 (m. 5 H). 5.53 (d, J = 4,8 Hz, i H), 4.62-4.47 (m. 3 Hi, 4.01.-3.9 (m, 1 H), 3.42 (dd, Ji = Π .6 Hz, J> =. 4,8 Hz, IH), 3,07 (dd, J; = 12.0 Hz, Λ ~ 4.0 Hz, 1.H): MS CES) m/< ^> 43 [M +l f.

EXAMPLE 50

3- Ptie:ny1etiiynyl}- 1 - -pyrazo 3,4«ti]pyTii):iidin- -aiiiiiie

To a solution of 3-! «!o-iH-pyrazolo[3,4-rfjpyrimidin-4-ansne (2.0 g. 7.7 mmol) was added sequentially, phenyl acetylene (3.1 g, 30.7 ninioi ), copper (I) iodide (0.3 g, I..5 mmal ) and triethylaniine (2.3 g, 23.0 mmol) in ΝΛ ^! di niethyifomiamide (20 raL). The reaction mixture was purged wifli nitrogen atmosphere and 1, 1 ^* ><^<phenylphospl»!io)ferf )cenq>aikdiuniUi) diehlortde

(F ^J d(dppf)Ci:, i ^' 0.6 g, 0.77 mmol) was slowly added at room temperature followed by heating at SO °C for 6 hours. The reaction mixture was cooled, filtered through, celite and then poured into ice water and was extracted with ethyl acetate. The combined organic layer extracts were dried over anhydrous N¾iS(¼ and concentrated in vacuo to give a crude oil which was purified by column, chromatography on silica gel {100-200 mesh), elating with 50% ethyl acetate: hexanes mixture to afford the title compound Ϊ0.3Ι g, J 7%) as a light brown solid. ^S H NMR i.DMS0-< 400 MHz): δ 13.83 {«„ I H ), 8.22 (s, IH), 7.72 (dd, Ji 7.6 Hz, h = 4.0 H¾, 2H), 7.46 (dd, ,/; = 5.2 Hz, .) ^■ > = 4,0 Hz, 3H); LCMS (retention time 5.0 minutes, m e 236 |M+1)\ 95.9%), Capcell pack C18 150*4.6, 3 μ column at 254 nm.

EXAMPLE 51

trans 3-(t4-Air»no-3-(phenylethynyl)-l M-pyra^^

To a solution of 3-(pheiiyieihynyl)- i- l /7-pyrazolo 3,4-tf pyTimidsn-4-amirie (0.5 g, 2, 1 mmol) in dry N,N dimethyllwmamide ( 15 mL) was added C&CQj (1 .0 g, 3.2 mmol) and was stirred for 10 minutes followed by the addition f tnms 5-((methyls li ^' onyl)oxy)- 2-dithian-4-yl benzoate (1.4 g, 4.2 mmol). The reaction mixture heated for 3 hours at 80 ' and then cooled and poured into water. The aqueous solution was extracted with ethyl acetate (3 s 200 mL) and the combined extracts were washed with water, dried over anhydrous Na_S(> , filtered and concentrated at reduced pressure. The pure product was obtained by column chromatography on silica gel ( 100-200 mesh) during with 40% ethyl acetate: hexanes to furnish the title compound as pale brown solid (200 nig. yield 17%). ^! H-NMR iDMSO 400 MHz) 5 8.27 is, I H), 7.90 (d. J = 7.6 Hz, 2H), 7.73-7.64 im, 4H), 7.53-7.47 (trt, 6H), 5.76 (d, J = 2 .Hz, IH), 4. 1 (d, ./ = 7.6 Hz, 2H), 4.35 (dd, = 7.0 .Hz, J ₂ = 5.4 Hz, 1.H ). 3.74 (dd, J, = i .0 Hz, ,h = 7.6 Hz, I H), 3.47 (dd. ./; = 1.2.8 Hz, J = 3.0 .Hz, I H); HPLC (retention time 9.6 minutes, 91.7%), Capcell pack CIS 150*4.6, 3 μ column at 254 nm. EXAMPLE 52

To a solution of trans 3-((4-amino-3-(phenyiethyny]}- I -1 //- rmolo[3,4-djp rifflΐdm-l- l)meth l-L2-#mΐol-ul-4- l- eri2øate· (100 mg, 0.2 ! mmoi) in tetrahydrofuran ( 10 m ^' L) and methanol

(1 m ^' L) was added LiOH (17 mg, 0.42 mmoi) and the reaction mixture was stirred for 3 hours at room temperature. The reaction mixture was quenched with ic water, acidified with citric acid and extracted with ethyl acetate. The extracts were combined, dried over anhydrous N-12SO , filtered and evaporated in vacuo to afford the title compound as a pale yellow solid (40 mg, $ ] %). Ή NMR (D SO- _t i, 400 MHz) δ 8.37 is, J H), 8,08 id, / = 6.0 Hz, !H). 7,61 -7,55 (m, 2H). 7,47-7,40 (m. 3M), 6. 12 (hs, 1 H). 4.62 (m, I H>, 4.51 (dd, ~ 14.5 .Hz, ~ 8.8 Hz, 1 H ), 4.09 (m, 1H), 3.25 fin, ill), 3.09 (d, J - 6.9 Hz. l H); LCMS (retention time 6.8 minutes, 1.7%). Capcell pack CI 8 150*4.6, 3 μ column at 254 nm.

EXAMPLE 53

s 3-({4-Amtiio-3-{phenylethynyl}- 4.W^yi¾zok![3,4^]pyiimidiii-l-yl)methyL l --oxido- l ,2-

To a solution of mm.i 3-((4-amj«o-3-(phenyletiiynyl :{ - 1 W-p>Tazolol ^' 3,4-< jpyri.raidm-l- yl)methyl- 1 ,2-dith lan-4~yl-berm>aie ( 100 tug. 0.21 mmoi) in glacial acetic acid (5 raL) was added 30% hydrogen peroxide (7 mg, 2.2 mmoi) in glacial acetic acid (2 rnL) at 0 ^i:' C and then stirred at room temperature for 16 hours. The reaction mixture was then carefully concentrated to dryness and the solvents were removed by co-distilling with toluene to afford the title compound as a light brown solid {50 mg, 49%). LC S (retention time 7.6 minutes, 55,2%), Capcell pack C1.8 350*4.6, 3 μ column at 254 nm,

EXAMPLE 54

To a solution of 3-icH!cvl i>ymzx>io 3,4-(: jp rinij.din--4-aoiine (2,0 g, 7.7 mmol) and benzo[«?]osazol-2-ansne (3.0 g. l i .5 ninioii in VyV dinietoylfofmamkle (20 mL) was added a solution of NaOH (0.61 g, 15,3 mmol) in water (1.0 mL). The reaction mixture was purged with nitrogen atmosphere and ! , ! ' (bi.sdipheny.ip.oospm^o)fen:ocenepaJjadiiini(li) dtc oride (Pd(dppf)C¾ (0.56 g, 0.76 nrmol) s slowly added at room temperature followed by heating at 120 °C for 1 hours. The reactioii mixture was cooled, poured into ice water and was extracted wit ethyl acetate. The combined organic layer extracts were dried over anhydrous NajSO,;, filtered, and concentrated in vacuo to give a crude oil which was purified by column cinematography on silica gel (100-200 mesh), eliding with 80% ethyl acetate: hexanes mixture to afford the title compound (0.32 g, 16%} as a tight brown solid. Ή NM 400 MHz): 5 13.56 is. iH>, 8.21 is. IH), 7.56 (d, J = 16.S Hz, 2H),

7.43 (dd, J, 2l .0 Hz, _^ 1.2 Hz, 2H), 7.23 (dd, J, 6.4 Hz. /> = 1.6 Hz, 1 H) 1XMS (retention time 3.6 minutes, m/e 268 |M+1)\ 97.5%), Capcell pack CI 8 150*4,6, 3 μ column at 254 nm.

EXAMPLE 55

irons 3-((4-Ammo-3-(2-arm nobe nzofiij oxazol-5-yl)- 1 /-/-p rai'.olo|3,4-a' j yrt midin- 1 -yl )me£hyi)- 1 ,2-

To a solution of 6-(4-arnino tf-pyrazoloi3,4-^ (200 mg, 0.74 inmol) in dry dimethylfonnamide (10 mL) was added (360 mg, 1.1 mmol) and was stirred for K) minutes followed by the addition of nmis 5-{(nie&yisulfonyl ioxy)- ! ,2-dj.t iari-4- l benzoate (480 irtg, L5 mmol). The reaction mixture heated for 3 hours at 80 *C and then cooled and poured into water. he aqueous solution was extracted with ethyl acetate (3 x 200 raL) and the combined extracts were washed with water, dried over anhydrous Na>S04. fiifcred and concentrated at reduced pressure. The pure product was obtained by column chromatography on. silica gel (100- 200 mesh) eluting with 2% methanol in diehioramethane to furnish the title compound as pale brown solid (50 rag, yield 13% ). 'H- MR (DMSO-sk 400 MHz) δ 8.26 (s, 1 H), 7.95 (m, 1 H), 7.86 (d, J = 6.0 H¾, 2H), 7.65 (t, J - 4.0 Hz, 2H), 7.53-7.47 (m, 3H), 7.35 <d, J - 1.2 Hz, I H), 7.1? (dd, 7, - 6.4 Hz, J; = 1.2 Hz, 1 H), 5.83 (m, IH), 4.74 idd, Jr^ U .2 Hz, ,h = 6.0 Hz, I H), 4.72 (dd, J, - 1 1.6 Hz, - 4.4 Hz, IH), 4.49 idt, J _} - 4.0 Hz, = 2.0 Hz, Hi ), 3.74 (dd, J, - 10.0 Hz, h = 4.0 Hz, 2H}, 3.4? dd, 7/ = 6.8 Hz, ₂ = 4,0 Hz, 2H); HPLC (retention time 6.2 minutes, {M+l |\ 82.0%), CapceSl pack CI8 150*4.6, 3 μ column at 254 ran.

EXAMPLE 56

nam 3-((4- A.niino- -i 2-ami oobe nzo[«fl oxazol-5-yJ )- 1 -py razoiol ,4-rfj rinii.di.n- 1 -yl )niethyl)~ j ,2-

To a solution of tram 3-{(4-amino-3-(2-aminobenzo[i/]oxazol-5-yl)- 1 //-p razolo(3,4- £/|pyriOTidin-l-yl}methyl)-l ,2-dithiolan-4-yl benzoate (100 mg, 0.19 mmol ) in teixahydrofuran (60 mL) and methanol ( 1 mL) was added LiOH (16 mg, 0.39 mmol) and the reaction mixture was stirred for 3 hours at room temperature-. The reaction mixture was quenched with ice water, acidified with citric acid and extracted with ethyl acetate. The extracts were combined, dried over anhydrous ajS(¾, filtered and evaporated in vacuo to afford th title compound as a pale yellow solid (60 mg, 34%). R _f =0,3, 10% methanol in dichloromethane); LCMS (retention time 3.7 minutes, 34.7%), Capcel.i pack C I 8 150*4.6, 3 μ column at 254 mil, EXAMPLE 57

urns 3-((4-Amiao-3-(2-ao)inobenzo! ^' i/joxa¾ol-5-yl

oxk - 1 ,2-dithiolan-4-y] benzoate

To a solution of tram 3-{(4-axnint)-3-(2-amii )benzo[rfjoxaz l-5-yi)-l #-pyrazolo(3,4- <i|pyrimidin-l -yl)methyl>- 1 ,2-dithiolan-4-ol (100 mg, 0.24 mmoi) in glacial acetic acid (5 mL) was added 30% hydrogen peroxide (9 mg, 2.7 mmoi) in glacial acetic acid (2 mL) at 0 °C and then stirred at room temperature for 16 hours. The reaction mixture was then carefully concentrated to dryness and the solvents were removed by co-distilling with toluene to afford the title compound as a light brown solid (50 mg, 49%), LCMS (2 diastereomers: retention time 7.3 minutes, 35.0 %, retention time 7.5 minutes, 28.0%), Capcell pack CIS 150*4-6, 3 μ column at 254 am.

BX AMPLE 58

irons 3-((4-Amin.o-3-(2-aniinor^:nzo[ ]osa?oi-5-yi)-l -pyrazo

hy ide

To a solution of trans 3-((4-ainino-3-(2-aml oben2o|<i|oxazol-5-yl)- 1 W-pyra2oio[3,4- <ijpyrimidin-l-yl methyl)- f ,2-dithioia«-4-yi benzoate (100 mg, 0,24 mmoi) in glacial acetic acid (5 mL) was added 30% hydrogen peroxide (9 mg, 2,7 mmoi) in glacial acetic acid (2 mL) at 0 "C and then stirred at room temperature for 16 hours. The reaction mixture was then carefully concentrated to dryness and the solvents were removed by co-distilling with toluene to afford the title compound as a light brown solid (50 mg, 49%), LCMS (2 diastereoroers: retention time 4.3 minutes, 12.0 %, retention time 5.2 minutes, 64.0%), Capcell pack C 18 ! 50*4.6, 3 μ column at 254 nro. EXAMPLE 59

l-( - it ⁾ Riophe!M>xy)-2-iluo«*enzene

io a solution, containing 2-tluorophenoJ (10 g, 89,2 mmol), copper (i) bromide ( 1 ,3 g, 107,0 mrnol ) and potassium ten butoxide (1 1.0 g, 98.1 mmol) in dry A^N di.meihyifonnan-ide i ^' 80 rnL) was heated for 4 hours at 50 °C and then, cooled to room temperature. The reaction, mixture was filtered through eelite and flic filtrate was dissolved in ethyl acetate and washed with brine and wafer. The combined organic extracts were dried over anhydrous NajSO.i, fiitered and evaporated iii vacuo to afford a crude compound which was purified by flash chromatography on silica gel (100-200 mesh) eluting with 40% ethyl acetate in exanes to afford the title compound as an off white solid (2.6 g, 1 5 %). ^S H-NM (CDCh, 400 MHz) δ 7.41 (d, / = 9.0 Hz, 2H), 7.18 (m, I H), 7.12 (m, 2H), 7.07 (in, IH), 6.85 (d, J - 9.0 Hz, 2H).

EXAMPLE 60

( 4-i 2 -Fl uoroph en l jboronic aei ά

To a solution of I -(4-bromophenoxy)-2-lluoroben2ene (10 g, 37.4 mmoi), in tetrahydtx>furan (150 mL) at -78 "C was added n-batyllithium (2,5 M, 22.4 mL, 56,2 mmol) and th reaction mixture was stirred at that temperature- for 1 hour. Triisopropyl borate ( 10.3 g, 44,9 mmol) was then added and the reaction was allowed to warm up to room temperature with stirring for 6 hours. The reaction mixture was then quenched with a saturated .solution of ammonium chloride and concentrated under reduced pressure. The resultant residue was diluted with an aqueous solution of 3 % KOH and neutral ized to pH 2-3 with dilute HQ. The resulting solution was extracted with ethyl acetate and the combined extracts were dried over anhydrous N¾iS(¼. filtered and evaporated in. vacuo to afford a crude compound which was purified by flash chromatography on silica gel ( 100-200 mesh) eluting with 40% ethyl acetate in hexanes to afford the title compound as art off white solid i ^' 2,6 g, 1 1 '¾ ). Ή- NMR (CDt¾, 400 MHz) 6 8. 1 (d, / = S.6 Hz, 2H), 7.20 (m, 4H), 7.06 id, J = 8.6 Hz, 2H). EXAMPLE 6 i

3-( -(2-Huorophfinoxy)p.heflyl-:i^

To a solution containing 3-iodo- f i/-pyxazoloP.4-< ]pyri«Md«i-4-amiae (3,0 g, I 1.5 romoi) and (4-(2-iliK>rophenoxy)phenyl)boronic acid in KN dimethylfonxutftode (20 mL) was added NaOH (900 mg, 22.9 trtmof). The reaction mixture was purged with nitrogen atmosphere and ί, {bisdfphciiyipiKLSphi o)ferrocciiepail diimi(Ii) dichloride (Pd(dppf)C ΐ 840 rag, 1 . 1 mmol) was slowly added at room temperature followed by beating at 1 0 °C for 16 hours. The reaction mixture was cooled, filtered through eeiite and then poured info ice water and was extracted with ethyl acetate. The combined organic layer extracts were dried over anhydrous Na_SO* and ccmcenirated in vacuo to give a crude oil which was purified by column chromatography on silica gel (100-200 mesh), eiuting with 50% ethyl acetate: hexanes mixture to afford the title compound (500 rag, 13.5%) as a light brown solid. Ή NMR ( DMS0-< 400 MHz): 5 13.55 (s, IH), 8.21 is, 1H), 7.? ! im, 2H), 7.66 (d, 8.6 Hz, 2H), 7.44 (m, H), 7.29 (m, 3H), 7, 12 (m, V » 8.4 Hz, 2H).

EXAMPLE 62

trans 3-((4- Amino-3-{4-( 2-i¾iorophenoxyphen yJ)- ! / -pyrazoiop,4-iijpyrimidin- 1 -yi) methyl)- 5 ,2- dithiol an -4- l be nzoate

To a solution of 3-(4-(2-fluorophenoxy)phenyl-l //-pyntzolo 3,4-<i|pyrimtdm-4-amine (500 mg, 1.6 mmol) in dry N,N dimethylformamide ( 15 mL) was added CsjCOs (750 mg, 2.3 mmol) and was stirred for 30 minutes followed by the addition of trans 5-((methylsulfonyi)oxy)-l,2-dkhian-4-yi benzoaie ( 1.03 g, 3. Ϊ mmol). The reaction mixture heated for 3 hours at 80 ^t; C and then cooled and poured into water. The aqueous solution was extracted with ethyl acetate (3 x 200 mL) and the combined extracts were washed with water, dried over anhydrous Na?J504, filtered and concentrated at reduced pressure. The pure product was obtained by column chromatography on silica gel ⁽ 100-200 mesh) ei tit!g with 50% ethyl acetate in hexanes to furnish the fifle compound as pale brown solid 000 mg, yield 35%). * H-NMR (DMSC 400 MHz) δ S.26 {s, 1H), 7.95 fin, i.H), 7.86 (d, ./ = 6,0 Hz. 2H), 7.65 (t, J = 4.0 Hz, 2H>, 7.53-7.47 im, 3H >, 7.35 id, 7 = 1.2 Hz, 1 H .), 7.Π kid, = 6.4 Hz, Js ^ 1.2 Hz, 1H), 5.S3 (ra, 1H), 4.74 (dd, - i l .2 Hz, . j = 6.0 H&, 1 H), 4.72 (dd, J.< = 1 1.6 Hz, /> = 4.4 Hz, 1H), 449 idt, J, ^ 4.0 Hz, J ₂ = 2.0 Hz, 1 H ), 3.74 (dd, 10.0 Hz, J; = 4.0 Hz, 2H ), 3.4? (dd, J) - 6.8 Hz, Jj - 4.0 Hz, 2H); HPLC (retention time 10.0 minutes, |.M+iV\ 85,0%), Capcell pack C [8 150*4.6, 3 μ column at 254 tmi.

EXAMPLE 63

trans 3- (4-Amino-3-(4-(2-fluorophenoxyphenyi)- 1 //-pyra-X>lo|3,4-«f3pyrimidin-i-yl)methyl)- 1 ,2- dkhioian-4-ol

To a solution of mw« 3-((4-βηιίϊίο-3-(4-(2-β«οιχ>^δϊίοχνρ¾ δϊί>Ί)-1 /-ρνι·3ζο1ο[3,4- rf]pv ijmidm-l-yl)n5!ea y )-l,2-dithiolan-4-yl benzoate (200 rog, 0,35 mmol) in tetrahydrofiiran (10 mL) and methanol (1 roL) was added LiOH (20 nig, 0,71. mmoi) and the reaction mixture was stirred for 3 hours at room temperature. The reaction mixture was quenched with tee water, acidified with citric acid and extracted with efliyi acetate. The extracts were combined, dried over anhydrous aiSOi, filtered and evaporated in vacuo to afford the tide compound as a pale yellcsw solid (90 trig, 57%). ¾ NMR (CDC .,400 MHz) δ S.35 is, ill), 8.09 (d, J - 7 J Hz, ill), 7.63 (d, J ^ S.6 Hz, 1H), 7.60 (d, J - 8.6 Hz, 1H), 7.4? (in, 1H), 7.21 (m, 4H), 7.14 (d, 8.6 Hz, 2H), 4.68 (in, iH). 4.62 (m, 1 H), 4.54 (dd, Λ * 14.5 Hz, J ₂ = 9.0 Hz, 2H), 4.09 (m, 1 H), 3.51 (m, 1 H), 3.25 (dd, = 1 1.6 Hz, = 2.3 Hz, 1H); MS : ro/e 456{M+l.j ^* ; 1XMS (retention time 6.0 minutes, 77.4%), Capcell pack CI S 150*4.6, 3 μ column at 254 urn. EXAMPLE 64

4-Bromo-2-fluoro- ! -phenoxbenzene

To a solution, containing 4d>rc iio-241uorophen.oi (10.0 g, 52.7 mmol), phenyl horonic acid

(193 g, 157.9 mmol), copper (11) acetate (1.2 g _< 5.8 mmol) and triethvl amine (36.7 mL, 263.3 mmol) in diehioroniethane ( ^' 200 mL) was stirred at room temperature for 1.6 hours. The reaction mi ture was filtered through ceiite and the filtrate was washed with brine and water. The combined organic extracts were dried over anhydrous a^SO filtered and evaporated in vacuo to afford a crude compound which was purified by Slash chromatography on silica gel (100-200 mesh) elating with 5% efhyi acetate in hexanes to afford the title compound as an off white solid (4.1 g, 1 1 %). Ή NM (CDCb, 400 MHz) 5 7.35 im, 2H), 7.24 (d, J « 1.6 Hz, I H), 7.21 im, IH), 7.1 1 (t, J = 7.6 H¾, IH), 6.96 (m, 3H).

EXAMPLE 65

(3- c acid

To a solution of 4-bron >-2-tluoro-l -phenoxbenzene ( 10 g, 37.4 mmol), in tetrahydrofuran ( 150 mL) at -78 ^: C was added «-butyHhhium (2.5 M. 22.4 mL, 56.2 ramol) and the reaction mixture was stirred at that temperature for 1 hour. Triisopropyl borate ( 10.3 g, 44.9 mmol) was then added and the reaction was allowed to warm up to room temperature with stirring for 6 hours. Th reaction mixture was then quenched with a saturated solution of ammonium chloride and concentrated under reduced pressure. The resultant residue was dilated with an aqueous solution of 30% OH and neutralized to pH 2-3 with dilute HQ. The resulting solution was extracted with ethyl acetate and the combined extracts were dried over anhydrous Na.S<>4, filtered and evaporated in vacuo to afford a crude compound which was purified by flash, chromatography on silica gel (100-200 mesh) eiuting with 30% ethyl acetate in hexan.es to afford the title compound as an off white solid (3,9 g, 45%), 'H-NMR (CDCb, 400 MHz) δ 8, 1.6 (d, J - 8,6 Hz, 2H), 7.20 (m, 4H). 7.06 (d, J = 8,6 Hz, 2H); LCMS (retention time 6.9 minutes, 82.5% ), Capcell pack. C 18 150*4.6, 3 μ column at 254 am. EXAMPLE 66

3-(3-FIu©ro-4-phenoxyp.henY!- f i/-pytazoloP,4^]pyrijtmdm- -amine

To a solution containing 3-jodo-lH-pyrazoloi3,4-rfjpyrimidin-4-ansne (2.0 g, 7.7 mmoJ) and (3-fltioro-4-p enoxyp eny!)boi-onic acid in A'„¥ dimemyltormamide (15 nil.) was added NaOH (610 nig, 15,3 nun l). The reaction mixture was purged with nitrogen atmosphere and h i ^' (bisdtphenylp osphino)fefrocenepaJladi«niOi) dicMorsde (P (dppf)C (560 mg, 0.77 roroo!) was slowly added at room temperature followed by heating at 120 °C for 1 hours. The reaction mixture was cooled, filtered through celite and then poured into ice water and was extracted with ethyl acetate. The combined organic layer extracts were dried over anhydrous and concentrated in vacuo to give a crude oil which was purified by column chromatography on silica gel i 100-200 mesh), eluting with 50% ethyl acetate: hexanes mixture to afford the title compound (450 rug, 18.2%) as a light yellow solid. LCMS (retention time 7.3 minutes, 95.5%), Capcell pack C 18 150*4.6, 3 μ column at 254 am.

EXAMPLE 67

traits 3-ii4-Amino-3-(3-(3-fiuotx>-4-phenoxyphenyi)-I/^

benzoate

To a solution of 3-(3-fluoro-4-phenoxyphenyl- 1 W-pyras«>}ol ^' 3,4-<ijpyriraidin-4-aimne (500 rag, 1.6 raraol) in dry N,N ditnethySformatnide ( 10 raL) was added CsiCO.i (750 rog, 2.3 mmol) and was stirred for 10 minutes followed by the addition of trans 5-((me$lrylsulfonyl)oxy)- 1 ,2-duhian-4-yl benzoate (1.03 g, 3.1 mmol}. The reaction mixture heated for 3 hours at 80 ^C C and then cooled and poured into water. The aqueous solution was extracted with ethyl acetate and the combined extracts were washed with water, dried over anhydrous ajSO*, filtered and concentrated at reduced pressure. The pure product was obtained by column chromatography on silica gel (100-200 mesh) eluting with 40% ethyl acetate in fiexanes to furnish the title compound as pak brown solid (200 mg. yield 23%), Ή-NM (DMSO-ii, 400 MHz) δ 8.41. (s, I H), 8.02 (bs, 3H), 7.88 (d, / = 6.0 Hz, 2M), 7.55-7,34 (m, lOH), 7. 15 (dd, Js = 8. Hz, J _z = 7.2 Hz, I H), 7.05 (d, J = 6.4 Hz. 1H). 5.43 (bs, i.H), 4.83 (d. J = 7.8 Hz. 2H), 4.40 (f , ./= 4.0 Hz, 1 H ), 3.74 (dd, J> = 10.0 Hz, J ₂ ~ 4.4 Hz, IH), 3.29 (d, Jj = 6.0 Hz, IH); HPLC (retention lime 10.7 minutes, jM+ i f, 95.0%), Capcell pack CI S 150*4.6, 3 μ column at 254 am.

EXAMPLE 68

trims 3-( {4-Amino-3-(3-( -ilitoro-4-pheuoxypheuyi )- i -i-pyrazolo[3,4-£ijpyrinvidit)- ί -yl imethyl)- i ,2-

To a solution of tram 3-i(4-afflino-3-(3-(3-fl ^' uofo-4-phenox ^' yphenyi)- 1 / -pyrazolof 3,4- <i|pyrimidin- 1 -yl)methyl>- 1 ,2-dithiolan-4-yl benzoate (100 mg, 0. 17 mmoi) in tetrahydrofuran (10 mL) and methanol (1 mL) was added an aqueous sokition of LiOH (20 mg, 0.71 mmoi ) in water (2 mL) and the reaction mixture was stirred for 3 hours at room temperature. The reaction mixture was quenche with ice water, acidified w ith citric acid and extracted with ethyl acetate. Tfie extracts were combined, dried over anhydrous filtered and evaporated in vacuo to afford the title compound as a pale yellow solid (30 mg, 31%); LCMS (retention time 7, 15 minutes, 53%), Capcell pack C18 1 0*4.6, 3 μ column at 254 nm.

FORMULATIONS

Tlie present invention also relates to compositions or formulations which comprise the kinase inhibitors according to the present invention. In general, the compositions of the present invention comprise an effecti ve amount of one or more 1 ,2-dithiolane and salts thereof according to the present invention which are effective for providing treatment or prevention of diseases that involve modulation of tyrosine kinases including N Ts such as SRFs and Tec and, RTKs such as FLT3, RET, FR families. Said diseases include, for example, neurodegeneraf.ion, neuroprotection, Alzheimer's disease, ischemic stroke, autoimmune diseases, T-cell disorders, cancer such as, melanoma, adenocarcinoma, carcinoma, leukemia, chronic lymphoblastic leukemia, acute myeloid leukemia, adenocarcinoma, thyroid cancer, papillary thyroid carcinoma, medullary thyroid carcinoma, non-small cell lung cancer, small ceil lung cancer, glioblastoma multiforme, colon, breast, prostate, testicular cancer malignant peripheral nerve sheath tumors. The method comprises administering to a subject an effective amount of a compound or composition, according to the present invention and an exeipient

For the purposes of the present invention the terns "exeipient" and "carrier" are used interchangeably throughout the description of the present invention and said terms are defined herein as, "ingredients which are used in the practice of formulating a safe and effecti ve pharmaceutical composition."

The forraulaior will understand that exeipients are used primarily to serve in delivering a safe, stable, and functional pharmaceutical, servin not only as pan of the overall vehicle for delivery but also as a means for achieving effective absorption by the recipient of the active ingredient. An exeipient may fill a role as simple and direct as being an inert filler, or an exeipient as used herein ma be part of a pH stabilizing system or coating to insure delivery of the ingredients safely to the stomach. The iormulator can also take advantage of the fact the compounds of the present invention have improved cellular potency, pharmacokinetic properties, as well as improved oral bioavailability.

The present teachings also provide pharmaceutical compositions that include at least one compound described herein and one or more pharmaceutically acceptable carriers, exeipients, or diluents. Examples of such carriers are well known to those skilled in the art and can be prepared in accordance with acceptable pharmaceutical procedures, such, as, for example, those described in Retnington 's Pharmaceutical Sciences, 17th edition, ed. Alfonoso R. Ciennaro, M ck Publishing Company, Easton, PA (1985), the entire disclosure of which is incorporated by reference herein for all purposes. As used herein, ^pharmaceutically acceptable" refers to a substance that is acceptable for use in pharmaceutical applications from a toxicoiogical perspective and does not adversely interact with the active ingredient. Accordingly, pharmaceutically acceptable carriers are those that are compatible with the other ingredients it! the formulation and are biologically acceptable. Supplementary active ingredients can als be incorporated into the pharmaceutical compositions.

Compounds of the present teachings can be administered orally or parentera!iy, neat or in combination with conventional pharmaceutical carriers. Applicable solid carriers can include one or more substances which can also act as flavoring agents, lubricants, soiubifeers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents, or encapsulating materials. The compounds can be formulated in conventional manner, for example, in a manner similar to that used for known kinase inhibitors. Oral formulations containing a compound disclosed herein can comprise any conventionally used oral form, including tablets, capsules, buccal forms, troches, lozenges and oral liquids, suspensions or solutions. In powders, the carrier can be a finely divided sol id, which is an. admixture with a finely divided compound, in tablets, a compound disclosed herein can be mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets can contain tip to 99% of t he compound. Capsules can contain, mixtures of one or more compound(s) disclosed herein with inert fil!er(s) and/or dsluent(s) such as pharmaceutically acceptable starches (e.g.. corn, potato or tapioca starch), sugars, artificial sweetening agents, powdered celluloses {<?.¾., crystalline and oiierocrystalh tie celluloses), flours, gelatins, gums, and the like.

Useful tablet formulations can he made by conventional compression, wet granulation or dry granulation methods and utilize pharmaceutically acceptable diluents, binding agents, lubricants, di&imegrams, surface modifying agents (including surfactants), suspending or stabilizing agents, including, but not. limited to, magnesium stearate, stearic acid, sodium lauryi sulfate, tale, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, mieroerystaiiine cellulose, sodium carboxy methyl cellulose, carboxytnethyScellulose calcium, poiyvin lpyrrolidine, a!ginie acid, acacia gam, xanthan gum, sodium citrate, complex silicates, calcium carbonate, glycine, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitoi, sodium chloride, low melting waxes, and ion exchange resins. Surface modifying agents include nonionic and anionic surface modifying agents. Representative examples of surface modifying agents include, but are not limited to, poloxamer 188. henz.aikoni.um chloride, calcium stearate. cetosteafJ. alcohol, cetomacrogol emulsifying wax, sorbitan esters, colloidal silicon dioxide, phosphates, sodium dodecylsulfate, magnesi um aluminum silicate, and ttiethanoiamine. Oral formulations herein can utilize standard delay or time-release formulations to alter the absorption of the eoiiipound(s). The oral formulation cat! also consist of administering a compound disclosed herein, in water or fruit juice, containing appropriate solubilizers or emulsifiers as needed.

Liquid carriers can be used in preparing solutions, suspensions, emulsions, syrups, elixirs, and for inhaled delivery. A compound of the present teachings can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an. organic solvent, or a mixture of both, or a pharmaceutically acceptable oils or fats. The liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosit regulators, stabilizers, and osmo-regulators. Examples of liquid carriers for oral and parenteral administration include, but are not limited to, water (particularly containing additives as described herein, e.g., cellulose derivatives such as a sodium carbox methyl cellulose solution), alcohols (including monohydrie alcohols and polyhydric alcohols, e.g.. glycols) and their derivatives, and oils ⁽ e.g., fractionated coconut oil and arachis oil). For parenteral administration, the carrier can be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration. The liquid carrier for pressurized compositions can be haiosenateci hydrocarbon or other pharmaceutically ace cpta bl e prope Hani s.

Liquid pharmaceutical compositions, which are sterile solutions or suspensions, can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. Compositions for oral administration can be in either liquid or solid torso.

Preferably the pharmaceutical composition is in unit dosage form, for example, as tablets, capsules, powders, solutions, suspensions, emulsions, granules, or suppositories. In such form, the pharmaceutical composition can be sub-divided in unit dose(s) contai ning appropriate quantities of the compound. The unit dosage forms can be packaged compositions, for example, packete i powders, vials, ampoules, prefilled syringes or sachets containing liquids. Alternatively, the unit dosage form can be a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form. Such unit dosage form can contain from about 1 tng/kg of compound to about 500 nig/kg of compound, and can be given in a single dose or in two or more doses. Such doses can be administered in any maimer useful in directing the compound! ^' s) to the recipient's bloodstream, including orally, via implants, parenteraily (including intravenous, intraperitoneal and subcutaneous injections), rectally, vaginally, and transdermally.

When administered for the treatment, or inhibition of & particular disease state or disorder, it is understood that an effective dosage can vary depending upon the particular compound utilized, the mode of administration, and severity of the condition being treated, as well as the various physical factors related to the individual being treated, in therapeutic applications, a compound of the present teachings can be provided to a patient already sufferi ng from, a disease in an amount sufficient to cure or at least partially ameliorate the symptoms of the disease and its complications. The dosage to be used in the treatment of a specific individual typically must be subjectively determined by the attending physician. The variables involved include the specific condition and its state as well as the size, age and response pattern of the patient,

in some cases if may be desirable to administer a compound directly to the airways of the patient, using devices such as, but not limited to. metered dose inhalers, breath-operated inhalers, muitidose dry-powder inhalers, pumps, squeeze-actuated nebulized spray dispensers, aerosol dispensers, and aerosol nebulizers. For administration by intranasal or intrabronchia! inhalation, the compounds of the present teachings can be formulated into a liquid composition, a solid composition, or an aerosol composition. The liquid composition can include, by wa of illustration, one or more compounds of the present teachings dissolved, partially dissolved, or suspended in one or more pharmaceutically acceptable solvents and can be administered by, for example, a pump or a squeeze- actuated nebulized spray dispenser. The solvents can be, for example, isotonic saline or bacteriostatic water. The solid composition can be, by way of illustration, a powder preparation including one or more compounds of the present teachings intermixed with lactose or other inert powders that are acceptable for intrabronchial use, and can be administered by, for example, an aerosol dispenser or a device that breaks or punctures a capsule encasing the solid composition and delivers the solid composition for inhalation. The aerosol composition can include, by way of illustration, one or more compounds of the present teachings, propellents, surfactants, and co-solvents, and can be administered by, for example, a metered device. The propel.iants can be a cMorofluorocarbon (CFC), a hydrofinoroalkarte (KP.A), or other psrope!iants that are physiologically and environmentally acceptable.

Compounds described herein can be administered parenierally or intraperitoneal!)'. Solutions or suspensions of these compounds or a pharmaceutically acceptable salts, hydrates, or esters thereof can be prepared in water suitabl mixed with a surfactant: such as hy iro yh-propyiceiiuio e. Dispersions can also be prepared in glycerol, liquid polyethylene g!ycois, and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations typically contain a preservative to inhibit the growth of microorganisms.

The pharmaceutical forms suitable for injection can include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In some embodiments, the form can sterile and its viscosity permits it to flow through a syringe. The form preferably is stable under the conditions of manufacture and storage and can be preserved against the contaminating action, of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, etbanol, po!yol (e,g,, glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

Compounds described herein can. be administered transdermaily, i .e., administered across the surface of the body and die inner linings of bodily passages including epitheltal and mucosal tissues. Such administration can be carried out using the compounds of the present teachings including pharmaceutically acceptable salts, hydrates, or esters thereof, in lotions, creams, foams, patches, suspensions, solutions, and suppositories {rectal and vaginal).

Transdermal administration can be accomplished through the use of a transdermal patch containing a compound, such as a compound disclosed herein, and a carrier that can be inert to the compound, can be non-toxic to the skin, and can allow delivery of the compound for systemic absorption into the blood stream via the skin. The carrier can take any number of forms such as creams and ointments, pastes, gels, and occlusive devices. The creams and ointments can be viscous liquid or semisolid emulsions of either the oil-in-water or water-in-oil type. Pastes comprised of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the compound can also be suitable. A variety of occlusive devices can be used to release the compound into the blood stream, such as a semi -permeable membrane covering a reservoir containing the compound with or without a carrier, or a matrix containing the compound. Other occlusive devices are known in the literature.

Compounds described herein can be administered rectally or vaginally in the form of a conventional suppository. Suppository formulations can be made from traditional materials, including cocoa butter, with or without the addition of waxes to alter the suppository's rneifing point, and glycerin. Water-soluble suppository bases, such as polyethylene gl cols of various molecular weights, can also be used. Lipid formulations or nanoeapstiJ.es can be used to introduce compounds of the present, teachings into host ceils either in vitro or in vim Lipid formulations and nanocapstiJ.es can be prepared by methods known in the art.

To increase the effectiveness of compounds of the present teachings, if can be desirable to combine a compound with other agents effective in the treatment of the target disease. For example, other active compounds {i.e., other active ingredients or agents) effective in treating the target disease can be administered with compounds of the present teachings. The other agents can be administered at the same time or at different times than the compounds disclosed herein.

Compounds of the present teachings can be useful for the treatment or inhibition of a pathological condition or disorder in a mammal fo example, a hitman subject. The present teachings accordi ngly provide methods of treating or inhibiting a pathological condition or disorder by providing to a mammal a compound of the present teachings including its pharmaceutically acceptable sail) or a pharmaceutical composition that includes on or more compounds of the present teachings in combination or association with pharmaceutically acceptable carriers. Compounds of the present teachings can be administered alone or in combination with other therapeutically effective compounds or therapies for the treatment or inhibition of the pathological condition or disorder.

Non-limiting examples of compositions according to the present invention, include from about 0.001 mg to about 1000 trig of one or more compounds of the disclosure according to the present invention and one or more exeipients: from about 0.01. trig to about 100 mg of one or more compounds of the disclosure according to the present invention and one or more excipients; and from about 0.1 mg to about 10 mg of one or more compounds of the disclosure according to the present invention and one or more excipients.

BIOLOGICAL ACTIVITY

The following are abbreviations used in this section:

qPCR- quanti tative polymerase chain reaction

BSA- bovine serum albumin

DTT- dithiothreitoi

PBS- phosphate buffer saline

TWEEN 20- polyethoxylated sorbttan and oleic acid

He pes - 4- (2 -hyd ro x yet h y Ϊ )- 1 - p i perazi nee th an esul f n i c acid

EGTA-ethyiene g!yco!-b!S(2-aminoethy.l ether /V, v V ^' .. "-tetraacetic acid

Brij 35- poiyoxyeihyleneg!ycoi dodecy! ether

ATP- adenosi e triphosphate

ADP-adenosine diphosphate

Kiii-Michaclis constant

The compounds of this invention are tested in the following Standard Pharmacological Test Procedures.

Methods for in Vitro Evaluation

Assays kiiowii in ihe art for testing compounds are used to test compounds of tilts invention and to assess the biological activities. In order to suppoit that this invention described herein, i he following biological a sa s are set forth. Examples are for illustrative purposes only and are not me to be limiting.

Representative compounds of this invention, when tested in the assays described below demonstrated a binding constant d (nM) or IC.% activity level (nM) as set forth in tables 5-22 wherein:

"A" refers to a Kd or ICss activity level of < 5 nM;

"B" refers to a Kd or K¼e activity level of from 5 nM to 99 nM;

"C refers to a Kd or K¾ activity level of from i(K) nM to 999 nM;

"D" refers to a Kd or IC* activity level of 1,000 to 10,000 nM.

Data in fables 5-7 were obtained in the rabbit reticulocyte lysate assay. Data in tables 8-12 were obtained in the KfNO Brau*™ assay. Data in tables 13-20 were obtained in the radioisotope filter binding assay. Data in table 1 were obtained in kinase binding assay CaPBA and data in table 22 were obtained in radiometric ^PanQinase ¹ ' ^" assay,

1. Rabbit Reticulocyte Lysate Assay Design: Kin xeSeckcr is a homogeneous competition binding assay where the displacement of an active site dependent probe by an inhibitor is measured by a change in luminescence signal. Luinincscenec readout translates into a highly sensitive and robust assay with low background and minimal interference from test compounds.

10 mM stock .solutions of test compounds were serially diluted in DMSO to make assay stocks. Prior to initiating ICso determinations, the test compounds were evaluated for false positive against spiit-lueiferase.

Each test compound was screened in duplicate against target kinase at 7 different concentrations. For kinase assays, Cfiiie-kinase was translated along with Fos-Niluc using a cell-free system (rabbit reticulocyte lysate) at 30°C for 90 rain. 24 uL aliquot, of this lysate containing either I uL of DMSO (for no-inhibitor control) or compound solution, in DMSO was incubated for 30 minutes at room temperature followed by 1 hour in presence of a kinase specific probe, 80 uL of Juctferin assay reagent was added to each solution and luminescence was immediately measured on a iuminometer.

The % Inhibition and % Activity Remaining was calculated using the following equation: % Inhibition = [(ALUQ,™,,? - ALUs»»pfe) ALUGHKRS] X. 100

% Activity Remaining = 100 ·· % Inhibition

The % Activity was plotted against compound concentration and. the IC$o was determined for each compound usi g a 7-point curve (Jester, B. . ; et. l. J. Am. Che . Sac. 2010, 132, I J 727- ί. 1735, Jester, B.W., i. al J. Med. Ciuwn. 2012, 55, 1526-1537). Biological activity of representati ve compounds of the disclosure are described in Table 5.

Table 5. IC.w Activity Levels Against SRC Family Kinases in nM

Table 6, % Inhibition Against SRC Family Kinases at 1

Compounds Compound ame SRC CSK PGR FY YES i HCK LYN Of

Example #

33 A. (35,4 i)-3-{{4-a:mino-3-{4- 12 6 y 15 52

methoxyphenyl)- i /·/- pyrazoioj 3,4~i/jpyri«iidm- i - yDmethyi )- ί ,2-dithioian-4-al

33 B. (3#,4S)-3-((4-amino-3-(4- 12 6 3 6 13

methoxypheny 1 )- 1 H- {>yraz{tlo[3,4-(:/]pyrtniidi.tv-l - yl}methyl)--,2-dithiolaii-4-oi

44 A. i ^' 3S,4/ )-3-i{4-£tmiiio-3-(4- 49 50 84 33 90 73 33 phenoxyptienyi)- 1 H- pyrazo i j 3 A-d] pyxins d\n-l- yDmethyi)- ! ,2-dithiolan-4-ol

43 B. (3/<',4S)-3-{{4-a:mino-3-{4- 70 57 phenoxyphenyl )- 1 //·

pyrazoioj 3,4~i/jpyri«iidm- 1 - yDmethyl H ,2-dtthioian-4-oi Table 7. iCsc> Activity Levels Against Bruton Tyrosine Kinase in oM

2. ina e assay (Kd): . iNO Esriwi™ is based on a competition binding assay ihat quantitatively measures the ability of a test compound of the invention to compete with an immobilized, active-site directed !igand. The Kinase assay is performed by combining three components: DNA-tagged kinase; immobilized ligand; and a test compound. The abiiity of the test compound to compete with the immobilized !igand is measured via quantitative PGR of the DNA tag.

For most assays, kinase-tagged T7 phage strains were prepared in an E. coli host derived from the BL21 strain. £ ^' . coli were grown to log-phase and infected with 17 phage and incubated with shaking at 32%: until lysis. The l sates were cenirifuged and filtered to remove ceil debris. The remaining kinases were produced in HEK-293 cells and subsequently tagged with DNA for qPCR detection. Streptavidin-coated magnetic beads were treated with biotinylated small molecule ligands for 30 minutes at room temperature to generate affinity resins for kinase assays. The !iganded beads were blocked with excess bkrtin and washed with blocking buffet (SeaBlock (Pierce), \ % BSA, 0.05% Tween 20, 1 mM DTT) to remove unbound ligand and to reduce nonspecific binding. Binding reactions were assembled by combining kinases, iiganded affinity beads, and test compounds in ix binding buffer {20% SeaBlock, 0.17x PBS, 0.05% Tween 20. 6 inM DTT). Ail reactions were performed in polystyrene 96-well plates in a final volume of 0435 ml. The assay plates were incubated at room temperature with shaking for 1 hour and the affinity beads were washed with wash buffer (lx PBS, 0.05% Tween 20). The beads were then re-suspended in eiution buffer (Ix PBS. 0.05% Tween 20, 0.5 μΜ non-biotinylated affinity ligand) and incubated at room temperature with shaking for 30 minutes. The kinase concentration in the eiuates was measured by PCR. Table 8. Kd Values in nM Against Representative TEC Family inases

Table 9. Kd Values in nM Against Representative MEK5 Kinase Compounds Compound Name ΜΈ 5 Of Example

#

1 2'-di£hiolan-4»o.i

37 trims 1 -((4-methoxy-l ,2-dithiolan-3- A yl)methyi)-3-(4-phenoxy phenyl)- 1 - py razoiof 3 ,4-rf]pyri midin-4-aimiK!

38 li f.H ^' (4-medioxy-l,2-dkhiolan-3- A

yi)methyl )-3-(4-phenoxyphenyl }- 1 H- p razoio 13 ,4-< | py ri mi di n -4-amme

39 trans 1 ~((4-(benzyio.xy>- f ,2-dith.ioian-3- B

yl)methyl)-3-(4-phenoxypheoy! -lH- py n\/.x >lo f 3.4 -d] py d i din- 4 - am i ne

40 cis 1 H(4-( enzyloxyH ,2-dithiolan-3- B yi )«iethyl)-3-(4-p enoxy-p enyi)- ! Ff- pyrazo ioj 3,4 -d] pyrum di n-4-a m ine

43 A. {3&4 ?)-3 -((4-ainmo-3 -{4-pheiioxypheiiyl)- A

1 -/-pyTazoi o f 3 ,4-f / j pyri midin - 1 - yl )met:hy t)~ l ,2-dithioian-4-ol

Table 10. Kd Values; in iiM Against loTOR Kinase

Compounds Compound Name niTOR Of Example

#

36 B. (3 f _> 4i?)-3-{{4-aoiini>3-(4-i»alM>xyplienyl)- C lff-pynizolof3,4-i/|pyriiiiidiii- l -yltiiici yi)- 1 ,2-dithioian-4-oi

37 irans I -((4-metbosy-l .2-dithi.oian-3- D

yl)merhyl)-3-(4-phenoxypheny lff- pyf¾zoloi3,4-iijpyiim!dtn-4-aniine

43 A. (35,4i? --3-{(4-ani.mo--3-(4-phenoxyphenyl}- D

! /-i-pyra2oio 3,4-ii]pyrimidin- 1 ·\ i mwtiiyl )-- ! ,2-tSithioian-4-oi

43 B. (3-? _> 45)-3-((4-an«.no-3-(4-phenoxypheny ^} )- C lff-pynizolof3,4-i/|pyriiiiid:iii- l -yltiiici yi)- l 2-dit k>Ian-4-oI SAB29? Compounds, Compound Name m ^' TOR Of Exam le

#

46 A. 35.45)-3-{(4-3ΐηϊικ»-3-{4-ρ1κ;ικ»χ ρ1κ;η>·1.)- C

l. i-pyra? ilo3,4-rfjp iimjdiii-l- l)Htethy].)-

K2-diEhioian-4-c)i

46 B. (. ^: 5-? _> 4/i)-3-((4-amino-3-(4-phenoxyphenyi)- c

i 2-ditb:ioia«-4-oi

Tabic 51. Kd Values in nM Against MAPK Pathway Kinases

Table 12. K ^' d Values in nM Against MEK Kinases Isoforms

3. Radioisotope Filter Binding Assay: in this assay format, it directly detects the true product without the use of modified substrates or coupling enzymes (Uiidehaag, J.C., et at. Br. . Pharmacol. 2012, 166, 858-876; Hasiie, C.J., et at N l. Proloc. 2006, 1, 968-971) according to equation i .

Substrate + ! P] - ATP P-Substrate + ADP eq I

Toe protocol calls for test compound of the invention to be incubated with kinase, substrate, cofactors, and radio-isotope -labeled ATP ( ^w P-gamma-A P). The reaction, mixtures are then spotted onto filter papers which bind the radioisotope labeled catalytic product, Urtreacted phosphate is removed via washing. The reagents used include base reaction buffer, 20 raM Hepes (p.H 7.5), 1.0 rnM MgCl2, 1 niM EGTA, 0.02% Brij35, 0.02 rng/ioi BSA, 0. 1 mM NajVO,, 2 raM DTT, 1% DMSO. The reaction procedure include the following steps: (1) prepare indicated substrate in freshly prepared base reaction buffer, i ^' 2) deliver any required cefaclors to the substrate solution above, (3) deliver indicated kinase into the substrate solution, and gently mix, (4) deliver compounds in DMSO into the kinase reaction mixture by Acoustic technology (BchoSSO: nanohter range), mclubate for 20 minutes at room temperature, i ^' 5) deli ver (specific activity i.O μΟ/μΤ into die reaction mixture t initiat the reaction, (6) incubat kinase reaction for 2 hours at room temperature, (7) reactions are spotted ont P81 ion exchange paper, (8) detect kinase activity by filter-binding method. Table 13. iC¾ Activity Levels Against SRC Family Kinases in nM

Compounds, Compound ame SRC YES1 PGR FYN BLK LC HC LYN CS Of

Exam pie #

37 trans }.-({4-methoxy- B

1 ,2-dt thioian -3- yl)methyi)-3-(4- phenoxyphenyi )- iH- pyrazoio(3,4- ifjpyrimidin-4-ainine

40 as 1 -((4"{benzy loxy)- D

l,2-dithiolan-3- y 1 } niei li y ί ) - 3 - (4- iien phen i } - 1. H- f / j pyr i m i din -4-ami ne

43 A. (3A',4 ?)-3~((4-amino-3- C A A A A A A B

{4-plieiioxvpheiiyl)- \ H~

pyTaH>io 3,4- ifjpynniidif!-- i - yl jmethyi) - i ,2-di tiiioian-

4-oi

43 B. (3J¾,4S)-3-((4-amino-3- B A A A B A A B B i4-phetioxyphetiy] )- I II- pyt¾zolo[3,4- iijpyTimidtn-l- y!)methylH 2-dithk>lan-

4~ol

46 A. (3&4S)-3-((4-armno-3- C A B B B B B C

(4-phenoxyp enyl)- 1 H- pyraa iol ^' 3,4- . jpyrimidin- l - yi imethyi}- i ,2-di tbiolan- 4-oJ.

46 B. {3 ?,4Κ)-3- ί4-<ίηιίπο-3- B A A A A A B B

{4-phenoxyphenyl )- IH~ Compounds, Compound ame SRC YES1 PGR FYN BL LC HC LYN CS Of

Exam pie #

p a«io[3, "

ifjp nniidif!--i- y meth l )- i ,2-dithioian- ·;.<»!

62 trans 3 - ( (4- ami n.o-3- (4- B

(2- fiuorophenoxyphenyi)- lH-py raz«lo[3.4- jpyrimidin-i- yl)tnefiiyi}- i,2-ditMolan.- 4-yi benzoate

63 irons 3-((4-ammo-3-(4- B

(2- ftuorophenoxy phenyl )-

! //-pyrazoiof 3,4- iijpyrimidifv-i- yl jmethyi) - i ,2-di tiiioian-

·;.<»!

67 tram 3 (4- ana no-3 - ( ^' 3 - C

(3-f!uoro-4- ptienoxyptien i)- Mi- pyi¾zolo[3,4- fijpyrimidin-l- yl)tnefiiyi}- i,2-ditMolan.- 4-yi benzcsate Table 1.4. Κ¾& Activity Levels Against FYN Mutant in «

Table 16. ICso Activity Leveis Against Type IH N T Kinases in nM Compounds Compound Name FLT3 FLT3 -WD Of

Exampie #

43 B. (3f,4S)- ^■ 3-({4-amino--?-(4-p.henoxypheny} )-lH-pyrazolo[3.4- C C

d]p yiiinidin- i -yl)methyl)- 1 ,2 -di£hio.ian-4 ^« o.i

46 A. (3SAS) - 3 -{(4-a m ino-3 -( -phen ox y phenyl ) - 1 /f-pyrazolo [3,4- B c

ίί jpyrimidin- 1 -yl}m¾ yi)- 1 ,2-di£ ioian-4-oi

46 B. (3?,4Af)-- ((4-amino-- (4-pheiK!xyphenyl)-li¾-pyrazolo(3 _! 4- B c

iij yr imiiiu- ί -yi )methy 1}- 1 ,2-dithio!an-4-o!

Table 17, K¾o Activity Levels Against FR ^' K Family Kinases in oM

Table 18. iC.% Activity Levels Against MAPK Pathway Kinases nM

Compounds Compound Name ARAF BRAF CRAF KDR/VBGFR2 Of

Exam le #

43 A. (35,4/?)-3-((4-ao)ioo-3-(4-pbfiooxypbfioyi)-l//- C D

pyrazo!oi3.4^|pyrimidin- ! -yDmet yi)- 1,2- di£hiolan-4»o.i

43 B. {3?,45)-3-{i -amino-3-{4-p enoxyp enyf)- 5 H- py razc*H>[3,4-i/]py rimidi n-i-yl )methyl }- ! ,2- dit iolaii-4-oi

46 A, i 35.4S)-3-((4-affiiiK!-3-(4-phenoxyphenyl)- 1 H- D D D D

pyrazoloP,4-rf]pj iinidm-J-y{)methyl)-i,2- dithiolan-4-ol I 46 B. ί 3R AH V3 - ( (4-ami no-3 -{+- p h enox y p h en yi )- 1 H- C D j D D pyrazolo| ^" 3,4^]pj iinidm-J -y{)methyl)- i ,2- dithioian-4-ol

Table 1 JCso Acti vity Levels Against RTKs (c-Kit, RET, HER4) and AurA, CHK2 Kinases in nM

Table 20, ΪΟβ Activity ^' Levels Against Various ΡΪ3Κ and mTor Kinases in n ^' M

4, Kiitast ¹ binding assay CaPBA; This assay is based on a competitive binder which can interact with a latent pocket formed only in the inactive state of the kinase, A fluorescent probe is used to bind to the inactive form of the enzyme and is displaced competitively by a binder upon shining light. Table 21 , 1C¾ Activity Levels Against FYN isofoims, YES 3 and MFK5 in oM

5, Radiometric " PanQiBase ^B assay: ^' This, assay referred to as FiashPlate-based Protein Kinase Assay uses recombinant protein kinase and ATP concentration corresponding to the apparent ATP- Km of the respective kinase. Testing of inhibitors is done at app. ATP Km.

Table 22. iCso Activity Levels Against YN Kinase in nM