NZ762863B2 - Heteroaryl substituted pyrrolo[2,3-b]pyridines and pyrrolo[2,3-b]pyrimidines as janus kinase inhibitors - Google Patents

Abstract

Disclosed are compositions of Ruxolitinib, more particularly a pharmaceutical composition comprising a compound, which is 3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; wherein said composition is to be orally administered and provides sustained release. rein said composition is to be orally administered and provides sustained release.

Description

(12) d patent specificaon (19) NZ (11) 762863 (13) B2 (47) Publicaon date: 2021.12.24 (54) Heteroaryl substuted pyrrolo[2,3-b]pyridines and pyrrolo[2,3-b]pyrimidines as janus kinase inhibitors (51) Internaonal Patent Classificaon(s): A61P 17/00 A61P 35/00 A61P 37/00 A61K 31/519 (22) Filing date: (73) Owner(s): 2006.12.12 Incyte Holdings Corporation (23) Complete specificaon filing date: (74) Contact: 2006.12.12 HOULIHAN2 PTY LTD (62) Divided out of 748000 (72) Inventor(s): RODGERS, James D. (30) Internaonal Priority Data: SHEPARD, Stacey US 60/859,404 2006.11.16 MADUSKUIE, Thomas P.

US 60/856,872 1.03 WANG, Haisheng US 60/850,625 2006.10.10 FALAHATPISHEH, Nikoo US 60/810,231 2006.06.02 KI, Maria US 60/749,905 2005.12.13 ARVANITIS, Argyrios G.

STORACE, Louis JALLURI, Ravi Kumar FRIDMAN, Jordan S.

VADDI, Krishna (57) Abstract: Disclosed are ions of nib, more parcularly a pharmaceucal composion comprising a compound, which is 3-cyclopentyl[4-(7H-pyrrolo[2,3-d]pyrimidinyl)-1H- pyrazolyl]propanenitrile, or a pharmaceucally acceptable salt thereof, and a pharmaceucally able carrier; wherein said composion is to be orally administered and provides sustained release. 762863 B2 PATENTS FORM NO. TS FORM NO. 5 Complete icationComplete Specification New Zealand s Act 1953 New d Patents Act 1953 Divisional application out of NZ 748000Divisional application out of NZ 748000 In turn a divisional application out of NZ 733104In turn a onal application out of NZ 733104 In turn a divisional application out of NZ 715022In turn a divisional application out of NZ 715022 In turn a divisional application out of NZ 625189In turn a divisional application out of NZ 625189 In turn a divisional application out of NZ 603809In turn a divisional application out of NZ 603809 In turn a divisional application out of NZ 593031In turn a divisional application out of NZ 593031 In turn a divisional application out of NZ 569015In turn a divisional application out of NZ 569015 Title:Title: Heteroaryl substituted pyrrolo[2,3-b]pyridines and pyrrolo[2,3-b]Heteroaryl substituted o[2,3-b]pyridines and pyrrolo[2,3-b] dines as janus kinase inhibitors pyrimidines as janus kinase inhibitors Applicant: Incyte Holdings CorporationApplicant: Incyte Holdings Corporation Address: 1801 Augustine Cut-Off, gton, 19803, DelawaAddress: 1801 Augustine Cut-Off, Wilmington, 19803, Delawarere United States of AmericaUnited States of America Nationality: USNationality: US We, Incyte Holdings Corporation, hereby declare the invention, for which we pray that aWe, Incyte Holdings Corporation, hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularlypatent may be granted to us, and the method by which it is to be performed, to be particularly bed in and by the following statement:described in and by the following statement: - l - (next page is page 1a)(next page is page la) Street Address for Service:Srreer Arlrlressfor .S‘eri‘ice.‘ Post Office Box Address for ePosr Office Box Arlzlressfbr Se ri‘ice All Correspondence T0:All Correspondence To: Houlihan2Houlihanl Houlihan2Houlihanl Houlihan2Houlihanl Rapid 31Rapid 31 PO Box 722PO Box 722 PO Box 611PO Box 611 Mountain View RoadMountain View Road QueenstownQueenstown Balwyn North wyn North VIC 31043104 DalefieldDalefield New ZealandNew Zealand Australia Australia New ZealandNew Zealand 2006/047369 HETEROARYL SUBSTITUTED PYRROLO[2,3—b1PYRIDlNES AND PYRROLO[2,3—b]PYRIlVIIDINES AS JANUS KINASE INHIBITORS FIELD OF THE lNVENTION The present invention provides heteroaryl tuted pyrrolo[2,3-b]pyridines and heteroaryl substituted pyrrolo[2,3-b]pyrimidines that modulate the activity of Janus kinases and are useful in the treatment of diseases related to activity of Janus kinases including, for example, immune-related diseases, skin disorders, myeloid proliferative disorders, cancer, and other diseases.

BACKGROUND OF THE INVENTION Protein kinases (PKs) are a group of enzymes that regulate diverse, important biological ses including cell growth, survival and differentiation, organ ion and morphogenesis, cularization, tissue repair and "regeneration, among others. n kinases exert their physiological fiinctions through catalyzing the phosphorylation of proteins (or substrates) and thereby modulating the cellular activities of the substrates in s biological contexts. In addition to the functions in normal tissues/organs, many protein s also play more specialized roles in a host of human diseases including cancer. A subset of protein kinases (also referred to as oncogenic protein kinases), when dysregulated, can cause tumor formation and growth, and further contribute to tumor maintenance and progression (Blume-Jensen P et al, Nature 200], 411(6835):355—365). Thus far, oncogenic protein kinases ent one of the largest and most attractive groups of protein targets for cancer intervention and drug development.

Protein kinases can be rized as receptor type and non—receptor type. or tyrosine kinases (RTKs) have an extracellular portion, a transmembrane domain, and an intracellular n, while non—receptor tyrosine kinases are entirely intracellular. RTK mediated signal transduction is typically initiated by extracellular interaction with a specific growth factor (ligand), typically ed by receptor dimerization, stimulation of the sic n tyrosine kinase activity, and receptor transphosphorylation. Binding sites are thereby created for intracellular signal transduction molecules and lead to the formation of complexes with a spectrum of cytoplasmic signaling molecules that facilitate the appropriate cellular response such as cell division, differentiation, metabolic s, and changes in the extracellular microenvironment At present, at least nineteen (19) distinct RTK subfamilies have been fied. One RTK subfamily, designated the HER ily, includes EGFR, HERZ, HERE and HER4, and bind such ligands as epithelial growth factor (EGF), TGF-OL, amphiregulin, I-IB-EGF, betacellulin and heregulin. la (next page is page 2‘) A second family of RTKs, designated the insulin subfamily, includes the INS-R, the IGF-lR and the IR—R. A third family, the "PDGF" subfamily, includes the PDGF alpha and beta receptors, CSFIR, c- kit and FLK-II. Another subfamily of RTKs, referred to as the FLK subfamily, encompasses the Kinase insert Domain-Receptor fetal liver -1 (KDR/FLK-l), the fetal liver kinase 4 (FLK-4) and the ke tyrosine kinase 1 (flt-l). Two other ilies ofRTKs have been ated as the FGF receptor family (FGFRI, FGFRZ, FGFR3 and FGFR4) and the Met subfamily , Ron and Sea). For a detailed discussion of protein kinases, see for example, Blume-Jensen, P. et al., Nature. 2001, 411(6835):355-365, and Manning, G. et al., Science. 2002, 298(5600):1912-l934.

The non—receptor type of tyrosine kinases is also composed of numerous subfamilies, including Src, Btk, Abl, Fak, and Jak. Each of these subfamilies can be further subdivided into le members that have been frequently linked to oncogenesis. The Src family, for example, is the t and includes Src, Fyn, Lck and Fgr among others. For a detailed discussion of these kinases, see Bolen JB. Nonreceptor ne protein kinases. Oncogene. 1993, 8(8):2025-31.

A significant number of ne kinases tboth receptor and nonreceptor) are associated with cancer (see Madhusudan S, Ganesan TS. Tyrosine kinase inhibitors in cancer therapy. Clin m. 2004, 37(7):618~35.). Clinical studies suggest that overexpression or dysregulation of tyrosine s may also be of prognostic value. For example, members of the HER family of RTKs have been ated with poor prognosis in breast, colorectal, head and neck and lung cancer. Mutation of c-Kit tyrosine kinase is associated with decreased survival in gastrointestinal stromal tumors. In acute myelogenous leukemia, Flt-3 mutation predicts shorter disease free survival. VEGFR expression, which is important for tumor angiogenesis, is associated with a lower survival rate in lung cancer.

Tie—1 kinase expression ely correlates with survival in gastric cancer. BCR-Abl expression is an important predictor of response in chronic myelogenous leukemia and Src tyrosine kinase is an indicator ofpoor prognosis in all stages of colorectal .

The immune system responds to injury and threats fiom pathogens. Qytokines are low- molecular weight polypeptides or glycoproteins that stimulate biological responses in Virtually all cell types. .For example, cytokines regulate many of the pathways involved in the host inflammatory response to sepsis. Cytokines influence cell differentiation, eration and activation, and they can modulate both proinflammatory and anti-inflammatory responses to allow the host to react appropriately to pathogens.

Binding of a cytokine to its cell surface receptor initiates intracellular signaling es that transduce the extracellular signal to the nucleus, ultimately leading to changes in gene sion. The pathway involving the Janus kinase family of protein tyrosine kinases (JAKS) and Signal ucers and Activators of ription (STATS) is engaged in the signaling of a wide range of cytokines.

Generally, cytokine receptors do not have intrinsic tyrosine kinase activity, and thus require receptor- associated kinases to propagate a phosphorylation cascade. JAKs fulfill this function. Cytokines bind to their receptors, causing receptor dimerization, and this enables JAKs to phosphorylate each other as 2006/047369 well as specific tyrosine motifs within the cytokine receptors. STATS that recognize these phosphotyrosine motifs are recruited to the receptor, and are then themselves activated by a JAK- dependent tyrosine orylation event. Upon activation, STATS dissociate from the ors, dimerize, and translocate to the nucleus to bind to c DNA sites and alter transcription (Scott, M. 1., C. J. Godshall, et a1. (2002). "Jaks, STATS, Cytokines, and Sepsis." Clz'n Diagn Lab Immunol 9(6): 1153-9). ‘ The JAK family plays a role in the cytokine-dependent regulation of proliferation and on of cells ed in immune response. tly, there are four known mammalian JAK family members: JAKl (also known as Janus kinase-1), JAK2 (also known as Janus kinase-2), JAK3 (also known as Janus kinase, leukocyterJAKL; L—JAK and Janus kinase-3) and TYK2 (also known as protein-tyrosine kinase 2). The JAK proteins range in size from 120 to 140 kDa and comprise seven conserved JAK homology (JH) domains; one of these is a functional catalytic kinase domain, and another is a pseudokinase domain potentially serving a regulatory function and/or serving as a g site for STATS (Scott, Godshall et al. 2002, supra).

While JAK], JAK2 and TYK2 are ubiquitously expressed, JAK3 is reported to be preferentially expressed in natural killer (NK) cells and not resting T cells, suggesting a role in id activation (Kawamura, M., D. W. McVicar, et al. (1994). "Molecular cloning of L—JAK, a Janus family n-tyrosine kinase expressed in natural killer cells and activated leukocytes." Proc Natl Acad Sci U S A 91(14): 6374—8).

Not only do the cytokine-stimulated immune and inflammatory responses contribute to normal host defense, they also play roles in the pathogenesis of diseases: pathologies such as severe combined immunodeficiency (SCID) arise from hypoactivity and suppression of the immune system, and a hyperactive or opriate immune / inflammatory response contributes to the pathology of autoimmune diseases such as rheumatoid and psoriatic arthritis, asthma and systemic lupus erythematosus, inflammatory bowel e, multiple sclerosis, type I diabetes mellitus, myasthenia gravis, thyroiditis, immunoglobulin nephropathies, myocarditis as well as illnesses such as scleroderma and osteoarthritis (Ortmann, R. A., T. Cheng, et al. (2000). "Janus kinases and signal transducers and activators of transcription: their roles in cytokine signaling, development and immunoregulation." Arthritis Res 2(1): 16-32). Furthermore, syndromes with a mixed presentation of autoimmune and immunodeficiency disease are quite common (Candotti, F., L. Notarangelo, et al. (2002). "Molecular aspects of primary immunodeficiencies: lessons from cytokine and other signaling pathways." J Clin Invest 109(10): 1261-9). Thus, therapeutic agents are lly aimed at tation or suppression of the immune and inflammatory pathways, accordingly.

Deficiencies in expression of JAK family members are associated with disease states. Jakl —/- mice are runted at birth, fail to nurse, and die tally (Rodig, S.

J., M. A. Meraz, et al. .

"Disruption of the Jakl gene demonstrates obligatory and nonredundant roles of the Jaks in cytokine- induced biologic responses." Cell 93(3): 373-83). Jak2-/- mouse embryos are anemic and die around 2006/047369 day 12.5 postcoitum due to the absence of definitive erythmpoiesis. JAKZ—deficient fibroblasts do not respond to [EN gamma, although responses to IFNalpha/beta and IL-6 are unaffected. JAK2 functions in signal transduction of a c group of cytokine receptors required in definitive erythropoiesis (Neubauer, H., A. Cumano, et a1. (1998). Cell 93(3): 397—409; Parganas, 13., D. Wang, et al. (1998).

Cell 93(3): 385-95.). JAK3 appears to play a role in normal development and function of B and T lymphocytes. Mutations of JAK3 are reported to be responsible for autosomal recessive severe combined immunodeficiency (SCID) in humans (Candotti, F., S. A. Cakes, et al. (1997). "Structural and functional basis for eficient severe combined immunodeficiency." Blood 90(10): 3996- 4003).

The JAK/STAT pathway, and in particular all four members of the JAK family, are believed to play a role in the pathogenesis of the asthmatic se, chronic ctive pulmonary disease, bronchitis, and other related inflammatory diseases of the lower atory tract. For instance, the inappropriate immune responses that terize asthma are orchestrated by a subset of CD4+ T helper cells termed T helper 2 (Th2) cells. Signaling through the cytokine receptor IL-4 stimulates JAKI and JAK3 to activate STAT6, and signaling through IL—12 stimulates tion of JAK2 and TYK2, and subsequent phosphorylation of STAT4. STAT4 and STAT6 control multiple aspects of CD4+ T helper cell entiation , A. B. and P. B. Rothman (2002). "JAK-STAT signaling in asthma." J Clin Invest 109(10): 1279-83). Furthermore, TYKZ-deficient mice were found to have enhanced Th2 cell-mediated allergic airway inflammation (Seto, Y., H. Nakajima, et a1. (2003).

"Enhanced Th2 cell—mediated allergic inflammation in Tyk2-deficient mice." J Immunol 170(2): 1077-83). Moreover, multiple cytokines that signal through JAK kinases have been linked to inflammatory diseases or conditions of the upper respiratory tract such as those affecting the nose and sinuses (e.g. rhinitis, sinusitis) whether classically allergic reactions or not.

The JAK/STAT pathway has also been implicated to play a role in atory £5 diseases/conditions of the eye including, but not d to, iritis, uveitis, scleritis, conjunctivitis, as well as chronic allergic ses. Therefore, inhibition of JAK kinases may have a beneficial role in the therapeutic treatment of these diseases.

The JAK/STAT pathway, and in particular, JAK3, also plays a role in cancers of the immune system. In adult T cell leukemia/lymphoma (ATLL), human CD4+ T cells acquire a transformed 50 phenotype, an event that correlates with acquisition of constitutive phosphorylation of JAKs and STATS. Furthermore, an ation between JAK3 and STAT—1, STAT—3, and STAT—5 activation and ycle ssion was demonstrated by both propidium iodide staining and bromodeoxyuridine incorporation in cells of four ATLL patients tested. These results imply that JAK/STAT activation is associated with replication of ic cells and that therapeutic approaches 55 aimed at JAK/STAT inhibition may be considered to halt stic growth oto, S., J. C.

Mulloy, et al. (1997). "Proliferation of adult T cell leukemia/lymphoma cells is associated with the tutive activation ofJAK]STAT proteins." Proc Natl Acad Sci U S A 94(25): 13897-902). 2006/047369 Blocking signal transduction at the level of the JAK kinases holds promise for developing treatments for human cancers. nes of the interleukin 6 (IL-6) family, which te the signal transducer gpl30, are major survival and growth factors for human multiple myeloma (MM) cells.

The signal transduction of gpl30 is believed to e JAKl, JAK2 and Tyk2 and the downstream effectors STAT3 and the mitogen-activated protein kinase (MAPK) pathways. In IL—6-dependent MM cell lines treated with the JAK2 tor tyrphostin AG490, JAK2 kinase activity and ERK2 and STAT3 phosphorylation were inhibited. Furthermore, cell eration was suppressed and apoptosis was induced (De V03, 1, M. Jourdan, et al. (2000). "JAKZ tyrosine kinase inhibitor tyrphostin A0490 downregulates the mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription (STAT) pathways and induces apoptosis in myeloma cells." Br J Haematol 109(4): 823- 8). However, in some cases, AG490 can induce dormancy of tumor cells and actually then protect them from death.

Activation of JAK/STAT in cancers may occur by multiple mechanisms including ne stimulation (e.g. IL—6 or GM—CSF) or by a reduction in the endogenous suppressors of JAK signaling such as SOCS (suppressor or cytokine signaling) or PIAS (protein inhibitor of activated STAT) y, V., and Kovarik, J., Neoplasm.-49:349-355, 2002). Importantly, activation of STAT signaling, as well as other pathways downstream of JAKs (e.g. Akt), has been correlated with poor prognosis in many cancer types (Bowman, T., et al. Oncogene 19:2474-2488, 2000). Moreover, elevated levels of circulating cytokines that signal through JAK/STAT may adversely impact patient health as they are thought to play a causal role in cachexia and/or chronic e. As such, JAK inhibition may be therapeutic for the treatment of cancer patients for reasons that extend beyond ial anti-tumor activity. The cachexia indication may gain further mechanistic support with realization that the satiety factor leptin signals through JAKs. cological targeting of Janus kinase 3 (JAK3) has been employed successfully to control allograft ion and graft versus host disease (GVHD). In addition to its involvement in signaling of cytokine receptors, JAK3 is also engaged in the CD40 signaling pathway of peripheral blood monocytes. During CD40—induced maturation of myeloid tic cells (DCS), JAK3 activity is induced, and increases in costimulatory le expression, IL—lZ production, and potent allogeneic atory capacity are observed. A rationally designed JAK3 inhibitor WHI-P-154 prevented these effects arresting the DCs at an re level, suggesting that immunosuppressive therapies targeting the tyrosine kinase JAK3 may also affect the function of myeloid cells (Saemann, M. D., C. Diakos, et al. (2003). "Prevention of riggered dendritic cell maturation and induction of T-cell hyporeactivity by ing of Janus kinase 3." Am J Transplant 3(11): 1341-9). In the mouse model system, JAK3 was also shown to be an important molecular target for treatment of autoimmune insulin-dependent (type 1) diabetes mellitus. The rationally designed JAK3 inhibitor JANEX-l exhibited potent immunomodulatory activity and delayed the onset of diabetes in the NOD mouse model of autoimmune type 1 diabetes (Cetkovic-Cvrlje, M., A. L. Dragt, et al. (2003).

"Targeting JAK3 with JANEX—l for prevention of autoimmune type 1 diabetes in NOD mice." Clin Immunol 106(3): 213-25).

It has been suggested that inhibition of JAK2 tyrosine kinase can be beneficial for patients with roliferative disorder. (Levin, et al., Cancer Cell, vol. 7, 2005: 387-397) Myeloproliferative disorder (MPD) includes polycythemia vera (PV), essential thrombocythemia (ET), myeloid metaplasia with myelofibrosis (MMM), chronic myelogenous leukemia (CML), c myelomonocytic leukemia (CMML), hypereosinophilic syndrome (HES) and systemic mast cell disease (SMCD). Although the myeloproliferative disorder (such as PV, ET and MMM) are t to be caused by acquired somatic mutation in hematopoietic progenitors, the genetic basis for [0 these diseases has not been known. However, it has been reported that hematopoietic cells from a majority of ts with PV and a significant number of patients with ET and MMM possess a recurrent somatic activating mutation in the JAKZ tyrosine kinase. It has also been ed that tion of the JAK2V617F kinase with a small molecule inhibitor leads to inhibition of proliferation of hematopoietic cells, suggesting that the JAK2 tyrosine kinase is a potential target for phannacologic inhibition in patients with PV, ET and MMM. tion of the JAK kinases is also envisioned to have therapeutic benefits in patients suffering from skin immune disorders such as psoriasis, and skin sensitization. In psoriasis vulgaris, the most common form of psoriasis, it has been lly accepted that activated T lymphocytes are important for the maintenance of the disease and its associated psoriatic plaques ieb, A.B., et al, Nat Rev Drug Disc, 4:19-34). Psoriatic plaques contain a cant immune infiltrate, including leukocytes and tes, as well as multiple epidermal layers with increased keratinocyte proliferation. While the initial activation of immune cells in psoriasis occurs by an ill defined mechanism, the maintenance is believed to be dependent on a number of inflammatory cytokines, in addition to various chemokines and growth factors (JCI, 64-1675). Many of these, including interleukins -2, ~4, -6, -7, -12, -15, -18, and -23 as well as GM-CSF and IFNg, signal through the Janus (JAK) kinases (Adv Pharmacol. 2000;47:113-74). As such, blocking signal transduction at the level of JAK kinases may result in therapeutic benefits in patients suffering from sis or other immune disorders of the skin.

It has been known that certain therapeutics can cause immune reactions such as skin rash or diarrhea in some patients. For instance, administration of some of the new targeted anti-cancer agents such as Iressa, x, and Tarceva has induced orm rash with some patients. Another example is that some eutics used topically induce skin imitation, skin rash, contact dermatitis or ic contact sensitization. For some patients, these immune reactions may be bothersome, but for others, the immune reactions such as rash or diarrhea may result in inability to continue the treatment.

Although the driving force behind these immune reactions has not been elucidated completely at the present time, these immune reactions are likely linked to immune infiltrate.

Inhibitors of Janus kinases or related kinases are widely sought and several publications report effective classes of compounds. For example, certain inhibitors are reported in WO 99/65909, US 2004/0198737; WO 99204; ; and WO 01/42246. Heteroaryl tuted pyrroles and other nds are reported in W0 2004/72063 and WO 99/62908.

Thus, new or improved agents which inhibit kinases such as Janus kinases are continually needed that act as immunosuppressive agents for organ transplants, as well as agents for the prevention and treatment of mune diseases (e.g., multiple sclerosis, rheumatoid arthritis, , type I diabetes, inflammatory bowel disease, Crohn’s e, autoimmune thyroid disorders, Alzheimer’s disease), diseases involving a hyperactive inflammatory response (e.g., eczema), allergies, cancer (e.g., prostate, leukemia, multiple myeloma), and some immune reactions (e.g., skin rash or contact dermatitis or diarrhea) caused by other therapeutics, to name a few. The compounds, compositions and methods described herein are directed toward these needs and other ends.

SUMMARY OF THE INVENTION The t invention provides compounds ofFormula I: (Y)n‘"z T:A2 I \\ U\\ 19V or ceutically acceptable salt forms or prodrugs thereof, wherein tuent members are defined herein.

The present invention further provides compositions comprising a compound of Formula I, or phannaceutically acceptable salt f, and a pharrnaceutically acceptable carrier.

The present invention further provides methods of modulating an activity of JAK sing contacting JAK with a compound ofFormula I, or pharmaceutically acceptable salt thereof.

The present invention further es s of treating a disease in a patient, wherein the disease is associated with JAK activity, comprising administering to the patient a therapeutically effective amount of a nd ofFormula I, or pharmaceutically acceptable salt thereof.

The present ion further provides compounds of Formula I for use in therapy.

The present invention further provides compounds of Formula I for the preparation of a medicament for use in therapy.

DETAILED DESCRIPTION The present invention provides, inter alia, compounds that te the activity of one or more JAKs and are useful, for example, in the treatment of diseases associated with JAK sion or activity. The nds ofthe invention have Formula I: 'l'_-;:A2 I, \‘ UK~ 19V including pharmaceutically acceptable salt forms or prodrugs thereof, wherein: Al and A2 are independently selected from C and N; T, U, and V are independently selected from O, S, N, CR5, and NR6; wherein the 5-membered ring formed by Al, A2, U, T, and V is aromatic; X is N or CR4; Y is CH; alkylene, 02.8 alkenylene, Cu alkynylene, (CR'IR‘2)p—(Cg_w cycloalkylene)— (CR' ‘R'2),, (CR1 ‘R‘2),-(ary1ene)-(CR' ‘R‘2)q, ((21:<"R‘2),,-(c...0 heterocycloalkylene)—(CR"R'2)q, (CRl lR12)l,,-(heteroarylene)-(CRI 'R12)q, (CRI l1{'2),,O(CRl lRn)q, (CRl 1R12),,S(CRl I182),], (CR' ‘R‘2)pC(O)(CR' ‘11"), (CR1 IR"),,C(0)1\1R°(CR‘ 1R"), (CR' ‘R12)pC(O)O(CR"R‘2)q, (CR1'R12)pOC(0)(CR"R'2)q, (CR"R"),0C(0)NR°(CR"R‘2),, 2),,NR°(CR"R"),, (CR‘ 'R'2)pNR°C(O)NRd(CR‘ '12"), (CR' 1R"),S(0)(CR‘ '11"), (CR‘ 'R"),S(0)NR°(CR' 1R"), (CR"R'2)pS(O)2(CR"R")q, or(CR!1R12)pS(O)2NR°(CR"R12)q, wherein said CH, alkylene, CM alkenylene, Cm alkynylene, cycloalkylene, e, heterocycloalkylene, or heteroarylene, is 50 optionally substituted with 1, 2, or 3 substituents independently selected from —D1—D2—D3—D4; Z is H, halo, CM alkyl, C24 l, C24 alkynyl, CM haloalkyl, halosulfanyl, CM hydroxyalkyl, CM cyanoalkyl, =C—Ri, =N-Ri, Cy', CN, N02, OR", SR", C(O)Rb, C(O)NRcRd, C(O)OR"‘, OC(O)Rb, OC(O)NR°Rd, NRCR", NR°C(O)R", NR°C(O)NR°R", NR°C(O)OR", C(=NRi)NR°R", NR‘)NRCR", S(O)R", S(O)NR°R", S(O)2R", )2R", C(=NOH)R", C1-5 Rb, and S(O)2NR°Rd, wherein said CH; alkyl, C24; alkenyl, or CH alkynyl, is optionally substituted with l, 2, 3, 4, 5, or 6 substituents independently selected from halo, CM alkyl, C24 alkenyl, C24 alkynyl, CM haloalkyl, lfanyl, CM hydroxyalkyl, CM cyanoalkyl, Cy', CN, N02, OR", SR", C(O)Rb, C(O)NR°R", C(O)OR", OC(O)R", OC(O)NR°Rd, NR°Rd, NR°C(O)R", NR°C(O)NR°Rd, NR°C(O)OR", C(=NR‘)NR°R", NR°C(=NR‘)NR°R", S(O)Rb, S(O)NR°R", S(O)2R", NR°S(O)2Rb, C(=NOH)R", C(=NO(C1_6 alkyl))Rb, and S(O)2NR°R"; wherein when Z is H, n is 1; or the Z moiety is taken together with i) A2 to which the moiety is ed, ii) R5 or R6 of either T or V, and iii) the C or N atom to which the R5 or R6 of either T or V is attached to form a 4- to 20-membered aryl, cycloalkyl, heteroaiyl, or heterocycloalkyl ring fused to the 5-membered ring formed by A], A2, U, T, and V, wherein said 4- to 20-membered aryl, cycloalkyl, aryl, or heterocycloalkyl ring is optionally tuted by l, 2, 3, 4, or 5 substituents independently selected from —(W)m—Q; W is CH; alkylenyl, 02-8 alkenylenyl, 02.3 alkynylenyl, 0, S, C(O), C(O)NR°', C(O)O, 00(0), R°', NR", NR°’C(0)NR"’, 3(0), S(O)NRC', 5(0),, or S(O)2NR°'; Q is H, halo, CN, N02, 01-8 alkyl, Cm alkenyl, 02.3 alkynyl, Cm haloalkyl, halosulfanyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, wherein said CH; alkyl, C" alkenyl, CM alkynyl, CH; haloalkyl, ar‘y], cycloalkyl, heteroaryl, or heterocycloalkyl is ally substituted with l, 2, 3 or 4 substituents independently selected from halo, CM alkyl, 02-4 alkenyl, C24 alkynyl, CM haloalkyl, halosulfanyl, c._4 hydroxyalkyl, cM cyanoalkyl, Cyz, CN, N02, OR‘", SRa', C(O)Rb', C(0)NR°’R"', C(0)0R"’, OC(0)R"', OC(O)NR°'R"‘, NR°'Rd’, NR°’C(0)R"', NR°'C(0)NR‘=‘R"‘, NR°’C(O)0R"', [5 S(O)Rb', S(O)NR°'R"', S(O)2Rb’, NR°’S(0)2R"', and 3(0)2NR°’R°"; Cyl and Cy2 are independently selected from aryl, heteroaryl, cycloalkyl, and cycloalkyl, each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from halo, CM alkyl, C" alkenyl, C24 l, CM haloalkyl, halosulfanyl, CM hydroxyalkyl, CM cyanoalkyl, CN, N02, 0R8", SR", C(0)Rb", C(O)NR°"R"", C(0)0Ra", OC(O)R"", 0C(0)NR°"R"", NR°"Rd", NR°"C(O)R"", NR°"C(O)OR"", NR°"S(0)R"", NR°"S(0)2R"", S(O)Rb", S(0)NR°"R‘*", "", and S(O)2NR°"R""; R‘, R2, R3, and R4 are independently selected from H, halo, CM alkyl, CH alkenyl, 02.4 alkynyl, CM haloalkyl, halosulfanyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, N02, 0R7, SR7, C(O)R3, C(0)NR9R‘°, C(O)OR7 OC(O)R8, R9R‘°, NR9R‘°, NR9C(0)R8, NR°C(O)OR7, S(O)R8, S(O)NR9R'°, 5(0),,118, )2R8, and S(O)2NR9R‘°; R5 is H, halo, CM alkyl, CM alkenyl, C2-4 alkynyl, CM haloalkyl, lfanyl, CN, N02, 0R7, SR7, , C(0)NR9R‘°, C(O)OR7, OC(O)R8, OC(O)NR9R‘°, NR9R‘°, NR90(O)R8, NR°C(O)0R7, S(O)R8, S(O)NR9R‘°, S(O)2RB, )2R8, or S(O)2NR9R'°; R6 is H, (3..., alkyl, (32‘1 alkenyl, 02., alkynyl, cM haloalkyl, 0R7, C(O)R8, C(O)NR9R'°, C(O)OR7, S(O)R8, S(O)NR9R'°, s, or S(O)2NR ‘0; R7 is H, CM alkyl, CM haloalkyl, CM alkenyl, CM l, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylallcyl or heterocycloalkylalkyl; R8 is H, CM alkyl, 01-5 haloalkyl, 02-5 alkenyl, CM, alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or cycloalkylalkyl; R9 and R'° are independently selected from H, cHO alkyl, 01-, haloalkyl, 02.5 alkenyl, 02., alkynyl, C1_5 arbonyl, arylcarbonyl, C1-6 alkylsulfonyl, arylsulfonyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl; 2006/047369 or R9 and R'0 together with the N atom to which they are ed form a 4-, 5—, 6- or 7— membered heterocycloalkyl group; Ru and R'2 are independently selected from H and -El-E2—E3-E4; D1 and El are independently absent or independently selected from CW ne, CM alkenylene, CM alkynylene, arylene, cycloalkylene, heteroarylene, and heterocycloalkylene, wherein each of the CH; alkylene, CM alkenylene, CM alkynylene, arylene, cycloalkylene, heteroarylene, and heterocycloalkylene is optionally substituted by l, 2 or 3 substituents independently selected from halo, CN, N02, N3, SCN, OH, Cm alkyl, loalkyl, Cm alkoxyalkyl, CH, alkoxy, C1_5haloalkoxy, amino, CH; mino, and C24; dialkylamino; D2 and E2 are independently absent or independently selected from C", alkylene, alkenylene, CM alkynylene, (CH; ne),-O-( CH; alkylene)s, (Cm alkylene),—S-(C,_5 alkylene)5, (CM alkylene),-NR‘-(C._6 alkylene)" (C 1.6 ne),—CO—(Cl_5 alkylene)s, (CH; alkylene),-COO—(C,.6 alkylene)s, (01.5 alkylene),-CONRc-(C1-6 ne)s, (CH; alkylene),-SO-(C1-(, alkylene)s, (CM alkylene),-SOz-(C1.5 alkylene),, (C 1.6 alkylene),-SONR‘-(C 1-5 alkylene)5, and (CM alkylene),- NRCCONRf-(Cm alkylene)s, wherein each of the CH; alkylene, C2_5 alkenylene, and (32-6 alkynylene is optionally substituted by 1, 2 or 3 substituents independently selected from halo, CN, N02, N3, SCN, OH, C 1-5 alkyl, CM haloalkyl, CM alkoxyalkyl, CH; alkoxy, CH; haloalkoxy, amino, CH; alkylamino, and Cm dialkylamino; D3 and E3 are independently absent or independently selected from CH; alkylene, CM alkenylene, CM alkynylene, arylene, cycloalkylene, heteroarylene, and heterocycloalkylene, wherein each of the CM alkylene, CM alkenylene, CM alkynylene, arylene, cycloalkylene, heteroarylene, and heterocycloalkylene is optionally tuted by 1, 2 or 3 substituents independently selected from halo, CN, N02, N3, SCN, OH, C1_6alkyl, C1.5haloalkyl, Cm alkoxyalkyl, Cm alkoxy, CH haloalkoxy, amino, CH; alkylamino, and CM dialkylamino; D4 and E4 are independently selected from H, halo, CH alkyl, C24 alkenyl, C24 alkynyl, haloalkyl, halosulfanyl, CM hydroxyalkyl, C14 cyanoalkyl, Cy', CN, N02, 0R8, SR3, C(O)Rb, C(0)NR°R", °, b, OC(O)NR°Rd, NR°Rd, NR°C(0)R", NR°C(0)NR°R", NR°C(O)OR", C(=NR‘)NR°R", NR°C(=NR‘)NR°R", S(O)Rb, S(O)NR°R°, S(O)2R", NR°S(O)2Rb, C(=NOH)R", C.-5 alkyl)Rb, and S(O)2NR°Rd, wherein said CH; alkyl, C" alkenyl, or CH alkynyl, is Optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently ed from halo, CM alkyl, C24 alkenyl, C" alkynyl, CM haloalkyl, halosulfanyl, CM hydroxyalkyl, CM cyanoalkyl, Cy', CN, N02, OR", SR", C(O)Rb, C(O)NR°R", C(O)OR3, ", OC(O)N'R°Rd, NR°Rd, )R", NR°C(O)NR°R", NR°C(O)OR", C(=NR‘)NR°R", NR°C(=NR‘)NR°R", S(O)Rb, S(O)NR°R", b, NR°S(0)2R", C(=NOH)R", C(=N0(c..6 )Rb, and S(O)2NR°R"; R3 is H, Cy', -(C._5 alkyl)-Cy', CH; alkyl, CM haloalkyl, CH alkenyl, CM alkynyl, wherein said CH, alkyl, CM haloalkyl, CM alkenyl, or CM alkynyl is optionally substituted with 1, 2, or 3 tuents independently selected from OH, CN, amino, halo, C145 alkyl, CH; haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; Rb is H, Cy', -(C1_5 -Cy', CH, alkyl, CM haloalkyl, CM alkenyl, CM alkynyl, n said CH; alkyl, CH; haloalkyl, 02.5 l, or C24; alkynyl is optionally substituted with 1, 2, or 3 substituents ndently selected from OH, CN, amino, halo, CM alkyl, CM haloalkyl, 01.5 haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; RB’ and R8" are independently selected from H, 0,.6 alkyl, (3..6 haloalkyl, (32.5 alkenyl, 02.6 alkynyl, aryl, lkyl, aryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said CM alkyl, C16 haloalkyl, Cm alkenyl, C245 alkynyl, aryl, lO cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or cycloalkylalkyl is optionally substituted with l, 2, or 3 substituents independently selected from OH, CN, amino, halo, CM alkyl, CM haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; R‘" and R"" are independently selected from H, CM alkyl, CH5 haloalkyl, c2.6 alkenyl, [5 CM alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, lkylalkyl and heterocycloalkylalkyl, wherein said C._5 alkyl, C", haloalkyl, CM alkenyl, CM l, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 tuents independently selected from OH, CN, amino, halo, CH; alkyl, C,.5haloa1ky1, Cm haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl, R° and R" are independently selected from H, Cy‘, -(c,_6 —Cy', cHo alkyl, c._6 haloalkyl, CM alkenyl, 02.6 alkynyl, wherein said C140 alkyl, C1_5 haloalkyl, CM alkenyl, or C24; alkynyl, is optionally substituted with l, 2, or 3 tuents ndently selected from Cy', —(Cl.6 alkyl)—Cy', OH, CN, amino, halo, C1-5alkyl, C._5haloalky1, C1_5 haloalkyl,and halosulfanyl; or Rc and Rd together with the N atom to which they are attached form a 4-, 5-, 6- or 7- membered cycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from Cy', -(c._6 alkyl)—Cy', OH, CN, amino, halo, lcyl, c,_,haloalkyl, C1_5haloalky1, and halosulfanyl; R6 and Rd. are independently selected from H, CHO alkyl, CH; haloalkyl, CM alkenyl, CM 50 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said CHO alkyl, CH; haloalkyl, CM alkenyl, (32.6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, CH. alkyl, 01-6 kyl, (31.5 haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, 55 heteroarylalkyl, cycloalkyl and heterocycloalkyl; or R". and RP er with the N atom to which they are attached form a 4-, 5-, 6- or 7- membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, CH; alkyl, CH; haloalkyl, CH, haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; R°" and R"" are ndently selected from H, cHo alkyl, on, haloalkyl, 02., alkenyl, (32-, l, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, arylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said €1.10 alkyl, 01.5 haloalkyl, 02.6 alkenyl, CM alkynyl, aryl, heteroaryl, lkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylallcyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected fiom OH, CN, amino, halo, Cm alkyl, C..5haloa1kyl, halosulfanyl, CH, haloalkyl, aryl, arylalkyl, heteroaryl, arylalkyl, cycloalkyl and heterocycloalkyl; O or RC" and Rd" together with the N atom to which they are attached form a 4-, 5-, 6- or 7- membered heterocycloalkyl group optionally substituted with I, 2, or 3 substituents independently selected from OH, CN, amino, halo, CH alkyl, loa1ky], loalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; Ri is H, CN, N02, or CH; alkyl; Re and Rf are independently selected from H and C16 alkyl; R‘ is H, CN, or N02; m is 0 or 1; n is O or 1; p is 0,1, 2, 3, 4, 5, or 6; ;0 qisO,l,2,3,4,50r6; r is O or 1; and s is 0 or 1.

In some embodiments, when X is N, n is 1, and the moiety formed by A', A2, U, T, V, and —(Y)n-Z has the formula: (Y)n—Z ww then Y is other than (CR' ‘R‘Z)pC(O)NR°(CR‘ 'R'2)q.

In some embodiments, when X is N, the 5-membered ring formed by Al, A2, U, T, and V is other than pyrrolyl.

In some embodiments, when X is CH, 11 is l, and the moiety formed by A1, A2, U, T, V, and 0 —(Y)..-Z has the formula: (Y)n~z then —(Y)n-Z is other than COOH.

In some embodiments, when X is CH or C-halo, R', R2, and R3 are each H, n is 1, and the moiety formed by A1, A2, U, T, V, and —(Y)n-Z has the formula: (Yb—Z (Y)n_z (Y)n—Z __ S S / \ \ S \ IWV’ WW ’ or M then Y is other than (CR' ‘R‘2),,C(O)NR°(CR"R‘2)q or (CR'1R12)pC(O)(CR"R'2)q.

In some embodiments, when X is CH or C-halo, R', R2, and R3 are each H, n is O, and the moiety formed by A', A2, U, T, V, and —(Y)n-Z has the formula: (Y)n-Z (Y)n-Z (Y)n-Z __ S S / \ \ S \ AMP ml or NVV‘ 7 ’ then Z is other than CN, halo, or CH alkyl.

In some embodiments, when X is CH or C—halo, R', R2, and R3 are each H, n is 1, and the moiety formed by A', A2, U, T, V, and —(Y)n—Z has the formula: (Y)n-Z (Y)n-Z at a %/N' SIN then Y is other than (CR1 ‘R‘2)pC(O)NR°(CR"R‘2 , or(CR1'R'2)pC(O)(CR"R12)q.

In some embodiments, when X is CH or , R], R2, and R3 are each H, n is 1, and the moiety formed by A}, A2, U, T, V, and —(Y)n-Z has the a: (Y)n_Z then Y is other than (CR‘‘R'2),,I~IR°(CR"R12 In some embodiments, when X is CH or C-halo and R‘, R2, and R3 are each H, then the moiety formed by A', A2, U, T, V, and ~(Y)n-Z has a formula other than: 0/ S/ / NW, NVV‘,OI‘ uvvv In some embodiments: Z is H, halo, CN, N02, CH; alkyl, C" alkenyl, C24; alkynyl, CH; haloalkyl, aryl, cycloalkyl, heteroaryl, or cycloalkyl, wherein said C 1-3 alkyl, C24; alkenyl, (32.8 alkynyl, CH; haloalkyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl is optionally tuted with l, 2, 3, 4, 5, or 6 substituents independently selected from halo, CM alkyl, C24 alkenyl, 02-4 alkynyl, CM haloalkyl, CM hydroxyalkyl, C._4 cyanoalkyl, Cy‘, CN, N02, OR", SR", C(O)Rb, C(O)NR°R", ", OC(O)R", OC(O)NR°R", NR°Rd, NR°C(O)Rb, NR°C(O)NR°Rd, NR°C(O)OR", C(=NRi)NR°Rd, NR°C(=NR‘)NR¢R", S(O)R", S(O)NR°R", S(O)2Rb, NR°S(O)2R", and S(O)2NR°R"; Q is H, halo, CN, N02, CH; alkyl, C24; alkenyl, C24; alkynyl, CH; kyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, wherein said C1_g alkyl, Cm alkenyl, CH alkynyl, CH; haloalkyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from halo, CM alkyl, 02-4 l, CM alkynyl, CM haloalkyl, CM hydroxy— alkyl, cM lkyl, Cyz, CN, N02, 0R"; SR") C(0)R'°’, °'R‘*’, C(0)0R"’, OC(O)R"’, OC(O)NR°'R"', NRC’R‘", NR°’C(0)R"', 0)NR"R"‘, NR°'C(O)OR3', S(0)Rb’, S(O)NRC'R"', b', NR°’S(0)2R"’, and S(O)ZNRC‘R"’; Cyl and Cy2 are independently selected from aryl, heteroaryl, cycloalkyl, and heterocyclo- alkyl, each optionally substituted by l, 2, 3, 4 or 5 substituents independently selected from halo, alkyl, C24 alkenyl, CM alkynyl, CM haloalkyl, CM hydroxyallcyl, CM cyanoalkyl, CN, N02, 0R6", SR3", C(0)R"", C(0)NR°"R"", C(O)OR"", "", OC(O)NRC"R"", NR°"R"", NR°"C(0)R"", NR°"C(O)ORB", NR°"S(0)R"", NR°"S(O)2R"", S(O)R"", S(O)NR°"R"", b", and S(O)2NR°"R""; R1, R2, R3, and R4 are independently selected from'H, halo, CM alkyl, 02-4 alkenyl, C24 alkynyl, CM haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, N02, 0R7, SR7, C(O)R8, C(O)NR9R'°, C(O)OR7 00(0)}?3‘, OC(O)NR9R'°, NR9R‘°, NRQC(O)R8, NRCC(O)OR7, S(O)R8, S(O)NR9R-'°, S(O)2R8, NR98(O)2R8, and R9R'°; R5 is H, halo, CM alkyl, 02.4 alkenyl, (32.4 alkynyl, C._4 haloalkyl, CN, N02, 0R7, SR7, C(O)R8, C(0)NR9R‘°, C(O)OR7, OC(O)R8, 0C(0)NR9R‘°, NR9R‘°, NR9C(O)R8, NR9C(0)0R7, S(O)R8, S(O)NR9R‘°, S(O)2R8, NR93(0)2R8, or S(O)2NR9R'°; R6 is H, cM alkyl, CM alkenyl, C24 alkynyl, CM kyl, 0R7, C(O)R8, C(0)NR9R‘°, C(O)OR7, S(O)R8, S(O)NR9R‘°, S(O)2R8, or S(O)2NR9R‘°; R7 is H, Cm alkyl, CM haloalkyl, CM l, CM alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, kyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl; R8 is H, C._5 alkyl, CH; haloalkyl, CN, alkenyl, C245 alkynyl, aryl, cycloalkyl, aryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl; R9 and R10 are independently selected from H, C140 alkyl, CW haloalkyl, CM alkenyl, CM alkynyl, CM alkylcarbonyl, arylcarbonyl, Cm alkylsulfonyl, arylsulfonyl, aryl, heteroaryl, lkyl, cycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl; WO 70514 or R9 and Rl0 together with the N atom to which they are attached form a 4-, 5-, 6- or 7— membered heterocycloalkyl group; R" and R'2 are independently selected from H, halo, OH, CN, CM alkyl, CM haloalkyl, C2... l, C24 alkynyl, CH hydroxyalkyl, CM cyanoalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; R", R8,, and R8" are independently selected from H, CM alkyl, C"; haloalkyl, CH l, C245 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, kyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said CH; alkyl, CH, haloalkyl, CM l, CM alkynyl, aryl, cyclo— alkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, CH; alkyl, C._6 haloalkyl, aryl, arylalkyl, aryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; R", R" and Rb" are independently selected from H, (31-5 alkyl, C", haloalkyl, CM alkenyl, C245 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylallcyl, cycloalkylalkyl and theterocycloalkylallcyl, wherein said Cm alkyl, (31.5 haloalkyl, CM alkenyl, C24; alkynyl, aryl, cyclo- alkyl, heteroaryl, heterocycloalkyl, arylalkyl, arylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with l, 2, or 3 substituents independently selected fi‘om OH, CN, amino, halo, Cm alkyl, 01-5 kyl, CH; haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; R° and Rd are independently ed from H, C140 alkyl, CH; haloalkyl, CM alkenyl, CM alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said CHO alkyl, CH; haloalkyl, CM l, C2_6 alkynyl, aryl, hetero- aryl, lkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or cycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, CH; alkyl, CM kyl, Cm kyl, aryl, arylalkyl, heteroaryl, heteroarylallcyl, cycloalkyl or heterocycloalkyl; or R‘2 and Rd together with the N atom to which they are attached form a 4-, 5-, 6- or 7- membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, CH; alkyl, Cm haloalkyl, CM haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; R°' and Rd' are independently selected from H, C 1-10 alkyl, C ._6 kyl, 02-6 alkenyl, CM alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said C1. ,0 alkyl, CM haloalkyl, CM alkenyl, CM alkynyl, aryl, hetero- aryl, cycloalkyl, heterocycloalkyl, kyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, CH; alkyl, C._5 haloalkyl, C1_5haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; or Rc’ and Rd, together with the N atom to which they are attached form a 4-, 5—, 6- or 7- membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents ndently selected from OH, CN, amino, halo, CH; alky], CH haloalkyl, CH; kyl, aryl, kyl, heteroaryl, heteroarylallcyl, cycloalkyl and heterocycloalkyl; R"" and RC" are independently selected from H, cHo alkyl, c1.6 haloalkyl, 02.6 alkenyl, 02.6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, arylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said C1,") alkyl, Cm haloalkyl, C24; alkenyl, C26 alkynyl, aryl, hetero- aryl, cycloalkyl, heterocycloalkyl, arylallcyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with l, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1-5 alkyl, CM kyl, CM haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; and or RC" and Rd" together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, CH; alkyl, C1_6haloalkyl, CH3 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl.

In some embodiments, X is N.

In some embodiments, X is CR4.

In some embodiments, Al is C.

In some embodiments, A1 is N.

In some ments, A2 is C.

In some embodiments, A2 is N.

In some ments, at least one of A], A2, U, T, and V is N.

In some embodiments, the 5-membered ring fonned by A], A2, U, T, and V is pyrrolyl, lyl, imidazolyl, oxazolyl, thiazolyl, or oxadiazolyl.

Ul In some embodiments, the 5-membered ring formed by A', A2, U, T, and V is selected from: "‘63.. ""53, ME "'51 6 "‘43, N/ \ / \ 7wN/ N [KN—i N / / \ \N uJ." «L, W b ,Jw m, b b b b ""5" ,"5" ’"3", 0' weak ms. at m — N S / [L "r if" "8" "EM and? ; wherein: a designates the site of attachment of moiety Z; b designates the site of attachment to the core moiety: it \ R2 R3 N IN! ; and ’ designate the two sites of attachment of the fused 4— to 20-membered aryl, cycloalkyl, c and c heteroaryl, or heterocycloalkyl ring.

In some ments, the 5-membered ringaformed by Al, A2, U, T, and V is selected from: Ug— 0% b b b b , ’ 5 S ’ C' "at 0' "~55, "a"; I \ — [i "BM 4‘8" and "‘3" ’ ; wherein: a designates the site of attachment ofmoiety —(Y)n-Z; b designates the site of attachment to the core moiety: XI \ \ R3J\N/ R2 H ; and ’ designate the two sites of attachment of the fused 4— c and c to 20—membered aryl, cycloalkyl, heteroaryl, or heterocycloalky] ring.

In some embodiments, the 5—membered ring formed by Al, A2, U, T, and V is selected from: Km?3%?"MERE "’3, ,and b ; a designates the site of attachment of moiety —(Y),.—Z; [O b designates the site of attachment to the core : x \ \ A / R2 R3 N N H ; and ’ designate the two sites of attachment of the fused 4- c and c to ZO-membered aryl, cycloalkyl, heteroaryl, or cycloalkyl ring. [5 In some embodiments, the 5-membered ring formed by A', A2, U, T, and V is selected from: NW8 mi "vi "mi "‘49: "6?, "'3 N—N/ R6 2 N—< s—<\ N::< _ \ \ Io—< %/N \ \ N \ S \ S N \ N N Y 1) I "3", w JVVV ww MN uvw W b b b b b b b , , ’ , , and , ’ , wherein: a designates the site of attachment of moiety —(Y)n-Z; b designates the site of attachment to the core moiety: fi\ \ ’R2 R3 N/ y, In some embodiments, the 5—membered ring formed by Al, A2, U, T, and V is selected from: 7‘2 ""3. R? "‘42. a "‘44..

N—N Nj N—‘\< N.— w "JVV vvw W b b b b , , , and , wherein: a designates the site of attachment of moiety —(Y)n-Z; b designates the site of attachment to the core moiety: JXL \ \ R2 R3 N/ :3 In some embodiments, the 5-membered ring formed by A1, A2, U, T, and V is selected from: 7‘4, "‘8" wherein: a designates the site of attachment of moiety —(Y)n-Z; b ates the site of ment to the core moiety: 1 \ \ R2 R3 N/ fl In some embodiments, n is O.

In some embodiments, n is 1.

In some embodiments, n is 1 and Y is CH; alkylene, C2.3 alkenylene, 50 (CR‘ C(O)(CR' ‘R")q, (CR' 'R'2)pC(O)NR°(CR‘ 'R'2)q, (CR‘ 'R'2)pC(O)O(CR' ‘R‘2)q, (CRl OC(O)(CR"Rn)q, wherein said CM; alkylene or CH alkenylene, is optionally substituted with 1, 2, or 3 halo, OH, CN, amino, CH alkylamino, or CH dialkylamino.

In some embodiments, n is l and Y is C]_g alkylene, (CR"R"),,C(O)(CR"R12 (CR"R‘2),C(0)NR°(CR1'R"),, (CR‘ ‘R‘2)pC(O)O(CR"R‘2)q, wherein said c,_8 alkylene is optionally substituted with 1, 2, or 3 halo, OH, CN, amino, CM alkylamino, or CH dialkylamino.

In some embodiments, n is 1 and Y is CH; alkylene optionally substituted with l, 2, or 3 halo, OH, CN, amino, CM alkylamino, or C" dialkylamino.

In some embodiments, n is 1 and Y is ne optionally substituted with l, 2, or 3 halo, OH, CN, amino, CM alkylamino, or 02-3 lamino.

In some embodiments, n is 1 and Y is (CRHR'Z),,C(O)(CR"R'2)q (CRl lR"),,C(O)NR‘3- (CRl , or (CRl lR"),,C(O)O(CRl 1R121].

In some embodiments, Y is CH; alkylene, C24; alkenylene, C24; lene, (CR"R‘2)p-(C3_m cycloalkylene)—(CR‘1R'2)q, (CR1 ‘R‘2),-(ary1ene)-(CR‘ 'R'2)q, (CR'1R‘2)p-(C1_lo heterocycloalkylene)- (CR"R'2)q, (CR' lR12)p—(heteroarylene)-(CRI '11"), (CR' 'R"),0(CR‘ 'R'2)q, or ),S(CR1 ‘11"), wherein said C |.g alkylene, C24; alkenylene, CM alkynylene, cycloalkylene, arylene, cycloalkylene, or heteroarylene, is optionally substituted with 1, 2, or 3 substituents l 5 independently selected from -—D'-D2-D3-D4.

In some embodiments, Y is CH; alkylene, C24; alkenylene, Cu alkynylene, (CR"R'2)p-(C3_w cycloalkylene)—(CR‘1R12)q, (CRl lR'2)},—(arylene)-(CRI lRn)q, (CRI lR12),,-(C1.10 heterocycloalkylene)— (CR1 '11"), (CR' 'R'2)p—(heteroarylene)—(CR' ‘11"), (CR‘ ‘R‘2)pO(CR] ‘R'2).,, or (CRl 'R")pS(CR' 'R"),, wherein said CH; alkylene, C243 alkenylene, 02-8 alkynylene, cycloalkylene, arylene, cycloalkylene, or heteroarylene, is ally substituted with 1, 2, or 3 tuents independently selected from D".

In some embodiments, Y is CH; alkylene, C24; alkenylene, CH alkynylene, or (CRHR'2)p—(C3_ .0 cycloalkylene)-(CR"R'2)q, wherein said CH; alkylene, CH lene, CM alkynylene, or lkylene, is optionally substituted with 1, 2, or 3 substituents independently ed from -—D'- DZ-D3-D".

In some embodiments, Y is CH; alkylene, CH lene, C24; alkynylene, or (CR'IR'2)p-(C3- IO cycloalkylene)-(CR1'R'2)q, wherein said CH, alkylene, CM alkenylene, CH alkynylene, or cycloalkylene, is optionally substituted with 1, 2, or 3 substituents independently selected from D".

In some embodiments, Y is CH; alkylene, C24; alkenylene, or CH alkynylene, each optionally 50 substituted with 1, 2, or 3 substituents ndently selected from —D'-D2-D3-D4.

In some embodiments, Y is CH; alkylene optionally substituted with l, 2, or 3 substituents independently selected from ——D'-D2-D3-D4.

In some embodiments, Y is C..3 alkylene ally substituted with l, 2, or 3 substituents independently selected fi'om D". 55 In some embodiments, Y is C|.3 alkylene, CM alkenylene, Cm alkynylene, (CRI'R‘2)pO- (CRHR'2)q, (CRHR‘Z)pS(CR"R‘2)q, (CR"R'2)pC(O)(CR"R]2)q, (CR"R'2)pC(O)NR°(CR"R'2)q, (CR1lR12)pC(O)O(CR"RIZ)q, (CR1 lR'z)pOC(O)(CRI 1R12)q, (CR1 'R'2)pOC(O)NR°(CR} 1R12)q, (CR"R'2)P °(CR"R12)q, (CR"R12)pNR°C(O)NRd(CR"R'2)q, (CR' 1R‘2)pS(O)(CR"R'2)q, (CR"R'2)pS(O)NR°(CR"R'2)q, (CR‘'R'Z),,S(0)2(CR"R‘2 or (CR"R'2)pS(O)2NR°(CR"R'2)q, wherein said 01-3 alkylene, 02.3 alkenylene, Cm alkynylene is optionally substituted with l, 2, or 3 substituents independently selected from halo, OH, CN, amino, CM alkylamino, and CH dialkylamino.

In some embodiments, Y is CH, alkylene, CM alkenylene, CM alkynylene, (CRl lR'z),,—(C3,..o cycloalkylene)-(CR1'R'2)q, '2)p-(arylene)-(CRl'R'2)q, (CR"R'2)p—(C1_loheterocycloalkylene)— (CR"R‘2),, (CR"R'2)p-(heteroarylene)-(CR‘ 'R‘2)q, (CR1 'R")p0(CR"R‘2)q, (CR"R‘2)pS(CR"R’2)q, (CR' 'R‘2)pC(O)(CR' ‘18:), (CR‘ ’R")PC(O)NR°(CR"R'2)Q, (CR‘ ‘R‘z)pC(O)O(CR"R’2)q, [0 (CR"R‘2)pOC(O)(CR"R12)q, (CR'IR‘Z),,OC(O)NR°(CR"R12)q, (CRI'R'2)p °(CR"R")q, (CR‘ IR12)pN-RCC(O)N'Rd(CRl IR'2)q, (CR11R12)pS(O)(CR' 1R12)q, (CR‘ 'R'2)pS(O)NR°(CRl 'R'2)q, (CR' 'R'2)pS(0)2(CR‘ , or (CR1‘R‘2),,S(0)2NR°(CRl 'R").,, wherein said (3,.3 alkylene, cl.8 alkenylene, C" alkynylene, cycloalkylene, arylene, heterocycloalkylene, or arylene, is optionally substituted with 1, 2, or 3 substituents independently selected from halo, OH, CN, amino, CM alkylamino, and C2_g lamino.

In some embodiments, p is 0.

In some embodiments, p is 1.

In some embodiments, p is 2.

In some embodiments, q is 0.

In some embodiments, q is 1.

In some embodiments, q is 2.

In some embodiments, one of p and q is 0 and the other of p and q is 1, 2, or 3.

In some embodiments, Z is H, halo, CM alkyl, C24 l, C24 alkynyl, CM haloalkyl, halosulfanyl, CM hydroxyalkyl, CM lkyl, Cy], CN, N02, OR", SR", C(O)Rb, °Rd, C(O)OR°, OC(O)R", OC(O)NR°R", NR°Rd, NR°C(0)R", NR°C(O)NR°R", NR°C(O)OR", C(=NR‘)NR°R", NR°C(=NR‘)NR°R", S(O)Rb, S(O)NR°R", S(O)2Rb, )2Rb, )Rb, C(=NO(C,_6 alkyl)Rb, and S(O)2NR°Rd, wherein said C1.g alkyl, CM alkenyl, or C" alkynyl, is optionally substituted with l, 2, 3, 4, 5, or 6 substituents independently selected from halo, CM alkyl, CM alkenyl, CM alkynyl, CM haloalkyl, halosulfanyl, CM hydroxyalkyl, CM cyanoalkyl, Cy], CN, N02, OR", SR3, C(O)R", "R", C(O)OR", OC(O)R", OC(O)NR°R", NR°Rd, )R", NR°C(0)NR°R", NR°C(O)OR", C(=NR‘)NR°R", NR°C(=NR‘)NR°R", scomb, S(O)NR°R", S(O)2R", NR"S(O)2R", C(=NOH)R", C(=N0(C,_6 alkyl))Rb, and S(O)2NR°Rd.

In some ments, Z is aryl, cycloallcyl, heteroaryl, or heterocycloallcyl, each ally substituted with 1, 2, 3, 4, 5, or 6 tuents selected from halo, CM alkyl, 02.4 alkenyl, CM alkynyl 55 CM haloalkyl, halosulfanyl, CM hydroxyalkyl, CM cyanoalkyl, Cy', CN, N02, OR", SR", C(O)Rb, C(O)NR°R", C(O)OR3, OC(O)R", R°R", mend, NR°C(O)R", NR°C(O)NR°R", NR°C(O)OR°, C(=NR‘)NRCR", NR°C(=NR‘)NR°R", S(O)Rb, S(O)NR°R", S(O)2R", NR°S(O)2R", and S(O)2NR°Rd.

WO 70514 In some embodiments, Z is aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected fiom halo, CM alkyl, C24 alkenyl, C24 alkynyl, C1.4 haloalkyl, CM hydroxyalkyl, CM cyanoalkyl, Cy', CN, N02, OR", SR", , C(O)NR°Rd, C(O)OR", OC(O)R", OC(O)NR°Rd, NR°Rd, NRCC(O)R", NR°C(O)NR°R", )OR3, C(=NR‘)NR°R", NR°C(=NR‘)NR°R", , S(O)NR"R‘1, S(O)2Rb, NR°S(O)2Rb, and S(O)2NR°R".

In some embodiments, Z is aryl or heteroaryl, each optionally substituted with l, 2, 3, 4, 5, or 6 substituents selected from halo, CM alkyl, 02.4 alkenyl, 02.4 alkynyl, CM haloalkyl, halosulfanyl, cM hydroxyalkyl, (3,.4 cyanoalkyl, cy', CN, N02, OR", SR3, C(O)R", °R", C(O)OR", OC(O)R", R"R", NR°R‘*, NR°C(O)R", NR°C(O)NR"R", NR°C(O)OR", C(=NR‘)NR°R", lO NR°C(=NR‘)NR°R", S(O)Rb, S(O)NR°R", b, NR°S(O)2Rb, and S(O)2NR°R".

In some embodiments, Z is aryl or heteroaryl, each optionally substituted with l, 2, 3, 4, 5, or 6 tuents selected from halo, CM alkyl, C24 alkenyl, C24 alkynyl, CM haloalkyl, CM hydroxyalkyl, (3..4 cyanoalkyl, Cy', CN, N02, OR", SR", C(O)R", C(0)NR°R", C(O)OR", OC(O)R", OC(O)NR°R", NRcRd, NR°C(O)Rb, NR°C(O)NR°Rd, NR°C(O)OR3, C(=NRi)NR°Rd, [5 NR°C(=NRi)NRCRd, S(O)R", S(O)NR°R", S(O)2R", NRCS(O)sz, and RCR°‘.

In some embodiments, Z is phenyl or 5— or 6-membered heteroaryl, each optionally substituted with l, 2, 3, 4, 5, or 6 substituents selected from halo, CH alkyl, C24 alkenyl, C24 alkynyl CM haloalkyl, halosulfanyl, CM hydroxyalkyl, CM cyanoalkyl, Cy‘, CN, N02, OR", SR", C(O)Rb, C(0)NR°R°, C(O)OR", 00mm", OC(O)NR°Rd, NRcRd, NR°C(0)R", NR"C(O)NR°Rd, NR°C(0)0R", )NR°R", NR°C(=NR‘)NR°R", S(O)Rb, S(O)NR°R", S(O)2R", NR"S(O)2R", and S(O)2NR°R".

In some embodiments, Z is phenyl or 5- or 6-membered aryl, each optionally substituted with 1, 2, 3, 4, 5, or 6 tuents ed from halo, CM alkyl, C24 alkenyl, C2... alkynyl, (3..4 haloalkyl, C._4 hydroxyalkyl, cM cyanoalkyl, Cy‘, CN, N02, OR", SR", C(O)R", C(O)NR°Rd, C(O)OR", OC(O)R", OC(O)NR°R", NR°R", NR°C(O)Rb, NR"C(O)NR°R", NR°C(O)OR3, £5 C(=NR‘)NR°Rd, NR°C(=NR‘)NR°Rd, S(O)Rb, S(O)NR°Rd, S(O)2R", NR°S(O)2Rb, and S(O)2NR°R".

In some embodiments, Z is phenyl optionally substituted with l, 2, 3, 4, 5, or 6 substituents selected from halo, CM alkyl, C24 alkenyl, C24 l, CM kyl, halosulfanyl, C M hydroxy- alkyl, CM cyanoalkyl, Cy‘, CN, N02, 0R3, SR", C(O)R", C(O)NR°Rd, C(O)OR", OC(O)R", OC(O)NR°R", NR°Rd, )Rb, )NR°Rd, NR°C(O)OR", C(=NRi)NR°R", 50 NR°C(=NR‘)NR°R", S(O)Rb, S(O)NR°R", S(O)2Rb, NR°S(O)2R", and S(O)2NR°R".

In some embodiments, Z is phenyl optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected from halo, CM alkyl, C24 alkenyl, C24 alkynyl, CM haloalkyl, CM hydroxyalkyl, CM cyanoalkyl, Cy‘, CN, N02, OR", SR", C(O)Rb, C(O)NR°Rd, C(O)OR", OC(O)R", OC(O)NR°Rd, NRCR", NR°C(O)R", NR°C(O)NR°Rd, NR°C(O)OR", C(=NR‘)NR°R", NR°C(=N‘Ri)NR°R", S(O)Rb, ;5, S(O)NR°R", S(O)2R", NR°S(O)2R", and S(O)2NR°Rd.

In some embodiments, Z is cycloalkyl or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected from halo, CM alkyl, C24 alkenyl, 02.4 alkynyl, CM haloalkyl, halosulfanyl, c._, yalkyl, c._4 lkyl, Cy’, CN, N02, OR", SR", C(O)Rb, C(0)NR°R", C(O)OR3, OC(O)R", OC(O)NR"R", NR°Rd, NR°C(O)R", NR°C(0)NR°R", NR"C(O)OR3, C(=NR‘)NR°R", NR"C(=NR‘)NR°R", S(O)Rb, S(O)NR°Rd, S(O)2Rb, )2R", and S(O)2NR°R".

In some embodiments, Z is cycloalkyl or heteroeycloalkyl, each optionally substituted with l, 2, 3, 4, 5, or 6 substituents ed from halo, CM alkyl, C24 alkenyl, C24 alkynyl, CM haloalkyl, C 1.4 hydroxyalkyl, CM cyanoalkyl, Cy‘, CN, N02, OR", SR", C(om", C(0)NR°R", C(O)OR", OC(O)R", OC(O)NR°R", NR°Rd, NR°C(O)Rb, NR°C(O)NR°R", NR°C(O)OR", )NR°Rd, NR°C(=NRi)NR°Rd, S(O)Rb, S(O)NR°R", S(O)2R", )2R", and S(O)2NR°R".

In some embodiments, Z is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, each ally substituted with l, 2, 3, 4, 5, or 6 substituents selected from halo, CM alkyl, C24 alkenyl, C24 alkynyl, CM haloalkyl, halosulfanyl, CM hydroxyalkyl, CM cyanoalkyl, Cy‘, CN, N02, OR", SR", C(O)Rb, C(O)NR"Rd, C(O)OR", OC(O)R", OC(O)NR°R°, NR°Rd, NR"C(O)R", NR°C(O)NR°R", NR°C(O)OR3, C(=NRi)NR°Rd, NR"C(=NR‘)NR°R", S(O)Rb, °R", S(O)2Rb, NR°S(O)2R", and S(O)2NR°Rd. ' In some embodiments, Z is CH; alkyl, CM alkenyl, or Cm l, each optionally substituted with l, 2, 3, 4, 5, or 6 substituents selected from halo, CM alkyl, C24 alkenyl, C24 alkynyl, CM haloalkyl, halosulfanyl, CM hydroxyalkyl, C1.4.cyanoalkyl, Cy', CN, N02, OR", SR3, C(O)Rb, C(O)NR°R", C(O)ORB, OC(O)R", OC(O)NR°Rd, NRCR", NR°C(O)Rb, NR°C(O)NR°R", NR°C(O)OR", C(=NRi)NR°Rd, NR"C(=NR‘)NR°R", S(O)Rb, S(O)NR°R", S(O)2Rb, NR°S(O)2R", and S(O)2NR°R".

In some embodiments, Z is CH; alkyl, C24; alkenyl, or C" alkynyl, each optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected from halo, CM alkyl, C" alkenyl, C24 alkynyl, C haloalkyl, CM hydroxyalkyl, CM cyanoalkyl, Cyl, CN, N02, OR", SR", C(O)Rb, °Rd, C(O)OR", OC(O)R", OC(O)NR°R", NR°Rd, NR°C(O)R", NR"C(O)NR°R", NRcC(O)OR", C(=NR‘)NR°R", NR°C(=NR‘)NR°R‘1, S(O)R", S(O)NR°R", S(O)2R", NR°S(O)2R", and S(O)2NR°R".

In some embodiments, Z is aryl, cycloalkyl, heteroaryl, or cycloalkyl, each optionally substituted with 1, 2, 3, 4, 5, or 6 substituents ndently ed from halo, CM alkyl, C24 alkenyl, C24 l, CM haloalkyl, halosulfanyl, CM hydroxyalkyl, CM cyanoallcyl, Cy‘, CN, N02, 0R9, SR", , C(O)NR"R", C(O)OR", OC(O)R", R°R", NR°Rd, NR°C(O)R", NR°C(O)NR°Rd, NR°C(O)OR", S(O)R", S(O)NR°Rd, S(O)2Rb,NRcS(O)1Rb, and S(O)2NR°Rd. 3O In some embodiments, Z is aryl, cycloalkyl, heteroaryl, or cycloalkyl, each optionally substituted with l, 2, 3, 4, 5, or 6 substituents independently selected from halo, CM alkyl, CM alkenyl, C24 l, CM haloalkyl, CM yallcyl, CM cyanoalkyl, Cyl, CN, N02, OR", SR", C(O)Rb, C(0)NR°R", C(O)OR", occom", OC(O)NR°R", NR°Rd, NR°C(O)R", NR°C(O)NR°R", NR°C(O)OR", S(O)Rb, S(O)NR°R", S(O)2Rb, NR"S(O)2R", and S(O)2NR°Rd.

In some embodiments, Z is aryl or heteroaryl, each optionally substituted with 1, 2, 3, 4, S, or 6 substituents independently selected from halo, CM alkyl, C24 alkenyl, C24 alkynyl, CM haloalkyl, halosulfanyl, CM hydroxyalkyl, c,_4 cyanoalkyl, Cy’, CN, N02, OR", SR", C(0)R", C(0)NR°R", C(O)OR", b, OC(O)NR°R", Mend, )R", NR°C(0)NR°R", NR°C(O)OR", , S(O)NR°Rd, b, NR°S(O)2R", and S(O)2NR°R".

In some embodiments, Z is aryl or heteroaryl, each optionally substituted with l, 2, 3, 4, 5, or 6 substituents independently selected from halo, CM alkyl, C24 alkenyl, C24 alkynyl, CM haloalkyl, CM hydroxyalkyl, cM cyanoalky1,Cy', CN, N02, OR", SR", C(O)R", C(O)NR°Rd, C(O)OR", OC(O)R", OC(O)NR°R", NR°R", NR°C(O)R", NR°C(O)NR°R", NR°C(O)OR", S(O)Rb, S(O)NR°R", S(O)2R", NR°S(O)2R", and S(O)2NR°R".

In some embodiments, Z is phenyl or 5- or 6-membered heteroaryl, each optionally substituted with 1, 2, 3, 4, S, or 6 substituents independently selected fiom halo, CM alkyl, C24 [0 alkenyl, C24 alkynyl, CM haloalkyl, halosulfanyl, CM hydroxyalkyl, CM cyanoalkyl, Cy], CN, N02, OR", SR", C(O)Rb, C(0)NR°R", C(O)OR3, OC(O)R", OC(O)NR°R", NRCR", NR°C(0)R", NR°C(O)NR"R", )OR", S(O)R", S(O)NR°R", S(O)2Rb, NR°S(O)2R", and S(O)2NR°R".

In some embodiments, Z is phenyl or 5- or 6-membered heteroa'ryl, each optionally substituted with l, 2, 3, 4, 5, or 6 substituents independently selected from halo, CM alkyl, C24 [5 alkenyl, CM alkynyl, CM kyl, CM hydroxyalkyl, CM cyanoalkyl, Cy', CN, N02, OR", SR", C(O)Rb, C(O)NR°R", C(O)0Ra, ", OC(O)NR°Rd, NR°Rd, NR°C(O)Rb, NR°C(O)NR°R", NR°C(O)OR'°‘, S(O)Rb, S(O)NR°R", S(O)2Rb, NR°S(O)2Rb, and S(O)2NR°Rd.

In some embodiments, Z is phenyl ally substituted with l, 2, 3, 4, 5, or 6 substituents ndently ed from halo, CM alkyl, C24 alkenyl, CM alkynyl, CM kyl, halosulfanyl, CM hydroxyalkyl, cl.4 cyanoalkyl, Cy‘, CN, N02, 0R3, SR", C(O)Rb, C(O)NR°Rd, C(O)OR", OC(O)R", OC(O)NR°R", NR‘R", NR°C(O)R", NR°C(O)NR°R", NR°C(O)ORa, S(O)Rb, S(O)NR°R", b, NR°S(O)2R*’, and S(O)2NR°Rd.

In some ments, Z is phenyl optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from halo, CM alkyl, C24 alkenyl, 02-4 l, CM haloalkyl, CM hydroxyalkyl, CM cyanoalkyl, Cy‘, CN, N02, ORa, SR", C(O)Rb, C(O)NR°Rd, C(O)OR", OC(O)Rb, OC(O)NR°R", NR°Rd, NR°C(O)R", NR°C(O)NR°R", NR°C(O)OR3, S(O)R", S(O)NR°R", S(O)2R", NR°S(O)2R", and S(O)2NR°R".

In some embodiments, Z is cycloalkyl or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from halo, CM alkyl, C24 alkenyl, C24 alkynyl, CM 50 haloalkyl, halosulfanyl, CM hydroxyalkyl, CM cyanoalkyl, Cy', CN, N02, OR", SR8, C(O)Rb, C(O)NR°R", ", 0C(O)Rb, R°R", NRcRd, NR°C(O)R", NR°C(0)NR°R", NR°C(O)OR", S(O)R", S(O)NR"R", S(O)2Rb, NR°S(O)2R", and S(O)2NR°R".

In some embodiments, Z is cycloalkyl or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4, 5, or 6 substituents ndently selected from halo, CM alkyl, C2", alkenyl, 02.4 alkynyl, CM $5 haloalkyl, c,_4 hydroxyallcyl, c1.4 cyanoalkyl, Cy‘, CN, N02, OR", SR", C(O)Rb, C(0)NR"R", ", OC(O)R", OC(O)NR°R", NR°R°, NR°C(0)R", NR°C(O)NR°R", NR°C(O)OR", S(O)R", S(O)NR°R", S(O)2R", NR°S(O)2R", and S(O)2NR°R". 2006/047369 In some embodiments, Z is CH; alkyl, C24; alkenyl, or CH alkynyl, each optionally tuted with 1, 2, 3, 4, 5, or 6 substituents independently selected from halo, CM alkyl, C24 alkenyl, C24 alkynyl, CM haloalkyl, halosulfanyl, CH hydroxyalkyl, CM cyanoalkyl, Cy', CN, N02, OR", SR3, C(O)Rb, C(O)NR°Rd, C(O)OR", OC(O)R", OC(O)NR°R", NR°Rd, NR°C(O)R", NR°C(O)NR°R", NR°C(O)OR", S(O)Rb, S(O)NR°R", S(O)2R", NR°S(O)2R", and R°R".

In some embodiments, Z is C]_g alkyl, Cm alkenyl, or CH alkynyl, each optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from halo, CM alkyl, 02-4 l, C24 alkynyl, CM haloalkyl, CH hydroxyalkyl, CM cyanoalkyl, Cy', CN, N02, OR", SR3, C(O)Rb, C(O)NR°R", C(O)OR", OC(O)R", 0C(O)NR°R", NRcRd, NR°C(O)Rb, NR°C(O)NR"R", NR°C(O)OR", S(O)R", S(O)NR°R", S(O)2Rb, NR°S(O)2R", and' S(O)2NR°Rd.

In some embodiments, Z is C,_3 alkyl, Cm alkenyl, C" alkynyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from halo, CH alkyl, C14 haloalkyl, halosulfanyl, CM yalky], CM llcyl, Cy', CN, N02, OR", C(O)NR°R", C(O)OR", NR°Rd, NR°C(O)R", and S(O)2Rb.

In some embodiments, Z is CH; alkyl, CH alkenyl, CH l, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from halo, CM alkyl, CM haloalkyl, CM hydroxyalkyl, CM cyanoalkyl, Cy', CN, N02, 0R3, C(O)NR°R", C(O)ORa, NR°Rd, NR°C(0)R", and S(O)2Rb. .

In some embodiments, Z is CH; alkyl, 02-3 alkenyl, C242 alkynyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, each optionally tuted with l, 2, or 3 substituents ndently selected from halo, CM alkyl, CM haloalkyl, halosulfanyl, CM hydroxyalkyl, CH cyanoalkyl, Cy', CN, N02, 018‘, C(O)NR°Rd, C(O)OR", NRcR", NR°C(0)R", and S(O)2R".

In some embodiments, Z is CH; alkyl, C24; alkenyl, CH alkynyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, each ally substituted with I, 2, or 3 substituents independently selected from halo, CM alkyl, CM kyl, CM hydroxyalkyl, CM cyanoalkyl, Cy], CN, N02, OR", C(0)NR°R°, C(O)OR", NR°R", NR°C(O)R", and S(O)2Rb.

In some embodiments, Z is substituted with at least one substituent comprising at least one CN group.

In some embodiments, Z is CH; alkyl, C243 alkenyl, CH alkynyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, each tuted with at least one ON or CH lkyl and optionally substituted with 1, 2, 3, 4, or 5 further substituents selected from halo, CM alkyl, 02.4 alkenyl, C24 alkynyl, CM haloalkyl, halosulfanyl, CM hydroxyalkyl, CM cyanoalkyl, Cy', CN, N02, OR", SR", C(O)Rb, C(O)NR°R", C(O)OR", OC(O)R", OC(O)NR°Rd, NR°Rd, NRCC(O)Rb, )NR°R°, NR°C(O)OR", S(O)R", S(O)NR°R", S(O)2Rb, NR°S(O)7_R", and S(O)2NR°R".

In some embodiments, Z is CH; alkyl, Cm alkenyl, CM l, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, each tuted with at least one ON or CH cyanoalkyl and optionally substituted with 1, 2, 3, 4, or 5 further substituents selected from halo, CM alkyl, C24 alkenyl, C24 alkynyl, CM haloalkyl, CM hydroxyalkyl, CM cyanoalkyl, Cy', CN, N02, OR", SR", C(O)Rb, C(0)NR°R", C(O)OR", OC(O)R", OC(O)NR°R", NR°Rd, NR°C(0)R", NR°C(O)NR°R", NR°C(0)0R°, S(O)Rb, S(O)NR°R", S(O)2R", NR°S(O)2Rb, and S(O)2NR°Rd.

In some ments, n the —(Y)n-Z moiety is taken together with i) A2 to which said moiety is attached, ii) R5 or R6 of either T or V, and iii) the C or N atom to which said R5 or R6 of either T or V is attached to form a 4— to 20-membered aryl, cycloalkyl, aryl, or heterocycloalkyl ring fused to the 5—membered ring formed by A', A2, U, T, and V, wherein said 4- to 20-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from —(W)m-Q.

In some embodiments, wherein the —(Y)n—Z moiety is taken together with i) A2 to which said moiety is attached, ii) R5 or R6 of either T or V, and iii) the C or N atom to which said R5 or R6 of either T or V is attached to form a 4— to 8-membered aryl, lkyl, heteroaryl, or heterocycloalkyl ring fused to the 5-membered ring formed by A', A2, U, T, and V, wherein said 4— to ered aryl, lkyl, heteroaryl, or heterocycloalkyl ring is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from —(W)m-Q.

In some embodiments, the —(Y).,—Z moiety is taken together with i) A2 to which said moiety is attached, ii) R5 or R6 of either T or V, and iii) the C or N atom to which said R5 or R6 of either T or V is attached to form a 6-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring fused to the 5- membered ring formed by A', A2, U, T, and V, wherein said 6-membered aryl, cycloalkyl, heteroaryl, or cycloalkyl ring is optionally tuted by 1, 2, or 3 tuents ndently selected from halo, CN, N02, CH; alkyl, C24; alkenyl, CM alkynyl, CH; haloalkyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl wherein said CH; alkyl, 02.3 alkenyl, Cm alkynyl, C]_g haloalkyl, aryl, lkyl, heteroaryl, or heterocycloalkyl is optionally substituted by l, 2 or 3 CN.

In some embodiments, Cy1 and Cy2 are independently selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, each optionally substituted by 1, 2, 3, 4 or 5 tuents independently selected from halo, CM alkyl, C24 alkenyl, CM alkynyl, CM haloalkyl, CM hydroxyalkyl, Ct, cyanoalkyl, CN, N02, on", SR8", ", C(0)NR°"R"", C(O)OR"", 00(0)Rb", 00(0)NR°"R"", NR""R°‘", NR°"C(0)R"", NR°"C(O)OR"", S(O)Rb", 5(0)NR°"R"", S(0)2R"", and S(O)2NR°"R°‘".

In some embodiments, Cyl and Cy2 are independently selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from halo, CM alkyl, C24 alkenyl, C24 alkynyl, CM haloalkyl, CN, N02, OR", SRn", C(O)Rb", C(O)NR°"Rd", C(O)OR3", b", OC(O)NR°"R"", ", NR°"C(0)R"", NR°"C(0)0R8", S(O)R"", 3(0)NR°"R"", S(O)2Rb", and R°"R"".

In some embodiments, Cyl and Cf are independently selected from cycloalkyl and heterocycloalkyl, each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from halo, cm alkyl, cu alkenyl, 02.4 alkynyl, CM haloalkyl, CN, N02, OR", SR", C(O)R"", C(0)NR°"R"", "", OC(O)R"", OC(O)NR¢"R"", NR""R"", NR°"C(0)R"", NR°"C(O)OR°", S(O)R"", S(O)NR°"R"", S(O)2Rb", and S(O)ZNR°"R"".

In some embodiments, CyI and Cf are independently ed fi'om cycloalkyl Optionally substituted by l, 2, 3, 4 or 5 substituents independently selected from halo, CM alkyl, C24 alkenyl, 0;. 4 alkynyl, c._4 haloalkyl, CN, N02, 011"", SR"", C(0)R"", C(0)NR°"R"", "", OC(O)R°", OC(0)NR°"R"", NR°"R"", NR°"C(0)R"", NR°"C(O)OR"", °", S(O)NR°"R"", "", and S(O)2NR°"R"".

In some embodiments, R1, R2, R3, and R4 are independently selected from H, halo, CM alkyl, C24 alkenyl, C24 alkynyl, CM haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, N02, 0R7, SR7, C(O)R8, C(O)NR9R'°, C(O)OR7 OC(O)R8, OC(O)NR9R'°, NRgR'o, NR9C(O)R8, NR°C(0)0R7, S(O)R8, S(O)NR9R'°, S(O)2R8, )2R8, and S(O)2NR9R‘°.

In some embodiments, R', R2, R3, and R4 are independently selected from H, halo, and CM alkyl.

In some ments, R1, R2, R3, and R4 are each H.

In some embodiments, R1 is H, halo, or CH alkyl.

In some embodiments, R5 is H, halo, CH alkyl, CH alkenyl, C24 alkynyl, CM haloalkyl, CN, N02, 0R7, SR7, C(O)R8, C(0)NR°R'°, C(O)OR7, OC(O)R8, OC(O)NR9R'°, NR9R‘0, NRQC(O)R8, NR9C(0)0R7, S(O)R8, S(O)NR9R'°, S(O)2R8, NR93(0)2R3, or S(O)2NR9R'°.

In some embodiments, R5 is H, halo, (3..4 alkyl, cM haloalkyl, halosulfanyl, CN, or NR9R'0.

In some embodiments, R5 is H, halo, CM alkyl, CM kyl, CN, or NRgRlo.

In some embodiments, R5 is H.

In some ments, R6 is H or CH alkyl.

In some embodiments, R6 is H.

In some embodiments, R1’ and R12 are independently selected from H, halo, Cl-.. alkyl, 02.4 alkenyl, C24 alkynyl, CM haloalkyl, halosulfanyl, CM hydroxyalkyl, CM lkyl, Cy‘, CN, N02, OR", SR", C(O)R", C(O)NR°R", C(O)OR", OC(O)Rb, OC(O)NR°R", NRCR", NR°C(O)Rb, NR°C(O)NR°R", NR°C(O)OR°, C(=NR‘)NR°R", NR‘)NR°R", scom", S(O)NR°R", S(O)2Rb, )2R", C(=NOH)Rb, C(=N0(c,.6 alkyl)Rb, and S(O)2NR°R", wherein said cl.8 alkyl, 02., alkenyl, or CH alkynyl, is optionally substituted with 1, 2, 3, 4, 5, or 6 substituents ndently selected fiom halo, CM alkyl, C24 alkenyl, C24 alkynyl, CM haloalkyl, halosulfanyl, CM hydroxyalkyl, CM cyanoalkyl, Cy‘, CN, N02, OR", SR", C(O)Rb, C(O)NR°R", ", OC(O)R", OC(O)NR"R", NR°Rd, NR°C(0)R", NR°C(O)NR°R", NR°C(O)OR", C(=NR‘)NR"R", NR°C(=NR‘)NR°R", S(O)Rb, S(O)NR°R", S(O)2Rb, NR°S(O)2R", C(=NOI—I)Rb, C(=NO(C,.6 alkyl))Rb, and S(O)2NR°Rd.

In some embodiments, RH and R12 are independently ed from H, halo, OH, CN, CM alkyl, CM haloalkyl, halosulfanyl, SCN, CM alkenyl, 02.4 l, CM hydroxyalkyl, CM cyanoalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl.

In some embodiments, R" and R12 are independently selected from H, halo, OH, CN, CM alkyl, CM haloalkyl, C24 alkenyl, CM alkynyl, CM hydroxyalkyl, C 1.4 cyanoalkyl, aryl, heteroaryl, lkyl, and heterocycloalkyl.

In some embodiments, the compound has a Ia or Ib: (Y)n"z (Y)n—Z / / _—_A2 'I'.—:A2 d:x 9\\V d:x 9\\V \A1 \A1 R1 R1 \ \ N \ I \ R2 R2 / AL / R3 N 3 N N N R H H Ia Ib.

In some embodiments, the compound has Formula II: (Y)n_z 71—h! JXL /\ \ R2 R3 N g In some embodiments, the compound has Formula IIIa or IIIb: (Y)n-—Z (Y)n-Z / / I Dl—N / / R1 R1 \ \ I \ R2 1 / \ R2 R3 N {1" R3 N fl IIIa IIIb.

In some embodiments, the compound has Formula IV: (Y)n—Z r;l—N "t \ \ N N In some embodiments, the nd has Formula Va: R3 N u In some embodiments, the compound has Formula Vb: N\\K In some embodiments, the compound has Formula VIa: Y__/ l \ R2 R3 N N H VIa.

In some embodiments, the compound has Formula VIb: |\ \ N H VIb- At various places in the present specification, substituents of compounds of the invention are sed in groups or in ranges. It is specifically intended that the invention include each and every individual subcombination of the members of such groups and ranges. For example, the term "Cm alkyl" is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and 05 alkyl.

It is further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment.

Conversely, various features of the invention which are, for brevity, described in the context of a single ment, can also be provided separately or in any suitable subcombination.

At various places in the t specification, linking tuents are described. It is specifically intended that each linking substituent e both the forward and backward forms of the linking substituent. For example, ‘R"),,- includes both NR(CR’R")n and —(CR’R")n -.

Where the structure clearly requires a g group, the Markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl" then it is understood that the "alkyl" or "aryl" represents a linking alkylene group or mylene group, respectively.

The term "n—membered" where n is an r typically describes the number of ring—forming atoms in a moiety where the number of ring-forming atoms is n. For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring and 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl group.

As used herein, the term " is meant to refer to a saturated hydrocarbon group which is straight-chained or branched. Example alkyl groups e methyl (Me), ethyl (Et), propyl (e.g., n— propyl and isopropyl), butyl (e. g., n-butyl, isobutyl, l), pentyl (e.g., n-pentyl, tyl, neopentyl), and the like. An alkyl group can contain from 1 to about 20, from 2 to about 20, from 1 to about 10, from 1 to about 8, from 1 to about 6, from 1 to about 4, or from 1 to about 3 carbon atoms.

A linking alkyl group is referred to herein as "alkylene." As used herein, "alkenyl" refers to an alkyl group having one or more double carbon-carbon bonds. Example l groups include ethenyl, propenyl, cyclohexenyl, and the like. A linking alkenyl group is referred to herein as "alkenylene." As used herein, "alkynyl" refers to an alkyl group having one or more triple carbon-carbon bonds. e alkynyl groups include ethynyl, propynyl, and the like. A linking alkynyl group is referred to herein as "alkynylene." As used herein, "haloalkyl" refers to an alkyl group having one or more n substituents.

Example kyl groups include CF3, CZFS, CHFg, C013, CHClz, C2C15, and the like.

As used herein, "halosulfanyl" refers to a sulfur group having one or more halogen substituents. Example halosulfanyl groups include pentahalosulfanyl groups such as SF5.

As used herein, "aryl" refers to monocyclic or polycyclic (e.g., having 2, 3 or 4 fiised rings) ic hydrocarbons such as, for example, phenyl, naphthyl, anthracenyl, phenanthrenyl, l, indenyl, and the like. In some embodiments, aryl groups have from 6 to about 20 carbon atoms. A linking aryl group is referred to herein as "arylene." As used herein, "cycloalkyl" refers to non-aromatic cyclic hydrocarbons including ed alkyl, alkenyl, and l groups. Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) groups and spirocycles. Ring-forming carbon atoms of a cycloalkyl group can be optionally substituted by oxo or sulfido. Cycloalkyl groups also e cycloalkylidenes. Example cycloalkyl groups include cyclopropyl, utyl, cyclopentyl, exyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbomyl, norpinyl, norcarnyl, tyl, and the like. Also included in the definition of cycloalkyl are es that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo or thienyl derivatives of pentane, pentene, hexane, and the like. A cycloalkyl group containing a fiised aromatic ring can be attached through any ring—forming atom including a ring-forming atom of the fused aromatic ring. A linking cycloalkyl group is ed to herein as "cycloalkylene." As used herein, "heteroaryl" refers to an aromatic heterocycle having at least one heteroatom ring member such as sulfur, oxygen, or nitrogen. aryl groups include monocyclic and polycyclic (e.g., having 2, 3 or 4 fused rings) systems. Examples of heteroaryl groups include without limitation, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, nyl, furyl, quinolyl, nolyl, thienyl, 3O imidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, and the like. In some embodiments, the heteroaryl group has from 1 to about 20 carbon atoms, and in further embodiments from about 3 to about 20 carbon atoms.

In some embodiments, the heteroaryl group contains 3 to about 14, 4 to about 14, 3 to about 7, or 5 to 6 ring—forming atoms. In some embodiments, the heteroaryl group has 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms. A g heteroaryl group is referred to herein as "heteroarylene." As used herein, "heterocycloalkyl" refers to omatic heterocycles including cyclized alkyl, alkenyl, and alkynyl groups where one or more of the ring-forming carbon atoms is replaced by a heteroatom such as an O, N, or S atom. Heterocycloalkyl groups include monocyclic and polycyclic (cg, having 2, 3 or 4 fiised rings) systems as well as spirocycles. Example "heterocycloalkyl" groups include morpholino, thiomorpholino, piperazinyl, ydrofuranyl, tetrahydrothienyl, 2,3- dihydrobenzofuryl, 1,3—benzodioxole, benzo-l,4—dioxane, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, and the like. orming carbon atoms and heteroatoms of a heterocycloalkyl group can be optionally substituted by oxo or sulfido. Also included in the definition of hete‘rocycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the nonaromatic heterocyclic ring, for example phthalimidyl, naphthalimidyl, and benzo derivatives of heterocycles. The cycloalkyl group can be attached through a ring-forming carbon atom or a orming heteroatom. The heterocycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring—forming atom of the fused aromatic ring. In some embodiments, the heterocycloalkyl group has from 1 to about 20 carbon atoms, and in filrther embodiments from about 3 to about 20 carbon atoms. In some embodiments, the heterocycloalky] group ns 3 to about 14, 4 to about 14, 3 to about 7, or 5 to 6 ring—forming atoms. In some embodiments, the heterocycloalkyl group has 1 to about 4, l to about 3, or 1 to 2 heteroatoms. In some ments, the heterocycloalkyl group contains 0 to 3 double or triple bonds. In some ments, the heterocycloalkyl group contains 0 to 2 double or triple bonds. A linking heterocycloallcyl group is referred to herein as "heterocycloalkylene." As used herein, "halo" or "halogen" includes , chloro, bromo, and iodo.

As used herein, "arylalkyl" refers to alkyl substituted by aryl and "cycloalkylalkyl" refers to alkyl substituted by cycloalkyl. An example arylalkyl group is benzyl.

As used herein, oarylalkyl" refers to alkyl substituted by heteroaryl and "heterocycloalkylalkyl" refers to alkyl substituted by heterocycloalkyl.

As used herein, "amino" refers to NH;.

As used herein, "alkylamino" refers to an amino group substituted by an alkyl group.

As used herein, "dialkylamino" refers to an amino group tuted by two alkyl groups. 3O As used herein, "hydroxylalkyl" refers to an alkyl group substituted by hydroxyl.

As used , "cyanoallcyl" refers to an alkyl group substituted by cyano. The carbon of the cyano group is typically not counted if a carbon count precedes the term. For example, cyanomethyl is considered herein to be a Cl lkyl group.

The compounds described herein can be asymmetric (e.g., having one or more stereocenters).

All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated.

Compounds of the present invention that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically active starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present ion. Cis and trans geometric isomers of the compounds of the t invention are bed and may be ed as a e of isomers or as separated isomeric forms.

Resolution of racemic mixtures of compounds can be carried out by any of numerous methods known in the art. An example method includes onal tallizaion using a chiral resolving acid which is an optically , salt—forming c acid. le resolving agents for fractional recrystallization methods are, for example, optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartan'c acid, ic acid, malic acid, lactic acid or the various optically active camphorsulfom‘c acids such as B-camphorsulfonic acid. Other resolving agents suitable for fractional crystallization methods include stereoisomerically pure forms of (Jr-methyl— benzylamine (e.g., S and R forms, or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ine, N—methylephedrine, cyclohexylethylamine, 1,2—diaminocyclohexane, and the like.

Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., obenzoylphenylglycine). Suitable elution solvent composition can be determined by one skilled in the art.

Compounds of the invention also e eric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric fonns include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge. Example prototropic tautomers include ketone — enol pairs, amide — imidic acid pairs, lactam — lactim pairs, amide - imidic acid pairs, enamine — imine pairs, and r forms Where a proton can occupy two or more positions of a heterocyclic system, for example, ll-l- and 3H-imidazole, lH-, 2H— and 4H- 1,2,4-triazole, 1H- and 2H- isoindole, and 1H- and 2H-pyrazole. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.

Compounds of the invention further include hydrates and solvates, as well as anhydrous and non~solvated forms.

Compounds of the invention can also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes ofhydrogen include tritium and deuterium.

In some embodiments, the compounds of the invention, and salts thereof, are substantially isolated. By "substantially isolated" is meant that the compound is at least partially or substantially separated from the environment in which is was formed or detected. Partial separation can include, for example, a composition enriched in the compound of the invention. Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the nd of the invention, or salt thereof. Methods for isolating compounds and their salts are routine in the art.

The expressions, "ambient temperature" and "room temperature," as used herein, are understood in the art, and refer generally to a temperature, e.g a reaction temperature, that is about the temperature of the room in which the on is d out, for example, a temperature from about °C to about 30 °C.

The phrase "pharmaceutically acceptable" is ed herein to refer to those nds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

The present invention also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, "pharmaceutically acceptable salts" refers to tives of the disclosed compounds wherein the parent compound is d by converting an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic es such as carboxylic acids; and the like. The pharmaceutically able salts of the present invention include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically able salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile (MeCN) are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack'Publishing Company, Easton, Pa., 1985, p. 1418 and Journal ofPharmaceutical e, 66, 2 , each of which is incorporated herein by reference in its entirety.

The present invention also includes prodrugs of the compounds described herein. As used herein, "prodrugs" refer to any covalently bonded carriers which release the active parent drug when stered to a mammalian subject. Prodrugs can be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in e manipulation or in vivo, to the parent compounds. Prodrugs include compounds wherein hydroxyl, amino, sulfhydryl, or yl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, amino, sulfhydryl, or carboxyl group respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine nal groups in the nds of the invention. Preparation WO 70514 and use of prodrugs is sed in T. i and V. Stella, "Pro-drugs as Novel Delivery s," Vol. 14 of the A.C.S. Sympositlm Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American ceutical Association and Pergamon Press, 1987, both of which are hereby incorporated by reference in their entirety.

Synthesis Compounds of the invention, including salts thereof, can be prepared using lmown organic synthesis techniques and can be synthesized according to any of numerous le synthetic routes.

The reactions for preparing compounds of the invention can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis. Suitable solvents can be substantially nonreactive with the ng materials (reactants), the ediates, or products at the temperatures at which the reactions are carried out, e.g., temperatures which can range from the solvent's freezing temperature to the solvent's boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one t. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected by the skilled artisan.

Preparation of compounds of the invention can involve the protection and deprotection of various chemical . 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 ting groups can be found, for example, in T.W. Green and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd. Ed., Wiley & Sons, Inc., New York (1999), which is incorporated herein by reference in its entirety. ons can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear ic resonance spectroscopy (e.g., 1H or 13C) infrared spectroscopy, spectrophotometry (e.g., UV-visible), or mass spectrometry, or by chromatography such as high performance liquid chromatography (HPLC) or thin layer chromatography.

Compounds of the invention can be ed according to us preparatory routes known in the literature. Example synthetic methods for preparing compounds of the invention are provided in the Schemes below.

As shown in Scheme 1, pyrazole—containing cores 1-9 and 1-6 can be synthesized starting with pyrrolo[2,3-b]pyridine or pyrrolo[2,3—b]pyrimidine 1-1. The compound 1-1 can be converted to an active species such as an N-oxide analog (1-2) by using an oxidant such as m-CPBA. The N—oxide 1—2 can be nated with a halogenating agent such as a combination of ethylammonium bromide and methanesulfonic anhydride to form a 4-halo compound 1-3 such as a 4-brorno compound while the N—oxide is d at the same time. The amine group of the compound 1-3 can be protected by a suitable amine protecting group to afford the protected compound 1—7, which subsequently undergoes a Suzuki coupling with a boric acid 1-8 to afford the pyrazole-containing cores 1-9a which can be further reacted with reagent L—(Y)n~Z (where L is a leaving group) to give compounds of the ion 1-9b. Alternatively, the N—oxide 1-2 can be halogenated with a halogenating agent such as MeSOZCI to form a 4—halo compound 1-4 such as a 4-chloro compound while the N—oxide is reduced at the same time. The 4-halo compound 1-4 can be coupled to a bromo- substituted le compound 1-5 under suitable conditions such as heating to afford the pyrazole- containing core 1-6, which may contain some functional groups such as bromo or cyano suitable for flirther chemical modification.

Similarly, an imidazole core 1-11 can be synthesized by coupling of the 4-halo compound 1-4 to an imidazole derivative 1-10 under suitable ions such as heating to afford the imidazole— containing core 1-11, which may contain some fimctional groups such as bromo or cyano suitable for fithhcr chemical ation.

Scheme‘l l)mCPBA, EtOAc R1 3:337 Br R1 aim\ N\ 2) N33003 R2 \ DMF """""1 R2 x \ \ R2 1-1 N\ r / T12 R3 N u 1-3 MesozCl protection of DMF amine group Br R1 R3 N/ 'f 1-7 P N—NH Ll, /\V Suzuki Y coupling B(OH)2 1-8 MH U /V JXL\ \ R2 R3 N/ '3 1-9a L-(Y)n-Z (Y)n'z U /V 1—11 R1 JXL\ \ R2 R3 N/ '3 As shown in §cheme 2, pyrazole-containing cores 2—3, 2-5 and 2-6 can be synthesized ng with a bromo—substituted pyrazole tive 2-1 (a compound 1—6 in Scheme 1 wherein one of R5 is Br). The bromo-substituted le derivative 2—1 can be coupled to boron—containing ic species such as an aromatic boric acid 2—2 using Suzuki coupling n Ar is aryl or heteroaryl, each ofwhich can be optionally tuted by one or more substituents such as alky, aryl, CN, nitro, alkoxy, etc. Alternatively, an alkene- or alkyne—containing compound such as an alkene—containing 2- unsaturated can be obtained by ng the bromo-substituted pyrazole derivative 2-1 to an compound such as an alkene 2—4 in the presence of a metal catalyst such as bis(triphenylphos- phine)palladium (II) chloride wherein t can be 0, 1, 2, and the like; and-R can be a substituent such as alkyl, aryl, CN, nitro, alkoxy, etc. The alkene group of nd 2-5 can be reduced by hydrogenation to afford the corresponding compound 2-6.

Scheme2 R5 Ar Ar B(OH)' 22 \ 2 ' N\ R5 Suzuki coupling X \ \ 2 JL / R R3 N N R5 __ R R5 t / \ N\ R5 N/ \ N —-——> x R5 catalyst R1 reduction R1 Xi \ \ R2 X \ 3k / \ 2 R N N JL / R R3 N N As shown in Scheme 3, imidazole-containing cores 3-7 can be synthesized starting with an N- protected o-pyrrolo[2,3—b]pyridine or an N—protected 4-bromo-pyrrolo[2,3—b]pyrimidine .3-1 wherein P is a suitable amine protecting group such as {[2-(trimethylsilyl)ethoxy]methyl} (SEM).

Compound 3-1 can be reacted with a Grignard reagent such as isopropyl magnesium chloride to generate an aromatic anion through ion exchange. The subsequent addition of a chloroacetyl— containing compound such as 2-chloro-N-methoxy-N-methylacetamide 3-2 to the anion will typically afford the chloroacetyl derivative 3-3. The derivative 3-3 can be reacted with an organic acid salt ’0 such as a cesium salt RSCOZCs to afford a compound 3-4. In the presence of a suitable ammonia source such as um acetate, the compound 3—4 can react with ammonia under suitable conditions such as at a high ature to form the imidazole ring of the compound 3—5. The free amine en of the imidazole derivative 3-5 can undergo further modification such as reacting with a compound X-(Y),,-Z where X is a leaving group such as chloro, bromo or iodo so as to afford compound 3—6. The protecting group of compound 3—6 can be removed by an appropriate method ing to the nature of the protecting group to yield compound 3-7. It should be noted that if there are functional groups present within the R, R5, and ——(Y)n—Z group, r modification can be made.

For example, a CN group can be hydrolyzed to afford an amide group; a carboxylic acid can be converted to a ester, which in turn can be further reduced to an alcohol, which in turn can be further modified. One skilled in the art will recognize appropriate further modifications.

Scheme 3 O/U\R5 Br O 'PngCl R1 R1 R5—-CO 0 x/ 2 s | \ THF, 0°C tort R 1 x/ x/ \ NH40Ac | R2 a1K N J\\ Cl\/U\ NCH3(OCH3) Ht. Moon—z >‘N(Y)n‘z R1 R1 1/ X-(Y)n-Z X/ I \ R2 \ deprotection R2 R2 \ \ X\/ R3 N \N E N N 3-5 3-6 W As shown in Scheme 4, thiazole-containing cores 4-3 can be synthesized staning with an N- ted chloroacetyl derivative 4-1 wherein P is a suitable amine ting group such as SEM.

Compound 4-] can be reacted with a thioamide 4—2 to form the thiazole ring, followed by deprotection of the amine nitrogen of the pyrrole ring by removal of the P group to afford the compound 4-3. Various thioureas 4—5 (equivalent to compound 4-2 wherein ~(Y)n-Z is NR’R"; and R’ and R" are H, alkyl, aryl or the like; or R’ and R" er with the N atom to which they are attached form a heterocycloalkyl) useful in preparing the thiazole compounds 4-3 can be made from secondary amines 4-4. A ary amine 4-4 can be reacted with 1,1 ’~thiocarbonyldiimidazole; and the resulting intermediate can fiirther be reacted with ammonia to afford a thiourea 4-5.

Scheme4 (Y)n—Z O \ N R2 Z—(Y)n)LNH2 R2 j;/ l \ R1 \ R1 - 1/ I R3 N I?! 2) deprotection R3 \N a 4-1 4-3 ‘ S 1)Im2CS H R'\ J‘L Rv/ ‘Rn . II" NH2 2) NH3/MeOH R 44 4_5 As shown in Scheme 5, thiazole—containing cores 5-5 can be synthesized starting with a thiazole compound 5—1. The compound 5-1 can be reacted with a metal alkyl such as l lithium via ion exchange to generate an aromatic anion in situ. The subsequent addition of boric acid trimethyl ester followed by hydrolysis will typically afford the boric acid 5—2. The boric acid 5—2 can undergo Suzuki coupling with an N—protected o—pyrrolo[2,3—b]pyridine or an N—protected 4— bromo-pyrrolo[2,3-b]pyrimidine 5—3 wherein P is a suitable amine protecting group such as SEM.

The protecting group P of the coupling product 5—4 can be removed by an riate method ing to the nature of the protecting group to yield the compound of the invention 5—5.

Scheme 5 Br R2 X/ \ 1 R /Z z J\\ I (Y)n (Y): R3 N K" /I\ 1. nBuLi, Hexanes )\ P \_—../ 2. B(0Me)a \=< B(OH)2 Pd(Ph3P)4 '2 heat (Y)n-Z (Y),,—z N:( N_ \ S deprotection \ S _________ R2 X/ \ 1 x/ R3J§N I R J\\ I \ R1 \ R3 N n -4 5.5 As shown in Scheme 6, pyrazole-containing compounds 6-1 can r be modified by substitution on the pyrazole NH group with appropriate reagents. For example, a compound 6-1 wherein P is a suitable amine protecting group such as SEM can be reacted with L-mn—Z where L represents a g group such as halo, triflate or the like to afford compound 6-2 under basic condition. If there are some functional groups present within the Y and/or Z group, further ation can be made. For example, a CN group can be hydrolyzed to afford an amide group; a carboxylic acid can be converted to a ester, which in turn can be further reduced to alcohol. One skilled in the art will recognize the further modifications if appropriate.

Additionally, compound 6-1 can be d with alkene 6-3 (wherein R’ and R" can be H, alkyl, cycloalkyl and the like; and 2’ can be an electron withdrawing group such as an ester or CN) to afford the compound 6-4. Further, substitution can be made on alkene 6-3 at the alpha position (alpha to Z’) to generate a substituted derivatives of product, 6-4 (see, e.g., Example 68).

Compounds 6-2 and 6-4 can be deprotected by appropriate methods according to the nature of the protecting group used to afford their corresponding de-protected counterpart.

Scheme 6 L-(Y)n-Z As shown in Scheme 7, bromo pyrazole containing compounds 7—1 can be further modified by ation with reagents like butyl lithium and reaction with electrophiles like aldehydes to give the alcohol containing compounds 7-2 which can be deprotected to yield compounds of the invention having formula 7-3. One skilled in the art will ize the further modifications where appropriate.

Scheme 7 R5 Br R5 R N;{ \; \ BuLl TFA Ni N NH4OH N R1 THF R1 R1 JXL \ aldehyde \ RaiN/\ R2 ketone etc. |\\| / mRZN 3 N NSEM R3 R N N \ H 74 7_2 7-3 As shown in Scheme 8, pyrazole—containing compounds 8-4 and 8—5 can be prepared by reaction of the N—protected bromo compound 8-1 with hydrazine in an appropriate solvent such as MN-dimethylformamide (DMF) to give the hydrazine intermediate 8-2. The hydrazino intermediate 8-2 is reacted with an appropriately substituted 1,3 dehyde like 8-3 to give the pyrazole containing compound 8-4. If there are some functional groups present within the Y and/or Z group, further modification can be made. For example, a CN group can be hydrolyzed to afford an amide in turn can be further reduced to alcohol. group; a ylic acid can be converted to a ester, which One skilled in the art will recognize r potential modifications.

Scheme 8 mn—z (Y)n"-Z Br / R‘ _ HgNtNH R200" \ N‘NS \ NHZNHZ R1 {IZAOH R1 \ HH8-3 4 R3J\N/ R2 _, \ NSEM RaiN/\ R10 RaiN/\ I: R21 JXL \ \ R2 NSEM NSEM R3 ,( INl 8-1 8-2 3.4 8-5 As shown in Scheme 9, the oxadiazole compound 9-6 can prepared from the N- protected bromo nd 9-1 by treatment with zinc cyanide in DMF in the ce of a catalyst like bis(tributyl) ium to give the N—protected cyano compound 9-2. The N—hydroxy carbox- with ide compound 9-3 can be prepared by heating the N-protected cyano compound 9-2 hydroxylamine hydrochloride in an appropriate solvent like ethanol and a base like potassium carbonate at a temperature below the boiling point of the solvent. The N—protected 1,2,4-oxadiazole compound can be prepared by treating the N—hydroxy carboximidamide compound 9-3 with an appropriately substituted acid chloride compound 9-4 in a solvent like pyridine at a sufficient temperature to complete the ring e. If there are some functional groups present within the Y and/or Z group, further modification can be made. For example, a CN group can be hydrolyzed to WO 70514 afford an amide group; a carboxylic acid can be converted to an ester, which in turn can be further reduced to l. One skilled in the art will recognize further modifications where appropriate.

Schemes) Br R1 CN R1 DMF R 310W"z N NH OH-HCI thz fw R3 N/ N (BUaP)2Pd N EtOH R3J\ / N N R3 N/ ‘SEM ‘ K2003 SEM ‘SEM reflux 94 9.2 9_3 ("n—z mn-z Z(Y)n—<_ ,0 \ [0—K N\ N N\ N Cl TFA R1 R1 9-4 NH4OH As shown in Scheme 10, the 3— and 4-arylpyrazolo compounds 10—9 can be prepared by reaction of the respective 3-arylpyrazolo compound 10-4 or 4-aryl pyrazolo compound 10-7 with an appropriately substituted bromo compound 10-8 as previously described. The 3-aryl lo compound 10-4 can be prepared by reacting an appropriately substituted aryl group containing a halogen like bromo or a triflate with the N-protected boronic acid or boronic acid ester le nd 10-2 under Suzuki—like conditions known in the literature. The N—protecting group of 10-3 can be removed by conditions previously described and known in the literature for ng groups like SEM.

The 4-arylpyrazolo compounds 10-7 can be prepared by reacting the appropriately substituted acetophenone compound 10-5 with DMF acetal in DMF at elevated temperatures to give the dimethylamino compound 10-6. The 4—arylpyrazolo compounds 10-7 can be prepared by treating the dimethylamino compound 10-6 with hydrazine in a solvent such as ethanol.

Scheme 1 0 0\ DMF ‘1 ’0 Ar Ar B TFA __ Ar-L (S (S / / / ,N—N _. HN—N HN N— ,N—N SEM SEM . 10-4 \ A, -1 conditions 10-3 104 "-1 \ Br R1 N‘N R1 N Jitg‘Rz\ R3JLN/ H R3 N u -8 -9 DMF-acetal | NH2NH2 _. Arm /‘ \ 1 0-5 1 0-6 As shown in Scheme 11 the substituted pyrazole compound 11-5 can be prepared by a variety of methods, such as by removing the protecting group e.g., SEM from compound 11-4 under conditions previously described. For example the tuted pyrazole N-protected compound 11-4 can be prepared by reaction of the intermediate pyrazole N—protected compound 11-3 with an appropriately substituted alkyl halide, benzyl halide, alkyl sulfonates, e. g., mesylate or tosylate, or other suitable leaving group L, in an appropriate solvent such as MeCN, DMF or tetrahydrofuran (TI-IF), in the presence of a base such a sodium hydride or cesium carbonate. The N—aryl pyrazole 11— 4 (wherein Y is ic) may be ed by reacting the intermediate pyrazole 11-3 with an appropriately substituted aryl c acid in a solvent such as dichloromethane (DCM) with copper e and pyridine. Alternatively the N-aryl pyrazole 11-4 (wherein Y is aromatic) can be prepared by ng the intermediate pyrazole 11-3 with an appropriately substituted aryl-fluoride in a solvent such as DMF at elevated temperature. Or, the substituted pyrazole compounds 11-4 (wherein Z is a group such as nitrile or ester and Y is at least two carbons) can be prepared by the reaction of intermediate pyrazole 11-3 with an appropriately substituted acrylate, acrylonitrile or other Michael- like ors in a t such as DMF in the presence of a base such as 1,8- diazabicyclo[5.4.0]undecene (DBU) or triethylamine (TEA) and at a temperature below the boiling point of the solvent. If there are some functional groups present within the Y and/or Z group, r modification can be made. For example, a CN group can be hydrolyzed to afford an amide group; a carboxylic acid can be converted to a ester, which in turn can be further reduced to alcohol. One skilled in the art will recognize the r modifications if appropriate.

Scheme 11 Z-(Y)n-Br NaH/DMF ,(Y)n-Z OR N—N CszcoalAcCN / K8I DMF / .

/ / ' \ K2003/H20 1 Ph-B(OH) xI 2 \ R X \ J\ / R2 7-10%TetraKis CU(OAC)2 + I ,B\ —————> R3 N N 0 0 -—‘—* X \ N/ ‘ \ MeClzler R3 11-1 M heat R3J\N/I N 11-4 SEM Ph-F 11.2 DMF 11_3 heat (Y)n' 7- "Michael" Addition / —-——> DBU/ DMF As shown in Scheme 12, le 12-1 wherein P is a suitable amine protecting group such as SEM can be reacted with an alkyne-containing conjugate acceptor such as 12—2, wherein Z is an electron-withdrawing group (for example, -CN) optionally in the presence of a base (DBU or K2C03 and the like) in a solvent such as DMF or MeCN for variable lengths of time to provide olefin- containing adducts 12-3. Compounds represented by the formula 12-3 can be deprotected by appropriate methods according to the nature of the protecting group used to afford compounds of the invention 12-4.

Scheme 12 N—NH _ / : z [)1 N Z . / R1 12-2 deprotectton R1 JNL /\ \ R2 \ R2 \ R2 R3 N N 1 \ R3 N/ N p H 12-1 12-4 As shown in Scheme 13, oxazole- or le-containing compounds 13—6 can be prepared starting with N—protected ro-pyrroloI2,3—b]pyrimidine 13-1 wherein P is a suitable amine protecting group such as SEM. Oxazole- or thiazole-containing products of formula 13—2 can be prepared by palladium-catalyzed coupling of 13-1 with oxazole or thiazole. The nd 13-2 can be reacted with a metal alkyl such as n-butyllithium to te the aromatic anion in situ to which can be added at low temperatures (preferably between —78°C and 0°C) derivatives of carboxylic acids 13-3 (wherein W = N(Me)(OMe) when X'=S; and W = Cl when X1=O), in the presence of other additives such as zinc chloride and copper(l) iodide when X'=O, in a suitable solvent such as THF to generate a variety of ketones 13-4. Ketones 13-4 can be caused to react with a variety of reagents such as diethyl (cyanomethyl)phosphonate or triethylphosphonoacetate in the presence of a base like potassium tert-butoxide followed by reduction (including hydrogenation or a —hydride catalyzed conjugate reduction), or with reagents such as tosylmethyl isocyanide to provide ts of formula 13-5 wherein Z is an electron-withdrawing group such as ester or -—CN. If there are functional be made, groups present within the R group or encompassed by the Z group, further modification can and such appropriate finther modifications will be recognized by one skilled in the art. Compounds 13-5 can be deprotected by appropriate methods according to the nature of the ting group used to afford their corresponding deprotected counterparts 13-6.

Scheme 13 \=\X‘ \x1 C' R1 R1 base. ves R1 \ Pd PPh NP KOAC *N/ N DMA \ heat R-133W P 13-1 13-2 13-4 /2 Z (Y)n (Y) R R N— N 1 1 \ X \ X R1 deprotectlon /N‘k : \ R2 JNL \ \ R2 R3 N "t R3 N/ N 13-5 13-6 As shown in Scheme 14, aminothiazole-containing cores 14-5 can be synthesized starting with thiazole-containing core 14-1 wherein P is a suitable amine protecting group such as SEM. The nd 14-1 can be treated with a metal alkyl such as n-butyllithium to generate the aromatic anion in situ to which can be added a suitable source of electrophilic halogen such as carbon tetrabromide to afford the halogenated derivative 14-2. The protecting group P of 14-2 can be removed by an riate method according to the nature of the protecting group to yield product WO 70514 14—3. The compound 14-3 can be reacted with amines 14—4 at elevated temperatures in a le solvent such as DMF to afford the compound of the invention, 14-5.

Scheme 14 N=\ N_ nBuLI \ S R1 R1 deprotectnon_ CBr4 JNL /\ \ \ _.

R2 THF \ R2 N JNL R3 N -78°C Ra N In P P 144 14-2 Br N\Ru N— N— \ S R\N,R" \ S H R1 ji ,\ \ 14-4 JNL /\ R2 \ R2 R3 N g heat R3 N N 14-3 14—5 As shown in Scheme 15, pyrrole-containing cores 15-4 can be synthesized starting with N— protected ro—pyrrolo[2,3-b]pyrimidine 15-1 wherein P is a suitable amine protecting group such as DEM (diethoxymethyl). The compound 15-1 can be reacted with I-(triisopropylsilyl)pyrrole boronic acid under Suzuki coupling conditions to afford the simultaneously e-deprotected core —2. Pyrrole-containing compounds 15-2 can be reacted with alkenes 153 containing an electron- withdrawing group Z (such as ~CN) in the presence of an appropriate base (such as DBU) at various temperatures (e.g., between room temperature and 40° C) followed by an in situ or separate deprotection step that is suitable for the selected protecting group to afford compounds of the invention 15—4.

Scheme 15 TIPS R / z // NH NW Cl R1 / Z / 1' RN / N \ B(OH)2 R‘ 15-3 \ R1 JL R2 N \ DBU MeCN R3 N/ N Pd(PPh3)4 \ R2 ' N \ JL / \ J'x R2 P Na2003 R3 N N / 2. TFA R3 N DME/HQO i: N heat -1 15-2 15-4 As shown in Scheme 16, a substituted pyrazole compound containing a sulfone or sulfoxide functionality as in 16-6 can be ed by a variety of s, such as starting with an appropriately substituted bromo enyl ether 16-2. Thioether 16-2 may be readily prepared by alkylation of the thiophenol 16—1 with an alkyl halide, mesylate or the like using a base like DBU, potassium carbonate or sodium hydride. The cinnamyl nitrile 16-3 may be prepared by Heck chemistry and the like, using ium acetate and triphenylphosphine in DMF at an appropriate temperature with acrylonitrile. The SEM protected intermediate 16-4 may be prepared by methods usly described for ming the Michael like addition of the pyrazole core to an appropriately substituted oc—B unsaturated nitrile like 16-3. The sulfoxide 16-5, where n=1, and sulfone 16-5, where n=2, may be prepared by methods well known in the literature for the oxidation of the thio ether 16-4 like m-chloroperbenzoic acid (MCPBA) in DCM. The final nds 16-6, where n= 0, l or 2, may be prepared by methods previously bed for the removal of the SEM protecting group. atively, the sulfur oxidation may be med on compounds 16-2 or 16-3 depending on the compatibility of the substitution in the synthetic scheme.

Scheme 16 Br SH Br I Cm.» USxR s\ ——» R——» 16-1 16-2 16-3 //N 4N ( //N (o n n n ‘R ‘R g /N\N /N~N /N\N / / / R2 R2 X/ R2 X/ x/ R3’4\N / N\ Rs/QN / N\ R1 R1 R3/K / \ sEM sEM H 16-4 16-5 16-6 Also, as shown in Scheme 17, substituted pyrazole compounds containing a sulfonamide functionality, such as 17-6 can be prepared by a variety of methods. For e, one may start with an appropriately substituted bromo phenyl sulfonamide 17—2, where Re and Rd are suitable substituents. A compound 17-2 may be readily prepared by reaction of the bromo phenyl sulfonyl chloride 17-1 and an appropriately substituted amine such as an aniline, or a primary or secondary amine in a suitable solvent such as DCM, THF or pyridine. The cinnamyl nitrile 17-3 may be prepared by Heck chemistry or the like, using palladium acetate and tn'phenylphosphine in DMF at an WO 70514 appropriate temperature with acrylom'trile. The final compounds 17—6 where Rc and Rd are part of the sulfonamide functional group may be prepared by methods analogous to those described in Scheme 16 starting with the cinnamyl nitrile 17-3.

Scheme 17 O O 0 O \\// Br \SLN,R°\/ Br 3020! S\N,R° O —> U e -—> an 17-1 17-2 //N 17-3 \\//0 Re S\l\\l’ /N\N Rd ———>— ————>— R2 A / \ N R1 H 17-6 Also, as shown in Scheme 18, substituted pyrazole compounds containing an alpha- allyl cyclopentylmethylene functionality, such as 18-8, can be prepared by, for example, reacting a pyrazole 18-3, wherein P is a suitable amine ting group such as SEM and X is N or C, with a cyclopentylacrylate ester 18—4 to form the ester 18-5. The ester 18-5 may then be d to the corresponding aldehyde, 18—6, for example, by the two-step procedure of reducing to the l and selectively oxidizing the intermediate alcohol to the aldehyde, then be converted to the corresponding e.g., via a Swem oxidation. The aldehyde, 18-6, may olefin, 18—7, for example by reaction with a Wittig t. The olefin 18-7, may then be deprotected, as described earlier, to e the formula 18-7 compound. The intermediate, 18—4, may be prepared, for example as shown in Scheme 18, stearting with cyclopentylaldehyde.

Scheme 18 COZH CH0 HOgCACOZH__.> I 0/ pyridine piperidine 18-1 18-2 1. i 2. MeOHi N? CHO COzMe 002MB I)!N / 1. DIBALH / 18-4 ——-)- R1 X \ N\ 2. Swem IN R ——-> X \ \ 2 /PQA~/\DBU/ACN X \ \ JL R JL R2 NIB-3 " 3 N / R N R3 N N 18 6_ l3 18~5 P "IQ/Tabb l/fl‘N _N deprotection / <—-———-—-——-— I/ R1 R1 f\ 1\ \ R2 R2 R3 N/ N R3 N/ N H 13‘7 F’ 18-8 Also, as shown in Scheme 19, the cyanoguanidine derivative 19—6 can be prepared starting is a suitable protecting group from tuted pyrazole compounds such as pyrazole 18-3, wherein P such as SEM and X is N or C. A compound 18-3 may, for example, be reacted with olefin 19-1, prepared by Homer-Wadsworth Emmons reaction of the corresponding Boo-protected piperidone, The intermediate 19—2 is the presence of a le basic catalyst, in a suitable solvent, to form 19—2. which then deprotected using a suitable deprotection reaction, to provide the amine compound 19-3, solvent at a suitable reacts selectively with a midocarbonate reagent such as 19-4, in a polar such as 19-5, which can then temperature, for example, about 20 °C to give a cyanoimidocarbamate be reacted with any of a variety of amines at ed temperature to give product 19-6.

Scheme 19 NBoc NH NC < > NC < > N—NH R1 flu—N /N—N / / X \ \ El R1 k /I R2 ection 19-1 X \ \ .——>— x \ \ R3 N N\ —-> JL R2 i R2 18-3 P R3 N/ N\ R3 N/ [N1 19-2 /CN /CN /19'3I l . s s N N \ \ / T NH2 3 194 N \CN NC > NH Nc\—7C)N : 100°C / / R1 R1 x \ \ x \ \ JL / R2 JL / R2 R3 N N R3 N N H H 19-6 ) 19-5 in the The intermediate compounds 20-5 and 20-6 may be prepared by a variety of methods -3 ture, for example, methods such as are outlined in Scheme 20. The intermediate compound —1 with an appropriately tuted Wittig may be ed by reaction of the aldehyde compound —3. reagent or Homer Emmons reagents to give the OL-B unsubstituted ester Alternatively, 20-3 may and an acrylic be prepared by a Heck—like reaction with an appropriately substituted aryl bromide 20-2 ester in the presence of a palladium reagent at ed temperatures. The compound 20-4 may be prepared by s previously described for the Michael—like addition of an appropriately 20-5 substituted pyrrole 18-3 on the OL-B unsaturated ester compound 20-3. The aldehyde compound -4 with reagents such as diisobutyl aluminium may be prepared by reduction of the ester nd hydride at low temperatures such as about -78 °C in an appropriate solvent. The aldehyde compound —5 can be further d to the corresponding alcohol compound 20-6 with reagents such as sodium borohydride in methanol. Alternatively the alcohol compound 20-6 may be prepared directly by reduction of the ester 20-4 with reagents such as lithium aluminium hydride in appropriate solvent and at appropriate temperatures.

Scheme 20 o o/ H \ l __ NH -1:r—:32MeM6020 //7' R i R1 N_N or 1+X \\— / Br /—RN/k \ R2 —" \— R1 I / R3 N The nds 21-2 and 21-3 may be prepared by using a variety of methods in the literature, such as, for example, methods outlined in Scheme 21. The olefin nd 21-1 may be prepared by the reaction of de compound 20-5 with an appropriately tuted Wittig reagent in an or Homer Emmons reagents using a base such as sodium hydride or potassium t-butoxide appropriate solvent and conducted at temperature. The olefin compound nd 21-1 may be reduced to the saturated compound 21—2, for example, using hydrogenation conditions well known in the literature, e.g., en in the presence of palladium on carbon in a solvent such as methanol.

The acetylenic compound 21-3 may be prepared by methods previously described, or by reaction of the aldehyde 20—5 with Bestmann-Ohira reagent (E. Quesada et at, Tetrahedron, 62 (2006) 6673- 6680) as described in the literature. Alternatively the alcohol compound 20—6 in Scheme 20 may be oxidized to the aldehyde 20-5 with methods well known in the literature, e.g., Swem oxidation conditions, followed by reaction with the Bestmann-Ohira reagent, wherein this reaction sequence on steps. may be carried out either as a one pot two—step reaction sequence, or in two separate Scheme 21 4R3/|\N/X. 21-3 P The compounds 22—1 and 22-3 may be ed by using a variety of methods in the ture, for example, via methods outlined in Scheme 22. The oxygen—substituted compound 22-1 substituted alcohol 20-6 (in Scheme may be prepared, for example, by reaction of an riately ), wherein X is N or C, and P is a protecting group, with a base such as sodium hydride and an appropriate agent such as an alkyl iodide, carbonate, or isocyanate, carried out in a suitable t and at a suitable temperature. Alternatively, the alcohol group on the compound 20-6 may be converted to a leaving group LG, as in compound 22-2, where the leaving group can be, for example, bromide or mesylate. The compound 22-2 serves as a substrate for subsequent reaction with a nucleophile, such as, for example, sodium ethoxide (Nuc = ethoxy).

Scheme 22 It should noted that in all of the Schemes described herein, if there are functional groups present on a tuent group such as Y, Z, R, R', R2, R5, etc., further modification can be made if appropriate and desired. For example, a CN group can be hydrolyzed to afford an amide group; a which in turn ylic acid can be converted to a ester, which in turn can be reduced to an alcohol, can be fiirther modified. In another example, an OH group can be converted into a better leaving for nucleophilic substitution, such as by CN. One group such as mesylate, which in turn is suitable skilled in the art will recognize such further modifications.

Methods -Compounds of the invention can te activity of one or more Janus kinases (JAKs). term "modulate" is meant to refer to an ability to increase or decrease the activity of one or more members of the JAK family of kinases. ingly, compounds of the invention can be used in methods of modulating a JAK by contacting the JAK with any one or more of the compounds or compositions bed herein. In some embodiments, compounds of the present invention can act as inhibitors of one or more JAKs. In some ments, compounds of the present invention can act to stimulate the activity of one or more JAKs. In further embodiments, the compounds of the invention in need of modulation of the receptor by can be used to modulate activity of a JAK in an dual administering a ting amount of a compound ula Ia, lb, or Ic. of the JAK JAKs to which the present compounds bind and/or modulate include any member family. In some embodiments, the JAK is JAKl, JAK2, JAK3 or TYK2. In some embodiments, the JAK is JAK] or JAK2. In some ments, the JAK is JAK2. In some ments, the JAK is JAK3.

The compounds of the invention can be selective. By "selective" is meant that the compound other binds to or inhibits a JAK with greater affinity or potency, tively, ed to at least one of JAKI or JAK2 IAK. In some embodiments, the compounds of the invention are selective inhibitors selective over JAK3 and/or TYK2. In some embodiments, the compounds of the invention are inhibitors of JAK2 (e.g., over JAK], JAK3 and TYKZ). Without wishing to be bound by theory, selective for because inhibitors of JAK3 can lead to immunosuppressive effects, a compound which is JAK2 over JAK3 and which is usefiil in the treatment of cancer (such as multiple myeloma, example) advantage fewer immunosuppressive side effects. can offer the additional of having Selectivity can be at least about 5—fold, 10—fold, at least about 20—fold, at least about 50-fold, at least about IOO-fold, at least about ZOO-fold, at least about SOO—fold or at least about IOOO-fold. Selectivity can be measured by methods routine in the art. In some embodiments, selectivity can be tested at the JAK2 over Km of each enzyme. In some embodiments, ivity of compounds of the invention for JAK3 can be determined by the ar ATP concentration.

Another aspect of the present invention pertains to methods of treating a sociated such disease or disorder in an dual (e.g., patient) by administering to the individual in need of invention or a treatment a therapeutically ive amount or dose of a compound of the present pharmaceutical composition thereof. A JAK—associated disease can include any disease, disorder or ion that is directly or indirectly linked to expression or activity of the JAK, including over- expression and/or abnormal activity levels. A JAK—associated'disease can also e any disease, disorder or condition that can be prevented, ameliorated, or cured by modulating JAK activity.

Examples of JAK—associated diseases include diseases involving the immune system including, for example, host organ transplant rejection (e.g., aft rejection and graft versus disease).

Further examples of JAK-associated diseases include autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, juvenile arthritis, type I diabetes, lupus, psoriasis, inflammatory bowel disease, ulcerative colitis, Crohn’s disease, myasthenia gravis, immunoglobulin nephropathies, autoimmune thyroid disorders, and the like. In some embodiments, the autoimmune disease is an autoimmune bullous skin disorder such as pemphigus vulgaris (PV) or bullous pemphigoid (BP).

Further examples of JAK-associated diseases include allergic conditions such as asthma, food ies, atopic dermatitis and rhinitis. Further examples of JAK-associated diseases include viral diseases such as Epstein Barr Virus (EBV), Hepatitis B, Hepatitis C, HIV, HTLV 1, Varicella-Zoster Virus (VZV) and Human Papilloma Virus (HPV). such as Further examples of JAK-associated diseases or conditions include skin ers sis (for example, psoriasis vulgaris), atopic itis, skin rash, skin irritation, skin sensitization (e.g., contact dermatitis or allergic contact dermatitis). For example, certain substances including some pharmaceuticals when lly applied can cause skin sensitization. In some embodiments, co-administration or sequential administration of at least one JAK inhibitor of the invention together with the agent causing unwanted sensitization can be l in treating such unwanted sensitization or dermatitis. In some embodiments, the skin disorder is treated by topical administration of at least one JAK inhibitor of the invention.

In further embodiments, the JAK-associated e is cancer including those characterized by solid tumors (e.g., prostate cancer, renal cancer, hepatic cancer, pancreatic , gastric cancer, breast cancer, lung cancer, cancers of the head and neck, thyroid cancer, glioblastoma, Kaposi’s leukemia such sarcoma, Castleman’s disease, melanoma etc), logical cancers (e.g., lymphoma, cancer such as cutaneous T—cell as acute lymphoblastic leukemia, or multiple myeloma), and skin lymphoma (CTCL) and cutaneous B—cell lymphoma. Example cutaneous T—cell lymphomas include Sezary syndrome and mycosis fungoides.

JAK—associated es can further include those characterized by expression of a mutant JAK2 such as those having at least one mutation in the pseudo-kinase domain (e.g., JAK2V617F).

JAK—associated es can further include myeloproliferative disorders (MPDs) such as polycythemia vera (PV), essential thrombocythemia (ET), myeloid metaplasia with myelofibrosis (MMM), chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia , osinophilic syndrome (HES), systemic mast cell disease (SMCD), and the like.

Further JAK—associated diseases e inflammation and inflammatory diseases. Example inflammatory diseases include inflammatory es of the eye (e.g., iritis, uveitis, tis, conjunctivitis, tract the upper or related disease), inflammatory diseases of the respiratory (e.g., lower respiratory respiratory tract including the nose and sinuses such as rhinitis or sinusitis or the tract including bronchitis, chronic obstructive pulmonary disease, and the like), inflammatory myOpathy such as myocarditis, and other inflammatory diseases.

The JAK inhibitors described herein can further be used to treat ischemia reperfusion injuries as stroke or cardiac arrest. or a disease or condition related to an inflammatory ischemic event such The JAK inhibitors described herein can further be used to treat anorexia, ia, or e such as that resulting from or associated with cancer. The JAK inhibitors described herein can further be used further be used to treat restenosis, sclerodermitis, or fibrosis. The JAK inhibitors described herein can diabetic retinopathy, to treat conditions ated with hypoxia or astrogliosis such as, for e, cancer, or neurodegeneration. See, e.g., Dudley, A.C. et al. Biochem. J. 2005, 390(Pt —36 and Sriram, K. et al. J. Biol. Chem. 2004, 279(19):]9936-47. Epub 2004 Mar 2.

As used herein, the term "contacting" refers to the bringing together of indicated moieties in in vitro system or an in vivo system. For example, "contacting" a JAK with a compound of the invention includes the administration of a compound of the present invention to an dual or patient, such as a human, having a JAK, as well as, for example, introducing a compound of the invention into a sample containing a cellular or purified preparation ning the JAK.

As used herein, the tenn "individual" or "patient," used interchangeably, refers to any animal, ing mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.

As used herein, the phrase "therapeutically effective amount" refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which es one or more of the following: (1) preventing the disease; for example, preventing a disease, ion or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the ogy or symptomatology of the disease; (2) inhibiting the disease; for example, ting a disease, condition or disorder in an dual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology), (3) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (lie. , reversing the pathology and/or symptomatology).

Combination Therapies One or more additional ceutical agents such as, for e, chemotherapeutics, anti— inflarnmatory agents, steroids, immunosuppressants, as well as Bcr-Abl, Flt-3, RAF and FAK kinase inhibitors such as, for example, those described in , or other agents can be used in combination with the compounds of the present invention for treatment of JAK-associated diseases, disorders or conditions. The one or more additional pharmaceutical agents can be stered to patient simultaneously or sequentially.

Example chemotherapeutic include proteosome tors (e.g., bortezomib), thalidomide, revlimid, and DNA-damaging agents such as melphalan, doxorubicin, cyclophosphamide, vincristine, ide, carmustine, and the like.

Example steroids include costeroids such as dexamethasone or prednisone.

Example 1 inhibitors include the compounds, and pharmaceutically acceptable salts thereof, of the genera and s sed in US. Pat. No. 5,521,184, W0 04/005281, EP2005/009967, /010408, and US. Ser. No. 60/578,491.

Example suitable Flt—3 inhibitors include compounds, and their pharmaceutically acceptable salts, as disclosed in WC 03/037347, W0 03/099771, and W0 04/046120.

Example suitable RAF inhibitors include compounds, and their phannaceutically acceptable salts, as disclosed in WO 00/09495 and W0 444.

Example suitable FAK inhibitors include compounds, and their pharmaceutically acceptable salts, as disclosed in W0 04/080980, W0 04/056786, W0 03/024967, W0 01/064655, W0 595, and W0 01/014402.

In some embodiments, one or more JAK inhibitors of the invention can be used in combination with a chemotherapeutic in the treatment of cancer, such as multiple myeloma, and may improve the treatment response as compared to the response to the chemotherapeutic agent alone, without bation of its toxic effects. Examples of additional pharmaceutical agents used in the treatment of multiple myeloma, for example, can include, without limitation, melphalan, melphalan plus prednisone [MP], doxorubicin, dexamethasone, and Velcade (bortezomib). Further additional agents used in the treatment of multiple myeloma include Ber-Ab], Flt—3, RAF and FAK kinase inhibitors. Additive or synergistic effects are ble outcomes of combining a JAK inhibitor of the present invention with an additional agent. rmore, resistance of multiple myeloma cells to agents such as dexamethasone may be reversible upon ent with a JAK inhibitor of the present invention. The agents can be combined with the present nds in a single or continuous dosage form, or the agents can be administered simultaneously or sequentially as separate dosage forms.

In some embodiments, a corticosteroid such as dexamethasone is administered to a patient in combination with at least one JAK inhibitor where the dexamethasone is administered intermittently as. opposed to continuously.

In some further ments, ations of one or more JAK tors of the ion with other therapeutic agents can be administered to a patient prior to, during, and/or afier a bone marrow transplant or stem cell lant.

Pharmaceutical Formulations and Dosage Forms When employed as pharmaceuticals, the compounds of the invention can be administered in the form of pharmaceutical compositions. These compositions can be prepared in a manner well 3O known in the pharmaceutical art, and can be administered by a variety of routes, depending upon r local or systemic treatment is desired and upon the area to be treated. Administration may be topical (including transdermal, mal, ophthalmic and to mucous membranes including intranasal, l and rectal delivery), pulmonary (e.g., by inhalation or insufflation of s or ls, including by nebulizer; intratracheal or intranasal), oral or parenteral. Parenteral administration includes intravenous, rterial, subcutaneous, intraperitoneal intramuscular or injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration. Parenteral administration can be in the form of a single bolus dose, or may be, for example, by a continuous perfusion pump.

Pharmaceutical compositions and formulations for topical administration may include eimal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders.

Conventional Pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable. Coated condoms, gloves and the like may also be useful.

This invention also includes pharmaceutical compositions which contain, as the active ingredient, one or more of the compounds of the invention above in ation with one or more pharmaceutically acceptable carriers (excipients). In making the itions of the invention, the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other ner. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a e, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, sions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

In preparing a formulation, the active compound can be milled to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it can be milled to a particle size of less than 200 mesh. If the active nd is substantially water soluble, the particle size can be adjusted by milling to e a substantially uniform distribution in the formulation, e.g. about 40 mesh.

Some examples of suitable ents e lactose, dextrose, sucrose, ol, mannitol, starches, gum , calcium phOSphate, alginates, tragacanth, gelatin, m silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents such as talc, magnesium te, and l oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl— and propylhydroxy-benzoates; sweetening agents; and flavoring agents. The compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.

The compositions can be formulated in a unit dosage form, each dosage containing from about 5 to about 1000 mg (l g), more usually about 100 to about 500 mg, of the active ingredient. The term "unit dosage forms" refers to physically discrete units suitable as y dosages for human subjects and other mammals, each unit containing a predetermined quantity of active al calculated to produce the d therapeutic effect, in association with a suitable pharmaceutical excipient.

The active compound can be ive over a wide dosage range and is generally administered in a pharmaceutically effective amount. It will be understood, however, that the amount of the compound actually administered will usually be determined by a physician, according to the relevant actual circumstances, including the condition to be treated, the chosen route of stration, the compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

For preparing solid compositions such as tablets, the principal active ingredient is mixed with a homogeneous a pharmaceutical excipient to form a solid preformulation ition containing mixture of a compound of the present invention. When referring to these preformulation compositions as homogeneous, the active ingredient is typically sed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as of the tablets, pills and capsules. This solid preformulation is then subdivided into unit dosage forms about 0.1 to about 1000 mg of the active type bed above containing from, for example, ient of the present invention.

The s or pills of the present invention can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For e, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope resist which serves to over the former. The two components can be separated by an enteric layer egration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.

The liquid forms in which the compounds and compositions of the present invention can be orated for stration orally or by ion include aqueous solutions, suitably flavored with edible oils such as cottonseed oil, syrups, aqueous or oil suspensions, and flavored emulsions vehicles. sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical Compositions for inhalation or ation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain le pharmaceutically acceptable excipients as described the compositions are administered by the oral or nasal respiratory route supra. In some embodiments, for local or ic effect. Compositions in can be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device can be ed to a face masks tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered orally or nasally from devices which deliver the ation in an appropriate manner.

The amount of compound or composition administered to a patient will vary depending upon what is being administered, the purpose of the administration, such as prophylaxis or therapy, the state of the patient, the manner of administration, and the like. In therapeutic applications, compositions sufficient to cure or at can be administered to a patient already suffering from a disease in an amount least partially arrest the symptoms of the disease and its cations. Effective doses will depend on clinician depending the disease condition being d as well as by the judgment of the attending of the disease, the age, weight and general condition of the patient, upon factors such as the severity and the like.

The compositions administered to a patient can be in the form of pharmaceutical itions described above. These itions can be sterilized by conventional sterilization ques, or may be sterile filtered. Aqueous solutions can be packaged for use as is, or lyophilized, stration. The the lyophilized preparation being ed with a sterile aqueous carrier prior to from 5 to 9 and pH of the compound ations typically will be between 3 and 11, more preferably most preferably from 7 to 8. It will be understood that use of certain of the foregoing excipients, rs, or stabilizers will result in the formation of pharmaceutical salts.

The therapeutic dosage of the compounds of the present invention can vary according to, example, the ular use for which the treatment is made, the manner of stration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. proportion or concentration of a compound of the invention in a pharmaceutical composition can vary depending upon a number of factors including dosage, chemical characteristics (e.g., hydrophobicity), in an and the route of administration. For example, the nds of the invention can be provided about 0.1 to about 10% w/v of the compound for aqueous physiological buffer solution containing parenteral administration. Some typical dose ranges are from about 1 pig/kg to about 1 g/kg of body about 100 mg/kg weight per day. In some embodiments, the dose range is from about 0.01 mg/kg to and extent of of body weight per day. The dosage is likely to depend on such variables as the type the relative ssion of the disease or disorder, the overall health status of the particular patient, of the compound selected, formulation of the excipient, and its route of biological efficacy from in vitro administration. Effective doses can be extrapolated from dose-response curves d or animal model test systems.

The compositions of the invention can further include one or more additional pharmaceutical agents such as a chemotherapeutic, steroid, anti—inflammatory compound, or immunosuppressant, examples of which are listed hereinabove. d Compounds and Assay Methods Another aspect of the t invention relates to labeled compounds of the invention (radio- labeled, fluorescent-labeled, etc.) that would be useful not only in imaging techniques but also in lassays, both in vitro and in viva, for localizing and quantitating JAK in tissue samples, including human, and for identifying JAK ligands by inhibition binding of a labeled compound. Accordingly, the present invention includes JAK assays that contain such labeled compounds.

The present ion further includes isotopically-labeled compounds of the invention. An "isotopically" or —labeled" compound is a compound of the invention where one or more atoms number different from the are replaced or substituted by an atom having an atomic mass or mass atomic mass or mass number typically found in nature (i.e., naturally occurring). Suitable uclides that may be incorporated in compounds of the present invention include but are not limited to 2H (also written as D for ium), 3H (also written as T for tritium), llC, 13C, I4C, "N, I5N, '50, 17o, 1"o, "‘F, 35s, 3501, 82Br, 75Br, 76Br, "Br, 123I, ""1, 125I and mI. The radionuclide that is incorporated in the instant radio—labeled nds will depend on the specific application of that radio-labeled compound. For example, for in vitro metalloprotease labeling and competition assays, compounds that incorporate 3I-I, MC, 82Br, I25I 1311, 3SS or will generally be most useful. For radio- imaging applications HC, 18F, "SI, 123I, ml, l3II, 75Br, 76Br or 77Br will generally be most .

It is understood that a "radio-labeled " or "labeled compound" is a compound that has incorporated at least one radionuclide. In some embodiments the radionuclide is selected from the 35S and 82Br. group consisting of 3H, l"C, "SI , The present invention can further include synthetic methods for incorporating radio-isotopes into compounds of the invention. Synthetic methods for orating radio-isotopes into organic compounds are well known in the art, and an ordinary skill in the art will readily recognize the methods able for the compounds of invention.

A labeled compound of the invention can be used in a screening assay to fy/evaluate compounds. For example, a newly synthesized or identified compound (i. 2., test nd) which is d can be evaluated for its ability to bind a JAK by monitoring its concentration variation when contacting with the JAK, through tracking of the labeling. For example, a test compound (labeled) can be ted for its ability to reduce binding of another compound which is known to bind to a JAK (i.e., standard compound). Accordingly, the y of a test compound to compete with the standard compound for binding to the JAK directly correlates to its binding affinity. Conversely, in some other screening assays, the standard compound is labeled and test nds are unlabeled.

Accordingly, the concentration of the labeled standard compound is monitored in order to te the competition between the standard compound and the test compound, and the relative g affinity of the test compound is thus ascertained.

Kits The present invention also includes pharmaceutical kits useful, for e, in the treatment or prevention of sociated diseases or disorders, such as cancer, which include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention. Such kits can further e, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically able carriers, onal containers, etc., as will be readily apparent to those skilled in the art. Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components, can also be included in the kit.

The invention will be bed in greater detail by way of specific examples. The following examples are offered for illustrative purposes, and are not ed to limit the invention in any manner. Those of skill in the art will readily recognize a variety of noncritical parameters which be changed or modified to yield essentially the same results. The compounds of the Examples have been found to be JAK inhibitors ing to at least one assay bed herein.

EXAMPLES Example 1: 3-[3-Methyl-l-(lH—pyrrolo[2,3-b]pyridin—4—yl)—1H—pyrazol—4-yl]benzonitrile / \ N/ {3 Step 1. IH-Pyrrolo[2,3—b]pyrz'dine 7—0xide To a solution of 1H-pyrrolo[2,3-b]pyridine (4.90 g, 0.0415 mol) in ethyl acetate (41 mL, 0.42 mol) was added a solution of meta-chloroperbenzoic acid (MCPBA; 9.3 g, 0.054 mol) in ethyl acetate (27 mL, 0.28 mol) at 0 °C. The reaction mixture was fied when ~20 mL on of MCPBA was added. An additional ~10 mL of ethyl acetate was added so that a solution resulted. The reaction mixture was allowed to warm to room temperature (rt) and stirred overnight, then was cooled at 0 °C, d and washed with ethyl acetate three times to give 10.94 g wet solid. The wet solid (8.45 g) was then suspended in water (35 mL), and to the suspension was added 13 mL of sat. Na2C03 dropwise, and the resulting mixture was stirred at room temperature overnight. The e was then cooled at 0° C, filtered and washed with water (x4) to give 3.55 g of pale purple solid which was dried at 40° C overnight to give the desired product (2.47 g, 44.4% yield). 1H NMR (400 MHz, : 8 8.2 (1H, d); 7.95 (1H, d); 7.5 (1H, d); 7.2 (1H, m); 6.65 (1H, d). MS (M+H)+: 136.

Step 2. 4-Chloro-1H-pyrrolo[2, 3-b]pyridine To a pink solution of 1H-pyrrolo[2,3-b]pyridine 7—oxide (2.47 g, 0.0184 mol) in dimethylformamide (DMF) (13.3 mL, 0.172 mol) was added methanesulfonyl chloride (4.0 mL, 0.052 mol) at 50 °C, and the pink color changed to orange. The reaction mixture was heated at 73 °C for 2h, then cooled to 40 °C. Water (35 mL) was added, and the resulting suspension was cooled at 0 °C.

NaOH was added to adjust the pH of the mixture to about 7. The mixture was filtered and washed with water (x3) to give 3.8 g of a wet pale orange solid that was dried at 40 °C overnight to give the product (2.35 g, 82.2% yield). 1H NMR (400 MHz, CDC13): 8 10.8 (1H, br); 8.21 (1H, d); 7.41(1H, d); 7.18 (1H, d); 6.61 (1H, (1).

MS (‘M+H)+: 153.

Step 3. 4—(4—Bromo-3—methyl—IH—pyrazol-I-yl)-1H—pyrrolo[2, 3-b]pyridine I \ I \ N N A mixture of 4-chloro-1H-pyrrolo[2,3-b]pyridine (0.050 g, 0.00033 mol) and 4-bromo methyl—1H-pyrazole (0.10 g, 0.00066 mol) was heated at 130 °C overnight. The reaction mixture then on silica gel) was subjected to column chromatography (eluting with 5% MeOH/DCM, 0.5% NH40H, to give 80 mg pale yellow solid which was triturated with MeOH (1.5 mL) to yield the product as a pale yellow solid (44 mg, 44% yield).

]H NMR (400 MHz, : 5 8.32 (1H, s); 8.25 (1H, d); 7.6 (1H, s); 7.45 (1H, d); 7.37 (1H, d); 6.96 (1H, d); 2.4 (3H, s). MS (M+H)+: 276.

Step 4. 3-[3-Methyl—1-(1H-pyrrolo[2,3—b]pyridin—4—yl)-1H—pyrazolyl]benzonitrile A e of 4-(4-bromomethy1-1H-pyrazol-l H-pyrrolo[2,3.-b]pyridine (0.032 g, 0.00012 mol), (3-cyanophenyl)boronic acid (0.027 g, 0.00018 mol), sodium ate (0.032 g, 0.00030 mol) and tetrakis(triphenylphosphine)palladium(0) (7.0 mg, 0.0000060 mol) in 1,2— dimethoxyethane (0.3 mL, 0.003 mol) and water (0.3 mL, 0.02 mol) was heated at 130 °C (a liquid resulted, but with two layers) for 4 h. The reaction mixture then was cooled to room temperature (rt), filtered and was washed with water (x2) and dimethyl ether (DME) (x2) to give the product as a pale orange solid (15 mg, 44% yield).

'H NMR (400 MHz, CD3OD): 3 8.57 (1H, s); 8.31 (1H, d); 7.8 (2H, m); 7.75 (2H, m); 7.55 (1H, s); 7.45 (2H, m); 7.01 (1H, d); 2.6 (3H, 5). MS (M+H)+: 299.

Example 2: -[3-Methyl-l-(lH-pyrrolol2,3-b]pyridinyl)-lH—pyrazolyl]acrylonitrile trifluoroacetate salt H TFA Step I. 4-Brom0-IH—pyrrolo[2,3—b]pyridz'ne To the a solution of rolo[2,3-b]pyridine 7—oxide (8.0 g, 0.060 mol), prepared by ure outlined in Example 1, Step 1 in DMF (100 mL, 1 mol) was added methanesulphonic anhydride (20.8 stirred at 0 °C for an g, 0.119 mol, in four portions) at 0 °C. The mixture was additional 20 min followed by an on oftetramethylammonium bromide (23.0 g, 0.149 mol). The resulting mixture was stirred overnight. Water (0.1 L) was added, and a slight exotherm was observed. A solution of sodium hydroxide in water (12.5 M, 12 mL) was added to adjust the pH of the mixture to about 8, followed by an on of ~O.25 L of water. The resulting mixture was stirred for onal 2 h then filtered. The solid obtained was washed with water x3 to give 6.72 g of 49% yield). a reddish solid which was dried at 50 °C over a weekend to give the product (5.75 g, 1H NMR (400 MHz, CDC13): 510.8 (1H, br); 8.2 (1H, d); 7.41(1H, d); 7.19 (1H, d); 6.61 (1H, d). MS (M+H)+: 196.

Step 2. 4—Bromo-I-[2—(trifnethylsilyDethoxyjmethyl—1H—pyrrolo[2,3—bjpyrz'dine To solution of 4-bromo-1H-pyrrolo[2,3-b]pyridine (6.2 g, 0.031 mol) and a [B— (trimethylsilyl)ethoxy]methyl chloride (6.7 mL, 0.038 mol) in DMF (62 mL, 0.80 mol) was added sodium hydride (1.5 g, 0.038 mol) at 0 °C, and the resulting solution turned opaque. The e was stirred for additional 4 h, then diluted with methyl tert-butyl ether (MTBE). The organic layer was separated and washed with water (x2) and brine aqueous solution successively. The organic phase was dried and concentrated in vacuo to give 14.1 g of a product as a pale orange oil. The oil was purified by column chromatography eluting with 5—20% ethyl acetate/hexanes to give the purified t as a colorless oil (9.66 g 94% yield). 1H NMR (400 MHz, CDC13): 5 8.2 (1H, d); 7.49 (1H, d); 7.19 (1H, d); 6.62 (1H, d); 5.78 (2H, s); 3.6 (2H, t); 0.98 (2H, t); 0.0 (9H, 5). MS (M+H)+: 326.

Step 3. (2E)—3-[3-Methyl-I-(IH—pyrrolo[2,3—b]pyridin—4—yl)—IH—pyrazol—4—yljacrylonitrile A on of enenitrile (0.043 mL, 0.00065 mol), bis(triphenylphosphine)palladium(II) chloride (0.0091 g, 0.000013 mol), 4-(4-bromo—3-methy1—1H-pyrazoly1)-1H-pyrrolo[2,3-b]pyridine (0.036 g, 0.00013 mol), and tetraethylamine (TEA) (0.15 mL, 0.0011 mol) in DMF (0.15 mL, 0.0019 mol) was microwaved at 120 °C for 2 h. The solution was then diluted with ethyl acetate and washed 2006/047369 in vacuo to with water (x2) and brine successively. The organic phase was dried and concentrated to give 12 give 62 mg of the t as an orange solid. The orange solid was purified by prep-LCMS acid (TFA) salt which was triturated with MTBE (1 mL) mg of an ite solid as a trifluoroacetic 4 h, 9 mg 28% yield). to provide the purified product as a pale green solid. (dried at 60 °C for , 1H NMR (400 MHz, CD30D): 2 :l of trans : cis isomers. For trans: 5 8.95 (NH,1H, s); 7.75 (olefin, 1H, d); 6.1 (olefin, 1H, d); 2.45 (Me, 3H, 5). MS (M+H)+: 249.

Example 3: 3-[3-Methyl—l-(1H-pyrrolo[2,3—b]pyridin—4-yl)—lH—pyrazol—4-yl]propanenitrile, trifluoroacetate salt N{N\ fl TFA A mixture of -[3—methyl-l—(lH—pytrolo[2,3—b]pyridiny1)-lH—pyrazolyl]acrylo- nitrile, TFA salt, (0.0050 g, 0.000020 mol, prepared according to Example 2) and palladium (5.8 mg, 0.0000054 mol) in ol (1 mL, 0.02 mol) and chloroethane (1 mL, 0.01 mol) was degassed then was filtered and then was stirred under an atmosphere of hydrogen for 3 h. The reaction mixture solid. The crude and the filtrate was concentrated in vacuo to give 8 mg of the product as an off-white material was purified by prep-LCMS to give 5.1 mg of a white solid as a TFA salt which was triturated with MTB (1 mL) to give the product as a white solid (1.7 mg, 34% yield). 1H NMR (400 MHz, CD30D): 8 8.52 (1H, s); 8.35 (1H, d); 7.72(1H, d); 7.6 (1H, s); 7.38 (1H, d); 6.96 (1H, d); 2.7-2.9(4H, m); 2.4 (3H, 5). MS (M+H)+: 251.

Example 13: henyl—1H—imidazol—1-yl)—1H—pyrrolo[2,3-b]pyridinc '>'\ mN/N A melt of 4-chloro-1H-pyrrolo[2,3-b]pyridine (0.050 g, 0.00033 mol) in 4-phenyl-1H- between imidazole (0.24 g, 0.0016 mol) was heated at 200 °C overnight. The reaction was partitioned with brine. The ethyl acetate and saturated NaHCO3, separated and the organic phase was washed WO 70514 organic layer was then dried and evaporated to give 250 mg of an orange oil. The oil was chromatographed with 7% MeOH/DCM, 0.7% NH40H, sample in solvent system. Collected 74 mg of the product as an orange glass. The glass was triturated with hot DCE (1.5 mL) to give 51 mg of a brown solid which was dried at 60 °C for 4 h to afford the desired product (50 mg, 59 yield). 1H NMR (400 MHz, dimethylsulxoxide (DMSO)): 8 12.5 (1H, s); 8.5 (1H, s); 8.4 (1H, s); 8.38 (1H, d); 7.8 (2H, m); 7.62 (1H, d); 7.4 (3H, m); 7.3 (1H, m); 6.81 (1H, (1). MS (M+H)+: 260 Example 14: [3—Methyl—l-(lH—pyrrolo [2,3—b]pyridinyl)-1H-pyrazol-4—yl]-piperidin—l-yl- methanone Step 1. 3-Methyl—1-(1~[2—(trimethylsilyl)ethoxyjmethyl—1H-pyrr010[2, 3-b]pyridin—4—yl)-IH-pyrazole- 4-carboxylic acid To a -70 °C solution of 4-(4-bromo—3-methy1—1H—pyrazol—1-yl)[2-(trimethy1silyl)ethoxy]— methyl—1H-pyrrolo[2,3—b]pyridine (0.107 g, 0.000263 mol) in THF (1 mL, 0.01 mol), and n— butyllithium in hexane (0.23 mL of 1.6M), 0.5g of C02 solid was added. After 15 min, the reaction was quenched with NH4C1. Ethyl acetate and water were added. The organic phase was washed with brine, and was evaporated to give 84 mg of an ite glass/solid. The solid was chromatographed with 50% ethyl acetate/hexanes, 0.5% AcOH, sample on silica gel to give 40 mg of a d product as a white solid (37% yield). 1H NMR (400 MHz, CDC13): 6 8.5 (1H, d); 7.45 (1H, d); 7.25 (1H, d); 7.02 (1H, s); 6.6 (1H, d); 5.75 (2H, s); 3.6 (2H, t); 2.48 (3H, s); 0.98 (3H, t); 0.0 (9H, 3). MS : 372.

Step 2. 4—[3—Methyl—4—(piperidin—I—ylcarbonyl)-1H—pyrazol—1 -yl][2—(trimethylsz'lyl)ethoxyjmethyl- IH-pyrrolo[2, 3-b]pyridine A solution of 3—methyl(l-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridiny1)- 1H-pyrazolecarboxylic acid (0.040 g, 0.00011 mol) (1:1 of AcOH) and N,N—carbonyldiimidazole (0.035 g, 0.00021 mol) in THF (1 mL, 0.01 mol) was d for 1.2h, afier which time piperidine (32 uL, 0.00032 mol) was added. After another 2h, r portion of piperidine (15 14L) was added and the resulting mixture was stirred overnight. The reaction mixture was then partitioned between ethyl acetate and water, and washed sequentially with sat. NaHCO; and brine. The organic phase was dried and evaporated to give 49 mg of the crude product as an orange oil/glass. The crude product was chromatographed with 75-100% ethyl e/hexanes, sample in DCM. Collected 25 mg of the purified product as a colorless glass/oil (50% yield).

'H NMR (400 MHz, CDClg): 5 8.45 (1H, d); 8.23 (1H, s); 7.5 (1H, d); 7.4 (1H, d); 7.05 (1H, d); 5.8 (2H, s); 3.7 (4H, br); 3.6 (2H, t); 2.55 (3H, s); 1.7 (6H, br); 1.0 (3H,. t); 0.0 (9H, s). Ms (M+H)+: 439.

Step 3. yl—I—(IH—pyrrolo[2, 3-b]pyridinyl)—1H-pyrazol—4—yU-pzperidin—1—yl—methan0ne A solution of 4—[3—methyl—4—(piperidin-1—ylcarbonyl)-1H-pyr2tzol-l-yl]~1-[2—(trimethylsily1)— ethoxy]methyl-1H—pyrrolo[2,3—b]pyridine (0.025 g, 0.000057 mol) in TFA (1 mL, 0.01 mol) was stirred for 1.5 h. The reaction mixture was then concentrated and partitioned between DCM and sat.

NaHCO3 x2, and brine. The organic layer was then dried and concentrated to give 28 mg of the product as a white foam. The foam was dissolved in ol (1 mL, 0.02 mol) and treated with ammonium hydroxide in water (8.0M, 1 mL) for 1.5h. The reaction was concentrated using a rotary evaporator to give 24 mg of a pale yellow glass. The glass was triturated with methyl t-butyl ether (MTBE) to give 13 mg of a white solid which was dried at It over a weekend. A total of 8 mg of the product was obtained after drying (45% yield). 1H NMR (400 MHz, : 8 9.7 (1H, s); 8.4 (1H, d); 8.2 (1H, s); 7.42 (1H, d); 7.4 (1H, d); 6.99 (1H, d); 3.4-3.8 (4H, br); 2.47 (3H, s); 1.5-1.8 (6H, br). MS (M+H)+: 309.

Example 15: [3-Methyl-l—(lH—pyrrolol2,3;b]pyridin—4-yl)—1H—pyrazolylmethyl]-phenyl-amine NHPh N\\/ (is’ N N Step 1. 3-Methyl-J-(J-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2, 3—b]pyridin-4—yl)—IH-pyrazole— 4—carbaldehyde To a ~70 °C solution of 4—(4-bromo—3-methy1-1H—pyrazol-l—y1)-1—[2-(trimethylsily1)ethoxy]- methyl—1H—pyrrolo[2,3-b]pyridine (0.25 g, 0.00061 mol) in THF (2 mL, 0.03 mol), 1.6 M n- ithium in hexane (0.54 mL). After 10 min, DMF (120 uL, 0.0015 mol) was added. The reaction was allowed to warm to rt and stirred overnight. The on was then quenched with NH4C1. Ethyl acetate/water was added. The organic phase was separated and washed with brine, then dried and 2006/047369 concentrated to give 180 mg of an orange oil. The crude product was chromatographed with 25% ethyl acetate/hexanes, sample in DCM. Collected 40 mg of a pale yellow oil (18% yield). 1H NMR (400 MHz, : 8 10.15 (1H, s); 8.7 (1H, s); 8.47 (1H, d); 7.58 (1H, d); 7.5 (1H, d); 7.05 (1H, d); 5.8 (2H, s); 3.63 (2H, t); 2.7 (3H, s); 0.98 (3H, t); 0.0 (9H, 3). MS (M+H)+: 356.

Step 2. N—[3—Methyl—I—(1-[2—(trimethylsilyDethoxyjmethyl—IH—pyrrolo[2,3—b]pyridinyl)—1H~ pyrazolyl]methylaniline A solution of 3-methyl-1~(l-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridinyl)- 1H-pyrazole—4-carbaldehyde (0.025 g, 0.000070 mol) and aniline (1M in DCM, 0.070 mL), in DCM (1 mL, 0.02 mol) was stirred for l min. Acetic acid (20 pL, 0.0004 mol), aniline (1M in DCM, 140 0L) and sodium triacetoxyborohydride (0.022 g, 0 mol) were added. The reaction was stirred overnight and partitioned between DCM and sat. NaHCO3, washed with brine. The c phase was .dried and evaporated to give 21 mg of a product as a pale orange glass (70% yield). 1H NMR (400 MHz, CD013): 5 8.4 (1H, d); 8.15 (1H, s); 7.65 (1H, d); 7.35 (3H, m); 7.09 (1H, d); 6.82 (1H, m); 6.89 (2H, m); 5.8 (2H, s); 4.35 (2H, s); 3.6 (2H, t); 2.5 (3H, s); 0.99 (3H, t); 0.0 (9H, 3).

MS (M+H)+: 433.

Step 3. [3-Methyl—I-(1H—pyrrolo[2, 3-b]pyridin-4—yl)-IH-pyrazol—4-ylmethyIJ-phenyl-amine Deprotection of N—[3 -methy1-1 —(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3~b]pyridin~ 2O 4-yl)-lH—pyrazolyl]methylaniline was carried out ing to the procedures of Example 14, Step 3 to give the desired product (58% yield).

‘H NMR (400 MHz, (31301.): 5 9.9 (1H, s); 8.38 (1H, d); 8.1 (1H, s); 7.4 (1H, d); 7.35 (1H, d); 7.3 (2H, m); 7.0 (1H, d); 6.79 (1H, m); 6.77 (2H, m); 4.25 (2H, s); 3.81 (1H, s); 2.41 (3H, s). MS (M+H)+: 303.

Example 25: 3-[3-Methyl-l-(lH-pyrrolo[2,3-b]pyridin—4-yl)—1H—pyrazolyll-cyclohexanol N\\/ N N Step 1. 3—Ethoxy-1—[3-methyl—I—(1-[2—(trimethylsilyl)ethoxyjmethyl—IH-pyrrolo[2,3-b]pyridinyl)— 1H—pyrazol-4—yl]cyclohex—Z-en-I -01 / \ H2)2Si(CH3)3 To a -75 °C solution of 4-(4-bromomethyl-1H-pyrazol-l—y1)-1—[2~(trimethylsilyl)ethoxy]- methyl-1H—pyrrolo[2,3-b]pyridine (0.11 g, 0.00027 mol) in THF (1.5 mL, 0.018 mol) was added 1.6 M n-butyllithium in hexane (0.22 mL). The reaction mixture turned dark orange. Afier ~10 min, 1.0 M magnesium dibromide in ether (0.35 mL) was added. After another 50 min, a solution of 3-ethoxy— ohexenone (41.5 uL, 0.000308 mol) in THF (~0.3 mL) was added. The resulting mixture was warmed to —40 °C over ~1h and quenched with NH4CL Then ethyl acetate/water was added. The organic phase was washed with brine, and trated to give 145 mg of an orange oil. The crude product was chromatographed with 0-50% ethyl acetate/hexane nt, sample in DCM. Collected 35 mg of the produce as an oil (30% yield).

IH NMR (400 MHz, CDC13): 8 8.49 (1H, d); 8.38 (1H, s); 7.55 (1H, d); 7.4 (1H, d); 7.1 (1H, d); 6.0 (2H, s); 3.6 (2H, t); 2.81 (2H, m); 2.62 (3H, s); 2.58 (2H, m); 2.27 (2H, m); 1.0 (3H, t); 0.0 (9H, 5).

MS (M+H)+: 422.

Step 2. 3—[3-Methyl—1-(1—[2—(trimethylsiéyDethoxyjmethyl-IH-pyrrola[2, 3—b]pyridin-4~yl)-1H- pyrazolyl]cyclohexanol A mixture of 3-[3-methy1-l-(1-[2-(tn'methylsilyl)ethoxy]methyl—lH-pyrrolo[2,3-b]pyridin—4~ yl)-1H-pyrazol-4—yl]cyclohex-Z-en-1—one (0.019 g, 0.000045 mol) and palladium on carbon (Pd/C) (0.018 g, 0.000017 mol) in ol (2 mL, 0.05 mol) was degassed and was stirred under a hydrogen atmosphere overnight. An additional 48 mg of 10% Pd/C was added and stirred under a hydrogen atmosphere for 8h. The palladium was filtered and the filtrate was stirred with sodium ydroborate (0.032 g, 0.00084 mol) for 5h. The reaction was purified by prep-HPLC to give 5 of the desired product. MS (M+H)+: 426.

Step 3. 3—[3-Methyl(1H-pyrrolo[2,3-b]pyridin-4—y1)—IH-pyrazoIyl]-cyclohexanol Deprotection of 3-[3-methyl(1-[2-(tiimethylsily1)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin- 4—yl)—1H-pyrazolyl]cyclohexanol was carried out according to the procedures of Example 14, Step 3 to give the desired product (40% yield).

'H NMR (400 MHz, CDClg): 8 9.72 (1H, s); 8.35 (1H, d); 7.95 (1H, s); 7.41 (1H, d); 7.35 (1H, d); 7.02 (1H, d); 3.78 (1H, m); 2.6 (1H, m); 2.4 (3H, s); 1.2—2.4 (8H, m). MS (M+H)+: 296.

Example 40: 4—[1-(3-Methoxy—l-methyl-propyl)-1H—pyrazol—4-yl]-1H—pyrrolo[2,3-b]pyridine O..— | t \ N Ll Step 1. 4-[1-(3-Methoxymethylpropr-1H—pyrazol—4-yU—I-[2-(trimethylsilyDethoxyj-methyl—1H- pyrrolo[2,3-b]pyridine To a 0 °C solution of 3-[4-(1-[2-(trimethylsi1yl)ethoxy]methyl-1H—pyrrolo[2,3-b]pyridin yl)—1H-pyrazol-l—yl]butanol (the alcohol was made by DIBAL reduction of the ester in Example 58) (0.056 g, 0.00014 mol)) in DMF (1 mL, 0.01 mol), was added sodium hydride (0.0107 g, 0.000268 mol). After 5 min, methyl iodide (18 "L, 0.00029 mol) was added and the resulting mixture was stirred over a weekend. The mixture was then partitioned between ethyl acetate and water, separated and the organic phase was washed with brine. The organic phase was concentrated to give a pale orange oil.

'H NMR (400 MHz, CDCl3): 5 8.4 (1H, d); 8.3 (1H, s); 8.0 (1H, s); 7.65 (1H, d); 7.27 (1H, d); 6.8 (1H, d); 5.8 (2H, s); 4.7 (1H, m); 3.63 (2H, t); 4 (2H, m); 3.38 (3H, s); 2.1-2.3 (2H, m); 1.7 (3H, d); 1.0 (2H, t); 0.0 (9H, 8). MS (M+H)+: 400.

Step 2. 4-[1-(3—Methoxy-I-methyl-propyl)— azol—4—yl]—JH-pyrrolo[2, 3-b]pyridine Deprotection of 4—[1 thoxy-1 —methy1propyl)— 1 H—pyrazoly1]-1 -[2—(trimethylsilyl)- ethoxy]—methy1-1H-pyrrolo[2,3-b]pyridine was carried out ing to the procedures of Example 14, Step 3 to give the desired product (25% yield). 1H NMR (400 MHz, CDC13): 5 10.0 (1H, s); 8.35 (1H, d); 8.18 (1H, s); 7.95 (1H, s); 7.41 (1H, d); 7.21 (1H, d); 6.75 (1H, d); 4.63 (1H, m); 3.15-3.4 (2H, m); 3.35 (3H, s); .05 (2H, m); 1.6 (3H, d). MS (M+H)+: 270.

Example 42: 4—[1—(l-Methylpyrazolyl-propyl)—1H-pyrazolyl]-1H-pyrrolo[2,3-b]pyridine Step 1 . 4—1-[1-Methyl—3-(IH-pyrazol—I -yI)propyl]-1H—pyrazolyl—1-[2-(trimethylsilyDethoxyjmethyl— IH-pyrrolo[2,3-b]pyridine To a 0 °C solution of 3—[4—(1 -[2-(trimethylsi1yl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridin yl)—1H-pyrazolyl]butyl esulfonate (prepared by mesylation of the l as in Example 59, Step 1) (0.055 g, 0.00012 mol) and lH-pyrazole (0.025 g, 0.00036 mol) in DMF (1 mL, 0.01 mol) was added sodium hydride (0.014 g, 0.00036 mol). The ing solution was stirred overnight and then partitioned between ethyl acetate and 0.1 N HCl, water. the c phase was separated and washed with brine. The organic layer was then concentrated to give 49 mg of a pale orange glass (87% yield).

‘H NMR (400 MHz, CDC13): 8 8.4 (1H, d); 8.18 (1H, s); 7.99 (1H, s); 7.6 (1H, t); 7.5 (1H, d); 7.4 (1H, t); 7.27 (1H, d); 6.8 (1H, d); 6.3 (1H, m); 5.8 (2H, s); 4.2 (1H, m); 4.0-4.2 (2H, m); 3.61 (2H, t); 2.58 (2H, m); 1.65 (3H, d); 1.0 (2H, t); 0.0 (9H, 5). MS (M+H)+: 436.

Step 2. 4-[1—(1 -Methyl-3—pyrazol—l—yl—pr0pyl)~1H—pyrazol—4—yl]—1H—pyrrolo[2, 3~b]pyridine Deprotection of 4-1 -[1 -methyl-3—(lH-pyrazol-1—y1)propyl]-lH-pyrazoly1-1 -[2-(trimethyl- .silyl)ethoxy]methyl—1H-pyrrolo[2,3-b]pyridine was carried out according to the procedures of Example 14, Step 3 to give the desired product (38% yield). lH NMR (400 MHz, CDC13): 5 9.7 (1H, s); 8.38 (1H, d); 8.1 (1H, s); 7.7(1H, s); 7.59 (1H, t); 7.4 (1H, d); 7.35 (1H, t); 7.21 (1H, d); 6.75 (1H, d); 6.25 (1H, rn); 4.4 (1H, m);3.9—4.15(2H, m); 2.55 (2H, m); 1.63 (3H, (1). MS (M+H)+: 306.

The following compounds in Table 1 were made by methods ous to the procedures above as indicated. "Purification A" indicates that the product following deprotection was purified by preparative-HPLC under the following conditions: C18 eluting with a nt of MeCN/Hzo containing 0.15% NH40H. 1-(1H-Pyrrolo[2,3-b]pyridin—4- yl)—1H-pyrazolecarboxylic acid ethyl ester 4-(3—Methy1—4-phenyl—pyrazol-1 - yl)-1H—pyrrolo[2,3-b]pyridine 4-(3 -Phcnyl-pyrazoly1)-lH- [2,3-b]pyridine 4-(4-Brom0-imidazol-l -yl)—1H- pyrrolo[2,3-b]pyridine 4—(4—Bromo—3—methyl—pyrazol—1 — yl)-1H-pyrrolo[2,3-b]pyn'dine 3-[3-Methy1(1H-pyrrolo[2,3- b1PyTidin-4—yl)-1H—pyrazol—4—yl]— benzonitrile 4-![3-Methyl(1H-pyrrolo[2,3- b]pyridin—4—yl)-lH-pyrazol—4-y1]- benzonitrile 4-[4—(3—F1uoro-phenyl)methyl- pyrazol-l -y1]—1H-pyrrolo[2,3- b]pyridine 4-[4-(3,5-Bis-trifluoromethyl- phenyl)methyl-pyrazol-1 —y1]- 1 olo[2,3-b]pyridine 4-[443,5-Difluoro-pheny1) methyl-pyraZOI-l 'y11'1H‘ pynolo[2,3-b]pyridine {3 -[3 -Methyl-1 -(1H—pyrrolo[2,3 - b1PWidinyl)-l zolyl] - pheny1}—methanol 4-(3-Methyl-4—pyrimidin-5—yl- pyrazol—l—yl)—1H—pyrrolo[2,3-b]— pyridine 4-[3-Methyl—4-(1 l-1H- indol-S—yl)-pyrazol-1 -yl]-1 H- pyrrolo[2,3-b]pyridine 4-(3-Methy1~4-thiophen—3-yl— pyrazol-l —yl)-1H-pyrrolo[2,3—b]~ pyridine N,N-Dimethyl—4-[3-methy1—1 — (1 H—pyrrolo[2,3-b]pyridinyl)- 1H-pyrazolyl]- benzenesulfonamide N— Methyl—l -(1H- pyrrolo[2,3—b]pyridin—4-yl)-I H— pyrazol-4—yl]-phenyl} —acetamide 3-tert-Butyl-l -( l H-pyrrolo[2,3— b]pyridinyl)~1 H—pyrazole—4— carbonitrile WO 70514 4-Bromo-1—(1H-pyrrolo[2,3‘-b]- pyridin—4—yl)~1H—pyrazole—3— carbonitrile 4-(3—Cyano-phenyl)-1 -(1H- o[2,3—b]pyridiny1)—1 H- pyrazolecarbonitrile 3—[1-(lH-Pyrrolo[2,3-b]pyridin yl)trifluoromethyl—1 H-pyrazol — 4—yl]—propan-1 -ol 3—[3—Methyl(lH-pyrrolo[2,3- b]pyridin—4-y1)—1 H-pyrazol—4-yl]- prop-Z-en—l —ol 2-[4-Bromo-l -(1H—pyrrolo[2,3- b]pyridin-4—y1)— 1 H—pyrazoly1] — isoindole-l ,3-dione 4-[4-(2,6-Dimethyl-phenyl)'3‘ methyl-pyrazol-l -y1]-1H' pyrrolo[2,3-b]pyridinc 3—[3-Amino—1 -(l H—pyn'olo[2,3- b]pyridin—4-yl)—1H—pyrazolyl]— benzonitrile 3-[3—Benzylamino—1 -(1H— pyrrolo[2,3—b]pyridin—4-yl)—1 H- l-4—y1]-benzonitfile N-[4-(3-Cyano-phenyl)-1 -(1H— pyrrolo[2,3—b]pyridinyl)-l H- pyrazolyl]-acetamide 3 -[4-(1H-Pyrrolo[2,3-b]pyridin—4— . razol—1 —yl]-propan—l -01 Purification A 3—[4-(1H-Pyrrolo[2,3-b]pyridin 58 yl)-pyrazol-1 utan-1 —ol Purification A 4—[4—(1H-Pyrrolo[2,3-b]pyridin-4— 59 yl)-pyrazol-1 -yl]-pentanenitrile Purification A 4-[4—(1H-Pyrrolo[2,3-b]pyridin 60 yl)-pyrazol-1 -y1] -pcntanoic acid Purification A amide 4-D -(3-Imidazol-1 -ylmcthyl- propyl)—1H—pyrazol—4—yl]-1 H— pyrrolo[2,3-b]pyridine opentyl—4-[4-(1H- 59 pyrrolo[2,3—b]pyridin—4-yl)- Punficatlon A. . pyrazol—l-yn-butyronitrile WO 70514 2006/047369 4-Cyclopentyl—4—[4-(1 H— 60 pyrrolo[2,3-b]pyridin—4-yl)— Purification A pyrazol-l -y1]-butyramide 3—Cyclopropyl—3 —[4—(7H— pyrrolo[2,3-d]py1imidin-4—yl)- 61 pyrazol-l -y1]-pr0pionitrile Purification A Example 46: 4-(2-tert—Butylmethyl-lH—imidazol-4—yl)—lH—pyrrolo[2,3-b]pyridine trifluoro— acetate salt KN// OTFA |\ \ N N Step I. 4—(2—tert—butyl—1H—imidazol—5—y0-1—[2—(trimethylsilyl)ethoxyjmethyl—1H—pyrrolo[2,3— bjpyridine To a solution of trimethylacetic acid (0.169 mL, 0.00147 mol) in ethanol (6 mL, 0.1 mol) was added cesium carbonate (0.24 g, 0.00073 mol), and the resulting mixture was stirred for 2 hours. The solvent was removed in vacuo to afford cesium pivalate.

To a solution of 2—chloro—1—(1-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridin—4- yl)ethanone (prepared, e.g., as in Ex. 50, Step 1) (0.054 g, 0.00017 mol) in DMF (1.8 mL, 0.023 mol) was added cesium te (0.0389 g, 0.000166 mol) and the reaction was stirred at room ature for 16 hours. Ammonium acetate (0.45 g, 0.0058 mol) was added, and the reaction was heated in the microwave to 170 °C for 5 minutes. Water was added and the product was extracted with MTBE. The combined organic extracts were dried over sodium sulfate, then filtered and concentrated. The crude residue was d by flash column chromatography (2.5% MeOI—I/DCM) to yield 4-(2-tert-buty1— lH—imidazol—S-yl)[2—(trimethy1silyl)ethoxy]methyl-lH—pyrrolo[2,3-b]pyridine (32 mg, 52%). lH NMR (400 MHz, CDC13): 5 8.31 (d, 1H), 7.50 (s, 1H), 7.40 (d, 1H), 7.37 (d, 1H), 6.94 (d, 1H), 5.69 (s, 2H), 3.52 (dd, 2H), 1.46 (s, 9H), 0.90 (dd, 2H), -0.08 (s, 9H); MS(ES):371(M+1).

WO 70514 Step 2. 4—(2—tert—butyl—1-methyl-1H-imidazol—4-yD-1 -[2-(trimethylsilyl)ethoagzjmethyl-IH-pyrrolo— [2,3-bjpyridine To a mixture of 4-(2-tert-butyl—1H—imidazol-S-yl)[2-(trimethylsi1y1)ethoxy]methyl-1H- pyrrolo[2,3—b]pyridine (0.019 g, 0.000051 mol) and potassium carbonate (0.15 g, 0.0011 mol) in DMF (3 mL, 0.04 mol) was added methyl iodide (0.01 mL, 0.00015 mol) in two portions over 48 hours. Water was then added and the product was extracted with MTBE. The combined extracts were dried with sodium e, filtered, and concentrated in vacuo, then purified by silica gel chromatography (20% ethyl acetate/hexanes) to afford 4—(2-tert—butylmethyl—1H-imidazolyl)—1- [2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine (10 mg, 51%). 1H NMR (400 MHz, CDCl;): 5, 8.37 (d, 1H), 7.54 (d, 1H), 7.44-7.22 (m, 2H), 7.19 (d, 1H), 5.78 (s, 2H), 3.93 (s, 3H),.3.60 (dd, 2H), 1.61 (s, 9H), 0.98 (dd, 2H), 0.00 (s, 9H); MS(ES):385(M+1).

Step 3.

A solution of ‘ 4—(2-tert-butylmethyl-1H—imidazol-4—yl)-l-[2—(trimethylsi1y1)-ethoxy]- methyl-1H—pyrrolo[2,3—b]pyridine (0.010 g, 0.000026 mol) in TFA (3 mL, 0.04 mol) was stirred for 2 hours. Then the excess TFA was evaporated and the residue was stirred in methanol (3 mL, 0.07 mol) and NI-LOH (1 mL) for 16 hours. The solvents were removed and the product was purified by preparative-HPLC (C18 eluting with a gradient of ACN/HgO containing 0.1% TFA) to afford 4-(2— tert-butyl-l~methyl-1H—imidazoly1)-1H-pyrrolo[2,3-b]pyridine, tn'fluoroacetate salt (9 mg, 90%). 1H NMR (400 MHz, d5-DMSO): 6, 12.24 (s, 1H), 8.38 (br s, 1H), 8.24 (s, 1H), 7.70-7.63 (m, 2H), 7.08 (br s, 1H), 2.55 (s, 3H), 1.51 (s, 9H); MS(ES):255(M+1). onal analogs were prepared as shown in Table 2 using analogous procedures to those described in Example 46 with different starting materials such as alternative carboxylic acids in Step 1. When the analogs were obtained as the free base, the product was obtained by preparative—HPLC (C18 eluting with a gradient of o ning 0.15% . The results are summarized in Table 2 according to the following structure: 4-(2—phenyl-1H-imidazol—5-yl)-1H- pyrrolo[2,3—b]pyridine 4-(2-benzyl-lH-imidazol-S-yl)— 3L 1H—pyrrolo[2,3—b]pyridine /\© oroacetate salt 4-[2—(1-pheny1ethyl)-1H—imidazol-S- (racemic) y1]-l H-pyrrolo[2,3-b]pyridine trifluoroacetate salt e 50: 4—(2—Phenyl-l,3~thiazol—4-yl)—1H—pyrrolo[2,3-b]pyridine trifluoroacetate salt H'TFA Step 1. 2-Chloro-1—(1-[2-(trimethylsilyDethoxyjmethyl—IH-pyrrolo[2,3-b]pyridinyl)ethanone To a solution of 4-bromo—1 rimethy1silyl)ethoxy]methy1—1H-pyrrolo[2,3—b]pyridine (2.05 g, 6 mol) in THF (10 mL, 0.123 mol) at 0 "C was added dropwise a solution of isopropylmagnesium chloride in ether (2.0 M, 9.4 mL). The mixture was allowed to warm to room temperature and stirred for 4 hours. This mixture was then transferred via cannula to a solution of 2— chloro-N-methoxy—N-methylacetamide (2.84 g, 0.0207 mol) in THF (10 ml). Afier 30 minutes reaction time, the solution was quenched by the addition of ted ammonium chloride aqueous solution. The product was extracted with ethyl acetate, the combined organic extracts were washed with brine, dried over Na2304, d and concentrated. The crude residue was purified by flash column chromatography (0-20% ethyl acetate/hexanes) to afford 2—chloro(1-[2-(trimethylsilyl)- ethoxy]methyl-lH—pyrrolo[2,3-b]py1idin—4-yl)ethanone (711 mg, 35%). ‘H NMR (400 MHz, CDC13): 5_ 8.56 (d, 1H), 7.66 (d, 1H), 7.60 (d, 1H), 7.23 (d, 1H), 5.80 (s, 2H), 4.91 (s, 2H), 3.60 (dd, 2H), 0.98 (dd, 2H), 0.01 (s, 9H); MS(ES):325(M+1).

Step 2. 4—(2-Phenyl—1,3-thiazol—4—yD-1H-pyrrolo[2,3-b]pyridine trifluoroacetate salt A solution of 2—chloro-l-(1—[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridiny1)— ethanone (0.050 g, 0.00015 mol) and ecarbothioamide (0.031 g, 0.00022 mol) in ethanol (2 mL, 0.03 mol) was heated to reflux for 1 hour. The solvent was removed in vacuo. Ethyl acetate was added, and the resulting solid was isolated by filtration. The crude solid was stirred with TFA for 1 hour, then excess TFA was removed in vacuo. The crude residue was then stirred with aq. NH40H and MeOH for 16 hours. The solvent was removed and the product was purified by preparative-HPLC (C18 eluting with a nt of ACN/HzO containing 0.1% TFA) to afford 4—(2—pheny1—1,3-thiazol WO 70514 —pyrrolo[2,3-b]pyridine as the trifluoroacetate salt (11 mg, 18%). 1H NMR (400 MHz, d5- DMSO): 5, 12.01 (s, 1H), 8.58 (s, 1H), 8.39 (br s, 1H), 8.13-8.07 (m, 2H), 7.81 (d, 1H), .64 (m, 1H), 7.62—7.52 (m, 3H), 7.22 (d, 1H); MS(ES):278(NI+1).

Example 51: N—Methyl-N-propyl(lH-pyrrolo[2,3-b]pyridin—4—yl)-1,3-thiazol—2-amine, trifluoroacetate salt Step I. N—Methyl—N—propylthiourea N—Methyl—N-propylamine (0.501 mL, 0.00488 mol) was added to a solution of 1,1'- thiocarbonyldiimidazole (0.957 g, 0.00537 mol) in THF (9 mL, 0.1 mol), and the resulting on was stirred for 16 hours. The intermediate from the reaction mixture was isolated by silica gel chromatography (5% MeOH in DCM) and this intermediate was stirred with ammonia (7M solution in MeOH) (6 mL) for 48 hours. The solvent was removed in vacuo. yl~N—propylthiourea was obtained after flash column chromatography (4% MeOH in DCM).

Step 2.

A solution of ro-l-(1-[2—(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin—4—yl)- ethanone (0.050 g, 0.00015 mol) and N—methyl—N-propylthiourea (0.030 g, 0.00022 mol) in ethanol (2 mL, 0.03 mol) was heated to reflux for 2 hours. Then, the ethanol was removed in vacuo and the residue was dissolved in 2 mL TFA and stirred for 40 minutes. The excess TFA was removed in vacuo and the residue was dissolved in 3 mL ofMeOH. To this was added 0.5 mL OH and 100 uL of ethylenediamine, and the resulting solution was stirred for 16 hours. Solvent was removed, then water was added to give a white precipitate which was purified by preparative-HPLC (C18 eluting with a gradient of ACN/HzO containing 0.1% TFA) to afford N—methyl-N-propyl(1H-py1rolo[2,3— b]pyridin—4-yl)—1,3-thiazolamine as the trifluoroacetate salt (39 mg, 67%). 1H NMR (300 MHz, CD30D): 5, 8.46-8.12 (br s, 1H), 7.92 (br s, 1H), 7.72 (s, 1H), 7.63 (d, 1H), 7.45 (br s, 1H), 3.56 (t, 2H), 3.20 (s, 3H), 1.78 (dq, 2H), 1.00 (t, 3H); MS(ES):273(M+1).

Additional aminothiazole analogs were prepared by procedures analogous to those bed in Example 51, using different starting materials such as alternative thioureas in Step 2. In Examples 52 and 53, the white precipitate ed by the procedure of Example 51 was isolated by filtration, washed with water and dried under high vacuum to afford the analogs as the free amine. The results are ized in Table 3 according to the following structure: (Y)n—Z N—phenyl—4—( 1H—pyrrolo[2,3-b]pyridin—4— yl)-l ,3-thiazol—2—amine N—methyl-N—phenyl—4-(lH-pyrrolo[2,3- b]pyridinyl)-1 azol-2—amine Example 54: 4-(2-Phenyl—1,3-thiazol—S-yl)-1H-pyrrolo[2,3-blpyridine trifluoroacetate salt N...

I t \ N E TFA Step I. (2-Phenyl—1,3-thiazol—5—y0boronic acid To a solution of n-butyllithium in hexane (1.6 M, 2.1 mL) in ether (20 mL) at -78 °C, a on of 2-phenyl—1,3—thiazole (449 mg, 0.00278 mol) in ether (5 mL) was added dropwise. The mixture was stirred for one hour at -78 °C followed by the addition of boric acid trimethyl ester (0.949 mL, 0.00835 mol). The mixture was stirred at ~78 °C for 15 minutes, then was allowed to warm to room temperature and stirred for an additional 40 minutes. Saturated NH4CI aqueous solution was added, followed by 1.0 N aqueous HCl. The acidified mixture was stirred for 15 minutes, and the desired product was extracted with four portions of DCM containing 15% isopropanol. The combined organic extracts were dried over sodium sulfate and concentrated to give 566 mg of a white solid containing the desired (2-pheny1—1,3-thiazol-5—y1)boronic acid as a e with 2-phenyl-1,3- thiazole. This mixture was used in Step 2 without finther purification. MS(ES):206(M+1). 2006/047369 Step 2. and 4- To a mixture of (2—pheny1-1,3-thiazol—5-yl)boronic acid (75.0 mg, 0.000366 mol) bromo—l-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine (80 mg, 0.000244 mol) in DMF in water (1 (4 mL, 0.0516 mol) was added a on of potassium carbonate (101 mg, 0.000732 mol) minutes. mL, 0.0555 mol). The mixture was purged with a steady stream of nitrogen for is(triphenylphosphine)palladium(0) (20 mg, 0.000018 mol) was added and the resulting mixture was heated to 125 °C for 30 minutes. The product was purified by preparative—HPLC (C18 eluting with a gradient of ACN/I-IZO containing 0.1% TFA) to afford 12 mg of a yellow solid for 1 containing the desired product as the major component. The mixture was d in TFA (1 ml.) 2 mL MeOH, hour. Then excess TFA was removed in vacuo and the resulting residue was stirred with 0.5 mL NH40H and 100 uL ethylenediamine for 16 hours. The product was isolated by ative— HPLC (€18 eluting with a gradient of O containing 0.1% TFA) to afford 4—(2-phenyl-1,3- thiazol-S-yl)-lH—pyrrolo[2,3-b]pyridine trifluoroacetate salt (5 mg, 5%). 1H NMR (400 MHz, CD30D): 5 8.64 (s, 1H), 8.34 (d, 1H), 8.10-8.04 (m, 2H), 7.73 (d, 1H), 7.71 (d, 1H), 7.56-7.51 (m, 3H), 7.14 (d, 1H); MS(ES):278(M+1).

Example 55: Ethyl 2-methyl—2-[4-(1H—pyrrolo[2,3-b]pyridin—4-yl)—lH-pyrazol-l-yl]propanoate trifluoroacetate salt (55a) 2-Methyl—2—[4-(1H—pyrrolo[2,3-b]pyridin-4—yl)—1H—pyrazol—l-yl]propanoic acid (55b) 7 Example 56: 2—Methyl-2—[4-(1H-pyrrolo[2,3-blpyridinyl)-lH—pyrazolyl]propanamide A mixture of 2-methyl[4-(lH-pyrrolo[2,3-b]pyridinyl)-lH—pyrazol-l~yl]propanoic acid (23 mg, 0.000085 mol) and N,N-carbonyldiimidazole (CD1) (21 mg, 0.00013 mol) in 2 mL of DMF and this was was stirred for 3 hours. An excess of solid NH4C1 and TEA was added to the mixture d for 3 hours. The majority of solvent was removed in vacuo, and the crude residue was purified by preparative-HPLC (C18 eluting with a gradient of ACN/HZO containing 0.1% TFA) followed by re—purification via preparative-HPLC (C18 eluting with a gradient of ACN/I-Izo containing 0.15% NH40H) to afford 2-methyl[4-(lH-pyrrolo[2,3-b]pyridinyl)-lH—pyrazol-l-yl]propanamide (6 mg, 26%). 1H NMR (400 MHz, d5-DMSO): 5 11.63 (s, 1H), 8.44 (55 1H), 8.16 (s, 1H), 8.14 (s, 1H), 7.47 (t, 1H), 7.29 (d, 1H), 7.21 (s, 1H), 6.93 (s, 1H), 6.80 (dd, 1H), 1.77 (s, 6H); MS(ES):270(M+1). e 57: Ethyl 3—methyl—3-[4-(lH-pyrrolo[2,3—b]pyridin—4-yl)-1H—pyrazol—l-yl]butanoate trifluoroacetate salt l\ \ N N H -TFA Step 1. Ethyl yl—3—[4—(I-[2-(trimethylsilyl)ethoxyjmethyl—IH—pyrrolo[2,3-b]pyridin-4—yl)~1H- Pyrazol-1 -yl]butanoate 2006/047369 4-(1H-Pyrazol—4—yl)—1—[2—(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine (220 mg, dissolved in 0.0006996 mol) and 3-methylbutenoic acid ethyl ester (292 uL, 0.00210 mol) were mixture was DMF (10 mL). Cesium carbonate (912 mg, 0 mol) was added and the resulting and the product stirred at room temperature for 3 hours. The reaction mixture was diluted with water, ts were dried over sodium sulfate and was extracted with MTBE several times. The combined concentrated. The crude residue was purified by flash column chromatography (0-60% Hexanes) to afford ethyl 3-methyl[4-(1—[2-(trimethylsilyl)ethoxy]methyl—1H-pyrrolo[2,3- b]pyridin—4—yl)-1H-pyrazol—l-yl]butanoate (244 mg, 79%). 1H NMR (300 MHz, CDCl3): 5, 8.37 (d, 1H), 8.11 (s, 1H), 8.09 (s, 1H), 7.45 (d, 1H), 7.24 (d, 1H), 6.79 (d, 1H), 5.77 (s, 2H), 4.10 (q, 2H), 3.62 (dd, 2H), 3.04 (s, 2H), 1.88 (s, 6H), 1.20 (t, 3H), 0.98 (dd, 2H), 0.00 (s, 9H); :443(M+1).

Step 2.

Ethyl 3-methy1[4-(l -[2-(trimethylsilyl)ethoxy]methyl-1H—pyrrolo[2,3-b]pyridiny1)—1H- pyrazol—l —y1]butanoate (20 mg, 0.0000452 mol) was stirred in 1 mL TFA for 1 hour. Then excess 0.5 mL TFA was removed in vacuo. The residue was stirred for 16 hours in 2 mL MeOH containing NH40H. Evaporation of the les was followed by ation by preparative—HPLC (C18 eluting with a gradient of ACN/HZO containing 0.1% TFA) to afford ethyl 3-methy1-3—[4-(1H-pyrrolo[2,3—b]— pyridin-4—y1)—lH—pyrazol—1—yl]butanoate, tn'fluoroacetate salt (5 mg, 26%). 1H NMR (400 MHz, d5- 7.02 DMSO): 6 12.19 (s, 1H), 8.61 (br s, 1H), 8.34—8.22 (br m, 2H), 7.62 (br s, 1H), 7.51 (br d, 1H), (br s, 1H), 3.91 (q, 2H), 2.96 (s, 2H), 1.70 (s, 6H), 1.02 (t, 3H); MS(ES):313(M+1).

Example 58: 3-Methy1[4-(1H-pyrrolo[2,3-b]pyridin—4-yl)-IH-pyrazol-l-yl]butan-l-ol trifluoroacetate salt l \ N H ~TFA To a solution of ethyl 3-methyl—3-[4-(1-[2—(trimethylsilyl)ethoxy]methyl—lH-pyrrolo[2,3-b]— pyridinyl)-1H-pyrazol-l-yl]butanoate (213 mg, 0.000481 mol) in THF (5 mL, 0.0616 mol) at -78 °C was added diisobutylaluminurn hydride in DCM (1.00 M, 1.1 mL) dropwise. The reaction mixture was stirred for 3 hours during which time the reaction slowly warmed to -10 0C. To the mixture at -10 °C was carefully added K/Na taitrate tetrahydrate in water. The mixture was stirred for 2 hours, then was extracted with three portions of ethyl acetate. The combined organic extracts were washed with two portions of water and one n of brine, then dried over sodium sulfate, filtered and concentrated to afford 3-methy1-3—[4-(1-[2-(trimethylsilyl)ethoxy]methyl-lH—pyrrolo[2,3-b]- (185 without r pyridiny1)-lH-pyrazol—1 —yl]butan—1-ol mg, 95%), which was used stirred in TFA (1 mL) purification. A portion of the alcohol so obtained (15 mg, 37 mol) was with 2 mL MeOH containing for 2 hours. The TFA was removed in vacuo and the residue was stirred 0.5 mL NH40H for 16 hours. Volatiles were removed and the product was purified by ative- afford 3-methyl[4-(1H- HPLC (C18 eluting with a gradient of ACN/HZO containing 0.1% TFA) to pyrrolo[2,3-b]pyridiny1)-1H-pyrazol-l —yl]butanol as the trifluoroacetate salt (8.0 mg, 57%).

NMR (300 MHz, dé-DMSO): 5 12.17 (s, 1H), 8.58 (br s, 1H), 8.32-8.22 (br m, 2H), 7.62 (br s, 1H), 7.53 (br (1, 1H), 7.03 (br s, 1H), 3.25 (t, 2H), 2.07 (t, 2H), 1.62 (s, 6H); MS(ES):271(M+1). e 59: 4-Methyl[4-(lH-pyrrolo[2,3—b]pyridin—4-yl)-lH—pyrazol—l-yl]pentanenitrile trifluoroacetate salt I \ N iii -TFA Step I. yl-4—[4-(1—[2—(trimethylsilyl)ethoxy]methyl—1H—pyrrolo[2,3—b]pyridin—4-yl)—1H— pyrazol—I-yl]pentanenitrile TEA (38.0 tLL, 0.000273 mol) and methanesulfonyl chloride (21.1 uL, 0.000273 mol) were added sequentially to a solution of 3-methyl—3—[4—(l -[2-(trimethylsilyl)ethoxy]methyl—lI-I—pyrrolo[2,3— b]pyridinyl)—lH—pyrazolyl]butan-l-ol (prepared as in Example 58) (81 mg, 0.00020 mol) in for 1.5 hours, then DCM (4 mL, 0.05 mol) at 0° C. The reaction mixture was held at this temperature mixture was extracted with DCM four times. The was quenched by the addition of water. The reaction afford crude 3—methylcombined extracts were dried over sodium sulfate, filtered and concentrated to 3-[4-(1 -[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridiny1)-1H—pyrazoi-l -yl]butyl methanesulfonate (87 mg). MS(ES):479(M+1).

A mixture of 3—methyl[4-(l-[2—(trimethylsilyl)ethoxy]methyl-lH—pyrrolo[2,3-b]pyridin —pyrazol-l-y1]butyl methanesulfonate (42 mg, 0.000088 mol) and potassium cyanide (46 mg, "C followed by 0.000702 mol) in DMF (1 mL) was heated in the microwave reactor for 30 min at 125 extracted additional 30 min at 135 0C. The mixture was then diluted with water, and the product was with three ns of MTBE. The combined extracts were dried over sodium sulfate, filtered trated to give 61 mg of crude 4-methy1—4-[4—(l-[2-(trimethy1silyl)ethoxy]methyl-lH-pyrrolo- [2,3-b]pyridin—4—yl)-lH-pyrazol—l—yl]pentanenitrile, which was used without further purification.

MS(ES):410(M+1).

Step 2. 4-Methy1—4-[4-(1 -[2~(trimethylsilyl)ethoxy]methyl-1H—pyrrolo[2,3-b]pyridinyl)-1H- pyrazol-l-yl]pentanenitrile (57 mg, 0.00014 mol) was stirred in DCM (4 m1) and TFA (1 mL) for 2 hours. The solvents were removed in vacuo and the e was d in 2 mL MeOH containing 0.2 from mL ethylenediamine for 16 hours. The volatiles were evaporated and the product was isolated the reaction mixture by preparative-HPLC (C18 eluting with a gradient of ACN/Hzo containing 0.1% TFA) affording 4-methyl-4—[4-(lH-pyrrolo[2,3-b]pyridinyl)-lH—pyrazol-l—yl]pentanenjtrile as the trifluoroacetate salt (10 mg, 18%). 1H NMR (400 MHz, d5-DMSO): 6, 12.09 (s, 1H), 8.58 (s, 1H), 8.29 (s, 1H), 8.25 (d, 1H), 7.60 (t, 1H), 7.48 (d, 1H), 7.00 (br s, 1H), 2.33-2.21 (m, 4H), 1.61 (s, 6H); MS(ES):280(M+1).

Example 60: 4-Methyl—4-[4-(1H-pyrrolo[2,3-b]pyridinyl)—1H—pyrazol—1-yl]pentanamide trifluoroacetate salt l \ N N H -TFA The crude 4-methyl[4-(1-[2-(trimethy1silyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridinyl)- lH-pyrazol-l-y1]pentanenitrile (36 mg, 0.000088 moi, see preparation in Example 59), was stirred in TFA (2 mL) for 1 hour. The mixture was trated to remove excess TFA, and the resulting residue was stirred in 2 mL methanol containing 0.5 mL NI-LOH for 16 hours. The product was purified by ative—HPLC (C18 eluting with a gradient of ACN/HZO containing 0.1% TFA) to afford y1—4—[4—(1H—pyrrolo[2,3—b]pyridin-4—yl)-1H—pyrazol-l—yl]pentanarriide as the tn'fluoro— acetate salt (21 mg, 58%). 1H NMR (400 MHz, d5-DMSO): 5 12.18 (s, 1H), 8.60 (s, 1H), 8.33—8.21 (m, 2H), 7.62 (br s, 1H), 7.53 (d, 1H), 7.22 (br s, 1H), 7.04 (br s, 1H), 6.71 (br s, 1H), 2.14-2.07 (m, 2H), 1.86-1.79 (m, 2H), 1.58 (s, 6H); MS(ES):298(M+1).

Example 61: (SS)[4-(1H-Pyrrolo[2,3-b]pyridinyl)-lH—pyrazol-l-yl]butanenitrile trifluoro- acetate salt , (3R)[4-(1H—Pyrrolo[2,3-b]pyridin-4—yl)—lH—pyrazol—l-yl]butanenitrile trifluoroacetate salt To a solution of 4—(1H—pyrazol—4—yl)-1—[2—(trimethylsilyl)ethoxy]methy1-lH-pyrrolo[2,3— b]pyridine (0.050 g, 0.00016 mol) in ACN were added 2—butenenitrile (0.014 mL, 0.00017 mol) and DBU (0.029 mL, 0 mol). The resulting mixture was stirred for 16 hours. Then the volatiles were evaporated and the e was dissolved in ethyl acetate. The resulting solution was washed successively with 1.0 N HCl, water, and brine, then was dried over sodium sulfate, filtered and concentrated. To obtain the enantiomers in substantially pure form, Method A (vide infra) was used.

The crude residue was dissolved in TFA (7 mL, 0.09 mol) and the solution was stirred for 1 ‘10 hour. Then excess TFA was evaporated and the residue was then d with ethylenediamine (0.1 mL, 0.001 mol) in methanol (4 mL, 0.09 mol) for 16 hours. The mixture was concentrated, and the product was purified by preparative—HPLC (C18 eluting with a gradient of 0 containing 0.1% TFA) to afford 3-[4—(1H—pyrrolo[2,3—b]pyridin-4—yl)-1H-pyrazol-l—yl]butanenitri1e trifluoroacetate salt (35 mg, 61%). lH NMR (300 MHz, O): 5 12.16 (s, 1H), 8.73 (s, 1H), 8.32 (s, 1H), 8.28 (d, 1H), 7.65—7.61 (m, 1H), 7.48 (d, 1H), 6.99 (d, 1H), 4.86 (q, 1H), 3.17 (d, 2H), 1.57 (d, 3H); MS(ES):252(M+1).

Additional analogs were prepared by procedures analogous to those described in Example 61 using different starting materials for alkylation of the pyrazole ring. For example, the 0L,13-unsaturated nitriles were prepared by pro'cedures analogous to the ing, illustrated for (2E)- and (2Z)- hexenenitrile: To a solution of 1.00 M potassium tert-butoxide in THF at 0 °C (24.2 mL) was added a solution of diethyl ethylphosphonate (4.10 mL, 0.025 mol) in THF (30 mL) dropwise. The bath was removed and the solution was allowed to warm to room temperature. After reaching room ature, the solution was re-cooled to 0°C and a solution of butanal (2.00 mL, 0.023 mol) in THF (7 mL) was added dropwise. The reaction mixture was allowed to warm to room temperature and stir overnight. The e was diluted with ethyl acetate and water. The layers were separated and the s layer was extracted with three portions of ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and trated. This afforded 1.6 g of a crude mixture containing both (2E)— and (ZZ)-hexenenitrile, which was used without further purification in the subsequent alkylation step. 1H NMR (400 MHz, CDClg): 8, 6.72 (dt, 1H trans olefin), 6.48 (dt, 1H cis olefin), 5.34 (dt, 1H trans olefin), .30 (m, 1H cis olefin).

Where it was desirable to obtain the enantiomers in substantially pure form, chiral separation was performed by one of the following methods: A) The separation was performed on the SEEM-protected intermediate after silica gel tography (ethyl acetate/hexanes) by preparative chiral HPLC (OD-H column, eluting with % ethanol in hexanes); B) The separation was performed on the deprotected free base by preparative chiral HPLC (OD—H column, eluting with 15% l in hexanes); C) The separation was performed on the SEM-protected intermediate after silica gel chromatography (ethyl acetate/hexanes) by preparative chiral HPLC (AD-H , eluting with % ethanol in hexanes); D) The separation was performed on the SEM—protected intermediate afler silica gel chromatography (ethyl acetate/hexanes) by preparative chiral HPLC (AD-H column, eluting with % ethanol in s); E) The tion was performed on the SEM—protected intermediate alter silica gel chromatography (ethyl acetate/hexanes) by preparative chiral HPLC (OD-H column, eluting with % ethanol in hexanes; or F) The separation was performed on the SEM-protectcd ediate after silica gel chromatography (ethyl acetate/hexanes) by preparative chiral HPLC (OD—H column, eluting with % ethanol in hexanes. An OD-H column refers to Chiralcel QD-H from Chiral Technologies, Inc 3x25 cm, 5 um. An AD-H column refers to ChiralPak AD-H from Chiral Technologies, Inc. 2x25 cm, 5 pm. The results are summarized for compounds in Table 4 below.

RHCN I \ N N H Table4 Method of preparation and chiral separation 3-[4—(lH-pyrrolo[2,3-b]pyridinyl)-1H- pyrazol-l -yl]propanenitrile trifluoroacetate salt (3 S)—3-[4—(lH-pyrrolo[2,3-b]pyridin-4— yl)-1 H—pyrazol- 1 —yl]hexanenitrile trifluroracetate salt Ex. 61 Method B (3R)'3-[4-(lH—pyrrolo[2,3-b]pyridin -pyrazolyl]hexanenitrile trifluroracetate salt —cyclopenty1[4-(1 olo[2,3- b]pyridinyl)- l H—pyrazol-l -yl]- propanenitrilc trifluoroacetate salt Ex. 61 MathOd C (3R)cyclopentyl[4-(1H-pyrrolo[2,3- dinyl)—1H-pyrazol-l -yl]- propanenitrile trifluoroacetate salt (3 S)cyclohexyl-3—[4-(1H-pyrrolo[2,3 - b]pyridinyl)— l H-pyrazol-l -yl]- propanenitrile Ex. 61 (3R)cyclohexyl—3-[4—( 1 H-pyrrolo[2,3- b]pyridin—4~yl)—1H—pyrazol—1 ~yl] ~ propanenitrile Example 65: (3R)[4-(7H-Pyrrolo[2,3-d]pyrimidinyl)—1H—pyrazol-1—yl]hexanenitrile trifluoroacetate salt (SS)[4—(7H-Pyrrolo[2,3-d]pyrimidinyl)—lH—pyrazol-l-yl]hexanenitrile trifluoroacetate salt ON ON N-N N—N // TFA // TFA N\r/b} N\ N {/3 H andN H Step 1 . 4—Chloro—7—[2—(trimethylsilyDethoxy]methyl— 7H—pyrrolo[2,3-d]pyrimidine To a solution of 4-chloropyrrolo[2,3-d]pyrimidinc (0.86 g, 0.0056 mol) in DMF (20 mL, 0.2 mol) at 0 °C was added sodium hydride (0.27 g, 0.0067 mol) in several portions. The reaction mixture was stirred for an additional 45 minutes ed by a se addition of B—(trimethylsilyl)ethoxy]— methyl chloride (1.2 mL, 0.0067 mol). The resulting reaction mixture was stirred at 0 °C for 45 min, then was quenched with water and extracted with ethyl e. The organic extract was washed with water, brine, dried over sodium sulfate, filtered and concentrated to give an oil. The crude residue was purified by flash column chromatography (0-15% ethyl acetate/hexanes) to yield 4—chloro[2— (trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (1.40 g, 88%). 1H NMR (400 MHz, CDCl3): 8, 8.71 (s, 1H), 7.46 (d, 1H), 6.72 (d, 1H), 5.71 (s, 2H), 3.59 (dd, 2H), 0.97 (dd, 2H), 0.00 (s, 9H); MS(ES):284(M+1).

Step 2. 4-(1H-Pyrazol—4-y0[2-(trimetlzylsiéyvethoxyjmethyl-7H-pyrrolo[2,3-djpyrimidine To a mixture of 4-chloro[2-(trimethylsilyl)ethoxy]methyl-7H—pyrrolo[2,3-d]pyrimidine (1.4 g, 0.0049 mol) and 4-(4,4,5,5-tetramethyl~l,3,2-dioxaborolan—2—yl)—lH-pyrazole (1.4 g, 0.0074 mol) in DMF (40 mL, 0.5 mol) was added potassium carbonate (2.0 g, 0.015 mol) in 15 mL of water.

The mixture was purged with a steady stream of en for 15 minutes. is(triphenyl- phosphine)palladium(0) (0.41 g, 0.00036 mol) was added and the on was heated to 125 °C for 30 min. The mixture was allowed to cool then d with ethyl acetate. The diluted on e was washed with water, brine, dried over NaZSO4 and concentrated to give a solution in a small volume ofDMF (about 2-3 mL). Water was added, causing the material to form a gum on the walls of the flask. Then water was decanted, and the solids were dissolved in ethyl acetate. The solution was dried over Na2S04, and concentrated in vacuo to afford a yellow solid. The product was triturated with ethyl ether to yield 4-(1H-pyrazol-4—yl)[2-(trimethylsily1)ethoxy]methyl-7H-pyrrolo[2,3- d]pyrimidine as a white powder which was dried under vacuum (1 g, 60%). 1H NMR (300 MHZ, CDC13): 8 10.80 (br s, 1H), 8.93 (s, 1H), 8.46 (s, 2H), 7.46 (d, 1H), 6.88 (d, 1H), 5.73 (s, 2H), 3.61 (dd, 2H), 0.98 (dd, 2H), 0.00 (s, 9H); MS(ES):316(M+1).

Step 3.

To a solution of 4—(1H-pyrazol-4—yl)—7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3- d]pyrimidine (0.050 g, 0.00016 mol) in ACN (1 mL, 0.02 mol) was added hex-Z-enenitrile (0.100 g, 0.00105 mol) (as a mixture of cis and trans isomers), followed by DBU(60 uL, 0.0004 mol). The resulting mixture was stirred at room temperature for 16 hours. The ACN was removed in vacuo. The crude residue was dissolved in ethyl acetate, and was washed with 1.0 N HCl, brine, dried over NaZSO4 and concentrated. The crude e was purified by flash column chromatography (0-70% EtOAc/Hexane) to afford 56 mg of product, which was stirred with 1:1 TFA/DCM for 1 hour and the solvents were evaporated. The resulting product was stirred with methanol (4 mL, 0.1 mol) containing ethylenediamine (0.1 mL, 0.001 mol) overnight. The solvent was evaporated and the product was purified by ative-HPLC (C18 eluting with a gradient of ACN/H20 containing 0.1% TFA) to afford 3-[4-(7H—pyrrolo[2,3-d]pyrimidin—4—yl)—lH—pyrazol—1—yl]hexanenitrile as the trifluroacetate salt. Where desired, the enantiomers were isolated in substantially pure form by Method A described above for Example 61. 1H NMR (300 MHz, CD30D): 6_ 8.93 (s, 1H), 8.88 (s, 1H), 8.52 (s, 1H), 7.85 (d, 1H), 7.28 (d, 1H), 4.87-4.77 (m, 1H), 3.26-3.05 (m, 2H), .05 (m, 1H), 2.00-1.86 (m, 1H), 1.40-1.10 (m, 2H), 0.95 (t, 3H); MS(ES):281(M+1).

Example 67: (3R)- and (3S)Cyclopentyl—3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4—yl)—IH-pyrazol- 1—yl]propanenitrile r0CN E CN ‘2IZ N—Z \ and N / / N t \ t \/\ N 3:2 N 3:2 Step 1. (2E)- and (2Z)—3—Cyclopentflacrylonitrile To a on of 1.0 M potassium tert—butoxide in THF (235 mL) at 0 0C was added dropwise a solution of diethyl cyanomethylphosphonate (39.9 mL, 0.246 mol) in THF (300 mL). The cold bath was removed and the reaction was warmed to room temperature followed by recooling to 0 0C, at which time a solution of cyclopentanecarbaldehyde (22.0 g, 0.224 mol) in THF (60 mL) was added dropwise. The bath was removed and the reaction warmed to ambient temperature and stirred for 64 hours. The e was partitioned between diethyl ether and water, the aqueous was extracted with three portions of ether, followed by two portions of ethyl acetate. The combined extracts were washed with brine, then dried over sodium sulfate, filtered and concentrated in vacuo to afford a mixture containing 24.4 g of olefin isomers which was used without further purification (89%). 1H NMR (400 MHz, CDC13): 5 6.69 (dd, 1H, trans olefin), 6.37 (t, 1H, cis olefin), 5.29 (dd, 1H, trans olefin), 5.20 (d, 1H, cis olefin), 3.07—2.95 (m, 1H, cis t), 2.64-2.52 (m, 1H, trans product), 1.98- 1.26 (m, 16H).

Step 2. (3R)- and (35)-3—Cyclopentyl—3-[4-(7-[2-(trimethylsilyDethoxy]methyl—7H-pyrrolo[2,3-d]- pyrimidinyl)-1H-pyrazol—1-yl]propanenitrile To a solution of 4—(1H-pyrazol-4—yl)—7-[2-(trimethylsilyl)ethoxy]methyl-7H—pyrrolo[2,3-d]~ pyrimidine (15.0 g, 0.0476 mol) in ACN (300 mL) was added 3-cyclopentylacrylonitrile (15 g, 0.12 mol) (as a e of cis and trans isomers), followed by DBU (15 mL, 0.10 mol). The ing mixture was stirred at room ature overnight. The ACN was evaporated. The mixture was diluted with ethyl acetate, and the solution was washed with 1.0 N HCl. The organic layer was back- extracted with three portions of ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, d and concentrated. The crude t was purified by silica gel chromatography (gradient of ethyl acetate/hexanes) to yield a viscous clear syrup, which was dissolved in ethanol and evaporated several times to remove ethyl acetate, to afford 19.4 g of racemic adduct (93%). The enantiomers were separated by preparative-HPLC, (OD~H, 15% ethanol/hexanes) and used tely in the next step to generate their corresponding final product. The final products (see Step 3) ng from each of the separated omers were found to be active JAK inhibitors; however, the final product stemming from the second peak to elute from the preparative-HPLC was more active than its enantiomer.

WO 70514 1H NMR (300 MHz, CD013): 8 8.85 (s, 1H), 8.32 (s, 2H), 7.39 (d, 1H), 6.80 (d, 1H), 5.68 (s, 2H), 1.80— 4.26 (dt, 1H), 3.54 (t, 2H), 3.14 (dd, 1H), 2.95 (dd, 1H), 2.67—2.50 (m, 1H), 2.03—1.88 (m, 1H), 1.15 (m, 7H), 0.92 (t, 2H), -0.06 (s, 9H); MS(ES):437 (M+1).

Step 3.

To a solution of 3-cyclopenty1—3-[4-(7-[2—(trimethylsilyl)ethoxy]methyl—7H-pyrrolo[2,3-d]- pyrimidin—4-yl)-lH-pyrazol—l—yl]propanenitrile (6.5 g, 0.015 mol, R or S enantiomer as isolated The solvent and above) in DCM (40 mL) was added TFA (16 mL) and this was stirred for 6 hours.

TFA were removed in vacuo. The e was dissolved in DCM and concentrated using a rotary of the TFA. Following this, the residue ator two further times to remove as much as le The solvent was was stirred with ethylenediamine (4 mL, 0.06 mol) in methanol (30 mL) overnight. of ethyl acetate. removed in vacuo, water was added and the product was extracted into three portions and concentrated The combined extracts were washed with brine, dried over sodium e, decanted to afford the crude product which was purified by flash column chromatography (eluting with a gradient of methanol/DCM). The resulting mixture was further purified by preparative—HPLC/MS (C18 eluting with a gradient of O containing 0.15% NH40H) to afford product (2.68 g, 58%). 1H NMR (400 MHz, D6—dmso): 5 12.11 (br s, 1H), 8.80 (s, 1H), 8.67 (s, 1H), 8.37 (s, 1H), 7.60 (d, 1H), 6.98 (d, 1H), 4.53 (dt, 1H), 3.27 (dd, 1H), 3.19 (dd, 1H), .36 (m, 1H), 1.86-1.76 (m, 1H), .13 (m, 7H); MS(ES):307(M+1).

Additional analogs provided in the following Tables were prepared by procedures analogous such as to those described in, for example, Examples 61 and 65, using different starting materials ent (LB—unsaturated nitriles in Step 3. Isolation of the enantiomers in substantially pure form described above (A-F) preceding Table 4. was achieved by the indicated chiral separation method Where the product was isolated as the free amine, the product following deprotection was purified by instead of preparative-HPLC (C18 eluting with a gradient of ACN/HZO containing 0.15% NILOH) referred ative-HPLC (C18 eluting with a gradient of ACN/Hgo containing 0.1% TFA). This is to the following structure: to as "modification G". The results are summarized in Table 5 according N—N R" N‘k \ \ N N Tables Method of preparation and chiral se - aration (3R)—3-[4-(7H—pyrrolo[2,3—d]pyrimidin— l H-pyrazol—l -yl]butanenitrile trifluoroacetate salt Example 65, Method A (3 S)[4-(7H—pyrrolo[2,3-d]pyrimidin— 4-yl)-1H-pyrazol-l -yl]butanenitrile oroacetate salt (3R)cyclopenty1—3-[4~(7H-pyrrolo- [2,3 -d]py1imidin—4-yl)—lH-pyrazol-l - yl]propanenitrile trifluoroacetate salt and Example 67 (3 S)—3~cyclopentyl—3—[4-(7H—pyrrolo— [2,3—d]pyrimidinyl)~ lH-pyrazol-l — ro » anenitrile trifluoroacetate salt 2-methyl[4—(7H—pyrrolo[2,3- d]pyrimidinyl)-l H-pyrazol-l - r0 . anenitrile trifluoroacetate salt (3R)[4-(7H—pyrrolo[2,3-d]pyrimidin— 4-yl)-1H-pyrazol-l -yl]pentanenitrile Example 65, and modification G, (3S)-3—[4-(7H-pyrrolo[2,3-d]pyrimidin— Method B .entanenitrile (3R)—5-methyl[4-(7H-pyrrolo[2,3- d]pyrimidin—4-yl)—l H—pyrazol— 1 — yl]hexanenitrile e 65 , and modification G, (3 S)—5-methyl—3 —[4-(7H-pyrrolo[2,3- Method A midin—4—yl)—1H—pyrazol—l — 1 hexanenitrile (3R)—3-cyclohexyl[4-(7H- pyrrolo[2,3-d]pyrimidin—4-yl)—1 H- pyrazoI-l -yl]propanenitrile Example 65, and modification G, (3 S)—3—cyclohexyl[4-(7H- Method A pyrrolo[2,3-d]pyrimidinyl)—1H- :- r0 . anenitrile —cyclopropyl—3—[4—(7H- pyIT'olo[2,3-d]pyrimidin—4-y1)—l H— pyrazol—l tanenitrile Example 65, and modification G, (3S)cyclopropy1—3-[4-(7H— Method F pyrrolo[2,3—d]pyrimidiny1)-1H- Example 69: 4-{1-[(1S)-l-Methylbutyl]-1H-pyrazol-4—yl}-7H-pyrrolo[2,3-d]pyrimidine trifluoroacetate salt 4-{1-[(1R)—l-Methylbutyl]-1H-pyrazol—4—yl}-7H-pyrrolo[2,3-d1pyrimidine trifluoroacetate salt N—N N—N / I / / TFA N \ N \ m / S 'k / N N .7 H and H A solution of pyrazol—4—yl)[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]- this was pyrimidine (0.050 g, 6 mol) in DMF (2 mL, 0.02 mol) was cooled in an ice bath and to added sodium hydride (0.013 stirred for 10 minutes, g, 2 mol). The resulting mixture was followed by an addition of opentane (0.030 mL, 0.00024 mol). The cooling bath was then removed and the reaction was stirred at room temperature for 3 hours, at which time a further portion of opentane (0.015 mL, 0.00012 mol) was added. Afier 45 minutes, water was added and the reaction mixture was extracted with three ns of ethyl acetate. The combined extracts were with Washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was stirred TFA (3 mL, 0.04 mol) and DCM (3 mL, 0.05 mol) for 3.5 hours, then the solvent was removed for 16 hours. The solvent vacuo. The residue was then stirred with NI-LOH (1.5 mL) in MeOH (4 mL) with a gradient of was evaporated and the product was purified by preparative-HPLC (C18 eluting ACN/H20 containing 0.1% TFA) to afford 4-[1-(1-methylbutyl)-1H-pyrazolyl]-7H—pyrrolo[2,3- d]pyrimidine as the trifluoroacetate salt (25 mg, 44%). 1H NMR (300 MHz, CD30D): 5 8.83 (s, 1H), 8.75 (s, 1H), 8.43 (s, 1H), 7.77 (d, 1H), 7.24 (d, 1H), 4.63-4.50 (m, 1H), .91 (m, 1H), 1.88-1.74 (m, 1H), 1.58 (d, 3H), 1.38-1.09 (m, 2H), 0.93 (t, 3H); MS(ES):256(M+1).

Isolation of the omers in substantially pure form was achieved by separation of the racemic free base (isolated by flash column chromatography afier deprotection, eluting with a MeOH/DCM gradient) using HPLC (OD-H, eIuting with 5% isopropanol/hexanes).

Example 69a: 4—Methyl—4—[4-(7H-pyrrolo[2,3—d]pyrimidinyl)-lH-pyrazol-l-yl]pentanenitrile Step 1. Ethyl 3—methy1[4-(7-[2-(trimethylsilyl)ethongzjmethyl- 7H-pyrrolo[2,3-d]pyrimidin—4—yl)—1H— pyrazolyl]butanoate A solution of 4—(1H—pyrazol—4—y1)—7—[2—(trimethy1silyl)ethoxy]methyl-7H-pyrrolo[2,3-d]— pyrimidine (12.1 0.115 mol) and g, 0.0384 mol), 2-butenoic acid, 3—methy1-, ethyl ester (16.0 mL, DBU (14.3 mL, 0.0959 mol) in ACN (100 mL) was heated at reflux for 3.5 hours. The solvent was removed in vacuo. The e was diluted with water, extracted with ethyl acetate, and the combined organic extracts were washed with saturated. ammonium chloride, dried over sodium sulfate, and concentrated. The crude residue was purified by flash column chromatography (ethyl acetate/hexanes) to yield the desired product (15.5 g, 91%).

'H NMR (400 MHz, CDC13): 8, 8.83 (s, 1H), 8.36 (5, 11-1), 8.27 (s, 1H), 7.37 (d, 1H), 6.80 (d, 1H), .66 (s, 2H), 4.03 (q, 2H), 3.54 (dd, 2H), 2.98 (s, 2H), 1.80 (s, 6H), 1.13 (t, 3H), 0.91 (dd, 2H), -0.07 (s, 9H); MS(ES):444(M+1).

Step 2. 3-Methyl-3—[4-(7-[2-(trz'methylsilyl)ethoxy]methyl-7H~pyrrolo[2,3-d]pyrimidinyl)—1H- pyrazolyl]butan-I~01 To a solution of ethyl 3-methy1—3-[4-(7—[2—(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]~ pyrimidinyl)-1H-pyrazolyl]butanoate (15.4 g, 0.0347 mol) in THF (151 mL) at -78 °C was added 1.00 M diisobutylaluminum hydride in DCM (84.5 mL) dropwise. The reaction was stirred for 2 hours with slow warming to -10 °C. The mixture was quenched with water, then was treated with potassium sodium tartrate ydrate and water. The mixture was d for 1 hour, then was extracted with ethyl acetate. The extracts were washed with water and brine, then dried with sodium sulfate, filtered, and trated in vacuo. The crude e was purified by flash column chromatography to yield the desired product (13.8 g, 99%). 1H NMR (300 MHz, CD013): 8 8.83 (s, 1H), 8.38 (s, 1H), 8.26 (s, 1H), 7.38 (d, 1H), 6.80 (d, 1H), 5.67 (s, 2H), 3.65 (dd, 2H), 3.54 (dd, 2H), 2.21 (t, 2H), 1.72 (s, 6H), 0.91 (dd, 2H), -0.07 (s, 9H); :402(M+1).

Step 3. 3-Methyl[4—(7H-pyrrolo[2,3-d]pyrimidinyl)-IH-pyrazol-I-yl]butan—1 -01 A solution of 3—methyl[4—(7—[2—(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)-1H—pyrazol-l—yl]butanol (13.8 g, 0.0344 mol) in TFA (20 mL) was stirred for 1 hour. The mixture was then concentrated in vacuo and the residue was stirred for 2 hours in a mixture of methanol (30 mL), ammonium hydroxide (30 mL), and ethylenediamine (8 mL). The mixture was then concentrated, and the residue was diluted with water and extracted with l portions of 15% 2C12. The combined extracts were dried over sodium sulfate and concentrated in vacuo to give 20 g of white solid. The solid was triturated with ether and the product was isolated by filtration to give the product as a white solid (7.75 g, 83%).

'H NMR (400 MHz, CD013): 5 9.99 (s, 1H), 8.83 (s, 1H), 8.39 (s, 1H), 8.28 (s, 1H), 7.38 (dd, 1H), 6.80 (dd, 1H), 3.66 (t, 2H), 2.72 (br s, 1H), 2.22 (t, 2H), 1.74 (s, 6H); MS(ES):272(M+1).

Step 4. 3-Methyl-3—[4—(7H-pyrrolo[2,3—d]pyrimidin—4—yl)-IH—pyrazol-I-yljbmfivl methanesuéfonate A solution of 3-methyl[4-(7H-pyrrolo[2,3-d]pyrimidinyl)-lH-pyrazol-l~yl]butanol (6.61 g, 0.0244 mol) in DCM (300 mL) at 0 °C was d with TEA (3.74 mL, 0.0268 mol), followed by methanesulfonyl chloride (2.07 mL, 0.0268 mol). The reaction was stirred for 1 hour, and was then concentrated in vacuo. The crude residue was purified by flash column atography to afford the desired product (4.9 g, 57%).

IH NMR (400 MHz, (16-de0): 8_ 12.45 (s, 1H), 9.50 (s, 1H), 9.35 (s, 1H), 8.83 (s, 1H), 7.79 (dd, 1H), 7.11 (dd, 1H), 4.75 (t, 1H), 3.30 (s, 3H), 2.85 (t, 1H), 1.75 (s, 6H); MS(ES):254(M-CH3303H+1).

Step 5. 4-MethyI[4-(7H—pyrrolo[2,3—d]pyrimidinyl)-IH-pyrazol-I-yl]pentanenitrile 3—methyl[4-(7H-pyrrolo[2,3-d]pyrimidinyl)—l H-pyrazol-l -yl]butyl methanesulfonate (2.97 8.50 mmol), DMF (120 mL) and sodium cyanide (6.21 g, g, 0.127 mol) were distributed evenly into six 20 mL microwavable vessels, each of which was heated in the microwave reactor mL water 4000 s at 125 l’C. The contents of the vials were combined and were diluted with 400 and extracted with five 150 mL ns of ethyl acetate. The combined extracts were dried over sodium sulfate, and the solvent was removed in vacuo. The crude residue was purified by flash column chromatography to yield the desired product (1.40 g, 59%). 1H NMR (400 MHz, CDClg): (S 9.52 (br s, 1H), 8.83 (s, 1H), 8.34 (s, 1H), 8.29 (s, 1H), 7.39 (dd, 1H), 6.81 (dd, 1H), 2.38 (dd, 2H), 2.16 (dd, 2H), 1.73 (s, 6H); MS(ES):281(M+1).

The analogs in Table Sa were prepared according to the above method described for Example 69a. For Example 69b, a conjugate acceptor was used and prepared as described in Perkin Trans. 1, 2000, (17), 2968-2976, and Steps 4&5 were performed before Step 3.

Table 53 MS (ES) 3[4-(7H-pyrrolo[2,3-d]— pyrimidinyl)-1H—pyrazol—l - 279 yl]cyclopropylpropanenitrile (4S)— and -[4(7H- pyirolo[2 ,3-d]pyn'midinyl)- lH—pyrazol-l -yl]pentanenitn'le Example 69d: 3-Methyl[4-(7H-pyrrolo[2,3-d]pyrimidin—4-yl)—lH—pyrazol—l-yl]butanenitrile : CN Step 1. Senecionim'le To a solution of 1.0 M potassium tert-butoxide in TI-IF (2.0 mL) at 0 "C was added a solution of diethyl cyanomethylphosphonate (0.33 mL, 2.06 mmol) in THF (4 mL) dropwise. The cold bath was removed and the reaction was warmed to room temperature. The reaction was then led to 0 °C and acetone (0.20 mL, 2.81 mmol) was added dropwise. The cooling bath was then d and the reaction was allowed to warm to room temperature and stir ght. The reaction was diluted with water, the layers separated, and the aqueous extracted with ethyl acetate. The extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The product was used without further purification (339 mg, 67%).

'H NMR (300 MHz, CDCla): 8_ 5.10 (br s, 1H), 2.05 (s, 3H), 1.92 (s, 3H).

Step 2. 3—Methyl-3—[4—(7H—pyrrolo[2,3-d]pyrimidinyl)—IH—pyrazol—1~yl]butanenitrile To a solution of 4-(1H-pyrazolyl)[2-(tn'methylsilyl)ethoxy]methyl-7H—pyrrolo[2,3-d]— pyrimidine (0.216 g, 0.684 mmol) in ACN (4 mL, 0.08 mol) was added crude senecionitrile (0.111 g, 1.37 mmol), followed by DBU (200 111., 0.002 mol) and the resulting e was heated to 60 "C for 23 hours. The e was cooled to room temperature and the ACN was evaporated. The mixture was diluted with ethyl acetate and washed with dilute HCl and brine. The organic solution was dried over sodium e, filtered and concentrated. Purification by silica gel chromatography (ethyl acetate/hexanes) afforded the desired product. 1H NMR (300 MHz, ds—dmso): 8 8.83 (s, 1H), 8.38 (s, 1H), 8.28 (s, 1H), 7.39 (d, 1H), 6.80 (d, 1H), .66 (s, 2H), 3.54 (dd, 2H), 3.08 (s, 2H), 1.84 (s, 6H), 0.91 (dd, 2H), —0.07 (s, 9H); MS(ES):397(M+1).

To a on of this product in DCM at 0 °C was added TFA sufficient to comprise 20% of the total volume. The solution was stirred at this temperature for 30 min, then at t temperature for 2 hours and 15 minutes. The solvents were removed in vacuo and the residue was stirred with methanol (10 mL) and ethylenediamine (0.4 mL, 0.006 mol) overnight. The solvent was evaporated and the product was purified by preparative-HIPLC/MS (C18 column g with a gradient of ACN/HZO containing 0.15% NH40H) to afford the product (25 mg, 14%).

IH NMR (300 MHz, d5-dmso): 6, 12.08 (s, 1H), 8.68 (s, 2H), 8.39 (s, 1H), 7.59 (d, 1H), 7.05 (d, 1H), ' 3.32 (s, 2H), 1.73 (s, 6H); MS(ES):267(M+1). es 69e and 69f in Table 5b were ed by a method analogous to that described above for Example 69d, with unsaturated nitriles prepared either according to published literature procedures, or by the method in Step 1.

Table 5b MS (ES) 3-ethyl—3—[4-(7H—pyrrolo[2,3- d]pyrimidin—4-yl)—1H—pyrazol— 295 1 —y1]pentanenitrile 1—[4-(7H-pyrrolo[2,3-d]— pyrimidin-4—yl)-1H-pyrazol-l - y1]cyclopropylacetonitrile Additional analogs were prepared by procedures analogous to those described in Example 69, using different ng materials such as alternative bromide or mesylate compounds for the philic substitution step. Where the free amine was obtained as the product, the product was purified after deprotection either by silica gel chromatography (eluting with 5% methanol in DCM) or by ative—HPLC (C18 eluting with a gradient of ACN/HzO containing 0.15% NH40H). The results are summarized for compounds listed in Table 6.

/(Y)n—Z 4—1 —[(2R)—pyrrolidin—2-ylmethyl]-l H- pyrazolyl-7H-pyrrolo[2,3—d]- dine 4—(1 —[(2R)-1 -(methylsulfonyl)pyrrolidin- ethy1-lH—pyrazol72yl)-7H- o[2,3-d]pyrimidine ethyl 2-methyl[4-(7H-pyrrolo[2,3-d]- dinyl)-1H-pyrazol-l -yl] - propanoate trifluoroacetate salt Example 74: (2Z)Cyclopentyl-3—[4-(7H—pyrrolo[2,3-d]pyrimidinyl)-1H—pyrazolyllacrylonitrile Z Z\/\ \ Step 1. 3-CyclopenWIprop—2—ynenitrz‘le To a solution of cyclopentylacetylene (0.50 g, 5.3 mmol) in TI-IF (5 mL) at -78 0C was added 2.5 M n-butyllithium in hexane (2.23 mL). The mixture was stirred for 15 min followed by the dropwise addition of phenyl cyanate (0.70 g, 5.8 mmol) in THF (3 mL). The on was warmed to room temperature. Into the reaction mixture was poured 6 N NaOH, and the mixture was stirred for 5 minutes. The product was extracted with diethyl ether. The extracts were washed with 6 N NaOH and with brine, then dried over sodium sulfate, decanted and the solvent was removed in vacuo to afford product (600 mg, 95%). ‘H NMR (300 MHz, CDC13): 5. 2.81-2.68 (m, 1H), 2.07-1.54 (m, 8H).

Step 2. (ZZ)Cyclopentyl[4-(7-[2—(trimethylsilyDethoxyjmet/Iyl— 7H—pyrrolo[2,3-d]pyrimidin-4— 1 5 yl)-1H—pyrazol—I—y1]acrylonitrile To a mixture of 4-(1H-pyrazol—4—yl)-7~[2-(trimethylsilyl)ethonymethyl—7H-pyrrolo[2,3—d]~ pyrimidine (0.40 g, 1.2 mmol) and 3-cyclopentylprop-Z-ynenitrile (0.30 g, 2.5 mmol) in DMF (8 mL) was added potassium carbonate (0.09 g, 0.6 mmol). The mixture was stirred for 35 min. The reaction was diluted with ethyl acetate and brine, and the aqueous portion ted with three volumes of ethyl acetate. The combined organic extracts were washed with brine again, then were dried over sodium sulfate, decanted and concentrated in vacuo. The crude residue was purified by flash column chromatography (ethyl acetate/hexanes) to yield the desired product (290 mg, 53%). 1H NMR (400 MHz, CDC13): 6_ 8.98 (s, 1H), 8.87 (s, 1H), 8.46 (s, 1H), 7.42 (d, 11-1), 6.84 (d, 1H), .67 (s, 2H), 5.21 ‘(s, 1H), 3.64-3.55 (m, 1H), 3.53 (t, 2H), 2.13-2.01 (m, 2H), 1.83-1.66 (m, 4H), 1.57—1.46 (m, 2H), 0.91 (t, 2H), -0.07 (s, 9H); MS(ES):435(M+1).

Step 3. (2Z)Cyclopentyl[4—(7H-pyrrolo[2,3~d]pyrimidinyD-IH-pyrazol—1~yl]acrylonitrile A solution of (2Z)—3—cyclopentyl—3—[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H—pyrrolo[2,3«d1- pyrimidin-4—yl)-1H—pyrazol-l-yl]acrylonitrile (0.030 g, 0.069 mol) in DCM (3 mL) and TFA (2 mL) was stirred for 1 hour. The ts were d in vacuo and the product was stirred with TI-IF (1.5 mL), sodium hydroxide, 50% aqueous solution (0.75 mL) and water (0.75 mL) for 2 hours. The reaction mixture was neutralized by the se addition of cone. HCl. The product was extracted with ethyl acetate. The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by preparative-HPLC/MS (C18 column eluting with a gradient ofACN/H20 containing 0.15% NH40H) to afford the desired product (16 mg, 76%). 1H NMR (400 MHz, ds-dmso): 8_ 9.08 (s, 1H), 8.74 (s, 1H), 8.63 (s, 1H), 7.66 (d, 1H), 7.05 (d, 1H), .82 (d, 1H), .54 (m, 1H), 2.00-1.90 (m, 2H), 1.76—1.48 (m, 6H); :305(M+1).

Example 75 : opentylidene—3-[4-(7H-pyrrolo[2,3-d]pyrimidinyl)-1H—pyrazol—l—yl]- enitrile Step I . 3—Cyclopemylt'dene-3~[4—(7—[2~(trimetlzylsilyl)ethoxy]methyl— 7H-pyrralo[2, rimidin yl)—IH—pyrazol-I ~yl]propanenitrile To a suspension of 3-cyc1opentylprop—Z-ynenitrile (0.4 g, 0.003 mol) in ACN (10 mL) was added 4-(1H-pyrazol-4—yl)-7~[2-(trimethylsily1)ethoxy]methyl—7H—pyrrolo[2,3—d]pyrimidine (0.53 g, 1.7 mmol) and DBU (0.33 mL, 2.2 mmol). This mixture was stirred at room temperature for 50 minutes. The on mixture was partitioned between ethyl acetate and dilute HCl. The aqueous portion was separated and extracted with ethyl acetate. The combined organic extracts were washed with dilute HCl and brine, were dried over sodium sulfate, filtered and concentrated in vacuo. The WO 70514 crude residue was purified by flash column chromatography (ethyl acetate/hexanes) to yield the d product (540 mg, 74%). 1H NMR (300 MHz, : 8_ 8.85 (s, 1H), 8.36 (s, 1H), 8.35 (5, 11-1), 7.40 (d, 1H), 6.78 (d, 1H), .67 (s, 2H), 3.70 (s, 2H), 3.54 (dd, 2H), 2.55 (t, 2H), 2.45 (t, 2h), 1.85 (dddd, 2H), 1.73 (dddd, 2H), 0.91 (dd, 2H), -0.06 (s, 9H); MS(ES):435(M+1).

Step 2. 3—Cyclopentylidene—3-[4—(7H~pyrrolo[2, 3-djpyrimz'din-4—yl)—1H—pyrazol—1-yl]propanenitrile A solution of 3-cyclopentylidene—3-[4-(7-[2~(tn'methy1silyl)ethoxy]methy1-7H-pyrrolo[2,3-d]- pyrimidin—4-yl)-lH-pyrazol—1-yl]propanem'trile (0.030 g, 0.069 mmol) in DCM (3 mL) and TFA (2 mL) was stirred for 1 hour. The solvents were evaporated in vacuo and the product was stirred with sodium hydroxide, 50% aqueous solution (0.75 mL) and water (0.75 mL) and THF (1.5 mL) for 2 hours. The reaction mixture was neutralized by dropwise addition of concentrated HCl. The product was extracted with ethyl acetate. The combined organic extracts were dried over sodium e, filtered and concentrated in vacuo. The crude residue was purified by preparative-HPLC/MS (C18 column eluting with a gradient of ACN/H20 containing 0.15% NH4OH) to afford the desired product (7 mg, 33%). lH NMR (400 MHz, ds-dmso): E; 12.01 (br s, 1H), 8.78 (s, 1H), 8.69 (s, 1H), 8.46 (s, 1H), 7.60 (d, 1H), 7.04 (d, 1H), 3.95 (s, 2H), 2.53 (t, 2H), 2.42 (t, 2H), 1.76 (dddd, 2H), 1.65 (dddd, 2H); MS(ES):305(M+1).

Example 76: 3—Methyl[5-(7H-pyrrolo[2,3—d]pyrimidinyl)-l,3-thiazolyl]aminopropane— nitrile trifluoroacetate salt N——<\NfCN *TFA "l \ \ I\N/ a Step 1. 4- (I, 3—Thiazol—S-yD— 7-[2—(trimethylsilyDethoxyjmethy1~ 7H-pyrrolo[2, 3—djpyrimidine ro[2-(trimethylsilyl)ethoxy]methyl—7H-pyrrolo[2,3—d]pyrimidine (3.00 g, 0.0106 mol), and 1,3-thiazole (7.50 mL, 0.106 mol) were dissolved in N,N-dimethylacetamide (40.0 mL).

The solution was distributed in equal portions into four 20 mL microwavable s. Into each reaction vessel was then added potassium acetate (0.777 g, 7.93 mmol) followed by tetrakis(triphenyl— phosphine)palladium(0) (0.60 g, 2.1 mmol). Each reaction vessel was heated at 200 °C in the microwave reactor for 30 minutes. The reactions were combined and most of the solvent was removed in vacuo. The residue was diluted with DCM, filtered and concentrated. Purification by flash column chromatography (ethyl acetate/hexanes) afforded the desired product (2.25 g, 64%). 1H NMR (300 MHz, CDCl;): 5 8.99 (s, 1H), 8.90 (s, 1H), 8.72 (s, 1H), 7.49 (d, 1H), 6.91 (d, 11—1), .70 (s, 2H), 3.56 (dd, 2H), 0.93 (dd, 2H), -0.05 (s, 9H); MS(ES):333(M+1).

Step 2. 4-(2-Bromo-I,3-thiazol-5—yl)- 7-[2—(trimethylsilyDethoxyjmethyl— 7H-pyrrolo[2,3-d]pyrimidine 2.5 M n-Butyllithium in hexane (0.860 mL) was added dropwise to a —78 °C solution of 4- hiazol—5-yl)[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (550 mg, 0.0016 mol) in THF (20 mL). The mixture was stirred for 30 minutes at -78 °C, followed by the slow addition of carbon tetrabromide (658 mg, 0.00198 mol) as a solution in TI-IF (10 mL). After 30 minutes, the mixture was quenched with a small amount of saturated um chloride, diluted with ether, and dried over sodium sulfate. The residue obtained after filtration and tration was purified by flash column chromatography (ethyl acetate/hexanes) to afford the desired product (387 mg, 57%). r'H NMR (300 MHz, cock): 6 8.85 (s, 1H), 8.33 (s, 1H), 7.49 (d, 1H), 6.83 (d, 1H), 5.69 (s, 2H), 3.55 (dd, 2H), 0.92 (dd, 2H), —0.05 (s, 9H); MS(ES):411, 413(M+1).

Step 3. 4—(2—Bromo—1,3—thiazol—5-yl)— 7H—pyrrolo[2, 3-d]pyrimidine A solution of 4-(2—bromo-1,3—thiazol-5—yl)—7—[2—(trimethylsily1)ethoxy]methyl—7H—pyrrolo~ [2,3-d]pyrimidine (370 mg, 0.90 mmol) in DCM (5.0 mL) and TFA (1.0 mL) was stirred at room temperature for 7 hours. The mixture was then trated, re-dissolved in methanol (2 mL), and ethylenediamine (0.5 mL) was added. The mixture was stirred for 6 hours at room temperature. The mixture was diluted with DCM (10 mL), and the precipitate was isolated by filtration and washed with a small amount ofDCM to afford desired product (182 mg, 72%). lH NMR (300 MHz, dG—dmso): 5_ 8.74 (s, 1H), 8.70 (s, 1H), 7.76 (d, 1H), 7.15 (d, 1H); :281,283(M+1).

Step 4. 3—Methyl[5—(7H—pyrrolo[2,3—d]pyrimidin—4-yl)-1,3-thiazol—Z-yljaminopropanenitrile A solution of 4-(2—bromo-1,3-thiazoly1)—7H—pyrrolo[2,3-d]pyrimidine (31 mg, 0.11 mmol) and 3-(methylamino)propionitrile (103 uL, 0.00110 mol) in DMF (1.0 mL, 0.013 mol) was stirred at 90 °C for 2 hours. The crude reaction mixture was purified by ative—HPLC/MS (C18 column g with a gradient of ACN/HzO containing 0.15% NH4OH) and again by preparative-HPLC/MS (C18 column eluting with a gradient of ACN/HZO containing 0.1% TFA) to yield the desired t as the roacetate salt (30 mg, 68%). 1H NMR (300 MHz, dG—DMSO): :3 12.25 (s, 1H), 8.60 (s, 1H), 8.31 (s, 1H), 7.60 (dd, 1H), 7.00 (dd, 1H), 3.89 (t, 2H), 3.20 (s, 3H), 2.94 (t, 2H); MS(ES):285(M+1).

Example 77: (3S)- and (3R)[5-(7H-Pyrrolol2,3-d]pyrimidin—4-yl)—1,3-thiazol—2—yl]hexane- nitrile ON ON lll|/ . N- \ S \ S ~.\ \ Nb \ kN/ N I\N/ N H H Step I. N-Methoxy—N-methylbutanamide To a mixture of butanoic acid (1.01 g, 0.0115 mol) and N,O-dimethylhydroxylamine hydro— chloride (1.12 g, 0.0115 mol) in DCM (50 mL) was added benzotriazol-l -yloxytris(dimethylamino)- phosphom'um hexafluorophosphate (5.6 g, 0.013 mol) and TEA (3.2 mL, 0.023 mol). The mixture was stirred overnight at room temperature. The solution was then washed with water and brine, dried over sodium e, and concentrated in vacuo. The crude product was purified by flash column chromatography (ether/hexanes). The solvent was d (235 mbar/40 °C) to afford the product , 88%). 1H NMR (300 MHz, CDCIa): 3. 3.68 (s, 3H), 3.18 (s, 3H), 2.40 (t, 2H), 1.74-1.59 (m, 2H), 0.96 (t, 3H).

Step 2. 1—[5-(7-[2—(Trimethylsilyl)ethoxyjmethyl- 7H—pyrrolo[2, 3~d]pyrimz'diny0-1 , zolylj- butan-I-one 2.5 M n~Butyllithium in hexane (878 uL) was added slowly dropwise to a -78 °C solution of 4-(1,3-thiazol—S—y1)~7—[2—(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3—d]pyrimidine (501 mg, 1.37 mmol) in THF (20 mL). Afier 45 minutes, N—methoxy-N-methy1butanamide (0.360 g, 2.74 mmol) was added. The reaction was continued at -78 0C for 30 min, and was then allowed to reach room temperature. The reaction was quenched with saturated ammonium chloride, and was extracted with ethyl acetate. The extracts were washed with water and brine, dried over sodium sulfate and concentrated in vacuo. Flash column tography (ethyl acetate/hexanes) afforded the product (235 mg, 42%). 1H NMR (300 MHz, CDC13): 5_ 8.93 (s, 1H), 8.76 (5, 11-1), 7.52 (d, 1H), 6.92 (d, 1H), 5.71 (s, 2H), 3.56 (dd, 2H), 3.19 (t, 2H), 1.92-1.77 (m, 2H), 1.05 (t, 3H), 0.93 (dd, 2H), —0.05 (s, 9H); MS(ES):403(M+1).

Step 3. (2E)- and (2Z)[5—(7—[2—(Trimethylsilyl)ethoygz]methyl—7H-pyrrolo[2,3~d]pyrimidin—4—yl)~ I, 3-thiazol-Z—yUhex—Z—enenitrile To a solution of 1.0 M potassium tert-butoxide in THF (0.605 mL) in THF (4.0 mL) 0° C was added diethyl cyanomethylphosphonate (0.102 mL, 0.634 mmol) dropwise. The cooling bath was removed and the reaction was warmed to room temperature. After 30 minutes, a solution of 1—[5- (7-[2-(trimethylsilyl)ethoxy]methyl—7H~pyrrolo[2,3~d]pyrimidin—4—yl)—l ,3—thiazol~2—yl]butan-l —one (232 mg, 0.576 mmol) in THF (3.0 mL) was added dropwise. The reaction was stirred for 2 hours, and the crude mixture was then adsorbed onto silica gel'and purified by flash column chromatography (ethyl e/hexanes) to afford the product as a mixture of olefin isomers (225 mg, 92%). 1H NMR (300 MHz, CD013), major isomer: _5 8.89 (s, 1H), 8.65 (s, 1H), 7.52 (d, 1H), 6.89 (d, 1H), 6.35 (s, 1H), 5.70 (s, 2H), 3.56 (dd, 2H), 2.96 (t, 2H), .72 (m, 2H), 1.08 (t, 3H), 0.93 (dd, 2H), - 0.07 (s, 9H); :426(M+1).

Step 4. (3S)- and (3R)[5—(7—[2—(Trimethylsily0ethowjmethyl- 7H—pyrrolo[2,3-d]pyrimidinyl)— I,3—thiazol—Z—yUhexanenitrile Cupric acetate, monohydrate (0.7 mg, 0.004 mmol) and (oxydi-Z,1-phenylene)bis(diphenyl- phosphine) (2 mg, 0.004 mol) was mixed in toluene (0.24 mL). PMHS (30 uL) was added. The mixture was stirred for 25 minutes at room temperature followed by the addition of (2E)[5-(7-[2- (trimethylsilyl)ethoxy]methy1—7H-pyrrolo[2,3~d]pyrimidinyl)—l azolyl]hex~2-enenitrile (51 mg, 0.12 mol) in toluene (0.24 mL) and finally, tert-butyl alcohol (0.043 mL). The resulting mixture was stirred overnight. The crude mixture was purified directly by flash column chromatography (ethyl acetate/hexanes) to afford the desired product (39 mg, 76%). 1H NMR (300 MHz, CDC13)3 8_ 8.87 (s, 1H), 8.52 (s, 1H), 7.48 (d, 1H), 6.87 (d, 1H), 5.69 (s, 2H), 3.60-3.46 (m, 3H), .82 (m, 2H), 2.05—1.89 (m, 2H), 1.50-1.34 (m, 2H), 0.97 (t, 3H), 0.92 (t, 2H), -0.06 (s, 9H); MS(ES):428(M+1).

Step 5. (3.59— and (3R)~3—[5-(7H—Pyrrolo[2,3—d]pyrimidin~4—yl)-1,3~thiazol—2~yl]hexanenitrile TFA (1.0 mL) was added to a on of 3~[5~(7-[2—(trimethylsilyl)ethoxy]methyl-7H- o[2,3-d]pyrimidinyl)-1,3-thiazo1yl]hexanenitrile (36 mg, 0.084 mmol) in DCM (4.0 mL) and the mixture was stirred at room temperature for 3 hours.

The mixture was concentrated, and re- dissolved in methanol (3 mL), to which ethylenediamine (0.1 mL) was added. After 2 hours reaction time, the mixture was concentrated and directly purified by preparative-HPLC/MS (C18 column eluting with a gradient HZO containing 0.15% N11401:!) to afford the desired product (10 mg, 40%). 1H NMR (300 MHz, CDCI3)Z 8_ 9.96 (br 5, 11-1), 8.87 (s, 1H), 8.54 (s, 1H), 7.51-7.45 (m, 1H), 6.90-6.86 (m, 1H), 3.59-3.44 (m, 1H), 3.01 -2.82 (m, 2H), 2.06-1.87 (m, 2H), 1.51~l.34 (m, 2H), 0.98 (t, 3H); MS(ES):298(M+1).

Example 78: (3R)- and (3S)Cyclopentyl-3~[5—(7H—pyrrolo[2,3—d]pyrimidin—4~yl)-l,3-thiazol—2— yllpropanenitrile 2006/047369 CN CN 'lll/ N— N— \ S and \ S / / N N N N H H To a solution of (2E)~ and (ZZ)cyclopentyl-3—[5-(7~[2—(trimethylsi1y1)ethoxy]methyl~7H— pyrrolo[2,3—d]pyrimidinyl)—1,3—thiazolyl]acrylonitfile (199 mg, 0.440 mmol) (prepared, for example, as in Example 77, steps 1 through 3) in a mixture of ethanol (10 mL) and ethyl acetate (10 mL) was added a catalytic amount of 10% palladium on carbon. The mixture was stirred at room temperature under one atmosphere of hydrogen overnight. It was then subjected to 50 PSI H2 until the reaction was complete. Filtration and removal of t afforded an oil which was dissolved in DCM (4 mL) and TFA (1. mL). The solution was stirred until starting al was consumed and the mixture was then concentrated and re-dissolved in methanol (3 mL), to which ethylenediamine (0.4 mL) was added. The solution was stirred at room temperature for one hour, and was trated in vacuo. The crude mixture was purified by preparative—HPLC/MS (C18 column eluting with a nt ofACN/HZO containing 0.15% NH40H) to afford the desired product (36 mg, 25%). 1H NMR (400 MHz, CD013): 6_ 10.44 (br s, 1H), 8.89 (s, 1H), 8.56 (s, 1H), 7.50 (dd, 1H), 6.89 (dd, 1H), 3.34 (dt, 1H), 2.98 (dd, 1H), 2.89 (dd, 1H), 2.44-2.31 (m, 1H), 2.07~1.96 (m, 1H), 1.80-1.52 (m, 5H), .24 (m, 2H); MS(ES):324(M+1).

The following compounds of Table So were prepared (as racemic mixtures) as bed by Example 77, 78 or 86, as indicated in the following table, by using different Weinreb amides (as prepared in Example 77, Step 1): R CN "U \ / N N Table 5c EX- MS (ES) Method of yl~3-[5-(7H-pyrrolo[2,3-d]— pyrimidin—4-yl)-l ,3-thiazoly1] - 3 12 hexanenitrile :71 3-pyridin—3—yl—3—[5—(7H-pyrrolo[2,3—d]— . \ pyrimidinyl)-1,3-thiazolyl]— I 333 Ex. 78 . . N propanemtnle "a / 3-(5 -bromopyridinyl)—3—[5-(7H— pyrrolo[2,3-d]pyrimidinyl)-1,3-thiazol- 411 413 Ex. 77 2—yl]propanenitrile Ex. 77 through Step 4, ~2-cyano~1-[5-(7H-pyrrolo[2,3-d]— then Ex. 431 pyrimidin-4~yl)—1,3—thiazol~2-yl]— 358 excluding ethylnicotinonitrile purification, then Ex. 77, Ste. 5 Ex. 86, Step 3 . . . jgnéitions ted to 3-[5-(7H-pyrrolo[2,3-d]pyr1m1d1n~4-yl)- 1,3-thiazol-2~y1]butanenitrile Ex 77 Steps din—4-yl—3-[5-(7H—pyrrolo[2,3- d]pyrimidinyI)-1 ,3-thiazol-2— 333 yljpropanenitrile Ex. 77 through Step 3, then BX. 431 ' excluding 4—2—cyano-1—[5-(7H—pyrrolo[2,3-d]- lgfinfilgatlgg, pyrimidin-4—yl)-1,3-thiazolyl]- , 358 enf Xd b ethylpyridine-2—carbonitri1e pun 16 y trifluoroacetate salt Wig/RdS using H20/ACN containing 0.1% TFA din—2-y1[5-(7H-pyrrolo[2,3-d]~ pyrimidinyl)—1,3-thiazolylj- 333 Ex. 78 propanenitrile Example 84: (ZS)- and (2R)—2-[5-(7H—Pyrrolo[2,3-d]pyrimidinyl)—l,3-thiazol-2—yllpentane— nitrile \S and \ S N N / N N H H Step 1. (2S)- and (2R)[5-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H—pyrrolo[2,3-d]pyrimidinyl)— I,3-thiazol-Z-yUpentanenitrile To a e of 1—[5-(7—[2—(trimethylsilyl)ethoxy]methyl—7H~pyrrolo[2,3-d]pyrimidin—4—yl)— l,3-thiazol~2—yl]butan~1-one (prepared as in Example 77) (101 mg, 0.251 mmol) and p-tolylsulfonyl— methyl nide (147 mg, 0.753 mmol) in a mixture of DMSO (5.0 mL) and ethanol (61 uL) was added 1.0 M potassium tert-butoxide in THF (753 ML). The mixture was then heated to 45 °C for 2 hours. Upon cooling to room temperature, the mixture was quenched by the addition of ted . ammonium chloride, followed by water. The product was extracted with ether, and the extracts were washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. Flash column chromatography (ethyl e/hexanes) afforded the product (39 mg, 25%). 1H NMR (400 MHz, CD013): 6 8.88 (s, 1H), 8.52 (s, 1H), 7.50 (d, 1H), 6.87 (d, 1H), 5.70 (s, 2H), 4.32 (dd, 1H), 3.55 (dd, 2H), 2.20—2.11 (m, 2H), 1.71-1.57 (m, 2H), 1.03 (t, 3H), 0.93 (dd, 2H); MS(ES):414(M+1).

Step 2. (2S)- and (2R)[5-(7H—Pyrr010[2,3-djpyrimidinyD-1,3-ZhiazoIyljpentanenitrile A solution of 2-[5-(7-[2-(trimethylsilyl)ethoxy]methyl—7H—pyrrolo[2,3—d]pyrimidin-4—yl)~l,3- thiazolyl]pentanenitrile (59 mg, 0.093 mmol) in DCM (3 mL) and TFA (0.5 mL) was stirred at room temperature for 4 hours. The mixture was then concentrated, and the residue was then dissolved in methanol (3 mL) to which nediamine (0.3 mL) was then added. The solution was stirred at room temperature for 40 minutes. The solvent was removed in vacuo, and the crude mixture purified by preparative-HPLC/MS (C18 column eluting with a gradient of ACN/HZO containing 0.15% NI-LOI-I) to afford the d product (20 mg, 76%). 1H NMR (400 MHz, CDC13)I 6, 9.66 (br s, 1H), 8.88 (s, 1H), 8.54 (s, 1H), 7.49 (dd, 1H), 6.88 (dd, 1H), 4.33 (dd, 1H), 2.23-2.12 (m, 2H), .60 (m, 2H), 1.04 (t, 3H); MS(ES):284(M+1).

Example 85: (4S)- and (4R)[5-(7H—Pyrrolo[2,3-d]pyrimidin—4-yl)-l,3-thiazol-2—yllheptane- nitrile CN CN I'll’ N— N.— \ S \ S N \ \ NI \ \ H H To a solution of triethyl phosphonoacetate (188 mg, 0.838 mmol) in THF (6.0 mL) at 0 °C was added 1.0 M potassium utoxide in THE (840 uL). The mixture was then allowed to warm to room temperature followed by re-cooling to 0 °C, at which time 1-[5-(7-[2-(trimethylsilyl)ethoxy]— methyl-7H-pyrrolo[2,3-d]pyrimidinyl)-1,3-thiazolyl}butanone (prepared as in Example 77) (225 mg, 0.559 mmol) in THF (4.0 mL) was added. The mixture was stirred at room ature for 1.5 hours, at which time it was quenched with water and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over sodium sulfate and concentrated in vacuo.

Flash column chromatography afforded the product as a mixture of olefin isomers (222 mg, 84%).

MS(ES):473(M+1).

Ethyl 3-[5—(7~[2-(trimethy1silyl)ethoxy]methyl~7H-pyrrolo[2,3-d]pyrimidin—4-yl)-l,3-thiazol- 2-yl]hex—2-enoate as a mixture of (2E)- and (2Z)- isomers (222 mg, 0.470 mmol) was dissolved in ethanol (10 mL), and a catalytic amount of 10% Pd-C was added. The e was stirred under an atmosphere of hydrogen, ed by a balloon, for 16 hours. Filtration and concentration in vacuo afforded the desired product (201 mg, 90%). MS(ES):475(M+1).

To a solution of ethyl 3—[5—(7—[2—(trimethylsilyI)ethoxy]methyl—7H—pyrrolof2,3—d]pyrimidin— 4—y1)—1,3—thiazol;2—yl]hexanoate (201 mg, 0.423 mmol) in THF (5.0 mL) at —78 °C was added 1.00 M diisobutylaluminum hydride in DCM (1.06 mL). The mixture was allowed to warm to -10 °C slowly over 1.5 hours, followed by the addition of potassium sodium tartrate tetrahydrate, water, and ether.

The mixture was stirred for 1 hour, then layers were separated, and the aqueous layer was extracted fiirther with ethyl acetate. The c extracts were washed with water and brine, dried over sodium sulfate and concentrated in vacuo to afford desired product (176 mg, 96%). MS(ES):433(M+1).

A solution of 3-[5-(7-[2-(trimethylsilyl)ethoxy]methyl—7H—pyrrolo[2,3-d]pyrimidinyl)-1,3- thiazol-Z—yl]hexan—1—ol (88 mg, 0.20 mmol) in TFA (2 mL) was stirred for 30 minutes. The TFA was then evaporated and the e was stirred in ol (2 mL) containing ethylenediamine (0.2 and a drop of water for 30 minutes. ation via preparative—HPLC/MS (C18 eluting with a nt of ACN/HZO containing 0.15% NH40H) afforded the desired product (36 mg, 58%).

MS(ES):303(M+1).

To a mixture of 3-[5-(7H-pyrrolo[2,3~d]pyrimidin-4—yl)~1,3-thiazolyl]hexan-l~01 (36 0.12 mmol) and TEA (19.9 uL, 0.143 mmol) in DCM (5 mL) at 0 °C was added methanesulfonyl chloride (11.0 uL, 0.143 mmol). After stirring for 10 s, the solution was concentrated and dissolved in DMSO (1.6 mL) and sodium cyanide (23 mg, 0.48 mmol) was added. The e was then heated at 125 °C in the microwave for 30 minutes. The mixture was then purified directly using preparative—HPLC/MS (C18 eluting with a gradient ofACN/H20 containing 0.15% NH40H) to afford the desired product (10 mg, 27%). 1H NMR (400 MHz, CDClg): 5, 9.37 (br s, 1H), 8.86 (s, 1H), 8.52 (s, 1H), 7.46 (dd, 1H), 6.88 (dd, 1H), 3.34—3.25 (m, 1H), 2.47~2.30 (m, 2H), 2.22-2.12 (m, 2H), 1.95-1.71 (m, 2H), .31 (m, 2H), 0.94 (t, 3H); MS(ES):312(M+1). e 86: 3~[5-(7H—Pyrrolo[2,3-d]pyrimidin—4—yD-1,3-thiazol—2—yl]pentanedinitrile "l \ \ ti Step 1. N-Methoxy‘2«[(4-methoxybenzyl)oxyj-N—methylacetamide To a mixture of [(4-methoxybenzyl)oxy]acetic acid (Bioorgam'c and Medicinal Chemistry Letters, 2001, pp. 2837—2841) (6.86 g, 0.0350 mol) and methylhydroxylamine hydrochloride (3.41 g, 0.0350 mol) in DCM (100 mL) was added benzotriazol~1—yloxytris(dimethylamino)— phosphonium orophosphate (17 g, 0.038 mol) followed by TEA (9.7 mL, 0.070 mol). The resulting mixture was stirred overnight at room temperature. The solution was then washed with water, 0.5 M HCl, saturated NaHCO3, and brine, then was dried over sodium sulfate, filtered and concentrated in vacuo. Flash column tography /hexanes) afforded the desired product (5.75 g, 69%).

Step 2. 2—[(4—Met/toxybenzyl)oxy]—1—[5—(7—[2—(trimethylsib20ethoxyjmethyl- 7H—pyrrolo[2,3—d]- pyrimidinyU-1,3~thiazol—2-yl]ethanone To a solution of 4-(1,3-thiazol-5~yl)-7—[2-(trimethylsilyl)ethoxy]methyl~7H-pyrrolo[2,3-d]— pyrimidine (2.12 g, 6.38 mmol) in THF (70 mL) at ~78 °C was added 2.5 M n-butyllithium in hexane (3.06 mL) slowly dropwise. After stirring for 30 minutes, N-methoxy[(4-methoxybenzyl)oxy]-N— methylacetamide (2.29 g, 9.56 mmol) was added. The reaction was continued for 30 minutes following the addition, at -78 °C, then the cooling bath was d and the reaction was quenched with ted ammonium chloride and extracted with ether. The extracts were dried with sodium sulfate and concentrated in vacuo. The crude mixture was purified by flash column chromatography (ethyl acetate/hexanes) to afford desired product (2.16 g, 66%).

'H NMR (300 MHz, CDClg): a 8.93 (s, 1H), 8.72 (s, 1H), 7.53 (d, 1H), 7.37 (d, 2H), 6.91 (d, 2H), 6.89 (d, 1H), 5.70 (s, 2H), 5.00 (s, 2H), 4.70 (s, 2H), 3.81 (s, 3H), 3.56 (dd, 2h), 0.93 (dd, 2H), .0.05 (s, 9H); MS(ES):511(M+1).

Step 3. (2E)- and (2Z)[(4-Meth0xybenzy00xy]-3—[5-(7-[2-(trz'methylsily1)ethoxflmethyl-7H- pyrrolo[2, 3-d]pyrimidinyl)-1, 3-thiazol—2—yljbut-Z-enenitrile To a solution of 1 M potassium tert-butoxide in THF (4.44 mL) in TI—[F (30 mL) at 0° C was added diethyl cyanomethylphosphonate (820 mg, 0.0046 mol) dropwise. The bath was removed and the reaction was warmed to room temperature. After 30 minutes, a solution of 2-[(4-methoxybenzyl)- oxy] —l -[5-(7—[2~(trimethylsilyl)ethonymethyl—7H—pyrrolo[2,3-d]pyrimidin—4—yl)—1 ,3-thiazol-2~y1] - ne (2.16 g, 0.00423 mol) in THF (20 mL) was added se. The reaction was stirred for 1 hour, and was then quenched with a small amount of saturated ammonium chloride, diluted with ether, dried over sodium sulfate and concentrated in vacuo. Purification by flash column chromatography, eluting with a gradient of 0—35% ethyl acetate/hexanes afforded the desired product as a e ofolefin isomers in nearly equal amounts (1.76 g, 78%). 1H NMR (400 MHz, CDC13): 8 8.90 (s, 1H), 8.88 (s, 1H), 8.71 (s, 1H), 8.67 (s, 1H), 7.50 (d, 2H), 7.35 (dd, 2H), 7.31 (dd, 2H), 6.92 (dd, 2H), 6.90 (dd, 2H), 6.86 (d, 2H), 6.62 (s, 1H), 6.10 (t, 1H), 5.70 (5, 41:1), 4.75 (s, 2H), 4.72 (d, 2H), 4.64 (s, 4H), 3.82 (s, 3H), 3.81 (s, 3H), 3.56 (dd, 2H), 3.55 (dd, 2H), 0.96—0.90 (m, 4H), -0.05 (s, 9H), -0.054 (s, 9H); MS(ES):534(M+1).

Step 4. Meth03qybenzyl)oxy][5—(7—[2—(trimethylsibzl)ethoag/jmethyl- 7H-pyrrolo[2,3-d]— pyrt'mz'din-4—yD-J, zolyl]butanenitrile (2E)- and (2Z)-4—[(4—Methoxybenzyl)oxy]-3—[5—(7~[2—(trimethylsilyl)ethoxy]methyl-7H— pyrrolo[2,3—d]pyrimidin—4-yl)-l,3-thiazol-2—yl]but—2~enenitrile (880 mg, 1.6 mmol) was dissolved in a mixture of ethanol (20 mL) and ethyl acetate (20 mL). A catalytic amount of 10% Pd-C was added.

The mixture was shaken under 50 PSI of hydrogen. The mixture was filtered and concentrated in vacuo to afford the desired t (0.85 g, 99%). MS(ES):536(M+1).

Step 5. 3-[5-(7H~Pyrrolo[2, 3-d]pyrimidin-4—yl)—1, 3-thz'azol—2—yUpentanedim'trile 4—[(4—Methoxybenzyl)oxy][5-(7-[2-(trimethylsilyl)ethonymethy1—7H—pyrrolo[2,3—d]- pyrimidin—4—yl)-1,3~thiazoly1]butanenit1ile (251 mg, 0.468 mmol) in DCM (10 mL) was treated with dichlorodicyanoquinone (DDQ) (434 mg, 1.87 mmol), followed by water (376 uL). After 1.5 hours, saturated sodium bicarbonate and water were added, and the reaction was extracted with ethyl acetate three times. The extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford the crude product which was used t r purification.

A solution of the above prepared 4-hydroxy—3—[5-(7-[2-(trimethylsily1)ethoxy]methyl-7H— pyrrolo[2,3-d]pyrimidin—4-yl)—1,3~thiazol—2—yl]hutanenitrile in DCM (12 mL) at 0 °C was treated sequentially with TEA (130 uL, 0.94 mmol) and methanesulfonyl chloride (73 pL, 0.94 mmol). Afier 1 hour reaction time, the mixture was diluted with water and extracted with ethyl acetate three times.

The extracts were washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was then dissolved in DMSO (5 mL) and sodium cyanide (110 mg, 2.3 mmol) was added. After 30 minutes, the e was diluted with water, ted with ether, washed with water, brine and dried over sodium sulfate. Concentration and purification by flash column chromatography (ethyl acetate/hexanes) afforded the desired product (14 mg, 7%). MS(ES):425(M+1).

A solution of 3-[5—(7-[2—(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidinyl)-l,3- thiazol-Z-yl]pentanedinitn'le (14 mg, 0.033 mmol) in DCM (3 mL) containing TFA (0.6 mL) was stirred for 4 hours. The mixture was then concentrated and the residue was redissolved in methanol (2 mL) to which nediamine (0.4 mL) was then added. After 1 hour on time, the product was purified by preparative-HPLC/MS (C18 g with a gradient of ACN/H20 ning 0.15% NH40H) to afford the desired product (6 mg, 62%). 1H NMR (400 MHz, dG-dmso): 8, 12.27 (br s, 1H), 8.84 (s, 1H), 8.76 (s, 1H), 7.75 (d, 1H), 7.14 (d, 1H), 4.14 (m, 1H), 3.17 (d, 4H); :295(M+1).

Example 87: (3R)-3—Cyclopentyl[5-(7H—pyrrolo[2,3—d]pyrimidin-4—yl)—1,3-oxazol—2—yll— propanenitrile, (3S)—3—Cyclopentyl[5-(7H-pyrrolo [2,3-d]pyrimidin-4—yl)—1,3-oxazol—2-yllpropanenitrile ON ON 'IUI/ N— N— \ O and \ O "i\ \ \ / hi\/ N N N N H H Step 1. 4—(1,3-0xazolyl)—7—[2—(trimethylsibilkthoxyjmethyl-7H-pyrrolo[2,3-d]pyrimidine A mixture of 4—chloro[2—(trimethylsilyl)ethoxy]methyl-7H—pyrrolo[2,3—d]pyrimidine (0.440 g, 1.55 mmol), 1,3-oxazole (0.306 mL, 4.65 mmol), potassium acetate (0.456 g, 4.65 mmol) and tetrakis(ttiphenylphosphine)palladium(0) (0.179 g, 0.155 mmol) in N,N—dimcthylacetamide (8.0 mL) was heated to 200 °C in the microwave reactor for 30 minutes. Most of the solvent was removed in v_acuo. The resulting residue was d with DCM, and was filtered and concentrated. Flash column chromatography (ethyl acetate/hexanes) afforded the product (330 mg, 67%). lH NMR (400 MHz, CDCl3): 8 8.96 (s, 1H), 8.21 (s, 1H), 8.08 (s, 1H), 7.54 (d, 1H), 7.08 (d, 1H), .76 (s, 2H), 3.60 (t, 2H), 0.98 (t, 2H), 0.00 (s, 9H); MS(ES):3l7(I\/I+1).

Step 2. Cyclopentyl[5—(7—[2—(trimethylsibzuethoxyjmethyl— 7H—pyrrolo[2, 3-d]pyrimidin-4—yl)~1 , 3— oxazol—Z-yljmethanone n-Butyllithium in hexane (1.6 M, 0.30 mL) was added slowly dropwise to a —78 °C solution of 4-(1,3-oxazolyl)[2—(trimethylsilyl)ethoxy]methyl-7H-pyrroloi2,3—d]pyrimidine (140.0 mg, 0.44 mmol) in THF (10.0 mL). After 20 minutes, 1.0 M zinc dichloride in ether (0.53 mL) was added. The reaction mixture was then stirred for 60 min at 0 °C. ing this, copperfl) iodide (84 mg, 0.44 mmol) was added, and this mixture was allowed to stir for 10 minutes. Cyclopentanecarbonyl chloride (108 uL, 0.885 mmol) was then added. The reaction was d at 0 °C for a further 1 hour, at which time it was allowed to warm to room temperature. The reaction was ed by the addition of saturated NH4C1 solution, and was extracted with ethyl acetate. The extracts were washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. Flash column chromatography (ethyl acetate/hexanes) afforded the product (97 mg, 53%). 1H NMR (400 MHz, CDC13): 5 8.96 (s, 1H), 8.21 (s, 1H), 7.56 (d, 1H), 7.22 (d, 1H), 5.76 (s, 2H), 3.60 (t, 2H), 3.56 (t, 1H), 2.23-1.56 (m, 8H), 0.98 (t, 2H), 0.00 (s, 9H); :413(M+1).

Step 3. (3R)- and -Cyclopenbzl[5-(7—[2-(trimethylsilyDeth0xy]methyl—7H—pyrrolo[2,3- d]pyrimz'dz‘n-4~yl)-1 , 3—0xazol-2—yljpropanenitrile To a solution of 1.0 M ium tert—butoxide in THF (0.355 mL) and THF (3 mL) at 0° C was added diethyl cyanomethylphosphonate (66 mg, 0.37 mmol) dropwise. The cold bath was removed and the reaction was warmed to room temperature. After 30 s, a solution of cyclopentyl[5-(7—[2-(trimethylsilyl)ethoxy]methyl-7H—pyrrolo[2,3-d]pyrimidin—4-yl)-l ,3-oxazol y1]methanone (1.40E2 mg, 0.338 mmol) in THF (2.0 mL) was added dropwise. After 3 hours reaction time, the mixture was adsorbed onto silica gel, and flash column chromatography (ethyl acetate/hexanes) afforded the desired product as a mixture of olefin isomers (89 mg, 60%).

MS(ES):436(M+1).

To a mixture of cupric acetate, drate (4.0 mg, 0.020 mmol) and (oxydi—2,1— phenylene)bis(diphenylphosphine) (11 mg, 0.020 mmol) in toluene (0.40 mL, 0.0038 mol) was added PMHS (50 uL). The resulting mixture was stirred for 25 minutes at room ature, followed by the addition of (2E)- and (2Z)cyclopentyl[5-(7-[2—(trimethylsilyl)ethoxy]methyl~7H—pyrrolo— [2,3-d]pyrimidin—4—yl)—l,3-oxazolyl]acrylonitrile (88 mg, 0.20 mmol) in toluene (0.40 mL), and then tert-butyl alcohol (0.072 mL). After failure to react at room temperature over 16 hours, additional cupric acetate, monohydrate and (oxydi-2,1—phenylene)bis(diphenylphosphine) (0.10 mol equivalent each) Were added and the reaction mixture was heated at 60 °C for 16 hours. The crude WO 70514 mixture was subjected to flash column chromatography (ethyl acetate/hexanes) to afford the desired product (21 mg, 23%).

’H NMR (400 MHz, CDCl3): 6 8.96 (s, 1H), 8.02 (s, 1H), 7.56 (d, 1H), 7.10 (d, 1H), 5.76 (s, 2H), 3.60 (t, 2H), 3.38-3.30 (m, 1H), 3.03 (dd, 1H), 2.95 (dd, 1H), 2.60—2.40 (m, 1H), 2.10-2.00 (m, 1H), 1.85-1.15 (m, 7H), 0.98 (t, 2H), 0.00 (s, 9H); MS(ES):438(M+1).

Step 4. (3R)— and (3S)—3-Cyclopentyl—3-[5~(7H—pyrrolo[2,3-d]pyrimidin—4—yl)—1,3-oxazol~2-yl]- propanenitrile A on of 3-cyclopentyl—3-[5-(7-[2~(trimethylsilyl)ethoxy]methyl~7H-pyrrolo[2,3-d]- pyrimidin—4-yl)-1,3-oxazolyl]propanenitn'le (20.0 mg, 0.0457 mmol) was stirred with TFA (0.1 mL) in DCM (0.2 mL) for 6 hours. The solvent was removed, and the resulting residue was stirred overnight with ethylenediamine (0.1 mL) in methanol (0.2 mL). The solvent was removed in vacuo.

The desired t was obtained via preparative-HPLC/MS (C18 column eluting with a gradient of ACN/H20 containing 0.15% NH40H) (5.3 mg, 38%). 1H NMR (400 MHz, CDC]3)Z 5 10.25 (br s, 1H), 8.90 (s, 1H), 8.00 (s, 1H), 7.50 (d, 1H), 7.06 (d, 1H), 3.36-3.28 (m, 1H), 2.98 (dd, 1H), 2.90 (dd, 1H), 2.51—2.38 (m, 1H), 2.08~l.96 (m, 1H), 1.80-1.51 (m, 5H), 1.44—1.30 (m, 2H); :308(M+1).

The following nd of Table 5d was also prepared as a racemic mixture, ing to the procedure of the above Example 87.

Table 5d 3—[5—(7H—pyrrolo[2,3-d]— pyrimidin-4—yl)-l ,3-oxazoly1] - hexanenitrile Example 90: 5—(1VIethylthio)-3—[4-(7H-pyrrolo[2,3-d]pyrimidinyl)-1H—pyrazol—l-yl]pentane- nitrile N. \ I\N" N Step 1. (2E)—5—(Methylthio)pent-2—enenitrile To a 0 °C mixture of [chloro(triphenyl)phosphoranyl]ACN (2.5 g, 0.0073 mol) in THF (10 mL, 0.1 mol) was added TEA (2.0 mL, 0.014 mol), and the resulting mixture was stirred for 30 min.

The ice bath was removed for 30 min, then the mixture was re~cooled back to 0 °C, A solution of 3— (methylthio)~pr0panol (0.68 mL, 0.0072 mol) in THF (1 mL, 0.02 mol) was added and the mixture was d overnight. Water was added and the mixture was filtered. The filtrate was washed with water x3 and brine. The organic phase was dried and the t was removed by rotary evaporation to give 2.1 g of an off-white solid. The solid was triturated with MTBE and was filtered. The filtrate was washed with 1N HCI, water, sat. NaHCO3 and brine. The organic phase was dried and was concentrated using a rotary evaporator to give 0.62 g orange oil (44% yield, trans : cis ~ 2 : 1). 1H NMR for trans (400 MHZ, CDC13): 5 6.68 (1H, m); 5.14 (1H, d); 2.6 (2H, m); 2.55 (2H, t); 2.1 (3H, 3).

Step 2. 5—(Methylthi0)—3—[4-(7-[2-(trimethylsilyDet/zoxy]methyl— 7H-pyrrolo[2,3—d]pyrimidin-4—yl)-1H— pyrazol-1«yl]pentanenitrile A mixture of 4—(1H—pyrazo]y1)[2~(trimethylsilyl)ethoxy]methyl-7H—pyrrolo[2,3-d]— pyrimidine (0.30 g, 0.00095 mol), -(rnethylthio)pent-2enenitrile (0.28 g, 0.0016 mol) and DBU (45 uL, 0.00030 mol) in ACN (3 mL, 0.06 mol) was stirred at rt for 5 days. The solvent was removed by rotary evaporation to give an orange oil. The crude oil was tographed with 30-70 ethyl acetate/her to give 0.35 g of a colorless oil (83% yield).

’H NMR (400 MHz, CD013): 5 8.95 (1H, s); 8.41 (1H, s); 8.4 (1H, s); 7.48 (1H, d); 6.84 (1H, d); 5.75 (2H, s); 4.95 (1H, br); 3.6 (2H, t); 3.1 (2H, m); 2.58 (2H, m); 2.28 (2H, m); 2.1 (3H, s); 1.99 (2H, t); 0.0 (9H, 5). MS ("M-PH): 443.

Step 3. 5—(Methylthio)~3—[4—(7H-pyrrolo[2,3—d]pyrimidin-4—yl)—1H-pyrazol-I—yUpentanenitrile A solution of hylthio)—3-[4—(7—[2—(trimethylsily1)ethoxy]methyl~7H~pyrrolo[2,3—d]— pyrimidinyl)—1H-pyrazol-l -yl]pentanenitrile (0.35 g, 0.00079 mol) in THF (4 mL, 0.05 mol) and 3.0 M HCI (HCl) in water (4 mL) was heated to reflux overnight. The t was removed by rotary evaporation to give a pale orange oil. The oil was stirred in ethanol (3 mL, 0.05 mol) and 8.0 M ammonium hydroxide in water (1 mL) overnight. The on was concentrated and purified by prep LCMS (C18 column eluting with a gradient of O containing 0.15% NI-LOH) to give 125 mg of a white foam. The white foam was triturated with MTBE (~ 1.5 mL). The resulting solid was filtered, washed and dried to give 80 mg of the product (32% yield). 1H NMR (400 MHz, CD013): 5 10.38 (1H, s); 8.88 (1H, s); 8.39 (1H, s); 8.38 (1H, s); 7.44 (1H, d); 6.8 (1H, d); 5.75 (2H, s); 4.9 (1H, br); 3.05 (2H, m); 2.5 (2H, m); 2.23 (2H, d); 2.1 (3H, 5). MS ('M-t-H): 313.

Example 91: 5—(Methylsulfinyl)[4-(7H—pyrrolo[2,3-d]pyrimidin-4—yl)—1H—pyrazal—l-yl]- pentanenitrile NU \ / N N A solution of 5—(methylthio)-3—[4—(7H—pyrrolo[2,3—d]pyrimidin—4-yl)-1H—pyrazol-l~yl]— pentanenitrile (0.065 g, 0.00021 mol) and hydrogen peroxide (0.022 mL, 0.00023 mol) in ACN (1 mL, 0.02 mol) was stirred overnight. The reaction was concentrated and purified by HPLC to give 21 mg of a solid. The solid was triturated with MTBE (l mL)/DCM (10 drops). The solid was filtered and washed to give 13 mg of a white solid (20% yield) which was dried rt to 50 °C for 2 h.

IH NMR (400 MHz, CDC13)I 5 9.95 (1H, s); 8.85 (1H, s); 8.4 (2H, m); 7.4 (1H, d); 6.8 (1H, s); 4.9 (1 H, br); 3.15 (2H, m); 3.0 (2H, m); 2.8-2.5 (2H, m); 2.6(31-1, 5). MS (M+H): 329.

Example 92: 5-(Methylsulfonyl)[4-(7H-pyrrolo[2,3-d]pyrimidin—4—yl)-IH-pyrazol-l-yl]- pentanenitrile A on of hy1thio)[4-(7H-pyrrolo[2,3~d]pyrimidin—4-yl)—1H—pyrazol-l~yl]- pentanenitn'le (0.040 g, 3 mol) and hydrogen peroxide (0.5 mL, 0.005 mol) in ACN (1 mL, WO 70514 0.02 mol) was refluxed ght. The reaction was purified by HPLC to give 16 mg of a white glass/solid which was tn'turated With EtOH (~0.8 mL) to give 13 mg of a white solid (30% .

'H NMR (400 MHz, CDCl;): 8 8.75 (1H, s); 8.48 (1H, d); 8.4 (1H, d); 7.43 (1H, d); 6.8 (1H, s); 5.0 (1H, br); 3.4 (2H, In); 323.0 (2H, m); 2.8—2.5 (2H, m); 2.95 (3H, s). MS (M+H): 345. e 93: 4,4,4—Trifluoro[4-(7H-pyrrolo[2,3-d]pyrimidinyl)—pyrazol-l-yII-butyronitrile F3C’ Step 2. 4, 4, 4-Trifluoro[4—(7H—pyrrolo[2, 3-d]pyrimidinyl)-pyrazol—1~yl]—butyronitrile A solution of 4,4,4-trifluoro—3—[4—(7—[2—(trimethylsilyl)ethoxy]methy1—7H—pyrrolo[2,3-d]— pyrimidinyl)-lH-pyrazol-l-yl]butanenitrile (3.1 g, 0.007] mol) from Step 1 in THF (35 mL, 0.43 mol) and 3.0 M HCl in water (35 mL) was heated to reflux overnight. The solvent was removed by rotary evaporation to give a greenish orange oil/glass. The oil was stirred with ethyl acetate and sat.

NaHC03 (50 mL). The aqueous phase was extracted with ethyl acetate. The organic layers were washed with brine and reduced by rotary ation to give an ass residue. The residue was stirred in ethanol (20 mL, 0.3 mol) and 8.0 M um hydroxide in water (10 mL) over a weekend. The solvent was removed by rotary evaporation to give a pale orange foam/solid. The crude was chromatographed with 0-7% MeOH/DCM, 0‘:O.7% NH4OH to give 3 g of a pale orange paste/solid. The solid was recrystallized from EtOH to give 1.6 g of an off-white ls (74% yield).

‘H NMR (400 MHz, DMSO): 8 12.2 (1H, s); 8.95 (1H, s); 8.7 (1H, s); 8.5 (1H, s); 7.63 (1H, d); 6.96 (1H, d); 6.01 (1H, m); 3.7 (2H, m). MS (M+I—I): 306.

The following compounds of Table 5e were prepared as indicated in the column labeled "Prep. Ex. No." Table 5e ,5-Dimethyl[4-(7H- pyrrolo[2,3-d]pyrimidin-4—yl)- 61 pyrazol-l exanenitrile modification G 4—[1 —(2—Methanesu1fonyI—ethyl)- 1H—pyrazo(13:31:11]igniyrro O[2’31 6] - - - l - modification G ,5,5-Trifluoro—4-[4-(7H— pyrrolo[2,3-d]pyrimidin—4~yl)— 59 . . pyrazol-l -y]]-pentanenitrile modlficatron G Example 97: 3-(2-Cyano[4-(7H-pyrrolo[2,3-d}pyrimidinyl)-lH-pyrazolyl]ethyl)-cyclo-n" p'entane-carbonitrile trifluoroacetate / TFA "IO \ N/ 0 Step 1.‘ 3—(DimethoszmethyDcyclopentanecarbaldehyde.

Into a 3—neck round bottom flask 2~norbornene (5.500 g, 0.05841 mol) was ved in DCM (198.0 mL,) and methanol (38.5 mL) and was cooled at -78 °C. Ozone was passed through the reaction until it turned blue and was stirred at —78 °C for 30 minutes. Then nitrogen was passed through for 20 minutes and p-toluenesulfonic acid (0.95 g, 0.0055 mol) was added The reaction was allowed to warm at 20 °C and was stirred for 90 minutes. Into the reaction was added sodium bicarbonate (1.67 g, 0.0199 mol) and the resulting e was stirred at 20 °C for 30 minutes and dimethyl sulfide (9.4 mL, 0.13 mol) was added. The reaction was stirred for 16 hoursand was reduced by rotary evaporation to ~50 mL The on was extracted with DCM and the organic extracts were washed with water and brine, dried ), and stripped in vacuo. The on was distilled at 135 °C (bath temperature) at high pump vacuum to give the product (7:5! g) as‘a ~2:1 mixture of diastereomers. 'H NMR (300 MHz, CDC13): 9.64 & 9.62 (d, 1H), 4.15 ~& 412 (s, 1H), 3.35 & 3.34 (s, 6H), 2.77 m, 1H), 2.34 (m, 1H), 1.35-2.00 (m, 6H).

Step 2. (2E, Z)—3—[3-(Dimethoxymethyl)cyclopentyl]acrylonz'trile.

Into a flask containing a 0 °C solution of t-BuOK in THF (1.0 M, 6,10 mL) was added a solution of diethyl cyanomethylphosphonate (1.1 g, 6.4 mmol) in THF (8 mL). The cooling bath was removed and the reaction was warmed to ambient ature, then a on of 3-(dimethoxy- methyl)cyclopentanecarbaldehyde (1.00 g, 5.81 mmol) in THF (2 mL) was added dropwise. y after completion of the addition orange gel-like particulates began to form, afier approximately 1 hour the reaction was gelatinous. The reaction was held with stirring at ambient temperature for 16 hours at which time tlc indicated complete reaction. The reaction was partitioned between water and EtOAc and the aqueous phase was washed with additional EtOAc.

The combined organic phase was washed with water, then sat'd NaCl, and then was dried over MgSO4 and reduced in vacuo, and the resulting residue was purified by column chromatography with 6:1 szEtOAc + 1% TBA to obtain the product as a 1:1 mixture of E/Z isomers (760 mg, 61%). 1H NMR (400 MHz, CDC13): 8 vinylic protons at 6.69 (m, 0.5H), 6.37 (m, 0.5H), 5.32 (m, 0.5H), 5.23 (m, 0.5H), acetal methine proton at 4.14 (m, 1H), methyl protons at 3.34 (s, 6H).

Step 3. 3—[3-(Dimethoxymethyl)cyclopentyU-3—[4—(7—[2-(trimethylsinDelhoxyjmethyl- 7H- pyrrolo[2,3—d]pyrimidin—4—yD-1H-pyrazol—I~yl]pr0panenitrile.

To a solution of 4—(1H—pyrazol~4-y1)[2-(trimethylsilyl)ethoxy]methyI—7H-pyrrolo[2,3- d]pyrimidine (230 mg, 0.74 mmol) in ACN (5 mL) was added (2E,Z)-3—[3-(dimethoxymethyl)cyclo- pentyl]acrylonitrile (289 mg, 1.48 mmol), followed by DBU (300 uL, 2.0 mmol). The mixture was stirred at ambient temperature for 16 hours, at which point LCMS and TLC indicated complete reaction. The reaction was reduced to dryness in vacuo, and the residue was purified by column chromatography to obtain the product as a mixture of diastereomers (293 mg, 77%). 1H NMR (400 MHz, : 8 8.85 (s, 1H), 8.31 (s, 2H), 7.40 (d, 1H), 6.80 (d, 1H), 5.68 (s, 2H), 4.28 (m, 1H), 4.11 (m, 1H), 3.54 (t, 2H), 3.36 (s, 1.5H), 3.34 (s, 1.5H), 3.30 (s, 1.5H), 3.26 (s, 1.5H), 3.12 (m, 1H), 2.94 (m, 1H), 2.65 (m, 1H), 2.34 (m, 1H), 2.0-1.0 (m, 6H), 0.92 (t, 2H), -0.56 (s, 9H). MS (EI) m/z = 511.3 (M+H).

Step 4. 3—(3-Formylcyclopentyl)—3—[4-(7-[2-(trimethylsilyljethoxyjmethyl- 7H-pyrrolo[2,3—d]- pyrimidinyI)-1H—pyrazol—1-yl]pr0panenitrile.

To a solution of 3-[3-(dimethoxymethyl)cyclopentyl]~3-[4-(7-[2-(trimethylsilyl)ethoxy]- methyl-7H-pyrrolo[2,3—d]pyrimidin_—4—yl)-1H-pyrazol—l—yl]propanenitrile (293 mg, 0.574 mmol) in THF (4.5 mL) was added aqueous HCl (1.0 M, 1.5 mL). The reaction was held at t temperature for 2.5 hours at which point TLC and LCMS indicated complete deprotection to the corresponding de. The reaction was ioned between water and EtOAc and the aqueous phase was extracted with additional EtOAc. The combined organic phase was washed with water, then sat'd NaHCO3, then sat'd NaCl, and then was dried over MgSO4 and filtered and stripped to dryness to leave the crude product as a mixture of diastereomers. 1H NMR (400 MHz, CDC13)Z 8 9.69 (d, 0.5H), 9.64 (d, 0.5H), 8.85 (s, 0.5H), 8.84 (s, 0.5H), 8.35 (s, 0.5H), 8.34 (s, 0.5H), 8.32 (s, 0.5H), 8.30 (s, 0.5H), 7.41 (d, 0.5H), 7.40 (d, 0.5H), 6.80 (d, 0.5H), 6.79 (d, 0.5H), 5.68 (s, 1H), 5.67 (s, 1H), 4.32 (m, 1H), 3.54 (m, 2H), 3.14 (m, 1H),‘2.96 (m, 2H), 2.76 (m, 1H), 2.1-1.1 (m, 6H), 0.92 (m, 2H), ~0.058 (s, 9H). MS (EI) m/z= 465.1 (M+H).

Step 5. 3—3-[(E,Z)-(Hydroxyimino)methyl]cyclopentyl—3-[4-(7—[2-(trimethylsilyl)ethoxyjmethyl— 7H— pyrr0l0[2,3—d]pyrimidin—4-yD—1H—pyrazol—1—yl]propanenitrile.

To a solution of 3—(3-formylcyclopenty1)-3—[4-(7—[2-(trimethylsilyl)ethoxy]methyl—7H- pyrrolo[2,3-d]pyrimidin-4—yl)-1H—pyrazol-l-yl]propanenitrile (336 mg, 0.000723 mol) in H (5.0 mL, 0.12 mol) was added hydroxylamine hydrochloride (60 mg, 0.00087 mol) and KHCO3 (110 mg, 0.0011 mol) and the reaction was held at ambient temperature for 16 hours, at which point LCMS indicated complete reaction. The reaction was reduced to dryness in vacuo and the residue was ioned between water and EtOAc, and the s phase was extracted with additional EtOAc.

The combined organic phase was washed with water, then sat'd NaCl, then was dried over MgSO4 and concentrated to leave the crude product, which was cam'ed forward to the subsequent reaction without ation. NMR indicated disappearance ofaldehydic protonS. MS (EI) m/z = 480.2 (M+H).

Step 6. 3-(2—Cyan0—1 —[4~(7—[2-(trimethylsilyl)ethoxyjmethyl— 7H—pyrrolo[2, 3—d]pyrimidin-4—yD—1H- pyrazol-I—yljethyocyclopentanecarbonitrile.

To a solution of 3[(E,Z)-(hydroxyimino)methyl]cyclopentyl—3-[4-(7-[2—(trimethylsiIyl)- ethoxy]-methy1-7H—pyrrolo[2,3—d]pyrimidin—4—yl)-lH-pyrazol-l -y1]propanenitri1e (324 mg, 0.67 mmol) in pyridine (1.2 mL), was added methanesulfonyl chloride (210 pL, 2.7 mmol) se. The reaction was heated to 60 °C for 2.5 hours, at which point LCMS indicated complete reaction. The reaction was partitioned between water and EtOAc, and the s phase was extracted with additional EtOAc. The combined organic phase was washed with water, then 0.1N HCl, then sat‘d NaCl, and then was dried over MgSO4. The crude product was purified by column chromatography to obtain the product as a mixture of reomers (164 mg, 52%). The diastereomers were then separated by chiral HPLC to provide four ct diastercomers, which were taken directly on to the deprotection step. MS (EI) m/z = 462.1 (M+H).

Step 7. 3-(2—Cyan0-I—[4—(7H-pyrrolo[2,3-djpyrimidinyl)-IH-pyrazol-1~yl]ethyl)-cyc10pentane- carbonitrile trzfluoroacetate.

The four reomers were then separately deprotected in this representative manner. To 3— 2—cyano-1 -[4—(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4—y1)—lH-pyrazol-l - yl]ethylcyclopentanecarbonitn'le (35 mg, 0.076 mmol) dissolved in CHZCIZ (2.0 mL) was added TFA (1.0 mL) and the on was stirred for 2 hours at ambient temperature at which point LCMS indicated complete cleavage to the N—hydroxymethyl intermediate. The solvent was removed and to the residue was added methanol (1.0 mL) followed by ethylenediamine (40 nL, 0.61 mmol), the reaction was stirred for 16 hours at which point LCMS indicated complete reaction. The solvent was d and the residue was purified by preparative LCMS to provide the product as a TFA salt.

NOE experiments confirm that all isomers have cis geometry on cyc10pentyl ring. Isomers 1 and 2: 1H NMR (400 MHz, CD3OD)Z 6 8.95 (s, 1H), 8.89 (s, 1H), 8.54 (s, 1H), 7.86 (d, 1H), 7.29 (d, 1H), 3O 4.72 (m, 1H), 3.27 (m, 1H), 3.19 (m, 1H), 2.95 (m, 1H), 2.72 (m, 1H), 2.2-1.9 (m, 4H), 1.67 (m, 2H).

Isomers 3 and 4: 1H NMR (400 MHz, CD3OD): 5 8.95 (s, 1H), 8.88 (s, 1H), 8.52 (s, 1H), 7.85 (d, 1H), 7.28 (d, 1H), 4.72 (m, 1H), 3.27 (m, 1H), 3.19 (m, 1H), 3.05 (m, 1H), 2.71 (m, 1H), 2.44 (m, 1H), 2.05 (m, 1H), 1.92 (m, 1H), 1.72 (m, 1H), 1.58 (m, 2H).MS (El) m/z = 332.2 (M+H).

Example 98: 3—[3-(Hydroxymethyl)cyclopentyl]-3—[4-(7H—pyrrolo[2,3-d]pyrimidin-4~yl)-1H- pyrazol-l-yl]propanenitrile NP \ / N N Step I.‘ 3-[3-(Hydroxymethyl)cyclopentylj[4-(7—[2-(trimethylsibiljethoxy]methyl- 7H—pyrrolo[2, 3- d]pyrimidinyl)-1H-pyrazol-I-yI]propanenitrile A on of 3—(3~fonnylcyclopentyl)[4—(7—[2-(trimethylsilyl)ethoxy]methyl-7H—pyrrolo- [2,3-d]pyrimidinyl)-1H—pyrazol—l-yl]propanenitrile (50.0 mg, 0.108 mmol) in methanol (280 uL) was cooled to 0 °C, then sodium tetrahydroborate (14 mg, 0.37 mmol) was added. The reaction was held at 0 °C for 10 minutes, at which point LCMS and TLC indicated complete reaction.

The reaction was ed by us addition of 1N HCI (3 drops) and methanol (1 mL), followed by addition of aqueous NaHCO; and CHClg. The phases were separated and the aqueous phase was washed with additional CHC13. The combined organic phase was washed with sat'd NaCl, dried over MgSO4 and reduced to dryness. The residue was purified by column chromatography to obtain the product as a mixture of diastereomers (37.4 mg, 74%). 1H NMR (400 MHz, : 5_ 8.84 (s, 1H), 8.31 (s, 2H), 7.40 (d, 1H), 6.80 (d, 1H), 5.67 (s, 2H), 4.29 (m, 1H), 3.53 (m, 1H), 3.53 (t, 2H), 3.14 (m, 1H), 2.95 (m, 1H), 2.68 (m, 1H), 2.2-1.0 (m, 9H), 0.92 (t, 2H), ~0.059 (s, 9H). MS (EI) m/z = 467.2 (M+H).

Step 2. 3-[3—(Hydroxymethyl)cyclopentyl]~3—[4—(7H-pyrrolo[2,3-d]pyrimidin—4—yl)—1H—pyrazol—1 - yljpropanenim'le To 3-[3—(hydroxymethyl)cyclopentyl][4-(7-[2~(trimethylsi1yl)ethoxy]methyl-7H—pyrrolo— [2,3-d}pyrimidin~4-yl)-1H-pyrazol-l—yl]propanenitrile (60.4 mg, 0.129 mmol) dissolved in CHZCIZ (2.0 mL) was added TFA (1.0 mL) and the reaction was stirred for 1 hour at which point LCMS indicated complete cleavage to the N~hydroxymethyl intermediate (m/z = 367). The trifluoroacetate ester of the hydroxymethyl of the cyclopentyl ring was also observed (m/z = 463). The solvent was removed and to the residue was added methanol (1.0 mL) followed by ethylenediamine (80 uL, 1.19 mmol). The resulting e was stirred for 16 hours at which point LCMS indicated complete reaction to the desired product. The solvent was removed and the e was purified by chiral HPLC to provide four distinct diastereomers (20.2 mg total of four isomers, 46%). NOE experiments suggest that all isomers have cz's geometry on the cyclopentyl ring. Isomers l and 2: IH NMR (400 MHz, : 8 8.65 (s, 1H), 8.62 (s, 1H), 8.38 (s, 1H), 7.50 (d, 1H), 6.95 (d, 1H), 4.51 (m, 1H), 3.40 (m, 2H), 3.22 (m, 1H), 3.11 (m, 1H), 2.61 (m, 1H), 2.10 (m, 1H), 1.94 (m, 1H), 1.82 (m, 1H), 1.6—1.4 (m, 3H), 1.03 (m, 1H). s 3 and 4: IH NMR (400 MHz, CD3OD): 8 8.66 (s, 1H), 8.62 WO 70514 (s, 1H), 8.37 (s, 1H), 7.50 (d, 1H), 6.95 (d, 1H), 4.51 (m, 1H), 3.46 (m, 2H), 3.21 (m, 1H), 3.11 (m, 1H), 2.61 (m, 1H), 2.22 (m, 1H), 2.09 (m, 1H), 1.71 (m; 1H), 1.55-1.25 (m, 3H); 1.04 (m, 1H). MS (EI) m/z = 337.1 (M+H).

Example 100: 1—(1H—Pyrrolo[2,3-b]pyridin—4—yl)—lH—indazole (100a) and 2—(1H-pyrrolol2,3-b]- pyridin-4—yl)-2H—indazole (100b) 8% 2 \ ,N \ \ l \ 12 N N p: 4—Bromo-1H—pyrrolo[2,3—b]pyridine (0.078 g, 0.00040 mol) and lH-indazole (0.283 g, 0 mol) was heated neat in a sealed tube at 200 °C (an oil bath) overnight with stirring. The on was allowed to cool to rt and the crude product was purified by prep LC-MS on a C-18 column eluting with a water/ACN gradient containing 0.2% TFA to give the title compound (0.015 gm, 15%), as an amorphous white solid, LC /MS (M+H)* 235, 'H NMR (DMSO-dé) 5 12.01 (bs, 1H) 9.17(s, 1H), 8.31(s, 1H), 7.73(d, 1H, J=9.0), 7.67(m, 2H), 7.58(m, 1H), 7.28(m, 1H), 7.07(m, 2H).

Example 106: 3-[3-(1‘H-Pyrrolo[2,3-b]pyridinyl)—1,2,4-oxadiazolyl]benzonitrile Step 1. trimethylsilyl)ethoxy]methyl-JH—pyrrolo[2,3-b]pyridinecarbonitrile CH20(CH2)2Si(CH3)a 4-Bromo~1-[2-(trimethylsilyl)ethoxy]methy1—lH-pyrrolo[2,3—b]pyridine (0.300 g, 0.000917 mol) was dissolved in DMF (6.5 mL, 0.084 mol) and then zinc cyanide (0.30 g, 0.0026 mol) was added. The solution was degassed with nitrogen and then bis(tri—t-buty1phosphine)pa11adium (0.1 g, 0.0002 mol) was added. The reaction was sealed and heated in the microwave to 100 °C for 30 minutes. The reaction was allowed to cool to rt, taken up in ethyl acetate and washed with water saturated sodium carbonate, brine, dried over magnesium e and concentrated to give an oil. The crude product was purified by flash column chromatography (FCC) on silica gel, eluting with a hexane: ethyl acetate gradient to give the product (0.25 gm) as a colorless oil. LC/M S (M+H)+ 274, lH NMR (CDClg) 8 8.22 (d, 1H), 7.53(d, 1H), 7.40(d, 1H), 6.73(d, 1H), 5.65(s, 2H), 3.50(m, 2H), 0.90(m, 2H), 0.0(s, 9H).

Step 2. N-Hydroxy-1 -[2-(trimethylsilyDethowjmethyl—IH—pyrrolo[2,3-b]pyrz'dine—4—carboximidamide HN NHOH | \, \ N N IO CH20(CH2)ZSi(CH3)3 1-[2—(Trimethylsilyl)ethoxy]methyl—1H—pyrrolo[2,3-b]pyridine—4-carbonitrile (0.05 g, 0.0002 mol) was dissolved in ethanol (2.0 mL, 0.034 mol), and then hydroxylamine hydrochloride (0.023 g, 0.00033 mol) and ium carbonate (0.10 g, 0.00073 mol) were added. The reaction was heated to reflux for 5 h, and the reaction was then allowed to cool to rt and filtered to remove the solids. The filtrate was concentrated to give the product 0.06 g as yellow oily residue, LC/MS (M+H)+ 307.

Step 3. 3-[3-(1«[2-(TrimethylsilyDethoxyjmethyl-IH-pyrrola[2, 3-b]pyridin-4—yl)—1,2;4—0xadiqzol—5- yljbenzom'trile N\ N l \ N/ N.

H2)ZSi(CH3)3 The crude product oxy-l-[2-(trimethylsilyl)ethoxy]rnethyl—lH-pyrrolo[2,3-b]pyridine- 4-carboximidamide (0.06 gm, 0.0002 mol) was ved in pyridine (1.0 mL, 0.012 mol) and then 3- cyanobenzoyl chloride (0.040 g, 0.00024 mol) was added at rt. This e was stirred for 1 h and heated to 80 0C in an oil bath. After heating for 18 h the reaction was d to cool to it and then diluted with ACN and concentrated in vacuo to give 3-[3-(1-[2-(trimethylsilyl)ethoxy]methyl—lH- pyrrolo[2,3-b]pyridinyl)-1,2,4-oxadiazolyl]benzonitrile 0.08 gm as an off white residue, LC/M S (M+H)+ 418.

Step 4. 3-[3-(1H-Pyrrolo[2,3-b]pyridinyl)—1,2,4-oxadiazol-5~yl]benzonitrile The crude 3-[3-(1—[2-(trimethylsilyl)eth0xy]methyl-lH-pyrrolo[2,3-b]pyridinyl)-I,2,4-0xa- diazol—S—yljbenzonitrile (0.08 g, 0.0002 mol) was dissolved in TFA (3.0 mL, 0.039 mol) under nitrogen and then heated to 60 °C. Afier heating for 2 h the reaction was allowed to cool to rt and concentrated in vacuo. The ing residue was taken up in ol and concentrated to remove as much of the TFA as possible. The residue was taken up in methanol (2.0 mL, 0.049 mol) and ammonium hydroxide (1 mL). This mixture was stirred at rt for 2 h and the on was then complete. The reaction was concentrated in vacuo to give the crude product which was purified by prep HPLC on a C-18 column eluting with a ACNzwater nt with 0.2% TFA to give the title compound (0.025 gm, 43%) (M+H)+ 288. 'H NMR (DMSO-ds) 5 12.1 (bs, 1H), 8.65(s, 1H), 8.48(d, 1H,J=6.4), 8.39(d, 1H, J=4.8), 8.16(d, 1H, J=6.4), 7.840;, 1H, J=6.4), 7.75(d, 1H, , 7.68(m, 1H), 6.99 (m, 1H).

Example 107: 4-(1-Benzothien-2—yl)-lH—pyrrolo[2,3-b]pyridine Z\/\ \ Step 1. 4-(’1-Benzothienyl)-1~[2-(trimethylsilyl)ethoxy] methyl-1H—pyrrolo[2, 3-b]pyridine ‘CH203 l-Benzothien—z—ylboronic acid (0.05 g, 0.0003 mol) and 4-bromo-l —[2-(trimethylsilyl)- ethonymethyl-lH—pyrrolo[2,3-b]pyridine (0.10 g, 0.00031 mol) were combined in toluene (3.0 mL, 0.028 mol) and ethanol (1.0 mL, 0.017 mol).

Potassium carbonate (0.085 g, 0.00062 mol) dissolved in water (1.0 mL) then was added and the on was degassed with nitrogen. Then tetrakis(triphenylphosphine)palladium(0) (0.05 g, 0.00004 mol) was added and the on was heated to 120 °C in a sealed tube in the microwave for 60 minutes. This was allowed to cool to rt, taken up in ethyl acetate and washed with water 2X, brine, dried over magnesium sulfate and concentrated to give enzothien—2—yl)-l-[2-(trimethylsilyl)ethoxy]methyl-1H—pyrrolo[2,3-b]— pyridine (0.10 gm) as an oil, LC /MS (M+H)+ 381.

Step 2. 4—(1-Benzothien-Z—yD-IH—pyrrolo[2,3-b]pyridine Using a procedure ous to Example 106, Step 4, but using 4—(1-benzothien—27yl)—1-[2— (trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine, the title compound was ed as a yellow powder (0.015 g, 18%), LC IMS (M+H)+: 251, 1H NMR (DMSO—dG) 8 11.95 (bs, 1H), 8.28(d, 1H, J=5.4), 8.15(s, 1H), 8.03(m, 1H), 7.96(m, 1H), 7.64(m, 1H), 7.42(m, 2H), 7.39(d, 1H, J=5.4), 6.95(m, 1H).

Example 120: 4-Fluoro[l-(lH—pyrrolo[2,3-b]pyridinyl)-lH—pyrazol—3-yl]phenol / \ OH N N 4—Bromo-1H-pyrrolo[2,3-b]pyridine (0.050 g, 5 mol) and 4-fluoro—2—(1H-pyrazol yl)phenol (0.150 g, 0.000842 mol) were heated neat to 160 °C for 5 h. The reaction was allowed to cool to It and the residue was purified by prep LC-MS on a C-18 column eluting with a water/ACN gradient containing 0.2% TFA to give the title compound, (0.052 g, 20%, as an amorphous white solid, LC IMS (M+H)+ 295, 'H NMR (DMSO-da) 5 12.01 (bs, 1H), 10.25(bs, 1H), 8.81(s,1H), 8.35(d, 1H, J: 5.5), 7.77(d, 1H, J=9.5), 7.64(m, 1H), 7.59(d, 1H, , 7.32(s, 1H), 7.09(m, 1H), 7.05(m, 1H), 7.01(m, 1H).

Example 127 : 4[3—(Trifluoromethyl)phenyl]—1H—pyrazol-l—yl-IH-pyrrolo[2,3-b] pyridine Step 1. (2E)—3—(Dimethylamino)—1-[3—(trifluoromethprhenyljprop-Z-en—1—one Trifluoromethyl)phenyl]ethanone (0.20 mL, 0.0013 mol) and l,1—dimethoxy—N,N- dimethylmethanamine (0.17 mL, 0.0013 mol) were ed in a sealed tube and heated in a microwave to 120 °C for 15 minutes, the reaction was d to cool and was trated to remove the residual DMF acetal, to give (2E)—3-(dimethy1amino)[3—(trifluoromethyl)phenyl]prop- 2—en—1vone, 0.32 gm, as a red oil, LC /MS (M+H)*: 244.

Step 2: 3-[3-(Trifluoromethprhenylj-IH-pyrazole F30 ‘ \ N‘NH The (2E)(dimethylamin0)[3-(trifluoromethyl)phenyl]propen—1-one (0.32 g, 0.0013 mol) was dissolved in ethanol (10.0 mL, 0.171 mol) and hydrazine (0.24 mL, 0.0078 mol) under nitrogen and heated to reflux. The reaction was monitored by HPLC and was complete almost immediately. The mixture was allowed to cool to rt and concentrated to give the crude product as an oil. The product was purified by FCC on silica gel eluting with a hexane: ethyl acetate gradient to give 3~[3-(trifluoromethyl)phenyl]—1H—pyrazole as an oil (0.25 g, 89% ), LC /MS (M+H)+: 213, 1H NMR (CDC13) 5 8.06 (s, 1H), , 1H, J=7.5), 7.66(d, 1H, J= 2.4), 7.57(m, 1H), 7.55(d, 1H, J=7.5), 6.69(d, 1H, J= 2.4).

Step 3. 4[3—(Triflu0romethprhenyl]-1H—pyrazol-I-yl-1H-pyrrolo[2,3-b]pyridine 4-Bromo-l H-pyrrolo[2,3-b]pyridine (0.028 g, 0.00014 mol) and 3-[3-(trifluoromethyl)- ]-1H-pyrazole (0.03 g, 0.0001 mol) were combined neat. The reaction was heated in a sealed tube in an oil bath to 175 °C for 20 to produce a crude t that was a black viscous gum. The crude product was purified by HPLC on a C—1 8 column eluting with a waterzACN gradient with 0.2% TFA to give the title product (0.025 gm, 50%) as a white amorphous solid, LC [MS (M+H)+: 329, IH NMR (DMSO—ds) 6 11.95 (bs, 1H), 8.83(d, 1H, J=2.7), 8.31(m, 3H), 7.75(m, 2H), 7.60(m, 2H), 7.35(d, 1H, J=2.7), 7.14(m, 1H).

Example 128: 3-[1-(1H-Pyrrolo[2,3-b]pyridinyl)—1H—pyrazolyl]benzonitrile {ThI,N Step 1. 3—[(2E)—3-(Dimethylamin0)prop—2—enoyl]benzonitrile 3-Acetylbenzonitrile (0.435 g, 0 mol) and 1,1—dimethox‘y—N,N-dimethylmethanamine (0.400 mL, 0.00301 mol) were combined and heated in sealed tube to 120 °C in the ave for 15 min. The reaction was then allowed to cool to rt giving the 3-[(2E)(dimethylamino)propenoyl]- benzonitrile as a red-orange crystalline material, LC IMS (M+H)+: 201.

Step 2. 3-(1H—Pyrazol—3—yl)benzonitrile The 3—[(2E)—3—(dimethylamino)prop—2—enoyl]benzonitrile (0.600 g, 0.00300 mol) was dissolved in ethanol (20.0 mL, 0.342 mol) and hydrazine (0.56 mL, 0.018 mol) under an atmosphere of nitrogen was stirred at room temperature for 1.5 h. The reaction was concentrated in vacuo to give a dark product which was purified by FCC on silica gel, g with ethyl acetate-hexane 1:1 to give 3—(1H—pyrazol—3-y1)benzonitrile as an oil (0.430g, 84%), LC /MS (M+H)+: 170.

Step 3. 3-[1-(1H—Pyrrolo[2,3-b]pyridinyl)-IH-pyrazol—3-yl]benzonitrile 4~Bromo~1H-pyrrolo[2,3-b]pyridine (0.075 g, 0.00038 mol) and 3-(1H-pyrazolyl)benzo- e (0.161 g, 0.000952 mol) were heated in sealed tube to 160 °C for 18 h. The resulting product, dark viscous gum, was purified by I-IPLC on a C—18 column eluting with a waterzACN gradient with 0.2% TFA to give the title product (0.030 g, 27%) as a white amorphous solid, LC /MS (M+H)+: 286, 'H NMR (DMSO—da) 5 11.95 (bs, 1H), , 1H), 8.36(s, 1H), 8.29(d, 1H, J=7.5), 8.25(d, 1H, J=5.0), 7.79(d, 1H, J= 7.5), 7.62(t, 1H, J= 7.5), 7.53(m, 2H), 7.25(s, 1H), 7.11(m, 1H).

Example 153: 3-[1-(1H—Pyrrolo[2,3-b]pyridin—4-yl)—lH-pyrazol-4—yl]benzonitrile 2 12/ Step I. ,5,5-Tezramethyl—1,3,2-dioxaborolany0-I—[2-(trimethylsilyl)ethoxyjmethyl-1H- pyrazole A solution of 4-(4,4,5,5-tetramethyl—l,3,2-dioxaborolanyl)-lH—pyrazole (2.0 g, 0.010 mol) and DMF (30.0 mL, 0.387 mol) was cooled to 0 °C. Sodium hydride (320 mg, 0.013 mol) (60% in oil) was added and the mixture was stirred for 10 min. [B—(Trimethylsily1)ethoxy]methyl chloride (2.4 mL, 0.013 mol) was added and the ing mixture was stirred for 20 min at 0° C and 2 h at room temperature. The reaction was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over Mg804 and concentrated to give 4-(4,4,5,5-tetrarnethy1—l,3,2- dioxaborolan-Z-yl)-l-[2-(trimethylsilyl)ethoxy]methyl-1H—pyrazole as a crude material. LC/MS (M+H)*: 325, 'H NMR (CDCl3) 5 7.85 (s, 1H), , 1H), 5.45(s, 2H), 3.55(t, 2H), 1.35(s, 12H), 0.95(t, 2H), 0.0(s, 9H).

Step 2. 3-(1-[2-(TrimethylsilyDet/onyjmethy]—IH-pyrazol—4—y0benzonitrile A mixture of 4—(4,4,5,5-tetramethyl—l,3,2—dioxaborolanyl)[2-(trimethylsilyl)ethoxy]- methyl-lH-pyrazole (150.0 mg, 0.0004625 mol) and 3-bromobenzonitrile (0.10 g, 0.00056 mol) in toluene (2.0 mL, 0.019 mol) and ethanol (0.3 mL, 0.005 mol) was treated with sodium carbonate (98 mg, 0.00092 mol) in water (0.5 mL, 0.03 mol). The mixture was degassed by bubbling nitrogen.

Tetrakis(triphenylphosphine)palladium(0) (53 mg, 0.000046 mol) was added and nitrogen was bubbled for 3 min. The reaction was heated in a microwave at 80 °C for 30 min, then allowed to cool to rt and taken up in water and ethyl acetate. The organic layer was dried over MgSO4, d and concentrated to give a crude product, which was purified by FCC on silica gel, eluting with EtOAc/Hexanes (1:5) to give 3—(1-[2-(trimethylsi1y1)ethoxy]methyl—lH—pyrazol—4—yl)benzonitrile, as anmLLcnwsoanfl3mi Step 3. 3-(1H—Pyrazol-4—yl)benzonitrile trifluoroacetate N‘NH A solution of 3-(1-[2-(tn'methylsilyl)ethoxy]methyl-lH—pyrazol—4—yl)benzonitrile (110.0 0.0003673 mol) was taken up in TFA (3.0 mL, 0.039 mol) and the mixture was heated in microwave at 120 °C for 3 min. The reaction mixture was d to cool to rt, and then concentrated to give a crude residue. The t was purified by I-IPLC on a C-18 column g with a water/ACN gradient containing 0.2% TFA to give 3-(1H-pyrazol~4-yl)benzonitrile trifluoroacetate as an amorphous white solid, LC /MS (M+H)+: 170.

Step 4. 3—[1-(1H—Pyrrolo[2,3-b]pyridin—4—yl)—IH—pyrazolyl]benzonitrile A mixture of 4-bromo;1H-pyrrolo[2,3-b]pyridine (25.0 mg, 0.000127 mol) and 3-(lH- pyrazolyl)benzonitrile trifluoroacetate (23.6 mg, 0.0000833 mol) was heated at 180 °C, neat overnight. The crude residue was purified by HPLC on a C-18 column eluting with a water; ACN gradient containing 0.2% TFA to give the title compound as an amorphous white solid, LC/MS (M+H)+: 286, 1H NMR (DMSO-ds) 8 11.85 (bs, 1H), 9.18(s, 1H), 8.42(s, 1H), 8.28(s, 1H), 8.25(d, 1H, J=5.0), 8.07(d, 1H, J=7.0), 7.64(d, 1H, J=7.0), 7.56(t, 1H, J= 7.0), 7.51(m, 1H), 7.47(d, 1H, J=5.0), 7.03(m,lH).

Example 170: 2-[1-(1H-Pyrrolo[2,3-b]pyridinyl)-1H—pyrazol-4—yl]-l,3-benzoxazole N\ ; NT;0 N fi Step 1. 4—Hydrazz'no—1—[2—(trimethylsilyDethquyjmethyl-1H-pyrrolo[2,3—bjpyrz‘dine HZN‘NH I j \ N N bH20(CH2)28i(CH3)3 To 4-bromo[2—(trimethylsilyl)ethoxy]methyl-lH—pyrrolo[2,3-b]pyridine (1.98 g, 0.00605 mol) was added hydrazine (11.0 mL, 0.350 mol) followed by addition of methanol (1.0 mL, 0.025 mol) (to e lity). The on mixture was heated in a sealed tube at 97 °C (an oil bath) for 18 h. The reaction mixture was cooled to it and formed an off-white solid precipitate. The solid was filtered off and rinsed with cold water and dried to give 4-hydrazino-l-[2-(trimethylsi1yl)ethoxy]- methyl-lH—pyrrolo[2,3-b]pyridine (1.55gm) as a light yellow solid, LC/MS (M+H)+:279, 1H NMR a'fi) 8 7.98(d, 1H), 7.91(s, 1H), , 1H), 6.69(s, 1H), , 1H), 5.58(s, 2H), 4.37(s, 2H), 3.56(t, 2H), 0.90(t, 2H), 0.0(s, 9H).

Step 2. 2-[1-(1-[2-(Trimethylsilyl)eth0xy]methyl—1H—pyrrolo[2, 3—bjpyridinyl)-1H-pyrazol—4—yl]— 1, 3-benzoxazole / \ . N/ N\ CH20(CH2)23i(CH3)3 To 4—hydrazino[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine (0.083 g, 0.00030 mol) 37821 and nzoxazolylmalonaldehyde (0.056 g, 0.00030 mol) in toluene (1.5 mL, 0.014 mol) was added lar sieves. The mixture was heated in a sealed tube at 70 °C (an oil bath) with stirring for 2 h. The solvent was removed in vacuo and the crude t was purified by FCC on silica using ethyl acetatezhexanes 3:7 to give 2-[1-(1-[2-(tn'methy1silyl)ethoxy]- methyl-1H-pyrrolo[2,3-b]pyridinyl)-—1H-pyrazol—4-yl]-1,3-benzoxazole (0.090gm) as an oil, LC/MS (M+H)+: 432.

Step 3.

Using a procedure analogous to Example 106, Step 4, but using 1—[2-(trimethylsilyl)- ethonymethyl—lH-pyrrolo[2,3-b]pyridinyl)-lH-pyrazol—4-yl]-1,3—benzoxazole, the title compound was prepared as a white amorphous powder (0.015 gm, 18%), LC IMS (M+H)+:302, 1H NMR (DMSO-ds) 5 11.85 (bs, 1H), 9.45(s,1H), 8.53(s, 1H), 8.36(bs, 1H), 7.7—7.6(m, 2H), 7.65(d, 1H), 7.56(bs, 1H), 7.38«7.34(m, 2H),7.0l(d,lH).

Example 172: Cyclohexyfll-(lH—pyrrolo[2,3-b]pyridin—4-yl)—1H—pyrazol—4-yl]methanol N N Step 1 . 4—(4-Br0mo-1H-pyrazol—I—yl)-1H-pyrrolo[2,3—b]pyridine A mixture of 4-bromo~1H-pyrrolo[2,3-b]pyridine (1.10 g, 0.00558 mol) and 4-bromo~lH— pyrazole (1.2 g, 0.0084 mol) was heated neat to 150 °C for 2 h. DMF was added to dissolve the crude residue. This residue was taken up in EtOAc and washed with 1N NaOH. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated to give a crude 4-(4-bromo-1H— l—l-yl)~1H-pyrrolo[2,3-b]pyridine residue, LC [MS : 263,265.

Step 2. 4—(4—Bromo~1H—pyrazol~1-yl)~1—[2-(trimethylsibxl)ethoxy]methyl—1H-pyrrolo[2,3-b]pyridine the/ N N CH20(CH2)28i(CH3)3 A on of 4-(4-br0mo-1H-pyrazol—I—ylj-I-[2-(trimethylsilyDet/zosty]methyl chloride (1.4 mL, 0.0079 mol) was added and stirred for 20 min at 0 °C. The reaction was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgSO4 and concentrated to give the crude material. The product was purified by FCC on silica gel (EtOAc/Hexanes, 1/10) to give 4-(4-bromo-1H—pyrazol-l~yl)—l —-[2—(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-bjpyridine as a solid product, LC [MS (M+H)+: 393, 394, 1H NMR (CDC13) 8 8.47(d, 1H, J=7.0), 8.27(s, 1H), 7.88(s, 1H), 7.52(d, 1H, J=4.5), 7.39(d, 1H, , d, 1H, J=4.5), 5.80(s, 2H), 3.6(t, 2H), 1.95(t, 2H), 0.0(s, 9H).

Step 3. Cycloheaazlfl—(J-[2—(trimethylsilyl)ethoxyjmethyfl1H—pyrrolo[2, 3—b]pyridin~4—yl)—1H—pyrazol— 4uyljmethanol N‘\/ CH20(CH2)25i(CH3)3 A mixture of 4~(4~bromo~1H-pyrazol—1 —y1)-1 ~[2—(trimethylsi1y1)ethoxy]rnethyl—1 H— pyrrolo[2,3-b]pyridine (50.0 mg, 27 mol) in THF (2.0 mL, 0.025 mol) under a nitrogen atmosphere was cooled to ~78 °C and 1.6 M n-butyllithium in water (1.00 mL, 0.0555 mol). The mixture was d for 3 min. The reaction was partitioned n water and EtOAc. The organic layer was dried over MgSO4, d and concentrated to give the cyclohexyl[1-(1:5) to give 4-yl)- lH—pyrazol-4—y1]methanol as a crude residue, LC IMS : 417.

Step 4. CyclohexyIfl—phenylvinyD-IH—pyrazol-4—yUmethanol Using a procedure analogous to Example 106, Step 4, but using cyclohexyl[l—(1-[2- (trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine, the title compound was prepared as a white amorphous powder (0.015 gm, 18%), LC /MS (M+H)*: 297. ‘H NMR (DMSO-dé) 5 11.85 (bs, 1H), 8.44(s, 1H), , 1H), 7.50(m, 1H), 7.44(d, 1H, J=6.5.70(s, 1H), 5.37(s, 1H).

Example 173: 4-[4-(1-Phenylvinyl)—1H-pyrazol-l-yl]-lH-pyrrolo[2,3—blpyridine / \ ‘N TFA the)’N Step 1. 4—[4—(1~Phenylvz'nyl)—1H—pyrazol~1—yl]-J-[2—(trimethylsilyl)ethoxyj—methyl-IH-pyrrolo[2, 3~ bjpyridz'ne N". \E - N N N CH20(CH2)28i(CH3)3 A mixture of (l-phenylvinyl)boronic acid (24.0 mg, 0.000162 mol) and 4—(4-bromo-1H— pyrazol-l-yl)[2-(trimethylsilyl)ethoxy]methy1—lH—pyrrolo[2,3-b]pyridine (50.0 mg, 0.000127 mol) in toluene (2.00 mL, 0.0188 mol) and ethanol (0.50 mL, 0.0086 mol) was treated with potassium carbonate (35 mg, 0.00025 mol) in water (1.00 mL, 0.0555 mol). The mixture was degassed by bubbling nitrogen. Tetrakis(tfiphenylphosphine)palladium(0) (10 mg, 0.00001 mol) was added and nitrogen was bubbled for 3 min. The reaction was heated in a sealed tube in the microwave at 100 °C for 30 min. The reaction was allowed to cool to rt and partitioned between ethyl acetate and water.

The combined organic layer was dried over MgSO4, filtered and concentrated to give the crude material The crude product was purified by FCC on silica gel eluting with EtOAc/Hexanes (1:5) to give 4-[4-(1—phenylvinyl)—1H—pyrazol-l -y1] -l -[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3 -b]- pyridine as a solid residue, LC /MS : 417.

Step 2.

Using a procedure analogous to Example 106, Step 4, but using 4-[4-(1-phenylvinyl)-1H- pyrazol—l-yl]—1—[2-(trimethylsilyl)ethoxy]methyl—lH—pyrrolo[2,3-b]pyridine, the title compound was prepared as an white amorphous powder (0.015 gm, 31%), LC IMS (M+I-l)+: 287, IH NMR (DMSO- d5) 8 11.85 (bs, 1H), 8.63(s, 1H), 7.99(s, 1H), 7.55(bs, 1H), , 2H), 7.43-7.37(m, 5H), 7.01(m,lH), 5.70(s, 1H), 5.37(s, 1H).

Example 200: 4-(l-Benzyl-lH—pyrazolyl)—1H-pyrrolo[2,3-b]pyridine l, \ N N H Step 1 . 4-‘(1-Benzyl—IH-pyrazol—4—yl)—1—[2—(trimethylsilyl)ethoxyjmethyl—1H~pyrrolo[2, 3—b]pyridine N—N@ l \ N N CH20(CH2)ZSi(CH3)3 o-l-[2-(trimethylsilyl)ethoxy]methyl-1H—pyrrolo[2,3-b]pyridine (0.100 g, 0.000306 mol) was combined with yl(4,4,5,5-tetramethyl-l,3,2-dioxaborolan—2-yl)-lH—pyrazole (0.113 g, 0.000398 mol) in toluene (3.0 mL, 0.028 mol) and ethanol (0.5 mL, 0.008 mol). Potassium carbonate (0.084 g, 0.00061 mol) dissolved in water (1.0 mL, 0.056 mol) was added and the reaction mixture was degassed with nitrogen. Tetrakis(triphenylphosphine)palladium(0) (0.080 g, 0.000069 mol) was added, and again the mixture was degassed with nitrogen for 5 min. The reaction was heated in sealed tube to 100 °C in a microwave for 30 s. The reaction was ioned n ethyl acetate and water. The organic layer was washed with water, brine, dried over magnesium sulfate and concentrated to give a crude residue. The t was purified by FCC on silica gel using ethyl acetatethexane 3:7, to give 4-(1-benzy1—lH-pyrazolyl)—1-[2-(trimethylsilyl)ethoxy]methyl—1H— pyrrolo[2,3-b]pyridine 0.092g as a semisolid residue, LC /MS (M+H)+: 405.

Step 2. 4-(1-Benzyl—1H—pyrazolyD-1H-pyrrolo[2,3-bjpyridine Using a procedure analogous to Example 106, Step 4, but using 4-(1-benzy1—lH-pyrazol yl)-l—[2-(trimethylsilyl)ethoxy]methyl-1H—pyrrolo[2,3—b]pyridine, the title compound was prepared as a white amorphous powder (0.054 gm), LC [MS (M+H)+: 275, 1H NMR (DMSO—d5) 5 12.21 (135, 1H), 8.80(s, 1H), 8.25(vbs, 1H), , 1H), 7.63(s, 1H), 7.49035, 1H), 7.4—7.2(m, 5H), , 1H), 5.42(s, 2H).

Example 201 : 4—[1-(2-Naphthylmethyl)-1H—pyrazolyl]-1H-pyrrolo[2,3-b]pyridine N N Step 1. 1-(2-Naphthylmethyl)(4, 4,5,5-tetramethyl—1,3,2-dioxaborolan—2-yl)—1H~pyrazole The 4-(4,4,5,5-tetramethy1-1,3,2-dioxaborolanyl)-1H—pyrazole (0.10 g, 0.00052 mol) was combined with naphthalene, momethyl)— (0.12 g, 0.00057 mol) in ACN (3.0 mL, 0.057 mol) under nitrogen at rt. Then cesium carbonate (0.50 g, 0.0015 mol) was added and the reaction was complete after stirring for 1 h. This was partitioned between ethyl acetate and brine. The organic layer was washed with brine, dried over magnesium sulfate and concentrated to give 1—(2- naphthylmethyl)(4,4,5,5-tetramethyl-1,3,2—dioxaborolan—2-yl)—lH—pyrazole 0.17 gm, as an oil, LC/MS (M+H)+: 335, 'H NMR (CDC13) 8 7.89 (s, 1H), 7.79-7.84(m, 3H), 7.69(bs, 2H), .4(m, 2H), 7.46-7.33(m, 1H), 5.47(s, 2H), , 12H).

Step 2. 4—[1 -(Z—Naphthylmethyl)-1H—pyrazolylj—1~[2—(trimethylsilyDethoxyjmethyl-1H—pyrrolof2, 3- bprrz'dine I \ N N CH20(CH2)ZSi(CH3)3 4-Bromo-1—[2-(trimethylsily1)ethoxy]methyl—1H-pyrrolo[2,3-b]pyridine (0.06 g, 0.0002 mol) and 1-(2-naphthy1methyl)—4—(4,4,5,5-tetramethyl—l,3,2-dioxaborolan—2-y1)-1H—pyrazole (0.074 g, 2 mol) were combined in toluene (2.0 mL, 0.019 mol) and ethanol (1.0 mL, 0.017 mol), and then potassium carbonate (0.063 g, 0.00046 mol, in 1 mL water) was added. The reaction mixture was degassed with nitrogen, then tetrakis(triphenylphosphine)palladium(0) (0.02 g, 0.00002 mol) was added, sealed in a tube and heated to 120 °C in a microwave for 30 minutes. This was allowed to cool and then partitioned between ethyl acetate and brine. The organic layer was dried over ium sulfate and concentrated to give 4-[1-(2—naphthylmethyl)-lH-pyrazolyl]—l-[2- (trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine 0.08 g, as an oily residue, LC /MS (M+H)+: 455.

Step 3 Using a procedure analogous to Example 106, Step 4, but using 4-[1-(2-naphthylmethyl)-1H- pyrazol—4-y1][2-(trimethylsily1)ethoxy]methyl—1H-pyrrolo[2,3-b]pyridine, the title compound was prepared as a white amorphous powder (0.053 g, 88%), LC /MS (M+H)+: 325, lH NMR dg) 5 12.0(bs, 1H), 8.79(s, 1H), 8.24(s, 1H), 8.19(d, 1H, J=5.7), 7.82(m, 4H), 7.56(m, 1H), 7.43(m, 4H), 6.92(m, 1H), , 2H).

Example 219: 4-(1-Phenyl-lH—pyrazol—4-yl)—1H-pyrrolo[2,3-b]pyridine N N H Step 1 . 1—phenyl—4-(4, 4, 5, amethyl—1, 3.Z—dz'oxaborolan—Z—yD—IH-pyrazole 4—(4,4,5,5-Tetramethyl-l,3,2-dioxaborolanyl)-1I—l-pyrazole (0.07 g, 0.0003 mol) and phenylboronic acid (0.083 g, 0.00068 mol) were combined in DMF (1.50 mL, 0.0194 mol). Then copper(II) diacetate (0.010 g, 0.000055 mol) and pyridine (0.069 mL, 0.00085 mol) were added. The reaction was heated in an open tube to 80 °C for 40 minutes. The reaction was complete by I-IPLC, d to cool to rt, taken up in ethyl acetate, and washed with water saturated with sodium carbonate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated to give 1-phenyl—4-(4,4,5,S-tetramethyl-l,3,2-dioxaborolanyl)-1H-pyrazo, 0.09 gm as an oily e, LC/MS (M+H)+: 271.

Step 2. 4-(1—Phenyl—1H-pyrazol—4-yl)-I—[2—(trimethylsilyl)ethoxyjmethyl—IH—pyrrolo[2, 3—b]pyridine Using a procedure analogous to Example 201, Steps B and C, but using yI(4,4,5,5- tetramethyl~1,3,2-dioxaborolanyl)—1H—pyrazo, the title compound was prepared as an white amorphous powder (0.015 gm, 18%), LC/MS (M+H)+: 261, 1H NMR (DMSO-d.;) 5 12.05 (bs, 1H), 9.23(s, 1H), 8.53(s, 1H), 8.3l(m, 1H), 8.01(m, 2H), 7.63(m, 1H), .52 (m, 3H), 7.36(m, 1H), 7.13(m, 1H).

Example 231: 3-[4-(1H-Pyrrolo[2,3-b]pyridin—4-yl)—1H—pyrazol—l-yl]benzonitrile l/ \ N N Step 1. 4—(1H-Pyrazol—4—yD-I-[2—(trimethylsilyl)eth0x32]methyl—1H-pyrrolo[2,3-b]pyridine N-NH I j \ N N CH2)ZSi(CH3)3 4—Bromo—1-[2—(trimethylsilyl)ethoxy]methyl—1H—pyrrolo[2,3-b]pyridine (0.20 g, 1 mol) and ,5,5-tetramethyl~l,3,2-dioxaborolan-2—yl)-lH—pyrazole (0.15 g, 0.00079 mol) were combined in DMF (5.0 mL, 0.064 mol) and then potassium carbonate (0.25 g, 0.0018 mol) in 1 mL water was added. The reaction was degassed with nitrogen, then tetrakis(triphenylphosphine)— palladium(0) (0.08 g, 0.00007 mol) was added and in a sealed tube the reaction was heated to 120 °C oil bath. The on was heated for 30 minutes, allowed to cool and then taken up in ethyl acetate.

The reaction mixture was washed with brine, dried over magnesium sulfate and concentrated to give an oil. The product was purified by FCC on silica gel eluting with a hexanezethyl acetate gradient to give 4-(1H-pyrazol—4-yl)—1—[2~(trimethylsilyl)ethoxy]methyl—1H-pynolo[2,3-b]pyridine (0.13 gm, 70%) as a crystalline white powder, LC /MS (M+H)+: 315, lH NMR (DMSO-ds) 5 13.35 (bs, 1H), 8.59Cbs, 1H), 8.32(d, 1H, J=8.5), 8.26(bs, 1H), 7.76(d, 1H, J=6.0), 7.45(d, 1H, J=8.5), 7.01(d, J=6.0), 5.73(s, 2H), , 2H), 0.92(t, 2H), 0.0(s, 9H).

Step 2. 3-[4-(1-[.2-(TrimethylsilyDethoxy]methyl—1H-pyrrolo[2,3-b]pyridz'n-4—yl)-1H-pyrazol—I yl]benzonitrile N N\ CH20(CH2)281(CH3)3 4—(1H—Pyrazol—4—yl)[2-(trimethylsilyl)ethoxy]methyl—1H-pyirolo[2,3-b]pyridine (0.025 g, 0.000080 mol) and (3-cyanophenyl)boronic acid (0.023 g, 0.00016 mol) were combined in DMF (1.50 mL, 0.0194 mol). Then (II) diacetate (0.002 g, 0.00001 mol) and pyridine (0.019 mL, 0.00024 mol) were added. The reaction was heated in an open tube to 125 °C for 40 minutes, allowed to cool to rt, taken up in ethyl acetate, and washed with water saturated with sodium carbonate. The c layer was washed with brine, dried over ium sulfate and concentrated to give 3—[4-(1—[2—(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridin-4—yl)-1H—pyrazol-1 -yl]- benzonitrile (0.025 gm, 92%) as an oily residue, LC /MS (M+H)+: 316.

Step 3 Using a procedure analogous to Example 106, Step 4, but using 3-[4-(1—[2-(trimethylsilyl)- ethoxy]methyl-1H—pyrrolo[2,3-b]pyridin—4-yl)-lH—pyrazol—l—yl]benzonitrile, the title compound was prepared as an white crystalline powder (0.012 gm, 60%), LC/MS (M+H)+: 286, 1H NMR (DMSO— d5) 5 12.05 (bs, 1H), 9.32(s, 1H), 8.59(m, 1H), 8.55(m, 1H), 8.36(m, 1H), 8.30(d, 1H, J=5.2), 7.83(m, 1H), 7.75(m, 1H), 7.63(m, 1H), 7.51(d, 1H, J=5.2), , 1H).

Example 250: 4-{l-[(1R)—1—Methylbutyl]-1H-pyrazol—4—yl}-1H—pyrrolo[2,3-b]pyridine (250a) and 4-{1—[(IS)-l-Methylbutyl]-lH-pyrazolyl}-lH—pyrrolo[2,3-b]pyridine (250b) 54— >..../* NN_ N_N / ’/ l\\ |\\ / / N N N H andN H Step 1. 1—Methylbutyl)—1H-pyrazol—4—ylj—I—[2-(trimetliylsilyDethmqyj-methyl—1H-pyrrolo[2, 3- b]pyridine 2006/047369 4—(1H—Pyrazol—4—yl)—1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine (50 mg, 0.0002 mol) (see, Example 231, Step 1) was dissolved in DMF (2 mL, 0.02 mol) and cooled at 0 °C.

This solution was treated with sodium hydride (7.0 mg, 0.00029 mol) (60% in oil) and stirred for 15 min. The e was then treated with 2—bromopentane (40 mg, 0.0002 mol) and was d for 5 h.

The reaction was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated to give the crude product 4-[1—(1-methylbutyl)-1H- pyrazolyl]-l—[2-(trimethylsilyl)ethoxy]methyl-1H—pyrrolo[2,3-b]py1idine as an oil, LC/MS (M+H)+: 286.

Step 2. 4-[1-(1-Methylbutyl)~1H-pyrazolyl]-1H-pyrrolo[2, 3-bjpyridine Using a procedure analogous to Example 106, Step 4, but using l-methylbutyl)-1H— pyrazol-4—yl]—1—[2-(trimethylsilyl)ethoxy]methyl-lH—pyrrolo[2,3-b]py1idine, the title compound was prepared as an white amorphous powder (0.025 gm, 60%), LC [MS (M+H)+: 255, 'H NMR (DMSO- d5) 8 12.21 (bs, 1H), , 1H), 8.27(bs, 1H), 8.25(s, 1H), 7.62(m, 1H), 7.49(m, 1H), 7.02(m, 1H), 4.46011, 1H), 1.9—1.8(m, 1H), 1.7—1.6(m, 1H), 1.47(d, 3H), 1.2-1.0(m, 2H), 0.83(t, 3H).

Step 3. Separation tz'omers The tion of the enantiomers of 4-[1-(1-methylbutyl)-lH-pyrazol—4—yl]—lH—pyrrolo[2,3— b]pyridine from Step 2 was performed by chiral column preparative HPLC separation using an OD—H column eluting with an isopropanolzhexane gradient to give the title compounds as amorphous white residues, LC IMS (M+H)+: 255, 1H NMR (DMSO-d5) 8 12.21 (bs, 1H), 8.66(s, 1H), 8.27(bs, 1H), 8.25(s, 1H), 7.62(m, 1H), 7.49(rn, 1H), 7.02(m, 1H), 4.46(m, 1H), 8(m, 1H), 1.7-1.6(m, 1H), l.47(d, 3H), 1.2—1.0(m, 2H), 0.83(t, 3H).

Example 286: 4-Methyl—3-[4-(1H—pyrrolo[2,3-b]pyridin—4-yl)—lH-pyrazol-l—yl]benzonitrile 1?CN N I \ N N Step 1 . 4—Methyl—3—[4-(1 -[2-(trimethylsilyDethoxy]methyl-1H—pyrrolo[2,3-bjpyridinyD—1H- pyrazol-I-yljbenzonitrile 2006/047369 l \ N/ N\ CH20(CH2)ZSi(CH3)3 To a mixture of 4-(1H-pyrazoly1)-1—[2~(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]— pyridine (0.050 g, 0.00016 mol) (see, e 231, Step 1) and cesium ate (0.10 g, 0.00032 mol) in dry DMF (1.0 mL, 0.013 mol) was added 3-fluoro-4—methy1benzonitrile (0.043 g, 0.00032 mol). The reaction mixture was heated in sealed tube to 120 °C for 5.5 hours. The reaction was allowed to cool and partitioned between ethyl acetate and water. The organic layer was washed with water, brine, dried over magnesium sulfate, filtered, and concentrated to give 4-methyl[4-(l-[2- (trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3—b]pyridin—4—yl)—lH-pyrazol—l—yl]benzonitrile as a crude product, LC /MS (M+H)+: 430.

Step 2. 4-Methyl—3—[4~(1H—pyrrolo[2, ridin-4—yl)—IH—pyrazol—1—yl]benzonitrile Using a procedure analogous to Example 106, Step 4, but using yl—3—[4-(l-[2- (trimethylsilyl)ethoxy]methyl-lH—pyrrolo[2,3-b]pyridin~4—yl)-lH—pyrazoLl-yl]benzonitrile, the title compound was prepared as a white amorphous powder (0.037 gm, 88%), LC /MS (M+H)+: 300, 1H NMR d5) 8 12.19 (bs, 1H), 8.98(s, 1H), 8.57(s, 1H), 8.31(d, 1H, J=7.0), 8.08(s, 1H), 7.89(d, 1H, 1:10), 7.66(d, 1H, J=10), 7.63(m, 1H), 7.55(d, 1H), 7.07(m, 1H), 2.4(s, 3H).

Further example compounds of the invention are provided in Tables 7, 8, 9, 10, and 11 below.

The compounds listed in Tables 7, 8, 9, 10 and 11 are racemic unless the enantiomers are indicated separately.

Table 7 2-(lH-pyn‘olo[2,3-b]pyridin yl)—4,5,6,7-tetrahydro-2H- indazole -nitro(1H—pyrrolo[2,3-b]— pyridin—4-yl)~2H—indazole 6-nitro-2—(1H-pyrrolo [2,3—b]— pyridin—4-yl)-2H-indazole 3—[1 yrrolo[2,3—b]pyridin- 4-y1)-1H—imidazolyl]- benzonitrile 4-[4-(3-methoxyphenyl)—1H- imidazol-l-yl]-1H-pyrrolo[2,3- b]pyridine 4-(5—phenylthienyl)-1H— pyrrolo[2,3-b]pyn'dine 4-[3-(4-fluorophenyl)~l H-pyrazol-l - BX 120 yl]-1H—pyrrolo[2,3-b]pyridine 4-[3-(3—nitrophenyl)-1H~pyrazol-1 — ’22 E/©\N02 306 E" 120 yl]-1H-pyrrolo[2,3-b]pyridine 9/CI 4—[3~(4~chlorophenyl)—1H—pyrazol-1 - 123 295 Ex 12° yl]—IH—pyrrolo[2,3~b]pyridine 4—[3—(4-methoxyphenyl)- I H—pyrazol- Ex 120 1-yl]-1H-pyrrolo[2,3~b]pyfidine 4-[1 -(1H-pyrrolo[2,3-b]pyridin—4-yl)- Ex 120 lH—pyrazol—3-yIJbenzonitn'le 1H—pyrrolo[2,3—b]pyridinyl)— BX 120 azol-B -yl]anilinc 4-[3-(3~methoxyphenyl)- I H-pyrazol- Ex 128 l-yI]—l H-pyrrolo[2,3-b]pyridine {3-[1 -(1H—pyrrolo[2,3-b]pyridin-4~ Wi/©\OCHZCN 316 yl)-1H—pyrazolyl]- phenoxy} acetonitrile o-N- {3-[1 -(1H-pyrrolo[2,3-b]- 31 pyridin—4-yl)—1H—pyrazolyl]- phenyl}acetamide 3-cyano-N- {3-[1 -( 1 H-pyrrolo[2,3-b]- 132 405 pyridin-4—yl)-l H—pyrazolyl]— "aI)CONH(3-CN-Ph) phenyl}benzamide Table 9 (Y)n—Z N N 4-[4—(4—nitrophenyl)— 1 H-pyrazol-l -y1]- BX 153 lH-pyrrolo[2,3-b]pyridine (]H-pyrrolo[2,3-b]Pyridin'4'yl)' ' Ex 153 1H-pyrazolyl]aniline 152 261 4-(4-pheny1-1H—pyrazol—1-y1)-1H- Ex153 pyrrolo[2,3-b1pyridine \ . . 154 I 262 4—(4-pyr1dmY1'1H'PyraF9l‘1‘YD'IH' BX 153 pyrrolo[2,3-b]Pyndlne 2—[1-(1H-pyrrolo[2,3-b]pyridinyl)- Ex 153 1H-pyrazol~4—y1]benzonitri1e {2"[1'(1H—pyrrolo[2,3—b]pyridin—4-y1)- Ex 153, 1 H-pyrazol-4—yl]phenyl} acetonitrile 3—nitrophenyl)- l H—pyrazol—l -y1] — Ex 153 lH-pyrrolo[2,3-b]pyridine 3-[1-(1H-pyrrolo[2,3-b]pyridinyl)- Ex 153 1H—pyrazolyl]aniline WO 70514 Q {3—[1-(1H—pynolo[2,3-b1pyridiny1)- ‘ CHch 1H—pyrazol—4-yl]pheny1}acetonitrile 4-[1 ~(1H-pyrrolOIZ,3-b]pyridin—4—y1)- 1 H-pyrazoly1]bcnzonitrile NJ"- 3-[1-(lH-pyrrolo[2,3-b]pyridin—4-y1)- 0H 1H-pyrazoly1]phenol methyl 3-[1—(lH-pyrrolo[2,3-b]pyridin- ‘777.Q COZCH3 4-y1)-1H—pyrazolyl]benzoate CHch 1 63E 300 {4-[1—(1H-pyrrolo[2,3.b]pyridin—4-y1)— lH—pyrazolyl]phcnyl} acetom'trile o-N- {3 -[1 -(l H-pyrrolo[2,3-b]'- 164 $11/£:\NHC0CHZCN 343 pyridin-4—yl)—lH-pyrazoI—4-y11- phenyl} acetamide 165 277 4'[1'(1H‘Pyn'010[2,3-b]pyridin-4—y1)- it 1H-pyrazolyl]pheno1 -[1-(lH-pyrrolo[2,3-b]pyn'din—4-yl)- 1H—pyrazo]—4-y1]nicotinonitrile {4-[1-(1H—pyrrolo[2,3-b]pyridinyl)- 1I‘I'Pyl'a'slzol-4—yl]phenoxy} acetonitrile E! 4-(4-cyclohex-1 -en-l -y1-1 H-pyrazol-l - yl)—1H—pyrrolo[2,3 -b]pyridine 4—[4—(4-methoxyphenyl)—1 H—pyrazol—l - yl]— l H-pyrrolq[2,3-b]pyridine Z Z 4-(4-pyrimidinyl-1H-pyrazol-l -yl)- 1H—pyrrolo[2,3-b]pyridine 0Z 3-{hydroxy[l -(1H-pyrrolo[2,3-b]- NH pyridin-4—yl)— l H—pyrazol~4-yl] — methyl} itrile E 4-[4—(cyclohex-1 ~en-l-y1methyl)-1H- pyrazol-l —y1]-1H-pyrrolo[2,3-b]pyridine Table 10 (fin—z 4—[1 dimethoxybenzyl)-1H— pyrazol—4-yl]-1H-pyrrolo[2,3- b]pyridine 4-[1 -(l -phenylethy1)-1H-pyrazol yl]-lH-pyrrolo[2,3-b]pyridine (1H—pynolo[2,3-b]pyridin~4- yl)-1H-pyrazol-l — Ex 201 yl]methyl} benzonitrile 2‘{[4-(1H—pyrrolo[2,3—b]pyridin yl)-lH-pyrazol-1 - Ex 201 yl]methyl} benzonitrile 4- {[4-( lH—pyrrolo[2,3-b]pyridin yl)-1H—pyrazol-1 - BX 201 yl]methyl} benzonitrile l~phenyl—2-[4-( l H—pyrrolo[2,3- b]pyridinyl)-1H—pyrazol-1 - BX 201 yl]ethanone 3,3-dimethyl-l -[4—(1H—pyrrolo[2,3- b]pyridin—4—yl)- 1H-pyrazol-l - yl]butan—2-one 4—{ l -[(5-methy1isoxazol yl)methyl]-1H-pyrazol—4—yl } —1 H- pyrrolo[2,3-b]pyridine 4-[1 —(tetrahydro—2H-pyran yl)-lH-pyrazoly1]- 1 H- pyrrolo[2,3-b]pyridine 4-(1 —cyclohexen-l-y1-1H—pyrazol- 4—y1)—lH—pyrrolo[2,3—b]pyridine 4-[1 -( l -ethylpropyl)- 1 H-pyrazol yl]—l H-pyrrolo[2,3-b]pyridine 267 4-(1-cyclohexyl-lH-pyrazolyl)— lH—pyrrolo[2,3-b]pyfidine 2-[4-(1H—pyrrolo[2,3-b]pyn'din—4-yl)- l H-pyrazol— 1 -yl]acetamide 4'-{[4-(1H—pyrrolo[2,3-b]pyridin yl)-1H-pyrazol-l -y1]methyl} yl- 2—carbonitrile 4-[1-(2-nitrobenzyl)-1H—pyrazol—4- y1]—1H-pyrrolo[2,3-b]pyridine 2,6-dichloro oromethyl)phenyl]- l H—pyrazol- 4-3/1} -1 H—pyrro]o[2,3-b]pyridinc 220 320 e"\/©\ 4-[1 -(3-nitrobenzyl)-1H—pyrazoI No2 —pyrrolo[2,3 -b]pyridine 221 I1») U1 "W (II U: 4—[1 —(2-bromobenzyl)-1H-pyrazol "M6 yl]-lH-pyrrolo[2,3-b]py1idine 222 332 ENNHCGW N-phenyl-Z-[4-(1 H~pyrrolo[2,3 - b]pyridinyl)-1H-pyrazol~l — yl]propanamide 4- { 1-[3 -(trifluoromethoxy)benzy1]- 1H-pyrazol—4—yl} ~l H-pyrrolo[2,3- b]pyridine 4-{ l -[2—fluoro—5—(trifluoromethyl)— benzyl]-lH-pyrazoIy1}-1H- pyrrolo[2,3-b]pyridine 4- {1 —[3~(tn'fluoromethyl)benzyl] -1 H— pyrazol—4~yl} -1 H—pyrrolo[2,3- b]pyridine 4-[1-(pyridinylmethyl)-1H- pyrazolA~yl]—1H-pyrrolo[2,3— dine 4— { l —[( l S)-l —phenylbuty1]-l H- pyrazol—4-yl} -1H-pyn-olo[2,3— b]pyridine 4-{1-[(1R)phenylbutyl]-1H- pyrazol—4—yl} —1H—pyrrolo[2,3— b]pyridine 1—phenyl—2-[4-( l H-pyrrolo[2,3- b]pyridin—4—yl)-1H-pyrazoI—1 - yl]propan-1 -one 4-[1—(2,6-dichlorobenzyl)—1H- 343, 345 pyrazolyl]-1H—pyrrolo[2,3- b]pyridine 4-[1 -(2,6-dimethylphenyl)-1H— pyrazol—4—yl]~1H—pyrrolo[2,3- b]pyridine 2—[4—( 1H-pyrrolo[2,3 -b]pyridiny1)- lH-pyrazolyl](trifluoromethyl)- itrile 4—[1 —(4—bromo—3,5,6-trifluoropyridin- 393, 395 _—Z 2—yl)-1H-pyrazolyl]-1H- w 'I DJ.1 pyrrolo[2,3-b]pyridine 4-[1 -(cyclopropylmethyl)—1 H- pyrazolyl]-1 H—pyrrolo[2,3— b]pyridine 4-[1-(2,5—dimethylphenyl)-lH— pyrazoly1]-1H-pyrrolo[2,3- b]pyn'dine 4-[1 -(2-methy1phenyl)-lH—pyrazol —pynolo[2,3-b]pyridine 4-[1-(2-methoxyphenyl)-1H-pyrazol— 4—y1]—1H—pyrrolo[2,3-b]pyridine 3—{1-[4-(1H—pyrrolo[2,3-b]pyridin—4- yl)-1H—pyrazol—l - yl]ethyl} benzonitrile 3-chloro[4-(1H-pyrrolo[2,3- b]pyn'dinyl)-1H—pyrazol-l - yl]benzonitn'le 4-[1 -(1 -cyclohexylethyl)-1 H—pyrazol- 4-ylj—l H-pyrrolo[2,3-b]pyridine 4-fluoro[4-(1H-pyrrolo[2,3- b]pyridin—4~yl)—l H-pyrazol-l - y1]benzonitrile 2-fluoro[4-(1H-pyrrolo[2,3 ~ b]pyridin—4-y1)-1H—pyrazol-l - zonitrile 3-fluoro[4—(1H-pyrrolo[2,3- b]pyridin-4—y1)-1 H-pyrazol-l - yl]benzonitrile 4—(1 - { 1-[3—(triflu0romethyl)— ]ethy1}—1H-pyrazoly1)-1H~ pyrrolo[2,3-b]pyridine 4—[1 -(3,5-dimethylphenyl)-1H- pyrazol—4—yl]—lH—pyrrolo[2,3- b]pyridine 4~[4-(1H—pyrrolo[2,3—b]pyridin~4-yl)- lH-pyrazol-l -y]]benzonitrile (1H-pyrrolo[2,3—b]pyridin—4— yI)-1H-pyrazol—1 - yl]pheny1} acetonitn'le 1 -methy1hexyl)- 1 H-pyrazol—4- yIJ—I H—pynolo[2,3~b]pyridine 4~(] -sec-butyl—1H-pyrazo]yl)-1H— pyrrolo[2,3—b]pyridine 4—[ l -(l -phenylpropyl)—1H—pyrazol-4— yl]-lH-pyrrolo[2,3-b]pyridine 4-(1—{ l -[4-(methylsulfonyl)- phenyl]ethyl} -1 H-pyrazol—4-yl)- 1H- pyrrolo[2,3-b]pyridine YCE:CH3 4-{1 -[1 —(3-fluoro-4—methoxy- pheny1)ethy1]-1H-pyrazol-4—yl}-I H- BX 250 pyn‘olo[2,3-b]pyridine 4-(1 - {‘1 -[2-(trifluoromethyl)- 255 357 RD pheny1]ethyl}-lH-pyrazolyl)-1H— BX 250 pyrrolo[2,3—b]pyridine 4—(1 -{ l — [3 ,5—bis(tn’fluoromethyl)— 256 425 £50 phenyl]ethyl} -1H-pyrazolyl)-1H- BX 250 pyrrolo[2,3-b]pyridine 4-{1 -[4-(l H-pyrrolo[2,3~b]pyridin—4— 257 314 50 yl)-1H-pyrazol BX 250 yl]ethyl} benzonitrile 4— {1 tro—2— 258 374 6:: (tn'fluoromethyl)phenyl]—1 H—pyrazol- BX 286 4—yl} - 1 H—pyrrolo[2,3-b]pyridine 3—methyl[4—(1H-pyrrolo[2,3— 259 b]pyridinyl)-1H-pyrazol-l - BX 286 1L," yl]benzonitri1e :6 4-[1 -(2—chlorophenyl)-1H-pyrazol—4- Ex 231 3-bromo—4—[4-(l H-pyrrolo[2,3- 261 64, 366 b]pyridin—4-yl)—1 H—pyrazol—l - BX 286 ‘lLL yl]benzonitri1e COzcsz 262 ethyl 4-[4-( 1 H-pyrrolo[2,3-b]pyn'din— BX 286 N 4-y1)-lH-pyrazol-l-y1]benzoate 4-{ 1 -[2-chloronitro(trifluoro- 263 408, 410 ‘1‘; methyl)pheny1]—1H—pyrazol—4-y1}-1H- BX 286 pyrrolo[2,3-b]pyridine 4—( l -{1 -[4-(trifluoromethy1)— 264 phenyl]ethyl} -1H—pyrazolyl)-1H- BX 250 o[2,3-b]pyridine 4—[1—(2,3~dihydro~lH—inden~1~yl)—1H— pyrazol—4-yl]—1H—pyrrolo[2,3 - Ex 250 b]pyridine l4-[1-(1,2,3,4-tetrahydronaphthalen-l- -pyrazolyl]-lH-pyrrolo[2,3- b]pyridine 4-(1 — { I -[2-chloro(trifluoromethyl)- phenyl]ethyl} -1H—pyrazol-4—yl)~l H- pyrrolo[2,3-b]pyridine 4—{1-[1-(2,4-dichlorofluoro- phenyl)ethy1]-lH—pyrazol-4—yl}-1H- pyrrolo[2,3-b]pyridine 4-[1-(1 -cyclopentylethyl)-1H- pyrazol»4~yl]—1H-pyrrolo[2,3- b]pyridine 4-[1 -(1 -methy1-3 -phenylpropyl)-1H- pyrazol—4—yl]-1H—pyrrolo[2,3— b]pyridine 4—[1-(1 butylethyl)— l H—pyrazol- 4-y1]-1H-pyrrolo[2,3-b]pyridine [2-[4-(1H—pyrrolo[2,3—b]pyridin y1)-1 H-pyrazol-l -yl] (trifluoromethyl)phenyl]acetonitrile [5-[4-(1H-pyrrolo[2,3-b]pyridin-4— yl)-l zol-l - (trifluoromethyl)phenyl]acetonitrile (3E)—penteny1]-1H— pyrazol-4—yl} -1 H-pyrrolo[2,3 — b]pyridine 2—[4—(1H-pyrrolo[2,3—b]pyridiny1)- lH—pyrazol-l -yl]propanenitrile 4-{ 1 —[(3E)—4-pheny1but—3—en-l -yl] - lH-pyrazol—4—yl} -1H-pyrrolo[2,3- b]pyridine 6—[4-(1H-pyrrolo[2,3-b]pyridin—4-yl)— lH-pyrazol-l —yl]hexanenitrile ethyl 3—amino { [4-(1 H-pyrrolo [2,3— b]pyridin—4-yl)-1 H—pyrazol-l -yl] - methyl}propanoate ethyl 2—[4—(lH—pynolo[2,3—b]pyridin— 4-yl)-l H-pyrazol-l -yl]propanoate WO 70514 4-[1 -(1 -propylbutyl)— l H—pyrazol-4— yl]-lH—pyrrolo[2,3-b]pyridine 4'[4'(1H-pyrrolo[2,3-b]pyridin—4-y1)- 1 H'Pyl‘azol—l -yl]butanenitrile [3-chloro[4-(1H-pyrrolo[2,3- 402, 404 diny1)-1H-pyrazol-l -yl] (trifluoromethyl)phenyl]acetonitrile 1H—pyrrolo[2,3-b]pyridinyl)- lH-pyrazol—l -yl](trifluoromethyl)- benzonitrile 4- { I - [2-chloro(trifluoromethyl)- 363, 365 ' pheny1]—1H-pyrazolyl}-1H- pyrrolo[2,3-b]pyridine 4-[4-(1H—pyrrolo[2,3-b]pyridin—4-yl)- 1 H-pyrazol(trifluoromethyl)- benzonitn'le 2-[4—(1H-pyrrolo[2,3—b]pyridin-4—y1)_ lH-pyrazol-l-yubenzonitrile 3-chloro—2-[4-(1H-pyrrolo[2,3- 320, 322 b]pyridin—4-yl)-1H-pyrazol-1 — yl]benzonitrile 4-amino—5,6-difluoro-2—[4-(1H- pyrrolo[2,3-b]pyfidinyl)-1H- pyrazol-l-yl]isophthalonitrile 1- { [4-( l H-pyrrolo[2,3-b]pyridin yl)-1H—pyrazolyl]methy]}- cyclopropanccarbonitrile -[4-(1H-pyrrolo[2,3-b]pyridin-4—yl)- lH—pyrazol-l -yl]hexanenitrile 2,2-dimethyl[4-(1 H-pyrrolo[2,3 - b]pyridin-4—yl)-1H—pyrazol-1 -yl]- hexanenitrile 4-[1 -(1 -ethylmethylpropyl)—1H- pyrazol-4—y1]-1H—pyrrolo[2,3— b]pyridine WO 70514 —br0mo[4-(1H-pyrrolo[2,3- 294 364, 366 .771 b]pyridin—4-yl)-1H—pyrazoI-l - yl]benzonitrile 3-[4-(1H—pyrrolo[2,3-b]pyfidinyl)- 1 H-pyrazol- 1 ~yl](trifluoromethyl)- benzonitrile 2~[4-(1H—pyrrolo[2,3-b]pyridin—4—y1). lH-pyrazoI-l-yl](mfluoromcthy1)- benzonitrile 3-[4-(1H-pyrrolo[2,3-b1pyridin.4.y1)- lH-pyrazol-l -(trifluoromethy1)- benzamide 3-[4-(1H—pyrrolo[2,3-b]pyridin—4-yl)- 1H-pyrazolyl]cyclohexanone 2'[4'(1H'PYIT010[2,3-b]pyn'dinyl)— lH-pyrazol—l -y1] cyclohexanol 4-(1 — {[1 -(methylsulfony1)piperidin—4- yl]methyl} —l H—pyrazol—4~yl)— 1 H— pyrrolo[2,3-b]pyn'dine 2-[4-(1H-pyrrolo[2,3—b]pyridinyl)- 1 H—pyrazol-l - yl]cyclohexanecarbonitrile 4- { 1 -[2-(trifluoromethyl)phenyl]-1 H- pyrazoly1} -1 H-pyrrolo[2,3- b]pyridine 4-[1-(2,6-dichlorophenyl)-1H- U.) [\J"\0 DJ ()3 r—A pyrazol- 4-y1]-1 H-pyrrolo[2,3 -b]pyridinc (4— {[4-(1H—pyrrolo[2,3-b]pyridin yl)-1H-pyrazol-1 -yl]methyl} — cyclohexyl)methanol 4-[1 -(tetrahydrofi1rany1methyl)- azol—4-yl]—1H-pyrrolo[2,3- b]pyridine 4-[1 -(1 pentylpropyl)—l H- pyrazol- 1H—pyrrolo[2,3-b}pyridine 4-[1 -(tetrahydrofuranylmethyl)- 1H-pyrazolyl]—l H~pyrrolo[2,3- b]pyridine 2-chloro[4—(1H-pyrrolo[2,3- b]pyridin—4-yl)—lH—pyrazol-l - y1]benzonitn'le 3-[4-(1H—pyrrolo[2,3—b]pyridin—4-yl)— lH—pyrazol-l -y1]—3~(1 ,3-thiazol—5-yl)- .propanenitrile l —benzy1-4~ {[4-(1H-pyITolo[2,3-b] — pyridinyl)-lH—pyrazol-l -yl]- methyl}pyrrolidin—Z-one 3-(1-methyl-lH-imidazol-S-y1)[4- (1H-pyrrolo[2,3-b]pyridiny1)-1H- pyrazolyl]propanenitrile 3-[4-(1H-pyrrolo[2,3—b]pyridin—4—yl)— 1H-pyrazol-1—y1](3- thienyl)propanenitn'1e { 1~[4-(1H—pyrrolo[2,3—b]pyridin—4— yl)-1H-pyrazol y1]cyclopenty1} acetonitrile 4-chloro[4-(1H-pyrrolo[2,3— 314 320, 322 b]pyridin—4—y1)-1H—pyrazol-l - zonitrile 4-[4-(1H—pyrrolo[2,3-b]pyridin—4-yl)— l H-pyrazol-l —yl]phthalonitrile 3—methyl—4-[4—(1H-pyrrolo[2,3- b]pyridin—4-y1)-l H—pyrazol-l - yl]benzaldehyde 2-methyl—4-nitrophenyl)-1H- pyrazol—4-yl]-I H-pyrrolo[2,3- dine 3-[4-( l H-pynolo[2,3-b]pyridin—4—,yl)- BX 201 1 H—pyrazol-l -yl]cyclopentanone 4-[1 rylmethy1)—l H—pyrazol—4— BX 201 yl]-lH-pyrrolo[2 3-b]pynd1ne 4-[1 -(2-furylmethyl)-lH—pyrazol—4- Ex 20‘ yl]-1H—pyrrolo[2,3—b]pyridine 3—{2Qcyano-1~[4—(1H~pynoio[2,3.b]- pyridin—4-y1)-1H—pyrazol-I -yl]ethyl}- benzonitrile {3~methyl-4—[4-(1H—pyrrolo[2,3-b]- pyridin—4-yl)-lH-pyrazol-l —yl]- }methanol 4—methyl-4—[4—(1H-pyrrolo[2,3- b]pyridiny1)—1H-pyrazol-1 - yl]pentan-2—one 3-(1 furan~2—yl)—3-[4—(1H— pyrrolo[2,3—b]pyridin—4-yl)-1 H- pyrazol~1 -yl]propanenitrile trifluoroacetate 3-(3-furyl)[4-(1H-pyrrolo[2,3—b]- pyridinyl)-lH-pyrazol—1 -yl]~ propanenitn'le {3—methyl[4-( 1H—pyIro10[2,3—b]- pyn'dinyl)-lH-pyrazol-1 -y1]- phenyl} acetonitrile 4-methyl-3—[4-(7H—pyrrolo[2,3-d]— din—4—yl)—1H-pyrazol-l—yl]- benzonitrile trifluoroacetate 4-[1 -(l —cyclopentylpropyl)- lH- pyrazoly11-7H-pyrrolo{2,3—d]— pyrimidine tn'fluoroacetate { 1—[4—(7H—pyrrolo[2,3—d]pyrimidin~ 4-yl)-lH-pyrazol~l -y1]cyclo- pentyl}acetonitri1e trifluoroacetate 3—{(1R)cyano[4-(7H- o[2,3—d]pyrimidinyl)— 1H- pyrazol-l hy1}benzonitrile trifluoroacetate 3- {(1 S)—2-cyano-1 —[4-(7H- pyrrolo[2,3-d]pyrimidin—4-yl)-lH- pyrazol— 1 -y1]ethyl}benzonitrile tn'fluoroacetate 7H-pyrrolo[2,3-d]pyrimidin- 4—y1)-1H-pyrazol-1 -yl]—3 -(3 - thienyl)propanenitrile trifluoroacetate 4-chloro-3 —[4—(7H-pyrrolo[2,3-d]- 321, 323 pyrimidin-4—yl)-1H-pyrazol-1 -yl]- benzonitrile 3—(3—fi1ry1)[4-(7H-pyrrolo[2,3—d]- 305 pyrimidin—4—yI)—1 H—pyrazol-l -yl]- propanenitrile 3-[4—(7H—pyrrolo[2,3-d]pyrirnidin- 4-yl)—1H—pyrazol-1 -yl]- pentanedinitrile 3-{1—[4-(7H—pynolo[2,3—d]— pyrimidinyl)-1 H-pyrazol-l -y1]- cyclopenty1}propanenitrile { l -[4—(7H—pyrrolo[2,3—d1pyrimidin- 4-yl)-1H-pyrazol—1-yl]cyclohexyl}- acetonitrile tn'fluoroacetate {3-methyl-4—[4-(7H-pyrrolo[2,3-d]— pyrimidin—4—yl)-l H-pyrazol-l -yl] — phenyl}mcthanol roacctatc 3-pyridinyl-3—[4—(7H—pyrrolo~ ]pyrimidin—4-yl)-lH-pyrazolyl]propanenitrile 3-pyridin-3 -yl[4-(7H—pyrrolo- [2,3-d]pyrimidin—4-yl)—1H-pyrazol- 1-yl]propanenitrile trifluoroacetate 3-[4-(methylthio)phenyl]—3—[4-(7H— pyrrolo[2,3-d]pyrimidiny1)-1H- pyrazol-l ~y1]propanenitrile trifluoroacetate 3—(3-methoxyphenyl)—3—[4—(7H— pynolo[2,3-d]pyrimidin—4-y1)—1H- pyrazol-l opanenitrile trifluoroacetate 3-(4-methoxyphenyl)—3-[4—(7H- pyrrolo[2,3-d]pyrimidin—4-yl)— 1H- pyrazol-l -yl]propanenitrilc {3—methyl—4-[4-(7H—pyn'olo[2,3-d]- pyrimidinyl)-1 H-pyrazol-l ~yl]- pheny1}acetonitrile trifluoroacetate 3-[4—(methylsulfinyl)phenyl][4— (7H—pyrrolo[2,3-d]pyrimidin—4-yl)— lH-pyrazol-l -yl]propanenitrile 3-[4-(methylsulfonyl)pheny1][4- (7H—pyrrolo[2,3—d]pyrimidin»4—yl)- 1 H-pyrazol-l -y1]propanenitrile 3—[3—(cyanomethoxy)phenyl]—3-[4- (7H-pyrrolo[2,3-d]pyrimidin-4—y1)- lH-pyrazol-l -yl]propanenitrile 3-(6-chloropyridin—3—yl)—3—[4-(7H- o[2,3-d]pyrimidinyl)-1H— pyrazol-l -y1]propanenitrile - {2-cyano-1 -[4-(7H-pyrrolo- [2,3-d]pyrimidin—4—y1)—1H-pyrazol- 1 hyl}pyridine-2—carbonitrile trifluoroacetate 3—(3,5—dimethy1isoxazolyl)[4— Trolo[2,3-d]pyrimidin—4-yl)— lH—pyrazol—1 -y1]propanenitrile trifluoroacetate 3-[4-(7H—pyrrolo[2,3-d]pyrimidin- 4-y1)—1 H—pyrazol—l —yl][6— (trifluoromethyl)pyridin-3 -yl]- propanenitfile trifluoroacetate 3-(6-mcthoxypyridiny1)~3-[4- (7H-pyrrolo[2,3 ~d]pyrimidinyl)- 1 zol— 1 -yl]propancnitrile trifluoroacetate 3-pyridiny1[4-(7H—pyrrolo- [2,3»d]pyrimidiny1)-1 H—pyrazoly]] propancnitrile 3-(6-bromopyridinyl)[4-(7H— pyrrolo[2,3-d]pyrimidin—4-yl)—1H- pyrazol—l —y1]propancnitrile roacetate 6— {2—cyano- l -[4-(7H—pyrrolo[2,3- d]pyrimidin—4-yl)—1H—pyrazol-l -yl] — ethyl}pyridine-Z—carbonitrile trifluoroacetate 4-[4-(7H-pyrrolo[2,3-d]pyrimidin- 4-y1)-1H—pyrazol—1—yl]- heptanedinitrile 3-(5—bromopyridin—3-yl)—3—[4-(7H- pyrrolo[2,3-d]pyn'midin—4-yl)-1H- pyrazol—l opanenitrile 4-[4-(7H-pyrrolo[2,3-d]pyrimidin- 4-yl)- l H-pyrazol-l —yl] - heptanedinitrile — {2-cyano-1 ~[4—(7H—pyrrolo— ]pyrimidin—4-yl)-1H—pyrazol- 1 —yl] ethyl} nicotinonitrile trifluoroacetate 3-(2-methoxypyridin—3-y1)[4- (7H-pyrrolo[2,3-d]pyrimidin—4-yl)- 1 H-pyrazol— 1 -yl]propanenitrile trifluoroacetate 3-[4-(cyanomethoxy)phenyl]-3 -[4- (7H-pyrrolo[2,3-d]pyfimidin—4—yl)— 1 H-pyrazol- 1 opanenitn'le trifluoroacetate 3-[2-(cyanomethoxy)pheny1]-3 -[4- (7H-pyrrolo[2,3-d]pyrimidin~4-yl)— 1 H—pyrazol-l -yl]propanenitrile trifluoroacetate 3-(3 ,5—dibromophcnyI)[4—(7H- pyrrolo[2,3-d]pyrimidin—4—yl)—1 H— pyrazol-l -yl]propanenitrile — {2-cyano-1 H-pyrrolo- [2,3-d]pyrimidin—4-yl)-1 H-pyrazolyl] ethyl} isophthalonitrile trifluoroacetate 3—[6-(dimethylamino)pyridin—2—y1]— 3-[4-(7H-pyrrolo[2,3 -d]pyfimidin- 4-yl)-1 H—pyrazol-l —yl]propane- e trifluoroacetate romothienyl)[4—(7H- pyrrolo[2,3-d]pyrimidin—4-yl)-1H- pyrazol—l -yl]propanenitrile trifluoroacetate — {2-cyano-1 -[4-(7H—pyrrolo~ [2,3-d]pyrimidin—4-yl)-1 H-pyrazoly1] ethyl} thiophenecarbonitrile trifluoroacetate 3-(5-bromofluoropheny1)—3-[4- (7H—pyrrolo[2,3-d]pyrimidin—4—yl)- lH-pyrazol-l -yl]propanenitrile trifluoroacetate 3—(3-nitrophenyl)[4—(7H— o[2,3-d]pyrimidin-4—yl)-1H- pyrazol-l -y1]propanenitrile trifluoroacetate 3-(5-bromomethoxyphenyl)—3- [4-(7H—pyrrolo[2,3-d]pyrimidin yl)-1H—pyrazol—l opanenitrile 3— {2—cyano—1 —[4—(7H-pyrrolo- [2,3—d]pyrimidin—4-yl)-lH-pyrazolyl] ethyl} methoxybenzonitrile trifluoroacetate 3-(3-bromophcnyl)—3—[4-(7H— pyrrolo[2,3—d]pyrimidin~4-yl)-lH- l-l -yl]propanenitrile trifluoroacetate 3- {2-cyano-1 -[4-(7I-I-pyrrolo- [2,3-d]pyrimidinyl)—lH—pyrazol- 1 —yl]ethyl } —4—fluorobenzonitrile roacetate 3-[5-bromo(cyanomethoxy)- phenyl]—3-[4-(7H—pyrrolo[2,3-d] - pyrimidin—4-yl)—1H-pyrazol-1 -y1]- propanenitrile 3-(4-bromofuryl)-3 -[4-(7H— pyrrolo[2,3-d]pyrimidin—4-yl)-1H- pyrazol-l -yl]propanenitrile 4—(cyanomethoxy)—3—{Z-cyano—l — -pyrrolo[2,3-d]pyrimidin~4- —pyrazol-1 -y1]ethy1} - benzonitrile trifluoroacetate 3—(4—bromopyridin—2-yl)—3 -[4—(7H— pyrrolo[2,3-d]pyrimidinyl)—1H- pyrazol-l —yl]propanenitrile 2- {2-cyano-1 -[4-(7H-pyrrolo- [2,3-d]pyrimidin—4-yl)—1H-pyrazol- l —y1] ethyl} isonicotinonitrile tn'fluoroacetate —{2-cyano-1—[4—(7H—pyrrolo[2,3- d]pyrimidinyl)—1H—pyrazol— 1 —y1]~ ethyl} -3 -fi1ronitn'le trifluoroacetate 3-[2-bromo(cyanomethoxy)- phenyl]—3-[4~(7H—pyrrolo[2,3-d]— pyrimidinyl)—1 H—pyrazol-l —yl]- propanenitrile 4—(cyanomethoxy)-2— {2-cyano-1— [4-(7H—pyrrolo[2,3-d]pyrimidin—4- -pyrazol-1 -yl]ethyl} - benzonitrile trifluoroacetate 3-pyrirnidin—5~yl—3—[4-(7H—pyrrolo- [2,3—d]pyrimidin—4-yl)-lH—pyrazol— l-yl]propanenitrile trifluoroacetate 3—(2—bromopyridin—4—yl)—3 ~[4—(7H— pynolo[2,3-d]pyrimidin-4—yl)—1H- pyrazol- 1 —y1]propan§nitrile trifluoroacetate 4- {2-cyano-1 -[4-(7H-pyrrolo- [2,3-d]pyrimidinyl)-lH-pyrazol- 1-yl]ethyl}pyridine-Z-carbonitrile roacetate 3-(5—methoxypyridiny1)[4- rrolo[2,3-d]pyrimidin-4—yl)- 1H-pyrazol-l -yl]propanenitrile trifluoroacetate 3-(3-chloropheny1)-3 -[4-(7H- pyrIolo[2,3-d]pyrimidin—4-yl)-1H- pyrazol-l opanenitrile trifluoroacetate 3-[4-(7H-pyrrolo[2,3-d]pyrimidin— 4—y1)-1H-pyrazol-1 -yl]-3 -[3 - (trifluoromethyl)phcnyl] - propanenitrile roacetate 3-(3 ~phenoxyphenyl)—3 -[4-(7H- pyrrolo[2,3-d]pyrimidinyl)-1H- pyrazoly1]propanenitrile trifluoroacetate 3-[4—(7H-pyrrolo[2,3-d]pyrimidin- 4—yl)—1H-pyrazol-l -yl][3- (trifluoromethoxy)phenyl]propane- nitrile trifluoroacetate methyl 3- no-l ~[4-(7H- pyrrolo[2,3—d]pyrimidin—4-yl)-1H- pyrazol-l -y1]ethyl}benzoate 3-{2-cyano-1 H—pyrrolo- [2,3-d]pyrimidinyl)- 1H-pyrazol- l-yl]ethyl} benzoic acid 3-[3 -( l H-pyrazol—4-yl)phenyl]—3 —[4— (7H-pyrrolo[2,3-d]pyrimidin—4-yl)- 1 H-pyrazol—l -yI]propanenitn'le 3-(3-aminophenyl)-3 —[4—(7H- pyrrolo[2,3-d]pyrimidin—4-yl)— 1H— pyrazol—l -y1]propanenitrile Bis trifluoroacetate N-(3-{2-cyano—1-[4—(7H— pyrrolo[2,3—d]pyrimidin—4—yl)— 1H— pyrazol-l —y1]ethyl }phenyl)- acetamide roacetate N-(3-{2-cyano[4—(7H- pyrrolo[2,3-d]pyrimidinyl)—1H- pyrazoI-l -yl]ethyl}phenyl)- methanesulfonamide 4-{2-cyano[4-(7H—pynrolo- [2,3 -d]pyrimidinyl)-1H-pyrazol— l -yl] ethyl} ene—Z—cafbonitrile trifluoroacetate S-{2—cyano-1—[4—(7H-pyrrolo— [2,3 -d]pyrimidin—4—yl)-lH—pyrazolyl]ethyl} thiophene-Z-carbonitrile trifluoroacetate 3-[3-(morpholinylcarbonyl)- phenyl]—3-[4-(7H-pyrrolo[2,3-d]- pyrimidin—4-yl)-l H-pyrazol-l -yl] - propanenitrile trifluoroacetate N—(2-aminoethyl){2—cyano—1 -[4- rrolo[2,3-d]pyrimidin—4-yl)- lH-pyrazol-l -yl]ethyl} benzamide Bis trifluoroacetate 3—(5-formyl-3 ~thienyl)[4-(7H— o[2,3-d]pyrimidinyl)—1H- pyrazol—l -yl]propanenitrile trifluoroacetate 3—{2—cyano-1—[4—(7H-pyrrolo- [2,3—d]pyrimidin-4—yl)~1H—pyrazolyl] ethyl} -N-methy1benzamide roacetate 2—cyano—N—(3— {2—cyano-1 H« o[2,3-d]pyrimidin—4-yl)-1H- pyrazoI—l —yl]ethyl} phenyl)- acetamide trifluoroacetate N-(3-{2-cyano-l -[4-(7H- pyrrolo[2,3-d]pyrimidiny1)-1H- pyrazol—l -yl]ethyl }phenyl)- nicotinamide Bis trifluoroacetate N—(3-{2-cyano[4-(7H- pyrrolo[2, 3—d]pyrimidinyl)-1 H- pyrazol-l -yl]ethyl}phcnyI)-N'- isopropylurea trifluoroacetate pyl (3— {Z-cyano—l -[4—(7H— pyrrolo[2,3-d]pyrimidinyl)-1H— pyrazol—l ~y1]ethyl}phenyl)— carbamatc tn'fluoroacetate 3-(5-phenylpyridin—3-yl)—3-[4-(7H- pyrr010[2,3-d]pyrimidinyl)—1H- pyrazol-l —yl]propanenitrile- trifluoroacetate 3—(3,3'—bipyridin-5—y1)[4—(7H— pyrrolo[2,3-d]pyrimidin-4—yl)-1H- pyrazol-l -y1]propanenitrile- roacetate 3-(5-pyrimidin—S~ylpyridin—3~y1)-3 - [4-(7H—pyrrolo[2,3—d]pyrimidin yl)—1H—pyrazolyl]propanenitrile 3-[5-(1-methyl—lH-pyrazolyl)- pyridin—3~y1]~3—[4-(7H—pyrrolo[2,3- d]pyrimidin—4-yl)—lH—pyrazol-l -yl]- propanenitrile trifluoroacetate 3-(5—ethynylpyfidin—3—yl)—3—[4-(7H— pyrrolo[2,3-d]pyrimidin—4-yl)-I H- pyrazol—l ~yl]propanenitrile trifluoroacetate 3—[5-(phenylthio)pyridin—3—yl]-3—[4— (7H—pyrrolo[2,3-d]pyrimidin—4—yl)- lH—pyrazol-l -y1]propanenitrile trifluoroacetate 3-(2-bromo-1 ,3-thiazolyl)[4- (7H-pyrrolo[2,3—d]pyzimidin-4—yl)— lH-pyrazol-1 -yl]propancnitn'lc ethyl 3-[4-(7H-pyrrolo[2,3-d]- din—4—yl)-1H-pyrazolyl]- butanoate 3 rpholinylpyridin-3 -yl)-3 - -pyrrolo[2,3-d]pyrimidin—4— y1)-1H-pyrazol-1 -y1]propanenitn'le 3-(1-methyl—1H-pyrazol—4-y1)[4— (7H-pyrrolo[2,3-d]pyrimidin—4—yl)- lH-pyrazol—l —y1]propanenitrile 4-{1—[1-pheny1(lH-1,2,4-triazol- l -yl)ethyl]-1 H-pyrazolyl} -7H- pyrrolo[2,3—d]pyrimidine 4-{1-[1 -phenyl(4H-1 ,2,4—triazol— 4-yl)ethyl]-l H-pyrazolyl} ~7H— pyrrolo[2,3-d]pyrimidine 3—(3-pyridin—3 —ylphenyl)-3 H— pyrrolo[2,3—d]pyrimidin—4—yl)—1 H- pyrazol-l -yl]propanenitrile 2006/047369 3~[5-(phenylsulfinyl)pyridiny1]- 3—[4-(7H—pyrrolo[2,3—d]pyrimidin— 4—yl)-1H-pyrazol—1 -yl]propane- e trifluoroacetate 3-[5 -(phenylsu1fony1)pyridin—3~yl] — 3-[4-(7I-I—pyrrolo[2,3-d]pyrimidin- 4-yl)-1H-pyrazol-1 -y1]propane~ nitrile roacetate 3-[4—(7H—pyrrolo[2,3—d]pyrimidin- 4-yl)-1 H—pyrazol-l -yl]pentan-1—ol methyl 3-[4-(7H~pyrrolo[2,3-d]— pyrimidinyl)—1H-pyrazol—l -y1] — pentyl carbonate (1 E)—3~[4~(7H—pyrrolo[2,3—d]- pyrimidinyl)-1H-pyrazol-l -yl]- pentanal oxime (1E)—3~[4—(7H-pyrrolo[2,3-d]- pyrimidin-4—y1)-1H—pyrazol-1 ~yl]- pentanal O-methyloxime (lZ)—3-[4—(7H—pyrrolo[2,3-d]- pyrimidin—4~yl)— 1 H—pyrazol—l -yI] — pentanal O-methyloxime 4-[1 -(4,4-dibromo-1 —ethylbut—3-en— 1 —yl)-1H~pyrazol—4-yl]-7H— pyrrolo[2,3—d]pyrimidine trifluoroacetate 3-[4-(7H-pyrrolo[2,3-d]pyrimidin- 4—yl)-1H—pyrazol-l-yl][5-(l,3- thiazol—Z—ylthio)pyridin-3 -y1]- propanenitrile bis(trifluoroacetate) 3-[5~(ethylthio)pyridin-3 -yl]—3 -[4- (7H—pyrrolo[2,3-d]pyn'midin-4—yl)— lH—pyrazol-l -y1]propanenitrile WO 70514 2006/047369 4-[1 ~(1 ~ethylbutynyl)-1H- pyrazol—4-yl]-7H-pyrrolo[2,3— d]pyrimidine trifluoroacetate 4-{1—[l—methyl—2-(1H-1,2,4-triazol~ 1 -y1)ethyl]-1H—pyrazolyl} -7H- pyrrolo[2,3-d]pyrimidine 4-[4-(7H-pyrrolo[2,3—d]pyn'midin— 4-y1)-1 H—pyrazol-l —yl]pentanone trifluoroacetate 1 -phenyl[4-(7H-pyrrolo- [2,3-d]pyrimidinyl)-1H-pyrazolyl]propan—1 —one 3—[5—(ethylsulfinyl)pyn'din—3-yl] [4-(7H-pyrrolo[2,3 -d]pyrimidin y1)-1 H-pyrazol— 1 -yl]propanenitrile 3-[5-(ethylsulfonyl)pyn'din-3—y1] [4-(7H-pyrrolo[2,3-d]pyrimidin—4— yl)-1H-pyrazol-1—yl]propanenitrile 3-[5-(cyclohexy1thio)pyridinyl]- 3-[4-(7H-pyr:rolo[2,3-d]pyrimidin- 4—yl)-lH-pyrazol—l —y1]- propanenitrile 1 -phenyl[4-(7H-pyrrolo— [2,3-d]pyrimidin—4—yl)—] H—pyrazol- 1 opan-1 -ol 1 -phenyl[4-(7H—pyrrolo[2,3—d]- pyrimidinyl)—1H-pyrazol-1 -y1]- —l -ol 3 -[3 —(ethylthio)phenyl]-3 ~[4-(7H— pyrrolo[2,3—d]pyrimidin—4-y1)—l H- pyrazol-l -yl]propanenitrile 3-[3-(ethylsu1finyl)phenyl][4- (7H-pyrrolo[2,3-d]pyrimidiny1)— lH-pyrazol-l -y1]propanenitn'1e 3-[3-(ethylsulfony1)phenyl][4- (7H-pyrrolo[2,3—d]pyn’midiny1)- 407 lH-pyrazol- l -yl]propanenitrile 3-[3-(ethylsulfonyl)phenyl]-3—[4- (7H-pyrrolo[2,3-d]pyrimidinyl)- l H—pyrazolyl]propanenitrilc 3-[5-(cyclohexy1sulfonyl)pyridin—3- yl][4—(7H-pynolo[2,3-d]- pyrimidin-4—y1)-1H—pyrazol-l -yl]- propanenitrile 3-[5-(cyclohexylsulfinyl)pyridin—3 — yl]-3 —[4-(7H—pyrrolo[2,3—d]— pyrimidin—4—yl)-1H-pyrazol—l —yl]- propanenitrile 4-[1 -(1 —methyl—2~phenylethy1)—1H— pyrazol~4-y1] -7H-pyrrolo[2,3-d] - pyrimidine 4- {1 -[1 -methyl-2 -(3 -thienyl)ethyl]- 1H-pyrazolyl } -7H-pyrrolo— [2,3-d]pyrimidine 3-{1-[4-(7H-pyrrolo[2,3-d]- pyrimidin—4-yl)-1H—pyrazol-l -yl]- ethy1}benzonitrile 4-{1-[2-(lH-imidazol-l-yl)-l- methylethyl]-1 H—pyrazol—4-y1} -7H— pyrrolo[2,3-d]pyrimidinc 4-{1-[l-methyI(3-mcthyl-1 ,2,4- oxadiazol-S-yl)ethyl]-1H-pyrazol-4— yl} rrolo[2,3 imidine 3—[3—(methylsulfony1)phenyl]-3—[4— rrolo[2,3-d]pyrimidin~4—yl)— azol— l —y1]propanenitrile 3—(3~pyridin-4~ylphenyl)—3-[4-(7H- pyrrolo[2,3-d]pyrimidin~4-yl)-1H- pyrazol-l -yl]propanenitrile 4— [1 -(l ~ethylbut-3—en—1 ~yI)-l H— l—4—yIJ-7H-pyrrolo[2,3-d]- pyrimidine 4-[1-(l,3-dimethylbut—3’eny1)- 1H—pyrazolyl]e7H-pyrrolo[2,3— d]pyrimidine isopropylthio)pyridinyl] [4-(7H-pyrrolo[2,3-d]pyrimidin-4— yl)-1H-pyrazol-l -yl]propanenitrile 3-[5-(isopropylsulfinyl)pyridin—3 - yl]-3 -[4-(7H-pyrrolo[2,3 -d] - pyrimidinyl)-1 H-pyrazol-l -yl]- enitrile 3-[S-(isopropylsulfony1)pyridin-3 - yl]—3-[4—(7H-pyrrolo[2,3-d] - pyrimidin—4-yl)-1 H-pyrazol-l ~yl] - propanenitrile 3-[4-(7H~pyrrolo[2,3-d]pyrimidin- 4-yI)-lH—pyrazol-l -yl][5- (trifluoromethyl)pyridinyl] - propanenitrile 3-[4—(7H—pyrrolo[2,3~d]pyrimidin- 4-yl)- 1 H-pyrazol-l -yl]-3 -[5- (trifluoromethyl)pyridin-3—yl]- enitn'le 2-[4-(7H-pyrrolo[2,3-d]pyrimidin- 4-yl)—lH—pyrazolyl]-N-[3- (tn’fluoromethyl)phenyl]- propanamide Nnaphthyl—2-[4-(7H-pyrrolo- [2,3-d]pyrimidinyl)—1H—pyrazoly1]propanamide N—l ~naphthyl—2—[4-(7H—pyrrolo— [2,3-d]pyrimidinyl)-1H-pyrazol— 1 —yl]propanamide N-(3-cyanophenyl)—2-[4-(7H- pyrrolo[2,3-d]pyrimidinyl)-1 H- pyrazol—l -yl]pr0panamide yl-Z—[4-(7H—pyrrolo- [2,3-d]pyrimidin~4-yl)- 1H-pyrazol— 1 -yl]propanamide N-phenyl-Z-[4-(7H-pyrrolo[2,3-d]- pyn'midin—4—yl)-1H-pyrazol-l —y1]- butanamide N-(4-phenoxyphenyD[4-(7H~ pyrrolo[2,3-d]pyrimidin—4-yl)~1 H— pyrazol-l -yl]butanamide N-Z-naphthyl-Z-[4-(7H-pyrrolo- [2,3-d]pyrimidin—4-yl)-IH-pyrazol- I'-yl]butanamide N-(3-cyanophenyl)-2—[4-(7H— pyrrolo[2,3-d]pyrimidin—4-yl)— 1 H- pyrazol-l —y]]butanamide N—biphenyl—4-yl[4-(7H— pyn'olo[2,3-d]pyrimidinyl)-1H- l—l tanamide N-(biphenylylmethyl)~2-[4-(7H— pyrrolo[2,3—d]pyrimidin—4—yl)-1 H- l~1 -yl]butanamide N-(biphenyl-B-ylmethyl)—2-[4-(7H- pyrrolo[2,3-d]pyrimidin-4~y1)—l H~ pyrazol-l -yl]butanamidc N-(4-cyanophenyl)—2—[4—(7H— pyrrolo[2,3-d]pyrimidiny1)—1H- pyrazol— 1 ~yl]butanamide N-l -naphthyl[4-(7H—pyrrolo- [2,3-d]pyrimidin—4-yl)—l zolyl]butanamide -{2-cyano-1 -[4-(7H-pyrrolo- [2,3-d]pyrimidiny1) -1H-pyrazol- thyl } —N-phenylnicotinamide tn'fluoroacetate 4- { 1 -[1 —(5-bromopyridiny1)-4,4- difluorobute n-l -y1]-1H-pyrazol- 4-y1} -7H—pyrrolo[2,3-d]pyrimidine 430, 432 - {4,4-difluoro-1 -[4—(7H- pyrrolo[2,3—d]pyrimidin— 4-y1)—1H- pyrazol-l -yl]but-3 -en-l - yl } nicotinonitrile (I CN Step 1: Dimethyl 3-[4—(7-{[2-(trimethylsilyl)eth0xy]methyl}-7H-pyrrolo[2, 3-d]pyrimidin-4—yl)-1H- pyrazolyl]pentanedioate 4—(1H-Pyrazol—4—y1)-7—[2—(trimethylsilyl)ethoxy]methyl-7H—pyrrolo[2,3-d]pyrimidine (31.0 g, 0.0983 mol) was ded in ACN (620 mL, 12 mol), and DBU (9.3 mL, 0.062 mol) was added under nitrogen. The reaction was heated to 65 °C and yl (2E)-pentenedioate (16 mL, 0.12 mol) was added in 5 mL portions over 2 h. After stirring overnight, the reaction was complete. The reaction was allowed to cool to room temperature and was concentrated in vacuo to give a dark oil.

The oil was partitioned between ethyl acetate and water. The organic layer was washed with 1.0 N HCl, brine, dried over magnesium sulfate, and then trated to give a dark oil. The viscous oil was triturated with ethyl ether 3X 500 mL to give a dark precipitate. The oil was taken up in ethyl acetate to form a solid. The solids were collected, Washed with ethyl ether and dried to give dimethyl 3~[4-(7— {[2-(trimethylsilyl)ethoxy]methyl} -7H—pyrrolo[2,3-d]pyrimidin—4-y1)-lH-pyrazol-l - yl]pentanedioate as a white powder (29.5 gm, 64%), LC IMS (M+H)+: 474, 1H NMR (DMSO-dfi) 5 9.1 (s,lH), 9.02 (s,1H), 8.65 (s, 1H), 8.11 (d, 1H), 7.42(d, 1H), 5.78(s, 2H), , 1H), 3.65(m, 8H), 3.15(m, 4H), 0.950, 2H), 0.1(s, 9H).

Step 2: 3-[4—(7-[2-(Trimethylsilyl)ethoxy]methyl—7H-pyrrolo[2,3-d]pyrimidin—4~yl)-1H—pyrazol—I-y[]— pentanedioic acid Dimethyl 7-{[2~(trimethylsilyl)ethoxy]methyl}—7H—pyrrolo[2,3—d]pyrimidinyl)~lH- pyrazol-l—yl]pentanedioate (43.0 g, 0.0908 mol) was dissolved in methanol (271.2 mL, 6.695 mol) and lithium hydroxide monohydrate (15 g, 0.36 mol) dissolved in water (125 mL) was added. The reaction was stirred at rt for 2 h. The methanol was removed in vacuo and a ing aqueous layer was cooled in an ice bath. The solution was made acidic pH~4 with 1N HCl to give a white precipitate. The solid precipitate was collected, washed with water, dried to give 3-[4~(7-[2- (trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3—d]pyn'midin—4—y1)-lH-pyrazol-l -y1]pentanedioic acid as a white crystalline powder (31.8 gm, 80%), LC /MS (M+H)+: 446, IH NMR (DMSO-d5) 5 8.85_slI-l), 8.75(s, 1H), , 1H), 7.85(d, 1H), 7.17(d, 1H), 5.7l(s, 2H), 5.18(m,1H), 3.65(t, 2H), ,4I-I), 0.920;, 2H), 0.1(s, 9H).

Step 3: 3-[4-(7—[2-(TrimethylsilyDethonymethyl-7H-pyrrolo[2,3—d]pyrimidin-4~yl)-1H—pyrazol—l—yl]— pentanediamide 3—[4-(7—[2—(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidinyl)-l H-pyrazol-l - yl]pentanedioic acid (31.80 g, 0.07137 mol) was dissolved in DMF (636 mL, 8.21 mol) under nitrogen cooled in an ice bath and CD1 (34.7 g, 0.214 mol) was added. This mixture was allowed to stir for 30 minutes and then allowed to warm to rt. Afier stirring for 2 h ammonia (12.2 g, 0.714 mol) was bubbled through the solution for 30 minutes giving a cloudy sion. The on mixture was concentrated to remove some of the DMF (~200 mL) and then water was added slowly to give a white precipitate. This mixture was cooled in an ice bath and the solid precipitate was collected, washed with water and dried in vacuo to give 3—[4-(7—[2-(trimethylsilyl)ethoxy]methyl~7H- pyrrolo[2,3-d]pyrimidinyl)—1H-pyrazoly1]pentanediamide as a white powder (29.0 gm, 91%), LC /MS (M+H)+: 444, 1H NMR (DMSO—a'a) 5 8.85(s, 1H), 8.59(s, 1H), 8.40(s, 1H), 7.87(d,1H), 7.75(s,2H), 7.15(d, 1H), 6.95(s, 2H), 5.73(s, 2H), 5.29(m,1H), 3.63(t, 2H), , 2H), 2.73(m, 2H), O.90(t, 2H), 0.1(s, 9H).

Step 4: 7—[2-(Trimethylsibl)ethoxyjmethyl-7H-pyrrolo[2,3-d]pyrimidin—4—yl)-1H~pyrazol—1~yl]- pentanedinitrile 3—[4'(7—[2{Trimethylsilyl)eth0xy]methyl-7H—pyn'olo[2,3-d]pyrimidin—4—yl)~1H—pyrazol-l - yl]pentanediamide (29.0 g, 0.0654 mol) was partially dissolved in DMF (200 mL, 2 mol), DCM (200 mL, 3 mol) and TEA (36 mL, 0.26 mol) and cooled in an ice bath under nitrogen atmosphere. The trichloroacetyl chloride (15 mL, 0.14 mol) was added dropwise turning the reaction to a dark solution.

This was stirred at 0 °C for 1/2 h. The reaction was then concentrated to remove the DOM and the resulting DMF solution was d with water to precipitate the product. The solid precipitate was collected and washed with water to give a dark solid. The solid was then dissolved in DCM and washed with brine, dried over magnesium sulfate and concentrated to give a very dark oily residue.

The residue was taken up in DCM, and hexane was added until the solution became slightly cloudy.

This was stirred at rt to precipitate 3—[4—(7-[2-(trimethylsilyl)ethoxy]methyl—7H—pyrrolo[2,3-d]- pyrimidin—4-yl)-1H-pyrazol-l —y1]pentanedinitrile as whiteneedle—like crystals (22.7 gm, 85%), LC /MS T': 408, 1H NMR (DMSO-ds) 8 9.07(s, 1H), , 1H), 8.59(s, 1H), 7.88(d, 1H), 7.19(d, 1H), 5.75(s, 2H), 5.30(m,1H), 3.62(t, 2H), , 4H), O.91(t, 2H), 0.10(s, 9H).

Step 5: 3-[4-(7H—Pyrrolo[2, 3-djpyrz'midin—4-yD-1H—pyrazol—I—yUpentanedinitrile 3—[4-(7-[2~(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidinyl)- l H-pyrazol-l - yl]pentanedinitrile (10.0 g, 0.0245 mol) was dissolved in ACN (200 mL, 3.83 mol) and water (20 g, 1.1 mol) at rt. To this lithium tetrafluoroborate (23.0 g, 0.245 mol) was added giving a cloudy solution. The reaction was heated to reflux and monitored by HPLC. Afier heating for 24 h the reaction was allowed to cool to It and then cooled in an ice bath. To this, ammonium hydroxide (23 mL, 0.59 mol) was added slowly. The reaction was allowed to warm to rt. After stirring for 18 hs the reaction was diluted with water and trated in vacuo to remove the ACN, giving a itate.

The solids were collected, washed with water and dried to give the title compound as an off—white solid (6. 2 gm, 91%), LC [MS (M+H)+: 278, 'H NMR dé) 5 8.9(s, 1H), 8.72(s,1H), 8.43(s, 1H), 7.59(d, 1H), 6.92(d, 1H), 5.21(m,1H), 3.25(m, 4H).

Example 421: 5—{2-Cyano—l-[4-(7H-pyrrolo[2,3-d]pyrimidin—4—yl)—lH—pyrazol-l-yl]ethyl}- ne-Z-carbonitrile trifluoroacetate WO 70514 \ / CN "'0 \ N/ [:1 Step 1: 3-(6—Chloropyridin-3—yl)—3—[4—(7H-pyrrolo[2,3-d]pyrimidin—4—yl)—IH—pyrazol—I-yl]propane— nitrile 3—(6-Chloropyridinyl)[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H—pyrrolo[2,3-d]— pyrimidin-4—yl)-lH~pyrazolyl]propanenitrile (prepared by methods analogous to those bed for Example 61) (0.070 g, 0.00014 mol) in TFA (3.0 mL, 0.039 mol) and DCM (3.0 mL, 0.047 mol) was stirred at room temperature for 1 hour. Solvent was removed in vacuo, and the residue was dissolved in methanol (4.0 mL, 0.099 mol) and ethylenediamine (0.07 mL, 0.001 mol). The reaction mixture was stirred at room temperature overnight. Solvent was removed in vacuo, the crude product was purified by ative HPLC eluting with an ACN; water gradient buffered with ammonium hydroxide to pH=10, to give 3—(6-chloropyridinyl)[4-(7H-pyrrolo[2,3-d]pyn'midinyl)—1H— pyrazol-l—yl]propanenitrile as a white powder (35mg,69%), LCMS (M+l)+:3so, ‘H NMR (DMSO-dd) 12.21 (b,1H), 9.00 (5,111), 8.78 (s,1H), 8.62 (s,1H), 8.58 (s,1H), 8.00(m,IH), 7.70(m,2H), 7.00(s,1H), 6.22(m,1H), 3.90(m,1H), 3.78(m,1H) Step 2: 5—2—Cyano—I~[4—(7H-pyrrolo[2, 3~d]pyrimidin—4—yl)~1H-pyrazol-1—yl]ethylpyridine—Z—carbo- nitrile trifluoroacetate A mixture of 3—(6-chloropyridin—3—yl)—3—[4-(7H—pyrrolo[2,3-d]pyrimidin—4—yl)—1H-pyrazol-l— yl]propanenitrile (0.025 g, 0.000071 mol) and zinc cyanide (0.08 g, 0.0007 mol) in DMF (1.0 mL, 0.013 mol) was degassed with nitrogen. To this mixture, tetrakis(triphenylphosphine)pailadium(0) (0.04 g, 0.00004 mol) was added and the resulting mixture ed again with dinitrogen. The reaction mixture was heated in a sealed tube at 170 °C for 15 minutes in a microwave nal try). After cooling to room temperature, the solids were filtered, rinsed with DMF and the combined solvent was concentrated in vacuo. The e was tn'turated with hexanes (3x), and hexanes washes were discarded. The crude product was purified by preparative HPLC eluting with ACN; water gradient containing 0.2% TFA to give the title compound as; a white powder (16 mg, 49.27%), LCMS (M+l)+: 341, 1H NMR (DMSO-ds) 8 b,1H), 9.05(s,1H), 8,89(s,1H), 8,80(s,1H), 8.58(s,1H), 8.18(m,2H), 7.78(s,1H), 7.05(s,1H), 6.20(m,1H), 3.90(m,1H), 3.77(m,1H).

Example 428: 4—[4-(7H-Pyrrolo[2,3-d]pyrimidin—4-yl)—1H—pyrazol-l—yl]heptanedinitrile N \ \ "\ N/ Step I .' 3—[4—(7—[2-(Trimethylsilyl)ethoxyjmethyl- 7H—pyrralo[2, 3-d]pyrimidinyl)—IH—pyrazol—I - yl]pentane-I,5-diol Diethyl 3—[4—(7—[2-(trimethylsily1)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidinyl)-1H- pyrazol-l-y1]pentanedioate, prepared substantially as described in Example 407 (0.80 g, 0.0016 mol), was dissolved in THF (40 mL, 0.49 mol) and cooled in an ice bath under a nitrogen atmosphere. To this mixture, 1.0 M lithium ydroaluminate in THF (3.2 mL) was added slowly. The reaction was d for 1h, quenched with ice and partitioned between ethyl acetate and 1 N HCl. The organic layer was washed with brine, dried over magnesium sulfate and concentrated to give an amber oil.

The product was purified by FCC on silica gel eluting with an ethyl acetate: methanol gradient to give 3-[4—(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidinyl)-l H-pyrazol-l -yl]pentane- 1,5-diol as a clear s oil (0.51 gm, 76%), LC /MS (M+H)+: 418, 1H NMR (DMSO-ds) 5, 8.85(s, 1H), 8.4l(s, 1H), 8.37(s, 1H), ,1H), , 1H), 5.73(s, 2H), 4.91(m, 1H), 3.75(m,2H), 3.59(m, 2H), 3.45(rn,2H), , 4H), ,2H), 0.1(s, 9H).

Step 2: 3-[4—(7—[2-(Trimethylsilyl)ethoxyjmethyl— 7H—pyrrolo[2,3-d]pyrz'midin—4—yl)—JH-pyrazol-I- yljpentane-I, 5—diyl dimethanesulfonate A mixture of 3—[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3—d]pyrimidinyl)—lH- pyrazolyl]pentane-1,5-diol (50 mg, 0.0001 mol) in DCM (2 mL, 0.03 mol) was cooled at 0 °C. To this e, TBA (50 uL, 0.0004 mol) was added. The reaction was stirred for 15 minutes. esulfonyl chloride (23 uL, 0.00030 mol) was added and the resulting mixture was stirred for 1 hour. Water was added and the product was extracted with ethyl acetate. The combined extracts were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give 3-[4-(7—[2-(trimethylsilyl)ethoxy]methyl—7H—pyrrolo [2,3-d]pyrimidinyl)-l H-pyrazol-l ~yl] - pentane—l,5-diyl dimethanesulfonate (57 mg, 80 %) as an oil. MS(ES): 574 (M+1).

Step 3: 4—[4—(7—[2—(Trimethylsilyl)ethoxyjmethyl- 7H—pyrrolo[2, 3-d]pyrimidin—4—yl)—1H—pyrazol—I— yljheptanedinitrile WO 70514 To a mixture of 3~[4-(7-[2—(trimethylsilyl)ethoxy]methyl—7H—pyrrolo[2,3-d]pyrimidin—4—yl)— -. lH—pyrazol-l-yl]pentane-l,5-diyl dimethanesulfonate (57 mg, 0.000099 mol) in DMSO (1 mL, 0.01 mol), sodium cyanide (10 mg, 0.0003 mol) was added and the mixture was d for 2 hours. The mixture was heated at 60 °C for 1 hour. Water was added and the product was extracted with ethyl acetate. The combined extracts were washed with saturated sodium de, dried over magnesium sulfate, d and concentrated to give 4-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3— d]pyrimidin-4—yl)-lH—pyrazolyl]heptanedinitrile (40 mg, 90 %) as an oil. MS(ES): 436 (M+1).

Step 4: 4-[4-(7H-Pyrrolo[2, 3-d]pyrimidin-4—yD—1H—pyrazolyl]heptanedinitrile Using a procedure analogous to e 61 for the removal of the SEM protecting group, the title nd was prepared as a white amorphous solid, (17 mg, 60%) lH NMR (400 MHz, DMSO): 6, 8.75 (s, 1H), 8.65 (s, 1H), 8.4 (s, 1H), 7.6 (d, 1H), 7.0 (d, 1H), 4.5 (m, 1H), 2.35 (m, 4 H), 2.2 (m, 4H). MS(ES): 306 (M+1).

IS Example 429: 3-(5—Bromopyridin—3-yl)[4-(7H—pyrrolo[2,3-d]pyrimidin-4—yl)—1H—pyrazol—l— yllpropanenitrile // Br N\'L/\ Step 1: (ZZ&E)(5-Brom0pyridinyl)acrylonitrile Nc/ -— Br To a mixture of 1.0 M potassium tert-butoxide in THE (2.7 mL) at 0 °C (water-ice bath, under an atmosphere of nitrogen) was added diethyl cyanomethylphosphonate (0.48 mL, 0.0030 mol) in TI-IF (4.0 mL, 0.049 mol), dropwise. The reaction mixture was warmed to room temperature, and then was cooled to 0 °C, followed by dropwise addition of 5-bromonicotinaldehyde (0.5 g, 0.003 mol) in THF (1.0 mL, 0.012 mol). After stirring at room temperature for 20 hours, the reaction mixture quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to give a crude product as a dark oil.

The crude product was d by flash chromatography on silica gel using ethyl acetate-hexanes as eluent to give a mixture of cis and trans isomers (2)—3 -(5-bromopyridinyl)acrylonitn'le as an off- 2006/047369 white solid (268 mg, ). LCMS (M+l)+: 209,211, 1H NMR (400 MHz, CD013): 5, 8.75(s,1H), 8.62(s,1H), 7.90(s,1H), ,1H), , 1H).

Step 2: 3-(5-Bromopyridiny1)-3~[4-(7-[2—(trimethylsilyDethoxyjmethyl— 7H-pyrrolo[2, 3-d]pyr— imidin~4-yl)-JH-pyrazol—1~y1]propanenitrile To 4-(1 H-pyrazol—4-y1)—7—[2-(trimethylsilyl)ethoxy]methyl-7H—pyrrolo[2,3-d]pyrimidine (0.200 g, 0.000634 mol) in 1.0 mL of dry ACN was added DBU (0.10 mL, 0.00067 mol), f0110Wed by the addition of (2Z&E)~3-(5-bromopyridinyl)acrylonitri1e (0.234 g, 0.00112 mol) in 1.0 mL of ACN. The reaction mixture was stirred at 67 °C for 4 hours. Upon cooling, the mixture was partitioned between dilute hydrochloric acid and ethyl e. The organic layer was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by flash chromatography on silica gel using ethyl acetate : hexanes (7:3) to give 3-(5- bromopyridin-3~yl)—3—[4—(7-[2-(trimethy1silyl)-ethoxy]-methyl—7H—pyrrolo[2,3-d]pyrimidin—4—y1)-1H- pyrazol~1~yl]propanenit1ile as an off-white solid (225 mg, 67.66%). LCMS (M+l)+:524,526: 1H NMR (400 MHz, CD013): 5 8.90(s, 1H), 8.80(s, 1H), 8.70(s, 1H), 8.42(s, 1H), 8.40(s, 1H), 8.00(s, 1H), 7.50(d, 1H), 6.82(d, 1H), S.81(m, 1H), , 2H), 3.70(m,1H), 3.60(m, 2H), 3.42(m, 1H), 1.00(m, 2H), 0.08(s, 9H).

Step 3 .' 3-(5-Brom0pyridinyU—3-[4-(7H-pyrrolofl,3-d]pyrimidin-4—yl)-1H-pyrazal—1-yl]pr0pane— ‘ nitrile The 3-(5-bromopyridinyl)-3—[4-(7—[2-(trimethylsily1)ethoxy]methyl-7H-pyrrolo[2,3-d]- pyrimidin—4-yl)—lH—pyrazol-l-yl]propanenitrile (0.220 g, 0.000419 mol) in DCM (9.0 mL, 0.14 mol) and TFA (9.0 mL, 0.12 mol) was. stirred at room temperature for 1 hour. The reaction was concentrated in to give a residue. This crude ediate was dissolved in methanol (12 mL, 0.30 mol) and ethylenediamine (0.2 mL, 0.003 mol) and Was stirred overnight at room ature. The reaction was concentrated in vacuo to give the crude product which was purified by preparative HIPLC eluting with a water : ACN gradient buffered with ammonium hydroxide (pl-1:10) to give (5-bromopyridinyl)[4-(7H-pyrrolo[2,3-d]pyn'midinyl)-1H—pyrazol-l-y1]propanenitrile as an amorphous white powder (118 mg, 71.36%). LCMS (M+l)+:394,396, IH NMR (400 MHz, DMSO- d6): 5,12.05(bs,11-I), 8.98(s, 1H), 7.0(s, 1H), 6.50(m, 2H), 8.50(s, 1H), , 1H), 7.80(s, 1H), 6.98(s, '1 H), 6.21(m, 1H), 3.90(m, 1H), , 1H).

Example 430: 3-[4-(7H-Pyrrolo[2,3—d]pyrimidinyI)—lH—pyrazol-l-yl]pentane—l,5—diol hi\\N/ Using a procedure analogous to Example 61 for the removal of the SEM ting group but using 3-[4-(7—[2-(trimethylsilyl)ethoxy]methyl—7H-pyrrolo[2,3-d]pyrimidinyl)-lH-pyrazol-l —yl]- pentane-1,S—diol from e 428, the title compound was prepared as a white amorphous solid, (25 mg, 70%) 'H NMR (400 MHz, DMSO): 5, 8.65 (s, 1H), 8.6 (s, 1H), 8.25 (s, 1H), 7.6 (d, 1H), 6.0 (d, 1H), 4.6 (m, 1H), 3.3 (m, 2H), 3.2 (m, 2H), 2.1 (m, 2H), , 2H). MS(ES): 288 (M+1).

Example 431: 5-(2-Cyano[4-(7H—pyrrolo[2,3-d]pyrimidiny1)—1H-pyrazol-l-yl]ethyl)- nicotinonitrile bis(trifluoroacetate) //, CN 2TFA Nt\\/ N N A slurry of 3-(5-bromopyridinyl)-3—[4-(7H—pyrrolo[2,3-d]pyn'midinyl)—l H-pyrazol-l- yl]propanenitrile (0.050 g, 0.00013 mol) (from Example 429), DMF (2.0 mL, 0.026 mol) and zinc cyanide (0.1 g, 0.001 mol) was degassed by purging with nitrogen. Then tetrakis(triphenyl— phosphine)palladium(0) (0.07 g, 0.00006 mol) was added and the resulting slurry again was degassed with en. The reaction was sealed and heated at 170 °C for 15 s in a microwave (Personal try). The reaction was allowed to cool and the solids were filtered off. The combined DMF fractions were concentrated in vacuo. The residue was triturated with ethyl acetate—hexanes 2:8, then with ethyl ether to removed by-products. The crude productwas purified by preparative HPLC eluting with a water : acetontrile gradient containing 0.2% TFA to give the racemic title compound (43 59.65%). LCMS (M+1)+:341, 1H NMR (400 MHz, DMSO'dG): 5, 12.60(bs, 1H), 9.10(s, 1H), 8.90(s, 1H), 8.80(s, 1H), 8.50(s, 1H), , 1H), 7.78(s, 1H), 7.10(s, 1H), 6.30(m, 1H), 3.90(m, 1H), 3.70(m,1H).

Example 431R and Example 431s The enantiomers -cyano-l -[4-(7H-pyrrolo[2,3-d]pyn'midin-4—yl)—1H-pyrazol-l -y1]- ethyl)nicotinonitrile and S(2-cyano-1~[4—(7H-pyrrolo[2,3—d]pyrimidinyl)~lH—pyrazol-l-yl]- ethyl)nicotinonitrile were separated by chiral column HPLC.

Example 467: 3-(3—Aminophenyl)—3—[4-(7H-pyrrolo[2,3-d]pyrimidinyl)-1H-pyrazol-l-yl]- propanenitrile bis(trifluoroacetate) / NH2 2TFA NC \ / N N Step 1 : 3-(3-NitrophenyD[4-(7-[2—(trimethylsilyDethwqyjmethyl- 7H-pyrrolo[2, 3-d]pyrimidin-4—yl)— 1H-pyrazol—J-yl]propanenim'le l 5 To 4-(1 H—pyrazol—4-yl)-7—[2—(trimethylsi1y1)ethoxy]methyl—7H—pyrrolo[2,3—d]pyrimidine (0.500 g, 0.00158 mol) in 8.0 mL of dry ACN was added DBU (0.24 mL, 0.0016 mol) followed by addition of (2Z)—3-(3-nitrophenyl)acrylonitrile (0.36 g, 0.0021 mol) in 2.0 mL of ACN. The reaction e was heated at 67 °C for 18 hours. This was cooled to room temperature, and the mixture was partitioned between d hydrochloric acid and ethyl acetate. The organic layer was washed with ted sodium chloride, dried over anhydrous magnesium sulfate, and concentrated. The crude product was purified by flash chromatography on silica gel using ethyl acetate-hexanes 6:4, to give 3- (3 -nitrophenyl)—3-[4-(7-[2-(trimethylsi1yl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrirnidinyl)-1 H- pyrazol-l ~yl]propanenitrile as a dark orange oil, (688 mg, 88.65%). LCMS (M+1)+:490 Step 2. 3-(3-Aminophenyl)—3—(4[2—(trimethylsilyOethoxyj-7H—pyrrolo[2,3-d]pyrimidinyl—IH— pyrazol-J —yl)pr0panenitrile The 3-(3~nitrophenyl)~3-[4-(7-[2-(trimethylsily1)ethoxy]methyl—7H-pyrrolo[2,3-d]py1imidin- 4-yl)-1H—pyrazol-l-y1]propanenitrile (0.630 g, 0.00129 mol) was dissolved in ethanol (65 mL, 1.1 mol), degassed with nitrogen, and then palladium (0.55 g, 0.0052 mol) (10% on carbon) was added.

The on mixture was again purged with en, and it was then charged at 50 psi hydrogen in a Parr shaker for 60 minutes. The reaction e was filtered and concentrated to give 3-(3-amino- phenyl)—3 -(4—7—[2-(trimethylsilyl)ethoxy]—7H-pyrrolo[2,3—d]pyrimidiny1-1H-pyrazol-l opane- nitrile as a colorless oil (550 mg, 95.92%), LCMS (M+l)+=460, Step 3. 3-(3-AminophenyD[4-(7H-pyrrolo[2,3-d]pyrimidinyD-1H.pyrazol—I-yl]propanenitrile bis(trifluor0acetate) Using a procedure analogous to that of Example 61 for the removal of the SEM ting group, the title nd was prepared as a white amorphous solid (18 mg, 38%), LCMS (M+1)+=329: lH NMR (DMSO-ds) 8 12.61 (b,lH), 9.00 (s,1H), 8.80 (s,1H), 8.50 (s,1H),7.78 (m,1H), 7.25( m,1H), 7.18(m,lH), ,2H), 6.02 (m.1H), 3.78(m,1H), 3.60 .

Example 468: N—(3-(2-Cyano-l-[4-(7H—pyrrolo[2,3-d]pyrimidinyl)-1H—pyrazol—l-yl] ethyl)— phenyl)acetamide trifluoroacetate N—N o / HN—< MIC \ N N Step 1 —(3-2—Cyano—1-[4-(7-[2-(trimethylsilyl)ethoxyjmethyl- 7H—pyrrolo[2, 3-d]pyrimidin—4-yl)-1H— pyrazol—I—yl]ethylphenyl)acetamide To minophenyl)—3-[4—(7-[2-(trimethylsi1yl)ethoxy]methyl—7H-pyrrolo[2,3-d]pyrimidin- 4-yl)—1H-pyrazol-1—yl]propanenitn'le (0.070 g, 0.00015 mol) (from Example 467) in dry DCM (1.0 2O mL, 0.016 mol) was added TEA (0.042 mL, 0.00030 mol). The reaction was cooled in an ice bath and acetyl chloride (0.016 mL, 0.00023 mol) was added. The reaction mixture stirred for 30 minutes and was diluted with water and ted with ethyl acetate (2x). The combined organic layers were washed with saturated sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give N—(S—Z—cyano-l—[4—(7-[2-(trimethylsilyl)ethoxy]methyl—7H-pyrrolo[2,3— d]pyrimidinyl)-lH-pyrazol—l—yl]ethylphenyl)acetamide as a colorless oil, (65 mg, 85.08%), LCMS(M+1)+= 502.

Step 2 N-(3—2—Cyano—1—[4-(7H—pyrrolo[2,3—djpyrz'midin—4—yl)—1H—pyrazol—1—yUethylphenyDacetamide trzfluoroacetate Using a ure analogous to that of Example 61 for the removal of the SEM protecting group, the title compound was prepared as a white amorphous solid (40 mg, 68.9%), LCMS(M+1)+=372, ‘H NMR (DMSO-d5) 5 12.61 (b,lH), 9.05 (s,1H), 8.79 (s,1H), 8.44 (s,1H), 7.85 (s,1H), 7.55 (s,1H), 7.48 (d,1H), 7.24 , 7.10 (m,2H)), 6.05 (m,1H), 3.70 (m,lH), 3.48 , 1.98 (5,3H).

Example 470: yano—1-[4—(7H-pyrrolo[2,3-d]pyrimidinyl)-1H—pyrazol—l-yl]ethyl)- thiophene—Z-carbonitrile trifluoroacetate NU \ ./ N N Step 1 4-Br0ma-2~(diethoxymethyl)thiophene A mixture of 4—bromothiophene-Z-carbaldehyde (1.2 g, 0.0063 mol) in ethanol (10 mL, 0.2 mol) was treated with ammonium chloride (0.42 g, 0.0078 mol) and ethyl orthoformate (1.2 g, 0.0078 mol). The mixture was d at 60 °C for 2 hours. The reaction was quenched with water and extracted with ethyl acetate. The combined organic layer was washed with saturated sodium chloride, dried over magnesium sulfate, d and concentrated to give 4-bromo—2-(diethoxymethyl)thio- phene as an oil (1.3 g, 81% ). 1H NMR (400 MHz, CDCl3): 5 7.22 (s, 1H), 6.99 (s, 1H), 5.68 (s, 1H), 3.63 (q, 4H) 1.24 (t, 6H).

Step 2 5—(Diethoagzmethyl)thiophenecarbaldehyde A solution of 4-bromo(diethoxymethyl)thiophene (500 mg, 0.002 mol) in ether (5 mL, 0.05 mol) was cooled at -78 °C. To this solution, 2.5 M n-butyllithium in hexane (0.83 mL) was added dropwise. The reaction was stirred at —78 °C for 1 hour. To the reaction was added DMF (0.4 g, 0.006 mol) at —78 °C and the mixture was stirred for 30 minutes. The reaction was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by flash column tography to yield the thoxymethyl)thiophenecarbaldehyde as an oil (170 mg, 42.0%). By 1B NMR two different regioisomers of aldehydes were formed and were not separated; (note: NMR shifts are for the major isomer only) 1H NMR (400 MHZ, CDClg): 8_ 9.85 (s, 1H), 8.05, 7.7 (s, 1H), 7.45, 7.15 (s, 1H), 5.7 (s, 1H), 3.65 (m, 2H), 1.25 (m, 2H).

Step 3 (2E)[5—(Dieth0xymethyl)~3—thienyljacrylonitrile To a on of diethyl cyanomethylphosphonate (100 mg, 0.0008 mol) in THF (2 mL, 0.02 mol) cooled at 0 °C and 1.0 M potassium tert-butoxide in THF (0.8 mL) was added dropwise. The 178 ' 2006/047369 bath was removed and the reaction was warmed to room temperature for 30 minutes. The reaction was cooled to 0 °C and a solution of 5-(diethoxymethyl)thiophenecarbaldehyde (170 mg, 0.00079 mol) in THF (2 mL, 0.02 mol) was added drop wise. The reaction was stirred overnight at room temperature. The reaction was partitioned between water and ethyl acetate. The combined extracts were washed with ted sodium chloride, dried over magnesium sulfate, filtered and concentrated.

The crude residue was purified by flash column chromatography on silica gel eluting (ethyl acetatezhexane, 1:5) to give (2E)[5-(diethoxymethyl)thienyl]acrylonitrile as an oil (160 mg, 84.9%). lH NMR (300 MHz, CDC13): 5 7.4—7.0 (m, 3H), 5.65 (m 1H), 4.2 (m, 1H), 3.65 (m, 4H), 1.25 (m, 6H).

Step 4 3—[5—(DiethoxymethyD-3—thienyl]-3—[4-(7—[2-(trimethylsibzlkthoxyjmethyl- 7H—pyrrol0[2,3- d]pyrimidinyl)-IH—pyrazol-I-yl]pr0panenitrile To a solution of 4-(1H—pyrazolyl)[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3—d]- pyrimidine (200 mg, 0.0007 mol) in ACN (2 mL, 0.04 mol) and (2E)—3-[5-(diethoxymethyl)—3- thienyl]acrylonitrile (160 mg, 0.00067 mol) (mixture of regioisomers) DBU (80 uL, 0.0005 mol) was added. The on was stirred overnight than water was added and the product was extracted with ethyl acetate. The combined extracts were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and trated. The crude residue was purified by flash column chromatography on silica gel eluting (50% EtOAc/Hexane) to give diethoxymethyl)—3—thienyl]- 3-[4-(7-[2-(trimethylsilyl)ethonymethyl-7H-pyrrolo [2,3—d]pyrimidinyl)-l zol-l —yl]propane- e (160 mg, 43%). 'H NMR (400 MHz, CDC13): 5 8.92 (s, 1H), 8.41 (s, 1H), 8.29 (b, 1H), 7.45(d, 1H), 7.4l(d, 1H), 7.15 (s, 1H), 7.05 (d, 1H), 6.82 (m, 1H), 5.74 (d, 2H), 3.74 (m, 2H), 3.71 (m, 8H), 3.59 (m, 1H), 1.32 (m, 4H), 0.95 (m, 2H), -0.08 (s, 9H); MS(ES):553 (M+1).

Step 5 ormylthienyl)[4-(7—[2—(trimethylsilyl)ethopgzjmethyl— 7H-pyrrolo[2,3-d]pyrimidin- 4-y1)-IH-pyrazolyljpr0panenitrile A solution of 3-[5-(diethoxymethyl)—3~thieny1][4-(7-[2—(trimethylsilyl)ethoxy]methyl-7H— pyrrolo[2,3-d]pyrimidin—4-y1)-lH-pyrazol-l-yl]propanenitrile (70 mg, 0.0001 mol) in TI-[F (1 mL, 0.01 mol) was treated with 1 M HCl in water (400 uL). The reaction was d at room temperature.

Water was added and the product was extracted with ethyl acetate. The combined extracts were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give 3—(5~fonnyl—3—thienyl)[4-(7-[2-(trimethylsilyl)ethoxy]methyl—7H-pyrrolo[2,3-d]pyrimidin—4— yl)—lH—pyrazol—1—y1]propanenitn'le as a lid residue (60 mg, 98%). IH NMR (400 MHz, CDClg): 5_ 9.96 (s, 1H), 8.89 (s, 1H), 8.44 (m, 2H), 7.46 (1H), 5.73 (s, 2H), 4.15 (m, 1H), 3.73—3.43 (m, 3H), 1.35 (m, 1H), 1.01 (m, 2H), 0.03 (s, 9H); MS(ES): 479 (M+1).

Step 6: 5-[(E)~(fiydroxyimino)methyl]—3-thienyl-3~[4~(7—[2—(trimethylsilyDethaxyjmethyl- 7H- pyrrolo[2, 3~d]pyrimidin-4—yD-1H-pyrazoL1-yUpropanenitrile A solution of 3—(5-formylthienyl)[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H—pyrrolo- [2,3-d]pyrimidin-4—yl)-lH-pyrazol—l—yl]propanenitrile (65 mg, 0.00014 mol) in methanol (2 mL, 0.05 mol) was treated with hydroxylamine hydrochloride (11 mg, 0.00016 mol) and potassium bicarbonate (23 mg, 0.00023 mol). The reaction was stirred at room temperature for 4 hours. Water was added and the product was ted with ethyl acetate. The combined extracts were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give 3[(E)- (hydroxyimino)methyl]—3—thienyl—3-[4-(7—[2{trimethylsily1)ethoxy]methyl~7H-pyrrolo[2,3—d]~ IO pyrimidin-4—yl)-lH—pyrazol-I-yl]propanenitn'le as a semisolid oil (60 mg, 89.5%). (The crude product contained both isomers of oxime and also both regioisomers of ene). MS (ES): 494 (M+l).

Step 7: 4-(2-Cyano-1—[4-(7-[2~(z‘rimethylsilyflethoxyjmethyl- 7H-pyrrolo[2, 3-d]pyrimidin—4—yl)~1H— l—I—yl]ethyl)thz'ophene—Z—carbon e To a mixture of 3[(E)-(hydroxyimino)methyl]thieny1-3—[4-(7-[2—(trimethylsilyl)ethoxy]- methyl-7H-pyrrolo[2,3-d]pyrimidin—4—yl)-lH-pyrazol-l;yl]propaneni‘tn'le (70 mg, 0.0001 mol) in ne (1 mL, 0.01 mol), methanesulfonyl chloride (100 pL, 0.001 mol) was added. The mixture was stirred at 60 °C for 2 hours. Water was added and the product was extracted with ethyl acetate.

The combined ts were washed with 0.1 N HCl, brine, dried over magnesium sulfate, filtered and concentrated to give yano[4-(7~[2-(trimethylsi1yl)ethoxy]methyl-7H—pyrrolo[2,3-d]— pyn'midinyl)-lH-pyrazol-l-yl]ethyl)thiophene—2—carbonitrile as a crude product (30 mg, 44%). MS (ES): 476 (M+1).

Step 8: 4~(2—Cyano~1-[4—(7H—pyrrolo[2,3-d]pyrimidin—4—yl)—IH—pyrazol—1-yl]ethyl)thi0phene-2— carbonitrz'le trifluoroacetate A mixture of 4-(2-cyano-l—[4-(7—[2-(trimethylsilyl)ethoxy]methyl~7H—pyrrolo[2,3—d]— pyrimidin—4-yl)—lH—pyrazol—l-yl]ethyl)thiophene—Z-carbonitrile (50 mg, 0.000] mol) in DCM (2 mL, 0.03 mol) and TFA (1 mL, 0.01 mol) was stirred for 1 hour: The starting material was consumed and the desired methyl hydroxy compound was formed. The mixture was concentrated in vacuo to remove TFA. The crude intermediate was dissolved in methanol (3 mL, 0.07 mol) and was d with ethylenediamine (1 mL, 0.01 mol). The mixture was stirred overnight and concentrated in vacuo. The products were purified by preparative I-IPLC eluting with ACN: water with 0.2% TFA to give two regioisomers, the title compound as an amorphous white solid (30 mg, 60 %).

'H NMR (500 MHz, DMSO): (3 8.95 (s, 1H), 8.76 (s, 1H), 8.48 (s, 1H), 8.06 (s, 1H), 8.04 (s, 1H), 7.70 (d, 1H), 7.05 (d, 1H), 6.25 (m, 1H), 3.80—3.60 (m, 2H); MS (ES): 346 (M+1).

Example 471 : S-(2-Cyano[4-(7H—pyrrolo[2,3-d]pyrimidin—4—yl)~1H-pyrazol—l-yl]ethyl)- thiophene-Z-carbonitrile trifluoroacetate Dl—N CN "It i \ N fl Isolated as the second regioisomer from e 470, the title compound was isolated as an amorphous white solid (4 mg, 8%). 1H NMR (500 MHz, DMSO): 8_ 9.0 (s, 1H0, 8.75 (s, 1H), 8.50 (s, 1H), 7.95 (s, 1H), 7.65 (s, 1H), 7.45 (s, 1H), 7.0 (d, 1H), 6.45 (m, 1H), 3.8 (dd, 2 H); MS (ES): 346 (MM).

Example 472 : 3-[3-(N10rpholin—4-ylcarbonyl)phenyI][4-(7H-pyrrolo[2,3-d]pyrimidinyl)- azol-l-yl]propanenitrile trifluoroacetate rf-N N o 0 L] NU \ / N TFA Step I: 3-(2—cyano[4—(7-[2-(trimethylsily0eth0xy]methyl—7H—pyrrolo[2,3-d]pyrimidin—4—yl)—1H- l-I—yUethyDbenzoic acid To a solution of methyl 3cyano-l-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3- d]pyrimidinyl)-lH-pyrazol-l—yl]ethylbenzoate (50 mg, 0.0001 mol) (prepared as in e 61) in methanol (2 mL, 0.05 mol), lithium hydroxide (1 mg, 0.0001 mol) in water (1 mL, 0.06 mol) was added slowly. Water was added and also some 1N HCI was added until the solution was slightly acidic. The aqueous layer was extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered and concentrated to give 3-(2-cyano[4-(7-[2-(trimethylsilyl)ethoxy]- methyl-7H—pyrrolo[2,3-d]pyrimidinyl)-1H-pyrazol-l-y1]ethyl)benzoic acid as a crude residue (35 mg, 72.0%). MS (ES): 489 (M+l).

Step 2: 3-[3-(Morpholine—I—ylcarb0nyl)phenyl]~3~[4~(7-{[2-(trimethylsilyDethoxy]methyl}- 7H- pyrrolo[2,3—d]pyrimidine~4—yl)-IH-pyrazole—I~yl]propanenim'[e To a solution of 3-(2-cyano-1~[4-(7-[2-(trimethylsilyl)ethoxy]methyl—7H—pyrrolo[2,3-d]- pyrimidin—4-yl)-1H-pyrazol—l hyl)benzoic acid (40 mg, 0.00008 mol) in DMF (1 mL, 0.01 mol), N,N,N’,N'-tetramethyl-O-(7-azabenzotriazol-l-yl)uroniurn hexafluorophosphate (36 mg, 0.000095 mol) and DIPEA (30 uL, 0.0002 mol) were added. The reaction was stirred for 10 minutes and then morpholine (10 mg, 0.00012 mol) was added and the resulting mixture was stirred for 3 hours. Water was added and the product was extracted with ethyl e. The combined c extracts were washed with 1N HCl, brine, dried over magnesium e, filtered and concentrated to give 3-[3- l 0 (morpholine-l —ylcarbonyl)phenyl]~3 -[4—(7- {[2—(trimethylsilyl)ethoxy]methyl } -7H-pyrrolo[2,3- d]pyrimidiney1)-1H-pyrazole-l-y1]propanenitrile as a crude (40 mg, 88%) product. MS (BS): 558 (M+1).

Step 3.' 3-[3-(Morpholiny1carbonyl)phenyU[4-(7H—pyrroIo[2, 3-d]pyrimidiny1)-1H-pyrazol—I — yljpropanenitrile trifluoroacetate Using a procedure analogous to that of Example 61 for the removal of the SEM protecting group, the title compound was isolated as an amorphous white solid (18 mg, 50 %). 1H NMR (400 MHz, DMSO): 8_ 9.05 (s, 1H), 8.75 (s, 1H), 8.44 (s, 1H), 7.85 (b, 1H), 7.665 (s, 1H), 7.55- 7.35 (m, 3H), 7.15 (s, 1H), 6.15 (m, 1H), 3.85 (m, 1H), 3.65-3.4 (m, 6H), 3.25 (m, 2H), 3.05 (m, 1H); MS(ES): 428 (M+1). e 482: 3-(5-Phenylpyridin-3—yl)[4-(7H—pyrrolo[2,3-d]pyrimidinyl)-lH-pyrazol-l- yl] propanenitrile trifluoroacetate N N TFA Step 1 .’ 3—(5-Phenylpyridin-3~yl)—3—[4-(7—[2-(trimethylsilyl)ethoxyjmethyl- 7H~pyrrolo[2,3-d]— pyrimidin—4~yl)—1H—pyrazol~I—yl]propanenitrile To a solution of 3-(5-bromopyridin—3—yl)-3—[4-(7—[2-(trimethylsi1yl)ethoxy]methyl—7H- pyrrolo[2,3—d]pyrimidin-4—yl)-lH—pyrazol-l -y1]propanenitrile (from Example 429) (60 mg, 0.0001 mol) in 1,4-dioxane (2 mL, 0.02 mol), phenylboronic acid (15 mg, 0.00012 mol) and sodium bicarbonate (30 mg, 0.0003 mol) in water (0.5 mL, 0.03 mol) were added. The resulting mixture was degassed using nitrogen. Tetrakis(triphenylphosphine)palladium(0) (10 mg, 1 mol) was added and nitrogen was bubbled through the reaction again. The reaction was heated at 80 °C in oil bath for lhour. Water was added and the product was extracted with ethyl acetate. The combined extracts were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give heny1pyridin—3-y1)[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]- dinyl)-1H-pyrazol-l -y1]propanenitrile (50 mg, 80%) as a crude product. MS (ES): 522 (M+1).

Step 2: 3-(5~Phenylpyridz‘nyl)-3—[4—(7H—pyrrolo[2,3—d]pyrimz'din—4—yI)—1H—pyrazol—I—yl]propane— nitrile trifluoroacetate Using a procedure analogous to that of Example 61 for the l of the SEM protecting group, the title compound was isolated as an amorphous white solid (20 mg, 40 %). IH NMR (400 MHz, DMSO): 5, 9.15 (s, 1H), 8.85 (s, 1H), 8.80 (s, 1H), 8.65 (s, 1H), 8.45 (s, 1H), 8.22 (5,1H), 7.85 (b, 1H), 7.67 (m, 2H), 7.45(m 2 H), 7.43 (m, 1H), 7.15 (s, 1H), 6.25 (m 1H), 3.95 (dd, 1H), 3.80 (dd, 1H), 3.0 (m, 1H); MS (ES): 392.1 (I\/I+1) Example 486: 3-(S-Ethynylpyridinyl)[4-(7H-pyrrolo[2,3-d]pyrimidinyl)-1H-pyrazol—l- yl] propaneuitrile trifluoroacetate \ / / \\ N \ \ "\N/ m TFA Step I .' 3-[4—(7—[2-(TrimethylsilyDethoxyjmethyl- 7H-pyrrolo[2, 3-d]pyrimidin-4—yD-1H—pyrazol—I -yl_]- 3[(trimethylsilyDethynyljpyridin—3—ylpr0panenitrile .

To a solution of 3-(5—bromopyridinyl)[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H- pyrrolo[2,3-d]pyrimidin-4—y1)~lH—pyrazol—l-yl]propanenitrile (from Example 429) (0.080 g, 0.00015 mol) in TEA (0.300 mL, 0.00215 mol) was degassed with en, and then copper(I) iodide (0.005 g, 0.00003 mol), thylsilyl)acetylene, and bis(triphenylphosphine)palladium(II)chloride were added. The reaction mixture was sealed in a tube and stirred at room temperature overnight. The resulting black solution was partitioned between water (10 mL) and ethyl ether. The organic layer was washed with saturated sodium chloride, dried over magnesium sulfate and trated in vacuo to give 3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl—7H-pyrrolo[2,3-d]pyrimidin-4—yl)- 1 H—pyrazol-l ~y1] —[(tn'methylsilyl)ethynyl]pyridinylpropanenitrile as a yellow oil (60 mg,72.6), LCMS (M+1>*:542).

Step 2: 3-(5-Ethyny1pyridinyl)—3—[4-(7H-pyrrolo[2, 3—d]pyrim[dinyD-JH-pyrazol-I —yl]pr0pane- nitrile trifluoroacetate 3—[4-(7~[2-(Trimethylsilyl)ethoxy]methyl—7H-pyrrolo[2,3-d]pyrimidin-4—yl)-1 H-pyrazol-l - y1]-3—5-[(trimethylsilyl)ethynyl]pyridinylpropanenitrile (0.050 g, 0.000092 mol) was dissolved in DCM (5.0 mL, 0.078 mol) and TFA (2.0 mL, 0.026 mol). The reaction mixture was d at room temperature, for 90 minutes and was concentrated in vacuo. The dry residue dissolved in methanol cooled in an ice bath and a solution of potassium hydroxide (0.482 g, 0.00859 mol) in methanol (10 mL, 0.2 mol) was added. The reaction solution was stirred for 30 min was concentrated and the crude product was purified by preparative HPLC eluting with a water: ACN gradient with 0.2% TFA, to give the title compound as a white amorphous solid (15 mg, 35.85%). LCMS :340, 'H NMR (400 MHz, DMSd-da): 8, 12.1(bs, 1H), 9.02(s, 1H), 8.80(s, 1H), , 2H), , 1H), 8.00(s, 1H), 7.80(d, 1H), , 1H), 6.20(m, 1H), , 1H), , 1H), 3.70(m, 1H).

Example 488: 3-[5-(Phenylthio)pyridin-3—yI]—3-[4-(7H—pyrrolo[2,3—d]pyrimidin—4-yl)—1H— pyrazol-l-yl]propanenitrile trifluoroacetate Q’s CN N\ \ l/NN Step 1 .' 3-[5—(Phenylthiojpyridin—3—yl]—3-[4—(7—[2—(trimethylsilyl)ethoxy]methyl— 7H—pyrrolo[2,3—d]— pyrimidin-4—yl)-1H-pyrazol—1 opanenitrile To the 3-(5-bromopyridin-3~y1)[4-(7—[2-(tn'methylsilyl)ethoxy]methyl-7H—pyrrolo[2,3-d]- pyrimidinyl)-1H—pyrazol—1 -yl]propanenitrile (0.130 g, 0.000248 mol) from Example 429 Step 2, in dry 1,4—dioxane (1.60 mL, 0.0205 mol) was added DIPEA (0.085 mL, 0.00049 mol). The solution was degassed with nitrogen, followed by addition of (9,9—dimethy1—9H—xanthene—4,5- diyl)bis(diphenylphosphine) (0.007 g, 0.0000] mol), bis(dibenzylideneacetone)palladium(0) (0.0036 g, 0.0000062 mol), and benzenethiol (0.025 mL, 0.00025 mol). Again the solution was purged with nitrogen. The reaction mixture in a sealed tube was heated to reflux for 3h. The-reaction mixture was diluted with ethyl acetate, washed with water (2X), brine (1X), dried over magnesium sulfate, filtered, and the solvent was evaporated in vacuo. The crude product was ated with hexane-ethyl acetate WO 70514 9:1 to yield 3-[5-(phenylthio)pyridin-3—yl]—3-[4—(7-[2-(trimethylsilyl)ethoxy]methyl-7H—pyrrolo[2,3- d]pyrimidin-4—yl)-lH—pyrazol—l—yl]propanenitrile (110 mg, 80%). LC/MS (M+H)+: m/z = 554.2.

Step 2: 3-[5—(Phenylthio)pyridin—3-yl]—3-[4—(7H-pyrrolo[2,3-d]pyrimidin—4-yl)—1H—pyrazol-J-yl]- propanenizrile trifluoroacetate The 3-[5-(phenylthio)pyridiny1]—3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3— d]pyrimidinyl)—lH—pyrazol-l-yl]propanenitrile (0.110 g, 0.000199 mol) was dissolved in DCM (5.0 for 1 mL, 0.078 mol) and TFA (2.0 mL, 0.026 mol), and the mixture was stirred at room temperature hour. The solvent was removed in vacuo, and the resulting residue was dissolved in ol (5.0 mL, 0.12 mol), and ethylenediamine (0.1 mL, 0.002 mol) was added. This on mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo, and the crude product was purified by LCMS ( pH=2) to yield the title compound as an amorphous solid (62 mg, 58.07%).

IH NMR (400 MHz, DMSO): 3, 12.80 (s), 9.10 (s) 8.87(d), 8.60 (s), 8.50 (s), 8.43 (s), 7.82 (s), 7.78 (m), 7.39 (m), 7.25 (m), 7.18 (d), 6.20 (m), 3.84 (m), 3.70 (m). LC/MS (M+H)+: m/z = 424.15 Example 491: 3—(S—Morpholin—4—ylpyridin—3—yl)—3-[4—(7H-pyrrolo[2,3—d]pyrimidin-4—yl)-1H— pyrazol—l~yl]propanenitrile Step I : 4-(5-Brom0pyrz'din—3—yl)morpholine To a on of ibromopyridine (1000 mg, 0.004 mol) in 1,4-dioxane (8 mL, 0.1 mol), morpholine (400 mg, 0.004 mol) and sodium tert—butoxide (400 mg, 0.004 mol) were added. The reaction was bubbled with nitrogen. Tetrakis(triphenylphosphine)palladium(0) (200 mg, 0.0002 mol) was heated at 80 °C was added and nitrogen was d h for couple of minutes. The mixture overnight. The reaction was allowed to cool to it and was then partitioned between water and ethyl acetate. The organic layer was washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give a crude residue. The crude product was purified by FCC on silica gel eluting with 1:1, EtOAC:Hexane gave to give 4-(5-bromopyn‘din—3-yl)morpholine as a viscous oil (400 mg, 40 %). 'H NMR (400 MHz, CD013): 8. 8.2 (s, 1H), 8.1 (5, 11-1), 7.2 (s, 1H), 3.8 (m, 4H), 3.2 (m, 4H).

Step 2: 5-Morpholin—4—ylnicotinaldehyde A solution of 4-(5-bromopyridinyl)morpholine (100 mg, 0.0004 mol) in ether (2 mL, 0.02 mol) cooled at -78 °C was treated with 2.5 M n-butyllithium in hexane (0.2 mL) and was stirred for 1h. To this mixture was added DMF (0.5 mL, 0.006 mol) dropwise. The reaction was quenched with water and extracted with ethyl e. The combined organic layers were washed with saturated sodium chloride, dried over magnesium sulfate, d and concentrated to give 5-morpholin-4— ylnicotinaldehyde (70 mg, 90%) as a crude product. 1H NMR (400 MHz, CDC13): 5 10.1 (s, 1H), 8.0 (s, 2H), 7.6 (s, 1H), 3.8 (m, 4H), 3.2 (m, 4H).

Step 3: (2E)-3~(5—Morpholin—4-ylpyridinyl)acrylonitrile To a solution of diethyl cyanomethylphosphonate (70 mg, 0.0004 mol) in THF (2 mL, 0.02 mol) cooled at 0 °C was added 1.0 M potassium tert-butoxide in THF (0.50 mL) dropwise. The cold bath was removed and the reaction was warmed to room temperature over 30 minutes. The reaction was cooled to 0 °C and a solution of 5~morpholinylnicotinaldehyde (70 mg, 0.0004 mol) in THF (2 mL, 0.02 mol) was added dropwise. The reaction was stirred at room temperature for 4 h, quenched with water and extracted with ethyl acetate. The combined c layers were washed with ted sodium de, dried over magnesium sulfate, filtered and concentrated to give (2E)(5- morpholiny1pyridin—3—yl)acrylonitri1e (75 mg, 100%) as a mixture of isomers; LC/MS: 216 (M+1).

Step 4: 3—(5—Morpholin-4—ylpyridin-3cyU-3~[4-(7—[2-(trimethylsilyl)ethoxy]methyl—7H—pyrrolo[2,3—d]- pyrimidin—4—yl)-1H-pyrazol—1 -yl]pr0panenitrile To a solution of 4—(1H—pyrazol—4—yl)~7-[2-(trimethylsi1y1)ethoxy]methyl—7H-pyrrolo[2,3-d]- pyrimidine (120 mg, 0.00038 mol) in ACN (10 mL, 0.2 mol) and (2E)-3—(5-morpholinylpyridin yl)acrylonitrile (70 mg, 0.0003 mol) ( mixture of isomers), DBU (50 uL, 0.0003 mol) was added and the resulting mixture was stirred ght. The mixture was partitioned between water and ethyl acetate. The combined organic layers were washed with ted sodium chloride, dried over magnesium sulfate, filtered and concentrated to give 3-(5—morpholinylpyridin—3-yl)-3—[4—(7-[2~ (trimethylsilyl)ethoxy]methyl-7H—pyrrolo[2,3-d]pyrimidin—4-yl)-1H-pyrazol-l-yl]propanenitrile (200 mg, 100%) as a crude product; L/MS = 531 (M+1).

Step 5: orph01in~4-ylpyridin-3—yl)-3—[4—(7H—pyrrolo[2, 3-d]pyrimz'din—4-yl)-IH-pyrazol-I-yl]- propanen itrile Using a procedure ous to Example 61 for the removal of the SEM protecting the title compound was ed as an amorphous white solid (18 mg, 50 %). IH NMR (400 MHz, DMSO): 5 8.8 (s, 1H), 8.6 (s, 1H), 8.4 (s, 1H), 8.2 (s, 1H), 8.0 (s, 1H), 7.6 (d, 1H), 7.4 (m, 1H), 6.9 (d, 1H), 6 (m, 1H), 3.8 (dd, 1H), 3.7(m, 4H), 3.6 (dd, 1H), 3.1 (m, 4 H); LC/MS: 401(M+1).

Example 496: 3-[S-(Pheuylsulfinyl)pyridin—3—yl][4-(7H~pyrrolo[2,3-d]pyrimidinyl)-1H- pyrazol—l-yl]propanenitrile, e 497: 3-[5-(Phenylsulfonyl)pyridin—3-yl][4—(7H-pyrrolo{2,3-d]pyrimidinyl)-1H- l-l-yl]propanenitrile N/ W, N—N \ N \ \ "C \ N .> "r: H N N To the solution of 3~[5-(phenylthio)pyn'din—3-yl]-3~[4-(7H-pyrrolo[2,3—d]pyrimidinyl)~1H— pyrazol~l—yl]propanenitrile trifluoroacetate (0.050 g, 0.000093 mol) from Example 488, Step 2, in THF (1.0 mL, 0.012 mol) was added MCPBA (0.022 g, 0.00013 mo!) (0.031g of 77% in water), in a water ice bath. The reaction mixture was stirred for 1h at room temperature. The crude products were purified by LCMS (pH=lO). Two peaks were collected : # 1 ~— to yield phenylsulfinyl)pyridin—3-yl]-3—[4-(7H-pyrrolo[2,3-d]pyrimidinyl)-lH- pyrazol-l-yl]propanenitrile (8 mg, 19.57%). 1H NMR (400 MHz, DMSO): 5_ 12.1 (s), 8.89 (d), 8.80 (d), 8.70 (s), 8.62 (s), 8.40 (s), 8.19 (s), 7.70 (m), 7.58 (s), 7.42 (m), 6.90 (s), 6.20 (m), 3.82 (m), 3.65 (m). LC/MS (M+H)+: m/z = 440.0 # 2 — to yield 3-[5-(phenylsulfonyl)pyridin—3—yl}-3~[4-(7H—pyrrolo[2,3—d]pyrimidinyl)-1H- pyrazol-l-y1]propanenitrile (21 mg, 50%). ‘H NMR (400 MHz, DMSO): 8_ 12.1 (s), 9.10 (s), 8.86 (m), 8.6l(s), 8.40 (m), 7.98 (m), 7.62 (m), 7.58 (m), 6.90 (s), 6.20 (m), 3-82 (In), 3.65 (m). LC/MS (M+H)+; m/z = 456.0 Example 498: 3-[4-(7H—Pyrrolo[2,3-d]pyrimidinyl)-lH-pyrazol—l-yllpentan-l-ol C/‘OH N\ \ N NH Step I: 3-[4-(7—[2-(TrimethylsilyDethoxy]methyl~7H—pyrrolo[2,3-d]pyrimidin-4—yl)—IH— pyrazol—I—yl]pentanal To a solution of 4—(1H-pyrazolyl)[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]- pyrimidine (100 mg, 0.0003 mol) in ACN (2 mL, 0.04 mol) and DBU (50 uL, 0.0003 mol), the (2B)- pent-Z—enal (4.0El mg, 0.00048 mol) in lml ACN was added drop wise. The reaction was stirred for 1 h, and then water was added and the resulting mixture extracted with ethyl acetate. The combined organic layers were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give the crude as the hydrated product form. LC/MS (M+H)+: m/z = 400.

Step 2: 3-[4-(7«[2—(Trimethylsilyl)ethoxyjmethyl- 7H-pyrrolo[2,3-d]pyrimidin-4—yl)-IH-pyrazol—J — yUpentan—I—01 A mixture of [3-[4-(7—[2-(trimethylsilyl)ethoxy]methyl—7H-pyrrolo[2,3-d]pyrimidin-4—yl)—lH— pyrazol—l-yl]pentanal (50 mg, 0.0001 mol) in methanol (2 mL, 0.05 mol) was treated with sodium tetrahydroborate (8 mg, 0.0002 mol). The mixture was stirred at room temperature for l h, and then water was added and the product was ted with ethyl e. The combined organic layers were washed with ted sodium chloride, dried over magnesium sulfate, filtered and concentrated to give the desired product as an oil. LC/MS (M+H)+: m/z = 402.

Step 3: Using a procedure analogous to Example 61 for the removal of the SEM protecting group the title nd was ed as an amorphous white solid (6 mg, 20 %). 1H NMR (400 MHz, DMSO): ,5 8.65 (d, 1H), 8.60 (d, 1H), 7.55 (s, 1H), 6.95 (s, 1H), 4.50 (b, 1H), 4.4 (m, 11-1), 3.4 (m, 1H), 3.2 (m, 1H), 2.1 (m, 1H), 1.8-2.0 (m, 3H), 0.7(t, 3H); LC/MS (M+H)+: m/z = 272.

Example 499: Methyl 3-[4-(7H-pyrrolo[2,3-d]pyrimidin—4—yl)—1H—pyrazol-l-yllpentyl carbonate be?" Iii \ \ N NH Step 1: Methyl 3—[4—(7—[2-(trimethylsilyDethoxyjmethyl— 7H—pyrrolo[2, 3-djpyrimidinyD—1H- pyrazol—I—yl]pentyl carbonate To a solution of [3—[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H—pyrrolo[2,3-d]pyrimidinyl)- lH-pyrazol—l-yl]pentan-l-ol (50 mg, 0.000] mol) from e 498 Step 2 in pyridine (1 mL, 0.01 mol), methyl chloroformate (30 uL, 0.0003 mol) was added. The reaction was stirred for 3h, water was added and the product was extracted with ethyl acetate. The combined organic layers were washed 1N HCl, brine, dried over magnesium sulfate, filtered and concentrated to give methyl 3-[4- (7-[2—(trimethylsi1y1)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidiny1)-1 H—pyrazolyl]pentyl carbonate as a semisolid residue (30 mg, 50%). LC/MS (M+H)+: m/z = 460.

Step 2: Using a procedure analogous‘to Example 61 for the removal of the SEM protecting the title compound was ed as an amorphous white solid (8 mg, 20 %). 1H NMR (400 MHz, DMSO): 5 12.0 (b, 1H), 8.65 (d, 1H), 8.35 (s, 1H), 7.65 (b, 1H), 7.600 , (s, 1H), 7.0 (s, 1H), 4.4 (m, 1H), 4.0 (m, 1H), 3.8 (m, 1H), 3.6 (s, 3H), 2.1 (m, 1H), 2.2 (m, 1H), 1.95 (m, 2H), 0.75 (t, 3H); LC/MS (M+H)+:m/z= 330. e 500(21): (1E)[4-(7H-Pyrrolol2,3-d]pyrimidinyl)-1H—pyrazol-1—yl]pentanal oxime Step 1: (1E)[4-(7-[2-(TrimethylsilyDethostyjmethyl-7H-pyrrolo[2, 3-djpyrimidinyD-IH-pyrazol— 1 -yl]pentanal oxime To a on of 7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin—4—yl)— 1H—pyrazolyl]pentanal (60 mg, 0.0002 mol) from Example 498, Step 2 in methanol (2 mL, 0.05 mol) was added hydroxylamine hydrochloride (16 mg, 0.00022 mol) and potassium bicarbonate (22 mg, 0.00022 mol). The on was stirred at room temperature for 2h, water was added and the product was extracted with ethyl acetate. The ed extracts were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give (1E)[4-(7-[2—(trimethyl- ethoxy}methyl-7H-pyrrolo[2,3—d]pyrimidin—4-yl)-lH-pyrazol—l —yl]pentanal oxime as a semisolid residue (50 mg, 80%). LC/MS (M+H)+: m/z = 415.

Step 2: Using a procedure analogous to Example 61 for the removal of the SEM protecting the title compound was isolated as an amorphous white solid. 1H NMR (400 MHz, DMSO): 5 12.0 (b, 1H), 8.6 (m, 2H), 8.2 (m, 1H), 7.5 (d, 1H), 7.1 and 6.5 (t, 1H), 4.6 (m, 1H), 4.4 (m, 1H), 2.6-2.8 (m, 2H), 1.8 (m, 2H), 0.65 (t, 3H); LC/MS (M+H)+: m/z = 285.

Example 501(a): (lE)[4-(7H-Pyrrolo[2,3-d]pyrimidin—4-yl)-lH—pyrazol—l-yl]pentanal 0- methyloxime, Example 502(11): (1Z)[4-(7H-Pyrrolo[2,3-d]pyrimidin—4-yl)—lH—pyrazol—l-yl]pentanal 0- methyloxime Step 1: (1E)—3-[4—(7—[2-(TrimethylsilyDethoxyjmethyl—7H—pyrrolo[2,3-d]pyrimidinyl)—JH-pyrazol- 1-yl]pentanal O-methyloxime and (1Z)[4—(7-[2-(Trimethylsilyl)ethquy]methyl—7H-pyrr010[2,3—d]pyrimidiny1)-1H—pyrazol—1- yljpentanal O-methyloxime To a solution of 7-[2-(trimethylsilyl)ethoxy]methyl—7H-pyrrolo[2,3-d]pyrimidinyl)- azolyl]pentanal (70 mg, 0.0002 mol) in methanol (2 mL, 0.05 mol) was added methoxylamine hydrochloride (19 mg, 0.00022 mol) and potassium bicarbonate (22 mg, 0.00022 mol). The reaction was stirred at room temperature for 2h, water was added and the product was extracted with ethyl acetate.‘ The combined extracts were washed with saturated sodium chloride, dried over magnesium sulfate, was d and was concentrated to give 7-[2-(trimethylsilyl)- ethoxy]methy1—7H-pyrrolo[2,3-d]pyrimidinyl)-1H—pyrazol—l-yl]pentanal ‘O-methyloxime as a mixture of s (70 mg, 90%) crude product. LC/MS (M+H)+: m/z = 429.

Step 2: Using a procedure analogous to Example 61 for the removal of the SEM protecting the title compound was ed as an amorphous white solid (4 mg, 25 %). Isomer 1, 1H NMR (400 MHz, DMSO): 6. 8.7 (s, 2H), 8.3 (s, 1H), 7.6 (s, 1H), 7.3 (t, 1H), 7.0 (s, 1H), 4.6(m, 1H), 3.3 (s, 3H), 2.8 (m, 2H), 1.9 (m, 2H), 0.8 (t, 3H); LC/S (M+H)+: m/z = 299.Isomer 2 (3 mg, 22%), lH NMR (400 MHz, DMSO): ,8 8.7 (s, 2H), 8.3 (s, 1H), 7.6 (s, 1H), 7.0 (s, 1H), 6.7 (t, 1H), 4.5(m, 1H), 3.3 (s, 3H), 2.8-3.0 (m, 2H), 1.9 (m, 2H), 0.8 (t, 3H); LC/MS (M+H)+: m/z = 299.

Example 503: 4- [1-(4,4-Dibromo-l—ethylbut—3—en-l—yl)—1H—pyrazol—4-yl]-7H—pyrrolo [2,3-d]— pyrimidine trifluoroacetate Step I .’ 4—[1—(4, 4—Dibromo—1—ethylbut—3—en—I—yl)—1H—pyrazol-4—yl]—7—[2-(trimethylsilyl)ethoxyjmethyl— 7H-pyrrolo[2, 3-d]pyrimidine To a solution of 3-[4-(7-[2—(trimethylsi1y1)ethoxy]methyl-7H—pyrrolo[2,3-d]pyn'midin—4—yl)— lH-pyrazol—l—yl]pentanal (300 mg, 0.0008 mol) in DCM (4 mL, 0.06 mol) cooled at 0 °C, triphenylphosphine (800 mg, 0.003 mol) and carbon tetrabromide (500 mg, 0.002 mol) were added.

The reaction was stirred at 0 °C for 10 min, water was added and extracted with ethyl acetate. The ed c ts were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by prep LC-MS (ACN, water, NH4OH) to give 4-[1-(4,4—dibromo-l -ethylbut—3-en—l—yl)-1I-I-pyrazoly1][2-(trimethylsilyl)- ethoxy]methyl-7H-pyrrolo[2,3—d]pyrimidine as an amorphous solid (50 mg, 10%). 1H NMR (400 MHz, CDC13): 5 8.9 (s, 2H), 8.4 (s, 1H), 8.3 _ (s, 1H), 7.4 (m, 1H), 7.3 (s, 1H), 6.9 (m, 1H), 6.4 (m, 1H), 5.7 (s, 2H), 4.2 (m, 1H), 3.6 (m, 2H), 2.8 (m, 2H), 2.1 (m, 1H), 2.0 (m, 1H), 1.0 (m, 5H), LC/MS : m/z = 556 Step 2: Using a procedure analogous to Example 61 for the removal of the SEM protecting the title compound was isolated as an amorphous white solid (8 mg, 40 %). 1H NMR (400 MHz, DMSO): 8, 8.8 (s, 2H), 8.4 (s, 1H), 7.7 (b, 1H), 7.2 (b, 1H), 6.5 (t, 1H), 4.4 (m, 1H), 2.6 (m, 2H), 1.8 (m, 21-1), 0.8 (t, 3H); LC/MS CM+H)+: m/z =: 426.

Example 506: 4-[1-(l—Ethylbut—3-yn—1-yl)-1H-pyrazolyl]~7H-pyrrolo[2,3-d]pyrimidine trifluoroacetate Step I .' 4—[1—(1-Ethylbut—3-yn-I-yl)-1H-pyrazoI—4—yl]- 7—[2-(trimethylsilyDethoxy]methyl-7H- pyrrolo[2,3—d]pyrimidine A solution of 4—[1-(4,4-dibromoethy1but—3—enyl)-lH-pyrazolyl]—7-[2-(trimethylsilyl)— ethoxy]methyl~7H—pyrrolo[2,3-d]pyrimidine (20 mg, 0.00004 mol) (from Example 503 Step 1) in THF (1 mL, 0.01 mol) at -78 °C was treated with 2.5 M n-butyllithium in hexane (0.032 mL). The mixture was stirred at -78 °C for lb and then at room temperature for 1h. The reaction was quenched with water (1 mL, 0.06 mol) and 1N HCl. The reaction was partitioned n water and ethyl acetate. The organic extract was washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give 4-[1—(1-ethylbut—3—yn—1—y1)—1H—pyrazoly1]-7—[2—(tri— methylsilyl)ethoxy]methyl-7H-pyrrolo[2,3—d]pyrimidine as a semisolid (12 mg, 80%). LC/MS (M+H)+: m/z = 396.

Step 2: Using a procedure analogous to Example 61 for the l of the SEM protecting the title nd was isolated as an ous white solid (4 mg, 30 %). 1H NMR (400 MHz, DMSO): ,5 12.2 (b, 1H), 8.8 (s, 2H), 8.4 (s, 1H), 7.6 (s, 1H), 7.1 (s, 1H), 4.4 (m, 1H), 2.8 (m, 3H), 1.9 (m, 2H), 0.8 (t, 3H); LC/MS(M+H)+: m/z = 266.

Example 516: (R)[3-(Ethylsulfonyl)phenyl]-3—[4-(7H—pyrrolo[2,3-d]pyrimidinyl)-1H- pyrazol-l-yl]propanenitrile, 2O (S)—3-[3-(Ethylsulfonyl)phenyl][4-(7H-pyrrolo[2,3-d]pyrimidinyl)-1H—pyrazol-l-yl]— propanenitrile Step 1: I-Bromo—3-(ethylthi0)benzene Iodoethane (0.46 mL, 0.0058 mol) was added to a suspension of 3-bromothiophenol (0.50 mL, 0.0048 mol), ACN (7.11 mL, 0.136 mol) and ium carbonate (2.0 g, 0.014 mol). The reaction was stirred for 2 h at rt, was diluted with ethyl acetate and filtered to remove the solids. The on was concentrated in vacuo to give 1~bromo(ethylthio)benzene as a colorless oil 1.0 gm, 100% Step 2: I-Bromo—3—(ethylsulfonylflaenzene WO 70514 The MCPBA (2.37 g, 10.6 mmol) Was added to a on of 1-bromo(ethylthio)benzene (1.00 g, 4.80 mmol) in DCM (10 ml, 156 mmol) cooled to 0 °C. The reaction was stirred for 1 h and then was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried with magnesium sulfate, filtered, and concentrated in vacuo. The resulting crude residue was d by flash column tography with a hexane: ethyl acetate gradient to give l—bromo- 3-(ethylsulfonyl)benzene as a colorless oil 1.1 gm 92%, lH NMR (300 MHz, CDC13): 68.09(m, 1H), 7.85(d,1H), 7.78(d, 1H) ,1H), 3.14(q, 2H), l.25(t, 3H).

Step 3: (ZE & Z)—3-[3-(Ethylsulfonybphenyljacrylonitrile 1-Bromo(ethylsulfonyl)benzene (1.3 g, 0.0052 mol) was dissolved in the DMF (15.0 mL, 0.194 mol) and 2~propenenitrile (0.68 mL, 0.010 mol), TEA (1.4 mL, 0.010 mol) and triphenylphosphine (0.23 g, 0.00089 mol) were added. The resulting solution was ed with nitrogen, and palladium acetate (0.07 g, 0.0003 mol) was added. Again the reaction was degassed with nitrogen and then heated to 110 0C in a sealed tube for 8 hrs. The reaction was complete by HPLC, and was then allowed to cool to rt and then partitioned between ethyl acetate and water. The c layer was washed with brine, dried over ium sulfate and concentrated. The t was purified by FCC on silica gel eluting with a hexane; ethyl acetate gradient to give (2E&Z)—3—[3— (ethylsulfonyl)phenyl]acrylonitrile as an amber oil (1.1 gm, 92%) LC/MS (Mi-HY: m/z = 222.

Step 4: 3-[3—(Ethylsulfonprhenylj—3~[4-(7—[2-(trimethylsilyl)ethoxyjmethyl-7H-pyrrolo[2,3- djpyrimidin~4—yl)—1H—pyrazol—I—yUpropanenitrile The (2E&Z)—3-[3~(ethylsulfonyl)phenyl]acrylonitrile (1.0 g, 0.0045 mol) was combined with 4~(1H—pyrazolyl)-7—[2-(trimethylsilyl)ethoxy]methyl-7H—pyrrolo[2,3-d]pyrimidine (1.3 g, 0.0041 mol) and DBU (0.61 mL, 0.0041 mol) in ACN (10.0 mL, 0.191 mol) under nitrogen at rt. The reaction was stirred at rt for 24 h. This was partitioned between ethyl acetate and water, and 0.]N HCl was added to adjust the pH to 7. The combined organic extracts were washed with brine, dried over magnesium sulfate and concentrated to give a crude oil. The product was purified by FCC on silica gel eluting with a hexane: ethyl acetate gradient to give 3—[3~(ethylsulfonyl)phenyl][4-(7-[2- (trimethylsilyl)ethoxy]methyl-7H—pyrrolo[2,3-d]pyrimidin~4-yl)-lH—pyrazol-l-yl]propanenitrile as an oil (1.5 gm, 68%). LC/MS (M+H)+: m/z = 537. The oil was a racimate, which was separated by chiral column chromatography (Chiracel OD-H, eluting with ethanol: ol: hexane 30:30:40, Rt 13.2 and 17.1 minutes) to give the two enantiomers, each as a glass (0.51 gm) LC/MS (M+H)+: m/z = 537, 1H NMR (300 MHz, CDC13): 8 8.89(s, 1H), 8.45(s, 1H), 8.35(s,1H), 8.09(s, 1h), 8.05(d, 1H), 7.75(d, 1H), 7.71(t, 1H), , 1H), 6.83(d, 1H), 5.85(t, 1H), 5.75(s, 2H), 3.78-3.42(m, 4H), 3.18(m, 2H), 1.35(t, 3H), 0.97(t, 2H), 0.05(s, 9H).

WO 70514 Step 5: Using a procedure analogous to Example 61 for the l of the SEM protecting group the title compounds were prepared to give isomer #1 as an amorphous white solid (300 mg, 80 %). 1H NMR (400 MHz, DMSO): 5 9.1 (s, 1H), 8.8 (s, 1H), 8.5 (s, 1H), 8.0 (s, 1H), 7.6-7.9 (m, 4H), 7.1 (s, 1H), 6.3 (m, 1H), 3.9 (m, 1H), 3.7 (m, 1H) 3.2 (q, 2H), 1.0 (t, 3H); MS(ES) : m/z = 407.

Using a procedure analogous to Example 61 for the removal of the SEM protecting group the title compounds were prepared to give isomer #2 as an amorphous white solid (300 mg, 80 %). lH NMP (400 MHz, DMSO): 8, 9.1 (s, 1H), 8.8 (s, 1H), 8.5 (s, 1H), 8.0 (s, 1H), 7.6-7.9 (m, 4H), 7.1 (s, 1H), 6.3 (m, 1H), 3.9 (m, 1H), 3.7 (m, 1H) 3.2 (q, 2H), 1.0 (t, 3H); MS(ES) (M+H)+: m/z = 407.

Example 526: 1-Ethylbutenyl)-lH—pyrazol—4-yl]-7H-pyrrolo[2,3-d]pyrimidine N \ \ N NH Step 1: 4-[1-(1-Ethy1but—3-en-1~yl)-1H—pyrazol—4-yl]—7—[2-(trimethylsz‘lyl)ethonymethyl-7H-pyrrolo- [2, 3-djpyrimidine To an ice cooled on of methyl triphenylphosphonium bromide (100 mg, 0.0004 mol) in THF (2 mL, 002 mol) was added 0.5 M potassium bis(trimethylsilyl)amide in toluene (0.8 mL). The mixture was stirred for 1h at 0 °C ice bath, and was then cooled to -78 °C and treated with 3-[4—(7-[2- (trimethylsilyl)ethoxy]methyl—7H-pyrrolo[2,3-d]pyrimidinyl)-1H-pyrazol-l-yl]pentanal (80 mg, 0.0002 mol) (from Example 498). The reaction was stirred at -78 °C and gradually was warmed to room temperature overnight. The reaction was partitioned between water and ethyl acetate. The organic layer was washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give 4—[1-(1-ethylbuten-1—yl)-1H-pyrazolyl][2-(trimethylsilyl)ethoxy]methyl- 7H-pyrrolo[2,3-d]pyrimidine 150 mg as a crude product. LC/NIS = 398 (M+1).

Step 2: 4—[1-(1—Ethylbut—3—enyD-1H—pyrazol—4—yU—7H—pyrrolo[2, 3—d]pyrimidine Using a procedure analogous to Example 61 for the removal of the SEM protecting group the title compound was isolated as an ous white solid (25 mg, 1%). 1H NMR (400 MHz, DMSO): 8, 8.6 (s, 2H), 8.2 (s, 1H), 7.4 (s, 1H), 6.9 (s, 1H), 5.8 (m, 1H), 5.0 (dd, 2H), 4.2 (m, 1H), 2.4—2.6 (m, 2H), 1.7—1.9 (m, 2H), 0.6 (t, 3H); LC/MS: 268 CM+1). 2006/047369 Example 500: (3R)- and (3S)-4,4,4-Trifluoro~3—[3-(7H—pyrrolo[2,3-d]pyrimidinyl)—1H—pyrrol— utanenitrile F F F F FA34 F . . . , /CN N N / // N\b.) N\ N 'k/SN H H Step I. 4-Chloro— thoxymethy0- rolo[2,3—d]pyrimidine A mixture of 4-chloropyrrolo[2,3—d]pyrirnidine (2.00 g, 0.0130 mol) and ethyl orthoformate (25 mL, 0.15 mol) was heated to reflux for 2 hours. The solvent was evaporated, and the residue was purified by flash column chromatography (eluting with ethyl acetate/hexanes) to yield the desired product (1.13 g, 34%).

‘H NMR (400 MHz, CDC13'): 8 8.63 (s, 1H), 7.58 (d, 1H), 6.71 (s, 1H), 6.65 (d, 1H), 3.77-3.67 (m, 2H), 3.58—3.49 (m, 2H), 1.23 (t, 3H), 1.23 (t, 3H).

Step 2. 7-(DiethoxymethyD(IH-pyrrol—3-yl)— 7H—pyrrolo[2, 3-djpyrimidine To a degassed solution of 4-chloro(diethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine (1.13 g, 0.00442 mol) and 1-(triisopropylsi1yl)-3—boronic acid (1.00 g, 0.00374 mol) and sodium carbonate (0.396 g, 0.00374 mol) in 1,2—dimethoxyethane (15 mL) and water (3 mL) was added tetrakis(triphenylphosphine)palladium(0) (0.22 g, 0.00019 mol). This mixture was d at ambient ature for 2 hours, and then was heated to reflux for 4 hours. The mixture was then cooled, concentrated, and purified by flash column chromatography (eluting with ethyl acetate/hexanes) to afford a residue as an oil. ACN was added to the residue, and the product which precipitated was filtered off and washed with a small quantity ofACN (165 mg, 13%). 1H NMR (400 MHz, Ds—dmso): 8_ 11.44 (br s, 1H), 8.66 (s, 1H), 7.80—7.78 (m, 1H), 7.58 (d, 1H), 7.03 (d, 1H), 6.94 (dd, 1H), 6.90 (dd, 1H), 6.75 (s, 1H), 3.74-3.65 (m, 2H), 3.59-3.50 (m, 2H), 1.15 (t, 6H); MS(ES): M+H = 287.

Step 3.

To a on of 7-(diethoxymethyl)(1H-pyrrolyl)-7H-pyrrolo[2,3-d]pyrimidine (0.125 0.480 mmol) in ACN g, 0.436 mmol) and 4,4,4-trifluorobut—Z-enenitn'le (0.0476 rnL, (1 mL) was added DBU (0.0653 mL, 0.436 mmol). TFA (0.5 mL) was added and the mixture was stirred for 1 hour. The TFA and solvent was removed in vacuo. The residue was purified by preparative- HPLC/MS (C-18 eluting with a gradient of Hzo/ACN containing 0.15% NH40H) to afford the product (102 mg, 76%). Where desired, the enantiomers were separated in substantially pure form by chiral I-IPLC (AD-H, 20% EtOH/Hexane). 1H NMR (300 MHz, DG-dmso): 8 12.05 (br s, 1H), 8.65 (s, 1H), 8.04 (s, 1H), 7.56 (dd, 1H), 7.21 (t, 1H), 7.02 (dd, 1H), 6.93 (dd, 1H), 5.89—5.74 (m, 1H), 3.95 (dd, 1H), 3.66 (dd, 1H); MS(ES): M+H = 306.

The analog in Table 12 was prepared in racemic form according to the same procedure, using a ent conjugate acceptor and with the exception that in the conjugate addition in Step 3, the reaction was carried out at 40 0C for 3 days.

Table 12 Method of preparation and chiral separation 3-[3-(7H—pyrrolo[2,3-d]pyrimidinyl)- . . enantiomers lH-pyrrol—l —yl]butanen1tnle not separated The following nds in Table 13 were prepared as indicated in the column labeled "Method of Prep." and the details of n exemplary synthetic procedures are provided ing Table 13.

N-(3-{2~cyano-l -[4-(7H- pyrrolo[2,3-d]pyrirnidinyl)- lH-pyrazol-l -yl]ethyl}phenyl)- 3-(trifluoromethyl)benzamide N-(3-{[4-(7H-pyn‘olo[2,3- d]pyrimidinyl)—l H-pyrazol— 1 -yI]methy1}phenyl) (trifluoromethyl)benzamide 3-[3-(methylsulfonyl)phenyl]-3 - Ex516 393 [4-(7H—pyrrolo[2,3 -d]pyrimidin- cnch $02CH3 4-yl)-1H-pyrazol-l -yl]- propanenitrile methylsulfonyl)phenyl]-3 - BX 516 393 [4-(7H—py1rolo[2,3-d]pyrimidin— CHZCN soch3 4-yl)-1H—pyrazol-1 -yl]- propanenitrile [4-(7H-pyrrolo[2,3-d]- BX 469 43 1 pyrimidinyl)-lH—pyrazol-l - yl]methyl}phenyl)benzene- sulfonamide H 3- { [4-(7H—pyrrolo[2,3-d]- Ex 472 a" N CFa 463 pyrimidin—4—yl)~lH-pyrazol-l-’ 605 H yl]methy1}-N-[3-(trifluoro- methyl)phenyl]benzamide 3-{2-cyano—1-[4-(7H- Ex 649 606 422 pyrrolo[2,3-d]pyrimidinyl)- CH CN2 ee#l lH-pyrazol-l'-y1]ethyl}—N,N- dimethylbcnzenesulfonamide 3- {2—cyano-l -[4-(7H— BX 649 606 422 o[2,3-d]pyrimidinyl)— CH CN2 ee#2 lH—pyrazol—l-yl]ethyl}—N,N— dimethylbenzenesulfonamide N—benzyl—3 — {2—cyano—l —[4-(7H— BX 649 484 pyrrolo[2,3—d]pyrimidinyl)- 607 CHZCN lH-pyrazol—l -yl]ethyl} benzene- sulfonamide trifluoroacetate N—benzyl-3 - {2-cyano-l -[4-(7H- BX 472 H\/© 448 o[2,3-d]pyrimidinyl)- 608 CHZCN Vgin/N lH—pyrazol-l -yl]ethyl}- ° benzamide 3-{2—cyano[4-(7H- 04;; 434 pyrrolo[2,3-d]pyrimidin—4-yl)— CHZCN © 1H-pyrazol-l -yl]ethyl} -N- phenylbenzamide trifluoroacetate yano[4-(7H— "H. 2:1: 0J‘ 502 pyrrolo[2,3-d]pyrimidin—4—yl)— CH2CN o=< lH—pyrazol-l hyl} -N-[3 - (trifluoromethyl)phenyl]— benzamide trifluoroacetate N—(3—cyanophenyl) {[4—(7H- C2 420 pyrrolo[2,3-d]pyrimidin-4—yl)— lH—pyrazol—l —yl] - methyl }benzamide N-benzyl—S-{[4-(7H—pyrrolo— [2,3-d]pyrimidin—4-yl)- 1H- pyrazol—l -y1]methyl }benzamide N—l -naphthy1—3 - { [4-(7H- pyrrolo[2,3—d]pyrimidin—4~yl)— azol-l -y1]methyl} — benzamide Nnaphthy1—3- {[4-(7H- pyrrolo[2,3—d]pyrimidin—4—yl)— lH—pyrazol-l -yl]methyl} - N—(3~{[4—(7H-pyrrolo[2,3—d]- pyrimidin—4—yl)-1H-pyrazoI-l - yl]methyl}'phenyl)—2— naphthamide tn'fluoroacetate N-(3~ {[4-(7H~pyrrolo[2,3~d]~ pyrimidin-4—yl)-1H-pyrazol-1 - yl]methyl}phenyl)—1 - naphthamide trifluoroacetate 2-pheny1—N-(3— {[4-(7H- pyrrolo[2,3-d]pyrimidinyl)- azol— 1 —y1]methyl} — phenyl)acetamide trifluoroacetate 3-chloro-N-(3-{[4-(7H-pyrrolo- ]pyrimidin-4—yl)-1H- pyrazol-l -yl]methyl}pheny1)- ide trifluoroacetate N—(3—{2-cyano-l -[4-(7H- pyrrolo[2,3-d]pyrimidin—4-yl)~ 1 H-pyrazol-l -y1]ethyl } pheny1)- 2-naphthamide trifluoroacetate N-(3—{2-cyano-l -[4—(7H- pyrrolo[2,3—d]pyrimidin—4—yl)— lH-pyrazol-l hyl}phenyl)- l—naphthamide tn'fluoroacetate N—(3- {2-cyano-l -[4-(7H- pyn'olo[2,3-d]pyrimidinyl)- lH-pyrazol-l -y1]-ethyl}pheny1)- 2—phenylacetamide trifluoroacetate 3-cyano-N-(3-{2-cyano[4- (7H-pyrrolo[2,3—d]pyrimidin—4- yl)-1H-pyrazol-l ~yl]- ethyl}phenyl)benzamide tn'fluoroacetate N—(3- {Z-cyano-l —[4-(7H— pyrrolo[2,3-d]pyrimidin—4-y1)- lH—pyrazol-l —yl]ethyl} - phenyl)benzamide trifluoroacetate N-(3-{2-cyano-1—{4-(7H— pyrrolo[2,3 -d]pyrimidinyl)— lH-pyrazol-l —yl]ethyl }phenyl)- 4—(tr1'fluoromethyl)benzamide trifluoroacetate N-(3-{2-cyano[4—(7H- pyrrolo[2,3-d]pyrimidin-4~yl)- 1 H—pyrazol-l ~y1]ethyl}phenyl)- N'-phenylurea trifluoroacetate 3- {2—cyano-1 —[4-(7I-I-pyrrolo- [2,3-d]pyrimidinyl)-1H- pyrazol—l -y1] ethyl} -N-[4- (tfifluoromethyl)phenyl]- benzamide trifluoroacetate 3— {2-cyano-1—[4—(7H—pyrrolo— [2,3 -d]pyrimidin-4—yl) - lH- pyrazolyl]ethyl} -N-(4- methylphenyl)benzamide roacetate N—(4—cyanophenyl)-3~ no- 1-[4—(7H-pyrrolo[2,3—d] - pyrimidin—4—yl)-1H—pyrazol-l — yl]ethyl } benzamide tn'fluoroacetate 3- {2-cyano-1 -[4—(7H—pyrrolo- [2,3-d]pyrimidin—4-yl) -1H— pyrazol—l -yl]ethyl } -N-2— naphthylbenzamide trifluoro- acetate 3- no-l -[4-(7H-pyrrolo- [2,3-d]pyrimidinyl) -1H— l-l —yl]ethyl}—N-l - ylbenzamide tri- fluoroacetate 3- {2-cyano[4-(‘7H—pyrrolo- [2,3-d]pyrimidin~4-yl) -l H- pyrazol-l -yl]ethyl} -N,N— ylbenzamide tri- fluoroacetate 3-{2—cyano[4-(7H-pyrrolo- [2,3—d]pyrimidin—4—y1) —1H- CHZCN pyrazol-l hyl} -N-pyridin- nzamide trifluoroacetate 3-{2-cyano[4-(7H-pyrrolo— Z-O 448 [2,3-d]pyrimidinyl) —1H— CHZCN 04"" pyrazol-l -y1] ethyl} -N—methyl- .C; N—phenylbenzamide trifluoroacetate 3-{2-cyano-1—[4—(7H—pyrrolo- 04; 440 [2,3—d]pyrimidin-4—yl) —1H— CHZCN O pyrazol-l ~yl]ethyl} -N- cyclohexylbenzamide tri- fluoroacetate 3-{2-cyano[4-(7H-pyrrolo- 526 [2,3—d]pyrimidin—4—yl) -1H- CHZCN 9<3 pyrazol-l -yl]ethyl} -N-(4- phenoxyphenyl)benzamide trifluoroacetate N—(3—cyanophenyl)—3-{2-cyano— "ai: l-[4-(7H—pyrrolo[2,3 -d]- CHZCN pyrimidin—4-yl)—lH—pyrazol—l — yl]ethyl }benzamide trifluoroacetate 0:3"21 N—biphenylyl—3- {2-cyano-l - Ex 472 10 [4—(7H-pyrrolo[2,3-d CHZCN ]pyrimidinyl)—1H—pyrazol-l - yl]ethy1}benzamide trifluoroacetate hlorophenyl)-3 - {2-cyano- BX 472 ‘ N 468 1-[4-(7H—pyrrolo[2, 3-d]- CHzCN YO pyrimidinyl)-1 H-pyrazol-l - 0 yl]ethyl }benzamide trifluoroacetate 3—{2—cyano[4-(7H-py1rolo- Bx 472 99 CH3 462 [2,3-d]pyrimidin—4-yl) ~1H- N CH;CN Ya pyrazol-l -yl]ethyl} -N-(3,4- 0 dimethylphenyl)benzamide trifluoroacetate 3-{2-cyano[4-(7H-pyrrolo- N OCH3 464 [2,3—d]pyrimidinyl) —1H— CHzCN l-l -y1]ethyl}-N—(3- o methoxyphcnyl)benzamide trifluoroacetate 3-{2-cyano—1-[4-(7H-pyrrolo- ]pyrimidinyl) —l H— CHZCN pyrazol-l -yl]ethyl}-N—(4— methoxyphenyl)benzamide trifluoroacetate 3-{2-cyano-l -[4—(7H—pyrrolo- [2,3-d]pyrimidinyl) ~1H- pyrazol-l -yl]ethyl}-N-isoxazol- 3—ylbenzamide trifluoroacetate yano—1~[4-(7H—pyrrolo- [2,3-d]pyrimidin—4~yl)—1 H- pyrazol—l —y1]ethyl} ~N—methy1— N-phenylbenzenesulfonamide 3- {2-cyano-1 —[4-(7H—pyrrolo- [2, 3 —d]pyrimidin-4—yl)—1H- pyrazol—l -yl]ethyl} —N— propylbenzenesulfonamide 3- {Z—cyano—I -[4-(7H—pyrrolo- [2,3-d]pyrimidin—4-yl)—l H- pyrazol-l hyl} -N— phenylbenzenesulfonamide 3-{2-cyano[4-(7H-pyn'olo- [2,3-d]pyrimidin—4—yl) -1H- pyrazol—l hyl} -N naphthylbenzene- sulfonamide 3- {2-cyano-l -[4—(7H—pyrrolo- ]pyrimidin-4~yl) -1H— pyrazol~1 —yl]ethyl} —N— cyclopropylbenzene— sulfonamide piperidin—1 ~ylsulfonyl)— phenyl][4—(7H~pyrrolo[2,3~ d]pyrimidin—4—yl)-1H-pyrazol- l —yl]propanenitrile 3-[3-(morpholin—4-ylsulfonyl)- phenyl][4—(7H~pyrrolo[2,3- d]pyrimidin—4-yl)-1H-pyrazoL 1 —yl]propanenitrile 3-{2—cyano~l -[4-(7H-py1rolo- [2,3-d]pyrimidin-4~yl)-1H- pyrazol-l -yl]ethyl} -N-(4— methylphenyl)benzene- sulfonamide trifluoroacetate 3 - {2-cyano-1 -[4-(7H-pyrrolo- [2,3-d]pyrimidin—4-yl)-1H- pyrazol-l -yl]ethyl } -N-(3 ,4— dimethylphenyl)benzene— sulfonamjde roacetate 3-{2-cyano—1-[4—(7H—pyrrolo— [2,3-d]pyrimidin~4-yl) -1H- pyrazol-l -yl]ethyl} -N—(3- yphenyl)benzene~ sulfonamide trifluoroacetate 3- {2-cyano-l -[4-(7H-pyrrolo- ]pyrimidin—4—yl) ~1H— pyrazol-l hyl} -N-(4- methoxyphenyl)benzene— sulfonamide trifluoroacetate 3- {2-cyano[4-(7H-pyn'olo— [2,3—d]pyrimidin—4-yl) -1H— l-l —yl] ethyl} -N-(3,5— dimethoxyphenyl)benzamide trifluoroacetate 3—{2-cyano[4-(7H-pyrrolo- ]pyrimidinyl) -1H— l-l -yl]ethyl} -N-[4- (dimethylamino)phenyl]- benzamide tn'fluoroacetate 3—[3—(benzy1su1fonyl)phenyl] [4-(7H-pyrrolo[2,3-d]pyrimidin- 4-y1)-1 H—pyrazol—l -yl] — propanenitrile 3-[3-(benzylthio)phenyl] [4- (7H—pyrrolo[2,3-d]pyrimidin yl)-1H-pyrazol-1 -yl] - propanenitrile 4-{[(3-{2-cyano[4-(7H- pyrrolo[2,3—d]pyrimidin—4—yl)— lH-pyrazol-l -yl]ethyl}phenyl)- sulfonyl]methyl}benzonitrile yano—1-[4-(7H-pyrrolo- [2,3—d]pyrimidinyl)-1H- pyrazol-l —y1]ethyl} —N—methyl— benzenesulfonamide 3-{2-cyano[4—(7H-pyrrolo- [2,3-d]pyrimidin-4—yl) -1H- pyrazol- l -y1]ethyl} -N-l - naphthylbenzenesulfonamide N—biphenyl-4—yl {2-cyano-1 - [4-(7H—pyrrolo[2,3-d]pyrimidin- 4-yl)-1H~pyrazol-l -yl]ethyl} - benzenesulfonamide 3-{2—cyano—1—[4-(7H—pyrrolo- [2,3-d]pyrimidinyl) ~1H— pyrazol-l —yl]ethyl}-N—[4— (trifluoromethoxy)phenyl]~ benzamide trifluoroacetatc yano[4-(7H-pyn'olo- [2,3-d]pyrimidin—4-yl)—1H— pyrazoI-l -yl]ethyl} -N-(2- methoxyphenyl)benzamide tn'fluoroacetate 3-[3-(benzyloxy)phenyl][4- rrolo[2,3-d]pyrimidin y1)- lH—pyrazol-l -yl] - propanenitrile 3—{2—cyano-l -[4-(7H-pyrrolo— [2,3—d]pyrimidin—4-yl)-1 H- pyrazol-l -yl]ethyl} -N- cyclohexylbenzenesulfonamide trifluoroacetate 3 -[3 -(3 ,4-dihydroisoquinolin- 2(1 H)—ylsulfony1)phenyl]-3—[4— (7H-pyrrolo[2,3-d]pyrimidin yl)-1H—p yrazol-l -y1]propane- nitn'le trifluoroacetate 3-{2-cyano[4-(7H-pyrrolo— [2,3-d]pyrimidin—4—y1)-1 H— pyrazol-l -y1]ethyl} -N—(2- methoxyethyl)benzene- sulfonamide tn'fluoroacetate 3-{2-cyano[4-(7H—pyrrolo- [2,3-d]pyrimidin—4—y1)—1H— pyrazol-l —yl]ethyl} -N,N- lbenzenesulfonamide 3-{3-[(4-ethylpiperazin—1-yl)- sulfonyl]phenyl} [4-(7H— pyrrolo[2,3-d]-pyrimidinyl)— lH-pyrazol—l -yl]propanenitrile N—l ,3~benzodioxol—5—yl—3 — {2— l -[4-(7H-pyrrolo[2,3-d] - pyrimidin—4—yl)— l H—pyrazol-l - yl]ethyl }benzenesulfonamide 3— {3-[(3—methoxybenzy1)- sulfonyl]phenyl } -3—[4-(7H- pyrrolo[2,3-d]pyrimidin—4-yl)- azol—l —yl]-propanenitrile 3- {3-[(4—methoxybenzyl)— sulfonyl]phenyl } —3—[4—(7H— pyrrolo[2,3-d]pyrimidin—4-yl)- lH—pyrazol-l -yl]-propanenitrile 3— {3 -dimethylmorpholin— 4-yl)sulfonyl]phcnyl }[4— (7H-pyrrolo[2,3-d1pyrimidin y1)-1 H—pyra zol-l -yl] - propanenitrile 3 —{3-[(4-oxopiperidin—1 —y1)- sulfonyl]pheny1} [4— (7H- o[2,3-d] —pyrimidin—4-y1)- 1 H-pyrazol-l -yl]propanenitrile trifluoroacetate 3-[3 -(isopropylsulfonyl)p henyl][4-(7H—pyrrolo[2,3-d]— pyrimidin—4—yl)-lH-pyrazol-l - yl]propanenitrile trifluoroacetate 3- {3 -[(cyclohexylmethyl)— sulfonyl]phenyl} (7H- o[2,3-d]pyrimidin—4-yl)- IH-pyrazol—l -y1]-propanenitrile trifluoroacetate 3-[3 -(octahydroisoquinolin- 2(1 H)—ylsulfony1)phenyl][4— (7H—pyrrolo[2,3—d]pyrimidin—4- yl)-lH—pyr azol-l -y1]propane- nitrile roacetate 3-{2—cyano[4-(7H-pyrrolo- [2,3-d]pyrimidin-4—yl) -l H— pyrazolyl]ethyl } -N-(2- phenylethyl)benzene sulfonamide roacetate 3-[3 -(_pyrrolidin—l -ylsu1fonyl)— phenyl]~3—[4-(7H-pyrrolo[2,3-d]- pyrimidin—4—yl)-1H—pyrazol-1 - yl]propanenitrile N-benzyl-B— {2-cyano—1 H- pyrrolo[2,3-d]pyrimi din—4—yl)- lH—pyrazol-l —yl]ethyl} -N- methylbenzenesulfonamide 3 -{ [(3- {2-cyano-1 -[4-(7H- pyrrolo[2,3—d]pyrimidin— 4—y1)- lH-pyrazol-l ~yl]ethyl} - pheny1)sulfonyl]methyl} - benzonitrile 3 - {3 - [(2—naphthylmethyl)- sulfonyl]phenyl } [4-(7H- pyrrolo[2,3-d]pyrimidiny1)- lH—pyrazol-l —y1]propanenitn'le 204_ 3-{3-[( l -phenylethyl)sulfonyl]- phenyl} -3—[4-(7H—pyrrolo[2,3-d]- pyrimidin—4—yl)-lH—pyrazol—l - yl]propanenitrile 3- {2-cyano-l —[4-(7H-pyrrolo- [2,3-d]pyrimidin—4—yl)- lH— pyrazol-l ~y1]ethyl} —N—(2- morpholin~4~ylethyl)— benzenesulfonamide N-(2-aminoethy1) {[(3 - {2— cyano-l -[4-(7H—pyrrolo [2,3-d]- pyrimidinyl)-1 zol-l - yl]ethyl }phc nyl)sulfonyl] - amino} ide 3 -{2-cyano—1—[4-(7H-pyrrolo- [2,3-d]pyrimidin-4—yl) -1H~ pyrazol-l -yl]ethyl} ~N-[(1 S)-l - phenylethyl]benzenesulfonamide 3 - no— l —[4—(7H—pyrrolo— [2,3-d]pyn'midin-4—yl) ~1H- pyrazol-l —y1]ethyl} -N-phenyl— ide trifluoroacetatc 3 -{2—cyano[4-(7H-pyrrolo- [2,3-d]pyrimidin-4—yl) —1H— pyrazol-l -yl]ethyl } nyl - ‘benzamide trifluoroacetate 3- {2-cyano-l —[4-(7H-pyrrolo- [2,3-d]pyrimidinyl) -1H- pyrazol-l -y1]ethyl}-N- hydrofuran—Z-yl- methyl)benzenesulfonamide 3 - {3 —[(cyclopropy1methyl) sulfony1]phenyl} —3-[4—(7 H— pyrrolo[2,3-d]py:rimidinyl)- lH-pyrazol-l -yl]propanenitrile tri fluoroacetate 3- {3-[(4-methylpiperazin—1 -yl)- sulfonyIJphenyl} —3 — [4—(7H— pyrrolo[2,3-d]pyrimidin—4-yl)- 1 H—pyrazol—l -yl]propanenitrile l-[(3- {2-cyano—l H—pyrrolo— [2,3-d]pyrimidin—4 -yl)—1H- pyrazol-l -yl]ethy1} - phenyl)sulfonyl]~N,N—diethyl— . i - eridine—S-carboxamidc 3-{3-{(1-oxidothiomorpholin—4— y1)sulfonyl]pheny1}-3—[4-(7H- CHzCN pyrrolo[2,3-d]pyrimidin—4-yl)- az 01-1 opanenitrile piperazin— 1 —ylsulfonyl)— Ex 472 phenyl][4-(7H-pyrrolo[2,3—d] - CHZCN pyrimidinyl)- l H-pyrazol-l - yl]propanenitrile 480 3-[4-(7H—pyrrolo[2,3—d]— BX 472 pyrimidinyl)-1 H-pyrazol -1 - CH2CN yl]-3—[3-(thiomorpholin—4—yl- sulfonyl)phenyl]propanenitrilc 478 3- —hydroxypiperidin—l -yl)- BX 472 sulfonyl]phenyl} -3 —[4-(7H- CH2CN pyrrolo[2,3-d]pyrimidinyl)- lH-pyrazol- 1-yl]propanenitrile tri fluoroacetate 435 3-[3-(isobutylsulfonyl)phcny1]~3- BX 516 -pyrrolo[2 ,3-d]pyn'midin- CHZCN 4—yl)—1H—pyrazol-1 -yl]propane- nitrile roacetate 477 3-[4-(7H—py1rolo[2,3-d]- Ex516 pyrimidin—4—yl)— 1 H—pyrazol-l - yl] {3 -[(tetrahydro-2H-pyran- 697 CH2CN 4—ylmethyl)sulfonyl] - phenyl } propanenitrile trifluoroacetate 437 3-{3-[(2-methoxyethyl)sulfonyl]- Ex516 is": phenyl}[4-(7H-p yrrolo[2,3— 698 CHZCN "SW \O d]pyrimidin—4-yl)-lH—pyrazol-l — O O yl]propanenitrile trifluoroacetate 459 3-{3-[(3 -fury1methyl)sulfonyl]- Ex516 phenyl} -3—[4—(7H-py nolo[2,3- CHZCN d]pyrimidin—4-yl)-1H-pyrazol—1- yl]propanenitrile trifluoroacetate 512 3- {3 -[(1,1-dioxidothiomorpholin- Ex 649 4—y1)sulfonyl]phenyl}-3—[4-(7H- CH2CN pyrrolo[2,3-d]pyrimidinyl)— lH-p yrazol-l ~y1]propanenitrile 3- {3—[(4-acetylpiperazin— 1 -y1)- sulfonyl]phenyl} [4—(7H— pyrrolo[2,3—d]pyrimidin—4-yl)- CH2CN lH-pyrazol-l -yl]propanenitrile WO 70514 3 — {3-[(pyridin-4—ylmethyl)— sulfony11phenyl}-3—[4-(7H— pyrrolo[2,3-d]pyrimidin~4-yl)— azol-l —y1]pr0panenitrile 314 4-[1-(1 —phenylbut-3~yn—1 511%}H- pyrazol-4—yl]—7H— pyrrolo[2,3-d]- 703 CHgC ECH H pyrimidine trifluoroacetate 463 4-(1-{1-[3—(morpholin—4—yl- yl)phenyl]but—3—yn—1 -yl } — 704 CH2C £I-I azol—4—y1)—7H-pyrrolo[2,3- d]pyrimidine 339 3-{ 1 ~[4—(7H—pyrmlo[2,3—d]— pyrimidin—4—yl)-1H—pyrazol—l — 705 CH2C ECH CN yl]butyny1}benzonitrile trifluoroacetate 342 3-{ l —[4—(7H-pyrrolo[2,3-d]— pyrimidin-4—yl)- lH-pyrazol-l - 706 CH2C £14 CH=O yl]but—3—yny1}benzaldehyde trifluoroacetate 373 methyl 3-(3—cyanophenyl)[4— . (7H-pyrrolo[2,3-d]pyn'midin y1)-1 H-pyrazol—l opanoate trifluoroacetatc N,N-dimethyl{ 1 -[4-(7H- pyrrolo[2,3-d]pyrimidin- 4-yl)- lH—pyrazol-l -yl]butyn-1 -y1}- CH2C26H benzenesulfonamide trifluoroacetate 3- {2-cyano-1 -[4-(7H-pyrro -d]pyrimidiny1) ~1H- pyrazol-l -y1]ethyl} -N-[4- CH2CN (dimethylamino)phen y1]- benzenesulfonamide 3- {3-mcthoxy—l -[4-(7H-pyrrolo- [2,3—d]pyrimidiny l)-l H— pyrazol-l -y1]propyl} -N,N- dimethylbenzenesulfonamide trifluoroace’cate N-phenyl-3 - { 1 —[4—(7H-pyrrolo- [2,3-d]pyrimidinyl )-1H- pyrazol—l -yl]but—3 -yn-1 —yl} - benzamide trifluoroacctate 4-[ l -(3-methoxy-1 —phenyl— CH2CH2- propy1)—1H—pyrazolyl]~7H- OCH3 pyrrolo[2,3-d]pyrimidine trifluoroacctatc N-[4-(dimethy1amino)pheny1] { l —[4-(7H-pyrrolo[2 ,3—d]— 713 CH2C SCH pyrimidinyl)-1H~pyrazol yl]but-3 -yn-1 nzamide trifluoroacetate 3 - {3—hydroxy-1 -[4-(7H—pyrrolo- [2,3-d]pyrimidinyl)- 1H— 714 pyrazol- 1 opyl } -N,N— dimethylbenzenesulfonamidc trifluoroacetate ' 341 3— {1 -[4—(7H—pyrrolo[2,3~d]- CH;- pyrimidinyl)-1H-pyrazol-l - 71 5 CN CH=CH2 yl]but—3-en—1 —yl}benzonitrile trifluoroacetate 4- { 1 -[ l ~(3-bromophenyl)but-3 — en-l -yl]-1H—pyrazol- 4—yl} —7H-— pyrrolo[2,3—d]pyrimidine trifluoroacetate 3-{4,4-difluoro[4-(7H— . pyrrolo[2,3-d]pyrimidin- 4-y1)- 717 CH2CH=CF2 lH-pyrazol-l -y1]buten-1 -y1} - ‘benzonitrile 4—(1—{4,4-difluoro-l-[3— olin—4-ylsulfonyl)- 718 CF2 phenyl]but—3-en-1 ~yl} -1H- Iy1)~7H-pyrrolo[2,3-d]- pyrimidine trifluoroacetate 4-(1 — {1 —[3 -(ethylsulfonyl)— phenyl]-4,4—difluorobuten—l - 7 1 9 CF2 yl} - l H—pyrazol—4-yl)-7H— pyrrolo[-2,3—d]pyrimidine trifluoroacetate 4—(1 - {1 -[3-(benzyloxy)phenyl]~ 4,4—difluorobut—3-e n—l -y1}-1H- 720 CHZCH=CF2 pyrazol—4-y])-7H—pyrrolo[2,3—d]- pyrimidine trifluoroacetate 320 4-[1 —(2-methoxy—1 -phenylethy1)- CH20CH3 H 1H—pyrazolyl]-7H-pyrrolo~ [2,3-d]pyrimidine 4-(1-{4,4-difluoro[3-(methyl- sulfonyl)phenyl]but—3 -en-1 -yl} - 1H—pyrazol-4—yl)-7H-pyrrolo- [2,3-d]pyrimidine trifluoroacetate 3-{[4—(7H—pyrrolo[2,3-d]- pyrimidin—4-yl)-lH-pyrazol-l - y1]methyl} benzonitrile 343 3- {1 -[4-(7H-pyrmlo[2,3-d]- pyrimidin-4—yl)-l H—pyrazol—l — 724 CH2CH2CH3 CN yl]butyl}benzonitrile 4-(1-{1—[3-(ethylsulfonyl)- phenyl]—4,4-difluorobutyl} -l H- pyrazol—4-yl)-7H—pyrrolo[2,3-d]- pyrimidine trifluoroacetate 4—[1-(4,4—difluoro—1—{3-[(2— methoxyethyl)sulfonyl]phenyl} - but-3—en— 1 -y1)—1H-pyrazolyl]— CHch=CF2 7H-pyrrolo[2,3-d]pyrimidine trifluoroacetate Example 649: 3—[3-(Morpholin—4-ylsulfonyl)pheuyl][4-(7H-pyrrolo[2,3-d]pyrimidinyl)—l H- pyrazol-l—yl]propanenitrile q /0 N \ \ Step I: 4-[(3-Bromophenstulfonyljmorpholine line (0.19 mL, 0.0022 mol) in 1.0 ml of THF was added dropwise to a solution of 3- bromobenzenesulfonyl chloride (0.3 mL, 0.002 mol) and TEA (0.30 mL, 0.0022 mol) in dry 4.0 mL ofTHF cooled in an ice bath. The on mixture was stirred overnight at room temperature and was then partitioned n 0.05N HCl and ethyl e. The organic layer was washed with water (2X), and brine (IX), and was then dried over anhydrous magnesium sulfate, filtered and then was concentrated in vacuo to give 4-[(3-bromophenyl)sulfonyl]morpholine as a white crystalline t (470 mg, 78%). LCMS (M+H)+: m/z = 306, 308.

Step 2: (2E&Z)—3—[3-(Morph01in—4—ylsulfonyl)phenyl]acrylonitrile The 4-[(3-brornophenyl)sulfonyl]morpholine (0.250 g, 16 mol) was dissolved in dry DMF (2.5 mL, 0.032 mol) and the mixture was degassed using a stream of nitrogen. To this mixture was added TEA (0.23 mL, 0.0016 mol), 2-propenenitrile (0.11 mL, 0.0016 mol), palladium acetate (0.011 g, 0.000049 mol), and triphenylphosphine (0.0364 g, 0.000139 mol) and again the mixture was ed with nitrogen. The reaction e in a sealed tube was heated at 110 °C for 16 hours. The reaction mixture, after cooling to room temperature, was partitioned between 0.05N HCl and ethyl acetate. The organic layer was washed with water (2X), and brine (1X), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo, to give (2E&Z)—3-[3-(morpholinyl- sulfonyl)phenyl]acrylonitrile as an oil (0.240gm, 85%) which was a mixture of cis and trans isomers.

LCMS (M+H)+: m/z = 279.

Step 3: 3-[3-(Morph01inylsulf0nyl)phenyl][4-(7-[2-(trimethylsilyl)ethoxyjmethyl- 7H—pyrrolo- [2, 3-d]pyrimidin—4—yl)-IH-pyrazol—I—y1]propanenitrile To a mixture of 4-(1H-pyrazol—4—yl)-7—[2—(trimethylsilyl)ethoxy]methyl-7H—pyrrolo[2,3-d]- pyrimidine (0.100 g, 0.000317 mol) and (2E&Z)—3-[3-(morpholinylsu1fonyl)phenyl]acrylonitrile (0.097 g, 0.00035 mol) in dry ACN (2.0 mL, 0.038 mol) was added DBU (0.095 mL, 0.00063 mol), and the resulting mixture was stirred at room temperature overnight. The on mixture was then diluted with water and extracted with ethyl acetate. The combined organic phase was washed with water (2X), and brine (1X), dried over magnesium sulfate, filtered and then concentrated in vacuo to give the crude product. The crude product was purified by silica gel flash column chromatography using ethyl acetate-hexanes (6:4) as an eluent to give morpholin~4~ylsulfonyl)phenyl]—3-[4-(7— [2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidinyl)-1H—pyrazol-l —yl]propanenitm'le as a s oil (62 mg, 32.94%). LCMS (IvI+H)+: m/z = 594 Step 4: Using a ure analogous to Example 61 for the removal of the SEM protecting the title compound was ed as an amorphous white solid (30 mg, 63.84%. LCMS (M+H)+: m/z = 464. 1H NMR (400 MHz, DMSO—d6): 6 8.88 (s), 8.62 (s), 8.1(s), 7.78(m), 7.70(m), 7.58(m), 6.95(m), 6.20(m), 3.84(m), 3.70(m),3.45(m), 2.78(m).

Example 679: [4—(7H-Pyrrolo[2,3-d]pyrimidin—4-yl)—1H—pyrazol—1-yl]cyclohexyl— acetonitrile 2006/047369 IL / N 0 Step 1: 4-(Hydroxymethylkyclohexanol .

Ethyl 4-oxocyclohexanecarboxylate (2.0 g, 0.012 mol) was dissolved in ether (20.0 mL) and was then cooled at 0 °C Into the mixture was added 1 M lithium tetrahydroaluminate in ether (20 mL) and the resulting mixture was stirred at 0 °C for 2 hours. The reaction was quenched with water (2 mL) and 1 N NaOH (2 mL) and ether was added (100 mL). The itated solids were filtered off and the residue was used in the next reaction. lH NMR(CDC13):5 4.02 and 3.75 (m, 1H), 3.45-3.61 (m, 2H), 2.02 (m, 2H), 1.84 (m, 1H), 1.52—1.80 (m, 2H), 1.44 (m, 1H), 1,32 (m, 2H), 1.03 (m, 1H).

Step 2.‘ 4-[(Trityloxy)methyljcyclohexanol. 4-(Hdroxymethyl)cyclohexanol (2.0 g, 0.015 mol) was dissolved in pyridine (15.0 mL) and the mixture was cooled to 0 °C. To the reaction was added triphenylmethyl chloride (4.7 g, 0.017 mol) and the resulting mixture was stirred at 0 °C for 2 hours and at 25 °C for 16 hours. The reaction was then concentrated using a rotary evaporator, and the concentrate was extracted with ethyl acetate.

The organic ts were washed with water, saturated NaCl, dried (MgSO4) and then concentrated in vacuo. The reaction was chromatographed on silica gel using 30% EtOAc/hexanes to give the cis isomer (0.74 g) 1H NMR(CDC13):8 7.52 (m, 6H), 7.27 (m, 9H), 3.98 (m, 1H), 2.93 (m, 2H), .68 (m, 9H); and the trans isomer (2.72 g) 1H NMR(CDC13):5 7.44 (m, 6H), 7.20-7.31 (m, 9H), 3.54 (m, 1H), 2.88 (m, 2H), 1. 98 (m, 2H), 1.88 (m, 2H), 1.60 (m, 1H), .37 (m, 4H).

Step 3: trans—4—[(Trigiloxy)methyl]cyclohwgll methanesulfonate. trans—4-[(Trityloxy)methyl]cyclohexanol (2.72 g, 0.00730 mol) was dissolved in chloroform (30.0 mL) and the mixture was cooled at 0 °C To this mixture was added TEA (1.4 mL, 0.010 mol) and methanesulfonyl chloride (0.68 mL, 0.0088 mol) and the resulting e was stirred at 0 °C for 2 hours The reaction was then extracted with ethyl acetate and the c extracts were washed with water, saturated NaCl, dried (MgSO4) and the concentrated in vacuo. 1H NMR (CDC13):8 7.43 (m, 6H), 7.20-7.31 (m, 9H), 4.57 (m, 1H), 3.00 (m, 3H), 2.90 (m, 2H), 2.16 (m, 2H1, 1.93 (m, 2H), 1.09—1.60 (m, SH).

Step 4.’ 7-[2~(Trimethylsilyl)ethoxyjmethyl-4—(I-cis[(trityloxy)methyl_]cyclohexyl—IH—pyrazol—4—yl)— 7H-pyrrolo[2,3-djpyrimidz'ne . 4-(1H-Pyrazol—4—yl)-7~[2-(trimethylsily1)ethoxy]methyl—7H-pyrrolo[2,3-d]pyrimidine (1.5 g, 0.0048 mol) was mixed with sodium hydride (0.34 g, 0.0086 mol) and trans—4- [(trityloxy)methyl]cyclohexyl methanesulfonate (3.00 g, 0.00666 mol) and the mixture was cooled to ~78 °C. To this mixture was added DMF (8.3 mL) and the mixture was allowed to warm to 25 °C and was stirred for 20 minutes. The warmed mixture was d at 55 °C for 48 hours. The reaction was extracted with ethyl acetate and the organic extracts were washed with water, saturated NaCl, dried (MgSO4) and then concentrated in vacuo. The concentrate was tographed on silica gel using 40% EtOAc/hexanes to give the product. LC/MS (M+H)+: 670, 1H NMR(CDC13):8 8.89 (s, 1H), 8.27 (s, 1H), 8.24 (s, 1H), 6.84—7.51 (m, 10H), 6.87 (d, 1H), 5.73 (s, 2H), 4.39 (m, 1H), 3.60 (m, 2H), 3.12 (m, 2H), 1.76-2.11 (m, 9H), 0.96 (m, 2H), 0.00 (s, 9H).

Step 5: cis~4—[4—(7-[2-(Trimethylsibzlkthowjmethyl— 7H-pyrrolo[2,3-d]pyrimidin-4—yD-1H—pyrazol—1 - yljcyclohexylmethanol. 7-[2-(Trimethylsily1)ethoxy]methyl(1 -cis[(trityloxy)methyl]cyclohexyl-1 H—pyrazol—4— yl)-7H—pyrrolo[2,3-d]pyrimidine (0.3 g, 0.0004 mol) was dissolved in methanol (7.0 mL) and THF (2.0 mL, 0.025 mol) and 4.0 M HCl in 1,4-dioxane (0.5 mL) was added. The reaction was then stirred at 25 °C for 2 hours TLC analysis showed no starting material present and LCMS analysis showed the ce of the product. The on was added to a ted NaHCO; solution and was extracted with ethyl acetate. The organic extracts were washed with water, saturated NaCl, dried (MgSO4) and concentrated in vacuo. The concentrate was chromatographed on silica gel using EtOAc as eluent to give the product. LC/MS (Mi-HY: 428 lH NMR (CDC13):5 8.89 (s, 1H), 8.37 (s, 1H), 8.31 (s, 1H), 7.44 (d, 1H), 6.87 (d, 1H), 5.73 (d, 2H), 4.41 (m, 1H), 3.51—3.71 (m, 4H), 2.31 (m, 2H), 2.08 (m, 3H), 1.70—1.93 (m, 4H), 0.98 (m, 2H), 0.00 (s, 9H).

Step 6: cis—4—[4—(7—[2—(Trimethylsilyljethoxyjmethyl—7H—pyrrolo[2, 3-djpyrimidin-4—y0-JH—pyrazol—I — yUcyclohexylmethyl esulfonate. 3O cis[4-(7—[2—(Trimethylsilyl)ethoxy]methyl-7H—pyrrolo[2,3-d]pyrimidinyl)-l H—pyrazol- 1-yl]cyclohexylrnethanol was dissolved in chloroform (3.00 mL) and was cooled to 0 °C To the reaction was added TBA (0.10 mL, 0.00072 mol) and methanesulfonyl chloride (0.05 mL, 0.0006 mol) and this mixture was stirred at 0 °C for 2 hours at which time LCMS analysis showed mainly the product present in the mixture. The reaction was extracted with ethyl e and the c extracts were washed with water, saturated NaCl, dried (MgSO4) and trated in vacuo. LC/MS (M+H)+: 506 Step 7: cis—4—[4—(7—[2-(Trimethylsr'lyljethoxfyjmethyl-7H-pyrrolo[2, 3—djpyrimia'inyD-1H-pyrazol~1- yUcycIoheJleac-etonitrile . cis—4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4—y1)-lH—pyrazol- l—yl]cyc10hexylmethyl methanesulfonate (0.10 g, 0.00020 mol) and sodium cyanide (0.050 g, 0.0010 mol) and DMSO (1.0 mL) were mixed. The mixture was stirred at 60 °C for 24 hours, at which time LCMS analysis showed most of the starting material had been consumed. The on was extracted with ethyl acetate and the organic ts were washed with water, saturated NaC], dried (MgSO4) and concentrated in vacuo. The concentrate was chromatographed on silica gel using EtOAc as eluent to give the product. LC/MS (M+H)+: 437, 1H NMR(CDC13):6 8.90 (s, 1H), 8.36 (s, 1H), 8.31 (s, 1H), 7.45 (d, 1H), 6.87 (d, 1H), 5.73 (S, 2H), 4.43 (m, 1H), 3.60 (m, 2H), 2.45(d, 2H, J = 7.6 Hz), 2.37 (m, 2H), 2.10 (m, 4H), 1.70-1.93 (m, 3H), 0.98 (m, 2H), 0.00 (s, 9H).

Step 8: cis-4~[4~(7H—Pyrrolo[2,3—d]pyrimidin~4~yl)—1H—pyrazol—I —yl]cycloh exylacetom'trile . ci s[4—(7—[2-(Trimethylsilyl)ethoxy]methyl-7H—pyrrolo[2,3-d]pyrimidinyl)— l H-pyrazol - l~yl]cyclohexylacetonitrile (0.080 g, 0.00018 mol) and TFA (0.50 mL, 0.0065 mol) were added to DCM (3.00 mL, 0.0468 mol) and the mixture was stirred at 25 °C for 16 hours. The reaction concentrated by rota-evaporation and the concentrate was dissolved in ol (3.0 mL, 0.074 mol) and ammonium hydroxide (0.5 mL, 0.01 mol) was added This reaction was stirred at 25 °C for 6 hours at which time LCMS analysis showed no starting material t. The reaction was chromatographed on silica gel using 5% MeOH/EtOAc to give the product.

LC/MS (M+H)+:307, 'H 30D):6 8.64 (s, 1H), 8.55 (s, 1H), 8.31 (s, 1H), 7.50 (d, 1H), 6.96 (d, 1H), 4.42 (m, 1H), 2.61(d, 2H, J = 8.0 Hz), 2.27 (m, 2H), 1.70-2.15 (m, 7H).

Example 680: cis[4-(7H-Pyrrolo[2,3-d]pyrimidinyl)-1H-pyrazol~l-yl]cyclohexylmethyl thiocyanate l/\l—N N'k \ \ N/ g Step I .' cis[4—(7-[2—(TrimethylsilyDethoxyjmethyl—7H-pyrrolo[2, 3-d ]pyrimidin—4—yl)—IH-pyrazol-1~ yljcyclohexylmethyl anate [4-(7—[2-(Trimethylsilyl)ethoxy]methyl—7H—pyrrolo [2,3~d]pyrimidinyl)- l H-pyrazol- 1-yl]cyclohexylmethyl methanesulfonate (0.10 g, 0.00020 mol) was dissolved in DMSO (1.00 with potassium thiocyanate (0.082 g, 0.00084 mol). The reaction was heated at 68 °C for 4 days at which time LCMS analysis showed ~4:1 product/starting material ratio. The reaction was extracted with ethyl acetate and the c extracts were washed with water, saturated NaCl, dried (MgSO4) and concentrated in vacuo. The concentrate was chromatographed on silica gel using 1:1 EtOAc/hexanes to give the product. LC/MS (Mi-HY: 469, lH NMR(CDC13):5 8.89 (s, 1H), 8.36 (s, 1H), 8.31 (s, 1H), 7.45 (d, 1H), 6.87 (d, 1H), 5.73 (S, 2H), 4.45 (m, 1H), 3.60 (m, 2H), 3.05 (m, 2H), 2.37 (m, 2H), 2.10 (m, 4H), 1.70-1.93 (m, 3H), 0.98 (m, 2H), 0.00 (s, 9H).

Step 2: cis[4-(7H—Pyrrolo[2,3-d]pyrimidin-4—yl)—1H~pyrazol—J-yUcyclohng/lmethyl thiocyanate). 1 0 [4-(7~[2—(Trimethylsily1)ethoxy]rnethy1—7H-py1rolo[2,3-d]pyrimidinyl)-lH—pyrazol- 1—yl]cyclohexylmethyl thiocyanate was dissolved in methanol (2.0 mL, 0.049 mol) and DCM (2.0 mL, 0.031 mol), and TFA (0.5 mL, 0.006 mol) was added. The resulting mixture was stirred at 25 °C for 16 hours. TLC analysis showed no starting material present and LCMS is showed product.

The reaction was concentrated using a rotary evaporator and the concentrate was chromatographed on silica gel using 2% tOAc to give the product. LC/MS (M+H)+:339, lH 30D) 5 8.65 (s, 1H), 8.55 (s, 1H), 8.31 (s, 1H), 7.50 (d, 1H), 6.96 (d, 1H), 4.43 (m, 1H), 3.20 (d, 2H, J = 7.6 Hz), 2.24 (m, 2H), 1.80-2.17 (m, 7H).

Example 681: N-S-[(cis[4-(7H—Pyrrolo[2,3—d]pyrimidinyl)-1H-pyrazolyl]cyclohexyl— methyl)thio]~4H—1,2,4—triazol—3-ylpyrimidin—2—amine trifluoroacetate ’N NH l/V‘N "1C \ N N H TFA Step 1: 5-[(cis[4-(7-[2—(Trimethylsilyl)ethoxyjmethyl-7H—pyrrolo[2.3—d]pyrimidin—4—yl)-1H~ pyrazolyl]cyclohexylmethy1)thio]—4H-1,2, 4—triazal—3-amin cis-4—[4-(7~[2-(Trimethylsilyl)cthoxy]rnethyl-7H-pyrrolo[2,3-d]pyrimidin~4-yl)-1H-pyrazol- l-yl]cyclohexylmethyl methanesulfonate (124.56 mg, 0.00024 mol), and 5-amino—4H-1,2,4-triazole- 3—thiol (43.00 mg, 0.0003702 mol) were ved in DMF (1.20 mL) and potassium carbonate (0.122 g, 0.000887 mol) was added. The on was stirred at 50 °C for 18h, at which time LCMS showed nearly complete reaction, and product present. The reaction was extracted with ethyl acetate and the WO 70514 organic extracts were washed with water, ted NaCl, dried (MgSO4) and concentrated in vacuo.

The concentrate was chromatographed on silica gel using EtOAc as eluent to give the product.

LC/MS (M+H)+: 526,1H NMR(CDCI3):8 8.90 (s, 1H), 8.40 (s, 1H), 8.30 (s, 1H), 7.45 (d, 1H), 6.87 1H), 5.73 (S, 2H), 4.45 (brs, 2H), 4.41 (m, 1H), 3.60 (m, 2H), 3.22 (d, 2H, J=7.2 Hz), 2.29 (m, 2H), 1.70-2.10 (m, 7H), 0.98 (m, 2H), 0.00 (s, 9H).

Step 2: 5—[(cis-4—[4—(7H—Pyrrolo[2,3-djpyrimia’in—4—yl)—1H~pyrazol—1 clohexylmethyl)thio]-4H— 1,2,4—triazol—3—amine -[(cis[4—(7-[2—(Trimethylsilyl)ethoxy]rnethyl-7H-pyrrolo[2,3-d]pyrimidin-4—yl)-1H- pyrazoly1]cyclohexylmethyl)thio]—4H—1,2,4-triazolamine (9a) was dissolved in TFA (1 mL) and was stirred for 2h. The solution was concentrated using a rotary evaporator to remove TFA. The residue was dissolved in methanol (1 mL) and ammonium hydroxide (1 mL) added.

The solution was stirred overnight. LCMS showed complete de—protection. The solution was concentrated using a rotary evaporator. The product was isolated by prep LCMS using a 30mm x 100mm C18 column; 11%C‘H3CN—H20 (0.1%TFA), 1.5 min, to 33% at 6 min; 60 mL/min; or set at m/z 396; retention time, 5.5min (2 runs). The eluate was freeze dried. Yield 21 mg (di-TFA salt). LC/MS (M+H)+:396, lH NMR (dd-DMSO) 8 12.9 (br s, 1H, NH); 8.9 (2 singlets, 2H); 8.5 (s, 1H); 7.9 (m, 1H); 7.3 (m, 1H); 4.4 (m, 1H, NCH); 3.1 (d, 2H); 2.2 (m, 2H); 1.9 (m, 3H); 1.7 (m, 2H); 1.6 (m, 2H). MS(ES) 396 Example 682: N-5~[(cis-4—[4—(7H—Pyrrolo[2,3—d]pyrimidinyl)—1H—pyrazolyl]cyclohexyl- methyl)thio]~4H—1,2,4-triazol—3-ylpyrimidin-2—amine trifluoroacetate N’N\ "\7/N S)—NH NJ\ / \ [IV—N "l \ \ kN/ N H TFA Step 1: N[(cz's—4—[ -(7-[2-(Trimethylsilyl)ethaxyjmethyl—7H-pyrrolo[2,3-d]pyrimidin-4~y1)-1H— pyrazol-I-yl]cyclohexylmethyDthioj-4H-1,2,4—triazol—3-ylpyrz'midin-2—amine In a vial [A] 5—[(cis—4—[4-(7—[2—(trimethylsilyl)ethoxy]methyl-7H~pyrrolo[2,3-d]pyrimidin—4- yl)—1H—pyrazolyl]oyclohexylmethyl)thio]—4H-1,2,4-tn'azolamine (0.047 g, 0.000089 mol) was heated with ropyrimidine (0.011 g, 0.000096 mol) in 1,4—dioxane (1.00 mL, 0.0128 mol) at 150 °C for 40 minutes in a microwave reactor. LCMS analysis showed that no reaction had taken place. To the reaction was added 2-chloropyrimidine (0.020 g, 0.00017 mol) with cesium carbonate (0.033 g, 0.00010 mol) and copper(I) iodide (4.00 mg, 0.0000210 mol) and this mixture was heated at 115 °C for 3 hours, at which time LCMS analysis showed no starting material present and mainly product was t. The reaction was chromatographed on silica gel using 2% MeOH/EtOAc to give the product. LC/MS (M+1)+:604, lNMR(CDC13): 8.89 (s, 1H), 8.82 m, 2H), 8.43 (s, 1H), 8.30 (s, 1H), 7.44 (d, 1H), 7.23 (m, 1H), 7.03 (br s, 2H), 6.88 (d, 1H), 5.73 (s, 2H), 4.40 (m, 1H), 3.60 (m, 2H), 3.35 (d, 2H), 2.34 (m, 2H), 1.80—2.15 (m, 7H), 0.98 (m, 2H), 0.00 (s, 9H).

Step 2: N[(cis[4-(7H—Pyrr0lo[2, 3—d]pyrimidinyl)-IH-pyrazol—J-yl]cyclohexylmethyl)thio]- 4H-1, 2, 4—triazol—3—ylpyrimfdz'n-2~amine .

N-S—[(ci&4-[4—(7—[2—(Trimethylsily1)ethoxy]methyl—7H—pyrroIo[2,3-d]pyrimidinyl)- 1 H— pyrazol-l-y1]cyclohexylmethyl)thio]-4H-1,2,4~triazoly1pyrimidinarnine (0.024 g, 0.000040 mol) was dissolved in DCM (4.00 mL), and TFA (0.50 mL, 0.0065 mol) was added. The on was stirred at 25 °C for 16 hours and was concentrated in vacuo. The residue was dissolved in methanol (3.00 mL) and concentrated um hydroxide (0.50 mL) was added. This reaction was stirred at °C for 2 hours at which time LCMS analysis showed mostly product. The reaction was concentrated using a rotary ator and the concentrate was purified by prep LC to give the product as the roacetate salt. LC/MS (M+H)+:474, lI-I NMR(CD30D) 5 8.87 (s, 1H), 8.85 (s, 1H), 8.81 (s, 1H), 8.79 (s, 1H), 8.45 (s, 1H), 7.85 (d, 1H), 7.34 (m, 2H), 4.43 (m, 1H), 3.20 (d, 2H, J = 7.6 Hz), 2.24 (m, 2H), 1.80-2.17 (m, 7H). ' Example 683: 3~cis—4-[4-(7H-Pyrrolo[2,3-d]pyrimidinyl)—lH—pyrazol—l-yl]cyclohexylpropane— e trifluoroacetate KN N N\ I HN / Step 1: 2-(1,4—Dioxaspiro[4.5]dec—8—yl)ethanol.

Ethyl 1,4-dioxaspiro[4.5]dec—S—ylacetate (3.40 g, 0.0149 mol) prepared according to the procedure of Itagaki, Noriaki; Kimura, Mari; Sugahara, Tsutomu; Iwabuchi, Yoshiharu. (Organic Letters 2005; 7(19); 4181-4183.) was dissolved in ether (30.00 mL) and the mixture was cooled to 0 °C. To the reaction was added 1.00 M m tetrahydroaluminate in ether (15.0 mL) and the resulting mixture was d at 0 °C for 60 minutes and at 25 °C for 2 hours. The reaction was WO 70514 cooled and water (0.40 mL, 0.022 mol) was added, followed by 1.00 M sodium hydroxide (0 .40 mL).

To the reaction was then added ether (100.00 mL) and the solid that precipitated was filtered off. The filtrate was trated using a rotary evaporator to give the product. lH NMR(CDC13): 3.94 (s, 4H), 3.67 (t, 2H), 1.204.80 (m, 11H).

Step 2: ydroayethyl)cyclohexanone. 2-(1,4-Dioxaspiro[4.5]dec~8-yl)ethanol (2.70 g, 0.0145 mol) was ved in acetone (10.00 mL) and THF (10.00 mL) and 6.00 M HCl (6.00 mL) was added. The reaction was stirred at 25 °C for 16 hours, neutralized with NaHC03 solution and was then extracted with ethyl acetate. The c extracts were washed with water, and with saturated NaCl, then dried (MgSO4) and concentrated in vacuo. The crude product was used in the next reaction without further purification.

'H NMR(CDC13): 3.75 (m, 2H), 2.36 (m, 4H), 1.20-2.13 (m, 7H).

Step 3: 4—(2-Hydroayethy1)cyclohexanol. 4-(2-Hydroxyethyl)cyclohexanone (2.00 g, 0.0141 mol) was dissolved in ether (30.00 mL) and was cooled at 0 °C. To the reaction was added 1.0 M lithium tetrahydroaluminate in ether (14.1 mL) and the resulting mixture was stirred at 0 °C for 2 hours and at 25 °C for 16 hours. To the reaction was added THF (20.00 mL) and this mixture was cooled at 0 °C and then water (0.40 mL, 0.022 mol) was added, followed by 1.00 M sodium hydroxide (0.40 mL). To the reaction was then added ether ( 100.00 mL) and the resulting mixture was stirred for 10 minutes, then was filtered and the filtrate was concentrated using a rotary evaporator to provide the crude product. The crude product was used in the next reaction without r purification. lI-I NMR(CDC13): 3.96 and 3.57 (m, 1H) minor and major CHOH (~1 :5 ratio) 3.70(m, 2H), 0.94-2.02 (m, 11H).

Step 4: Tritylqu)ethyl]cyclohexan01. 4—(2—Hydroxyethyl)cyclohexanol (crude from the previous reaction) (1.88 g, 0.0130 mol) was dissolved in pyridine (20.00 mL) and was cooled at 0 °C. To the reaction was added tn'phenylmethyl chloride (4.0 g, 0.014 mol) and this mixture was stirred at 0 °C for 2 hours and at 25 °C for 16 hours.

The reaction was concentrated using a rotary evaporator and the concentrate was ted with ethyl acetate. The organic extracts were washed with water, and saturated NaCl, then dried (MgSO4) and trated in vacuo. The concentrate was chromatographed on silica gel (30%EtOAc/hexanes) to give the trans isomer (1.98 g) 1H NMR(CDC13): 7.42—7.45 (m, 6H), 7.20—7.30 (m, 9H), 3.50 (m, 1H), 3.07 (m, 2H), 1.93 (m, 2H), 1.66 (m, 2H), 1.17-1.60 (m, 5H), 0.89 (m, 2H).

Step 5: trans[2—(Trigil0391)ethyl]cyclohexyl methanesulfonate. trans-4—[2—(Trity1oxy)ethy1]cyclohexanol (1.95 g, 0.00504 mol) was ved in chloroform (40.00 mL) and the mixture was cooled to 0 °C. To the reaction was added TEA (0.98 mL, 0.0071 mol) and methanesulfonyl chloride (0.47 mL, 0.0060 mol) and this mixture was stirred at 0 °C for 2 hours The reaction was then extracted with ethyl acetate and the organic extracts were washed with water, and saturated NaCl, then dried (MgSO4) and concentrated in vacuo.

IH NMR(CDC13): 7.41—7.45 (m, 6H), 7.20~7.32 (m, 9H), 4.55 (m, 1H), 3.07 (m, 2H), 2.10 (m, 2H), 1.70 (m, 2H), 1.20-1.60 (m, 5H), 0.95 (m, 2H).

Step 6: 7—[2—(TrimethylsilyDezhoxyjmethyl~4—(1-cz‘s—4—[2—(trityloxy)ethyl]cyclohexyl—1H—pyrazol-4—y0— rolo[2,3-d]pyrimidine. 4—(1H-Pyrazol—4—yl)—7—[2—(trimethylsilyl)ethonymethy1-7H-pyrrolo[2,3-d]pyrirnidine (1.0 g, 0.0032 mol) was mixed with sodium hydride (0.23 g, 0.0058 mol) and trans—4—[2— (trityloxy)ethyl]cyclohexyl methanesulfonate (2.10 g, 0.00452 mol) and this mixture was cooled to -78 °C. To the reaction was added DMF (6.00 mL) and this mixture was allowed to warm to 25 °C and was then stirred for 20 s. The reaction was stirred at 55 °C for 48 hours at which time LCMS analysis showed mostly product. The reaction was extracted with ethyl e and the organic extracts were washed with water and saturated NaCl, then dried ) and concentrated in vacuo.

The concentrate was chromatographed on silica gel using 40% EtOAc/hexanes to give the product.

LC/MS (M+H)+:684, 'H NMR(CDC13): 8.89 (s, 1H), 8.35 (br s, 1H), 8.30 (s, 1H), 7.50 (m, 6H), 7.44 (d, 1H), .32 (m, 9H), 6.87 (d, 1H), 5.73 (s, 2H), 4.33 (m, 1H), 3.60 (m, 2H), 3.17 (t, 2H), 1.50- 2.25 (m, 11H). 0.98 (m, 2H), 0.00(s, 9H).

Step 7.‘ 2-cis[4—(7-[2-(Trimethylsilyl)eth0xy]methyl— 7H—pyrrolo[2, 3—djpyrimidin-4—yl)—1H-pyrazol— 1-yUcyclohngvlethanol (7b). 7-[2-(Trimethylsilyl)ethoxy]methy1~4-(1 -[2—(trityloxy)ethyl]cyclohexyl—1H-pyrazol-4— yl)-7I-I-pyrrolo[2,3-d]pyrimidine (1.45 and g, 2 mol) was dissolved in methanol (30.00 mL) TI-IF (10.00 mL) and 4.0 M HCl in 1,4-dioxane (2.00 mL) was added. The mixture was stirred at °C for 2 hours, at which time, TLC analysis showed no starting material present and LCMS analysis showed the presence of the product. The reaction was added into a saturated NaHC03 3O solution, and was then extracted with ethyl acetate. The organic extracts were washed with water and saturated NaCl, then dried (Mgsoo and concentrated in vacuo. The concentrate was chromatographed on silica gel using EtOAc as eluent to give the product. LC/MS (Mi—HT: 442 Step 8: 2—cis—4-[4—(7-[2-(Trimethylsileethonymethyl—7H-pyrrolo[2,3-djpyrimz‘din~4—yD-1H—pyrazol— clo/zexylethyl methanesulfonate (8b). 2-cis[4-(7-[2-(Trimethylsilyl)ethoxy]rnethyl-7H~pyrrolo[2,3-d]pyrimidinyl)-1H~ pyrazol-1—yl]cyclohexylethanol (0.89 g, 0.0020 mol) was dissolved in DCM (12.00 mL, 0.1872 mol) and was cooled at 0 °C To the reaction was added TEA (0.43 mL, 0.0031 mol) and methanesulfonyl chloride (0.19 mL, 0.0024 mol) and this mixture was stirred at 0 °C for 2 hours at which time LCMS analysis showed mainly product present. The reaction was extracted with ethyl acetate and the organic extracts were washed with water and saturated NaCl, then dried (MgSOi) and trated in vacuo.

LC/MS (M+H)+:520, lH CI3): 8.90 (s, 1H), 8.38 (br s, 1H), 8.31 (s, 1H), 7.45 (d, 1H), 6.88 (d, 1H), 5.73 (s, 2H), 4.40 (m, 1H), 4.27 (t, 2H), 3.60 (m, 2H), 3.07 (s, 3H), .40 (m, 11H). 0.98 (In, 2H), 0.00(s, 9H) Step 9: 3—cis[4-(7H-Pyrrolo[2,3—djpyrz'midt'ny0-IH-pyrazol-I~yljcyclohaxyh2ropanenitrile oroacetate (9b). 2—cis[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin—4—yl)-1H- pyrazol-l-yl]cyclohexylethyl methanesulfonate (0.075 g, 0.00014 mol) was dissolved in DMSO (1.50 mL) and sodium e (0.035 g, 0.00072 mol) was added. The reaction was stirred at 40 °C for 16 hours at which time LCMS analysis showed no starting material present. The on was then extracted with ethyl acetate and the organic extracts were washed with water and saturated NaCl, then dried (Mgsog and concentrated in vacuo. The residue was dissolved in DCM (3.00 mL) and TFA (0.50 mL, 0.0065 mol) was added. This mixture was stirred at 25 °C for 16 hours at which time LCMS analysis showed mostly the hydroxymethyl intermediate. The mixture was concentrated using a rotary evaporator and the concentrate was dissolved in ol (3.00 mL) and concentrated ammonium hydroxide (0.50 mL) was added. The reaction was stirred at 25 °C for 3 hours at which time LCMS analysis showed no starting material present. The reaction was then concentrated using a rotary evaporator and the concentrate was purified by prep LC to give the product as the TFA salt (47.8 mg). LC/MS (M+H)+:321, 'H NMR(CD30D): 8.86 (s, 1H), 8.81(s, 1H), 8.44 (s, 1H), 7.84 (d, 1H), 7.31 (d, 1H), 4.48 (m, 1H), 2.51 (m, 2H), 2.28 (m, 2H), 2.00 (m, 2H), 1.80 (m, 5H), 1.67 (m, 2H).

Example 684: 5-[(2-cis—4—[4—(7H-Pyrrolo[2,3~d]pyrimidin—4—yl)—1H—pyrazol—l—yl]cyclohexyl- cthyl)thio]-4H-l,2,4-triazolamine trifluoroacetate N NH2 % T \2\zl z Z\/ IZ/ TFA 2-cis[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin—4-yl)-1H— pyrazol—l-yl]cyclohexy1ethyl methanesulfonate (0.060 g, 2 mol) was dissolved in DMF (1.31 mL) with 5-amino-4H-1,2,4-triazolethiol (0.020 g, 0.00017 mol) and potassium carbonate (0.024 g, 0.00017 mol). This mixture was heated at 40 °C for 18 hours at which time LCMS analysis showed no starting material t. The reaction was diluted with EtOAc, filtered and was then concentrated using a rotary evaporator. The residue was dissolved in DCM (3.60 mL) and TFA (0.60 mL, 0.0078 mol) was added. This mixture was stirred at 25 °C for 5 hours and was then concentrated using rotary evaporator. The residue was dissolved in methanol (3.60 mL) and concentrated ammonium hydroxide (0.60 mL) was added and this mixture was d at 25 °C for 2 hours. The reaction concentrated using a rotary evaporator and the concentrate was purified by prep. LC to give the product. LC/MS (M+H)+:410, lH NMR(CD30D): 8.85 (s, 1H), 8.80(s, 1H), 8.44 (s, 1H), 7.83 (d, 1H), 7.30 (d, 1H), 4.46 (m, 1H), 3.17 (m, 2H), 2.27 (m, 2H), 2.00 (m, 2H), 1.62-1.90 (m, 7H).

Example 685: 4-[4—(7H-Pyrr01012,3-d]pyrimidin—4—yl)—1H-pyrazol—l-yl]cyclohexylideneaceto- nitrile trifluoroacetate / CN N/ \ / T \=N /" Step 1: I, 4-Dioxaspiro[4.5]decan-8—ol 1,4-Dioxa-spiro[4.5]dccanone (2.00 g, 0.0128 mol) was dissolved in ether (50 mL) and the mixture was cooled to 0 °C. To the reaction was added 1 M lithium tetrahydroaluminate in ether (7.0 mL) and this mixture was stirred at 0 °C for 2 hours at which time TLC analysis showed no starting material present. The reaction was then quenched with water and l N NaOH (0.5 mL of each) and then filtered. The filtered solid was washed with ether and the ed ether filtrate was concentrated using a rotary evaporator to give the product. NMR ): 3.94 (m, 4H), 3.81 (m, 1H), 1.79-1.92 (m, 4H), 1.54—1.70 (m, 4H).

Step 2: 1,4vDioxaspiro[4.5]dec-8~yl esulfonate. l,4-Dioxaspiro[4.5]decan—S-ol (0.40 g, 0.0025 mol) 'was dissolved in chloroform (10.0 mL) and the ing e was cooled at 0 °C. To the e was added TEA (0.49 mL, 0.0035 mol) and methanesulfonyl chloride (0.23 mL, 0.0030 mol) and this mixture was stirred at 0 °C for 2 heurs.

The reaction was extracted with ethyl e and the organic extracts were washed with water, and saturated NaCl, then dried (MgSO4) and concentrated in vacuo. The crude product was used in the next reaction without fiirther purification.

‘H NMR(CDC13): 4.85 (m, 1H), 3.95 (m, 4H), 3.02 (s, 3H), 1.98-2.05 (m, 4H), 1.82-1.89 (m, 2H), 1.61-1.70 (m, 2H).

Step 3: 1, aspiro[4.5]dec~8—yl)—1H—pyrazol-4—yl]—7—[2—(trimethylsz'lyl)ethoxyjmethyl—7H- pyrrolo[2,3—d]pyrimidine .

A mixture of 1,4-dioxaspiro[4.5]decyl esulfonate (0.50 g, 0.0015 mol) with 4-(1H— pyrazolyl)[2-(trimethylsily1)ethoxy]methyl-7H-pyrrolo[2,3-d]pyn'midine (0.36 g, 0.0011 mol) and sodium hydride (0.082 g, 0.0020 mol) was cooled at —78 °C and DMF (2.0 mL) was added. The reaction was allowed to warm to 25 °C and was then stirred for 20 minutes and was then heated to 55 °C for 24 hours. The reaction was then extracted with ethyl acetate. The organic extracts were washed with water and saturated NaCl, then dried (MgSO4) and concentrated in vacuo. The concentrate was chromatographed on silica gel using 1:1 EtOAc/hexanes to give the t. LC/MS :456, IH NMR(CDC13): 8.89 (s, 1H), 8.35 (s, 1H), 8.30 (s, 1H), 7.44 (d, 1H), 6.87 (d, 1H), .73 (s, 2H), 4.38 (m, 1H), 4.06 (s, 4H), 3.60 (m, 2H), 2.22-2.31 (m, 4H), 2.00 (m, 2H), 1.86 (m, 2H), 0.98 (m, 2H), 0.00(s, 9H) Step 4: 4-[4—(7—[2—(Trimethylsilyl)ethaw]methyl-7H—pyrr0lo[2,3-djpyrimidinyl)~1H-pyrazol~1— yUcyclohexanone To 4—[1-(1 ,4~dioxaspiro[4.5]dec—8—yl)—lH—pyrazol-4—yl]-7~[2~(trimethylsilyl)ethoxy]methyl- 7H-pyrrolo[2,3—d]pyrimidine (2.13 g, 0.00467 mol), was added acetone (85 mL) followed by 12 M HCl in water (4.0 mL). The reaction was stirred at RT. After 1 h, LCMS analysis showed 66% reaction. After 4 h, HPLC showed 80% reaction. Afier 20 h, HPLC showed no change (and no loss of SEM). The on mixture was quenched into excess sat'd NaHCO3. The acetone was removed by rote-evaporation. The resulting mixture of aqueous bicarbonate and a white solid was then extracted with EtOAc. The combined organic extract was shaken with sat'd NaCl, dried over Na2S04, then concentrated to dryness to leave 2.0 g of a crude product. TLC (5% iPrOH—40% EtOAc-hexane): product Rf 0.12 (ketal 0.22). The crude product was purified by tic flash chromatography on silica gel. Used a 40g column; flow 40 mL/min; [A= 2% iPrOH-hexane] [B= 6% 50% EtOAc/hexane]; A, 2 min; Gradient to B in 25 min, then B for 10 min. The eluent was concentrated 3O using a rotary evaporator to give 1.3 g of a white solid. HPLC Method: Zorbax SB C18, 5 pm, 15 cm, °C, flow 1.2 mL/min, 10% CH3CN-H20 (0.05% TFA), to 100% CH3CN in 9.0 min; stop time 12.3 min; detector 268 nm; retention time starting material, 7.4 min; product, 6.9 min (UV max 220, 268, 300, 322 nm). 'H NMR (CDC13) 8 8.8 (s, 1H); 8.3 (m, 2H); 7.4 (d, 1H); 7.3 (s, 1H); 6.8 (d, 1H); 5.7 (s, 2H); 4.7 (m, 1H, NCH); 3.6 (t, 2H); 2.3-2.5 (m, 8H); 0.9 (t, 2H); ~0.1 (s, 9H). MS(ES) 412 (M+l).

Step 5: 4—[4-(7—[Z—(TrimethylsilyDethoxy]methyl- 7H—pyrrolo[2,3—djpyrimidin—4—yl)—IH-pyrazoI—1 yljcyclohexylz'deneacetonitrile To a solution of 1.0 M ium tert-butoxide in THF (1.90 mL) at 0 "C was added a solution of diethyl ethylphosphonate (321 uL, 0.00198 mol) in THF (4 mL) dropwise. The reaction was held for 10 min, then it was added to a solution of 4—[4-(7-[2-(trimethylsilyl)- ethoxy]methyl-7H-pyrrolo[2,3~d]pyrimidin—4—yl)-lH-pyrazol-l -y1]cyclohexanone (743 mg, 0.00180 mol) in TI-IF (5 mL) stirring at 0 °C under a nitrogen atmosphere. The on was stirred 1.5 h at rt.

LCMS analysis showed clean conversion to the desired product. To the reaction mixture was then added water and EtOAc. The phases were separated and the aqueous phase was extracted with EtOAc. ‘10 The ed c extract was washed with water, then sat'd NaCl, then dried over NaZSO4, and concentrated to dryness to yield 0.76 g of a white crystalline solid (TLC (EtOAc) Rf 0.33). product was purified by automatic flash chromatography on silica gel. Used 40g column; flow 40 mL/min; [A= ] [B= EtOAc]; A, 2 min; Gradient to B in 20 min. Rotary evaporation yielded 0.70 g of a white crystalline solid (89% yield). 1H NMR (CDC13) 6 8.9 (s, 1H); 8.3 (s, 2H); 7.4 (d, 1H); 7.3 (s, 1H); 6.9 (d, 1H); 5.7 (s, 2H); 5.3 (s, 1H, olefin); 4.5 (m, 1H, NCH); 3.6 (m, 2H); 3.2 (m, 1H); 2.7 (m, 1H); 2.5 (m, 4H); 2.1 (m, 2H); 1.0 (m, 2H); -O.1 (s, 9H). MS(ES) 435 (M+1).

Step 6: 4—[4—(7H—Pyrrolo[2,3-djpyrimidin-4—y0-IH—pyrazol-J-yl]cyclohexylideneacetom'trile A solution of TFA (0.5 mL, 0.006 mol) and 4-[4~(7~[2—(trimethylsilyl)ethoxy]methyl-7H- pyrrolo[2,3-d]pyrimidinyl)-1H-pyrazol-l-yl]cyclohexylideneacetonitrile (22.7 mg, 0.0000522 mol), was d for 1.5h. The solution was then concentrated using a rotary evaporator to remove TFA. LCMS analysis showed conversion to the ymethyl intermediate, M+H 335. Methanol was added; and the methanol mixture was concentrated again using a rotary evaporator. The resulting residue was dissolved in methanol (1 mL) and ammonium hydroxide (0.25 mL, 0.0064 mol) was added. The resulting solution was stirred for 16 h. LCMS analysis showed complete de-protection.

The solution was then concentrated using a rotary ator. The product was isolated by prep HPLC using a 30 mm x 100 mm C18 column; 18% CH3CN-H20 (0.1%TFA), 1min, to 35% at 6min; 60 mL/min; detector set at 254nm; retention time, 4.4mm. The eluate was freeze dried. yield 7.6 mg of a white solid (TFA salt; racemic; 34.6%). 1H NMR (déDMSO) 8 12.9 (br s, 1H, NH); 8.9 (s, 2H); 8.5 (s, 1H); 7.8 (m, 1H); 7.3 (m, 1H); 5.6 (s, 1H, olefin); 4.6 (m, 1H,.NCH); 2.8 (m, 1H); 2.6 (m, 1H); 2.5 (m, 2H); 2.3 (m, 2H) 2.0 (m, 2H). MS(ES) 305 (M+1).

Example 686: cis[4-(7H-Pyrrolo[2,3-d]pyrimidinyl)-lH-pyrazol—1-yl] cyclohexanecarbo- e trifluoroacetate WO 70514 Step 1: cis—4-[4—(7—[2-(Trimethylsilyl)ethoxyjmethyl-7H—pyrrolo[2, 3—djpyrimidz‘n-4—yl)—1H-pyraizol—1- yljcyclohexanecarbaldehyde oxime A solution of sulfur de-pyridine complex (53.4 mg, 36 mol) in DMSO (0.3 mL, 0.004 mol) was added to a solution of cis-4~[4-(7-[2-(trimethylsilyl)ethoxy]methyl—7H—pyrrolo[2,3- d]pyrimidin—4-yl)—1H-pyrazol-l—y1]cyclohexylmethanol (57.4 mg, 0.000134 mol) and TEA (56.1 uL, 0.000403 mol) in DCM (0.3 mL, 0.004 mol) at -10 °C. The mixture was stirred usly at 10-20 0C for one hour. LCMS analysis showed conversion to the aldehyde. The mixture was then poured into ice-water, and extracted with DCM. The extracts were washed with 10 % citric acid, water, ted 1‘0 aqueous sodium onate, water, and brine, and then dried over sodium sulfate. Concentration gave 57 mg of a residue.

To the resulting residue was added hydroxylamine-HCI (50mg), 1 mL 20% K2C03, and 3 mL MeOH and this mixture was stirred at rt until LCMS showed conversion to the corresponding oxime, M+H 441 . The product was isolated by prep HPLCMS using a 30 mm x 10, 0 mm, C18 column; 30% CH3CN-H20 (0.1%TFA), 1 min, to 60% at 6 min; 60 mL/min; detector set at m/z 441; retention time, 6.0min. freeze-dried. yield 17.4 mg of a white solid.

Step 2: ciS[4-(7H-Pyrrolo[2,3—d]pyrimidin~4»yl)-IH-pyrazol-I-yUcyclohexanecarbonitrile [A] cis[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidinyl)-1H- pyrazol-l—yl]cyclohexanecarbaldehyde oxime (11.0 mg, 0.0000250 mol) was dissolved in pyridine (0.25 mL, 0.0031 mol), and benzenesulfonyl chloride (10.0 uL, 0.0000784 mol) was added and the resulting mixture was stirred at rt. Afier stirring 15 h, LCMS analysis showed formation of the product, M+H 423. The product was isolated by prep HPLCMS using a 19 mm x 100 mm C18 column; 45% CHgCN—Hzo (0.1% NH40H), 1min, to 75% at 6 min; 30 mL/min; detector set at m/z 423; ion time, 4.8 min. The eluent was concentrated using a rotary evaporator to give 8 mg of the desired t.

The product was dissolved in TFA (0.25 mL). stirred for 2h. The solution was concentrated using a rotary evaporator to remove TFA. Methanol was added and the mixture was trated again. LCMS showed clean conversion to the hydroxymethyl intermediate (M+H 323). The residue was dissolved in methanol (1 mL) and ammonium hydroxide (0.25 mL) was added. The solution was stirred 0.5 h, at which time, LCMS showed complete tection to the desired product M+H 293.

The mixture was then concentrated by row-evaporation, and the product was isolated by prep HPLCMS using a 19 mm x 100 mm C18 column; 15% CH3CN-H20 (0.1% TFA), 1.5 min, to 30% 6 min; 30 mL/min; detector set at m/z 293; retention time, 5.2 min. The eluate was freeze dried to yield 5.5 mg of the product as a TFA salt. 1H NMR (dd-DMSO) 5 12.82 (br s, 1H, NH); 8.87 (s, 1H); 8.85 (s, 1H); 8.48 (s, 1H); 7.82 (m, 1H); 7.24 (m, 1H); 4.40 (m, 1H, NCH); 3.22 (m, 1H); 2.05 (m, 6H); 1.79 (m, 2H). MS(ES) 293 (M+1).

Example 687: 2—[(cis-4—[4-(7H—Pyrrolo[2,3-d]pyrimidin—4—yl)-lI~I—pyrazol-l-yl]cyclohexyl- methyl)sulfinyl]benzonitrile trifluoroacetate Step I: 4—[1~(cis-4—[(2-Brom0phenyDthiojmethylcyclohexyl)—1H-pyrazol—4-yl]~7-[2—(trimethylsily0— ethoxyfmethyl— 7H-pyrr010[2,3-d]pyrimidine This compound was ed from (cis[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H- pyrrolo[2,3—d]pyrimidin—4—yl)—1H—pyrazolyl]cyclohexylmethyl esulfonate as in Example 686[A]. Yield 73%. The product was purified using the following I-[PLC method: Zorbax SB C18, 5 pm, 15cm, 35 C, flow 1.2 mL/min, 10% CH3CN-H20 (0.05% TFA), to 100% CH3CN in 9.0 min; stop time 12.3 min; detector 254 nm; retention time ng mesylate, 7.5 min; product, 9.9 min (UV 215, 258, 300, & 326 nm). TLC: Rf 0.3 using 35% EtOAc/5% iPrOH/hexane. The t was purified by automated silica gel flash chromatography using 30% EtOAc/5% iPrOH/hexane. lH NMR (CDCl3) 8 8.84 (s, 1H); 8.31 (s, 1H); 8.26 (s, 1H); 7.55 (m, 1H); 7.39 (d, 1H); 7.27 (m, 2H); 7.03 (m, 1H); 6.82 (d, 1H); 5.67 (s, 2H); 4.34 (m, 1H, NCH); 3.55 (m, 2H); 2.98 (d, 2H); 2.28 (m, 2H); 2.02 (m, 3H); 1.83 (m, 4H); 0.92 (m, 2H); ~0.06 (s, 9H). MS(ES) 598/600 1:1 (M—l-l).

Step 2: s~4-[4-(7-[2-(Trimethylsilyl)ethoxyjmethyl-7H-pyrrolo[2,3-d]pyrimidinyl)—1H- pyrazol—1-yl]cyclohexylmethyDthiojbenzonitrile 4-[1 -(cis—4—[(2—Bromopheny1)thio]methylcyclohexyl)- l H—pyrazolyl]—7-[2-(trimethylsilyl)- ethoxy]methy1-7H—pyrrolo[2,3-d]pyrimidine (62.7 mg, 0.000105 mol), zinc cyanide (123 mg, 0.00105 mol), and tetrakis(triphenylphosphine)palladium(0) (30.2 mg, 0.0000262 mol) were stirred in DMF (3 mL) and the solution was flushed with nitrogen. The solution was then heated to 100 °C for 25 min in a microwave reactor. LCMS and HPLC analyses showed > 90% reaction. The product was isolated by prep HPLCMS using a 30 mm x 100 mm C18 column; CN-H20 (0.1%TFA), 1.5 min, to 75% at 6 min; 60 mL/min; or set at 545 nm. The eluent was concentrated using a rotary evaporator to give 37 mg of the 2~cyanophenylsulfide TFA salt. HPLC Method: Zorbax SB C18, 5 pm, 15 cm, 35 WO 70514 C, flow 1.2 mL/min, 10% CH3CN—HZO (0.05% TFA), to 100% CH3CN in 9.0 min; stop time 12.3 min; detector 265 nm; retention time starting material, 9.9 min; product, 8.9 min. MS(ES) 545 (M+1).

Step 3: 2—[(ciS[4-(7H-Pyrrolo[2, 3-d]pyrimidin-4—yl)-1H—pyrazol~1-yl]cyclohexylmethstulj'inyU— benzonitrile A solution of 2-[(cis-4~[4—(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4— yl)-1H-pyrazolyl]cyclohexylmethyl)thio]benzonitrile (30.6 mg, 0.0000562 mol), in TFA (1 mL) was stirred for 2 h. The solution was concentrated using a rotary evaporator to remove TFA. Methanol was added, and the mixture was concentrated again. The resulting residue was dissolved in methanol (1 mL) and ammonium ide (1 mL) was added. The ing solution was stirred overnight, at which time HIPLC showed complete deprotection. The product was isolated by prep I-H’LCMS using a 19 mm x 100 mm C18 column; 30% CH3CN-H20 (0.1% TFA), 1.5 min, to 59% at 6 min; 30 mL/min; detector set at m/z 415 nm; retention time, 4.7 min. The eluate was concentrated using a rotary evaporator to give 36 mg of the sulfide TFA salt, a colorless glassy al. NMR SO) 8 12.82 (br s, 1H, NH); 8.84 (2 singlets, 2H); 8.45 (s, 1H); 7.8 (m, 2H); 7.64 (m, 2H); 7.34 (td, 1H); 7.24 (s, 1H); 4.39 (m, 1H, NCH); 3.23 (d, 2H); 2.19 (m, 2H); 1.89 (m, 3H); 1.72 (m, 4H). MS(ES) 415 (M+1). This material was then dissolved in CHzClz and cooled to 0 °C. To the cooled mixture was added MCPBA(12.9 mg, 0.0000562 mol), and the resulting mixture was stirred for 1 h. LCMS showed conversion to the product, and no remaining sulfide. The reaction mixture was concentrated by p, and the product was isolated by prep I-IPLCMS using a 19 mm x 100 mm C18 column; 18% CH3CN-H20 (0.1% TFA), 1. 0 min, to 35% at 6 min; 30 mL/min; or set at m/z 431 nm; retention time, 5.6 min. The product was isolated from the eluent by freeze—drying. The yield was 27.6 mg of the TFA salt. The I-[PLC method was: Zorbax SB C18, 5 um, 15 cm, 35 °C, flow 1.2 mL/min, 10% CH3CN~H20 (0.05% TFA), to 100% CH3CN in 9.0 min; stop time 12.3 min; detector 268 nm; retention time starting material, 5.6 min; sulfoxide, 4.8 min; sulfone, 5.2 min; MCPBA, 6.0 min. 1H NMR (CDC13) 5 12.1 (br s, 1H, NH); 9.0 (s, 1H); 8.9 (s, 1H); 8.3 (s, 1H); 8.1 (m, 1H); 7.9 (m, 1H); 7.8 (m, 1H); 7.6 (m, 2H); 7.0 (m, 1H); 4.4 (m, 1H, NCH); 3.1 (dd, 1H); 2.9 (dd, 1H); 2.5 (m, 1H); 2.3 (m, 1H); 2.3-1.7 (m, 7H). MS(ES) 431 (M+1).

Example 688: s—4—[4-(7H—Pyrrolo[2,3—d]pyrimidin-4—yl)-1H—pyrazol—1-yl]cyclohexyl- methyl)sulfonyllbenzonitrile trifluoroacetate 2-[(cis~4-[4-(7H-Pyrrolo[2,3-d]pyrimidin—4-yl)—l H—pyrazol-l -y1]cyclohexylmethyl)su1finyl]- benzonitn'le (17.2 mg, 0.0000400 mol) (21 mg TFA salt), was dissolved in DCM (10 mL) and cooled to 0 0C. To this mixture was added MCPBA (18 mg, 0.0000800 mol). The resulting mixture was d for 1h at 0 0C, and then for 16 h at rt. HPLC and LCMS showed 80 area% product, and 3 area% sulfoxide. The MCPBA was removed using a sat'd NaHCO3 wash, and the resulting washed mixture was concentrated by row—evaporation. The t was isolated by prep HPLCMS using a 19 mm x 100 mm C18 column; 23%CH3CN-H20 (0.1%TFA), 1.0 min, to 43% at 6 min; 30 mL/min; detector set at m/z 447 nm; retention time, 5.1 min. The product was isolated from the eluent by freeze-drying. The yield was 5 mg of the TFA salt. 1H NMR (do-DMSO) 5 12.70 (br s, 1H, NH); 8.83 (s, 1H); 8.82 (s, 1H); 8.41 (s, 1H); 8.21 (dd, 1H); 8.16 (dd, 1H); 8.01 (td, 1H); 7.95 (td, 1H); 7.78 (s, 1H); 7.19 (s, 1H); 4.34 (m, 1H, NCH); 3.62 (d, 2H); 2.28 (m, 1H); 2.10 (m, 2H); 1.90 (m, 2H); 1.72 (m, 4H). MS(ES) 447 (M+1).

Example 689: 3—[4-(7H-Pyrrolo[2,3—d]pyrimidin-4—yl)-1H—pyrazol—l—yl]cyclohexylacetonitrile trifluoroacetate NI \ kN/ H TFA Step 1 : 7—[2—(TrimethylsilyDethoxyjmezhyl- 7H-pyrrolo[2,3-d]pyrimidinyl)-IH-pyrazol-I-ylj— cyclohexanone To a solution of pyrazoly1)—7—[2-(tn‘methylsilyl)ethoxy]methy1-7H-pyrrolo[2,3—d]- pyrimidine (309 mg, 0.980 mmol) in ACN (6 mL) was added 2-cyclohexen-l—one (190 1.1L, 01.96 mmol), followed by DBU (40 uL, 0.3 mmol). The resulting mixture was stirred for one hour at which point LCMS indicated complete on. The mixture was reduced in vacuo and the crude product was d by column chromatography to obtain the product (397 mg, 98%). 1H NMR (400 MHz, CDC13): 5 8.84 (s, 1H), 8.27 (s, 1H), 8.25 (s, 1H), 7.45 (d, 1H), 6.79 (d, 1H), 5.67 (s, 2H), 4.61 (m, 1H), 3.55 (m, 2H), 3.05-2.90 (m, 2H), 2.45-2.30 (m, 4H), 2.05 (m, 1H), 1.90 (m, 1H), 0.92 (m, 2H), —0.06 (s, 9H). MS (EI) m/z = 412.2 (M+H).

Step 2: (2E, Z)-3—[4—(7—[2-(TrimethylsilyDethoxyjmezhyl— 7H-pyrrolo[2,3-d]pyrimidin-4—yl)—1H— pyrazol—I—yl]cyclohexylideneacetonitrile To a solution of t—BuOK in THF (1.0 M, 0.255 mL, 0.255 mol) at 0 °C was added a solution of diethyl cyanomethylphosphonate (43 uL, 0.27 mmol) in THF (0.6 mL) se. The reaction was held for 10 minutes, then a solution of 3-[4—(7-[2-(trimethylsi1yl)ethoxy]methyl-7H-pyrrolo[2,3—d]— pyrimidin-4—y1)—1H—pyrazol-l —yl]cyclohexanone (100.0 mg, 0.2430 mmol) in TI-IF (0.34 mL) was added dropwise. After complete addition, the cooling bath was removed and the reaction was held at ambient temperature for 16 hours, at which point LCMS indicated complete on to yield the desired product as a mixture ofE and Z s (87.9 mg, 83%). 1H NMR (400 MHz, CD013): 5 8.84 (s, 0.5H), 8.83 (s, 0.5 H), 8.27 (d, 1H), 8.25 (s, 1H), 7.40 (3, 051-1), 7.39 (s, 0.511), 6.81 (d, 0.5H), 6.79 (d, 0.5H), 5.67 (s, 2H), 5.28 (s, 0.5H), 5.24 (s, 0.5H), 4.4 (m, 1H), 3.55 (m, 2H), 3.1—2.8 (m, 2H), 2.5- 2.1 (m, 6H), 0.92 (m, 2H), -0.06 (s, 9H). MS (EI) m/z = 435.2 (M+H).

Step 3: 7-[2—(Trimethylsilyl)ethoxy]methyl— 7H-pyrrolo[2, 3—d]pyrimidin-4—yl)-1H—pyrazolyl]- cyclohexylacetonitrile To (2E, Z)—3-[4—(7-[2—(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidinyl)—1H- pyrazol-l-y1]cyclohexylideneacetonitrile (42.0 mg, 0.0966 mmol) was added THF (0.5 mL). The resulting solution was cooled to -78 °C, and then 1.0 M L-Selectride® in THF (120 uL, 0.12 mmol) was added dropwise. The reaction was held at -78 °C for 1h at which point LCMS ted complete reduction. The reaction was quenched at -78 °C by addition of saturated aqueous NH4C1 and EtOAc, and was then allowed to warm to ambient temperature. The phases were separated and the aqueous phase was ted with additional EtOAc. The combined organic phase was washed with water, then saturated NaCl, and then was dried over MgSO4. The crude product was purified by column chromatography to obtain the t (26.5 mg, 63%). 1H NMR (400 MHz, : 8 8.84 (s, 1H), 8.32 (s, 1H), 8.25 (s, 1H), 7.39 (d, 1H), 6.81 (d, 1H), 5.67 (s, 2H), 4.53 (m, 1H), 3.52 (m, 2H), 2.6—1.4 (m, 11H), 0.92 (m, 2H), -0.06 (s, 9H). MS (EI) m/z = 437.2 (M+H).

Step 4: 3-[4—(7H—Pyrrolo[2, 3—djpyrimidin-4—yD—IH—pyrazol—I—yljcycloheagvlacetonitrile trifluoroacetate To 3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidinyl)-1 H-pyrazol-l — yl]cyclohexylacetonitrile (30.1 mg, 0.0689 mmol) was added DCM (1.0 mL) and TFA (1.0 mL). The ing mixture was stirred for 1 hour at ambient temperature, at which point LCMS indicated complete cleavage to the N—hydroxymethyl intermediate. The solvent was removed and to the residue was added methanol (1.0 mL) followed by ethylenediamine (37 uL, 0.55 mmol), afier which the reaction was stirred for 5 hours, at which point LCMS indicated complete reaction. The solvent was removed and the residue was purified by ative LCMS to provide the product as a TFA salt (24 mg, 83%). 1H NMR (400 MHz, CD3OD)I 5 8.91 (s, 1H), 8.82 (s, 1H), 8.45 (s, 1H), 7.84 (s, 1H), 7.31 (s, 1H), 4.69 (s, 1H), 2.58 (d, 2H), 2.54.5 (m, 9H). MS (EI) m/z = 307.10 (M+H).

Example 690: 5—({cis[4-(7H-Pyrrolo[2,3-d]pyrimidinyl)-lH—pyrazol—l-yl]cyclohexyl}thio)— 1H—1,2,4-triazolamine bis(trifluoroacetate) QS\( "'I‘\ l/U'rN '\5:3 2TFA N N Step I : trans-4—[4—(7-[2—(Trimethylsily0ethoxyjmethyl— 7H-pyrrolo[2, 3—d]pyrimidinyl)—IH— pyrazol—I-yl]cyclohexanol A solution of 4—[4-(7-[2—(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4—yl)-1 H- pyrazol-l-yl]cyclohexanone (662 mg, 1.61 mmol) in THF (5 mL) was cooled to 0 °C and m tetrahydroaluminate (2M in THF, 0.804 mL, 1.61 mmol) was added slowly. The mixture was allowed to warm slowly to ambient ature until LCMS indicated complete reduction. The on was cooled to 0 °C and quenched with dropwise addition of water (0.5 mL). DCM was added, and the e was stirred for 1 hour at ambient temperature, after which the precipitated solids were removed by filtration. The filtrate was reduced in vacuo to leave a white solid (0.63g, 99%). HPLC of the solid showed an approximately 4:1 ratio of trans to cis product. Tlc (6:3:1 EtOAc:hexaneszisopropanol) gave an Rf of 0.25 for the cis product , and 0.18 for the trans product.

The t was purified by flash chromatography on silica gel to recover 230 mg of the pure trans alcohol and 25 mg pure of the cis alcohol, and 350 mg ofmixed isomers. 1H NMR (400 MHz, CDC13)I 5 8.83 (s, 1H), 8.27 (s, 1H), 8.24 (s, 1H), 7.39 (d, 1H), 6.81 (d, 1H), .67 (s, 2H), 4.24 (m, 1H), 3.79 (m, 1H), 3.54 (m, 2H), 2.28 (m, 2H), 2.17 (m, 2H), 1.94 (m, 2H), 1.53 (m, 2H), 0.92 (m, 2H), 0.06 (s, 9H). MS (EI) m/z = 414 (M+H).

Step 2: trans-4—[4-(7—[2—(Trimethylsilyl)ethoxy]methyl— 7H-pyrrolo[2,3—djpyrimz'din-4—yD-1H—pyrazol— J—yljcyclohexyl methanesulfonate To trans[4—(7-[2—(trimethylsilyl)ethoxy]methyl—7H-pyrrolo[2,3-d]pyrimidinyl)-1 H- l—l-y1]cyclohexanol (154 mg, 0.372 mmol) was added DCM (1.0 mL) and TBA (73 uL, 0.52 mmol). The ing solution was then cooled to O "C and methanesulfonyl chloride (34 uL, 0.45 mmol) was added. The reaction was held for 2 hours, at which point tlc and LCMS indicated complete reaction. The reaction was partitioned between water and DCM, the phases were separated and the aqueous phase was extracted with additional solvent. The combined organic phase was washed with water, then saturated NaCl, then was dried over MgSO4 and reduced in vacuo to give the crude 2006/047369 product which was used without r purification (173 mg, 95%). 'H NMR (400 MHz, CDClg): 8 8.83 (s, 1H), 8-24 (s, 2H), 8.24 (s, 1H), 7.39 (d, 1H), 6.80 (d, 1H), 5.67 (s, 2H), 4.77 (m, 1H), 4.27 (m, 1H), 3.54 (m, 2H), 3.06 (s, 3H), 2.36 (m, 4H), 2.03 (m, 2H), 1.82 (m, 2H), 1.53 (m, 2H), 0.92 (m, 2H), —0.06 (s, 9H). MS (EI) m/z = 492.1 (M+H).

Step 3: 5-({cis[4-(7H-Pyrrolo[2,3-djpyrimidin—4-y0-IH-pyrazol—I-yl]cyclohexyl}thio)—IH-I.2,4- triazol-S-amine z_'fluoroacetate) To a solution of trans~4-[4-(7—[2-(trimethylsilyl)ethoxy]methyl-7H~pyrrolo[2,3-d]pyrimidin— 4-yl)-lH-pyrazol—1-yl]cyclohexyl methanesulfonate (42 mg, 0.085 mmol) in DMF (800 uL) was ‘ added 3-amino-lH-l,2,4—triazolethiol (30 mg, 0.26 mmol) and KZCOJ (36 mg, 0.26 mmol). The reaction was sealed and held at 100 0C for 2 hours at which point LCMS indicated conversion to desired product. The reaction was diluted with water and extracted successively with ether, ethyl acetate, and 3:1 chlorofonn:isopropyl alcohol. The combined organic phase was washed with water, then ted NaCl, dried over MgSO4 and d in vacuo, and the crude product was purified by column tography to give 5-( {cis[4—(7—{[2-(trimethylsilyl)ethoxy]methyl}—7H-pyrrolo[2,3- d]pyrimidinyl)-lH—pyrazol-l—yl]cyclohexyl}thio)—1H—l,2,4-triazol-3—amine (27.3 mg, 63%). To the product was added DCM (0.5 mL) and TFA (0.5 mL), and the reaction was stirred for 1 hour at ambient temperature at which point LCMS indicated complete cleavage to the N-hydroxymethyl intermediate. The solvent was removed and to the residue was added methanol (1.0 mL) followed by NH40H (0.3 mL), the reaction was stirred for 16 hours at which point LCMS indicated complete deprotection. The solvent was removed and the residue was purified by preparative LCMS to provide the product as a bis-TFA salt (15.1 mg, 29%). 'H NMR (400 MHz, CD3OD)I 8 8.77 (s, 1H), 8.72 (s, 1H), 8.37 (s, 1H), 7.74 (d, 1H), 7.21 (d, 1H), 4.40 (m, 1H), 3.97 (m, 1H), 2.25(m, 2H), 2.04 (m, 6H).

MS (EDQm/z = 382.2 (M+H).

Example 691: ({cis[4-(7H—Pyrrolo[2,3-d]pyrimidin-4—yl)-lH—pyrazol-l-yl]cyclohexyl}- methyl)thio]—4H—l,2 ,4-triazol-3—yl}methanesulfonamide trifluoroacetate ,— HN. ,o / 003; "l? \ N N Step I. N[(cis[4—(7—[2—(Trimethylsilyl)ethoxyjmethyl- 7H-pyrrolo[2, 3-d]pyrimidinyl)-IH— l-I-yljcyclohexylmethyljthioj-4H-1,2,4-triazol~3-ylmethanesulfonamide —[(cis—4—[4~(7~[2~(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3—d]pyrimidin—4-yl)-l H- l-l—yl]cyclohexylmethyl)thio]~4H-1,2,4-triazolamine (30.00 mg, 5.706E-5 mol) was dissolved in DCM (2.00 mL, 0.0312 mol) with TEA (0.024 mL, 0.00017 mol) and was cooled at 0 °C.

To the reaction was added methanesulfonyl chloride 6 mL, 86 mol) and the resulting mixture was stirred at 0 °C for 60 minutes, at which time LCMS analysis showed mostly product.

The reaction was chromatographed on silica gel using EtOAc as eluent to give the product. LC/MS (M+1)+:604 Step 2. N[(cis-4—[4-(7H-Pyrrolo[2, 3-d]pyrimidinyl)-1H—pyrazol-I -yl]cyclohexylmethyl)thio]— 4H—1, 2,4—triazol—3~ylmethanesulfonamide Into a l-neck round—bottom flask [A] cis[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H- pyrrolo[2,3-d]pyrimidinyl)-l H—pyrazol-l ~yl]cyclohexylmethyl)thio]~4H-1 riazol-3 -ylmethane- ulfonamide (0.025 g, 0-000041 mol) was dissolved in DCM (3.00 mL, 0.0468 mol) and TFA (mL, 0.006 mol) was added. The reaction was stirred at 25 °C for 16 hours at which time LCMS analysis showed no starting material present. The reaction was concentrated using a rotary evaporator and was dissolved in methanol (2.00 mL, 0.0494 mol) and 16 M ammonia in water (0.2 mL) was added. The reaction was stirred at 25 °C for 3 hours at which time LCMS analysis showed no starting al present. The reaction was concentrated using a rotary evaporator and was purified by prep LC to give the product as the tfifluoroacetate salt. LC/MS (M+l)+:474, 1H NMR(CD3OD): 8.87 (s, 1H), 8.82 (s, 1H), 8.45 (s, 1H), 7.85 (d, 1H), 7.33 (d, 1H), 4.48 (m, 1H), 3.36 (s, 3H), 3.23 (d, 2H), 2.30 (m, 2H), 2.04 (m, 3H), 1.85 (m, 4H).

Example 692: [cis[4-(7H-Pyrrolo [2,3-d]pyrimidin-4—yl)-lH-pyrazol-l-yl]-l-(1H-1,2,4-triazol- 1—yl)cyclohexyl] acetonitrile «"17 N ‘ N AN HNWNOW— H 1H-1,2,4-Triazole (91.0 mg, 0.00132 mol), DBU (174 uL, 0.00070 mol), [A] 4-[4-(7-[2- (trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidiny1)-1H—pyrazol-l ~yl]cyclohexylidene~ acetonitrile (86.4 mg, 0.000199 mol), and ACN (2.0 mL) were stirred at It. After 4d, LCMS showed about 58 area% t (two peaks, M+H 504, ratio 1:1). The DBU in the reaction was neutralized with TFA. The product was isolated by prep HPLC using a 30 mm x 100 mm C18 column; 32% CH3CN—H20 (0.1%TFA), 1 min, to 47% at 6 min; 60 mL/min; detector set at 254 nm; retention time, .1(A) & 5.4 (13) min. The eluent was concentrated using a rotary evaporator to give 22 mg of (A) & 36 mg of (B). ection: The products were dissolved separately in TFA (0.5 mL) and stirred for 1h.

LCMS showed sion to the hydroxymethyl derivative (M+H 404). The solutions were concentrated using a rotary evaporator to remove TFA. Methanol was added, and the resulting mixtures were concentrated again. The resulting residue was ved in methanol (1 mL), and ammonium ide (0.25 mL) added. The on was stirred 0.5h. LCMS showed complete de- protection (M+H 374) and the mixture was then concentrated by roto—evaporation. Each isomer was isolated by prep HPLCMS using a 19 mm x 100 mm C18 column; 15% CH3CN-HZO (0.1% TFA.), 1.5 min, to 32% at 6 min; 30 mL/min; detector set at m/z 374; retention time, 4.5 min (A) & 4.7 min (B) .

The eluates were freeze dried. Yield 13 mg isomer A and 24 mg isomer B (TFA salts, white solids).

NMR is (including NOE & COSY) was consistent with expectation for the structures, with A=cis, and B=trans. NMR (erMSO) 5 cis: 12.94 (br s, 1H, NH); 8.95 (s, 1H); 8.87 (s, 1H); 8.81 (s, 1H); 8.42 (s, 1H); 8.14 (s, 1H); 7.85 (m, 1H); 7.22 (m, 1H); 4.48 (m, 1H, NCH); 3.12 (s, 2H); 2.84 (m, 2H); 2.07 (m, 4H); 1.69 (m, 2H). MS(ES) 374 (M+l). trans: 12.85 (br s, 1H, NH); 8.94 (s, 1H); 8.89 (s, 1H); 8.84 (s, 1H); 8.47 (s, 1H); 8.11 (s, 1H); 7.84 (m, 1H); 7.26 (m, 1H); 4.50 (m, 1H, NCH); 3.48 (s, 2H); 2.42—2.10 (m, 8H). MS(ES) 374 (M+l).

Example 705: 3—1—[4—(7H—Pyrrolo[2,3—d]pyrimidin—4—yl)-IH-pyrazol-l—yl]but—3—yn—1—yl-benzo- nitrile trifluoroacetate "t \ \ N/ pg Step 1: 3—{1—[4~(7—{[2—(Trimezhylsilyl)ethoxy]methy1}— 7H-pyrrolo[2,3—d]pyrimidin~4~yl)~1H-pyrazol— 1 -y.’]but-3—yn-J —yl}benzonitrile "t \ V— N/ N 1 M Diisobutylaluminum hydride in hexane (0.31 mL) was added dropwise to a solution of methyl 3-(3-cyanophenyl)-3~[4-(7-[2-(t1imethylsilyl)ethoxy]methyl-7H—pyrrolo[2,3-d]pyrimidin yl)-1H-pyrazol—l~y1]propanoate (100 mg, 0.0002 mol) (prepared by using a procedure analogous to Example 712, Step 1) in DCM (3 mL, 0.05 mol) and the e was cooled to -78 °C. The reaction ‘ mixture was stirred at —78 °C for 4 h and was afterward quenched with cold methanol (3 mL, 0.07 mol). The reaction was allowed to wann to 0 °C and ium ate (60 mg, 0.0004 mol) and Bestmann-Ohira reagent (1.5 eq, 57 mg) (E. Quesada et al, Tetrahedron, 62 (2006) 6673—6680) were added. The reaction was stirred at room temperature overnight, and then partitioned between ethyl acetate and water. The organic layer was washed with saturated NaCl, dried over MgSO4, filtered and concentrated to give the crude product. The crude product was purified using silica gel /I-Iexane 1:3 to 1:1) to give the desired product, 3—{1—[4-(7-{[2-(trimethylsilyl)ethoxy]- }-7H-pyrrolo[2,3-d]pyrimidin-4—yl)-lH-pyrazol-l—yl]but—3—yn—l—yl}benzonitrile (40 mg of mixture). m/z = 469 (M+1).

Step 2: 3-1 -[4-(7H-Pyrrolo[2, 3-djpyrimidin-4~yl)-1H—pyrazol—I-yl]but~3-yn—1-ylbenzonitrile trifluoroacetate Using a procedure analogous to Example 712, Step 4, the title compound was prepared (4.5 mg, 46%) as an amorphous white solid. 1H NMR (500 MHz, DMSO): 5_ 12.5 (b, 1H), 9 (s, 1H), 8.8 (s, 1H), 8.4 (s, 1H), 8 (s, 1H), 7.8 (m 2H), 7.7 (s, 1H), 7.6 (m, 1H), 7 (m, 1H), 5.9 (m, 1H), 3.4 (dd, 1H), 3.2 (dd, 1H), 2.9 (s, 1H). m/z = 339 (M+1). e 706: 3-{1-[4-(7H—Pyrrolo[2,3~d]pyrimidin-4—yl)—1H-pyra zol-l—yl]but—3—yn—1—yl}benz— aldehyde trifluoroacetate Using the procedure of Example 705, the title compound was prepared as a secondary product (4.5 mg, 46%) as an amorphous white solid. 1H NMR (400 MHz, CD013): ,5 10 (s, 1H), 9 (s, 1H), 8.8 (s, 1H), 8.4 (s, 1H), 8 (s, 1H), 7.9 (m 1H), 7.8 (m, 1H), 7.7 s, 1H), 7.6 (m, 1H), 7.1 (s, 1H), 5.9 (m, 1H), 3.4 (dd, 1H), 3.2 (dd, 1H), 2.9 (s, 1H). m/z= 342.

Example 712: 4-[1-(3-Methoxyphenylpropyl)-1H-pyrazolyl]- rolo[2,3-d]pyrimidine trifluoroacetate N-N<© " o HOJW’FF.

N," \ F 1‘ ’ N NH Step 1: Methyl y1—3-[4—(7-[2-(trimethylsilyl)ethoxyjmethyl-7H—pyrrolo[2,3-d]pyrimidin~4—yl)— IH-pyrazol-I-yl]propanoate A solution of methyl (2E)-3—phenylacrylate (500 mg, 0.003 mol) in ACN (2 mL, 0.04 mol) was slowly added to a solution of 4-(1H-pyrazolyl)[2-(trimethylsilyl)ethoxy]methyl-7H- o[2,3~d]pyrimidine (0.5 g, 0.002 mol) in ACN (2 mL, 0.04 mol) and DBU (500 "L, 0.003 mol).

The on was stirred at room temperature over the weekend. The reaction was partitioned between water and EtOAc. The organic layer was washed with saturated sodium chloride, dried over MgSO4, filtered and concentrated to give an oil. The product was purified by FCC on silica gel using EtOAc/Hexane (1:2 to 1:1) gave methyl 3-phenyl[4-(7—[2-(trimethylsilyl)ethoxy]methyl-7H— pyrrolo[2,3-d]pyrimidinyl)—lH-pyrazol-l -yl]propanoate (500 mg, 70%) as a semisolid residue. 1H NMR (400 MHz, CD013): ii 8.9 (s, 1H), 8.4 (s, 2H), 7.4 (m, 5H), 6.8 (d, 1H), 6 (m, 1H), 5.7 (s, 2H), 3.7-3.8 (m, 3H), 3.6 (m, 2H), 2.2 (m, 1H), 1.4 (m, 2H), 1.1 (m, 2H), 0.02 (s, 9H), m/z = 478 (M+1).

WO 70514 Step 2: 3-Phenyl—3—[4—(7-[2-(trz'methylsilyDet/zoxyjmethyl- 7H—pyrrolo[2,3—dprrimidin—4-yl)—1H— pyrazol-I-yl]propan-1 ~01 ll \ x I N N Diisobutylaluminum hydride in hexane (1 M, 0.69 mL) was added to a solution of methyl 3— phenyl[4—(7—[2—(trimethylsilyl)ethoxy]methyl—7H—pyrrolo[2,3—d]pyrimidin—4—yl)—l H—pyrazolyl]- propanoate (150 mg, 0.00031 mol) in DCM (3 mL, 0.05 mol) and the e was cooled to -78 °C under a nitrogen atmosPhere. The reaction was stirred for 1 h at -78 °C and was allowed to warm to room temperature for 4 hrs. The reaction was quenched with methanol (100 uL), and saturated ammonium chloride (100 pL), and then taken up in ethyl acetate dried over MgSO4 and filtered. The filtrate was concentrated to give y1~3-[4—(7-[2-(tn'methylsilyl)ethoxy]methyl—7H-pyrrolo[2,3- d]pyrimidin—4-yl)-lH—pyrazol—l-yl]propan-1—ol (130 mg, 92%) as an oil. m/z = 450 (M+l).

Step 3: 4»[1—(3—Methoxy—I—phenylpropyl)-IH-pyrazol—4-ylj- 7—[2-(trimethylsilyvethoxyjmethyl-7H- pyrrolo[2, rimidine [:12\ \ \I’ Si...

N N l__/ Sodium hydride (9.6 mg, 0.00040 mol) was added to a solution of 3-phenyl-3—[4-(7-[2-(tri- methylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin—4-yl)-lH—pyrazol-l —yl]propan-l-ol (120 mg, 0.00027 mol) in DMF (3 mL, 0.04 mol) and the mixture was cooled to 0 °C. The on was stirred for 20 min and methyl iodide (22 uL, 0.00035 mol) was added. The reaction was allowed to warm to room temperature and stirred overnight. The reaction was partitioned between water and EtOAc. The organic layer was washed with saturated NaCl, dried over MgSO4, filtered and'concentrated to give 4— WO 70514 [1 ~(3~methoxy-l —phenylpropyl)v1 H-pyrazol—4—yl][2-(tn‘methylsily1)ethoxy]methyl-7H-pyrrolo[2,3 - midine (100 mg, 88%) as a semisolid. m/z = 464 (M+1).

Step 4: 3—Methoxy—I—phenylpmpyD-IH-pyrazolyl]- 7H—pyrrola[2,3-d]pyrz'midine trifluoroacetate Trifluoroacetic Acid (2 mL, 0.02 mol) was added to a mixture of 4-[1-(3—methoxy-l— propyl)-lH-pyrazol—4-yl]-7~[2-(trimethylsilyl)ethoxy]methyl-7H—pyrrolo[2,3-d]pyrimidine (80 mg, 0.0002 mol) in DCM (3 mL, 0.05 mol) at room ature. The starting material was consumed after stirring for 2hrs and the reaction solution was concentrated to remove the TFA. The crude reaction was diluted with methanol (3 mL, 0.07 mol) and was treated with ethylenediamine (0.3 mL, 0.004 mol) at room temperature. The reaction mixture was stirred for 18 he and was concentrated and purified using HPLC on a C-18 column eluting with an ACN: water gradient containing 0.2% TFA, to give the title compound (43 mg, 60%) as a white amorphous solid. 1H NMR (400 MHz, CDClg): 358.9 (s, 1H), 8.8 (s, 1H), 8.4 (s, 1H), 7.8 (s, 1H), 7.4 (m, 1H), 7.3 (m, 5H), 7.2 (b, 1H), 5.7 (m, 1H), 3.3 (m, 1H), 3.2 (s, 3H), 2.7 (m, 1H), 2.4 (m, 1H). m/z = 334 (M+1).

Example 715: —(7H-Pyrrolo[2,3-d]pyrimidin-4—yl)-lH—pyrazol—1-yl]hut—3-en-l-ylbenzo- nitrile trifluoroacetate i //N N-N .

/ Ho’ufi/F . FF "i \ \ N NH A mixture of [4[1-(3-bromophenyl)but-3—en-l—y1]~1H—pyrazolA—yl—7H~pyrrolo[2,3-d]~ pyrimidine (20 mg, 0.00005 mol) in DMF (2 mL, 0.02 mol) and zinc cyanide (60 mg, 0.0005 mol) was degassed with a nitrogen stream. The mixture was then treated with tetrakis(triphenyl- phosphine)palladium(0) (40 mg, 0.00003 mol), again degassed with nitrogen, and was then heated in a microwave reactor to 170 °C for 15 min. The reaction was allowed to cool, was filtered and purified by HPLC on a C-18 column eluting with an ACN/water/TFA gradient to give the title compound (10 mg, 40%) as a white amorphous solid.

‘H NMR (400 MHz, DMSO): ,5 8.9 (s, 1H), 8.8 (s, 1H), 8.4 (s, 1H), 7.9 (s, 1H), 7.8 (m, 3H), 7.6 (m, 1H), 7.1 (b, 1H), 5.6-5.8 (m, 2H), 5.1 (d, 1H), 5 (d, 1H), 3.3 (m, 1H), 3 (m, 1H). m/z= 341 (M+1).

Example 716: 4-1—[1-(3-Bromophenyl)but-3—en-l—ylj—1H—pyrazolyl-7H-pyrrolo[2,3-d1- pyrimidine N / 'L Zx/ Step I: 3-(3—Brom0phenyl)—3—[4-(7—[2—(trimethylsilyUethonymethyl- 7H—pyrrolo[2, 3-d]pyrimidin-4— yl)-IH—pyrazol—I—ylj’propanal "Ex\SifLL ’ N utylaluminum hydride in hexane (1 M, 4 mL) was added to a ~78 °C on of ethyl 3-(3-bromophenyl)-3—[4—(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyxrolo[2,3—d]pyrimidinyl)-lH- pyrazol—l—yl]propanoate (600 mg, 0.001 mol) in DCM (6 mL, 0.09 mol). After stirringfor 4 h, the reaction was quenched with cold methanol (300 pL), and then saturated ammonium chloride (500 uL) was added and the resulting solution was stirred for 1 h. The reaction was partitioned between water and EtOAc. The organic layer was washed with brine, dried over Mgsoq, filtered and trated.

The product was d by flash chromatography on silica gel eluting with hexane: EtOAc, (2:1 to 1:2), to give 3-(3~bromophenyl)-3—[4—(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]- pyrimidin—4—yl)—1H—pyrazol-l—yl]propanal (400 mg, 70%) as an oil.. II-I NMR (400 MHz, CDC13): 6 9.9 (s, 1H), 8.9 (s, 1H), 8.4 (s, 2H), 7.6 (d, 1H), 7.5 (cl, 1H), 7.4 (d, 1H), 7.3-7.4 (m, 2H), 6.8 (d, 1H), 6.1 (m, 1H), 5.7 (s, 2H), 4 (m, 1H), 3.6 (m, 2H), 3.3 (dd, 1H), 1.0 (m, 2H), 0.01(s, 9H). m/z = 526, 528 (NI-H).- Step 2: 4[1~(3—BromophenyUbut—3-en—J321]-1H-pyrazol—4-yl[2—(trimethylsilyDethoxy]methyl— 7H—pyrrolo[2, 3—d]pyrimidine ‘ 236 2006/047369 le \ x z N N Potassium tert—butoxide in THF (EM, 200 uL) was added to a solution of methyltriphenyl- phosphonium iodide (80 mg, 0.0002 mol) in THF (2 mL, 0.02 mol) at 0 °C. The reaction was stirred at room temperature for 1h and then cooled to ~78 °C. The 3~(3~bromophenyl)~3-[4-(7—[2-(trimethyl- ethoxy]methyl-7H-pyrrolo[2,3—d]pyrimidiny1)-lH-pyrazol-l-yl]propanal (90 mg, 0.0002 mol) in THF (2 mL, 0.02 mol) was added dropwise. The reaction was allowed to warm to room temperature gradually. The reaction was partitioned between water and EtOAc. The organic layer was washed with saturated NaCl, dried over MgSO4, filtered and concentrated to give an oil. The product was purified by FCC on silica gel eluting with EtOAczHexane, (1:1). to give 4[1-(3- bromophenyl)but—3-en~1 —yl]-1H—pyrazolyl[2—(trimethylsilyl)ethoxy]methy1-7H-pyrrolo[2,3— d]pyrimidine (35 mg, 40%) as an oil. m/z = 524, 526 (M+1).

Step 3: 4-1—[1 —(3—Bramophenyl)but—3—en—1—yl]—1H—pyrazol~4—yl—7H—pyrrolo[2, 3-d]pyrimidine Using a procedure analogous to Example 712, Step 4, but using 4[1-(3-bromophenyl)but— 3—enyl]—1H-pyrazol—4—yl-7—[2-(trimethylsilyl)ethoxy]methyl~7H-pynolo[2,3—d]pyrimidine the title compound was prepared (10 mg, 30%) as a white amorphous solid, lH NMR (400 MHz, DMSO): {5 8.9(s,1H), 8.8(s,1H), 8.4(s,1H), 7.8(s,1H), 7.7(s,1H), 7.5 (m,2H), 1H), 7.1(s,lH), 2H), .2(d,1H), 5.0(d,lH), 3.2(m,1H), 3.0(m,1H). m/z = 394, 396 (M+1).

Example 717: -Difluoro)—1—[4~(7H-pyrrolo[2,3-d]pyrimidin—4—yl)—lH—pyrazol-l-yl]but en-l-ylbenzonitrile N\ux\ N NH WO 70514 Step 1: 4—{1-[1—(3—Br0mopheny1)-4, 4-difluorobut—3—en—1~yl]—1H-pyrazol—4~yl} —7—{[2—(trimethylsilyD- ethoxy]methyl}—7H—pyrrolo[2,3-d]pyrimidine N \ "\N/ N \Si/x 00/" To a solution of 3-(3~bromopheny1)[4-(7-[2—(trimethylsilyl)ethoxy]methyl-7H—py1rolo[2,3- d]pyrimidin—4~yl)—1H-pyrazol—l—yl]propanal (0.05 g, 9 mol) in MN—dimethylacetamide (2 mL, 0.02 mol) was added triphenylphosphine (0.1 g, 0.0006 mol), dibromodifluoromethane (50 uL, 0.0006 mol) and 0.76 M zinc in THF (0.7 mL). The reaction was stirred at room temperature for 18 113. The reaction was partitioned between water and EtOAc. The organic layer was washed with saturated NaCl, dried over MgSO4, filtered and concentrated to give an oil. The product was purified by FCC ID on silica gel eluting with EtOAc, Hexane (1:2) to give 4~{1-[1~(3-bromophenyl)~4,4—difluorobut—3-en- 1H-pyrazol-4—yl}~7-{[2-(trimethylsilyl)ethoxy]methyl}—7H-pyrrolo[2,3—d]pyrimidine (20 mg, 40%) as a clear oil. m/z = 560, 562 (M+1).

Step 2: 4-1 -[1~(3-Bromophenyl)—4, 4-difluor0butenyl]-1H'—pyrazol-4—yl- 7H—pyrralo[2, 3-d]- 1 5 pyrimidine MK x \ N NH Using a procedure analogous to Example 712, Step 4, but using 4-{1-[1-(3—bromophenyl)—4,4- difluorobut-B-cn-l -yl]-1H-pyrazolyl} {[2-(trimethylsi1y1)ethoxy]methyl} ~7H-pyrrolo [2,3— d]pyrimidine, the compound 4—1—[1-(3—bromophenyl)-4,4-difluor0butenyl]-1H—pyrazolyl-7H- pyrrolo[2,3-d]pyrimidine was prepared (30 mg, 99%) as an oil. m/z = 430, 432 (M+1).

Step 3: 3-4, 4-Difluor0-1 ~[4-(7H-pyrrolo[2, 3-d]pyrimidinyl)—IH-pyrazol-I~yl]but—3-en-—I—yl— benzonitrile N\ \ N NH A mixture of 4[1~(3-brornophenyl)-4,4-difluorobutenyl]-lH-pyrazol—4—yl—7H— pyrrolo[2,3—d]pyrimidine (30 mg, 0.00007 mol) in DMF (2 mL, 0.02 mol) and zinc cyanide (80 0.0007 mol) was degassed with nitrogen. The e was then treated with tetrakis(tripheny1- phosphine)palladium(0) (50 mg, 0.00004 mol) and was degassed with nitrogen, and then was heated in microwave at 170 °C for 15 min. The reaction was then allowed to cool, filtered and purified by HPLC on a C-18 column g with an ACN/water/TFA gradient to give the title compound (10 mg, %) as a white amorphous solid. 1H NMR (400 MHz, DMSO): 58.9 (s, 1H), 8.7 (s, 1H), 8.4 (s, 1H), 7.9 (s, 1H), 7.7 ~7.8 (m, 3H), 7.5 (m, 1H), 7.1 (m, 1H), 5.7 (m, 1H), 4.3—4.4 (m, 1H), 3.1 (m, 1H), 2.9 (m, 1H). m/z = 377 (M+1).

The following compounds in Table 14 were prepared as ted in the column labeled "Prep. Ex. No." and the details of certain ary synthetic procedures are provided following Table 14.

Table 14 4—D -( 1 -cyclopenty1buten-1 - yl)-lH-pyrazol—4-y1]-7H— pyrrolo[2,3-d]pyrimidine- tn'fluoroacetate salt 4—[1 -(l -methy1buten-1 -yl)-1H- pyrazol—4—yl]-7H-pyrrolo[2,3-d]- pyrimidinptrifluoroacetatesalt 1 pentyl-2— ropylethy1)- 1 H—pyrazol yl]-7H-pyrrolo[2,3~d]- pyrimidinptrifluoroacetate salt 4-[1 -(1-cyclopentylbutyn—l - yl)—1H-pyrazol—4—yl]—7H- pyrrolo[2,3-d]pyrimidine trifluoroacetate salt 4-[1 -(1 -cyclopenty]butyl)-1H— pyrazolyl]—7H—pyrrolo[2,3—d]— pyrimidinga trifluoroacetate salt 4-[1-(1-cyclopentyl-4,4- difluorobut—3-en-1 H- pyrazol-4—yl]-7H-pyrrolo[2,3-d]— pyrimidine trifluoroacetate salt 4—1 -[4,4—difluoro- l —(tetrahydro- furan-S-y1)buten~1 -yl}—1H- pyrazoly1-7H-pyrrolo[2,3-d]- pyrimidine trifluoroacetate salt 4-[1-(1 -methylbuten—l —yl)- 1H- pyrazolyl]-7H—pyrrolo[2,3-d]- pyrimidine roacetate salt 4-[1-(1-cyclopropyl-4,4—difluoro- but-3—en-l —y1)—l H—pyrazol—4-yl]— 7H-pyrrolo[2,3-d]pyrimidine trifluoroacetate salt 4-[1-(1-cyclopentyl-4,4—difluoro- buty1)-lH-pyrazol—4-yIJ-7H- pyrrolo[2,3-d]pyrimidine trifluoroacetate salt 3-(1 -methylcyclopentyl)-3—[4- (7H—pyrrolo[2,3-d]pyrimidin yl)—1H—pyrazol-l -yl]propane- nitrile trifluoroacetate salt (3R)- and (3S)—4,4-dimethyl—3- [4—(7—[2—(trimethylsi1yl)ethoxy]— methyl-7H—pyrrolo[2,3-d]— pyrimidin—4—yl)-l H-pyrazol—l — yl]pentanenitrile trifluoroacetate salt ano[4-(7H—pyrrolo[2,3— d]pyn'midin—4-yl)—1H~pyrazol-l -' yl]ethylcyclopropanecarbonitrile trifluoroacetate salt N-[(1cyano[4-(7H- pyrrolo[2,3-d]pyrimidinyl)- lH-pyrazol—l ~yl]ethylcyclo— pentyl)methy]]benzamide 3-1 -[(Benzyloxy)methyl]cyclo- pentyl[4-(7H-pyrrolo[2,3-d]— pyrimidinyl)-1 H—pyrazol-I - yl]propanenitrile tn'fluoroacetate salt 3-[1 {methylsulfonyl)pyrrolidin- 3-y1][4-(7H-pyrrolo[2,3-d]~ pyrimidin—4-yl)—1H—pyrazol-1 - yl]propanenitrile trifluoroacetate salt N‘-cyano(cyanomethyl)[4- (7H-pyrrolo[2,3-d]pyrimidin-4‘ yl)-1 H-pyrazol-l-y1]pipen'dine-l - carboximidamide 4[2,2,2-trifluoro—1 -(1H— imidazol-Z-y1methyl)ethyl]-1 H- pyrazol-4—yl~7H—pyrrolo[2,3-d]— pyrimidine 4-(1-(1R)—2,2,2-trifluoro-l -[(4- —1 ,3—thiazol—2-y1)— ]ethyl—1H-pyrazoly])- 7H-pyrrolo[2,3-d]pyrimidine 4-1 -[1 -(trifluoromethyl)but—3—yn- 1-y1]—1H—pyrazol—4—y1-7H- pyrrolo[2,3-d]pyrimidine 4-1 —[ l —(trifluoromethyl)but-3—en- 1-yl]-1H—pyrazol~4-yl-7H— pyrrolo[2,3-d]pyrimidine 4-1 -[1 -(trifluoromethy1)butyl] ~ 1H-pyrazol—4-yl—7H-pyrrolo- [2,3-d]pyrimidine 4[4,4—difluoro-l uoro— )but-3~en-1 -yl]- lH- lyl~7H—pyrrolo[2,3—d]- 'midine 4—1—[4,4—difluoro-l-(trifluoro- methyl)butyl]-1H-pyrazolyl— 7H-pyrrolo[2,3—d]pyrimidine "' Step 1 of example 731 was modified as follows: The Ph3P and CFzBrz were combined in DMAC at 0 °C and then allowed to warm to room temperature until the ylid ion was complete as determined by LCMS. The solution of the ylid was then re-cooled to 0 °C and the aldehyde and zinc were added to the ylid solution and the reaction was slowly warmed to room temperature. e 727: 4-[1-(l-Cyclopentylbuten-l-yl)-1H—pyrazolyl]-7H-pyrrolo[2,3-dlpyrimidine trifluoroacetate salt N \ \ N NH 'TFA Step 1: (2E)—3—Cyclopentylacrylic acid To a solution of malonic acid (1.06 g, 10.2 mol) in pyridine (1.2; mL) was added piperidine (0.15 mL) and cyclopentaneearbaldehyde (1.00 g, 10.2 mmol). The mixture was heated to 40 °C for 2 hours, followed by stirring at room temperature for 16 hours. The mixture was then cooled in an ice bath and 2N HCl was added to acidify. The product was extracted with ether. The ether extract was washed with aq. HCl and brine, dried over sodium sulfate, filtered, and the solvent was removed in vacuo to afford the product (1.30 g, 77%), which was used without fmther purification. 1H NMR (300 MHz, CD013): 57.06 (dd, 1H), 5.80 (dd, 1H), 2.70-2.54 (m, 1H), 1.93-1.32 (m, 8H); MS(ES):141(M+H).

Step 2. Methyl (2E)cyclopentylac;ylate To a solution of (2E)-3~cyclopentylacrylic acid (1.3 g, 9.3 mmol) in DCM (65 mL) at 0 °C was added oxalyl chloride (3.1 mL, 37 mmol), dropwise. The resulting solution was stirred at 0 °C for 40 minutes, then at room temperature for 2 hours. The volatiles were ated to afford - cyclopentylacryloyl chloride as a colorless liquid. A n of this (2E)—3~cyclopentylacryloyl chloride (0.75 g, 4.7 mol) was dissolved in methanol (10 mL) and the resulting solution was d for 2 hours. The solvent was evaporated to afford the product (700 mg, 96%). 1H NMR (300 MHz, CDC13): 56.94 (dd, 1H), 5.79 (dd, 1H), 3.71 (s, 3H), 2.66—2.50 (m, 1H), 1.92- 1.27 (m, 8H).

Step 3. Methyl 3—cyclopentyl—3-[4—(7—[2-(trimethylsilyDethoxyjmethyl~7H—pyrrolo[2,3—d]pyrimidin—4— -pyrazol— I~yl]propanoate To a solution of 4—(1H-pyrazolyl)[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3- d]pyn'midine (2.9 g, 9.2 mmol) and methyl (2E)-3—cyclopentylacrylate (1.70 g, 11.0 mmol) in ACN (100 mL), was added DBU (2.7 mL, 18 mmol). The resulting mixture was stirred for 96 hours. The ACN was d in vacuo, and the resulting residue was dissolved in ethyl acetate. This on was washed with 1.0 N HCl, followed by brine, and then dried over sodium sulfate, and the solvent removed in vacuo. Flash column chromatography (eluting with a gradient from 0-70% ethyl acetate in hexanes) afforded the product (2.73 g, 63%). 1H NMR (300 MHZ, CDC13): 5, 8.84 (s, 1H), 8.28 (s, 2H), 7.39 (d, 1H), 6.81 (d, 1H), 5.67 (s, 2H), 4.46 (dt, 1H), 3.60 (s, 3H), 3.54 (t, 2H), 3.18 (dd, 1H), 2.89 (dd, 1H), 2.59-2.42 (m, 1H), 1.95—1.80 (m, 1H), 1.75—1.10 (m, 7H), 0.92 (t, 2H), -0.06 (s, 9H); MS(ES):470(M+H).

Step 4. 3-Cyclopentyl—3-[4-(7-[2-(trimethylsibzl)ethoxy]methyl—7H—pyrrolo[2,3-d]pyrimidin—4—yl)~1H- pyrazol—I—yUpropanal To a solution of methyl 3-cyclopenty1—3—[4-(7~[2~(trimethylsilyl)ethoxy]methyl-7H—pyrrolo- [2,3-d]pyrimidinyl)-lH-pyrazol—l opanoate (0.501 g, 1.07 mmol) in THF (5.0 mL) at -78 l’C was added 1.00 M diisobutylaluminum e in DCM (2.35 mL) dropwise. The on was stirred with gradual warming to ~10 °C over the course of 2 hours. At this temperature, a further portion of 1.0 M diisobutylaluminum hydride in DCM (1.50 mL) was added. When the reaction was determined to be complete by LCMS, a saturated solution of K/Na taitrate was added, followed by ether. The resulting mixture was stirred for two hours at room temperature. The organic layer was separated and washed with water, and brine, then dried over sodium sulfate and the solvent was removed in vacuo to give a viscous oil, which was used without further purification.

MS(ES):442(M+H).

To a solution of oxalyl chloride (0.108 mL, 1.28 mmol) in DCM (10.0 mL) at -78 °C was added DMSO (151 uL, 2.13 mmol). After ng for 5 minutes, 3—cyclopenty1—3~[4—(7—[2— (trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidinyl)-1H-pyrazol-l -yl]propan01 (47 1 mg, 1.07 mmol) in DCM (3.00 mL) was added. The mixture was stirred for 30 minutes at -78 °C.

TEA (594 uL, 4.26 mmol) was then added. The resulting mixture was then allowed to warm to room ature over the course of 30 minutes. Water was added, and the layers were separated. The organic layer was washed successively with 0.1 N HCl, water, saturated sodium bicarbonate solution, and brine, and was then dried over sodium sulfate and the solvent was removed in vacuo. Flash column chromatography (eluting with a gradient of 0-60% ethyl e in hexanes) afforded the product (384 mg, 82%). lH NMR (300 MHz, CDCls): 8 9.73 (s, 1H), 8.87 (s, 1H), 8.71 (br s, 1H), 8.30 (s, 1H), 7.47 (br s, 1H), 6.88 (br s, 1H), 5.69 (s, 2H), 4.66~4.49 (m, 1H), 3.54 (t, 2H), 3.40 (ddd, 1H), 2.95 (ddd, 1H), 2.55-2.44 (m, 1H), 2.01—1.21 (m, 8H), 0.98 (t, 2H), 0.00 (s, 9H); MS(ES):440(M+H).

Step 5. 4—[1—(1—Cyclopentylbut-3—en—1~yl)—1H—pyrazol—4~yl]—7—[2—(trimethylsilyDethoxyjmethyl—7H— pyrrclo[2,3-d]pyrimidine To a solution of 1.0 M ium tert—butoxide in THF (0.207 mL) in THF (2.0 mL) at 0 °C was added tn'phenylmethylphosphonium bromide (77.8 mg, 0.218 mmol). The resulting mixture warmed to room ature and allowed to stir for 30 minutes. A solution of 3-cyclopentyl[4-(7- [2—(tn'methylsilyl)ethoxy]methyl-7H-pyrrolo[2,3—d]pyrimidinyl)—lH~pyrazol~1 —y1]propanal (0.100 g, 0.228 mmol) in THF (2.0 mL) was added. After 30 minutes, the mixture was ed by the addition of saturated ammonium chloride solution and the product was then extracted with ether. The ether extract was dried over sodium sulfate and the solvent was removed in vacuo. Flash column chromatography (eluting with a nt of 0-40% ethyl acetate in hexanes) afforded the product (40 mg, 44%). 1H NMR (400 MHz, CDC13): 5 8.84 (s, 1H), 8.26 (s, 1H), 8.19 (br s, 1H), 7.40 (s, 1H), 6.83 (br s, 1H), .67 (s, 2H), 5.60 (ddt, 1H), 5.01 (dq, 1H), .93 (m, 1H), 3.99 (dt, 1H), 3.54 (t, 2H), 2.79—2.60 (m, 2H), 2.60-2.40 (m, 1H), 1.99-1.89 (m, 1H), 1.75-1.41 (m, 5H), 1.37—1.12 (m, 2H), 0.92 (t, 2H), - 0.06 (s, 9H); MS(ES):43'8(M+H).

Step 6. 4-[1-(1-Cyclopentylbuten-I-y1)-IH—pyrazolyl]-7H-pyrrolo[2,3-djpyrimidine trifluoroacetate salt 4-[1 ~(1 —Cyclopenty1but—3-en—1 -yl)-l H-pyrazol-4—yl]-7—[2{trimethylsilyl)ethoxy]methyl-7H— pyirolo[2,3—d]pyrimidine (13 mg, 0.030 mmol) was dissolved in DCM (3 mL) and TFA (0.5 mL) was added. The resulting on was stirred at room temperature for 3 hours. The solvent was removed in vacuo. The residue was dissolved in THF (2 mL), and 6 N NaOH (1 mL) was added. The mixture was stirred at room temperature for 1 hour, and then was partitioned between water and ethyl acetate.

The organic layer was dried over sodium sulfate and the solvent was removed in vacuo. Purification via ative-HPLC/MS (C18 eluting with a gradient of H20 and ACN containing 0.1% TFA) afforded the product (10 mg, 80%). 1H NMR (400 MHz, d5—DMSO): 612.73 (s, 1H), 8.88 (s, 2H), 8.43 (s, 1H), 7.79 (t, 1H), 7.19 (dd, 1H), .60 (ddt, 1H), 5.00-4.93 (m, 1H), .87 (m, 1H), 4.23 (dt, 1H), 2.76-2.59 (m, 2H), 2.47-2.34 (m, 1H), 1.92-1.82 (m, 1H), 1.68-1.22 (m, 6H), 1.21-1.09 (m, 1H); MS(ES):308(M+H).

Example 729: 4-[1-(l—Cyclopentylcyclopropylethyl)—lH—pyrazolyl]-7H—pyrrolo[2,3-d]- pyrimidine oroacetate salt £11 'TFA Step 1. 4-[1 clopenwl—Z—cyclopropylethyl}!H—pyrazol-4—yl]—7-[2-(trimethylsily0ethoxyjmethyl- 7H—pyrrolo[2,3—djpyrimidine trifluoroacetate salt A solution of 4-[1-(1-cyclopentylbuteny1)-1H-pyrazolyl][2—(trimethylsilyl)- ethoxy]methy1-7H-pyrrolo[2,3-d]pyrimidine red in Example 727, Step 5) (54.0 mg, 0.123 mmol) in DCM (1 mL) was added to a freshly prepared ethereal solution of excess CHzNz held at 0 °C. Palladium acetate (10.0 mg, 0.044 mol) was added. After standing for 2 hours, the excess ‘CI‘IzNz was quenched by the addition of acetic acid. The solution was then diluted with timber DCM, washed successively with saturated sodium bicarbonate solution, water, and brine, and dried over sodium e, and the solvent was removed in vacuo. ation via preparative—HPLC/MS (C18 eluting with a gradient of H20 and ACN containing 0.1% TFA) afforded the product (13 mg, 18%). 1H NMR (300 MHz, CDClg): 5 9.05 (s, 1H), 8.81 (d, 1H), 8.35 (s, 1H), 7.59 (t, 1H), 7.03 (t, 1H), 5.76 (s, 2H), 4.10 (t, 1H), 3.59 (t, 2H), 2.57—2.36 (m, 1H), 2.15—2.00 (m, 1H), 2.00-1.83 (m, 1H), 1.79—1.40 (m, 6H), l.37~l.09 (m, 2H), 0.97 (t, 2H), 0.55—0.26 (m, 3H), 0.07- '0.15 (m, 11H); MS(ES):452(M+H).

Step 2. 4—[1-(1-Cyclopenwl—Z-cyclopropyletlzyD-IH-pyrazol—4—yU—7H-pyrrolo[2, 3—d]pyrimidin,e trifluoroacetate salt 4-[1 -(l —Cyclopentylcyclopropylethyl)—1H-pyrazol—4-yl]-7~[2—(trimethylsilyl)ethoxy]- methyl-7H-pyrrolo[2,3—d]pyrimidine trifluoroacetate salt (13 mg, 0.023 mol) was stirred at room temperature in a solution of DCM (2 mL) ning TFA (1.5 mL) for two hours. The solvent was and 6N NaOH (2 mL) was removed in vacuo. The resulting residue was redissolved in THF (3 mL), between water and ethyl acetate. The added. After stirring for one hour, the mixture was partitioned removed in vacuo. Purification via organic layer was dried over sodium sulfate and the solvent was afforded preparative-HPLC/MS (C18 eluting with a gradient ofH20 and ACN ning 0.1% TFA) the product (9 mg, 90%). .

IH NMR (400 MHz, dG—DMSO): _8 12.75 (s, 1H), 8.90 (s, 1H), 8.84 (s, 1H), 8.47 (s, 1H), 7.81 (s, 1H), 1.88-1.76 (m, 1H), 1.68—1.37 (m, 7.22 (s, 1H), 4.19 (dt, 1H), 2.43-2.29 (m, 1H), 2.03-1.92 (m, 1H), "0.14- '0.24 (m, 5H), 1.35—1.08 (m, 3H), 0.43-0.26 (m, 2H), 0.24—0.13 (m, 1H), 0.07— '0.03 (m, 1H), 1H); MS(ES):322(M+H).

Example 730: 4-[1-(1-Cyclopentylbut—3—yn-l—yl)-1H—pyrazolyl]-7H-pyrrolo[2,3-d] pyrimidine trifluoroacetate salt "t i \ N H 'TFA Step I . 4—[1 clopentylbut-3—yn-I-yl)-IH—pyrazol—4-yl]—7-[2—(trimethylsilyDethoxyjmethyl- pyrrolo[2,3-d]pyrimidine ) at 0 °C To a mixture of potassium carbonate (38.4 mg, 0.278 mmol) in methanol (2.0 mL) was added a solution of 3-cyclopentyl[4-(7—[2-(tn'methylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]- pyrimidin—4-yl)—1H—pyrazol-l—yl]propanal (prepared as in Example 727, step 4) (61.0 mg, 0.139 mmol) in methanol (1.0 mL), followed by a on of dimethyl (l-diazooxopropyl)phosphonate (40.0 mg, 0.208 mmol) in methanol (1.0 mL). The mixture was slowly warmed to ambient diluted with water and extracted with ethyl temperature and stirred for 16 hours. The mixture was then ammonium chloride, and then dried acetate. The combined extracts Were washed with water, saturated over sodium sulfate and the solvent was d in vacuo to afford the product, which was used without further purification (52 mg, 86%).

'H NMR (300 MHz, CDC13): 5 8.85 (s, 1H), 8.47 (s, 1H), 8.29 (s, 1H), 7.41 (d, 1H), 6.84 (d, 1H), .67 (s, 2H), 4.14 (ddd, 1H), 3.53 (t, 2H), 2.90 (ddd, 1H), 2.79 (ddd, 1H), 2.66-2.49 (m, 1H), 1.98 (t, 1H), 2.00-1.88 (m, 1H), .44 (m, 5H), 1.39—1.11 (m, 2H), 0.92 (t, 2H), -0.06 (s, 9H); MS(ES):436(M+H). 2006/047369 Step 2. 4—[1-(1-Cyclopentylbut-3—yn-1~yD-IH-pyrazol—4-ylj-7H—pyrrolo[2,3-d]pyrimidin_e trifluoroacetate salt A solution of 4-[1-(1-cyclopentylbutyn-1~y1)-1H—pyrazoly1][2-(trimethylsilyl)- ethoxyjmethyl-7H-pyrrolo[2,3—d]pyrimidine (52 mg, 0.12 mmol) in DCM (3 mL) and TFA (1 mL) was stirred for 2 hours. The solvents were d in vacuo. The ing residue was dissolved in THF (3 mL) and 6N NaOH (2 mL) was added. After stirring for 1 hour, the mixture was partitioned between water and ethyl acetate. The organic layer was dried over sodium e and the solvent was removed in vacuo. Purification via preparative-HPLC/MS (€18 g with a gradient of H20 and ACN containing 0.1% TFA) afforded product (30 mg, 60%). 1H NMR (300 MHz, dé—DMSO): 6, 12.72 (s, 1H), 8.91 (s, 1H), 8.84 (s, 1H), 8.47 (s, 1H), 7.80 (s, 1H), 7.19 (s, 1H), 4.34 (dt, 1H), 2.97-2.69 (m, 3H), 2.50-2.32 (m, 1H), 1.93-1.77 (m, 1H), 1.70-1.09 (m, 7H); MS(ES):306(M+H).

Example 731: l—Cyclopentylbutyl)-1H-pyrazol—4-yl]-7H-pyrrolo[2,3—d]pyrimidine trifluoroacetate salt If—N K/NN H 'TFA 4—[1 -(1 -Cyclopenty1but-3—yn-1 —y1)—1H—pyrazolyl]-7H-pyrrolo[2,3-d]pyrimidine trifluoro- acetate salt red in Example 729) (20 mg, 0.048 mmol) was dissolved in methanol (2 mL) and a catalytic amount of 5% Pd—C was added. The mixture was stirred under 1 atmosphere of hydrogen via an affixed balloon. Afier 2 hours, the mixture was filtered and purified via preparative-HPLC/MS (C18 eluting with a gradient of H20 and ACN containing 0.1% TFA) to afford the product (14 mg, 69%).

‘H NMR (400 MHz, d5-DMSO)Z 5 12.73 (s, 1H), 8.86 (s, 1H), 8.83 (s, 1H), 8.45 (s, 1H), 7.79 (t, 1H), 7.20 (d, 1H), 4.11 (dt, 1H), 2.43-2.26 (m, 1H), 2.02-1.70 (m, 3H), 1.68-1.35 (m, 4H), 1.33-0.89 (m, 5H), 0.83 (t, 3H); MS(ES):310(M+H).

Example 732: 4-[l-(l-Cyclopentyl-4,4-difluorobuten-l-yl)-1H—pyrazol—4-yl]-7H-pyrrolo[2,3— d]pyrimidin_e trifluoroacetate salt 1/\ \ N N H 'TFA Step 1. 4—[1—(1-Cyclopentyl—4,4~difluor0but~3-enyl)—1H—pyrazol—4—yl]- 7-[2—(trimethylsilyDethoxyj— methyl—7H—pyrrolo[2,3—d]pyrimidine To a solution of openty1—3-[4—(7—[2-(trimethylsilyl)ethoxy]methyl—7H—pyrrolo[2,3—d]— pyrimidinyl)-1H-pyrazol-l-yl]propanal (prepared as in Example 727, Step 4) (181 mg, 0.41 mmol) 1.12 mmol) followed by in MN-dimethylacetamide (3.6 mL) was added nylphosphine (294 mg, of 2.5 g in 50 dibromodifluoromethane (235 mg, 1.12 mmol). Rieke® Zinc (1.8 mL of a sion for 4.5 ml THF) was then added in one portion. The resulting mixture was'stirred at room temperature hours. The mixture was filtered through diatomaceous earth. The filtrate was partitioned between dried over sodium sulfate, ether and water. The ether layer was washed with water, and brine, then with a gradient from O- and the solvent was removed in vacuo. Flash column chromatography (eluting % ethyl acetate in hexanes) afforded product (104 mg, 53%). 1H NMR (400 MHz, CDC13): {5 8.91 (3, 11-1), 8.51 (br s, 1H), 8.34 (s, 1H), 7.51 (d, 1H), 6.93 (d, 1H), 5.74 (s, 2H), 4.05 (ddd, 1H), 4.04—3.96 (m, 1H), 3.60 (t, 2H), 2.78—2.62 (m, 2H), .45 (m, 1H), 2.07-0.87 (m, 10H), 0.00 (s, 9H); MS(ES):474(M+H). 3-d]pyrimidin,e Step 2. 4—[1 ~(J-Cyclopentyl—4, 4—dz'flu0robut-3—en-1 -yl)-1H-pyrazol—4—yl]- 7H—pyrrolo[2, trifluoroacetate salt A solution of 4-[1—(1-cyclopentyl—4,4-difluorobut—3-en—1—yl)—lH—pyrazoly1][2-(tri- methylsilyl)ethoxy]methyl-7H—pyrrolo[2,3-d]pyrimidine (41 mg, 0.086 mmol) in DCM (3 mL) and then concentrated in TFA (1.5 mL) was stirred for two hours at room temperature. The solution was THF (3 mL), and 6N NaOH (2 mL) was added. After vacuo. The resulting residue was redissolved in The organic layer was stirring for 1 hour, the mixture was partitioned between water and ethyl acetate. dried Purification via preparative- over sodium sulfate and the t was removed in vacuo. afforded the desired S (C18 eluting with a gradient of H20 and ACN ning 0.1% TFA) product (39 mg, 98%). 1H NMR (400 MHz, ds-DMSO): 5 12.72 (s, 1H), 8.84 (s, 1H), 8.83 (s, 1H), 8.45 (s, 1H), 7.80 (t, 1H), .06 (m, 7H); 7.18 (d, 1H), 4.32 (ddt 1H), 4.20 (dt, 1H), 2.72-2.37 (m, 3H), 1.95-1.81 (m, 1H), MS(ES):344(M+H). 2006/047369 Where ate acceptors, such as were used in Example 737, Step 3 were not commercially ble, such compounds were generated according to the procedure provided below for ethyl (2E)- 3~(tetrahydrofuran—3-yl)acry1ate (toward the preparation of Example 733).

Preparation of ethyl (2E)—3—(tetrahydrofiiranyl)acrylate: Step A: ydrofurancarbaldehyde To a solution of Dess-Martin periodinane (3.37 g, 7.95 mmol) in DCM (20 mL) was added tetrahydrofuran-B—ylmethanol (0.701 mL, 7.23 mmol). The reaction was stirred at ambient temperature for 2 hours, and the solvent was then removed in vacuo. Flash column chromatography (using DCM as eluent) ed the product as a clear oil, which was used without further purification. lH NMR (400 MHz, CDC13)I _5 9.65 (d, 1H), 4.12-4.07 (m, 1H), 3.92-3.85 (m, 2H), 3.80—3.73 (m, 1H), 3.10-3.02 (m, 1H), 2.26-2.10 (m, 2H).

Step B: Ethyl —(tetrahydrofuran—3—yl)acrylate To a 0 °C mixture of sodium hydride (60% in mineral oil) (382 mg, 9.40 mmol) in DMF (15.0 mL) (TI-IF may also be used) was added yl phosphonoacetate (1.72 mL, 8.68 mmol) dropwise.

The resulting mixture was warmed to room temperature and stirred for 30 minutes, then was re~cooled to 0 °C, at which time a solution of tetrahydrofuran-B-carbaldehyde (724 mg, 7.23 mmol) in DMF (4.0 mL) was added dropwise. The resulting mixture was stirred at this temperature for 1.5 hours, at which time the mixture was diluted with water and the t was extracted with ether. The combined extracts were washed with water and brine, dried over sodium sulfate and the solvent removed in vacuo. Flash column chromatography (eluting with a gradient from 0-40% ethyl acetate in hexanes) afforded the product (640 mg, 52%). lH NMR (400 MHz, CDC13)I 5 6.87 (dd, 1H), 5.86 (dd, 1H), 3.96—3.88 (m, 2H), 3.81 (dd, 1H), 3.53 (dd, 1H), 3.04-2.93 (m, 1H), 2.20—2.10 (m, 1H), 2.03 (s, 3H), 1.79 (dq, 1H).

Example 736: 4-[1-(1-Cyclopentyl—4,4-difluorobutyl)—lH—pyrazolyl]~7H—pyrrolo[2,3-d]- pyrimidine trifluoroacetate salt N\ \ ‘K/NN H -TFA 4-[1 -(1 —Cyclopentyl-4,4—difluorobut-3—en~1~yl)—1H—pyrazol—4—yl]—7H—pyrrolo[2,3 —d]- pyrimidine roacetate salt (prepared as in Example 731) (20.0 mg, 0.041 mmol) was dissolved in methanol (3 mL), and a tic amount of 5% Pd on C was added. The e was stirred at room ature for 2 hours, under an atmosphere of hydrogen provided by an affixed balloon. The mixture was filtered and purified via preparative-HPLC/MS (C18 eluting with a gradient of H20 and ACN containing 0.1% TFA) to afford product (4 mg, 21%). 1H NMR (400 MHz, d5—DMSO): 8 12.74 (s, 1H), 8.88 (s, 1H), 8.85 (s, 1H), 8.48 (s, 1H), 7.80 (t, 1H), 7.20 (dd, 1H), 6.05 (tt, 1H), 4.17 (dt, 1H), 2.47-2.34 (m, 1H), 2.14-1.08 (m, 12H); MS(ES):346(M+I-I).

Example 737: 3-(1-Methylcyclopentyl)[4-(7H—pyrrolo[2,3—d]pyrimidin-4~yl)-1H—pyrazol-l- yllpropanenitrile trifluoroacetate salt fl -TFA Step 1. 1—Methylcyclopentanecarbaldehyde To a solution of cyclopentanecarbaldehyde (1.00 mL, 9.36 mmol) in DCM (47 mL) at 0 °C was added solid potassium tert—butoxide (1.44 g, 12.2 mmol) in one portion followed by methyl iodide (1.7 mL, 28 mmol) in one portion. Afier 30 minutes at 0 °C, the reaction mixture was allowed to warm to room temperature and stirred at that temperature for 16 hours. The e was poured into brine, and the layers were separated. The organic layer was dried over sodium sulfate, decanted and concentrated, and used without further purification in Step 2.

Step 2: (ZZ)- and (2E)(1~Methylcyclopenty0acrylonitrile To a solution of 1.0 M potassium tert—butoxide in THF (9.36 mL) at 0 °C was added a solution of diethyl cyanomethylphosphonate (1.59 mL, 9.8] mmol) in THF (10 mL) dropwise. The cooling bath was removed and the on was warmed to room temperature followed by re-cooling to 0 "C, at which time a solution of 1-methylcyclopentanecarbaldehyde (1.0 g, ted in Step 1) in THF (2 mL) was added dropwise. The bath was removed and the reaction was stirred at ambient ature for 3 hours. To the mixture was added water and ethyl ether. The aqueous layer was further extracted with ethyl ether. The combined extracts were washed with brine, dried over sodium sulfate, filtered and adsorbed onto silica gel in vacuo. Flash column chromatography (eluting with a gradient from 0-10% ethyl acetate in hexanes) afforded t as a mixture with hexanes, which product was used without further purification in Step 3.

Step 3: 3-(1-Methylcyclopentyl)[4-(7H-pyrrolo[2, 3«djpyrimz'din-4—yl)-1H—pyrazol-I-yl]pr0pane- nitrile trifluoroacetate salt To a mixture of 4-(1H-pyrazolyl)~7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3- deyrimidine (0.134 g, 0.426 mmol) in ACN (3 mL) was added a mixture of (2Z)- and (2E)~3-(1- methylcyclopenty1)acrylonitn'1e (0.12 g, 0.9 mmol) ed by DBU (0.13 mL, 0.90 mmol). The reaction was heated to 60 °C for 6 h. The ACN was removed in vacuo. Ethyl acetate was added, followed by 0.1 N HCl. The aqueous layer was extracted with three portions of ethyl e. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and the solvent was evaporated. The crude material was deprotected by stirring with TFA (2 mL) in DCM (8 mL) for 2 hours. The solvent and TFA were removed in vacuo. TI-IF (8 mL) was used to dissolve the residue, and 6.0 M sodium hydroxide in water (8 mL) was added. The reaction was stirred in this basic mixture for 2 hours. Ethyl acetate was used to extract the product. The ed extracts were dried (NaZSO4) and the solvent was removed in vacuo. Purification via preparative-HPLC/MS (C18 eluting with a gradient of H20 and ACN containing 0.1% TFA) afforded t (44 mg, 24%).

‘H NMR (400 MHz, erMSO): 5 12.71 (s, 1H), 9.00 (s, 1H), 8.85 (s, 1H), 8.51 (s, 1H), 7.81 (s, 1H), 7.18 (s, 1H), 4.72 (dd, 1H), 3.47 (dd, 1H), 3.21 (dd, 1H), 1.74-1.51 (m, 6H), 1.44-1.32 (m, 1H), 1.09- 1.00 (m, 1H), 0.97 (s, 3H); MS(ES):321(M+H).

Example 739: 1-2—Cyano-l-[4~(7H—pyrrolo[2,3-d]pyrimidin—4-yl)—IH-pyrazol-l-yl]ethylcyclo~ propanecarbonitrile trifluoroacetate salt N N H -TFA Step1 : 1—(HydroxymethyDcyclopr-opanecarbonitrile Ethyl 1-cyanocyclopropanecarboxylate (801 mg, 5.76 mmol) in THF (12.0 mL) was treated with lithium tetrahydroborate (251 mg, 11.5 mmol). The solution was heated to reflux for 1.5 hours.

Upon cooling to room temperature, the reaction was quenched with water, and extracted with ethyl acetate. The combined extracts were dried over MgSO4, filtered and trated to afford a clear oil, which was used t further purification in the following step (482 mg, 86%). 1H NMR (400 MHz, : 5 3.61 (s, 2H), 1.27 (dd, 2H), 0.98 (dd, 2H).

Step2: I~F0rmylcyclopropanecarbom'trile Dess—Martin periodinane (1.11 g, 2.62 mmol) was dissolved in DCM (12 mL) and 1- (hydroxymethyl)cyclopropanecarbonitrile (231 mg, 2.38 mmol) was added. The reaction was stirred at t temperature for one hour. The mixture was then purified by flash column chromatography (eluting with a gradient from 0-80% ethyl acetate in hexanes) to afford the product (106 mg, 46%). 1H NMR (400 MHz, CD013): 5 9.35 (s, 1H), 1.79-1.74 (m, 4H).

Step 3 .' 1-[(E)Cyanovinyljcyclopropanecarbonitrz'le To a solution of 1.0 M potassium tert-butoxide in THF (1.12 mL) at 0 °C was added slowly dropwise a solution of l cyanomethylphosphonate (210 mg, 1.2 mmol) in THF (2 mL). The cold bath was removed and the reaction was warmed to t temperature. The solution was then re- cooled to 0 °C and a solution of 1~formylcyclopropanecarbonitrile (101 mg, 1.06 mmol) in THF (1.0 mL) was added dropwise. The cold bath was removed and the reaction was stirred for 3 hours at ambient temperature. The mixture was then d with ether and water, the ether solution was separated, washed with brine, dried over sodium sulfate, filtered and the solvent was removed in vacuo. Flash column chromatography (eluting with a gradient from 0-60% ethyl ether in hexanes) afforded the product (24 mg, 19%). lH NMR (400 MHz, CD013): 5 5.94 (d, 1H), 5.82 (d, 1H), 1.80 (dd, 2H), 1.39 (dd, 2H).

Step 4: 1—2-Cyan0—1-[4-(7—[2—(trimethylsilyl)ethoxy]methyl- 7H-pyrrolo[2, 3-d]pyrimidin~4-yl)—1H— pyrazol-I—yl]ethylcyclopropanecarbonitrile To a solution of 4—(1H-pyrazolyl)-7~[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3—d]- pyrimidine (61.4 mg, 0.195 mmol) and 1~[(E)cyanoviny1]cyclopropanecarbonitrile (23 mg, 0.19 mmol) in ACN (2 mL) was added DBU (58 uL, 0.39 mmol) and the resulting mixture was stirred for 16 hours. The ACN was evaporated, and the residue was dissolved in ethyl acetate. This solution washed with 1.0 N HCl, water, and brine, and dried over sodium sulfate, and the solvent removed in vacuo. Flash column chromatography (eluting with a gradient from 0-80% ethyl acetate in hexanes) afforded the product (49 mg, 58%).

'H NMR (400 MHz, CDCl3): _8 8.85 (s, 1H), 8.43 (s, 1H), 8.34 (s, 1H), 7.43 (d, 1H), 6.80 (d, 1H), .68 (s, 2H), 3.54 (dd, 1H), 3.51 (dd, 1H), 3.36 (dd, 1H), 1.62 (ddd, 1H), 1.45 (ddd, 1H), 1.34 (ddd, 1H), 1.25 (ddd, 1H), 0.92 (t, 2H), -0.06 (s, 9H); MS(ES):434(M+H).

Step 5.‘ an0—I—[4-(7H—pyrrolo[2, 3-d]pyrimidin-4—yl)—IH—pyrazol-J~yl]ethylcyclopropane- izrile trifluoroacetate salt 1 ~2—cyano— 1 —[4—(7—[2—(trimethylsi1yl)ethoxy]methyl—7H-pyrrolo[2,3—d]pyrimidin-4—yl)— 1H- pyrazol-l-yI]ethylcyclopropanecarbonitrile (48 mg, 0.11 mmol) was stirred in a e of DCM (3 mL) and TFA (2 mL) for 3 hours. The solvents were removed in vacua and the residue was re- dissolved in THF (3 mL). 6N NaOH (2 mL) was added and the resulting mixture was stirred at t temperature for 3 hours. The crude reaction e was partitioned between ethyl acetate and water. The layers were separated and the organic layer was dried over sodium sulfate and the solvent was removed in vacuo. Purification via preparative-HPLC/MS (C18 eluting with a gradient of H20 and ACN containing 0.1% TFA) afforded product (20 mg, 43%).

IH NMR (400 MHz, d6-DMSO): 512.74 (s, 1H), 8.99 (s, 1H), 8.88 (s, 1H), 8.60 (s, 1H), 7.83 (t, 1H), 7.17 (dd, 1H), 4.55 (dd, 1H), 3.66 (dd, 1H), 3.54 (dd, 1H), 1.55—1.30 (m, 4H); MSCES):304(M+H). e 740: N-[(1Cyano-1—{4-(7H—pyrrolo[2,3-d]pyrimidin—4-yl)-—1H-pyrazol—1-yl]ethyl- cyc10pentyl)methyl]benzamide °>—© . 0;...

N—‘N "t\\/ Step 1: Methyl 1~cyanocyclopentanecarboxylate To a on of acetic acid, cyano—, methyl ester (2.66 mL, 30.3 mmol) and 1,4— dibromobutane, (3.62 mL, 30.3 mmol) in acetone (50 mL) was added potassium carbonate (8.37 g, 60.6 mmol). The reaction was stirred at ambient temperature for 16 hours. The reaction was filtered through diatomaceous earth and concentrated._ The resulting residue was partitioned between ether and ted l solution, and the aqueous layer was extracted with two further portions of ether.

The combined ethereal extracts were washed with brine, and dried over sodium sulfate, then filtered and the solvent was removed in vacuo. Flash column chromatography (eluting with a gradient from 0-30% ethyl acetate in hexanes) afforded the product (2.92 g, 63%).

'H NMR (300 MHz, CDClg): 53.82 (s, 3H), 2.30-2.21 (m, 4H), 1.93-1.82 (m, 4H).

Step 2: Methyl 1-[(tert-butoxycarbonyl)amino]methylcyclopentanecarboxylate To a solution of methyl 1-cyanocyclopentanecarboxylate (1.26 g, 8.22 mmol) in ol (100 mL) was added cobalt ride (2.1 g, 16.0 mmol). The purple mixture was cooled in an ice- water bath. Sodium ydroborate (3.11 g, 82.2 mmol) was added portionwise with caution (exothermic) to provide a black mixture. Upon complete on, cooling was discontinued and the reaction was stirred for 40 minutes under nitrogen and the reaction was quenched by the careful '15 addition of 1N HCI (700 ml). The methanol was removed in vacuo, and the solution was then made alkaline (pH ~ 9) by the addition of concentrated NH40H(aq). The mixture was extracted with DCM (6 times), and the ed DCM extracts were dried over sodium sulfate and concentrated to afford the crude product as a light yellow oil. To this crude amine in DCM (50 ml) was added di—tert- icarbonate (1.31 g, 6.01 mmol) and the reaction was stirred at 25 °C for 30 minutes. The reaction was diluted with water and extracted with ethyl acetate three times. The combined extracts were dried over sodium sulfate, filtered, and the solvent removed in vacuo. The crude residue was purified by flash column chromatography to yield the d product (1.5 g, 71%). 1H NMR (300 MHz, CDC13): 5 5.03 (s, 1H), 3.69 (s, 3H), 3.26 (d, 2H), 2.02-1.33 (m, 17H).

Step 3: tert—Butyl [1{hydrwgzmethybcyclopentyljmethylcarbamate To a solution of methyl l—[(tert—butoxycarbonyl)amino]methylcyclopentanecarboxylate (1.50 g, 5.83 mmol) in THF (25.0 mL) at ~78 0C was added dropwise 1.0 M diisobutylaluminum hydride in DCM (17.5 mL). The on was stirred for 2 hours with slow warming to —10 °C. A saturated on of K/Na tartrate was added, followed by ether. This mixture was stirred for 30 minutes at 3O ambient temperature and the c layer was separated and washed with water, and brine. The organic layer was then dried over sodium sulfate, and the solvent was removed in vacuo to afford the product (1.03 g, 77%). lHNMR (300 MHz, CDCla): 8_ 4.90 (br s, 1H), 3.27 (s, 2H), 3.06 (d, 2H), 1.5- 1.17 (m, 8H), 1.44 (s, 9H).

Step 4: tert-Butyl [(1formylcyclopenbiDmethyl]carbamate To a solution of oxalyl chloride (456 uL, 5.38 mmol) in DCM (30.0 mL) at ~78 °C was added DMSO (637 uL, 8.97 mmol) and the resulting mixture was stirred for 5 minutes. tert~Butyl [l- xymethyl)cyclopentyl]methylcarbamate (1.03 g, 4.48 mmol) in DCM (10.0 mL) was added and the resulting mixture was stirred for 30 s at -78 0C. TEA (2.50 mL, 17.9 mmol) was added and the resulting mixture was allowed to warm to ambient temperature over 30 minutes. Water was added.

The organic phase was washed sequentially with 0.1 N HCl, water, saturated sodium bicarbonate solution, and brine, and then dried over sodium sulfate and the solvent was removed in vacuo to afford the t (957 mg, 94%). 1H NMR (300 MHz, CDC13): 5 9.39 (s, 1H), 4.94 (br s, 1H), 3.25 (d, 2H), 1.89-1.46 (m, 8H), 1.41 (s, 9H).

Step 5: rem-Bug)! (I-[(E)~2-cyanovinyl]cyclopentylmethyl)carbamate and tert—bulyl (1—[(Z)—2-cyano- vinyl]cyclopentylmethyDcarbamate To a solution of 1.0 M potassium tert-butoxide in THF (4.4 mL) at 0 °C was added a solution of diethyl cyanomethylphosphonate (820 mg, 4.6 mmol) in THF (6.0 mL) dropwise. The cold bath was removed and the reaction was warmed to ambient temperature. The mixture was then re—cooled to 0 °C and a solution of tert-butyl [(1~formy1cyclopentyl)methyl]carbamate (952 mg, 4.19 mmol) in TI-IF (4.0 mL) was added dropwise. The reaction was allowed to warm to ambient temperature and the warmed e was stir for 16 hours. The reaction mixture was then d with ether and water.

The organic layer was separated and washed sequentially with water and brine, then dried over sodium sulfate, then filtered, and the solvent was removed in vacuo to afford the t (1.05 g, 99%) as a mixture of (E) and (Z) isomers. 1H NMR (300 MHZ, CD013): 5 6.71 (d, 1H, E), 6.46 (d, 1H, Z), 5.36 (d, 1H, Z), 5.36 (d, 1H, E), 4.70 (br s, 1H, 2), 4.51 (br s, 1H, E), 3.25 (d, 2H, Z), 3.13 (d, 2H, E), 1.88-1.48 (m, 8H (E) and 8H (2)), 1.43 (s, 9H (E) and 9H (2)); MS(ES):151(M+H-Boc).

Step 6: tert-Butyl cyano-I—[4—(7-[2—(trimethylsilyl)ethoxy]methyl—7H-pyrrolo[2,3-d]pyrimiiiin- 4—yl)~1H-pyrazol—1—yl]ethylcyclopentyl)methyl]carbamate To a solution of 4—(1H—pyrazol~4—yl)—7—[2—(trimethylsilyl)ethoxy]methyl—7H—pyrrolo[2,3-d]- pyrimidine (355 mg, 1.12 mmol) and tert—butyl (1-[(E)—2—cyanovinyl]cyclopentylmethyl)carbamate and tert-butyl (l—[(Z)—2-cyanovinyl]cyclopentylmethyl)carbamate as a mixture of isomers (329 mg, 1.31 mmol)-in ACN (10 mL) was added DBU (0.168 mL, 1.12 mmol). The resulting mixture was stirred at ambient temperature for 3 hours followed by heating to 60 0C for 2.5 hours. The ACN was removed in vacuo and the resulting residue was purified by flash column chromatography (eluting with 0-55% ethyl e in hexanes) to afford the product (350 mg, 55%).

‘H NMR (300 MHz, (31301,): ,8 8.85 (s, 1H), 8.37 (br s, 1H), 8.34 (s, 1H), 7.41 (d, 1H), 6.82 (d, 1H), .68 (s, 2H), 5.37 (br s, 1H), 4.52 (dd, 1H), 3.54 (t, 2H), 3.40 (dd, 1H), 3.23 (dd, 1H), 3.08 (d, 1H), 2.90 (dd, 1H), 1.84-1.47 (m, 8H), 1.45 (s, 9H), 0.92 (t, 2H), -0.06 (s, 9H); MS(ES):566(M+H).

Step 7: N-[(I—2—Cyan0-1—[4-(7H-pyrrolo[2, 3-d]pyrimidin—4-yl)—1H—pyrazol—I-yUethylcyclopentyl)— methyljbenzamide A solution of tert—butyl [(1cyano-1—[4-(7-[2—(trimethylsilyl)ethoxy]methyl—7H-pyrrolo[2,3— d]pyrimidinyl)-lH-pyrazol-l-yl]ethylcyclopenty1)methyl]carbamate (175 mg, 0.309 mmol) in DCM (5 mL) and TFA (5 mL) was stirred for 3 hours and the solvents were then removed in vacuo.

The resulting residue was stirred in a mixture of THF (3 mL) and 6N NaOH (3 mL) for 3 hours. The THF was removed in vacuo, and water (10 mL) was added. The mixture was extracted with several ns of DCM containing 15% isopropanol. The combined extracts were dried over sodium sulfate and the solvents were d in vacuo to afford the product, which was used without fiirther purification. MS(ES):336(M+H).

To a on of 3—[1~(aminomethyl)cyclopentyl]-3—[4—(7H—pyrrolo[2,3~d]pyrimidin~4—yl)—l H- pyrazol—l-yl]propanenitrile (31 mg, 0.060 mmol) and benzoyl chloride (7.0 uL, 0.060 mol) in DCM (1.0 mL), was added TBA (17 uL, 0.12 mmol). After 15 minutes, the solvent was removed in vacuo and the mixture was purified via preparative-HPLC/MS (C18 eluting first with a gradient of H20 and ACN containing 0.1% TFA, followed by chromatographic purification, eluting with a gradient of H20 and ACN ning 0.15% NH40H) to afford the product (7 mg, 27%). 1H NMR (400 MHz, O): 512.12 (s, 1H), 8.95 (s, 1H), 8.68 (s, 1H), 8.55 (s, 1H), 8.41 (s, 1H), 7.92-7.87 (m, 2H), 7.60 (d, 1H), 7.59-7.48 (m, 3H), 7.02 (d, 1H), 4.83 (dd, 1H), 3.52—3.45 (m, 2H), 3.42 (dd, 1H), 3.27 (dd, 1H), 2.06—1.95 (m, 1H), 1.68-1.12 (m, 7H); MS(ES):440(M+H).

Example 741: 3[(Benzyloxy)methyl]cyclopentyl—3~[4-(7H—pyrrolo[2,3-d]pyrimidinyl)-1H— l-l-yl]propanenitrile trifluoroacetate salt 0Q...OBn H -TFA Step 1: 1—(HydrowmethyDcyclopentanecarbonitrile A mixture ofmethyl l—cyanocyclopentanecarboxylate (prepared in Example 740, Step 1) (500 mg, 3.0 mmol) in THF (7 mL) was treated with lithium tetrahydroborate (100 mg, 6.0 mmol). The resulting solution was heated to reflux for 3 hours, then stirred at ambient temperature for 16 hours.

The mixture was quenched by the addition of water, and was extracted with ethyl acetate. The combined organic extracts were dried over NaZSO4, then filtered and the solvent was removed in vacuo to afford the product (387 mg, 95%). 1H NMR (300 MHz, CDCI3): 53 .62 (s, 2H), 2.39-1.60 (m, 8H).

Step 2: nazloxy)methy1]cyclopentanecarbom'trile To a solution of 1—(hydroxymethyl)cyclopentanecarbonitrile (0.30 g, 2.0 mmol) in DMF (4 mL) was added sodium hydride (60% sion in mineral oil, 0.101 g, 2.52 mol). The resulting mixture was stirred for 20 minutes, followed by the addition of benzyl bromide (0.28 mL, 2.4 mmol).

The reaction was stirred at ambient temperature for 64 hours. Additional sodium hydride (60% dispersion in mineral oil, 0.060 g, 1.5 mmol) and benzyl e (0.18 mL, 1.5 mmol) were added and the reaction was stirred for an additional 30 minutes. Water was then added to the mixture, followed by brine, and the aqueous layer was ted with ethyl acetate. The extracts were combined and dried over sodium sulfate, and the t was then removed in vacuo. To the resulting residue was added water. The product was isolated by extraction with diethyl ether. The ethereal extracts were dried over sodium sulfate, and the solvent was evaporated. Flash column chromatography (eluting with a gradient from 0-30% ethyl e in s) afforded product (330 mg, 64%). 1H NMR (300 MHz, CD013): 67.40-727 (m, 5H), 4.62 (s, 2H), 3.44 (s, 2H), 2.18—2.03 (m, 2H), 1.90— 1.62 (m, 6H).

Step 3: 1-[(Benzyloxy)methyl]cyclopentanecarbaldehyde To a mixture containing l-[(benzyloxy)methyl]cyclopentanecarbonitn'le (0.16 g, 0.75 mmol) in toluene (5 mL) at 0 °C was added 1.0 M diisobutylaluminum hydride in hexanes (0.8 mL). The reaction was stirred at 0 °C for 1.5 hours, during which time the starting nitrile was consumed. The on was cooled to ~78 0C and quenched by the addition of methanol. The mixture was warmed to ambient temperature and 3 N HCl was added. Following stirring for 45 minutes, solid NaCl was added, and the mixture was extracted with three portions of ethyl acetate. The combined extracts were 3O dried (Na2804), and filtered, and the solvent was d in vacuo. Flash column chromatography of the resulting residue (eluting with a gradient from 0-30% ethyl acetate in hexanes) afforded the product (20 mg, 12%). lH NMR (300 MHz, CDC13): f) 9.60 (s, 1H), 7.38-7.26 (m, 5H), 4.52 (s, 2H), 3.54 (s, 2H), .89 (m, 2H), 1.66-1.46 (m, 6H).

Step 4: (2E)- and (2Z)1-[(Benzyloxy)methyl]cyclopentylacrylonitrile To a stirred solution of diethyl cyanomethylphosphonate (18 uL, 0.11 mmol) in THF (1 mL) was added 1.0 M potassium tert-butoxide in THF (0.10 mL). The resulting mixture was stirred 30 minutes, afier which a on of 1—[(benzyloxy)methyl]cyclopentanecarbaldehyde (0.020 g, 0.092 mmol) in THF (1 mL) was added. The resulting mixture was d for 16 hours. Water was then added to the reaction and the resulting mixture was extracted with three ns of ethyl ether. The ed ts were washed with brine, then dried over sodium sulfate, decanted fiorn the sodium sulfate, and the solvent was removed in vacuo to afford the product, which was used without further purification in the uent ate addition step. 1H NMR (400 MHz, CDC13): 5, 7.37—7.27 (m, 5H), 6.80 (d, 1H (E)), 6.59 (d, 1H (Z)), 5.34 (d, 1H (E)), 5.33 (d, 1H (Z)), 4.53 (s, 2H (Z)), 4.50 (s, 2H (E)), 3.45 (s, 2H (Z)), 3.31 (s, 2H (E)), 1.80-1.55 (m, 8H); MS(ES)=242(M+H).

Step 5: 3-1 -[(Benzylo;gz)methyl]cyclopen31—3-[4-(7H-pyrrolofi2, 3~d]pyrz'midt'n—4-yD-IH~pyrazol yljpropanenitrile trifluoroacetate salt To a mixture of (2E)- and (2Z)—3-1~[(benzyloxy)methy1]cyclopentylacrylonitrile (generated in Step 4) and 4—(1H-pyrazol~4-yl)[2-(trimethylsilyl)ethoxy]methyl—7H—pyrrolo[2,3—d]pyrimidine (0.037 g, 0.12 mmol) in ACN (1.5 mL) was added DBU (18 uL, 0.12 mmol). The resulting mixture was stirred at ambient temperature for 3 hours, and then was heated to 60 0C for 28 hours. The reaction mixture was diluted with l ether and 0.1 N HCl. The layers were separated and the aqueous layer was extracted with ethyl acetate. The ethyl acetate extract was washed with brine, dried over sodium sulfate, decanted, and the solvent was removed in vacuo. The resulting residue Was dissolved in DCM (3 mL) and TFA (0.75 mL), and this solution was stirred for 3 hours. The solvents were removed in vacuo, and the resulting residue was dissolved in THF (5 mL) and 6.0 M sodium hydroxide in water (3 mL) and stirred for 2 hours. The reaction mixture was extracted with three portions of ethyl acetate. The combined ts were washed with brine, dried over sodium sulfate, decanted, and the solvent was removed in vacuo. The crude mixture was purified by preparative- HPLC/MS (C18 eluting with a gradient of H20 and ACN containing 0.1% TFA) and lized to afford the desired product (10 mg, 20% over the two steps). 1H NMR (400 MHz, dG—DMSO): 512.71 (br s, 1H), 8.99 (s, 1H), 8.86 (s, 1H), 8.52 (s, 1H), 7.80 (s, 3O 1H), 7.38-7.23 (m, 5H), 7.19-7.16 (m, 1H), 4.92 (dd, 1H), 4.50 (d, 1H), 4.44 (d, 1H), 3.49 (dd, 1H), 3.35 (d, 1H), 3.23 (dd, 1H), 3.05 (d, 1H), 1.92-1.82 (m, 1H), 1.66-1.27 (m, 7H); MS(ES):427(M+H).

Example 742: 3-[l-(Methylsulfonyl)pyrrolidin—3—yll—3-[4-(7H-pyrrolo[2,3—d]pyrimidin—4—yl)-1H— pyrazol-l-yl]propanenitrile trifluoroacetate salt u 'TFA Step I: Benzyl 3-(hydroxymethpryrrolidine—I-carboxylate To a solution of 1-[(benzyloxy)carbonyl]pyrrolidine—3-carboxy1ic acid (1.0 g, 4.0 mmol) in THZF (37 mL) at 0 °C was added dropwise a on of 1.0 M borane in THF (16.4 mL). The on was allowed to warm to room temperature and stir for 16 hours. The mixture was cooled to 0 °C and 10% HCl (50 mL) was added. After the addition, the mixture was extracted with DCM, and the extract was washed sequentially with saturated NaI-ICO; solution and brine, then dried over sodium e, filtered and the solvent was removed in vacuo. The product was used without further purification in the subsequent oxidation step.

]H NMR (300 MHz, CD013): 5 7.39-7.26 (m, 5H), 5.11 (s, 2H), 3.61-3.31 (m, 5H), 3.18 (dt, 1H), 2.75 (br s, 0.45H), 2.59 (br s, 0.45H), 2.49-2.31 (m, 1H), 2.19 (br s, 0.1H), 2.05-1.89 (m, 1H), 1.77- 1.58 (m, 1H); MS(ES):236(M+H).

Step 2: Benzyl 3-f0rmylpyrrolidine-1~carboxylate DMSO (597 nL, 8.42 mmol) was added to a solution of oxalyl chloride (427 uL, 5.05 mmol) in DCM (25 mL) at -78 °C. After 5 minutes, benzyl 3—(hydroxymethyl)pyrrolidinecarboxylate (generated in Step 1) was added. The reaction was continued for 30 s at -78 °C. TEA (2.3 mL, 17 mmol) was then added. The resulting mixture was then allowed to warm to room temperature over the course of 30 minutes. Water was then added. The layers were separated and the organic phase was washed sequentially with 0.1 N HCl, water, saturated NaHC03, and brine. The organic phase was then dried over sodium sulfate and the solvent was d in vacuo to afford the product (0.82 88% over two steps). 1H NMR (300 MHz, CDCl3): 6 9.68 (d, 1H), 7.38—7.28 (m, 5H), 5.13 (s, 2H), 3.79 (dd, 1H), 3.65-3.35 (m, 3H), 3.11~2.99 (m, 1H), 2.32-2.04 (m, 2H).

Step 3: Benzyl —2—cyan0vinyljpyrrolidine-I-carboxylate and benzyl 3—[(Z)-2—cyanovinyl]— pyrrolidine—I-carb0xylate To a on of 1.0 M potassium tert-butoxide in THF (4.40 mL) at 0 °C was added a solution of diethyl cyanomethylphosphonate (820 mg, 4.6 mmol) in THE (6.0 mL) dropwise. The cold bath was removed and the reaction was warmed to room temperature and d for 15 minutes. The mixture was cooled to 0 °C and a solution of benzyl 3-formylpyrrolidine—1—carboxylate (0.82 g, 2.3 mmol) in THF (4.00 mL) was added dropwise. Cooling was discontinued and the reaction d for 16 hours at ambient temperature. The mixture was diluted with ether and water, the layers were separated and the organic layer was washed with water, followed by brine, and then dried over sodium sulfate, d and the solvent was removed in vacuo. The resulting residue was purified by flash column chromatography (eluting with a gradient from 0—35% ethyl acetate in hexanes) to afford the product as a mixture ofE and Z s (246 mg, 42%). 1H NMR (300 MHz, CDClg): 8 7.41—7.27 (m, 5H), 6.70—6.58 (m, 0.3H (E)), 6.38 (dt, 0.7H (Z)), 5.50- .30 (m, 1H), 5.14 (s, 2H), 3.79-3.11 (m, 5H), 2.27-2.06 (m, 1H), 1.90—1.70 (m, 1H); MS(ES):279(M+Na).

Step 4.’ Benzyl ano~1—[4—(7—[2-(trimethylsilyDethoaqyjmethyl— 7H—pyrrolo[2, 3—d]pyrimidin-4—yl)- IH—pyrazol—J—yl]ethylpyrrolidine—l-carboxylate To a mixture of benzyl 3-[(E)cyanovinyl]pyrrolidinecarboxylate and benzyl 3-[(Z) inyIprrrolidine-l~carboxylate (241 mg, 0.940 mmol) and DBU (234 uL, 1.57 mmol) in ACN (13 mL) was added 4-(1H—pyrazolyl)[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3— d]pyrimidine (250 mg, 0.78 mmol). The mixture was stirred at ambient ature for 3 hours. The solvent was removed in vacuo. The resulting residue was dissolved in ethyl acetate, and the organic layer was washed sequentially with 1N HCl, water, saturated NaI-IC03, and brine. The washed solution was dried over sodium sulfate and the solvent was removed in vacuo. Purification via flash column chromatography (eluting with a gradient of 0-100% [5% MeOH/DCM] in hexanes) afforded the e as a mixture of diastereomers (400 mg, 89%).

'H NMR (400 MHz, CDC]; a mixture of diastereomers):5 8.85 (s, 1H), 8.35-8.28 (m, 2H), 7.42-7.25 (m, 6H), 6.80-6.76 (m, 1H), .66 (m, 2H), 5.15-5.04 (m, 2H), 4.464.32 (m, 1H), 3.84-3.84 (m, 6H), 3.54 (t, 2H), 2.26-2.13 (m, 1H), 1.84-1.54 (m, 2H), 0.95-0.89 (m, 2H), -0.06 (s, 9H); MS(ES):572(M+H).

Step 5. 3-Pyrrolidin-3—yl—3-[4-(7-[2-(trimethylsilyl)ethoxyflnethyl- 7H—pyrrolo[2,3-d]pyrimidin-4—y1)- azol—I-yl]pr0panenitrile Benzyl 3-2—cyano—1 -[4-(7-[2-(trimethylsilyl)ethoxy]methyl—7H—pyrrolo[2,3—d1pyrimidin-4— yl)—1H-pyrazol—1-y1]ethylpyrrolidine—1-carboxylate (161 mg, 0.282 mmol) was dissolved in methanol (5 mL), and a catalytic amount of 5% Pd-C was added, The suspension was stirred at ambient temperature for 1 hour under an atmosphere of hydrogen provided by a balloon. A catalytic amount of % Pd-C was then added, and the reaction stirred for 2 hours under an atmosphere of hydrogen provided by a balloon. The mixture was then filtered, and purified via preparative—I-IPLC/MS (C18 eluting with a gradient of H20 and ACN containing 0.15% NH40H) to afford the t as a mixture of diastereomers (57 mg, 46%). ' IH NMR (400 MHz, CDClg, a mixture of diastereomers): 5 8.84 (s, 1H), 8.34-8.32 (m, 2H), 7.40 (d, 1H), 6.81—6.78 (m, 1H), 5.67 (s, 2H), 4.38 (dt, 1H), 3.54 (t, 2H), 3.30—1.38 (m, 9H), 0.92 (t, 2H), -0.06 (s, 9H); MS(ES):438(M+H).

Step 6.‘ 3-[1-(MethylsulfonpryrrolidinyU[4-(7H-pyrrolo[2, 3-d]pyrimidin-4—yl)~1H-pyrazol—1- yljpropanenitrile trifluoroacetate salt To a on of 3-pyirolidinyl-3—[4-(7-{[2-(trimethylsilyl)ethoxy]methyl} ~7H—pyrrolo[2,3- d]pyrimidinyl)1H—pyrazol—1—yl]propanenitrile (25 mg, 0.057 mmol) and TBA (10 ML, 0.074 mmol) in DCM (1.0 mL) at 0 "C was added methanesulfonyl chloride (6 uL, 0.074 mmol). The reaction was d to reach ambient temperature and stir for 16 hours. Half of the solvent was removed in vacuo and TFA (1 mL) was added. to the vial. Afier stirring for 1 hour at room ature, the solvents were removed in vacuo and the resulting residue reconstituted in THF (0.5 mL). To this was added 6 N NaOH (1 mL) and this solution was stirred for 2 hours. The reaction mixture was extracted with five portions of ethyl acetate. The combined extracts were dried (NaZSO4), decanted and concentrated.

Preparative-HPLC/MS (C18 eluting with a nt ofH20 and ACN containing 0.1% TFA) was used to afford the product (16 mg, 57%). lH NMR (400 MHz, ds—DMSO, a e of diastereomers): 5 12.69 (s, 1H), 8.98 (s, 0.5H), 8.95 (s, 0.5H), 8.84 (s, 1H), 8.53—8.51 (m, 1H), .77 (m, 1H), 7.16-7.13 (m, 1H), 4.86-4.75 (m, 1H), 3.55~3.48 (m, 1H), 3.42-3 .08 (m, 4H), 2.99-2.91 (m, 1H), 2.90 (s, 1.5H), 2.85 (s, 1.5H), 2.16-2.07 (m, 1H), 1.82—1.70 (m, 1H), 1.64-1.48 (m, 1H); MS(BS):386(M+H).

Example 743: N'-Cyano(cyanomethyl)—4-[4-(7H-pyrrolo[2,3—d]pyrimidin-4~yl)—lH—pyrazol-l— yl]piperidine—l-carboximidamide N N u \\ \ N / NH N\\’_ / 2 Step I: tert-Butyl 4-(cyanomethylene)pzperidine—1-carboxy1ate To a solution of 1.0 M potassium utoxide in THF (10.1 mL) at 0 °C was added a solution of diethyl ethylphosphonate (1.66 mL, 0.0102 mol) in THF (20 mL) dropwise. The reaction was held for 10 min, then added to a solution of tert—butyl 4-0x0piperidinecarboxylate (2.00 g, 0.0100 mol) in THF (30 mL) stirring at 0 °C under an atmosphere of en. After completeaddition, the cold bath was removed and the reaction was allowed to stir 1.0 h at 20 °C.

LCMS analysis showed the desired product and no remaining starting material. HPLC showed the product UVmax at 200 & 230 nm. Water and EtOAc were added to the reaction mixture. The phases were separated, and the aqueous phase was extracted with EtOAc. The combined organic phase was washed with water, then saturated NaCl, then dried over Na2804, and concentrated to dryness to provide 2.5 g of the product as a yellow oil. TLC (25% EtOAc/hexane) Rf 0.22. The product was purified by tic flash chromatography on silica gel. Used a 40g column; flow 40 mL/min; [A= hexane] [B= EtOAc]. A, 4 min; Gradient to 20% B in 30 min. Collected 44 mL ons. The product eluted in 21-27 min. The fractions were contrated to yield 0.67 g of a white solid. 1H NMR (CDC13) 5 5.19 (s, 1H); 3.51 (m, 4H); 2.56 (t, 2H); 2.33 (t, 2H); 1.50 (s, 9H). MS(ES) 245 (M+Na, weak; base peak M+H—56 = 167).

Step 2: tert-Butyl 4-(cyanomethyl)—4—[4-(7—[2-(trimethylsilyl)ethoxy]methyl—7H~pyrrolo[2,3—d]- pyrimidin-4—yl)~1H—pyrazolyl]piperidinecarbo.xy1ate 4-(1H-Pyrazolyl)—7-[2-(trimethylsilyl)ethoxy]methy1—7H—pyrrolo[2,3—d]pyrimidine (0.840 g, 2.66 mmol) was slurried in a mixture of ACN (20 mL) and DBU (398 uL, 2.66 mmol), and tert~ butyl 4-(cyanomethylene)piperidine—1—carboxylate (0.651 g, 2.93 mmol) was added, The pyrazole did not dissolve at 20° C, but a solution was formed when the e was heated to 40 °C for 1h. LCMS and HPLC es showed about 20% sion to product. The e was d at 40-45 0C overnight. HPLC showed 60 area% product. The ACN was removed by retory evaporator at 20 °C. To the resulting residue was added saturated NaHCO; and EtOAc. The organic layer was shaken with more aqueous saturated NaHCO3, then dried (Nazson and rotovaped to give 1.6g of a brown oil residue. TLC (60% EtOAc/hexane): product Rf = 0.25. The product was purified by automatic flash chromatography on silica gel, using a 40g column, at a flow of 40 mL/min; [A= hexane] [B= EtOAc].

A, 3min; Gradient to 100% B in 50 min. Collected 44 mL fractions. The product eluted in 24—29 min; the pyrazole in 39-46 min; and the olefin in 13-15 min. Solvent was removed in vacuo for the appropriate fractions to give 0.27 g olefin; 0.30 g pyrazole; and a yield of 0.67 g of the product, all of which were ed as white solids. 1H NMR (CDCI3) 6 8.84 (s, 1H); 8.42 (s, 1H); 8.33 (s, 1H); 7.40 3O (d, 1H); 6.79 (d, 1H); 5.67 (s, 2H); 3.94 (m, 2H); 3.54 (m, 2H); 3.07 (m, 2H); 2.90 (s, 2H); 2.72 (m, 2H); 2.08 (m, 2H); 1.45 (s, 9H); 0.91 (m, 2H); -0.06 (s, 9H). MS(ES) 538 (M+H).

Step 3: 4-[4-(7H-Pyrrolo[2, 3—d]pyrimidin—4-yl)—IH—pyrazol—1-yl]piperidin-4—ylacetom'trr'le tert—Butyl 4-(cyanomethyl)~4-[4-(7-[2-(trimcthylsilyl)ethoxy]methyl-7H-pyrrolo[2,3—d]- pyrimidin—4-yl)—1H—pyrazol—l -yl]piperidine—l -carboxylate (0.670 g, 1.24 mmol) was dissolved in TFA (5.0 mL, 65 mmol) and was stirred for 1.3 h. LCMS showed conversion to the hydroxymethyl ediate, M+H 338. The solution was concentrated to remove the TFA. Methanol was added to the resulting e, and the resulting mixture was concentrated. The resulting residue was dissolved in methanol (10 mL) and 15.0 M ammonium hydroxide in water (1.66 mL) was added. The resulting solution was stirred for 2 h. LCMS and HPLC analyses showed complete deprotection. The mixture was concentrated. Toluene was added to the resulting residue and the resulting mixture was concentrated to provide a white semisolid. Most of this intermediate product was used for the next step. The rest was purified by prep HPLC using a 30 mm x 100 mm C18 column; 8% O (0.1% NILOH), , to 27% at 6min; 60 mL/min; detector set at m/z 308; retention time, 5.4 min.

Tubes containing pure product were combined and freeze dried to give 13.6 mg of the product. 1H NMR (dg-DMSO) 5 12.07 (s, 1H); 8.68 (s, 1H); 8.62 (s, 1H); 8.36 (s, 1H); 7.54 (d, 1H); 7.00 (d, 1H); 3.16 (s, 2H); 2.87 (m, 2H); 2.55 (m, 4H); 1.94 (m, 2H). MS(ES) 308 (M+H).

Step 4: Methyl N-cyan0(cyanomethyD[4-(7H-pyrrolo[2,3—d]pyrimidinyl)—1H-pyrazol—I -yl]- dine—I -carbimid0thioate 4-[4-(7H~Pyrrolo[2,3-d]pyrimidin—4-yl)-1H—pyrazol-l—yl]piperidin—4~ylacetonitrile (361 mg, 1.17 mmol) and N-cyano-S,S’-dimethyldithioimido carbonate (344 mg, 2.35 mmol) were ved in isopropyl alcohol (2.5 mL) and DMSO (2.5 mL) at 20 °C. After 16 h reaction time, LCMS analysis showed the presence of some product, M+H 406; of the reagent, M+H 147; and of the piperidine, M+H 308. HPLC analysis showed about 2% reaction. The HPLC method was: Zorbax SB C18, Sum, cm, 35 DC, flow 1.2 mL/min, 5% ACN—HzO (0.05% TFA), 1.5 min, to 100% ACN in 15.0 min; or set at 324, 225, and 265 nm. The retention time of the ng material was 4.9 min (UV max 224, 262, 292, & 325 nm); of the product, 6.5 min (UV max 226, 262, 290, & 324nm); and of the reagent, 7.7min (UV max 265nm). To the product was added TEA (327 uL, 2.35 mmol), and the ing mixture was stirred at RT. After stirring for 3 h, HPLC and LCMS analyses showed 60% reaction. The product and the unreacted piperidine were isolated by prep HPLC using a 30 mm x 100 mm C18 column; 5%ACN-H20 (0.1%TFA), 1.0min, to 35% at 6min; 60 mL/min; detector set at 326 nm. The retention time for the t was 5.9 min; and for the starting piperidine was 3.5—4.3 min.

The product was freeze dried to yield 301 mg of a white solid TFA salt. 1H NMR (d6-DMSO) 6 12.85 (s, 1H); 9.01 (s, 1H); 8.90 (s, 1H); 8.59 (s, 1H); 7.85 (m, 1H); 7.30 (m, 1H); 4.23 (m, 2H); 3.35 (m, 2H); 3.30 (s, 2H); 2.78 (m, 2H); 2.68 (s, 3H); 2.16 (m, 2H). MS(ES) 406 (M+H).

Step 5: NLCyano—4-(cyanomethy1)—4-[4-(7H~pyrrolo[2, 3-d]pyrimidinyl)—1H—pyrazol—1-yl]piperi— dine-1—carb0ximidamide Methyl N—cyanoA—(cyanomethyl)—4-[4—(7H-pyrrolo[2,3~d]pyrimidin—4—y1)—lH—pyrazol-l—yl]- piperidine-l-carbimidothioate (41.3 mg, 0.102 mmol) (53 mg TFA salt) was dissolved in 2.0 M ammonia in isopropyl alcohol (4.00 mL). The ing mixture was heated to 100 °C for 1 h in a microwave reactor. Analysis by HPLC and LCMS showed 60% reaction to give the expected M+H 375 (50 area%)._ To this mixture was added 2 mL of 7 N NH3/MeOH. The resulting mixture was heated at 120 °C for one hour. HPLC and LCMS analyses showed no remaining starting material.

The on mixture was trated on a rotory ator. The product was isolated by prep HPLCMS using a 30 mm x 100 mm C18 column, eluting with a solvent gradient; 10% ACN—Hzo (0.1%TFA), 1.5min, to 30% at 6min; 60mL/min; detector set at m/z 375; ion time, 4.7 min. The eluate was freeze-dried to yield 11.7 mg of the product TFA salt as a white solid. 1H NMR (d6- DMSO) 6 12.69 (s, 1H, NH); 8.92 (s, 1H); 8.81 (s, 1H); 8.51 (s, 1H); 7.75 (m, 1H); 7.22 (m, 1H); 7.18 (s, 2H, NH2); 3.84 (m, 2H); 3.23 (s, 2H); 2.99 (m, 2H); 2.60 (m, 2H); 1.97 (m, 2H). MS(ES) 375 (M+H).

Example 744: 4[2,2,2—Trifluoro—l-(lH—imidazol-Z-ylmethyl)ethyl]—1H—pyrazol—4-yl-7H-pyr— rolo[2,3—d]pyrimidine F ""3 N‘\ \ N NH Step1 .' (3R)-4, 4, 4-Trifluoro[4-(7-[2-flrz’methylsilyDethoxyj’methyl— 7H-pyrrolo[2, 3—d]pyrimidin~4- yl)-IH-pyrazol-I~yl]butanal F N'N N\ \ N N To a ~70 °C solution of (3R)-4,4,4-trifluoro[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyr- ,3-d]pyrimidin-4—yl)-lH—pyrazol-l-yl]butanenitrile (1.06 g, 0.00243 mol) (see, Example 93, Step1) in DCM (10 mL, 0.2 mol) was added 1.0 M diisobutylaluminum hydride in DCM (4.8 mL).

The resulting mixture was stirred for 3h and allowed to warm during this time interval from —70 to ~25 °C, afier which the reaction was cooled back at -70 °C. Methanol (1.5 mL, 0.037 mol) was added, followed by 2.0 M HCl in water (15 mL). ble material was then filtered from the reaction mixture. The organic filtrate was washed sequentially with: 2.0 M HCl in water, water and saturated aqueous NaCl. The washed organic phase was dried over sodium sulfate and was concentrated using a rotory evaporator to give 0.58 g of the crude product as a pale yellow foam/solid. The crude product was chromatographed with 0—80% ethyl acetate/hexanes to give the purified product (0.9 g) as a pale orange oil (47% yield). 1H NMR (400 MHz, CDC13): 8 9.85 (1H, s); 8.95 (1H, s); 8.5 (1H, s); 8.4 (1H, s); 7.5 (1H, d); 6.85 (1H, d); 5.75 (2H, s); 5.5 (1H, m); 4.0 (1H, dd); 3.6 (2H, t); 3.3 (1H, dd); 1.99 (2H, t); 0.0 (9H, 3). MS (M+H): 440.

Step2: 4—1-[2,2,2-Trifluoro-I—(1H;imidazol—2—ylmethyDethylj-IH—pyrazol—4—yl— 7-[2—(trimethylsily0- ethoxyjmethyl- 7H-pyrrolo[2, 3—d]pyrimidine ("NH F 'N‘ N N \ \ N N A solution of 4,4,4-trifluoro-3—[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyn'olo[2,3-d]— pyrimidin—4—yl)—1H—pyrazolyl]butanal (0.138 g, 0.000314 mol), 7.0 M ammonia in methanol (1 mL), dial (0.5 mL, 0.004 mol) and acetic acid (20 uL, 0.0004 mol) in methanol (2 mL, 0.05 mol) was microwaved on 100 watts, at 80 °C for 60 minutes. Following the microwave reaction, ethyl acetate/water was added. The organic phase was separated and washed with saturated NaHCO; and ted NaCl. The washed organic phase was dried and concentrated (rotory evaporator) to give 196 mg of the crude product as an orange glass. The crude product was purified by chromatography with 0—100% ethyl acetate/hexanes to give 57 mg fied product as an off—white solid (38% yield).

‘H NMR (400 MHz, CD013): 8 8.91 (1H, s); 8.4 (1H, s); 8.2 (1H, s); 7.5 (1H, d); 7.0 (2H, s); 6.83 (1H, d); 5.75 (2H, s); 5.62 (1H, m); 4.15 (1H, dd); 3.8 (1H, dd); 3.6 (2H, t); 1.99 (2H, t); 0.0 (9H, 5).

MS (M+H): 478.

Step3: 4—1 —[2, ifluoro—1—(JH—imidazol—Z—ylmethyl)ethylj—IH—pyrazol—4—yl— rolo[2, 3-d]— pyrimidine A solution of 4—1—[2,2,2-trifluoro(1H-imidazolylmethyl)ethyl]-1H-pyrazol—4—yl-7—[2- (trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (0.055 g, 0.12 mmol) in 1,2-dichloro— ethane (1 mL, 10 mmol) and TFA (0.5 mL, 6 mmol) was stirred overnight. The On was concentrated to provide an orange oil. The oil was stirred in methanol (1 mL, 20 mmol) and 8.0 M WO 70514 ammonium hydroxide in water (1 mL) for 4h. This mixture was then concentrated to provide a crude product as an orange solid. The crude product was purified by Prep HPLC (leO) to give 28 mg of purified product as a colorless glass, which was triturated with 2—methoxy—2-methylpropane (1 mL, 8 mmol), and then filtered and washed to provide 15 mg of the product as a white solid (38% yield) which then was dried rt-50 °C for 3h. lH NMR (400 MHz, DMSO): 5 12.13 (1H, 5); 11.89 (1H, s); 8.65 (1H, s); 8.37 (1H, s); 7.6 (1H, d); 6.95 (1H, d); 6.92 (1H, d); 5.91 (1H, m); 3.78 (1H, dd); 3.47 (H, dd). MS (M+H): 348.

Example 745: 4-(1-(1R)-2,2,2-Trifluoro—l~[(4-methyl-l,3-thiazolyl)methyl]ethyl-IH-pyrazol- 4-yl)-7H-pyrrolo[2,3-d1pyrimidine F N43 N'\i/\ Step 1: (3R)—4, 4, 4-Trifluoro[4-(7H-pyrrolo[2, rimidinyl)-IH-pyrazol—I -yl]butane— thioamz'de .- 2} F N ' N N '\ \ 'L , N NH A suspension ofphosphorus pentasulfide (0.46 g, 1.0 mmol) in ethanol (0.5 mL, 8 mmol) was stirred for lh. (3R)-4,4,4-Trifluoro[4-(7H-pyrro]o[2,3—d]pyrirnidin~4-yl)—1H-pyrazol-Llebutane- nitrile (0.15 g, 0.50 mmol) (see, e 93) was added and the resulting mixture was heated at 80 °C in a sealed vial for 0.5h, during which reaction the mixture became a yellow solution. The reaction was heated ovemight. The reaction was then cooled to rt. Water (1 g, 60 mmol) and ethyl acetate were added to the mixture. The organic phase was separated and washed with ted NaHC03 and saturated aqueous NaCl. The washed organic phase was then dried and concentrated to give 387 mg of a crude product as a white glass/oil. The crude product was chromatographcd With 0- % MeOI-I/DCM, 0-1%NH40H to give 0.13 g of the purified t as a white solid (76% yield).

‘H NMR (400 MHz, CDClg): 8 8.7 (1H, s); 8.5 (1H, s); 8.3 (1H, s); 7.4 (1H, d); 7.0 6.75 (1H, d); 5.82 (1H, In); 3.75 (1H, dd); 3.2 (1H, dd). MS (M+H): 341.

A suspension of (3R)-4,4,4-trifluoro—3-[4-(7H-pyrrolo[2,3—d]pyrimidinyl)-lH—pyrazol-l— yl]butanethioamide (0.038 g, 0.00011 mol), chloroacetone (15 uL, 0.00019 mol) in ethanol (1 mL, 0.02 mol) and 1,2-dichloroethane (1 mL, 0.01 mol) was heated to reflux overnight. Following this, the reaction mixture was filtered to remove insoluble material. The filtrate was dissolved in MeOH (1 -mL) and DMF (1 mL) and purified by prep HPLC at leO to e 6 mg of the d product as a colorless glass/oil, which was then triturated with MTBE/hexanes and was dried at 40 °C overnight to give 5.2 mg of the purified product as an off-white solid (13% yield). l0 1H NMR (400 MHz, CD013): 8 10.11 (1H, s); 8.88 (1H, s); 8.42 (1H, s); 8.38 (1H, s); 7.45 (1H, d); 6.79 (1H, s); 6.65 (1H, d); 5.41 (1H, m); 4.15 (1H, dd); 3.75 (H, dd); 2.18 (3H, 5). MS (M+H): 379.

Example A: In vitro JAK Kinase Assay Compounds herein were tested for inhibitory activity of JAK s according to the following in vitro assay described in Park et al., Analytical Biochemistry 1999, 269, 94-104. The catalytic domains of human JAKl (a.a. 837-1142), Jak2 (a.a. 828-1132) and Jak3 (a.a. 781-1124) with an N~terminal His tag were expressed using baculovirus in insect cells and purified. The catalytic activity of JAK], JAKZ or JAK3 was assayed by ing the phosphorylation of a ylated peptide. The phosphorylated peptide was detected by homogenous time resolved fluorescence . 10505 of compounds were measured for each kinase in the reactions that contain the enzyme, ATP and 500 nM peptide in 50 mM Tris (pH 7.8) buffer with 100 mM NaCl, 5 mM DTT, and 0.1 mg/mL (0.01%) BSA. The ATP concentration in the reactions was 90 uM for Jakl, 30 M for Jak2 and 3 M for Jak3. Reactions were carried out at room temperature for 1 hr and then stopped with 20 "L 45 mM EDTA, 300 nM SA—APC, 6 nM 0 in assay buffer n Elmer, Boston, MA).

Binding to the Europium labeled antibody took place for 40 minutes and HTRF signal was measured on a Fusion plate reader (Perkin Elmer, , MA). Compounds having an [cm of 10 M or less for any of the above-mentioned JAK targets were considered active.

Example B: Cellular Assays One or more compounds herein were tested for tory ty ofJAK targets according to at least one of the following cellular assays.

Cancer cell lines dependent on nes and hence JAK/STAT signal transduction, for growth, were plated at 6000 cells per well (96 well plate format) in RPMI 1640, 10% FBS, and l nG/mL of appropriate cytokine. Compounds were added to the cells in DMSO/media (final concentration 0.2% DMSO) and incubated for 72 hours at 37 °C, 5% 002. The effect of compound on cell viability was assessed using the CellTiter-Glo Luminescent Cell Viability Assay (Promega) ed by TopCount n Elmer, Boston, MA) quantitation. Potential off—target effects of compounds were measured in parallel using a non-JAK driven cell line with the same assay readout.

Compounds having an 1050 of 10 1.1M or less with selectivity for JAK driven proliferation were considered active. All experiments were performed in duplicate.

The above cell lines can also be used to examine the effects of compounds on phosphorylation of JAK kinases or potential downstream substrates such as STAT proteins, Akt, ShpZ, or Erk. These experiments can be performed following an ght cytokine tion, followed by a brief preincubation with compound (2 hours or less) and cytokine stimulation of approximately 1 hour or less. Proteins are then ted from cells and analyzed by techniques familiar to those schooled in the art including Western blotting or ELISAs using antibodies that differentiate between phosphorylated and total protein. These experiments can utilize normal or cancer cells to investigate the activity of compounds on tumor cell al biology or on mediators of inflammatory disease. For example, with regards to the latter, cytokines such as IL-6, IL—12, IL—23, or IFN can be used to stimulate JAK activation resulting in phosphorylation of STAT protein(s) and potentially in transcriptional profiles sed by array or qPCR technology) or production and/or secretion of proteins, such as IL—17. The ability of compounds to inhibit these cytokine ed effects can be measured using techniques common to those schooled in the art.

Compounds herein can also be tested in cellular models designed to evaluate their potency and activity against mutant JAKs, for example, the JAK2V617F mutation found in myeloid proliferative disorders. These ments often utilize cytokine dependent cells of hematological lineage (eg. BaF/3) into which the wild-type or mutant JAK kinases are ectopically expressed (James, C., et al. Nature 434:1144-1148; Staerk, J., et a1. JBC 280:41893—41899). Endpoints e the effects of compounds on cell survival, proliferation, and orylated JAK, STAT, Akt, or Erk Certain compounds herein have been or can be evaluated for their activity inhibiting T-cell eration. Such as assay can be considered a second cytokine (i. e. JAK) driven proliferation assay and also a stic assay of immune suppression or inhibition of immune activation. The following is a brief e of how such experiments can be performed. Peripheral blood mononuclear cells (PBMCs) are prepared from human whole blood s using Ficoll Hypaque separation method and T—cells (fraction 2000) can be obtained from PBMCs by elutriation. Freshly isolated human T- cells can be maintained in culture medium (RPMI 1640 supplemented witth% fetal bovine serum, 100 U/ml penicillin, 100 gig/m] streptomycin) at a density of 2 x 106 ml at 37 °C for up to 2 days.

For IL—2 stimulated cell proliferation analysis, T—cells are first treated with Phytohemagglutinin (PHA) at a final concentration of 10 ug/mL for 72h. After washing once with PBS, 6000 cells/Well are plated in 96-well plates and treated with compounds at different concentrations in the culture medium in the ce of 100 U/mL human IL-2 (ProSpec-Tany TechnoGene; Rehovot, Israel). The plates are incubated at 37 °C for 72h and the proliferation index is assessed using CellTiter—Glo Luminescent reagents following the manufactory suggested protocol ga; Madison, WI).

Example C: In vivo anti~tumor efficacy Compounds herein can be ted in human tumor xenografi models in immune compromised mice. For example, a tumorigenic variant of the INA-6 plasmacytoma cell line can be used to inoculate SCID mice subcutaneously (Burger, R., et a1. Hematol J. 2:42—53, 2001). Tumor bearing animals can then be randomized into drug or vehicle treatment groups and different doses of compounds can be administered by any number of the usual routes including oral, i.p., or continuous infusion using implantable pumps. Tumor growth is followed over time using calipers. Further, tumor samples can be harvested at any time alter the tion of treatment for analysis as described above (Example B) to evaluate nd effects on JAK activity and downstream signaling pathways. In addition, selectivity of the nd(s) can be assessed using xenograft tumor models that are driven by other know kinases (e. g. Bcr—Abl) such as the K562 tumor model.

Example D: Murine Skin Contact Delayed Hypersensitivity Response Test Compounds herein can also be tested for their efficacies (of inhibiting JAK targets) in the T— cell driven murine delayed hypersensitivity test model. The murine skin t delayed-type hypersensitivity (DTH) response is considered to be a valid model of clinical contact dermatitis, and other T—lymphocyte mediated immune disorders of the skin, such as psoriasis ol Today. 1998 Jan;l9(1):37—44). Murine DTH shares multiple characteristics with psoriasis, including the immune infiltrate, the accompanying increase in inflammatory cytokines, and keratinocyte hyperproliferation.

Furthermore, many classes of agents that are efficacious in treating psoriasis in the clinic are also effective inhibitors of the DTH response in mice s s. 1993 Jan;38(1-2):1 16—21).

On Day 0 and l, Balb/c mice are sensitized with a topical ation, to their shaved abdomen with the antigen 2,4,dinitro—fluorobenzene (DNFB). On day 5, cars are measured for thickness using an er’s micrometer. This measurement is recorded and used as a baseline. Both of the animals’ ears are then challenged by a topical application of DNFB in a total of 20 ,uL (10 [IL on the internal pinna and 10 ML on the external pinna) at a concentration of 0.2%. Twenty—four to seventy-two hours alter the challenge, ears are measured again. Treatment with the test compounds was given throughout the sensitization and challenge phases (day -1 to day 7) or prior to and 3O throughout the challenge phase ly afiemoon of day 4 to day 7). Treatment of the test compounds (in different concentration) was stered either ically or topically (topical application of the treatment to the cars). Efficacies of the test compounds are indicated by a reduction in ear swelling comparing to the situation t the treatment. Compounds causing a reduction of % or more were considered ious. In some experiments, the mice are challenged but not sensitized (negative control).

The inhibitive effect (inhibiting activation of the JAK-STAT pathways) of the test compounds can be confirmed by immunohistochemical analysis. Activation of the JAK~STAT pathway(s) results in the formation and translocation of onal transcription s. Further, the influx of immune cells and the increased proliferation of keratinocytes should also provide unique expression profile changes in the ear that can be investigated and quantified. Formalin fixed and paraffin ed ear sections (harvested after the challenge phase in the DTH model) are subjected to histochemical analysis using an antibody that specifically interacts with phosphorylated STAT3 (clone 58E12, Cell Signaling Technologies). The mouse ears are treated with test compounds, vehicle, or thasone (a clinically ious treatment for psoriasis), or without any treatment, in the DTH model for comparisons. Test compounds and the dexamethasonc can produce similar transcriptional changes both qualitatively and quantitatively, and both the test compounds and thasone can reduce the number of infiltrating cells. Both systemically and tOpical administration of the test compounds can produce inhibitive effects, i.e., reduction in the number of infiltrating cells and inhibition of the transcriptional changes.

Example E: In vivo anti-inflammatory activity Compounds herein can be or have been evaluated in rodent or dent models ed to replicate a single or complex inflammation response. For instance, rodent models of arthritis can be used to evaluate the therapeutic potential of compounds dosed preventatively or therapeutically.

These models include but are not limited to mouse or rat collagen—induced arthritis, rat adjuvant— d arthritis, and collagen antibody—induced tis. Autoimmune diseases ing, but not limited to, multiple sclerosis, type I-diabetes mellitus, uveoretinitis, thyroditis, myasthenia gravis, immunoglobulin nephropathies, ditis, airway sensitization (asthma), lupus, or colitis may also be used to evaluate the therapeutic potential of compounds herein. These models are well ished in the research community and are familiar to those schooled in the art (Current Protocols in Immunology, Vol 3., Coligan, J.E. et al, Wiley Press; Methods in Molecular Biology: Vol. 225, Inflammation Protocols, d, P.G. and Willoughby, D.A., Humana Press, 2003.).

Various modifications of the invention, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in the present application is incorporated herein by reference in its entirety.

Claims (10)

What is claimed is:

1. 1. A ceutical composition sing a compound, which is 3-cyclopentyl[4-A pharmaceutical composition comprising a compound, Which is 3—cyclopentyl—3—[4— (7H-pyrrolo[2,3-d]pyrimidinyl)-1H-pyrazolyl]propanenitrile, or a pharmaceutically(7H—pyrrolo[2,3—d]pyrimidin—4—yl)—1H—pyrazol—1—yl]propanenitrile, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; wherein said composition is toacceptable salt thereof, and a pharmaceutically acceptable carrier; Wherein said composition is to be orally administered and provides sustained release of said compound or said salt. be orally administered and provides ned release of said compound or said salt.

2. 2. The pharmaceutical composition of claim 1, wherein the compound is (3R)The pharmaceutical composition of claim 1, n the compound is (3R)—3— cyclopentyl[4-(7H-pyrrolo[2,3-d]pyrimidinyl)-1H-pyrazolyl]propanenitrile, or acyclopentyl—3—[4—(7H—pyrrolo[2,3—d]pyrimidin—4—yl)— 1H—pyrazol— 1 opanenitrile, or a pharmaceutically acceptable salt thereof. pharmaceutically acceptable salt thereof.

3. 3. The pharmaceutical composition of claim 2, wherein said composition is a unit The pharmaceutical composition of claim 2, Wherein said composition is a unit dosage form. form.

4. 4. The pharmaceutical composition of claim 3, wherein said unit dosage form is a tablet. The pharmaceutical ition of claim 3, Wherein said unit dosage form is a tablet.

5. 5. The pharmaceutical composition of claim 3, wherein said unit dosage form is a capsule. The pharmaceutical composition of claim 3, Wherein said unit dosage form is a capsule.

6. 6. The pharmaceutical composition of claim 3, wherein said unit dosage form furtherThe pharmaceutical composition of claim 3, Wherein said unit dosage form further comprises an enteric coating. comprises an enteric coating.

7. 7. The pharmaceutical ition of claim 3, wherein the unit dosage form comprisesThe pharmaceutical composition of claim 3, Wherein the unit dosage form comprises from about 5 to about 1000 mg of said nd or said salt. from about 5 to about 1000 mg of said compound or said salt.

8. 8. The pharmaceutical composition of claim 2, further comprising one or more excipientsThe pharmaceutical ition of claim 2, further comprising one or more excipients selected from lactose, dextrose, sucrose, sorbitol, ol, starches, gum acacia, calciumselected from lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, n, calcium silicate, microcrystalline cellulose,phosphate, alginates, tragacanth, gelatin, calcium te, rystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. polyVinylpyrrolidone, cellulose, water, syrup, and methyl ose.

9. 9. The pharmaceutical composition of claim 2, further comprising microcrystallineThe pharmaceutical composition of claim 2, further comprising microcrystalline cellulose. cellulose. 271 271

10. 10. The pharmaceutical composition of claim 2, further comprising e. The pharmaceutical composition of claim 2, further comprising lactose. 272 272