AU2012201894A1 - Heteroaryl substituted pyrrolo[2,3-b]pyridines and pyrrolo[2,3-b]pyrimidines as Janus kinase inhibitors - Google Patents

Abstract

The present invention provides heteroaryl substituted pyrrolo[2,3 b]pyridines (1) 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. (Y nZ z T=A 2 /11 \N R3 N N H(I

Description

AUSTRALIA Patents Act 1990 INCYTE CORPORATION COMPLETE SPECIFICATION STANDARD PATENT Invention Title: Heteroaryl substituted pyrrolo[2,3-b]pyridines and pyrrolo[2,3 b]pyrimidines as Janus kinase inhibitors The following statement is a full description of this invention including the best method of performing it known to us:- HETEROARYL SUBSTITUTED PYRROLO[2,3-b]PYRIDINES AND PYRROLO[2,3-b]PYRIMIINES AS JANUS KINASE INHIBITORS FIELD OF THE INVENTION The present invention provides heteroaryl substituted 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 processes including cell growth, survival and differentiation, organ formation and morphogenesis, neovascularization, tissue repair and -regeneration, among others. Protein kinases exert their physiological functions through catalyzing the phosphorylation of proteins (or substrates) and thereby modulating the cellular activities of the substrates in various biological contexts. In addition to the functions in normal tissues/organs, many protein kinases 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 2001, 411(6835):355-365). Thus far, oncogenic protein kinases represent one of the largest and most attractive groups of protein targets for cancer intervention and drug development. Protein kinases can be categorized as receptor type and non-receptor type. Receptor tyrosine kinases (RTKs) have an extracellular portion, a transmembrane domain, and an intracellular portion, 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 followed by receptor dimerization, stimulation of the intrinsic protein 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 effects, and changes in the extracellular microenvironment At present, at least nineteen (19) distinct RTK subfamilies have been identified. One RTK subfamily, designated the HER subfamily, includes EGFR, HER2, HER3 and HER4, and bind such ligands as epithelial growth factor (EGF), TGF-a., amphiregulin, HB-EGF, betacellulin and heregulin. 16 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 kinase-1 (KDR/FLK-1), the fetal liver kinase 4 (FLK-4) and the fins-like tyrosine kinase I (flt-1). Two other subfamilies of RTKs have been designated as the FGF receptor family (FGFRI, FGFR2, FGFR3 and FGFR4) and the Met subfamily (c-Met, 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):1912-1934. 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 multiple members that have been frequently linked to oncogenesis. The Src family, for example, is the largest and includes Src, Fyn, Lck and Fgr among others. For a detailed discussion of these kinases, see Bolen JB. Nonreceptor tyrosine protein kinases. Oncogene. 1993, 8(8):2025-3 1. A significant number of tyrosine kinases (both receptor and nonreceptor) are associated with cancer (see Madhusudan S, Ganesan TS. Tyrosine kinase inhibitors in cancer therapy. Clin Biochem. 2004, 37(7):618-35.). Clinical studies suggest that overexpression or dysregulation of tyrosine kinases may also be of prognostic value. For example, members of the HER family of RTKs have been associated 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-i kinase expression inversely 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 of poor prognosis in all stages of colorectal cancer. The immune system responds to injury and threats from pathogens. Cytokines 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, proliferation 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 cascades that transduce the extracellular signal to the nucleus, ultimately leading to changes in gene expression. The pathway involving the Janus kinase family of protein tyrosine kinases (JAKs) and Signal Transducers and Activators of Transcription (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 2 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 phosphorylation event. Upon activation, STATs dissociate from the receptors, dimerize, and translocate to the nucleus to bind to specific DNA sites and alter transcription (Scott, M. J., C. J. Godshall, et al. (2002). "Jaks, STATs, Cytokines, and Sepsis." Clin Diagn Lab Immunol 9(6): 1153-9). The JAK family plays a role in the cytokine-dependent regulation of proliferation and function of cells involved in immune response. Currently, there are four known mammalian JAK family members: JAKI (also known as Janus kinase-1), JAK2 (also known as Janus kinase-2), JAK3 (also known as Janus kinase, leukocyte; JAKL; 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 docking site for STATs (Scott, Godshall et al. 2002, supra). While JAKI, 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 lymphoid activation (Kawamura, M., D. W. McVicar, et al. (1994). "Molecular cloning of L-JAK, a Janus family protein-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 inappropriate immune / inflammatory response contributes to the pathology of autoimmune diseases such as rheumatoid and psoriatic arthritis, asthma and systemic lupus erythematosus, inflammatory bowel disease, 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 typically aimed at augmentation or suppression of the immune and inflammatory pathways, accordingly. Deficiencies in expression of JAK family members are associated with disease states. Jakl-/ mice are rented at birth, fail to nurse, and die perinatally (Rodig, S. J., M. A. Meraz, et al. (1998). "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 3 day 12.5 postcoitum due to the absence of definitive erythropoiesis. JAK2-deficient fibroblasts do not respond to IFN gamma, although responses to IFNalphalbeta and IL-6 are unaffected. JAK2 functions in signal transduction of a specific group of cytokine receptors required in definitive erythropoiesis (Neubauer, H., A. Cumano, et al. (1998). Cell 93(3): 397-409; Parganas, E., 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. Oakes, et al. (1997). "Structural and functional basis for JAK3-deficient 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 response, chronic obstructive pulmonary disease, bronchitis, and other related inflammatory diseases of the lower respiratory tract. For instance, the inappropriate immune responses that characterize 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 JAK1 and JAK3 to activate STAT6, and signaling through IL-12 stimulates activation of JAK2 and TYK2, and subsequent phosphorylation of STAT4. STAT4 and STAT6 control multiple aspects of CD4+ T helper cell differentiation (Pernis, A. B. and P. B. Rothman (2002). "JAK-STAT signaling in asthma." J Clin Invest 109(10): 1279-83). Furthermore, TYK2-deficient mice were found to have enhanced Th2 cell-mediated allergic airway inflammation (Seto, Y., H. Nakajima, et al. (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 inflammatory 5 diseases/conditions of the eye including, but not limited to, iritis, uveitis, scleritis, conjunctivitis, as well as chronic allergic responses. 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 0 phenotype, an event that correlates with acquisition of constitutive phosphorylation of JAKs and STATs. Furthermore, an association between JAK3 and STAT-1, STAT-3, and STAT-5 activation and cell-cycle progression 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 leukemic cells and that therapeutic approaches 5 aimed at JAK/STAT inhibition may be considered to halt neoplastic growth (Takemoto, S., J. C. Mulloy, et al. (1997). "Proliferation of adult T cell leukemia/lymphoma cells is associated with the constitutive activation of JAK/STAT proteins." Proc Nall Acad Sci U S A 94(25): 13897-902). 4 Blocking signal transduction at the level of the JAK kinases holds promise for developing treatments for human cancers. Cytokines of the interleukin 6 (IL-6) family, which activate the signal transducer gpl30, are major survival and growth factors for human multiple myeloma (MM) cells. The signal transduction of gp 130 is believed to involve JAKI, 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 inhibitor tyrphostin AG490, JAK2 kinase activity and ERK2 and STAT3 phosphorylation were inhibited. Furthermore, cell proliferation was suppressed and apoptosis was induced (De Vos, J., M. Jourdan, et al. (2000). "JAK2 tyrosine kinase inhibitor tyrphostin AG490 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 cytokine 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) (Boudny, 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 fatigue. As such, JAK inhibition may be therapeutic for the treatment of cancer patients for reasons that extend beyond potential anti-tumor activity. The cachexia indication may gain further mechanistic support with realization that the satiety factor leptin signals through JAKs. Pharmacological targeting of Janus kinase 3 (JAK3) has been employed successfully to control allograft rejection 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 dendritic cells (DCs), JAK3 activity is induced, and increases in costimulatory molecule expression, IL-12 production, and potent allogeneic stimulatory capacity are observed. A rationally designed JAK3 inhibitor WIl-P-154 prevented these effects arresting the DCs at an immature 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 CD40-triggered dendritic cell maturation and induction of T-cell hyporeactivity by targeting 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-1 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). 5 "Targeting JAK3 with JANEX-1 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 myeloproliferative 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), chronic myelomonocytic leukemia (CMML), hypereosinophilic syndrome (HES) and systemic mast cell disease (SMCD). Although the myeloproliferative disorder (such as PV, ET and MMM) are thought to be caused by acquired somatic mutation in hematopoietic progenitors, the genetic basis for these diseases has not been known. However, it has been reported that hematopoietic cells from a majority of patients with PV and a significant number of patients with ET and MMM possess a recurrent somatic activating mutation in the JAK2 tyrosine kinase. It has also been reported that inhibition 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 pharmacologic inhibition in patients with PV, ET and MMM. Inhibition 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 generally accepted that activated T lymphocytes are important for the maintenance of the disease and its associated psoriatic plaques (Gottlieb, A.B., et al, Nat Rev Drug Disc., 4:19-34). Psoriatic plaques contain a significant immune infiltrate, including leukocytes and monocytes, 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 (CI, 113:1664-1675). 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 psoriasis 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, Erbitux, and Tarceva has induced acneiform rash with some patients. Another example is that some therapeutics used topically induce skin irritation, skin rash, contact dermatitis or allergic 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. 6 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 2004/099204; WO 2004/099205; and WO 01/42246. Heteroaryl substituted pyrroles and other compounds are reported in WO 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 autoimmune diseases (e.g., multiple sclerosis, rheumatoid arthritis, asthma, type I diabetes, inflammatory bowel disease, Crohn's disease, 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 present invention provides compounds of Formula I: Y)n-Z T:-A2 // \\ "Al

R

1 x NR 2

R

3 N N H or pharmaceutically acceptable salt forms or prodrugs thereof, wherein constituent members are defined herein. The present invention further provides compositions comprising a compound of Formula I, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The present invention further provides methods of modulating an activity of JAK comprising contacting JAK with a compound of Formula I, or pharmaceutically acceptable salt thereof. The present invention further provides methods 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 compound of Formula 1, or pharmaceutically acceptable salt thereof. The present invention 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. 7 DETAILED DESCRIPTION The present invention provides, inter alia, compounds that modulate the activity of one or more JAKs and are useful, for example, in the treatment of diseases associated with JAK expression or activity. The compounds of the invention have Formula I: (Y)"-Z

T=A

2 /i \\ U V ' X

R

2

R

3 N N H including pharmaceutically acceptable salt forms or prodrugs thereof, wherein: A' and A 2 are independently selected from C and N; T, U, and V are independently selected from 0, S, N, CR 5 , and NR'; wherein the 5-membered ring formed by A', A 2 , U, T, and V is aromatic; X is N or CR 4 ; Y is C,.& alkylene, C 2 -s alkenylene, C 2

.

8 alkynylene, (CR"R1 2

),-(C

3 .Io cycloalkylene)

(CR"R

2 ),, (CR"R' 2 ),-(arylene)-(CR'"R] 2 )q, (CRR1 2 ),-(CI.Ie heterocycloalkylene)-(CR"R2 )q,

(CR"R

"

),-(heteroarylene)-(CR'

'R

12 )q, (CR"R'z),O(CR"R 12 ),, (CR"R1 2 ),S(CR"1R 2 )q,

(CR"R

2 ),C(O)(CR"R'2)q,

(CR"R

2

),C(O)NR(CR"RI

2 ),, (CR"R1 2 )pC(O)O(CR"R 2 ), (CR"R 2 ),OC(O)(CR"R )q, (CR' "R 12 )pOC(O)NR'(CR"1R")q,

(CR"R

12 )pNR*(CR"R 2 )q, (CR"R'),NR*C(O)NRd(CR"1R 2 )q, (CR"R 2

),S(O)(CR"RI

2 ),, (CR' R1 2 ),S(O)NRC(CR"RI )q, (CR"R'4),S(O) 2 (CR"R )q, or (CR"1R1 2 ),S(O)2NR'(CR"R2)q, wherein said CI.

8 alkylene, C 2

.

8 alkenylene, C 2 . alkynylene, cycloalkylene, arylene, heterocycloalkylene, or heteroarylene, is D optionally substituted with 1, 2, or 3 substituents independently selected from -D'-D 2

-D

3

-D

4 ; Z is H, halo, CI4 alkyl, C 2 .4 alkenyl, C 2 .4 alkynyl, C,.4 haloalkyl, halosulfanyl, CI.4 hydroxyalkyl, C1.4 cyanoalkyl, =C-R, =N-R, Cy', CN, NO 2 , OR", SR", C(O)R, C(O)NR"Rd, C(O)OR", OC(O)Rb, OC(O)NRcRd, NRcRd, NRCC(O)Rb, NcC(O)NCRd, NCC(O)OR C(=NR')NR"Rd, N'C(=NR')NR*Rd, S(O)Rb, S(O)NR*Rd, S(O) 2 R, NR'S(O) 2 Rb, C(=NOH)Rb, 5 C(=NO(C.

6 alkyl)R, and S(O) 2 NR!Rd, wherein said C,.S alkyl, C 2 -s alkenyl, or C 2

.

8 alkynyl, is optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from halo, CI.4 alkyl,

C

2

.

4 alkenyl, C 2

.

4 alkynyl, CI4 haloalkyl, halosulfanyl, C14 hydroxyalkyl, CI 4 cyanoalkyl, Cy', CN,

NO

2 , OR", SR", C(O)Rb, C(O)NRCRd, C(O)ORS, OC(O)Rb, OC(O)NRCRd NRCRd, NR*C(O)R , NRcC(O)NRd, NR"C(O)OR", C(=NR)NRRd, NRC(=NR)NRRd, S(O)Rb, S(O)NR'Rd, S(O) 2 Rb, 3 NRcS(O) 2 Rb, C(=-NOH)Rb, C(=NO(C, 6 alkyl))Rb, and S(0) 2 NR"Rd; wherein when Z is H, n is 1; 8 or the -(Y).-Z moiety is taken together with i) A 2 to which the moiety is attached, ii) R 5 or R6 of either T or V, and iii) the C or N atom to which the R 5 or R 6 of either T or V is attached to form a 4- to 20-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring fused to the 5-membered ring formed by A', A 2 , 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; W is C1.

8 alkylenyl, C 2 .s alkenylenyl, C 2 .s alkynylenyl, 0, S, C(O), C(O)NR', C(O)O, OC(O), OC(O)NR*, NR', NR"'C(O)NR', S(O), S(O)NRC', S(O) 2 , or S(O) 2 NRc'; Q is H, halo, CN, NO 2 , CI.s alkyl, C 2

.

8 alkenyl, C 2 . alkynyl, C,.g haloalkyl, halosulfanyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, wherein said C,.s alkyl, C 2

.

8 alkenyl, C 2 .- alkynyl, C,.s haloalkyl, arryl, cycloalkyl, heteroaryl, or heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from halo, C1.4 alkyl, C2.4 alkenyl, C 2

.

4 alkynyl, Ci.4 haloalkyl, halosulfanyl, C,.4 hydroxyalkyl, C.

4 cyanoalkyl, Cy 2 , CN, NO 2 , OR', SR', C(O)Rb', C(O)NRC'Rd', C(O)OR'', OC(O)Rb', OC(O)NRC'Rd', NI'R', dN 'C(O)Rb', 'C(O)NR'Rd NR''C(O)OR"', S(O)Rb', S(O)NRc'Rd', S(O) 2 Rb', NR''S(O)2Rb', and S(O) 2 NR'Rd'; Cy' 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, C1.4 alkyl, C2.4 alkenyl, C 2 4 alkynyl, CI.

4 haloalkyl, halosulfanyl, C1.

4 hydroxyalkyl, C,.

4 cyanoalkyl, CN, NO 2 , OR"', SRa", C(O)R", C(O)NRC"Rd", C(O)OW", OC(O)Rb", OC(O)NRc"Rd', NRC"Rd", NRC"C(O)Rb" R'"C(O)ORB", NRC"S(O)R", NR"S(O) 2 R", S(O)Rb", S(O)NRc"Rd",

S(O)

2 Rb", and S(O) 2 NR"Rd" R', R 2 , R 3 , and R 4 are independently selected from H, halo, C,.

4 alkyl, C 24 alkenyl, C 2 -4 alkynyl, C,.

4 haloalkyl, halosulfanyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO 2 , OR,

SR

7 , C(O)R', C(O)NR 9

R'

0 , C(O)OR 7 OC(O)R, OC(O)NR 9 R'*, NR 9 R', NR 9

C(O)R

8 , NRCC(O)OR7, 5 S(O)R, S(O)NR!R'*, S(O) 2 R', NRS(O) 2 R, and S(O) 2

NR

9 R'*;

R

5 is H, halo, CI.4 alkyl, C 2

.

4 alkenyl, C 2

.

4 alkynyl, C,.4 haloalkyl, halosulfanyl, CN, NO 2 , OR, SR', C(O)R, C(O)NR 9 R'*, C(O)OR', OC(O)R', OC(O)NR 9 R'*, NR 9

R

10 , NRC(O)R',

NR

9 C(O)OR , S(O)R', S(O)NR 9 R'*, S(O) 2 R, NRS(O) 2 R, or S(O)2NRR'; R' is H, C.4 alkyl, C24 alkenyl, C 2

.

4 alkynyl, C.4 haloalkyl, OR 7 , C(O)R", C(O)NR!R'*, 0 C(O)OR', S(O)R, S(O)NR 9 R'*, S(O) 2 R, or S(O) 2 NRR'";

R

7 is H, CI.

6 alkyl, C, 4 haloalkyl, C2-6 alkenyl, C 2

.

6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl; R is H, C,.

6 alkyl, C1.4 haloalkyl, C2. alkenyl, C 2

.

6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl; 5 R 9 and R'* are independently selected from H, C1.,o alkyl, C1.6 haloalkyl, C2-4 alkenyl, C2.6 alkynyl, C,.

6 alkylcarbonyl, arylcarbonyl, C 1 6 alkylsulfonyl, arylsulfonyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl; 9 or R 9 and R' 0 together with the N atom to which they are attached form a 4-, 5-, 6- or 7 membered heterocycloalkyl group; R" and R1 2 are independently selected from H and -E'-E 2

-E

3

-E

4 ; D' and E' are independently absent or independently selected from C1.6 alkylene, C 2

.

6 alkenylene, C2.6 alkynylene, arylene, cycloalkylene, heteroarylene, and heterocycloalkylene, wherein each of the C1.6 alkylene, C 2

.

6 alkenylene, C2.6 alkynylene, arylene, cycloalkylene, heteroarylene, and heterocycloalkylene is optionally substituted by 1, 2 or 3 substituents independently selected from halo, CN, NO 2 , N 3 , SCN, OH, CI.

6 alkyl, Ci.6 haloalkyl, C 2 .s alkoxyalkyl, C1.6 alkoxy, C1.6 haloalkoxy, amino, C1.6 alkylamino, and C2- dialkylamino;

D

2 and E 2 are independently absent or independently selected from C1.6 alkylene, C2.6 alkenylene, C2.6 alkynylene, (Cl. alkylene),-O-( C.6 alkylene),

(C,.

6 alkylene),-S-(C.6 alkylene),,

(C.

6 alkylene),-NR*-(Ci -alkylene),, (CI. alkylene),-CO-(C.6 alkylene),, (Cf. alkylene),-COO-(CI-6 alkylene)., (C.6 alkylene),-CONR*-(CI 6 alkylene),, (C,. alkylene)r-SO-(CI-6 alkylene),, (C-6 alkylene),-S0 2 -(Cl. alkylene).,, (C. alkylene),-SONRC-(C- 6alkylene),, and (C,. alkylene), NR'CONR(C,. alkylene),, wherein each of the C.6 alkylene, C2.6 alkenylene, and C2.4 alkynylene is optionally substituted by 1, 2 or 3 substituents independently selected from halo, CN, NO 2 , N 3 , SCN, OH, C1.

6 alkyl, CI,- haloalkyl, C2-s alkoxyalkyl, Cjs alkoxy, C. haloalkoxy, amino, CI-3 alkylamino, and C2.8 dialkylamino;

D

3 and E 3 are independently absent or independently selected from C.6 alkylene, C2. alkenylene, C2.6alkynylene, arylene, cycloalkylene, heteroarylene, and heterocycloalkylene, wherein each of the C.6 alkylene, C2.6 alkenylene, C2-6 alkynylene, arylene, cycloalkylene, heteroarylene, and heterocycloalkylene is optionally substituted by 1, 2 or 3 substituents independently selected from halo, CN, NO 2 , N 3 , SCN, OH, C 1

.

6 alkyl, C.

6 haloalkyl, C2-s alkoxyalkyl, C,.6 alkoxy, CI.6haloalkoxy, amino, C,.

4 alkylamino, and C2- dialkylamino;

D

4 and E 4 are independently selected from H, halo, C.4 alkyl, C24 alkenyl, C2.4 alkynyl, C.4 haloalkyl, halosulfanyl, C.4 hydroxyalkyl, C4 cyanoalkyl, Cy', CN, NO 2 , OR*, SW, C(O)Rb, C(O)NRRd, C(O)ORa, OC(O)R, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NR*C(O)NR*Rd NR*C(O)OR", C(=NR')NRRd, N C(=NR,)NRcRd, S(O)Rb, S(O)NRRd,

S(O)

2 RbR, WcS(O) 2 Rb, C(-NOH)Rb,

C(=NO(C.

6 alkyl)Rb, and S(O) 2 NRcRd, wherein said C-a alkyl, Cz. alkenyl, or C2.8 alkynyl, is optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from halo, C4 alkyl, C2.4 alkenyl, C2.4 alkynyl, C.4 haloalkyl, halosulfanyl, C.4 hydroxyalkyl, C.4 cyanoalkyl, Cy', CN,

NO

2 , OR", SW, C(O)Rb, C(O)NRRd, C(O)ORa, OC(O)Rb, OC(O)NRCRd, NR*Rd cC(O)Rb, NRCC(O)NRCRd, NR"C(O)OR", C(=NR=RNRRd, jC(=W)NRRd, S(O)Rb, S(O)NRRd, S(O) 2 Rb,

NR"S(O)

2 Rb, C(=NOH)R , C(=NO(C,.

6 alkyl))Rb, and S(O) 2 NR"Rd; R* is H, Cy', -(C.6 alkyl)-Cy', C34 alkyl, C.6 haloalkyl, C2-6 alkenyl, C2.6 alkynyl, wherein said C.6 alkyl, C1.6 haloalkyl, C2-6 alkenyl, or C2.6 alkynyl is optionally substituted with 1, 2, or 3 10 substituents independently selected from OH, CN, amino, halo, C,.

4 alkyl, C,.

6 haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; Rb is H, Cy', -(CI- 6 alkyl)-Cy', CI.

6 alkyl, C,.

6 haloalkyl, C 2

.

6 alkenyl, C 2 -6 alkynyl, wherein said C,.

4 alkyl, C1.

6 haloalkyl, C 2 . alkenyl, or C 2

.

6 alkynyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1.

6 alkyl, CI.

6 haloalkyl, C 1

.

6 haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; R'' and R" are independently selected from H, C,.

6 alkyl, Cr-6 haloalkyl, C 2 .6 alkenyl, C 2

-

6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said C,.

6 alkyl, CI-6 haloalkyl, C 2 -6 alkenyl, C 2

.

6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, CI.

6 alkyl, C,.

6 haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; Rb' and Rb" are independently selected from H, CI.

6 alkyl, C 1

.

6 haloalkyl, C 2

.

4 alkenyl,

C

2

.

6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said C,.6 alkyl, Ci.

6 haloalkyl, C 2

.

4 alkenyl, C 2

.

6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C 14 alkyl, C,.

6 haloalkyl, C,.

6 haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; R and Rd are independently selected from H, Cy', -(C.3 6 alkyl)-Cy', C 1

.,

0 alkyl, CI-6 haloalkyl, C 2

.

6 alkenyl, C 2

-

4 alkynyl, wherein said C,.1 0 alkyl, C,.

6 haloalkyl, C 2 -6 alkenyl, or C 2

-

4 alkynyl, is optionally substituted with 1, 2, or 3 substituents independently selected from Cy', -(C.

6 alkyl)-Cy', OH, CN, amino, halo, CI- alkyl, C1.

6 haloalkyl, C 1

.

6 haloalkyl,and halosulfanyl; 5 or R 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 Cy', -(C,.

6 alkyl)-Cy', OH, CN, amino, halo, CI.

6 alkyl, CI, haloalkyl, CI, haloalkyl, and halosulfanyl; RC' and Rd' are independently selected from H, C,.i 0 alkyl, CI.

6 haloalkyl, C 2

.

6 alkenyl, C2- 4 0 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said C 1 .,o alkyl, C,.- haloalkyl, C2.s alkenyl, C2.s 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, C,.

6 alkyl, C 1 .6haloalkyl, C,.

6 haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, 5 heteroarylalkyl, cycloalkyl and heterocycloalkyl; or R"' 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 I1 selected from OH, CN, amino, halo, C,.

6 alkyl, Ct. haloalkyl, C,.6 haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; RC" and Rd" are independently selected from H, C-,o alkyl, C,.6 haloalkyl, Cz-6 alkenyl, C2.6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said Caio alkyl, CI-6 haloalkyl, C 2

.

6 alkenyl, C 2

.

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, C1.6 alkyl, C,. haloalkyl, halosulfanyl, C,.

6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; or R'- 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, CI.6 alkyl, C1.6 haloalkyl, CI.6 haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; R' is H, CN, NO 2 , or C.6 alkyl; R* and Rfare independently selected from H and C1-6 alkyl; R is H, CN, or NO 2 ; m is 0 or 1; n is 0 or 1; p is 0, 1, 2, 3, 4, 5, or 6; q is 0, 1, 2,3,4, 5 or 6; r isO or 1; and s is 0 or 1. In some embodiments, when X is N, n is 1, and the moiety formed by A', A 2 , U, T, V, and -(Y).-Z has the formula: (Y)n-Z HN then Y is other than (CR"R, 2 ),C(O)NR*(CR"R 1 2 )q. In some embodiments, when X is N, the 5-membered ring formed by A', A 2 , U, T, and V is other than pyrrolyl. In some embodiments, when X is CH, n is 1, and the moiety formed by A', A 2 , U, T, V, and -(Y)-Z has the formula: (Y)n-Z HN 12 then -(Y).-Z is other than COOH. In some embodiments, when X is CH or C-halo, R', R 2 , and R 3 are each H, n is 1, and the moiety formed by A', A 2 , U, T, V, and -(Y),-Z has the formula: (Y)n--Z (Y)rl-Z (Y)n-Z - s ,or then Y is other than (CR"RI),C(O)NRc(CR"R2)q or (CR"R 32 )pC(O)(CR"R 1 2 )q. In some embodiments, when X is CH or C-halo, R', R 2 , and R 3 are each H, n is 0, and the moiety formed by A', A 2 , U, T, V, and -(Y).-Z has the formula: (Y)n--Z (Y)n-Z (Y)n-Z - S S S ,or ~ then Z is other than CN, halo, or C 1

.

4 alkyl. In some embodiments, when X is CH or C-halo, R', R 2 , and R 3 are each H, n is 1, and the moiety formed by A', A 2 , U, T, V, and -(Y)h-Z has the formula: (Y)n-Z (Y)n-Z N. S N or then Y is other than (CR'R 1

"

2 )PC(O)NRc(CR"R12)q or (CR"R" 1 2 ),C(O)(CR" IR1 2 )q. In some embodiments, when X is CH or C-halo, R', R 2 , and R are each H, n is 1, and the moiety formed by A', A 2 , U, T, V, and -(Y).-Z has the formula: (Y)n-Z 07 then Y is other than (CR"R 12 )pNR(CR"IR 2 q. In some embodiments, when X is CH or C-halo and R', R 2 , and R 3 are each H, then the moiety formed by A', A 2 , U, T, V, and -(Y).-Z has a formula other than: / \ / \ S 07 S 7 ,or ~ 13 In some embodiments: Z is H, halo, CN, NO 2 , C 1

.

8 alkyl, C 2 - alkenyl, C 2 -g alkynyl, C 1 .& haloalkyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, wherein said CI.

8 alkyl, C 2

.

8 alkenyl, C 2 . alkynyl, C1.8 haloalkyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from halo, C1 4 alkyl, C 2

.

4 alkenyl, C 2

.

4 alkynyl, C1.

4 haloalkyl, C 1.

4 hydroxyalkyl, C14 cyanoalkyl, Cy', CN, NO 2 , OR', SR", C(O)R, C(O)NWRRd, C(O)OR", OC(O)Rb, OC(O)NRRd, NRd, NRcC(O)Rb, NR"C(O)N Rd, NRcC(O)OR", C(=NR)NR"Rd, NR"C=NR)NR'Rd, S(O)Rb, S(O)NRcRd,

S(O)

2 Rb, NRS(O)2Rb, and S(O)2NR*Rd; Q is H, halo, CN, NO 2 , C,.s alkyl, C 2

.

8 alkenyl, C 2 . alkynyl, C,.s haloalkyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, wherein said C,.

8 alkyl, C 2

.

8 alkenyl, C 2

-

8 alkynyl, Cl.

8 haloalkyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from halo, C1.

4 alkyl, C 2 .4 alkenyl, C 2 .4 alkynyl, C 1 . haloalkyl, C1 4 hydroxy alkyl, C1.

4 cyanoalkyl, Cy2, CN, NO 2 , OR"', SR"', C(O)R', C(O)N*R''R, C(O)OR"', OC(O)Rb', OC(O)NR'Rd" NRCRd', NR''C(O)Rb', NRC'C(O)NR'Rd NRc'C(O)ORa-, S(O)Rb', S(O)NR"'Rd

S(O)

2 Rb, NR* S(O) 2 Rb', and S(O)2NR'R'; Cy' and Cy2 are independently selected from aryl, heteroaryl, cycloalkyl, and heterocyclo alkyl, each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from halo, C, 4 alkyl, C 2

.

4 alkenyl, C 2 .4 alkynyl, C.

4 haloalkyl, C,.

4 hydroxyalkyl, C.4 cyanoalkyl, CN, NO 2 , OR'", SR", C(O)R", C(O)NR"Rd", C(O)OR'", OC(O)Rb'", OC(O)NRC"Rd", NRc"Rd", Nc'"C(O)R", NR"C(O)OR ", NR'S(O)Rb",

NR*"S(O)

2 Rb", S(O)Rb", S(O)NR*"Rd",

S(O)

2 Rb", and S(O) 2 NR"'Rd"; R', R 2 , R 3 , and R 4 are independently selected from H, halo, C.

4 alkyl, C 2

.

4 alkenyl, C 2 -4 alkynyl, C,.

4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO 2 , OR 7 , SR', C(O)R 8 ,

C(O)NR

9 R'*, C(O)OR OC(O)R,

OC(O)NR

9 R"', NR 9

R'

0 , NR 9 C(O)R', NR"C(O)OR , S(O)R",

S(O)NR

9 R'*, S(O) 2

R

8 , NR 9

S(O)

2

R

8 , and S(O) 2

NR

9 R'*; Rs is H, halo, CI.4 alkyl, C 2 .4 alkenyl, C 2

.

4 alkynyl, C1.4 haloalkyl, CN, NO 2 , OR, SR , C(O)R', C(O)NR 9 R'*, C(O)OR 7 , OC(O)R, OC(O)N R', NR9R'*, NR 9 C(O)R', NR 9 C(O)OR , S(O)R, S(O)NR 9 R'*, S(O) 2 R', NR'S(O) 2

R

8 , or S(O) 2 NRR'*;

R

6 is H, C1.4 alkyl, C 2 .4 alkenyl, C 2 .4 alkynyl, C1.4 haloalkyl, OR', C(O)R 8 , C(O)NR!R' 0 , C(O)OR', S(O)R 8 , S(O)NR 9

R'

0 , S(O) 2 R", or S(O) 2

NR

9 R'*;

R

7 is H, Cj.

6 alkyl, C,- 6 haloalkyl, C 2 .6 alkenyl, C 2 -6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl; R is H, C,., alkyl, C1.6 haloalkyl, C 2 . alkenyl, C 2 . alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl;

R

9 and R'* are independently selected from H, C,.

0 alkyl, C1.

6 haloalkyl, C 2

.

6 alkenyl, C 2

.

6 alkynyl, C 1 .6 alkylcarbonyl, arylcarbonyl,

C

1 .6 alkylsulfonyl, arylsulfonyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl; 14 or R! and R'" together with the N atom to which they are attached form a 4-, 5-, 6- or 7 membered heterocycloalkyl group; R" and R1 2 are independently selected from H, halo, OH, CN, C.4 alkyl, C1.4 haloalkyl, C2.4 alkenyl, C 2

.

4 alkynyl, CI.4 hydroxyalkyl, C.4 cyanoalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; R, R', and R" are independently selected from H, C,.6 alkyl, C1.6 haloalkyl, C2.6 alkenyl, C2.6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said C1.6 alkyl, CI.6 haloalkyl, C2.6 alkenyl, C2.6 alkynyl, aryl, cyclo alkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalcylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C-6 alkyl, C1.6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; Rb, Rb' and Rb" are independently selected from H, CI.6 alkyl, C1.6 haloalkyl, C2.6 alkenyl, C2.6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said C1.6 alkyl, C1. haloalkyl, C2.6 alkenyl, C2.6 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, CI-6alkyl, C.6 haloalkyl, C 1.haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; R* and Rd are independently selected from H, C1.1o alkyl, C1.6 haloalkyl, C2.6 alkenyl, C2.6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said Caio alkyl, CI-6 haloalkyl, C2.6 alkenyl, C2-6 alkynyl, aryl, hetero aryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1.6 alkyl, C1.6 haloalkyl, C1.6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; or R! 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, C.6 alkyl, C 1

.

6 haloalkyl, C1.6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; R*' and R 6 are independently selected from H, CI10 alkyl, C1.6 haloalkyl, C2.6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalicyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said C1.10 alkyl, C,- haloalkyl, C2.6 alkenyl, C2.6 alkynyl, aryl, hetero aryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C.6 alkyl, CI.6 haloalkyl, C1.6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; 15 or R' 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, CI,6 alkyl, C.6 haloalkyl, CI-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; R" and Rd" are independently selected from H, C1.,o alkyl, C.6 haloalkyl, C2.6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said Ci.10 alkyl, C, 4 6 haloalkyl, C 2

.

6 alkenyl, C2.6 alkynyl, aryl, hetero aryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1.6 alkyl, C.6 haloalkyl, CI.

6 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, C.6 alkyl, C. haloalkyl, CI-,haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl. In some embodiments, X is N. In some embodiments, X is CR 4 . In some embodiments, A' is C. In some embodiments, A' is N. In some embodiments,

A

2 is C. In some embodiments,

A

2 is N. In some embodiments, at least one of A', A 2 , U, T, and V is N. In some embodiments, the 5-membered ring formed by A', A 2 , U, T, and V is pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, or oxadiazolyl. In some embodiments, the 5-membered ring formed by A', A 2 , U, T, and V is selected from: a a a a -~ / N~R6 /\ /\ N-N ~ N N RN N 16W b ,b b 6b0 b - a aa a s

-

-i' N - - N b ,b b ,b , b 16 0 S N b b b C. C~ C. C C NN N c' b b ,and b wherein: a designates the site of attachment of moiety -(Y),-Z; b designates the site of attachment to the core moiety: X

R

2

R

3 A N N H ;and c and c' designate the two sites of attachment of the fused 4- to 20-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring. In some embodiments, the 5-membered ring formed by A', A 2 , U, T, and V is selected from: /1 a - 6 a N-N N N R b b b b a aa a a S N N4 N S 0 S N N b b I b b b . C C. C C N1% S N N c b , b ,and b wherein: 0 a designates the site of attachment of moiety -(Y),-Z; b designates the site of attachment to the core moiety: 17 x I R2

R

3 N N H ;and c and c' designate the two sites of attachment of the fused 4- to 20-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring. In some embodiments, the 5-membered ring formed by A', A 2 , U, T, and V is selected from: /a "Aa a a a a N-N N N S N O N N N N S S N N t jJ NI b b b , b b b b b C, C C. C C N N C b b ,and b wherein: a designates the site of attachment of moiety -(Y).-Z; b designates the site of attachment to the core moiety:

R

3 N N H ;and c and c' designate the two sites of attachment of the fused 4- to 20-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring. 5 In some embodiments, the 5-membered ring formed by A', A 2 , U, T, and V is selected from: a a a . a a a a

/-R

6 ' N-N N N S N- 0 N N N N S \ S N N N N Y " N b b , b , b , b b b ,and b wherein: a designates the site of attachment of moiety -(Y).-Z; b designates the site of attachment to the core moiety: 18

R

3 N N H In some embodiments, the 5-membered ring formed by A', A 2 , U, T, and V is selected from: aR a a N-N N N N N N b , b , b ,ad b wherein: a designates the site of attachment of moiety -(Y)..Z; b designates the site of attachment to the core moiety:

R

3 NR2 H In some embodiments, the 5-membered ring formed by A', A 2 , U, T, and V is selected from: a N-N b wherein: a designates the site of attachment of moiety -(Y)n-Z; b designates the site of attachment to the core moiety: 3 R2

R

3 1 N N H In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 1 and Y is Cl.

8 alkylene, C2- 8 alkenylene, (CR"R 1 2

),C(O)(CR'"R'

2 )q, (CR"Rz),C(O)NRc(CR"R 1 2 )q, (CR"R' 2 ),C(O)O(CR' 'R1 2 )q,

(CR"R

2 )POC(O)(CR"R2)q, wherein said Ci-s alkylene or C2.s alkenylene, is optionally substituted with 1, 2, or 3 halo, OH, CN, amino, C1 alkylamino, or C2- 8 dialkylamino. 19 In some embodiments, n is 1 and Y is C1.s alkylene, (CR"R4)pC(O)(CR"R' 2 )q, (CR" IRI 2 )pC(O)NR'(CR" 'R 12 )q, (CR' 'R 2 )PC(O)O(CR"R1 2 )q, wherein said C1.

8 alkylene is optionally substituted with 1, 2, or 3 halo, OH, CN, amino, CI.4 alkylamino, or C 2 . dialkylamino. In some embodiments, n is I and Y is C1. alkylene optionally substituted with 1, 2, or 3 halo, OH, CN, amino, C.4 alkylamino, or C 2 . dialkylamino. In some embodiments, n is I and Y is ethylene optionally substituted with 1, 2, or 3 halo, OH, CN, amino, CI.

4 alkylamino, or C 2 . dialkylamino. In some embodiments, n is 1 and Y is (CR' 'R 2 ),C(O)(CR"R 1 2 ), (CR'Rl 2 ),C(O)NR. (CR"R" 2 )q, or (CR"R 2 ),C(O)O(CR"R 1 2 ). In some embodiments, Y is C,.s alkylene, C 2 -s alkenylene, C 2

-

8 alkynylene, (CR"RI 2

),-(C

3

.

0 cycloalkylene)-(CR' "R1 2 )q, (CR' 'R1 2 ),-(arylene)-(CR'R 1 2 )q, (CR"R "),-(C .o heterocycloalkylene) (CR 'R' 2 )q, (CR"R'"),-(heteroarylene)-(CR"R')q, (CR' 'R' 2 ),O(CR' 'R1 2 )q, or (CR' 'R1 2 ),S(CR"R 1 2 )q, wherein said C,.S alkylene, C 2 - alkenylene, C 2

.

8 alkynylene, cycloalkylene, arylene, heterocycloalkylene, or heteroarylene, is optionally substituted with 1, 2, or 3 substituents independently selected from -D'-D -D-D 4 . In some embodiments, Y is CI.

8 alkylene, C 2

-

8 alkenylene, C 2

-

8 alkynylene, (CR"R' 2

),-(C

3 .rO cycloalkylene)-(CR"R 1 2 )q, (CR' 'R1 2 ),-(arylene)-(CR'R 1 2 )q, (CR"R 1 2 ),-(C,.,o heterocycloalkylene)

(CR"R'

2 )q, (CR"R 2 ),-(heteroarylene)-(CR"R 2 )q, (CR"R 2 ),O(CR'R 1 2 )q, or (CR"R' 2 ),S(CR"R 1 2 )q, wherein said CI., alkylene, C 2

.

8 alkenylene, C 2 . alkynylene, cycloalkylene, arylene, heterocycloalkylene, or heteroarylene, is optionally substituted with 1, 2, or 3 substituents independently selected from D 4 . In some embodiments, Y is CI.

8 alkylene, C 2 - alkenylene, C 2

-

8 alkynylene, or (CR"R' 2

),-(C

3 . 1o cycloalkylene)-(CR"R' 2 ),, wherein said CI., alkylene, C 2

.

8 alkenylene, C 2

-

8 alkynylene, or cycloalkylene, is optionally substituted with 1, 2, or 3 substituents independently selected from -D'

DD

3

-D

4 . In some embodiments, Y is C,.s alkylene, C 2

.

8 alkenylene, C 2 . alkynylene, or (CR"R 2

)-(C

3 . 1o cycloalkylene)-(CR"R" 2 )q, wherein said C,.s alkylene, C 2 -M alkenylene, C 2

.

8 alkynylene, or cycloalkylene, is optionally substituted with 1, 2, or 3 substituents independently selected from D 4 . In some embodiments, Y is CI.

8 alkylene, C 2 .S alkenylene, or C 2

.

8 alkynylene, each optionally substituted with 1, 2, or 3 substituents independently selected from -D'-D 2 -D3 -D 4 . In some embodiments, Y is CI. alkylene optionally substituted with 1, 2, or 3 substituents independently selected from -D'-D -D 3

-D

4 . In some embodiments, Y is C,.

8 alkylene optionally substituted with 1, 2, or 3 substituents independently selected from D 4 . In some embodiments, Y is Cj.

8 alkylene, C 2

-

8 alkenylene, C 2

-

8 alkynylene, (CR"R 2

),O

(CR"R1 2 ),, (CR 1

R

12

)PS(CR"R

2 )q, (CR"R 1 2

)PC(O)(CR"R

12 )q, (CR"R 1 2

)PC(O)NR'(CR"R

2 )q, (CR"R 2

),C(O)O(CR"R

12 )q, (CR"R' 2 ),OC(O)(CR"R 12 )q, (CR"R 2 ),OC(O)NRc(CR 'R1 2 )q, 20 (CR"R1 2 )R'(CR"RG 1 2 )q, (CR"Rl?),NRcC(O)NRd(CR"R 1 2 )4, (CR"R 2 ),S(O)(CR' "R 12 )q, (CR"R 4 2 ),S(O)NR*(CR"R4 1 2 )q, (CR"R' 2

),S(O)

2 (CR"R' R 2 )., or (CR"R I)PS(O)zNR*(CR"R 1 2 )q, wherein said CI, 4 alkylene, C 2 .s alkenylene, C 2

.

8 alkynylene is optionally substituted with 1, 2, or 3 substituents independently selected from halo, OH, CN, amino, CIA alkylamino, and C 2

-

8 dialkylamino. In some embodiments, Y is C,.g alkylene, C 2 -& alkenylene, C 2

.

8 alkynylene, (CR"R 2

),-(C

3 .,' cycloalkylene)-(CR"R' 2 )q, (CR"R ),-(arylene)-(CR"R )q, (CR"R 2 ),-(C,.,o heterocycloalkylene)

(CR"R

12 ),, (CR"R 1 2 ),-(heteroarylene)-(CR"R 2 ),, (CR"R 2 ),O(CR 'R' 2 ),, (CR' R),S(CR"R. )q,

(CR"R'

2 ),C(O)(CR' 'R' 2 )q, (CR' "R 2 ),C(O)NR*(CR"R" 1 2 )q, (CR"R] 2 ),C(O)O(CR"R 1 2 ).,

(CR"R

2 ),OC(O)(CR"R" 1 2 )q, (CR"R "),OC(O)NR(CR'R 2 )q, (CR"R" 1 2 ),NRc(CR 'R' 2 )q, (CR"R II)NRCC(O)NRd(CR

'R

2 )q, (CR' 'R 2 ),S(O)(CR' 'R) 2 )q, (CR' "R 2 ),S(O)NR*(CR 'R 2 )q,

(CR"R'

2

),S(O)

2 (CR"IR12)q, or (CR"R4),S(O) 2 NRC(CR 'R1 2 )q, wherein said C,., alkylene, C 2 . alkenylene, C 2 .- s alkynylene, cycloalkylene, arylene, heterocycloalkylene, or heteroarylene, is optionally substituted with 1, 2, or 3 substituents independently selected from halo, OH, CN, amino, CI.4 alkylamino, and C 2 -s dialkylamino. 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, C, 4 alkyl, C 2

.

4 alkenyl, C 2

.

4 alkynyl, CA.

4 haloalkyl, halosulfanyl, C.

4 hydroxyalkyl, C, 4 cyanoalkyl, Cy', CN, NO 2 , OR", SR", C(O)R', C(O)NRRd, 5 C(O)OR", OC(O)Rb, OC(O)NRCRd, NRcRd, NRC(O)Rb, McC(O)NR*Rd, N*C(O)OR', C(=NR)NRCRd, NR*C(=NR)NRCRd, S(O)Rb, S(O)NR*Rd, S(O) 2 Rb, N*S(O) 2 Rb, C(=NOH)R b,

C(=NO(C.

6 alkyl)R, and S(O) 2 NRRd, wherein said C,.

8 alkyl, C 2 . alkenyl, or C 2 . alkynyl, is optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from halo, CI 4 alkyl,

C

24 alkenyl, C 24 alkynyl, C, 4 haloalkyl, halosulfanyl, C, 4 hydroxyalkyl, C, 4 cyanoalkyl, Cy', CN, 0 NO 2 , ORa, SR8, C(O)Rb, C(O)NRRd, C(O)OR", OC(O)Rb, OC(O)NRRd, N*Rd, NcC(O)R, NRC(O)NR*Rd, NRC(O)OR, C(=NR)NR*RC, M*C(=NRi)NR*Rd, S(O)R, S(O)NR*Rd, S(O) 2 Rb, NRcS(O) 2 R, C(=NOH)R, C(=NO(C,.

6 alkyl))R, and S(O) 2 NR*Rd. In some embodiments, Z is aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected from halo, C1 4 alkyl, C 2

.

4 alkenyl, C 24 alkynyl, 5 C,.

4 haloalkyl, halosulfanyl, C, 4 hydroxyalkyl, CI 4 cyanoalkyl, Cy', CN, NO 2 , ORA, SR", C(O)R, C(O)NRCRd, C(O)OR8, OC(O)Rb, OC(O)NRCRd, N*Rd, P*C(O)R, NR*C(O)NRcRd, NRcC(O)OR C(=NR)NRRd NR*C(=NRI)NRCRd, S(O)Rb, S(O)NRRd, S(O) 2 Rb, NR*S(O) 2 Rb, and S(O) 2 NR*Rd. 21 In some embodiments, Z is aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected from halo, CI. alkyl, C2.4 alkenyl, C2.4 alkynyl, CA.4 haloalkyl, CI.4 hydroxyalkyl, C.4 cyanoalkyl, Cy', CN, NO 2 , OR", SR", C(O)Rb, C(O)NRRd, C(O)OR", OC(O)Rb, OC(O)NW*Rd, CRd, WC(O)Rb, NRcC(O)NCRd, NRC(O)OR" , C(=NR')NR*Rd, NRC(=NR)NRCRd, S(O)R, S(O)NR*Rd, S(O) 2 RRb, NS(0) 2 Rb, and S(O) 2 NRCRd. In some embodiments, Z is aryl or heteroaryl, each optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected from halo, CA.4 alkyl, C2.4 alkenyl, C2.4 alkynyl, CI.4 haloalkyl, halosulfanyl,

C

14 hydroxyalkyl, CI. cyanoalkyl, Cy', CN, NO 2 , OR', SW, C(O)Rb, C(O)NRCRd, C(O)OR", OC(O)Rb, OC(O)NRRd, NR*Rd, NRC(O)R, NR*C(O)NR*Rd, N*C(O)OR", C(=NR')NRRd, NR*C(=NRi)NR*Rd, S(O)Rb, S(O)NR*Rd, S(O) 2 Rb, NRcS(O) 2 Rb, and S(O) 2 NR*Rd. In some embodiments, Z is aryl or heteroaryl, each optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected from halo, C.4 alkyl, C 2

.

4 alkenyl, C2.4 alkynyl, C,.4 haloalkyl, C.4 hydroxyalkyl, C.4 cyanoalkyl, Cy', CN, NO 2 , OR", SR", C(O)Rb, C(O)NRRd, C(O)OW, OC(O)Rb, OC(O)NRRd, NRcRd, N C(O)Rb, NRcC(O)NR*Rd, NRcC(O)ORa, C(=NRi)NRRd, NRcC(=NRi)NRRd, S(O)Rb, S(O)NRRd, S(O) 2 Rb, NR*S(O) 2 Rb, and S(O) 2 NR*Rd. In some embodiments, Z is phenyl or 5- or 6-membered heteroaryl, each optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected from halo, CI.4 alkyl, C2.4 alkenyl, C2.4 allcynyl, C,.4 haloalkyl, halosulfanyl, CI.4 hydroxyalkyl, C.

4 cyanoalkyl, Cy', CN, NO 2 , OW, SR", C(O)R, C(O)NRRd, C(O)OR, OC(O)Rb, OC(O)NRRd, *Rd, NRC(O)Rb, N'C(O)NRcRd, NR*C(O)OR", C(=NR')NR*Rd, NR*C(=NRi)NR*Rd, S(O)R, S(O)NRRd, S(O) 2 Rb, N*S(O) 2 Rb, and S(O) 2 NRRd. In some embodiments, Z is phenyl or 5- or 6-membered heteroaryl, each optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected from halo, C,.4 alkyl, C2.4 alkenyl, C2.4 alkynyl, CI.4 haloalkyl, C1.4 hydroxyalkyl, C.4 cyanoalkyl, Cy', CN, NO 2 , OR", SW, C(O)R', C(O)NR*Rd, C(O)OR", OC(O)Rb, OC(O)NRRd, NRcRd, cC(O)Rb, NWcC(O)NReRd, NcC(O)OR 5 C(=NRi)NR*Rd, NRcC(=NR')NRCRd, S(O)Rb, S(O)NR*Rd, S(O) 2 R', NR*S(O) 2 Rb, and S(O) 2 NRRd. In some embodiments, Z is phenyl optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected from halo, C.4 alkyl, C2.4 alkenyl, C2.4 alkynyl, C14 haloalkyl, halosulfanyl, CA.4 hydroxy alkyl, C.4 cyanoalkyl, Cy', CN, NO 2 , ORA, SR", C(O)R, C(O)NR*Rd, C(O)OR', OC(O)R', OC(O)NR*RdR, Rcd, NRC(O)R, NR*C(O)NRR NR*C(O)OR, C(=NR')NRcd, 0 NRcC(=NR)NRRd, S(O)Rb, S(O)NRCRd, S(O) 2 Rb, MCS(O) 2 R, and S(O) 2 NRCRd. In some embodiments, Z is phenyl optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected from halo, CI4 alkyl, C2.4 alkenyl, C2.4 alkynyl, CI.4 haloalkyl, C.

4 hydroxyalkyl, C1.4 cyanoalkyl, Cy', CN, NO 2 , OR!, SR, C(O)Rb, C(O)NRCRd, C(O)ORB, OC(O)Rb, OC(O)NRcd, NRcRd, NWC(O)Rb, N'C(O)NReRd, N C(O)OR", C(=NR')NRcRd RC(=NR')NR*R , S(O)R, 5. S(O)NR*R , S(O) 2 R", MCS(O) 2 Rb, and S(O) 2 NRRd. In some embodiments, Z is cycloalkyl or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected from halo, CI4 alkyl, C2.-4 alkenyl, C2-4 alkynyl, C1.4 haloalkyl, 22 halosulfanyl, C.4 hydroxyalkyl, C,.4 cyanoalkyl, Cy', CN, NO 2 , ORO, SR", C(O)Rb, C(O)NR Rd, C(O)OR", OC(O)Rb, OC(O)NR*Rd, NWRd NR*C(O)Rb, NRC(O)NR*Rd, NRcC(O)OR9, C(=NRi)NR*Rd, NR"C(=NR')RRd, S(O)Rb, S(O)NRRd, S(0) 2 R, NRCS(O) 2 Rb, and S(O) 2 NR*Rd. In some embodiments, Z is cycloalkyl or heterocycloalkyl, each optionally substituted with 1, 5 2, 3, 4, 5, or 6 substituents selected from halo, C .4 alkyl, C2.4 alkenyl, C2.4 alkynyl, C,.14 haloalkyl, C.4 hydroxyalkyl, C1.4 cyanoalkyl, Cy', CN, NO 2 , ORO, SR, C(O)Rb, C(O)NR*Rd, C(O)ORa, OC(O)Re, OC(O)NR*Rd, NRRd R*C(O)Rb, N'C(O)NRCRd, NR*C(O)OR, C(=NR')NR*Rd, NRcC(=NR)NRRd, S(O)R, S(O)NRRd, S(O) 2 Rb, McS(0) 2 Rb, and S(O) 2 NRCRd. In some embodiments, Z is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, ) each optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected from halo, C1.4 alkyl, C 2

.

4 alkenyl, C2-4 alkynyl, C.

4 haloalcyl, halosulfanyl, C1.4 hydroxyalkyl, C1.4 cyanoalkyl, Cy', CN, NO 2 , OR!, SR", C(O)Rb, C(O)NR*Rd, C(O)OR, OC(O)Rb, OC(O)NR*d, NRcRd R*C(O)Rb, NR*C(O)NR*Rd N*C(O)OR", C(=NR)NR*Rd, NR*C(=NR)Rd S(O)Rb, S(O)NRRd, S(O)Rb

NR*S(O)

2 Rb, and S(0) 2 NRRd. 5 In some embodiments, Z is CI.

8 alkyl, C2. alkenyl, or C2. alkynyl, each optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected from halo, C.4 alkyl, C 2

.

4 alkenyl, C2.4 alkynyl, C1.4 haloalkyl, halosulfanyl, C 1

.

4 hydroxyalkyl, C.4.cyanoalkyl, Cy', CN, NO 2 , ORO, SR", C(O)R , C(O)NRcRd, C(O)ORa, OC(O)R, OC(O)NRRd, NRCRd, NRcC(O)R , NRcC(O)NRRd , NRC(O)OR" C(=NR')NRCRd, NRC(=NRi)NRRd, S(O)Rb, S(O)NRd, S(O) 2 Rb, NR'S(O) 2 Rb, and S(O) 2 NR Rd. ) In some embodiments, Z is C,.s alkyl, C2. alkenyl, or C2- alkynyl, each optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected from halo, C.4 alkyl, C2.4 alkenyl, C2.4 alkynyl, C.4 haloalkyl, C 1

.

4 hydroxyalkyl, CI.

4 cyanoalkyl, Cy', CN, NO 2 , OR!, SR', C(O)Rb, C(O)NRRd, C(O)OR", OC(O)Rb, OC(O)NRCRd, NRCRd, NCC(O)Rb, NRcC(O)NRRd, NCC(O)ORA, C(=NR')NRR, NRcC(=NRi)NRCRd, S(O)Rb, S(O)NRRd, S(O) 2 Rb, NRCS(O) 2 Rb, and S(O) 2 NR*Rd. 5 In some embodiments, Z is aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from halo, C,.

4 alkyl, C2.4 alkenyl, C2.4 alkynyl, C.4 haloalkyl, halosulfanyl, C1.

4 hydroxyalkyl, C,.4 cyanoalkyl, Cy', CN, NO 2 , ORO, SR", C(O)R, C(O)NR*Rd, C(O)OR", OC(O)R', OC(O)NRCRd, NRRd, NRcC(O)R, NRcC(O)NR*Rd, NR*C(O)OR", S(O)Rb, S(O)NRRd, S(O) 2 Rb, NRCS(O)2Rb, and S(O) 2 NR*Rd. 0 In some embodiments, Z is aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from halo, C1.4 alkyl, C2.4 alkenyl, C2.4 alkynyl, C.4 haloalkyl, C.4 hydroxyallcyl, C.4 cyanoalkyl, Cy', CN, NO 2 , OR', SR, C(O)R, C(O)NRRd, C(O)OW, OC(O)R, OC(O)NR*Rd, WRd, NRcC(O)R, NR*C(0)NRRd, NRCC(O)OR, S(O)R, S(O)NRCRd, S(O) 2 Rb, NR'S(O) 2 Rb, and S(O) 2 NRRd. 5 In some embodiments, Z is aryl or heteroaryl, each optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from halo, C1.4 alkyl, C2.4 alkenyl, C 2

.

4 alkynyl, C.4 haloalkyl, halosulfanyl, C.4 hydroxyalkyl, C.4 cyanoalkyl, Cy', CN, NO 2 , OR!, SRO, C(O)Rb, C(O)NRRd, 23 C(O)ORa, OC(O)R, OC(O)NRd R Rd, NRC(O)R, NR"C(O)NRRd, NRcC(O)OR', S(O)R, S(O)NR*Rd, S(O) 2 Rb, N"S(O) 2 R, and S(O) 2 NR*Rd. In some embodiments, Z is aryl or heteroaryl, each optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from halo, C1.4 alkyl, C2.4 alkenyl, C 2 .4 alkynyl, C .4 haloalkyl, CI.4 hydroxyalkyl, CI.4 cyanoalkyl, Cy', CN, NO 2 , ORB, SR", C(O)Rb, C(O)NR*Rd, C(O)OR', OC(O)Rb, OC(O)NRRd, NRcRd, *C(O)Rb, M*C(O)NR*Rd, N*C()OR", S(O)Rb, S(O)NRRd,

S(O)

2 Rb, N"S(O) 2 R, and S(0) 2 NR*Rd. In some embodiments, Z is phenyl or 5- or 6-membered heteroaryl, each optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from halo, C1.4 alkyl, C 2 -4 alkenyl, C 2

.

4 alkynyl, CI.4 haloalkyl, halosulfanyl, C1.4 hydroxyalkyl, CI.4 cyanoalkyl, Cy', CN, NO 2 , ORB, SR", C(O)Rb, C(O)NRRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd NRcC(O)Rb, NRC(O)NRRd, N*C(O)ORa, S(O)R, S(O)NRRd, S(O)2R, NR*S(O)2R, and S(O) 2 NRRd. In some embodiments, Z is phenyl or 5- or 6-membered heteroaryl, each optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from halo, C 1 .4 alkyl, C2-4 alkenyl, C 2

.

4 alkynyl, CI.4 haloalkyl, C 1 .4 hydroxyalkyl, C 1

.

4 cyanoalkyl, Cy', CN, NO 2 , OR', SR', C(O)Rb, C(O)NRcRd, C(O)OR, OC(O)Rb, OC(O)NRcRd, NR*Rd, N'C(O)Rb, NRC(O)NR*Rd, NRcC(O)ORa, S(O)R, S(O)NR*Rd, S(O) 2 Rb, NRS() 2 R, and S(O) 2 NR*Rd. In some embodiments, Z is phenyl optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from halo, C 1

.

4 alkyl, C 2 .4 alkenyl, C2.4 alkynyl, C,.4 haloalkyl, halosulfanyl, C1.4 hydroxyalkyl, C1.4 cyanoalkyl, Cy', CN, NO 2 , OR', SR', C(O)Rb, C(O)NR*Rd, C(O)ORa, OC(O)Rb, OC(O)NR*Rd, cRd, NR*C(O)Rb, NRC(O)NRRd, NR*C(O)OR", S(O)Rb, S(O)NRRd,

S(O)

2 Rb, NR*S(O) 2 R , and S(O) 2 NRRd. In some embodiments, Z is phenyl optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from halo, C.-4 alkyl, C2.4 alkenyl, C2.4 alkynyl, Ci.

4 haloalkyl, C3.4 5 hydroxyalkyl, C1.4 cyanoalkyl, Cy', CN, NO 2 , OR', SR', C(O)Rb, C(O)NRCRd, C(O)OR', OC(O)R, OC(O)NRRd, N*Rd, NR*C(O)R'b R*C(O)NRRd NRC(O)ORa, S(O)Rb, S(O)NRRd, S(O) 2 R,

NRS(O)

2 Rb, and S(O) 2 NRRd. In some embodiments, Z is cycloalkyl or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from halo, C,.

4 alkyl, C 2 .4 alkenyl, C 2 .4 alkynyl, C,.

4 haloalkyl, halosulfanyl, C 1 .4 hydroxyalkyl, C,.4 cyanoalkyl, Cy', CN, NO 2 , OR", SR', C(O)Rb, C(O)NR*Rd, C(O)OR", OC(O)Rb, OC(O)NRcRd, NRcRd, N*C(O)Rb, NRC(O)NRcRd, NR*C(O)OR", S(O)Rb, S(O)NR*Rd, S(O) 2 R, NRcS(O) 2 R , and S(O) 2 NR*Rd. In some embodiments, Z is cycloalkyl or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from halo, C,.4 alkyl, C2.4 alkenyl, C2.4 alkynyl, C1.4 5 haloalkyl, C1.4 hydroxyalkyl, C,.

4 cyanoalkyl, Cy', CN, NO 2 , OR", SR', C(O)R, C(O)NRRd, C(O)OR", OC(O)Rb, OC(O)NRRd, kRd, NR*C(O)Rb, NcC(O)NRRd NR*C(O)OR", S(O)R, S(O)NR*Rd, S(O) 2 Rb, NRS(O) 2 Rb, and S(O) 2 NR*Rd. 24 In some embodiments, Z is C.8 alkyl, C2.s alkenyl, or C2-s alkynyl, each optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from halo, CI.4 alkyl, C 2 .4 alkenyl, C 2 .4 alkynyl, C2.4 haloalkyl, halosulfanyl, C 1 4 hydroxyalkyl, C1.4 cyanoalkyl, Cy', CN, NO 2 , OR", SR", C(O)Rb, C(O)NRRd, C(O)OR., OC(O)Rb, OC(O)NRcRd, NR*Rd, NRC(O)Rb, N*C(O)NR*d, NR*C(O)OR", S(O)Rb, S(O)NRRd, S(O) 2 Rb, NRS(O)2Rb, and S(O) 2 NR*Rd. In some embodiments, Z is C.s alkyl, C2.s alkenyl, or C2.8 alkynyl, each optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from halo, C.4 alkyl, C2-4 alkenyl, C2.4 alkynyl, C1.4 haloalkyl, C.4 hydroxyalkyl, C.4 cyanoalkyl, Cy', CN, NO 2 , OR", SR!, C(O)R, C(O)NRRd, C(O)OR", OC(O)Rb, OC(O)NR*Rd, NWRd, N'eC(O)Rb, NR*C(O)NRRdb, R"C(O)OR", S(O)Rb, S(O)NR*Rd, S(O) 2 Rb, N*S(O) 2 Rb, and'S(O) 2 NR*Rd. In some embodiments, Z is CI-s alkyl, C2.M alkenyl, C2-8 alkynyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from halo, C.4 alkyl, C1.

4 haloalkyl, halosulfanyl, C.4 hydroxyalkyl, Cs.4 cyanoalkyl, Cy', CN, NO 2 , OR", C(O)NRRd, C(O)OR", NRcRd, NRGC(O)Rb, and S(O) 2 Rb. In some embodiments, Z is C,.s alkyl, C2M alkenyl, C2-s alkynyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from halo, C.4 alkyl, C4 haloalkyl, C.4 hydroxyalkyl, C.4 cyanoalkyl, Cy', CN, NO 2 , OR, C(O)NR*Rd, C(O)OR", NRcRd, N'C(O)Rb, and S(O) 2 R. In some embodiments, Z is CI.s alkyl, C2-8 alkenyl, C2-M alkynyl, aryl, cycloalkyl, heteroaryl, I or heterocycloalkyl, each optionally substituted with 1, 2, or 3 substituents independently selected from halo, C1.4 alkyl, C1.4 haloalkyl, halosulfanyl, C,.4 hydroxyalkyl, C.4 cyanoalkyl, Cy', CN, NO 2 , OR", C(O)NR*Rd, C(O)OR", NR*Rd, NRcC(O)Rb, and S(O) 2 Rb. In some embodiments, Z is CI.s alkyl, C2-& alkenyl, C 2 -g alkynyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, each optionally substituted with 1, 2, or 3 substituents independently selected 5 from halo, C.A alkyl, C14 haloalkyl, C14 hydroxyalkyl, CI.4 cyanoalkyl, Cy', CN, NO 2 , OR, C(O)NRRd, C(O)OR", NRcRd, NR*C(O)R, and S(O) 2 R. In some embodiments, Z is substituted with at least one substituent comprising at least one CN group. In some embodiments, Z is C.g alkyl, C2.M alkenyl, C2- alkynyl, aryl, cycloalkyl, heteroaryl, 0 or heterocycloalkyl, each substituted with at least one CN or C,.. cyanoalkyl and optionally substituted with 1, 2, 3, 4, or 5 further substituents selected from halo, C, alkyl, C2-4 alkenyl, C 2 -4 alkynyl, C1.4 haloalkyl, halosulfanyl, C4 hydroxyalkyl, C.4 cyanoalky, Cy', CN, NO 2 , OR, SR", C(O)Rb, C(O)NR*Rd, C(O)OR", OC(O)Rb, OC(O)NRRd, NRcRd, NR*C(O)Rb, NRcC(O)NRRd, NRVC(O)ORa, S(O)Rb, S(O)NRCRd, S(O) 2 Rb, RCS(O) 2 Rb, and S(O) 2 NRRd. 5 In some embodiments, Z is CI.8 alkyl, C2.g alkenyl, C2-8 alkynyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, each substituted with at least one CN or C- cyanoalkyl and optionally substituted with 1, 2, 3, 4, or 5 further substituents selected from halo, C.4 alkyl, C2.4 alkenyl, C2.4 25 alkynyl, Ci.4 haloalkyl, C,4 hydroxyalkyl, CI.4 cyanoalkyl, Cy', CN, NO 2 , OR, SR", C(O)Rb, C(O)NR*Rd, C(O)OR", OC(O)Rb, OC(O)NR*Rd, NR*Rd, NR*C(O)Rb, NR"C(O)NR*Rd, NRC(O)OR", S(O)Rb, S(O)NR*Rd, S(O) 2 Rb, NRcS(O) 2 R, and S(O) 2 NR*Rd. In some embodiments, wherein the -(Y)O-Z moiety is taken together with i) A 2 to which said 5 moiety is attached, ii) R 5 or R 6 of either T or V, and iii) the C or N atom to which said R 5 or R 6 of either T or V is attached to form a 4- to 20-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring fused to the 5-membered ring formed by A', A 2 , 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),-Q. D In some embodiments, wherein the -(Y).-Z moiety is taken together with i) A 2 to which said moiety is attached, ii) R' or R 6 of either T or V, and iii) the C or N atom to which said R 5 or R6 of either T or V is attached to form a 4- to 8-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring fused to the 5-membered ring formed by A', A 2 , U, T, and V, wherein said 4- to 8-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring is optionally substituted by 1, 2, 3, 4, or 5 5 substituents independently selected from --(W),-Q. In some embodiments, the -- (Y)-Z moiety is taken together with i) A 2 to which said moiety is attached, ii) Rs or R 6 of either T or V, and iii) the C or N atom to which said R 5 or R 6 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', A 2 , U, T, and V, wherein said 6-membered aryl, cycloalkyl, heteroaryl, D or heterocycloalkyl ring is optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, NO 2 , C1.8 alkyl, C2.s alkenyl, C 2 .s alkynyl, C,.

8 haloalkyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl wherein said C1.

0 alkyl, C2-8 alkenyl, C2.8 alkynyl, CI.8 haloalkyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl is optionally substituted by 1, 2 or 3 CN. In some embodiments, Cy' and Cy 2 are independently selected from aryl, heteroaryl, 5 cycloalkyl, and heterocycloalkyl, each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from halo, C.4 alkyl, C2.4 alkenyl, C 2

-

4 alkynyl, C4 haloalkyl, C,.

4 hydroxyalkyl, C*.4 cyanoalkyl, CN, NO 2 , ORa", SRO", C(O)Rb", C(O)NR*"Rd", C(O)OR", OC(O)Rb", OC(O)NR'"Rd', NRC"Rd", NR*"C(O)Rb", ,'"C(O)OR'", S(O)Rb", S(O)NR'"Rd", S(O) 2 RW", and

S(O)

2 NR'"R". 0 In some embodiments, Cy' and Cy 2 are independently selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from halo, C1.4 alkyl, C2.4 alkenyl, C2.4 alkynyl, CI.

4 haloalkyl, CN, NO 2 , OR"", SR"", C(O)R", C(O)NRc"Rd", C(O)OR'", OC(O)R", OC(O)NRc"Rd", NR'"Rd", NRc"C(O)R , NR''C(O)0R8', S(O)Rb", S(O)NR""Rd", S(O) 2 Rb", and S(O) 2 NR*"Rd". 5 In some embodiments, Cy' and Cy2 are independently selected from cycloalkyl and heterocycloalkyl, each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from halo, C,.

4 alkyl, C24 alkenyl, C2-4 alkynyl, C1.4 haloalkyl, CN, NO 2 , OR", SR", C(O)Rb", 26 C(O)NR"Rd", C(O)OR'", OC(O)R'", OC(O)NR"Rd", NR"Rd", NR*"C(O)Rb', NR.C(O)OR" S(O)Rb'", S(O)NR*"Rd", S(O) 2 Rb', and S(O) 2 NR4"Rd". In some embodiments, Cy and Cy2 are independently selected from cycloalcyl optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from halo, CI alkyl, C 2 ., alkenyl, C2 5 4 alkynyl, C 1

.

4 haloalcyl, CN, NO 2 , OR', SR!", C(O)Rb", C(O)NRc-Rd", C(O)OR'", OC(O)R'", OC(O)NRC"Rd", N""Rd' 'C()R", NRC"C(O)OR"", S(O)Rb", S(O)NRC"Rd", S(O) 2 Rb", and

S(O)

2 NRC"Rd". In some embodiments, R', R 2 , R 3 , and R 4 are independently selected from H, halo, C.4 alkyl, C2.4 alkenyl, C2.4 alkynyl, CI.4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO 2 , OR', ) SR 7 , C(O)R 8 , C(O)NRR', C(O)OR 7 OC(O)R'. OC(O)NR'R' 0 , NR 9 R'*, NR 9 C(O)Rs, NR*C(O)OR', S(O)R, S(O)NR 9

R'

0 , S(O) 2

R

8 , NR 9

S(O)

2 R', and S(O) 2

NR

9

R'

0 . In some embodiments, R', R 2 , R 3 , and R 4 are independently selected from H, halo, and C.4 alkyl. In some embodiments, R', R 2 , R, and R 4 are each H. 5 In some embodiments, R1 is H, halo, or C1.4 alkyl. In some embodiments, R5 is H, halo, C- alkyl, C2.4 alkenyl, C2.4 alkynyl, C.4 haloalkyl, CN,

NO

2 , OR 7 , SR', C(O)R', C(O)NR 9 R'*, C(O)OR 7 , OC(O)R', OC(O)NR!R' 0 , NR 9 R'", NR'C(O)Rs,

NR

9

C(O)OR

7 , S(O)R!, S(O)NRR'O, S(O) 2

R

8 , NR 9

S(O)

2 R', or S(O) 2 NR!R'*. In some embodiments, RW is H, halo, C.4 alkyl, C14 haloalkyl, halosulfanyl, CN, or NR 9

R'

0 . ) In some embodiments, R 5 is H, halo, C alkyl, C14 haloalkyl, CN, or NRR'". In some embodiments, R5 is H. In some embodiments, R 6 is H or C.4 alkyl. In some embodiments, R 6 is H. In some embodiments, R" and R 2 are independently selected from H, halo, C4 alkyl, C2.4 5 alkenyl, C2.4 alkynyl, C.4 haloalkyl, halosulfanyl, C1 hydroxyalkyl, C14 cyanoalkyl, Cy', CN, NO 2 , OR, SR, C(O)Rb, C(O)NRRd, C(O)OR", OC(O)R, OC(O)NRRd, NRRd, NRcC(O)R', NRcC(O)NR*Rd, N*C(O)OR", C(=NRi)NR*Rd, c*C(=NR')NRRd, S(O)R, S(O)NRRd, S(O) 2 Rb,

NR'S(O)

2 Rb, C(=NOH)R, C(=NO(C.

6 alkyl)Rb, and S(O) 2 NR'Rd, wherein said C3.8 alkyl, C2.8 alkenyl, or C2.S alkynyl, is optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently 0 selected from halo, C4 alkyl, C2.4 alkenyl, C2.4 alkynyl, CIA haloalkyl, halosulfanyl, C.4 hydroxyalkyl, C.4 cyanoalkyl, Cy', CN, NO 2 , OR", SRI, C(O)Rb, C(O)NRCRd, C(O)OR", OC(O)R, OC(O)NRRd, NRCRd, NRcC(O)Rb, NRcC(O)NR*Rd, N*C(O)OR", C(=NR')NRRd, NRCC(=NR)NRCRd, S(O)Rb, S(O)NR*Rd, S(O) 2 R CS(O) 2 R, C(=NOH)Rb, C(=NO(C 3.6 alkyl))Rb, and S(O) 2 NR*Rd. 5 In some embodiments, R" and R1 2 are independently selected from H, halo, OH, CN, C4 alkyl, CI.

4 haloalkyl, halosulfanyl, SCN, C2.4 alkenyl, C2-4 alkynyl, C4 hydroxyalkyl, C cyanoalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl. 27 In some embodiments, R" and R1 2 are independently selected from H, halo, OH, CN, CI 4 alkyl, C:.4 haloalkyl, C 2

.

4 alkenyl, C2.4 alkynyl, C.4 hydroxyalkyl, C.4 cyanoalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl. In some embodiments, the compound has Formula Ia or Ib: (Y)n-z (Y)n-z.

T=-A

2 T-A2 / N\ // \\ U.. \ R2 RaR2

R

3 1N' N WIN N H H Ia Ib. In some embodiments, the compound has Formula II: (Y)c-z N-N R' x '- ~\2

R

3 N N H II1. In some embodiments, the compound has Formula I1a or IIb: (Y)n-z (y)-z N-N N-N Ri R R2 N R 2

R

3 N N R 3 N N H H Ia IIMb. 5 In some embodiments, the compound has Formula IV: (Y)n-Z N-N N \ N N H IV. 28 In some embodiments, the compound has Formula Va: CN -Z N-N R1 R 2

R

3 N N H Va. In some embodiments, the compound has Formula Vb: CN z N-N N N N H Vb. In some embodiments, the compound has Formula VIa: CN N-N R1 R R 2 R 3 N N 0 R N Via. In some embodiments, the compound has Formula VIb: 29 CN Y N-N N N H VII. At various places in the present specification, substituents of compounds of the invention are disclosed 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 "C,.

6 alkyl" is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C 4 alkyl, C5 alkyl, and C6 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 embodiment, can also be provided separately or in any suitable subcombination. At various places in the present specification, linking substituents are described. It is specifically intended that each linking substituent include both the forward and backward forms of the linking substituent. For example, -NR(CR'R").- includes both NR(CR'R"), and -(CR'R").NR-. Where the structure clearly requires a linking 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 arylene group, respectively. 0 The term "n-membered" where n is an integer 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 1 0-membered cycloalkyl group. As used herein, the term "alkyl" is meant to refer to a saturated hydrocarbon group which is 5 straight-chained or branched. Example alkyl groups include methyl (Me), ethyl (Et), propyl (e.g., n propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), pentyl (e.g., n-pentyl, isopentyl, 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 I 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." 30 As used herein, "alkenyl" refers to an alkyl group having one or more double carbon-carbon bonds. Example alkenyl 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 5 bonds. Example 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 halogen substituents. Example haloalkyl groups include CF 3 , C 2 Fs, CHF 2 , CCl 3 , CHCl 2 , C 2

C

5 , and the like. As used herein, "halosulfanyl" refers to a sulfur group having one or more halogen D substituents. Example halosulfanyl groups include pentahalosulfanyl groups such as SFs. As used herein, "aryl" refers to monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings) aromatic hydrocarbons such as, for example, phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, 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." 5 As used herein, "cycloalkyl" refers to non-aromatic cyclic hydrocarbons including cyclized alkyl, alkenyl, and alkynyl 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 include cycloalkylidenes. Example cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, D cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, adamantyl, and the like. Also included in the definition of cycloalkyl are moieties 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 fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom 5 of the fused aromatic ring. A linking cycloalkyl group is referred 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. Heteroaryl 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, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, 0 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 I 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 5 6 ring-forming atoms. In some embodiments, the heteroaryl group has 1 to about 4, 1 to about 3, or I to 2 heteroatoms. A linking heteroaryl group is referred to herein as "heteroarylene." 31 As used herein, "heterocycloalkyl" refers to non-aromatic 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 0, N, or S atom. Heterocycloalkyl groups include monocyclic and polycyclic (e.g., having 2, 3 or 4 fused rings) systems as well as spirocycles. Example "heterocycloalkyl" groups 5 include morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, 2,3 dihydrobenzofuryl, 1,3-benzodioxole, benzo-1,4-dioxane, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, and the like. Ring-forming 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 D 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 heterocycloalkyl group can be attached through a ring-forming carbon atom or a ring-forming 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 5 heterocycloalkyl group has from I to about 20 carbon atoms, and in further embodiments from about 3 to about 20 carbon atoms. In some embodiments, the heterocycloalkyl 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 heterocycloalkyl group has I to about 4, 1 to about 3, or I to 2 heteroatoms. In some embodiments, the heterocycloalkyl group contains 0 to 3 double or triple bonds. In some embodiments, the ) heterocycloalkyl group contains 0 to 2 double or triple bonds. A linking heterocycloalkyl group is referred to herein as "heterocycloalkylene." As used herein, "halo" or "halogen" includes fluoro, 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. 5 As used herein, "heteroarylalkyl" refers to alkyl substituted by heteroaryl and "heterocycloalkylalkyl" refers to alkyl substituted by heterocycloalkyl. As used herein, "amino" refers to NH 2 . As used herein, "alkylamino" refers to an amino group substituted by an alkyl group. As used herein, "dialkylamino" refers to an amino group substituted by two alkyl groups. 0 As used herein, "hydroxylalkyl" refers to an alkyl group substituted by hydroxyl. As used herein, "cyanoalkyl" 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 C, cyanoalkyl group. The compounds described herein can be asymmetric (e.g., having one or more stereocenters). 5 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 32 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 invention. Cis and trans geometric isomers of the compounds of the present invention are 5 described and may be isolated as a mixture 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 fractional recrystallizaion using a chiral resolving acid which is an optically active, salt-forming organic acid. Suitable resolving agents for fractional recrystallization methods are, for example, optically active acids, such as the D and L forms of tartaric 0 acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids such as P-camphorsulfonic acid. Other resolving agents suitable for fractional crystallization methods include stereoisomerically pure forms of a.-methyl benzylamine (e.g., S and R forms, or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like. 5 Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). Suitable elution solvent composition can be determined by one skilled in the art. Compounds of the invention also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a D proton. Tautomeric forms 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 annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, IH- and 3H-imidazole, IH-, 2H- and 4H- 1,2,4-triazole, 1 H- and 2H- isoindole, and IH 5 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 0 intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen 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, 5 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 33 about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compound 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 S 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 reaction is carried out, for example, a temperature from about 20 *C to about 30 *C. The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, 0 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 derivatives of the 5 disclosed compounds wherein the parent compound is modified 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 residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the present invention include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic 0 inorganic or organic acids. The pharmaceutically acceptable 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, Z5 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 of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety. The present invention also includes prodrugs of the compounds described herein. As used 0 herein, "prodrugs" refer to any covalently bonded carriers which release the active parent drug when administered 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 routine manipulation or in vivo, to the parent compounds. Prodrugs include compounds wherein hydroxyl, amino, sulfhydryl, or carboxyl groups are bonded to any group that, when administered to a 5 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 functional groups in the compounds of the invention. Preparation 34 and use of prodrugs is discussed in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are hereby incorporated by reference in their entirety. 5 Synthesis Compounds of the invention, including salts thereof, can be prepared using known organic synthesis techniques and can be synthesized according to any of numerous possible 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 starting materials (reactants), the intermediates, 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 solvent. Depending on the particular reaction step, 5 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 groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in 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. Reactions 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 magnetic resonance spectroscopy (e.g., 'H or 1 3 C) infrared spectroscopy, spectrophotometry (e.g., UV-visible), or mass 5 spectrometry, or by chromatography such as high performance liquid chromatography (HPLC) or thin layer chromatography. Compounds of the invention can be prepared according to numerous preparatory routes known in the literature. Example synthetic methods for preparing compounds of the invention are provided in the Schemes below. 0 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 halogenated with a halogenating agent such as a combination of tetramethylammonium bromide and methanesulfonic anhydride to form a 4-halo compound 1-3 such as a 4-bromo compound 5 while the N-oxide is reduced 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 35 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 invention 1-9b. Alternatively, the N-oxide 1-2 can be halogenated with a halogenating agent such as MeSO 2 C1 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 pyrazole 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 further 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 conditions such as heating to afford the imidazole containing core 1-11, which may contain some functional groups such as bromo or cyano suitable for further chemical modification. Scheme I R 1)mCPBA, EtOAc

R

1 Me 4 NBr Br 1 Ra 1 1 2) Na 2 CO 3 RRDM 3 ~O

R

3 NN .2 H R 3 N N H R NH 1-3 McSOC protection of C DM amine group R R2 3 r R 1 1-4 R3 N

R

5 (Y)-Z N M-NH 1-7 p heat -NH1 N, s U / Suzuki N R. coupling RS (Y)n-Z H 1-s

B(OH)

2 1-a N-NH NN \RE (Y)n-Z U V heat

R

3 R2 H 1 1 0

R

3 N N 1.6 M6Z1-9a R N R5 L-(Y)n-Z R 3 AlN N N-N H 1 RR R n2

R

3 N N 1-9b As shown in Scheme 2, pyrazole-containing cores 2-3, 2-5 and 2-6 can be synthesized starting with a bromo-substituted pyrazole derivative 2-1 (a compound 1-6 in Scheme I wherein one of Rs is 36 Br). The bromo-substituted pyrazole derivative 2-1 can be coupled to boron-containing aromatic species such as an aromatic boric acid 2-2 using Suzuki coupling wherein Ar is aryl or heteroaryl, each of which can be optionally substituted 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 5 can be obtained by coupling the bromo-substituted pyrazole derivative 2-1 to an unsaturated 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 compound 2-5 can be reduced by hydrogenation to afford the corresponding compound 2-6. ) Scheme 2

R

5 Br

R

5 Ar N Ar-B(OH) 2 2.2 N> R5 RI I__ _ N X RSuzuki R2 coupling X R 2

R

3 N N H R 3 N N 2-1 H 2-3 4 1 R S - - t RR R RR 2-4 N.N R 5 N R catalyst RI reduction N \ R 2 R R2 RA N N H R 3 N N 2-5 2.6 H As shown in Scheme 3, imidazole-containing cores 3-7 can be synthesized starting with an N protected 4-bromo-pyrrolo(2,3-b]pyridine or an N-protected 4-bromo-pyrrolo(2,3-b]pyrimidine -3-1 5 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 RCO 2 Cs to afford a compound 3-4. In the presence of a suitable ammonia source such as ammonium acetate, the compound 3-4 can react with ammonia under suitable conditions such as at a high temperature to form the imidazole ring of the compound 3-5. The free 37 amine nitrogen 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 according to the nature of the protecting group to yield compound 3-7. It should be noted that if there 5 are functional groups present within the R, R, and -(Y),-Z group, further 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 0 CI O R 5 Br R 2 0 0 'PrMgC R 5CR \ X R 1 THF,0uCtor.t- X R-CO 2 Cs X NH40Ac R3 N 3-1 O R 3 N R3N N34 heat CK-k.NCH3(OCH3) R3-2

R

5 (Y)n-Z

R

5 (Y)n-Z -NHN R' Ri R' X \ 2 X-(Y)-Z X '2 deprotection X

R

3 N 3 R 3 N 3 Ra N N P 0 As shown in Scheme 4, thiazole-containing cores 4-3 can be synthesized starting with an N protected chloroacetyl derivative 4-1 wherein P is a suitable amine protecting group such as SEM. Compound 4-1 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 15 R' and R" are H, alkyl, aryl or the like; or R' and R" together 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 secondary amine 4-4 can be reacted with 1,1'-thiocarbonyldiimidazole; and the resulting intermediate can further be reacted with ammonia to afford a thiourea 4-5.

Scheme 4 (Y)n-Z Cl 1) s

R

2 Z-(Y), NH 2 R2 I 4-2 R I R' R3 N Ri 2) deprotection R 3 N N P H 4-1 P 4-3 1)Im 2 CS S R' R" N NH 2 4..4 2) NH 3 /MeOH R" 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 n-butyl lithium via ion exchange to generate an aromatic anion in situ. The subsequent addition of boric acid 5 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 4-bromo-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 appropriate method according to the nature of the protecting group to yield the compound of the invention 5-5. 0 Scheme 5 Br 2 Z R' (Y)n (y)Z R 3 N N 1. nBuU, Hexanes 5-3 N S - N S 2. B(OMe) 3 .1

B(OH)

2 Pd(Ph 3

P)

4 5-1

K

2 C0 3

H

2 0/DMF 5-2 heat (Y)n-Z (Y)n-Z N=- N N S deprotection S

R

2 R Ri~ t \ R' R3N NR 3 N N P H 5-4 5-5 As shown in Scheme 6, pyrazole-containing compounds 6-1 can further be modified by substitution on the pyrazole NH group with appropriate reagents. For example, a compound 6-1 12 WO 2007/070514 PCT/US2006/047369 wherein P is a suitable amine protecting group such as SEM can be reacted with L-(Y),-Z where L represents a leaving 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 modification can be made. For example, a CN group can be hydrolyzed to afford an amide group; a S 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 reacted with alkene 6-3 (wherein R' and R" can be H, alkyl, cycloalkyl and the like; and Z' 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 10 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 N-NH N-N R 5 -R 5

R

5 R5 R1 L-(Y)n-Z R1 x x \ R 2 \ R 2 R3 N R R 3 N N P P 6-1 6-2 R' Z' N-N / 5 ,, R5

R

5 R R 6-3 x R2

R

3 N N P 6-4 15 As shown in Scheme 7, bromo pyrazole containing compounds 7-1 can be further modified by metallation 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 recognize the further modifications where appropriate. 20 40 Scheme 7 HO HO

R

5 Br R 5 R R 5 R BuLi N TFA N N R1 THF N R 1

NH

4 0H N R 1

R

3 2 aldehyde X R 2 2 R3 N -etc. R R 3 .L N 7-1 SEM 7-2 SEM 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 5 NN-dimethylformamide (DMF) to give the hydrazine intermediate 8-2. The hydrazino intermediate 8-2 is reacted with an appropriately substituted 1,3 bis-aldehyde 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 group; a carboxylic acid can be converted to a ester, which in turn can be further reduced to alcohol. 10 One skilled in the art will recognize further potential modifications. Scheme 8 Br

R

1

.

H2N . H R ) N0 (Y)A- Z (Y) -Z 3 M NH 2

NH

2 O H N R' NH 4 OH R R3 NRR SEM RN H3 N 8-1 8-2 8-4 SEM 8-5 H As shown in Scheme 9, the 1,2,4-oxadiazole compound 9-6 can prepared from the N 15 protected bromo compound 9-1 by treatment with zinc cyanide in DMF in the presence of a catalyst like bis(tributyl) palladium to give the N-protected cyano compound 9-2. The N-hydroxy carbox imidamide compound 9-3 can be prepared by heating the N-protected cyano compound 9-2 with 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 20 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 closure. 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 41 afford an amide group; a carboxylic acid can be converted to an ester, which in turn can be further reduced to alcohol. One skilled in the art will recognize further modifications where appropriate. Scheme 9 HN HN-OH Br Ri DMF CN RI R1 X~ \ ZnCN

NH

2 OH-HCI X \,

R

3 NRN (Bu 3

P)

2 Pd 3 N EtOHHR3 N R

R

3 % K 2 C0 3

%

3 N SEM SEM reflux 93 SEM 9-1 9-29 (Y)n(Y)-Z Z-(Y),I -- I Ns N N Cl 1 TFA NN 9.4 NH 4 OH x R2 xR2 R31N N R3 N" SEM 9-6 5 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 pyrazolo compound 10-4 can be prepared by reacting an appropriately substituted aryl group containing a 0 halogen like bromo or a triflate with the N-protected boronic acid or boronic acid ester pyrazole compound 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 removing groups like SEM. The 4-arylpyrazolo compounds 10-7 can be prepared by reacting the appropriately 15 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. 42 Scheme 10 NaH 01 B DMF B Ar-L Ar TFA Ar Sem-C e~l NH40H - - N-N HN-N HN-N N-N SM SENf Suzuki SEM 10-4 10-1 10-2 conditions 10-3 Br R1 NN R R3 N R

R

2 H R 3 N N 10-B H 10-9 DMF-acetal NH 2

NH

2 Ar Ar -- Ar...<.Ns -NNH 0 0 10-5 10-6 10-7 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 5 conditions previously described. For example the substituted 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-F), in the presence of a base such a sodium hydride or cesium carbonate. The N-aryl pyrazole 11 10 4 (wherein Y is aromatic) may be prepared by reacting the intermediate pyrazole 11-3 with an appropriately substituted aryl boronic acid in a solvent such as dichloromethane (DCM) with copper acetate and pyridine. Alternatively the N-aryl pyrazole 11-4 (wherein Y is aromatic) can be prepared by reacting 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 15 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 acceptors in a solvent such as DMF in the presence of a base such as 1,8 diazabicyclo[5.4.0]undec-7-ene (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, further 20 modification can be made. For example, a CN group can be hydrolyzed to afford an aide 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.

Scheme 11 Z-(Y),-Br NaH/DMF OR N-N Br R1 N-NH N-NH Cs 2

CO

3 /AcCN DMF/R X K2C O 3/H 2O P h-B (O H ) 2

R

2 7-10%TetraKisR Cu(OAc) 2 R

R

3 N * 0 'B~ 0 X 3 SEM heat RR N2 MeCl 2 /Pyr R 3 N N R3.1,R N "11- SEM SEM Ph-F 11-2 11-3 DMF heat (Y)n-Z N-N "Michael" Addition DBU/ DMF X ~ 'RI R3 N N H 11-5 As shown in Scheme 12, pyrazole 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 5 electron-withdrawing group (for example, -CN) optionally in the presence of a base (DBU or K 2 C0 3 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. 10 Scheme 12 N-NH N-N z N-N z R 12-2 RI deprotection R N R2 N \ 2 N R N

R

3 N N R 3 N N % H P 'pH 12-1 12-3 12-4 As shown in Scheme 13, oxazole- or thiazole-containing compounds 13-6 can be prepared starting with N-protected 4-chloro-pyrrolo[2,3-b]pyrimidine 13-1 wherein P is a suitable amine 15 protecting group such as SEM. Oxazole- or thiazole-containing products of formula 13-2 can be 44 prepared by palladium-catalyzed coupling of 13-1 with oxazole or thiazole. The compound 13-2 can be reacted with a metal alkyl such as n-butyllithium to generate 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 X'=0), in the presence of other 5 additives such as zinc chloride and copper(I) 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 copper-hydride catalyzed conjugate reduction), or with reagents such as tosylmethyl isocyanide to provide products of 10 formula 13-5 wherein Z is an electron-withdrawing group such as ester or -CN. If there are functional groups present within the R group or encompassed by the Z group, further modification can be made, and such appropriate further 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 protecting group used to afford their corresponding deprotected counterparts 13-6. 15 Scheme 13 _R Ng N==_\ IN R_ c R XR R1 base, additives RI NR Pd(PPh 3

)

4 N

R

3 NKOAc J-'t k R3 N A RI N R R W RP N N heat p 13-3 P 13-1 13-2 13-4 Z Z (Y)n, (Y). N R N -R N XR 1 deprotection R I R N R2 R 3 N R2 p H 13-5 13-4 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 20 compound 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 appropriate method according to the nature of the protecting group to yield product 45 14-3. The compound 14-3 can be reacted with amines 14-4 at elevated -temperatures in a suitable solvent such as DMF to afford the compound of the invention, 14-5. Scheme 14 Br N-=\ N=\ S 1 nBuLi S R CBr 4 R 1 deprotection NN R 2 TH NN \ 2 N -78 0 C R3)N N P ' 14-1 14-2 R'N Br N'R" N N= N R2 14-4 NR2 R3 N R2 heat R 3 N N H H 14-3 14-5 5 As shown in Scheme 15, pyrrole-containing cores 15-4 can be synthesized starting with N protected 4 -chloro-pyrrolo[2,3-bpyrimidine 15-1 wherein P is a suitable amine protecting group such as DEM (diethoxymethyl). The compound 15-1 can be reacted with 1-(triisopropylsilyl)pyrrole-3 10 boronic acid under Suzuki coupling conditions to afford the simultaneously pyrrole-deprotected core 15-2. Pyrrole-containing compounds 15-2 can be reacted with alkenes 15-3 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 15 invention 15-4. Scheme 15 ,TIPS R Z HNN C1 R 1 .. N 1Rz Z N N B(OH) 2 R1 15-3 R1 R3 N R Pd(PPh 3 )4 N R 2 DBU,MeCN N RN p Na 2

CO

3

R

3 N N 2. TFA R 3 'N R 2

DME/H

2 0 H heat 15-1 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 prepared by a variety of methods, such as starting with an appropriately substituted bromo thiophenyl 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 palladium acetate and 5 triphenylphosphine in DMF at an appropriate temperature with acrylonitrile. The SEM protected intermediate 16-4 may be prepared by methods previously described for performing the Michael like addition of the pyrazole core to an appropriately substituted a-P unsaturated nitrile like 16-3. The sulfoxide 16-5, where n=l, 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 D m-chloroperbenzoic acid (MCPBA) in DCM. The final compounds 16-6, where n= 0, 1 or 2, may be prepared by methods previously described for the removal of the SEM protecting group. Alternatively, the sulfur oxidation may be performed on compounds 16-2 or 16-3 depending on the compatibility of the substitution in the synthetic scheme. Scheme 16 NC Br SH Br SR S' 16-1 16-2 16-3 N N N N-N R -4R N R 2 R2R2R2 R3~N X Y0-' RNN R1 R N N RF N R 1 SEM SEM H 5 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 example, one may start with 0 an appropriately substituted bromo phenyl sulfonamide 17-2, where R' 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 triphenylphosphine in DMF at an appropriate temperature with acrylonitrile. The final compounds 17-6 where R 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 NC Br SO 2 CI Br S N,Rc r r 17-1 17-2 N 17-3 0 RC N-.-N ,N \ d --- a-R2 R3 N R1 5 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 protecting group such as SEM and X 10 is N or C, with a cyclopentylacrylate ester 18-4 to form the ester 18-5. The ester 18-5 may then be reduced to the corresponding aldehyde, 18-6, for example, by the two-step procedure of reducing to the alcohol and selectively oxidizing the intermediate alcohol to the aldehyde, e.g., via a Swem oxidation.. The aldehyde, 18-6, may then be converted to the corresponding olefin, 18-7, for example by reaction with a Wittig reagent. The olefin 18-7, may then be 15 deprotected, as described earlier, to produce the formula 18-7 compound. The intermediate, 18-4, may be prepared, for example as shown in Scheme 18, stearting with cyclopentylaldehyde.

Scheme 18 CO 2 H CHO H 2 C CO 2 H pyridine piperidine 18-1 A 18-2 1. (COC) 2 I 2. MeOH N-NH

CO

2 Me CO 2 Me CHO CON N N-N N-N R1 1. DIBALH 18-4 1R' X NRR 2. Swern R2 X \

R

3 N N DBU/ACN X \ R 18-3 P R3 N N R 3 N 5 18-6 p 18-5 P #"PhP=CH 2 N-N . N-N / deprotection / R' RI X 2 X \R2

R

3 N N R 3 N N 18-8 H 18-7 p Also, as shown in Scheme 19, the cyanoguanidine derivative 19-6 can be prepared starting from substituted pyrazole compounds such as pyrazole 18-3, wherein P is a suitable protecting group 5 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 Boc-protected piperidone, in the presence of a suitable basic catalyst, in a suitable solvent, to form 19-2. The intermediate 19-2 is deprotected using a suitable deprotection reaction, to provide the amine compound 19-3, which then reacts selectively with a cyanoimidocarbonate reagent such as 19-4, in a polar solvent at a suitable 10 temperature, for example, about 20 "C to give a cyanoimidocarbamate such as 19-5, which can then be reacted with any of a variety of amines at elevated temperature to give product 19-6.

Scheme 19 NBoc NH CN NC NC N-NH N-N N-N R1 X Boc R R2 deprotection R 19-1 X X N N R2R 18-3 P R 3 N N R 3 N N H 19-2 P 19-3 CN ,CN

NH

2 s194 N NCN NC NC N-N 3 N-N 100 0 C R1 R' R2 R2

R

3 N N R3 N N H H 19-6 19-5 The intermediate compounds 20-5 and 20-6 may be prepared by a variety of methods in the literature, for example, methods such as are outlined in Scheme 20. The intermediate compound 20-3 5 may be prepared by reaction of the aldehyde compound 20-1 with an appropriately substituted Wittig reagent or Homer Emmons reagents to give the a-p unsubstituted ester 20-3. Alternatively, 20-3 may be prepared by a Heck-like reaction with an appropriately substituted aryl bromide 20-2 and an acrylic ester in the presence of a palladium reagent at elevated temperatures. The compound 20-4 may be prepared by methods previously described for the Michael-like addition of an appropriately 10 substituted pyrrole 18-3 on the a-p unsaturated ester compound 20-3. The aldehyde compound 20-5 may be prepared by reduction of the ester compound 20-4 with reagents such as diisobutyl aluminium hydride at low temperatures such as about -78 *C in an appropriate solvent. The aldehyde compound 20-5 can be further reduced 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 15 by reduction of the ester 20-4 with reagents such as lithium aluminium hydride in appropriate solvent and at appropriate temperatures. 50 Scheme 20 H 0 N-NH MeR R 20-1 WCORI N- N or H R RR B20-3

R

2 R

R

3 N N 18-3 P 20-2 H R

R

3 N N 204\ R ~ H N-N O or R N-N 1 R R3 N 2-P R2

R

3 N N 20-s The compounds 21-2 and 21-3 may be prepared by using a variety of methods in the 5 literature, such as, for example, methods outlined in Scheme 21. The olefin compound 21-1 may be prepared by the reaction of aldehyde compound 20-5 with an appropriately substituted Wittig reagent or Homer Emmons reagents using a base such as sodium hydride or potassium t-butoxide in an appropriate solvent and conducted at temperature. The olefin compound compound 21-1 may be reduced to the saturated compound 21-2, for example, using hydrogenation conditions well known in 10 the literature, e.g., hydrogen 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 al, 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., Swern oxidation 15 conditions, followed by reaction with the Bestmann-Ohira reagent, wherein this reaction sequence may be carried out either as a one pot two-step reaction sequence, or in two separate reaction steps. 51 Scheme 21 Z z Z Z R R N-N N--N H R O R2 X R2 ---- R 3 N N R 3 N 21-1 P 21-2 P z X R2

R

3 N R 20-5 N-N R1 X R2

R

3 N N 21-3 P The compounds 22-1 and 22-3 may be prepared by using a variety of methods in the literature, for example, via methods outlined in Scheme 22. The oxygen-substituted compound 22-1 5 may be prepared, for example, by reaction of an appropriately substituted alcohol 20-6 (in Scheme 20), 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 solvent 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, 10 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). 52 Scheme 22 0-R' N-N RI OH 7 X R2

R

3 --- N N N-N P 22-1 L G Nuc RG R - R R2 N-N N-N

R

3 N 20-6 P R : R \ R2 \ R2 R3 KN N R2

R

3 N N 22-3 P 22-2 It should noted that in all of the Schemes described herein, if there are functional groups 5 present on a substituent group such as Y, Z, R, R', R 2 , R 5 , etc., further modification can be made if appropriate and desired. 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 reduced to an alcohol, which in turn can be further modified. In another example, an OH group can be converted into a better leaving group such as mesylate, which in turn is suitable for nucleophilic substitution, such as by CN. One 10 skilled in the art will recognize such further modifications. Methods -Compounds of the invention can modulate activity of one or more Janus kinases (JAKs). The term "modulate" is meant to refer to an ability to increase or decrease the activity of one or more 15 members of the JAK family of kinases. Accordingly, 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 described herein. In some embodiments, compounds of the present invention can act as inhibitors of one or more JAKs. In some embodiments, compounds of the present invention can act to stimulate the activity of one or more JAKs. In further embodiments, the compounds of the invention can be used to modulate activity of a JAK in an individual in need of modulation of the receptor by administering a modulating amount of a compound of Formula la, Ib, or Ic. JAKs to which the present compounds bind and/or modulate include any member of the JAK family. In some embodiments, the JAK is JAKI, JAK2, JAK3 or TYK2. In some embodiments, the 5 JAK is JAKI or JAK2. In some embodiments, the JAK is JAK2. In some embodiments, the JAK is JAK3. The compounds of the invention can be selective. By "selective" is meant that the compound binds to or inhibits a JAK with greater affinity or potency, respectively, compared to at least one other JAK. In some embodiments, the compounds of the invention are selective inhibitors of JAK I or JAK2 0 over JAK3 and/or TYK2. In some embodiments, the compounds of the invention are selective inhibitors of JAK2 (e.g., over JAKI, JAK3 and TYK2). Without wishing to be bound by theory, because inhibitors of JAK3 can lead to immunosuppressive effects, a compound which is selective for JAK2 over JAK3 and which is useful in the treatment of cancer (such as multiple myeloma, for example) can offer the additional advantage of having fewer immunosuppressive side effects. 15 Selectivity can be at least about 5-fold, 10-fold, at least about 20-fold, at least about 50-fold, at least about 100-fold, at least about 200-fold, at least about 500-fold or at least about 1000-fold. Selectivity can be measured by methods routine in the art. In some embodiments, selectivity can be tested at the Km of each enzyme. In some embodiments, selectivity of compounds of the invention for JAK2 over JAK3 can be determined by the cellular ATP concentration. 20 Another aspect of the present invention pertains to methods of treating a JAK-associated disease or disorder in an individual (e.g., patient) by administering to the individual in need of such treatment a therapeutically effective amount or dose of a compound of the present invention or a pharmaceutical composition thereof. A JAK-associated disease can include any disease, disorder or condition that is directly or indirectly linked to expression or activity of the JAK, including over 25 expression and/or abnormal activity levels. A JAK-associated disease can also include 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, organ transplant rejection (e.g., allograft rejection and graft versus host disease). 30 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). 35 Further examples of JAK-associated diseases include allergic conditions such as asthma, food allergies, atopic dermatitis and rhinitis. Further examples of JAK-associated diseases include viral 54 diseases such as Epstein Barr Virus (EBV), Hepatitis B, Hepatitis C, HIV, HTLV 1, Varicella-Zoster Virus (VZV) and Human Papilloma Virus (HPV). Further examples of JAK-associated diseases or conditions include skin disorders such as psoriasis (for example, psoriasis vulgaris), atopic dermatitis, skin rash, skin irritation, skin 5 sensitization (e.g., contact dermatitis or allergic contact dermatitis). For example, certain substances including some pharmaceuticals when topically 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 helpful in treating such unwanted sensitization or dermatitis. In some embodiments, the skin disorder is treated by topical 0 administration of at least one JAK inhibitor of the invention. In further embodiments, the JAK-associated disease is cancer including those characterized by solid tumors (e.g., prostate cancer, renal cancer, hepatic cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, cancers of the head and neck, thyroid cancer, glioblastoma, Kaposi's sarcoma, Castleman's disease, melanoma etc.), hematological cancers (e.g., lymphoma, leukemia such 5 as acute lymphoblastic leukemia, or multiple myeloma), and skin cancer such as cutaneous T-cell lymphoma (CTCL) and cutaneous B-cell lymphoma. Example cutaneous T-cell lymphomas include Sezary syndrome and mycosis fungoides. JAK-associated diseases 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). to JAK-associated diseases 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 (CMML), hypereosinophilic syndrome (HES), systemic mast cell disease (SMCD), and the like. Further JAK-associated diseases include inflammation and inflammatory diseases. Example 25 inflammatory diseases include inflammatory diseases of the eye (e.g., iritis, uveitis, scleritis, conjunctivitis, or related disease), inflammatory diseases of the respiratory tract (e.g., the upper respiratory tract including the nose and sinuses such as rhinitis or sinusitis or the lower respiratory tract including bronchitis, chronic obstructive pulmonary disease, and the like), inflammatory myopathy such as myocarditis, and other inflammatory diseases. 30 The JAK inhibitors described herein can further be used to treat ischemia reperfusion injuries or a disease or condition related to an inflammatory ischemic event such as stroke or cardiac arrest. The JAK inhibitors described herein can further be used to treat anorexia, cachexia, or fatigue such as that resulting from or associated with cancer. The JAK inhibitors described herein can further be used to treat restenosis, sclerodermitis, or fibrosis. The JAK inhibitors described herein can further be used 35 to treat conditions associated with hypoxia or astrogliosis such as, for example, diabetic retinopathy, cancer, or neurodegeneration. See, e.g., Dudley, A.C. et aL. Biochem. J. 2005, 390(Pt 2):427-36 and Sriram, K. el al. J. Biol. Chem. 2004, 279(19):19936-47. Epub 2004 Mar 2.

As used herein, the term "contacting" refers to the bringing together of indicated moieties in an 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 individual or patient, such as a human, having a JAK, as well as, for example, introducing a compound of the 5 invention into a sample containing a cellular or purified preparation containing the JAK. As used herein, the term "individual" or "patient," used interchangeably, refers to any animal, including 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 10 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 includes one or more of the following: (1) preventing the disease; for example, preventing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or 15 display the pathology or symptomatology of the disease; (2) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual 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), and 20 (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 (i.e., reversing the pathology and/or symptomatology). Combination Therapies 25 One or more additional pharmaceutical agents such as, for example, chemotherapeutics, anti inflammatory agents, steroids, immunosuppressants, as well as Bcr-Abl, Flt-3, RAF and FAK kinase inhibitors such as, for example, those described in WO 2006/056399, 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 administered to a 30 patient simultaneously or sequentially. Example chemotherapeutic include proteosome inhibitors (e.g., bortezomib), thalidomide, revlimid, and DNA-damaging agents such as melphalan, doxorubicin, cyclophosphamide, vincristine, etoposide, carmustine, and the like. Example steroids include coriticosteroids such as dexamethasone or prednisone. 35 Example Bcr-Abl inhibitors include the compounds, and pharmaceutically acceptable salts thereof, of the genera and species disclosed in U.S. Pat. No. 5,521,184, WO 04/005281, EP2005/009967, EP2005/010408, and U.S. Ser. No. 60/578,491.

Example suitable Flt-3 inhibitors include compounds, and their pharmaceutically acceptable salts, as disclosed in WO 03/037347, WO 03/099771, and WO 04/046120. Example suitable RAF inhibitors include compounds, and their pharmaceutically acceptable salts, as disclosed in WO 00/09495 and WO 05/028444. 5 Example suitable FAK inhibitors include compounds, and their pharmaceutically acceptable salts, as disclosed in WO 04/080980, WO 04/056786, WO 03/024967, WO 01/064655, WO 00/053595, and WO 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 0 improve the treatment response as compared to the response to the chemotherapeutic agent alone, without exacerbation 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 Bcr-Abl, Flt-3, RAF and FAK kinase 5 inhibitors. Additive or synergistic effects are desirable outcomes of combining a JAK inhibitor of the present invention with an additional agent. Furthermore, resistance of multiple myeloma cells to agents such as dexamethasone may be reversible upon treatment with a JAK inhibitor of the present invention. The agents can be combined with the present compounds in a single or continuous dosage form, or the agents can be administered simultaneously or sequentially as separate dosage forms. o 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 embodiments, combinations of one or more JAK inhibitors of the invention with other therapeutic agents can be administered to a patient prior to, during, and/or after a bone 25 marrow transplant or stem cell transplant. 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 30 known in the pharmaceutical art, and can be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration may be topical (including transdermal, epidermal, ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal or intranasal), oral or parenteral. Parenteral administration 35 includes intravenous, intraarterial, 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 transdermal 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. 5 This invention also includes pharmaceutical compositions which contain, as the active ingredient, one or more of the compounds of the invention above in combination with one or more pharmaceutically acceptable carriers (excipients). In making the compositions 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 container. When the excipient 10 serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, 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 15 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 compound is substantially water soluble, the particle size can be adjusted by milling to provide a substantially 20 uniform distribution in the formulation, e.g. about 40 mesh. Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate, and 25 mineral 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 30 about 5 to about 1000 mg (1 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 unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. 35 The active compound can be effective 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 58 circumstances, including the condition to be treated, the chosen route of administration, the actual 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 5 a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention. When referring to these preformulation compositions as homogeneous, the active ingredient is typically dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation is then subdivided into unit dosage forms of the [.0 type described above containing from, for example, about 0.1 to about 1000 mg of the active ingredient of the present invention. The tablets or pills of the present invention can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope 15 over the former. The two components can be separated by an enteric layer which serves to resist disintegration 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. 20 The liquid forms in which the compounds and compositions of the present invention can be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Compositions for inhalation or insufflation include solutions and suspensions in 25 pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic 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 30 attached 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 formulation 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 35 of the patient, the manner of administration, and the like. In therapeutic applications, compositions can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. Effective doses will depend on 59 the disease condition being treated as well as by the judgment of the attending clinician depending upon factors such as the severity of the disease, the age, weight and general condition of the patient, and the like. The compositions administered to a patient can be in the form of pharmaceutical 5 compositions described above. These compositions can be sterilized by conventional sterilization techniques, or may be sterile filtered. Aqueous solutions can be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration. The pH of the compound preparations typically will be between 3 and 11, more preferably from 5 to 9 and most preferably from 7 to 8. It will be understood that use of certain of the foregoing recipients, 0 carriers, or stabilizers will result in the formation of pharmaceutical salts. The therapeutic dosage of the compounds of the present invention can vary according to, for example, the particular use for which the treatment is made, the manner of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of a compound of the invention in a pharmaceutical composition can vary 15 depending upon a number of factors including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration. For example, the compounds of the invention can be provided in an aqueous physiological buffer solution containing about 0.1 to about 10% w/v of the compound for parenteral administration. Some typical dose ranges are from about 1 ptg/kg to about I g/kg of body weight per day. In some embodiments, the dose range is from about 0.01 mg/kg to about 100 mg/kg 20 of body weight per day. The dosage is likely to depend on such variables as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the compound selected, formulation of the excipient, and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems. 25 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. Labeled Compounds and Assay Methods 30 Another aspect of the present 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 assays, both in vitro and in vivo, 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. 35 The present invention further includes isotopically-labeled compounds of the invention. An "isotopically" or "radio-labeled" compound is a compound of the invention where one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the 60 atomic mass or mass number typically found in nature (i.e., naturally occurring). Suitable radionuclides that may be incorporated in compounds of the present invention include but are not limited to 2 H (also written as D for deuterium), 3 H (also written as T for tritium), "C, 3 C, 1'C, 3 N, 5 N, "O, "0, ' 8 O, ' 8 F, 35 S, 36 C1, 9 2 Br, "Br, "Br, "Br, 1 3, 124j, 1251 and 1'1. The radionuclide that is 5 incorporated in the instant radio-labeled compounds will depend on the specific application of that radio-labeled compound. For example, for in vitro metalloprotease labeling and competition assays, compounds that incorporate 3 H, '4C, 2Br, '2I , ''I, "S or will generally be most useful. For radio imaging applications "1C, ' 8 F, 1231 1241 1311 7Br, "Br or "Br will generally be most useful. It is understood that a "radio-labeled " or "labeled compound" is a compound that has 10 incorporated at least one radionuclide. In some embodiments the radionuclide is selected from the group consisting of 3 H, '4C, 12s, sS and 82 Br. The present invention can further include synthetic methods for incorporating radio-isotopes into compounds of the invention. Synthetic methods for incorporating radio-isotopes into organic compounds are well known in the art, and an ordinary skill in the art will readily recognize the 15 methods applicable for the compounds of invention. A labeled compound of the invention can be used in a screening assay to identify/evaluate compounds. For example, a newly synthesized or identified compound (i.e., test compound) which is labeled 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) 20 can be evaluated for its ability to reduce binding of another compound which is known to bind to a JAK (i.e., standard compound). Accordingly, the ability 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 compounds are unlabeled. Accordingly, the concentration of the labeled standard compound is monitored in order to evaluate the 25 competition between the standard compound and the test compound, and the relative binding affinity of the test compound is thus ascertained. Kits The present invention also includes pharmaceutical kits useful, for example, in the treatment 30 or prevention of JAK-associated 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 include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those 35 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 described in greater detail by way of specific examples. The following examples are offered for illustrative purposes, and are not intended to limit the invention in any manner. Those of skill in the art will readily recognize a variety of noncritical parameters which can be changed or modified to yield essentially the same results. The compounds of the Examples 5 have been found to be JAK inhibitors according to at least one assay described herein. EXAMPLES Example 1: 3-[3-Methyl-1-(1H-pyrrolol2,3-bjpyridin-4-yl)--IH-pyrazol-4-yl]benzonitrile / \ C CN N N H 0 Step 1. JH-Pyrrolo[2,3-bipyridine 7-oxide To a solution of IH-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 solidified when -20 mL solution of MCPBA 15 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, filtered 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. Na 2

CO

3 dropwise, and the resulting mixture was stirred at room temperature overnight. The mixture was then 20 cooled at 0* C, filtered and washed with water (x4) to give 3.55 g of pale purple solid which was dried at 400 C overnight to give the desired product (2.47 g, 44.4% yield). 'H NMiR (400 MHz, CD 3 OD): 8 8.2 (1H, d); 7.95 (11H, d); 7.5 (11H, d); 7.2 (1H, in); 6.65 (1H, d). MS (M+H)*: 136. 25 Step 2. 4-Chloro-JH-pyrrolo[2,3-bjpyridine To a pink solution of IH-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. 30 NaOH was added to adjust the pH of the mixture to about 7. The mixture was filtered and washed 62 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). 'H NMR (400 MHz, CDCl 3 ): 8 10.8 (1H, br); 8.21 (IH, d); 7.41(IH, d); 7.18 (1H, d); 6.61 (1H, d). MS (M+H)*: 153. 5 Step 3. 4-(4-Bromo-3-methyl-IH-pyrazol-1-yl)-JH-pyrrolo(2,3-b]pyridine Br N'N N N H A mixture of 4-chloro-1H-pyrrolo[2,3-b)pyridine (0.050 g, 0.00033 mol) and 4-bromo-3 methyl-1H-pyrazole (0.10 g, 0.00066 mol) was heated at 130 *C overnight. The reaction mixture then 0 was subjected to column chromatography (eluting with 5% MeOH/DCM, 0.5% NH 4 0H, on silica gel) 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, CD 3 OD): 8 8.32 (IH, s); 8.25 (lH, 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. [5 Step 4. 3-[3-Methyl---(IH-pyrrolo[2.3-b]pyridin-4-yl)-JH-pyrazol-4-ylJbenzonitrile A mixture of 4-(4-bromo-3-methyl-1H-pyrazol-1-yl)-IH-pyrrolo[2,3-b]pyridine (0.032 g, 0.00012 mol), (3-cyanophenyl)boronic acid (0.027 g, 0.00018 mol), sodium carbonate (0.032 g, 0.00030 mol) and tetrakis(triphenylphosphine)palladium(0) (7.0 mg, 0.0000060 mol) in 1,2 20 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, CD 3 OD): S 8.57 (1H, s); 8.31 (IH, d); 7.8 (2H, m); 7.75 (2H, m); 7.55 (1H, s); 25 7.45 (2H, m); 7.01 (1H, d); 2.6 (3H, s). MS (M+H)*: 299. Example 2: (2E)-3-13-Methyl-1-(IH-pyrrolo[2,3-bpyridin-4-yl)-1H-pyrazol-4-yllacrylonitrile trifluoroacetate salt ~~1 CN Nq N H TFA Step I. 4-Bromo-JH-pyrrolo[2,3-bipyridine To a solution of IH-pyrrolo[2,3-b]pyridine 7-oxide (8.0 g, 0.060 mol), prepared by the procedure outlined in Example 1, Step I in DMF (100 mL, I mol) was added methanesulphonic 5 anhydride (20.8 g, 0.119 mol, in four portions) at 0 *C. The mixture was stirred at 0 *C for an additional 20 min followed by an addition of tetramethylammonium 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 addition of -0.25 L of water. The resulting mixture was 10 stirred for additional 2 h then filtered. The solid obtained was washed with water x3 to give 6.72 g of a reddish solid which was dried at 50 *C over a weekend to give the product (5.75 g, 49% yield). 'H NMR (400 MHz, CDCl 3 ): 810.8 (1H, br); 8.2 (1H, d); 7.41 (IH, d); 7.19 (IH, d); 6.61 (1H, d). MS (M+H)*: 196. 15 Step 2. 4-Bromo-I-[2-(triinethylsilyl)ethoxy]methyl-IH-pyrrolo[2,3-bjpyridine To a solution of 4-bromo-1H-pyrrolo[2,3-b]pyridine (6.2 g, 0.031 mol) and [3 (trimethylsilyl)ethoxylmethyl 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 mixture was stirred for additional 4 h, then diluted with methyl tert-butyl ether (MTBE). The organic layer was 20 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 product as a colorless oil (9.66 g, 94% yield). 'H NMR (400 MHz, CDC 3 ): 8 8.2 (1H, d); 7.49 (1 H, d); 7.19 (1H, d); 6.62 (1H, d); 5.78 (2H, s); 3.6 25 (2H, t); 0.98 (2H, t); 0.0 (9H, s). MS (M+H)*: 326. Step 3. (2E)-3-[3-Methyl-l-(IH-pyrrolo(2,3-b]pyridin-4-yl)-)H-pyrazol-4-yl~acrylonitrile A solution of 2-propenenitrile (0.043 mL, 0.00065 mol), bis(triphenylphosphine)palladium(I) chloride (0.0091 g, 0.000013 mol), 4-(4-bromo-3-methyl-1H-pyrazol-1-yl)-IH-pyrrolo[2,3-b]pyridine 30 (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 with water (x2) and brine successively. The organic phase was dried and concentrated in vacuo to give 62 mg of the product as an orange solid. The orange solid was purified by prep-LCMS to give 12 mg of an off-white solid as a trifluoroacetic acid (TFA) salt which was triturated with MTBE (1 mL) to provide the purified product as a pale green solid. (dried at 60 *C for 4 h, 9 mg , 28% yield). 5 'H NMR (400 MHz, CD 3 OD): 2 :1 of trans: cis isomers. For trans: 8 8.95 (NH,IH, s); 7.75 (olefin, 1 H, d); 6.1 (olefin, I H, d); 2.45 (Me, 3H, s). MS (M+H)*: 249. Example 3: 3-[3-Methyl-1-(1H-pyrrolo[2,3-blpyridin-4-yI)-1H-pyrazol-4-yllpropanenitrile, trifluoroacetate salt CN N N N .0 H TFA A mixture of (2E)-3-[3-methyl-1-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-4-yl]acrylo nitrile, TFA salt, (0.0050 g, 0.000020 mot, prepared according to Example 2) and palladium (5.8 mg, 0.0000054 mol) in methanol (1 mL, 0.02 mol) and 1,2-dichloroethane (1 mL, 0.01 mol) was degassed and then was stirred under an atmosphere of hydrogen for 3 h. The reaction mixture then was filtered 15 and the filtrate was concentrated in vacuo to give 8 mg of the product as an off-white solid. The crude 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). 'H NMR (400 MHz, CD 3 0D): 8 8.52 (IH, s); 8.35 (lH, d); 7.72(IH, d); 7.6 (IH, s); 7.38 (lH, d); 6.96 (H, d); 2.7-2.9 (4H, in); 2.4 (3H, s). MS (M+H)*: 251. 20 Example 13: 4-(4-Phenyl-1H-imidazol-1-yI)-1H-pyrrolo[2,3-blpyridine N/ N N H A melt of 4-chloro-1H-pyrrolo[2,3-b]pyridine (0.050 g, 0.00033 mol) in 4-phenyl-lH imidazole (0.24 g, 0.0016 mol) was heated at 200 *C overnight. The reaction was partitioned between 25 ethyl acetate and saturated NaHCO 3 , separated and the organic phase was washed with brine. The 65 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% NH 4 0H, 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). 5 'H NMR (400 MHz, dimethylsulxoxide (DMSO)): 8 12.5 (I H, s); 8.5 (1H, s); 8.4 (11H, s); 8.38 (1H, d); 7.8 (2H, m); 7.62 (lH, d); 7.4 (3H, m); 7.3 (1H, m); 6.81 (1H, d). MS (M+H)*: 260 Example 14: 13-Methyl-1-(1H-pyrrolo[2,3-blpyridin-4-yI)-1H-pyrazol-4-yl]-piperidin-1-yl methanone Q 0 N N t0 H Step 1. 3-Methyl-1-(1-[2-(trimethylsilyl)ethoxy]methyl-JH-pyrrolo[2, 3-b]pyridin-4-yl)-IH-pyrazole 4-carboxylic acid To a -70 *C solution of 4-(4-bromo-3-methyl-1H-pyrazol-1-y)-1-[2-(trimethylsilyl)ethoxy] methyl-IH-pyrrolo[2,3-b]pyridine (0.107 g, 0.000263 mol) in THF (I mL, 0.01 mol), and n [5 butyllithium in hexane (0.23 mL of 1.6M), 0.5g of CO 2 solid was added. After 15 min, the reaction was quenched with NI 4 CL. Ethyl acetate and water were added. The organic phase was washed with brine, and was evaporated to give 84 mg of an off-white glass/solid. The solid was chromatographed with 50% ethyl acetate/hexanes, 0.5% AcOH, sample on silica gel to give 40 mg of a purified product as a white solid (37% yield). 20 'H NMR (400 MHz, CDCl 3 ): 8 8.5 (1H, d); 7.45 (1H, d); 7.25 (1H, d); 7.02 (1H, s); 6.6 (lH, d); 5.75 (2H, s); 3.6 (2H, t); 2.48 (3H, s); 0.98 (3H, t); 0.0 (9H, s). MS (M+H)*: 372. Step 2. 4-[3-Methyl-4-(piperidin-1-ylcarbonyl)-JH-pyrazol-1-yl]-1-[2-(trimethylsilyl)ethoxy]methyl IH-pyrrolo[2,3-bipyridine 25 A solution of 3-methyl-I-(1-[ 2 -(trimethylsilyl)ethoxy]methyl-IH-pyrrolo[2,3-b]pyridin-4-yl) 1H-pyrazole-4-carboxylic 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 stirred for 1.2h, after which time piperidine (32 p.L, 0.00032 mol) was added. After another 2h, another portion of piperidine (15 jpL) was added and the resulting mixture was stirred overnight. The reaction mixture was then partitioned between ethyl 30 acetate and water, and washed sequentially with sat. NaHCO 3 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 acetate/hexanes, sample in DCM. Collected 25 mg of the purified product as a colorless glass/oil (50% yield). 'H NMR (400 MHz, CDCl 3 ): 5 8.45 (lH, d); 8.23 (1H, s); 7.5 (1H, d); 7.4 (IH, d); 7.05 (1H, d); 5.8 5 (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. 3-Methyl-1-(lH-pyrrolo[2,3-b]pyridin-4-yl)-JH-pyrazol-4-yl]-piperidin-1-yl-methanone A solution of 4-[3-methyl-4-(piperidin-1-ylcarbonyl)-1H-pyrazol-1-yl]-1-[2-(trimethylsilyl) ethoxy]methyl-IH-pyrrolo[2,3-b]pyridine (0.025 g, 0.000057 mol) in TFA (1 mL, 0.01 mol) was 10 stirred for 1.5 h. The reaction mixture was then concentrated and partitioned between DCM and sat. NaHCO 3 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 methanol (1 mL, 0.02 mol) and treated with ammonium hydroxide in water (8.OM, 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 15 (MTBE) to give 13 mg of a white solid which was dried at rt over a weekend. A total of 8 mg of the product was obtained after drying (45% yield). 'H NMR (400 MHz, CDC13): 5 9.7 (1H, s); 8.4 (1 H, d); 8.2 (1H, s); 7.42 (1H, d); 7.4 (1H, d); 6.99 (IH, d); 3.4-3.8 (4H, br); 2.47 (3H, s); 1.5-1.8 (6H, br). MS (M+H)*: 309. 20 Example 15: [3-Methyl-1-(1H-pyrrolo[2,3-bpyridin-4-yl)-1H-pyrazol-4-ylmethyl]-phenyl-amine NHPh N N H Step 1. 3-Methyl-1-(-[2-(trimethylsilyl)ethoxyjmethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazole 25 4-carbaldehyde To a -70 "C solution of 4-(4-bromo-3-methyl-lH-pyrazol-1-yl)-1-[2-(trimethylsilyl)ethoxy] methyl-lH-pyrrolo[2,3-b]pyridine (0.25 g, 0.00061 mol) in THF (2 mL, 0.03 mol), 1.6 M n butyllithium in hexane (0.54 mL). After 10 min, DMF (120 pL, 0.0015 mol) was added. The reaction was allowed to warm to rt and stirred overnight. The reaction was then quenched with NH4Cl. Ethyl 30 acetate/water was added. The organic phase was separated and washed with brine, then dried and 67 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, CDCl 3 ): 8 10.15 (1H, s); 8.7 (IH, s); 8.47 (IH, d); 7.58 (1H, d); 7.5 (IH, d); 7.05 (1 H, d); 5.8 (2H, s); 3.63 (2H, t); 2.7 (3H, s); 0.98 (311, t); 0.0 (9H, s). MS (M+H)*: 356. 5 Step 2. N-[ 3 -Methyl-I-(I-[2-(trimethylsilyl)ethoxymethyl-1H-pyrrolo[2,3-bpyridin-4-yl)-JH pyrazol-4-yl]methylaniline A solution of 3-methyl-1-(1-(2-(trimethylsilyl)ethoxy]methyl-IH-pyrrolo[2,3-b]pyridin-4-yl) IH-pyrazole-4-carbaldehyde (0.025 g, 0.000070 mol) and aniline (IM in DCM, 0.070 mL), in DCM 10 (1 mL, 0.02 mol) was stirred for I min. Acetic acid (20 iL, 0.0004 mol), aniline (IM in DCM, 140 pL) and sodium triacetoxyborohydride (0.022 g, 0.00010 mol) were added. The reaction was stirred overnight and partitioned between DCM and sat. NaHCO 3 , washed with brine. The organic phase was .dried and evaporated to give 21 mg of a product as a pale orange glass (70% yield). 'H NMR (400 MHz, CDCI 3 ): 5 8.4 (IH, d); 8.15 (1H, s); 7.65 (1H, d); 7.35 (31, m); 7.09 (1H, d); 15 6.82 (IH, 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, s). MS (M+H)*: 433. Step 3. [3-Methyl-1-(JH-pyrrolo[2, 3 -b]pyridin-4-y)-IH-pyrazol-4-ylmethyl]-phenyl-amine Deprotection of N-[3-methyl-1-(I-[ 2 -(trimethylsilyl)ethoxy]methy-1 H-pyrrolo[2,3-b]pyridin 20 4 -yl)-1H-pyrazol-4-yl]methylaniline was carried out according to the procedures of Example 14, Step 3 to give the desired product (58% yield). 'H NMR (400 MHz, CDCl 3 ): 8 9.9 (lH, s); 8.38 (1H, d); 8.1 (1H, s); 7.4 (IH, d); 7.35 (IH, 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. 25 Example 25: 3 -3-Methyl-1-(1H-pyrrolo[2,3-bpyridin-4-yl)-1H-pyrazol-4-yi]-cyclobexanol OH N H Step 1. 3-Ethoxy-1-[3-methyl- 1-(-[2-(trimethylsilyl)ethoxyjmethyl-1H-pyrrolo[2,3-bjpyridin-4-yl) 30 IH-pyrazol-4-yl]cyclohex-2.en-J-ol 0 N N

CH

2

O(CH

2

)

2 Si(CH 3

)

3 To a -75 *C solution of 4

-(

4 -bromo-3-methyl-1H-pyrazol-1-yl)-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. After -10 min, 1.0 5 M magnesium dibromide in ether (0.35 rnL) was added. After another 50 min, a solution of 3-ethoxy 2 -cyclohexen-1-one (41.5 pL, 0.000308 mol) in THF (-0.3 mL) was added. The resulting mixture was warmed to -40 *C over -lh and quenched with NH 4 Cl. Then ethyl acetate/water was added. The organic phase was washed with brine, and concentrated to give 145 mg of an orange oil. The crude product was chromatographed with 0-50% ethyl acetate/hexane gradient, sample in DCM. Collected 10 35 mg of the produce as an oil (30% yield). 'H NMR (400 MHz, CDCl 3 ): 5 8.49 (IH, d); 8.38 (LH, s); 7.55 (1H, d); 7.4 (IH, d); 7.1 (1H, d); 6.0 (2H, s); 3.6 (2H, t); 2.81 (2H, m); 2.62 (311, s); 2.58 (2H, in); 2.27 (2H, m); 1.0 (3H, t); 0.0 (9H, s). MS (M+H)*: 422. \5 Step 2. 3

-[

3 -Methyl--(-{2-(trimethylsilyl)ethoxymethyl-H-pyrrolo[2,3-b]pyridin-4-yl)-1H pyrazol-4-yljcyclohexanol A mixture of 3-[3-methyl-1-(1-[ 2 -(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-bpyridin-4 yl)-IH-pyrazol-4-yl]cyclohex-2-en-1 -one (0.019 g, 0.000045 mol) and palladium on carbon (Pd/C) (0.018 g, 0.000017 mol) in methanol (2 mL, 0.05 mol) was degassed and was stirred under a 20 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 tetrahydroborate (0.032 g, 0.00084 mol) for 5h. The reaction was purified by prep-HPLC to give 5 mg of the desired product. MS (M+H)*: 426. 25 Step 3. 3-[3-Methyl-1-(IH-pyrrolo[2, 3 -b]pyridin-4-yl)-H-pyrazol-4-yI]-cyclohexanoI Deprotection of 3-[3-methyl-1-(1-[ 2 -(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin 4 -yl)-IH-pyrazol-4-yl]cyclohexanol was carried out according to the procedures of Example 14, Step 3 to give the desired product (40% yield). 'H NMR (400 MHz, CDCI 3 ): 5 9.72 (11H, s); 8.35 (1H, d); 7.95 (1H, s); 7.41 (IH, d); 7.35 (1H, d); 30 7.02 (1H, d); 3.78 (l H, m); 2.6 (1 H, m); 2.4 (3H, s); 1.2-2.4 (8H, i). MS (M+H)*: 296. 69 Example 40: 4-{1-(3-Methoxy-1-methyl-propyl)-1H-pyrazol-4-yl]-1H-pyrrolo[2,3-blpyridine 0 N-N N N H Step 1. 4-[I-(3-Methoxy-J-methylpropyl)-JH-pyrazol-4-yl]-J-[2-(trimethylsilyl)ethoxy]-methyl-H pyrrolo[2,3-b]pyridine 5 To a 0 *C solution of 3-[4-(l-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4 yl)-lH-pyrazol-1-yl]butan-1-ol (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 pL, 0.00029 mol) was added and the resulting mixture was stirred over a weekend. The mixture was then partitioned between ethyl acetate and water, 0 separated and the organic phase was washed with brine. The organic phase was concentrated to give a pale orange oil. 'H NMR (400 MHz, CDCI,): 8 8.4 (1H, d); 8.3 (IH, 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); 3.2-3.4 (2H, m); 3.38 (3H, s); 2.1-2.3 (2H, m); 1.7 (3H, d); 1.0 (2H, t); 0.0 (9H, s). MS (M+H)*: 400. 5 Step 2. 4-[]-(3-Methoxy-J-methyl-propyl)-JH-pyrazol-4-yI]-JH-pyrrolo[2,3-blpyridine Deprotection of 4-[1-(3-methoxy-1-methylpropyl)-lH-pyrazol-4-yl]-1-[2-(trimethylsilyl) ethoxy]-methyl-IH-pyrrolo[2,3-b]pyridine was carried out according to the procedures of Example 14, Step 3 to give the desired product (25% yield). 20 'H NMR (400 MHz, CDC1 3 ): 5 10.0 (1H, s); 8.35 (IH, d); 8.18 (IH, s); 7.95 (IH, s); 7.41 (IH, d); 7.21 (IH, d); 6.75 (1H, d); 4.63 (1H, m); 3.15-3.4 (2H, m); 3.35 (3H, s); 2.21-2.05 (2H, in); 1.6 (3H, d). MS (M+H): 270. Example 42: 4-[1-(1-Methyl-3-pyrazol-1-yI-propyl)-1H-pyrazol-4-yl]-1H-pyrrolo[2,3-bpyridine N-Y N N-N 25 N H 70 Step 1. 4-1-[1-Methyl-3-(H-pyrazol-1.-yl)propyl]-JH-pyrazol-4-yI-1-[2-(trimethylsily)ethoxy]methyl 1H-pyrrolo[2,3-bipyridine To a 0 "C solution of 3-[4-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4 5 yl)-1H-pyrazol-1-yl]butyl methanesulfonate (prepared by mesylation of the alcohol 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 resulting solution was stirred overnight and then partitioned between ethyl acetate and 0.1 N HCI, water. the organic phase was separated and washed with brine. The organic layer was then concentrated to give 49 mg of a pale orange glass 0 (87% yield). 'H NMR (400 MHz, CDC 3 ): 8 8.4 (1H, d); 8.18 (IH, s); 7.99 (1H, s); 7.6 (1H, t); 7.5 (IH, d); 7.4 (IH, t); 7.27 (11H, d); 6.8 (1H, d); 6.3 (1 H, in); 5.8 (2H, s); 4.2 (1H, in); 4.0-4.2 (2H, in); 3.61 (2H, t); 2.58 (2H, m); 1.65 (3H, d); 1.0 (2H, t); 0.0 (9H, s). MS (M+H)*: 436. 15 Step 2. 4-[J-(1-Methyl-3-pyrazol-1-y-propyl)-H-pyrazol-4-ylJ-JH-pyrrolo[2.3-b]pyridine Deprotection of 4-1-[1-methyl-3-(1H-pyrazol-1-yl)propyl]-1H-pyrazol-4-yl-1-[2-(trimethyl .silyl)ethoxy]methyl-IH-pyrrolo[2,3-b]pyridine was carried out according to the procedures of Example 14, Step 3 to give the desired product (38% yield). 'H NMR (400 MHz, CDC1 3 ): 89.7 (1H, s); 8.38 (1 H, d); 8.1 (1H, s); 7.7(lH, s); 7.59 (1 H, t); 7.4 (1H, 20 d); 7.35 (1H, t); 7.21 (1H, d); 6.75 (IH, d); 6.25 (1H, m); 4.4 (1H, m); 3.9-4.15 (2H, m); 2.55 (2H, m); 1.63 (3H, d). MS (M+H)*: 306. The following compounds in Table I were made by methods analogous 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 gradient of MeCN/H 2 0 25 containing 0.15% NH40H. Table 1 Ex. MS No. Structure Name Prep. Ex. No. 0 N 1-(1H-Pyrrolo[2,3-b]pyridin-4 4 yl)-1H-pyrazole-4-carboxylic acid 256 1 ethyl ester S N Ph N. N 4-(3-Methyl-4-phenyl-pyrazol-l - 2741 yl)-l H-pyrrolo[2,3-blpyridine N N Ph 6 N4-(3-Phenyl-pyrazol-1 -yl)-I H- 2601 ~ pyrrolo[2,3-b]pyridine NN Br N 4-(4-Bromo-imidazol-1-yl)-1H- 262 13 . pyrrolo[2,3-b]pyridine (N N r 8 N.N 4-(4-Bromo-3-methyl-pyrazol-l- 2621 yl)-l H-pyrrolo[2,3-b]pyridine / CN I \ 3-[3-Methyl-I -(lH-pyrrolo[2,3 9 NsN b]pyridin-4-yl)-IH-pyrazol-4-yl]- 2991 N benzonitrile NN CN 4-!3-Methyl-l-(1H-pyrrolo[2,3 '0 N b]pyridin-4-yl)-IH-pyrazol-4-yl]- 299 N benzonitrile (NNH 72 F / 4 -[4-(3-Fluoro-phenyl)-3-methyl 16 N, N pyrazol-l -yl]-l H-pyrrolo[2,3- 292 b]pyridine CNN

F

3 C

CF

3 4 -[4-(3,5-Bis-trifluoromethyl 17 N' phenyl)-3-methyl-pyrazol-1 -yl]- 410 N I H-pyrrolo[2,3-b]pyridine N N H F F 4-r4-(3,s-Difluoro-phenyl)-3 18 N, metliyl-pyrazol-I -yl]-ln- 310 N pyrrolo[2,3-b]pyridine N r_ _ OH {3[3 -Methyl-i -(I H-pyrrolo[2,3 19 N, N b]pyridin..4-yi)-1 H-pyrazolA...yl] 304 phenyl) -methanol (N N N 20 N' + 4-(3-Methyl-4-pyrimidin-5-yi.. 2'N pyrazol- I -yl)-lI H-pyrrol o,2,3 -b - 276 pyridine _______ H__ _ _ _ _ _ _ _ _ _ _ _ _ 73 N 4-[3-Methyl-4-(1 -methyl-i - 21 N, indol-5-yl)-pyrazol-1 -yl].l - 327 NN pyrrolo[2,3-b]pyridine CNN N2 q \ 4-(3-Methyl-4-thiophe-3-yi.. 2'N pyrazol-1I-yI)-I H-pyrrolo[2,3-b. 280 pyridine N H H 'ij~ N,N-Dimethyl-4-[3-mthyl.I 23 /(IH-pyrrolo[2,3-b]pyridin4yly. 381 N, IH-pyrazol-4-yl] N benzenesulfonamide N N 0 NH N- {4-[3 -Methyl-i -(1H 24 ,,pyrrolo[2,3-b]pyridin-4y)- I H- 331 Nl-P\pyrazol-4-yl] -phenyl) -acetaniide N CN N CN 3 -tezt-Butyl--(I Hpyrrolo[2,3 26 N blpyridin.4.yl)-1 H-pyrazole-4- 265 C - t \,carbonitrile 74 NC Br NN 4-Bromo-I -(I H-pyrroio[2,3-b] 27 pyridin-4-y>.11-pyrazole-3- 287 fj~j'~jrcarbonitrile H NCN N C~l4-(3-Cyano-phenyl)--(IH 28 N Npyrrolo[2,3-b]pyridin-4-yl)-l H- 310 pyrazole-3-carbonitrile _ (~QW_ _ _ HO F \ 3-[1 -(1 H-Pyrrolo[2,3-b]pyridin-4 29 N' _ yI)-3-trifluoromethyl-I H-pyrazol- 254 N 4-yl]-propan-1 -ol (N N H ____

CH

2 0H N 3-[3-Methyl- I-(I H-pyrrolo[2,3 30 N N b]pyridin-4-yl)-1H-pyrazol-4-yI]- 310 prop-2-en-1 -01 N N 0 ,?Nr Br 31 0 r 2-[4-Bromo.1-(1H-pyrrolo[2,3 31 N b]pyridin-4-yl)-1H-pyrazol-3-yl]- 408 N isoindole-1 ,3-dione N N 75 I 4-[4-(2,6-Dimethyl-phenyl)-3 32 N, N methyl-pyrazol-1 .yll- IH- 302 pyrrolo[2,3-b]pyridine N

H

2 N

-

N I \ 3-[3-Amino-I -(I H-pyrrolo[2,3 33 Nb]pyridin-4-yi)-l H-pyrazo1-4-y1]- 300 benzonitrile H

CH

2 Ph HN /\C / 3-[3-Benzylamino-I -(I1H 34 Npyrrolo(2,3-b~pyridin-4-yl)-lH- 390 1, is N pyrazol-4-yl]-benzonitrile H CN HN N,\ N-[4-(3-Cyano-phenyl)- 1-(1 H- 11 35 N ~ pyrrolo[2,3-b]pyridin-4-yI)-IH- 3421,4 pyrazol-3-yiJ-acetamide OH N-N 36 3-[4.(1H-Pyrrolo[2,3-b]pyridin-4- 242 58 yl)-pyrazo 1-1 -yl]-propan-I -ol Purification A N N H _ _ _ _ _ _ _ _ _ _ 76 OH N-N 5 37 3-[4(HPyroo[2,3b]pyri-din-4- 256 Pui5ato8 yI)-pyrazol-l -yl]-butan-I -ol Prfcto N N H____ CN N-N 4-[4-(IH-Pyrrolo[2,3-b]pyridin-4- 265 38yl)-pyrazol.1 -yl]-pentanenitrile 25 Purification A N N

NH

2 N-N 4-[4-(lH-Pyrrolo[2,3-b]pyridin-4- 60 39 yl)-pyrazol-1-yl]-pentanoic acid 283 Purification A amiide N N 41 N-N 4-[1 -(3 -Tmidazol-1 -yil-methyl 41NNpropyl)-IH-pyrazol-4-yl]-l H- 306 42 pyrrolo[2,3-b]pyridine N N H________ CN 0 N-IN 4-Cyclopentyl-4-[4-(lN- 5 43 Kpyrrolo[2,3-b]pyridin-4-yl)- 319 Prfcto pyrazol-l -yl]-butyronitrile Prfcto N N

H

0

NH

2 N-N 4-Cyclopentyl-4-[4-(1 H- 60 44 pyrrolo[2,3-b]pyridin-4-yl)- 337 pyrazol-1-yl]-butyramide Purification A N N H CN N-N 3-Cyclopropyl-3-[4-(7H 45 pyrrolo[2,3-d]pyrimidin-4-yl)- 278 61 pyrazol-1-yl]-propionitrile Purification A N N H Example 46: 4-(2-tert-Butyl-1-methyl-1H-imidazol-4-yl)-1IH-pyrrolo[2,3-blpyridine trifluoro acetate salt N N / eTFA N N H 5 Step 1. 4-(2-tert-butyl-JH-imidazol-5-yI)-1-[2-(trimethylsilyl)ethoxyjmethyl-IH-pyrrolo[2,3 b]pyridine To a solution of trimethylacetic acid (0.169 mL, 0.00 147 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. 10 To a solution of 2-chloro-1-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-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 pivalate (0.03 89 g, 0.000166 mol) and the reaction was stirred at room temperature 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 15 combined organic extracts were dried over sodium sulfate, then filtered and concentrated. The crude residue was purified by flash column chromatography (2.5% MeOH/DCM) to yield 4-(2-tert-butyl 1H-imidazol-5-y)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine (32 mg, 52%). 'H NMR (400 MHz, CDC 3 ): 4 8.31 (d, 1H), 7.50 (s, 1H), 7.40 (d, IH), 7.37 (d, 11-1), 6.94 (d, IH), 5.69 (s, 2H), 3.52 (dd, 211), 1.46 (s, 9H), 0.90 (dd, 2H), -0.08 (s, 9H); MS(ES):371(M+1). 20 78 Step 2. 4-(2-tert-butyl-i-methyl-IH-imidazol-4-yl)-1-[2-(trimethylsilyl)ethoxy]methyl-HH-pyrrolo [2,3-blpyridine To a mixture of 4-(2-tert-butyl-1H-imidazol-5-yl)-1-[2-(trimethylsilyl)ethoxy]methyl-l

H

pyrrolo[2,3-b]pyridine (0.019 g, 0.000051 mol) and potassium carbonate (0.15 g, 0.0011 mol) in 5 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 sulfate, filtered, and concentrated in vacuo, then purified by silica gel chromatography (20% ethyl acetate/hexanes) to afford 4-(2-tert-butyl-1-methyl-lH-imidazol-4-yl)-1

[

2 -(trimethylsilyl)ethoxy]methyl-1 H-pyrrolo[2,3-b]pyridine (10 mg, 51%). 0 'H NMR (400 MHz, CDC 3 ): & 8.37 (d, 1H), 7.54 (d, 111), 7.44-7.22 (m, 2H), 7.19 (d, IH), 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-butyl-1-methyl-IH-imidazol-4-yl)-1-[2-(trimethylsilyl)-ethoxy] 5 methyl-IH-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 NH40H (I mL) for 16 hours. The solvents were removed and the product was purified by preparative-HPLC (C18 eluting with a gradient of ACN/H 2 0 containing 0.1% TFA) to afford 4-(2 tert-butyl-1-methyl-IH-imidazol-4-yl)-1H-pyrrolo[2,3-b]pyridine, trifluoroacetate salt (9 mg, 90%). O I NMR (400 MHz, d 6 -DMSO): & 12.24 (s, IH), 8.38 (br s, I H), 8.24 (s. I H), 7.70-7.63 (m, 2H), 7.08 (br s, 1H), 2.55 (s, 3H), 1.51 (s, 9H); MS(ES):255(M+1). Additional 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 25 (C 18 eluting with a gradient of ACN/H 2 0 containing 0.15% NI 4 OH). The results are summarized in Table 2 according to the following structure: (Y)n-Z

HN-

\N N N H Table 2 Ex.Name MS No. -(Y)-Z (ES) (M+1) 47 4-(2-phenyl-1H-imidazol-5-yl)-1H- 261 pyrrolo[2,3-b]pyridine 79 4-(2-benzyl-IH-imidazol-5-yl) 48 1 H-pyrrolo[2,3-b]pyridine 275 trifluoroacetate salt 4-[2-(1-phenylethyl)-1H-imidazol-5- racemicc) 49 yl]-1H-pyrrolo(2,3-b]pyridine 289 trifluoroacetate salt Example 50: 4-(2-Phenyl-1,3-thiazol-4-yl)-1H-pyrrolo[2,3-bjpyridine trifluoroacetate salt SP N N N H -TFA Step 1. 2-Chloro-J-(-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)ethanone S To a solution of 4 -bromo-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine (2.05 g, 0.00626 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). After 30 minutes 10 reaction time, the solution was quenched by the addition of saturated ammonium chloride aqueous solution. The product was extracted with ethyl acetate, the combined organic extracts were washed with brine, dried over Na 2

SO

4 , filtered and concentrated. The crude residue was purified by flash column chromatography (0-20% ethyl acetate/hexanes) to afford 2-chloro-1-(1-[2-(trimethylsilyl) ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)ethanone (711 mg, 35%). 'H NMR (400 MHz, CDCl 3 ): 15 & 8.56 (d, I H), 7.66 (d, I H), 7.60 (d, 1H), 7.23 (d, I H), 5.80 (s, 2H), 4.91 (s, 211), 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-yl)-JH-pyrrolo[2,3-bipyridine trifluoroacetate salt A solution of 2-chloro-1-(l-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridin-4-yl) 20 ethanone (0.050 g, 0.00015 mol) and benzenecarbothioamide (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 I 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 25 (C18 eluting with a gradient of ACN/H 2 0 containing 0.1% TFA) to afford 4-(2-phenyl-1,3-thiazol-4 80 yl)-IH-pyrrolo[2,3-b]pyridine as the trifluoroacetate salt (11 mg, 18%). 'H NMR (400 MHz, d DMSO): & 12.01 (s, 1H), 8.58 (s, IH), 8.39 (br s, 1H), 8.13-8.07 (m, 2H), 7.81 (d, IH), 7.67-7.64 (in, 1H), 7.62-7.52 (m, 3H), 7.22 (d, 1H); MS(ES):278(M+1). 5 Example 51: N-Methyl-N-propyl-4-(1H-pyrrolol2,3-b]pyridin-4-yl)-1,3-thiazol-2-amine, trifluoroacetate salt

N

S-

N N N H -TFA Step 1. N-Methyl-N-propylthiourea 10 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 solution 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. N-methyl-N-propylthiourea was 15 obtained after flash column chromatography (4% MeOH in DCM). Step 2. A solution of 2-chloro-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 20 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 of MeOH. To this was added 0.5 mL of N1H40H and 100 iL 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 (CI8 eluting 25 with a gradient of ACN/H 2 0 containing 0.1% TFA) to afford N-methyl-N-propyl-4-(1H-pyrrolo[2,3 b]pyridin-4-yl)-1,3-thiazol-2-amine as the trifluoroacetate salt (39 mg, 67%). 'H NMR (300 MHz,

CD

3 OD): 4 8.46-8.12 (br s, IH), 7.92 (br s, 1H), 7.72 (s, 1H), 7.63 (d, IH), 7.45 (br s, 111), 3.56 (t, 21), 3.20 (s, 3H), 1.78 (dq, 2H), 1.00 (t, 311); MS(ES):273(M+1). Additional aminothiazole analogs were prepared by procedures analogous to those described 30 in Example 51, using different starting materials such as alternative thioureas in Step 2. In Examples 52 and 53, the white precipitate obtained by the procedure of Example 51 was isolated by filtration, 81 washed with water and dried under high vacuum to afford the analogs as the free amine. The results are summarized in Table 3 according to the following structure: (Y)n-Z N N N H 5 Table 3 Ex. NaeRMS No.Name R (ES) (M+1) 52 N-phenyl-4-(1 H-pyrrolo[2,3-b]pyridin-4- N 293 yl)-1,3-thiazol-2-amine 53 N-methyl-N-phenyl-4-(1H-pyrrolo[2,3- N 307 b]pyridin-4-yl)-1,3-thiazol-2-amine Example 54: 4-(2-Phenyl-1,3-thiazol-5-yl)-1H-pyrrolo[2,3-bpyridine trifluoroacetate salt

N

S N N H TFA 10 Step 1. (2-Phenyl-1,3-thiazol-5-yl)boronic acid To a solution of n-butyllithium in hexane (1.6 M, 2.1 mL) in ether (20 mL) at -78 *C, a solution 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 15 room temperature and stirred for an additional 40 minutes. Saturated NH 4 CI 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-phenyl-1,3-thiazol-5-yl)boronic acid as a mixture with 2-phenyl-1,3 20 thiazole. This mixture was used in Step 2 without further purification. MS(ES):206(M+1). 82 Step 2. To a mixture of (2-phenyl-1,3-thiazol-5-yl)boronic acid (75.0 mg, 0.000366 mot) and 4 bromo-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine (80 mg, 0.000244 mol) in DMF (4 mL, 0.0516 mol) was added a solution of potassium carbonate (101 mg, 0.000732 mol) in water (1 5 mL, 0.0555 mol). The mixture was purged with a steady stream of nitrogen for 15 minutes. Tetrakis(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/H 2 0 containing 0.1% TFA) to afford 12 mg of a yellow solid containing the desired product as the major component. The mixture was stirred in TFA (1 mi.) for 1 0 hour. Then excess TFA was removed in vacuo and the resulting residue was stirred with 2 mL MeOH, 0.5 mL NH40H and 100 piL ethylenedianine for 16 hours. The product was isolated by preparative HPLC (C18 eluting with a gradient of ACN/H 2 0 containing 0.1% TFA) to afford 4-(2-phenyl-1,3 thiazol-5-yl)-1H-pyrrolo[2,3-b]pyridine trifluoroacetate salt (5 mg, 5%). 'H NMR (400 MHz,

CD

3 OD): & 8.64 (s, 1H), 8.34 (d, lH), 8.10-8.04 (m, 2H), 7.73 (d, IH), 7.71 (d, 1H), 7.56-7.51 (m, 5 3H), 7.14 (d, IH); MS(ES):278(M+1). Example 55: Ethyl 2-methyl-2-[4-(1H-pyrrolo(2,3-blpyridin-4-yl)-IH-pyrazol-1-yl]propanoate trifluoroacetate salt (55a) AND ,0 2-Methyl-2-14-(1H-pyrrolol2,3-blpyridin-4-yl)-1H-pyrazol-1-yl]propanoic acid (55b)

CO

2 Et Y-CO 2 H N-N N-N TFA N N N N H H 4-(IH-Pyrazol-4-yl)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine (60 mg, 0.00019 mol) was dissolved in DMF (1.5 mL), and the solution was cooled to 0 "C with a cold bath. Sodium hydride (15 mg, 0.00038 mol) was added. After stirring for 10 min, 2-bromo-2-methyl 25 propanoic acid ethyl ester (42 piL, 0.00028 mol) was added. The cold bath was then removed and the reaction mixture was allowed to warm to room temperature over 1 hour. The reaction mixture was quenched with saturated ammonium chloride solution. More water was added, and the product was extracted with MTBE. The combined extracts were dried over sodium sulfate, filtered and concentrated. The residue was dissolved in 2 mL TFA and stirred for 1 h. Then excess TFA was 30 removed in vacuo and the resulting residue was stirred in 2 mL EtOH containing 0.6 mL NH 4 0H solution for 16 hours. Volatiles were removed, and purification of the mixture was carried out via preparative-HPLC (Cl 8 eluting with a gradient of ACN/H 2 O containing 0.1% TFA) afforded ethyl 2 83 methyl-2-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]propanoate trifluoroacetate salt (13 mg, 17%): 'H NMR (300 MHz, d 6 -DMSO): & 12.03 (s, I H), 8.67 (s, I H), 8.3 1-8.19 (m, 2H), 7.59 (t, 1H), 7.48 (d, IH), 6.98 (br s, IH), 4.10 (q, 2H), 1.84 (s, 6H), 1.12 (t, 3H); MS(ES):299(M+1) and 2 methyl-2-[4-(IH-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]propanoic acid (27 mg, 53%): 'H NMR 5 (300 MHz, d 6 -DMSO): & 12.04 (s, I H), 8.64 (s, 1 H), 8.26 (s, 2H), 7.59 (br s, I H), 7.48 (d, I H), 6.99 (br s, 1H), 1.83 (s, 6H); MS(ES):271(M+H). Example 56: 2-Methyl-2-[4-(1H-pyrrolo[2,3-blpyridin-4-yl)-1H-pyrazol-1-yllpropanamide 0 N-N N1H 2

I

N N 0 H A mixture of 2-methyl-2-[4-(IH-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]propanoic acid (23 mg, 0.000085 mol) and N,N-carbonyldiimidazole (CD1) (21 mg, 0.00013 mol) in 2 mL of DMF was stirred for 3 hours. An excess of solid NH 4 C1 and TEA was added to the mixture and this was stirred for 3 hours. The majority of solvent was removed in vacuo, and the crude residue was purified 5 by preparative-HPLC (C 18 eluting with a gradient of ACN/H 2 O containing 0.1% TFA) followed by re-purification via preparative-HPLC (C18 eluting with a gradient of ACN/H4 2 0 containing 0.15% NH4OH) to afford 2-methyl-2-[4-(1H-pyrrolo[2,3-b]pyridin-4-y)-1H-pyrazol--1-yl]propanamide (6 mg, 26%). 'H NMR (400 MHz, d6-DMSO): & 11.63 (s, 1H), 8.44 (s, 1H), 8.16 (s, I H), 8.14 (s, IH), 7.47 (t, I H), 7.29 (d, 1 H), 7.21 (s, IH), 6.93 (s, I H), 6.80 (dd, 1 H), 1.77 (s, 6H); MS(ES):270(M+1). 20 Example 57: Ethyl 3-methyl-3-[4-(IH-pyrrolo[2,3-blpyridin-4-yl)-1H-pyrazol-1-yllbutanoate trifluoroacetate salt j OEt N-N N N H -TFA Step 1. Ethyl 3-methyl-3-[4-(1-[2-(rimethylsilyl)ethoxy]methyl-IH-pyrrolo[2.3-b]pyridin-4-yl)-JH 25 pyrazol-i-yl]butanoate 84 4-(1H-Pyrazol-4-yl)-1-[2-(trimethylsilyl)ethoxylmethyl-1H-pyrrolo[2,3-b]pyridine (220 mg, 0.0006996 mol) and 3-methyl-2-butenoic acid ethyl ester (292 pL, 0.00210 mol) were dissolved in DMF (10 mL). Cesium carbonate (912 mg, 0.00280 mol) was added and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water, and the product 5 was extracted with MTBE several times. The combined extracts were dried over sodium sulfate and concentrated. The crude residue was purified by flash column chromatography (0-60% EtOAc/Hexanes) to afford ethyl 3-methyl-3-[4-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3 b]pyridin-4-yl)-IH-pyrazol-1-yl]butanoate (244 mg, 79%). 'H NMR (300 MHz, CDC 3 ): & 8.37 (d, IH), 8.11 (s, IH), 8.09 (s, IH), 7.45 (d, IH), 7.24 (d, 1H), 6.79 (d, 1H), 5.77 (s, 2H), 4.10 (q, 2H), 0 3.62 (dd, 2H), 3.04 (s, 2H), 1.88 (s, 6H), 1.20 (t, 3H), 0.98 (dd, 2H), 0.00 (s, 91); MS(ES):443(M+1). Step 2. Ethyl 3-methyl-3-[4-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo(2,3-b]pyridin-4-yl)-lH pyrazol-1-yl]butanoate (20 mg, 0.0000452 mol) was stirred in I mL TFA for 1 hour. Then excess 5 TFA was removed in vacuo. The residue was stirred for 16 hours in 2 mL MeOH containing 0.5 mL

NH

4 0H. Evaporation of the volatiles was followed by purification by preparative-HPLC (C18 eluting with a gradient of ACN/.H 2 0 containing 0.1% TFA) to afford ethyl 3-methyl-3-[4-(1H-pyrrolo[2,3-b] pyridin-4-yl)-IH-pyrazol-1-yl]butanoate, trifluoroacetate salt (5 mg, 26%). '1H NMR (400 MHz, d 6 DMSO): S 12.19 (s, IH), 8.61 (br s, IH), 8.34-8.22 (br m, 2H), 7.62 (br s, 1H), 7.51 (br d, 1H), 7.02 ,0 (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-Methyl-3-[4-(1H-pyrrolo(2,3-bpyridin-4-yl)-1H-pyrazol-1-ylbutan-1-ol trifluoroacetate salt OH N-N N N H -TFA 25 To a solution of ethyl 3-methyl-3-[4-(1-[2-(trimethylsilyl)ethoxy]methyl-IH-pyrrolo[2,3-b] pyridin-4-yl)-IH-pyrazol-1-y1]butanoate (213 mg, 0.000481 mol) in THF (5 mL, 0.0616 mol) at -78 "C was added diisobutylaluminum 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 *C. To the mixture at -10 *C was carefully added K/Na tartrate tetrahydrate in water. The mixture was stirred for 30 2 hours, then was extracted with three portions of ethyl acetate. The combined organic extracts were washed with two portions of water and one portion of brine, then dried over sodium sulfate, filtered 85 and concentrated to afford 3-methyl-3-[4-(1-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b] pyridin-4-yl)-1H-pyrazol-1-yl]butan-1-o (185 mg, 96%), which was used without further purification. A portion of the alcohol so obtained (15 mg, 0.000037 mol) was stirred in TFA (1 miL) for 2 hours. The TFA was removed in vacuo and the residue was stirred with 2 mL MeOH containing 0.5 mL NH 4 0H for 16 hours. Volatiles were removed and the product was purified by preparative HPLC (C18 eluting with a gradient of ACN/H 2 0 containing 0.1% TFA) to afford 3-methyl-3-[4-(lH pyrrolo[2,3-b]pyridin-4-yl)-IH-pyrazol-1-yl]butan-1-ol as the trifluoroacetate salt (8.0 mg, 57%). 'H NMR (300 MHz, 4-DMSO): & 12.17 (s, 11-), 8.58 (br s, 1H), 8.32-8.22 (br m, 21), 7.62 (br s, 11H), 7.53 (br d, 1H), 7.03 (br s, 1H), 3.25 (t, 2H), 2.07 (t, 211), 1.62 (s, 6H); MS(ES):271(M+1). ) Example 59: 4-Methyl-4-14-(IH-pyrrolo[2,3-bpyridin-4-yl)-1H-pyrazol-1-yl]pentanenitrile trifluoroacetate salt CN N-N N N H TFA Step 1. 4-Methyl-4-[4-(J-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-JH 5 pyrazol-1-yl]pentanenitrile TEA (38.0 pL, 0.000273 mol) and methanesulfonyl chloride (21.1 gL, 0.000273 mol) were added sequentially to a solution of 3-methyl-3-[4-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3 b]pyridin-4.yl)-lH-pyrazol-l-yl)butan-1-ol (prepared as in Example 58) (81 mg, 0.00020 mol) in DCM (4 mL, 0.05 mol) at 00 C. The reaction mixture' was held at this temperature for 1.5 hours, then 20 was quenched by the addition of water. The reaction mixture was extracted with DCM four times. The combined extracts were dried over sodium sulfate, filtered and concentrated to afford crude 3-methyl 3-[4-(1-[2-(trimethylsilyl)ethoxy]methy-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-pyrazol-I -yl]butyl methanesulfonate (87 mg). MS(ES):479(M+1). A mixture of 3-methyl-3-[4-(l-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4 25- yl)-1H-pyrazol-1-yl]butyl methanesulfonate (42 mg, 0.000088 mol) and potassium cyanide (46 mg, 0.000702 mol) in DMF (1 mL) was heated in the microwave reactor for 30 min at 125 *C followed by additional 30 min at 135 *C. The mixture was then diluted with water, and the product was extracted with three portions of MTBE. The combined extracts were dried over sodium sulfate, filtered and concentrated to give 61 mg of crude 4-methyl-4-[4-(1 -[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo 30 (2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]pentanenitrile, which was used without further purification. MS(ES):410(M+1). 86 Step 2. 4-Methyl-4-[4-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-blpyridin-4-yl)-1H pyrazol-1-yl]pentanenitrile (57 mg, 0.00014 mol) was stirred in DCM (4 ml) and TFA (1 mL) for 2 hours. The solvents were removed in vacuo and the residue was stirred in 2 mL MeOH containing 0.2 5 mL ethylenediamine for 16 hours. The volatiles were evaporated and the product was isolated from the reaction mixture by preparative-HPLC (C 18 eluting with a gradient of ACN/H 2 0 containing 0.1% TFA) affording 4-methyl-4-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]pentanenitrile as the trifluoroacetate salt (10 mg, 18%). 'H NMR (400 MHz, d 6 -DMSO): 12.09 (s, IH), 8.58 (s, IH), 8.29 (s, 1H), 8.25 (d, IH), 7.60 (t, 1H), 7.48 (d, 1H), 7.00 (br s, IH), 2.33-2.21 (m, 4H), 1.61 (s, 6H); 0 MS(ES):280(M+I). Example 60: 4-Methyl-4-14-(IH-pyrrolo(2,3-b]pyridin-4-yl)-1H-pyrazol-1-yllpentanamide trifluoroacetate salt

NH

2 O N-N N N H TFA 5 The crude 4-methyl-4-[4-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl) 1H-pyrazol-1-yl]pentanenitrile (36 mg, 0.000088 mol, see preparation in Example 59), was stirred in TFA (2 nL) for 1 hour. The mixture was concentrated to remove excess TFA, and the resulting residue was stirred in 2 mL methanol containing 0.5 mL NH40H for 16 hours. The product was purified by preparative-HPLC (C18 eluting with a gradient of ACN/H 2 0 containing 0.1% TFA) to 20 afford 4-methyl-4-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]pentananiide as the trifluoro acetate salt (21 mg, 58%). 'H NMR (400 MHz, d 6 -DMSO): & 12.18 (s, IH), 8.60 (s, I H), 8.33-8.21 (m, 2H), 7.62 (br s, 1H), 7.53 (d, IH), 7.22 (br s, 1H), 7.04 (br s, IH), 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). 25 Example 61: (3S)-3-[4-(1H-Pyrrolol2,3-b]pyridin-4-yl)-1H-pyrazol-i-ylJbutanenitrile trifluoro acetate salt , AND (3R)-3-[4-(1H-Pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]butanenitrile trifluoroacetate salt 87 CN 1 CN N-N N-N TFA / TFA N N N N H and H To a solution of 4-(1H-pyrazol-4-yl)-1-[2-(trimethylsilyl)ethoxy)methyl-IH-pyrrolo[2,3 b]pyridine (0.050 g, 0.00016 mol) in ACN were added 2-butenenitrile (0.014 mL, 0.00017 mol) and 5 DBU (0.029 mL, 0.00020 mol). The resulting mixture was stirred for 16 hours. Then the volatiles were evaporated and the residue was dissolved in ethyl acetate. The resulting solution was washed successively with 1.0 N HCI, 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 0 hour. Then excess TFA was evaporated and the residue was then stirred 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 ACN/H 2 0 containing 0.1% TFA) to afford 3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]butanenitrile trifluoroacetate salt (35 mg, 61%). 'H NMR (300 MHz, d 6 -DMSO): 8 12.16 (s, IH), 8.73 (s, IH), 8.32 (s, I H), 8.28 5 (d, IH), 7.65-7.61 (m, 1H), 7.48 (d, 1H), 6.99 (d, 1H), 4.86 (q, 111), 3.17 (d, 2H), 1.57 (d, 3H); MS(ES):252(M+l). 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 ct,-unsaturated nitriles were prepared by procedures analogous to the following, illustrated for (2E)- and (2Z) 20 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 cyanomethylphosphonate (4.10 mL, 0.025 mol) in THE (30 mL) dropwise. The bath was removed and the solution was allowed to warm to room temperature. After reaching room temperature, 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 25 and stir overnight. The mixture was diluted with ethyl acetate and water. The layers were separated and the aqueous layer was extracted with three portions of ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. This afforded 1.6 g of a crude mixture containing both (2E)- and (2Z)-hexenenitrile, which was used without further purification in the subsequent alkylation step. 'H NMR (400 MHz, CDC1 3 ): & 6.72 (dt, IH trans 30 olefin), 6.48 (dt, IH cis olefin), 5.34 (dt, 1H trans olefin), 5.31-5.30 (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: 88 A) The separation was performed on the SEM-protected intermediate after silica gel chromatography (ethyl acetate/hexanes) by preparative chiral HPLC (OD-H column, eluting with 15% ethanol in hexanes); B) The separation was performed on the deprotected free base by preparative chiral HPLC 5 (OD-H column, eluting with 15% ethanol 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 column, eluting with 10% ethanol in hexanes); D) The separation was performed on the SEM-protected intermediate after silica gel 0 chromatography (ethyl acetate/hexanes) by preparative chiral HPLC (AD-H column, eluting with 15% ethanol in hexanes); E) The separation was performed on the SEM-protected intermediate after silica gel chromatography (ethyl acetate/hexanes) by preparative chiral HPLC (OD-H column, eluting with 20% ethanol in hexanes; or 5 F) The separation was performed on the SEM-protected intermediate after silica gel chromatography (ethyl acetate/hexanes) by preparative chiral HPLC (OD-H column, eluting with 30% ethanol in hexanes. An OD-H column refers to Chiralcel OD-H from Chiral Technologies, Inc 3x25 cm, 5 pm. An AD-H column refers to ChiralPak AD-H from Chiral Technologies, Inc. 2x25 cm, 5 gm. The results are summarized for compounds in Table 4 below. R CN N-N N N 20 H Table 4 MS Method of Ex. Name R (ES) preparation No. (M+1) and chiral separation 3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H 62 pyrazol-1-yl]propanenitrile HI 238 Ex. 61 trifluoroacetate salt (3S)-3-[4-(lH-pyrrolo[2,3-b]pyridin-4 yl)-1H-pyrazol-1-yl]hexanenitrile trifluroracetate salt Ex. 61 63 and Pr 280 Method B (3R)-3-[4-(IH-pyrrolo[2,3-b]pyridin-4 yl)-1H-pyrazol-1-yl]hexanenitrile trifluroracetate salt 89 (3S)-3-cyclopentyl-3-[4-(1 H-pyrrolo[2,3 b]pyridin-4-yl)-1H-pyrazol-1 -yl] propanenitrile trifluoroacetate salt 64 and 306 ex. 6 (3R)-3-cyclopentyl-3-[4-(1 H-pyrrolo[2,3- - Method C b]pyridin-4-yl)-1H-pyrazol- -yl] propanenitrile trifluoroacetate salt (3S)-3-cyclohexyl-3-[4-(lH-pyrrolo[2,3 b]pyridin-4-yl)-1H-pyrazol-l -yl] propanenitrile Ex. 61 64a and 320 ex. 6 (3R)-3-cyclohexyl-3-[4-(lH-pyrrolo(2,3- MethodD b]pyridin-4-yl)- IH-pyrazol- I-yl] propanenitrile Exam ple 65: (3R)-3-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-IH-pyrazol-1-ylJhexanenitrile trifluoroacetate salt and 5 (3S)-3-14-(7H-Pyrrolo[2, 3 -dlpyrimidin-4-yl)-1H-pyrazol-1-yljhexanenitrile trifluoroacetate salt CN ON N-N N-N TFA i TFA N'N \ N '- \ N N N N N' H and N Step 1. 4-Chloro- 7 -[2-(trimethylsilyl)ethoxy]methyl- 7 H-pyrrolo[2,3-d]pyrimidine To a solution of 4-chloropyrrolo[2,3-d]pyrimidine (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 10 was stirred for an additional 45 minutes followed by a dropwise addition of 0-(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 acetate. 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-7-[2 15 (trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (1.40 g, 88%). 'H NMR (400 MHz, CDCl 3 ): § 8.71 (s, 1H), 7.46 (d, 1H), 6.72 (d, 1H), 5.71 (s, 2H), 3.59 (dd, 2H), 0.97 (dd, 21), 0.00 (s, 91H); MS(ES):284(M+1). Step 2. 4-(JH-Pyrazol-4-yI)- 7

-[

2 -(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-dipyrimidine 20 To a mixture of 4 -chloro-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (1.4 g, 0.0049 mol) and 4 -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.4 g, 0.0074 90 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 nitrogen for 15 minutes. Tetrakis(triphenyl phosphine)palladium(0) (0.41 g, 0.00036 mol) was added and the reaction was heated to 125 *C for 30 min. The mixture was allowed to cool then diluted with ethyl acetate. The diluted reaction mixture 5 was washed with water, brine, dried over Na 2

SO

4 and concentrated to give a solution in a small volume of DMF (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 Na 2

SO

4 , and concentrated in vacuo to afford a yellow solid. The product was triturated with ethyl ether to yield 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3 0 d]pyrimidine as a white powder which was dried under vacuum (1g, 60%). 'H NMR (300 MHz, CDCl 3 ): & 10.80 (br s, IH), 8.93 (s, 1H), 8.46 (s, 2H), 7.46 (d, IH), 6.88 (d, I H), 5.73 (s, 2H), 3.61 (dd, 2H), 0.98 (dd, 2H), 0.00 (s, 9H); MS(ES):316(M+1). Step 3. 5 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 (I mL, 0.02 mol) was added hex-2-enenitrile (0.100 g, 0.00105 mol) (as a mixture of cis and trans isomers), followed by DBU(60 giL, 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 .0 Na 2

SO

4 and concentrated. The crude residue 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 preparative-HPLC (C18 eluting with a gradient of ACN/H 2 0 containing 0.1% TFA) to 25 afford 3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-IH-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. 'H NMR (300 MHz, CD 3 OD): 8 8.93 (s, 1H), 8.88 (s, IH), 8.52 (s, IH), 7.85 (d, 1H), 7.28 (d, IH), 4.87-4.77 (m, 1H), 3.26-3.05 (m, 2H), 2.20-2.05 (m, 1H), 2.00-1.86 (m, IH), 1.40-1.10 (m, 2H), 0.95 (t, 3H); MS(ES):281(M+1). 30 Example 67: (3R)- and (3S)-3-Cyclopentyl-3-{4-(7H-pyrrolo[2,3-djpyrimidin-4-yl)-IH-pyrazol 1-yllpropanenitrile 91 CN /CN N-N N-N and N \N \ N N N N . H H Step I. (2E)- and ( 2 Z)-3-Cyclopentylacrylonitrile To a solution of 1.0 M potassium tert-butoxide in THF (235 mL) at 0 "C was added dropwise a solution of diethyl cyanomethylphosphonate (39.9 mL, 0.246 mol) in THF (300 mL). The cold bath 5 was removed and the reaction was warmed to room temperature followed by recooling to 0 "C, 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 mixture 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 0 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%). 'H NMR (400 MHz, CDC 3 ): 8 6.69 (dd, IH, trans olefin), 6.37 (t, IH, cis olefin), 5.29 (dd, IH, trans olefin), 5.20 (d, 1 H, cis olefin), 3.07-2.95 (in, IH, cis product), 2.64-2.52 (m, IH, trans product), 1.98 1.26 (m, 16H). 5 Step 2. (3R)- and ( 3

S)-

3 -Cyclopentyl-3-[4-(7-[2-(rimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d] pyrimidin-4-yi)-JH-pyrazol-1-ylpropanenitrile To a solution of 4-(IH-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 20 mol) (as a mixture of cis and trans isomers), followed by DBU (15 mL, 0.10 mol). The resulting mixture was stirred at room temperature 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, filtered and concentrated. The crude product was purified by silica gel 25 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 separately in the next step to generate their corresponding final product. The final products (see Step 3) stemming from each of the separated enantiomers were found to be active JAK inhibitors; 30 however, the final product stemming from the second peak to elute from the preparative-HPLC was more active than its enantiomer. 92 'H NMR (300 MHz, CDCL 3 ): 8 8.85 (s, I1), 8.32 (s, 2H), 7.39 (d, IH), 6.80 (d, 1H), 5.68 (s, 2H), 4.26 (dt, 1H), 3.54 (t, 2H), 3.14 (dd, 1H), 2.95 (dd, 1H), 2.67-2.50 (m, 111), 2.03-1.88 (m, 1H), 1.80 1.15 (m, 7H), 0.92 (t, 21), -0.06 (s, 9H); MS(ES):437 (M+ 1). Step 3. To a solution of 3-cyclopentyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d] pyrimidin-4-yl)-IH-pyrazol-1-yl)propanenitrile (6.5 g, 0.015 mol, R or S enantiomer as isolated above) in DCM (40 mL) was added TFA (16 mL) and this was stirred for 6 hours. The solvent and TFA were removed in vacuo. The residue was dissolved in DCM and concentrated using a rotary ) evaporator two further times to remove as much as possible of the TFA. Following this, the residue was stirred with ethylenediamine (4 mL, 0.06 mol) in methanol (30 mL) overnight. The solvent was removed in vacuo, water was added and the product was extracted into three portions of ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate, decanted and concentrated to afford the crude product which was purified by flash column chromatography (eluting with a 5 gradient of methanol/DCM). The resulting mixture was further purified by preparative-HPLC/MS (C18 eluting with a gradient of ACN/H 2 0 containing 0.15% NH 4 0H) to afford product (2.68 g, 58%). 'H NMR (400 MHz, D 6 -dmso): 5 12.11 (br s, 1H), 8.80 (s, 11), 8.67 (s, 11), 8.37 (s, 1H), 7.60 (d, IH), 6.98 (d, 1H), 4.53 (dt, 11), 3.27 (dd, 1H), 3.19 (dd, 11), 2.48-2.36 (m, 1H), 1.86-1.76 (m, 1H), 1.68-1.13 (m, 7H); MS(ES):307(M+I). 0 Additional analogs provided in the following Tables were prepared by procedures analogous to those described in, for example, Examples 61 and 65, using different starting materials such as different cA-unsaturated nitriles in Step 3. Isolation of the enantiomers in substantially pure form was achieved by the indicated chiral separation method described above (A-F) preceding Table 4. Where the product was isolated as the free amine, the product following deprotection was purified by 25 preparative-HPLC (C18 eluting with a gradient of ACN/H 2 0 containing 0.15% NH 4 0H) instead of preparative-HPLC (C 18 eluting with a gradient of ACN/H20 containing 0.1% TFA). This is referred to as "modification G". The results are summarized in Table 5 according to the following structure: R' CN N-N R" N \ N N H 30 Table 5 93 Ex. MS Metbod of No. Name R', R" (ES) preparation and (3R)-3-[4-(7H-pyrrolo[2,3-dlpyrimidin- brlspato 4-yl)-l H-pyrazol-1 -yl]butanenitrile trifluoroacetate salt Example 65, 66 and MH253 Mto (3S)-3-[4-(7H-pyrrolo[2,3-d~pyrimidin- MHMto 4-yl)-l H-pyrazol-l -yl]butanenitrile trifluoroacetate salt (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo [2,3-djpyrimidin-4-yl)-lH-py-azol-I . yl]prapanenitrile trifluoroacetate salt 67 and 307 Example 67 (3 S)-3-cyclopentyl-3-[4-(7H-pyrrolo [2,3-d~pyrimidin-4-yl)-lH-pyrazol4 I__ yllpropanenitrile trifluoroacetate salt _____________________ 2-methyl-3 -r4-(7H-pyrolo[2,3- -Example 65, 68 d]pyrimidin-4-yl)-l H-pyrazol-lI - H, Me 253 Not separated ___ yllpropanenitrile trifluoroacetate salt _______ (3R)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin 4-yl)-l H-pyrazol- 1 -yl]pentanenitrile Example 65, 68a and Et, H 267 modification G, (3 S)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin- Method E ___ 4-yl)-l H-pyrazol-1 -yl]pentanenitrile _______ (3R>-5-metbyl-3 -[4-(7H-pyrrolo[2,3 d]pyrimidin-4-yl)-l H-pyrazol- 1 yl]hexanenit-ile Example 65, 68b and 295 modification G, (3S)-5-methyl-3-[4-(7H-pyrrolo[2,3- ' HMethod A d]pyrimidin-4-yl)-1 H-pyrazol- 1 Yflhexanenitrile _______ ________ (3R)-3-cyclohexyl-3-[4-(7H pyrrolo[2,3-d]pyrimidin-4-yl)-l H pyrazol- I -yllpropanenitrile Example 65, 68c and xKJH321 modification G, (3S)-3-cyclahexyl-3-[4-(7H- Method A pyrrolo[2,3-d]pyrimidin-4-yl)-l

H

pyrazol- I -yl]propanenitrile _______________ (3R)-4-cyclopropyl-3-[4-(7H pyrr-olo[2,3-d]pyrimidin-4-yl)-l

H

pyrazol-l -yl]butanenitrile Example 65, 68d and y279 modification G, (3S)-4-cyclopropyl-3 [-(7H- -[H Method F pyrrolo[2,3-d]pyrimidin-4-yl)- I H pyrazol-I -yllbutanenitrile _____________________ Example 69: 4-1 ]-(S--ehluy]I-yaol-l-Hproo23dprm dine trifluoroacetate salt and 5 1[I)lMtyluyjl-yaol4y)7-yrlo23dprmdn trifluoroacetate salt 94 N-N N-N / TFA / TFA NN \ N'N \ N N N N H and H 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 DMF (2 mL, 0.02 mol) was cooled in an ice bath and to this was added sodium hydride (0.013 g, 0.00032 mol). The resulting mixture was stirred for 10 minutes, 5 followed by an addition of 2-bromopentane (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 2-bromopentane (0.015 mL, 0.00012 mol) was added. After 45 minutes, water was added and the reaction mixture was extracted with three portions of ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was stirred with 0 TFA (3 mL, 0.04 mol) and DCM (3 mL, 0.05 mol) for 3.5 hours, then the solvent was removed in vacuo. The residue was then stirred with NH 4 OH (1.5 mL) in MeOH (4 mL) for 16 hours. The solvent was evaporated and the product was purified by preparative-HPLC (C 18 eluting with a gradient of

ACN/H

2 0 containing 0.1% TFA) to afford 4-[1-(l-methylbutyl)-1H-pyrazol-4-yl]-7H-pyrrolo[2,3 djpyrimidine as the trifluoroacetate salt (25 mg, 44%). 'H NMR (300 MHz, CD 3 0D): 8 8.83 (s, IH), 5 8.75 (s, 1H), 8.43 (s, 1H), 7.77 (d, 1H), 7.24 (d, IH), 4.63-4.50 (m, IH), 2.07-1.91 (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 enantiomers in substantially pure form was achieved by separation of the racemic free base (isolated by flash column chromatography after deprotection, eluting with a MeOH/DCM gradient) using HPLC (OD-H, eluting with 5% isopropanol/hexanes). 20 Example 69a: 4-Methyl-4-14-(7H-pyrrolo[2,3-dlpyrimidin-4-yl)-1H-pyrazol-1-ylpentanenitrile CN N-N N N N H Step 1. Ethyl 3-methyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-JH pyrazol-1-ylfbutanoate 25 A solution of 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d] pyrimidine (12.1 g, 0.0384 mol), 2-butenoic acid, 3-methyl-, ethyl ester (16.0 mL, 0.115 mol) and DBU (14.3 mL, 0.0959 mol) in ACN (100 mL) was heated at reflux for 3.5 hours. The solvent was 95 removed in vacuo. The residue 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%). 5 'H NIR (400 MHz, CDC1 3 ): 8. 8.83 (s, IH), 8.36 (s, IH), 8.27 (s, IH), 7.37 (d, IH), 6.80 (d, IH), 5.66 (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-(trimethylsilyl)ethoxyJmethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-JH 0 pyrazo1-1-ylJbutan-1-o1 To a solution of ethyl 3-methyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d] pyrimidin-4-yl)-IH-pyrazol-1-yl]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 5 potassium sodium tartrate tetrahydrate and water. The mixture was stirred for 1 hour, then was extracted with ethyl acetate. The extracts were washed with water and brine, then dried with sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash column chromatography to yield the desired product (13.8 g, 99%). 'H NMR (300 MHz, CDC 3 ): 8 8.83 (s, 1H), 8.38 (s, 1H), 8.26 (s, 111), 7.38 (d, 111), 6.80 (d, 11H), ,0 5.67 (s, 2H), 3.65 (dd, 2H), 3.54 (dd, 2H), 2.21 (t, 2H), 1.72 (s, 61H), 0.91 (dd, 2H), -0.07 (s, 9H); MS(ES):402(M+1). Step 3. 3-Methyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-JH-pyrazol-1-ylfbutan-i-of A solution of 3-methyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin 25 4-yl)-1H-pyrazol-l -yl]butan-l-ol (13.8 g, 0.0344 mol) in TFA (20 mL) was stirred for I 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 several portions of 15%

IPA/CH

2 C1 2 . The combined extracts were dried over sodium sulfate and concentrated in vacuo to give 30 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, CDCl 3 ): . 9.99 (s, 1H), 8.83 (s, 1 H), 8.39 (s, 1H), 8.28 (s, 1 H), 7.38 (dd, I H), 6.80 (dd, 1 H), 3.66 (t, 21), 2.72 (br s, 1H), 2.22 (t, 2H), 1.74 (s, 6H); MS(ES):272(M+1). 35 Step 4. 3-Methyl-3-[4-(7H-pyrrolo[2,3-dpyrimidin-4-y)-1H-pyrazol-1-ygbutyl methanesulfonate 96 A solution of 3-methyl-3-[4-(7H-pyr-rolo[2,3-d]pyrimidin-4-yl)-H-pyrazol-1-yl]butan-l-ol (6.61 g, 0.0244 mol) in DCM (300 mL) at 0 *C was treated 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 chromatography 5 to afford the desired product (4.9 g, 57%). 'H NMR (400 MHz, d 6 -dmso): 12.45 (s, 1H), 9.50 (s, IH), 9.35 (s, 1H), 8.83 (s, I H), 7.79 (dd, I H), 7.11 (dd, IH), 4.75 (t, 1H), 3.30 (s, 3H), 2.85 (t, 1H), 1.75 (s, 6H); MS(ES):254(M-CH 3

SO

3 H+1). Step 5. 4-Methyl-4-[4-(7H-pyrrolo[2,3-d pyrimidin-4-yl)- H-pyrazol-1-yljpentanenitrile 3 3-methyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1 H-pyrazol-1 -yl)butyl methanesulfonate (2.97 g, 8.50 mmol), DMF (120 mL) and sodium cyanide (6.21 g, 0.127 mol) were distributed evenly into six 20 mL microwavable vessels, each of which was heated in the microwave reactor for 4000 seconds at 125 *C. The contents of the vials were combined and were diluted with 400 mL water and extracted with five 150 mL portions of ethyl acetate. The combined extracts were dried over 5 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%). 'H NMR (400 MHz, CDCl 3 ): 9.52 (br s, 1 H), 8.83 (s, 1 H), 8.34 (s, I H), 8.29 (s, 11H), 7.39 (dd, I H), 6.81 (dd, IH), 2.38 (dd, 211), 2.16 (dd, 2H), 1.73 (s, 6H); MS(ES):281(M+1). The analogs in Table 5a were prepared according to the above method described for Example 0 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 5a Ex. MS (ES) No. Structure Name CN N-N 3-1-[4-(7H-pyrrolo[2,3-d] 69b pyrimidin-4-yl)-1H-pyrazol-1 - 279 N yl]cyclopropylpropanenitrile N N H CN N-N (4S)- and (4R)-4-[4(7H 69c pyrrolo[2,3-d]pyrimidin-4-yl)- 267 N \ 1H-pyrazol-1-yl]pentanenitrile N N H 97 Example 69d: 3-Methyl-3-[4-(7H-pyrrolo[2,3-dl pyrimidin-4-yl)-IH-pyrazol-1-yllbutanenitrile CN N-N N N N H 5 Step 1. Senecionitrile To a solution of 1.0 M potassium tert-butoxide in THF (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 re-cooled to 3 0 *C and acetone (0.20 mL, 2.81 mmol) was added dropwise. The cooling bath was then removed and the reaction was allowed to warm to room temperature and stir overnight. 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%). 5 'H NMR (300 MHz, CDC 3 ): § 5.10 (br s, I H), 2.05 (s, 3H), 1.92 (s, 3H). Step 2. 3-Methyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1 -yl]butanenitrile To a solution of 4-(1H-pyrazol- 4 -yl)-7-[2-(trimethylsilyl)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, 0 1.37 mmol), followed by DBU (200 pL, 0.002 mol) and the resulting mixture was heated to 60 "C for 23 hours. The mixture was cooled to room temperature and the ACN was evaporated. The mixture was diluted with ethyl acetate and washed with dilute HCI and brine. The organic solution was dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (ethyl acetate/hexanes) afforded the desired product. 5 'H NMR (300 MHz, d 6 -dmso): & 8.83 (s, 1H), 8.38 (s, I H), 8.28 (s, I H), 7.39 (d, IH), 6.80 (d, IH), 5.66 (s, 2H), 3.54 (dd, 2H), 3.08 (s, 2H), 1.84 (s, 6H), 0.91 (dd, 2H), -0.07 (s, 91H); MS(ES):397(M+l). To a solution 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 ambient temperature 0 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 98 and the product was purified by preparative-HPLC/MS (CI8 column eluting with a gradient of

ACN/H

2 0 containing 0.15% NH 4 01) to afford the product (25 mg, 14%). 'H NMR (300 MI-Iz, d 6 -dmso): & 12.08 (s, IH), 8.68 (s, 2H), 8.39 (s, 1H), 7.59 (d, I H), 7.05 (d, I H), 3.32 (s, 2H), 1.73 (s, 6H); MS(ES):267(M+1). 5 Examples 69e and 69f in Table 5b were prepared 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. 0 Table 5b No. Structure Name M(E) CN N-N 3-ethyl-3-[4-(7H-pyrrolo[2,3 69e d]pyrimidin-4-yl)-1 H-pyrazol- 295 N~I -yl)pentanenitrile N NCN N-N 1-[4-(7H-pyrrolo[2,3-d] 69f pyrimidin-4-yl)-l H-pyrazol-1- 265 yl]cyclopropylacetonitrile N I N Additional analogs were prepared by procedures analogous to those described in Example 69, using different starting materials such as alternative bromide or mesylate compounds for the nucleophilic substitution step. Where the free amine was obtained as the product, the product was 15 purified after deprotection either by silica gel chromatography (eluting with 5% methanol in DCM) or by preparative-HPLC (CI 8 eluting with a gradient of ACN/H 2 0 containing 0.15% NH40H). The results are summarized for compounds listed in Table 6. (Y)n-Z N-N' N \ N N H 20 Table 6 99 Ex. Nm I No.Name (Y)Z (MS+) 4-1-[(2R)-pyrrolidin-2-ylmethyl]-lH 70 pyrazol-4-yl-7H-pyrrolo[2,3-d]- 269 pyrimidine NH 4-(1-[(2R)-1 -(methylsulfonyl)pyrrolidin- mu 71 2-yl]methyl-1H-pyrazol-4-72yl)-7H- N / 347 pyrrolo[2,3-d]pyrimidine

'SO

2 Me ethyl 2-methyl-2-[4-(7H-pyrrolo[2,3-d]- EtO 73 pyrimidin-4-yl)-H-pyrazol-1-yl]- EtO / 300 propanoate trifluoroacetate salt Example 74: (2Z)-3-Cyclopentyl-3-[4-(7H-pyrrolo[2,3-djpyrimidin-4-yl)-1H-pyrazol-1-yll acrylonitrile N-N CN NN \ N N H 5 Step 1. 3-Cyclopentylprop-2-ynenitrile To a solution of cyclopentylacetylene (0.50 g, 5.3 mmol) in THF (5 mL) at -78 *C 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 reaction was warmed to room temperature. Into the reaction mixture was poured 6 N NaOH, and the mixture was stirred for 5 10 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, CDCl 3 ): & 2.81-2.68 (m, 1H), 2.07-1.54 (m, 8H). Step 2. ( 2

Z)-

3 -Cyclopentyl-3-[4-(7-[2-(rimethylsilyl)ethoxy]methyl-7H-pyrrolo(2,3-d]pyrimidin-4 15 yI)-JH-pyrazol-1-yl]acrylonitrile To a mixture of 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d].

pyrimidine (0.40 g, 1.2 mmol) and 3-cyclopentylprop-2-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 extracted with three volumes of 100 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%). 'H NMR (400 MHz, CDC 3 ): . 8.98 (s, 11H), 8.87 (s, 1-H), 8.46 (s, IH), 7.42 (d, IH), 6.84 (d, 11H), 5 5.67 (s, 2H), 5.21 (s, 1Hl), 3.64-3.55 (in, 1H), 3.53 (t, 2H), 2.13-2.01 (m, 2H), 1.83-1.66 (in, 4H), 1.57-1.46 (in, 2H), 0.91 (t, 2H), -0.07 (s, 9H); MS(ES):435(M+1). Step 3. (2Z)-3-Cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yljacrylonitrile A solution of ( 2

Z)-

3 -cyclopentyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-] 10 pyrimidin-4-yl)--H-pyrazol-1-yl]acrylonitrile (0.030 g, 0.069 mol) in DCM (3 mL) and TFA (2 mL) was stirred for I hour. The solvents were removed in vacuo and the product was stirred with THF (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 dropwise addition of conc. HCI. The product was extracted with ethyl acetate. The combined organics were dried over sodium sulfate, filtered and concentrated in 5 vacuo. The crude residue was purified by preparative-HyPLCMS (C18 column eluting with a gradient of ACN/H 2 0 containing 0.15% NH 4 OH) to afford the desired product (16 mg, 76%). 'H NMR (400 MHz, ds-dmso): 8 9.08 (s, 1H), 8.74 (s, 1 H), 8.63 (s, IH), 7.66 (d, 1H), 7.05 (d, I H), 5.82 (d, 1H), 3.62-3.54 (in, 1H), 2.00-1.90 (in, 21), 1.76-1.48 (in, 6H); MS(ES):305(M+1). 0 Example 75: 3 -Cyclopentylidene-3-[4-(7H-pyrrolo[2,3-dpyrimidin-4-yl)-H-pyrazol-1-yl] propanenitrile CN N-N N's N N H Step 1. 3-Cyclopentylidene-3-[4-(7-[2-(trimethylsilyl)ethoxy methyl-7H-pyrrolo[2,3-d]pyrimidin-4 yl)-)H-pyrazol-1-yl]propanenitrile 5 To a suspension of 3 -cyclopentylprop-2-ynenitrile (-.4 g, 0.003 mol) in ACN (10 mL) was added 4-(lH-pyrazol-4-y))-7-[2-(trimethylsilyl)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 reaction 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 0 with dilute HC! and brine, were dried over sodium sulfate, filtered and concentrated in vacuo. The 101 crude residue was purified by flash column chromatography (ethyl acetate/hexanes) to yield the desired product (540 mg, 74%). 'H NMR (300 MHz, CDC1 3 ): S. 8.85 (s, 1H), 8.36 (s, 1H), 8.35 (s, 1H), 7.40 (d, IH), 6.78 (d, IH), 5.67 (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), 5 0.91 (dd, 2H), -0.06 (s, 9H); MS(ES):435(M+1). Step 2. 3 -Cyclopentylidene- 3 -[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yi)-H-pyrazol-1-yl]propanenitrile A solution of 3 -cyclopentylidene-3-[4-(7-[2-(trimethylsilyl)ethoxy)methyl-7H-pyrrolo[2,3-d] pyrimidin- 4 -yl)-lH-pyrazol-1-yl]propanenitrile (0.030 g, 0.069 mmol) in DCM (3 mL) and TFA (2 0 mL) was stirred for I 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 nmL) 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 sulfate, filtered and concentrated in vacuo. The crude residue was purified by preparative-HPLC/MS (C18 5 column eluting with a gradient of ACN/H 2 O containing 0.15% NH 4 0H) to afford the desired product (7 mg, 33%). 'H NMR (400 MHz, d 6 -dmso): S 12.23-12.01 (br s, 1H), 8.78 (s, 1H), 8.69 (s, 1H), 8.46 (s, 1H), 7.60 (d, 1H), 7.04 (d, IH), 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). 0 Example 76: 3 -Methyl[5-(7H-pyrrolo[2,3-dpyrimidin-4-y)-1,3-tbiazol-2-ylaminopropane nitrile trifluoroacetate salt _/ CN *TFA N N N H Step 1. 4-(1,3-Thiazol-5--y!)-7-[ 2 -(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine 25 4 -Chloro- 7

-[

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 vessels. 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 0 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%). 102 'H NMR (300 MHz, CDC1 3 ): 8 8.99 (s, 1H), 8.90 (s, 1H), 8.72 (s, 1H), 7.49 (d, 1H), 6.91 (d, IH), 5.70 (s, 2H), 3.56 (dd, 2H), 0.93 (dd, 211), -0.05 (s, 9H); MS(ES):333(M+1). Step 2. 4-(2-Bromo-1,3-thiazol-5-yi)-7-[2-(trimethylsilyl)ethoxylmethyl-7H-pyrrolo[2,3-d]pyrimidine 5 2.5 M n-Butyllithium in hexane (0.860 mL) was added dropwise to a -78 *C solution of 4 (1,3-thiazol-5-yl)-7-[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 THF (10 mL). After 30 minutes, the mixture was quenched with a small amount of saturated ammonium chloride, diluted with ether, and 0 dried over sodium sulfate. The residue obtained after filtration and concentration was purified by flash column chromatography (ethyl acetate/hexanes) to afford the desired product (387 mg, 57%). 'H NMR (300 MHz, CDCl 3 ): 8 8.85 (s, IH), 8.33 (s, IH), 7.49 (d, 1H), 6.83 (d, 1H), 5.69 (s, 2H), 3.55 (dd, 2H), 0.92 (dd, 21-1), -0.05 (s, 9H); MS(ES):411, 413(M+1). 15 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-(trimethylsilyl)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 concentrated, re-dissolved in methanol (2 mL), and ethylenediamine (0.5 mL) was added. The mixture was stirred for 6 hours at room temperature. The 10 mixture was diluted with DCM (10 mL), and the precipitate was isolated by filtration and washed with a small amount of DCM to afford desired product (182 mg, 72%). 'H NMR (300 MHz, d 6 -dmso): 5.8.74 (s, 1H), 8.70 (s, 1H), 7.76 (d, 1H), 7.15 (d, IH); MS(ES):281,283(M+1). 25 Step 4. 3-Methyl[5-(7H-pyrrolo[2,3-d]pyrimidin-4-y)-1,3-thiazol-2-ylJaminopropanenitrile A solution of 4-(2-bromo-1,3-thiazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidine (31 mg, 0.11 mmol) and 3-(methylamino)propionitrile (103 RL, 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 preparative-HPLC/MS (C18 column eluting with a gradient of ACN/H 2 0 containing 0.15% N1H 4 0H) and again by preparative-HPLC/MS 30 (C 18 column eluting with a gradient of ACN/H 2 0 containing 0.1% TFA) to yield the desired product as the trifluoroacetate salt (30 mg, 68%). 'H NMR (300 MHz, d 6 -DMSO): 8. 12.25 (s, I H), 8.60 (s, I H), 8.31 (s, I H), 7.60 (dd, I H), 7.00 (dd, I1H), 3.89 (t, 211), 3.20 (s, 311), 2.94 (t, 2H); MS(ES):285(M+1). 35 Example 77: (3S)- and (3R)-3-[5-(7H-Pyrrolot2,3-djpyrimidin-4-y)-1,3-thiazol-2-yllhexane nitrile 103 CN CN N- N S and N N N N N N H H Step 1. N-Methoxy-N-methylbutanamide To a mixture of butanoic acid (1.01 g, 0.0115 mol) and N,O-dimethylhydroxylamine hydro 5 chloride (1.12 g, 0.0115 mol) in DCM (50 mL) was added benzotriazol-1-yloxytris(dimethylamino) phosphonium 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 sulfate, and concentrated in vacua. The crude product was purified by flash column chromatography (ether/hexanes). The solvent was removed (235 mbar/40 *C) to afford the product 0 (1.33g, 88%). 'H NMR (300 MJIz, CDC1 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)ehoxymethyl- 7H-pyrrolo[2,3-dpyrimidin-4-yl)-1, 3-thiazol-2-yl] butan-1-one 5 2.5 M n-Butyllithium in hexane (878 pL) was added slowly dropwise to a -78 *C solution of 4-( 1, 3 -thiazol-5-yl)-7-[ 2 -(trimethylsilyl)ethoxy)methyl-7H-pyrrolo(2,3-d]pyrimidine (501 mg, 1.37 mmol) in THF (20 mL). After 45 minutes, N-methoxy-N-methylbutanamide (0.360 g, 2.74 mmol) was added. The reaction was continued at -78 "C for 30 min, and was then allowed to reach room temperature. The reaction was quenched with saturated ammonium chloride, and was extracted with 20 ethyl acetate. The extracts were washed with water and brine, dried over sodium sulfate and concentrated in vacua. Flash column chromatography (ethyl acetate/hexanes) afforded the product (235 mg, 42%). 'H NMR (300 MHz, CDCI,): 8. 8.93 (s, IH), 8.76 (s, 1H), 7.52 (d, 1H), 6.92 (d, 11H), 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); 25 MS(ES):403(M+1). Step 3. (2E)- and ( 2 Z)-3-[5-(7-[2-(Trimethylsilyl)ethoxymetlyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl) 1, 3 -thiazol-2-yl]hex-2-enenitrile To a solution of 1.0 M potassium tert-butoxide in THF (0.605 mL) in THF (4.0 riiL) at 30 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-[5 104

(

7

-[

2 -(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,3-thiazol-2-yl]butan- -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 acetate/hexanes) to afford the product as a mixture of olefin isomers (225 mg, 92%). 5 'H NMR (300 MHz, CDCJ), major isomer: 5 8.89 (s, 1M), 8.65 (s, 1H), 7.52 (d, IH), 6.89 (d, 1H), 6.35 (s, 1H), 5.70 (s, 2H), 3.56 (dd, 2H), 2.96 (t, 2H), 1.88-1.72 (m, 2H), 1.08 (t, 3H), 0.93 (dd, 2H), 0.07 (s, 9H); MS(ES):426(M+1). Step 4. (3S)- and (3R)-3-[5-(7-[2-(Trimethylsilyl)ethoxyjmethyl-7H-pyrrolo[2,3-djpyrimidin-4-yl) t0 1, 3 -thiazol-2-yl]hexanenitrile Cupric acetate, monohydrate (0.7 mg, 0.004 mmol) and (oxydi-2, 1 -phenylene)bis(diphenyl phosphine) (2 mg, 0.004 mol) was mixed in toluene (0.24 mL). PMHS (30 pL) was added. The mixture was stirred for 25 minutes at room temperature followed by the addition of (2E)-3-[5-(7-[2 (trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,3-thiazol-2-yl~hex-2-enenitrile (51 5 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%). 'H NMR (300 MHz, CDCl 3 ): S. 8.87 (s, 1 H), 8.52 (s, IH), 7.48 (d, I H), 6.87 (d, 114), 5.69 (s, 21H), 3.60-3.46 (m, 3H), 2.99-2.82 (m, 2H), 2.05-1.89 (in, 2H), 1.50-1.34 (in, 2H), 0.97 (t, 3H), 0.92 (t, 0 2H), -0.06 (s, 9H); MS(ES):428(M+1). Step 5. (3S)- and ( 3 R)-3-[5-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1,3-thiazol-2-ylhexanenitrie TFA (1.0 mL) was added to a solution of 3

-[S-(

7

-[

2 -(trimethylsilyl)ethoxy]methyl-7H pyrrolo[2,3-d~pyrimidin-4-yl)-1,3-thiazol-2-yl)hexanenitrile (36 mg, 0.084 mmol) in DCM (4.0 mL) 25 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 of ACN/H 2 0 containing 0.15% NH 4 0H) to afford the desired product (10 mg, 40%). 'H NMR (300 MHz, CDCl 3 ): 6 9.96 (br s, I H), 8.87 (s, I H), 8.54 (s, 11H), 7.51-7.45 (m, IH), 0 6.90-6.86 (m, 1H), 3.59-3.44 (m, 1H), 3.01-2.82 (in, 2H), 2.06-1.87 (m, 2H), 1.51-1.34 (m, 2H), 0.98 (t, 3H); MS(BS):298(M+I). Example 78: (3R)- and ( 3

S)-

3 -Cyclopentyl-3-[5-(7H-pyrrolo[2,3-dlpyrimidin-4-y)-1,3-thiazol-2 yllpropanenitrile 105 CN CN N- N S and NS N \ N N \ N N NN H H To a solution of (2E)- and ( 2

Z)-

3 -cyclopentyl-3-[5-(7-(2-(trimethylsilyl)ethoxy]methyl-7H pyrrolo[ 2

,

3 -d]pyrimidin-4-y)-1,3-thiazol-2-yl]acrylonitrile (199 mg, 0.440 mmol) (prepared, for 5 example, as in Example 77, steps I 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 H 2 until the reaction was complete. Filtration and removal of solvent afforded an oil which was dissolved in DCM (4 mL) and TFA (1 mL). The solution was stirred until starting material was consumed and the 10 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 concentrated in vacuo. The crude mixture was purified by preparative-HPLC/MS (C18 column eluting with a gradient of ACN/H 2 O containing 0.15% NILOH) to afford the desired product (36 mg, 25%). 'H NMR (400 MHz, CDC 3 ): 8 10.44 (br s, IH), 8.89 (s, IH), 8.56 (s, 1H), 7.50 (dd, IH), 6.89 (dd, .5 IH), 3.34 (dt, IH), 2.98 (dd, IH), 2.89 (dd, 11H), 2.44-2.31 (m, 1H), 2.07-1.96 (m, IH), 1.80-1.52 (m, SH), 1.40-1.24 (m, 2H); MS(ES):324(M+1). The following compounds of Table 5c were prepared (as racemic mixtures) as described by Example 77, 78 or 86, as indicated in the following table, by using different Weinreb amides (as prepared in Example 77, Step 1): 20 R CN

N

S N N N H Table Sc Ex Name R MS (ES) Method of No. (M+) preparation 106 5-methyl-3-[5-(7H-pyrrolo[2,3-d] 79 pyrimidin-4-yl)- 1,3-thiazol-2-yl]- 312 Ex. 77 hexanenitrile 3-pyridin-3-yl-3-[5-(7H-pyrrolo[2,3-d] 80 pyrimidin-4-yl)-1,3-thiazol-2-yl]- N 333 Ex. 78 propanenitrile 3-(5-bromopyridin-3-yl)-3-[5-(7H- Br 81 pyrrolo[2,3-d]pyrimidin-4-yl)-1,3-thiazol- 411,413 Ex. 77 2 -yl]propanenitrile N Ex. 77 through CN Step 4, 5-2-cyano-1 -[5-(7H-pyrrolo(2,3-d]- then Ex. 431 82 pyrimidin-4-yl)-1,3-thiazol-2-y]- 358 excluding ethylnicotinonitrile N purification, then Ex. 77, Step 5 Ex. 86, Step 3 3-[5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- subjected to 83 3 1,3-thiazol-2-yl]butanenitrile Me 270 conditions of Ex. 77, Steps 4&5 3-pyridin-4-yl-3-[5-(7H-pyrrolo[2,3- N 83A d]pyrimidin-4-yl)-1,3-thiazol-2- 333 Ex. 78 yl]propanenitrile Ex. 77 through Step 3, then Ex. 431 excluding 4-2-cyano-I [5-(7H-pyrrolo[2,3-d]- purification, pyrimidin-4-yl)-1,3-thiaol-2-yl]- N then Ex. 78, ethylpyridine-2-carbonitrile 358 purified by trifluoroacetate salt CN prep HPLC/MS using

H

2 0/ACN containing 0.1% TFA 3 -pyridin-2-yl-3-[5-(7H-pyrrolo[2,3-d] 83C pyrimidin-4-yl)-1,3-thiazol-2-y1]- 333 Ex. 78 propanenitrile N Example 84: (2S)- and (2R)-2-[5-(7H-PyrroloI2,3-dlpyrimidin-4-yl)-1,3-thiazol-2-ylpentane nitrile 107 CN CN N- N=.. S and S N \ N \ N N N N H H Step 1. (2S)- and ( 2 R)-2-[5-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl) 1, 3 -thiazol-2-yI]pentanenitrile 5 To a mixture of 1-[5-( 7

-(

2 -(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl) 1,3-thiazol-2-yl]butan-l -one (prepared as in Example 77) (101 mg, 0.251 mmol) and p-tolylsulfonyl methyl isocyanide (147 mg, 0.753 mmol) in a mixture of DMSO (5.0 mL) and ethanol (61 ;iL) 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 saturated 10 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 acetate/hexanes) afforded the product (39 mg, 25%). 'H NMR (400 MHz, CDCl 3 ): 8 8.88 (s, 1H), 8.52 (s, 1H), 7.50 (d, 1H), 6.87 (d, IH), 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); t5 MS(ES):414(M+1). Step 2. (2S)- and (2R)-2-[5-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1, 3 -thiazol-2-yl]pentanenitrile A solution of 2

-[S-(

7 -(2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin--4-yl)-1,3 thiazol-2-yl]pentanenitrile (59 mg, 0.093 mmol) in DCM (3 mL) and TFA (0.5 mL) was stored at 20 room temperature for 4 hours. The mixture was then concentrated, and the residue was then dissolved in methanol (3 mL) to which ethylenediamine (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 was purified by preparative-HPLC/MS (C18 column eluting with a gradient of ACN/H 2 0 containing 0.15% NH 4 0H) to afford the desired product (20 mg, 76%). 25 'H NMR (400 MHz, CDC1 3 ): 8 9.66 (br s, IH), 8.88 (s, I H), 8.54 (s, I H), 7.49 (dd, I H), 6.88 (dd, 1H), 4.33 (dd, 11), 2.23-2.12 (m, 2H), 1.75-1.60 (m, 211), 1.04 (t, 3H); MS(ES):284(M+1). Example 85: (4S)- and ( 4

R)-

4 -[5-( 7 H-Pyrrolo[2,3-djpyrimidin-4-yi)-1,3-thiazol-2-yllheptane nitrile 108 CN f-CN N- N and N N N N 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 tert-butoxide in THF (840 pL). 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) 5 methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,3-thiazol-2-yl]butan-1 -one (prepared as in Example 77) (225 mg, 0.559 mmol) in THF (4.0 mL) was added. The mixture was stirred at room temperature 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%). 10 MS(ES):473(M+1). Ethyl 3

-[S-(

7

-[

2 -(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,3-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 mixture was stirred under an atmosphere of hydrogen, provided by a balloon, for 16 hours. Filtration and concentration in vacuo 15 afforded the desired product (201 mg, 90%). MS(ES):475(M+1). To a solution of ethyl 3 -[5-( 7

-[

2 -(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin 4-yl)-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. 20 The mixture was stirred for 1 hour, then layers were separated, and the aqueous layer was extracted further with ethyl acetate. The organic 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

-[S-(

7 -[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,3 thiazol-2-yl]hexan-1-ol (88 mg, 0.20 mmol) in TFA (2 mL) was stirred for 30 minutes. The TFA was 25 then evaporated and the residue was stirred in methanol (2 mL) containing ethylenediamine (0.2 mL) and a drop of water for 30 minutes. Purification via preparative-HPLC/MS (Cl8 eluting with a gradient of ACN/HzO containing 0.15% NH40H) afforded the desired product (36 mg, 58%). MS(ES):303(M+l). To a mixture of 3 -[5-( 7 H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,3-thiazol-2-yl]hexan-1-l (36 mg, 30 0.12 mmol) and TEA (19.9 giL, 0.143 mmol) in DCM (5 mL) at 0 *C was added methanesulfonyl chloride (11.0 pL, 0.143 mumol). After stirring for 10 minutes, the solution was concentrated and 109 dissolved in DMSO (1.6 mL) and sodium cyanide (23 mg, 0.48 mmol) was added. The mixture 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 of ACN/4 2 O containing 0.15% NH 4 0H) to afford the desired product (10 mg, 27%). 5 'H NMR (400 MHz, CDC1 3 ): S 9.37 (br s, IH), 8.86 (s, I H), 8.52 (s, IH), 7.46 (dd, I H), 6.88 (dd, 1H), 3.34-3.25 (m, I H), 2.47-2.30 (m, 2H), 2.22-2.12 (m, 2H), 1.95-1.71 (in, 2H), 1.44-1.31 (m, 2H), 0.94 (t, 3H); MS(ES):312(M+1). Example 86: 3 -1 5 -(7H-Pyrrolo[2,3-dpyrimidin-4-y)-1,3-thiazol-2-yllpentanedinitrile CN CN N \-S

N

N N 10 H Step 1. N-Methoxy-2-[(4-methoxybenzyl)oxy]-N-methylacetamide To a mixture of [(4-methoxybenzyl)oxy]acetic acid (Bicorganic and Medicinal Chemistry Letters, 2001, pp. 2837-2841) (6.86 g, 0.0350 mol) and N,O-dimethylhydroxylamine hydrochloride (3.41 g, 0.0350 mol) in DCM (100 mL) was added benzotriazol-1-yloxytris(dimethylamino) 15 phosphonium hexafluorophosphate (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 HC], saturated NaHCO 3 , and brine, then was dried over sodium sulfate, filtered and concentrated in vacuo. Flash column chromatography (ether/hexanes) afforded the desired product (5.75 g, 69%). 20 Step 2. 2 -[(4-Methoxybenzyl)oxy]-I-[5-(7-[2-(trimethylsilyl)ethoxylmethyl-7H-pyrrolo[2,3-d] pyrimidin-4-yl)-1,3-thiazol-2-yljethanone 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 25 (3.06 mL) slowly dropwise. After stirring for 30 minutes, N-methoxy-2-[(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 removed and the reaction was quenched with saturated 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 30 (ethyl acetate/hexanes) to afford desired product (2.16 g, 66%). 110 'H NMR (300 MHz, CDCI): . 8.93 (s, 1H), 8.72 (s, 1H), 7.53 (d, 111), 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+I1). 5 Step 3. (2E)- and ( 2 Z)-4-[(4-Methoxybenzyl)oxy]-3-[5-(7-[2-(trimethylsilyl)ethoxymethyl- 7

H

pyrrolo[2,3-d pyrimidin-4-yl)-l.3-thiaziol-2-ylbut-2-enenitrile To a solution of I M potassium tert-butoxide in THF (4.44 mL) in THF (30 mL) at 00 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) 10 oxy]-1-[5-( 7

-[

2 -(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,3-thiazol-2-yl] ethanone (2.16 g, 0.00423 mol) in THF (20 mL) was added dropwise. 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 15 as a mixture of olefin isomers in nearly equal amounts (1.76 g, 78%). 'H NMR (400 MHz, CDCl 3 ): 8 8.90 (s, 111), 8.88 (s, 1H), 8.71 (s, IH), 8.67 (s, IH), 7.50 (d, 2H), 7.35 (dd, 2H), 7.31 (dd, 2H), 6.92 (dd, 2ff), 6.90 (dd, 211), 6.86 (d, 2H), 6.62 (s, 1H), 6.10 (t, 111), 5.70 (s, 4H), 4.75 (s, 2H), 4.72 (d, 21H), 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, 411), -0.05 (s, 9H), -0.054 (s, 9H); MS(ES):534(M+I1). 20 Step 4. 4 -[(4-Methoxybenzyl)oxy]-3-[5-(7-[2-(trimethylsilyl)ethoxy]methy -7H-pyrrolo[2,3-d] pyrimidin-4-yl)-1, 3 -thiazol-2-y]butanenitrile (2E)- and (2Z)-4-[(4-Methoxybenzyl)oxy]-3-[5-(7-[2-(trimethylsilyl)ethoxylmethyl-7H pyrrolo[2,3-d pyrimidin-4-yl)-1,3-thiazol-2-yl]but-2-enenitrile(880 mg, 1.6 mmol) was dissolved in a 25 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 product (0.85 g, 99%). MS(ES):536(M+1). Step 5. 3-[5-(7H-Pyrrolo[2,3-djpyrimidin-4-yl)-1,3-thiazol-2-yl]pentanedinitrile 30 4-[(4-Methoxybenzy1)oxy]-3-[5-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d] pyrimidin-4-yl)-1,3-thiazol-2-yl~butanenitrile (251 mg, 0.468 mmol) in DCM (10 mL) was treated with dichlorodicyanoquinone (DDQ) (434 mg, 1.87 mmol), followed by water (376 yL). 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 35 and concentrated in vacuo to afford the crude product which was used without further purification. 111 A solution of the above prepared 4-hydroxy-3-[5-(7-[2-(trimethylsilyl)ethoxy]methyl-7H pyrrolo[2,3-d]pyrimidin-4-yl)-1,3-thiazol-2-yl]butanenitrile in DCM (12 mL) at 0 *C was treated sequentially with TEA (130 pL, 0.94 mmol) and methanesulfonyl chloride (73 tiL, 0.94 mmol). After 1 hour reaction time, the mixture was diluted with water and extracted with ethyl acetate three times. 5 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 mixture was diluted with water, extracted 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-dlpyrimidin-4-yl)-1,3 thiazol-2-yl]pentanedinitrile (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 ethylenediamine (0.4 mL) was then added. After I hour reaction time, the product was purified by preparative-HPLC/MS (C18 eluting with a gradient of ACN/H 2 0 containing 0.15% 5 NH40H) to afford the desired product (6 mg, 62%). 'H NMR (400 M:Hz, d,-dmso): . 12.27 (br s, 1H), 8.84 (s, 1H), 8.76 (s, 1H), 7.75 (d, 11), 7.14 (d, 114), 4.14 (m, 1H), 3.17 (d, 41H); MS(ES):295(M+1). Example 87: (3R)-3-Cyclopentyl-3-[5-(7H-pyrrolo[2,3-d]pyrimidin-4-y)-1,3-oxazo-2-yl] D propanenitrile, and

(

3

S)-

3 -Cyclopentyl-3-[5-(7H-pyrrolo[2,3-djpyrimidin-4-yl)-1,3-oxazol-2-yllpropanenitrile CN N N- N O and N O N N N N ,N N N H H 5 Step 1. 4-(1, 3-Oxazol-5-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo(2,3-d]pyrimidine A mixture of 4 -chloro-7-[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(triphenylphosphine)palladium(0) (0.179 g, 0.155 mmol) in NN-dimethylacetamide (8.0 mL) was heated to 200 *C in the microwave reactor for 30 minutes. Most of the solvent was removed 0 in vacuo. The resulting residue was diluted with DCM, and was filtered and concentrated. Flash column chromatography (ethyl acetate/hexanes) afforded the product (330 mg, 67%). 1 1 2 'H NMR (400 MHz, CDCl 3 ): 8 8.96 (s, IH), 8.21 (s, 1H), 8.08 (s, 1H), 7.54 (d, IH), 7.08 (d, 1H), 5.76 (s, 2H), 3.60 (t, 211), 0.98 (t, 211), 0.00 (s, 9H); MS(ES):317(M+1). Step 2. Cyclopentyl[5-(7-[2-(trimethylsilyl)ethoxy]methyl- 7 H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,3 5 oxazol-2-yl]methanone n-Butyllithium in hexane (1.6 M, 0.30 mL) was added slowly dropwise to a -78 *C solution of 4-(1,3-oxazol-5-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-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. Following this, copper(I) iodide (84 mg, 0.44 0 mmol) was added, and this mixture was allowed to stir for 10 minutes. Cyclopentanecarbonyl chloride (108 yL, 0.885 mmol) was then added. The reaction was stirred at 0 *C for a further 1 hour, at which time it was allowed to warm to room temperature. The reaction was quenched by the addition of saturated NH 4 Cl 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 5 chromatography (ethyl acetate/hexanes) afforded the product (97 mg, 53%). 'H NMR (400 MHz, CDCl 3 ): 5 8.96 (s, IH), 8.21 (s, 1H), 7.56 (d, 1H), 7.22 (d, IH), 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); MS(ES):413(M+1). Step 3. (3R)- and (3S)-3-Cyclopentyl-3-[S-(7-[2-(rimethylsilyl)ethoxyjmethyl-7H-pyrrolo[2,3 d]pyrimdin-4-yl)-1, 3 -oxazol-2-yl]propanenitrile D To a solution of 1.0 M potassium 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 minutes, a solution of cyclopentyl[5-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,3-oxazol-2 yl]methanone (1.40E2 mg, 0.338 mmol) in THP (2.0 m.L) was added dropwise. After 3 hours reaction 5 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, monohydrate (4.0 mg, 0.020 mmol) and (oxydi-2, 1 phenylene)bis(diphenylphosphine) (II mg, 0.020 mol) in toluene (0.40 mL, 0.0038 mol) was added 0 PMHS (50 jiL). The resulting mixture was stirred for 25 minutes at room temperature, followed by the addition of (2E)- and ( 2

Z)-

3 -cyclopentyl-3-[5-(7-[2-(trimethylsilyl)ethoxymetyl-7H-pyrrolo [2,3-d]pyrimidin-4-y)-1, 3 -oxazol-2-yllacrylonitrile (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 5 equivalent each) were added and the reaction mixture was heated at 60 *C for 16 hours. The crude 113 mixture was subjected to flash column chromatography (ethyl acetate/hexanes) to afford the desired product (21 mg, 23%). 'H NMR (400 MHz, CDC 3 ): 8 8.96 (s, 1H), 8.02 (s, IH), 7.56 (d, 1H), 7.10 (d, 1H), 5.76 (s, 2H), 3.60 (t, 2H), 3.38-3.30 (m, IH), 3.03 (dd, lH), 2.95 (dd, IH), 2.60-2.40 (m, 1H), 2.10-2.00 (m, IH), 5 1.85-1.15 (m, 7H), 0.98 (t, 2H), 0.00 (s, 9H); MS(ES):438(M+1). Step 4. (3R)- and ( 3

S)-

3 -Cyclopentyl-3-[S-(7H-pyrrolo[2,3-d]pyrimidin-4-y)-1,3-oxazol-2-yl] propanenitrile A solution of 3 -cyclopentyl-3-[5-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d] 10 pyrimidin-4-yl)-1,3-oxazol-2-yllpropanenitrile (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 product was obtained via preparative-HPLC/MS (C18 column eluting with a gradient of

ACN/H

2 0 containing 0.15% NH 4 OH) (5.3 mg, 38%). 15 'H NMR (400 M14Hz, CDC1 3 ): & 10.25 (br s, 1H), 8.90 (s, 1H), 8.00 (s, 1H), 7.50 (d, IH), 7.06 (d, IH), 3.36-3.28 (m, 1H), 2.98 (dd, IH), 2.90 (dd, 1H), 2.51-2.38 (m, 1H), 2.08-1.96 (m, lH), 1.80-1.51 (m, 5H), 1.44-1.30 (m, 2H); MS(ES):308(M+1). The following compound of Table 5d was also prepared as a racemic mixture, according to the procedure of the above Example 87. .O Table 5d Ex. No. Structure Name R MS (ES) (M+1) CN N- 3 -[5-(7H-pyrrolo[2,3-d] 88 0 pyrimidin-4-yi).-1, 3 -oxazol-2-yl]- Pr 282 hexanenitrile N N N H Example 90: 5-(Methylthio)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin- 4 -yl)-1Hn-pyrazol-1-yll pentane nitrile 114 CN SCH3 N-N N N N H Step 1. (2E)-5-(Methylthio)pent-2-enenitrile To a 0 "C mixture of [chloro(triphenyl)phosphoranyi]ACN (2.5 g, 0.0073 mol) in THF (10 5 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)-propanol (0.68 mL, 0.0072 mol) in THF (I mL, 0.02 mol) was added and the mixture was stirred 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 solvent was removed by rotary evaporation 10 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. NaHCO 3 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). 'H NMR for trans (400 MHz, CDCl 3 ): 8 6.68 (1H, in); 5.14 (1H, d); 2.6 (2H, in); 2.55 (2H, t); 2.1 (3H. s). 15 Step 2. S-(Methylthio)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-H pyrazol-1-yljpentanenitrile A mixture of 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d] pyrimidine (0.30 g, 0.00095 mol), (2E)-5-(metbylthio)pent-2-enenitrile (0.28 g, 0.0016 mol) and DBU 20 (45 pL, 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 chromatographed with 30-70 ethyl acetate/hex, to give 0.35 g of a colorless oil (83% yield). 'H NMR (400 MHz, CDC 3 ): 5 8.95 (1H, s); 8.41 (1 H, s); 8.4 (11H, s); 7.48 (1 H, d); 6.84 (111, d); 5.75 (2H, s); 4.95 (1H, br); 3.6 (2H, t); 3.1 (2H, in); 2.58 (21H, in); 2.28 (21R, m); 2.1 (3H, s); 1.99 (2H, t); 25 0.0 (9H, s). MS (M+H): 443. Step 3. 5-(MethylIhio)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-IH-pyrazol-1-yl)pentanenitrile A solution of 5-(methylthio)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d] pyrimidin-4-yl)-1H-pyrazol-1-yl]pentanenitrile (0.35 g, 0.00079 mol) in THF (4 mL, 0.05 mol) and 30 3.0 M HCI (HCI) in water (4 mL) was heated to reflux overnight. The solvent 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 115 ammoniurn hydroxide in water (1 mL) overnight. The reaction was concentrated and purified by prep LCMS (C 18 column eluting with a gradient of ACN/H 2 0 containing 0.15% NH 4 OH) to give 125 ng of a white foam. The white foam was triturated with MTBE (- 1.5 rL). The resulting solid was filtered, washed and dried to give 80 mg of the product (32% yield). 5 'H NMR (400 MHz, CDCI 3 ): 8 10.38 (IH, s); 8.88 (1H, s); 8.39 (IH, s); 8.38 (1H, s); 7.44 (1H, d); 6.8 (1H, d); 5.75 (2H, s); 4.9 (IH, br); 3.05 (21H, in); 2.5 (2H, m); 2.23 (2H, d); 2.1 (3H, s). MS (M+H): 313. Example 91: 5-(Methylsuinyl)-3-[4-(7H-pyrrolo[2,3-dpyrimidin-4-y)-1H-pyrazol-1-yl] 10 pentanenitrile C ,CH 3 N-N N \ N N H A solution of 5-(methylthio)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-IH-pyrazol-1-y1) 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 5 mg of a solid. The solid was triturated with MTBE (1 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. 'H NMR (400 MHz, CDCl 3 ): & 9.95 (1H, s); 8.85 (1H, s); 8.4 (2H, n); 7.4 (1H, d); 6.8 (1H, s); 4.9 (I H, br); 3.15 (2H, n); 3.0 (2H, n); 2.8-2.5 (2H, in); 2.6 (3H, s). MS (M+H): 329. 20 Example 92: 5-(Methylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yi)-1H--pyrazol-1-y1] pentanenitrile CN

H

3 N-N 0 N \ N N H A solution of 5-(methylthio)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]. pentanenitrile (0.040 g, 0.00013 mol) and hydrogen peroxide (0.5 mL, 0.005 mol) in ACN (1 mL, 116 0.02 mol) was refluxed overnight. The reaction was purified by HPLC to give 16 mg of a white glass/solid which was triturated with EtOH (-0.8 mL) to give 13 mg of a white solid (30% yield). 'H NMR (400 MHz, CDC 3 ): 8 8.75 (1H1, s); 8.48 (IH, d); 8.4 (1H, d); 7.43 (1H, d); 6.8 (1H, s); 5.0 (1H, br); 3.4 (2H, m); 3.2-3.0 (2H, in); 2.8-2.5 (2H, in); 2.95 (3H, s). MS (M+H): 345. 5 Example 93: 4,4,4-Trifluoro-3-[4-(7H-pyrrolo[2,3-dpyrimidin-4-yl)-pyrazol-1-yl]-butyronitrie CN

F

3 C N-N N N H Step 1. 4,4,4-Trifluoro-3-[4-(7-[2-(trimethylsilyl)ethoxy methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl) JH-pyrazol-1-yi]butanenitrile 10 A mixture of 4-(IH-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methy-7H-pyrrolo(2,3-d] pyrimidine (6.9 g, 0.022 mol), ( 2

E)-

4 ,4,4-trifluorobut-2-enenitrile (2.8 g, 0.023 mol) and DBU (0.18 mL, 0.0012 mol) in ACN (70 mL, I mol) was stirred for 20 min. The reaction was filtered and filtrate was removed by rotary evaporation to give an orange oil. The crude oil was chromatographed with 20-50% ethyl acetate/hex to give to give 9.1 g of a solid/oil (96% yield). A single enantiomer (peak 2) 15 was separated by chiral column chromatography (OD-H column, 30%EtOH/hex) as a greenish solid/glass (3.3 g, 32% yield). 'H NMR (400 MHz, CDC 3 ): 8 8.93 (1H, s); 8.46 (1H, s); 8.45 (1H, s); 7.5 (1 H, d); 6.85 (1 H, d); 5.75 (2H, s); 5.2 (1H, m); 3.6 (2H, t); 3.7-3.3 (2H, m); 1.99 (2H, t); 0.0 (9H, s). MS (M+H): 438. 20 Step 2. 4,4,4-Trifluoro-3-[4-(7H-pyrrolo[2,3-d pyrimidin-4-yl)-pyrazol-1-yl]-butyronitile A solution of 4,4,4-trifluoro-3-[4-(7-[2-(trimethylsilyl)ethoxymethyl-7H-pyrrolo[2,3-d] pyrimidin-4-yl)-lH-pyrazol-1-y]]butanenitrile (3.1 g, 0.0071 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. 25 NaHCO 3 (50 mL). The aqueous phase was extracted with ethyl acetate. The organic layers were washed with brine and reduced by rotary evaporation to give an oil/glass residue. The residue was stirred in ethanol (20 mL, 0.3 mol) and 8.0 M ammonium hydroxide in water (10 rmL) 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.-0.7% NH40H to give 3 g of a pale orange 30 paste/solid. The solid was recrystallized from EtOl to give 1.6 g of an off-white crystals (74% yield). 117 'H NMR (400 MHz, DMSO): 5 12.2 (1H, s); 8.95 (1H, s); 8.7 (1H, s); 8.5 (I H, s); 7.63 (1H, d); 6.96 (I H, d); 6.01 (1 H, m); 3.7 (2H, n). MS (M+H): 306. The following compounds of Table 5e were prepared as indicated in the column labeled 5 "Prep. Ex. No." Table Se Ex. No. Structure Name MS Prep. (M+H) Ex. No. CN N-N 5,5-Dimethyl-3-[4-(7H pyrrolo[2,3-d]pyrimidin-4-yl)- 308 61 N pyrazol-l -yl]-hexanenitrile modification G N N H 0 -S N-N 4 -[l-(2-Methanesulfony-ethyl) 95 lH-pyrazol-4-yl]-7H-pyrrolo[2,3- 291 61 d]pyrimidine modification N N N H O_ N N-N 5,5,5-Trif]uoro-4-[4-(7H 96 \ pyrrolo[2,3-d]pyrimidin-4-yl)- 320 59 pyrazol-! -yl]-pentanenitrile modification G N N N H Exam ple 97: 3-(2-Cyano-1-1 4 -(7H-pyrrolo[2,3-dpyrimidin-4-yl)-lH-pyrazol-1-yllethyI)-cyclo pentane-carbonitrile trifluoroacetate 118 CN CN N-N T TFA NN N N H Step 1: 3 -(Dimethoxymethyl)cyclopentanecarbaldehyde. Into a 3-neck round bottom flask 2-norbornene (5.500 g, 0.05841 mol) was dissolved in DCM (198.0 mL,) and methanol (38.5 mL) and was cooled at -78 0C. Ozone was passed through the 5 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 0C and was stir-red for 90 minutes. Into the reaction was added sodium bicarbonate (1.67 g, 0.0199 mol) and the resulting mixture was stirred at 20 0C for 30 minutes and dimethyl sulfide (9.4 mL, 0.13 mol) wag added. The reaction was stirred for 16 hours-and was 10 reduced by rotary evaporation to -50 mL The reaction was extracted with DCM and the organic extracts were washed with water and brine, dried (MgSO 4 ), and stripped in vacuo. The reaction 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. 'HNMR (300 MHz, CDC1 3 ): 9.64 & 9.62 (d, IH), 4.15 & 4.i2 (s, 1H), 3.35 & 3.34 (s, 6H), 2.77 m, 1H), 2.34 (m, IN), 1.35-2.00 (m, 6H). 15 Step 2. (2EZ)- 3

-[

3 -(Dimethoxymethyl)cyclopentyl]acrylonitrile. 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 temperature, then a solution of 3-(dimethoxy. 20 methyl)cyclopentanecarbaldehyde (1.00 g, 5.81 mmol) in THF (2 mL) was added dropwise. Shortly after completion of the addition orange gel-like particulates began to form, after 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 25 with water, then sat'd NaCl, and then was dried over MgSO 4 and reduced in vacuo, and the resulting residue was purified by column chromatography with 6:1 hexanes:EtOAc + 1% TEA to obtain the product as a 1:1 mixture of E/Z isomers (760 mg, 61%). 'H NMR (400 MHz, CDC1 3 ): 5 vinylic protons at 6.69 (m, 0.5H), 6.37 (m, 0.5H), 5.32 (m, 0.5H), 5.23 (in, 0.5H), acetal methine proton at 4.14 (m, I H), methyl protons at 3.34 (s, 6H). 30 119 Step 3. 3

-[

3 -(Dimethoxymethyl)cyclopentyl]-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H pyrrolo[2,3-dJpyrimidin-4-yl)-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 (230 mg, 0.74 mmol) in ACN (5 mL) was added (2E,Z)-3-[3-(dimethoxymethyl)cyclo 5 pentyl]acrylonitrile (289 mg, 1.48 mmol), followed by DBU (300 pL, 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, CDC 3 ): S 8.85 (s, 1H), 8.31 (s, 211), 7.40 (d, 1H), 6.80 (d, 1H), 5.68 (s, 2H), 4.28 (m, 1H), 4.11 0 (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, 1 H), 2.65 (m, IH), 2.34 (m, 1H), 2.0-1.0 (m, 6H), 0.92 (t, 2H), -0.56 (s, 911). MS.(EI) m/z = 511.3 (M+H). Step 4. 3

-(

3 -Formylcyclopentyl)-3-[4-(7-[2-(trimethylsilyl)ethoxymethyl- 7H-pyrrolo[2,3-d] .5 pyrimidin-4-yl)-1H-pyrazol-1-y]propanenitrile. To a solution of 3

-[

3 -(dimethoxymethyl)cyclopentyl]-3-[4-(7-[2-(trimethylsilyl)ethoxy] methyl-7H-pyrrolo[2,3-d]pyrimidin.-4-yl)-lH-pyrazol-1-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 ambient temperature for 2.5 hours at which point TLC and LCMS indicated complete deprotection to the !0 corresponding aldehyde. The reaction was partitioned between water and EtOAc and the aqueous phase was extracted with additional EtOAc. The combined organic phase was washed with water, then sat'd NaHCO 3 , then sat'd NaCl, and then was dried over MgSO 4 and filtered and stripped to dryness to leave the crude product as a mixture of diastereomers. 'H NMR (400 MHz, CDCI 3 ): 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), 25 8.30 (s, 0.5H), 7.41 (d, 0.511), 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 (El) m/z = 465.1 (M+H). Step 5. 3- 3 -[(EZ)-(Hydroxymino)methyl]cyclopentyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H 30 pyrrolo[ 2

,

3 -d]pyrimidin-4-yl)-iH-pyrazol-1-yi]propanenitrile. To a solution of 3 -(3-formylcyclopentyl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl--7H pyrrolo[2,3-d]pyrimidin-4-yl)-1 H-pyrazol-1 -yl]propanenitrile (336 mg, 0.000723 mol) in CH 3 OH (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 35 indicated complete reaction. The reaction was reduced to dryness in vacuo and the residue was partitioned between water and EtOAc, and the aqueous phase was extracted with additional EtOAc. 120 The combined organic phase was washed with water, then sat'd NaCl, then was dried over MgSO 4 and concentrated to leave the crude product, which was carried forward to the subsequent reaction without purification. NMR indicated disappearance of aldehydic protons. MS (EI) m./z = 480.2 (M+H). S Step 6. 3 -(2-Cyano-J-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-fH pyrazol-1-yl]ethyl)cyclopentanecarbonitrile. To a solution of 3

-

3 -[(E,Z)-(hydroxyimino)methyl]cyclopentyl-3-[4-( 7

-[

2 -(trimethylsilyi) ethoxy]-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile (324 mg, 0.67 mmol) in pyridine (1.2 mL), was added methanesulfonyl chloride (210 .L, 2.7 mmol) dropwise. The 10 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 aqueous phase was extracted with additional EtOAc. The combined organic phase was washed with water, then 0.iN HCI, then sat'd NaCl, and then was dried over MgSO 4 . The crude product was purified by column chromatography to obtain the product as a mixture of diastereomers (164 mg, 52%). The diastereomers were then 5 separated by chiral HPLC to provide four distinct diastereomers, which were taken directly on to the deprotection step. MS (EI) m/z = 462.1 (M+H). Step 7. 3-(2-Cyano-)-[4-(7H-pyrrolo[2,3-dpyrimidin-4-yl)-H-pyrazol-1-yl ethyl)-cyclopentane carbonitrile trifluoroacetate. 0 The four diastereomers were then separately deprotected in this representative manner. To 3 2-cyano-l-[ 4

-(

7

-[

2 -(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1 yl]ethylcyclopentanecarbonitrile (35 mg, 0.076 mmol) dissolved in CH 2

CI

2 (2.0 mL) was added TFA (1.0 mL) and the reaction 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 Z5 the residue was added methanol (1.0 mL) followed by ethylenediamine (40 yL, 0.61 mmol), the reaction was stirred for 16 hours at which point LCMS indicated complete reaction. The solvent was removed 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 cyclopentyl ring. Isomers 1 and 2: 'H NMR (400 MHz, CD 3 OD): 8 8.95 (s, IH), 8.89 (s, I H), 8.54 (s, I H), 7.86 (d, IH), 7.29 (d, I H), 0 4.72 (in, 1H), 3.27 (m, 11), 3.19 (m, IH), 2.95 (m, 1H), 2.72 (m, IH), 2.2-1.9 (in, 411), 1.67 (m, 2H). Isomers 3 and 4: 'H NMR (400 MHz, CD 3 OD): 8 8.95 (s, 1H), 8.88 (s, IH), 8.52 (s, IH), 7.85 (d, 1-I), 7.28 (d, 1H), 4.72 (m, 1H), 3.27 (m, IH), 3.19 (m, 1H), 3.05 (m, IH), 2.71 (in, 1H), 2.44 (in, IH), 2.05 (m, IH), 1.92 (in, 1H), 1.72 (m, IH), 1.58 (m, 2H).MS (El) m/z= 332.2 (M+H). 5 Example 98: 3-[3-(Hydroxymethyl)cyclopentyll-3-[4-(7H-pyrrolo[2,3-dlpyrimidin-4-yl)-1H. pyrazol-1-yl]propanenitrile 121 OH CN N-N N' Step 1: 3 -[3-(Hydroxymethyl)cyclopentyl]-3-[4-( 7 -[2-(rimethylsilyl)ethoxy]methyl-7H-pyrrolo[2.3 d]pyrimidin-4-yI)-lH-pyrazol-1-yIlpropanenitrile A solution of 3

-(

3 -formylcyclopentyl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo 5 [ 2

,

3 -d]pyrimidin-4-yl)-lH-pyrazol-1-yl]propanenitrile (50.0 mg, 0.108 mmol) in methanol (280 pL) 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 quenched by cautious addition of IN HC (3 drops) and methanol (1 mL), followed by addition of aqueous NaHCO 3 and CHCl 3 . The phases were separated and the aqueous phase was washed with 10 additional CHC1 3 . The combined organic phase was washed with sat'd NaCl, dried over MgSO 4 and reduced to dryness. The residue was purified by column chromatography to obtain the product as a mixture of diastereomers (37.4 mg, 74%). 'H NMR (400 MHz, CDCl 3 ): 8 8.84 (s, IH), 8.31 (s, 2H), 7.40 (d, 1H), 6.80 (d, 1H), 5.67 (s, 2H), 4.29 (m, IH), 3.53 (M, IH), 3.53 (t, 2H), 3.14 (m, 1H), 2.95 (n, IH), 2.68 (in, IH), 2.2-1.0 (m, 9H), 0.92 (t, 2H), -0.059 (s, 9H). MS (EI) m/z = 467.2 (M+H). 15 Step 2. 3 -[3-(ydroxymethyl)cyclopentyl]-3-[4-(7H-pyrrolo[2.3-d]pyrimidin-4-yl)-1H-pyrazol-1 yllpropanenitrile To 3

-[

3 -(hydroxymethyl)cyclopentyl]-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yllpropanenitrile (60.4 mg, 0.129 mmol) dissolved in CH 2

C

1 2 20 (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 pL, 1.19 mmol). The resulting mixture was stirred for 16 hours at which point LCMS .indicated complete 25 reaction to the desired product. The solvent was removed and the residue 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 cis geometry on the cyclopentyl ring. Isomers 1 and 2: 'H NMR (400 MHz, CD 3 0D): 8 8.65 (s, 1H), 8.62 (s, 1H), 8.38 (s, IH), 7.50 (d, 1H), 6.95 (d, 1H), 4.51 (m, IH), 3.40 (m, 2H), 3.22 (m, IH), 3.11 (m, 1H), 2.61 (m, IH), 2.10 (m, IH), 1.94 (m, IH), 1.82 (m, 1H), 30 1.6-1.4 (m, 3H), 1.03 (m, IH). Isomers 3 and 4: 'H NMR (400 MHz, CD 3 0D): 8 8.66 (s, 1H), 8.62 122 (s, 1H), 8.37 (s, 1H), 7.50 (d, 1H), 6.95 (d, IH), 4.51 (m, IH), 3.46 (m, 2H), 3.21 (m, 1H), 3.11 (m, 1H), 2.61 (m, IH), 2.22 (m, 11-1), 2.09 (m, IH), 1.71 (m, 1H), 1.55-1.25 (m, 3H), 1.04 (in, 1H). MS (EI) m/z= 337.1 (M+H). 5 Example 100: 1-(1H-Pyrrolo[2,3-bjpyridin-4-yl)-1H-indazole (100a) and 2-(IH-pyrrolo[2,3-bj pyridin-4-yl)-2H-indazole (100b) NN N H 4 -Bromo-1H-pyrrolo(2,3-b]pyridine (0.078 g, 0.00040 mol) and IH-indazole (0.283 g, 0 0.00240 mol) was heated neat in a sealed tube at 200 "C (an oil bath) overnight with stirring. The reaction 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-d 6 ) S 12.01 (bs, IH), 9.17(s, IH), 8 .31(s, 1H), 7.73(d, II, J=9.0), 7.67(m, 2H), 7 .58(m, 1H, 7 .2 8 (m, I), 7

.

0 7(m, 2H). Example 106: 3

-[

3 -(lH-Pyrrolo2,3-bpyridin-4-yl)-1,2,4-oxadiazol-5-yljbenzonitrile CN N N N N H Step 1. J-[ 2 -Trimethylsilyl)ethoxymethyl-H-pyrrolo[2, 3 -bjpyridine-4-carbonitrile CN (N N, 0

CH

2

O(CH

2

)

2 Si(CH 3

)

3 4-Bromo-l-[ 2 -(trimethylsilyl)ethoxyJmethyl-1H-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-butylphosphine)palladium (0.1 g, 123 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 sulfate and concentrated to give an oil. The crude product was purified by flash column chromatography (FCC) on silica gel, eluting with a 5 hexane: ethyl acetate gradient to give the product (0.25 gm) as a colorless oil. LC/M S (M+H)* 274, H NMR (CDCl 3 ) & 8.22 (d, IH), 7.53(d, 1H), 7.40(d, 1H), 6.73(d, Hi), 5.65(s, 2H), 3.50(m, 2H), 0.90(m, 2H), 0.0(s, 9H). Step 2. N-Hydroxy-J-[2-(trimethylsilyl)ethoxy]methyl-IH-pyrrolo[2,3-b]pyridine-4-carboximidamide HN NHOH N N 0 CH 2

O(CH

2

)

2 Si(CH 3

)

3 1-[2-(Trimethylsilyl)ethoxy]methyl-IH-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 potassium carbonate (0.10 g, 0.00073 mol) were added. The reaction was heated to .5 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-(Trimethylsilyl)ethoxy]methyl-IH-pyrrolo[2,3-bpyridin-4-yl)-1,2, 4-oxadiazol-5 yl]benzonitrile CN N s N N N 20 CH 2

O(CH

2

)

2 Si(CH 3

)

3 The crude product N-hydroxy-1-[2-(trimethylsilyl)ethoxy]methyl-IH-pyrrolo[2,3-b]pyridine 4-carboximidamide (0.06 gm, 0.0002 mol) was dissolved in pyridine (1.0 mL, 0.012 mol) and then 3 cyanobenzoyl chloride (0.040 g, 0.00024 mol) was added at rt. This mixture was stirred for I h and 25 heated to 80 *C in an oil bath. After heating for 18 h the reaction was allowed to cool to rt and then diluted with ACN and concentrated in vacuo to give 3-[3-(1-[2-(trimethylsilyl)ethoxy]methyl-IH pyrrolo[2,3-b]pyridin-4-yl)-1,2,4-oxadiazol-5-yl]benzonitrile 0.08 gm as an off white residue, LC/M S (M+H)* 418. 124 Step 4. 3

-[

3 -()H-Pyrrolo[2,3-bpyidin-4-yl)-1,2. 4 -oxadiazol-5.ylbenzonitrile The crude 3-[3-(1-[ 2 -(trimethylsilyl)ethoxy]methyl-1 H-pyrrolo[2,3-b]pyridin-4-yl)-1,2,4-oxa diazol-5-yl]benzonitrile (0.08 g, 0.0002 mol) was dissolved in TFA (3.0 mL, 0.039 mol) under 5 nitrogen and then heated to 60 *C. After heating for 2 h the reaction was allowed to cool to rt and concentrated in vacuo. The resulting residue was taken up in methanol 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 reaction was then complete. The reaction was concentrated in vacuo to give the crude product which was purified by 10 prep HPLC on a C-18 column eluting with a ACN:water gradient with 0.2% TFA to give the title compound (0.025 gm, 43%) (M+H) 288. 'H NMR (DMSO-d 6 ) 8 12.1 (bs, IH), 8.65(s, IH), 8.48(d. 1H,J=6.4), 8.39(d, IH, J=4.8), 8.16(d, IH, J=6.4), 7.84(t, 1 H, J=6.4), 7.75(d, IH, J=4.8), 7.68(m, I H), 6.99 (m, IH). 15 Example 107: 4 -(1-Benzothien-2-yl)-1H-pyrrolo[2,3-blpyridine S N N H Step 1. 4-(1-Benzothien-2-y)--[2-(trimethylsilyl)ethoxy methyl-1H-pyrrolo[2,3-bipyridine S N N

CH

2

O(CH

2

)

2 Si(CH 3

)

3 20 1-Benzothien-2-ylboronic acid (0.05 g, 0.0003 mol) and 4-bromo-1-[ 2 -(trimethylsilyl) ethoxyjmethyl-H-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 reaction was degassed with nitrogen. Then tetrakis(triphenylphosphine)palladium(O) (0.05 g, 0.00004 mol) was added and the reaction was 5 heated to 120 "C in a scaled 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 125 concentrated to give 4-(1-benzothien-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-(J-Benzothien-2-yl)-IH-pyrrolo[2,3-b]pyridine 5 Using a procedure analogous to Example 106, Step 4, but using 4-(I-benzothien-2-yl)-1-[2 (trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-blpyridine, the title compound was prepared as a yellow powder (0.015 g, 18%), LC /MS (M+H)*: 251, 'H NMR (DMSO-d) & 11.95 (bs, 1H), 8.28(d, IH, J=5.4), 8.15(s, IH), 8.03(m, 1H), 7.96(m, 1H), 7.64(m, IH), 7.42(m, 211), 7.39(d, IH, J=5.4), 6.95(m, 1H). 10 Example 120: 4-Fluoro-2-[1-(1 H-pyrrolo[2,3-blpyridin-4-yl)-1H-pyrazol-3-yl phenol F /N \ ' OH N.N H 4-Bromo-IH-pyrrolo[2,3-b]pyridine (0.050 g, 0.00025 mol) and 4-fluoro-2-(IH-pyrazol-3 15 yl)phenol (0.150 g, 0.000842 mol) were heated neat to 160 "C for 5 h. The reaction was allowed to cool to rt and the residue was purified by prep LC-MS on a C-l 8 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 /MS (M+H)* 295, 'H NMR (DMSO-ds) 8 12.01 (bs, 1 H), 10.25(bs, 1H), 8.81(s,1H), 8.35(d, 1H, J= 5.5), 7.77(d, IH, J=9.5), 7.64(m, IH), 7.59(d, 1H, J=5.5), 7.32(s, 1H), 7.09(m, 1H), 7.05(m, 20 1H), 7.01(m, 1H). Example 127: 4-3-13-(Trifluoromethyl)phenylj-1H-pyrazol-1-yl-1H.-pyrrolo[2,3-blpyridine

CF

3 NN H 25 Step 1. ( 2

E)-

3 -(Dimethylamino)-1-[3-(rifluoromethyl)phenylprop-2-en-1 -one 126

F

3 C -- O N, 1-[5-(Trifluoromethyl)phenyl]ethanone (0.20 mL, 0.0013 mol) and 1,1-dimethoxy-N,N dimethylmethanamine (0.17 mL, 0.0013 mol) were combined in a sealed tube and heated in a microwave to 120 *C for 15 minutes, the reaction was allowed to cool and was concentrated to 5 remove the residual DMF acetal, to give (2E)-3-(dimethylamino)-1-[3-(trifluoromethyl)phenyl]prop 2-en-I -one, 0.32 gm, as a red oil, LC [MS (M+H)*: 244. Step 2: 3

-[

3 -(Trifluoromethyl)phenyl]-1H-pyrazole

F

3 C N--NH 10 The (2E)-3-(dimethylamino)-1-[3-(trifluoromethyl)phenyllprop-2-en-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 15 give 3-[3-(trifluoromethyl)phenyl]-1H-pyrazole as an oil (0.25 g, 89% ), LC /MS (M+H)*: 213, 'H NMR (CDCl 3 ) 5 8.06 (s, IH), 7.99(d, 1H, J=7.5), 7.66(d, IH, 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-[3-(Trifluoromethyl)phenyl]-1H-pyrazol-1-yl-IH-pyrrolo[2,3-bipyridine 20 4-Bromo-IH-pyrrolo[2,3-b]pyridine (0.028 g, 0.00014 mol) and 3-[3-(trifluoromethyl) phenyl]-IH-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 product that was a black viscous gum. The crude product was purified by HPLC on a C-I 8 column eluting with a water:ACN gradient with 0.2% TFA to give the title product (0.025 gin, 50%) as a white amorphous solid, LC [MS (M+H)': 329, 'H 25 NMR (DMSO-d) 8 11.95 (bs, IH), 8.83(d, IH, J=2.7), 8.31(m, 3H), 7.75(m, 21H), 7.60(m, 2H), 7.35(d, IH, J=2.7), 7.14(m, 1H). Example 128: 3-[1-(1H-Pyrrolo[ 2

,

3 -bipyridin-4-yl)-1H-pyrazol-3-yl]benzonitrile 127 CN N N N H Step 1. 3

-[(

2 E)-3-(Dimethylamino)prop-2-enoylfbenzonitrile 3-Acetylbenzonitrile (0.435 g, 0.00300 mol) and 1,1-dimethoxy-N,N-dimethylmethanamine 5 (0.400 mL, 0.00301 mol) were combined and heated in sealed tube to 120 *C in the microwave for 15 min. The reaction was then allowed to cool to rt giving the 3-[(2E)-3-(dimethylamino)prop-2-enoyl] benzonitrile as a red-orange crystalline material, LC /MS (M+H): 201. Step 2. 3-(JH-Pyrazo-3-y)benzonitrile .0 The 3

-[(

2 E)-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, eluting with ethyl acetate-hexane 1:1 to give 3-(IH-pyrazol-3-yl)benzonitrile as an oil (0.430g, 84%), LC /MS (M+H)*: 170. 5 Step 3. 3-[1-(H-Pyrrolo[2, 3 -b]pyridin-4-yI)-IH-pyrazol-3-ylqbenzonitrile 4-Bromo-1H-pyrrolo[2,3-b)pyridine (0.075 g, 0.00038 mol) and 3-(lH-pyrazol-3-yl)benzo nitrile (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 HPLC on a C-1 8 column eluting with a water:ACN gradient with 20 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-d 6 ) 8 11.95 (bs, 1H), 8.76(s, IH), 8.36(s, 1H), 8.29(d, 1H, J=7.5), 8.25(d, IH, J=5.0), 7.79(d, IH, J= 7.5), 7.62(t, IH, J= 7.5), 7.53(m, 2H), 7.25(s, 1H), 7.11(m, 1H). Example 153: 3-[1-(lH-Pyrrolo[2,3-b]pyridin4-y)-1H-pyrazol-4-yljbenzonitrile NC \ / N N N 25 H 128 Step 1. 4-(4,4,5,5-Tetramethyl-1,3, 2 -dioxaborolan-2-yI)-1-[2-(trimethylsilyl)ethoxy]methyl-1H pyrazole A solution of 4

-(

4

,

4 ,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.0 g, 0.010 mol) and DMF (30.0 mL, 0.387 mol) was cooled to O *C. Sodium hydride (320 mg, 0.0 13 mol) (60% in oil) 5 was added and the mixture was stirred for 10 min. [0-(Trimethylsilyl)ethoxy]methyl chloride (2.4 mL, 0.013 mol) was added and the resulting 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 MgSO 4 and concentrated to give 4-(4,4,5,5-tetramethyl-1,3,2 dioxaborolan-2-yl)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrazole as a crude material. LC/MS 10 (M+H)*: 325, 'H NMR (CDCl 3 ) 8 7.85 (s, 1H), 7.80(s, IH), 5.45(s, 2H), 3.55(t, 2H), 1.35(s, 12H), 0.95(t, 2H), 0.0(s, 9H). Step 2. 3

-(J-[

2 -(Trimethylsilyl)ethoxy]methyl-1H-pyrazol-4-yl)benzonitrile A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-[2-(trimethylsilyl)ethoxy] 15 methyl-IH-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(o) (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 !0 to rt and taken up in water and ethyl acetate. The organic layer was dried over MgSO 4 , filtered and concentrated to give a crude product, which was purified by FCC on silica gel, eluting with EtOAc/Hexanes (1:5) to give 3-(I-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrazol-4-yl)benzonitrile, as an oil, LC /MS (M+H)*: 300. 25 Step 3. 3-(IH-Pyrazol-4-y)benzonitrile trifluoroacetate \ CN N-NH A solution of 3 -(1-[ 2 -(trimethylsilyl)ethoxy]methyl-IH-pyrazol-4-yl)benzonitrile (110.0 mg, 0.0003673 mol) was taken up in TFA (3.0 mL, 0.039 mol) and the mixture was heated in microwave 30 at 120 *C for 3 min. The reaction mixture was allowed to cool to rt, and then concentrated to give a crude residue. The product was purified by HPLC on a C-18 column eluting with a water/ACN gradient containing 0.2% TFA to give 3 -(lH-pyrazol-4-yl)benzonitrile trifluoroacetate as an amorphous white solid, LC /MS (M+H)*: 170. 129 Step 4. 3-[1-(1H-Pyrrolo[2,3-b]pyridin-4-yl)-IH-pyrazol-4-ylbenzonitrile A mixture of 4-bromo-IH-pyrrolo[2,3-b]pyridine (25.0 mg, 0.000127 mol) and 3-(IH pyrazol-4-yl)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-l8 column eluting with a water; ACN 5 gradient containing 0.2% TFA to give the title compound as an amorphous white solid, LC/MS (M+H)*: 286, 'H NMR (DMSO-d 6 ) 8 11.85 (bs, 1H), 9.18(s, IH), 8.42(s, IH), 8.28(s, IH), 8.25(d, 1H4, J-5.0), 8.07(d, IH, J=7.0), 7.64(d, 1H, J=7.0), 7.56(t, 1H, J= 7.0), 7.51(m, 1H4), 7.47(d, 1H, J=5.0), 7.03(m,1H). [0 Example 170: 2-11-(1H-Pyrrolo[2,3-bpyridin-4-yl)-1H-pyrazol-4-yll-1,3-benzoxazole N N N QN H Step 1. 4-Hydrazino-J-[2-(rimethylsilyl)ethoxy]methyl-JH-pyrrolo[23-bipyridine H2N, NH

CH

2

O(CH

2

)

2 Si(CH 3

)

3 15 To 4-bromo-1-[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 improve solubility). The reaction mixture was heated in a sealed tube at 97 *C (an oil bath) for 18 h. The reaction mixture was cooled to rt and formed an off-white solid precipitate. The solid 20 was filtered off and rinsed with cold water and dried to give 4-hydrazino-1-[2-(trimethylsilyl)ethoxy] methyl-IH-pyrrolo[2,3-b~pyridine (1.55gm) as a light yellow solid, LC/MS (M+H)*:279, 'H4 NMR (DMSO-d 6 ) 8 7.98(d, IH), 7.91(s, 1H), 7.28(d, 1H), 6.69(s, 1H), 6.61(d, 1H), 5.58(s, 2H), 4.37(s, 2H), 3.56(t, 2H), 0.90(t, 2H), 0.0(s, 91). 25 Step 2. 2-[J-(1-[ 2 -(Trimethylsiyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4.yl)-1H-pyrazol-4-yl] 1, 3-benzoxazole 130 N-9 N N ON

CH

2

O(CH

2

)

2 Si(CH 3

)

3 To 4-hydrazino-l-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine (0.083 g, 0.00030 mol) 3782-117-1 and 1,3-benzoxazol-2-ylmalonaldehyde (0.056 g, 0.00030 mol) in toluene 5 (1.5 mL, 0.014 mol) was added molecular 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 product was purified by FCC on silica using ethyl acetate:hexanes 3:7 to give 2-[1-(1-[2-(trimethylsilyl)ethoxy] methyl-IH-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-4-yl]-1,3-benzoxazole (0.090gm) as an oil, LC/MS (M+H) 4 : 432. L0 Step 3. Using a procedure analogous to Example 106, Step 4, but using 2-[1-(1-[2-(trimethylsilyl) ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-4-yl]-1,3-benzoxazole, the title compound was prepared as a white amorphous powder (0.015 gm, 18%), LC /MS (M+H)*:302, 'H NMR [5 (DMSO-d 6 ) & 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, 1f), 7.56(bs, 1H), 7.38-7.34(m, 2H),7.01(d,1H). Example 172: Cyclohexyl[1-(1H-pyrrolo[2,3-bIpyridin-4-yl)-1H-pyrazol-4-yl]metbanol HO N.N H 20 Step 1. 4 -(4-Bromo-JH-pyrazol-1-yl)-JH-pyrrolo[2,3-b]pyridine 131 Br N QN H A mixture of 4-bromo-1H-pyrrolo[2,3-b]pyridine (1.10 g, 0.00558 mol) and 4-bromo-]H 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 IN NaOH. The organic layer 5 was washed with brine, dried over MgSO 4 , filtered and concentrated to give a crude 4-(4-bromo-IH pyrazol-1 -yl)-IH-pyrrolo(2,3-b)pyridine residue, LC /MS (M+H)*: 263,265. Step 2. 4-(4-Bromo-1H-pyrazol-1-yl)-1-[2-(trimethylsilyl)ethoxy]methyl-JH-pyrrolo[2,3-b]pyridine Br N N NN

CH

2 O(CHz) 2 Si(CH 3

)

3 0 A solution of 4-(4-bromo-fH-pyrazol-1-yl]-1-(2-(trimetlhylsilyl)ethoxy]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 MgSO 4 and concentrated to give the crude material. The product was purified by FCC on silica gel (EtOAc/Hexanes, 1/10) to give 15 4-(4-bromo-1 H-pyrazol-1 -yl)-l -[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-bJpyridine as a solid product, LC /MS (M+H): 393, 394, 'H NMR (CDCl 3 ) 8 8.47(d, 1H, J=7.0), 8.27(s, 1 H), 7.88(s, I H), 7.52(d, 1H, J=4.5), 7.39(d, 1H, J=7.0), 7.069(d, 1H, J=4.5), 5.80(s, 214), 3.6(t, 214), 1.95(t, 2H), 0.0(s, 9H). 20 Step 3. Cyclohexyl[J-(J-[2-(trimethylsilyl)ethoxy]methyl-JH-pyrrolo[2,3-b]pyridin-4-yl)-IH-pyrazol 4-yl/methanol 'HO N*N N

CH

2

O(CH

2

)

2 Si(CH 3

)

3 132 A mixture of 4-(4-bromo-I H-pyrazol-1 -yl)-1 -[2-(trimethylsilyl)ethoxymethyl-1

H

pyrrolo[2,3-b]pyridine (50.0 mg, 0.000127 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 5 mixture was stirred for 3 min. The reaction was partitioned between water and EtOAc. The organic layer was dried over MgSO 4 , filtered and concentrated to give the cyclohexyl[1-(1:5) to give 4-yl) IH-pyrazol-4-yl]methanol as a crude residue, LC /MS (M+H)*: 417. Step 4. Cyclohexyl[1-phenylvinyl)-IH-pyrazol-4-ylmethanol 10 Using a procedure analogous to Example 106, Step 4, but using cyclohexyl[1-(1-[2 (trimethylsilyl)ethoxy]methyl-lH-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-ds) 8 11.85 (bs, IH), 8.44(s, IH), 7.74(s, 1H), 7.50(m, IH), 7.44(d, IH, J=6.5.70(s, IH), 5.37(s, IH). 15 Example 173: 4

-[

4 -(l-Phenylvinyl)-1H-pyrazol-1-yl)-1H-pyrrool2,3-b]pyridine N. N TFA

I

H Step 1. 4-[4-(-Phenylvinyl)-1H-pyrazol-1-yljf]-[2-(trimethylsilyl)ethoxy]-methy-1H-pyrrolo[ 2 ,3~ bipyridine N, N NN 20 C H 2 0(CH 2

)

2

SI(CH

3

)

3 A mixture of (1-phenylvinyl)boronic acid (24.0 mg, 0.000162 mol) and 4-(4-bromo-1H pyrazol-1-yl)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-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 25 carbonate (35 mg, 0.00025 mol) in water (1.00 mL, 0.0555 mol). The mixture was degassed by bubbling nitrogen. Tetrakis(triphenylphosphine)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 133 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 MgSO 4 , 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-(I-phenylvinyl)-lH-pyrazol-1-yl]-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b) 5 pyridine as a solid residue, LC /MS (M+H)*: 417. Step 2. Using a procedure analogous to Example 106, Step 4, but using 4-[4-(l-phenylvinyl)-lH pyrazol-1-yl]-1-[2-(trimethylsilyl)ethoxy]methyl-IH-pyrrolo[2,3-b]pyridine, the title compound was 10 prepared as an white amorphous powder (0.015 gm, 31%), LC /MS (M+H)*: 287, 'H NMR (DMSO d) 8 11.85 (bs, 1H), 8.63(s, 1H), 7.99(s, 1H), 7.55(bs, 1H), 7.48(m, 2H), 7.43-7.37(m, 5H), 7.01(m,1H), 5.70(s, 1H), 5.37(s, 1H). Example 200: 4-(1-Benzyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine N-N N N 15 H Step 1. 4 -(-Benzyl-JH-pyrazol-4-yl)-1-[2-(rimethylsilyl)ethoxy]methyl-IH-pyrrolo[2,3-bipyridine N-N/ N N

CH

2

O(CH

2

)

2 Si(CH 3

)

3 20 4-Bromo-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine (0.100 g, 0.000306 mol) was combined with 1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-IH-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 25 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 minutes. The reaction was partitioned between ethyl acetate and water. The organic layer was washed with water, brine, dried over magnesium sulfate and 134 concentrated to give a crude residue. The product was purified by FCC on silica gel using ethyl acetate:hexane 3:7, to give 4-(1-benzyl-1H-pyrazol-4-yl)-1-[2-(trimethylsilyl)ethoxy]methyl-lH pyrrolo[2,3-b]pyridine 0.092g as a semisolid residue, LC /MS (M+H)*: 405. 5 Step 2. 4-(1-Benzyl-IH-pyrazol-4-yl)-!H-pyrrolo[2,3-b]pyridine Using a procedure analogous to Example 106, Step 4, but using 4-(1-benzyl-IH-pyrazol-4 yl)-1-[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, 'H NMR (DMSO-d 6 ) 8 12.21 (bs, IH), 8.80(s, IH), 8.25(vbs, 1H), 8.23(s, 1H), 7.63(s, 1H), 7.49(bs, 1H), 7.4-7.2(m, 5H), 6.99(s, 1H), 5.42(s, 10 2H). Example 201: 4 -(1-(2-Naphthylmethyl)-1H-pyrazo4-yl]-1H-pyrrolo[2,3-blpyridine N-N N N H 15 Step 1. 1-(2-Naphthylmethyl)-4-(4,4,5.5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole The 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.10 g, 0.00052 mol) was combined with naphthalene, 2-(bromomethyl)- (0.12 g, 0.00057 mol) in ACN (3.0 mL, 0.057 mol) under nitrogen at it. Then cesium carbonate (0.50 g, 0.0015 mol) was added and the reaction was complete after stirring for I h. This was partitioned between ethyl acetate and brine. The organic 20 layer was washed with brine, dried over magnesium sulfate and concentrated to give 1-(2 naphthylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-y)-1H-pyrazole 0.17 gm, as an oil, LC/MS (M+H)*: 335, 'H NMR (CDCl 3 ) 8 7.89 (s, 1H), 7.79-7.84(m, 3H), 7.69(bs, 2H), 7 .49-7.4(m, 2H), 7.46-7.33(m, I H), 5.47(s, 2H), 1.31(s, 12H). 25 Step 2. 4

-[]-(

2 -Naphthylmethyl)-JH-pyrazol-4-yl]-1-[2-(trimethylsilyl)ethoxy]methyl-qH-pyrrolo[2,3 bjpyridine N-N N N

CH

2

O(CH

2

)

2 Si(CH 3

)

3 135 4-Bromo-]--[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-blpyridine (0.06 g, 0.0002 mol) and 1-(2-naphthylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.074 g, 0.00022 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 5 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 magnesium sulfate and concentrated to give 4-[1-(2-napbthylmethyl)-1H-pyrazol-4-yl]-1-[2 (trimethylsilyl)ethoxylmethyl-lH-pyrrolo[2,3-b]pyridine 0.08 g, as an oily residue, LC /MS (M+H)': 10 455. Step 3 Using a procedure analogous to Example 106, Step 4, but using 4-[1-(2-naphthylmethyl)-lH pyrazol-4-yl]-I-(2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine, the title compound was 15 prepared as a white amorphous powder (0.053 g, 88%), LC /MS (M+H)*: 325, 'H NMR (DMSO-d) . 12.0(bs, 1H1), 8.79(s, 1H), 8.24(s, 1H), 8.19(d, IH, J=5.7), 7.82(m, 4H), 7.56(m, 1H), 7.43(m, 4H), 6.92(m, 1H), 5.54(s, 2H). Example 219: 4 -(1-Phenyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-bjpyridine N-N 20 N N 20 H Step 1. 1-phenyl-4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-IH-pyrazole 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-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 25 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 HPLC, allowed 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-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-lH-pyrazo, 0.09 gm as an oily 30 residue, LC/MS (M+H)*: 271. 136 Step 2. 4 -(I -Phenyl-1 H-pyrazol-4-yl)-I-[2-(trimethylsilyl)ethoxy/methyl-1H-pyrrolo[2,3-bjpyridine Using a procedure analogous to Example 201, Steps B and C, but using I -phenyl-4-(4,4,5,5 tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazo, the title compound was prepared as an white amorphous powder (0.015 gin, 18%), LCIMS (M+H)*: 261, 'H NMR (DMSO-d) 5 12.05 (bs, 1H), 5 9.23(s, 1H), 8.53(s, 1H), 8.31(m, 1H), 8.01(m, 2H), 7.63(m, 1H1), 7.57-7.52 (in, 311), 7 .3 6 (m, 1H), 7.13(m, 1H). Example 231: 3 -[4-(1H-Pyrrolo[2,3-blpyridin-4-yl)-1H-pyrazol-1-yl]benzonitrile QLCN N-N N N H 0 Step 1. 4 -(1H-Pyrazol-4-yl)-1-[2-(trimethylsilyl)ethoxy]methy!-H-pyrrolo[2, 3-bipyridine N-NH N N CH2O(CH 2

)

2 Sl(CH 3

)

3 4-Broino-1-[ 2 -(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine (0.20 g, 0.00061 mol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.15 g, 0.00079 mol) were 5 combined in DMF (5.0 mL, 0.064 mol) and then potassium carbonate (0.25 g, 0.0018 mol) in I 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 reaction 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 0 an oil. The product was purified by FCC on silica gel eluting with a hexane:ethyl acetate gradient to give 4-(IH-pyrazol-4-yl)-l-[ 2 -(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine (0.13 gm, 70%) as a crystalline white powder, LC /MS (M+H)*: 315, 'H NMR (DMSO-d 6 ) 8 13.35 (bs, IH), 8.59(bs, 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, 1H, J=6.0), 5.73(s, 2H), 3.6 1(t, 2H), 0.92(t, 2H), O.0(s, 91H). 5 Step 2. 3

-[

4 -(1-[2-(Trimethylsilyl)ethoxy]methyl-1H-ylo[23bpyridin-4-yl)- 1 pro ylJbenzonitrile 137 CN N-N N N

CH

2

O(CH

2

)

2 Si(CH 3

)

3 4-(1 H-Pyrazol-4-yl)- I-[2-(trimethylsilyl)ethoxy]methyl-1 H-pyrrolo[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 5 (1.50 mL, 0.0194 mol). Then copper(Ul) 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 organic layer was washed with brine, dried over magnesium sulfate and concentrated to give 3-[4-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yi)-1H-pyrazol-1-yl] L0 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)-1H-pyrazol-1-yl]benzonitrile, the title compound was 15 prepared as an white crystalline powder (0.012 gm, 60%), LC/MS (M+H)*: 286, 'H NMR (DMSO d,) 5 12.05 (bs, IH), 9.32(s, 1H), 8.59(m, IH), 8.55(m, IH), 8.36(m, IH), 8.30(d, IH, J=5.2), 7.83(m, 1H), 7.75(m, 1H), 7.63(m, IM), 7.51(d, IH, J=5.2), 7.12(m, IH). Example 250: 4-{1-[(1R)-1-Methylbutyl]-1H-pyrazol-4-yI)-1H-pyrrolo[2,3-bl pyridine (250a) 20 and 4-{1-[(1S)-1-Methylbutyl]-1H-pyrazol-4-yl}-1H-pyrrolo[2,3-bipyridine (250b) N-N N-N N N N N H and H Step 1. 4 -[l-(-Methylbutyl)-JH-pyrazol-4-yl]-J-[2-(trimethylsilyl)ethoxy]-methyl-1H-pyrrolo[2,3 25 blpyridine 138 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 mixture was then treated with 2-bromopentane (40 mg, 0.0002 mol) and was stirred for 5 h. 5 The reaction was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgSO 4 , filtered and concentrated to give the crude product 4-[ 1 -(1 -methylbutyl)- I H pyrazol-4-yl]-1-[ 2 -(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine as an oil, LC/MS (M+H)*: 286. 10 Step 2. 4-[1-(1-Methylbutyl)-JH-pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridine Using a procedure analogous to Example 106, Step 4, but using 4-[1-(1-methylbutyl)-1H pyrazol-4-yl]- 1 -[ 2 -(trimethylsilyl)ethoxy]methyl-1 H-pyrrolo[2,3-b]pyridine, the title compound was prepared as an white amorphous powder (0.025 gm, 60%), LC /MS (M+H)*: 255, 'H NMR (DMSO d) 8 12.21 (bs, 1H), 8.66(s, 1H), 8.27(bs, IH), 8.25(s, 1H), 7.62(m, 1H), 7.49(m, 1H), 7.02(m, lH), 15 4.46(m, IH), 1.9-1.8(m, 1HI), 1.7-1.6(m, LH), 1.47(d, 3H), 1.2-1.0(m, 2H), 0.83(t, 3H). Step 3. Separation ofEnantiomers The separation of the enantiomers of 4-[1-(I-methylbutyl)-1H-pyrazol-4-yl]-1H-pyrrolo[2,3 b]pyridine from Step 2 was performed by chiral column preparative HPLC separation using an OD-H !0 column eluting with an isopropanol:hexane gradient to give the title compounds as amorphous white residues, LC /MS (M+H)*: 255, 'H NMR (DMSO-d) 8 12.21 (bs, 1H), 8.66(s, IH), 8.27(bs, 1H), 8.25(s, II), 7.62(m, IH), 7.49(m, 1H), 7.02(m, 1H), 4.46(m, 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). 25 Example 286: 4-Methyl-3-14-(1H-pyrrolo[2,3-b]pyridin-4-y)-1IH-pyrazol-1-ylbenzonitrile CN N-N N N H Step 1. 4-Methyl-3-[4-(-[ 2 -(trimethylsilyl)ethoxy]methyl-H-pyrrolo[2,3-b]pyridin-4-yl)-H pyrazol-1-ylbenzonitrile 139 -. CN N-N N N

CH

2

O(CH

2

)

2

S(CH

3

)

3 To a mixture of 4-(1H-pyrazol-4-yl)-1-[ 2 -(trimethylsilyl)ethoxy]methyl-lH1I-pyrrolo[2,3-b] pyridine (0.050 g, 0.00016 mol) (see, Example 231, Step 1) and cesium carbonate (0.10 g, 0.00032 5 mol) in dry DMF (1.0 mL, 0.013 mol) was added 3 -fluoro-4-methylbenzonitrile (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-3-[4-(1-[2 (trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b)pyridinA-yl)-1H-pyrazol-1-yl]benzonitrile as a crude 10 product, LC /MS (M+H)*: 430. Step 2. 4 -Methyl-3-[4-(lH-pyrrolo[2,3-b pyridin-4-yl)-H-pyrazol-1-yljbenzonitrile Using a procedure analogous to Example 106, Step 4, but using 4-methyl-3-[4-(1-[2 (trimethylsilyl)ethoxy]methyl-IH-pyrrolo[2,3-b]pyridin4-yl)- H-pyrazol-1-yl]benzonitrile, the title 5 compound was prepared as a white amorphous powder (0.037 gm, 88%), LC /MS (M+H)*: 300, 'H NMR (DMSO-ds) 8 12.19 (bs, 1H), 8.98(s, 1H), 8.57(s, 1H), 8.31(d, 1H, J=7.0), 8.08(s, 11-), 7.89(d, IH, J=10), 7.66(d, 1H, J-10), 7

.

6 3 (m, IH), 7.55(d, IH), 7.07(m, IH), 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 20 separately. Table 7 R N N H Ex. MS No. (M+S)+ Name Preparation 2 -(lH-pyrrolo[2,3-b]pyridin-4 101 239 yl)- 4 ,5,6,7-tetrahydro-2H- Ex 100 indazole 102 F-N 280 5-nitro-2-(] H-pyrrolo[2,3-b]- Ex 100

NO

2 pyridin-4-yl)-2H-indazole 140 103 L..N0 2 8 6-nitro-2-(l H-pyrrolo[2,3-b]- E 0 ~- pyridin-4-yl)-2H-indazole -_ C 3-[1 -(1 H-pyrrolo[2,3-bllpyridin 104 286 4-yl)-IH-imidazol-4-yl- EX 100 benzonitrile 2913 4-[4-(3 -rethoxyphenyl)-1 H 105 29 imidazol-1-yl]-lfi-pyrrolo[2,3- Ex, 100 blpyridine / 4-(S-phenyl-2-thienyl)-1H 108 D 277 pyrolo[2,3.b]pyrdine Ex, 107 Table 8 (Y),-Z CN -N H Eo. 4(1114-Hr Name Preparation 121 I279 4-[I3-(4-fluorophenyl)- IH-pyrazol -I- Ex 120 yI)-1 H-pyrrolo[2,3-bjpyridine 122 306 4-[3-(3-nitrophenyl)-1H-pyrazol-1 - Ex 120 \)(] -N02yl]-l H-pyr-rolo[2,3-b]pyridine 123 I l 295 4-[3-(4-chlorophenyl)-1 H-pyrazol1-1 - Ex 120 IC-ayI]-IH-pyrrolo[2,3-b]pyridine 124 OCH 291 4-[3-(4-methoxyphenyl)- I H-pyrazol- Ex 120 \jc~r1-yl]-1H-pyrrolo[2,3-b]pyridinc 125 286 4-f1 -(I H-pyrrolo[2,3-b]pyridin-4-yJ)- Ex 120 1 H-pyrazol-3-y]benzonit-ile 126 276 3-[l-(IH-pyrrolo[2,3-b~pyridin-4-yl)- Ex 120 Y D NH 2 I1H-pyrazol-3 -yl] aniline 129 291 4-[3 -(3-methoxyphenyl)- IH-pyrazol- Ex 128 -11,r OCH 3 1 -yl)-I H-pyrrolo[2,3-b]pyridine 141 {3-[1 -(1 H-pyrrolo[2,3-b]pyridin-4 130 >L OCHCN 316 yl)-IH-pyrazol-3-yI]- Ex 128 ________________ phenoxy) acetonitrile _______ 2-cyano-N-{3-[1 -(I H-pyrrolo[2,3-b] 131 VI -HOHC 343 pyridin-4-yI)-1H-pyrazoI-3-yl]- Ex 128 - NHCOCH 2 CN phenyl)acetamide_______ 132 I 405 3-cyano-N-{3-[1-(111-pyrrolo[2,3-b] 132 CONH(3..CN..Ph) 45 pyridin-4-yI)-1H-pyrazoI-3-yl]- Ex 128 _______ phenyl~benzamide _______ Table 9 (Y).-Z N NN 5 (N H Ex. Mass No. Spec Name Prep. _____ _____________(M+ff)+ 150 N2306 4-[4-(4-nitrophenyl)-IH-pyrazol-1-yl]- Ex 153 1 H-pyrrolo[2,3-blpyridine 151 ~ NH 2 276 4 -[1-(IH-pyrrolo[2,3-b]pyridin-4-yl)- Ex 153 1 H-pyrazol-4-yI~aniline 152 261 4-(4-phenyIlH-pyrazol-I -yl)-l H- Ex 153 pyrrolo[2,3-blpyridine 154 N262 4-(4-pyridin-3-yl-lH-pyrazol-1 -yi)-lH- E S ______ pyrrolo[2,3-b]pyridine E 5 155 286 2-[l-(1H-pyrrolo[2,3-b]pyridin-4..yi). Ex 153 I H-pyrazol-4-ylbenzonitnile 156 300 { 2 -[I -(1 H-pyrrolo [2,3-b]pyrdin4-y). E 13 156 300 ~1 H-pyrazol-4-yl]phenyl} acetonitrile Ex13 NC 157 I306 4-[4-(3-nitrophenyl)-1 H-pyrazol-1 -y] Ex 153 -C N0 2 I H-pyrrolo[2,3-b~pyridine 158 I276 3-[1 -(1 H-pyrrolo[2,3-b]pyridin-4-yI). Ex 153 \)C NH 2 lI-pyrazo]-4-yI~anifine 142 159 I .C 2 N 300 (3-[l -(I H-pyrrolo[2,3-b]pyridin-4-yl). Ex 153 ',, H2NI H-pyrazol-4-yl]phenyl) acetonitrile CN 160 I286 4-[l -(I H-pyrrolo42,3-b]pyridin-4-yl)- Ex 153 - aIH-pyrazol-4-yl]benzonitrfle 161 I277 3-[l -(1 H-pyrrolo[2,3-b]pyridin-4-yl)- Ex 153 -ll OH IH-pyrazol-4-yl]phenol 162 I319 methyl 3-[1-(IH-pyrrolo[2,3-b~pyridin. Ex 153 - - -c CO 2

CH

3 4 -yI)- I H-pyrazol-4-yl]benzoate 163

CH

2 CN 300 {4-[1 -(l H-pyrrolo[2,3-blpyridin-4-yi)- Ex 153 1 H-pyrazol-4-yI]phenyl} acetonitrile 164 I 2-cyano-N- {3-[1 -(1 H-pyrrolo[2,3-b] 164 NHCOCH 2 CN 343 pyridin-4-yI)-1H-pyrazol-4-yl]- Ex 153 ___________ phenyll acetamide 165 IqkO 277 4 -[1 -(I H-pyrrolo[2,3-bjpyridin-4-yI)- Ex 153 ,do 11H-pyrazol-4-yI]phenol 166 I287 5-[1 -(I H-pyrrolo[2,3-b]pyridin--yl)- Ex 153 -~CN I H-pyrazol-4-yl]nicotinonitrile 167

OCH

2 CN 316 {4-[ 1-(1 H-pyrrolo[2,3-bjpyridin-4-yl)- Ex 153 141 IH-pyrazol-4-yljphenoxy} acetonitrile 168 I265 4-(4-cyclohex-1-en-1-y-l H-pyrazol-l- Ex 172 v OCH 3 -y~oo23-~yrdn 169 ;% OH 291 4-[4-(4-methoxyphenyl)-IH-pyrazol-1.. Ex 153 vc r yII-1H-pyrrolo[2,3-b]pyridine 171 N lN263 4-(4-pyrimidin-4-ylI-H-pyrazol- l-yI)- Ex 171 1 H-pyrrolo[2,3-b~pyridine OH CN 3- {hydroxy[1I -(l H-pyrrolo[2,3-b] 174 CN 316 pyridin-4--yl)-1H-pyrazol-4.yl]- Ex 172 methyl} benzonitrile 175 279 4-[4-(cyclohex- I -en- I-ylmethyl) I H- Ex 172 ______ _______________ _______pyrazol-l -yl]-1H-pyrrolo[2,3-b]pyridine 143 Table 10 ')n-Z N-N N N H Ex. MS No. (M+H) -(Y).-Z Name Prep.

OCH

3 4-[l-(3,5-dimethoxybenzyl)-IH 202 335 pyrazol-4-yl]-IH-pyrrolo(2,3- Ex 201

_CH

3 b]pyridine 203 289 4-[1 -(1 -phenylethyl)- lH-pyrazol-4- Ex 201 203 28yl]-1H-pyrrolo[2,3-b]pyridine 204 281 4-[1 -(cyclohexylmethyl)- 1 H-pyrazol- 201 4-yl]-1 H-pyrrolo[2,3-b]pyridine 3-{[4-(1H-pyrrolo[2,3-b]pyridin-4 205 300 yi)-IH-pyrazol-1- Ex 201 CN yl]methyl)benzonitrile 2-{[4-(1H-pyrrolo[2,3-b]pyridin-4 206 300 yi)-H-pyrazol-l- Ex 201 CN yl]methyl} benzonitrile CN 4

-{[

4 -(1H-pyrrolo[2,3-blpyridin-4 207 300 yl)-1H-pyrazol-l- Ex 201 yl]methyl} benzonitrile S1-phenyl-2-[4-( 1H-pyrrolo[2,3 208 303 /b]pyridin-4-yl)-IH-pyrazol-1 - Ex 201 0 yl]ethanone 3,3-dimethyl-1-(4-(1H-pyrrolo[2,3 209 283 b]pyridin-4-yl)-1H-pyrazol-1- Ex 201 yl]butan-2-one 4-{t-[(5-methylisoxazol-3. 210 280 yl)methyl]-1H-pyrazol-4-yl)-H- Ex 201

N-

0 pyrrolo[2,3-b]pyridine 4-[1 -(tetrahydro-2H-pyran-2 211 283 ylmethyl)-1H-pyrazol-4-yl)-l H- Ex 201 pyrrolo[2,3-b]pyridine 212 265 4-(1 -cyclohex-2-en-1-yl-l H-pyrazol- Ex 201 4 -yl)-1 H-pyrrolo[2,3-b)pyridine

IAA

213 255 4-[1 -(1 -ethylpropyl)-1 H-pyrazoil-4- Ex 201 yl]-1 H-pyrrolo[2,3-b]pyridine 214 267 f~h4-( I-cyclohexyl- IH-pyrazol-4-'yl)- E 0 1 H-pyrrolo[2,3-b]py-idine E 0 215 242

O~N

2 2

.{

4 -(IH-pyrTolo[2,3-b]pyrdin..yl). Ex 201 IH-pyrazol- 1 -yllacetamide 216 376 YI)- 1H-pyrazol-1 -yl~methyl) biphenyl- Ex 201 ________2-carbonitrile 0 2 N N. 4 -{l-( 2 -nitrobenzyl)-lH-pyrazoIA4 217 320 jEx 201I _______________ yl1-I -Hpyrrolo[2,3 -blpyridine 217, 4 -f1-[2,6-dichloro-4 28 399 (trifluoromethyl)phenyl]. I Hpyrazol- Ex 201 cl 4-yI} -1 H-pyrrolo[2,3-b)pyridine 220 320 / I4-[I -(3 -nitrobenzyl)-lH-pyrazol.4. x 0 ,,, NO 2 yll]IH-pyrrolo[2,3-b)pyridine E 0 221 353,3558 4- I -(2-bromobenzyl)-I H-pyrazcll-4- Ex 201 ________ / Iyl]-1H-pyrrolo[2,3-b]pyidine 222 332NHC 8

H

5 N-phenyl-2-[4-( 1H-pyrrolo[2,3 22 3 l~yblpyridin-4-yl)-H.py-azol.1.- Ex 201 0 yl]propanarnide N. 4- {11-[ 3 -(trifluoromethoxy)benzyl]. 223 359 1 H-pyrazol-4-yi} -1H-pyrrolo[2,3- Ex 201 Al- OCF 3 bjpyridine F N.4- { -[ 2 -fluoro-5-(trifluoromethyl). 224 361 Ibenyl-Hpyrazol.4y).H- Ex 201

_______CF

3 pyrrolo[2,3-b]pyridine N. 4. (1 -[3 -(trifluoromethyl)benzyl].1H 225 343 / Ipyrazol-4-ylI}- I Hpyrrolo[2,3. Ex 201 - - CF 3 bipyridine 226 276 N.

4 -[l -(pyridin-3-ylmethyl)-iH / -Npyrazol-4-yl]-I1I-pyrrolo[2,3.. Ex 201 bipyridine 4- (1 -((1 S)- 1 -phenylbuty]- I IH 227 317 N.pyrazoI-4-yI- IH-pyrrolo[2,3. Ex 201 _____ _______bipyridine 4-f 1 4(IR)-I -phenylbutyl]-IH. 228 317 N.pyraz0I- 4 -y1}-1H-pyrrolo(2,3.. Ex 201 b]pyridine 145

CH

3 1-phenyl-2-[4-(IH-pyrrolo[2,3 229 317 b]pyridin-4-yl)-IH-pyrazol-1- Ex 201 yl]propan-1 -one 4-[1-(2,6-dichlorobenzyl)-1H 230 343,345 pyrazol-4-yl]-IH-pyrrolo[2,3- Ex 201 b]pyridine H3C 4-[1-(2,6-dimethylphenyl)-1H 232 289 pyrazol-4-yl]-IH-pyrrolo[2,3- Ex 231

CH

3 b]pyridine

CF

3 233 32-[4-(1 H-pyrrolo[2.3-b]pyridin-4-yl) 233 354 1 H-pyrazol-1 -yi]-5-(trifluoromethyl)- Ex 286 benzonitrile F N F 4-[1-(4-bromo-3,5,6-trifluoropyridin 234 393,395 2-yl)-1H-pyrazol-4-yl]-H- Ex 286 Br pyrrolo[2,3-b]pyridine F 4-[1 -(cyclopropylmethyl)-1 H 235 239 pyrazol-4-yl]-1H-pyrrolo[2,3- Ex 201 b]pyridine

H

3 4-[1-(2,5-dimethylphenyl)-1 H 236 289 pyrazol-4-yl]-1H-pyrrolo[2,3- Ex 231 b]pyridine

CH

3 237 275 4-[1-(2-methylphenyl)-IH-pyrazol-4- Ex 231 yl]-IH-pyrrolo[2,3-b]pyridine _____ ~~CH 3 __ _ _ _ _ _ _ _ _ _ _ _ 238 291 4-[1-(2-methoxyphenyl)-1H-pyrazol- Ex 231 4-yl]-l H-pyrrolo[2,3-b]pyridine

OCH

3 3- {1-[4-(IH-pyrrolo[2,3-b]pyridin-4 239 314 CN yl)-1H-pyrazol-1- Ex 250

COH

3 yl]ethyl)benzonitrile CN 3-chloro-4-[4-(1 H-pyrrolo[2,3 240 320 blpyridin-4-yl)-IH-pyrazol-1- Ex 286 CI yl]benzonitrile 1 Af 241 295 4-[1 -(1 -cyclohexylethyl)-1 H-pyrazol- E 5 & 4 -yl]-1 H-pyrrolo[2.3-b]pyridine E 5

OH

3 F 242 3044-fluoro-2{[4-(l H-pyrrolo[2,3 242 04% b]pyridin-4-y)-l. H-pyrazol-I - Ex 286 CN yllbenzonitrile F 23 34CN 2-fluoroA4-[4-(l H-pyrrolo[2,3 243 304b]Pyridin-4-yl).1H-pyrazol.l. Ex 286 IV , C yllbenzonitrilce 3-fluoro-4-[4-(l H-pyrrolo[2,3 244 304 b]pyridin.4-y).1Hpyrazo..-. :Ex286] cq yl]benzonitrile 357 4-(lI -{-[3 -(trifluoromethyl).. 245 / a CF 3 phenyI]ethyl)-IHwpyrzo1.{-yl)IH- Ex 250

CH

3 pyrrolo[2,3..blpyridine

H

3 246 2894-[1 -( 3 ,5-dirnetbylphenyl).1H 246 28 NPYrazol-4-YI).lH-pyrrolo[2,3- Ex 231 C& CH 3 bipyridine .- 1 H-pyrazol-1 -y]]benzonitrile li- CH 2 CN {4-[4-(l ll-pyrrolo[2,3.b)pyrdin-4 248 300 yI)-IH-pyrazol-1- Ex 231 - H3 yljphenyl) acetonmtrile 249 283 H 3 4-[ 1-(1 -rethylhexyl).IHl-pyrazol.4.

CH

3 YI]-IN4-pyrrolo[2,3..b]pyridinc Ex 250 251 2414-(1 -se-buty..1H-pyrazol-4.y)H E H 253 367 4heny1]etby1}4H..pyrn)IH.4yrazol-4 Ex 250

CH

3 pyrrolo[2,3-b]pyridine 147 OCH3 4-{1 -[1-(3-fluoro-4-methoxy 254 337 F phenyl)ethyl]-1 H-pyrazol-4-yl} -1 H- Ex 250

H

3 pyrrolo[2,3-b]pyridine F3 4-(1-{1-[2-(trifluoromethyl) 255 357 phenyl]ethyl}-1H-pyrazol-4-yl)-IH- Ex 250

H

3 pyrrolo[2,3-b]pyridine

F

3 4-(1 -{ -[3,5-bis(trifluoromethyl) 256 425 phenyl]ethyl)-1H-pyrazol-4-yl)-1H- Ex 250

CF

3 pyrrolo[2,3-b]pyridine

CH

3 CN 4-{1-[4-(1H-pyrrolo[2,3-b]pyridin-4 257 314 yl)-IH-pyrazol-1- Ex 250 I aCH yl]ethyl)benzonitrile

F

3 C NO 2 4- (1 -[4-nitro-2 258 374 (trifluoromethyl)phenyl]-1 H-pyrazol- Ex 286 4 -yl}-1H-pyrrolo[2,3-b]pyridine

H

3 C CN 3-methyl-4-[4-(1H-pyrrolo[2,3 259 300 b)pyridin-4-yl)-1H-pyrazol-1- Ex 286 yl]benzonitrile 260 295, 297 4-[1-(2-chlorophenyl)-1H-pyrazol-4- Ex 231 yl]-1H-pyrrolo[2,3-b]pyridine Br CN 3-bromo-4-[4-(1 H-pyrrolo[2,3 261 364,366 b]pyridin-4-yl)-IH-pyrazol-1 - Ex 286 2 6 3 6 4 ,3 6y l]b en zo n itrile

*'~CO

2

C

2

H

5 262 333 ethyl 4-[4-(1H-pyrrolo[2,3-b]pyridin- Ex 286 Ia 4-yl)-IH-pyrazol-1-yl]benzoate 0 2 N

CF

3 4-{1-[2-chloro-6-nitro-4-(trifluoro 263 408, 410 methyl)phenyl]-IH-pyrazol-4-yl}-IH- Ex 286 pyrrolo[2,3-b]pyridine

CF

3 4-(1-{1-[4-(trifluoromethyl) 264 357 phenyl]ethyl}-IH-pyrazol-4-yl)-1H- Ex 250

CH

3 pyrrolo[2,3-b]pyridine 4-[1-(2,3-dihydro-lH-inden-1 -yl)-1 H 265 301 pyrazol-4-yl]-1H-pyrrolo[2,3- Ex 250 b]pyridine 148 4-[1-(1,2,3,4-tetrahydronaphthalen-1 266 315 yl)-1H-pyrazol-4-yl]-IH-pyrrolo[2,3- Ex 250 b]pyridine CI 4-(1-{1-[2-chloro-5-(trifluoromethyl) 267 391 CF3 phenyl]ethyl}-1H-pyrazol-4-yl)-IH- Ex 250

CHF

3 pyrrolo[2,3-b]pyridine _____ ~CH 3 _________ ____ CIl CI 4-{1-[1-(2,4-dichloro-5-fluoro 268 375 F phenyl)ethyl]-1H-pyrazol-4-yl}-lH- Ex 250 CH3 pyrrolo[2,3-b]pyridine 4-[1-(1 -cyclopentylethyl)-1H 269 281 pyrazol-4-yl]-1H-pyrrolo[2,3- Ex 250

CH

3 b]pyridine

C

6 Hs 4-[1 -(1 -methyl-3-phenylpropyl)-l H 270 317 pyrazol-4-yl]-1H-pyrrolo[2,3- Ex 250

CH

3 b]pyridine 271 267 4-[1-(1-cyclobutylethyl)-1H-pyrazol- Ex 250

CH

3 4-yl]-IH-pyrrolo[2,3-b]pyridine

CF

3 [2-[4-(1H-pyrrolo[2,3-b]pyridin-4 272 368 yl)-IH-pyrazol-1-yl]-5- Ex 286

CH

2 CN (trifluoromethyl)phenyl]acetonitrile

CF

3 [5-[4-(1H-pyrrolo[2,3-b]pyridin-4 273 368 yl)-IH-pyrazol-1-yl]-2- Ex 286

CH

2 CN (trifluoromethyl)phenyl]acetonitrile 4-{l-[(3E)-pent-3-en-1-yl]-lH 274 253 CH 3 pyrazol-4-yl}-1H-pyrrolo[2,3- Ex 250 b]pyridine 275 238 3 2-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl)- Ex 250 SZCN 1H-pyrazol-1-yl]propanenitrile 4-{1 -[(3E)-4-phenylbut-3-en-1 -yl] 276 315 1H-pyrazol-4-yl} -1 H-pyrrolo[2,3- Ex 250 b]pyridine 277 280 \-C--- 'cN 6-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)- Ex 250 I H-pyrazol-1-yl]hexanenitrile 0 2

C

2 HS ethyl 3-amino-2-{[4-(lH-pyrrolo(2,3 278 314

NH

2 b]pyridin-4-yl)-1H-pyrazol-1-yl]- Ex 250 methyl}propanoate 279 285 ethyl 2-[4-(1H-pyrrolo[2,3-b]pyridin- Ex 250 _______ - C0 2

C

2

H

5 4 -yi)-I H-pyrazol-1 -yllpropanoate 149 280 283 C 3

H

7 4-[1 -(1 -propylbutyl)-1H-pyrazol-4- 250 ____\ C 3

H

7 yl]-1H-pyrrolo[2,3-b]pyridine Ex 281 252 C 4

-[

4 -(lH-pyrrolo[2,3-blpyridin-4-yl)- Ex 250 1 H-pyrazol-1 -yl]butanenitrile CI ~ CF 3 [3-chloro-2-[4-(lH-pyrrolo[2,3 282 402, 404 blpyridin-4-yl)-1IH-pyrazol-1-yl]-S- Ex 286

CH

2 CN (trifluoromethyl)phenyl]acetonitrile

CF

3 5-[4-(l H-pyrrolo[2,3-b]pyridin-4-yl) 283 354 1H-pyrazol-1-yl]-2-(trifluoromethyl)- Ex 286 CN benzonitrile

CF

3 4-{ 1-[2-chloro-4-(trifluoromethyl) 284 363, 365 phenyl)-1H-pyrazol-4-yl}-1H- Ex 286 C1q pyrrolo[2,3-b]pyridine CN 4-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl) 285 354 1H-pyrazol-1-yl]-2-(trifluoromethyl)- Ex 286 __ ___CF 3 benzonitrile 287 286 2-[4-(IH-pyrrolo[2,3-b]pyridin-4-yl)- Ex 286 IH-pyrazol-1-yl]benzonitrile N 3-chloro-2-[4-(1 H-pyrrolo[2,3 288 320, 322 b]pyridin-4-yi)-1IH-pyrazol-1- Ex 286 yl]benzonitrile

NH

2 NC F 4-amino-5,6-difluoro-2-[4-(lH 289 362 pyrrolo[2,3-b]pyridin-4-yl)-1H- Ex 286 F pyrazol-1-yl]isophthalonitrile CN I -{[ 4 -(lH-pyrrolo[2,3-b]pyridin-4 290 264 yl)-1H-pyrazol-1 -yl]methyl} - Ex 250 cyclopropanecarbonitrile 291 280 CN 5

-[

4 -(IH-pyrrolo[2,3-b]pyridin-4-y)- Ex 250 291____ CH 3 1H-pyrazol-1 -yl)hexanenitrile 2,2-dimethyl-6-[4-( H-pyrrolo[2,3 292 308 \ CN b]pyridin-4-yI)-1H-pyrazol-1-yI]- Ex 250 _ hexanenitrile

C

2 Hs 4-[l -(I -ethyl-2-methylpropyl)-1H 293 269 pyrazol-4-yl]-1H-pyrrolo[2,3- Ex 250

H

3 C CH 3 b]pyridine 150 Br 5-bromo-2-[4-(1H-pyrrolo[2,3 294 364, 366 b]pyridin-4-yl)-1H-pyrazol-I- Ex 286 CN yl]benzonitrile

F

3 C N 3-[4-(lH-pyrrolo[2,3-b]pyridin-4-yl) 295 354 | 1H-pyrazol-1 -yl]-4-(trifluoromethyl)- Ex 286 _____ ______CN benzonitrile F3C 2-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl) 296 354 1 H-pyrazol-1-yl]-3-(trifluoromethyl)- Ex 286 benzonitrile

F

3 C 3-[4-(l H-pyrrolo[2,3-b]pyridin-4-yl) 297 372 1H-pyrazol-I-yl]-4-(trifluoromethyl)- Ex 286 ___ _CONH 2 benzamide 298 281 3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)- Ex 61 vO IH-pyrazol-1-yl]cyclohexanone HO 299 283 2-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)- Ex 250 IH-pyrazol-1-yl]cyclohexanol N.SO2CH3 4-(1 - {[1 -(methylsulfonyl)piperidin-4 300 360 yljmethyl}-1 H-pyrazol-4-yl)-IH- Ex 250 _ _ _ pyrrolo[2,3-b]pyridine NC 2-[4-(1 H-pyrrolo[2,3-b]pyridin-4-yl) 301 292 IH-pyrazol-1- Ex 61 yl]cyclohexanecarbonitrile F3C 3 4-{1-[2-(trifluoromethyl)phenyl]-1H 302 329 pyrazol-4-yl}-1 H-pyrrolo[2,3- Ex 286 b]pyridine 4-[I-(2,6-dichlorophenyl)-1

H

303 329,331 pyrazol- Ex 286 C1 4 -yl]-l H-pyrrolo[2,3-b]pyridine

CH

2 OH (4- ([4-(l H-pyrrolo[2,3-b]pyridin-4 304 311 yi)-1H-pyrazol-1 -yl]methyl) - Ex 250 cyclohexyl)methanol O 4-[1 -(tetrahydrofuran-2-ylmethyl) 305 269 IH-pyrazol-4-yl]-1H-pyrrolo[2,3- Ex 250 b]pyridine_ 4-[1-(1-cyclopentylpropyl)-1H 306 295 pyrazol- Ex 250

C

2 HS 4 -yl]-l H-pyrrolo[2,3-blpyridine 4-[1 -(tetrahydrofuran-3-ylmethyl) 307 269 1 H-pyrazol-4-yl]-1H-pyrrolo[2,3- Ex 250 b]pyridine 151 2-chloro-3-[4-(lH-pyrrolo[2,3 308 320 CNb] pyridin-4-yl)- 1H-pyrazol- I- Ex 286 IV CNyflbenzonitrile NC- / N 3-[4.( IH-pyrrolo[2,3-b pyridin-4-yl) 309 321 /3 IH-pyrazol-1-yl]-3-(1,3-thiazol-5-yl)- Ex 61 S propanenitrile _____ 0 I-benzyl-4- ([4-(1 H-pyrrolo[2,3-b] 31 7 N-\ pyridin-4-yI)-1H-pyrazol-1 -yl]- Ex 250

C

6

H

5 methyl} pyi-rolidin-2-one N C 3-(1 -methyl-1H-imidazol-5-yl)-3-[4 311 318 (1 H-pyrrolo[2,3-b]pyrdin-4-yl)-1 H- Ex6 N ~pyrazol-Ex6 H,,e ~ ~ N/N -yl]propanenitrile NC 3-[4-( 1H-pyrrolo[2,3-blpyridin-4-yl) 312 320 C,-IH-pyrazol-1-yl]-3-(3- Ex 61 S thienyl)propanenitrile N~ 1I -[4-(l H-pyrrolo[2,3-b]pyridin-4 313 292 yl)-]H-pyrazol-1- Ex 61 yl]cyclopentyl} acetonitrile CI 4-chloro-3-[4-(1H-pyrrolo[2,3 314 320,322 b]pyridin-4-yl)- IH-pyrazol-I - Ex286 C CN yl]benzonitrile CN 315 311 I4-[4-(1H-pyrolo[2,3-b]p>'iidin-4-y1)- Ex 286 VCN 1 H-pyrazo]-1I -yljphthalonitrile 0 316 303 H 3 . 3-methyl-4-[4-(1 H-pyrrolo[2,3 316 30 Hb~pyridin-4-yl)- IH-pyrazol- I - Ex 286 yl]benzaldehyde

H

3

NO

2 4-[ 1-(2-methyl-4-nitrophenyl)-1

H

317 320 pyrazol-4-yl]-1H-pyrrolo[2,3- Ex 286 _____ _______bipyridine 318 267 0 3-[4-( 1H-pyi-rolo[2,3-b]pyridin-4,yl)- Ex 201 1 H-pyrazol-1 -yllcyclopentanone 319 265 4-fl -(3-furylmethyl)-1 H-pyrazol-4- Ex 201 _______ _______________ yl]- IH-pyrrol o[2,3-b]pyri dine 320 265 0 4-fl -(2-furylmethyl)-1H-pyrazol-4. x 0 32 1 26 yl]-1H-pyrrolo[2,3-b]pyridine E 0 152 3- {2-cyano-1 -[4-(1 H-pyrrolo[2,3-b] 321 339 CN pyridin-4-yl)-1H-pyrazol-1-yl]ethyl}- Ex 61 benzonitrile CN

H

3 C : OH (3-methyl-4-[4-(I H-pyrrolo(2,3-b] 322 305 pyridin-4-yi)-1H-pyrazol-1 -yi]- Ex 286 phenyl}methanol O 4-methyl-4-[4-(1 H-pyrrolo[2,3 323 283

CH

3 b]pyridin-4-yI)-I-pyrazol-1 - Ex 61 \__CHs yi)pentan-2-one NC 3-(1 -benzofuran-2-yl)-3-[4-(LH 324 354 \ pyrrolo[2,3-b]pyridin-4-y)-1H- Ex 61 pyrazol-1-yl]propanenitrile trifluoroacetate N 3-(3-furyl)-3-[4-(1H-pyrrolo[2,3-b] 325 304 pyridin-4-yi)-IH-pyrazol-1 -yi]- Ex 61 0c propanenitrile

H

3 C r CN {3-methyl-4-[4-(1H-pyrrolo[2,3-b] 326 314 pyridin-4-yI)-IH-pyrazol-1-yl]- Ex 286 phenyt) acetonitrile Table 11 (Y)n-Z N-N N \ 5 N N 5 H Ex. No. -(Y)-Z MS ( M+Name Prep, H3C 4-methyl-3-[4-(7H-pyrrolo[2,3-d] 400 301 pyrimidin-4-yl)-1H-pyrazol-1-yl]- Ex 286 CN benzonitrile trifluoroacetate 4-[1 -(1-cyclopentylpropyl)-lH 401 296 pyrazol-4-yl]-7H-pyrrolo[2,3-d]- Ex 201

C

2

H

5 pyrimidine trifluoroacetate 153 {I -[4-(7H-pyrrolo[2,3-d]pyrimidin 402 293 4-yl)-IH-pyrazol-1-yl]cyclo- Ex 61 pentyl}acetonitrile trifluoroacetate 3-{( R)-2-cyano-1-[4-(7H 403R CN 340 pyrrolo[2,3-d]pyrimidin-4-yl)-IH- Ex 61 pyrazol-1-yl]ethyl}benzonitrile CN trifluoroacetate 3-{(1 S)-2-cyano-1 -[4-(7H 403S 340 pyrrolo[2,3-d]pyrimidin-4-yl)- I H SCN 340 pyrazol-1-yl]ethyl}benzonitrile Ex 61 CN trifluoroacetate NC 3 -[4-(7H-pyrrolo[2,3-d]pyrimidin 404 321 4-yl)-H-pyrazol-1-yl]-3-(3- Ex 61 thienyl)propanenitrileEx6 trifluoroacetate C ' 4-chloro-3-[4-(7H-pyrrolo[2,3-d] 405 321, 323 pyrimidin-4-yi)-iH-pyrazol-1-yl]- Ex 286 . Nbenzonitrile NC 3-(3-furyl)-3-[4-(7H-pyrrolo[2,3-d] 406 305 pyrimidin-4-yl)-1 H-pyrazol-1-yl]- Ex 61 propanenitrile NC 3

-[

4

-(

7 4 -pyrrolo[2,3-d)pyrimidin 407 CN 278 4 -yl)-1H-pyrazol-1-yl]- Ex 407 pentanedinitrile 3-{1-[4-(7H-pyrrolo[2,3-d] 408 307 pyrimidin-4-yi)-1 H-pyrazol-1 -yl]- Ex 61 cyclopentyl}propanenitrile {( -[ 4 -(7H-pyrrolo[2,3-d]pyrimidin 409 CN 307 4-yl)-1 H-pyrazol-1-yl]cyclohexyl)- Ex 61 acetonitrile trifluoroacetate H3COH {3-methyl-4-[4-(7H-pyrrolo[2,3

-

d] 410 306 pyrimidin-4-yI)-1H-pyrazol-1-yl]- Ex 286 phenyl)methanol trifluoroacetate 3 -pyridin-4-yl-3-[4-(7H-pyrrolo 411 316 [2,3-d]pyrimidin-4-yl)-IH-pyrazol- Ex 61 1-yl]propanenitrile ______ CN____ N 3-pyridin-3-yl-3-[4-(7H-pyrrolo 412 316 [2,3-dJpyrimidin-4-y)-IH-pyrazol- Ex 61 1-yl]propanenitrile trifluoroacetate 4CN 154 .~ SN3-[4-(methylthio)phenyl]-3-[4-(7H pyrrolo(2,3-d~pyrixnidin-4-yl)-IH 413 360 pyrazol-I -yl]propanenitrile Ex 61 trifluoroacetate CN 3-(3-methoxyphenyl)-3-[4-(7H 414 ~ o~ 345 pyrrolo[2,3-d]pyrimidin-4-yl)-I H- Ex6 pyrazol-I -yl]propanenitrile ON trifluoroacetate I 3-(4-methoxyphenyl)-3-[4-(7H 415 /c 345 pyrrolo[2,3-d]pyrimidin-4.-yI)-IH- Ex 61 pyrazol-1 -yi]propaneaitrile CN ____________

H

3 C {3-methyl-4-[4-(7H-pyrrolo[2,3-d] 416 ON 314 pyrimidin-4-yI)-l H-pyrazal- I -yI]- E 5 I ~phenyll acetonitrile trifluoroacetate E 5 0 .~ SN 3-[4-{methyls'ulfinyl)phenyl)-3-[4 417 J I376 (7H-pyrrolo(2,3-d]pyrimidin-4-y1)- Ex 61 /--ca IH-pyrazol-1 -yl]propanenitrile SI'- 3-[4-(methylsulfonyl)phenyl]-3-(4 418 392 (7H-pyrrolo[2,3-d]pyiidin-4-yI)- Ex 61 1H-pyrazol-1 -yl]propanenitrile ON 3-[3-(cyanomethoxy)phenyl]-3.{4 419 0 N 369 (7H-pyrrolo[2,3-d~pyrimidin-4-yl)- Ex 61 1 H-pyrazol-I -yl]propanenitrile CNI 420 - N 349 3-(6-chloropyridin-3-yl)-3-[4-(7H 31 pyrrolo[2,3-d]pyrixidin-4-yl)- 14- Ex 61 351 pyrazol- I -yl~propanenitrite ______CN I O* N 5-2-cyano- -[4-(7H-pyrrolo 421 N 340 1l-yl] ethyl) pyridine-2-carbonitrile E 2 CN trifluoroacetate 422 ON 3-(3,5-dimethylisoxazol-4-yl)-3-[4 42 334 (7H-pyrrolo[2,3-d]pylrnidin-4-yl)- Ex 61 1 H-pyrazol- 1 .- yl]propanenitrile trifluoroac-etate ______ ON _ _ _ _ _ _ _ _ _ _ _ _ 155

CF

3 3-[4-(7H-pyrrolo[2,3-d]pyrimidin 423 --N 384 4-yi)-1 H-pyraol-l-yl]-3-[6- Ex6 (trifluoromethyl)pyridin-3-yl]- Ex6 CN propanenitrile trifluoroac-etate

SOCH

3 3-(6-methoxypyridin-3-yl)-3-[4 424 N345 (7H-pyrrolo[2,3 -d]pyrimidin-4-yl). Ex 61 I H-pyrazoi-l -yl]propanenitrile ON trifluoroacetate 425 N 316 3-pyridin-2-yl-3-(4-(7H-pyrrolo 425 316 [2,3-d]pyrimidin-4-yl)-1H-pyrazol- Ex 61 I -y]]propanenitrile CN 3-(6-broniopyridin-2-yI)-3-[4-(7H 426 a Br 34 pyrrolo[2,3-d]pyrimidin-4-yl)-IH- Ex61 396 pyrazol-1 -y]]propanenitrile ____ N trifluoroacetate / I 6- {2-cyano- I -[4-(7H-pyrrolo[2,3 427 aN N 341 d]pyiimidin-4-yl)-IH-pyrazol-yI]- E 2 N ~ethyl) pyridine-2-carbonitrile E 2 ON tri fluoroacetate CN / 4-[4-(7H-pyrrolo(2,3-d~pyrimidin 428 306 4-yl)- I H-pyrazol- 1 -y!]- Ex 428 heptanedinitrile ON____ r 393 3-(5-bromopyridin-3-y)-3-14-(7H 429 -N 35 pyrrolo[2,3-d]pyrim-idin-4-yl)-lH- Ex 429 pyrazol-lI -yl)propanenitrile ON__ _ _ __ _ _ _ _ _ _ _ _ _ _ _ OH 4-[4-(7H-pyrrolo[2,3-d]pyrimidin 40288 4-yI)-l H-pyrazol-l -yl)- Ex 430 430 4<heptanedinitrile OH _______________ N 5-{(2-cyano- I 44-(7H-pyrrolo 431 / ..-N 340 2,3-d]pyrimidin-4-yl)-I H-pyrazol- E 3 431 N 340 1 -ylethyl) nicotinonitrile E 3 trifluoroacetate ______ ON__ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 156

H

3 CO ~3-(2-methoxypyridin-3-yl)-3-[4 432 345 (7H-pyrrolo[2,3-d]pyrimidin-4-yl)- Ex 61 1H-pyrazol-1-yl]propanenitrile ON trifluoroacetate 3-[ 4 -(cyanomethoxy)phenyl]-3-[4 433 CN 369 (7H-pyrrolo[2,3-d]pyrimidin-4-yl)- Ex 61 IH-pyrazol-1-yl]propanenitrile ON trifluoroacetate NC NCIN.O-0 N 3 -[2-(cyanomethoxy)phenyl]-3-[4 434 369 ( 7 H-pyrrolo[2,3-dlpyrimidin-4-yl)- Ex 61 IH-pyrazol-1-yl]propanenitrile ON trifluoroacetate r 3-(3,5-dibromophenyl)-3-[4-(7H 435 /473 pyrrolo[2,3-d]pyrimidin-4-ly)-1H- Ex 61 Br pyrazol-1-yl]propanenitrile CN CN 5- {2-cyano-1 -[4-(7H-pyrrolo 436 365 [ 2

,

3 -d]pyrimidin-4-yl)-lH-pyrazol- Ex 431 CN I -yl] ethyl) isophthalonitrile trifluoroacetate CN 3 -[6-(dimethylamino)pyridin-2-yl] 437 N N 359 3

-[

4

-(

7 H-pyrrolo[2,3-d]pyrimidin- Ex 421 4 -yl)-1 H-pyrazol-1 -yl]propane CN nitrile trifluoroacetate 4Br 401 3-(4-bromo-2-thienyl)-3-[4-(7H 438 41 pyrrolo[2,3-d]pyrimidin-4-yl)-1HF- Ex6 399 pyrazol-1-yl]propanenitrile Ex 61 CN trifluoroacetate CN 5-{ 2 -cyano-1-[4-(7H-pyrrolo 439 346 [2,3-d]pyrimidin--yl)-1 H-pyrazol- Ex 431 1 -yl]ethyl} thiophene-3-carbonitrile CN trifluoroacetate 1 41 3 -(5-bromo-2-fluorophenyl)-3-[4 440 Br (7H-pyrrolo[2,3-d]pyrimidin4-y)- Ex 61 412 1H-pyrazol-1-yl]propanenitrile N trifluoroacetate 3-(3-nitrophenyl)-3-[4-(7H 441

NO

2 359 pyrrolo[2,3-d)pyrimidin-4-yl)-IH- Ex 61 pyrazol-l -yl]propanenitrile CN trifluoroacetate 157 H3CO 422 3-(5-bromo-2-methoxyphenyl)-3 442 Br 424 [4-(7H-pyrrolo[2,3-d]pyrimidin-4- Ex 61 yl)-IH-pyrazol-1 -yl]propanenitrile CN H3CO 1 3 0 ~ 3-{2-cyano-1 -[4-(7H-pyrrolo 443 N 369 [2,3-d]pyrimidin-4-yl)-lH-pyrazol- Ex 61 1 -yl]ethyl) -4-methoxybenzonitrile CN trifluoroacetate 3-(3-bromophenyl)-3-[4-(7H 444 Br 392 pyrrolo[2,3-d]pyrimidin-4-yl)-1H- Ex 61 394 pyrazol-1-yl]propanenitrile ON trifluoroacetate - F 3-{2-cyano-1-[4-(7H-pyrrolo. 445 CN 357 [ 2 ,3-dlpyrinidin-4-yl)-IH-pyrazol- Ex 61 1 -yl]ethyl)-4-fluorobenzonitrile CN trifluoroacetate 3 -[S-bromo-2-(cyanomethoxy) 446 Br 447 phenyl]-3-[4-(7H-pyrrolo[2,3-d]- Ex 61 449 pyrimidin-4-yl)-lH-pyrazol-1-yl] CN propanenitrile 44 Br 385 3-(4-bromo-2-furyl)-3-[4-(7H 447 383 pyrrolo[2,3-d]pyrimidin-4-yl)-1H- Ex 61 CN pyrazol-1 -yl]propanenitrile I 4 -(cyanomethoxy)-3-{2-cyano-1 448 CN 394 [ 4 -(7H-pyr-olo[2,3-d]pyrimidin-4- Ex 61 yl)-l H-pyrazol-1-yl]ethyl} CN benzonitrile trifluoroacetate N 396 3-(4-bromopyridin-2-yl)-3-[4-(7H 449 Br 394 pyrrolo[2,3-d]pyrimidin-4-y)-lH- Ex 61 pyrazol-1 -yl]propanenitrile ______CN N ~' 2

-{

2 -cyano-1-[4-(7H-pyrrolo 450 CN 341 [2,3-d]pyrimidin-4-yl)-1H-pyrazol- Ex 431 I -yl]ethyl) isonicotinonitrile CN trifluoroacetate 4CN 5-{2-cyano-1 -[4-(7H-pyrrolo[2,3 451 330 d]pyrimidin-4-yl)-1H-pyrazol-1-yl]- Ex 431 N ethyl) -3-furonitrile trifluoroacetate 158 Br 3-[2-bromo-5-(cyanomethoxy) 452 447 phenyl]-3-[4-(7H-pyrrolo[2,3-d]- Ex 61 449 pyrimidin-4-yl)-1 H-pyrazol-1 -yl] CN NCA propanenitrile NCN NC 4-(cyanomethoxy)-2- {2-cyano-1 453 394 [4-(7H-pyrrolo[2,3-d]pyrimidin-4- Ex 61 yl)-1H-pyrazol-1 -yl]ethyl) CN NC 2 benzonitrile trifluoroacetate I 3-pyrimidin-5-yl-3-[4-(7H-pyrrolo 454 N 317 [2,3-d]pyrimidin-4-yl)-1H-pyrazol- Ex 61 1-yl]propanenitrile trifluoroacetate CN N 3-(2-bromopyridin-4-yI)-3-[4-(7H 455 Br 396 pyrrolo[2,3-d]pyrimidin-4-y)-11H- Ex 61 394 pyrazol-1-yl]propanenitrile CN trifluoroacetate N 4-{2-cyano-1 -[4-(7H-pyrrolo 456 CN 341 [2,3-d]pyrimidin-4-yl)-1H-pyrazol- Ex 421 1 -yl]ethyl)pyridine-2-carbonitrile _ _CN trifluoroacetate 3-(5-methoxypyridin-3-yl)-3-[4 457- 346 (7H-pyrrolo[2,3-d]pyrimidin-4-yI)- Ex 61 CH3 1 H-pyrazol-1 -ylpropanenitrile trifluoroacetate ______CN 3-(3-chlorophenyl)-3-[4-(7H 458 c 348 pyrrolo[2,3-d]pyrimidin-4-yl)-1H- Ex 61 pyrazol- 1 -yl]propanenitrile CN trifluoroacetate 3-[4-(7H-pyrrolo[2,3-d]pyrimidin 459 CF 382 4-yl)-IH-pyrazol-1-yl]-3-[3- Ex 61 3 (trifluorometbyl)phenyl] N propanenitrile trifluoroacetate I 3-(3-phenoxyphenyl)-3-[4-(7H 460 406 pyrrolo[2,3-d]pyrimidin-4-yl)-1H- Ex 61 pyrazol- I -yl]propanenitrile CN C 6

H

5 trifluoroacetate 3-[4-(7H-pyrrolo[2,3-d]pyrimidin 461 OCF 398 4-yl)-1H-pyrazol-1-yl]-3-(3- Ex 61 4 (trifluoromethoxy)phenyl]propane ___ _0CN nitrile trifluoroacetate 159 462 /methyl 3- (2-cyano-I -[4-(7H 462 373 pyrrolo[2,3-dlpyrimidin-4-yl)-lH- Ex 61 /---a- C0CH3pyrazol-1 -yl]ethyl~benzoate I 3- {2-cyano-1 -[4-(7H-pyrrolo 463 C0 2 H 359 [2,3-d]pyrimidin-4-yl)-LH-pyrazol- Ex 61 1 -yI]ethyl} benzoic acid 464 /- 380 3-[3-(lH-pyrazol-4-yl)phenyl]-3-[4 464 380 (7H-pyrrolo[2,3-dlpyrimidin-4-yl)- Ex48 NNI H I H-pyrazol-I -yl]propanenitile 3-(3-aminophenyl)-3 -[4-(7H 467 NH 2 329 pyrrolo[2,3-djpyrimidin-4-yl)-1H A-apyrazol-1 -yl]propanenitrile Bis Ex 467 ______ N trifluoroacetate 0 N-(3-{(2-cyano-I -[4-(7H 468 Nk 371 pyrrolo[2,3-d~pyrimidin-4-yI)-1H E46 Hpyrazol-1 -yljethyl)phenyI)- E 6 ON acetamnide trifluoroacetate 0N c1 ,, N-(3-{2-cyano-l-[4-(7H 469 A- -a N 407 pyrrolo[2,3-dlpyrimidin-4-yI)-lH- Ex 468 H pyrazol-I -yl]ethyl~phenyl) ON methariesulfonamide C N 4- (2-cyano-l -[ 4 -(7H-pyrrolo 470 346 [2,3d]pyiidin-4yl)Hpyrazo- Ex 470 1 -yl] ethyl) thiophene-2-catbonit-ile, ______ N trifluoroacetate ON 5-{2-cyano-I -[ 4 -(71{-pyrrolo 471 *.346

[

2 ,3-d]pyrimidinA-yl)-1H-pyrazol- Ex 471 1 -yIljethyl) thiophene-2-carbonitrile s ~trifhoroacetate Ir 0 3-[3-(morpholin-4-ylcarbonyl) 472 N 428 phenyl]-3-[4-(7H-pyrrolo[2,3-d) Ex47 0pyrimidin-4-yi)-i H-pyrazol-I - Ex 47 CN propanenitrile trifluoroacetate 475 A .C - NH 401 (7H-pyrrolo[2,3-dJpyrimidin-4-yi)- E 7 01H-pyrazol- 1 -yl]ethyl }benzamide E 7 ______ N 0Bis trifluoroacetate 160 3-(5-formyl-3 .thienyl)-3-[4-(7H 476 /349 pyrrolo[2,3-djpyrimidin-4-yI)-IH- Ex6 0pyrazol-lI -yI]propanenitrile Ex6 CN trifluoroacetate I 3-{(2-cyano- I-[4-(7H-pyrrolo 477 - H372 [2,3-d]pyrimidin-4-yl)-1I--pyrazol- Ex 472 0 1I-yl]ethyl) -N-methylbenzaniide CN 0trifluoroacetate 0 2-cyano-N-(3- {2-cyano- I -[4-(7H1 478 pN 396 pyrrolo[2,3-d~pyrimidin-4-yl)-IH- Ex 472 H pyrazol- I -yI]ethyl} phenyl) ON ON acetamide trifluoroacetate N-(3-{2-cyano-1 -[4-(7H 479 N llt 434 pyrrolo[2,3-djpyrimidin-4.yl)-1IH- Ex 478 H Ipyrazol-1 -yl]ethyl~phenyl) ___-a_0 -ON nicotinamide Bis trifluoroacetate N~'NHN-(3 -{(2-cyano- I -[4-(7H 480 N 1 pyrrolo [2,3 -d] pyrim idin-4-yl)- IH - E 6 H I pyrazol-! -yl]cthyl~phcnyl)-N'- E 6 ON isopropylurea trifluoroacetate I ~isopropyl (3 - (2-cyano- I -[4-(7H 481 N 415 pyrrolo[2,3-d]pyrimidin-4-yl)-1H- Ex 468 H ? pyrazol-1 -yllethyl) phenyl) _____CN 3 ,carbamate trifluoroacetate

C

6

H

5 3-(5-phenylpyridin-3-yI)-3-[4-(7H 482 392 pyrrolo[2,3-d]pyrimidin-4-yl)-H x 48 .- N pyrazol-I -yllpropanenitrile- E 8 trifluoroacetate CN ON 3-(3,3'-bipyridin-5-yl)-3-[4-(7H 483 N.~ N Pyrrolo[2,3-d]pyrimidin-4-yI)-IH- E 8 48I 9 pyrazol- 1 -yl~propanenitrile- E 8 N trifluoroacetate CNN) 484~IN 3-(5-pyrimidin-5-ylpyridin-3-yl)-3 484 N 394 [4-(7H-pyrrolo[2,3-d]pyrimidin-4. Ex 482 I yl)-l H-pyrazol-I -yl]propanenitrile CNN 485 N 396 pyridin-3-y1]-3-[4-(7H-pyrrolo[2,3- Ex 482 d]pyrirnidin-4-yi)-IH-pyrazol-1 -yI]. ______ N propanenitrile trifluoroacetate 161 CN 3-(5-ethynylpyridin-3-yl)-3-[4-(7H 486 339 pyrrolo[2,3-d]pyrimidin-4-yl)-1 H- Ex 486 pyrazol-1 -yl]propanenitrile trifluoroacetate N 3-[S-(phenylthio)pyridin-3-yl]-3-[4- Ex 488 488 424 (7H-pyrrolo[2,3-d)pyrimidin-4-yl) \ / S IH-pyrazol-1-yl]propanenitrile N trifluoroacetate Br 402 3-(2-bromo-1,3-thiazol-5-yl)-3-[4- Ex 61 489 N

(

7 H-pyrrolo[2,3-d]pyrimidin-4-yl) 400 IH-pyrazol-1-yl]propanenitrile CN CO 2 Et 490 300 ethyl 3-[4-(7H-pyrrolo[2,3-d]- Ex 61 CH3 pyrimidin-4-yl)- 1 H-pyrazol- 1-yl] _ _ butanoate ON 491 N 4 3 -(5-morpholin-4-ylpyridin-3-yl)-3- Ex 491 401

[

4

-(

7 H-pyrrolo[2,3-d]pyrimidin-4 yl)-1 H-pyrazol-1 -yl]propanenitrile ,CH3 N N 3 -(1-methyl-1H-pyrazol-4-yl)-3-[4- Ex 61 492 N 319 ( 7 H-pyrrolo[2,3-d]pyrimidin-4-yl) IH-pyrazol-1-yl]propanenitrile ON N4 N 4--[1 -phenyl-2-(1H-1,2,4-triazol- Ex 250 493 357 1-yl)ethyl]- 1H-pyrazol-4-yl}-7H -6 pyrrolo[2,3-d]pyrimidine rN N 4- 1-[1 -phenyl-2-(4H-1, 2 ,4-triazol- Ex 250 494 357 4-yl)ethyl]-1 H-pyrazol-4-yl} -7H pyrrolo[2,3-d]pyrimidine CN 495 392 3-(3-pyridin-3-ylphenyl)-3-[4-(7H- Ex 482 pyrrolo[2,3-d]pyrimidin-4-yl)-1

H

pyrazol- -yl]propanenitrile 162 CN 49 3-[5-(phenylsulfinyl)pyridin-3-yl]- Ex 496 496- 440 3

-[

4 -(7H-pyrrolo[2,3-d]pyrimidin \ / 4 -yl)-lH-pyrazol-1 -yl]propane. N nitrile trifluoroacetate CN 497 3-[5-(phenylsulfonyl)pyridin-3-yl]- Ex 497 --- 456 3

-[

4

-(

7 H-pyrrolo[2,3-d]pyrimidin - O ~ 4 -yl)-1H-pyrazol-1-yl]propane N nitrile trifluoroacetate

CH

3 498 272 3

-[

4 -(7H-pyrrolo[2,3-d]pyrimidin- Ex 498 OH 4 -yl)-1H-pyrazol-1 -yllpentan-1-o1 499 CH 3 3 30 methyl 3-[4-(7H-pyrrolo[2,3-d]. Ex 499 O O pyrimidin-4-yl)-1H-pyrazol-1 -yl] pentyl carbonate

CH

3 500(a) 285 (1E)-3-[4-(7H-pyrrolo[2,3-d]- Ex 500 N'-OH pynidin-4-yl)-1H-pyrazol-1-yl] pentanal oxime

CH

3 501

OCH

3 299 (1E)-3-[4-(7H-pyrrolo2,3-d]- Ex 501 N- 3pyrimidin-4-yl)-1H-pyrazol- -yl] ___ pentanal O-methyloxime

CH

3 502 N299 (1 Z)-3-[4-(7H-pyrrolo[2,3-d]- Ex 502 N pyrimidin-4-yl)-l H-pyrazol-1-yl] _CH3 pentanal 0-methyloxime

CH

3 4-[i-(4,4-dibromo-1-ethylbut-3-en- Ex 503 503 Br 426 1-yl)-1H-pyrazol-4-yl]-7H Br pyrrolo[2,3-d]pyrimidine trifluoroacetate CN S N 3

-[

4

-(

7 H-pyrrolo[2,3-dlpyrimidin- Ex 488 504 431 4 -yl)-IH-pyrazol-1-yl]-3-[5-(1,3 thiazol-2-ylthio)pyridin-3-yl] propanenitrile bis(trifluoroacetate)

H

3 C S 3-[5-(ethylthio)pyridin-3-yl]-3-[4- Ex 488 505 376 (7H-pyrrolo[2,3-d]pyrimidin4-yl) .- N 1H-pyrazol-1 -yl)propanenitrile

CN

CH

3 506 266 4-[1 -(1 -ethylbut-3-yn-1 -yl)-IH- Ex 506 506 6H pyrazol-4-yl]-7H-pyrrolo[2,3 d]pyrimidine trifluoroacetate 4- {1 -[1 -methyl-2-(l H-1,2,4-triazol- Ex 250 507 " N 295 1-yl)ethyl]-1H-pyrazol-4-yl)-7H \J CH3 pyrrolo[2,3-d]pyrimidine 4-[4-(7H-pyrrolo[2,3-d]pyrimidin- Ex 61 508 270 4-yl)-l H-pyrazol-1 -yl]pentan-2-one

CH

3 trifluoroacetate o 1-phenyl-2-[4-(7H-pyrrolo- Ex 250 509 0 318 [2,3-d]pyrimidin-4-yl)-1H-pyrazol

CH

3 1-yl]propan-1-one NC H3Ch NC5H C 392 3-[5-(ethylsulfinyl)pyridin-3-yl]-3- Ex 496 510 S, 392 [4-(7H-pyrrolo[2,3-d]pyrimidin-4 N yl)-l H-pyrazol- 1 -yl]propanenitrile NC,, H3Ch 3-[5-(ethylsulfonyl)pyridin-3-yl]-3- Ex 497 511 V O 408 [4-(7H-pyrrolo[2.3-d]pyrimidin-4 N yl)-lH-pyrazol-I -yl]propanenitrile N CN 3-[5-(cyclohexylthio)pyridin-3-yl]- Ex 488 512 430 3-[4-(7H-pyrrolo[2,3-d]pyrimidin S 4-yi)-IH-pyrazol-1-yl] propanenitrile N 513 HO 3 1 -phenyl-2-[4-(7H-pyrrolo- Ex 509 de#1 320 [2,3-d]pyrimidin-4-yl)-IH-pyrazol _\ CH 3 1 -yl]propan- 1 -ol 513 HO I -phenyl-2-[4-(7H-pyrrolo[2,3-d]- Ex 509 de#2 320 pyrimidin-4-yl)-IH-pyrazol-1-yl]

CH

3 propan-1-ol 514 1 s -CH 3 375 3-[3-(ethylthio)phenyl]-3-[4-(7H- Ex 516 SACH3 pyrrolo[2,3-d]pyrimidin-4-yl)-1H CN pyrazol-1 -yl]propanenitrile 1 iM 3-[3-(ethylsulfinyl)phenyl]-3-[4 (7H-pyrrolo[2,3-d]pyrimidin-4-yl)- Ex 516 515 s CH 3 391 1H-pyrazol-1-yl]propanenitrile CN O 3-[3-(ethylsulfonyl)phenyl]-3-[4 516 (7H-pyrrolo[2,3-d]pyrimidin-4-yl)- Ex 516 ee#1 S CH 3 407 1H-pyrazol-1-yl]propanenitrile CN 3-[3-(ethylsulfonyl)phenyl]-3-[4 516 (7H-pyrrolo[2,3-d]pyrimidin-4-yl)- Ex 516 ee#2 S CH3 407 1H-pyrazol-1-yl]propanenitrile CN 3-[5-(cyclohexylsulfonyl)pyridin-3 yl]-3-[4-(7H-pyrrolo[2,3-d]- Ex 497 517 462 pyrimidin-4-yl)-1H-pyrazol-1 -yl] d *o propanenitrile CN 3-[5-(cyclohexylsulfinyl)pyridin-3 yl]-3-[4-(7H-pyrrolo[2,3-d]- Ex 496 518 - 0 446 pyrimidin-4-yi)-1H-pyrazol-1 -yl] propanenitrile CN O 519 A 304 4-[1-(1-methyl-2-phenylethyl)-1H- Ex 250

CH

3 pyrazol-4-yl]-7H-pyrrolo[2,3-d] pyrimidine 520 / 310 4-{l -[1 -methyl-2-(3-thieayl)ethyl)- Ex 250 CHa 1H-pyrazol-4-yl}-7H-pyrrolo 3_ [2,3-d]pyrimidine 521 315 3-{1-[4-(7H-pyrrolo[2,3-d]- Ex 250 N pyrimidin-4-yl)-1H-pyrazol-1-yl]

H

3 ethyl} benzonitrile 522 N 294 4-{1-[2-(lH-imidazol-1-yl)-1- Ex 250

CH

3 methylethyl]-1 H-pyrazol-4-yl) -7H pyrrolo[2,3-d]pyrimidine 523 CH 3 310 4-{1-[I-methyl-2-(3-methyl-1,2,4- Ex 250

CH

3 O'N oxadiazol-5-yl)ethyl]-1H-pyrazol-4 yl}-7H-pyrrolo[2,3-d]pyrimidine 524 CH3 393 3-[3-(methylsulfonyl)phenyl]-3-[4- Ex 516 s (7H-pyrrolo(2,3-d]pyrimidin-4-yl) N H-pyrazol-1-yl)propanenitrile 165 3-(3-pyridin-4-ylphenyl)-3-[4-(7H pyrrolo[2,3-d]pyrimidin-4-yl)-IH- Ex 482 525 392 pyrazol-1-yl]propanenitrile CN -N CHa 526 268 4-[l -(1 -ethylbut-3-en-l -yl)-1 H- Ex 526 vCH 2 pyrazol-4-yl]-7H-pyrrolo[2,3-d] pyrimidine 527 CH3 CH3268 4-[-(1,3-dimethylbut-3-en-1-yl)- Ex 526 CH2 2H-pyrazol-4-yl]-7H-pyrrolo[2,3 d]pyrimidine NC H3CyCH3 52 S3C y3-[5-(isopropylthio)pyridin-3-y]]-3- Ex 488 528 S 390 [4-(7H-pyrrolo[2,3-d]pyrimidin-4 yl)-lH-pyrazol-1 -yl)propanenitrile NC H 3 C CH 3 3-[5-(isopropylsulfinyl)pyridin-3- Ex 496 529 S 406 yl]-3-[4-(7H-pyrrolo[2,3-d] pyrimidin-4-y)-1 H-pyrazol- I-y] N propanenitrile NC H 3 C CH 3 3-[5-(isopropylsulfonyl)pyridin-3- Ex 497 530 ., o 422 y]-3-[4-(7H-pyrrolo[2,3-d] 1 0 pyrimidin-4-yl)-IH-pyrazol-1-yl] N propanenitrile CN 531 3-[4-(7H-pyrrolo[2,3-d]pyrimidin- Ex 431 ee#1 CF 3 384 4-yl)-1H-pyrazol-1-yl]-3-[5 (trifluoromethyl)pyridin-3-yl] propanenitrile CN 531 CF 3-[4-(7H-pyrrolo[2,3-d]pyrimidin- Ex 431 ee#2 CF 3 384 4 -yl)-lHl-pyrazol-1-yl]-3-[5 (trifluoromethyl)pyridin-3-yl] propanenitrile 2-[4-(7H-pyrrolo[2,3-d]pyrimidin- Ex 250 532 N CF3 401 4-yl)-1H-pyrazol-1-yl]-N-[3

CH

3 H (trifluoromethyl)phenyl] ____ propanamide 533 N I383 N-2-naphthyl-2-[4-(7H-pyrrolo- Ex 250

H

3 [2,3-d]pyrimidin-4-yl)-1H-pyrazol H3 H I -yl]propanamide 166 N34 N 383 N-1 -naphthyl-2-[4-(7H-pyrrolo- Ex 250 H [2,3-dlpyriniidin-4-yl)-I H-pyrazol

H

3 NI -yl]propanamide 535 /"j N a C 35 N-(3-eyanophenyl)-2-[4-(7H- Ex 250 ON pyrrolo[2,3-d]pyrimidin-4-y)-l H _______ CH 3 pyrazol- I -yIlpropanamide ____ 536 37N-benzyi-2-[4-(711-pyrrolo- Ex 250 H [2,3-d)pyjrmidin-4-yl)-I H-pyrazol

C

3 I 1-yl]propanamide 57NIO- 347 N-phenyl-2-[4-(711-pyrrolo[2,3-d].. Ex 250

_____

2 HS H pyrimidin-4-yl)-1 H-pyrazol-1 -yl) ________butanamide 0 65S N-(4-phenoxypheny1)-2-[4-(7H- Ex 250 538NjN pyrrolo[2,3-dlpyrirmdin-4-y).1

H

AT H pyrazol-1 -yl]butanamide 539iiII 2 397 N-2-naphthyl-2-[4-(7H-pyrrojo- Ex 250 _______ C H H 2,3-d]pyrimidin-4-yI)- 1H-pyrazol ___________________ I'-yljbutanamide ____ 540 I N a N 372 N-(3-cyanophenyl)-2-[4-(7R.. Ex 250 NHO pyrrolo[2,3-d~pyrimidin4-y)-l H

C

2

H

5 H pyrazol-I -yflbutanamide ____ 541 A NN-biphenyl..4-yI.2-[4-(7H- Ex 250 54I 423 Pyrrolo[2,3-djpyzimidin-4-yl)-l H.. N N pyrazol- I -yl]butanamnide ,C)H-"H 0 N N N-(biphenyl-4-ylmethyl)-2-4.(7H.. Ex 250 542 A IH I 437 pyrrolo[2,3-d]pyrimidin-4.ylI

.H

C

2

H

5 pyrazol-1 -yI~butanamide 0 543 N 0 43 N-(biphenyl-3-ylmethyl)-2-[4.(7H.. Ex 250 10 37 pyrrolo[2,3-d]pyrinidin-4-yl)-l1H. 6____________H_ pyrazol- I -yl]butanamide 544 CNN-(4-cyanophenyl)-2-[4-(7H- Ex 250 N Na 372 pyrrolo[2,3-d~pyriniidin-4-yl)-I

H

______ C H pyrazol- I -yllbutanaxnide 545 N 397 N-1-naphthyl-2-[4-(7H-pyrrolo- Ex 250 H [2,3-djpyrimidin-4-yl)-1H-pyrazol

C

2

H

5 1-yl]butanamide CN 5-{2-cyano-1-[4-(7H-pyrrolo- Ex 431 546 435 [2,3-d]pyrimidin-4-yl) -1H-pyrazol NJ 1-yl]ethyl)-N-phenylnicotinamide N trifluoroacetate 4-(-[1-(5-bromopyridin-3-yl)-4,4 Br difluorobut-3-e n-1-yl]-1H-pyrazol 4-yl}-7H-pyrrolo[2,3-d]pyrimidine Ex 717 547 N 430,432 F F CN 5-{4,4-difluoro-1-[4-(7H pyrrolo[2,3-d]pyrimidin- 4-yl)-lH pyrazol-1-yl]but-3-en-1- Ex 717 548 ' 378 yl}nicotinonitrile F F Example 407: 3-[4-(7H-Pyrrolo[2,3-dpyrimidin-4-yI)-IH-pyrazol-1-yllpentanedinitrile CN CN N-N N 5 Step 1: Dimethyl 3

-[

4

-(

7

-([

2 -(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yI)-IH pyrazol-1-yl]pentanedioate 4-(lH-Pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (31.0 g, 0.0983 mol) was suspended in ACN (620 mL, 12 mol), and DBU (9.3 mL, 0.062 mol) was added 10 under nitrogen. The reaction was heated to 65 *C and dimethyl (2E)-pent-2-enedioate (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. 168 The oil was partitioned between ethyl acetate and water. The organic layer was washed with 1.0 N HC1, brine, dried over magnesium sulfate, and then concentrated 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 5 3-[4-(7-{[2-(trimethylsilyl)ethoxy)methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1 H-pyrazol-1 yl]pentanedioate as a white powder (29.5 gM, 64%), LC /MS (M+H)*: 474, 'H NMR (DMSO-d) S 9.1 (s,IH), 9.02 (s,1H), 8.65 (s, 1H), 8.11 (d, 1H), 7.42(d, IH), 5.78(s, 2H), 5.27(m, 1H), 3.65(m, 8H), 3.15(m, 4H), 0.95(t, 2H), 0.1(s, 9H). 0 Step 2: 3 -[4-( 7

-[

2 -(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-H-pyrazol-1-yl] pentanedioic acid Dimethyl 3-[4-(7-{[2-(trimethylsilyl)ethoxylmethyl}-7H-pyrrolo[2,3-d]pyrirnidin-4-yl)-1H pyrazol-1-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 5 reaction was stirred at rt for 2 h. The methanol was removed In vacuo and a resulting aqueous layer was cooled in an ice bath. The solution was made acidic pH-4 with IN HCI 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]pyrimidin-4-yl)-1H-pyrazol-1-yI)pentanedioic acid as a white crystalline powder (31.8 gm, 80%), LC /MS (M+H)*: 446, 'H NMR (DMSO-d) 5 8.85 1 H), 0 8.75(s, 1H), 8.42(s, 111), 7.85(d, 1H), 7.17(d, 1H), 5.71(s, 2H), 5.18(m,1IH), 3.65(t, 2H), 3.05(m,4H), 0.92(t, 211), 0.1(s, 9H). Step 3: 3-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-IH-pyrazol-1-ylj pentanediamide 25 3-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1 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 CDI (34.7 g, 0.214 mol) was added. This mixture was allowed to stir for 30 minutes and then allowed to warm to rt. After stirring for 2 h ammonia (12.2 g, 0.714 mol) was bubbled through the solution for 30 minutes giving a cloudy suspension. The reaction mixture 30 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)ethoxymethyl-7H pyrrolo[ 2

,

3 -d]pyrimidin-4-yl)-IH-pyrazol-1-yl]pentanediamide as a white powder (29.0 gm, 91%), LC /MS (M+H)*: 444, 'H NMR (DMSO-d) S 8.85(s, 1HI), 8.59(s, 1H), 8.40(s, 1H), 7.87(d,IH), 35 7.75(s,2H), 7.15(d, 1H), 6.95(s, 2H), 5.73(s, 2H), 5.29(m,1H), 3.63(t, 2H), 2.82(m, 2H), 2.73(m, 2H1), 0.90(t, 2H), 0.1(s, 9H). 1 to Step 4: 3-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2.3-d]pyrimidin-4-yl)-IH-pyrazol--yl] pentanedinitrile 3-[4-(7-[2-(Trimethylsilyl)ethoxylmethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-l 5 yllpentanediamide (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 DCM and the resulting DMF solution was diluted with water to precipitate the product. The solid precipitate was 10 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)-IH-pyrazol-1-yl]pentanedinitrile as white needle-like crystals (22.7 gm, 85%), LC 15 /MS (M+H)*: 408, 'H NMR (DMSO-d 6 ) 8 9.07(s, 1H), 8.87(s, 1H), 8.59(s, 1H), 7.88(d, 111), 7.19(d, 1H), 5.75(s, 2H), 5.30(m,IH), 3.62(t, 21H), 3.40(m, 4H), 0.91(t, 2H), 0.10(s, 9H). Step 5: 3-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-JH-pyrazol-f-yl]pentanedinitrile 3

-[

4

-(

7 -(2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-l 20 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. After heating for 24 h the reaction was allowed to cool to rt 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 25 reaction was diluted with water and concentrated in vacuo to remove the ACN, giving a precipitate. 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 (DMSO-d 6 ) S 8.9(s, 1H), 8.72(s,1H), 8.43(s, 1 H), 7.59(d, 1H), 6.92(d, I H), 5.21(m,IH), 3.25(m, 4H). 30 Example 421: 5-{ 2 -Cyano-1-[4-(7H-pyrrolo[2,3-dlpyrimidin-4-yl)-1H-pyrazol-1-ylI ethyl) pyridine-2-carbonitrile trifluoroacetate 170 CN N-N TFA N N Step 1: 3-(6-Chloropyridin-3-yl)-3-[4-(7H-pyrrolo[2,3-djpyrimidin-4-yl)-1H-pyrazol-1-yljpropane nitrile 5 3

-(

6 -Chloropyridin-3-y1)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d] pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile (prepared by methods analogous to those described 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 .0 mixture was stirred at room temperature overnight. Solvent was removed in vacuo, the crude product was purified by preparative HPLC eluting with an ACN; water gradient buffered with ammonium hydroxide to pH=10, to give 3

-(

6 -chloropyridin-3-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-IH pyrazol-l-yl]propanenitrile as a white powder (35mg,69%), LCMS (M+1)*:350, 'H NMR (DMSO-d6) 5 12.21 (b,1H), 9.00 (s,IH), 8.78 (s,IH), 8.62 (s,1H), 8.58 (s,11H), 8.00(m,IH), 7.70(m,2H), 5 7.00(s,1H), 6.22(m,l H), 3.90(m, IH), 3.78(m,1H) Step 2: 5-2-Cyano-1-[4-(7H-pyrrolo[2,3-dpyrimidin-4-yl)-1H-pyrazol-1-yljethylpyridine-2-carbo nitrile trifluoroacetate A mixture of 3

-(

6 -chloropyridin-3-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1 20 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)palladium() (0.04 g, 0.00004 mol) was added and the resulting mixture degassed again with dinitrogen. The reaction mixture was heated in a sealed tube at 170 "C for 15 minutes in a microwave (Personal Chemistry). After cooling to room temperature, the solids were filtered, rinsed with DMF and the 25 combined solvent was concentrated in vacuo. The residue was triturated with hexanes (3x), and hexanes washes were discarded. The crude product was purified by preparative HPLC eluting with an 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-d 6 ) 5 12.50(b,1IH), 9.05(s,1H), 8,89(s,IH), 8,80(s,lH), 8.58(s,1 H), 8.18(m,2H), 7.78(s,1H), 7.05(s,1H), 6.20(m,1 H), 3.90(m,1H), 3.77(m,1 H). 30 Example 428: 4-14-(7H-Pyrrolo[ 2

,

3 -dlpyrimidin-4-yl)-1H-pyrazol-1-yllheptanedinitrile 1-71 NC CN N-N N \ N Step 1: 3-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-) 5 yI]pentane-1,5-diol Diethyl 3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H pyrazol-1-yl]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 tetrahydroaluminate in THF (3.2 mL) was added slowly. The reaction 10 was stirred for I h, 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]pyrimidin-4-yl)-1 H-pyrazol-1 -yl]pentane 1,5-diol as a clear viscous oil (0.51 gM, 76%), LC /MS (M+1)4: 418, '14 NMR (DMSO-d) 8, 8.85(s, 15 1 H), 8.41(s, IH), 8.37(s, IH), 7.45(d, H), 6.83(d, 1H), 5.73(s, 214), 4.91(m, 1 H), 3.75(m,2H), 3.59(m, 2H), 3.45(m,2H), 2.18(m, 4H), 0.95(m,2H), 0.1(s, 914). Step 2: 3-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-JH-pyrazol-1 yI]pentane-J,5-diyl dimethanesulfonate 20 A mixture of 3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1HT pyrazol-1-yl]pentane-1,5-diol (50 mg, 0.0001 mol) in DCM (2 mL, 0.03 mol) was cooled at 0 *C. To this mixture, TEA (50 pL, 0.0004 mol) was added. The reaction was stirred for 15 minutes. Methanesulfonyl chloride (23 pL, 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 25 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]pyrimidin-4-yl)-1H-pyrazol-1 -yl] pentane-1,5-diyl dimethanesulfonate (57 mg, 80 %) as an oil. MS(ES): 574 (M+1). Step 3: 4

-[

4

-(

7 -[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-H-pyrazol-1 30 yl]heptanedinitrile 1'72 To a mixture of 3

-[

4

-(

7

-[

2 -(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin4-yl) IH-pyrazol-1-yl]pentane-1,5-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 stirred for 2 hours. The mixture was heated at 60 *C for 1 hour. Water was added and the product was extracted with ethyl 5 acetate. The combined extracts were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give 4

-(

4

-(

7

-[

2 -(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3 d]pyrimidin-4-yl)-1H-pyrazol-1-yl]heptanedinitrile (40 mg, 90 %) as an oil. MS(BS): 436 (M+1). Step 4: 4-[4-(7H-Pyrrolo(2, 3 -dlpyrimidin-4-yl)-l H-pyrazol-1-yl]heptanedinitrile 0 Using a procedure analogous to Example 61 for the removal of the SEM protecting group, the title compound was prepared as a white amorphous solid, (17 mg, 60%) 'H NMR (400 MHz, DMSO): 5. 8.75 (s, 1 H), 8.65 (s, I H), 8.4 (s, IH), 7.6 (d, I H), 7.0 (d, 1H), 4.5 (m, IH), 2.35 (m, 4 H), 2.2 (m, 4H). MS(ES): 306 (M+ 1). 5 Example 429: 3 -(S-Bromopyridin-3-yi)-3-[4-(7H-pyrrolo[2,3-dlpyrimidin-4-y)-IH-pyrazol-1 yllpropanenitrile CN -- N N-N Br N'\ NIy Step 1: ( 2

Z&E)-

3 -(5-Bromopyridin-3-yl)acrylonitrile CN 20 Br To a mixture of 1.0 M potassium tert-butoxide in THF (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 THIF (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 25 THF (1.0 mL, 0.012 mol). After stirring at room temperature for 20 hours, the reaction mixture was 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 purified by flash chromatography on silica gel using ethyl acetate-hexanes 3:7 as fluent to give a mixture of cis and trans isomers ( 2 )-3-(5-bromopyridin-3-yl)acrylonitrile as an off 1 7'] white solid (268 mg, 47.69%). LCMS (M+1)*: 209,211, 'H NMR (400 MHz, CDC1 3 ): 6. 8.75(s,1H), 8.62(s,IH), 7.90(s,IH), 7.40(d,IH), 6.00(d, IH). Step 2: 3 -(5-Bromopyridin-3-yl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]mehyl-7H-pyrrolo[2,3-d]pyr 5 imidin-4-yl)-l H-pyrazol-1-yljpropanenitrile To 4-(1 H-pyrazol-4-yl)-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), followed by the addition of ( 2 Z&E)-3-(5-bromopyridin-3-yl)acrylonitrile (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 10 partitioned between dilute hydrochloric acid and ethyl acetate. 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-(trimethylsilyl)-ethoxy]-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H pyrazol-1-yl]propanenitrile as an off-white solid (225 mg, 67.66%). LCMS (M+1)*:524,526: 'H t5 NMR (400 MHz, CDCl3): 8.90(s, 11), 8.80(s, 1H), 8.70(s, 1M), 8.42(s, 1H), 8.40(s, IH), 8.00(s, 1H), 7.50(d, 1H), 6.82(d, 1H), 5.81(m, 1H), 5.75(s, 2H), 3.70(m,1H), 3.60(m, 2H), 3.42(m, IH), 1.00(m, 21), 0.08(s, 9H). Step 3: 3 -(5-Bromopyridin-3-yl)-3-[4-(7H-pyrrolo[2. 3 -d]pyrimidin-4-yl)-H-pyrazol-1-yl]propane !0 nitrile The 3-(5-bromopyridin-3-yl)-3-[4-(7-[2-(trimethylsilyl)ethoxy~methyl-7H-pyrrolo[2,3-d] pyrimidin-4-yl)-1H-pyrazol-1-yljpropanenitrile (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 intermediate was dissolved in methanol (12 mL, 0.30 25 mol) and ethylenediamine (0.2 mL, 0.003 mol) and was stirred overnight at room temperature. The reaction was concentrated in vacuo to give the crude product which was purified by preparative HPLC eluting with a water: ACN gradient buffered with ammonium hydroxide (pH=10) to give 3 (5-bromopyridin-3-y )-3-[4-(7H-pyrrolo[2,3-djpyrimidin-4-yl)-lH-pyrazol-1-y]propanenitrile as an amorphous white powder (118 mg, 71.36%). LCMS (M+1)*:394,396, 'H NMR (400 MHz, DMSO 30 d6): 8. 12.05(bs,1H), 8.98(s, lH), 7 .0(s, 1H), 6 .50(m, 2H), 8.50(s, 1H), 8.10(s, 1H), 7 .80(s, IH), 6.98(s, IH), 6.21(m, 1H), 3.90(m, IH), 3 .70(m, I H). Example 430: 3-[4-(7H-Pyrrolo[2,3-dlpyrimidin-4-yl)-1H-pyrazol-1-yllpentane-1,5-diol 17A HO OH N-N N N N H Using a procedure analogous to Example 61 for the removal of the SEM protecting group but using 3

-[

4 -(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1 -yl] 5 pentane-1.5-diol from Example 428, the title compound was prepared as a white amorphous solid, (25 mg, 70%) 'H NMR (400 MHz, DMSO): 5. 8.65 (s, IH), 8.6 (s, 1H), 8.25 (s, 1H), 7.6 (d,I 1H), 6.0 (d, IH), 4.6 (m, 1H), 3.3 (m, 2H), 3.2 (m, 2H), 2.1 (m, 2H), 1.9.(m, 2H). MS(ES): 288 (M+1), Example 431: 5-(2-Cyano-1- [4-(7H-pyrrolo [2,3-djpyrimidin-4-yI)-1H-pyrazol-1-ylJethyl) 0 nicotinonitrile bis(trifluoroacetate) CN -N N-N CN 2TFA N N N H A slurry of 3 -(5-bromopyridin-3-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-IH-pyrazol-l 15 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 nitrogen. The reaction was sealed and heated at 170 *C for 15 minutes in a microwave (Personal Chemistry). The reaction was allowed to cool and the solids were filtered off. The combined DMF 20 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 product.was purified by preparative HPLC eluting with a water : acetontrile gradient containing 0.2% TFA to give the racemic title compound (43 mg, 59.65%). LCMS (M+l)*:341, 'H NMR (400 MHz, DMSO-d 6 ): 8. 12.60(bs, I H), 9.10(s, 1H), 8.90(s, 175 1H-), 8.80(s, IH), 8.50(s, 111), 8.42(s, 1H), 7

.

7 8(s, 1H), 7.10(s, 1H), 6.30(m, 1H), 3.90(m, 1H), 3.70(m, 1H). Example 431R and Example 431S 5 The enantiomers R-5-(2-cyano-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl] ethyl)nicotinonitrile and S-5-(2-cyano-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-y)-1H-pyrazol-1-yl] ethyl)nicotinonitrile were separated by chiral column HPLC. Example 467: 3-(3-Aminophenyl)-3-14-(7H-pyrrolol2,3-dpyrimidin-4-yl)-1H-pyrazol-1-yl] 0 propanenitrile bis(trifluoroacetate) CN N-N

NH

2 2 TFA N N N H Step 1: 3

-(

3 -Nitrophenyl)-3-[4-(7-[2-(trimethylsilyl)ethoxyjmethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yI) IH-pyrazol-1-yI]propanenitrile 5 To 4-(1 H-pyrazol- 4 -yl)-7-[2-(trimethylsilyl)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 ( 2 Z)-3-(3-nitrophenyl)acrylonitrile (0.36 g, 0.0021 mol) in 2.0 mL of ACN. The reaction mixture was heated at 67 *C for 18 hours. This was cooled to room temperature, and the mixture was partitioned between diluted hydrochloric acid and ethyl acetate. The organic layer was washed with 20 saturated 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-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo(2,3-d]pyrimidin-4-yl)-1

H

pyrazol-1-yl]propanenitrile as a dark orange oil, (688 mg, 88.65%). LCMS (M+1)*:490 Z5 Step 2. 3-(3-Aminophenyl)-3-(4-7-[2-(trimethylsilyl)ethoxy]-7fH-pyrrolo[2,3-d]pyrimidin-4-yl-JH pyrazol-1-yl)propanenitrile The 3-(3-nitrophenyl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-dlpyrimidin 4 -yl)-1H-pyrazol-1-yl]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. 50 The reaction mixture was again purged with nitrogen, and it was then charged at 50 psi hydrogen in a Parr shaker for 60 minutes. The reaction mixture was filtered and concentrated to give 3 -(3-amino 176 phenyl)-3-(4-7-[2-(trimethylsilyl)ethoxy]-7H-pyrrolo[2,3-d]pyrimidin-4-yl-1H-pyrazol-1 -yl)propane nitrile as a colorless oil (550 mg, 95.92%), LCMS (M+1)+=460, Step 3. 3-(3-Aminophenyl)-3-[4-(7H-pyrrolo[2,3-djpyrimidin-4-yl)-JH-pyrazol-I-ylpropanenitrile 5 bis(trifluoroacetate) Using a procedure analogous to that of Example 61 for the removal of the SEM protecting group, the title compound was prepared as a white amorphous solid (18 mg, 38%), LCMS (M+1)4'=329: 'H NMR (DMSO-d 6 ) 5 12.61 (b,lH), 9.00 (s,1H), 8.80 (s,1H), 8.50 (s,lH),7.78 (m,IH), 7.25( m,1H), 7.18(m,1H), 6.85(m,2H), 6.02 (m.lH), 3.78(m,1H), 3.60 (m,IH). t0 Example 468: N-(3-(2-Cyano-1-[4-(7H-pyrrolo[2,3-dpyrimidin-4-yl)-1H-pyrzol-1-yll ethyl) phemyl)acetamide trifluoroacetate CN N-N O / HN TFA N N N H 15 Step I -( 3

-

2 -Cyano-!-[4-(7-[2-(trimelhylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-IH pyrazol-1-yljethylphenyl)acetamide To 3 -(3-aminophenyl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin 4-yl)-1H-pyrazol-1-yl]propanenitrile (0.070 g, 0.00015 mol) (from Example 467) in dry DCM (1.0 20 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 extracted 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-(3-2-cyano-1-[4-(7-[2-(trimethylsilyl)ethoxyjmethyl-7H-pyrrolo[2,3 25 d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethylphenyl)acetamide as a colorless oil, (65 mg, 85.08%), LCMS(M+1)*= 502. Step 2 N-(3-2-Cyano-J-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yI)-JH-pyrazol-1-yljethylphenyl)acetamide trifluoroacetate 30 Using a procedure 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%), 177 LCMS(M+1)*=372, 'H NMR (DMSO-4) 8 12.61 (b,1H), 9.05 (s,1H), 8.79 (s,11), 8.44 (s,1H), 7.85 (s,IH), 7.55 (s,IH), 7.48 (d,IH), 7.24 (m,1H), 7.10 (m,2H)), 6.05 (m,lH), 3.70 (m,1H), 3.48 (m,IH), 1.98 (s,3H). 5 Example 470: 4-(2-Cyano-1-{4-(7H-pyrrolo[2,3-dI pyrimidin-4-yl)-IH-pyrazol-1-ylJ ethyl) thiophene-2-carbonitrile trifluoroacetate CN CN N-N TFA N N N H Step 1 4-Bromo-2-(diethoxymethyl)thiophene A mixture of 4-bromothiophene-2-carbaldehyde (1.2 g, 0.0063 mol) in ethanol (10 mL, 0.2 [0 mol) was treated with ammonium chloride (0.42 g, 0.0078 mol) and ethyl orthoformate (1.2 g, 0.0078 mol). The mixture was stirred 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, filtered and concentrated to give 4-bromo-2-(diethoxymethyl)thio phene as an oil (1.3 g, 81%). 'H NMR (400 MHz, CDCl 3 ): 8 7.22 (s, 1H), 6.99 (s, 1H), 5.68 (s, IH), L5 3.63 (q, 411) 1.24 (t, 6H). Step 2 5-(Diethoxymethyl)thiophene-3-carbaldehyde A solution of 4-bromo-2-(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 20 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 chromatography to yield the 5-(diethoxymethyl)thiophene-3-carbaldehyde as 25 an oil (170 mg, 42.0%). By 'H NMR two different regioisomers of aldehydes were formed and were not separated; (note: NMR shifts are for the major isomer only) 'H NMR (400 MHz, CDCl 3 ): 6 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 ( 2

E)-

3 -[5-(Diethoxymethyl)-3-thienylqacrylonitrile 30 To a solution 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 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)thiophene-3-carbaldehyde (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 5 were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel eluting (ethyl acetate:hexane, 1:5) to give (2E)-3-[5-(diethoxymethyl)-3-thienyl]acrylonitrile as an oil (160 mg, 84.9%). 'H NMR (300 MHz, CDC1 3 ): 6 7.4-7.0 (m, 3H), 5.65 (m 1H), 4.2 (in, 1H), 3.65 (in, 4H), 1.25 (m, 6H). L0 Step 4 3-[5-(Diethoxymethyl)-3-thienyl]-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7 H-pyrrolo(2,3 d]pyrimidin-4-yl)-JH-pyrazoI-1-yljpropanenitrile To a solution of 4-(1H-pyrazol-4-yl)-7-[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 15 thienyl]acrylonitrile (160 mg, 0.00067 mol) (mixture of regioisomers) DBU (80 p-L, 0.0005 mol) was added. The reaction 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 concentrated. The crude residue was purified by flash column chromatography on silica gel eluting (50% EtOAc/Hexane) to give 3-[5-(diethoxymethyl)-3-thienyl] 0 3

-[

4

-(

7 -[2-(trimethylsilyl)ethoxylmethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-I H-pyrazol-1-yl]propane nitrile (160 mg, 43%). 'H NMR (400 MHz, CDCl 3 ): 4 8.92 (s, 1H), 8.41 (s, 1H), 8.29 (b, 1H), 7.45(d, I H), 7.41(d, IH), 7.15 (s, 114), 7.05 (d, I1-1), 6.82 (m, 1H), 5.74 (d, 2H), 3.74 (in, 2H), 3.71 (m, 8H), 3.59 (m, 1H), 1.32 (in, 4H), 0.95 (m, 2H), -0.08 (s, 9H); MS(ES):553 (M+1). 25 Step 5 3-(5-Formyl-3-thienyl)-3-[4-(7-[2-(trimethylsilyl)ethoxy methyl-7H-pyrrolo[2,3-d]pyrimidin 4-yl)-JH-pyrazol-1-yl]propanenitrile A solution of 3-[5-(diethoxymethyl)-3-thienyl]-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-1-yl]propanenitrile (70 mg, 0.0001 mol) in THF (1 mL, 0.01 mol) was treated with I M HCl in water (400 pL). The reaction was stirred at room temperature. 30 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-formyl- 3 -thienyl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4 yl)-1H-pyrazol-1-yl]propanenitrile as a semisolid residue (60 mg, 98%). 'H NMR (400 MHz, CDCl 3 ): 8. 9.96 (s, 1H), 8.89 (s, 1H), 8.44 (m, 2H), 7.46 (1H), 5.73 (s, 2H), 4.15 (m, IH), 3.73-3.43 35 (m, 3H), 1.35 (m, 1H), 1.01 (m, 2H), 0.03 (s, 9H); MS(ES): 479 (M+1). 179 Step 6: 5-[(E)-(Hydroxyimino)methyl]-3-thienyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H pyrrolo[2,3-d]pyrimidin-4-yl)-H-pyrazol-1-ylpropanenitrile A solution of 3 -(5-formyl- 3 -thienyl)-3-4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo

[

2 ,3-d]pyrimidin-4-y)-lH-pyrazol-1-yl]propanenitrile (65 mg, 0.00014 mol) in methanol (2 mL, 0.05 5 ' 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 extracted with ethyl acetate. The combined extracts were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give 3-5-[(E) (hydroxyimino)methyl)-3-thienyl-3-[4-(7-[2-(trimethylsilyl)ethoxylmethyl-7H-pyrrolo[ 2 ,3-d] 10 pyrimidin-4-yl)-l H-pyrazol-I-yl]propanenitrile as a semisolid oil (60 mg, 89.5%). (The crude product contained both isomers of oxime and also both regioisomers of thiophene). MS (ES): 494 (M+l). Step 7: 4

-(

2 -Cyano-1-[4-(7-[2-(rimethylsilyl)ethoxy]methyl-7H-pyrrolo(2,3-d]pyrimidin-4-yl)-JH pyrazol-1-yl]ethyl)thiophene-2-carbonitrile 15 To a mixture of 3-5-[(E)-(hydroxyimino)methyl]-3-thienyl-3-[4-(7-[2-(trimethylsilyl)ethoxy] methyl-7H-pyrrolo[2,3-d]pyrimidin4-yl)-lH-pyrazol-1-yllpropanenitrile (70 mg, 0.0001 mol) in pyridine (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 extracts were washed with 0.1 N HClI, brine, dried over magnesium sulfate, filtered and !0 concentrated to give 4 -(2-cyano-I

-[

4

-(

7

-[

2 -(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d] pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl)thiophene-2-carbonitrile as a crude product (30 mg, 44%). MS (ES): 476 (M+1). Step 8: 4-(2-Cyano-l-[4-(7H-pyrrolo(2,3-djpyrimidin-4-yl)-1H-pyrazol-1-yljethyl)ihiophene-2 25 carbonitrile trifluoroacetate A mixture of 4

-(

2 -cyano-1 I-[ 4

-(

7

-[

2 -(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d] pyrimidin- 4 -yl)-IH-pyrazol-1-yl]ethyl)thiophene-2-carbonitrile (50 mg, 0.0001 mol) in DCM (2 mL, 0.03 mol) and TFA (1 m.L, 0.01 mol) was stirred for I hour. The starting material was consumed and the desired methyl hydroxy compound was formed. The mixture was concentrated in vacua to 30 remove TFA. The crude intermediate was dissolved in methanol (3 mL, 0.07 mol) and was treated with ethylenediamine (1 mL, 0.01 mol). The mixture was stirred overnight and concentrated in vacuo. The products were purified by preparative HPLC eluding 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): & 8.95 (s, 1H), 8.76 (s, 111), 8.48 (s, 1H), 8.06 (s, I1H), 8.04 (s, 1H1), '5 7.70 (d, IH), 7.05 (d, IH), 6.25 (in, 1H), 3.80-3.60 (m, 211); MS (BS): 346 (M+1). 180 Example 471 : 5-(2-Cyano-1-[4-(7H-pyrrolo[2,3-dlpyrimidin-4-yl)-1H-pyrazol-1-ylI ethyl) thiophene-2-carbonitrile trifluoroacetate CN N-N S CN TFA N N N H 5 Isolated as the second regioisomer from Example 470, the title compound was isolated as an amorphous white solid (4 mg, 8%). 'H NMR (500 MHz, DMSO): B. 9.0 (s, IHO, 8.75 (s, 1H), 8.50 (s, 1H), 7.95 (s, IH), 7.65 (s, 111), 7.45 (s, 1H), 7.0 (d, 1H), 6.45 (m, IH), 3.8 (dd, 2 H); MS (ES): 346 (M+1). 0 Example 472: 3

-[

3 -(Morpholin-4-ylcarbonyl)phenyl]-3-[4-(7H-pyrrolo[2,3-dpyrimidin-4-yl) 1H-pyrazol-1-yllpropanenitrile trifluoroacetate CN N-N N O 0 N\ N N TFA H Step 1: 3

-(

2 -cyano-1-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo(2,3-d]pyrimidin-4-yl)-H 15 pyrazol-1-yq]ethyl)benzoic acid To a solution of methyl 3-2-cyano-1 -[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3 d]pyrimidin-4-yl)-H-pyrazol-1-yl]ethylbenzoate (50 mg, 0.0001 mol) (prepared as in Example 61) in methanol (2 mL, 0.05 mol), lithium hydroxide (1 mg, 0.0001 mol) in water (I mL, 0.06 mol) was added slowly. Water was added and also some IN HCl was added until the solution was slightly 20 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-1-[4-(7-[2-(trimethylsilyl)ethoxy] methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl)benzoic acid as a crude residue (35 mg, 72.0%). MS (ES): 489 (M+1). 181 Step 2: 3

-[

3 -(Morpholine-1-ylcarbonyl)phenyl]-3-[4~(7-{[2-(trimethylsilyl)ethoxymethyl-7H pyrrolo[ 2 ,3-dlpyrimidine-4-y)-!H-pyrazole-I-ylpropanenitrile To a solution of 3-(2-cyano-1-[ 4 -(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d] pyrimidin-4-yl)-lH-pyrazol-1-yl]ethyl)benzoic acid (40 mg, 0.00008 mol) in DMF (1 mL, 0.01 mol), 5 N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (36 mg, 0.000095 mol) and DIPEA (30 pL, 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 acetate. The combined organic extracts were washed with IN HCl, brine, dried over magnesium sulfate, filtered and concentrated to give 3-[3 0 (morpholine-1-ylcarbonyl)phenyl].-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3 d]pyrimidine-4-yl)-IH-pyrazole-1-yl]propanenitrile as a crude (40 mg, 88%) product. MS (ES): 558 (M+1). Step 3: 3

-[

3 -(Morpholin-4-ylcarbonyl)phenylJ-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-JH-pyrazol-1 5 yI]propanenitrile 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 %). 'H NMR (400 MHz, DMSO): 8. 9.05 (s, IH), 8.75 (s, 1H), 8.44 (s, IH), 7.85 (b, IH), 7.665 (s, 1H), 7.55- 7.35 (m, 3H), 7.15 (s, 11), 6.15 (in, IH), 3.85 (in, 1H), 3.65-3.4 (m, 6H), 3.25 (in, 2H), 3.05 (m, IH); MS(ES): :0 428 (M+1). Example 482: 3 -(5-Phenylpyridi-3-yl)-3-[4-(7H-pyrrolo[2,3-dlpyrimidin-4-yl)-1H-pyrazol-1 yllpropanenitrile trifluoroacetate CN .- N N-N N~/ \ N TFA N 25 Step 1: 3 -(S-Phenylpyridin-3-yl)-3-[4-(7-[2-(trimethylsilyl)ethoxymethyl-7H-pyrrolo[2,3-d] pyrimidin-4-yl)-IH-pyrazol-1-ylqpropanenitrile To a solution of 3 -(5-bromopyridin-3-yl)-3-[4-(7-[2-(trimethylsilyl)ethoxy)methyl-7H pyrrolo[2,3-d]pyrimidin-4-y)-lH-pyrazol-1-yl)propanenitrile (from Example 429) (60 mg, 0.0001 30 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, 0.00001 mol) was added and nitrogen was bubbled through the reaction again. The reaction was heated at 80 *C in oil bath 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 5 to give 3-(5-phenylpyridin-3-yl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d] pyrimidin-4-yl)-IH-pyrazol-1-yl]propanenitrile (50 mg, 80%) as a crude product. MS (ES): 522 (M+1). Step 2: 3-(5-Phenylpyridin-3-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-y!]propane 0 nitrile 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 (20 mg, 40 %). 'H NMR (400 MHz, DMSO): 5. 9.15 (s, 1H), 8.85 (s, 1H), 8.80 (s, lH), 8.65 (s, IH), 8.45 (s, IH), 8.22 (s,IH), 7.85 (b, IH), 7.67 (m, 2H), 7.45(m 2 H), 7.43 (m, 1H), 7.15 (s, IH), 6.25 (m IH), 3.95 (dd, I H), 3.80 (dd, .5 1H), 3.0 (m, IH); MS (ES): 392.1 (M+1) Example 486: 3-(5-Ethynylpyridin-3-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-IH-pyrazol-1 yl]propancuitrile trifluoroacetate CN -N N-N N \ N N TFA H 20 Step 1: 3-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2.3-d]pyrimidin-4-yl)-JH-pyrazol-1-yl] 3-5-[(rimethylsilyl)ethynyl]pyridin-3-ylpropanenitrile . To a solution of 3-(5-bromopyridin-3-yl)-3-[4-(7-[2-(trimethylsilyl)ethoxy)methyl-7H pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile (from Example 429) (0.080 g, 0.00015 25 mol) in TEA (0.300 mL, 0.00215 mol) was degassed with nitrogen, and then copper(I) iodide (0.005 g, 0.00003 mol), (trimethylsilyl)acetylene, and bis(triphenylphosphine)palladium(H)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 concentrated in vacuo to 30 give 3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-3 183 5-[(trimetbylsilyl)ethynyl)pyridin-3-ylpropanenitrile as a yellow oil (60 mg,72.6), LCMS (M+1:542). Step 2: 3-(5-Ethynylpyridin-3-y)-3-[4-(7H-pyrrolo(2, 3 -d]pyrimidin-4-yl)-1H-pyrazol--ylpropane 5 nitrile trifluoroacetate 3

-[

4 -(7-[ 2 -(Trimethylsilyl)cthoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-I H-pyrazol-l yl]- 3 -5-[(trimethylsilyl)ethynyl]pyridin-3-ylpropanenitrilc (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 stirred at room temperature, for 90 minutes and was concentrated in vacuo. The dry residue dissolved in methanol 0 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 (M+1)*:340, 'H NMR (400 MHz, DMSO-d 6 ): 6. 12.1(bs, IH), 9.02(s, 1HI), 8.80(s, 1H), 8.70(m, 2H), 8.48(s, 1H4), 8.00(s, 5 1H), 7.80(d, IH), 7.15(d, 1H), 6.20(m, 1H), 4 .82(s, 1H), 3.90(m, 1H), 3.70(m, 1H). Example 488: 3 -IS-(Phenylthio)pyridin-3-yl]-3-[4-(7H-pyrrolo[2,3-dpyrimidin-4-y1)-IH pyrazol-1-yllpropanenitrile trifluoroacetate CN N TFA N \ N N H 20 Step 1: 3 -[5-(PhenylIthio)pyridin-3-yl]-3-[4-(7-[2-(trimehylsilyl)ethoxymethy-7H-pyrrolo[2,3-d] pyrimidin-4-yl)-JH-pyrazol-1-ylJpropanenitrile To the 3-(5-bromopyridin-3-y1)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d] pyrimidin-4-yl)-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 25 was degassed with nitrogen, followed by addition of (9,9-dimethyl-9H-xanthene-4,5 diyl)bis(diphenylphosphine) (0.007 g, 0.00001 mol), bis(dibenzylideneacetone)palladium(O) (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 (lX), dried over magnesium sulfate, filtered, 50 and the solvent was evaporated in vacuo. The crude product was triturated with hexane-ethyl acetate 9:1 to yield 3-[5-(phenylthio)pyridin-3-yl]-3-[4-(7-[2-(trimethylsilyl)ethoxyjmethyl-7H-pyrrolo[2,3 d)pyrimidin-4-yl)-H-pyrazol-1-yl]propanenitrile (110mg, 80%). LC/MS (M+H)*: n/z =554.2. Step 2: 3-[5-(Phenylthio)pyridin-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-IH-pyrazol-i-yl] 5 propanenitrile trifluoroacetate The 3-[5-(phenylthio)pyridin-3-yl]-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3 d]pyrimidin-4-yl)-IH-pyrazol--yl]propanenitrile (0.110 g, 0.000199 mol) was dissolved in DCM (5.0 mL, 0.078 mol) and TFA (2.0 mL, 0.026 mol), and the mixture was stirred at room temperature for I hour. The solvent was removed in vacuo, and the resulting residue was dissolved in methanol (5.0 0 mL, 0.12 mol), and ethylenediamine (0.1 mL, 0.002 mol) was added. This reaction 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%). 'H NMR (400 MHz, DMSO): S. 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 5 Example 491: 3-(5-Morpholin-4-yIpyridin-3-y)-3-[4-(7H-pyrrolo[2,3-dpyrimidin-4-yI)-1H pyrazol-1-yljpropanenitrile NN N N' \ NH N' NH Step 1: 4-(5-Bromopyridin-3-yl)morpholine 20 To a solution of [3,5-dibromopyridine (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 added and nitrogen was bubbled through for couple of minutes. The mixture was heated at 80 *C overnight. The reaction was allowed to cool to rt and was then partitioned between water and ethyl 25 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-bromopyridin-3-yl)morpholine as a viscous oil (400 mg, 40 %). 'H NMR (400 MHz, CDC13): 8. 8.2 (s, IH), 8.1 (s, 1H), 7.2 (s, IH), 3.8 (m, 4H), 3.2 (m, 4H). 30 Step 2: 5-Morpholin-4-yInicotinaldehyde 185 A solution of 4-(5-bromopyridin-3-yl)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 Ih. To this mixture was added DMF (0.5 mL, 0.006 mol) dropwise. The reaction was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with saturated 5 sodium chloride, dried over magnesium sulfate, filtered and concentrated to give 5-morpholin-4 ylnicotinaldehyde (70 mg, 90%) as a crude product. 'H NMR (400 MHz, CDCl3): & 10.1 (s, IH), 8.0 (s, 2H), 7.6 (s, 1H), 3.8 (m, 4H), 3.2 (m, 4H). Step 3: ( 2 E)-3-(5-Morpholin-4-ylpyridin-3-yl)acrylonitrile 0 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-morpholin-4-ylnicotinaldehyde (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 5 with water and extracted with ethyl acetate. The combined organic layers were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give (2E)-3-(5 morpholin-4-ylpyridin-3-yl)acrylonitrile (75 mg, 100%) as a mixture of isomers; LC/MS: 216 (M+1). Step 4: 3 -(5-Morpholin-4-ypyridin-3-yl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d] .0 pyrimidin-4-yl)-JH-pyrazol-J-yl]propanenitrile To a solution of 4-(IH-pyrazol-4-y)-7.-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d] pyrimidine (120 mg, 0.00038 mol) in ACN (10 mL, 0.2 mol) and (2E)-3-(5-morpholin-4-ylpyridin-3 yl)acrylonitrile (70 mg, 0.0003 mol) ( mixture of isomers), DBU (50 pL, 0.0003 mol) was added and 25 the resulting mixture was stirred overnight. The mixture was partitioned between water and ethyl acetate. The combined organic layers were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give 3-(5-morpholin-4-ylpyridin-3-yl)-3-[4-(7-[2 (trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile (200 mg, 100%) as a crude product; L/MS = 531 (M+1). 30 Step 5: 3 -(5-Morpholin-4-ylpyridin-3-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl] propanenitrile Using a procedure analogous to Example 61 for the removal of the SEM protecting the title compound was isolated as an amorphous white solid (18 mg, 50 %). 'H NMR (400 MHz, DMSO): 5 35 8.8 (s, IlH), 8.6 (s, 1H), 8.4 (s, 1 H), 8.2 (s, 1H), 8.0 (s, 1H), 7.6 (d, 1 H), 7.4 (m, 1 H), 6.9 (d, 1H), 6 (m, 1 H), 3.8 (dd, I H), 3.7(m, 4H), 3.6 (dd, 1 H), 3.1 (n, 4 H); LC/MS: 401(M+ 1). 186 Example 496: 3 -[5-(Phenylsuinyl)pyridin-3-yl]-3-[4-(7H-.pyrrolo[2,3-d]pyrimidin-4-y)-1Hf pyrazol-1-yllpropanenitrile, and 5 Example 497: 3 -(5-(Phenylsulfonyl)pyridin-3-y]-3-14-(7H-pyrrolo[2,3-djpyrimidin-4-yl)-1H pyrazol-1-yllpropanenitrile O 0 CN CN N N N-N N N) N~ N~ N N N N H H To the solution of 3 -[5-(phenylthio)pyridin-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- I H 0 pyrazol-1-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 mol) (0.031g of 77% in water), in a water ice bath. The reaction mixture was stirred for I h at room temperature. The crude products were purified by LCMS (pH=10). Two peaks were collected: # I - to yield 3 -[5-(phenylsulfinyl)pyridin-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH 5 pyrazol-1-yl]propanenitrile (8 mg, 19.57%). 'H NMR (400 MHz, DMSO): 8. 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]pyrimidin-4-yl)-1H pyrazol-1-yllpropanenitrile (21 mg, 50%). 'H NMR (400 MHz, DMSO): S. 12.1 (s), 9.10 (s), 20 8.86 (m), 8.61(s), 8.40 (m), 7.98 (m), 7.62 (m), 7.58 (m), 6.90 (s), 6.20 (m), 3.82 (m), 3.65 (m). LC/MS (M+H) 4 : m/z = 456.0 Example 498: 3

-[

4

-(

7 H-Pyrrolo[2,3-dipyrimidin-4-yl)-1H-pyrazol-1-yllpentan-1-ol OH N-N

N

N - NH 1 Q'7 Step 1: 3-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-JH pyrazol-1-yljpentanal To a solution of 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d] pyrimidine (100 mg, 0.0003 mol) in ACN (2 m.L, 0.04 mol) and DBU (50 gL, 0.0003 mol), the (2E) 5 pent-2-enal (4.OEI mg, 0.00048 mol) in Iml ACN was added drop wise. The reaction was stirred for I 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. 0 Step 2: 3-[4-(7-[2-(Trimethylsilyl)ethoxymethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-1 yl]pentan-1-ol A mixture of [3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yi)-IH pyrazol-1-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 1 h, and then 5 water was added and the product was extracted with ethyl acetate. The combined organic layers were washed with saturated 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: .0 Using a procedure analogous to Example 61 for the removal of the SEM protecting group the title compound was isolated as an amorphous white solid (6 mg, 20 %). 'H NMR (400 MHz, DMSO): 0 8.65 (d, 1H), 8.60 (d, 1H), 7.55 (s, I H), 6.95 (s, 1 H), 4.50 (b, I H), 4.4 (m, I H), 3.4 (m, 1fH), 3.2 (m, IH), 2.1 (m, 1 H), 1.8-2.0 (m, 3H), 0.7(t, 3H); LC/MS (M+H)*: m/z= 272. 25 Example 499: Methyl 3-[4-(7H-pyrrolo[2,3-dlpyrimidin-4-yl)-1H-pyrazol-1-yllpentyl carbonate 0 N-N N ~. NN N NH Step 1: Methyl 3 -[4-( 7 -[2-(rimethylsilyl)ethoxy]mcthyl-71{-pyrrolo[2,3-d]pyrimidin-4-y)-IH pyrarol-1-yl]pentyl carbonate To a solution of [ 3

-[

4 -(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl) 30 1H-pyrazol-1-yl]pentan-1.-ol (50 mg, 0.0001 mol) from Example 498 Step 2 in pyridine (1 mL, 0.01 188 mol), methyl chloroformate (30 pL, 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 HCI, brine, dried over magnesium sulfate, filtered and concentrated to give methyl 3-[4

(

7 -[2-(trimethylsily)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentyl 5 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 isolated as an amorphous white solid (8 mg, 20 %). 'H NMR (400 MHz, DMSO): 0 S. 12.0 (b, 111), 8.65 (d, 1H), 8.35 (s, 1H), 7.65 (b, 1H), 7.600 (s, IH), 7.0 (s, 1H), 4.4 (in, IH), 4.0 (in, 1H), 3.8 (in, 11), 3.6 (s, 3H), 2.1 (m, 1H), 2.2 (in, 1H), 1.95 (m, 2H), 0.75 (t, 311); LC/MS (M+4H)*: m/z = 330. Example 500(a): (1E)-3-[4-(7H-Pyrrolo[2,3-dpyrimidin-4-yI)-IH-pyrazol-1-yl pentanal oxime OH -N N N 5N Step 1: (IE)-3-[4-(7-[2-(Trimethylsilyl)ehoxy]methyl-7H-pyrrolo[2,3-dpyrimidin-4-yl)-JH-pyrazol I-yl]pentanal oxime To a solution of 3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl) IH-pyrazol-1-yl]pentanal (60 mg, 0.0002 mol) from Example 498, Step 2 in methanol (2 mL, 0.05 20 mol) was added hydroxylamine hydrochloride (16 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, filtered and concentrated to give (1E)-3-[4-(7-[2-(trimethyl silyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentanal oxime as a semisolid 25 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. 'H NMR (400 MHz, DMSO): 12.0 (b, 1H). 30 8.6 (m, 2H), 8.2 (in, 1 ), 7.5 (d, 1 H), 7.1 and 6.5 (t, IH), 4.6 (in, 1H), 4.4 (in, 1H), 2.6-2.8 (m, 2H), 1.8 (in, 211), 0.65 (t, 3H); LC/MS (M+H)*: m/z = 285. t oo Example 501(a): (1E)-3-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yllpentanal 0 methyloxime, and 5 Example 502(a): (0Z)-3-[4-(7H-Pyrrolo[2,3-d-pyrimidin4-yl)-1H-pyrazol-1-yljpentanal methyloxime ,0 N N-N N N H Step 1: (JE)-3-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-JH-pyrazol 1-yl]pentanal O-methyloxime 0 and (IZ)-3-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-JH-pyrazol-l yljpentanal 0-methyloxime To a solution of 3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-y) IH-pyrazol-1-yl]pentanal (70 mg, 0.0002 mol) in methanol (2 mL, 0.05 mol) was added 5 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 filtered and was concentrated to give 3-(4-(7-[2-(trimethylsilyl) ethoxy]nethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-H-pyrazol-1-ylpentanal 0-methyloxime as a 20 mixture of isomers (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 isolated as an amorphous white solid (4 mg, 25 %). Isomer 1, 'H NMR (400 MHz, 25 DMSO): 8. 8.7 (s, 2H), 8.3 (s, 1 H), 7.6 (s, I H), 7.3 (t, 1H), 7.0 (s, IH), 4.6(m, I H), 3.3 (s, 31H), 2.8 (m, 2H), 1.9 (m, 2H), 0.8 (t, 3H); LC/S (M+H)*: rn/z = 299.Isomer 2 (3 mg, 22/b), 'H NMR (400 MHz, DMSO): 5 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. 30 Example 503: 4-[1-(4,4-Dibromo-1-ethylbut-3-en-1-yl)-1HI-pyrazol-4-yl]-7H-pyrrolo[2,3-d] pyrimidine trifluoroacetate 190 Br N-N TFA N \ N N H Step 1: 4-[1-(4,4-Dibromo-1-ethylbut-3-en-1-yl)-JH-pyrazol-4-yl]-7-[2-(trimethylsilyl)ethoxy]methyl 7H-pyrrolo[2,3-d]pyrimidine To a solution of 3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyriinidin-4-yl) 5 1H-pyrazol-1-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 combined organic extracts were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by prep LC-MS (ACN, water, 10 NH 4 OH) to give 4-[1-(4,4-dibromo-l -ethylbut-3-en-1-yl)-1 H-pyrazol-4-yl]-7-[2-(trimethylsilyl) ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine as an amorphous solid (50 mg, 10%). 'H NMR (400 MHz, CDC]3): 8 . 8.9 (s, 2H), 8.4 (s, I H), 8.3 (s, 11), 7.4 (m, IH), 7.3 (s, IH), 6.9 (m, I H), 6.4 (m, 1H), 5.7 (s, 2H), 4.2 (in, lH), 3.6 (in, 2H), 2.8 (m, 211), 2.1 (m, 1H), 2.0 (in, 1H), 1.0 (in, 5H), LC/MS (M+H)*: m/z= 556 15 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 %). 'H NMR (400 MHz, DMSO): 5. 8.8 (s, 2H), 8.4 (s, IH), 7.7 (b, IH), 7.2 (b, 1H), 6.5 (t, IH), 4.4 (m, 11H), 2.6 (m, 2H), 1.8 (m, 2H), 20 0.8 (t, 3H); LC/MS (M+H)*: m/z=: 426. Example 506: 4-[1-(1-Ethylbut-3-yn-1-yl)-1H-pyrazol-4-yl]-7H-pyrrolo[2,3-djpyrimidine trifluoroacetate N-N TFA N \ N N H 25 Step 1: 4-[J-(1-Ethylbut-3-yn-1-yl)-JH-pyrazol-4-yl]-7-[2-(trimethylsilyl)ethoxy]methyl-7H pyrrolo[2,3-d]pyrimidine 101 A solution of 4-[1-(4,4-dibromo-1-ethylbut-3-en-1-yI)-lH-pyrazol-4-yI]-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 I h and then at room temperature for lh. The reaction was quenched 5 with water (1 mL, 0.06 mol) and 1N HCL. The reaction was partitioned between 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-yl)-1H-pyrazol-4-ylj-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. 0 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 (4 mg, 30 %). 'H NMR (400 MHz, DMSO): 5 12.2 (b, 111), 8.8 (s, 21), 8.4 (s, 1H), 7.6 (s, 1H), 7.1 (s, 1H), 4.4 (m, 11), 2.8 (m, 31), 1.9 (m, 21), .5 0.8 (t, 311); LC/MS(M+H)*: m/z = 266. Example 516: (R)-3-13-(Ethylsulfonyl)phenyll-3-[4-(7H-pyrrolo[2,3-dlpyrimidin-4-yl)-1H pyrazol-1-yljpropanenitrile, and !0 (S)-3-[3-(Ethylsulfonyl)phenyl]-3-[4-(7H-pyrrolo[2,3-dlpyrimidin-4-yl)-1H-pyrazol-1-yll propanenitrile CN 00 N-N TFA N \ N N H Step 1: 1-Bromo-3-(ethylthio)benzene Iodoethane (0.46 mL, 0.0058 mol) was added to a suspension of 3-bromothiophenol 25 (0.50 mL, 0.0048 mol), ACN (7.11 mL, 0.136 mol) and potassium 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 reaction was concentrated in vacuo to give 1-bromo-3-(ethylthio)benzene as a colorless oil 1.0 gm, 100% 30 Step 2: J-Bromo-3-(ethylsulfonyl)benzene The MCPBA (2.37 g, 10.6 mmnol) was added to a solution of 1-bromo-3-(ethylthio)benzene (1.00 g, 4.80 mmol) in DCM (10 ml, 156 mmol) cooled to 0 *C. The reaction was stirred for I 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 5 was purified by flash column chromatography with a hexane: ethyl acetate gradient to give 1 -bromo 3-(ethylsulfonyl)benzene as a colorless oil 1.1 gm 92%, 'H NMR (300 MHz, CDC 3 ): #8.09(m, I H), 7.85(d,1H), 7.78(d, 1H) 7.45(t,IH), 3.14(q, 2H), 1.25(t, 3H). Step 3. (2E & Z)- 3 -[3-(Ethylsulfony)phenyl]acrylonitrile 10 1-Bromo-3-(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 degassed 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 "C in a sealed tube for 8 hrs. The reaction was complete by 15 HPLC, and was then allowed to cool to rt and then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate and concentrated. The product 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 (M+H): m/z = 222. ZO Step 4: 3

-[

3 -(Ethylsulfonyl)phenyl]-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3 dlpyrimidin-4-yl)-IH-pyrazol-1-yL]propanenitrile The (2E&Z)-3-[3-(ethylsulfonyl)phonyl]acrylonitrile (1.0 g, 0.0045 mol) was combined with 4-(IH-pyrazol-4-yl)-7-[ 2 .- (trimethylsily)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 25 reaction was stirred at rt for 24 h. This was partitioned between ethyl acetate and water, and 0.IN HCI 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)-3-[4-(7-[2 (trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-y]]propanenitrile as an 30 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: methanol: hexane 30:30:40, Rt 13.2 and 37.1 minutes) to give the two enantiomers, each as a glass (0.51 gm) LC/MS (M+H)*: m/z = 537, 'H NMR (300 MHz, CDCl 3 ): 8 8.89(s, IH), 8.45(s, IH), 8.35(s,IH), 8.09(s, lh), 8.05(d, IH), 7.75(d, 111), 7.71(t, 1H), 7.45(d, 1H), 6.83(d, 111), 5.85(t, 111), 5.75(s, 211), 3.78-3.42(m, 4H), 3.18(m, 2H), 35 1.35(t, 3H), 0.97(t, 211), 0.05(s, 9H).

Step 5: Using a procedure analogous to Example 61 for the removal of the SEM protecting group the title compounds were prepared to give isomer #1 as an amorphous white solid (300 mg, 80 %). 'H NMR (400 MHz, DMSO): 8 9.1 (s, I H), 8.8 (s, I H), 8.5 (s, IH), 8.0 (s, I H), 7.6-7.9 (in, 4H), 7.1 (s, 5 1H), 6.3 (in, 1fH), 3.9 (in, IH), 3.7 (in, 1H) 3.2 (q, 2H), 1.0 (t, 3H); MS(ES) (M+H)*: 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 %). 'H NMP (400 MHz, DMSO): 6. 9.1 (s, I H), 8.8 (s, I H), 8.5 (s, I H), 8.0 (s, I H), 7.6-7.9 (m, 4H), 7.1 0 (s, I H), 6.3 (in, I H), 3.9 (in, 1H), 3.7 (in, 1H) 3.2 (q, 2H), 1.0 (t, 3H); MS(ES) (M+H)*: m/z = 407. Example 526; 4-[1-(1-Ethylbut-3-en-1-yl)-1H-pyrazol-4-yl]-7H-pyrrolo[2,3-dpyrimidine N-N N N NH Step 1: 4-[!-(1-Ethylbut- 3 -en-1-yl)-1H-pyrazol-4-yl]-7-[2-(trimethylsilyl)ethoxy]methy1-7H-pyrrolo 5 [2,3-d]pyrimidine To an ice cooled solution of methyl triphenylphosphonium bromide (100 mg, 0.0004 mol) in THF (2 mL, 0.02 mol) was added 0.5 M potassium bis(trimethylsilyl)amide in toluene (0.8 mL). The mixture was stirred for I h 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]pyrimidin-4-yl)-IH-pyrazol-1-yl]pentanal (80 mg, 0 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-ethylbut-3-en-1-yl)-lH-pyrazol-4-yl]-7-[2-(trimethylsilyl)ethoxy]methyl 7H-pyrrolo[2,3-d]pyrimidine 150 mg as a crude product. LC/MS = 398 (M+1). 5 Step 2: 4 -[I-(-Ethylbut-3-en-1-yl)-H-pyrazol-4-yl]-7H-pyrrolo[2,3-dipyrimidine Using a procedure analogous to Example 61 for the removal of the SEM protecting group the title compound was isolated as an amorphous white solid (25 mg, 1%). 'H NMR (400 MHz, DMSO): 8. 8.6 (s, 2H), 8.2 (s, I H), 7.4 (s, I H), 6.9 (s, I H), 5.8 (in, I H), 5.0 (dd, 2H), 4.2 (in, I H), 2.4-2.6 (in, 0 2H), 1.7-1.9 (in, 2H), 0.6 (t, 3H); LC/MS: 268 (M+l). 1 OA Example 500: (3R)- and (3S)-4,4,4-Trifluoro-3-[3-(7H-pyrrolo[2,3-dipyrimidiu-4.-y)-1H-pyrrol 1-yllbutanenitrile F CN F CN N N and N N \ N N N N H H Step 1. 4-Chloro-7-(diethoxymeihyl)-7H-pyrrolo[2.3-dipyrimidine 5 A mixture of 4-chloropyrrolo[2,3-dlpyrimidine (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, CDCI): 5 8.63 (s, 1H), 7.58 (d, IH), 6.71 (s, 1H), 6.65 (d, 1H), 3.77-3.67 (m, 0 2H), 3.58-3.49 (m, 2H), 1.23 (t, 3H), 1.23 (t, 3H). Step 2. 7-(Diethoxymethyl)-4-(1H-pyrrol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine To a degassed solution of 4-chloro-7-(diethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine (1.13 g, 0.00442 mol) and 1-(triisopropylsilyl)-3-boronic acid (1.00 g, 0.00374 mol) and sodium carbonate 5 (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 stirred at ambient temperature 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 20 filtered off and washed with a small quantity of ACN (165 mg, 13%). 'H NMR (400 MHz, D 6 -drnso): & 11.44 (br s, 1H), 8.66 (s, 1H), 7.80-7.78 (in, 1H), 7.58 (d, 1H), 7.03 (d, IH), 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. 25 Step 3. To a solution of 7-(diethoxymethyl)-4-(1H-pyrrol-3-yl)-7H-pyrrolo[2,3-d)pyrimidine (0.125 g, 0.436 mmol) and 4,4,4-trifluorobut-2-enenitrile (0.0476 mL, 0.480 mmol) in ACN (1 mL) was added DBU (0.0653 mL, 0.436 mmol). TFA (0.5 mL) was added and the mixture was stirred for I hour. The TFA and solvent was removed in vacuo. The residue was purified by preparative 30 HPLC/MS (C-18 eluting with a gradient of H 2 0/ACN containing 0.15% NH 4 0H) to afford the 195 product (102 mg, 76%). Where desired, the enantiomers were separated in substantially pure form by chiral HPLC (AD-H, 20% EtOH/Hexane). 'H NMR (300 MHz, D 6 -dmso): 8 12.05 (br s, IH), 8.65 (s, 1H), 8.04 (s, 1H), 7.56 (dd, 1H), 7.21 (t, 1H), 7.02 (dd, 1IH), 6.93 (dd, I H), 5.89-5.74 (m, IH), 3.95 (dd, IH), 3.66 (dd, 1H); MS(ES): M+H= 5 306. The analog in Table 12 was prepared in racemic form according to the same procedure, using a different conjugate acceptor and with the exception that in the conjugate addition in Step 3, the reaction was carried out at 40 *C for 3 days. Table 12 R CN N N \ N N H [0 MS Method of Ex. Name R (ES) preparation No. (M+1) and chiral separation 501 3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- Ex. 500, S1H-pyrrol-1 -yl]butanenitrile CH3 252 enantiomers not separated The following compounds in Table 13 were prepared as indicated in the column labeled "Method of Prep." and the details of certain exemplary synthetic procedures are provided following Table 13. 15 Table 13

R

R2 N N H Ex. # R' Rz M+1 Name Method of prep. 0 N-(3-{2-cyano-1 -[4-(7H- Ex 468 601 CH 2 CN N ) .. CF 3 502 pyrrolo[2,3-d]pyrimidin-4-yl) H IH-pyrazol-1-yl]ethyl}phenyl) 3-(trifluoromethyl)benzamide N-(3-{{4-(7H-pyrrolo[2,3- Ex 468 602 H N

CF

3 463 d]pyrimidin-4-yl)-1H-pyrazol H I -yl]methyl}phenyl)-3 (trifluoromethyl)benzamide 3-[3-(methylsulfonyl)phenyl]-3- Ex 516 603 CHCN S2CH 393 [4-(7H-pyrrolo[2,3-d]pyrimidin ee#l 4-yl)-lH-pyrazol-1-yl] propanenitrile 3-[3-(methylsulfonyl)phenyl]-3- Ex 516 603 CH2CN SO2CH3 393 [4-(7H-pyrrolo[2,3-d]pyrimidin ee#2 4-yl)-H-pyrazol- -yl propanenitrile O O N-(3-{[4-(7H-pyrrolo(2,3-d]- Ex 469 604 H N- 431 pyrimidin-4-yl)-1H-pyrazol-1 H yl]methyl) pbenyl)benzene sulfonamide H 3-([4-(7H-pyrrolo[2,3-d)- Ex 472 605 H N o- CF 3 463 pyrimidin-4-yl)-IH-pyrazol-l OI yl]methyl}-N-[3-(trifluoro 0 ~methyl)phenyl]benzamide

H

3 3-{2-cyano-l-[4-(7H- Ex 649 606 CN 422 pyrrolo[2,3-d]pyrimidin-4-yl) ee#1 /,S CH3 1H-pyrazol-1-yl]ethyl}-N,N O/ O dimethylbenzenesulfonamide

CH

3 3-(2-cyano-1-[4-(7H- Ex 649 ee#2 CH 2 CN A 422 pyrrolo[2,3-d)pyrimidin-4-yl) eS\ CH 3 lH-pyrazol-1 -yl]ethyl}-N,N o O dimethylbenzenesulfonamide N-benzyl-3-{2-cyano-1-[4-(7H- Ex 649 607 CH2CN N 484 pyrrolo[2,3-d]pyrimidin-4-yl) 6\S 1H-pyrazol-1-yl]ethyl) benzene o O sulfonamide trifluoroacetate N-benzyl-3-{2-cyano-1-[4-(7H- Ex 472 608 CH 2 CN N 448 pyrrolo[2,3-d]pyrimidin-4-yl) IH-pyrazol-1 -yl]ethyl) o benzamide 3-{2-cyano-l-[4-(7H- Ex 472 N 434 pyrrolo[2,3-d]pyrimidin-4-yl) 609 CH 2 CN 1H-pyrazol-l -yl]ethyl}-N O phenylbenzamide trifluoroacetate 3-{2-cyano-1-[4-(7H- Ex 472 N C CF 3 502 pyrrolo[2,3-d]pyrimidin-4-yl) 610 CH2CN 1H-pyrazol-1 -yl]ethyl)-N-[3 0 C (trifluoromethyl)phenyl] benzamide trifluoroacetate H N-(3-cyanophenyl)-3- {[4-(7H- Ex 472 611 H ItK(N - CN 420 pyrrolo[2,3-d)pyrimidin-4-yl) O 1H-pyrazol-1-yl] methyl)benzamide I n-7 N-benzyl-3-{[4-(7H-pyrrolo- Ex472 612 141 NW 409 [2,3-d]pyrimidin-4-yl)-1H "10pyrazol-1 -yljniethyl }berizamide H N-1 -naphthyl-3-{([4-(7H- Ex 472 N . 44 pyrrololj2,3-d~pyrimidin-4-yI) 613 H Y I IH-pyrazol-1 -yllmethyl} 11 benzamide H N-2-naphthyl-3- {[4-(7H- Ex 472 614 H Ily445 pyi-rolo[(2,3-d]pyrimidin-4-yl) 0I l i I H-pyrazol-I -yllmethyl)} _____benzamide N-(3-{ [4-(7H-pyrrolo42,3-d]- Ex 468 615 H IN .N 445 pyrimidin-4-yi).IH-pyrazol-l H yllmcthylyphenyl)-2 ~- naphtbamide trifluoroacetate N-(3- {[4-(7H--pyrrolc42,3-dI- Ex 468 KN 44:5 pyrimidin-4-yI)- 1H-pyrazol- 1 616 H H yl]methyl }phenyi)-1 naphthaniide trifluoroacetate __ K _ 2-phenyl-N-(3-{[4-(7H- Ex 468 61 H409 pyrrolo(2,3-d]pyrimidin-4-yl) 617 H I H-PYrazol- 1-yl]methyl} N phenyl)acetamide _____ _________ __________________trifluoroacetate 0 3-chloro-N-(3-f[4-(7H-pyrrolo- Ex 468 618 H 0 k, CI 429 [2,3-d~pyrimidin-4-yI)-1H H Ipyrazol-I -yI~methyl)phenyl) N.. benzamide trifluoroacetate N-(3-{2-eyano-1 -[4-(7H- Ex 468 619 GH 2 CN N. 484 pyrrolo[2,3-d]pyrirnidin-4-y) H l H-pyrazol-1 -yI]ethyl~phenyl) N.. 2-naphthamide trifluoroacetate N-(3-{(2-cyano-I -[4-(7H- Ex 468 ANN 484 pYrrolo[2,3-d]pyrimidin-4-yI) 620 CH2CN H l H-pytrazoIlyl]ethyl~phelyl). I -naphthamide trifluoroacetate N-(3- {2-cyano- I -(4-(7H- Ex 468 448 pyrrolo[2,3-d]pyrimidin-4-yI) 621 CH 2 CN I H-pyrazol-I -yl] -ethyl) phenyl) H 2-pheriylacetarmide ______trifluoroacetate 198 62N3-cyano-N-(3-(2-cyao1-4 Ex 468 CHC O (H-yro[2,3-d)PYrimidin-4 622 CII CN - yl)-lH-pyrazol-I -yI] H I ethyl) phenyl)benzainide __________trfluoroacetate CHN 34 N-(3-{2-cyano-1 -[4-(7H- Ex 468 434 NPYrrolo[2,3-d1PYrimidin-4-yl) 623~~ CHCI~ H-pyrazol-I -yl]ethyl) H I pheny!)benzaniide __________________trifluOroacetate N-(3-{2-cyano-I -[4-(7H- Ex 468 62 C2C 502 PYrrOIO[2,3-d]pyrimidin-4-yl) 624~ IHC N H-pyrazol-1 -yI]ethy) }phenyl) -- CF34-(trifluoromethyl)benzamide HF 3 trifluoroacetate HH5N N-(3-2-cyano-I -[4-(7H- Ex 480 65 CII2CN < yN.y 449 Pyrrolo[2,3-djpyimidin-4-yl). 0 N'-phenylurea trifluoroacetate H 3- {2-cyano-I -14-(7H-pyrrolo- Ex 472 626 CH 2 CN Ky 502 [2,3-dlpyriidin-4-yl)-lH 0I PYrazol-1l -yl] ethyl)}-N-[4 o - CF (trifluoronethyl)phenylI CF benzarnide trifluoroacetate H 3- (2-cyano-1 -[ 4 -(7H-pyrrolo- Ex 472 627 CH2N f N448 [2,3-dlpyrimidin-4-yl) -I H 627~ C CNIPYrazol-I -yIlethyl -N-(4 o " CH zethylphenyl)benzainide

CH

3 trifluoroacetate H N-(4-cyanophenyl)-3 - {2-cyano- Ex 472 628 H 2 C 459 1 -[4-(7H-pyrrolo[2,3-d] 0f Pyrimidin-4-yI)-lH-pyrazol-1 o2 CHC Oa N Yljethyl~benzam-ide _____trifluoroacetate

H

3

-{

2 -cyano-l-[4-(7H-pyrrolo. Ex 472 629 CH 2 CN N or414kz 484 [2,3-d]pyrimidin-4-yi) -11- 0 pyrazol- 1 -yllethyl } -N-2 o 1 o ~ naphthylbenzarnide trifluoro __ __ __ __ acetate N 3 -{(2-cyano- I-[4-(7H-pyrrolo. Ex 472 630 CHCN 1484 [2,3-d~pYridin-4-yI) -1W 630~~~ GICN.-PYrazOl-1 -yllethyll-N-I I naphthylbenzamide tri - 6 1 fluoroacetate C H3 ~ 3- f2-cyano-1I-[4-(7H-pyrrolo. ix 472 63OH 3 NA-- 386 2,3-d]PYrimidin-4-y) -I H. -N CH, PYrazol-I -yll ethyl)}-N,N 0 dimethylbenzamide tri ____________________fluoroacetate H 3-{2-cyano-l-[4-(7H-pyrrolo- Ex 472 632 CH2CN N 435 [2,3-d]pyrimidin-4-yi) -[H pyrazol-1-yl]ethyl}-N-pyridin N 3-ylbenzamide trifluoroacetate

H

3 3-{2-cyano-l-[4-(7H-pyrrolo- Ex 472 448 [2,3-d]pyrimidin-4-yl) -1H 633 CH 2 CN pyrazol-1 -yl]ethyl} -N-methyl N-phenylbenzamide trifluoroacetate 3-{2-cyano-l-[4-(7H-pyrrolo- Ex 472 N 440 [2,3-d]pyrimidin-4-yl) -1H 634 CHzCN pyrazol-1 -yl]ethyl} -N O cyclohexylbenzamide tri fluoroacetate 3-{2-cyano-1-[4-(7H-pyrrolo- Ex 472 N 526 [2,3-d]pyrimidin-4-yl) -[H 635 CH 2 CN pyrazol-1 -yl]ethyl} -N-(4 phenoxyphenyl)benzamide trifluoroacetate N-(3-cyanophenyl)-3-{2-cyano- Ex 472 N CN 459 1-[4-(7H-pyrrolo[2,3 -d] 636 CH 2 CN 4pyrimidin-4-yl)-IH-pyrazol-1 o yl]ethyl}benzamide trifluoroacetate N-biphenyl-4-yl-3-{2-cyano-1- Ex 472 510 [4-(7H-pyrrolo(2,3-d 637 CH 2 CN 0 ]pyrimidin-4-yl)-1H-pyrazol- 1 yl]ethyl}benzamide trifluoroacetate H N-(4-chlorophenyl)-3-{2-cyano- Ex 472 - N 468 1-[4-(7H-pyrrolo[2, 3-d] 638 CH2CN pyrimidin-4-yl)- 1 H-pyrazol-1 yl]ethyl}benzamide trifluoroacetate H 3-{2-cyano-1-[4-(7H-pyrrolo- Ex 472 N CH 3 462 [2,3-d]pyrimidin-4-yl) -I H 639 CH2CN j I T pyrazol-1 -yl]ethyl}-N-(3,4 O

H

3 dimethylphenyl)benzamide trifluoroacetate H 3-{2-cyano-1-[4-(7H-pyrrolo- Ex 472 N CH 3 464 [2,3-d]pyrimidin-4-yl) -IH 640 CH 2 CN A r pyrazol-1 -yl]ethyl}-N-(3 o methoxyphenyl)benzamide trifluoroacetate H 3- {2-cyano-1 -[4-(7H-pyrrolo- Ex 472 NAg a o 464 [2,3-d]pyrimidin-4-yl) -1H 641 CH2CN pyrazol-l -yl]ethyl}-N-(4 CH3 methoxyphenyl)benzamide trifluoroacetate 200 A H 3-{2-cyano-I -[4-(7H-pyrrolo- Ex 472 62 C C N N 425 [2,3-d]pyrimidin-4-yi)

-IH

64 HC ",*0 pyrazol- I -yl] ethyl I}-N-isoxazol o 3-ylbenzamide trifluoroacetate

CH

3 3

-{

2 -cyano-I.{4-(7H-pyrrolo- Ex 649 643 CH 2 C ~ 484 (2,3-d~pyrimidin-4-yI)-l H 2CN \pyal-1 -yl] ethyl) -N-methyl 0 N-phenylbenzenesulfonamide H 3 -{2-cyano--1-(4-(7H-pyrrolo. Ex 649 644 CHCN N436 [2,3-dlpyrimidin-4-yl)-IH o4 CHC pyrazol-lI -yllethyl) -N o________0 ___ propylbenzenesulfonamide H 3 -{2-cyano-l-[4-(71i-pyrrolo- Ex 649 645 CH 2 CN /,,-470 [2,3-dlpyriniidin-4-yl)- I H __ 2/ pyrazol- I -yl]ethyl) -N ___________ phenylbenzenesulfonamide H3- {2.cyano-l1-(4-(7H-pyrrolo- Ex 649 NI 520 [2,3-d]pyrimidin-4-yl) -IlH 646 CH 2 CN pyrzo ",S- pyao-1-yl]ethyl) -N-2 sulfonamide 3

-{

2 -cyano-l-[4-(7H-pyrrolo. Ex 649 H 44 [2,3-d]pyrimidin-4-yl) -1H 647 CH 2 CN A N pyrazol.1I-yl] ethyl}I-N 0 0cyclopropylbeuene __________________sulfonamide 3-[3-(piperidin-l -ylsulfonyl)- Ex 649 648 CHCN462 phenyl]-3-[4-(7H-pyrrolo[2,3. 648 H2CN141SN )d]pyrimidin-4-yl)-11llpyrazol ________ o0 1 -yl]propanenitile 3-[3-(morpholin-4-ylsulfonyl)- Ex 649 649 CI- 2 CN A N 464 phenyl]-3-[4-(711-pyrrolo[2,3 ,, ~ dlpyrimidin-4-yl)-IH-pyrazol _______________ o _____I -yI]propanenitie ____ H 3

-{(

2 -cyano-lI-[4-(7H-pyrolo. Ex 649 A.N 484 [2,3-d]pyrimidin-4-yl)-lH 650 CH2CN Apyrazol-lI -yl] ethyl) -N.(4 o 0 CH 3 methylpbenyl)benzene __________________sulfonamide trifluoroacetate

H

3

-{

2 -cyano-1-[4-(7H-pyrrolo- Ex 649 N ~N ~ CH 3 498 [2,3-d]pyrimidin-4-yl)-I H 651 CH 2 CN "I\-pyrazol-1 -yI]ethyl) -N-(3,4 o OK. CJ 3 dimethylphenyl)benzene

CH

3 sulfonamaide trifliuoroacetate A H3-{2-cyano-I -[4-(7H-pyn-rolo- Ex 649 652 CII 2 CN ASAN - OCH 3 500 [2,34lpyrimidin-4-yl) -I H //\\pyrazol-lI-yI]ethyl) -N-(3 methoxypheriyl)benzene ___ sulfonamide trifluoroacetate 201 H 3-{2-cyano-I -[4-(7H-pyrrolo- Ex 649 AIIN500 [2,3-d~pyrimidin-4-yI) -IH 653 CH 2 CN 0 0 pyrazol-1 -yl] ethyl) .- N-(4 00 ~ 0CH 3 methoxyphenyl)benzene '1a OCH3sulfonamide trifluoroacetate H 3-{2-cyano-1-[4-(7H-pyrrolo- Ex 472 ,j N ,q OCH 3 49 [2,3-d]pyrimidin-4-yl) -1H 654 CI- 2 CN pyrazol-1 -yl] ethyl) -N-(3,5 dimethoxypbenyl)benzamide

OCH

3 trifluoroacetate A H 3- (2-cyano-1 -[4-(7H-pyrrolo- Ex 472 N- 477 [2,3-dlpyrimidin-4-yl) -1H 655 CHzCN 0 OCH 3 pyrazol-1 -yl]ethyl} -N-(4 N (dimethylamino)phenyl] ____ O 3 benzamide trifluoroacetate 3-[3-(benzylsulfonyl)phenyl]-3- Ex 516 656 H 2 CN469 [4-(7H-pyrrolo[2,3-d]py-imidin IA 4-yl)-1H..pyrazol-1 -yl] __________propanenitrile 3-[3-(benizylthio)phenyl]-3-[4- Ex 514 657 OH 2 CN 437 (7H-pyrrolo[2,3-d]pyrimidin-4 yI)-lH-pyrazol-i -yi] ____ ________ ______________ ____propanenitrile 4-{[(3- {2-cyano-1 -[4-(7H- Ex 516 658 CH 2 C& 494 pyrrolo[2,3-d]pyrimidin-4-yI) 0 0 IH-pyrazol-1 -yl~ethyl}phenyl). ON ___ sulfonyl]methyllbenzonitrile ____ H 3-{2-cyano-l -[4-(7H-pyrrolo- Ex 649 659 OH 2 N N. 408 [2,3-d]pyrimidin-4-y1)-IH 65 HC 'H 3 pyrazol-l -yllethyl}-N-methyl d b benzenesulfonamide N 3- (2-cyano-1 -4-(7H-pyrrolo- Ex 649 s N520 [2,3-d]pyrimidin-4-y1) -111 660 CH 2 CN o" 'o ~ - pyrazol- I-yl] ethyl} -N-1 I naphthylbenzenesulfonamide H N-biphenyl-4-yi-3-{2-cyano-1 - Ex 649 N 546 [4-(7H-pyrrolo[2,3-d]pyrimidin 661 CH 2 CN 0~ 0~ 4-yl)-IH-pyrazol-1-yl]ethyl}. benzenesul fonamide H 3- {2-cyano-1 -[4-(7H-pyrrolo- Ex 472 66 HN 518 [2,3-d)pyrimidin-4-yl)

-IH

62 H 2 CN AYpyrazol- I-yI] ethyl I-N-[4 0 L C3(trifluoromethoxy)phenyl) 202 AYHZ 3 3..2-cyano-I -4-(7H-pyrrolo- Ex 472 N464 [2,3-d]pyrimidin-4-y)-IH 663 CH 2 CN pyrazol-1 -yI]ethyl) -N-(2 o0 methoxyphenyl)benzamide trifluoroacetate 3-[3-(benzyloxy)pbenyl]-3-[4- Ex 514 664 GH 2 CN 0' 421 (7H-pyrrolo[2,3-dllpyrimidin-4 ,00 yl)-1 H-pyrazol-l -yl] __________ propanenitrile ____ H3-{2-cyano-lI -[4-(7H-pyrro 10- Ex 649 H 476 [2,3-cl]pyrimidin-4-yl)-IH 665 CH 2 CN 'pyrazol- 1-yl] ethyl) -N o 0 cyclohexylbenzenesulfonamide trifluoroacetate o,3-[3 -(3 ,4-dihydroisoquinolin- Ex 649 510i 2(1 H)-ylsuffonyl)phenyl]-3-[4 666 CH 2 CN /,N. N.: - (7H-pyrrolo[2,3-dlpyrimidin-4 0/110 yl)-I H-p yrazol-I -yl)propane o 0 nitrile trifluoroacetate H3-12-cyano-1 -[4-(7H-pyrrolo- Ex 649 H452 [2,3-d]pyrimidin-4-yl)-1IH 667 CH 2 CN Ipyrazol-l -yl~ethyl} -N-(2 o 0 CH 3 methoxyethyl)benzene sulfonamide trifluoroacetate

CH

3 3- {2-cyano-I -[4-(7H-pyrrolo- Ex 649 668 CHCN450 [2,3-d]pyrimidin-4-yl)-l H 668 H2C -I,'N--,-CH3pyrazol-lI -yI]ethyl) -NN ________ o diethylbenzenesulfonamide ~N -CH3 3-{3-[(4-cthylpiperazin-1-yl)- Ex 649 I491 sulfonyl]phenyl}-3-[4-(7H 669 C2CN spyrrolo[2,3-d]-pyrimidin-4-yI) IH-pyrazol-1-yl]propanenitrile H N-1,3-benzodioxol-5-yi-3-{2- Ex 649 67 C-1 0 514 cyano-I -[4-(7H-pyrrolo[2,3-d] 0 0 Z I pyrimidin-4-yl)-l H-pyrazol-1 0 yI]cthyl) benzenesulfonamnide OCH 3-{(3-[(3-methoxybenzyl)- Ex 516 671 H 2 C A - 499 sulfonyIjphenyl}-3-[4-(7H. 07 0 2C pyrrolo[2,3-d]pyrimidin-4-yl) ______________________________ ____1H-pyrazol-1-yi]-propanenitrile ____ A3-(3-[(4-methoxybenzyl)- Ex 516 672 CH 2 CN A ~499 sulfonyl]phenyl)}-3-[4-(7H 0 0 - pyrrolo[2,3-d]pyrimidin-4-yl)

OCH

3 1H-pyrazol-1 -yl]-propanenitrile ____

CH

3 3-{3-((2,6-dimethylmorpholin- Ex 649 492 4-yl)sulfonyl]phenyl }-3-[4 673 CH 2 CN 0 (7H-pynrolo[2,3-d]pyrimidin-4 A s" A - CH 3 yJ)-I H-pyra zol-I -yl] propanenitrile _______ d 00b__ _ _ _ _ _ __ _ '0 3-f3-(4-oxopiperidin-I -yl)- Ex 649 FT 476 sulfonyl]phenyl} -3-[4- (7- 674 CH 2 CN / N~ ~ pyrrolo[2,3-d]-pyrimidin-4-yl) A 1 H-pyrazol-1 -yl~propanenitbile 0 0 trifluoroacetate o 9 H 3 3-[3 -(isopropylsulfonyl)p Ex 16 675 CH 2 CN 421 henyl]-3-[4-(7H-pyrrolo[2,3-dI A CH 3 pyrimidin-4-yl)-IH-pyrazol-l 0i yl~propanenitrile trifluoroacetate 3-{3 -[(cyclohexylmethyl)- Ex 516 475 sulfonyl]phenyl) -3-[4-(7H 676 CH 2 CN 0/\ pyrrolo[2,3-d~pyrimidin-4-yl) 0 0 1H-pyrazol-1 -yl]-propanenitrile trifluoroactate 3-[3 -(octahydroisoquinol in- Ex 649 [ I 516 2(l H)-ylsulfonyl)phenyl] -3-[4 677 CH 2 GN N: o(7H-pyrrolo[2,3-d]pyrimidin-4 4 '. yl)-1 H-pyr azol- I -yl~propane 0 0 nitrile trifluoroacetate 3-{(2-cyano-I -[4-(7H-pyrrolo- Ex 516 483 [2,3-cI]pyrimidin-4-yl) -111 678 H2CNpyrazol- 1 -yl] ethyl) -N-(2 0 0 phenylethyl)benzene 0 0 sulfonamide trifluoroacetate 448 3-[3-(pyrrolidin-1-ylsulfonyl)- Ex 649 phenyl]-3-[4-(7H4-pyrrolo[2,3-d] 679 CI- 2 CN Nopyrimidin-4-yl)-I H-pyrazol-1 AS yl]propanenitrile __~ ~ 0 498 Ex 649 N-benzyl-3- {2-cyano-I -[4-(7H 680 CH 2 CN A I-,Npyrrolo[2,3-d]pyrimi din-4.yl) // % IH-pyrazol-1-yI]ethyl}-N 10 0 methylbenzenesulfonamide ____ 494 Ex 516 N. pyrrolo[2,3-d]pyrimidin- 4 -yl) 681 CH 2 CN 1/\IH-pyrazol-1 -yI]ethyl} 0 0 phenyl)sulfonyljmethyl} benzonitrile 519 Ex 516 3- {3-[(2-naphthylmethyl) 682 CHCN . sulfonyl]phenyl)}-3-[4-(7H 0 pyi-rolo[2,3-d~pyrimidin-4-yl) 1 H-pyrazol-1I -yl]propanenitrile 483 3- {3-[( 1-phenylethyl)sulfonyll- Ex 516 683 H2CNphenyl) -3-[4-(7H-pyrrolo[2,3-d] 683 H 2 CNpyrimidin-4-yl)-1H-pyrazoI1 0 0 507 3-f{ 2 -cyano-1-[4-{7H-pyrrolo- Ex 649 H [2,3-d]pyrimidin-4-yI)- IH 684 CH 2 CN - N pyrazol-I -yl]ethyl} -N-(2 morpholin-4-ylethyl) beazenesulfonamide 494 N-(2.ami~noethyl).2-{[(3-{2- Ex 649 H 0 cyano-I -[4-(7H-pyrrolo [2,3-dl] 685 CH 2 CN )-sI pyrmidin--yl)-1 H-pyrazol-l /1\ yljethyl~phe nyl)sulfonyl] 0 0NH, amino) acetamide 498 3 -{f2-cyano-1I-[4-(7H-pyrrolo- Ex 649 H I(2,3-d]pyrimidin-4-yI) -I1H 686 CH 2 CN AK s -N T Opyrazol-1-yl]ethyl}-N-[(1S)-1 /~ \\ phenylethyl]benzenesulfonaxnide 0 0 (S) H 434 3-{2-cyano-I -[4-(7H-pyrrolo- Ex 472 687 ?(c ,N [2,3-d]pyrimidin-4-yl) -1H ee# l CH 2 CN 11pyrazol-1 -yl]ethyl} -N-phenyl 0 benzamide trifluoroacetate H 434 3-{(2-cyano-l-[4-(7H-pyrrolo- Ex 472 687 [oN, 2,3-d]pyrimidin-4-yl) -I H ee2 CH 2 CN Apyrazol- 1 -yl]ethyl)}-N-phenyl 0# benzamide trifluoroacetate 478 3-{2-cyano-I -[4-(7H-pyrrolo- Ex 472 H [,-d]pyrimidin-4-yI) -1H 688 H 2 C s~&~ 0pyrazol-1-yl]ethyl).N 68 (tetrahydrofuran-2-yI 0 0 methyl)benzenesulfonamide 433 3- {3-[(cyclopropylmethyl) Ex 516 sulfonyliphenyl) -3-[4-(7 H 689 H 2 CNpyrrolo[2,3-d]pyrimidin-4-y!) 08 CHC H-pyrazol-1..yl]propanenitrile N 477 3-{3-[(4-methylpiperazin-I -yl)- Ex 472 sulfonyl]phenyl} -3- [4-(7H 690 CH 2 CN .

5 N pyrrolo[2,3-d]pyrimidin-4-yI) 1/ \\I H-pyrazol-1I -yl]propanenitrile 0 0 561 1-[(3-{2-cyano-1-[4-(7H-pyrrolo- Ex 472 [2,3-d]pyrimidin-4 -yl)-1H 691 CH2CN /_~w 0 -_ pyrazol-1 -yl]ethyl} %0 0 phcnyl)sulfbnyl]-N,N-diethyl 0 _____I piperidine-3-carboxainide_ _ _ _ 205 r,- 0 496 3-{3-[(-oxidothiomorpolin-4- Ex 472 S yl)sulfonyl]phenyl)-3-[4-(7H 692 CH 2 CN '~~Npyrrolo[2,3-d]pyrimidin-4-yl) I H-pyraz olI -yl]propanenitrile NH 463 3-[3-{piperazin-1 -ylsulfonyl)- Ex 472 phenyl]-3-[4-(7H-pyrrolo[2,3-d] 693 CH 2 CN AS 8 N pyrimidin-4-yl)- IH-pyrazol-1 r yI]propanenitrile 0 0 480 3-[4-(7H-pyrrolo[2,3-d]- Ex 472 pyrimidin-4-yI)-1 H-pyrazol -1 694 CH 2 CN S N yl]-3-(3-(thiomorpholin-4-yI sulfonyl)phenyl]propanenitrile OH 478 3-{3-[(4-hydroxypiperidin-1-yl)- Ex 472 sulfonyllphenyl) -3 -[4-(7H 695 CH 2 CN $ Na pyrrolo[2,3-d~pyrimidin-4-yl). AS IH-pyrazol-1-yl]propanenitrile ti fluoroacetate 435 3-[3-(isobutylsulfonyl)phenyl]-3- Ex 516 [4-(7H-pyrrolo[2 ,3-d]pyrimidin. 696 CI- 2 CN // 4-yl)-IH-pyrazol-1-yl]propane 0/ %0 nitrile trifluoroacetate 477 3-[4-(7H-pyrrolo[2,3-d]- Ex 516 pyrimidin-4-yl)-1I 1-pyrazol- I S oyl]-3- {3-[(tetrahydro-2H-pyran 697 I-I 2 N //'~\4-ylmethyl)sulfonyl] o9 HC 0 0 phenyl~propanenitrile trifluoroacetate 437 3-f{3-[(2-methoxyethyl)sulfonyl]- Ex 516 phenyl)-3.[4-(7H-p yrrolo[2,3 698 CH 2 CN /\\d]pyrimidin-4-yl)-1H-pyrazol-1 00 yI]propanenitrile trifluoroacetate 459 3-f3-[(3-furylniethyl)sulfonyl]- Ex 516 phenyl)-3-f4-(7H-py rrolo[2,3 699 CH 2 CN b d]pyrimidin-4-yI)-1H-pyrazol-1 0 0 - yI~propanenitrile trifluoroacetate 40 512 3-{3-[I,1-dioxidothiomorpholin- Ex 649 o 4-yI)sulfonyl]phenyl) -3-[4-(7H 700 CH2CN N 0pyrrolo[2,3-d]pyrimidin-4-y) IH-p yrazol-1 -yllpropanenitrile 0 505 3-{3-[(4-acetylpiperazin-I -yl)- Ex 649 Jt,~ sulfonyl]phenyl} -3-[4-(7H 701 CH 2 CN N pyrrolo[2,3-d]pyrimidin4-yl) f3 IH-pyrazol-1 -yl]propanenitrile 0 0 f_ _ _ _ _ _ _ _ 470 3- (3-[(pyridin-4-y12nethYl)- Ex 516 sulfonyllphenyl)-3-[4-{TH 702 CH 2 CN Spyrrolo[2,3-d]pyrinhidifl 4 Y N 0 N H-pyrazol-1 -yl]propanenitrile 314 4-[1 -(1 -phenylbut-3-yn-I -yl)-l H- Ex 705 703 Hpyrazol-4-ylIF 7 H- pyrrolo[2,3-d) 73 CH 2 C srH H pyrimidine trifluoroacetate 0 463 4-(1-{1.{3-(morphlil4-yl- Ex 705 0 sulfonyl)phenylbut-3 -yf-1 -yl} 704 CH2C aCH /Sol 1H-pyrazol-4-yl)-7H-pyrrolo[ 2

,

3 d I d~pyrimidine 339 3-{l-[4-(7H-pyrrolo[2,3-dI- EIX 705 pyrimiddin-4-yl)-1H-pyrazol-l 705 CH 2 C =-CH CN yllbut-3-yn-I -yllbenzonitrile trifluoroacetate 342 3-{ 1-[4-(7H-pyrrolo[2,3-d]- Ex 706 706 CHpyrimidin-4-yi)-H-pyrazol-l 706 CH 2 CCH CH==O yl]but-3-yn-1 -yl)benzaldehyde tiifluoroacetate 373 methyl 3-(3-cyanophenyl)-3-[ 4 - Ex 712 (7H-pyrrolo[2,3-d]pyfimidifl-4 707 CH 2

CQ

2

CH

3 CN yl)-lH-pyrazol-I -yl]propanoate trifluoroacetate 421 NN-dimethyl-3- { I-[.4(7H- Ex 705 pyrrolo[2,3-dlpyrimidin- 4 -yl) 708 CH 2 C CH I H-pyrazol-1 -yllbut-3-yn-1 -yl} ss -S benzenesulfonam-ide o 0 trifluoroacetate H 513 3-{2-cyano-1-[4-(7H-pyrro Ex 649 s N lo[2,3-d]pyrimidin-4-yI) -1H 709 CH 2 GN c( pyrazo1-I -y1)ethyl) -N-[j4 00N ~ (dimethylamino)phen yl] benzenesulfonamide 441 3- {3-methoxy-l -[4-(7H-pyrrolo- Ex 712 [2,3-d]pyrimidin-4-y 1)-I H 710 CH 2

CH

2

-

Npyra zol-1 I.yl] propyl) -N,N

OCH

3 sdimethylbenzenesulfonamide 0 0 trifluoroacetate 433 N-pheny1-3-{1.[4-(7H-pyrroIo- Ex 705 [2,3-d]pyrimidin-4-yl )-I H 711 CH 2 CECH pyrazoI- I -yl] but-3 -yn-1I -yl} I benzamide trifluoroacetate 334 4-[I-(3-methoxy-1 -phenyl- Ex 712

CH

2

CH

2

-

propyl)-1H-pyrazol-4-yl]-7H 712 OCH 3 H pyrrolo[2,3-d]pyrimidine trifluoroacetate H 476 N-[4-(dinethylamino)phenyl]-3- Ex 705 /C N {1-[4-(7H-pyrrolo[2 ,3-d] 713 CH2C CH II pyrimidin-4-yl)-1H-pyrazol-l N yl]but-3-yn-1 -yl}benzamide trifluoroacetate 427 3-{3-hydroxy-1-[4-(7H-pyrrolo- Ex 712 [2,3-d]pyrimidin-4-yl)-IH 714 CH2CH2OH pyrazol- 1 -yl]propyl} -N,N dimethylbenzenesulfonamide 0 0 trifluoroacetate 341 3-{1-[4-(7H-pyrrolo[2,3-d]- Ex 715 CH2- pyrimidin-4-yl)-1H-pyrazol-1 715 CH=CH 2 CN yl]but-3-en-1-yl}benzonitrile trifluoroacetate 394, 4-{1-[1-(3-bromophenyl)but-3- Ex 716

CH

2 - 396 en-I -yl]-1 H-pyrazol- 4-yl) -7H 716 CH-CH 2 Br pyrrolo[2,3-d]pyrimidine trifluoroacetate 377 3-{4,4-difluoro-1 -[4-(7H- Ex 717 pyrrolo[2,3-djpyrimidin- 4-yI) 717 CH 2

CH-CF

2 CN 1 -pyrazo-1 -yl but-3-en- -yl} benzonitrile 501 4-(1-{4,4-difluoro-1-[3- Ex 717 0 (morpholin-4-ylsulfonyl) 718 CH 2

CH=CF

2 ) .N phenyl]but-3-en-1-yl}-IH 8 Apyrazol-4-y)-7H-pyrrolo[2,3-d] o 0 pyrimidine trifluoroacetate 444 4-(l -{ ~-[3-(ethylsulfonyl)- Ex 717 phenyl]-4,4-difluorobut-3-en-1 719 CH2CH=CF2 CH 3 yl)-1 H-pyrazol-4-yl)-7H 7// % pyrrolo[2,3-d]pyrimidine o 0 trifluoroacetate 458 4-(1-{1-[3-(benzyloxy)phenyl]- Ex 717 4,4-difluorobut-3-e n-I -yl}-1H 720 CH 2

CH=CF

2 pyrazol-4-yl)-7H-pyrrolo[2,3-d pyrimidine trifluoroacetate 320 4-[1-(2-methoxy-1-phenylethyl)- Ex 712 721 CH 2

OCH

3 H IH-pyrazol-4-yl)-7H-pyrrolo (2,3-d]pyrimidine 430 4-(1- {4,4-difluoro-1 -[3-(methyl- Ex 717 CH3 sulfonyl)phenyl]but-3-en-1 -yl) 722 CH 2

CH=CF

2 S 1H-pyrazol-4-yl)-7H-pyrrolo 0 0[2,3-d]pyimidine trifluoroacetate 301 3-{[4-(7H-pyrrolo[2,3-d]- Ex 250 723 H CN pyrimidin-4-yl)-1H-pyrazol-1 yl]methyl}benzonitrile 343 3-{1-[4-(7H-pyrrolo[2,3-d]- Ex 250 724 CH 2

CH

2 CH, CN pyrimidin-4-yl)-1H-pyrazol-l yl]butyl}benzonitrile 446 4-(1-(1-[3-(ethylsulfonyl)- Ex 717 phenyl]-4,4-difluorobutyl}-1

H

725 CH2CHCF CH3 pyrazol-4-yl)-7H-pyrrolo[2,3-d] 0 0 pyrimidine trifluoroacetate 474 4-[1-(4,4-difluoro-1 - {3-[(2- Ex 717 methoxyethyl)sulfonyl]phenyl} 726 CH 2

CH=CF

2 S- ' CH 3 but-3-en-1-yl)-1H-pyrazol-4-yl] / %\ 7H-pyrrolo[2,3-d]pyrimidine trifluoroacetate Example 649: 3-13-(Morpholin-4-ylsulfonyl)phenyl]-3-[4-(7H-pyrrolo[2,3-dipyrimidin-4-yl)-1H pyrazol-1-ylpropanenitrile NC Q9 CN N-N N \ N' H 5 Step 1: 4-[(3-Bromophenyl)sulfonyl~morpholine Morpholine (0.19 mL, 0.0022 mol) in 1.0 ml of THIF 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 of THF cooled in an ice bath. The reaction mixture was stirred overnight at room temperature and was then partitioned between 0.05N HC1 and ethyl acetate. The organic layer was washed with water (2X), 10 and brine (lX), 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 product (470 mg, 78%). LCMS (M+H)': m/z = 306, 308. Step 2: (2E&Z)-3-[3-(Morpholin-4-ylsulfonyl)phenyl]acrylonitrile 209 The 4-[(3-bromophenyl)sulfonyllmorpholine (0.250 g, 0.000816 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 5 degassed with nitrogen. The reaction mixture 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 HCI and ethyl acetate. The organic layer was washed with water (2X), and brine (IX), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo, to give (2E&Z)-3-[3-(morpholin-4-yl sulfonyl)phenyl]acrylonitrile as an oil (0.240gm, 85%) which was a mixture of cis and trans isomers. 0 LCMS (M+H): m/z= 279. Step 3: 3-[3-(Morpholin-4-ylsulfonyl)phenyl]-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo [2,3-d]pyrimidin-4-yl)-JH-pyrazol-1-yl]propanenitrile To a mixture of 4-(IH-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d] .5 pyrimidine (0.100 g, 0.000317 mol) and (2E&Z)-3-[3-(morpholin-4-ylsulfonyl)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 reaction mixture was then diluted with water and extracted with ethyl acetate. The combined organic phase was washed with water (2X), and brine (IX), dried over magnesium sulfate, filtered and then concentrated in vacuo to !0 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 3-[3-(morpholin-4-ylsulfonyl)phenyl]-3-[4-(7 [2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propanenitrile as a viscous oil (62 mg, 32.94%). LCMS (M+H)*: m/z - 594 25 Step 4. Using a procedure analogous to Example 61 for the removal of the SEM protecting the title compound was isolated as an amorphous white solid (30 mg, 63.84%. LCMS (M+H)*: m/z = 464. 'H NMR (400 MHz, DMSO-d6): 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). 30 Example 679; cis-4-14-(7H-Pyrrolo[2,3-dlpyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobexyl acetonitrile 210 -CN N-N N N H Step 1: 4-(Hydroxymethyl)cyclohexanol. 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 I M lithium tetrahydroaluminate in ether (20 5 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 precipitated solids were filtered off and the residue was used in the next reaction. 'H NMR(CDCI 3 ):8 4.02 and 3.75 (m, 1H), 3.45-3.61 (m, 2H), 2.02 (in, 2H), 1.84 (in, 1H), 1.52-1.80 (m, 2H), 1.44 (m, 1H), 1,32 (m, 2H), 1.03 (in, 1H). 0 Step 2: 4 -[(Trityloxy)methyl]cyclohexanol. 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 rotory evaporator, and the concentrate was extracted with ethyl acetate. 5 The organic extracts were washed with water, saturated NaCl, dried (MgSO 4 ) and then concentrated in vacuo. The reaction was chromatographed on silica gel using 30% EtOAc/hexanes to give the cis isomer (0.74 g) ' H NMR(CDC 3 ):S 7.52 (m, 6H), 7.27 (m, 9H), 3.98 (m, 1H), 2.93 (in, 2H), 1.21-1.68 (m, 9H); and the trans isomer (2.72 g) 'H NMR(CDCl 3 ):S 7.44 (m, 6H), 7.20-7.31 (m, 9H), 3.54 (m, 1H), 2.88 (in, 2H), 1. 98 (m, 2H), 1.88 (in, 2H), 1.60 (m, 1H), 0.99-1.37 (m, 4H). .0 Step 3: trans-4-[(Trityloxy)methyl]cyclohexyl 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 mixture was stirred at 15 0 *C for 2 hours The reaction was then extracted with ethyl acetate and the organic extracts were washed with water, saturated NaCl, dried (MgSO 4 ) and the concentrated in vacuo. 'H NMR (CDCl,):S 7.43 (in, 6H), 7.20-7.31 (m, 9H), 4.57 (in, 1H), 3.00 (in, 3H), 2.90 (m, 2H), 2.16 (m, 2H), 1.93 (m, 2H), 1.09-1.60 (in, SH). 211 Step 4: 7-[ 2 -(Trimethylsilyl)ethoxy]methyl-4-(I-cis-4-[(trityloxy)methylgcyclohexyl-1H-pyrazol-4-yi) 7H-pyrrolo[2,3-dipyrimidine. 4-(lIH-PyrazolA-yl)-7-[2-(trimethylsilyl)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 5 [(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 stirred at 55 *C for 48 hours. The reaction was extracted with ethyl acetate and the organic extracts were washed with water, saturated NaCl, dried (MgSO 4 ) and then concentrated in vacuo. The concentrate was chromatographed on silica gel l0 using 40% EtOAc/hexanes to give the product. LC/MS (M+H)*: 670, 'H NMR(CDC 3 ):S 8.89 (s, 111), 8.27 (s, IH), 8.24 (s, I H), 6.84-7.51 (m, 1011), 6.87 (d, 1H), 5.73 (s, 211), 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-(Trimethylsilyl)ethoxymethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-JH-pyrazol-1 15 y(]cyclohexylmethanol. 7-[2-(Trimethylsilyl)ethoxy]methyl-4-(1 -cis-4-[(trityloxy)methyl]cyclohexyl-1 H-pyrazol-4 yl)- 7 H-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 HCI 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 !0 the presence of the product. The reaction was added to a saturated NaHCO 3 solution and was extracted with ethyl acetate. The organic extracts were washed with water, saturated NaCl, dried (MgSO 4 ) and concentrated in vacuo. The concentrate was chromatographed on silica gel using EtOAc as eluent to give the product. LC/MS (M+H)*: 428 'H NMR (CDCl 3 ):S 8.89 (s, IH), 8.37 (s, IH), 8.31 (s, IH), 7.44 (d, 111), 6.87 (d, 1H), 5.73 (d, 2H), 25 4.41 (m, 1H), 3.51-3.71 (m, 4H), 2.31 (m, 21), 2.08 (m, 311), 1.70-1.93 (m, 4H), 0.98 (m, 2H), 0.00 (s, 9H). Step 6: cis-4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-IH-pyrazol-1 yI]cyclohexylnethyl methanesulfonate. 30 cis- 4

-[

4

-(

7

-[

2 -(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 1H-pyrazol 1-yl]cyclohexylrnethanol was dissolved in chloroform (3.00 mL) and was cooled to 0 *C To the reaction was added TEA (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 acetate and 35 the organic extracts were washed with water, saturated NaCl, dried (MgSO4) and concentrated in vacuo. LC/MS (M+H)*: 506 212 Step 7: cis-4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-y)-1H-pyrazol-1 yl]cyclohexylacetonitrile. cis-4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-H-pyrazol 5 1-yllcyclohexylmethyl 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 reaction was extracted with ethyl acetate and the organic extracts were washed with water, saturated NaCl, dried (MgSO 4 ) and concentrated in vacuo. The concentrate was chromatographed on silica gel using EtOAc as eluent 10 to give the product. LC/MS (M+H)*: 437, 'H NMR(CDC1 3 ):S 8.90 (s, IH), 8.36 (s, IH), 8.31 (s, IH), 7.45 (d, IH), 6.87 (d, IH), 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)-H-pyrazol-1-yljcyclohexylacetonitrile. 15 cis-4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol 1-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 was concentrated by roto-evaporation and the concentrate was dissolved in methanol (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 .0 hours at which time LCMS analysis showed no starting material present. The reaction was chromatographed on silica gel using 5% MeOH/EtOAc to give the product. LC/MS (M+H)*:307, 'H NMR(CD 3 0D):6 8.64 (s, IH), 8.55 (s, IH), 8.31 (s, IH), 7.50 (d, 111), 6.96 (d, IH), 4.42 (m, 1 H), 2.61(d, 2H, J = 8.0 Hz), 2.27 (m, 2H), 1.70-2.15 (m, 7H). 25 Example 680: cis-4-[4-(7H-Pyrrolo[2, 3 -dlpyrimidia-4-yl)-IH-pyrazol-1-yllcyclohexylmethy thiocyanate SCN N-N N N N H Step 1: cis-4-[4-( 7 -[2-(Trimethylsilyl)ethoxy/methyl-7H-pyrrolo[2, 3 -d]pyrimidin-4-yl)-1H-pyrazol-l yI]cyclohexylmethyl thiocyanate 0 cis-4-[4-(7-[2-(Trimethylsilyl)ethoxyimethyl-7H-pyrrolo[ 2 ,3-d]pyrimidin-4-yl)- H-pyrazol 1-yl]cyclohexylmethyl methanesulfonate (0.10 g, 0.00020 mol) was dissolved in DMSO (1.00 mL) 213 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 organic extracts were washed with water, saturated NaCl, dried (MgSO 4 ) and concentrated in vacuo. The concentrate was dhromatographed on silica gel using 1:1 5 EtOAc/hexanes to give the product. LC/MS (M+H)*: 469, 'H NMR(CDCI 3 ):S 8.89 (s, 1H), 8.36 (s, IH), 8.31 (s, 1H), 7.45 (d, lH), 6.87 (d, 1H), 5.73 (S, 211), 4.45 (m, 1H), 3.60 (m, 2H), 3.05 (m, 2H), 2.37 (m, 2H), 2.10 (m, 411), 1.70-1.93 (m, 311), 0.98 (m, 2H), 0.00 (s, 9H). Step 2: cis- 4

-[

4

-(

7 H-Pyrrolo[2,3-d]pyrimidin-4--y)-H-pyrazol-1-ylcyclohexylmethyI thiocyanate). 0 cis-4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-IH-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 analysis showed product. The reaction was concentrated using a rotary evaporator and the concentrate was chromatographed on 5 silica gel using 2% MeOH/EtOAc to give the product. LC/MS (M+H)*:339, 'H NMR(CD 3 0D) 5 8.65 (s, 1H), 8.55 (s, IH), 8.31 (s, 1H), 7.50 (d, IH), 6.96 (d, 1H), 4.43 (m, 1H), 3.20 (d, 211, J = 7.6 Hz), 2.24 (m, 2H), 1.80-2.17 (m, 7H). Example 681: N-5-[(cis-4-[4-(7H-Pyrrolo[2,3-d pyrimidin-4-yl)-H-pyrazol-1-yllyeylohexyl O methyl)thio]-4H-1,2,4-triazol-3-yipyrimidin-2-amine trifluoroacetate N'N NH 2 NH N-N N\ N N H TFA Step P 5-[(cis- 4

-[

4

-(

7 -[2-(Trimethylsilyl)ethoxymethyl-7H-pyrrolo[2,3-dJpyrimidin-4-yl)-)H pyrazol-1-yl]cyclohexylmethyl)thio]-4H-1,2,4-triazol-3-amin cis-4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyryolo[2,3-dopyrimidin-4-yl)-H-pyrazol 25 1-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 dissolved in DMF (1.20 mL) and potassium carbonate (0.122 g, 0.000887 mol) was added. The reaction 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 organic extracts were washed with water, saturated NaCl, dried (MgSO 4 ) and concentrated in vacuo. The concentrate was chromatographed on silica gel using EtOAc as eluent to give the product. LC/MS (M+H)y: 526, 'H NMR(CDCI 3 ):6 8.90 (s, 1H), 8.40 (s, 1H), 8.30 (s, IH), 7.45 (d, 1H), 6.87 (d, 1H), 5.73 (S, 2H), 4.45 (brs, 2H), 4.41 (m, IH), 3.60 (m, 2H), 3.22 (d, 2H, J=7.2 Hz), 2.29 (m, 2H), 5 1.70-2.10 (m, 7H), 0.98 (m, 211), 0.00 (s, 9H). Step 2: 5-[(cis- 4 -[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-y)-1H-pyrazol-1-ylcyclohexylmethyl)thioJ-4H 1,2,4-triazol-3-amine 5-[(cis- 4 -[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-dpyrimidin-4-yl)-H 10 pyrazol-1-yl]cyclohexylmethyl)thio]-4H-1, 2

,

4 -triazol-3-amine (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 (I 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; 5 1 1%CH 3 CN-H20 (0.1%TFA), 1.5 min, to 33% at 6 min; 60 m.L/min; detector set at m/z 396; retention time, 5.5min (2 runs). The eluate was freeze dried. Yield 21 mg (di-TFA salt). LCIMS (M+H)*:396, 'H NMR (d 6 -DMSO) 8 12.9 (br s, I H, NH); 8.9 (2 singlets, 21H); 8.5 (s, IH); 7.9 (m, 1H); 7.3 (m, I H); 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 (M+]). Example 682: N-5-[(eis-4-[4-(7H-Pyrrolo[2,3-dipyrimidin-4-yl)-H-pyrazol-1-yllcyclohexyl methyl)thiol-4H-1,2,4-triazol-3-ylpyrimidin-2-amine trifluoroacetate IN H N'-k N N ,-N H )<N S N N-N N\ N N H TFA Step 1: N-3-[(cis-4-[4-(7-[2-(Trimethylsilyl)ethoxy methyl-7H-pyrrolo[2,3-djpyrimidin-4-yl)-H Z5 pyrazol-1-yl]cyclohexylmethyl)tho]-4H-1,2,4 -triazol-3-ylpyrimidin-2-amine In a vial [A) 5-[(cis-4-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-dpyrimidin4 yl)-lH-pyrazol-1-yl]cyclohexylmethyl)thio]-4H-1, 2

,

4 -triazol-3-amine (0.047 g, 0.000089 mol) was 215 heated with 2-chloropyrimidine (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 5 115 *C for 3 hours, at which time LCMS analysis showed no starting material present and mainly product was present. The reaction was chromatographed on silica gel using 2% MeOH/EtOAc to give the product. LC/MS (M+1)*:604, 'NMR(CDCl 3 ): 8.89 (s, 1H), 8.82 m, 2H), 8.43 (s, 1H), 8.30 (s, IH), 7.44 (d, IH), 7.23 (m, IH), 7.03 (br s, 2H), 6.88 (d, 1H), 5.73 (s, 21'), 4.40 (m, 1H), 3.60 (m, 2H), 3.35 (d, 2H), 2.34 (m, 2H), 1.80-2.15 (m, 7H), 0.98 (in, 2H), 0.00 (s, 9H). 0 Step 2: N-5-[(cis-4-[4-(7H-Pyrrolo[2,3-djpyrimidin-4-yl)-1H-pyrazol-1-yljcyclohexylmethyl)thio] 4H-1,2, 4 -triazol-3-ylpyrimidin-2-amine. N-5-[(cis-4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin--yl)-1

H

pyrazol-1-yl]cyclohexylmethyl)thio]-4H-1, 2

,

4 -triazol-3-ylpyrimidin-2-amine (0.024 g, 0.000040 mol) 5 was dissolved in DCM (4.00 mL), and TFA (0.50 mL, 0.0065 mol) was added. The reaction was stirred at 25 *C for 16 hours and was concentrated in vacuo. The residue was dissolved in methanol (3.00 mL) and concentrated ammonium hydroxide (0.50 mL) was added. This reaction was stirred at 25 *C for 2 hours at which time LCMS analysis showed mostly product. The reaction was concentrated using a rotary evaporator and the concentrate was purified by prep LC to give the 0 product as the trifluoroacetate salt. LC/MS (M+H):474, 'H NMR(CD 3 0D) 5 8.87 (s, 1H), 8.85 (3, IH), 8.81 (s, I ), 8.79 (s, I H), 8.45 (s, 1H), 7.85 (d, IH), 7.34 (in, 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 -1 4 -(7H-Pyrrolo2,3-djpyrimidin-4-y)-1H-pyrazol-1-ylicyclohexylpropane 25 nitrile trifluoroacetate -N CN HN TFA Step 1: 2-(1, 4 -Dioxaspiro[4.5]dec-8-yl)ethanol. Ethyl 1, 4 -dioxaspiro[4.5]dec-8-ylacetate (3.40 g, 0.0149 mol) prepared according to the 0 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 lithium tetrahydroaluminate in ether (15.0 mL) and the resulting mixture was stirred at 0 *C for 60 minutes and at 25 *C for 2 hours. The reaction was 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 concentrated using a rotary evaporator to give the product. 'H NMR(CDC 3 ): 3.94 (s, 4H), 3.67 (t, 2H), 1.20-1.80 (in, 1 I). 5 Step 2: 4-(2-Hydroxyethyl)cyclohexanone. 2-(1,4-Dioxaspiro[4.5]dec-8-yl)ethanol (2.70 g, 0.0145 mol) was dissolved 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 NaHCO 3 solution and was then extracted with ethyl acetate. The 0 organic extracts were washed with water, and with saturated NaCl, then dried (MgSO 4 ) and concentrated in vacuo. The crude product was used in the next reaction without further purification. 'H NMR(CDC 3 ): 3.75 ( in, 2H), 2.36 (in, 4H), 1.20-2.13 (m, 7H). Step 3: 4-(2-Hydroxyethyl)cyclohexanol. 5 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 0 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 further purification. 'H NMR(CDCI 3 ): 3.96 and 3.57 (m, IH) minor and major CHOH (-1:5 ratio) 3.70(m, 2H), 0.94-2.02 (in, IIH). Z5 Step 4: 4-[2-(Trityloxy)ethyl]cyclohexanol. 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 triphenylmethyl 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. 30 The reaction was concentrated using a rotary evaporator and the concentrate was extracted with ethyl acetate. The organic extracts were washed with water, and saturated NaCi, then dried (MgSO 4 ) and concentrated in vacuo. The concentrate was chromatographed on silica gel (30%EtOAc/hexanes) to give the trans isomer (1.98 g) 'H NMR(CDC]3): 7.42-7.45 (m, 611), 7.20-7.30 (in, 9H), 3.50 (m, 1H), 3.07 (m, 2H), 1.93 (n, 2H), 35 1.66 (m, 2H), 1.17-1.60 (in, 5H), 0.89 (m, 2H). Step 5: trans-4-[2-(Trityloxy)ethyl]cyclohexyl methanesulfonate. 217 trans-4-[2-(Trityloxy)ethyljcyclohexanol (1.95 g, 0.00504 mol) was dissolved 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 5 washed with water, and saturated NaCl, then dried (MgSO 4 ) and concentrated in vacuo. '11 NMR(CDCls): 7.41-7.45 (m, 6H), 7.20-7.32 (m, 9H), 4.55 (m, IH), 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-(Trimethylsilyl)ethoxy]methyl-4-(J-cis-4-[2-(trityloxy)ethyl]cyclohexyl-H-pyrazol-4-y) 0 7H-pyrrolo[2,3-djpyrimidine. 4-(1H-Pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxyjmethyl-7H-pyrrolo[2,3-d)pyrimidine (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 5 and was then stirred for 20 minutes. The reaction was stirred at 55 *C for 48 hours at which time LCMS analysis showed mostly product. The reaction was extracted with ethyl acetate and the organic extracts were washed with water and saturated NaCI, then dried (MgSO 4 ) and concentrated in vacuo. The concentrate was chromatographed on silica gel using 40% EtOAc/hexanes to give the product. LCIMS (M+H)*:684,'H NMR(CDC 3 ): 8.89 (s, 1H4), 8.35 (br s, 1H), 8.30 (s, 1H), 7.50 (m, 6H), 7.44 :0 (d, I H), 7.27-7.32 (m, 914), 6.87 (d, 1 H), 5.73 (s, 214), 4.33 (m, 1H), 3.60 (m, 2H), 3.17 (t, 2H), 1.50 2.25 (m, 11I H). 0.98 (m, 2H), 0.00(s, 9H). Step 7: 2-cis-4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-JH-pyrazol 1-yI]cyclohexylethanol (7b). 25 7-[2-(Trimethylsilyl)ethoxy]methyl-4-(1 -cis-4-(2-(trityloxy)ethyl]cyclohexyl-1H-pyrazol-4 yl)-7H-pyrrolo(2,3-d]pyrimidine (1.45 g, 0.00212 mol) was dissolved in methanol (30.00 mL) and THF (10.00 mL) and 4.0 M HCI in 1,4-dioxane (2.00 mL) was added. The mixture was stirred at 25 *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 NaHC0 3 30 solution, and was then extracted with ethyl acetate. The organic extracts were washed with water and saturated NaCl, then dried (MgSO 4 ) and concentrated in vacuo. The concentrate was chromatographed on silica gel using EtOAc as fluent to give the product. LC/MS (M+H)*: 442 Step 8: 2-cis-4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl--7H-pyrrolo[2,3-d]pyrimidin-4-yl)-H-pyrazol 35 1-yl]cyclohexylethyl methanesulfonate (8b). 2-cis-4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo(2,3-d]pyrimidin-4-yl)- 1H pyrazol-l-yl]cyclohexylethanol (0.89 g, 0.0020 mol) was dissolved in DCM (12.00 mL, 0.1872 nol) 218 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 (MgSO 4 ) and concentrated in vacuo. 5 LC/MS (M+H)*:520, 'H NMR(CDCI 3 ): 8.90 (s, IH), 8.38 (br s, 1H), 8.31 (s, 1H), 7.45 (d, 111), 6.88 (d, 1H), 5.73 (s, 2H), 4.40 (m, 1H), 4.27 (t, 2H), 3.60 (in, 2H), 3.07 (s, 3H), 1.60-2.40 (m, I IH). 0.98 (m, 2H), 0.00(s, 9H) Step 9: 3 -cis-4-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yI]cyclohexylpropanenitrile 0 trifluoroacetate (9b). 2-cis-4-[4-(7-[2-(Trimethylsilyl)ethoxy~methyl-7H-pyrrolo[2,3-d~pyrimidin-4-yl)-1H pyrazol-1-yl]cyclohexylethyl methanesulfonate (0.075 g, 0.00014 mol) was dissolved in DMSO (1.50 rnL) and sodium cyanide (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 reaction was then 5 extracted with ethyl acetate and the organic extracts were washed with water and saturated NaCl, then dried (MgSO 4 ) 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 methanol (3.00 mL) and concentrated 0 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(CD 3 0D): 8.86 (s, 1H), 8.81(s, 1H), 8.44 (s, 1H), 7.84 (d, IH), 7.31 (d, 111), 4.48 (in, 1H), 2.51 (m, 2H), 2.28 (in, 2H), 2.00 (m, 2H), 1.80 (in, 5H), 1.67 (n, 25 2H). Example 684: 5-[(2-cis-4-[4-(7H-Pyrrolo[2,3-d)pyrimidin-4-yl)-H-pyrazol-1-yl)cyclohexyl cthyl)thiol-4H-1,2,4-triazol-3-amine trifluoroacetate 0 NH2 N-N N-N N\ N N H

TFA

2-cis-4-[4-(7-[2-(Trimethylsilyl)ethoxy]mnethyl-7H--pyrrolo[2,3-d~pyrimidin-4-yl)-1H pyrazol-1-yl]cyclohexylethyl methanesulfonate (0.060 g, 0.00012 mol) was dissolved in DMF (1.31 mL) with 5-amino-4H-1,2,4-triazole-3-thiol (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 LOMS analysis showed 5 no starting material present. 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 a rotary evaporator. The residue was dissolved in methanol (3.60 mL) and concentrated ammonium hydroxide (0.60 mL) was added and this mixture was stirred at 25 *C for 2 hours. The reaction was [0 concentrated using a rotary evaporator and the concentrate was purified by prep. LC to give the product. LC/MS (M+H)*:410, 'H NMR(CD 3 0D): 8.85 (s, 1H), 8.80(s, IH), 8.44 (s, 1H), 7.83 (d, 1H), 7.30 (d, IH), 4.46 (m, IH), 3.17 (in, 2H), 2.27 (in, 2H), 2.00 (in, 2H), 1.62-1.90 (in, 7H). Example 685: 4 -1 4

-(

7 H-Pyrrolo2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yllcyclohexylideneaceto 5 nitrile trifluoroacetate HN )CN N P N TFA Step 1: 1,4-Dioxaspiro[4.5)decan-8-oI l, 4 -Dioxa-spiro[4.5]decan-8-one (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 I M lithium tetrahydroaluminate in ether (7.0 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 I N NaOH (0.5 mL of each) and then filtered. The filtered solid was washed with ether and the combined ether filtrate was concentrated using a rotary evaporator to give the product. NMR (CDCI 3 ): 3.94 (in, 4H), 3.81 (m, IH), 1.79-1.92 (m, 4H), 1.54-1.70 (m, 41). 25 Step 2: 1,4-Dioxaspiro[4.5]dec-8-yI methanesulfonate.

I,

4 -Dioxaspiro[4.5]decan-8-ol (0.40 g, 0.0025 mol) was dissolved in chloroform (10.0 mL) and the resulting mixture was cooled at 0 "C. To the mixture 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 hours. '0 The reaction was extracted with ethyl acetate and the organic extracts were washed with water, and saturated NaCl, then dried (MgSO 4 ) and concentrated in vacuo. The crude product was used in the next reaction without further purification. 220 'H NMR(CDCl 3 ): 4.85 (m, 1H), 3.95 (m, 4H), 3.02 (s, 3H), 1.98-2.05 (m, 4H), 1.82-1.89 (in, 2H), 1.61-1.70 (in, 2H). Step 3: 4 -[I-(1,4-Dioxaspiro[4.5]dec-8-yl)-IH-pyrazol-4-yl]-7-[2-(trimethylsilyl)ethoxy]methyl-7H 5 pyrrolo[2,3-djpyrimidine. A mixture of 1,4-dioxaspiro[4.5]dcc-8-yl methanesulfonate (0.50 g, 0.0015 mol) with 4-(lH pyrazol- 4 -yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (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 OC 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 (MgSO 4 ) and concentrated in vacuo. The concentrate was chromatographed on silica gel using 1:1 EtOAc/hexanes to give the product. LC/MS (M+H)*:456, 'H NMR(CDCl 3 ): 8.89 (s, 1H), 8.35 (s, 1H), 8.30 (s, 1H), 7.44 (d, 11H), 6.87 (d, IMH), 5.73 (s, 2H), 4.38 (in, IH), 4.06 (s, 4H), 3.60 (m, 2H), 2.22-2.31 (m, 4H), 2.00 (m, 2H), 1.86 (m, 2H), 5 0.98 (m, 2H), 0.00(s, 9H) Step 4: 4-[4-( 7 -[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-dJpyrimidin-4-yl)-IH-pyrazol-1 y1]cyclohexanone To 4-[1-(1,4-dioxaspiro[4.5]dec-8-yl)-1H-pyrazol-4-yl]-7-[2-(trimethylsilyl)ethoxymethyl ) 7H-pyrrolo[2,3-d]pyrimidine (2.13 g, 0.00467 mol), was added acetone (85 mL) followed by 12 M HCI 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. After 20 h, HPLC showed no change (and no loss of SEM). The reaction mixture was quenched into excess sat'd NaHCO 3 . The acetone was removed by roto-evaporation. The resulting mixture of aqueous bicarbonate and a white solid was then extracted 5 with EtOAc. The combined organic extract was shaken with sat'd NaCl, dried over Na 2

SO

4 , 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 automatic flash chromatography on silica gel. Used a 40g column; flow 40 mIJmin; [A= 2% iPrOH-hexane] [B= 6% iPrOH-50% EtOAc/hexane]; A, 2 min; Gradient to B in 25 min, then B for 10 min. The eluent was concentrated 0 using a rotary evaporator to give 1.3 g of a white solid. HPLC Method: Zorbax SB Cl 8, 5 ptm, 15 cm, 35 *C, flow 1.2 mL/inin, 10% CH 3

CN-H

2 0 (0.05% TFA), to 100% CH 3 CN 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 (CDC1 3 ) 8 8.8 (s, 111); 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 (in, 8H); 0.9 (t, 2H); -0.1 (s, 9H). MS(ES) 412 (M+1). 5 Step 5: 4

-[

4

-(

7 -[2-(Trimethylsilyl)ethoxyJmethyl-7H-pyrrolo[2.3-d]pyrimidin-4-y)-Hpyrao yl]cyclohexylideneacetonitrile To a solution of 1.0 M potassium tert-butoxide in THF (1.90 mL) at 0 "C was added a solution of diethyl cyanomethylphosphonate (321 ;L, 0.00198 mol) in THF (4 mL) dropwise. The 5 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)-1H-pyrazol-1-yl]cyclohexanone (743 mg, 0.00180 mol) in THF (5 mL) stirring at 0 *C under a nitrogen atmosphere. The reaction 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 combined organic extract was washed with water, then sat'd NaCl, then dried over Na 2

SO

4 , and concentrated to dryness to yield 0.76 g of a white crystalline solid (TLC (EtOAc) Rf 0.33). The product was purified by automatic flash chromatography on silica gel. Used 40g column; flow 40 mL/min; [A= hexane] [B= EtOAc]; A, 2 min; Gradient to B in 20 min. Rotary evaporation yielded 0.70 g of a white crystalline solid (89% yield). 'H NMR (CDCl 3 ) 5 8.9 (s, 11-1); 8.3 (s, 2H); 7.4 (d, 5 IH); 7.3 (s, IH); 6.9 (d, IH); 5.7 (s, 2H); 5.3 (s, I H, olefin); 4.5 (m, I H, NCH); 3.6 (m, 2H); 3.2 (m, IH); 2.7 (m, 1H); 2.5 (m, 4H); 2.1 (m, 2H); 1.0 (m, 2H); -0.1 (s, 9H). MS(ES) 435 (M+1). Step 6: 4-[4-(7H-Pyrrolo[2,3-djpyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexylideneacetonitrile A solution of TFA (0.5 mL, 0.006 mol) and 4

-[

4

-(

7

-[

2 -(trimethylsilyl)ethoxy]methyl-7H .0 pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexylideneacetonitrile (22.7 mg, 0.0000522 mol), was stirred for 1.5h. The solution was then concentrated using a rotary evaporator to remove TFA. LCMS analysis showed conversion to the hydroxymethyl 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 25 added. The resulting solution was stirred for 16 h. LCMS analysis showed complete de-protection. The solution was then concentrated using a rotary evaporator. The product was isolated by prep HPLC using a 30 mm x 100 mm C18 column; 18% CH 3

CN-H

2 O (0.1%TFA), 1min, to 35% at 6min; 60 mL/min; detector set at 254nm; retention time, 4.4min. The eluate was freeze dried. yield 7.6 mg of a white solid (TFA salt; racemic; 34.6%). 'H NMR (d,.DMSO) 8 12.9 (br s, 1H, NH); 8.9 (s, 2H); 30 8.5 (s, 1H); 7.8 (m, 1H); 7.3 (in, IH); 5.6 (s, IH, olefin); 4.6 (m, 1H,. NCH); 2.8 (m, 1H); 2.6 (m, I H); 2.5 (m, 2H); 2.3 (m, 2H) 2.0 (m, 2H). MS(ES) 305 (M+]). Example 686: cis-4-[4-(7H-Pyrrolo[2,3--dpyrimidin-4-yl)-IH-pyrazol-1-yllcyclohexanecarbo nitrile trifluoroacetate 222 N - N N\ / \N N Step 1: cis-4-[4-(7-[2-(Trimethylsilyl)ehoxymethy-7H-pyrrolo[2,3-d]pyrimidin-4-yI)-IH-pyrazol-J yI]cyclohexanecarbaldehyde oxime A solution of sulfur trioxide-pyridine complex (53.4 mg, 0.000336 mol) in DMSO (0.3 mL, 5 0.004 mol) was added to a solution of cis- 4

-[

4 -(7-[2-(trimethylsilyl)ethoxy]inethyl-7H-pyrrolo[2,3 d]pyrimidin-4-yl)-1H-pyrazol-1-yllcyclohexylmethanol (57.4 mg, 0.000 134 mol) and TEA (56.1 L, 0.000403 mol) in DCM (0.3 mL, 0.004 mol) at -10 "C. The mixture was stirred vigorously at 10-20 "C 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, saturated 0 aqueous sodium bicarbonate, water, and brine, and then dried over sodium sulfate. Concentration gave 57 mg of a residue. To the resulting residue was added hydroxylamine-HCl (50mg), 1 mL 20% K 2 C0 3 , 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, Cl 8 column; 30% 5 CH 3

CN-H

2 0 (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-[4-(7H-Pyrrolo[2,3-d pyrimidin-4-yl)-]H-pyrazol-1-yljcyclohexanecarbonitrile [A) cis-4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-IH . pyrazol-1-yl]cyclohexanecarbaldehyde oxime (11.0 mg, 0.0000250 mol) was dissolved in pyridine (0.25 mL, 0.0031 mol), and benzenesulfonyl chloride (10.0 sL, 0.0000784 mol) was added and the resulting mixture was stirred at rt. After 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% CH 3

CN-H

2 0 (0.1% NH 4 0H), 1min, to 75% at 6 min; 30 mL/min; detector set at m/z 5 423; retention time, 4.8 min. The fluent was concentrated using a rotary evaporator to give 8 mg of the desired product. 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 concentrated again. LCMS showed clean conversion to the hydroxymethyl intermediate (M+H 323). The residue 0 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 de-protection to the desired product M+H 293. The mixture was then concentrated by roto-evaporation, and the product was isolated by prep HPLCMS using a 19 mm x 100 mm C18 column; 15% CH 3

CN-H

2 0 (0.1% TFA), 1.5 min, to 30% at -11 6 min; 30 mlimin; 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. 'H NMR (d 6 -DMSO) 8 12.82 (br s, IH, NH); 8.87 (s, 1H); 8.85 (s, 1H); 8.48 (s, 1H); 7.82 (m, IH); 7.24 (m, IH); 4.40 (m, 1H, NCH); 3.22 (m, IH); 2.05 (m, 611); 1.79 (m, 21). MS(ES) 293 (M+1). 5 Example 687: 2 -1(cis- 4

-[

4 -(7H-Pyrrolo[2,3-dipyrimidin-4-yl)-1H-pyrazol-1-ylcyclohexyl methyl)sulfinyllbenzonitrile trifluoroacetate NC S HN 0 Nc N \-N N Step 1: 4 -[]-(cis-4-[(2-Bromophenyl)thiojmethylcyclohexyl)-H-pyrazol-4-yl]- 7-[2-(trimethylsilyl) 0 ethoxyjmethyl- 7H-pyrrolo[2,3-djpyrimidine This compound was prepared from (cis-4-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H pyrrolo(2,3-d]pyrimidin-4-yl)-11-pyrazol-1-yl]cyclohexylmethyl methanesulfonate as in Example 686[A]. Yield 73%. The product was purified using the following HPLC method: Zorbax SB C18, 5 pm, 15cm, 35 C, flow 1.2 mL/min, 10% CH 3

CN-H

2 0 (0.05% TFA), to 100% CH 3 CN in 9.0 min; stop 5 time 12.3 min; detector 254 nm; retention time starting mesylate, 7.5 min; product, 9.9 min (UV max 215, 258, 300, & 326 nm). TLC: Rf 0.3 using 35% EtOAc/5% iPrOH/hexane. The product was purified by automated silica gel flash chromatography using 30% EtOAc/5% iPrOH/hexane. 'H NMR (CDC1 3 ) 8 8.84 (s, 1H); 8.31 (s, 1H); 8.26 (s, 1H); 7.55 (m, 1H); 7.39 (d, IH); 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 0 (m, 3H); 1.83 (in, 4H); 0.92 (in, 2H); -0.06 (s, 9H). MS(ES) 598/600 1:1 (M+1). Step 2: 2 -[(cis-4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-dpyrimidin-4-yl)-JH pyrazol-1-ylcyclohexylmethyl)hiojbenzonitrile 4-[1 -(cis-4-[(2-Bromophenyl)thio]methylcyclohexyl)-I H-pyrazol-4-yl]-7-(2-(trimethysilyl) 5 ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (62.7 mg, 0.000105 mol), zinc cyanide (123 mg, 0.00105 mol), and tetrakis(triphenylphosphine)palladium(O) (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; 52%CH 3

CN-H

2 0 (0.1%TFA), 1.5 min, to 75% 0 at 6 min; 60 mL/min; detector 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 tm, 15 cm, 35 C, flow 1.2 mL/min, 10% CH 3

CN-H

2 0 (0.05% TFA), to 100% CH 3 CN 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+]). Step 3: 2-[(cis-4-[4-(7H-Pyrrolo[2, 3 -d]pyrimidin-4-y)-1H-pyrazol-1-yl]cyclohexylmethy)sulfinyl] 5 benzonitrile A solution of 2 -[(cis- 4

-[

4 -(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4 yl)-IH-pyrazol-1-yl]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 0 (1 mL) and ammonium hydroxide (1 mL) was added. The resulting solution was stirred overnight, at which time HPLC showed complete deprotection. The product was isolated by prep HPLCMS using a 19 mm x 100 mm C18 column; 30% CH 3

CN-H

2 0 (0.1% TFA), 1.5 min, to 59% at 6 min; 30 nL/min; detector set at m/z 415 nm; retention time, 4.7 min. The cluate was concentrated using a rotary evaporator to give 36 mg of the sulfide TFA salt, a colorless glassy material. NMR (d 0 -DMSO) 8 5 12.82 (br s, I H, NH); 8.84 (2 singlets, 2H); 8.45 (s, 1H); 7.8 (m, 2H); 7.64 (m, 2H); 7.34 (td, IH); 7.24 (s, lH); 4.39 (m, 1H, NCH); 3.23 (d, 2H); 2.19 (m, 2H1); 1.89 (m, 3H); 1.72 (m, 4H). MS(ES) 415 (M+1). This material was then dissolved in CH 2 Clz 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 I h. LCMS showed conversion to the product, and no remaining sulfide. The reaction mixture was concentrated 0 by rotovap, and the product was isolated by prep HPLCMS using a 19 mm x 100 mm C18 column; 18% CH 3

CN-H

2 0 (0.1% TFA), 1. 0 min, to 35% at 6 min; 30 mL/min; detector 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 HPLC method was: Zorbax SB C18, 5 n, 15 cm, 35 *C, flow 1.2 mL/min, 10% CH 3

CN-H

2 0 (0.05% TFA), to 100% CH 3 CN in 9.0 min; stop time 12.3 min; detector !5 268 nm; retention time starting material, 5.6 min; sulfoxide, 4.8 min; sulfone, 5.2 min; MCPBA, 6.0 min. 'H NMR (CDCl 3 ) 5 12.1 (brs, lH, NH); 9.0 (s, 1H): 8.9 (s, IH); 8.3 (s, IH); 8.1 (m, IH); 7.9 (m, IH); 7.8 (m, IH); 7.6 (m, 2H); 7.0 (m, 1H); 4.4 (m, IH, 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+l). 0 Example 688: 2-[(cis-4-[4-(7H-Pyrrolo[2,3-dpyrimidin-4-yl)-IH-pyrazol-1-yl]cyclohexyl methyl)sulfonyllbenzonitrile trifluoroacetate NGD HN P0 NN N TFA 225 2-[(cis-4-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1 -yl]cyclohexylmethyl)sultinyl] benzonitrile (17.2 mg, 0.0000400 mol) (21 mg TFA salt), was dissolved in DCM (10 nL) and cooled to 0 "C. To this mixture was added MCPBA (18 mg, 0.0000800 mol). The resulting mixture was stirred for Ih at 0 "C, 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 NaHCO 3 wash, and the resulting washed mixture was concentrated by roto-evaporation. The product was isolated by prep HPLCMS using a 19 mm x 100 mm C18 column; 23%CH 3

CN-H

2 0 (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. 'H NMR (d-DMSO) 5 12.70 (br s, IH, NH); 8.83 (s, IH); 8.82 (s, IH); 8.41 (s, iH); 8.21 (dd, 1H); 8.16 (dd, 1H); 8.01 (td, IH); 7.95 (td, IH); 7.78 (s, IH); 7.19 (s, IH); 4.34 (m, 1H, NCH); 3.62 (d, 2H); 2.28 (m, 11); 2.10 (m, 2H); 1.90 (m, 2H); 1.72 (in, 4H). MS(ES) 447 (M+1). Example 689: 3 -1 4 -(7H-Pyrrolo[2,3-dpyrimidin-4-y)-1H-pyrazol-1-yll cyclobexylacetonitrile trifluoroacetate

NC

N N TFA Step 1: 3-[4-(7-[2-(Trimethylsilyl)ethoxymethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-IH-pyrazol-1-yl] cyclohexanone To a solution of 4-(IH-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d) 0 pyrimidine (309 mg, 0.980 mmol) in ACN (6 mL) was added 2-cyclohexen-1-one (190 L, 01.96 mmol), followed by DBU (40 pL, 0.3 mmol). The resulting mixture was stirred for one hour at which point LCMS indicated complete addition. The mixture was reduced in vacuo and the crude product was purified by column chromatography to obtain the product (397 mg, 98%). 'H NMR (400 MHz,

CDCI

3 ): 5 8.84 (s, IH), 8.27 (s, IH), 8.25 (s, lH), 7.45 (d, IH), 6.79 (d, IH), 5.67 (s, 2H), 4.61 (m, 5 1H), 3.55 (m, 2H), 3.05-2.90 (m, 2H), 2.45-2.30 (in, 4H), 2.05 (m, 1H), 1.90 (m, IH), 0.92 (m, 2H), -0.06 (s, 9H). MS (EI) m/z= 412.2 (M+-I). Step 2: (2EZ)-3-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-IH pyrazol-1-yl]cyclohexylideneacetonitrile To a solution of t-BuOK in THF (1.0 M, 0.255 mL, 0.255 mmol) at 0 "C was added a solution of diethyl cyanomethylphosphonate (43 jiL, 0.27 mmol) in TIF (0.6 mL) dropwise. The reaction was held for 10 minutes, then a solution of 3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d] pyrimidin-4-yl)-IH-pyrazol-1-yl)cyclohexanone (100.0 mg, 0.2430 mmol) in THF (0.34 mL) was 3 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 addition to yield the desired product as a mixture of E and Z isomers (87.9 mg, 83%). 'H NMR (400 MHz, CDCl 3 ): 8 8.84 (s, 0.5H), 8.83 (s, 0.5 H), 8.27 (d, I H), 8.25 (s, 1H), 7.40 (s, 0.5H), 7.39 (s, 0.5H), 6.81 (d, 0.511), 6.79 (d, 0.5H), 5.67 (s, 2H), 5.28 (s, 0.5H), 5.24 (s, 0.5H), 4.4 (m, IH), 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 (E) m/z= 435.2 (M+H). Step 3: 3-[4-(7-[2-(Trimethylsilyl)ethoxyjmethyl-7H-pyrrolo[2,3-djpyrimidin-4-yl)-IH-pyrazol-1-yl] cyclohexylacetonitrile To (2E, Z)- 3 -[4-(7-[2-(trimethylsilyl)ethoxy]metyl-7H-pyrrolo[2,3-dpyrimidin-4-yl)-1H 5 pyrazol-1-yl]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 pL, 0.12 mmol) was added dropwise. The reaction was held at -78 "C for lh at which point LCMS indicated complete reduction. The reaction was quenched at -78 "C by addition of saturated aqueous NH4 4 CI and EtOAc, and was then allowed to warm to ambient temperature. The phases were separated and the aqueous ) phase was extracted with additional EtOAc. The combined organic phase was washed with water, then saturated NaCl, and then was dried over MgSO 4 . The crude product was purified by column chromatography to obtain the product (26.5 mg, 63%). 'H NMR (400 MHz, CDCl 3 ): & 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, 111), 3.52 (m, 2H), 2.6-1.4 (m, 11H), 0.92 (m, 2H), -0.06 (s, 9H). MS (El) m/z 437.2 (M+H). 5 Step 4: 3-[4-(7H-Pyrrolo[2, 3 -djpyrimidin-4-yl)-JH-pyrazol-1-ylgcyclohexylacetonitrile trifluoroacetate To 3

-[

4

-(

7

-[

2 -(trimethylsilyl)ethoxy]methyl-7H-pyrrolo(2,3-d]pyriimidin-4-yl)-1H-pyrazol-l yl)cyclohexylacetonitrile (30.1 mg, 0.0689 mmol) was added DCM (1.0 mL) and TFA (1.0 mL). The 0 resulting 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 jtL, 0.55 mmol), after 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 preparative LCMS to provide the product as a TFA salt (24 5 mg, 83%). 'H NMR (400 MHz, CD 3 OD): 8 8.91 (s, 1H), 8.82 (s, 11H), 8.45 (s, 111), 7.84 (s, 11), 7.31 (s, 1H), 4.69 (s, 1H), 2.58 (d, 2H), 2.5-1.5 (m, 9H). MS (EI) rn/z = 307.10 (M+H). 227 Example 690: 5-({cis-4-[4-(7H-Pyrrolo(2,3-dlpyrimidin-4-yl)-H-pyrazol-1-yljcyclohexyl~thio) 1H-1,2,4-triazol-3-amine bis(trifluoroacetate) H NS N N N H2 N-N 2 TFA N \ N N H Step 1: trans-4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-)H pyrazol-1-yI]cyclohexanol A solution of 4-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H pyrazol-1-yl]cyclohexanone (662 mg, 1.61 mmol) in THF (5 mL) was cooled to 0 0C and lithium tetrahydroaluminate (2M in THF, 0.804 mL, 1.61 mnol) was added slowly. The mixture was allowed ) to warm slowly to ambient temperature until LCMS indicated complete reduction. The reaction was cooled to 0 "C and quenched with dropwise addition of water (0.5 mL). DCM was added, and the mixture 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. TIc (6:3:1 5 EtOAc:hexanes:isopropanol) gave an Rf of 0.25 for the cis product , and 0.18 for the trans product. The product 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 of mixed isomers. 'H NMR (400 MHz, CDCI 3 ): 5 8.83 (s, 1Hf), 8.27 (s, 1H), 8.24 (s, IH), 7.39 (d, IH), 6.81 (d, IH), 5.67 (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 0 (m, 211), 0.92 (m, 211), -0.06 (s, 91). MS (EI) m/z = 414 (M+H). Step 2: trans-4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-JH-pyrazol 1-yI]cyclohexyl methanesulfonate To trans-4-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 1H 5 pyrazol-1-yl]cyclohexanol (154 mg, 0.372 mmol) was added DCM (1.0 mL) and TEA (73 iL, 0.52 mmol). The resulting solution was then cooled to 0 0C and methanesulfonyl chloride (34 jiL, 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 30 water, then saturated NaCI, then was dried over MgSO 4 and reduced in vacuo to give the crude product which was used without further purification (173 mg, 95%). 'H NMR (400 MHz, CDCI 3 ): a 8.83 (s, 1H), 8.24 (s, 2H), 8.24 (s, IH), 7.39 (d, 1H), 6.80 (d, 1H), 5.67 (s, 2H), 4.77 (m, IH), 4.27 (in, 1H), 3.54 (in, 2H), 3.06 (s, 3H), 2.36 (m, 4H), 2.03 (n, 2H), 1.82 (in, 2H), 1.53 (m, 2H), 0.92 (m, 211), -0.06 (s, 9H). MS (EI) m/z= 492.1 (M+H). 5 Step 3: 5-((cis-4-[4-(7H-f-Pyrrolo[2,3-d]pyrimidin-4-y)-IH-pyrazol-1-yl]cyclohexyl}thio)-HH-1,2,4 triazol-3-amine bis(trifluoroacetate) To a solution of trans- 4

-[

4 -(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo(2,3-d]pyrimidin 4 -yl)-1H-pyrazol-1-yl]cyclohexyl methanesulfonate (42 mg, 0.085 mmol) in DMF (800 p.L) was 0' added 3-anino-1H-1,2,4-triazole-5-thiol (30 mg, 0.26 mmol) and K 2 C0 3 (36 mg, 0.26 mmol). The reaction was sealed and held at 100 *C 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 saturated NaCl, dried over MgSO 4 and reduced in vacuo, and the crude product was purified by 5 column chromatography to give 5-({cis-4-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3 d)pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexyl}thio)-1H-1,2,4-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 0 NILOH (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, CD 3 OD): 8 8.77 (s, IH), 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 (EI)m/z= 382.2 (M+H). Example 691: N-{ 5 -I({cis- 4 -[4-(7H-Pyrrolo[2,3-dpyrimidin-4-y)-1H-pyrazol-1-ylcycloexyl} methyl)thio]-4H-1,2,4-triazol-3-yl}methanesulfonamide trifluoroacetate iH NO HN HN, -1O N N H TFA 229 Step 1. N-5-[(cis-4-[4-(7-[2-(Trimethylsilyl)ethoxy methyl-7H-pyrrolo[2,3-dlpyrimidin-4-yl)-IH pyrazol-1-yljcyclohexylmethyl)thio-4H-1,2,4-triazol-3-ylmethanesulfonamide 5-[(cis- 4

-[

4 -(7-[2-(Trimethylsilyl)ethoxy]mthyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H pyrazol-1-yljcyclohexylmethyl)thio]-4H-1, 2

,

4 -triazol-3-amine (30.00 mg, 5.706E-5 mol) was 5 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 (0.0066 mL, 0.000086 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+1Y:604 Step 2. N-5-[(cis-4-[4-(7H-Pyrrolo[2,3-djpyrimidin-4-yl)-I H-pyrazol-1-yljcyclohexylmethyl)thio] 4H-1,2, 4 -triazol-3-ylmethanesulfonamide Into a 1-neck round-bottom flask [A] N-5-[(cis-4-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexylmethyl)thio]-4H-1,2,4-triazol-3-ylmethane 5 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 material 3 present. The reaction was concentrated using a rotary evaporator and was purified by prep LC to give the product as the trifluoroacetate salt. LC/MS (M+1)*:474, 1H NMR(CD 3 OD): 8.87 (s, 1H), 8.82 (s, 1H1), 8.45 (s, 1H), 7.85 (d, 1H), 7.33 (d, 1H), 4.48 (m, IH), 3.36 (s, 3H), 3.23 (d, 2H), 2.30 (m, 2H), 2.04 (in, 3H), 1.85 (in, 411). 5 Example 692: [cis-4-[4-(7H-Pyrrolo[2,3-dlpyrimidin-4-yl)-IH-pyrazol-1-yl-1-(1H-1,2,4-triazol 1-yl)cyclohexyllacetonitrile N N N ' NN 'N~ HN N lH-1,2,4-Triazole (91.0 mg, 0.00132 mol), DBU (174 pL, 0.00070 mol), [A] 4-[4-(7-[2 (trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexylidene 0 acetonitrile (86.4 mg, 0.000199 mol), and ACN (2.0 mL) were stirred at rt. After 4d, LCMS showed about 58 area% product (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%

CH

3

CN-H

2 0 (0.1%TFA), I min, to 47% at 6 min; 60 mUmin; detector set at 254 nm; retention time, 5.1(A) & 5.4 (B) min. The fluent was concentrated using a rotary evaporator to give 22 mg of (A) & 36 mg of (B). Deprotection: The products were dissolved separately in TFA (0.5 mL) and stirred for I h. 5 LCMS showed conversion 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 dissolved in methanol (1 mL), and ammonium hydroxide (0.25 mL) added. The solution was stirred 0.5h. LCMS showed complete de protection (M+H 374) and the mixture was then concentrated by roto-evaporation. Each isomer was D isolated by prep HPLCMS using a 19 mm x 100 mm C18 column; 15% CH 3

CN-H

2 0 (0.1% TFA), 1.5 min, to 32% at 6 mnin; 30 mILmin; 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 analysis (including NOE & COSY) was consistent with expectation for the structures, with A=cis, and B=trans. NMR (d 6 -DMSO) 5 cis: 12.94 (br s, 1H, NH); 8.95 (s, 1H); 8.87 (s, 1H); 8.81 (s, S 11H); 8.42 (s, 11); 8.14 (s, IH); 7.85 (m, IH); 7.22 (m, 1H); 4.48 (m, IH, NCH); 3.12 (s, 2H); 2.84 (m, 2H); 2.07 (m, 4H); 1.69 (m, 2H). MS(ES) 374 (M+1). trans: 12.85 (br s, 1H, NH); 8.94 (s, IH); 8.89 (s, IH); 8.84 (s, IH); 8.47 (s, IH); 8.11 (s, 1H); 7.84 (m, 1H); 7.26 (m, 1H); 4.50 (m, IH, NCH); 3.48 (s, 2H); 2.42-2.10 (m, 8H). MS(ES) 374 (M+I). D Example 705: 3-1-[4-(7H-Pyrrolo[2,3-djpyrimidin-4-yl)-H-pyrazol-1-yllbut-3-yn-1-yl-benzo nitrile trifluoroacetate AP CN TFA N Step 1: 3-{l-[4-(7-{[2-(Trimethylsilyl)ethoxy]methyl)-7H-pyrrolo[2,3-dpyrimidin-4-yl)-H-pyrazol J -y)but-3-yn-J-yl)benzonitrile 5 231 CN N N I M Diisobutylaluminum hydride in hexane (0.31 mL) was added dropwise to a solution of methyl 3-( 3 -cyanophenyl)- 3

-[

4 -(7-[2-(trimethylsilyl)ethoxy)methyl.-7H-pyrrolo[2,3-d]pyrimidin-4 yl)-IH-pyrazol-1-yl]propanoate (100 mg, 0.0002 mol) (prepared by using a procedure analogous to 5 Example 712, Step 1) in DCM (3 mL, 0.05 mol) and the mixture 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 warm to 0 "C and potassium carbonate (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 0 acetate and water. The organic layer was washed with saturated NaCl, dried over MgSO 4 , filtered and concentrated to give the crude product. The crude product was purified using silica gel (EtOAC/Hexane 1:3 to 1:1) to give the desired product, 3 -{--[4-(7-{(2-(trimethylsilyl)ethoxy] methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]but-3-yn-1--yl}benzonitrile (40 mg of mixture). m/z = 469 (M+1). 5 Step 2: 3-1-[4-(7H-Pyrrolo[2.

3 -dJpyrimidin-4-yl)-H-pyrazol-1-ylbut-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. 'H NMR (500 MiHz, DMSO): 8. 12.5 (b, IH), 9 (s, I H), 8.8 .0 (s, I H), 8.4 (s, I H), 8 (s, 1H), 7.8 (m 2H), 7.7 (s, 1H), 7.6 (m, IH), 7 (m, I H), 5.9 (m, IH), 3.4 (dd, 1H), 3.2 (dd, 1H), 2.9 (s, IH). m/z = 339 (M+1). Example 706: 3-{l-[4-(7H-Pyrrolo[2,3-dlpyrimidin-4-yl)-1H-pyra zol-1-yl]but-3-yn-1-yl}benz aldehyde trifluoro acetate H N-N TFA N 5N N Z5H Using the procedure of Example 705, the title compound was prepared as a secondary product (4.5 mg, 46%) as an amorphous white solid. 'H NMR (400 MHz, CDCl 3 ): & 10 (s, I H), 9 (s, IH), 8.8 (s, lH), 8.4 (s, lh), 8 (s, IH), 7.9 (m 1I), 7.8 (m, IH), 7.7 s, 1H), 7.6 (in, IH), 7.1 (s, IH), 5.9 (m, 5 1H), 3.4 (dd, IH), 3.2 (dd, IH), 2.9 (s, IH). m/z= 342. Example 712: 4-[1-( 3 -Methoxy-1-phenylpropyl)-1H-pyrazol-4-yll- 7H-pyrrolo[2,3-dipyrimidine trifluoroacetate 0 NN N / 0 F F N NH D Step 1: Methyl 3 -phenyl- 3 -[4-(7-[2-(rimethylsilyl)ethoxymethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl) JH-pyrazo!-1-yI]propanoaIe 0 , 0 N N / N N ~~0 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-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H 5 pyrrolo[2,3-d]pyrimidine (0.5 g, 0.002 mol) in ACN (2 mL, 0.04 mol) and DBU (500 1 .L, 0.003 mol). The reaction 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 MgSO 4 , 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-3-(4-(7-(2-(trimethylsilyl)ethoxy]methyl-7H 0 pyrrolo[2,3-d]pyrimidin-4-yl)-1 H-pyrazol- -yl]propanoate (500 mg, 70%) as a semisolid residue. 'H NMR (400 MHz, CDC 3 ): . 8.9 (s, 1H), 8.4 (s, 2H), 7.4 (in, 5H), 6.8 (d, IH), 6 (in, IH), 5.7 (s, 2H), 3.7-3.8 (in, 3H), 3.6 (m, 2H), 2.2 (m, IH), 1.4 (in, 2H), 1.1 (m, 2H), 0.02 (s, 9H), rn/z = 478 (M+1).

Step 2: 3 -Phenyl-3-[4-(7-[2-(trimethylsilyl)ethoxymethyl-7H-pyrrolo[2,3-dpyrimidin-4-yl)-JH pyrazol-1-yf]propan-1-of HO N-N N

SI

N N -0 5 Diisobutylaluminum hydride in hexane (1 M, 0.69 mL) was added to a solution of methyl 3 phenyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo(2,3-d]pyrimidin-4-yl)-H-pyrazol-1-yl) propanoate (150 mg, 0.00031 mol) in DCM (3 mL, 0.05 mol) and the mixture 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 gL), and saturated 0 ammonium chloride (100 pL), and then taken up in ethyl acetate dried over MgSO 4 and filtered. The filtrate was concentrated to give 3-phenyl-3-[4-(7-[2-(trinethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3 d~pyrimidin-4-yl)-1H-pyrazol-1-yljpropan-l-ol (130 mg, 92%) as an oil. m/z = 450 (M+I). Step 3: 4

-[J-(

3 -Methoxy--phenylpropyl)-IH-pyrazol-4-yl]-7-[2-(trimethylsilyl)ethoxy]methyl-7H 5 pyrrolo[2,3-d]pyrimidine 0 N -N N

SI

N N /-/ 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-pyrrolo2,3-d]pyrimidin-4-yl)-IH-pyrazol-1-yl]propan-1-ol (120 mg, 0.00027 mol) in DMF (3 mL, 0.04 mol) and the mixture was cooled to 0 C. The reaction was stirred 0 for 20 min and methyl iodide (22 gL, 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 MgS04, filtered and concentrated to give 4- [1-(3-methoxy-1 -phenylpropyl)-IH-pyrazol-4-yl]-7-[2-(trimetylsilyl)ethoxy]ethyl-7H-pyrrolo[2,3 d]pyrimidine (100 mg, 88%) as a semisolid. m/z= 464 (M+1). Step 4: 4 -[l-( 3 -Methoxy-1-phenylpropyl)-H-pyrazol-4-yJ)- ?H-pyrrolo[2,3-d]pyrimidine 5 trifluoroacetate Trifluoroacetic Acid (2 mL, 0.02 mol) was added to a mixture of 4-[1-(3-methoxy-1 phenylpropyl)-lH-pyrazol- 4 -yl]-7-[2-(trimethylsilyl)ethoxyjmethyl-7H-pyrrolo[2,3-d]pyrimidine (80 mg, 0.0002 mol) in DCM (3 mL, 0.05 mol) at room temperature. The starting material was consumed after stirring for 2hrs and the reaction solution was concentrated to remove the TFA. The crude 0 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 hs 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. 'H NMR (400 MHz, CDCI 3 ): R8.9 (s, I H), 8.8 (s, IH), 8.4 (s, I H), 7.8 (s, 1H), 7.4 (m, 1H), 7.3 (in, 5H), 7.2 (b, 1H), 5.7 (m, 1H), 3.3 (m, 5 1H), 3.2 (s, 3H), 2.7 (in, 1H-1), 2.4 (m, I H). m/z= 334 (M+1). Example 715: 3 -1-[ 4

-(

7 -Pyrroio[2,3-djpyrimidin-4-yi)-1H-pyrazol-1-ylybut-3-en-1-ylbenzo nitrile trifluoroacetate 'N HO F F F NH N N H 0 A mixture of [4-1-[1-(3-bromophenyl)but-3-en-1-yl]-1H-pyrazol-4-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 5 by HPLC on a C-18 column eluting with an ACN/water/TPFA gradient to give the title compound (10 mg, 40%) as a white amorphous solid. 'H NMR (400 MHz, DMSO): 8.9 (s, I H), 8.8 (s, I H), 8.4 (s, IH), 7.9 (s, 1IH), 7.8 (m, 3H), 7.6 (m, IH), 7.1 (b, 1H), 5.6-5.8 (m, 2H), 5.1 (d, 1H), 5 (d, IH), 3.3 (m, 1H), 3 (m, IH). mI/z- 341 (M+1). o Example 716: 4 -1-[1-( 3 -Bromophenyl)but-3-en-1-yll-1H-pyrazol-4-y-7H-pyrrolo(2,3-di pyrimidine 235 Br N-N \ / N \ . N NH Step]: 3 -(3-Bromophenyl)-3-[4-(7-[2-(rimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4 yI)-fH-pyrazol-1-yl]propanal 0 H Br N-N N ~N N - '-I 5 Diisobutylaluminum hydride in hexane (1 M, 4 mL) was added to a -78 "C solution of ethyl 3-(3-bromophenyl)-3-[4-(7-(2-(trimethylsilyl)cthoxy]methyl-7H-pyrrolo(2,3-dpyrimidin-4-yl)-I

H

pyrazol-1-yl]propanoate (600 mg, 0.001 mol) in DCM (6 mL, 0.09 mol). After stirring.for 4 h, the reaction was quenched with cold methanol (300 pL), and then saturated ammonium chloride (500 pL) was added and the resulting solution was stirred for I h. The reaction was partitioned between water 0 and EtOAc. The organic layer was washed with brine, dried over MgSO 4 , filtered and concentrated. The product was purified 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-1-yl]propanal (400 mg, 70%) as an oil.. 'H NMR (400 MHz, CDCl 3 ): 5 9.9 (s, IH), 8.9 (s, I H), 8.4 (s, 2H), 7.6 (d, IH), 7.5 (d, 1H), 7.4 (d, 1H), 7.3-7.4 (in, 2H), 6.8 (d, 1H), 5 6.1 (m, IH), 5.7 (s, 2H), 4 (m, 1IH), 3.6 (m, 2H), 3.3 (dd, 1H), 1.0 (m, 2H), 0.01(s, 9H). m/z = 526, 528 (M+1). Step 2: 4-1-[I-(3-Bromophenyl)but-3-en-1-yl]-1H-pyrazol-4-yl- 7 -[2-(trimethylsilyl)ethoxymethyl 7H-pyrrolo[2,3-d]pyrimidine r N- N NN \ NN r -O Potassium tert-butoxide in THF (!M, 200 pL) 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 I h and then cooled to -78 *C. The 3-(3-bromophenyl)-3-[4-(7-[2-(trimethyl 5 silyl)ethoxy]mcthyl-7H-pyrrolo[2,3-dpyrimidin-4-yl)-1H-pyrazol-1-yljpropanal (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 MgSO 4 , filtered and concentrated to give an oil. The product was purified by FCC on silica gel eluting with EtOAc:Hexane, (1:1) to give 4-1-[1-(3 0 bromophenyl)but-3-en-1-yl]-1H-pyrazol-4-yl-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3 d]pyrimidine (35 mg, 40%) as an oil. m/z = 524, 526 (M+1). Step 3: 4-1-[-( 3 -Bromophenyl)but-3-en-1-yl]-1H-pyrazol-4-yl-7H-pyrrolof2,3-dipyrimidine Using a procedure analogous to Example 712, Step 4, but using 4-1-[1-(3-bromophenyl)but 5 3-en-1-yl]-1H-pyrazol-4-yl-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine the title compound was prepared (10 mg, 30%) as a white amorphous solid, 'H NMR (400 MHz, DMSO): 8.9(s,1H), 8.8(s,1H), 8.4(s,1H), 7.8(s,IH), 7.7(s,1H), 7.5 (m,2H), 7.3(m,1H), 7.1(s,1H), 5.7(m,2H), 5.2(d,I H), 5.0(d,l H), 3.2(m,IH), 3.0(m,IH). m/z = 394, 396 (M+1). 20 Example 717: 3

-(

4

,

4 -Difluoro)-1-[4-(7H-pyrrolo[2,3-dlpyrimidin-4.y[)-1H-pyrazol-1-ylibut-3 en-1-ylbenzonitrile F F N N - N N N NH 237 Step 1: 4-(J-[-(3-Bromophenyl)-4,4-difluorobut-3-en-1-yl]-1H-pyrazol-4-yl}-7-{[2-(trimethylsilyl) ethoxy]methytj-7H-pyrrolo[2,3-d]pyrimidine F

F

Br

N

N \ i 'N N To a solution of 3

-(

3 -bromophenyl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H--pyrrolo[2,3 5 d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanal (0.05 g, 0.00009 mol) in NN-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 TFf (0.7 mL). The reaction was stirred at room temperature for 18 hs. The reaction was partitioned between water and EtOAc. The organic layer was washed with saturated NaCI, dried over MgSO 4 , filtered and concentrated to give an oil. The product was purified by FCC ) on silica gel eluting with EtOAc, Hexane (1:2) to give 4-f{l-[1-(3-bromophenyl)-4,4-difluorobut-3-en 1-yl]-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-BromophenyQ-4,4-difluorobut-3-en-1-yl]-H-pyrazol-4-yl-7H-pyrrolo[2,3-d] pyrimidine F F. Br N-N N / N N NH Using a procedure analogous to Example 712, Step 4, but using 4-{1-[1-(3-bromophenyl)-4,4 difluorobut-3-en-1 -yl]-1H-pyrazol-4-yl} -7-{{2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3 dipyrimidine, the compound 4-1-[1-(3-bromophenyl)-4,4-difluorobut-3-en-1-yl]-1H-pyrazol-4-yl-7H 0 pyrrolo(2,3-d]pyrimidine was prepared (30 mg, 99%) as an oil. m/z= 430, 432 (M+1). Step 3: 3-4,4-Difluoro-1 -[ 4

-(

7 H-pyrrolo(2,3-d]pyrimidin-4-yl)-4H-pyrazol-1-yl]but-3-en-1-yl benzonitrile F F N N -N NN N~ \ N NH A mixture of 4-1-[1-(3-bromophenyl)-4,4-difluorobut-3-en-1-yl]-1H-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 mg, 0.0007 mol) was degassed with nitrogen. The mixture was then treated with tetrakis(triphenyl 5 phosphine)palladium(O) (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 eluting with an ACN/water/TFA gradient to give the title compound (10 mg, 30%) as a white amorphous solid. 'H NMR (400 MHz, DMSO): p8.9 (s, IH), 8.7 (s, IH), 8.4 (s, IH), 7.9 (s, IH), 7.7 -7.8 (in, 3H), 7.5 (m, lH), 7.1 (m, IH), 5.7 (m, IH), 4.3-4.4 (m, 1H), 3.1 (m, IH), 2.9 0 (m, 1H). m/z= 377 (M+1). The following compounds in Table 14 were prepared as indicated in the column labeled "Prep. Ex. No." and the details of certain exemplary synthetic procedures are provided following Table 14. 5 Table 14 R N-N N N N H Ex. MS Name Prep. No. Structure of R (M+HI Ex. No. 308 4-[1-(1-cyclopentylbut-3-en-I1- 727 yl)-1H-pyrazol-4-yl)-7H 727 pyrrolo[2,3-d]pyrimidine trifluoroacetate salt 239 /254 4-[I-(1-methylbut-3-en-I -yl)-lH- 727 728 pyrazol-4-yl]-7H-pyrrolo[2,3-d] pyrimidinpetrifluoroacetate salt 452 4 -[(1 -cyclopentyl-2- 727 cyclopropylethyl)-1 H-pyrazol-4 729 yI]-7H-pyrrolo[2,3-dI pyrimidinptrifluoroacetate salt 306 4-(1 -(1 -cyclopentylbut-3-yn-I - 727 yl)-lI H-pyrazol-4-yl]-7H 730 pyrrolo[2,3-djpyrimidine trifluoroacetate salt 310 4-fl -(1 -cyclopentylbutyl)- 1 H1- 729 731 -~pyrazol-4-yl]-7H-pyrrolo[2,3-d] _________________________pyrimiding trifluoroacetate salt 344 4 -[1 -(1l-cyclopentyl-4,4- 727 difluorobut-3 -en- I -yl)-1 H 732 pyrazol-4-yl]-71{-pyrrolo[2,34]l - ~ CF 2 pyrimidine trifluoroacetate salt +8/ 0 727 4-1-[4,4-difluoro-I -(tetrahydro- Step 3 733 346 furan-3-yl)but-3-en-I -yl]-l H- & 4, pyrazol-4-yI-7H-pyrrolo[2,3-d]- then

CF

2 pyrimidine trifluoroacetate salt 731, ______________________________step I 727 4-[1l-(1 -methylbut-3-en-lI -yI)-lIH- Step 3 734

CF

2 254 pyrazol-4-yl]-7H-pyrrolo[2,3-d]- & 4, -C /pyrimidine trifluoroacetate salt then ________731 4-[l -(I -cyclopropyl-4,4-difluoro- 727 735316 but-3-en-1 -yl)-I H-pyrazol-4-yl]- Step 3 735

CF

2 36 7H-pyrrolo[2,3-d]pyrimidine &4 trifuorocetae ~then trifuoracette alt731 346 4-(1 -(1 -cyclopentyl-4,4-difluoro- 731 butyl)- lH-pyrazoI-4-yl)-7H 736 pyrrolo[2,3-d]pyrimidine Cl-IHF 2 trifluoroacetate salt 321 3-(1 -methylcyclopentyl)-3-[4- 737 (7H-pyrrolo[2,3-d]pyirimidin-4 737 yl)-l H-pyrazolI-yl]propane -~ nitrile trifluoroacetate salt -ON 240 295 (3R)- and (3S)-4,4-dimethyl-3- 737 t-Bu 14-(7-[2-(trimethylsilyl)ethoxy] 738 - methyl-711-pyrrolo[2,3-d] pyrimidin-4-yi)-1 H-pyrazol-1 -CN YlUPentanenitrile trifluoroacetate salt 304 1 -2-cyano-1 -[4-(7H-pyrrolo[2,3- 739 739 CNd]pyrimidin-4-yl)-IH-pyrazol-I yl]ethylcyclopropanecarbonitrile -CN trifluoroacetate salt 440 N-[(l -2-cyano-1 -[4-(7H- 740 pyrrolo[2,3-d]pyrirnidin-4-yl) 740 N-Q I 8-pyrazol- I -yl]ethylcyclo -CN 0pentyl)methyl]benzainide 427 3 -1 -[(Benzyloxy)methyl]cycto- 741 741OBn pentyl-3-[4-(711-pyrrolo[2,3-d] 741 pyrimidin-4-yl)-1 H-pyrazol-I yl]propanenitrile trifluoroacetate -CN salt 7' 386 3-[1 -(methylsulfonyl)pyrrolidin- 742 k 3-yl]-3-[4-(7H-pyrrolo[2,3-d]. N pyrimidin-4-yi)- I1-pyrazol- I 742 yljpropanenitrile trifluoroacetate salt CN CN 375 N'-cyano-4-(cyanomethyl)-4-[4- 743 N-CN (711-pyrrolo[2,3-djpyrimidin-4. 743 /yl)-I 11-pyrazol- I-yl]piperi dine- I N, carboximidamide

NH

2

CF

3 348 4-1-[2,2,2-trifluoro- I-(I H- 744 H imidazol-2-ylmethyl)ethyl)- I H 744 N pyrazol-4-yJ-7H-pyrrolo[2,3.d]. ~i1 pyriniidine

CF

3 379 4-(1 -(I R)-2,2,2-trifluoro-l1-[(4- 745 -S methyl-i .3-thiazol-2-yl) 745 Amethyl]ethyl-l 1-pyrazol-4-yl) \~j] 7H-pyrrolo[2,3-d]pyrimidine

CF

3 4-1 -[1 -(trifluoromethyl)but-3-yn- 730 746 -~306 1 -yl]-l H-pyrazol-4-yl-7H pyrrolo[2,3-dlpyrimidine 241

CF

3 4-1-[1 -(trifluoromethyl)but-3-en- 727 747 A 308 1-yl)-IH-pyrazol-4-yl-7H pyrrolo[2,3-d]pyrimidine

CF

3 4-1 -[1 -(trifluoromethyl)butyl]- 731 748 - 310 1H-pyrazol-4-yl-7H-pyrrolo (2,3-d]pyrinidine

F

3 F 4-1-[4,4-difluoro-1-(trifluoro- 732 749 - 344 methyl)but-3-en-1 -yl)-1H 79 Fpyrazol-4-yl-7H-pyrrolo[2,3-d] pyrimidine

CF

3 F 4-1-[4,4-difluoro-1-(trifluoro- 731 750 -~ F 346 methyl)butyl]-1H-pyrazol-4-yl 7H-pyrrolo[2,3-d]pyrimidine Step 1 of example 731 was modified as follows: The Ph 3 P and CF 2 Br 2 were combined in DMAC at 0 *C and then allowed to warm to room temperature until the ylid formation was complete as determined by LCMS. The solution of the ylid was then re-cooled to 0 *C and the aldehyde and 5 zinc were added to the ylid solution and the reaction was slowly warmed to room temperature. Example 727: 4 -[1-(I-Cyclopentylbut-3-en-1-yl)-1H-pyrazol-4-yll-7H-pyrrolo[2,3-dpyrimidine trifluoroacetate salt N N N NH -TFA 0 Step 1: (ZE)-3-Cyclopentylacrylic acid To a solution of malonic acid (1.06 g, 10.2 mol) in pyridine (1.25 mL) was added piperidine (0.15 mL) and cyclopentanecarbaldehyde (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 5 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 further purification. 'H NMR (300 MHz, CDCl 3 ): 57.06 (dd, IH), 5.80 (dd, IMH), 2.70-2.54 (m, lH), 1.93-1.32 (m, 8H); MS(ES): 141(M+H). 20 242 Siep 2. Methyl ( 2 E)-3-cyclopentylacrylate To a solution of ( 2 E)-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 evaporated to afford (2E)-3 5 cyclopentylacryloyl chloride as a colorless liquid. A portion of this (2E)-3-cyclopentylacryloyl chloride (0.75 g, 4.7 mol) was dissolved in methanol (10 mL) and the resulting solution was stirred for 2 hours. The solvent was evaporated to afford the product (700 mg, 96%). 'H NMR (300 MHz, CDCI 3 ): p6.94 (dd, lH), 5.79 (dd, 1H), 3.71 (s, 31H), 2.66-2.50 (m, IH), 1.92 1.27 (m, 8H). Step 3. Methyl 3 -cyclopentyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4 yl)-IH-pyrazol- l-yl]propanoate To a solution of 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3 d]pyrimidine (2.9 g, 9.2 mmol) and methyl (2E)-3-cyclopentylacrylate (1.70 g, 11.0 mmol) in ACN 5 (100 mL), was added DBU (2.7 mL, 18 mmol). The resulting mixture was stirred for 96 hours. The ACN was removed in vacuo, and the resulting residue was dissolved in ethyl acetate. This solution was washed with 1.0 N HCI, 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%). ) 'H NMR (300 MHz, CDC1 3 ): & 8.84 (s, 1H), 8.28 (s, 2H), 7.39 (d, 11), 6.81 (d, 1H), 5.67 (s, 2H), 4.46 (dt, IH), 3.60 (s, 3H), 3.54 (t, 2H), 3.18 (dd, 1H), 2.89 (dd, 1H), 2.59-2.42 (m, I), 1.95-1.80 (m, IH), 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-(rimethylsilyl)ethoxymethyl-7H-pyrroo[2,3-d]pyrimidin-4-yl)-1H 5 pyrazol-1-yljpropanal To a solution of methyl 3 -cyclopentyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo

[

2

,

3 -d]pyrimidin-4-yl)-1H-pyrazol-i-yl]propanoate (0.501 g, 1.07 mmol) in THF (5.0 mL) at -78 *C was added 1.00 M diisobutylaluminum hydride in DCM (2.35 mL) dropwise. The reaction was stirred with gradual warming to -10 *C over the course of 2 hours. At this temperature, a further 0 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 tartrate 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. 5 MS(ES):442(M+H). 243 To a solution of oxalyl chloride (0.108 mL, 1.28 mmol) in DCM (10.0 mL) at -78 "C was added DMSO (151 jiL, 2.13 mmol). After stirring for 5 minutes, 3-cyclopentyl-3-[4-(7-[2 (trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-H-pyrazol-1-yl]propan-1-ol (471 mg, 1.07 mmol) in DCM (3.00 mL) was added. The mixture was stirred for 30 minutes at -78 "C. 5 TEA (594 gL, 4.26 mmol) was then added. The resulting mixture was then allowed to warm to room temperature 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 acetate in hexanes) afforded the 0 product (384 mg, 82%). 'H NMR (300 MHz, CDC1 3 ): 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, IH), 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). 5 Step 5. 4-[1-(1-Cyclopentylbut-3-en-1-yl)- H-pyrazol-4-yl]-7-[2-(trimethylsilyl)ethoxyjmethyl-7H pyrrolo[2,3-d]pyrimidine To a solution of 1.0 M potassium tert-butoxide in THF (0.207 nL) in THF (2.0 mL) at 0 *C was added triphenylmethylphosphonium bromide (77.8 mg, 0.218 mmol). The resulting mixture was warmed to room temperature and allowed to stir for 30 minutes. A solution of 3-cyclopentyl-3-[4-(7 .0 [2-(trimethylsilyl)ethoxynmethyl-7H-pyrrolo[2,3-dlpyrimidin4-yl)-1H-pyrazol-1-yl]propal (0.100 g, 0.228 mmol) in THF (2.0 mL) was added. After 30 minutes, the mixture was quenched by the addition of saturated anmonium 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 gradient of 0-40% ethyl acetate in hexanes) afforded the product (40 25 mg, 44%). 'H NMR (400 MHz, CDCl 3 ): 5 8.84 (s, 1H), 8.26 (s, 1H), 8.19 (br s, IR), 7.40 (s, 1H), 6.83 (br s, 1H), 5.67 (s, 2H), 5.60 (ddt, 1H), 5.01 (dq, 1H), 4.974.93 (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):438(M+H). 30 Step 6. 4 -[J-(J-Cyclopentylbut-3-en-1-y)-4H-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidine trifluoroacetate salt 4-[1 -(1 -Cyclopentylbut-3-en-I -yl)-1H-pyrazol-4-yl]-7-[2-(trimethylsilyl)ethoxy]methyl-7H pyrrolo[2,3-d]pyrimidine (13 mg, 0.030 mmol) was dissolved in DCM (3 mL) and TFA (0.5 mL) was 35 added. The resulting solution 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 244 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 preparative-HPLC/MS (C18 eluting with a gradient of H 2 0 and ACN containing 0.1% TFA) afforded the product (10 mg, 80%). 5 'H NMR (400 Ml4z, d 6 -DMSO): 512.73 (s, I H), 8.88 (s, 2H), 8.43 (s, 1 H), 7.79 (t, I H), 7.19 (dd, I H), 5.60 (ddt, IH), 5.00-4.93 (m, IH), 4.91-4.87 (m, 1H), 4.23 (dt, IH), 2.76-2.59 (m, 2H), 2.47-2.34 (in, 1H1), 1.92-1.82 (in, 1H), 1.68-1.22 (in, 6H), 1.21-1.09 (in, 1H); MS(ES):308(M+H). Example 729: 4 -[1-(l-Cyclopentyl-2-cyclopropylethyl)-H-pyrazol-4-yl]-7H-pyrrolo[2,3-di 0 pyrimidine trifluoroacetate salt N-N N \ N N H TFA Step 1. 4 -[l-(-Cyclopentyl-2-cyclopropylethyl)-1 H-pyrazol-4-yl]-7-[2-(trimethylsilyl)ethoxy]methyl 7H-pyrrolo[2,3-d]pyrimidine trifluoroacetate salt 5 A solution of 4-[1-(1-cyclopentylbut-3-en-1-yl)-1H-pyrazol-4-y)]-7-[2-(trimethylsilyl) ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (prepared 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 CH 2

N

2 held at 0 "C. Palladium acetate (10.0 mg, 0.044 mol) was added. After standing for 2 hours, the excess

CH

2

N

2 was quenched by the addition of acetic acid. The solution was then diluted with further DCM, 20 washed successively with saturated sodium bicarbonate solution, water, and brine, and dried over sodium sulfate, and the solvent was removed in vacuo. Purification via preparative-HPLC/MS (C 18 eluting with a gradient of H20 and ACN containing 0.1% TFA) afforded the product (13 mg, 18%). 'H NMR (300 MHz, CDCl 3 ): § 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 (in, 1H), 2.15-2.00 (m, 1H), 2.00-1.83 (in, IH), 1.79-1.40 Z5 (in, 6H), 1.37-1.09 (in, 2H), 0.97 (t, 211), 0.55-0.26 (in, 3H), 0.07- -0.15 (in, 11H); MS(ES):452(M+H). Step 2. 4 -fl-(-Cyclopentyl-2-cyclopropylethyl)-IH-pyrazol-4-yl]-7H-pyrrolo[2,3-dipyrimidine trifluoroacetate salt 30 4-[1 -(1 -Cyclopentyl-2-cyclopropylethyl)-lH-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) containing TFA (1.5 mL) for two hours. The solvent was 245 removed in vacuo. The resulting residue was redissolved in THF (3 mL), and 6N NaOH (2 mL) was added. After stirring for one hour, the mixture was partitioned between water and ethyl acetate. 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 H 2 0 and ACN containing 0.1% TFA) afforded 5 the product (9 mg, 90%). 'H NMR (400 MHz, d 6 -DMSO): 6 12.75 (s, 1H), 8.90 (s, 1H), 8.84 (s, 1H), 8.47 (s, IH), 7.81 (s, I H), 7.22 (s, IH), 4.19 (dt, IH), 2.43-2.29 (m, IH), 2.03-1.92 (m, 1H), 1.88-1.76 (m, 1H1), 1.68-1.37 (m, SH), 1.35-1.08 (m, 3H), 0.43-0.26 (m, 2H), 0.24-0.13 (m, 1 H), 0.07- '0.03 (m, IH), -0.14- -0.24 (m, IH); MS(ES):322(M+H). 0 Example 730: 4-[1-(-Cyclopentylbut-3-yn-1-yl)-1H.-pyrazol-4-yl]-7F-pyrrolo[2,3-dpyrimidine trifluoroacetate salt N N 'TFA .5 Step 1. 4-[1-(I-Cyclopentylbut-3-yn-1-yl)-H-pyrazol-4-y]-7-[2-(trimethylsilyI)ethoxyjmethyl-7H pyrrolo(2,3-d]pyrimidine To a mixture of potassium carbonate (38.4 mg, 0.278 mmol) in methanol (2.0 mL) at 0 "C was added a solution of 3-cyclopentyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d] pyrimidin-4-yl)-IH-pyrazol-1-yl]propanal (prepared as in Example 727, step 4) (61.0 mg, 0.139 20 mmol) in methanol (1.0 mL), followed by a solution of dimethyl (1-diazo-2-oxopropyl)phosphonate (40.0 mg, 0.208 mmol) in methanol (1.0 mL). The mixture was slowly warmed to ambient temperature and stirred for 16 hours. The mixture was then diluted with water and extracted with ethyl acetate. The combined extracts were washed with water, saturated ammonium chloride, and then dried over sodium sulfate and the solvent was removed in vacuo to afford the product, which was used 25 without further purification (52 mg, 86%). '1H NMR (300 MHz, CDC1 3 ): & 8.85 (s, I H), 8.47 (s, IH), 8.29 (s, 1H), 7.41 (d, I H), 6.84 (d, IH), 5.67 (s, 2H), 4.14 (ddd, IH), 3.53 (t, 2H), 2.90 (ddd, 1H), 2.79 (ddd, 1H), 2.66-2.49 (m, IH), 1.98 (t, IH), 2.00-1.88 (m, 1H), 1.78-1.44 (m, 5H), 1.39-1.11 (m, 2H), 0.92 (t, 2H), -0.06 (s, 9H); MS(ES):436(M+H). 30 246 Step 2. 4-[-(1-Cyclopentylbut-3-yn-1-yl)-1H-pyrazol-4-yl]-7H -pyrrolo[2, 3-d]pyrimidin.e trifluoroacetate salt A solution of 4-[1-(1-cyclopentylbut-3-yn-1-y1)-1H-pyrazol-4-yi]-7-[2-(trimethylsilyl) ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (52 mg, 0.12 mmol) in DCM (3 mL) and TFA (I mL) 5 was stirred for 2 hours. The solvents were removed in vacua. The resulting 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 sulfate and the solvent was removed in vacuo. Purification via preparative-HPLC/MS (C18 eluting with a gradient of H 2 0 and ACN containing 0.1% TFA) afforded product (30 mg, 60%). 0 'H NMR (300 MHz, d 6 -DMSO): & 12.72 (s, I H), 8.91 (s, IH), 8.84 (s, I H), 8.47 (s, I H), 7.80 (s, I H), 7.19 (s, IH), 4.34 (dt, IH), 2.97-2.69 (in, 3H), 2.50-2.32 (in, 1H), 1.93-1.77 (m, IH), 1.70-1.09 (in, 7H); MS(ES):306(M+H). Example 731: 4 -Il-(1-Cyclopentylbutyl)-1H-pyrazol-4-yl]-7H-pyrrolo[2,3-dipyrimidine 5 trifluoroacetate salt

N

N N H -TFA 4-[1-(1-Cyclopentylbut-3-yn-1-yI)-1H-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidine trifluoro acetate salt (prepared in Example 729) (20 mg, 0.048 mmol) was dissolved in methanol (2 mL) and a .O catalytic amount of 5% Pd-C was added. The mixture was stirred under I atmosphere of hydrogen via an affixed balloon. After 2 hours, the mixture was filtered and purified via preparative-HPLC/MS (C 18 eluting with a gradient of H20 and ACN containing 0.1% TFA) to afford the product (14 mg, 69%). 'H NMR (400 MHz, d6-DMSO): 12.73 (s, 1H), 8.86 (s, IH), 8.83 (s, IH), 8.45 (s, I H), 7.79 (t, I H), .5 7.20 (d, IH), 4.11 (dt, IH), 2.43-2.26 (m, IH), 2.02-1.70 (in, 3H), 1.68-1.35 (m, 4H), 1.33-0.89 (in, 5H), 0.83 (t, 3H); MS(ES):310(M+H). Example 732: 4-[1-(1-Cyclopentyl4,4-difluorobut-3-en-1-yl)-1H-pyrazol-4-yil-7H-pyrrolol2,3 d~pyrimidine trifluoroacetate salt 247 F N N H 'TFA Step 1. 4-[l-(1-Cyclopentyl-4,4-difluorobut-3-en-1-y)-IH-pyrazol-4-yl]-7-[2-(trimethylsilyl)ethoxyj methyl- 7H-pyrrolo[2,3-dipyrimidine 5 To a solution of 3-cyclopentyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d] pyrimidin-4-yl)-IH-pyrazol-1-yl]propana (prepared as in Example 727, Step 4) (181 mg, 0.41 mmol) in NN-dimethylacetamide (3.6 mL) was added triphenylphosphine (294 mg, 1.12 mmol) followed by dibromodifluoromethane (235 mg, 1.12 mmol). Rieke@ Zinc (1.8 mL of a suspension of 2.5 g in 50 ml THF) was then added in one portion. The resulting mixture was stirred at room temperature for 4.5 0 hours. The mixture was filtered through diatomaceous earth. The filtrate was partitioned between ether and water. The ether layer was washed with water, and brine, then dried over sodium sulfate, and the solvent was removed in vacuo. Flash column chromatography (eluting with a gradient from 0 30% ethyl acetate in hexanes) afforded product (104 mg, 53%). 'H NMR (400 MHz, CDCl 3 ): 8 8.91 (s, IH), 8.51 (br s, 111), 8.34 (s, 1H), 7.51 (d, 1H), 6.93 (d, 1H), .5 5.74 (s, 2H), 4.05 (ddd, 1H), 4.04-3.96 (m, 1H), 3.60 (t, 2H), 2.78-2.62 (m, 2H), 2.58-2.45 (m, 1H), 2.07-0.87 (m, 10H), 0.00 (s, 9H); MS(ES):474(M+H). Step 2. 4-[ ]-(1-Cyclopentyl-4,4-difluorobut-3-en-1-yl)-JH-pyrazol-4-yl]-7H-pyrrolo[2,3-dpyrimidin.e trifluoroacetate salt 20 A solution of 4-[1-(1-cyclopentyl-4,4-difluorobut-3-en-1-yl)-1H-pyrazol-4-yl]-7-(2-(tri methylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (41 mg, 0.086 mmol) in DCM (3 mL) and TFA (1.5 mL) was stirred for two hours at room temperature. The solution was then concentrated in vacuo. The resulting residue was redissolved 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 25 dried over sodium sulfate and the solvent was removed in vacuo. Purification via'preparative HPLC/MS (Cl 8 eluting with a gradient of H20 and ACN containing 0.1% TFA) afforded the desired product (39 mg, 98%). 'H NMR (400 MHz, d 6 -DMSO): 8 12.72 (s, 1H), 8.84 (s, 1H), 8.83 (s, IH), 8.45 (s, 1 H), 7.80 (t, 1H), 7.18 (d, 1 H), 4.32 (ddt 1H), 4.20 (dt, 1H), 2.72-2.37 (in, 3H), 1.95-1.81 (m, 1 H), 1.69-1.06 (m, 7H); 30 MS(ES):344(M+H). 248 Where conjugate acceptors, such as were used in Example 737, Step 3 were not commercially available, such compounds were generated according to the procedure provided below for ethyl (2E) 3-(tetrahydrofuran-3-yl)acrylate (toward the preparation of Example 733). 5 Preparation of ethyl (2E)-3-(tetrahydrofuran-3-yl)acrylate: 0 o OEt Step A: Tetrahydrofuran-3-carbaldehyde To a solution of Dess-Martin periodinane (3.37 g, 7.95 mmol) in DCM (20 mL) was added tetrahydrofuran-3-ylmethanol (0.701 mL, 7.23 mmol). The reaction was stirred at ambient 0 temperature for 2 hours, and the solvent was then removed in vacuo. Flash column chromatography (using DCM as eluent) afforded the product as a clear oil, which was used without further purification. 'H NMR (400 MHz, CDCl 3 ): 5 9.65 (d, IH), 4.12-4.07 (m, IH), 3.92-3.85 (in, 2H), 3.80-3.73 (in, 1H), 3.10-3.02 (in, IH), 2.26-2.10 (m, 2H). 5 Step B: Ethyl ( 2 E)-3-(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) (THF may also be used) was added triethyl 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 .0 to 0 *C, at which time a solution of tetrahydrofuran-3-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 product 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 25 hexanes) afforded the product (640 ing, 52%). 'H NMR (400 MHz, CDC 3 ): & 6.87 (dd, 1H), 5.86 (dd, ITH), 3.96-3.88 (m, 2H), 3.81 (dd, I H), 3.53 (dd, 1H), 3.04-2.93 (in, 1H), 2.20-2.10 (m, 1H), 2.03 (s, 3H), 1.79 (dq, 1H-). Example 736: 4 -[1-(1-Cyclopentyl-4,4-difluorobutyl)-1H-pyrzol-4-yl-7H-pyrrolo12,3-d] 30 pyrimidine trifluoroacetate salt 249 F N- F N \ N N H -TFA 4-[1-(1-Cyclopentyl-4,4-difluorobut-3-en-1-yl)-1H-pyrazol-4-yl]-7H-pyrrolo(2,3-d] pyrimidine trifluoroacetate salt (prepared as in Example 731) (20.0 mg, 0.041 mmol) was dissolved in methanol (3 mL), and a catalytic amount of 5% Pd on C was added. The mixture was stirred at room 5 temperature 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 H 2 0 and ACN containing 0.1% TFA) to afford product (4 mg, 21%). 'H NMR (400 MHz, d-DMSO): 8 12.74 (s, IH), 8.88 (s, IH), 8.85 (s, 1H), 8.48 (s, 1H), 7.80 (t, IH), 7.20 (dd, 1H), 6.05 (tt, 1H), 4.17 (dt, 1H4), 2.47-2.34 (m, IH), 2.14-1.08 (m, 12H); 0 MS(ES):346(M+H). Example 737: 3 -(l-Methylcyclopentyl)-3-[4-(7-pyrrolo[2,3-dlpyrimidin-4--yl)-1H-pyrazol-l yllpropanenitrile trifluoroacetate salt %QJCN N-N N N H -TFA 5 Step 1. J-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 mnmol) in one portion followed by methyl iodide (1.7 mL, 28 mmol) in one portion. After 30 minutes at 0 *C, the reaction mixture was allowed to warm to room temperature and stirred at that temperature for 16 hours. The mixture was poured 0 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: (2Z)- and ( 2

E)-

3 -(-Methylcyclopentyl)acrylonitrile 250 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, 9.81 mmol) in THF (10 mL) dropwise. The cooling bath was removed and the reaction was warmed to room temperature followed by re-cooling to 0 *C, at which time a solution of 1-methylcyclopentanecarbaldehyde (1.0 g, generated in Step 1) in 5 THF (2 mL) was added dropwise. The bath was removed and the reaction was stirred at ambient temperature 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 product as a mixture with hexanes, which 0 product was used without further purification in Step 3. Step 3: 3-(l-Methylcyclopentyl)-3-[4-(7H-pyrrolo[2,3-dJpyrimidin-4-yl)-IH-pyrazol-)-yq]propane nitrile trifluoroacetate salt To a mixture of 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3 5 d]pyrimidine (0.134 g, 0.426 mol) in ACN (3 mL) was added a mixture of (2Z)- and (2E)-3-(l methylcyclopentyl)acrylonitrile (0.12 g, 0.9 mmol) followed 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 acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and the solvent 3 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. THF (8 rmL) 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 combined extracts were dried (Na 2

SO

4 ) and the solvent was removed in vacuo. Purification via preparative-HPLC/MS (C18 eluting 5 with a gradient of H 2 0 and ACN containing 0.1% TFA) afforded product (44 mg, 24%). 'H NMR (400 MHz, d 6 -DMSO): 6 12.71 (s, 1H), 9.00 (s, lH), 8.85 (s, 1H), 8.51 (s, IH), 7.81 (s, IH), 7.18 (s, 1H), 4.72 (dd, 1H), 3.47 (dd, 1H), 3.21 (dd, 1H), 1.74-1.51 (in, 6H), 1.44-1.32 (in, IH), 1.09 1.00 (m, lH), 0.97 (s, 3H); MS(ES):321(M+H). 0 Example 739: 1-2-Cyano-1-[ 4 -(7H-pyrrolo[2,3-dpyrimidin-4-yl)-1H-pyrazol-1-ylethylcyclo propanecarbonitrile trifluoroacetate salt 251 N-N N-N N N H -TFA Stepi: 1-(Hydroxymethyl)cyclopropanecarbonitrile 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. 5 Upon cooling to room temperature, the reaction was quenched with water, and extracted with ethyl acetate. The combined extracts were dried over MgSO 4 , filtered and concentrated to afford a clear oil, which was used without further purification in the following step (482 mg, 86%). 'H NMR (400 MHz, CDC 3 ): & 3.61 (s, 2H), 1.27 (dd, 2H), 0.98 (dd, 2H). 0 Step2: J-Formylcyclopropanecarbonitrile 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 ambient 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%). 5 'H NMR (400 MHz, CDC 3 ): 9.35 (s, 1H), 1.79-1.74 (m, 4H). Step 3: 1-[(E)- 2 -Cyanovinyl]cyclopropanecarbonitrile 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 diethyl cyanomethylphosphonate (210 mg, 1.2 mmol) in THF (2 mL). The cold !0 bath was removed and the reaction was warmed to ambient 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 diluted with ether and water, the ether solution was separated, washed with brine, dried over sodium sulfate, filtered and the solvent was removed in 5 vacuo. Flash column chromatography (eluting with a gradient from 0-60% ethyl ether in hexanes) afforded the product (24 mg, 19%). 'H NMR (400 MHz, CDC1 3 ): 5.94 (d, [H), 5.82 (d, IH), 1.80 (dd, 2H), 1.39 (dd, 2H). Step 4: 1- 2 -Cyano-l-[4-(7-[2-(rimethylsilyl)ehoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-JH 0 pyrazol-1-yl]ethylcyclopropanecarbonitrile 2S? To a solution of 4-(1H-pyrazol- 4 -yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d] pyrimidine (61.4 mg, 0.195 mmol) and 1-[(E)- 2 -cyanovinyl]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 was 5 washed with 1.0 N HCI, 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, CDCI,): 6 8.85 (s, IH), 8.43 (s, IH), 8.34 (s, 1H), 7.43 (d, 1H), 6.80 (d, IH), 5.68 (s, 2H), 3.54 (dd, IH), 3.51 (dd, 1H), 3.36 (dd, 1H), 1.62 (ddd, IH), 1.45 (ddd, IH), 1.34 (ddd, 0 1H), 1.25 (ddd, 1H), 0.92 (t, 2H), -0.06 (s, 9H); MS(ES):434(M+H). Step 5: 1- 2 -Cyano-J-[4-(7H-pyrrolo[2, 3 -d]pyrimidin-4-yl)-4H-pyrazol-1-yljethylcyclopropane carbonitrile trifluoroacetate salt 1-2-cyano-1-[ 4

-(

7

-[

2 -(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yi)-1H 5 pyrazol-J -yl]ethylcyclopropanecarbonitrile (48 mg, 0.11 mmol) was stirred in a mixture of DCM (3 mL) and TFA (2 mL) for 3 hours. The solvents were removed in vacuo and the residue was re dissolved in THF (3 mL). 6N NaOH (2 mL) was added and the resulting mixture was stirred at ambient temperature for 3 hours. The crude reaction mixture was partitioned between ethyl acetate and water. The layers were separated and the organic layer was dried over sodium sulfate and the 0 solvent was removed in vacuo. Purification via preparative-HIPLC/MS (C 18 eluting with a gradient of

H

2 0 and ACN containing 0.1% TFA) afforded product (20 mg, 43%). 'H NMR (400 MHz, d-DMSO): p12.74 (s, I H), 8.99 (s, I H), 8.88 (s, 1 H), 8.60 (s, 1 H), 7.83 (t, 1 H), 7.17 (dd, IH), 4.55 (dd, 111), 3.66 (dd, 1N), 3.54 (dd, IH), 1.55-1.30 (m, 4H); MS(ES):304(M+H). 25 Example 740: N-[(1-2-Cyano-1-[4-(7H-pyrrolol2,3-d pyrimidin4-yl)-H-pyrazol-1 -yllethyl.. cyclopentyl)methyllbenzamide CN N-N N N H Step 1: Methyl 1-cyanocyclopentanecarboxylate To a solution of acetic acid, cyano-, methyl ester (2.66 mL, 30.3 mmol) and 1,4 0 dibromobutane, (3.62 mL, 30.3 mmol) in acetone (50 mL) was added potassium carbonate (8.37 g, 253 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 saturated NH 4 C1 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 5 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, CDC 3 ): p3.82 (s, 3H), 2.30-2.21 (in, 4H), 1.93-1.82 (m, 4H). Step 2: Methyl l-[(tert-butoxycarbonyl)amino]methylcyclopentanecarboxylate 0 To a solution of methyl 1-cyanocyclopentanecarboxylate (1.26 g, 8.22 mmol) in methanol (100 mL) was added cobalt dichloride (2.1 g, 16.0 mmol). The purple mixture was cooled in an ice water bath. Sodium tetrahydroborate (3.11 g, 82.2 mmol) was added portionwise with caution (exothermic) to provide a black mixture. Upon complete addition, cooling was discontinued and the reaction was .stirred for 40 minutes under nitrogen and the reaction was quenched by the careful 5 addition of IN HCI (700 ml). The methanol was removed in vacuo, and the solution was then made alkaline (pH - 9) by the addition of concentrated NH 4 0H(aq). The mixture was extracted with DCM (6 times), and the combined 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 butyldicarbonate (1.31 g, 6.01 mmol) and the reaction was stirred at 25 "C for 30 minutes. The D 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 desired product (1.5 g, 71%). 'H NMR (300 MHz, CDC1 3 ): 5 5.03 (s, 1H), 3.69 (s, 3H), 3.26 (d, 2H), 2.02-1.33 (m, 17H). 5 Step 3: tert-Butyl [J-(hydroxymethyl)cyclopentyl]methylcarbamate To a solution of methyl 1-[(tert-butoxycarbonyl)amino]methylcyclopentanecarboxylate (1.50 g, 5.83 mmol) in THF (25.0 mL) at -78 "C was added dropwise 1.0 M diisobutylaluminum hydride in DCM (17.5 mL). The reaction was stirred for 2 hours with slow warming to -10 *C. A saturated solution of K/Na tartrate was added, followed by ether. This mixture was stirred for 30 minutes at 0 ambient temperature and the organic 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%). 'H NMR (300 MHz, CDCl 3 ): & 4.90 (br s, I H), 3.27 (s, 2H), 3.06 (d, 21-1), 1 .5 1.17 (in, 8H), 1.44 (s, 9H). 5 Step 4: tert-Butyl [(-formylcyclopentyl)methylqcarbamate 2S4 To a solution of oxalyl chloride (456 l.L, 5.38 mmol) in DCM (30.0 mL) at -78 *C was added DMSO (637 pL, 8.97 mmol) and the resulting mixture was stirred for 5 minutes. tert-Butyl [1 (hydroxymethyl)cyclopentyl]methylcarbamate (1.03 g, 4.48 mmol) in DCM (10.0 mL) was added and the resulting mixture was stirred for 30 minutes at -78 "C. TEA (2.50 mL, 17.9 mmol) was added and 5 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 HCI, water, saturated sodium bicarbonate solution, and brine, and then dried over sodium sulfate and the solvent was removed in vacuo to afford the product (957 mg, 94%). 'H NMR (300 MHz, CDCl 3 ): 9.39 (s, 1H), 4.94 (br s, 1H), 3.25 (d, 211), 1.89-1.46 (m, 8H), 1.41 (s, 9H). 0 Step 5: tert-Butyl (l-[(E)- 2 -cyanovinyl]cyclopentylmethyl)carbamate and tert-butyl (J-[(Z)-2-cyano vinyl]cyclopentylmethyl)carbamate 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 5 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.-formylcyclopentyl)methyl]carbamate (952 mg, 4.19 mmol) in THF (4.0 mL) was added dropwise. The reaction was allowed to warm to ambient temperature and the warmed mixture was stir for 16 hours. The reaction mixture was then diluted with ether and water. The organic layer was separated and washed sequentially with water and brine, then dried over 0 sodium sulfate, then filtered, and the solvent was removed in vacuo to afford the product (1.05 g, 99%) as a mixture of (E) and (Z) isomers. 'H NMR (300 MHz, CDCl 3 ): 8 6.71 (d, IH, E), 6.46 (d, I H, 2), 5.36 (d, 1H, Z), 5.36 (d, I H, E), 4.70 (br s, IH, Z), 4.51 (br s, IH, E), 3.25 (d, 2H, Z), 3.18 (d, 2H, E), 1.88-1.48 (m, 81 (E) and 8H (Z)), 1.43 (s, 9H (E) and 9H (Z)); MS(ES):151(M+H-Boc). .5 Step 6: tert-Butyl [(1-2-cyano-)-[ 4

-(

7

-[

2 -(trimethylsily)ethoxyjmethyl-7H-pyrrolo[2,3-d]pyrimidin 4 -yl)-JH-pyrazol-1-yl]ethylcyclopentyl)methyl]carbamate To a solution of 4-(l H-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 0 and tert-butyl (1-[(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 "C 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 acetate in hexanes) to afford the product (350 mg, 55%). 255 IH NMR (300 MHz, CDC 3 ): 8.85 (s, IH), 8.37 (br s, 1H), 8.34 (s, IH), 7.41 (d, iH), 6.82 (d, IH), 5.68 (s, 2H), 5.37 (br s, 1H), 4.52 (dd, 1H), 3.54 (1, 2H), 3.40 (dd, 1H), 3.23 (dd, 1H), 3.08 (d, IH), 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). 5 Step 7: N-[(1-2-Cyano--[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-IH-pyrazol-1-yl]ethylcyclopentyl) methyl]benzamide A solution of tert-butyl [(1-2-cyano-1-[ 4 -(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3 d]pyrimidin-4-yl)-IH-pyrazol-1-yl]ethylcyclopentyl)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. 0 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 portions of DCM containing 15% isopropanol. The combined extracts were dried over sodium sulfate and the solvents were removed in vacuo to afford the product, which was used without further purification. MS(ES):336(M+H). 5 To a solution of 3-[I-(aminomethyl)cyclopentyl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yi)-IH pyrazol-1-yl]propanenitrile (31 mg, 0.060 mmol) and benzoyl chloride (7.0 VL, 0.060 mol) in DCM (1.0 mL), was added TEA (17 gL, 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 H 2 0 and ACN containing 0.1% TFA, followed by chromatographic purification, eluting with a gradient of H 2 0 0 and ACN containing 0.15% NH40H) to afford the product (7 mg, 27%). 'H NMR (400 MHz, d 6 -DMSO): #12.12 (s, 1H), 8.95 (s, IH), 8.68 (s, 1H), 8.55 (s, 1H), 8.41 (s, I H), 7.92-7.87 (in, 2H), 7.60 (d, IH), 7.59-7.48 (m, 3H), 7.02 (d, IH), 4.83 (dd, IH), 3.52-3.45 (m, 2H), 3.42 (dd, IH), 3.27 (dd, 1H1), 2.06-1.95 (m, lH), 1.68-1.12 (m, 7H); MS(ES):440(M+H). .5 Example 741: 3 -1-[(Benzyloxy)methylcyclopentyl-3-[4-(7H-pyrrolo{2,3-dlpyrimidin-4-yi)-1IH pyrazol-1-yl)propanenitrile trifluoroacetate salt 0QOBn N-N N N H -TFA Step 1: l-(Hydroxymethyl)cyclopentanecarbonitrile 0 A mixture of methyl I-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 256 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 Na 2

SO

4 , then filtered and the solvent was removed in vacuo to afford the product (387 mg, 95%). 'H NMR (300 MHz, CDCl 3 ): p3.62 (s, 2H), 2.39-1.60 5 (m, 8H). Step 2: 1-[(Benzyloxy)methylqcyclopentanecarbonitrile To a solution of 1-(hydroxymethyl)cyclopentanecarbonitrile (0.30 g, 2.0 mmol) in DMF (4 mL) was added sodium hydride (60% dispersion in mineral oil, 0.101 g, 2.52 mol). The resulting D 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 bromide (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 extracted with ethyl acetate. The extracts were 5 combined and dried over sodium sulfate, and the solvent 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 acetate in hexanes) afforded product (330 mg, 64%). D 'H NMR (300 MHz, CDCl 3 ): 67.40-7.27 (in, 5H), 4.62 (s, 2H), 3.44 (s, 2H), 2.18-2.03 (m, 2H), 1.90 1.62 (m, 6H). Step 3: J-[(Benzyloxy)methyl]cyclopentanecarbaldehyde To a mixture containing 1-[(benzyloxy)methyl]cyclopentanecarbonitrile (0.16 g, 0.75 mmol) 5 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 reaction was cooled to -78 "C and quenched by the addition of methanol. The mixture was warmed to ambient temperature and 3 N HCI 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 0 dried (Na 2 SO4), and filtered, and the solvent was removed 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%). 'H NMR (300 MHz, CDC1): 5 9.60 (s, 1H), 7.38-7.26 (in, 5H), 4.52 (s, 2H), 3.54 (s, 21), 2.00-1.89 (m, 2H), 1.66-1.46 (m, 6H). 5 Step 4: (2E)- and ( 2

Z)-

3 -1-[(Benzyloxy)methyl]cyclopentylacrylonitrile 257 To a stirred solution of diethyl cyanomethylphosphonate (18 pL, 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, after which a solution of 1-[(benzyloxy)methyl]cyclopentanecarbaldehyde (0.020 g, 0.092 mmol) in THF (1 mL) was added. The resulting mixture was stirred for 16 hours. Water was then 5 added to the reaction and the resulting mixture was extracted with three portions of ethyl ether. The combined extracts were washed with brine, then dried over sodium sulfate, decanted from the sodium sulfate, and the solvent was removed in vacuo to afford the product, which was used without further purification in the subsequent conjugate addition step. 'Hi NMR (400 MHz, CDCl 3 ): 5 7.37-7.27 (m, 5H), 6.80 (d, 1 H (E)), 6.59 (d, I H (Z)), 5.34 (d, 1 H (E)), 0 5.33 (d, 1H (Z)), 4.53 (s, 2H (Z)), 4.50 (s, 214 (E)), 3.45 (s, 2H (Z)), 3.31 (s, 2H (E)), 1.80-1.55 (m, 8R); MS(ES)=242(M+H). Step 5: 3-1-[(Benzyloxy)methylJcyclopentyl-3-[4-(7H-pyrrolo[2,3-dJpyrimidin-4-yl)-IH-pyrazol-l ylpropanenitrile trifluoroacetate salt 5 To a mixture of (2E)- and (2Z)-3-1 -[(benzyloxy)methyl]cyclopentylacrylonitrile (generated in Step 4) and 4-(lH-pyrazol-4-yl)-7-[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 pL, 0.12 mmol). The resulting mixture was stirred at ambient temperature for 3 hours, and then was heated to 60 *C for 28 hours. The reaction mixture was diluted with diethyl ether and 0.1 N HCl. The layers were separated and the .0 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 THIF (5 mL) and 6.0 M sodium hydroxide in water (3 mL) and stirred for 2 hours. The reaction mixture was extracted with three 25 portions of ethyl acetate. The combined extracts 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 H 2 0 and ACN containing 0.1% TFA) and lyophilized to afford the desired product (10 mg, 20% over the two steps). 'H NMR (400 MHz, d-DMSO): 612.71 (br s, 11H), 8.99 (s, 11H), 8.86 (s, IH), 8.52 (s, I H), 7.80 (s, 0 1H), 7.38-7.23 (m, 5H), 7.19-7.16 (m, 1H), 4.92 (dd, 1H), 4.50 (d, IH), 4.44 (d, 1H), 3.49 (dd, 1H), 3.35 (d, 1H), 3.23 (dd, IH), 3.05 (d, 1H), 1.92-1.82 (m, 1H), 1.66-1.27 (in, 7H); MS(ES):427(M+H). Example 742: 3-[1-(Methylsulfonyl)pyrrolidin-3-yl]-3-[4-(7H-pyrrolo[2,3-djpyrimidin-4-yl)-H pyrazol-1-ylpropanenitrile trifluoroacetate salt '5 258 N CN

N

N N H -TFA Step 1: Benzyl 3 -(hydroxymethyl)pyrrolidine-1-carboxylate To a solution of 1-{(benzyloxy)carbonyl]pyrrolidine-3-carboxylic acid (1.0 g, 4.0 mol) in 5 THF (37 mL) at 0 *C was added dropwise a solution of 1.0 M borane in THF (16.4 mL). The reaction was allowed to warm to room temperature and stir for 16 hours. The mixture was cooled to 0 *C and 10% HCI (50 mL) was added. After the addition, the mixture was extracted with DCM, and the extract was washed sequentially with saturated NaHCO 3 solution and brine, then dried over sodium sulfate, filtered and the solvent was removed in vacuo. The product was used without further 0 purification in the subsequent oxidation step. 'H NMR (300 MHz, CDC].): 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 (in, 1H), 2.19 (br s, 0.1H), 2.05-1.89 (in, IH), 1.77 1.58 (m, 11); MS(ES):236(M+H). 5 Step 2: Benzyl 3 -formylpyrrolidine-1-carboxylate DMSO (597 pL, 8.42 mmol) was added to a solution of oxalyl chloride (427 p.L, 5.05 nmol) in DCM (25 mL) at -78 *C. After 5 minutes, bcnzyl 3-(hydroxymethyl)pyrrolidine-1 -carboxylate (generated in Step 1) was added. The reaction was continued for 30 minutes at -78 *C. TEA (2.3 mL, 17 mmol) was then added. The resulting mixture was then allowed to warm to room temperature over 20 the course of 30 minutes. Water was then added. The layers were separated and the organic phase was washed sequentially with 0.1 N HCI, water, saturated NaHCO 3 , and brine. The organic phase was then dried over sodium sulfate and the solvent was removed in vacuo to afford the product (0.82 g, 88% over two steps). 2H NMR (300 MHz, CDC1 3 ): # 9.68 (d, 1H), 7.38-7.28 (m, 5H), 5.13 (s, 211), 3.79 (dd, 111), 3.65-3.35 25 (in, 3H), 3.11-2.99 (m, IH), 2.32-2.04 (m, 2H). Step 3: Benzyl 3

-[(E)-

2 -cyanovinyl]pyrrolidine-1-carboxylate and benzyl 3-[(Z)-2-cyanovinyl] pyrrolidine-1-carboxylate 259 To a solution of 1.0 M potassium tert-butoxide in THF (4.40 nL) 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 room temperature and stirred for 15 minutes. The mixture was cooled to 0 *C and a solution of benzyl 3 -formylpyrrolidine-1-carboxylate (0.82 g, 2.3 5 mmol) in THF (4.00 mL) was added dropwise. Cooling was discontinued and the reaction stirred 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, filtered and the solvent was removed in vacuo. The resulting residue was purified by flash column chromatography elutingg with a gradient from 0-35% ethyl acetate in hexanes) to afford 10 the product as a mixture of E and Z isomers (246 mg, 42%). 'H NMR (300 MHz, CDCl 3 ): 8 7.41-7.27 (in, 5H), 6.70-6.58 (in, 0.3H (E)), 6.38 (dt, 0.7H (Z)), 5.50 5.30 (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). \5 Step 4: Benzyl 3

-

2 -cyano-1-[4-(7-[2- (trimethy1sily1)ethoxyjmethy- 7 H-pyrrolo[2,3-d]pyrimidin-4-y) I H-pyrazol-1-yljethylpyrrolidine-1-carboxylate To a mixture of benzyl 3

-[(E)-

2 -cyanovinyl]pyrrolidine-1-carboxylate and benzyl 3-[(Z)-2 cyanovinyl)pyrrolidine-1-carboxylate (241 mg, 0.940 mmol) and DBU (234 iL, 1.57 mmol) in ACN (13 mL) was added 4-(lH-pyrazol4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[ 2 ,3 .0 d)pyrimidine (250 mg, 0.78 mmol). The mixture was stirred at ambient temperature for 3 hours. The solvent was removed in vacua. The resulting residue was dissolved in ethyl acetate, and the organic layer was washed sequentially with IN HCI, water, saturated NaHCO 3 , and brine. The washed solution was dried over sodium sulfate and the solvent was removed in vacua. Purification via flash column chromatography elutingg with a gradient of 0-100% [5% MeOH/DCM] in hexanes) afforded 25 the produce as a mixture of diastereomers (400 mg, 89%). 'H NMR (400 MHz, CDC1 3 a mixture of diastereomers): 8.85 (s, I H), 8.35-8.28 (m, 21H), 7.42-7.25 (in, 6H), 6.80-6.76 (in, IH), 5.69-5.66 (m, 2H), 5.15-5.04 (m, 2H), 4.46-4.32 (in, 1H), 3.84-3.84 (in, 6H), 3.54 (t, 2H), 2.26-2.13 (in, 1H), 1.84-1.54 (m, 2H), 0.95-0.89 (in, 2H), -0.06 (s, 9H); MS(ES):572(M+H). 0 Step 5. 3 -Pyrrolidin-3-yl-3-[4.(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl) JH-pyrazol-1-ylgpropanenitriJe Benzyl 3 -2-cyano-1 -[4-(7-2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo(2,3-dlpyrimidin4 yl)-1H-pyrazol-1-yl]ethylpyrrolidine-1-carboxylate (161 mg, 0.282 mmol) was dissolved in methanol 5 (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 260 10% 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-HPLC/MS (C18 eluting with a gradient of H20 and ACN containing 0.15% NH 4 0H) to afford the product as a mixture of diastereomers (57 mg, 46%). 5 'H NMR (400 MHz, CDC 3 , a mixture of diastereomers): 5 8.84 (s, 1H), 8.34-8.32 (m, 2H), 7.40 (d, 1H), 6.81-6.78 (in, 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-(Methylsulfonyl)pyrrolidin-3-yl]-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-IH-pyrazol-1 0 yllpropanenitrile trifluoroacetate salt To a solution of 3-pyrrolidin-3-yl.-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl)-7H-pyrrolo[2,3 d]pyrimidinyl)1H-pyrazol-1-ylpropanenitrile (25 mg, 0.057 mmol) and TEA (10 pL, 0.074 mmol) in DCM (1.0 mL) at 0 "C was added methanesulfonyl chloride (6 L, 0.074 mmol). The reaction was allowed to reach ambient temperature and stir for 16 hours. Half of the solvent was removed in vacuo 5 and TFA (1 mL) was added to the vial. After stirring for 1 hour at room temperature, 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 (Na 2

SO

4 ), decanted and concentrated. Preparative-HPLC/MS (C18 eluting with a gradient of H20 and ACN containing 0.1% TFA) was used 0 to afford the product (16 mg, 57%). 'H NMR (400 MHz, d 6 -DMSO, a mixture of diastereomers): 8 12.69 (s, 1H), 8.98 (s, 0.51H), 8.95 (s, 0.51), 8.84 (s, 11), 8.53-8.51 (m, 111), 7.80-7.77 (m, 1H), 7.16-7.13 (m, 1H), 4.86-4.75 (m, 1H), 3.55-3.48 (m, 1H), 3.42-3.08 (in, 4H), 2.99-2.91 (m, 1H), 2.90 (s, 1.5H), 2.85 (s, 1.5H), 2.16-2.07 (in, IH), 1.82-1.70 (m, 1H), 1.64-1.48 (m, 1H); MS(ES):386(M+H). 25 Example 743: N'-Cyano4-(cyanomethyl)-4-4-(7H-pyrrolo{2,3-dpyrimidin-4-yl)-1H-pyrazol-1 yllpiperldine-1-carboximidamide N N HN N

NH

2 N- N Step 1: tert-Butyl 4 -(cyanomethylene)piperidine-1-carboxylate 50 To a solution of 1.0 M potassium tert-butoxide in THF (10.1 mL) at 0 *C was added a solution of diethyl cyanomethylphosphonate (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-oxo-l-piperidinecarboxylate 261 (2.00 g, 0.0100 mol) in THF (30 mL) stirring at 0 *C under an atmosphere of nitrogen. After complete' addition, 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 UV. at 200 & 230 nim. Water and EtOAc were added to the reaction mixture. The phases i were separated, and the aqueous phase was extracted with EtOAc. The combined organic phase was washed with water, then saturated NaCl, then dried over Na 2

SO

4 , and concentrated to dryness to provide 2.5 g of the product as a yellow oil. TLC (25% EtOAc/hexane) Rr 0.22. The product was purified by automatic 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 fractions. The ) product eluted in 21-27 min. The fractions were contrated to yield 0.67 g of a white solid. 'H NMR (CDCl 3 ) 6 5.19 (s, 1H); 3.51 (m, 4H); 2.56 (t, 2H); 2.33 (t, 211); 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)ethoxyqmethyl-7H-pyrrolo[2,3-dJ pyrimidin--4-yl)-H-pyrazol-1-yi]piperidine-1-carboxylate 4-(lH-Pyrazol-4-y)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (0.840 g, 2.66 mmol) was slurried in a mixture of ACN (20 mL) and DBU (398 pL, 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 200 C, but a solution was formed when the mixture was heated to 40 "C for lh. LCMS and HPLC analyses showed about 20% conversion to product. The mixture was stirred at 40-45 *C overnight. HPLC showed 60 area% product. The ACN was removed by retory evaporator at 20 *C. To the resulting residue was added saturated NaHCO 3 and EtOAc. The organic layer was shaken with more aqueous saturated NaHCO 3 , then dried (Na 2

SO

4 ) and rotovaped to give 1.6g of a brown oil residue. TLC (60% EtOAc/hexane): product Re= 0.25. The product was purified by automatic flash 5 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 isolated as white solids. 'H NMR (CDCl 3 ) 8 8.84 (s, 1H); 8.42 (s, 1H); 8.33 (s, 1H); 7.40 0 (d, 1H); 6.79 (d, IH); 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-djpyrimidin-4-yl)-1H-pyrazol-1-yljpiperidin-4-ylacetonitrile tert-Butyl 4 -(cyanomethyl)-4-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d] 5 pyrimidin-4-yl)-H-pyrazol-1-ylpiperidine-1-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 intermediate, M+H 338. The solution was concentrated to remove the TFA. Methanol was added to 262 the resulting residue, 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 5 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% ACN-H 2 0 (0.1% NH 4 0H), 1.0min, 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. 'H NMR (d6-DMSO) 6 12.07 (s, IMH); 8.68 (s, IH); 8.62 (s, 1H); 8.36 (s, 1H); 7.54 (d, IH); 0 7.00 (d, 1H); 3.16 (s, 2H); 2.87 (in, 2H); 2.55 (m, 4H); 1.94 (in, 2H). MS(ES) 308 (M+H). Step 4.- Methyl N-cyano-4-(cyanomethyl)-4-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-JH-pyrazol-I-yl] piperidine-1-carbimidothioate 4

-[

4

-(

7 H-Pyrrolo[2,3-d]pyrimidin-4-y)-lH-pyrazol-1-yllpiperidin-4-ylacetonitrile (361 mg, 5 1.17 mmol) and N-cyano-S,S'-dimethyldithioimido carbonate (344 mg, 2.35 mmol) were dissolved 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, Spm, 15 cm, 35 *C, flow 1.2 mUmin, 5% ACN-H 2 0 (0.05% TFA), 1.5 min, to 100% ACN in 15.0 min; D detector set at 324, 225, and 265 nm. The retention time of the starting 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 iL, 2.35 mmol), and the resulting 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 IPLC using a 30 mm x 100 5 mm C18 column; 5%ACN-H 2 0 (0.1%TFA), 1.0min, to 35% at 6min; 60 mljmin; detector set at 326 nm. The retention time for the product 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. 'H NMR (drDMSO) 6 12.85 (s, 1H); 9.01 (s, 1H); 8.90 (s, 1H); 8.59 (s, 1H1); 7.85 (m, 1H); 7.30 (m, 1H); 4.23 (m, 211); 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). 0 Step 5: N'-Cyano-4-(cyanomethyl)-4-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-]H-pyrazol-1-yl]piperi dine-] -carboximidamide Methyl N-cyano-4-(Cyanomethyl)-4-[4-(7H-pyrrolo[2,3-d]pyrimidin4-yl)-1H-pyrazol-1-yI]-. piperidine-1-carbimidothioate (41.3 mg, 0.102 mmol) (53 mg TFA salt) was dissolved in 2.0 M 5 ammonia in isopropyl alcohol (4.00 mL). The resulting mixture was heated to 100 *C for I h in a microwave reactor. Analysis by HPLC and LCMS showed 60% reaction to give the expected M+H 263 375 (50 area%). To this mixture was added 2 nL of 7 N N14T/MeOH. The resulting mixture was heated at 120 *C for one hour. HPLC and LCMS analyses showed no remaining starting material. The reaction mixture was concentrated on a rotory evaporator. The product was isolated by prep HPLCMS using a 30 mm x 100 mm C18 column, eluting with a solvent gradient; 10% ACN-H20 5 (0.1%TFA), 1.5min, to 30% at 6min; 60mL/min; detector set at m/z 375; retention time, 4.7 min. The eluate was freeze-dried to yield 11.7 mg of the product TFA salt as a white solid. 'H NMR (d 6 DMSO) 6 12.69 (s, 1H, NH); 8.92 (s, IH); 8.81 (s, 1H); 8.51 (s, 1 H); 7.75 (m, IH); 7.22 (m, I H); 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). 0 Example 744: 4 -1-[2,2, 2 -Trifluoro-1-(1B-imidazol-2-ylmethyl)ethyl-1lH-pyrazol-4-yl-7H-pyr rolo[2,3-djpyrimidine NH Fg F N-N N**\ N NH Step]: (3R)-4,4,4-Trifluoro-3-[4-(7-[2-(trimethylsilyl)ethoxy methyl-7H-pyrrolo[2,3-dpyrimidin-4 5 yI)-1H-pyrazo1-1-yljbutanal O F NN N) N N SEM To a -70 "C solution of ( 3 R)-4,4,4-trifluoro-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyr rolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile (1.06 g, 0.00243 mol) (see, Example 93, Step) in DCM (10 mL, 0.2 mol) was added 1.0 M diisobutylaluminum hydride in DCM (4.8 mL). 0 The resulting mixture was stirred for 3h and allowed to warm during this time interval from -70 to -25 *C, after 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). Insoluble material was then filtered from the reaction mixture. The organic filtrate was washed sequentially with: 2.0 M HCI in water, water and saturated 264 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). 5 'H NMR (400 MHz, CDCI 3 ): 8 9.85 (1H, s); 8.95 (lH, s); 8.5 (IH, s); 8.4 (IH, s); 7.5 (1H, d); 6.85 (IH, 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, s). MS (M+H): 440. Step2: 4-1-[2,2, 2 -Tri fluoro-1-(1H-imidazol-2-ylmethy!)ethyl]-IH-pyrazol-4-yl-7-[2-(trimethylsilyl) 0 ethoxy]methyl- 7H-pyrrolo[2.3-d]pyrimidine eNH F N-N N \ N N SEM A solution of 4 ,4, 4 -trifluoro-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrolo[2,3-d] pyrimidin-4-yl)-1H-pyrazol-1-yl]butanal (0.138 g, 0.000314 mol), 7.0 M ammonia in methanol (1 mL), ethanedial (0.5 mL, 0.004 mol) and acetic acid (20 uL, 0.0004 mol) in methanol (2 mL, 0.05 5 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 3 and saturated 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 of purified product as an off-white solid (38% yield). 0 'H NMR (400 MHz, CDC1 3 ): 8 8.91 (IH, s); 8.4 (1H, s); 8.2 (IH, s); 7.5 (1H, d); 7.0 (2H, s); 6.83 (IH, d); 5.75 (2H, s); 5.62 (1 H, m); 4.15 (1H, dd); 3.8 (1H, dd); 3.6 (2H, t); 1.99 (2H, t); 0.0 (9H, s). MS (M+H): 478. Step3: 4-1-[2, 2

,

2 -Trifluoro-1-(H-imidazol-2-ylmethyl)ethyl]-IH-pyrazol-4-yl-7H-pyrrolo[2,3-d] 5 pyrimidine A solution of 4-1-[2,2,2-trifluoro-l-(IH-imidazol-2-ylmethyl)ethyl]-H-pyrazol-4-yl-7-[2 (trimethylsilyl)ethoxy]methyl-7H-pyn-olo[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 reaction was concentrated to provide an orange oil. The oil was stirred in methanol (1 mL, 20 mmol) and 8.0 M 265 ammonium hydroxide in water (1 nL) for 4h. This mixture was then concentrated to provide a crude product as an orange glass/solid. The crude product was purified by Prep HPLC (pH1O) 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% i yield) which then was dried rt-50 *C for 3h. 'H NMR (400 MHz, DMSO): 8 12.13 (IH, s); 11.89 (lH, s); 8.65 (1H, s); 8.37 (1H, s); 7.6 (IH, d); 6.95 (lH, d); 6.92 (IH, d); 5.91 (IH, in); 3.78 (IH, dd); 3.47 (H, dd). MS (M+H): 348. Example 745: 4-(1-(1R)-2,2,2-Trifluoro-1-[(4-methyl-1,3-thiazol-2-yl)methyllethyl-1H-pyrazol ) 4 -yl)- 7 H-pyrrolo[2,3-dipyrimidine F N-N N \ N NH Step 1: (3R)-4,4,4-Trifluoro-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-y)-.H-pyrazol- 1-yl]butane thioamide H 2N F SF F N N N N NH 5 A suspension of phosphorus pentasulfide (0.46 g, 1.0 mmol) in ethanol (0.5 mL, 8 mmol) was stirred for 1h. (3R)-4,4,4-Trifluoro-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butane nitrile (0.15 g, 0.50 mmol) (see, Example 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 overnight. 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 saturated NaHCO 3 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 chromatographed with 0. 10% MeOH/DCM, 0-1 %NH 4 0H to give 0.13 g of the purified product as a white solid (76% yield). 266 'H NMR (400 MHz, CDC 3 ): 8 8.7 (IH, s); 8.5 (1H, s); 8.3 (iH, s); 7.4 (1H, d); 7.0 6.75 (111, d); 5.82 (1H, m); 3.75 (1H, dd); 3.2 (1H, dd). MS (M+H): 341. A suspension of ( 3 R)-4,4,4-trifluoro-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1 yl]butanethioamide (0.038 g, 0.00011 mol), chloroacetone (15 uL, 0.00019 mol) in ethanol (1 mL, 5 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 (I -mL) and DMF (1 mL) and purified by prep HPLC at pH10 to provide 6 mg of the purified 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). 0 'H NMR (400 MHz, CDC 3 ): 8 10.11 (1H, s); 8.88 (IH, s); 8.42 (1H, s); 8.38 (iH, s); 7.45 (IH, d); 6.79 (1H, s); 6.65 (I H, d); 5.41 (1 H, m); 4.15 (1 H, dd); 3.75 (H, dd); 2.18 (311, s). MS (M+H): 379. Example A: In vitro JAK Kinase Assay Compounds herein were tested for inhibitory activity of JAK targets according to the 5 following in vitro assay described in Park et al., Analytical Biochemistry 1999, 269, 94-104. The catalytic domains of human JAKI (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 JAY1, JAK2 or JAK3 was assayed by measuring the phosphorylation of a biotinylated peptide. The phosphorylated peptide was detected by homogenous time resolved fluorescence ) (HTRF). ICsos 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 DTI', and 0.1 mg/mL (0.01%) BSA. The ATP concentration in the reactions was 90 pM for Jak1, 30 gM for Jak2 and 3 pM for Jak3. Reactions were carried out at room temperature for I hr and then stopped with 20 pL 45 mM EDTA, 300 nM SA-APC, 6 nM Eu-Py20 in assay buffer (Perkin Elmer, Boston, MA). 5 Binding to the Europium labeled antibody took place for 40 minutes and HTRF signal was measured on a Fusion plate reader (Perkin Elmer, Boston, MA). Compounds having an IC 50 of 10 gM or less for any of the above-mentioned JAK targets were considered active. Example B: Cellular Assays 0 One or more compounds herein were tested for inhibitory activity of JAK targets according to at least one of the following cellular assays. Cancer cell lines dependent on cytokines 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 1 nG/mL of appropriate cytokine. Compounds were added to the cells in DMSO/media (final 5 concentration 0.2% DMSO) and incubated for 72 hours at 37 *C, 5% CO 2 . The effect of compound on cell viability was assessed using the CellTiter-Glo Luminescent Cell Viability Assay (Promega) 267 followed by TopCount (Perkin 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 ICso of 10 pM or less with selectivity for JAK driven proliferation were considered active. All experiments were performed in duplicate. 5 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, Shp2, or Erk. These experiments can be performed following an overnight cytokine starvation, followed by a brief preincubation with compound (2 hours or less) and cytokine stimulation of approximately I hour or less. Proteins are then extracted from cells and analyzed by techniques 0 familiar to those schooled in the art including Western blotting or ELISAs using antibodies that can differentiate between phosphorylated and total protein. These experiments can utilize normal or cancer cells to investigate the activity of compounds on tumor cell survival 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 5 potentially in transcriptional profiles (assessed by array or qPCR technology) or production and/or secretion of proteins, such as IL-17. The ability of compounds to inhibit these cytokine mediated 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 D proliferative disorders. These experiments often utilize cytokine dependent cells of hematological lineage (e.g. 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 al. JBC 280:41893-41899). Endpoints include the effects of compounds on cell survival, proliferation, and phosphorylated JAK, STAT, Akt, or Erk proteins. 5 Certain compounds herein have been or can be evaluated for their activity inhibiting T-cell proliferation. Such as assay can be considered a second cytokine (i.e. JAK) driven proliferation assay and also a simplistic assay of immune suppression or inhibition of immune activation. The following is a brief outline of how such experiments can be performed. Peripheral blood mononuclear cells (PBMCs) are prepared from human whole blood samples using Ficoll Hypaque separation method 0 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 withl0% fetal bovine serum, 100 U/mI penicillin, 100 jig/mI streptomycin) at a density of 2 x 1 06 cells/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 pg/mL for 72h. After washing once with PBS, 6000 cells/well are 5 plated in 96-well plates and treated with compounds at different concentrations in the culture medium in the presence of 100 U/mL human IL-2 (ProSpec-Tany TechnoGene; Rehovot, Israel). The plates 268 are incubated at 37 *C for 72h and the proliferation index is assessed using CellTiter-Glo Luminescent reagents following the manufactory suggested protocol (Promega; Madison, WI). Example C: In vivo anti-tumor efficacy Compounds herein can be evaluated in human tumor xenograft models in immune 5 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 a]. 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, 0 tumor samples can be harvested at any time after the initiation of treatment for analysis as described above (Example B) to evaluate compound effects on JAK activity and downstream signaling pathways. In addition, selectivity of the compound(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 5 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 contact 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 (Immunol Today. 1998 Jan;19(1):37-44). Murine DTH shares multiple characteristics with psoriasis, including the immune 3 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 (Agents Actions. 1993 Jan;38(1-2):116-21). On Day 0 and 1, Balb/c mice are sensitized with a topical application, to their shaved abdomen with the antigen 2

,

4 ,dinitro-fluorobenzene (DNFB). On day 5, ears are measured for 5 thickness using an engineer'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 AL (10 jiL on the internal pinna and 10 ILL on the external pinna) at a concentration of 0.2%. Twenty-four to seventy-two hours after 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 0 throughout the challenge phase (usually afternoon of day 4 to day 7). Treatment of the test compounds (in different concentration) was administered either systemically or topically (topical application of the treatment to the ears). Efficacies of the test compounds are indicated by a reduction in ear swelling comparing to the situation without the treatment. Compounds causing a reduction of 20% or more were considered efficacious. In some experiments, the mice are challenged but not 5 sensitized (negative control). 269 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 functional transcription factors. Further, the influx of immune cells and the increased proliferation of keratinocytes should also provide unique expression profile 5 changes in the ear that can be investigated and quantified. Formalin fixed and paraffin embedded ear sections (harvested after the challenge phase in the DTH model) are subjected to immunohistochemical 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 dexamethasone (a clinically efficacious treatment for psoriasis), or without 0 any treatment, in the DTH model for comparisons. Test compounds and the dexamcthasone can produce similar transcriptional changes both qualitatively and quantitatively, and both the test compounds and dexamethasone 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. 5 Example E: In vivo anti-inflammatory activity Compounds herein can be or have been evaluated in rodent or non-rodent models designed 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 9 induced arthritis, and collagen antibody-induced arthritis. Autoimmune diseases including, but not limited to, multiple sclerosis, type I-diabetes mellitus, uveoretinitis, thyroditis, myasthenia gravis, immunoglobulin nephropathies, myocarditis, airway sensitization (asthma), lupus, or colitis may also be used to evaluate the therapeutic potential of compounds herein. These models are well established in the research community and are familiar to those schooled in the art (Current Protocols in 5 Immunology, Vol 3., Coligan, J.E. et al, Wiley Press.; Methods in Molecular Biology: Vol. 225, Inflammation Protocols., Winyard, 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 0 incorporated herein by reference in its entirety. 270

Claims (85)

1. 4- to 20-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring fused to the 5-membered ring formed by A', A 2 , 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).-Q; W is C,.z alkylenyl, C2-s alkenylenyl, C 2 . alkynylenyl, 0, S, C(0), C(O)NRC', C(O)O, OC(O), OC(O)NRC', NRC', NR'C(O)NR', S(O), S(O)NR*', S(0)2, or S(O)2NR' Q is H, halo, CN, NO 2 , C,.8 alkyl, C2. alkenyl, C2.8 alkynyl, CI.8 haloalkyl, halosulfanyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, wherein said C1. 8 alkyl, C2.8 alkenyl, C2-8 alkynyl, Cl.s haloalkyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from halo, CIA alkyl, C2.4 alkenyl, C 2 . 4 alkynyl, C.4 haloalkyl, halosulfanyl, C:.4 hydroxyalkyl, C1.4 cyanoalkyl, Cy 2 , CN, NO 2 , ORa, SR', C(O)R, C(O)NR'Rd', C(O)OR"', OC(O)Rb, OC(O)NRc'Rd', ''R', NR*'C(O)Rb', NRc'C(O)Nc'Rd' NR''C(O)ORa S(O)Rb', S(O)NRc'R', S(O) 2 Rb', NR*'S(0) 2 Rb, and S(O)2NR*'Rd'; Cy' and Cy2 are independently selected from aryl, beteroaryl, cycloalkyl, and heterocycloalkyl, each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from halo, CI-4 alkyl, C 2 . 4 alkenyl, C 2 -4 alkynyl, C,.4 haloalkyl, balosulfanyl, CI. 4 hydroxyalkyl, C. cyanoalkyl, CN, NO 2 , OR'", SR'", C(O)Rb", C(O)NR'"Rd", C(O)OR'", OC(O)Rb'", OC(O)NR'"Rd", NR'"Rd", NR''C(O)Rb", NR'"C(O)ORa", NRC"S(O)R'", N "S(O) 2 Rb", S(O)R", S(O)NR"Rd", S(O) 2 Rb", and S(O)2NRc'"Rd"; R', R 2 , R 3 , and R 4 are independently selected from H, halo, C4 alkyl, C 2 . 4 alkenyl, C2-4 alkynyl, C1.4 haloalkyl, halosulfanyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO 2 , OR 7 , SR 7 , C(O)Rs, C(O)NR 9 R' 0 , C(O)OR 7 OC(O)R 8 , OC(O)NR 9 R'", NR'R' 0 , NROC(O)R, NRcC(O)OR, S(O)R', S(O)NRR'Ro, S(O) 2 R 8 , NR 9 S(O) 2 R', and S(O) 2 NR 9 R' 0 ; R 5 is H, halo, C1.4 alkyl, C2.4 alkenyl, C 2 . 4 alkynyl, C14 haloalkyl, halosulfanyl, CN, NO 2 , OR', SR 7 , C(O)R 8 , C(O)NRR'', C(O)OR, OC(O)R, OC(O)NRR'*, NR 9 R' 0 , NR'C(O)R, NRC(O)OR7, S(O)R', S(O)NRR'O, S(0) 2 R', NR 9 S(O) 2 R 8 , or S(0) 2 NRR' 0 ; R 6 is H, C1 alkyl, C 2 .4 alkenyl, C 2 4 alkynyl, Cj4 haloalkyl, OR7, C(O)R', C(O)NR!R' 0 , C(O)OR7, S(O)R, S(O)NR 9 R'", S(O)2R, or S(O) 2 NR 9 R'"; R7 is H, C,. alkyl, C1. 6 haloalkyl, C2.6 alkenyl, C2.6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl; R' is H, C,-6 alkyl, C,. 6 haloalkyl, C 2 . 6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl; R 9 and R'" are independently selected from H, C,.,o alkyl, C.6 haloalkyl, C2. 6 alkenyl, C2.6 alkynyl, C1.6 alkylcarbonyl, arylcarbonyl, C1.6 alkylsulfonyl, arylsulfonyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl; or R? and R' 0 together with the N atom to which they are attached form a 4-, 5-, 6- or 7 membered heterocycloalkyl group; 272 R" and R1 2 are independently selected from H and -E'-E 2 -E 3 -E 4 ; D' and El are independently absent or independently selected from C. 4 alkylene, C2.6 alkenylene, C2.6 alkynylene, arylene, cycloalkylene, heteroarylene, and heterocycloalkylene, wherein each of the C,. alkylene, C2.( alkenylene, C2.6 alkynylene, arylene, cycloalkylene, heteroarylene, and heterocycloalkylene is optionally substituted by 1, 2 or 3 substituents independently selected from halo, CN, NO 2 , N 3 , SCN, OH, C,.6 alkyl, C1. 6 haloalkyl, C 2 - alkoxyalkyl, C,. 6 alkoxy, C.4 haloalkoxy, amino, C1. 6 alkylamino, and C 2 . dialkylamino; D 2 and E 2 are independently absent or independently selected from C 1.6 alkylene, C2-6 alkenylene, C 2 .6 alkynylene, (C,. 6 alkylene),-O-( C.6 alkylene),, (C,. 6 alkylene)r-S-(C,. alkylene),, (CI. 6 alkylene)rNR*-(C I-6 alkylene),, (CI, alkylene),-CO-(C-6 alkylene),, (C1.6 alkylene),-COO-(C. 6 alkylene),, (C,. alkylene),.CONR*-(C,. -alkylene),, (CI. 6 alkylene),-SO-(CI.6 alkylene),, (C. 6 alkylene),SO 2 -(C,. 6 alkylene),, (C. 6 alkylene),-SONR"-(C,. 6 alkylene),, and (C,. 6 alkylene), NR*CONRe-(C.s 6 alkylene),, wherein each of the C.6 alkylene, C 2 . 6 alkenylene, and C2.6 alkynylene is optionally substituted by 1, 2 or 3 substituents independently selected from halo, CN, NO 2 , N 3 , SCN, OH, C1.6alkyl, Cg.6 haloalkyl, C2.8 alkoxyalkyl, C.6 alkoxy, C,. 6 haloalkoxy, amino, C,.6 alkylamino, and C2- dialkylamino; D 3 and E 3 are independently absent or independently selected from C.6 alkylene, C2.6 alkenylene, C2.6 alkynylene, arylene, cycloalkylene, heteroarylene, and heterocycloalkylene, wherein each of the C1. alkylene, C2.6 alkenylene, C2.6 alkynylene, arylene, cycloalkylene, heteroarylene, and heterocycloalkylene is optionally substituted by 1, 2 or 3 substituents independently selected from halo, CN, NO 2 , N 3 , SCN, OH, CI-6 alkyl, C,.6 haloalkyl, C 2 . alkoxyalkyl, C1.6 alkoxy, C1.6 haloalkoxy, amino, C,. 6 alkylamino, and C2.4 dialkylamino; D 4 and E 4 are independently selected from H, halo, C. 4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C.4 haloalkyl, halosulfanyl, C1.4 hydroxyalkyl, CI.4 cyanoalkyl, Cy', CN, NO 2 , OR, SR", C(O)Rb, C(O)NR*Rd, C(O)ORa, OC(O)R', OC(O)NRRd, NRd, NR*C(O)Rb NR*C(O)NR*Rd, NRcC(O)ORB, C(=NR)NRCRd, NRC(=NR)NR*Rd, S(O)Rb, S(O)NR*Rd, S(O) 2 Rb, RS(O) 2 R, C(=NOH)Rb, C(=NO(C,.6 alkyl)Rb, and S(O) 2 NR*Rd, wherein said C1.8 alkyl, C2.9 alkenyl, or C2. alkynyl, is optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from halo, C,.4 alkyl, C2-4 alkenyl, C 2 . 4 alkynyl, C14 haloalkyl, halosulfanyl, C, 4 hydroxyalkyl, C1.4 cyanoalkyl, Cy', CN, NO 2 , OR, SR", C(O)R, C(O)NR*Rd, C(O)OR", OC(O)R, OC(O)NRcRd, NR*Rd, NRcC(O)R, NRcC(O)NRRdN, N*C(O)OR", C(=NR)NR*Rd, *C(=NRNRR, S(O)Rb, S(O)NR*Rd, S(O) 2 R , NRcS(O) 2 Rb, C(=NOH)R, C(=NO(C.6 alkyl))R, and S(O) 2 NR"Rd; R is H, Cy', -(CI.6 alkyl)-Cy', C1.6 alkyl, C1. 6 haloalkyl, C2.6 alkenyl, C2-6 alkynyl, wherein said CI-6 alkyl, C1.6 haloalkyl, C2.6 alkenyl, or C2.6 alkynyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1.6 alkyl, C.6 haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; 273 Rb is H, Cy', -(C,.6 alkyl)-Cy', C1.6 alkyl, C 1 . 6 haloalkyl, C2.6 alkenyl, C2.6 alkynyl, wherein said C,.6 alkyl, C.6 haloalkyl, C2-6 alkenyl, or C2-6 alkynyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1.4 alkyl, C1. 6 haloalkyl, CI. 6 haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalky); R'' and R'" are independently selected from H, C.6 alkyl, C,. haloalkyl, C2.6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said C1.6 alkyl, C,. haloalkyl, C2-6 alkenyl, C2.6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C.6 alkyl, C..6haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; Rb' and R" are independently selected from H, C, 4 alky), C. 6 haloalkyl, C2.6 alkenyl, Cz.a alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said CI.6 alkyl, C1.6 haloalkyl, C2.6 alkenyl, C2., ailcynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1.6 alkyl, C,.6 haloalkyl, C.6 haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; R" and Rd are independently selected from H, Cy', -(C,. 6 alkyl)-Cy', C1.10 alkyl, C1.6 haloalkyl, C2.6 alkenyl, C 2 . 6 alkynyl, wherein said C.,- alkyl, C1.6 haloalkyl, C2.6 alkenyl, or C 2 . 6 alkynyl, is optionally substituted with 1, 2, or 3 substituents independently selected from Cy', -(CI-6 alkyl)-Cy', OH, CN, amino, halo, C1.6 alkyl, C.6 haloalkyl, C,. 6 haloalkyl,and halosulfanyl; or R and R together with the N atom to which they are attached form a 4-, 5-, 6- or 7 membered heterocycloalky group optionally substituted with 1, 2, or 3 substituents independently selected from Cy', -(CI.6 alkyl)-Cy', OH, CN, amino, halo, C.6 alkyl, C.6 haloalkyl, C,. haloalkyl, and halosulfanyl; R" and Rd' are independently selected from H, C1.1o alkyl, C.6 haloalkyl, C2-6 alkenyl, C2.6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said C1-1o alkyl, C1.6 haloalkyl, C2.6 alkenyl, C2-6 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, C1. 6 alkyl, C,.6 haloalkyl, C1.6 haloalkyl, halosulfanyl, 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 independently selected from OH, CN, amino, halo, C.6 alkyl, C1. 6 haloalkyl, CI.4 haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; 274 R* and R" are independently selected from H, C 1 .ro alkyl, Cr. haloalkyl, C 2 -6 alkenyl, C 2 ., alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said C,.1 0 alkyl, C 1 . 6 haloalkyl, C 2 . 6 alkenyl, C 2 .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, C . 4 alkyl, C,. 6 haloalkyl, halosulfanyl, C 1 .s haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; or R" 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, C 1 . 6 alkyl, C1. 6 haloalkyl, C 1 . 6 haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; R' is H, CN, NO 2 , or Cl.5 alkyl; R' and R' are independently selected from H and C1. alkyl; R' is H, CN, or NO 2 ; m is 0 or 1; n is 0 or 1; p is 0, 1, 2 , 3, 4, 5, or 6; q is 0, 1, 2 , 3,4, 5 or 6; r is 0 or 1; and s is 0 or 1; wherein when X is N, n is 1, and the moiety formed by A', A 2 , U, T, V, and -(Y).-Z has the formula: (Y)n-Z HN then Y is other than (CR" R 12 )PC(O)NR'(CRI "R 12 )q. 2. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein X is N. 3. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein X is CR 4 . 4. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein A' is C.
2. 5. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein A' is N. 275
3. 6. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein A2 is C.
4. 7. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein A 2 is N.
5. 8. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein at least one of A', A 2 , U, T, and V is N.
6. 9. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein the 5 membered ring formed by A', A 2 , U, T, and V is selected from: a a ~-R 6 "I N N N R0 b b b ,i S N N N N S Y O S IN N a a a O4 S / Y N C, a C NN N b , b ,and b wherein: a designates the site of attachment of moiety -(Y).-Z; b designates the site of attachment to the core moiety: RI R 3 N N H ; and c and c' designate the two sites of attachment of the fused 4- to 20-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring. 276
7. 10. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein n is 0.
8. 11. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein n is 1.
9. 12. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein n is I and Y is CI. 8 alkylene, C 2 .S alkenylene, (CR"R 2 ),C(O)(CR"R 1 2 )q, (CR"R 1 2 )pC(O)NR'(CR"R' 2 )q, (CR"R 2 ),C(O)O(CR" R")q, (CR"R 2 )POC(O)(CR"R2)q, wherein said C,. 8 alkylene or C 2 .8 alkenylene, is optionally substituted with 1, 2, or 3 halo, OH, CN, amino, C,- alkylamino, or C 2 -s dialkylamino.
10. 13. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein n is I and Y is CI-s alkylene, (CR"R 2 )PC(O)(CR"R 12 )q, (CR' "R 12 )pC(O)NR'(CR"R 2 )q, (CR"R 2 ),C(O)O(CR"R12)q, wherein said C,. 8 alkylene is optionally substituted with 1, 2, or 3 halo, OH, CN, amino, CI-4 alkylamino, or C 2 - dialkylamino.
11. 14. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein n is I and Y is C. 8 alkylene optionally substituted with 1, 2, or 3 halo, OH, CN, amino, C,- alkylamino, or C 2 -9 dialkylamino.
12. 15. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein n is I and Y is (CR"R 2 ),C(O)(CR"R' 2 )q (CR"R 2 ), C(O)NR'(CRR 1 2 )q, or (CR"R' 2 ),C(O)O(CR"R' 2 ).
13. 16. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein p is 0.
14. 17. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein p is 1.
15. 18. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein p is 2.
16. 19. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein q is 0.
17. 20. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein q is 1.
18. 21. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein q is 2.
19. 22. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein one of p and q is 0 and the other of p and q is 1, 2, or 3. 277
20. 23. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein Z is aryl, cycloalkyl, heteroaryl, or heterocycloalcyl, each optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected from halo, CI.4 alkyl, C2.4 alkenyl, C2.4 alkynyl, Ci.4 haloalkyl, halosulfanyl, C,. hydroxyalkyl, CI.4 cyanoalkyl, Cy', CN, NO 2 , OR', SR", C(O)Rb, C(O)NRCRd, C(O)OR", OC(O)Rb, OC(O)NRcRd, MR N*C(O)Rb, NR*C(O)NRRd, NR*C(O)OR", C(=NR)NRCRd, NRcC(=NR)NRRd, S(O)Rb, S(O)NR*Rd, S(O) 2 RR, NS(O) 2 Rb, and S(O) 2 NR*Rd.
21. 24. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein Z is aryl or heteroaryl, each optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected from halo, C.4 alkyl, C2.4 alkenyl, C2.4 alkynyl, C1.4 haloalkyl, halosulfanyl, C.4 hydroxyalkyl, C.4 cyanoalkyl, Cy', CN, NO 2 , OR, SR", C(O)R, C(O)NR*Rd, C(O)OR", OC(O)Rb, OC(O)NR*Rd, NR*Rd, NRCC(O)R, NR"C(O)NR*Rd, N'C(O)OR", C(=NR)NRRd, RC(=NR)NR*CRd, S(O)R, S(O)NRRd, S(O)2R, NRcS(O) 2 R, and S(O)2NR*Rd.
22. 25. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein Z is phenyl or 5- or 6-membered heteroaryl, each optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected from halo, C,.4 alkyl, C24 alkenyl, C2., alkynyl, Ci.4 haloalkyl, halosulfanyl, C.4 hydroxyalkyl, C,.4 cyanoalkyl, Cy', CN, NO 2 , OR', SR', C(O)Rb, C(O)NR*Rd, C(O)OR", OC(O)Rb, OC(O)NRRd, NRcRd, NRC(O)Rb, NR*C(O)NR*Rd, NR*C(O)OR, C(=NRi)NRRd, NR*C(=NR')NRRd, S(O)R, S(O)NRRd, S(O) 2 R, NR*S(0)2R, and S(O),NRRd.
23. 26. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein Z is phenyl optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected from halo, C.4 alkyl, C24 alkenyl, C2.4 alkynyl, C,.4 haloalkyl, halosulfanyl, C,.4 hydroxyalkyl, C1.4 cyanoalkyl, Cy', CN, NO 2 , OR!, SR, C(O)Rb, C(O)NRRd, C(O)OW, OC(O)Rb, OC(O)NRRd, N*Rd, NRC(O)Rb, NRcC(O)NR"Rd, NR*C(O)OR", C(=NR')NRRd, NWC(=NR")NR*Rd, S(O)Rb, S(O)NRRd, S(O) 2 Rb, NR'S(O) 2 Rb, and S(O)2NR*Rd.
24. 27. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein Z is cycloalkyl or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected from halo, C1.4 alkyl, C2.4 alkenyl, C24 alkynyl, C4 haloalkyl, halosulfanyl, C14 hydroxyalkyl, C.4 cyanoalkyl, Cy', CN, NO2, OR", SW, C(O)Rb, C(O)NR*Rd, C(O)OR", OC(O)R, OC(O)NRRd, NRcRd, NRcC(O)Rb, NRcC(O)NRRd, NRC(O)OR, C(=NR)NR*Rd, NR*C(=NR)NR*Rd, S(O)R, S(O)NRRd, S(O) 2 R, N*S(O) 2 Rb, and S(0)2NR*Rd. 278
25. 28. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein Z is C.g alkyl, C 2 . 8 alkenyl, or C2. 8 alkynyl, each optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected from halo, C 1 - alkyl, C2-4 alkenyl, C2 4 alkynyl, C 1 . 4 haloalkyl, halosulfanyl, C hydroxyalkyl, C 3 . 4 cyanoalkyl, Cy', CN, NO 2 , OR", SR", C(O)Rb, C(O)NR*Rd, C(O)OR", OC(O)R , OC(O)NRCRd, NRcRd, NRcC(O)Rb, NRcC(O)NR*Rd, NR"C(O)OR", C(=NR)NRCRd, NR*C(=NRi)NR"Rd, S(O)k, S(O)NRRd', S(O) 2 Rb, NRCS(O)2Rb, and S(O)2NRCRd.
26. 29. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein Z is Cj_& alkyl, C.s alkenyl, C 2 .- alkynyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected from halo, C 1 . 4 alkyl, C 1 4 haloalkyl, halosulfanyl, C 3 . hydroxyalkyl, C I cyanoalkyl, Cy', CN, NO2, ORO, C(O)NR*Rd, C(O)OR", NR*Rd, NRcC(O)R, and S(O)2R.
27. 30. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein Z is C1.8 alkyl, C 2 . 8 alkenyl, C 2 -s alkynyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, each optionally substituted with 1, 2, or 3 substituents selected from halo, C.4 alkyl, CM haloalkyl, halosulfany, C1.4 hydroxyalkyl, C14 cyanoalkyl, Cy', CN, NO 2 , OR, C(O)NRCRd, C(O)OR", NR*Rd, N'C(O)R, and S(O)2R.
28. 31. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein Z is substituted with at least one substituent comprising at least one CN group.
29. 32. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein Z is CI. 8 alkyl, C2-s alkenyl, C2-s alkynyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, each substituted with at least one CN or C 3 . cyanoalkyl and optionally substituted with 1, 2, 3, 4, or 5 further substituents selected from halo, C 4 alkyl, C2-4 alkenyl, C 2 - 4 alkynyl, C,.4 haloalkyl, halosulfanyl, C,.. hydroxyalkyl, C, cyanoalkyl, Cy', CN, NO 2 , OR", SR, C(O)R, C(O)NR*Rd, C(O)OR", OC(O)R, OC(O)NR*Rd, NR*, NRCC(O)Rb, NRcC(O)NRRd, NRCC(O)ORa, S(O)Rb, S(O)NRCRd, S(O)2R, NRcS(O)2Rb, and S(O),NR"Rd.
30. 33. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein the -(Y)b-Z moiety is taken together with i) A2 to which said moiety is attached, ii) R 5 or R6 of either T or V, and iii) the C or N atom to which said R 5 or R 6 of either T or V is attached to form a 4- to 2 0-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring fused to the 5-membered ring formed by A', A 2 , U, T, and V, wherein said 4- to 2 0-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from -(W),-Q. 279
31. 34. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein the -(Y).-Z moiety is taken together with i) A 2 to which said moiety is attached, ii) Rs or R 6 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, cycloalkyl, heteroaryl, or heterocycloalkyl ring fused to the 5-membered ring formed by A', A 2 , U, T, and V, wherein said 4- to 8-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from -(W)m-Q.
32. 35. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein the -(Y).-Z moiety is taken together with i) A2 to which said moiety is attached, ii) R 5 or R 6 of either T or V, and iii) the C or N atom to which said R' 5 or R 6 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', A 2 , U, T, and V, wherein said 6-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring is optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, NO 2 , CI.s alkyl, C 2 -s alkenyl, C 2 . 8 alkynyl, C1. 8 haloalkyl, halosulfanyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl wherein said C,.s alkyl, C 2 .s alkenyl, C 2 .9 alkynyl, C,.s haloalkyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl is optionally substituted by 1, 2 or 3 CN.
33. 36. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein R', R2, R, and R 4 are independently selected from H, halo, and C,. 4 alkyl.
34. 37. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein R', R 2 , R 3 , and R 4 are each H.
35. 38. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein R' is H, halo, or C,.4 alkyl.
36. 39. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein R 5 is H, halo, C,. 4 alkyl, C,. 4 haloalkyl, halosulfanyl, CN, or NR'R'*.
37. 40. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein RW is H.
38. 41. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein R* is H or C1.4 alkyl.
39. 42. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein R 6 is H.
40. 43. The compound of claim 1, or pharmaceutically acceptable salt thereof, having Formula II: 280 (Y)n-Z N-N R/ 3~2 R 3 N N H HI.
41. 44. The compound of claim 1, or pharmaceutically acceptable salt thereof, having Formula Illa or Mb: (Y)n-Z (Y)I--z N-N N-N R1 Ri R2 NCRz R 3 N N R 3 N N HH II1a TIb.
42. 45. The compound of claim 1, or pharmaceutically acceptable salt thereof, having Formula IV: (Y)--Z N-N NN \ N N H IV.
43. 46. The compound of claim I selected from: 3-[3-methyl-1-(1H-pyrrolo[2,3-b]pyridin-4-y)-1H-pyrazol-4-yl]benzonitrile; 3-[3-methyl-I -(1H-pyrrolo[2,3-b]pyridin-4-yl)- H-pyrazol-4-yl]acrylonitrile; 3-[3-methyl-l-(I H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-4-yl]propanenitrile; 4-(4-phenyl-lH-imidazol-I -yl)-lH-pyrrolo[2,3-b]pyridine; [3-methyl-I -(IH-pyrrolo[2,3-b]pyridin-4-yl)-H-pyrazol-4-yl]-piperidin- -yl-methanone; [3-methyl-I -(IH-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-4-ylmethyl]-phenyl-amine; 3-[3-methyl-1-(lH-pyrrolo[2,3-b]pyridin4-yl)-1H-pyrazol-4-yI]-cyclohexanol; 4-[1-(3-methoxy-1-methyl-propyl)-1H-pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridine; 4-[1 -(1 -methyl-3-pyrazol-I -yl-propyl)-1H-pyrazol-4-yl]-1 H-pyrrolo[2,3-b]pyridine; 281 1 -( lH-pyrrolo[2,3-b]pyridin-4-yl)-IH-pyrazole-4-carboxylic acid ethyl ester, 4 -(3-methyl-4-phenyl-pyrazol-I -yl)-1H-pyrrolo[2,3-b~pyridine; 4-(3-phenyl-pyrazol- I -yI)-1 H-pyrrolo[2,3-b]pyridine; 4-(4-bromo-imidazol-I -yl)- 1H-pyrrolo[2,3-b]pyridine; 4 -(4-bromo-3-metbyl-pyrazol-I -yI)-I H-pyrrolo[2,3 .b]pyridine; 34[3-methyl-I -(I H-pyrrolo[2,3-bjpyridin4-yl).. H-pyrazol-4-yl]-benzonitrjle; 4-[3-methyl-l -(I H-pyrrolo[2,3-b~pyridin-yl)-l H-pyrazol-4-yl]-benzonitrile; 4 -[ 4 -( 3 -fluoro-phenyl)-3-methy-pyrazol.1 .yl)-l I1-pyrrolo[2,3-blpyridine; 4 -[ 4 -( 3 ,5-bis-trifluoromethyl-phenyl)3.methyl-pyrazol-I l-yl]-l H-pyrrolo[2,3-b]pyridine; 4 -( 4 -( 3 , 5 -difluoro-phenyl)-3-methyl-pyrazol.l -ylI-lH-pyrrolo[2,3-b]pyridine; {3-[3-methyl-l -(1 H-pyrrolo[2,3-blpyx-idin-4.yI).. H-pyrazol-4-yl]-phenyl} -methanol; 4 -( 3 -methyl-4-pyrimidin-5-y-pyrazol-I. -yl)-I H-pyr-rolo[2,3-bjpyridine; 4-[3-methyl-4-(1 -methyl-I H-indol-5-yI)-pyrazol-I -yII- IH-pyrrolo[2,3-b]pyridine; 4-(3-methyl-4-thiophen-3-yi-pyrazoI -yl)-I11-pyrrolo[2,3 -blpyridine; N.N-dimethyl-44[3-methyl-I. -(1 H-pyrrolo[2,3.b~pyridin-4..yl)ylHl-pyrazol-4-yl]-benzene sulfonamide; N- (443-methyl-i -(1 H-pyrrolo[2,3-bpyridin-4-yl). 1H-pyrazol-4-yl)-pheny} -acetamide; 3-tert-butyl- 1 -(I H-pyrrolo[2,3-b)pyridin4-yl) lH-pyrazole-4-carbonitrile; 4-bromo-lI-(1 H-pyrrolo(2,3-b]pyridin4.ylIy.H-pyrazole-3-carbonitrile; 4-(3-cyanxo-phenyl)- I-(IH-pyrrolo[2,3-b~pyridinA..y).I H-pyrazole-3-carbonitrile; 3-[l -(I H-pyrrolo[2,3-b)pyridin-4-yl).3.trifluoromethy1. 1 H-pyrazol-4-yl]-propan- I-ol; 3-[3-methyl-1 -(1 H-pyrroloE2,3-blpyridin-4-yi)-I H-pyrazoI-4-yl]-prop-2-en-I -ol; 2-[4-bromo- I -(I H-pyrrolo[2,3-blpyridin-4.yly 1H-pyrazol-3-yII-isoindole-l ,3-dione; 4-4(,-iehy-hn -- ety-yao--yl]-1 H-pyrrolc42,3-b]pyridine; 3-[3-amino-1 -(1 H-pyrrolo[2,3-blpyridin-4-yl). 1H-pyrazol-4-yl]-benzonitrile; 3-[3-benzylamino-I -(1 H-pyrrolo[2,3-blpyridin-4.yl). 1H-pyrazol-4-yl]-benzonitrile; N-[4-(3-cyano-phenyl)-I -(I H-pyrrolo[2,3-b]pyridin..4-yl)- 1 H-pyrazol-3-yl]-acetamide; 3-[4-(lI H-pyrrolo[2,3-bjpyridin-4yl).pyrazol.1 -yl]-propan-1 -01; 3-[4-(I H-pyrrolo[2,3-b]pyridin4-y).pyrazol-I -yll-butan-I -ol; 4-[4-(1 H-pyrrolo[2,3 -b~pyridin-4-yl)-pyrazol-1 -yl]-pentancnitrile; 4-[14-(l H-pyrrolo[2,3-b]pyridin-4.yl).pyrazol.l -yl]-pentanoic acid amnide; 4-(I -(3-imidazol-1 -yI- I -metbyl-propyl)-1 H-pyrazol-4-yfl-l H-pyrrolo[2,3-b]pyridine; 4-cyclopentyl-4-[4-( lH-pyrrolo[2,3-b]pyridin.4-y)pyraoIl -yl]-butyronitrile; 4-cyclopentyl-[4-(1 H-pyrrolo[2,3-b]pyridin-4yl)pyazoI -yl]-butyramide; 3-ylpoy--4(Hproo2,-~~iii--l-yao- -yl]-propionitrile; 4-(2-tert-butyl-1 -methyl-I H-imidazol-4-yI)-l 1 -pyrrolo[2,3-b]pyridine; 4-(2-phenyl-l H-imidazol-5.yl)-I H-pyrrolo[2,3-b]pyridine; 282 4-(2-benzyl-1 H-inidazol-5-y1)-1H-pyrrolo[2,3-b~py-idine; 4-[2-(l -phenylethyl>-1 H-imidazol-5-yl)-1 H-pyrrolo[2,3-b]pyridine; 4-(2-phenyl-1 ,3-thiazol-4-yl)-1 H-pyrrolo(2,3-b]pyridine; N-methyl-N-propylA.{1l H-pyrrolo[2,3-b~pyridin-4-yly.1 ,3-tbiazol-2-amine; N-phenyl-4.{l U1-pyrrolo[2,3-blpyridin-4-yl)-1 ,3-thiazol-2-aniine; N-methyl-N-phenyl.4.( 1H-pyrrolo[2,3-blpyridin-4y).1,3-thiazol-2-amine; 4-{2-phenyl-1 ,3-thiazal-5-yl)-1 H-pyrrolo[2.3-blpyrjdine; ethyl 2-methyl-2-[4-(I H-pyrrolo[2,3-b]pyridin-4yl).1H-pyrazol-1 -yi]propanoate; 2-methyl-2-[4-(1 H-pyrrolo[2,3-blpyridin-4yl)..1H-pyrazol-1 -yl~propanoic acid; 2-rnethyl-2-[4-(l H-pyrrolo[2,3-b~pyridin-4y)..1H-pyrazol-1 -yl]propanamide; ethyl 3-methyl..3-[4-(1 H-pyrrolo[2,3-b]pyridin4-yly.1 H-pyrazol-1 -y1]butanoate; 3 -methyl-3-[4-(liH-pynrolof 2,3-b~pyridin-4-yl). 1H-pyrazoi-1 -yflbutan-I -ol; 4-methyl-4-(4-( lf-pyrrolo[2,3-blpyridin-4yl). 1H-pyrazol-1 -yI]pentanenitrile; 4-methyl-4-[4-(IHf-pyrrolo[2,3 -b~pyridin-4-yl) I H-pyrazol-1 -yl]pentanamride; 3-[4-(lH-pyrroIo[2,3-b~pyridil 4yl)-1H-pyrazok 1 -yllbutanenitrile; 3 -4.<II-..pyrrolo(2,3-b~pyidiii4yl).1H-pyrazoJ-I -yl]propanenitrile; 3 -[ 4 -(IH-pyrrolo[2,3-,]pyridin-4y1)-IH-pyrazol-I -yllhexanenitrile; 3 -cyclopentyl-3-[4.( IH yrl(,-~yiin4y)I-yao- -ylllpropanenitrile; 3-cyclohexyI-3-[4-(1 H-pyrrolo[2,3-b]pyridin- 4 -yl)-IH-pyrazol.1 -yllpropanenitrile; 3 -[ 4 -( 711 -pyrrolo[2,3.dlpyrimidin.4yl). H-pyrazol- I -yl]butanenitrile; 3 -cyclopenty1-3.4(7Hpyrlo[2,3d]pyrmidin.4.yl) -I-pyrazol-I -yI]propanenitrile; 2-ehl3[-7-yrl[,-~yiii--l-1-yao- -yl]propanennirile; 3 -( 4 -( 7 Hf-pyrrolo[2,3-dlpyrimidin4-yl)-1 H-pyrazol-I -yllpentaneait-ile; 5-ehl3[-7Hproo23dpyiii- l-H-pyrazol-l -yljhexanenitrile; 3-ylhxl3[-7-yroo23dprmdn4y)1 H-pyrazol-I -yl]propanenitrile; 4 -cyclopropyl-3 -[ 4 -( 7 H-pyrro1o[2,3-d]pyzimidin-4-y)..1 H-pyrazol-I -yi]butanenitrile; 4- (1 -[1 -rnethylbutyl]4 R-pyrazol-4-yl } -lH-pyrrolo[2,3-djpyijmidine; 4 -methyl- 4 -r4-(7H-pyroo23]primidin4yl)-IH-pyrazol-l -yI]pentanenitrile; 3-1 -[ 4 -( 7 H-pyrrolo[2,3-dpyrIimidin-4-.yi)-I H-pyrazol-1 -yl]cyclopropylpropanenitnile; 4 -[ 4 -( 7 H-pyrroo2,3d]pyrimidinyl)1R.pyao. 1 -yllpentanemitrile; 3 -methyI-3-[4-(7H-pyroo[23-d]pyrimidin4yl)l H-pyrazol-1 -yl~butanenitrile; 3 -thyl - 3 -4-(7BHpyrrolo[2,3d]pyriidin-4.ylI H-pyrazol-I -yl]pentanenitrile; l-[ 4 .( 7 H-pyrroo[2,3-dpyimidin..yI).. H-pyrazol- I -yIlcyclopropylacetonitrile; 4-1 -[Kpyrrolidin-2-ylmethy]] lH-pyrazol-4-y1-7H..pyrrolo[2,3-.f]pyrimidine; 4-(l -[I -(methylsulfony)pyrroidin2y]mtyl..1H-pyrazol-4-72y1)47H-pyrrolo[2,3 4 j]. pyrimidine; ethyl 2 -metlhyl-2-[4-(7H-pyrrolo[2,3-d]pyrimidii-4.yl). I 1--pyrazol- 1 -yflpropanoate; 283 3 -cyClopenty1-3-(4-(7H-pyrrolo[2,3..d]pyrijmidin-4yly.. H-pyrazol- I -yl]acrylonit-ile; 3 -cyclopentylidene34-(7H-pyrrolo[2,3-d]pyrimidin4-yljy H-pyrazol- I -yI]propanenitrile; 3 -methyl[5-(7H-pyrrolo[2,3.d~pyrimidin-4y).1 , 3 -thiazol- 2 -yllaniinopropanenitrile; 3 -[S-(7f1-pyrrolo[2,3 -dlpynimidin-4-yl)-1 , 3 -thiazol-2-yllhexanenitrile; 3 -cyclopentyl-3-[5-(7Hpyrrolo[2,3-d]pyrimidin4y).1, 3 -thiazol-2-yI]propanenitrie; 5-ehl3(-7Hproo23dpyiii- l-, 3 -thiazol-2.yI]hexanenitrile; 3 -i2yrdif-3-yl-3-[5-(7H-pyrroo2,3-d)pyrmidin-4yl1 3 -hiazol-2-yI]propanenitrile; 3-Sbooyii--i)3[-7-yr [,3dprmdn-l-, 3 -thiazol-2-yl]propane nitrile; S-(2-.cyano-I -[ 5 -( 7 H-pyrrolo[2,3-d]pyrimidin-4-yl)-.. 3 -thiazol-2-yflethyl)nicotinonitrile; 3 -[ 5 -( 7 H-pyzrolo[2,3-d]pyrimidin-4.yl).1 ,3-thiazol-2-yljbutanent-jle; 2-[ 5 -( 7 H-pyrroo2,3.d]pyrimdiA..y).1 , 3 -thiazol-2-yllheptanenitrile; 3 -[ 5 -( 7 H-pyrrolo[2,3-d]pyrimjiiny).1, 3 -thiazol.2-y]pentanedinitrile; 3 -cyiclopentyl - 3 -[ 5 -( 7 H-pyrrolo[2,3-djpyrimidna-4y11, 3 -oxazol-2-yI]propanenitrile; 3 -[5-( 7 H-pyrrolo[2,3-djpyrimidin4yl).1 , 3 -oxazoI-2-yI]hexanenitrile; 5-mtyti)3(-7-yroo23dprmdn4y I H-pyrazol.1 -yl]pentanenitrile; 5-mtyslon -- 4(H-yrl[,-dprmdn l{'-pyrazol-1 -yl]-pentanenitrile; 4,,-rfur--4(Hproo[,-~yiii--l-yao- -yI]-buty-onitrfle; 5,-iehl3[-7-yrl[,-~yiii--l-yao- -y11-hexanenitrile; 4-[ I-(2-methanesulfonyl-ethyl).I H-pyrazoI-4-yl]-7H.pyrroo[23-]pyfiiidine; 5,,-rfur--4(Hproo23phii--l-yao- -yI]-pentanernitrile; 3-(2-cyano-I -[ 4 -( 7 H-pyrrolo[2,3.djpyrimidinA..yI).1H-pyrazol- I -yI]ethyl)..uyclopentane. carbonitrile; 3 -[ 3 -(hydroxymnethyl)cycopenty]3[4(7Hpyrrolo[2,3-d)pyimidin4yi)-. H-pyrazol-I -yl] propanenitrile; 1 -(1 H-pyrrolo[2,3blpyridi-4..yl)4lH.4ndazole; 3-[3-(] H-pyrrolo[2,3 -b~pyridin-4-y)-1 , 2 , 4 -oxadiazol-S-yI]benzonitrile; 4-(l -benzothien.2-yi)- I H-pyrrolo[2,3-b]pyridine; 4-fluoro-2-(1 -(I H-pyrrolo[2,3bpyridin.4.yl)- H-pyrazol-3 -yIlphenol; 4 - 3 -[ 3 -(trifluorornethyl)phenyl].1 H-pyrazol-I -yl-IHI-pyrrolo[2,3-b]pyridine; 3-f1 -(1 H-pyrrolo[2,3-b]pyridin-4.yl)4 H-pyrazol-3-yl]benzonitrile; 3-[l -(1 H-pyrroo2,3-bjpridin-4-yI)4 H-pyrazol-4-ybenzonit-jle; 2-[l1 -(1 H-pyrroo[2,3bpyrdin4y)Hpzo14yi] 1 ,3-benzoxazole; cyclohexyl[ 1 -(1 H-pyrrolo[23.blpyridin4ylyl H-pyrazol-4-yI]methanol; 284 4-[4-(l -phenylviny1)-1H-pyrazol-I -yl]-1 I{-pyrrolo(2,3-b]pyridine; 4-(]I -benzyl-1 H-pyrazol..4-yI)-1 H-pyrrolo[2,3-b]pyiine; 4-(1 -(2-naphthylniethyl)-l H-pyrazol-4-yl]- 1 H-pyrrolo[2,3-b)pyzidine 4-(lI -phenyl-1 H-pyrazol-4-yl)-l I{-pyrrolo[2,3-b]pyridine; 1-[4-( I H-pyrrolo[2,3-b~pyridin-4.yl).1 H-pyrazol-1 -yl]benzonitrile; 4- (1 -[1 -inethylbutyl]- I H-pyrazol-4.yl} -1 H-pyrrolo[2,3-blpyridine; 4-methyl-3-[4-(] H-pyrrolo[2,3-b]pyx.idin4yI)-l H-pyrazol- 1 -yl]benzonitrile; 2-(l IH-pyrroo2,3b]pyridiny)-45,6,7tetraydro..2H-indazole; 5-nitro-2-(1 ll-pyrrolo2,3-bjpyridin4.y)2H..jndazole; 6-nitro-2-(l H-pyrrolo(2,3-bjpyridin4yi).2H-i.ndazoje; 3-[l -(1 H-pyrrolo[2,3-b]pyriin-y)-l H-iinidazo1-4-y1]benzonitrile; 4 -[ 4 -(3-methoxyphenyl)..i f-imidazol-1 -yl]-l H-pyrrolo[2,3-bjpyridine; 4 -(5-phenyl-2-thienyl) I H-pyrrolo[2,3-b]pyridine; 4 -[3-(4-fluorophenyl)-l H-pyrazol- 1 -yl]-1 H-pyrrolo[2,3-b~pyridine; 4 -[3-(3-nitrophenyl)-l H-pyrazol. Il-y]-l H-pyrralo[2,3-blpyridine; 4 -[3-(4-chlorophenyl)-I-1-pyrazol-1 -yI]-1 H-pyrrolo[2,3-blpyridine; 4 -[3-(4-niethoxyphenyl)-1 H-pyrazol-I -yl]-I H-pyrrolo[2,3-bjpyridine; 4-[ 1 -( lH-pyrrolo[2,3-blpyridin-4.yl)-I H-pyrazol-3-yl)bepzonitrile; 3-f1 -( IH-pyrrolo[2,3-b]pyridinA..y). li-pyrazol-3-yI]aniline; 4 -[3-(3-methoxyphenyl)- 1 H-pyrazol-I -yI]-I H-pyrrolo[2,3-bjpyridine; (3-[l1 -( li-pyrrolo[2,3-b~pyridin-4-yl)-l H-pyrazoi-3-yl]pbenoxy) acetonitrile; 2-cyano-N- {3-[l -(1 Il-pyrrolo[2,3-bjpyridin4-yl)-l H-pyrazol-3-yljphenyl} acetamide; 3-cyano-N- {3-[I -(IE*-pyrrolo[2,3..blpyridiuA..y).. H-pyrazol-3-y1]phenyI~benzarnide; 4 -[ 4 -(4-nitrophenyl)-IH-pyrazol.1 -yl]-l H-pyrrolo[2,3-b]pyridine; 441l -(I H-pyrrolo[2,3-blpyridin-4y). H-pyrazol-4-yl~aniline; 4-(4-phenyl-1 H-pyrazol-I -yI)-lH-pyrrolo[2,3-b~pyxidine; 4-(4-pyridin-3-yl-1 H-pyrazol-1 yI)-IH-pyrrolo[2,3-b]pyrjdjne; 2-[l 1-C H-pyrrolo(2,3-b~pyridin-4.ylyI H-pyrazo1A4-y]benzontr.ile; {2-[ 1-(11 proo23bpyii--l-Hpyao y~hnlacetonitrile; 4 -[ 4 -( 3 -nitrophenyl)-1H-pyrazol.1 -yI]- IH-pyrrolo[2,3-blpyridine; 3-[l (Hproo23bprn4y)I H-yao--laiie f{3-[l1 -(I H-pyrrolo[2,3.b~pyrdin4y)-. H--pyrazol-4-yi]phenyl} acetonitrile; 4-[lI -(I J{.pyrrolo[2,3-b]pyridin-4.y).j H-pyrazol-4-yl]benzonitrile; 3-[ 1 -( lHipyrrolo[2,3-blpyridin-4-yl..1 H-pyrazol-4-yl]phenol; methyl 3-fl -(1 H-pyrrolo[2,3-bjpyridin-4yl).I H-pyrazo1-4-yl]benzoate; {4-[ 1-( IH-pyrrao[o2,3-b~pyidin.4.ylI)H-pyrazol-4-yJlpheny} acetonitrile; 2-cyano-N- {3-[l1-(1 H-pyrrolo[2,3-b]pyridin.4-yl)1 H-pyrazol-4-yI]phenyl} acetaniide; 285 4-C 1 -(1 H-pyrrolo[2,3-blpyridin-4yl)-1 H-pyrazat-4-yl]phenol; 5-[ 1 -(1 H-py rolo[2,3-b]py-idin.4-yl)-I H-pyrazol-4-yl]nicotinonitrile; {4-[l -(IH-pyrrolo(2,3-b]pyridin-yl)-I H-pyrazol-4-yIlphenoxy} acetonitrile; 4-(4-cyclohex- 1 -en-i -yl-lH-pyrazol-I -yI)-l H-pyrrolo[2,3-b]pyridine; 4-[4-(4-naethoxyphenyl).I H-pyrazol-1 -yl]-lH-pyrrolo[2,3-bjpyridine; 4 -(4-pyrimidin-4-yl. IH-pyrazol- I -yI)-I H-pyrrolo[2,3-bjpyridine; 3- {hydroxy[ 1 -(1 H-pyrrolo[2,3-b]pyridin-4yi)HpyrazoA..yl]methyl} benzonitrile; 4 -(4-(cyclohex-l -en-I -ylmethyl)-l H-pyrazol-1 -yl]-lH-pyrrolo[2,3-b]pyridine; 441 -(3,5-dimethoxybenzyl)-l H-pyrazol-4-yl] -1 H-pyrrolo[2,3-b]pyridine; 4-[1 -(I -phenylethyl)-l H-pyrazol-4-yl]-1 H-pyrrolo[2,3-b~pyridine; 4-[l1 -(cyclohexylmethyl).1H-pyrazol-4-yl]- lH-pyrrolo[2,3-bjpyridine; 3-[f[4-(1 H-pyrroo[2,3bpyridin4y)Hpram1-yl]methyl~benzonitrile; 2- ([4-(1 H-pyrrola[2,3-blpyridin-4-ylI).1H-pyrazol-I -yI]methyl }benzonitrile; 4- ((4-( lH-pyrrolo[23-b]pyx-idin-4yly. 1H-pyrazol-1 -yl]methyl} benzonitrile; I -phenyl-2-[4-( IH-pyrrolo[2,3-b]pyridin-4y).1H-pyrazol- 1-yl]ethanone; 3,3 -dimethyl- I -[4-( lH-pyrrolo[2,3-blpyridin.4-y1).I H-pyrazol- 1 -yl~butan-2-one; 4-{l1 -[( 5 -methylisoxazol-3..yl)methyl] -1H-pyrazol-4-yl }-1 J-pyrrolo[2,3-b]pyridine; 4-[I-(tetrahydro-2H-pyran-2-ylmethy).1H-pyrazol-4-yl]-I H-pyrrolo[2,3-b]pyridine; 4-( 1 -cyclohex-2-en- 1 -yI-I Hpyrzol4yI)Hpyrrolo[23.bpyridne; 4-[l1 -(1 -ethylpropy1)-lH-pyrazolA..yI1H-pyrrolo[2,3-blpyjciine; 4 -(l-cyclohexy-1H-pyrazolA..yiy..I H-pyrrolo[2,3-b]pyridine; 2-[4-( 1H-pyrrolo[2,3-bjpyridin-4.y).1 H-pyrazol-1 -yljjacetamide; 4'- {[4-( Il-pyrrolo[2,3-b]pyridin-4.yl). 1H-pyrazol-1 -yllmethyl} peyl2crontie 4-[ I-(2-nitrobenzyl)- 1H-pyrazol-4-yl]- IH.-pyrrolo[2,3-b]pyridine; 4- { -[ 2 , 6 -dichloro-4-(trifluoromethyl)phenyl].1H-pyrazol-4-yl) - lH-pyrrolo[2,3-b]pyridine; 4-[ I-(3-nitrobenzyl)- IH-pyrazol-4-yl]- 1H-pyrrolo[2,3-b]pyrjdine; 4-[ 1-(2-broruobenzylyl H-pyrazol-4-yl].1H-pyrrolo[2,3-bjpyridine; N-phenyl-2-[4-( IH-pyrrola[2,3-b]pyridin4y)lHpyraz 0 o..I -yl]propanamide; 4- { 1 [ 3 -trifluoronlethoxy)bnzyl].1H-pyrazol-4-yI) -1 H-pyrrolo[2,3-bpyridine; 4-{ I-[ 2 -fluoro-5-(trifluorornethyI)benyl]1H-pyrazol-4-ylI} H-pyrrolo[2,3-b]pyridine; 4-{ 1-[3 -(trifluoromethyl)benzylpl H-pyrazol-4-yi) -1 H-pyrrolo[2,3-b~pyridine; 4-[lI -(pyridin-3 -ylmethyl)-1 H.-pyrazol-4-yl]-1 H-pyrrolo[2,3-b~pyridine; 4- (1 -[I -phenylbuty1]-IlipyrazoI-4y} - IH-pyrrolo[2,3-blpyridine; I -pbenyl-2-[4( H-pyrrolo[2,3-b]pyridin-4yl).1H-pyrazol-I -yl]propan-I -one; 4-I I-( 2 , 6 -dichlorobenzyil -H-pyrazolA4-yl] -lH-pyrrolo[2,3-b]pyridine; 4-41 -(2,6-dimethylphenyl)-. H-pyrazol-4-yI]- I H-pyrrolo[2,3..b]pyri dine; 2-[4-(l1H-pyrrolol2,3.b]pyridinA..yl).1IH-pyrazol..! -yfl-5-(tifluoromethy)-beaonitile; 286 4-[ I-(4-bromo-3,5,6-trifluoropyridin-2-y)-1 przl4yi-Hproo2,-~yiie 4-[ 1-(cyclopropylmethyl)-1 H-pyrazol-4-yI)-IH-pyrrolo[2,3-b]pyridine; 4-[1I-(2,5 -dimethylphenyl)- 1 I--pyrazol-4-yl]J-I H-pyrroio(2,3-b]pyri dine; 4-[1 -(2-methylphenyl)-1 H-pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridine; 4-[1 -(2-methoxypbenyl)- IHI-pyrazol-4-y]-1H-pyrrolo[2,3-b)pyridine; 3- (1-[4-(1 H-pyrrolo[2,3-b]pyridin-4-yl)- I-pyrazol-1 -yl]ethyl~benzonitri le; 3-chloro-4-[4-( 1H-pyrrolo[2,3-b]pyridin-4.yl). IH-pyrazol-1 -yl]benzonit-ile; 4-[1 -(1 -cyclohexylethyl)-1 H-pyrazol-4-yl)I 1H-pyrrolo[2,3-b]pyridine; 4-fluoro-2-[4{1 H-pyr-rolo[2,3-b]pyridin-4-y)-1 H-pyrazol-l -yl]benzonitrfle; 2-fluoro-4-[4-(1 H-pyrrolo[2,3-b~pyridin.4-y).1 -pyrazol-1I-yI]benzonitrile; 3-fluoro-4-[4-( I H-pyrrolo[2,3-b~pyridi..4-yI)-lH-pyrazol.1 -yl~benzonitrile; 4-(1- {I -[ 3 -{trifluorornethyl)phenyljethyl} -I H-pyrazo] -4-yl)-1 H-pyrrolo[2,3-bjpyridine; 4-( 1-(3 ,5-dimethylphenyl)-l H-pyrazol-4-yl]-I H-pyrrolo[2,3-bjpyridine; 4-[4-(1 H-pyrrolo[2,3-,Ipyridin-4.y)..1 H-pyrazol-I -yI~benzonitrile; {44.(l If-pyrroo[2,3-b]pyridn-4-yI).. H-pyrazol- I -yl)phenyl~acetonitrile; 4-[ 1 -(I -methylhexyl)-l H-pyrazol-4-yl].1 I--pyrrolo[2,3-b]pyridine; 4 -(1 -see-butyl-1 H-pyrazol-4yl).1 H-pyrrolo[2,3-b]pyridine; 4-[1 -(1 -phenylpropyl)-1 H-pyrazo14.yl].1U-pyrroo[23b]pyidine; 4-(1- (1 -[4-{niethylsulfonyl)phenyl]ethyl} -I H-pyrazol-4 -yl)-I H-pyrrolo[2,3-b]pyridine; 4- {1-[l-(3-fluoro-4-methoxyphenyl)ethyl]- 1 H-pyrazol-4-yl) -1I H-pyrrolo[2,3-b]pyridine; 4-( 1- {11-[2-(trifluoromethyl)phenyl]ethyl) -1 H-pyrazol-4-yI)-1 H-pyrrolo[2,3-b]pyridine; 4-( 1- (1 -[3,5-bis(trifluoromethyl)phenyljetby }-1 H-pyrazol-4-yi)4 H-pyrrolo[2,3-b]pyridine; 4- { 1-[4-( I H-pyrrolo[2,3-b]pyridin-4-yI)- 1H-pyrazol-I -yI]ethyl} benzonitrile; 4- { I -[ 4 -nitro- 2 -(trifluoromethy1)phenyl]-IHwpyrazo1A4-y -1 H-pyrrolol2,3-blpyridine; 3-methyl-4-[4-(l H-pyrrolo[2,3-b~pyridin-4-yl)-I. H-pyrazol-1 -yI]benzonit-ile; 4- I -(2-chlorophenyl)-1 H-pyrazol-4-yI]-1 H-pyrrolo[2,3-b]pyridine;.I 3-bromo-4-[4-( IH-pyrrolo[2,3-b]pyridin-4-yl H1-pyrazol-1 -yI]benzonit-ile; ethyl 4-[4-(1 H-pyrrolo[2,3-b]pyridin-4-yl)- lH-pyrazol-1I-yl)benzoate; 4- { I-( 2 -chloro-6-nitro-4-(trifluoromethyl)phenylp.I H-pyrazol-4-yl }-1 H-pyrrolo[2,3-b] pyridine; 4-(1 - { -[ 4 -(trifluoromethyl)phenyl]ethyl) -I H-pyrazol-4-yl)-l1H-pyrrolo[2,3 -blpyridine; 4-[ 1-(2,3-dihydro-I ll-inden-1 -yl)-l H-pyrazoI-4-yI]-IHI-pyrrolo[2,3-b~pyridine; 4-[l1-(1 . 2 , 3 , 4 -tetrahydronaphthalen- l-yI)-I H-pyrazol-4-yI]-1 H-pyri-olo[2,3-b]pyridine; 4-( 1- {I [ 2 -cbloro-5-(trifluoromethyl)phenyl]ethit-I H-pyrazo1-4-yI)-1 H-pyrrolo[2,3-b] pyridine; 4- {I-[l -( 2 , 4 -dichloro-5-fluorophenyl)ethyl]. 1H-pyrazol-4-ylI} H-pyrrolo[2,3-blpyridine; 4-fl -(1 -cyclopentylethyl)-l H-pyrazol-4-yl]- 1H-pyrrolo[2,3-b~pyridine; 287 4-fl -(I -methyl-3-phcnylpropyl)-1I{-pyrazol.4-yl]- 1 H-pyrrolo[2,3-blpyridine; 4-[1] -(1 -cyclobutylethyl)- H.-pyrazol- 4 .yl]-1H-pyrrolof2,3-blpyridine; (2-[4-(l H-pyrrolo[2,3-b]pyridin..4y1)- H-pyrazol- 1 -y]]-5-(trifluorornethyl)phenyl] acetonitrile; [5-[4-(l FI-pyrrolo[2,3-b]pyridin4yl)-l H-pyrazol-1 -yl]- 2 -(trifluoromethyl)phenyl] acetonitrile; 4- {(1 -[pent-3-en-l -yl]-1 H-pyrazol-4-yl } -1H-pyrrolo[2,3-blpyridine; 2 -[ 4 :-(IH-pyrrolo[2,3-bpyridin..y).H.pyrazol.1 -yl]propanenitrile; 4- { I -[4-phenylbut-3-en-I -yl]-IH-pyrazol-4-yl } -1 H-pyxrolo[2,3-b~pyridine; 6 -[ 4 -H-pyrroo[2,3bpyridin4.yIH.pyrazo..I -yl]hexanenitrile; ethyl 3-amino-2- {f4-(lIH-pyrrolo[2,3-blpyridin-4..yl) 1H-pyrazol-1 -yl]methyl)}-propanoate; ethyl 2-f4-(I H-pyrrolo[2,3-b)pyridin-4-yl).1I{-pyrazol-1 -yl]propanoate; 4-fl -(1-propylbutyl)- IH-pyrazol-4-y.- I H-pyrrolof2,3.b]pyridine; 4-[4-( 1H-pyrrolo[2,3-bpyridin-4.yly..1H-pyrazol-1 -yl]butanenitrile; [3-chloro-2.[4-(lil-pyrrolof 2,3-b]pyridin.4ylI).1H-pyrazol-I -yl]-5-(trifluorornethyl)phenyl.. acetonitrile; 5-[4.( IH-pyrrolo2,3-3]pyridin4.y).1 H-pyrazol-l -yII- 2 -(trifluoromethyl)-benonitjile; 4-f{ 1 - 2 -chloro-4-(trifluoromethyl)phenyl].l H-pyrazol-4-yl) -1H-pyrrolo[2,3-b]pyridine; 4-[4-(l1 H-pyrrolo[2,3-blpy-idin-4y)-. H-pyrazol-l -yI]- 2 -(trifluoromethyl)-benzonitrile; 2-[4-(l H-pyrrolo(2,3-bjpyridin-4.yl)-. H-pyrazol-l -yllbenzanitrile; 3-chloro-2-[4-(] H-pyrrolof2,3-b]pyridin-4-y1)-1 H-pyrazol-l -yljbenzonitrile; 4-amino-5,6difluoro-2f[4-( IH-pyrrolo[2,3-b~pyridin-4yl)-I H-pyrazol-1 -yl]isophthalonitrile; I- { f4-(I H-pyrrolo[2,3-b]pyridin4y)-. H-pyrazol-1 -yI]methyl } -cyclopropanecarbonitri le; 5 -[ 4 -(lH-pyrrolo2,3-b]pyridin4yI)Hpraoll -yllhexanenitrile; 2,2-dimethyl-6-f4-( I H-pyrrolo[2,3.-b]pyridin4-yl)-1 H-pyrazol- 1 -yI]hexanenitrile; 4-[l -(1 -ethyl-2-methylpropyl)-.i H-pyrazol-4-yl] -1 H-pyrrolo[2,3-b]pyridine; 5-bromo-2-[4-(l H-pyrrolo[2,3-bjpyridin-4.yl).I H-pyrazol-I -yl]benzonitrile; 3-[4-( 1H-pyrrolo[2,3 -blpyridinA-yl)-1 H-pyrazol-I -yl]A4-(trifluoromethyl)-benzonitrile; 2-[4-(]I H-pyrrolo[2,3-b~pyridin4y)..1 H-pyrazol-l -yI)-3 -(trifluoromethyl).-benzonitrile; 3-[4-(l H-pyrrolo[2,3 -b]pyridin-4.yI)- I H-pyrazol.1 -yl]- 4 -(trifluoromethy])benzamide, 3-(4-( I H-pyrrolo[2,3-b]pyridin-4yl)-1 H-pyrazol-l -yl]cyclohexanone; 2-[4-(] H-pyrrolo[2,3.-b]pyxidin4yI)-l H-pyrazol-1 -yl)cyclohexanol; 4-( 1-({[I -(methylsulfonyl)piperidin4..yl~methyl) -1 H-pyrazol-4-yl)-l l1-pyrrolo[2,3-b] pyridine; 2-f4-(1 H-pyrrolo[2,3-bpyridin4.y)-. H-pyrazol-1 -yl]cyclohexanecarbonit-ile 4- { 1-[2-(trifluorornethy])phenyl]]1H-pyrazol.4-yi} -1 H-pyrrolo[2,3-b~pyidine; 4-fl -(2,6-dichlorophenyl).1H-pyrazol-4..yI].I H-pyrrolo[2,3-b]pyridine; 288 (4- { 4.(l H-pyrrolo[2,3-b]pyridin.4-yl)-IH-pyrazo-1 -yl]methyl) cyclohexyl)methanol; 4-f 1 -(tetrahydrofuran-2-yl methyl)-] H-pyrazol-4-yi]-1 H-pyrrolof 2,3-b] pyridine; 4-f 1 -(1 -cyclopentylpropyl)- I H-pyrazol-4-yl]-l H-pyrrolof2,3-b]pyridine; 4-fl -(tetrahydrofuran-3 -ylmethyl)-1 H-pyrazol-4-yl]-1 H-pyrrolo[2,3-b]pyridine; 2-chioro-3-[4.{l H-pyrrolof2,3-b]pyridin-4-yl)- IH-pyrazol- 1 -yl]benzonitrile; 3-f 4-( IH-pyrrolo[2,3-bjpyridinA..yI)- H-pyrazol- 1 -yl]-3-(1I, 3 -thiazol-5-yl)propanenitrile; 1 -benzyl-4- {f4-(l H-pyrrolof 2,3-b]pyridin-4-yl)- I H-pyrazol-1 -yllmethyl) pyrrolidin-2-one; 3 -(1 -methyl-i H-imidazol-S-yl)-3-[44 I H-pyrrolo[2,3-b]pyridin-4-yl).l H-pyrazol-1 -yl] propanenitrile; 3 4[ 4 -(lH-pyrrolo[2,3-b]pyridinA..yl).1 H-pyrazol- I -yll- 3 -( 3 -thienyl)propanenitrile; f 1-[4.(l 1 f-pyrrolo[2,3-blpyridin-4yl..1H-pyrazol-1 -yllcyclopentyl) acetonitrile; 4-chloro-3-[4-(l H-pyrrolo[2,3-b]pyridin-4.ylI).1H-pyrazol-l -yl)benzonitrile; 4-[4-(l H-pyrrolo[2,3-b]pyridin4..yl)..t H-pyrazol- I -yl]phthalonitrile; 3-methyl-4-f4-( 1 H-pyrrolo[2,3-blpyiidin4-yl)..l H-pyrazol-1 -yl]benzaldehyde; 1 [-(2 -methyl-4-nitrophenyl). IH-pyrazol-4-yl]-1 H-pyr-rolo[2,3-b]pyridine; 3 -f4-(IH-pyrrolo[2,3-b]pyridin4-yl).l H-pyrazol- 1 -yI]cyclopentanone; 4-fl -(3-fUrylmethyl)-I H-yao4y]I-yrl(,-lyiie 4-fl -( 2 -furylmethy)l H-pyrazo4y)lHpyrrolof23b]pyidine; 3- {2-cyano-I1-(4-( 1 H-pyrrolof2,3-blpyrdinA...yI1H-pyrazol -l -yI]ethyl )benzonitrile; { 3-methyl-4-f 4-( I H-pyrrolo[2,3-blpyi-idin-4y).I fl-pyrazol- I -yI]phenyl} methanol; 4-methyl-4-[4-(l H-pyrrolo[2,3-b]pyridin.4-y). H-pyrazol-I -yl]pentan-2-one; 3 -( I -benzofiiran-2-yI)-3-[4-( IH-pyrrolo[2,3-b]pyridin4-yi)-IH-pyrazol-l -yl]propanenitrile; 3-(3-fuwyl)-3-f4-( IH-pyrrolo(2,3-b~pyridin.4.yI).H-pyrazol-1 -yl]propanenitrile; { 3-methyl-4-f4-( 1H-pyrrolo[2,3-b]pyridin-4yi).I H-pyrazol-1 -yl]phenyl} acetonitrile; 4 -methy]-3-[4-(7H-pyolof2,3-d]pyimidin.4-y)-I H-pyrazol-1 -yl]benzonitrile; 4-fl -(1 -cyclopentylpropyl)-l H-yao--i-Hprr~[,-~yiii { I 4 4 -(7Hi-pyrrolo[2,3-d]pyrimidin-4.y)-. H-pyrazol-1 -yijcyclopentyl} acetonitrile; 3- {(2-cyano -1I-[4-(7H-pyrrolo[2,3-d]py-imidinA..yl)-I H-pyrazol-l -yl]ethyl} benzonitrile; 3-[ 4 -(7H-pyrrolo[2,3-d~pyrimidin4-yl)- 1 -pyrazol-1 -yl)- 3 -(3-thienyl)propanenitrile; 4 -chloro-3-[4-(7H-pyrrolof2,3dpyrimidin.4.yl).I H-pyrazol-1I-yI]benzonitrilc; 3 -(3-fuiryl)- 3 -f4-(7H-pyrrolof2,3.d]pyrimidinA..yl).I H-pyrazol-l -yl]propanenitrile; 3 -[4-( 7 H-pyrrolo[2,3-d]pyrimidina-4ylI)H-pyrazol-1 -yI]pentanedinitrile; 3-fl -[4-(7H-pyrrolo [ 2 , 3 -d]pyrimidin.4.yl).1H-pyrazol- I -yl]cyclopentyl} -propanenitrile; (I -[ 4 -( 711 -pyrrolo[2,3-d]pyrirmidina-..yl)-I H-pyrazol-I -yllcyclohexyl) acetonitrile; { 3 -methyl-4-[4-(7Hpyrroo[23.d~pyimidin-4-yl)l H-pyrazol-l -yl]phenyl} methanol; 3 -pyidil-4-yl-3-[4-(7H-pyrrolo[23d]pyzimidin-4.y1)- H-pyrazol-l -yI]propanenitrile; 3 pyxidifl- 3 -YI-3-[4-(7H-pyrrolo[2,3Adpyrimidin-4-yl) I H-pyrazol- I -yllpropanenitrile; 289 3 -[ 4 -(methylthio)pheny]3[4-(7H-pyrrolo[2,3-dlpyrjidin-4-yy. 1 H-pyrazol-I -YI]propane nitrile; 3-3mtoyhnl--4(Hproo23dprmdn-l- H-pYrazol-1 -YIlpropanenitrile; 3 -( 4 -methoxyphenyl)-3[4(7H-pyrroo[23]pyrimidin-4yl).l H-pyrazol- 1 -yllpropanenitrile; { 3 -methyl-4-[4.{7H-pyrrolo[2,3.d]pyrimidin.4.yl)1H-pyrazol-I -yl]phenyl} acetonitrile; 3-4(ehlufnlpey]3[-7-yrl[,-jyiii--l- H-pyrazol-I -yl) propanenitrile; 3-4(ehlufnlpeyl3[-7-yrl[,-~yiii--l-Hprzl -yIlj pro panenitrile; 3 -[ 3 -(cyanomethoxy)pheny3[47Hproo23d~pymidin4yl)l IH-pyrazol-I -yl] propaneljtrjle; 3 -( 6 chloropyidin3y)3[4(7H-pyoo[2,3d]pimidin4yIyIH-pyrazol-I -yl] propanenitrile; 5- {2-cyano-I -(4-(7H-pyrrolo[2,3-d~py-imidin4yl)-. H-pyrazol-1 -yl]ethyl} pyridine-2 carbonitrile; 3-35dmtyioao4-l--4(Hproo2,- yiii--i-H-pyrazo1-1 -y) propanenitrile; 3 -[ 4 -( 7 H-pyrrolo[2,3-d]pyrimidinA..yl).I H-pyrazol- I-yl]- 3 -[ 6 -(trifluorolnethyl)pyridin-3.y). propanenitrile; 3-(6-methoxypyridin3yl)-3 - 4 -(7H-pyrrobo[2,3-d]pyriidin-4-yl-I-pyrazol-I -yljpropane nitrile; 3-pyridin-2 -yl- 3 -[4-(7H-pyrrolo[2,3-d~pyrimidin-4.yl)-I H-pyrazol-1 -yl]propanenitrile; 3 -(6-broropyridin2yi)34.(7H-pyr. 0 lo[ 2 , 3 -djpyrimidin-4-yi)- 1 H-pyrazol-1I-yl]propane niti-ile; 6- {2-cyano-1 -[4-(7H-pyrrolo[2,3 -d]pyrimidin-4-yl)-I. H-pyrazol-1 -yllethyl} pyridine-2 carbonitrile; 4 -[ 4 -(7H-pyrrolo[2,3-dpyrimidin4-yl)I-I-pyrazol- 1 -yllheptanedinitrile; 3-(5 .bromopyridin3.Yl)3[4(Hprolo2,3d]pyrimidin-4yI).lH-pyrazol- 1-yI]propane nitrule; 4 -( 4 -( 7 H-pyrrolo[2,3-d]pyrimidin.4.yl). I H-pyrazol.1 -yllheptanedinitrile; 5- 12-cyano- Il-[ 4 -( 7 H-pyrrolo[2,3-d]pyrimidin-4yly.I I1-pyrazol-I -yl]ethyl} nicotinonitrile; 3 -(2-methoxypyridim.3yl.3 -[ 4 -( 7 H-pyrrolo[2,3-d]pyrimidin.4yl).1 F-pyrazol-I -yl]propane nitrile; 3 -[ 4 -(cyanoiethoxy)phen y1)33[4-(7pyroo 2 3 -d)p idi-l)-I H-pyrazol-i -yI] propanenitrile; 3 -[ 2 (cyananmetoxy)pheny3[4(7Hpyroo[23dIPyimdi4yl)-IH-pyrazol.1 -yI] propanenitrile; 290 3-(3,5dboohny)3[-7-yroo23dpyiii y)I H-pyrazol-1 -Yllpropane ni trie; 5 -{2-cyano- I -( 4 -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-I H-pyrazol-I -yl]ethyl} isophtbalonitrile; 3 -[ 6 -(dimethylamino)pyrdin2yfl34(7Hpyro[2,3-d]pyrimidin- 4 -yj)- H-pyrazol-.I -yIJ propanenitrile; 3 -( 4 -bromo.2-thienyl).3.{4.{7H..pyrrolo[2,3.,Jpyrimidjn-4.yi).l H-pyrazol-I -yI]propane 5- {2-eyano-I -[ 4 -(7H-pyrrolo[2,3..dlpyimidin.4yl)-I. ll-pyrazol-1 -yllethyl) thiophene-3 carbonitrile; 3-(5-bromo-2-fluorophenyl).3 -[ 4 -( 7 H-pyrrolo[2,3.d]pyrimidin.4yl).. 1 -pyrazol- 1 -yI] propanenitrile; 3-(3 -nitrophenyl)..3.[4.(]pyrrolo[2,3.d~pyimidin.4yly.. H--pyrazol-1 -yI]propanenitrile; 3-5boo2mtoyhnl--4(7-yr (,-~yiii--i-H-pyrazol-l -yl] propanenitrile; 3-f 2-cyano-I -[ 4 .( 7 H-pyrrolo[2,3-d~pyrimidin-4.y).. H-pyrazol-1 -yl]ethyl} -4-methoxybenzo nitrile; 3 -( 3 -bromophenyl)..3.[4(7-pyroo[2,3]priidin-4 4 yJ). 1 H-pyrazol-lI-yllpropanenitrile; 3-f 2-cyano-I -[ 4 -( 7 H-pyrrolo[2,3.dpyrimidin4yl)1 H-pyrazol-I -yl]ethyl} -4-fluorobenzo nitrile; 3-5boo2(ynmtoypey]3 4(Hproo23dprmdn4y)IH-pyrazol-l yI]propanenitrile; 3-4boo2frl--4(Hpyrl[,-jyiii--l- H-pyrazol-1 -yljpropanenitrile; 4 -(cyanomcthoxy)-3. { 2 -cyano-1 -[ 4 -(7H-pyrroio[2,3-d]py-imidin-4y).1 H-pyrazol-] -yl] ethyl }benzonitrile; 3-4bdoyii--i--4(H-yrl[.-~yiii--l- H-pyrazol- 1-yl]propane niti-ile; 2- {2-cyano-I -[4-(7H-pyrrolo[2,3 -dlpyrimidin-4-yI)-I H--pyrazol-1 -yl]ethyl) isonicotinonitrile; 5- {2-cyano-I -[ 4 -(7H..py rolo[2,3..d]pyimidin4yl)-l H-pyrazol- I-ylethyl} -3-furonitrile; 3-2boo5(ynmtoypey]3[-7-yrl[,-~yiii--l- H-pyrazol-1 yl]propanenitrile; 4-(cyanomethoxy)-2- {2-cyano-l -[4-(7H-pyrTolo[2,3-d]pyrimidin-4.yl)..l H-pyrazol-l -yl] ethyl) benzonitrile; 3 -( 2 ..bromopyidin4y)3[4-(7H-pyroo2,3.d]pyrimidin- 4 y)- I H-pyrazol- I -yl]propane nitrile; 4- {2-cyano-I -{ 4 -(7H-pyrralo[2,3.d]pyzimidin-4.y).. H-pyrazol-l -yl] ethyl) pyridine-2-carbo. nitrile; 291 3-(5metoxyyridn-3yi)3-[4(7Hpyrolo[,3-~pyimidn-4yl)I H-pyrazol-1 .yl]propane nitrile; 3-(3-chlorophenyl)-3-[4(7H-pyrrolo[2,3-d]pyrimidin4y).1 H-pyrazol- 1 -yljpropanenitiile; 3-[4-(7H-pyrrolo[2,3-d]pyimidin-4-yI)- 1 H-pyrazol-1 -yl]-3-[3-(trifluoromethyl)phenyll.. propanenitrile; 3-(3-phenoxyphenyl)-3-[4-(7H-pyrrolo(2,3..d~pyrimidin-4y)..l H-pyrazol-I -yljpropanenitrile; 3-E4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1 H-pyrazol-I -yl]- 3 -[3-(trifluoroxnethoxy)-phenyl] propanenitrile; methyl 3- {2-cyano-1 -[4-(7H-pyrrolo[2,3-d]pyrimidin-4.yI)1H-pymazol-1 -yljethyl) benzoate; 3-{2-cyano-1 -E4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl).1 H-pyrazol- i-yllethyl)benzoic acid; 3 -[ 3 -(ll{-PYrazo-4-y)phenyl]-3-4-(7-pyrroo[2,3d]pimidin-y).I H-pyrazol-1 -yl] propanenit-ile; 3-(3 -aminophenyl)-3-[4-(7Hpyrroo[2,3.d]pyr.imidin-4-yl).I H-pyrazoi- 1-yl]propanenitrile; N-(3- {2-cyano-I -[4-(7H-pyrrolot2,3-d]pyrimidin-4-yl) 1 H-pyrazol-1 -yl)ethyl~phenyl) acetamide; N-(3- {2-cyano-lI-r4-(7H-pyrrolo[23-dlpyrimidinA.yly.1H-pyrazol- I -ylllethyl }phenyl) methanesulfonamide; 4 -{2-cyano-I -[ 4 -(7H-pyrrolo[2,3-d~pyrimidin..4-yl)4 11-pyrazo]- 1-yl]ethyl )thiophene-2 carbonitrile; 5- {2-cyano-1 -[ 4 -(7H-pyrrolo[2,3-d]pyrimidin-4y)..lH-pyrazol-1I-yllethyl }thiophene-2 carbonitrile; 3-[3- opoi--ycroy~hey]3[-7HpToo23-d]pyrimidin-4-yI)-I H-pyrazol-I1 yl)propanenitrile; N-(2-aminoethyl)-3- {2-cyano-l -[4-(7H-pyrrolo[2,3-d]pyrimidin.4..yl)-IH-pyrazol-1 -yl] ethyl) benzamide; 3-Sfry--hey)3[-7-yrl[,-jyiidn-l- H-pyrazol-1 -yI]propane nitrile; 3-{2-cyano-I -[ 4 -( 7 H-pyroto[2,3-d~pyriiidin.4.y).. H-pyrazol- I .- yl]ethyl) -N-methylbenz amide; 2-cyario-N-(3 - {2-cyano-1 -[ 4 -- (7H-pyrrolo(2,3-d~pyrimidin.4yl).I H-pyrazol- 1 -yl]ethyl } phenyl)acetaniide; N-(3- (2-cyano-I -[ 4 -(7H-pyr-oIo[2,3-.d]pyrimidinA..yl).1 H-pyrazol-1 -yI~ethyl~phenyl) nicotinamide; N-(3- (2-cyano-I -[ 4 -( 7 H-pyrrolo[2,3..d]pyrimidin-4yl..lHpyrazol.1 -yl~ethyl~phenyl)-N' isopropylurca; isopropyl (3- {2-cyano-I -[ 4 -(7H-pyrrolo[2,3-dlpyrimidin.4y1).j H-pyrazol-1 -yI]ethyl} phenyl)carbamate; 292 3-(5pheylpridn-3yl)3-[-(7~pyrol[2,-d~yriidi4-y)-IH-pyrazol-l -yllpropane nitrile; 3-(3 ,3 '-bipyridin-5-y)34-(7H-pyrrolo[2,3-d]pyriidin4-yi)-1 H-pyrazol-I -yl]propane nitrile; propanenitrile; 3-[5 -(I -methyl-IH yao--lprdn--i--4(Hprol[,- yiii--i) 114 pyrazol-l -yl~propanenitrile; 3-(5-ethynylpyridin-3 -y)- 3 -[4-(7H-pyrrolo(2,3..d~pyimidin4-yl)-1 H-pyrazol- I -yllpropane flitrile; 3 -[-;phenylthio)pyridin3y)3[4(7-pyoo23 pimidinyl)Hprzol-1 -yl] propanenitrile, 3-(2-bromo-1I,3-thiazol-5-yI)-3 -[ 4 -(7H-pyrralo[2,3..d~pyrimidin-4-yl> I H-pyrazol- I -yI) propanenitrile; ethyl 3 -[ 4 -(7H-pyrralo[2,3..d)pyrimidinA..y).lH-pyrazol-1I-yI]butanoate; 3 -(5-morpholinA--ylpyridin-.3-y1)-3 4 -( 7 1 {-pyrrolo[2,3-d]pyrimidin4yl)-I H-pyrazol- l-yl) propanenitrile; 3-(1 1-methyl-i 14-pyrazol-4-yI)-3-[4(7H-pyrolo[2,3-d~pyriidin-4 yl)-1 H-pyrazol-1 -yl] propanenitrile; 4- (1 -(1 -phenyi-2-( IH-l ,2,4-triazol-l -yl)ethyl]- I H-pyrazol-4-yI} -7H-pyrrolo[2,3.dJ pyrimidine; pyrimidine; 3-(3 -pyrdin- 3 -ylpheny)34-(7H-pyr2.oo[23.d]pyrimidin-4y).l H-pyrazol-l -yi] propanenitrile; 3 -[ 5 -(phenysulfiny)pyridin3y]3{47Hpyrr~.oI 0 [ 2 , 3 -djpyrimidin-4-yI)-] H-pyrazol-I -ylJ propanenitrile; 3-5peysloy~yii--l--4- -yrl[,-lyiii--l-H-pyrazol-I -y 1 3 propanenitrile; 3 4[ 4 -(7H-pyrroo[2,3.dpyrimidin..yI)-I 1-pyrazol-1I-yI]pentan-1 -ol; methyl 3 -[ 4 -(7H-pyrrolo[2,3..d~pyrimidin-4-yl)-l H-pyrazol-l -yI]pentyl carbonate; (I E)- 3 -[ 4 -( 7 1{.pyrrolo[2,3-d]pyrimidin4y).1 H-pyrazol-I -yl~pentanal oxirne; (1 E)- 3 { 4 -(7H-pyrrolo[2,3.-d]pyrixnidin-..yI). 1H-pyrazol-1 -yI]pentanaI O-rnethyloxime; (I Z)- 3 -4-.(7H-pyrrolo[2,3-dpyrimidil4.yl).1H-pyrazol-l -yl]pentanal O-rnethyloxime; 4-[1 -(4,4-dibromo-l -ethylbut-3-en-1 -yl)-I H-pyrazol-4-y]7Hpyrrolo[23d)pyjrnjdjie; 3 -[ 4 -( 7 H-pyrrolof2,3-dpyrimidin4yl)1 N-pyrazol-I -yI] -3-[5-(I ,3-thiazol-2-ylthio)pyridin 3 -yl~propanenitrile; 293 3-[5 -(tyti~yii--l--4(H-yrl[,-~yiii--l- H-pyrazol-1 -yl] propanenitrile; 4-[l -(I -ethylbut-3-yn-1 -yl)-1 H-pyrazo1-4-yI-7H-pyrrolo[2,3-d]pyrimidine trifluoroacetate; 4-{ 1 -[1 -niethyl-2-(l H-i ,2,4-triazol-1 -yl)ethyl]-l H-pyrazol-4-yl} -7H-pyrrolo[2,3-d] pyrimidine; 4 -[4-(7H-pyrrolo[2,3..djpyimidin.4-yl) iH-pyrazol-1I-yljpentan-2-one trifluoroacetate; 1 -phenyl.2-[4-(7H-pyrolo[2,3.d]pyrimidin-4y)-.1 H-pyrazol-l -yl~propan- 1 -one; 3-[5 -(ethyIsufiflY)pydin3-yI-3-4(7H.pyrrolo[2,3dpyrmidinA..yl)y 1H-pyrazol-I .- yI] propanenitrile; propanenitffle; 3 -[ 5 -(cyclohexylthio)pyridin3y]3[47H.pyrroo[23d]prmidin-4Ayl)- H-pyrazol-I -yl] propanenitrile; 1 -phenyl-2-[4-(7H-pyrroio[2,3-d]pyrimidin4 -yl)- I H-pyrazol-1 -yllpropan- 1 -ol; 1 -pheflk 2 -[4-(7H-pyrrolo[2,3.d]pyrimidin.4.yl)- Il-pyrazol- 1 -yI~propan- 1 -ol; 3 -[3-(ethylthio)phenyl]-3.{4..(7H-pyrrolo [2,3-dlpyrimidin-4-yl).l H-pyrazol-I -yll propanenitrile; 3-3(tysliy~hnl--4(Hproo23dprmdn-i- H-pyrazol-1 -yl] propanenitrile; 3 -( 3 -(ethylsulfony)pheny]3[4(7Hpyrolo[2,3.d]primidin4yl)-l H-pyrazol-I -ylj propanenitrile; 3 -fS-(cyclohexysufony)pyrdin3y]3[4(7prolo[2,3-d]pyrimidin- 4 .yl)-I H-pyrazol 1 -yI]propanenitrile; 3 -[5-(cyclohexylsulfinyl)pyridin3 -yl]- 3 -[ 4 -( 7 H-pyrrolo(2,3-d]pyrimidin-4yly. 1 H-pyrazol-l yl]propanenitrile; 4-( I -(I -methyl-2-phenylethyl)-l H-yao--i-Hprrl[,-lyiii 4- {] -[1I -methyl.2-(3 -thienyl)ethyl]-l H-pyrazol-4-yi) } 7 H-pyrrolo[2,3-d]pyrimidjne; 3- { I-( 4 -(7H-pyrrolo[2,3-d]pyrimidin-4.yl).I H-pyrazol-I -yl] ethyl) benzonitrile; 4-f 1 -[2-(l H-imidazol-1 -yl)-1 -nmethylethyl]IHl-pyrazol-4-yI} - 7 H-pyrrolo[2,3-d]pyrimidine; 4- (1 -[I -methyl-2-(3-methyl-1 , 2 , 4 -oxadiazo1-5-yl)cthy1]-t H-pyrazol-4-yl }-7H-pyrrolo[2,3-d] pyrimidine; 3 L[ 3 -(methylsulfonyl)phenyl]-3-[4(7Hpy.oo2,3rjpyrimidiA..y). 1 -pyrazol- l-yl] propanenitrile; 3-3prdi4ypey)3(-7Hproo23dprmdn4y I H-pyrazol-I -yI]propane nitrile, 4-1! -(1 -ethylbut-3-en-1I-yl)- IH-pyrazoIl4-yi]-7Hf-pyrrolo[2,3-d~]pyrimidine; 4-[1.-(1,3 -dimethylbut-3-en- 1-yl)-1 H-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidine; 294 3 -[S-(isopropylthia)pyidin3-y]-3-[4..(7H..pyrrolo[2,3-d]pyrimidin-4y)1H-pyrazol-1 .-yIJ propanenitrile; 3 -[5-(isopropylsulfinyl)pyridin-3-yI]-3.{4..(7H-pyrrolo[2,3-d~pyrimidin-4yy.1 H-pyrazol-I yI]propanenitrile; 3 -[5-(isopropylsulfonyl)pyridin-3-yl]--3-4-(7Hpy-rolo[2,3..d]pyrimidin.4-yI).l H-pyrazol-1 yllpropanenitrile; 3-[4-(7H-pyrrolo[2,3-d~pyrimidin-4-yly1 H-pyrazol-I -yl]-3-[5-(trifluoromethyl)pyridin-3-yIJ. propanenitrile; 3 -[ 4 -(7H-pyrrolo[2,3-dlpyrimidin-4-yl). 1H-pyrazol- 1 -yl]-3-[5-(trifluoromethyl)pyridin-3.yq.. propanenitrile; 2 -1 4 -(7H-pyrrolo[2,3-d]pyrimidin..4-yI)1I H-pyrazol-1 -yl].N-[3 -(trifluorometbyl)phenylj propanamide; N- 2 -naphthyl-2-[4(7H-pyrolo[2,3.d]pyrimidin-4y).1H-pyrazol- 1-yI]propananiide; N-1 -npty--4(Hproo[, lyindn-i-H-pyrazol-I -yI]propanamide; N-( 3 -cyanopheny1)-2-[4.-(7H-pyrrolo[2,3-d]py-imidin-4by) 1H-pyrazol-1 -yl]propanamide; N-be zyI-2-[4-(7H-pyrrolo[2,3.d~pyrim idin-4..yI)..H-pyrazol.1 -yl]propanamide; N-phenyl-2-[4-(7H-pyrroo[2,3-d]-py-imidin-4-yl). H-pyrazol-i1-yl]--butanamide; N-4peoyhnt--4(Hproo23dprmdn4y)I-yao- -yl]butanamide; N-2-naphthyl-2-[4(7H-pyrroo2,3.dpy-imidin4yI). H-pyrazol-1I-yl~butanamide; N-(3 -cyanophenyl)-2-[4-(7H-pyrrolo[2,3.d]pyrimidin4yl)-I H-pyrazol-1 -yI~butanamide; N-biphenyl-4-yl-2-[4-(71-pyrrolo(2,3.d]pyrimidin-4.yl)-.I H-pyrazol- 1 -yI]butananiide; N-(biphenyl-4-ylmethyl)-2-[4-(7H-pyrrolo[2,3-]pyrimidin-4yy..1H-pyrazol-I -yl) butanamide; N-(biphenyl-3 -ylmethyl)-2-[4-(7H-pyrrolo[2,3-djpyrimidin.4-yI).1H-pyrazol-I -yI] butanamide; N-(4-cyanophenyl)-2-[4-(7H-pyrrolo[2,3-djpyrimidin-4yi)1 H-pyrazol -I -yI]butanamide; N-I -naphthy1.2-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl>1 H-pyrazol-I -yllbutanamide; 5- {2-cyano-1 -f 4 -( 7 I 1 -pyrrolo(2,3-djpyrimidin-4-yl)- IH-pyrazo1-1 -yljethyl)}-N-phenylnicotin. amide; N-(3- (2-cyano-I -[4-(7H-pyrrolo[2,3-d]pyrimidin.4-yl..1 H-pyrazol-1 -yl]ethyl } phenyl)-3 (trifluoromethyl)benzamide; N4(3- {[ 4 -(7H-pyrrolo[2,3-d]pyrimidin-4.y])- 1 H-pyrazo]-1 -yl]methyl) phenyl)-3-(trifluoro methyl)benzamide; 3 -[ 3 -(methylsulfonyl)pheny]3[4(7H-pyrolo[2,3-d]pyimidin4y)-I H-pyrazol-I -yIIJ propanenitrile; 3 -[ 3 -(methylsulfonyl)phenyl]-3[4.(7Hpyrroo[2,3d~pyrimidin4.yl)-I H-pyrazol-I -yl] propanenitrile; 295 N-(3- {[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-I H-pyrazol-l -yl~methyl~phenyl)benzene sulfonamide; 3- {t4-(7H-pyrrolo[2,3-d]pyrimidin4-y)-1 H-pyi-azol-I -yl]rnethyl} -N-[3-(trifluoromethyl) phenyl]benzamide; 3- {2-cyano-I -[4-(7H-pyrrolo[2,3-djpyrimidin-4-y)-I H-pyrazol-1 -yl]ethyl) -N,N-dimethyl benzenesulfonamide; 3- {2-cyano-l -[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1 H-pyrazol-1 -yl]ethyl) -NN-dirnethyl benzenesulfonamide; N-benzyl-3- {2-cyano-I -[4-(7H-pyrrolo[2,3-dlpyinidin-4-y)-I H-pyrazol-I -yl]ethyl} benzenesulfonamide; N-benzyl-3 - 2-cyano- I -[4-(7H-pyi-rolo[2,3-d]pyrimidin-4-yl)- IH-pyrazol-I -yI]ethyl} benzaxnide; 3- {2-cyano- 1 -(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-l H-pyrazol-I -yl]cthyl) -N-phenyl benzamide; 3-f 2-cyano-1 -[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yI)-I H-pyrazol-1 -yl]ethyl) -N-[3 -(trifluoro methyl)phenyl]benzamide; N.(3-cyanophenyl)-3-{ [4-(7H-pyrrolo[2,3-d]pyrimidin-4-yI)-IH-pyrazol-I -yI]methyl } benzamide; N-benzyl-3- {14-(7H-pyrrolo-[2,3-dlpyrimidin-4-yl)- 1 H-pyrazol- 1 -yl]methyl} benzamide; N-I -naphthyl-3 -{[4-(7H-pyrrolo[2,3-d]py-imidin-4-yI)-1 H-pyrazol-I -yllmethyl }beuzamide; N-2-naphthyl-3 - {[4-(7H-pyrrolo[2,3-d]-pyrimidin4-yl)-1 H-pyrazol- I -yI]methyl }benzamnide; N-(3-{ [4-(7H-pyrrolo[2,3-d]pyrimidin-4-y)- IU-.pyrazol-1 -yI]methyl) phenyl)-2-naphtbamide; N-(3- {[4-{7H-pyrrolo[2,3 -d]pyrixnidin-4-yl)-1 N-pyrazol-l -yI)methyl) phenyl)-l -naphthamide; 2-phenyl-N-(3- ([4-(7H-pyrrolo[2,3-d]pyrimidin-4-yI)-lH-pyrazol-1 -yl]methyI) phenyl) acctamidc; 3-chloro-N-(3- { [4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1 H-pyrazol- 1 -yl]methyl }phenyl) benzamide; N-(3- {2-cyano- I -[4-(7H-pyrrolo[2,3-d~pyrimidin-4-y)-1 H-pyrazol- 1 -yl]ethyl) phenyl)-2 naphthainide; N-(3 -(2-cyano-l1 -[4-(7H-pyrrolo[2,3-djpyrimidin-4-y)-1 H-pyrazol-I -yl]ethyl) phenyl)-1 naphthamide; N-(3- (2-cyano- 1 -[4-(7H-pyrrolo[2,3-d~pyrimidin-4-yl)-1 H-pyrazol- I -yl]-ethyl} phenyl).2 phenylacetamide; 3-cyano-N-(3-{2-cyano-1 -[4-(7H-pyrrolo(2,3-d]pyrimidin-4-yI)-1 H-pyrazol-1 -yI]ethyl) phenyl)benzaxnide; N-C3- {2-cyano- 1 -f 4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-I il-pyrazol- I -yljethyl }phenyl) benzarnide; 296 N-(3- (2-cyano.1 -[ 4 -(7H-pyrrolo[2,3-d]pyrimidii.4-yl).1 H-pyrazol-I -yl]ethyl}pheriyl)-4. (trifluorornethyl)benzamide; N-(3-{2-cyano- 1-[4-(7H-pyrrolo[2,3-djpyrimidin-4-yl)-lI-pyrazol-1 -ylljethyl) phenyl)-N' phenylurca; 3- {2-eyano-I -[ 4 -( 7 H-pyi-rolo[2,3-djpyrimidin-4-yl).I H-pyrazol- 1 -yl]ethyl} -N-[4-(trifluoro methyl)phenyl]benzamide; 3- f{2-cyano-I -[ 4 -( 7 H-pyrrolo[2,3-d]pyrimidin-4-yl>1 H-pyrazol-I -yl~ctbylj -N-(4-methyI phenyl)benzamide; N-(4-cyanophcnyl)-3- {2-cyano- I -[4-(7H-pyrrolo[2,3 -dlpyrimidin-4-yI).1 H-pyrazol-1 -ylI ethyl) benzaniide; 3- {2-cyano-I -[ 4 -(7H-pyrrolo [2,3-d]pyrimidin4y).I H-pyrazol-lI -yllethyl} -N-2-naphthyl benzatnide; 3- {2-cyano- 1 -[4 -(7H-pyrrolo(2,3-d~pyrimidin-4 yl)-. I 11-pyrazol- 1 -yl~ethyl) -N- 1 -naphthyl benzamide; 3-{2-.cyano-l -[4-(7H-pyrroio[2,3-d]pyrimidin4yl) -1 H-pyrazol-1 -yl]ethyl} -N,N-dimethyl benzamide; 3- {2-cyano-l -[ 4 -(7H-pyrrolo[2,3-dlpyrimidin-4yl..1 H-pyrazol-1I-yljethyl }-N-pyridin-3-yl benzamide; 3- (2-cyano- 1-[ 4 -( 7 H-pyrrolo[2,3-d~pyrimidin.4.y1) I H-pyrazol. I-yI]ethyi }-N-methyl-N phenylbenzamide; 3- {2-cyano-1 -[4-( 7 H-pyrrolo[2,3-d]pyrimidin4yl)1 H-pyrazol- 1-yllethyl) -N-cyclohexyl benzamidc; 3- {2-cyano-I -[ 4 -( 7 H-pyrrolo[2,3.4lpyrimidin-4.yl)1 H-pyrazol-1I-yI]ethyl) -N-(4-phenoxy phenyl)benzamide; N-(3-cyanophenyl)-3- {2-cyano-l -[4-(7H-pyrrolo[2,3d]pyimidin4y).1H-pyrazo1- 1-yl] ethyl)} beazamide; N-biphenyl-4-yl-3. { 2 -cyano-l1-[4-(7H-pyrrolo[2,3-d ]pyrimidin-4-yl)-l H-pyrazol-1 -yI] ethyl) benzarnide; N-(4-chlorophenyl)-3 -{2-cyano- I-[ 4 -(7H-pyrrolo[2, 3-d)pyrimidin-4-yl)-1Ii-pyrazol-l -yl] ethyl) benzamide; 3- {2-cyano-l -[ 4 -( 7 H-pyrrolo(2,3-d~pyrimidin4yl) 1 H-pyrazol- 1-yl~ethyl) -N-(3 ,4-dimethyl phenyl)benzamide; 3- {2-cyano-lI-( 4 -( 7 H-pyrrolo(2,3..d]pyrimidin..4.yIyl I-pyrazal-1I-yllethyl) -N-(3-methoxy phenyl)benzamide; 3- {2-cyano- I-[ 4 -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)1 H-pyrazol-1I-yl]ethyl) -N-(4-methoxy phenyl)benzamide; 297 3- {2-eyano-I -[ 4 -( 7 H-pyrrolo(2,3-d]pyrjmidin-4.y)-I H-pyrazol-1 -yl]ethyll -N-isoxazol-3-yI benzamide; 3-{2-cyano-I -[ 4 -( 7 H-pyrrolo[2,3-dlpyrimidin-4yl)-I H-pyrazol-1 -yl]cthyl} -N-methyl-N phenylbenzenesulfonamide; 3- {2-cyano-I -[ 4 -( 7 H-pyrrolo[2,3-dpy-imidin-.4..yI)1 H-pyrazol- 1 -yl~ethyl) -N-propyl benzenesulfonaniide; 3-{2-cyano-I -[4-(7H-pyrrolo[2,3d]pyimdin-4yl)- H-pyrazol-1 -yl]ethyl} -N-phenyl benzenesulfonamide; 3-f 2-cyano- I -( 4 -(7H-pyrrolo[2,3-d]pyrimidin-4.y)..I I-pyrazo] -1 -yllethyl} -N-2-naphthyl benzenesulfonamide; 3- {2-cyano-I -[ 4 -( 7 H-pyrrolot2,3-dlpyrimidin.4.yI)4I i-pyrazol-]. -yljethyl} -N-cyclopropyl benzenesulfonaniide; 3-[3 -(piperidin- 1 -ylsulfonyl)phenyI]-3-[4.{7H-pyrrolo(2,3..d]pyrimidin-4-yi)-I H-pyrazol-l yl)propanenitrile; 3-[3-(morpholin-4-ylsulfonyi)phenyl] - 3 -[ 4 -( 7 H-pyrrolo[2,3..d]pyrimidin-4yl).1 H-pyrazol-1 yl]propanenitrile; 3- {2-cyano-l -[ 4 -( 7 H-pyrrolo[2,3-d]pyrimidin-4yl)-I. H-pyrazol-1 -yI]ethyl } -N-(4-methyl phenyl)benzenesulfonanide; 3-{2-cyano- I -[ 4 -(7H-pyrrolo[2,3..dlpyrimidin-4yl)-I l{-pyrazol-l -yI]ethyl) -N-(3,4-dimethyJ phenyl)benzenesulfonamide; 3-f 2-cyano-I -[ 4 -( 7 H-pyrrolo[2,3-d)pyrimidinA..yly..lHipyrazol-.I -yllethyl} -N-(3-methoxy phenyl)benzenesulfonamide; 3-{2-cyano-I -[ 4 -(7H-pyrrolo[2,3-d~pyrimidin-4-yl)I H-pyrazo!- 1 -yl]ethyl } -N-(4.-methoxy phenyl)benzenesulfonmide; 3-{2-cyano-1 -[ 4 -( 7 H-pyrrolo[2,3-d]pyrimidin.4yly.1 H-pyrazol- I -yllethyl} -N-(3,5 dimethoxyphenl)benzamidc; 3- (2-cyano-l -[ 4 -( 7 H-pyxrolo[2,3.d]pyrinidin4yI).. H-pyrazol-I -yl]ethyl} -N-[4-(dimethyl amino)phenyl]benzamide; 3-3(ezlufnlpey]3[-(Hproo23dprmdn-l- i-pyrazol-I -yi) propanenitrile; 3-3(ezlhopey]3[-7-yrl[,-lyiii--i- H-pyrazol-l -yl] propanenitrile; 4- {C(3- (2-cyano-) -[ 4 -( 7 H-pyrrolo[2,3..djpyrimidin-4y)-.I H-pyrazol- I -yllethyl )phenyl) sulfonyl]rnethyl~benzonitrile; 3 -{2-cyano-1 -[4-(7H-pyrrolo[2,3d~pimidin-4.yl)-I H-pyrazo!-1 -yl~ethyl) -N-methyl benzenesulfonamide; 298 3- {2-vyano-l -[ 4 -( 7 H-pyrrolo[2,3..d~pyrimidin-4-yI)-I H-pyrazol-I -yl)etbyl) -N-I -naphthyl benzenesulfonamide; N-biphenyl-4-yl-3- {2-cyano-I -[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- I H-pyrazol- I -yI]ethyll} benzenesulfonamide; 3- {2-cyano-I -[ 4 -(7H-pyn-olo[2,3-d]pyrimidin.4-y)-I H-pyrazol-1 -yI~ethyl) -N-[4-(trifluoro methoxy)phenyl]benzamide; 3-{2-cyano-I -[ 4 -( 7 H-pyrrolo[2,3-d]pyrimidin-4-yI)- 1 H-pyrazol-1 -yllethyl} -N-(2-methoxy phenyl)benzaniide; 3 4( 3 -(benzyloxy)pheny1]-3-[4.(7H-pyrrolo[2,3..dpyrimidin-4-yI)-.I H-pyrazol-I -yI] propanenitrile; 3- {2-cyano-I -[ 4 -( 7 H-pyrrolo[2,3-d]pyrimidin-4-yiI)H-pyrazol-1 -yl~ethyl} -N-cyclohexyl benzenesulfonamide; 3-[3-(3 1 4-dihydroisoquinolin-2( lH)-ylsulfonyl)phenyI]-3-[4-{7H-pyrrolo[2,3.d]py1-ridin-4. yI)-lI H-p yrazol- I -yI]propanenitrile; 3- f 2-cyano- 1 -[ 4 -(7H-pyrrolo[2,3-d~pyrimidin-4..yI)4H-pyrazol -1 -yl]ethyl) -N-(2-methoxy ethyl)benzenesulfonamide; 3- (2-cyano-1 -[4-(7H-pyrrolo[2,3-d]pyrimidin4-yl)-I H-pyrazol-1 -yllethyl} -N,N-diethyl benzenesulfonamide; 3- {3-[(4-ethylpiperazin-1 -yI)sulfonyllphenyl) -3-[ 4-(7H-pyrrolo[2,3-d]-pyrimidin-4-yI)- IH pyrazol- I -yl]propanenitrile; N-I ,3-benzodioxol-S-yl-3- {2-cyano-1 -[4-(7H-pyrroI o[2,3-d]pyrimidin-4-yl)-1 H-pyrazol-1 yl~ethyl) benzenesulfonamide; 3- (3-[(3-methoxybenzyl)sulfonyl~phenyl} -3-[4-(711- pyrrolo[2,3-d~pyrirnidin-4-yI) I H pyrazol-1 -yI]propanenitrile; 3- {3-[(4-methoxybenzyl)sulfonyi]phenyl)}-3-[4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)4 H pyrazol- 1 -yI]propanenitrile; 3- (3-[(2,6-dimetbylmorpholin-4-yl)sulfonyl]phenyl) -3-[4-(7H-pyrrolo[2,3-dlpyimidin-..yl) I H-pyrazol- I -yI~propanenitrile; 3- (3-[(4-oxopiperidin-I -yI)sulfanyllphenyl I -3-[4-(7H-pyrrolo[2,3..d]pyrimidin4yI). I Hi pyrazol-1 -yI]propanenitile; 3-[3 -(isopropylsulfonyI)phenyI]-3-[4..(7H-pyrrolc,[ 2,3-d]pyrirnidin-4-yl)-1 H-pyrazol-1 -yl] propanenitrle; 3-{3 -((cyclohexylmethyl)sulfonyl] phenyl} -3-[4-(7H -pyrrola(2,3-djpyrimidin-4-yI)-l H pyrazol-I -yl]propanenitrile; 3 -[3-(octahydroisoquinolin-2( 1H)-yIsulfonyI)pbenyl]344(7H-pyrrolo[2,3.-3pyrjmidin-4 yi)-IHl-pyrazo I-I -yl]propanenitrile; 299 3- {2-cyano-1 -[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-I H-pyrazol.1 -ylletliyl} -N-(2-phenyl ethyl)bernzenesulfonamide; cis- 4 .{4-(7H-pyrrolo(2,3.d]pyrimidin-4-yi)-.I H-pyrazol-I -yllcyclohcxylacetonitrile; cis- 4 -[ 4 -(7H-pyrrolo[2,3..d]pyrimidin-4-yi). H-pyrazol-1 -yllcyclohexylmethylthiocyanate; N-5-[(cis4-[4(7H-pyroo2,3d)pyimidin-4yl)-I H-pyrazol- 1 -yljcyclohexymethyl)thio]j. 4H{-I, 2 , 4 -triazol-3-yIpylimidin-2-amine; N- 5 -[(cisA-[4-(7H-pyrrolo[23d]pyrimidin-4y).. H-pyrazol- I -yllcyclohexylmethyl)thio]. 4H1, 2 ,4-triazol-3 -ylpyrimidin-2-amine; 3 -cis- 4 -[ 4 -(7H-pyrrolo[2,3.d]pyrimidin-4.yl).I H-pyrazol- I -yI)cyclohexylpr-opanenirile; 5 -[( 2 -cis- 4 -[ 4 -(7H-pyrrolo[2,3.d]pyrimidin-4.y)- I H-pyrazol- I -yI]cyclohexylethyl)thio]AH I , 2 , 4 -triazol-3-amine; 4 -1 4 -(7H-pyrrolo[2,3-d]pyrimidin4y)..1 H-pyrazol-1 -yl~cyclohexylideneacetonitrile; cis- 4 -[4.(7H-pyrol[2,3cpyr.imidin-4-y). I H-pyrazol- 1 -yllcyclohexanecarbonitjije; 2 -I(cis- 4 -[4-(7H-pyrrolo[2,3..d]pyrimidin-4y) IH-pyrazol-1 -yl]cyclohexylmethyl)sulfinyq.. benzonitrile; 2 -[(cis- 4 -(4.(7H-pyrrolo(2,3.Ijpyrimidin4-yl) IH-pyrazol- I -yI]cyclohexylmethyl)sulfonyl]. benzonitrile; 3 -[ 4 -( 7 1 -pyrrolo[2,3d]pyrimidin-4yl)- I H-pyrazol-1 -yljcyclohexylacetonitrile; 5-( cs-4(Hpyrl[,-~yrmdn-l- H-pyrazol-I -yIjcyclohexyl } thio)- 1 H-I ,2,4 triazol-3-amine; N- {5-[( {cis- 4 -[4-(7H-pyrrolo[2,3..d]pyimidin-4y)-I. H-pyrazol-1 -yllcyclohexyl) methyl). thio]-4H-1 ,2 ,4-triazol-3-yI} metbanesulfonamide; IcisA-( 4 -(7H-Pyrrolo[2,3..dlpyrimidin4-yl). I H-pyrazol-1 -yl]- I -(I H-I ,2,4-triazo!-I -yl)cyclo hexyllacetonitrile; 3-[3 -(piperazin-I -ylsul fonyl)phenyl-3-[4-(7H.py- rolo[ 2 ,3-d~pyrimidinA..yl..1 H-pyrazol-I yi]propanenitrile; 3 -[ 4 -{ 7 H-pyr01012,3-dlpyrimidin.4.y).. H-pyrazol-1 -yi]- 3 -[3-(thiomorpholin-4-ylsufonyl). phenyl]propanenit-ile; 3. {3-[(4-hydroxypiperid in-1I-yl)sulfonyl]phenyi }-3 -[ 4 -( 7 H-pyrrolo[2,3-d]pyrimdin.4yi). I li-pyrazol -1 -yl~propanenitrile; 3-[3 -(isobutylsulfonyl)phenyl]3-4(TH-.pyrrolo[ 2 ,3-d]pyrimidin-4-yi)-l H-pyrazol-1 -yI] propanenitrile; 3 -[ 4 ( 7 H-pyrrolo(2,3-d]pyrimidin-4yl)1IHpyraz 0 3 I -yI]-3- { 3 -((tetrahydro-2H-pyran-4. ylmethyl)sul fonyl]pbeny1}propanentrile; 3- { 3 -[(2-methoxyethyl)sulfonyl]phenyl) -3-[4-(7H-p yrrolo[2,3-d]pyrimidin..4-ylyl H pyrazol- I -yI]propanenitrile; 300 3- {3-[(3-fiuylmethyl)sulfonyllphenyl} - 3 -[ 4 -(7H-py rrolo[2,3-dlpyrimidin-4-y..1 i-pyrazol I -yl]propanenitrile; 3-134[(1,1-diaxidothiomorpholin-4-yl)sulfonyljphe nyl) - 3 -[ 4 -( 7 H-pyrrolo[2,3..d]pyrimidin-4. yl)-1 H-p yrazol-1 -yljpropanenitrile; 3- { 3 -[(4-acetylpiperaziri-1I-yl)sulfonyi]phenyl} -3- [ 4 -(7H-pyrrolot2,3-djpyrimidin.4-yl)-IH pyrazol-1 -yl]propanenitrile; 3- { 3 -[Qpyridin4-ylmethyI)sulfonyl]pheny1) -3-[4-( 7H-pyrrolo[2,3-d~pyrimidin-4-ylI).1H pyrazol- I -yl]propanenitrile; 4-[l -(I-phenylbut-3-yn- 1-yI)-1 H-pyrazol-4-yl]-7H- pyrrolo[2,3-d~pyrimidine; 4-(1 - {I-[3 -(morpholin-4-ylsulfonyl)phenyl]but-3-.yn-I -yl} -lH-pyrazol-4-yl)-7H-pyrroo[23 dipyrimidine; 3- {I-[ 4 -( 7 H-pyrrolo[2,3..d]pyrimidin-4yl).114-pyrazol- 1-yl]but-3 -yn-1 -yI}benzonitrile; 3- { -[ 4 -( 7 H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H..pyrazol-.1 -yl]but-3-yn- l-yI} benzaldehyde; methyl 3 -( 3 -cyanopheny)-344(7H-pyroo[2,3-'i]pyrimidin.4 yl) I H-pyrazol-1 -yI) propanoate; N,N-dimethyl-3- {l-[ 4 -(7H-pyrrolo2,3.d]py-imidin. 4 -yl)-I H-pyrazol- 1-yI]but-3-yn-l -yI) benzenesulfonamide; 3- {2-cyano-I -[ 4 -( 7 H-pyrrolo[2,3-d]pyrimidin-4.yl).1H-pyrazol-1 -yllethyl) -N-[4-(dimethyl amino)phenyl]benzenesulfonamide; 3- {3-methoxy-1 -[ 4 -(7H-pyrrolo[2,3-d]pyrimidin.4y 1)-i H-pyrazol-l -yljpropyl }-NN dimethyjbenzenesulfonamide; N-phcnyl-3- { I[ 4 -( 7 H-pyrrolo[2,3-d~pyrimidin.4y )- IH-pyrazol-1 -yljbut-3-yn-1 -yI} benzamide; 4-fl -(3-methoxy-lI-phenylpropyl)-1 H-pyrazol-4-yl)- 711 -pyrrolo[2,3-d]pyrimidine; N-[ 4 -(dimnethylamino)phenyl] -3- { I-[4-(7H-pyrrolo[2 ,3-d]-pyrimidin-4-yl).I H-pyrazol- 1 yI]but-3-yn-1 -yI} benzamide; 3-{3-hydroxy-l -[ 4 -( 7 H-pyrrolo[2,3-d~pyrimidin.4y 1)- lH-pyrazol-1 -yl]propyl -NN dimethylbenzenesulfonamide; 3-{ I-[ 4 -(7H-pyrrolo[2,3..d]pyIrimidin4-y) il-pyrazol-1I-yI]but-3-en-1I-yl }benzonitrile; 4-f{ 1-El -(3-bromophenyl)but.3en-1l-yl]-1 H-pyrazol-4-yl} - 7 H-pyrrolo[2,3-d]pyrimidine; 3- {4,4-difluoro-I -( 4 -( 7 H-pyrrolo[2,3..d]pyriidin- 4-yl)-1H-pyrazol-I -yl]but-3-en-I -yl } benzonitrile; 4-(1 - 4,4-difluoro-l -[ 3 -(morpholin-4-ylsulfony)pheny]but.3-en.1 -yl - IH-pyrazol-4-yl)711 pyrrolo[2,3-d]pyrimine~n; 4-(I - { l-[ 3 -(ethylsulfonyl)phenylpi,4.difluorobut3-en-1. -yI) -1H-pyrazol-4-yl)-7H-pyrrolo. [2,3 -dlpyrimidine; 3D] 4-( 1 -{1-[3-(benzyloxy)phenyl]-4.4-difluorobut-3-en.. I-yl) -1 H-pyrazolA4-yl)-7H-pyrrolo [2,3 dilpyrimidine; 4-[1 -(2-methoxy- 1 -phenylethyl)- 1 H-pyrazol-4-yli-7H-pyrrolo[2,3-d]pyrimjdine; 4-( 1- 4,4-difluoro-1 -[3-(methylsulfonyl)phenyl]but-3..en-I -yl} -1 H-pyrazol-4-yl)-7H pyrrolo[2,3-dlpyrimidine, 3- {[ 4 -( 7 H-pyrrolo[2,3-djpyrimidinA..yl).lH-pyrazol-I -yllmethyl} benzonitrile; 3- (1 -[ 4 -( 7 H-py -rolo[2,3-d]pyrimidin-4yly.1H-pyrao.. -yl]-butyl} benzonitrile; 4-(1 -( I-[3-(ethylsulfonyl)phenyl]-4,4-difluorobutyl) -1 H-pyrazoI-4-y!).7H-pyrroo[23]. pyrimidine; 4-[Il-(4,4-difluoro- - {3-[C2-methoxyethyl)sulfonyl]phenyl} -but-3-en- I -yI}- IH-pyrazol-4-yl] 711 -pyrrolo[2,3-d]pyrimidine; 4-(I -(1 -cyclopentylbut-3-en..l -yl)-lH-pyrazoI-4-yI].7H-py1-roo[2,3.dpyiidine; 4-[1 -(I -niethylbut-3-en-I -yI)-1 H-yao--l-Hprrl[,-~yiiie 441l -(I -cyclopentyl-2-cyclopropylethyl)-I H-pyrazo 4 y]7H-pynrolo[23-]pyrimidine; 4-[l1 -(1 -cyclopentylbut-3-yn..1 -yI)-I liprzl4y]7-yrl[,-~yiiie 4-[l1 -(1 -cyclopentylbutyl).IH-pyrazoIA..yI]-7H-pyrrolo[2,3d]pyimdineD; 4-[ 1 -(1 -cyclopentyI-4,4..difluorobut.3.en-I -yl)-l H-pyrazol-4-yII.7Hpyrrolo23d] pyrimiding; 4-I -[4,4-difluoro- I -(tetrahydrofi ran-3-yI)but.3-en. I-yl]-l H-pyrazol-4-yi-711-pyrroj o[2.3 d]pyrimidine; 4-[ 1 -(1 -methylbut-3-en-1 -yl)-l H-pyrazo1.4ypH.pyroo[23]pyriiidin; 4-[ 1-(1 -cyclopropyl-4,4..difluorobut-3-en-1I-yI)-1 H-pyrazol-4-y1]-7H-pyrrolo[23-J] pyrimidine: 4-[ 1-(1 -cyclopentyl-4,4-difluorobutyl).1H..pyrazol.4..y1].7H..pyrrolo[2,3-dr]pyimjdin; 3-( l-methylcyclopenty])..3.[47Hpyr.olo[2,3-d~pyrimidin-4 yl)-1H-pyrazol-1 -yl]propane nitffle; (3R)- and ( 3 S) 4 4 dimethyI.3[4(7[2(trimethysiy)ethoxy]methy7H-prrolo[ 2 3 d] pyrimidin-4-yI)-I H-pyrazol-1 -yI~pentanenitrile; 1 -2-cyano- l-[ 4 -( 7 H-pyrlo(o2,3.d]pyrimidin4yl).1H-pyrazolI -yI~ethylcyclopropane carbonitrile; N-[(1 -2-cyano-l .[ 4 .( 7 H-pyrrolo(2,3-cI]pyimidin4ylI).H-pyrazol- 1-yI]cthylcyclopentyl) methyl]benzamide; 3-1 4(benzyloxy)mcthyIlcycbopentyI.3.[4.(7H-pyrrolo[2,3..dpyrimijdin-4yI)l H-pyrazol- 1 yl]propanenitrile; 3-[1 l-(rethylsufony)pyrroidin3y3[4(7H-pyroo[2,3-d]pyrimidin-yl)-I. H-pyrazol-1 yllpropanenitrile; 302 N-cyano-4-(cyanomethyl)-4-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1 H-pyrazol-1 -yl] piperidine-1 -carboximidamide; 4-1-[2,2,2-trifluoro-1 -(1 H-imidazol-2-ylmethyl)ethyl]-l H-pyrazol-4-yl-7H-pyrrolo[2,3 d]pyrimidine; 4-(1 -(1 R)-2,2,2-trifluoro-I -[(4-methyl-1,3-thiazol-2-yl)methyljethyl-I1H-pyrazol-4-yl)-7H pyrrolo[2,3-d]pyrimidine; 4-1 -[1 -(trifluoromethyl)but-3-yn-1 -yl]- H-pyrazol-4-yl-7H-pyrrolo[2,3-d]pyrimidine; 4-1-[1 -(trifluoromethyl)but-3-en-1-yl]-1H-pyrazol-4-yl-7H-pyrrolo[2,3-d]pyimidine; 4-1 -[1 -(trifluoromethyl)butyl]-1 H-pyrazol-4-yl-7H-pyrrolo(2,3-d]pyrimidine; 4-1-[4,4-difluoro-1-(trifluoromethyl)but-3-en-1 -yl]-l H-pyrazol-4-yl-7H-pyrrolo[2,3-d] pyrimidine; 4-1-[ 4 ,4-difluoro- 1 -(trifluoromethyl)butyl]-1H-pyrazol-4-yl-7H-pyrrolo[2,3-d]pyrimidine; 3-pyridin-4-yl-3-[5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1, 3 -thiazol-2-yl]propanenitrile; 4-2-cyano- I-[ 5 -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1, 3 -thiazol-2-yl]ethylpyridine-2 carbonitrile; and 3 -pyridin- 2 -yl-3-[5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1, 3 -thiazol-2-yl]propanenitrile; and pharmaceutically acceptable salts thereof.
44. 47. A composition comprising a compound of any one of claims I to 46, or pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
45. 48. The composition of claim 47 which is suitable for topical administration.
46. 49. A method of modulating an activity of JAK comprising contacting JAK with a compound of Formula I: (Y)n-Z T=A 2 /! \\ Al R RaR 2 R 3 N N H I including pharmaceutically acceptable salt forms or prodrugs thereof, wherein: A' and A 2 are independently selected from C and N; T, U, and V are independently selected from 0, S, N, CR, and NR*; wherein the 5-membered ring formed by A', A 2 , U, T, and V is aromatic; 303 X is N or CR 4 ; Y is Cs alkylene, C 2 .s alkenylene, C 2 .s alkynylene, (CR"R)p-(C3.,o cycloalkylene) (CR'R 1 2 )q, (CR"RI 2 ),-(arylene)-(CR" R12)q, (CR' "R1 2 ),-(C,.,o heterocycloalkylene)-(CR' 'R12)qs (CR"R 2 ),-(heteroarylene)-(CR"R2)q, (CR"R' 2 ),O(CR"R 2 )q, (CR' 'R 2 ),S(CR"R 1 2 )q, (CR"R 1 2 ),C(O)(CR"R 12)q, (CR' 'R1 2 )pC(O)NR'(CR"R 1 2 )4, (CR"R 2 ),C(O)O(CR' 'R 12 )q, (CR"R 1 2 ),OC(O)(CR"R" )q, (CR"R 1 2 ),OC(O)NRc(CR"R 1 2 )q, (CR' "R1 2 ),NRc(CR"R' 2 )q, (CR"R' 2 )PNRC(O)NRd(CR"R' 2 )q, (CR"R1'),,S(O)(CR"R" 2 )q, (CR"R 2 ),S(O)NR'(CR 'R 2 )q, (CR"R 1 2 )pS(O)2(CR"R2)q, or (CR"lR 2 )pS(O) 2 NR*(CR"R2)q, wherein said Ci.s alkylene, C 2 -s alkenylene, C 2 . 8 alkynylene, cycloalkylene, arylene, heterocycloalkylene, or heteroarylene, is optionally substituted with 1, 2, or 3 substituents independently selected from -D'-D 2 -D 3 -D ; Z is H, halo, C,. 4 alkyl, C 2 .4 alkenyl, C 2 . 4 alkynyl, C1.4 haloalkyl, halosulfanyl, C1.4 hydroxyalkyl, C1. 4 cyanoalkyl, =C-R', =N-R', Cy', CN, NO 2 , OR", SR", C(O)Rb, C(O)NR*Rd, C(O)OR", OC(O)R, OC(O)NR*Rd, NcRd, N C(O)R, NRCC(O)NRRd, NRCC(O)OR", C(=NR)NR*Rd, NRCC(=NR)NR4Rd, S(O)R, S(O)NRRd, S(O) 2 Rb, M'S(O) 2 Rb, C(=NOH)Rb, C(=NO(CI- 6 alkyl)R, and S(O) 2 NR4Rd, wherein said C1. 8 alkyl, C 2 -s alkenyl, or C 2 - 8 alkynyl, is optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from halo, C. 4 alkyl, C 2 . 4 alkenyl, C 2 . 4 alkynyl, CI-4 haloalkyl, halosulfanyl, C1. 4 hydroxyalkyl, CI. 4 cyanoalkyl, Cy', CN, NO 2 , ORD, SR&, C(O)R , C(O)NRRd, C(O)OR", OC(O)R, OC(O)NRRd, NRRd, McC(O)Rb, NRcC(O)NRCRd, NRcC(O)ORB, C(=NR')NR*Rd, NRcC(=NR)NRRd, S(O)Rb, S(0)NR'Rd, S(0) 2 Rb, NR'S(O) 2 Rb, C(=NOH)Rb, C(=NO(C. 6 alkyl))Rb, and S(O) 2 NRCRd; wherein when Z is H, n is 1; or the -(Y).-Z moiety is taken together with i) A 2 to which the moiety is attached, ii) R or R" of either T or V, and iii) the C or N atom to which the R 5 or R 6 of either T or V is attached to form a 4- to 20-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring fused to the 5-membered ring formed by A', A 2 , 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).-Q; W is C,. 8 alkylenyl, C 2 . alkenylenyl, C 2 . 8 alkynylenyl, 0, S, C(O), C(O)NR'', C(O)O, OC(O), OC(O)NRC', NR"', NRC'C(O)NRd' S(O), S(O)NR"', S(O) 2 , or S(O) 2 NR"; Q is H, halo, CN, NO 2 , C,. 8 alkyl, C 2 . 8 alkenyl, C 2 - 8 alkynyl, C,. 8 haloalkyl, halosulfanyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, wherein said CI, 8 alkyl, C 2 -s alkenyl, C 2 . alkynyl, C,. 8 haloalkyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from halo, C1.4 alkyl, C 2 .4 alkenyl, C 2 . 4 alkynyl, CI. 4 haloalkyl, halosulfanyl, C14 hydroxyalkyl, C,. 4 cyanoalkyl, Cy 2 , CN, NO 2 , OR', SR"', C(O)Rb', C(O)NR*'Rd', C(O)OR", OC(O)Rb', OC(O)NR*'Rd', N''Rd', NR'C(O)Rb', N''C(O)NRc'R' R*'C(O)OR', S(O)Rb', S(O)NR''Rd', S(O) 2 R', NR''S(O) 2 R', and S(O) 2 NR''Rd'' 304 Cy' 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, C.4 alkyl, C2.4 alkenyl, C2.4 alkynyl, CI.4 haloalkyl, halosulfanyl, CI.4 hydroxyalkyl, C 1 .4 cyanoalkyl, CN, NO 2 , OR'", SR'", C(O)R'', C(O)NRRd", C(O)OR'", OC(O)R", OC(O)NR''Rd", NR"~Rd", N*"C(O)Rb', NI"C(O)OR'", NR'"S(O)Rb", NRC'"S(O) 2 Rb'", S(O)R b", S(O)NRCRd", S(O) 2 R", and S(O) 2 R*"Rd"; R', R 2 , R 3 , and R 4 are independently selected from H, halo, C.4 alkyl, C2.4 alkenyl, C 2 -4 alkynyl, C4 haloalkyl, halosulfanyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO 2 , OR 7 , SR 7 , C(O)R, C(O)NRR' 0 , C(O)OR 7 OC(O)R8, OC(O)NR 9 R' 0 , NRR' 0 , NR*C(O)R8, NR*C(O)OR, S(O)R8, S(O)NR*R' 0 , S(O) 2 R8, NR*S(O) 2 R", and S(O) 2 NR!R' 0 ; R 5 is H, halo, C4 alkyl, C2.4 alkenyl, C2.4 alkynyl, C1.4 haloalkyl, halosulfanyl, CN, NO 2 , OR 7 , SR.', C(O)RO, C(O)NRR'*, C(O)OR 7 , OC(O)R', OC(O)NR 9 R'*, NR 9 R'", NRC(O)Rs, NR 9 C(O)OR', S(O)R8, S(O)NR 9 R'4, S(O)2R', NRS(O) 2 R', or S(O) 2 NR 9 R'"; R' is H, C,.4 alkyl, C 2 .4 alkenyl, C 2 . 4 alkynyl, C-4 haloalkyl, OR 7 , C(O)R8, C(O)NR 9 R'", C(O)OR, S(O)R', S(O)NR 9 R'4, S(O) 2 R', or S(O) 2 NR 9 R'*; R 7 is H, C1.6 alkyl, CI.6 haloalkyl, C2.6 alkenyl, C 2 - 6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl; R8 is H, Ci.6 alkyl, Ci.6 haloalkyl, C2.6 alkenyl, C2.6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl; R 9 and R' 0 are independently selected from H, CI.1 0 alkyl, C1.6 haloalkyl, C2.6 alkenyl, C2-6 alkynyl, C.6 alkylcarbonyl, arylcarbonyl, Ci. 6 alkylsulfonyl, arylsulfonyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl; or R9 and R'0 together with the N atom to which they are attached form a 4-, 5-, 6- or 7 membered heterocycloalkyl group; R" and R1 2 are independently selected from H and -E'-E 2 -E 3 -E 4 ; D' and E' are independently absent or independently selected from C1.6 alkylene, C2.6 alkenylene, C2-6 alkynylene, arylene, cycloalkylene, heteroarylene, and heterocycloalkylene, wherein each of the C1.6 alkylene, C2.6 alkenylene, C2.6 alkynylene, arylene, cycloalkylene, heteroarylene, and heterocycloalkylene is optionally substituted by 1, 2 or 3 substituents independently selected from halo, CN, NO 2 , N 3 , SCN, OH, CI.6 alkyl, Ci. haloalkyl, C2., alkoxyalkyl, C1. 6 alkoxy, C1.6 haloalkoxy, amino, CI.4 alkylamino, and C2.- dialkylamino; D 2 and E 2 are independently absent or independently selected from CI.4 alkylene, C2.6 alkenylene, C2.6 alkynylene, (C.5 alkylene),-O-( Ci.5 alkylene),, (CI.6 alkylene)r-S-(C. 6 alkylene),, (C,. 6 alkylene),NR"-(CI. alkylene),, (Ci.s alkylene),-CO-(C. 6 alkylene),, (C.6 alkylene),-COO-(C1.s alkylene),, (C.6 alkylene),-CONR*-(Cl.s alkylene),, (CI.4 alkylene),-SO-(C. 6 alkylene),, (C1.6 alkylene)rSO 2 -(CI. alkylene),, (C.6 alkylene),-SONR*-(Ci-6 alkylene),, and (C34 alkylene), NR"CONRf-(C.6 alkylene),, wherein each of the C.6 alkylene, C2. alkenylene, and C2-6 alkynylene is 305 optionally substituted by 1, 2 or 3 substituents independently selected from halo, CN, NO 2 , N 3 , SCN, OH, C1.6 alkyl, C,.6 haloalkyl, C2.s alkoxyalkyl, C 1 . 6 alkoxy, CI- haloalkoxy, amino, CI.6 alkylamino, and C2.8 dialkylamino; D' and E 3 are independently absent or independently selected from Ci-6 alkylene, C2.6 alkenylene, C2.6 alkynylene, arylene, cycloalkylene, heteroarylene, and heterocycloalkylene, wherein each of the C1.6 alkylene, C2.6 alkenylene, C2. 6 alkynylene, arylene, cycloalkylene, heteroarylene, and heterocycloalkylene is optionally substituted by 1, 2 or 3 substituents independently selected from halo, CN, NO 2 , N 3 , SCN, OH, CI. alkyl, C.6 haloalkyl, C2. alkoxyalkyl, CI-6 alkoxy, C1.6 haloalkoxy, amino, C1.6 alkylamino, and C2.8 dialkylamino; D 4 and E 4 are independently selected from H, halo, C1.4 alkyl, C2.4 alkenyl, C 2 . 4 alkynyl, C1.4 haloalkyl, halosulfanyl, C,. 4 hydroxyalkyl, C.4 cyanoalkyl, Cy', CN, NO 2 , OR", SR", C(O)Rb, C(O)NRRd, C(O)OR", OC(O)R, OC(O)NRcRd, NRcRd, N*C(O)Rb, NRcC(O)NRRd, NRcC(O)OR', C(=NR)NRCRd, NR*C(=NR)NR,Rd S(O)R', S(O)NRCRd, S(O) 2 Rb, NRcS(O) 2 Rb, C(=NOH)R, C(=NO(C, 4 alkyl)Rb, and S(O) 2 NRCR, wherein said C1.8 alkyl, C2.8 alkenyl, or C2.8 alkynyl, is optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from halo, C1.4 alkyl, C2.4 alkenyl, C2.4 alkynyl, C4 haloalkyl, halosulfanyl, C,. 4 hydroxyalkyl, C-4 cyanoalkyl, Cy', CN, NO 2 , ORa, SR, C(O)R, C(O)NRcRd, C(O)ORa, OC(O)R, OC(O)NRCRd, NRcRd, NRcC(O)Rb, N C(O)NRCRd, NR*C(O)OR", C(=NR')NRCO, NRC(=NR)RRd, S(O)Rb, S(O)NRCRd, S(O) 2 R NRcS(O)2R C(=NOH)R, C(=NO(C. 6 alkyl))R, and S(Q)2NR*Rd. R' is H, Cy', -(C a6alkyl)-Cy', CI-6 alkyl, CI-6 haloalkyl, C2.6 alkenyl, C2.6 alkynyl, wherein said C1.6 alkyl, C1.6 haloalkyl, C2.6 alkenyl, or C2.6 alkynyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, CI-6 alkyl, C,. 6 haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; Rb is H, Cy', -(CI- alkyl)-Cy', CI-6 alkyl, C.6 haloalkyl, C2.6 alkenyl, C2.6 alkynyl, wherein said C,.6 alkyl, C,.6 haloalkyl, C 2 . 6 alkenyl, or C2.6 alkynyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, CI. 6 alkyl, C1. 6 haloalkyl, C,.6 haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; Ra and R' are independently selected from H, C1.6 alkyl, Ci.s haloalkyl, C2.6 alkenyl, C2.6 alkyny, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said C6 alkyl, C.6 haloalkyl, C2.6 alkenyl, C2.6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1.6 alkyl, C1.6 haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; Rb' and Rb" are independently selected from H, C.6 alkyl, CI.6 haloalkyl, C2.6 alkenyl, C2.6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said CI.6 alkyl, C6 haloalkyl, C2.6 alkenyl, C2-6 alkynyl, aryl, 306 cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C,. 6 alkyl, C.6 haloalkyl, C. 6 haloalkyl, halosulfanyl, aryl, arylalkyl, beteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; R' and Rd are independently selected from H, Cy', -(CI. 6 alkyl)-Cy', C1.,o alkyl, C,. 6 haloalkyl, C 2 - 6 alkenyl, C2.6 alkynyl, wherein said C,.1 0 alkyl, C1. 6 haloalkyl, C2-6 alkenyl, or C 2 -6 alkynyl, is optionally substituted with 1, 2, or 3 substituents independently selected from Cy', -(C.s alkyl)-Cy', OH, CN, amino, halo, C.6 alkyl, CI. 6 haloalkyl, CI.6haloalkyl,and halosulfanyl; or R' 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 Cy', -(C. 4 alkyl)-Cy', OH, CN, amino, halo, C. 6 alkyl, C1. 6 haloalkyl, C1.6 haloalkyl, and halosulfany); R' and Rd' are independently selected from H, C1.1 0 alkyl, CI, 4 haloalkyl, C 2 .6 alkenyl, C 2 . 6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said C,.1 0 alkyl, CI- 4 haloalkyl, C 2 . 6 alkenyl, C2.6 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, CI, alkyl, C,. 6 haloalkyl, C,. haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; or R' 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, C,. 6 alkyl, C,.6 haloalkyl, C,. 6 haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; R*" and Rd" are independently selected from H, C,., 0 alkyl, C1. 6 haloalkyl, C2.6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said C1.1 0 alkyl, C1. 6 haloalkyl, C2.6 alkenyl, C2.6 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, C.6 alkyl, C, 4 haloalkyl, halosulfanyl, C1.6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; or R'" and Rd" together with the N atom to which they are attached form a 4-, S-, 6- or 7 membered beterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, CI. 6 alkyl, C,.shaloalkyl, C14 haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; R' is H, CN, NO 2 , or C, 4 6 alkyl; R* and Rr are independently selected from H and CI-, alkyl; R' is H, CN, or NO 2 ; 307 m is 0 or 1; n is 0 or 1; p is 0, 1, 2 , 3 , 4, 5, or 6; q is 0, 1, 2, 3, 4, 5 or 6; r is 0 or 1; and s is 0 or 1.
47. 50. The method of claim 49 wherein said JAK is JAKI, JAK2, JAK3 or TYK2.
48. 51. The method of claim 49 wherein said JAK is JAKI or JAK2.
49. 52. The method of claim 49 wherein said JAK is JAK2.
50. 53. The method of claim 49 wherein said modulating is inhibiting.
51. 54. The method of claim 49 wherein said compound is a selective inhibitor of JAK2 over JAKI, JAK3 and TYK2.
52. 55. A method of treating a disease in a patient, wherein said disease is associated with JAK activity, comprising administering to said patient a therapeutically effective amount of a compound of Formula I: (Y)n-Z I!\ U I V R R R R2 RA N N H including pharmaceutically acceptable salt forms or prodrugs thereof, wherein: A' and A 2 are independently selected from C and N; T, U, and V are independently selected from 0, S, N, CR', and NR 6 ; wherein the 5-membered ring formed by A', Az, U, T, and V is aromatic; X is N or CR; Y is Cl.s alkylene, C 2 -& alkenylene, C 2 . 8 alkynylene, (CR"R " )p-(C3.,ocycloalkylene) (CR"R' ")q, (CR' 'R"))-(arylene)-(CR"R 2 )q, (CR'R' 2 ),-(C,.,o heterocycloalkylene)-(CR'"R' 2 )q, (CR"R 2 ),-(heteroarylene)-(CR' 'R1 2 )q, (CR"R 2 )PO(CR"R 1 2 )., (CR"R' 2 ),S(CR"R 2 )q, 308 (CR"R"),C(O)(CR"R),, (CR"R)),C(O)NR'(CR")R' 2 )q, (CR 2 CR"R), (CR"R 2 ),OC(O)(CR'"R1 2 )q, (CR"R 1 2 ),OC(O)NR(CR"RI 2 )q, (CR"RI2),NRC(CR"1R1 2 )q, (CR"R 2 ),NRC(O)NRd(CR"RI 1 2 )q, (CR"R 2 ),S(O)(CR"R 1 2 )q, (CR"R1 2 ),S(O)NR'(CR"1R 2 )q, (CR"R 2 ),S(O) 2 (CR"R 2)q, or (CR"R 12)PS(O)2NRc(CR"1R1 2 )q, wherein said CI-a alkylene, C 2 . 8 alkenylene, C2.8 alkynylene, cycloalkylene, arylene, heterocycloalkylene, or heteroarylene, is optionally substituted with 1, 2, or 3 substituents independently selected from -D'-D-D-D; Z is H, halo, CI 4 alkyl, C 2 .4 alkenyl, C 2 .4 alkynyl, CI.4 haloalkyl, halosulfanyl, CIA hydroxyalkyl, C,.4 cyanoalkyl, =C-R', =N-R', Cy', CN, NO 2 , ORO, SR", C(O)Rb, C(O)NRRd, C(O)OR", OC(O)Rb, OC(O)NRCRd, NR*Rd, N*C(O)R NR*C(O)NRNRd, 'C(O)OR, C(=NR)NR"R, NRC(=NR)NRCRd, S(O)Rb, S(O)NR"Rd, S(O) 2 R, NRCS(O) 2 Rb, C(=NOH)R, C(=NO(CI. 4 alkyl)Rb, and S(O) 2 NRRd, wherein said C1.8 alkyl, C 2 . 8 alkenyl, or C 2 - 8 alkynyl, is optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from halo, CI.4 alkyl, C2.4 alkenyl, C 2 . 4 alkynyl, C,. 4 haloalkyl, halosulfanyl, CI.4 hydroxyalkyl, CI 4 cyanoalkyl, Cy', CN, NO 2 , OR., SR", C(O)R, C(O)NRRd, C(O)OW, OC(O)R, OC(O)NRRd, NRCRd, N'C(O)R', NRcC(O)NRRj, NRcC(O)OR", C(=NR)NRRd, NRcC(=NRI)NRRd, S(O)R, S(O)NR Rd, S(O) 2 R, NR*S(O) 2 R', C(=NOH)Rb, C(=NO(CI. 6 alkyl))Rb, and S(O) 2 NR*Rd; wherein when Z is H, n is 1; or the -(Y).-Z moiety is taken together with i) A 2 to which the moiety is attached, ii) R- or R 6 of either T or V, and iii) the C or N atom to which the R' or R5 of either T or V is attached to form a 4- to 20-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring fused to the 5-membered ring formed by A', A 2 , 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).-Q; W is CI. 8 alkylenyl, C 2 .& alkenylenyl, C2.s alkynylenyl, 0, S, C(O), C(O)NR'', C(O)0, OC(O), OC(O)NR"', NRC', NR''C(O)NRd', S(O), S(O)NR4, S(O) 2 , or S(O) 2 NR'; Q is H, halo, CN, NO 2 , C,. 8 alkyl, C2.8 alkenyl, C2.8 alkynyl, C,.s haloalkyl, halosulfanyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, wherein said C. 8 alkyl, C2-8 alkenyl, C24 alkynyl, C1.8 haloalkyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from halo, CI 4 alkyl, C2.4 alkenyl, C2.4 alkynyl, C.4 haloalkyl, halosulfanyl, C14 hydroxyalkyl, C,. 4 cyanoalkyl, Cy2, CN, NO 2 , OR', SR'', C(O)Rb', C(O)NRc'Rd, C(O)OR-, OC(O)Rb', OC(O)NRC'R', N*'Rd', N*'C(O)R', NRc'C(O)NRC'Rd', NRC'C(O)OR", S(O)Rb', S(O)NR*'Rd', S(O) 2 Rb', NRC'S(O) 2 Rb', and S(O) 2 NR'Rd'; Cy' 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, CI.4 alkyl, C2.4 alkenyl, C 24 alkynyl, CI.4 haloalkyl, halosulfanyl, C1.4 hydroxyalkyl, C).4 cyanoalkyl, CN, NO 2 , OR'", SR'", C(O)Rb", C(O)NR'"Rd", C(O)OR"", OC(O)R', OC(O)NRcRd", 309 NRC"R", N*"C(O)R", NRC"C(O)OW", NR*"S(O)R", N'"S(O) 2 Rb", S(O)R", S(O)NRC"R 6 ", S(O) 2 Rb', and S(O) 2 NRc"Rd"; R', R 2 , R 3 , and R 4 are independently selected from H, halo, CI.4 alkyl, C2.4 alkenyl, C2-4 alkynyl, CI. haloalkyl, halosulfanyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO 2 , OR 7 , SR, C(O)R, C(O)NR!R', C(O)OR 7 OC(O)R 8 , OC(O)NR'R'*, NR 9 R'*, NR'C(O)R, NR*C(0)OR 7 , S(O)R", S(O)NR!R'*, S(0) 2 R, NR 9 S(O) 2 R 8 , and S(O) 2 NR 9 R'"; R5 is H, halo, C1. 4 alkyl, C2.4 alkenyl, C2.4 alkynyl, Ct.4 haloalkyl, halosulfanyl, CN, NO 2 , OR 7 , SR 7 , C(O)R!, C(O)NRR', C(O)OR7, OC(O)Ra, OC(O)NRR'", NR!R'*, NR'C(O)RV, NR 9 C(O)OR 7 , S(O)R 8 , S(O)NR 9 R' 0 , S(O) 2 R, NR'S(O) 2 R", or S(O) 2 NR'R'*; R 6 is H, C 1 .4 alkyl, C2-4 alkenyl, C 2 4 alkynyl, C.4 haloalkyl, OR', C(O)R 8 , C(O)NR 9 R'", C(O)OR', S(O)R, S(O)NR 9 R' 0 , S(O) 2 R', or S(0) 2 NR9R'*; R7 is H, C1.6 alkyl, C,. 6 haloalkyl, C 2 . 6 alkenyl, C2.6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl; R 8 is H, CI-6 alkyl, C.6 haloalkyl, C 2 . 6 ailcenyl, C2.6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl; R? and R' 0 are independently selected from H, CI.i 0 alkyl, C.6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C34 alkylcarbonyl, arylcarbonyl, C. alkylsulfonyl, arylsulfonyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl; or R 9 and R 10 together with the N atom to which they are attached form a 4-, 5-, 6- or 7 membered heterocycloalkyl group; R" and R 12 are independently selected from H and -E'-E 2 -E 3 -E 4 ; D' and E' are independently absent or independently selected from CI-6 alkylene, C2.6 alkenylene, C 2 -6 alkynylene, arylene, cycloalkylene, heteroarylene, and heterocycloalkylene, wherein each of the C1.6 alkylene, C2.6 alkenylene, C2.6 alkynylene, arylene, cycloalkylene, heteroarylene, and heterocycloalkylene is optionally substituted by 1, 2 or 3 substituents independently selected from halo, CN, NO 2 , N 3 , SCN, OH, C.6 alkyl, C.6 haloalkyl, C2.8 alkoxyalkyl, C.6 alkoxy, C1.6 haloalkoxy, amino, C1.6 alkylamino, and C2.8 dialkylamino; D 2 and E 2 are independently absent or independently selected from C.6 alkylene, C2.6 alkenylene, C2.6 alkynylene, (C,.6 alkylene),-O-( Cs alkylene),, (C 3 4 6 alkylene),-S-(Cz. 6 alkylene),, (C.6 alkylene)-NR*-(Cl-6 alkylene),, (C1.4 alkylene),-CO-(C - alkylene),, (CI.6 alkylene),-COO-(C1.6 alkylene),, (C.6 alkylene),-CONR*-(Ci. 6 alkylene),, (C.4 alkylene),-SO-(C. 6 alkylene),, (C.6 alkylene),-SOr(Cl.s alkylene),, (CI. 6 alkylene)rSONR*-(Ci- 6 alkylene),, and (Ci.6 alkylene), NR"CONR(C I. alkylene),, wherein each of the C1.6 alkylene, C2.6 alkenylene, and C2.6 alkynylene is optionally substituted by 1, 2 or 3 substituents independently selected from halo, CN, NO 2 , N 3 , SCN, OH, CI- 6 alkyl, C, 4 haloalkyl, C2.s alkoxyalkyl, C,- 6 alkoxy, C.ihaloalkoxy, amino, Cs6 alkylamino, and C2-9 dialkylamino; 310 D 3 and E 3 are independently absent or independently selected from C1. 6 alkylene, C2 alkenylene, C 2 . 6 alkynylene, arylene, cycloalkylene, heteroarylene, and heterocycloalkylene, wherein each of the C1. 6 alkylene, C2-6 alkenylene, C 2 . 6 alkynylene, arylene, cycloalkylene, heteroarylene, and heterocycloalkylene is optionally substituted by 1, 2 or 3 substituents independently selected from halo, CN, NO 2 , N 3 , SCN, OH, C,.6 alkyl, C,. 6 haloalkyl, C 2 . alkoxyalkyl, C,.6 alkoxy, C.6 haloalkoxy, amino, C1. 6 alkylamino, and C2.8 dialkylamino; D 4 and E 4 are independently selected from H, halo, C,.4 alkyl, C 2 -4 alkenyl, C2.4 alkynyl, C,. 4 haloalkyl, halosulfanyl, C,.4 hydroxyalkyl, C,.4 cyanoalkyl, Cy', CN, NO 2 , OR", SR, C(O)R, C(O)NRRa, C(O)OR", OC(O)R, OC(O)NRCRd CRdR C C(O)R, NR"C(O)NR"R, N C(O)OR", C(=NR)NRRd, NCC(=NRI)NCRd, S(O)R, S(O)NRCRd, S(O) 2 R, NcS(O) 2 R, C(=NOH)Rb, C(=NO(C,. 6 alkyl)Rb, and S(O) 2 NRCRd, wherein said C .s alkyl, C 2 - alkenyl, or C2-s alkynyl, is optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from halo, C.4 alkyl, C2.4 alkenyl, C2.4 alkynyl, CI. 4 haloalkyl, halosulfany1, C,. 4 hydroxyalkyl, CI.4 cyanoalkyl, Cy', CN, NO 2 , OR., SWI, C(O)Rb, C(O)NRCRd, C(O)OR", OC(O)Rb, OC(O)NRCRd, NRCRd, NcC(O)R, NR*C(O)NR"Rd, N"C(O)OR, C(NR)NRCRd, NRCC(=NR')NRcRd S(O)Rb, S(O)NRCRd, S(O) 2 R , NRcS(O)2Rb, C(=NOH)Rb, C(=NO(C. 6 alkyl))Rb, and S(O) 2 NRCRd; R" is H, Cy', -(C.6 alkyl)-Cy', CI.6 alkyl, C.6 haloalkyl, C 2 - 6 alkenyl, C2.6 alkynyl, wherein said C. 6 alkyl, CI.6 haloalkyl, C2.6 alkenyl, or C2.6 alkynyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, CI.6 alkyl, C1.6 haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; Rb is H, Cy', -(C1.6 alkyl)-Cy', C.6 alkyl, C1-6 haloalkyl, C2.6 alkenyl, C2.6 alkynyl, wherein said C.6 alkyl, C . haloalkyl, C2.6 alkenyl, or C2-6 alkynyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C.6 alkyl, C1.6 haloalkyl, C.6 haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; R' and R'" are independently selected from H, C.6 alkyl, C.6 haloalkyl, C2.6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said C.6 alkyl, CI.6 haloalkyl, C2-6 alkenyl, C2.6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C,.6alkyl, C1.6 haloalkyl, balosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; Rb' and Rb" are independently selected from H, C,.6 alkyl, C1.6 haloalkyl, C2.6 alkenyl, C2.6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said C.4 alkyl, C,.5 haloalkyl, C2.6 alkenyl, C2.6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from 311 OH, CN, amino, halo, C.6 alkyl, C1.6 haloalkyl, C.6 haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; R and Rd are independently selected from H, Cy', -(CI-6alkyl)-Cy', C1.10 alkyl, C,. haloalkyl, C2-6 alkenyl, C2.6 alkynyl, wherein said C1.10 alkyl, C.6 haloalkyl, C2.6 alkenyl, or C2.6 alkynyl, is optionally substituted with 1, 2, or 3 substituents independently selected from Cy', -(C,.6 alkyl)-Cy', OH, CN, amino, halo, C,.6 alkyl, C1.6 haloalkyl, C. haloalkyl,and halosulfanyl; or R* 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 Cy', -(C.6 alkyl)-Cy', OH, CN, amino, halo, C1.6 alkyl, C,.6haloalkyl, C,. 6 haloalkyl, and halosulfanyl; R* and Rd' are independently selected from H, C.-1 alkyl, C1. 6 haloalkyl, C2.6 alkenyl, C24 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said C1.,() alkyl, C1.6 haloalkyl, C2.6 alkenyl, C2.6 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, C1.6 alkyl, CI. 6 haloalkyl, C1.6 haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; or R* 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, C,. 6 alkyl, C.6haloalkyl, C.6 haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; R"' and Rd" are independently selected from H, CI.,o alkyl, C.6 haloalkyl, C2.6 alkenyl, C2.6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said CI.o alkyl, CI-6 haloalkyl, C2-6 alkenyl, C 2 . 6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloallcylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1.6 alkyl, C1.6 haloalkyl, halosulfanyl, C,. 6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; or R" 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, C1.6 alkyl, CI-6 haloalkyl, C1.6 haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; R' is H, CN, NO 2 , or C6 alkyl; R* and R'are independently selected from H and C1.6 alkyl; R' is H, CN, or NO 2 ; m is 0 or 1; n is 0 or 1; 312 p is 0, 1, 2, 3,4, 5, or 6; q is 0, 1, 2,3,4,5 or 6; r is 0 or 1; and s is 0 or 1.
53. 56. The method of claim 55 wherein said disease is allograft rejection or graft versus host disease.
54. 57. The method of claim 55 wherein said disease is an autoimmune disease.
55. 58. The method of claim 57 wherein said autoimmune disease is a skin disorder, multiple sclerosis, rheumatoid arthritis, juvenile arthritis, type I diabetes, lupus, inflammatory bowel disease, Crohn's disease, myasthenia gravis, immunoglobulin nephropathies, myocarditis, or autoimmune thyroid disorder.
56. 59. The method of claim 57 wherein said autoimmune disease is bullous skin disorder.
57. 60. The method of claim 59 wherein said bullous skin disorder is pemphigus vulgaris (PV) or bullous pemphigoid (BP).
58. 61. The method of claim 55 wherein said disease is a skin disorder.
59. 62. The method of claim 61 wherein said skin disorder is atopic dermatitis, psoriasis, skin sensitization, skin irritation, skin rash, contact dermatitis or allergic contact sensitization.
60. 63. The method of claim 55 wherein said disease is a viral disease.
61. 64. The method of claim 63 wherein said viral disease is Epstein Barr Virus (EBV), Hepatitis B, Hepatitis C, HIV, HTLV 1, Varicell-Zoster Virus (VZV) or Human Papilloma Virus (HPV).
62. 65. The method of claim 55 wherein said disease is cancer.
63. 66. The method of claim 65 wherein said cancer is a solid tumor
64. 67. The method of claim 66 wherein said cancer is prostate cancer, renal cancer, hepatic cancer, breast cancer, lung cancer, thyroid cancer, Kaposi's sarcoma, Castleman's disease or pancreatic cancer. 313
65. 68. The method of claim 66 wherein said cancer is prostate cancer.
66. 69. The method of claim 65 wherein said cancer is hematological.
67. 70. The method of claim 69 wherein said cancer is lymphoma, leukemia, or multiple myeloma.
68. 71. The method of claim 69 wherein said cancer is a skin cancer.
69. 72. The method of claim 71 wherein said skin cancer is cutaneous T-cell lymphoma or cutaneous B-cell lymphoma.
70. 73. The method of claim 69 wherein said cancer is multiple myeloma.
71. 74. The method of claim 55 said disease is characterized by a mutant JAK2.
72. 75. The method of claim 74 wherein at least one mutation of said mutant JAK2 resides in the pseudo-kinase domain of said JAK2.
73. 76. The method of claim 55 wherein said disease is a myeloproliferative disorder.
74. 77. The method of claim 76 wherein said myeloproliferative disorder (MPD) is polycythemia vera (PV), essential thrombocythemia (ET), myeloid metaplasia with myelofibrosis (MMM), chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), hypereosinophilic syndrome (HES), or systemic mast cell disease (SMCD).
75. 78. The method of claim 55 wherein said disease is an inflammatory disease.
76. 79. The method of claim 78 wherein said disease is an inflammatory disease of the eye.
77. 80. The method of claim 79 wherein said disease is iritis, uveitis, scleritis, or conjunctivitis..
78. 81. The method of claim 78 wherein said disease is an inflammatory disease of the respiratory tract.
79. 82. The method of claim 81 wherein said inflammatory disease concerns the upper respiratory tract. 314
80. 83. The method of claim 81 wherein said inflammatory disease concerns the lower respiratory tract.
81. 84. The method of claim 55 wherein said inflammatory disease is an inflammatory myopathy.
82. 85. The method of claim 84 wherein said inflammatory disease is myocarditis.
83. 86. The method of claim 55 wherein said disease is ischemia reperfusion or related to an ischemic event.
84. 87. The method of claim 55 wherein said disease is anorexia or cachexia resulting from or associated with cancer.
85. 88. The method of claim 55 wherein said disease is fatigue resulting from or associated with cancer. 315