The present invention relates to substituted 3-cyanopyridines as protein kinase inhibitors FIELD OF THE INVENTION The present teachings relate to substituted 3-cyanopyridines (also known as nicotinonitriles) that are capable of inhibiting protein kinases. The present teachings also relate to methods for the preparation of the substituted cyanopyridines and methods of their use. For example, the compounds of the present teachings can be useful for the treatment of autoimmune and inflammatory diseases such as asthma and arthritis. INTRODUCTION Protein kinases are enzymes that catalyze the transfer of a phosphate group from adenosine triphosphate (ATP) to an amino acid residue (e.g., tyrosine, serine, threonine or histidine) on a protein. Regulation of these protein kinases is essential for the control of a wide variety of cellular events including proliferation and migration. A large number of diseases including various inflammatory diseases and autoimmune diseases such as asthma, colitis, multiple sclerosis, psoriasis, arthritis, rheumatoid arthritis, osteoarthritis, and joint inflammation, are associated with abnormal cellular events that are mediated by these kinases. See, e.g., Salek-Ardakami, S. et al. (2004), J. Immunology, 173(10): 6440-47; Marsland, B. et al. (2004), J. Exp. Med., 200(2): 181-89; Tan, S, et al. (2006), J. Immunology, 176: 2872-79; Salek-Ardakami, S. et al. (2005), J. Immunology, 175(11): 7635-41; Anderson, K. et al. (2006), Autoimmunity, 39(6): 469-78; Healy, A. et al. (2006), J. Immunology, 177(3): 1886-93; Sun, Z. et al. (2000), Nature, 404: 402-7; and Pfeifhofer, C. et al. (2003), J. Exp. Med., 197(11): 1525-35. One class of serine/threonine kinases is the protein kinase C (PKC) family. This group of kinases consists of 10 members that share sequence and structural homology. The PKCs are divided into 3 groups and include the classic, the novel, and the atypical isoforms. The theta isoform (PKC6) is a member of the novel calcium-independent class of PKCs (Baier, G. et al. (1993), ./. Biol. Chem., 268: 4997-5004). PKC6 is highly expressed in T cells (Mischak, H. et al. (1993), FEBS Lett., 326: 51-5), with some expression reported in mast cells (Liu, Y. et al. (2001), J. Leukoc. Biol., 69: 831-40), endothelial cells (Mattila, P. et al. (1994), Life Sci., 55: 1253-60), and skeletal muscles (Baier, G. et al. (1994), Eur. J. Biochem., 225: 195-203). It has been shown that PKC6 plays an essential role in T cell receptor (TCR)-mediated signaling (Tan, S.L. et al. (2003), Biochem. J., 376: 545-52). Specifically, it has been observed that inhibiting PKC6 signal transduction, as demonstrated with two independent PKC6 knockout mouse lines, will result in defects in T cell activation and interleukin-2 (IL-2) production (Sun, Z. et al. (2000), Nature, 404: 402-7; Pfeifhofer, C. et al. (2003), J. Exp. Med., 197: 1525-35). It also has been shown that PKCθ-deficient mice show impaired pulmonary inflammation and airway hyperresponsiveness (AHR) in a Th2-dependent murine asthma model, with no defects; in viral clearance and Thl-dependent cytotoxic T cell function (Berg-Brown, N.N. et al. (2004), J. Exp. Med., 199: 743-52; Marsland, B.J. et al. (2004), J. Exp. Med., 200: 181-9). The impaired Th2 cell responses result in reduced levels of interleukin-4 (IL-4) and immunoglobulin E (IgE), contributing to the AHR and inflammatory patho physio logy. Evidence also exists that PKC6 participates in the IgE receptor (FceRI)-mediated response of mast cells (Liu, Y. et al. (2001), J. Leukoc. Biol., 69: 831-840). In human-cultured mast cells (HCMC), it has been demonstrated that PKC kinase activity rapidly localizes (in less than five minutes) to the membrane following FceRI cross-linking (Kimata, M. et al. (1999), Biochem. Biophys. Res. Commun., 257(3): 895-900). A recent study examining in vitro activation of bone marrow mast cells (BMMCs) derived from wild-type and PKCθ-cleficient mice shows that upon FceRI cross-linking, BMMCs from PKCθ-deficient mice produced reduced levels of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNFα), and interleukin-13 (IL-13) in comparison with BMMCs from wild-type mice, suggesting a potential role for PKCO in mast cell cytokine production in addition to T cell activation (Ciarletta, A.B. et al. (2005), poster presentation at the 2005 American Thorasic Society International Conference). Other serine/threonine kinases include those of the mitogen-activated protein kinase (MAPK) pathway which consists of the MAP kinases (MAPK) (e.g., erk) and the MAPK kinases (MAPKK) (e.g., mek and their substrates). Members of the raf family of kinases phosphorylate residues on mek. The cyclin-dependent kinases (cdks), including cdc2/cyclin B, cdk2/cyclin A, cdk2/cyclin E and cdk4/cyclin D, and others, are serine/threonine kinases that regulats mammalian cell division. Additional serine/threom'ne kinases include the protein kinases A and B. These kinases, known as PKA or cyclic AMP-dependent protein kinase and PKB (Akt), play key roles in signal transduction pathways. Tyrosine kinases (TKs) are divided into two classes: the non-transmembrane TKs and transmembrane growth factor receptor TKs (RTKs). Growth factors, such as epidermal growth factor (EGF), bind to the extracellular domain of their partner RTK on the cell surface which activates the RTK, initiating a signal transduction cascade that controls a wide variety of cellular responses. In addition to EGF, there are several other RTKs including FGFR (the receptor for fibroblast growth factor (FGF)); flk-1 (also known as KDR), and flt-1 (the receptors for vascular endothelial growth factor (VEGF)); and PDGFR (the receptor for platelet derived growth factor (PDGF)). Other RTKs include tie-1 and tie-2, colony stimulating factor receptor, the nerve growth factor receptor, and the insulin-like growth factor receptor. In addition to the RTKs there is another family of TKs termed the cytoplasmic protein or non-receptor TKs. The cytoplasmic protein TKs have intrinsic kinase activity, are present in the cytoplasm and nucleus, and participate in diverse signaling pathways. There are a large number of non-receptor TKs including Abl, Jak, Fak, Syk, Zap-70 and Csk, and the Src family of kinases (SFKs) which include Src, Lck, Lyn, Fyn and others. Certain pyridine and pyrimidine derivatives have been noted as kinase inhibitors. These compounds differ both in nature and placement of substituents at various positions when compared to the compounds of the present teachings. SUMMARY The present teachings relate to substituted 3-cyanopyridines of formula I: (Formula Removed) and their pharmaceutically acceptable salts, hydrates, and esters, wherein R1, R2, and X are defined as described herein. The present teachings also relate to pharmaceutical compositions that include a pharmaceutically effective amount of one or more compounds of formula I (including their pharmaceutically acceptable salts, hydrates, and esters) and a pharmaceutically acceptable carrier or excipient. Another aspect of the present teachings relates to methods of preparing the compounds of formula I and their pharmaceutically acceptable salts, hydrates, and esters. The present teachings also provide methods of using the compounds of formula I and their pharmaceutically acceptable salts, hydrates, and esters. In some embodiments, the present teachings provide methods of treating autoimmune and inflammatory diseases, such as asthma, colitis, multiple sclerosis, psoriasis, arthritis, rheumatoid arthritis, osteoarthritis, and joint inflammation, which include administering ,a therapeutically effective amount of one or more compounds of formula I (or their pharmaceutically acceptable salts, hydrates, or esters) to a mammal including a human. Detailed Description The present teachings provide compounds of formula I: (Formula Removed) N I and their pharmaceutically acceptable salts, hydrates, and esters, wherein: X is selected from a) ~NR3-Y-, b) -O-Y-, c) -S(O)m-Y-, d) -S(O)mNR3-Y-, e) -NR3S(0)m-Y-, f) -C(O)NR3-Y- g) -C(S)NR3-Y-, h) -NR3C(O)-Y-, i) -NR3C(S)-Y-, j) -C(O)O-Y , k) -OC(O)-Y-, and 1) a covalent bond; Y, at each occurrence, independently is selected from a) a divalent C1-10 alkyl group, b) a divalent C1-10 alkenyl group, c) a divalent C2-10 alkynyl group, d) a divalent C1-10 haloalkyl group, and e) a covalent bond; R1 is selected from a) a C1-10 alkyl group, b) a C3-14 cycloalkyl group, c) a 3-14 membered cycloheteroalkyl group, d) a C8-14 polycyclic aryl group, and e) a 5-14 membered heteroaryl group, wherein each group optionally is substituted with 1-4 -Y R4; R is a C6-14 aryl group or a 5-14 membered heteroaryl group, wherein each group optionally is substituted with 1-4 groups independently selected from -Y-R4or-0-Y-R4; R3, at each occurrence, independently is selected from a) H, b) a C1-10 alkyl group, c) a C1-10 alkenyl group, d) a C2-10 alkynyl group, and e) a C1-10 haloalkyl group; R4, at each occurrence, independently is selected from a) halogen, b) -CN, c) -NO2, d) oxo, e) -O-Y-R5, f) -NR6-Y-R7, g) -N(O)R6-Y-R7, h) -S(0)m-Y-R5, i) -S(0)mO-Y-R\ j) -S(0)mNR6-Y-R7, k) -C(O)-Y-R5, 1) -C(O)O-Y-R5, m) -C(O)NR6-Y-R7, n) -C(S)NR6-Y-R7, o) a C1-10 alkyl group, p) a C1-10 alkenyl group, q) a C2-10 alkynyl group, r) a C1-10 haloalkyl group, s) a C3-14 cycloalkyl group, t) a C6-14 aryl group, u) a 3-14 membered cycloheteroalkyl group, and v) a 5-14 membered heteroaryl group, wherein each of o) - v) optionally is substituled with 1-4 -Y-R groups; R5, at each occurrence, independently is selected from a) H, b) -C(O)R9, c) -C(O)OR9, d) a C1-10 alkyl group, e) a C2-10 alkenyl group, f) a C2-10 alkynyl group, g) a C1-10 haloalkyl group, h) a C3-14 cycloalkyl group, i) a C6-14 aryl group, j) a 3-14 membered cycloheteroalkyl group, and k) a 5-14 membered heteroaryl group, wherein each of d) - k) optionally is substituted with 1-4 -Y-R8 groups; R6 and R7, at each occurrence, independently are selected from a) H, b) -O-Y-R9, c) -S(0)m-Y-R9, d) -S(0)mO-Y-R9, e) -C(O)-Y-R9, f) -C(O)O-Y-R9, g) -C(0)NR10-Y-R11, h) -C(S)NR10-Y-R11, i) a C1-10 alkyl group, j) a C2-10 alkenyl group, k) a C1-10 alkynyl group, 1) a C1-10 haloalkyl group, m) a C3-14 cycloalkyl group, n) a C3-14 aryl group, o) a 3-14 membered cycloheteroalkyl group, and p) a 5-14 membered heteroaryl group, wherein each of i) - p) optionally is substituted with 1-4 -Y-R8 groups; R8, at each occurrence, independently is selected from a) halogen, b) -CN, c) -N02, d) oxo, e) -O-Y-R9, f) -NR10-Y-R", g) -N(O)R10-Y-R11, h) - S(0)m-Y-R9, i) -S(0)mO- Y-R9, j) -S(0)mNR10-Y-R11, k) -C(O)-Y-R9, 1) -C(0)0-Y-R9, m) -C(0)NR10-Y-R11, n) -C(S)NR10-Y-R11, o) a CLIO alkyl group, p) a C2-10 alkenyl group, q) a C2-10 alkynyl group, r) a C1-10 haloalkyl group, s) a C3-14 cycloalkyl group, t) a C6-14 aryl group, u) a 3-14 membered cycloheteroalkyl group, and v) a 5-14 membered heteroaryl group, wherein each of o) - v) optionally is substituted with 1-4 -Y-R12 groups; R , at each occurrence, independently is selected from a) H, b) -C(O)-C1-10 alkyl, c) -C(O)OH, d) C(O)O-C1-10 alkyl, e) a C1-10 alkyl group, f) a C2-10 alkenyl group, g) a C2-10 alkynyl group, h) a C1-10 haloalkyl group, i) aC3-14 cycloalkyl group, j) a C3-14 aryl group, k) a 3-14 membered cycloheteroalkyl group, and 1) a 5-14 membered heteroaryl group, wherein each of the C1-10 alkyl group, the C2-10 alkenyl group, the C2-10 alkynyl group, the C1-10 haloalkyl group, the C3-14 cycloalkyl group, the C6-14 aryl group, the 3-14 membered cycloheteroalkyl group, and the 5-14 membered heteroaryl group optionally is substituted with 1-4 -Y-R1' groups; R1 and R11, at each occurrence, independently are selected from a) H, b) -OH, c) -SH, d) -NH2, e) -NH-C1-10 alkyl, f) -N(C1-10 alkyl)2, g) -S(O)m-C1-10 alkyl, h) -S(O)2OH, i) -S(O)m-OC1-10 alkyl, j) -C(O)-C1-10 alkyl, k) -C(0)OH, 1) -C(0)-OC1-10 alkyl, m) --C(O)NH2, n) -C(O)NH-C1-10 alkyl, o) -C(0)N(C1-10 alkyl)2, p) -C(S)NH2, q) -C(S)NH-C1-10 alkyl, r) -C(S)N(Ci. 10 alkyl)2, s) a C1-10 alkyl group, t) a C2-10 alkenyl group, u) a C2-10 alkynyl group, v) a C1-10 alkoxy group, w) a C1-10 haloalkyl group, x) aC3.14 cycloalkyl group, y) a C3-14 aryl group, z) a 3-14 membered cycloheteroalkyl group, and aa) a 5-14 membered heteroaryl group, wherein each of the C1-10 alkyl group, the C2-10 alkenyl group, the C2-10 alkynyl group, the C1-10 alkoxy group, the C1-10 haloalkyl group, the C3-14 cycloalkyl group, the C3-14 aryl group, the 3-14 membered cycloheteroalkyl group, and the 5-14 membered heteroaryl group optionally is substituted with 1-4 -Y-R12 groups; R12, at each occurrence, independently is selected from a) halogen, b) -CN, c) -NO2, d) oxo, e) -OH, f) -NH2, g) -NH(C1-10 alkyl), h) -N(C1-10 alkyl)2, i) -SH, j) -S(0)m-C1-10 alkyl, k) -S(O)2OH, 1) -S(O)m-OC1-10 alkyl, m) -C(O)-C1-10 alkyl, n) -C(O)OH, o) -C(O)~OC1-10 alkyl, p) -C(O)NH2, q) -C(0)NH-C1-10 alkyl, r) -C(O)N(C,-13 alkyl)2, s) -C(S)NH2, t) -C(S)NH-C1-10 alkyl, u) -C(S)N(C1-10) alkyl)2, v) a C1-10 alkyl group, w) a C2-10 alkenyl group, x) a C2-10 alkynyl group, y) a C1-10 alkoxy group, z) a C1-10 haloalkyl group, aa) a C3-14 cycloalkyl group, ab) a C6-14 aryl group, ac) a 3-14 membered cycloheteroalkyl group, and ad) a 5-14 membered heteroaryl group; and m is 0, 1, or 2. In some embodiments, the pyridine ring can be oxidized on the nitrogen atom to provide the corresponding N-oxide having the formula I': (Formula Removed) wherein R1, R2, and X are as defined herein. In some embodiments, X can be selected from -NR3-Y-, -O-Y-, and a covalent bond. For example, X can be selected from -NH-, -N(CH3)-, -NH-CH2-, NH-CH2CH2-, -NH-CH2CH2CH2-, -O-, and a covalent bond. In particular embodiments, X can be -NH-. In certain embodiments, R1 can be a C8-14 polycyclic (e.g., bicyclic or tricyclic) aryl group or a 5-14 membered heleroaryl group, wherein each of these groups can be optionally substituted with 1 -4 -Y-R4 groups, wherein Y and R4 are as defined herein. For example, R1 can be selected from a benzimidazolyl group, a benzodioxolyl group, a benzodioxinyl group, a benzodioxanyl group, a benzofuranyl group, a benzothienyl group, a benzoxadiazolyl group, a benzoxazolyl group, a benzisoxazolyl group, a benzothiadiazolyl group, a benzothiazolyl group, a benzisothiazolyl group, a benzo[c]isothiazolyl group, a benzo[c]thienyl group, a benzotriazolyl group, an indazolyl group, an indenyl group, an indanyl group, an indolyl group, an isobenzofuranyl group, an isoindolyl group, an isoquinolinyl group, a naphthyl group, an indolinyl group, a pyrazolyl group, a pyridinyl group, a pyrrolopyridinyl group, a pyrrolyl group, a quinolinyl group, and a tetrahydronaphthalenyl group, wherein each of these groups can be optionally substituted with 1-4 -Y-R4 groups, wherein Y and R4 are as defined herein. In particular embodiments, R1 can be an indolyl group or a pyrrolopyridinyl group, wherein each of these groups can be optionally substituted with 1-4 -Y-R4 groups, wherein Y and R4 are as defined herein. For example, R1 can be a 1H-indol-4-yl group, a 1H-indol-5-yl group, a 1H-indol-6-yl group, or a 1H-indol-7-yl group, wherein each of these groups can be optionally substituted with 1-4 groups independently selected from a halogen, a C1-4 alkyl group, and a C1-4 alkoxy group. In other embodiments, R1 can be a C3-14 cycloalkyl group or a 3-14 membered cycloheteroalkyl group, wherein each of these groups can be optionally substituted with 1-4 -Y-R4 groups, wherein Y and R4 are as defined herein. For example, R1 can be selected from a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a morpholinyl group, and a thiomorpholmyl group, wherein each of these groups can be optionally substituted with 1 -4 -Y-R4 groups, wherein Y and R4 are as defined herein. In some embodiments, Y, at each occurrence, can be independently a divalent C1-4 alkyl group or a covalent bond, and R4, at each occurrence, can be independently (CH2)n-NR6-Y-R7 or a C1-4 alkyl group, wherein n can be 0, 1, 2, 3, or 4, and Y, R6, and R7 are as defined herein. In some embodiments, R can be selected from a phenyl group, a C8-14 aryl group, and a 5-14 membered heteroaryl group, wherein each of these groups can be optionally substituted with 1 -4 groups independently selected from -Y—R4 and -O--Y— R4, wherein Y and R are as defined herein. For example, R2 can be selected from a phenyl group, a pyridyl group, a pyrimidyl group, a pyrazinyl group, a furyl group, a thienyl group, a thiazolyl group, an oxazolyl group, a benzofuranyl group, a benzothienyl group, an indolyl group, a benzodioxinyl group, a benzodioxolyl group, a benzodioxanyl group, a dibenzofuranyl group, a dibenzothienyl group, a benzoindolyl group, an indanyl group, an indenyl group, an isothiazolyl group, a pyridazinyl group, a pyrazolyl group, a tetrahydronaphthyl group, an isoxazolyl group, a quinolinyl group, a naphthyl group, an imidazolyl group, and a pyrrolyl group, wherein each of these groups can be optionally substituted with 1-4 groups independently selected from -Y--R4 or -O-Y-R4, wherein Y and R4 are as defined herein. In certain embodiments, R2 can be (Formula Removed) wherein D1, D2, and D3 independently can be H, a -Y-R4 group, or an -O-Y-R4 group, wherein Y and R4 are as defined herein. For example, at least one of D1, D2, and D3 can be a -Y-R4 group or an -O-Y-R4 group, wherein Y, at each occurrence, can be independently a divalent C1-4 alkyl group or a covalent bond, and R4, at each occurrence, can be independently selected from a halogen, -CN, -NO2, -O-Y-R5, -NR6-Y~R7, ~S(O)2-Y-R5, -S(O)2NR6-Y-R7, -C(O)-Y-R5, -C(O)O-Y-R5, -C(O)NR6-Y-R7, a C1-10 alkyl group, a C1-10haloalkyl group, a C3-14 cycloalkyl group, a C1-14 aryl group, a 3-14 membered cycloheteroalkyl group, and a 5-14 membered heteroaryl group, v/herein each of the C1-10 alkyl group, the C1-10 haloalkyl group, the C3-14 cycloalkyl group, the C6-14 aryl group, the 3-14 membered cycloheteroalkyl group, and the 5-14 membered heteroaryl group can be optionally substituted with 1-4 -Y-R8 groups, wherein Y, R5, R6, R7, and R are as defined herein. In certain embodiments, at least one of D1, D , and D can be an -O— (CH2)n-R4 group, wherein n, at each occurrence, independently can be 0, 1, 2, 3, or 4, and R4, at each occurrence, can be independently selected from F, Cl, Br, -NO2, -O-Y-R5, -NR6-Y-R7, S(O)2-Y-R5, -S(O)2NR6-Y-R7, -C(O)NR6-Y-R7, a C1-10 alkyl group, a C3-14 cycloalkyl group, a C6-14 aryl group, a 3-14 membered cycloheteroalkyl group, and a 5-14 membered heteroaryl group, wherein each of the C1-10 alkyl group, the C3-14 cycloalkyl group, the C6-14 aryl group, the 3-14 membered cycloheteroalkyl group, and the 5-14 membered heteroaryl group can be optionally substituted with 1-4 -Y-R8 groups, wherein Y, R5, R6, R7, and R8 are as defined herein. In particular embodiments, at least one of D1, D2, and D3 can be -O-(CH2)nNR6-Y-R7 or an -O-(CH2)n-3-14 membered cycloheteroalkyl group, wherein the 3-14 membered cycloheteroalkyl group can be optionally substituted with 1-4 -Y-R groups, wherein Y, R6, R7, and R8 are as defined herein, and n, at each occurrence, independently can be 0, 1,2, 3, or 4. In some embodiments, at least one of D1, D2, and D3 can be -(CH2)nNR6-Y-R7 or a -(CH2)n-3-14 membered cycloheteroalkyl group, wherein the 3-14 membered cycloheteroalkyl group can be optionally substituted with 1-4 -Y-R8 groups, Y, R6, R7, and R8 are as defined herein, and n, at each occurrence, independently can be 0, 1, 2, 3, or 4. In embodiments where at least one of D1, D , and D3 can be an -O-(CH2)nNR6-Y-R7 group or a -(CH2)nNR6-Y R7 group, the -O-(CH2)nNR6-Y-R7 group and the -(CH2)nNR6-Y-R7 group can be -O-(CH2)nNH-Y-R7 or -O-(CH2)nN(CH3)-Y-R7, and -(CH2)nNH-Y-R7 or -{CH2)nN(CH3)-Y-R7, respectively, wherein Y, at each occurrence, can be independently a divalent C1-4 alkyl group or a covalent bond, and R7, at each occurrence, can be independently selected from -O-Y-R9, -C(O)-Y-R9, -C(O)O-Y-R9, -C(O)NR10-Y-R11, a C1-10 alkyl group, a C3-14 cycloalkyl group, a C6-14 aryl group, a 3-14 membered cycloheteroalkyl group, and a 5-14 membered heteroaryl group, wherein each of the C1-10 alkyl group, the C3-14 cycloalkyl group, the C6-14 aryl group, the 3-14 membered cycloheteroalkyl group, and the 5-14 membered heteroaryl group can be optionally substituted with 1-4 -Y-R12 groups, wherein Y and R12 are as defined herein. For example, the C3-14 cycloalkyl group, the C6-14 aryl group, the 3-14 membered cycloheteroalkyl group, and the 5-14 membered heteroaryl group can be selected from a cyclopentyl group, a cyclohexyl group, a phenyl group, a pyrrolidinyl group, a morpholinyl group, a piperazinyl group, a piperidinyl group, an azepanyl group, a diazepanyl group, a thiomorpholinyl group, a furyl group, an imidazolyl group, and a pyridinyl group, wherein each of these groups can be optionally substituted with 1-4 -Y-R12 groups, wherein Y and R12 are as defined herein. In embodiments where at least one of D1, D2, and D3 can be an -O-(CH2)n-3-14 membered cycloheteroalkyl group or a -(CH2)n-3-14 membered cycloheteroalkyl group, the 3-14 membered cycloheteroalkyl group can be selected from a pyrrolidinyl group, a morpholinyl group, a piperazinyl group, a piperidinyl group, an azepanyl group, a diazepanyl group, and a thiomorpholinyl group, wherein each of these groups can be optionally substituted with 1 -4 -Y-R8 groups, wherein Y and R8 are as defined herein. For example, Y, at each occurrence, can be independently a divalent C1-4 alkyl group or a covalent bond, and R8, at each occurrence, can be independently an oxo group, -0-Y-R9, -NR10-Y-R11, -S(O)m-Y-R9, -C(O)O-Y-R9, a C1-10 alkyl group, a C3-14 cycloalkyl group, a C6-14 aryl group, a 3-14 membered cycloheteroalkyl group, and a 5-14 membered heteroaryl group, wherein each of the C1-10 alkyl group, the C3-14 cycloalkyl group, the C6-14 aryl group, the 3-14 membered cycloheteroalkyl group, and the 5-14 membered heteroaryl group can be optionally substituted with 1-4 -Y-R12 groups, wherein Y and R12 are as defined herein. For example, the C3-14 cycloalkyl group, the C3-14 aryl group, the 3-14 membered cycloheteroalkyl group, and the 5-14 membered heteroaryl group can be selected from a cyclopentyl group, a cyclohexyl group, a phenyl group, a pyrrolidinyl group, a morpholinyl group, a piperazinyl group, a piperidinyl group, an azepanyl group, a diazepanyl group, a thiomorpholinyl group, a furyl group, an imidazolyl group, and a pyridinyl group, wherein each of these groups can be optionally substituted with 1-4 -Y-R12 groups, wherein Y and R12 are as defined herein. Alternatively or concurrently, at least one of D1, D2, and D3 can be selected from halogen, -CN, -NO2, -S(O)2-Y-R5, -S(O)2NR6-Y-R7, -C(O)O-Y-R5, -C(O)NR6-Y-R7, a C1-10 alkyl group, and a C1-10 haloalkyl group, wherein Y, R5, R6, and R7 are as defined herein. In some embodiments, at least two of D1, D2, and D3 can be -O-(CH2)n-R4 groups, wherein n, at each occurrence, independently can be 0, 1, 2, 3, or 4, and R4, at each occurrence, can be independently selected from F, Cl, Br, -NO2, -O-Y-R5, -NR6-Y-R7, -S(O)2-Y-R5, -S(O)2NR6-Y-R7, -C(O)NR6-Y-R7, a C1-10 alkyl group, a C3-14 cycloalkyl group, a C6-14 aryl group, a 3-14 membered cycloheteroalkyl group, and a 5-14 membered heteroaryl group, wherein each of the C1-10 alkyl group, the C3-14 cycloalkyl group, the C6-14 aryl group, the 3-14 membered cycloheteroalkyl group, and the 5-14 membered heteroaryl group can be optionally substituted with 1-4 —Y—R groups, wherein Y, R5, R6, R7, and R8 are as defined herein. In certain embodiments, at least two of D1, D2, and D3 can be independently an -O-CH3 group or an -O-(CH2)n-O-Y-R5 group, wherein Y and R5 are as defined herein, and n, at each occurrence, independently can be 0, 1, 2, 3, or 4. In certain embodiments, two of D1, D2, and D3 can be -O-CH3 groups. In other embodiments, two of D1, D2, and D3 can be -O-(CH2)n-O-Y-R5 groups or alternatively, an -O-CH3 group and an -O-(CH2)n-O-Y-Rs group, wherein Y and R5 are as defined herein, and n, at each occurrence, independently can be 0, 1, 2, 3, or 4. In certain embodiments, at least one; of D1, D , and D3 can be -O-CHs, and at least one of D1, D2, and D3 can be an -O-(C H2)nNR6-Y-R7 group or an -O-(CH2)n 3-14 membered cycloheteroalkyl group, wherein the 3-14 membered cycloheteroalkyl group can be optionally substituted with 1-4 -Y-R8 groups, wherein Y, R6, R7, and R8 are as defined herein, and n, at each occurrence, independently can be 0, 1, 2, 3, or 4. In some embodiments, one of D1, D'!, and D3 can be (Formula Removed) wherein R8, at each occurrence, independently can be selected from -O-Y-R9, -NR10-Y-R11, a C6-14 aryl group, and a 5-14 membered heteroaryl group, wherein each of the C6-14 aryl group and the 5-14 membered heteroaryl group can be optionally substituted with 1-4 -Y-R12 groups, wherein Y, R9, R10, R11, and R12 are as defined herein, and n, at each occurrence, independently can be 0, 1, 2, 3, or 4. In certain embodiments, at least one of D1, D2, and D3 can be a C6-14 aryl group or a 5-14 membered heteroaryl group, wherein each of these groups can be optionally substituted with 1 -4 —Y-R groups, wherein Y and R are as defined herein. For example, at least one of D1, D2, and D3 can be selected from a benzothienyl group, a benzofuryl group, a furyl group, a pyridyl group, a pyrimidinyl group, a pyrrolyl group, and a thienyl group, wherein each of these groups can be optionally substituted with 1-4 -Y-R8 groups, wherein Y and R8 are as defined herein. In particular embodiments, Y, at each occurrence, can be independently a C1-4 alkyl group or a covalent bond, and R8 can be independently selected from a halogen, -CN, -NO2, ~O-Y-R9, -NR10-Y-R11, -C(O)-Y-R9, -C(O)NR10-Y-R11, -S(O)2-Y-R9, -S(O)2NR10-Y-R11, and a 3-14 membered cycloheteroalkyl group optionally substituted with a C1-4 alkyl group, wherein Y, R9, R10, and R1' are as defined herein. In other embodiments, R2 can be a C8-14 bicyclic aryl group or a 5-14 membered heteroaryl group, where each of these groups can be optionally substituted with 1-4 groups independently selected from -Y-R groups and -O-Y-R4 groups, wherein Y and R4 are as defined herein. In particular embodiments, R2 can be selected from a benzothienyl group, a benzofuryl group, a furyl group, a pyridyl group, a pyrimidinyl group, a pyrazinyl group, a thienyl group, an imidazolyl group, an isoxazolyl group, a thiazolyl group, an oxazolyl group, an indolyl group, a benzodioxol} 1 group, a benzodioxanyl group, and a dibenzofuranyl group, wherein each of these groups can be optionally substituted with 1-4 groups independently selected from a -(CH2)n-R4 group and an -O-(CH2)n-R4 group, wherein n, at each occurrence, independently can be 0, 1, 2, 3, or 4, and R4, at each occurrence, can be independently -NR —Y-R or a 3-14 membered cycloheteroalkyl group optionally substituted with 1 -4 -Y-R group, wherein Y, R6, R7 and R8 are as defined herein. For example, R4 can be -O-(CH2)nNH-Y-R7, -CKCH2)nN(CH3)-Y-R7, -(CH2)nNH-Y-R7, or -(CH2)nN(CH3)-Y-R7, wherein Y, at each occurrence, can be independently a divalent d_4 alkyl group or a covalent bond, and R7, at each occurrence, can be independently selected from -O-Y-R9, -C(O)-Y-R9, -C(O)O-Y-R9, -C(O)NR10-Y-R11, a C1-10 alkyl group, a C3-14 cycloalkyl group, a C6-14 aryl group, a 3-14 membered cycloheteroalkyl group, and a 5-14 membered heteroaryl group, wherein each of the C1-10 alkyl group, the C3-14 cycloalkyl group, the C6-14 aryl group, the 3-14 membered cycloheteroalkyl group, and the 5-14 membered heteroaryl group can be optionally substituted with 1-4 -Y-R12 groups, wherein Y and R12 are as defined herein. In particular embodiments, R7 can be a C3-14 cycloalkyl group, aC6-14 aryl group, a 3-14 membered cycloheteroalkyl group, or a 5-14 membered heteroaryl group selected from a cyclopentyl group, a cyclohexyl group, a phenyl group, a pyrrolidinyl group, a morpholinyl group, a piperazinyl group, a piperidinyl group, an azepanyl group, a diazepanyl group, a thiomorpholinyl group, a furyl group, an imidazolyl group, and a pyridinyl group, wherein each of these groups can be optionally substituted with 1-4 -Y-R12 groups, wherein Y and R12 are as defined herein. Alternatively, R4 can be an -O-(CH2)n-3-14 membered cycloheteroalkyl group or a a -{CH2)n-3-14 membered cycloheteroalkyl group, wherein the 3-14 membered cycloheteroalkyl group can be selected from a pyrrolidinyl group, a morpholinyl group, a piperazinyl group, a piperidinyl group, an azepanyl group, a diazepanyl group, and a thiomorpholinyl group, wherein each of these groups can be optionally substituted with 1-4 -Y-R8 groups, wherein Y and R8 are as defined herein. For example, Y, at each occurrence, can be independently a divalent C1-4 alkyl group or a covalent bond, and R8, at each occurrence, can be independently an oxo group, -O-Y-R9, -NR10-Y-R11, -S(0)ra-Y-R9, -C(O)0-Y-R9, a CLIO alkyl group, a C3-14 cycloalkyl group, a C6-14 aryl group, a 3-14 membered cycloheteroalkyl group, and a 5-14 membered heteroaryl group, wherein each of the C1-10 alkyl group, theC3-14 cycloalkyl group, the C6-14 aryl group, the 3-14 membered cycloheteroalkyl group, and the 5-14 membered heteroaryl group can be optionally substituted with 1-4 -Y-R12 groups, wherein Y and R12 are as defined herein. For example, R8 can be a C3-14 cycloalkyl group, a C6-14 aryl group, a 3-14 membered cycloheteroalkyl group, and a 5-14 membered heteroaryl group selected from a cyclopentyl group, a cyclohexyl group, a phenyl group, a pyrrolidinyl group, a morpholinyl group, a piperazinyl group, a piperidinyl group, an azepanyl group, a diazepanyl group, a thiomorpholinyl group, a furyl group, an imidazolyl group, and a pyridinyl group, wherein each of these groups can be optionally substituted with 1-4 -Y-R12 groups, wherein Y and R12 are as defined herein. Compounds of the present teachings include the compounds presented in Table 1 below. Table 1 (Table Removed) Pharmaceutically acceptable salts of the compounds of formula I, which can have an acidic moiety, can be formed using organic and inorganic bases. Both mono and polyanionic salts are contemplated, depending on the number of acidic hydrogens available for deprotonation. Suitable salts formed with bases include metal salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium, or magnesium salts; ammonia salts and organic amine salts, such as those formed with morpholine, thiomorpholine, piperidine, pyrrolidine, a mono-, di- or tri-lower alkylamine (e.g., ethyl-tert-butyl-, diethyl-, diisopropyl-, triethyl-, tributyl- or dimethylpropylamine), or a mono-, di-, or trihydroxy lower alkylamine (e.g., mono-, di-or triethanolamine). Specific non-limiting examples of inorganic bases include NaHCO3, Na2CO3, KHCO3, K2CO3, Cs2CO3, LiOH, NaOH, KOH, NaH2PO4, Na2HPO4, and Na3PO4. Internal salts also can be formed. Similarly, when a compound disclosed herein contains a basic moiety, salts can be formed using organic and inorganic acids. For example, salts can be formed from the following acids: acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, dichloroacetic, ethenesulfonic, formic, fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, malonic, mandelic, methanesulfonic, mucic, naphthalenesulfonic, nitric, oxalic, pamoic, pantothenic, phosphoric, phthalic, propionic, succinic, sulfuric, tartaric, and toluenesulfonic, as well as other known pharmaceutically acceptable acids. Esters of the compounds of formula [ can include various pharmaceutically acceptable esters known in the art that can be metabolized into the free acid form (e.g., a free carboxylic acid form) in a mammal. Examples of such esters include alkyl esters (e.g., of 1 to 10 carbon atoms), cycloalkyl esters (e.g., of 3-10 carbon atoms), aryl esters (e.g., of 6-14 carbon atoms, including of 6-10 carbon atoms), and heterocyclic analogues thereof (e.g., of 3-14 ring atoms, 1-3 of which can be selected from oxygen, nitrogen, and sulfur heteroatoms), wherein the alcohol residue can include further substituents. In some embodiments, esters of the compounds disclosed herein can be C1-10 alkyl esters, such as methyl esters, ethyl esters, propyl esters, isopropyl esters, butyl esters, isobutyl esters, t-butyl esters, pentyl esters, isopentyl esters, neopentyl esters, and hexyl esters; C3-10 cycloalkyl esters, such as cyclopropyl esters, cyclopropylmethyl esters, cyclobutyl esters, cyelopentyl esters, and cyclohexyl esters; or aryl esters, such as phenyl esters, benzyl esters, and tolyl esters. Also provided in accordance with the present teachings are prodrugs of the compounds disclosed herein. As used herein, "prodrug" refers to a moiety that produces, generates or releases a compound of the present teachings 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 by routine manipulation or in vivo, from the parent compounds. Examples of prodrugs include compounds as described herein that contain one or more molecular moieties appended to a hydroxyl, amino, sulfhydryl, or carboxyl group of the compound, and that when administered to a mammalian subject, is cleaved in vivo to form the free hydroxyl, amino, sulfhydryl, or carboxyl group, respectively. Examples of prodrugs can include acetate, formate, and benzoate derivatives of alcohol and amine functional groups in the compounds of the present teachings. Preparation 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, the entire disclosures of which are incorporated by reference herein for all purposes. The present teachings also provide pharmaceutical compositions that include at least one compound described herein and one or more pharmaceutical!y acceptable carriers, excipients, or diluents. Examples of such carriers are well known to those skilled in the art and can be prepared in accordance with acceptable pharmaceutical procedures, such as, for example, those described in Remington: The Science and Practice of Pharmacy, 20th edition, ed. Alfonso R. Gennaro, Lippincott Williams & Wilkins, Baltimore, MD (2000), the entire disclosure of which is incorporated by reference herein for all purposes. As used herein, "pharmaceutically acceptable" refers to a substance that is acceptable for use in pharmaceutical applications from a toxicological perspective and does not adversely interact with the active ingredient. Accordingly, pharmaceuticaHy acceptable carriers are those that are compatible with the other ingredients in the formulation and are biologically acceptable. Supplementary active ingredients can also be incorporated into the pharmaceutical compositions. Compounds of the present teachings can be useful for treating a pathological condition or disorder in a mammal, for example, a human. As used herein, "treating" refers to partially or completely alleviating and'or ameliorating the condition and/or symptoms thereof. The present teachings accordingly include a method of providing to a mammal a pharmaceutical composition that includes a compound of the present teachings in combination or association with a pharmaceutically acceptable carrier. Compounds of the present teachings can be administered alone or in combination with other therapeutically effective compounds or therapies for the treatment of a pathological condition or disorder. As used herein, "therapeutically effective" refers to a substance or an amount that elicits a desirable b iological activity or effect. The present teachings also include use of the compounds disclosed herein as active therapeutic substances for the treatment of a pathological condition or disorder mediated by a protein kinase such as protein kinase C (PKC) and its theta isoform (PKC9). The pathological condition or disorder can include inflammatory diseases and autoimmune diseases such as asthma, colitis, multiple sclerosis, psoriasis, arthritis, rheumatoid arthritis, osteoarthritis, and joint inflammation. Accordingly, the present teachings further provide methods of treating these pathological conditions and disorders using the compounds described herein. In some embodiments, the methods include identifying a mammal having a pathological condition or disorder mediated by a protein kinase such as PKC and PKC6, and providing to the mammal an effective amount of a compound as described herein. In some embodiments, the method includes administering to a mammal a pharmaceutical composition that includes a compound disclosed herein in combination or association with a pharmaceutically acceptable carrier. The present teachings further include use of the compounds disclosed herein as active therapeutic substances for the prevention and/or inhibition of the pathological condition or disorder listed above. Accordingly, the present teachings further provide methods of preventing and/or inhibiting these pathological conditions and disorders using the compounds described herein. In some embodiments, the methods include identifying a mammal having a pathological condition or disorder mediated by a protein kinase such as PKC and PKCθ, and providing to the mammal an effective amount of a compound as described herein. In some embodiments, the method includes administering to a mammal a pharmaceutical composition that includes a compound disclosed herein in combination or association with a pharmaceutically acceptable carrier. Compounds of the present teachings can be administered orally or parenterally, neat or in combination with conventional pharmaceutical carriers. Applicable solid carriers can include one or more substances which can also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents, or encapsulating materials. The compounds can be formulated in conventional manner, for example, in a manner similar to that used for known antiinflammatory agents. Oral formulations containing an active compound disclosed herein can include any conventionally used oral form, including tablets, capsules, buccal forms, troches, lozenges and oral liquids, suspensions or solutions. In powders, the carrier can be a finely divided solid, which is an admixture with a finely divided active compound. In tablets, an active compound can be mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets may contain up to 99% of the active compound. Capsules can contain mixtures of active compound(s) with inert filler(s) and/or diluent(s) such as the pharmaceutically acceptable starches (e.g., corn, potato or tapioca starch), sugars, artificial sweetening agents, powdered celluloses (e.g., crystalline and microcrystalline celluloses), flours, gelatins, gums, and the like. Useful tablet formulations can be made by conventional compression, wet granulation or dry granulation methods and utilize pharmaceutically acceptable diluents, binding agents, lubricants, disintegrates, surface modifying agents (including surfactants), suspending or stabilizing agents, including magnesium stearate, stearic acid, sodium lauryl sulfate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, microcrystalline cellulose, sodium carboxymethyl cellulose, carboxymethylcellulose calcium, polyvinylpyrrolidine, alginic acid, acacia gum, xanthan gum, sodium citrate, complex silicates, calcium carbonate, glycine, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, low melting waxes, and ion exchange resins. Preferred surface modifying agents include nonionic and anionic surface modifying agents. Representative examples of surface modifying agents include poloxamer 188, benzalkonium chloride, calcium stearate, cetostearl alcohol, cetomacrogol emulsifying wax, sorbitan esters, colloidal silicon dioxide, phosphates, sodium dodecylsulfate, magnesium aluminum silicate, and triethanolamine. Oral formulations herein can utilize standard delay or time-release formulations to alter the absorption of the active compound(s). The oral formulation can also comprise a compound as described herein in water or fruit juice, containing appropriate solubilizers or emulsifiers as needed. Liquid carriers can be used in preparing solutions, suspensions, emulsions, syrups, elixirs, and for inhaled delivery. A compound described herein can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, or a mixture of both, or pharmaceutically acceptable oils or fats. The liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers, and osmo-regulators. Examples of liquid carriers for oral and parenteral administration include water (particularly containing additives as described above, e.g., cellulose derivatives such as a sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g., glycols) and their derivatives, and oils (e.g., fractionated coconut oil and arachis oil). For parenteral administration, the carrier can be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration. The liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellants. Liquid pharmaceutical compositions, which are sterile solutions or suspensions, can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. Compositions for oral administration can be in either liquid or solid form. Preferably the pharmaceutical composition is in unit dosage form, for example, as tablets, capsules, powders, solutions., suspensions, emulsions, granules, or suppositories. In such form, the pharmaceutical composition can be sub-divided in unit dose(s) containing appropriate quantities of the active compound. The unit dosage forms can be packaged compositions, for example, packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids. Alternatively, the unit dosage form can be a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form. Such unit dosage form may contain from about 1 mg/kg of active compound to about 500 mg/kg of active compound, and can be given in a single dose or in two or more doses. Such doses can be administered in any manner useful in directing the active compound(s) to the recipient's bloodstream, including orally, via implants, parenterally (including intravenous, intraperitoneal and subcutaneous injections), rectally, vaginally, and transdermally. Such administrations can be carried out using the compounds of the present teachings including pharmaceutically acceptable salts thereof, in lotions, creams, foams, patches, suspensions, solutions, and suppositories (rectal amd vaginal). When administered for the treatment or inhibition of a particular disease state or disorder, it is understood that an effective dosage can vary depending upon many factors such as the particular compound utilized, the mode of administration, and severity of the condition being treated, as well as. the various physical factors related to the individual being treated. In therapeutic applications, a compound of the present teachings can be provided to a patient already suffering from a disease in an amount sufficient to cure or at least partially ameliorate the symptoms of the disease and its complications. The dosage to be used in the treatment of a specific individual typically must be subjectively determined by the attending physician. The variables involved include the specific condition and its state as well as the size, age and response pattern of the patient. In some cases, for example those in which the lung is the targeted organ, it may be desirable to administer a compound directly to the airways of the patient, using devices such as metered dose inhalers, breath-operated inhalers, multidose dry-powder inhalers, pumps, squeeze-actuated nebulized spray dispensers, aerosol dispensers, and aerosol nebulizers. For administration by intranasal or intrabronchial inhalation, the compounds of the present teachings can be formulated into a liquid composition, a solid composition, or an aerosol composition. The liquid composition can include, by way of illustration, one or more compounds of the present teachings dissolved, partially dissolved, or suspended in one or more phammceutically acceptable solvents and can be administered by, for example, a pump or a squeeze-actuated nebulized spray dispenser. The solvents can be, for example, isotonic saline or bacteriostatic water. The solid composition can be, by way of illustration, a powder preparation including one or more compounds of the present teachings intermixed with lactose or other inert powders that are acceptable for intrabronchial use, and can be administered by, for example, an aerosol dispenser or a device that breaks or punctures a capsule encasing the solid composition and delivers the solid composition for inhalation. The aerosol composition can include, by way of illustration, one or more compounds of the present teachings, propellants, surfactants, and co-solvents, and can be administered by, for example, a metered device. The propellants can be a chlorofluorocarbon (CFC), a hydrofluoroalkane (HFA), or other propellants that are physiologically and environmentally acceptable. Compounds described herein can be administered parenterally or intraperitoneally. Solutions or suspensions of these active compounds or pharmaceutically acceptable salts, hydrates, or esters thereof can be prepared in water suitably mixed with a surfactant such as hydroxyl-propylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations typically contain a preservative to inhibit the growth of microorganisms. The pharmaceutical forms suitable for injection can include sterile aqueous solutions or dispersions and sterile powders lor the extemporaneous preparation of sterile injectable solutions or dispersions. In preferred embodiments, the form is sterile and its viscosity permits it to flow through a syringe. The form preferably is stable under the conditions of manufacture and storage and can be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils. Compounds described herein can be administered transdermally, i.e., administered across the surface of the body and the inner linings of bodily passages including epithelial and mucosal tissues. Such administration can be carried out using the compounds of the present teachings including pharmaceutically acceptable salts, hydrates, and esters thereof, in lotions, creams, foams, patches, suspensions, solutions, and suppositories (rectal and vaginal). Topical formulations that deliver active compound(s) through the epidermis can be useful for localized treatment of inflammation and arthritis. Transdermal administration can be accomplished through the use of a transdermal patch containing an active compound and a carrier that can be inert to the active compound, can be non-toxic to the skin, and can allow delivery of the active compound for systemic absorption into the blood stream via the skin. The carrier can take any number of forms such as creams and ointments, pastes, gels, and occlusive devices. The creams and ointments can be viscous liquid or semisolid emulsions of either the oil-in-water or water-in-oil type. Pastes comprised of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the active compound can also be suitable. A variety of occlusive devices can be used to release the active compound into the blood stream, such as a semi-permeable membrane covering a reservoir containing the active compound with or without a carrier, or a matrix containing the active compound. Other occlusive devices are known in the literature. Compounds described herein can be administered rectally or vaginally in the form of a conventional suppository. Suppository formulations can be made from traditional materials, including cocoa butter, with or without the addition of waxes to alter the suppository's melting point, and glycerin. Water-soluble suppository bases, such as polyethylene glycols of various molecular weights, can also be used. Lipid formulations or nanocapsules can be used to introduce compounds of the present teachings into host cells either in vitro or in vivo. Lipid formulations and nanocapsules can be prepared by methods known in the art. To increase the effectiveness of compounds of the present teachings, it can be desirable to combine a compound with other agents effective in the treatment of the target disease. For inflammatory diseases, other active compounds (i.e., other active ingredients or agents) effective in their treatment, and particularly in the treatment of asthma and arthritis, can be administered with active compounds of the present teachings. The other agents can be administered at the same time or at different times than the compounds disclosed herein. Throughout the description, where compositions are described as having, including, or comprising specific components, or where processes are described as having, including, or comprising specific process steps, it is contemplated that compositions of the present teachings also consist essentially of, or consist of, the recited components, and that the processes of the present teachings also consist essentially of, or consist of, the recited processing steps. In the application, where an element or component is said to be included in and/or selected from a list of recited elements or components, it should be understood that the element or component can be any one of the recited elements or components and can be selected from a group consisting of two or more of the recited elements or components. The use of the term "include" should be generally understood as open-ended and non-limiting unless specifically stated otherwise. The use of the singular herein includes the plural (and vice versa) unless specifically stated otherwise. In addition, where the use of the term "about" is before a quantitative value, the present teachings also include the specific quantitative value itself, unless specifically stated otherwise. It should be understood that the order of steps or order for performing certain actions is immaterial so long as the present teachings remain operable. Moreover, two or more steps or actions may be conducted simultaneously. As used herein, a "compound" refers to the compound itself and its pharmaceutically acceptable salts, hydrates and esters, unless otherwise understood from the context of the description or expressly limited to one particular form of the compound, i.e., the compound itself, or a pharmaceutically acceptable salt, hydrate or ester thereof. As used herein, "halo" or "halogen" refers to fluoro, chloro, bromo, and iodo. As used herein, "oxo" refers to a double-bonded oxygen (i.e., =O). As used herein, as a moiety or part of a moiety, "alky!" refers to a straight-chain or branched saturated hydrocarbon group. In some embodiments, an alkyl group can have from 1 to 10 carbon atoms (e.g, from 1 to 6 carbon atoms). Examples of alkyl groups include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, s-butyl, t-butyl), pentyl groups (e.g., n-pentyl, isopentyl, neopentyl), and the like. In some embodiments, alkyl groups can be substituted with up to four independently selected -Y R4, -Y-R8 or R12 groups, where Y, R4, R8 and R12 are as described herein. A lower alkyl group typically has up to 6 carbon atoms, i.e., one to six carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl (e.g., n-propyl and isopropyl), and butyl groups (e.g., n-butyl, isobutyl, s-butyl, t-butyl). As used herein, as a moiety or part of a moiety, "alkenyl" refers to a straight-chain or branched alkyl group having one or more carbon-carbon double bonds. In some embodiments, an alkenyl group can have from 2 to 10 carbon atoms (e.g., from 2 to 6 carbon atoms). Examples of alkenyl groups include ethenyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl groups, and the like. The one or more carbon-carbon double bonds can be internal (such as in 2-butene) or terminal (such as in 1-butene). In some embodiments, alkenyl groups can be substituted with up to four independently selected -Y-R8 or R12 groups, where Y, R8, and R12 are as described herein. As used herein, as a moiety or part of a moiety, "alkynyl" refers to a straight-chain or branched alkyl group having one or more carbon-carbon triple bonds. In some embodiments, an alkynyl group can have from 2 to 10 carbon atoms (e.g., from 2 to 6 carbon atoms). Examples of alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, and the like. The one or more carbon-carbon triple bonds can be internal (such as in 2-butyne) or terminal (such as in 1-butyne). In some embodiments, alkynyl groups can be substituted with up to four independently selected -Y-R8 or R12 groups, where Y, R8, and R12 are as described herein. As used herein, "alkoxy" refers to an -O-alkyl group. In some embodiments, an alkoxy group can have from 1 to 10 carbon atoms (e.g., from 1 to 6 carbon atoms). Examples of alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy groups, and the like. As used herein, "alkylthio" refers to an —S—alkyl group. Examples of alkylthio groups include methylthio, ethylthto, propylthio (e.g., n-propylthio and isopropylthio), t-butylthio groups, and the like. As used herein, "haloalkyl" refers to an alkyl group having one or more halogen substituents. In some embodiments, a haloalkyl group can have from 1 to 10 carbon atoms (e.g., from 1 to 6 carbon atoms). Examples of haloalkyl groups include CF3, C2F5, CHF2, CH2F, CC13, CHC12, CH2C1, C2C15, and the like. Perhaloalkyl groups, i.e., alkyl groups wherein all of the hydrogen atoms are replaced with halogen atoms (e.g., CF3 and C2F5), are included within the definition of "haloalkyl." As used herein, "cycloalkyl" refers to a non-aromatic carbocyclic group including cyclized alkyl, alkenyl, and alkynyl groups. A cycloalkyl group can be monocyclic (e.g., cyclohexyl) or polycyclic (e.g., containing fused, bridged, and/or spiro ring systems), wherein the carbon atoms are located inside or outside of the ring system. A cycloalkyl group, as a whole, can have from 3 to 14 ring atoms (e.g., from 3 to 8 carbon atoms for a monocyclic cycloalkyl group and from 7 to 14 carbon atoms for a polycyclic cycloalkyl group). Any suitable ring position of the cycloalkyl group can be covalently linked to the defined chemical structure. Examples of cycloalkyl groups include cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, cyclohexylethyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcaryl, adamantyl, and spiro[4.5]decanyl groups, as well as their hornologs, isomers, and the like. In some embodiments, cycloalkyl groups can be substituted with up to four independently selected -Y-R4, -Y-R8 or R12 groups, where Y, R4, R8, and R12 are as described herein. For example, cycloalkyl groups can include substitution of one or more oxo groups. As used herein, "heteroatom" refers to an atom of any element other than carbon or hydrogen and includes, for example, nitrogen, oxygen, sulfur, phosphorus, and selenium. As used herein, "cycloheteroalkyl" refers to a non-aromatic cycloalkyl group that contains at least one ring heteroatom selected from O, N and S, which may be the same or different, and optionally contains one or more double or triple bonds. A cycloheteroalkyl group, as a whole, can have, for example, from 3 to 14 ring atoms and contains from 1 to 5 ring heteroatoms (e.g., from 3-7 ring atoms for a monocyclic cycloheteroalkyl group and from 7 to 14 ring atoms for a polycyclic cycloheteroalkyl group). One or more N or S atoms in a cycloheteroalkyl ring may be oxidized (e.g., morpholine N-oxide, thiomorpholine S-oxide, thiomorpholine S,S-dioxide). In some embodiments, nitrogen atoms of cycloheteroalkyl groups can bear a substituent, for example, a -Y-R8 group or an R12 group, when; Y, R8, and R1 as described herein. Cycloheteroalkyl groups can also contain one or more oxo groups, such as piperidone, oxazolidinone, pyrimidine-2,4(lH,3H)-dione, pyridin-2(lH)-one, and the like. Examples of cycloheteroalkyl groups include, among others, morpholine, thiomorpholine, pyran, imidazolidine, imidazoline, oxazolidine, pyrazolidine, pyrazoline, pyrrolidine, pyrroline, terrahydrofuran, tetrahydrothiophene, piperidine, piperazine, and the like. In some embodiments, cycloheteroalkyl groups can be optionally substituted with up to four independently selected -Y-R4, -Y-R8 or R12 groups, where Y, R4, R8, and R12 are as described herein. As used herein, "aryl" refers to an aromatic monocyclic hydrocarbon ring system or a polycyclic ring system in which two or more aromatic hydrocarbon rings are fused (i.e., having a bond in common with) together or at least one aromatic monocyclic hydrocarbon ring is fused to one or more cycloalkyl and/or cycloheteroalkyl rings. An aryl group can have: from 6 to 14 carbon atoms in its ring system, which can include multiple fused rings. In some embodiments, a polycyclic aryl group can have from 8 to 14 carbon atoms. Any suitable ring position of the aryl group can be covalently linked to the defined chemical structure. Examples of aryl groups having only aromatic carbocyclic ring(s) include phenyl, 1-naphthyl (bicyclic), 2-naphthyl (bicyclic), anthracenyl (tricyclic), phenanthrenyl (tricyclic) and like groups. Examples of polycyclic ring systems in which at least one aromatic carbocyclic ring is fused to one or more cycloalkyl and/or cycloheteroalkyl rings include, among others, benzo derivatives of cyclopentane (i.e., an indanyl group, which is a 5,6-bicyclic cycloalkyl/aromatic ring system), cyclohexane (i.e., a tetrahydronaphthyl group, which is a 6,6-bicyclic cycloalkyl/aromatic ring system), imidazoline (i.e., a benzimidazolinyl group, which is a 5,6-bicyclic cycloheteroalkyl/aromatic ring system), and pyran (i.e., a chromenyl group, which is a 6,6-bicyclic cycloheteroalkyl/aromatic ring system). Other examples of aryl groups include benzodioxanyl, benzodioxolyl, chromanyl, indolinyl groups, and the like. In some embodiments, aryl groups optionally contain up to four independently selected R4, -Y-R4 , -O-Y-R4, -Y-R8, or R12 groups, where Y, R4, R , and R1 are as described herein. As used herein, "heteroaryl" refers lo an aromatic monocyclic ring system containing at least 1 ring heteroatom selected from oxygen (O), nitrogen (N) and sulfur (S) or a polycyclic ring system where at least one of the rings present in the ring system is aromatic and contains at least 1 ring heteroatom. When more than one ring heteroatoms are present they may be the same or different. Polycyclic heteroaryl groups include two or more heteroaryl rings fused together and monocyclic heteroaryl rings fused to one or more aromatic carbocyclic rings, non-aromatic carbocyclic rings, and/or non-aromatic cycloheteroalkyl rings. A heteroaryl group, as a whole, can have, for example, from 5 to 14 ring atoms and contain 1-5 ring heteroatoms. The heteroaryl group can be attached to the defined chemical structure at any heteroatom or carbon atom that results in a stable structure. Generally, heteroaryl rings do not contain O-O, S-S, or S-O bonds. However, one or more N or S atoms in a heteroaryl group can be oxidized (e.g., pyridine N-oxide, thiophene S-oxtde, thiophene S,S-dioxide). Examples of heteroaryl groups include, for example, the 5-membered monocyclic and 5-6 bicyclic ring systems shown below: (Formula Removed) wherein T is O, S, NH, N-Y-R4, N-Y-R8, or NR12; and Y, R4, R8, and R12 are as described herein. Examples of such heteroaryl rings include pyrrolyl, furyl, thienyl, pyridyl, pyrirnidyl, pyridazinyl, pyrazinyl, triaxolyl, tetrazolyl, pyrazolyl, imidazolyl, isothiazolyl, thiazolyl, thiadiazolyl, isoxazclyl, oxazolyl, oxadiazolyl, indolyl, isoindolyl, benzofuryl, benzothienyl, quinolyl, 2-methylquinolyl, isoquinolyl, quinoxalyl, quinazolyl, benzotriazolyl, benzimidazolyl, benzothiazolyl, benzisothiazolyl, benzisoxazolyl, benzoxadiazolyl, benzoxazolyl, cinnolinyl, 1H-indazolyl, 2H-indazolyl, indolizinyl, isobenzofuyl, naphthyridinyl, phthalazinyl, pteridinyl, purinyl, oxazolopyridinyl, thiazolopyridinyl, imidazopyridinyl, furopyridinyl, thienopyridrnyl, pyridopyrimidinyl, pyridopyrazinyl, pyridopyridazinyl, thienothiazolyl, thienoxazolyl, thienoimidazolyl groups, and the like. Further examples of heteroaryl groups include 4,5,6,7-tetrahydroindolyl, tetrahydroquinolinyl, benzothienopyridinyl, benzofuropyridinyl groups, and the like. In some embodiments, heteroaryl groups can be substituted with up to four substituents independently selected from R4, -Y-R4 , -O-Y-R4, -Y-R8, or R12 groups, where Y, R4, R8, and R12 are as described herein. The compounds of the present teachings can include a "divalent group" defined herein as a linking group capable of forming a covalent bond with two other moieties. For example, compounds described herein can include a divalent C1-10 alkyl group, such as, for example, a methylene group. At various places in the present specification, substituents of compounds are disclosed in groups or in ranges. It is specifically intended that the description include each and every individual subcombination of the members of such groups and ranges. For example, the term "C1-10 alky!" is specifically intended to individually disclose Ci, (Sequence Removed) alkyl. By way of other examples, the term "5-14 membered heteroaryl group" is specifically intended to individually disclose a heteroaryl group having 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 5-14, 5-13, 5-12, 5-11, 5-10, 5-9, 5-8, 5-7, 5-6, 6-14, 6-13, 6-12, 6-11, 6-10, 6-9, 6-8, 6-7, 7-14, 7-13, 7-12, 7-11, 7-10, 7-9, 7-8, 8-14, 8-13, 8-12, 8-11, 8-10, 8-9, 9-14, 9-13, 9-12, 9-11, 9-10, 10-14, 10-13, 10-12, 10-11, 11-14, 11-13, 11-12, 12-14, 12-13, and 13-14 ring atoms; and the phrase "optionally substituted with 1-4 substituents" is specifically intended to individually disclose a chemical group that can include 0, 1, 2, 3, 4, 0-4, 0-3, 0-2, 0-1, 1-4, 1-3, 1-2, 2-4, 2-3, and 3-4 substituents. Compounds described herein can contain an asymmetric atom (also referred as a chiral center), and some of the compounds can contain one or more asymmetric atoms or centers, which can thus give rise to optical isomers (enantiomers) and diastereomers. The present teachings and compounds disclosed herein include such optical isomers (enantiomers) and diastereomers (geometric isomers), as well as the racemic and resolved, enantiomerically pure and stereoisomers, as well as other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof. Optical isomers can be obtained in pure form by standard procedures known to those skilled in the art, which include diastereomeric salt formation, kinetic resolution, and asymmetric synthesis. The present teachings also encompass cis and trans isomers of compounds containing alkenyl moieties (e.g., alkenes and imines). It is also understood that the present teachings encompass all possible regioisomers, and mixtures thereof, which can be obtained in pure form by standard separation procedures known to those skilled in the art, and include column chromatography, thin-layer chromatography, and high-performance liquid chromatography. Throughout the specification, structures may or may not be presented with chemical names. Where any question arises as to nomenclature, the structure prevails. An aspect of the present teachings relates to methods of preparing the compounds disclosed herein. The compounds of the present teachings can be prepared in accordance with the procedures outlined in ]:he schemes below, from commercially available starting materials, compounds knowti in the literature, or readily prepared intermediates, by employing standard synthetic methods and procedures known to those skilled in the art. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be readily obtained from the relevant scientific literature or from standard textbooks in the field. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures. Those skilled in the art of organic synthesis will recognize that the nature and order of the synthetic steps presented may be varied for the purpose of optimizing the formation of the compounds described herein. The processes described herein can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 1H or C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), or mass spectrometry, and/or by chromatography such as high performance liquid chromatograpy (HPLC) or thin layer chromatography. Preparation of compounds 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, hi Greene, et al., Protective Groups in Organic Synthesis, 4th Ed., Wiley & Sons, 2006, the entire disclosure of which is incorporated by reference herein for all purposes. The reactions of the processes described herein can be carried out in suitable solvents which can be readily selected by one skilled in the art of organic synthesis. Suitable solvents typically are substantially nonreactive with the reactants, intermediates, and/or products at the temperatures at which the reactions are carried out, i.e., temperatures that 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, suitable solvents for a particular reaction step can be selected. Scheme 1 below depicts an exemplary synthetic route for the preparation of an intermediate of compounds of formula I. Scheme 1 (Scheme Removed) Acetic acid ester i is converted to 3-oxo-butyronitrile ii by reaction with the anion of acetonitrile prepared by reaction of acetonitrile (CH3CN) with a strong base such as n-butyl lithium (n-BuLi) in a solvent such as THF. Reaction of oxo-butyronitrile ii with dimethylformamide-dimethyl acetal (DMF-DMA) in a solvent such as DMF at high temperature (e.g., 122°C) results in the formation of bisdimethylaminomethylene intermediate Hi which is converted to 4-hydroxy-nicotinonitrile iv by reaction with ammonia (NH3) or ammonium acetate (NH4OAc) in a solvent such as ethanol at reflux. Reaction of the hydroxypyridine with refluxing phosphorous oxychloride (POCl2) with or without catalytic DMF for 2 to 6 hours results in conversion to 4-chloro-nicotinonitrile v. Scheme 2 below shows an alternative procedure for the preparation of 3-oxo-butyronitrile ii. This alternative procedure involves conversion of acetic acid vi to the corresponding acid chloride by reaction with a chlorinating agent such as thionyl chloride (SOCl2) followed by reaction of the anion of tert-butylcyanoacetate prepared by reaction of tert-butylcyanoacetate with a base such as sodium hydride (NaH) in a solvent such as THF to give 2-cyano-3-oxo-butanoic acid tert-butyl ester vii, which undergoes deprotection of the ester and decarboxylation to give 3-oxo-butyronitrile ii by reaction with an acid such as trifluoroacetic acid (TFA). Scheme 2 (Scheme Removed) Alternatively, as shown in Scheme 3 below, the bisdimethylaminemethylene intermediate iii obtained by reaction of 3-oxo-butyronitrile ii with DMF-DMA can be reacted with 3,4-dimethoxybenzylamine at reflux in a solvent such as toluene to give 1-(3,4-dimethoxybenzyl)-4-oxo-l,4-dihydro-pyridirie-3-carbomtrile viii. Reaction of viii with excess LiCl in refluxing POCls results in removal of the dimethoxybenzyl group and conversion to the corresponding 4-chloro-nicotinonitrile v. Scheme 3 (Scheme Removed) Scheme 4 below depicts an exemplar synthetic route for the preparation of compounds of formula I. Scheme 4 (Scheme Removed) To prepare compounds of formula I where X is -NR3-(CH2)n-, -NR3(CO)-, -O-, or -S-, where n = 0-10, a C-5 substituted 4-chloro-3-cyanopyridine v can be reacted with R.'XH under one of the following reaction conditions: 1) in a solvent such as ethanol (EtOH), propanol, butanol, 2-ethoxyethanol (EtEtOH), 2-methoxyethanol, or 2-butoxyethanol at elevated temperature of 60-180°C, optionally in the presence of pyridine hydrochloride (Pyr.HCl); 2) using an alkali base such as sodium hydride (NaH) in a solvent such as tetrahydrofuran (THF) or dimethylformamide (DMF) at elevated temperatures of 60-120°C; 3) using a palladium catalyst such as tris(dibenzylidene)acetone dipalladium (Pd2(dba)3) and a phosphine ligand such as 2-dicyclohexylphosphino-2'-(N, N-dimethylamino)biphenyl (DavePhos) or tributylphosphine, in the presence of a base such as potassium phosphate (K3PO4) or potassium t-butoxide at elevated temperatures of 80-150°C; 4) using an organic base such as triethylamine (TEA), pyridine, or diisopropylethylamine (DIEA) in a solvent such as DMF, N-methyl-2-pyrrolidone (NMP) or EtEtOH at elevated temperatures of 80-150°C; 5) using an inorganic base such as cesium carbonate (CS2CO3) in a solvent such as acetonitrile (CH3CN) or DMF at elevated temperatures of 80-150°C. When X is a covalent bond, compounds of formula I can be prepared by a coupling reaction of C-5 substituted 4-chloro-3-cyanopyridine v with a boronic acid of formula R'B(OH)2, or boronic ester of formula R'B(OR)2, where R is an alkyl group (e.g., a lower alkyl group), mediated by a palladium catalyst such as tetrakis(triphenylphosphine)-palladium (0) [(Ph3P)4Pd] or palladium (II) acetate (Pd(OAc)2) in a solvent such as a mixture of dimethoxyethane(DME) and aqueous sodium bicarbonate (aq. NaHCOs) or aqueous sodium carbonate (aq. Na2CO3), optionally in the presence of a phosphine ligand such as triphenyl phosphine (Ph3P). Alternatively, 4-chloro-3-cyanopyridine v can be treated with a stannane R SnR3, wherein R is an alkyl group (e.g., a lower alkyl group), to yield compounds of formula I. Referring to Scheme 5 below, additional compounds of formula I where R" is substituted with an R4 group selected from an aryl group, a heteroaryl group, an alkenyl group and an alkynyl group (formula Ib) can be prepared from compounds of formula I where R2 is substituted with a leaving group (LG) such as bromide (Br), iodide (I), chloride (Cl) or trifluoromethane sulfonate (OTf) (formula la) as described in Scheme 5 below. Scheme 5 (Scheme Removed) More specifically, compounds of formula Ib where R4 is an aryl group or a heteroaryl group can be prepared by treatment of compounds of formula la with a boronic acid (R4B(OH)2), a boronic ester (R4B(OR)2, where R is a lower alkyl group) or with an organic stannane reagent (e.g., R4SnBu3) mediated by a palladium catalyst (e.g., (Ph3P)4Pd or Pd(OAc)2) in a solvent such as a mixture of DME and aq. NaHCO3 or aq. Na2CO3, optionally in the presence of a phosphine ligand such as PhsP. Similarly, compounds of formula Ib where R4 is an alkenyl group or an alkynyl group can be prepared by treating compounds of formula la with an alkene or alkyne of formula R4-H or with a boronic acid or ester of or an organic stannane reagent in the presence of a palladium catalyst (e.g., (Ph3P)4Pd, dichlorobis(triphenylphosphine)palladium (II), or Pd(OAc)2) in a solvent such as DMF, NMP, dioxane, or DME, in the presence of a ligand such as Ph3P or tri-o-tolylphosphine and a base (e.g., potassium carbonate (K2SO4) or Na2CO3), optionally with the addition of an organic base such as TEA. A catalytic amount of copper(I) iodide can be optionally used for this coupling reaction. Scheme 6 depicts a synthetic route for preparing additional compounds of formula I where both R2 and R4 are aryl or heteroaryl groups and R4 is further substituted with an amide (formula Id). Scheme 6 (Scheme Removed) Compounds of formula I where R2 is substituted by an aryl or heteroaryl group substituted by a carboxylic acid (formula Ic) can be treated with an amine of formula NHR R in the presence of a catalyst (e.g., benzotriazol-1 -yloxytris(dimethyl amino)phosphonium hexafluorophosphate (BOP)) and an organic amine (e.g., TEA, DIEA, or pyridine) in a solvent such as MeOH or EtOH at ambient temperature to elevated temperatures of 50-80°C to provide compounds of formula Id as described. Additional compounds of formula I where R is substituted with -O-Y -NR6R7 (formula If) can be prepared as depicted in Scheme 7 below, by treating compounds of formula I where R2 is substituted with -O-Y-LG (formula le), where LG is Cl, Br, methanesulfonyl (mesyl, OMs), or p-toluenesulfonyl (tosyl, OTs), with an amine of formula NHR6R7 in a solvent such as EtOH, DME or DMF optionally in the presence of Nal or a base such as K2CO3. Scheme 7 (Scheme Removed) LG=C1, Br, OMs, OTs As depicted in Scheme 8, compounds of formula I wherein R2 is substituted by -CH2-NR6YR7 (formula Ih), can be prepared by treating compounds of formula I where R2 contains an aldehyde functionality (formula Ig), with an amine of formula HNR6YR7 in the presence of a reducing agent (e.g., sodium triacetoxyborohydride (Na(OAc)3BH) or sodium cyanoborohydride) in a solvent such as dichloromethane (CH2C12) or THF with the optional addition of DMF or NMP and preferably in the presence of acetic acid. Compounds of formula I wherein R2 is substituted by ~-CH2-OH (formula li) can be formed as a b-byproduct of this reductive amination reaction. Scheme 8 (Scheme Removed) As depicted in Scheme 9, compounds of formula I where R2 is substituted by -OYR5 (formula Ik) can be prepared by treating compounds of formula I where R2 contains a hydroxyl functionality( formula Ij), with an alcohol of formula R5YOH under Mitsunobu conditions. This reaction can be conducted in a solvent such as THF in the presence of Ph3P and either diethyl azodicarboxylate or di-t-butyl azodicarboxylate. Scheme 9 (Scheme Removed) Additional compounds of formula I wherein X is not a bond can be prepared as shown in Scheme 10, Scheme 11, and Scheme 12 below. Scheme 10 (Scheme Removed) A mixture of 3-aminobut-2-enenitrile ix is heated in acid (e.g., aqueous HC1) to yield acetoacetonitrile x. Acetoacetonitrile x is treated with t- butoxybis(dimethyl amino)methane and DMF-DMA at an elevated temperature to yield 5-(dimethylamino)-2-[(dimethylamino)methylene]-3-oxopent-4-enenitrile xi, which is then treated with ammonium acetate in EtOH at reflux to produce 4-hydroxynicotinonitrile xii. (An alternate synthesis of 4-hydroxynicotinonitrile was reported in the literature: Broekman, F. W. et al., Recueil des Travaux Chimiques des Pays-Bas, 81: 792-796 (1962)). A mixture of 4-hydroxynicotinonitrile xii, iodine and NaOH in water is heated overnight to yield 4-hydroxy-5-iodonicotinonitrile xiii, which is then treated with POCl3 at an elevated temperature to yield 4-chloro-5-iodonicotinonitrile xiv. Intermediate xiv can then be treated with R'XH, wherein X is not a bond (e.g., R'NH2, R'OH, R!SH, etc.) to yield the 4-substituted 5-iodo-nicotinonitrile xv. Further treatment with a boronic acid R2B(OH)2, boronic acid ester R B(OR)2 or stannane R2SnR3 (where R, in each case, is a lower alkyl group) yields compounds of formula I. Alternatively, intermediate xiv can be treated with a boronic acid R2B(OH)2, a boronic acid ester R2B(OR)2 or a stannane R2SnR3 (where R, in each case, is a lower alkyl group), followed by a reaction with R'XH to provide compounds of formula I. Scheme 11 (Scheme Removed) As depicted in Scheme 11, treatment of 4-chloro-5-iodonicotinonitrile xiv with an oxidizing agent, preferably hydrogen peroxide, in trifluoroacetic acid at temperatures of 0-50°C, provides 4-chloro-5-iodo-l-oxy-nicotinonitrile xiv'. Addition of R'XH under the conditions noted previously provides compounds of formula xv'. Addition of a boronic acid, ester, or an organostannane under the conditions noted previously provides compounds of formula I'. Scheme 12 (Scheme Removed) As shown in Scheme 12, treatment of compounds of formula v with CsF in a solvent such as DMF provides a 4-fluoro analog xvi. Subsequent displacement of the 4-fluoro group with R1XH in a solvent such as DMSO provides compounds of formula I. Aspects of the present teachings can be further understood in light of the following examples, which should not be construed as limiting the scope of the present teachings in any way. More specifically, the following examples illustrate various synthetic routes which can be used to prepare compounds of formula I. HPLC conditions used in the examples are listed as the following: (a): column: Prodigy ODS3, 4.6 x 150 mm, from Phenomenex (Torrance, CA); mobile phase A: 0.02% trifluoroacetic acid (TFA) in water; mobile phase B: 0.02% TFA in CH3CN, 10-95% B in 20 minutes (min.); flow rate: 1.0 mL/min.; column temperature: 40 °C; detection wavelength: 215 nm; (b): column: Prodigy ODS3, 4.6 x 150 mm, from Phenomenex (Torrance, CA); mobile phase A: 0.02% trifluoroacetic acid (TFA) in water; mobile phase B: CH3CN, 10-90% B; flow rate: 1.0 mL/min.; detection wavelength: 215 nm; (c): column: Prodigy ODS3, 4.6 x 150 mm, from Phenomenex (Torrance, CA); mobile phase A: 0.02% formic acid in water; mobile phase B: 0.02% formic acid in acetonitrile, 10-95% B in 3 min., 95-10% B in 1 min.; column temperature: 40 °C; detection wavelength: 215 nm; (d): column: YMC C18, 4.6 x 50 mm, 5 microns, from YMC (Kyoto, Japan); mobile phase A: 90% water + 10% MeOH + 0.02% H3PO4; mobile phase B: 90% MeOH + 10% water + 0.02% H3PO4, 1-100% B in 2 min., up to 10 min. 100% B, then 100-1% B in 1 min.; (e): column: Aquasil C18, 2.1 x 50 mm, from Thermo Fisher Scientific, Inc. (Waltham, MA); 5.5 min. gradient CH3CN in water/formic acid; flow rate: 0.8 mL/min.; detection wavelength: 254 nm; (f): column: Xterra MS C18, 3.5 µm, 2.1 x 30 mm, from Waters Corp. (Milford, MA); 5 min. gradient CH3CN in water/formic acid; flow rate: 1.0 mL/min.; detection wavelength: 215 nm; (g): column: Prodigy ODS3, 4.6 x 150 mm, from Phenomenex (Torrance, CA); 20 min. gradient CH3CN in water/TFA; flow rate: 1.0 mL/min.; detection wavelength: 215 nm; (h): column: Prodigy ODS3, 4.6 x 150 mm, from Phenomenex (Torrance, CA); 20 min. gradient methanol (MeOH) in water/TFA; flow rate: 1.0 mL/min.; detection wavelength: 215 nm; (i) column: XBridge C18, 4.6 x 50 mm, from Waters Corp. (Milford, MA); 5.5 min. gradient CH3CN in water/formic acid; flow rate: 0.8 mL/min.; detection wavelength: 254 nm; (j): column: Pursuit® PFP, 4.6 x 150 mm, from Varian, Inc. (Palo Alto, CA); 20 min. gradient CH3CN in water/TFA; flow irate: 1.0 mL/min.; detection wavelength: 215 nm; and (k): column: Aquasil C18, 2.1 x 50 mm, from Thermo Fisher Scientific, Inc. (Waltham, MA); mobile phase A: 0.1 % formic acid in water; mobile phase B: 0.1 % formic acid in CH3CN, 0 - 100 % B in 2.5 min; flow rate: 0.8 mL/min; column temperature: 40 °C; detection wavelength: 254 nm. Example 1: Preparation of 5-(3,4-dimethoxyphenyl)-4-(lH-indol-5-ylamino) nicotinonitrile 101 A solution of 3,4-dimethoxyphenyl acetic acid (50 mM) in MeOH (100 mL) with concentrated sulfuric acid (cone. H2SO4, 1 mL) or concentrated hydrochloric acid (cone. HC1) was heated at reflux overnight. Concentration to dryness on a rotary evaporator and high vacuum pump overnight gave the ester as an oil which was used directly in the next step. To a 1.0 L three-necked round-bottomed flask was added 50 mL of THF and the reaction mixture was cooled to -78°C. Butyl lithium (BuLi, 1.6 M, 14.4 mL, 23 mmol) was added dropwise keeping the temperature below -70°C. Acetonitrile (1.3 mL, 25 mmol) in 30 mL of THF was added dropwise to the flask amidst stirring and cooling. After 2 hours (h) of stirring, (3,4-dimethoxyphenyl)acetic acid methyl ester (2.3 g, 11 mmol) was added to the resulting white colloidal mixture in the flask. The reaction mixture was stirred for a further 2 h, followed by the addition of saturated ammonium chloride solution (NH4Cl, 75 mL) at -78°C. The organic layer was separated, dried with sodium sulfate (Na2SO4), filtered to remove the drying agent and evaporated to dryness to give the crude product. This crude product was purified by silica gel column chromatography, eluting with 30-70% ethyl acetate (EtOAc) in hexanes to yield 4-(3,4-dimethoxyphenyl)-3-oxo-butyronitrile in the form of a solidifying amber oil, 1.8 g (75%). To a solution of 4-(3,4-dimethoxyphenyl)-3-oxo-butyronitrile (5.0 g, 23 mmol) in DMF (12 mL) was added dimethylformamide-dimethylacetal (DMF-DMA, 13.5 mL, 101 mmol) and the solution heated at 122°C overnight. Concentration on a rotary evaporator under high vacuum gave an orange-red solid. This solid was dissolved in EtOH (100 mL) and excess ammonium acetate was added and the reaction mixture was heated at 85°C for 1 h. The reaction mixture was allowed to cool to room temperature (r.t.) for 1 h then the solids were collected by filtration and washed with EtOH (cold) to give 5-(3,4-dimethoxyphenyl)-4-hydroxynicotinonitrile (4.1 g, 69%) as a brown solid. The filtrate was concentrated on a rotary evaporator and the residue purified on silica gel with 0-25% MeOH in CH2Cl2 to give an additional amount of 5-(3,4-dimethoxyphenyl)-4-hydroxynicotinonitrile. A solution of 5-(3,4-dimethoxyphenyl)-4-hydroxynicotinonitrile (4 g, 15.7 mmol) in phosphorus oxychloride (POCls, 25 rnL) was heated at 125°C for 1.5 h, then cooled to r.t. and poured into an ice/3 N sodium hydroxide (NaOH)TEtOAc mixture. The mixture was stirred and the layers separated. The organic layer was dried over magnesium sulfate (MgSO4), filtered and concentrated to give 4-chloro-5-(3,4-dimethoxyphenyl)nicotinonitrile (3.9 g, 91%) as a brown solid. A mixture of 4-chloro-5-(3,4-dimethoxyphenyl)nicotinonitrile (824 mg, 3 mmol), 5-aminoindole (396 mg, 3 mmol) and Pyr.HCl (345 mg, 3 mmol) in EtEtOH (25 mL) was heated at reflux for 8 h, cooled to r.t. and concentrated. The residue was purified by flash silica gel column chromatography eluting with 0-25% MeOH in CH2Cl2 to give 977 mg (88% yield) of a yellow-brown oil, that was triturated with MeOH/ethyl ether to give 525 mg (47%) of .'5-(3,4-dimethoxyphenyl)-4-(lH-indol-5- ylamino)nicotinonitrile 101 as a yellow-brown solid. MS 371.2 (M+H), HPLC retention time: 1.70 min.(a). Following procedures analogous to those described for preparing compound 101 and using the appropriate amine in the last step, the compounds in Table 2 were prepared. Table 2 (Table Removed) Example 2: Preparation of 5-(3-taromophenyl)-4-(lH-indol-5-ylamino) nicotinonitrile 113 Following procedures analogous to those described for preparing 4-chloro-5-(3,4-dimethoxyphenyl) nicotinonitrile (Example 1), 5-(3-bromophenyl)-4-chloronicotinonitrile was prepared from 3-bromophenylacetic acid. 5-(3-Bromophenyl)-4-(lH-indol-5-ylamino)nicotinonitrile 113 was then prepared using two methods. Method A: Following procedures analogous to those described for preparing compound 101 (Example 1), the title compound was prepared from 5-(3-bromophenyl)-4-chloronicotinonitrile and purified by flash silica gel column chromatography eluting with 0-25% MeOH in CH2C12. MS: 389.0 (M+H), HPLC retention time: 1.92 min.(a). Method B: A solution of 5-(3-bromophenyl)-4-chloronicotinonitrile (4.42 g, 15 mmol), 5-aminoindole (1.99 g, 15 mmol) in EtEtOH (44 mL) was heated at reflux for 12 h, then cooled to r. t. The reaction mixture was poured into saturated aq. NaHCO3 solution, whereupon the crude product precipitated. The latter was filtered and the crude solid was dissolved in CH2Cl2, dried over Na2SO4, concentrated and purified by flash chromatography on silica gel eluting with 1:1 EtOAc/hexane to give 4.2 g (72% yield) of the title compound as a foamy yellow solid. MS: 389.0 (M+H), HPLC retention time: 1.92 min.(a). Example 3: Preparation of 5-(3-bromophenyl)-4-(lH-indol-4-ylamino) nicotinonitrile 114 Following procedures analogous to those described in Example 2, Method B, 5-(3-bromophenyl)-4-(lH-indol-4-ylamino) nicotinonitrile was prepared from 5-(3-bromophenyl)-4-chloronicotinonitrile and 4-aminoindole. MS: 389.2 (M+H). Example 4: Preparation of 5-(2-bromophenyl)-4-(lH-indol-5-ylamino) nicotinonitrile 115 Following procedures analogous to i:hose described for preparing 4-chloro-5-(3,4-dimethoxyphenyl) nicotinonitrile (Example 1), 5-(2-bromophenyl)-4-chloronicotinonitrile was prepared from 2-bromophenylacetic acid. Following procedures analogous to those described for preparing compound 113 (Example 2, Method B), 5-(2-bromophenyl)-4-(lH-indol-5-ylamino)nicotinonitrile 115 was prepared from 5-(2-bromophenyl)-4-chloronicotinomtrile. MS: 389.0 (M+H). Example 5: Preparation of 5-(4-bromophenyl)-4-(lH-indol-5-ylamino) nicotinonitrile 116 Following procedures analogous to those described for preparing 4-chloro-5-(3,4-dimethoxyphenyl) nicotinonitrile (Example 1), 5-(4-bromophenyl)-4-chloronicotinonitrile was prepared from 4-bromophenylacetic acid. Following procedures analogous to those described for preparing compound 113 (Example 2, Method B), 5-(4-bromophenyl)-4-(lH-indo]-5-ylamino)nicotinonitrile 116 was prepared from 5-(4-bromophenyl)-4-chloronicotinonitrile. MS: 389.0 (M+H). Example 6: Preparation of 5-[3-methosy-4-(2-methoxyethoxy)phenyl]-4-[(4-methyI-lH-indol-5-yl)amino | nicotinonitrile 478 Following procedures analogous to those described for preparing compound 113 (Method B), 5-[3-methoxy-4-(2-methoxyethoxy)phenyl]-4-[(4-methyl-lH-indol-5-yl)amino]nicotinonitrile was prepared. HPLC retention time: 8.0 min. (g); melting range: 208-210 °C; and HRMS: 429.19278. Example 7: Preparation of 5-(3'-aminobiphenyl-3-yl)-4-(lH-indol-5-ylamino)nicotinonitrile 117 A mixture of 5-(3-bromophenyl)-4-( lH-indol-5-ylamino)nicotinonitrile 113 (39 mg, 0.1 mmol), (Ph3P)4Pd (2.3 mg, 0.002 mmol) and 2M aq. Na2CO3 (0.1 mL) in DME (2 mL) was degassed by bubbling nitrogen for 5 min., then 3-aminophenylboronic acid (17 mg, 0.11 mmol) was added and the mixture was heated at reflux for 12 h. After cooling to r.t, the mixture was filtered and the filtrate was purified by preparative HPLC to give 5-(3'-aminobiphenyl-3-yl)-4-(lH-indol-5-ylamino)nicotinonitrile 117. MS: 402 (M+H), HPLC retention time: 1.72 min.(a). Following procedures analogous to those described for preparing compound 117, compounds 118-150 in Table 3 were synthesized from 5-(3-bromophenyl)-4-(lH-indol-5-ylamino)nicotinonitrile 113, 5-(3-bromophenyl)-4-(lH-indol-4-ylammo) nicotinonitrile 114, 5-(2-bromophenyl)-4-(lH-indol-5-ylamino)nicormonitrile 115 or 5-(4-bromophenyl)-4-(lH-indol-5-ylamino)nicotmonitrile 116 and the appropriate boronic acid. Table 3 (Table Removed) Example 8: Preparation of 4-(lH-indol-5-ylamino)-5-(3-nitrophenyl) nicotinonitrile 151 3-Nitrophenyl acetic acid (9.5 g, 52 mmol) and thionyl chloride (20 mL) were stirred overnight at r.t, then evaporated to dryness. In a separate flask NaH (60% • dispersion in oil, 5.5 g, 1.4 mmol) was suspended in THF (100 mL) and the mixture was cooled to 0°C and tert-butylcyanoacetate (8.8 g, 62 mmol) was added. After 15 min., a solution of 3-nitrophenylacetyl chloride from above in THF was added dropwise. The reaction mixture was allowed to warm to r.t. and stirred for 4 h, quenched by the addition of brine, and extracted with EtOAc (2 x 200 mL). The combined organic extracts were dried over MgSO4 and concentrated. The residue was used in the next step without further purification. To a solution of 2-cyano-4-(3-nitrophenyl)-3-oxo-butyric acid tert-butyl ester (9.5 g, 31 mmol) in toluene (40 mL) was added TFA (4 mL) and the solution was heated at reflux for 2 h, then the solvent evaporated in vacuo. The residue was purified by flash chromatography on silica gel to give 4.0 g of 4-(3-nitrophenyl)-3-oxo-butyronitrile (37% over 2 steps). Following procedures analogous to those described for preparing compound 101 (Example 1), 4-(3-nitrophenyl)-3-oxo-butyronitrile was converted to 4-(lH-indol-5-ylamino)-5-(3-nitrophenyl)-nicotinonitrile 151. MS: 356 (M+H), HPLC retention time: 2.50 min.(a). Example 9: Preparation of N-{3-[5-cyano-4-(lH-indol-5-ylamino)pyridin-3-yl|phenyl}acetamide 152 To a solution of 4-(lH-indol-5-ylamino)-5-(3-nitrophenyl)nicotinonitrile 151 (9 mg, 0.025 mmol) in MeOH (1 mL) were added hydrazine (20 uL) and Raney-Nickel (2-5 mg). The mixture was stirred for 2 h then filtered through celite and the filtrate was concentrated to give the crude reduced product which was then dissolved in CH2Cl2 (1 mL) and pyridine (20 uL), and acetyl chloride (20 uL) was added. After stirring for 1 h, the reaction mixture was evaporated and the residue was purified by preparative HPLC to give the title compound (4 mg). MS: 366.0 (M+H), HPLC retention time: 1.61 min.(a). Example 10: Preparation of 4-(lH-indol-4-ylamino)-5-[4-methoxy-3-(2- methoxyethoxy)phenyl] nicotinonitrile 153 To a stirred solution of 3-hydroxy-4-methoxyphenyl acetic acid (24.8 g, 136 mmol) in 200 mL of MeOH was added 1 mL of H2SO4 and the reaction mixture was heated at reflux overnight. The methanol was removed by evaporation in vacuo and the residue was poured into saturated NaHCO3 solution and extracted with EtOAc (3x150 mL). Combined organic extracts were then washed with brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo to yield 23.9 g (90% yield) of 3-hydroxy-4-methoxyphenyl acetic acid methyl ester as a yellow oil. To a stirred solution of 3-hydroxy-4-methoxyphenyl acetic acid methyl ester (5.0 g, 25.5 mmol), terrabutylammonium iodide (TBAI, 0.941 g, 2.5 mmol), and 2-bromoethylmethyl ether (4.6 mL, 50.9 mmol) m 150 mL of acetone was added Cs2CO3 (17.4 g, 53.4 mmol). The mixture was stirred for 21.5 h at reflux. The mixture was concentrated and the residue was partitioned between water and EtOAc. The combined organic extracts were dried over anhydrous Na2SO4 filtered, and concentrated in vacuo to yield 8.15 g of an orange oil, which was purified by flash chromatography on silica gel eluting with 10-50% EtOAc in hexane to give 5.33 g (82% yield) of 4-methoxy-3-(2-methoxyethoxy)phenylacetic acid methyl ester as a light yellow oil. To a 250 mL three-necked round-bottomed flask was added 10 mL of anhydrous THF and cooled to -78°C. n-Butyl lithium (2.5 M in hexane, 8.06 mL, 12.9 mmol) was added and the mixture was stirred for 5 min. Anhydrous CHjCN (0.696 mL, 13.3 mmol) in 5 mL of anhydrous THF was added dropwise at -78°C. After 1 h of stirring, 4-methoxy-3-(2-methoxyethoxy)phenylacetic acid methyl ester (1.10 g, 4.3 mmol) in 10 mL of anhydrous THF was added dropwise to the resulting white colloidal mixture. The reaction mixture was stirred for an additional 2 h, followed by the addition of saturated NH4Cl solution at -78°C. The solution was warmed to r.t., diluted with 100 mL water and extracted with EtOAc (3 x 100 mL). The combined organics were washed with brine, dried with anhydrous MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel eluting with gradient 30-60% EtOAc in hexanes to yield 769 mg (68% yield) of 4-[4-methoxy-3-(2-methoxyethoxy)phenyl]-3-oxo-butyrom'tri]e as a colorless oil. To a stirred solution of 4-[4-methoxy-3-(2-methoxyethoxy)phenyl]-3-oxo-butyronitrile (9.91 g, 34.5 mmol) in 20 mL of anhydrous DMF was added DMF-DMA (20.2 mL, 152 mmol). The resulting mixture was heated at 100° C for 15 h and was concentrated in vacuo. The crude material was mixed with 3,4-dimethoxybenzylamine (0.687 mL, 41.4 mmol) in 20 mL of anhydrous toluene and the mixture was heated at reflux for 2 h. The reaction mixture was cooled, concentrated in vacuo, and purified by flash chromatography on silica gel eluting with gradient 50-100% EtOAc/hexane to yield 8.5 g (55% yield) of l-(3,4-dimethoxybenzyl)-5-[4-methoxy-3-(2-methoxyethoxy)phenyl]-4-oxo-l,4-dihydro-pyndine-3-carbonitrile as a yellow/orange foam. A solution of l-(3,4-dimethoxybenzyl)-5-[4-methoxy-3-(2- methoxyethoxy)phenyl]-4-oxo-l,4-dihydro-pyridine-3-carbonitrile (300 mg, 0.666 mmol) and lithium chloride (LiCl, 254 mg, 6 mmol) in 2.5 mL of POCl3 was heated at reflux for 2.5 h. The excess POCl3 was removed by evaporating in vacuo and then was co-evaporated with toluene. The residue was dissolved in 100 mL ethyl acetate and washed with ice-cold 1 N aqueous sodium hydroxide. The organic layer was separated, dried over anhydrous MgSO4, filtered, and concentrated in vacuo, and the resulting solid was triturated with isopropyl alcohol to yield 166 mg (78% yield) of 4-chloro-5-[4-methoxy-3-(2-methoxyethoxy)phenyl]-nicotinonitrile as an off-white solid. To a stirred solution of 4-chloro-5-[4-methoxy-3-(2-methoxyethoxy)phenyl]-nicotinonitrile (100 mg, 0.313 mmol), 4-aminoindole (62 mg, 0.47 mmol,), DavePhos (37 mg, 0.094 mmol), and K3PO4 (99.8 mg, 0.47 mmol) in 4 mL of anhydrous ethylene glycol dimethyl ether was added Pd2(dba)3 (28.7 mg, 0.031 mmol). The mixture was heated to 90°C for 2 h, then cooled, filtered through celite, concentrated in vacuo, and crystallized by tritration with ether/hexane to yield 42.5 mg (33% yield) of the title compound 153 as a tan solid. MS: 415.1 (M+H), HPLC retention time: 7.70 min(b). Following procedures analogous to those described for preparing compound 153 and using the appropriate amine, the compounds in Table 4 were prepared. Table 4 (Table Removed) Example 11: Preparation of 4-(lH-indol-4-ylamino)-5-[3-methoxy-4-(2-methoxyethoxy)phenyl]nicotinonitrile 159 Following procedures analogous to those described for preparing 4-methoxy-3-(2-methoxyethoxy)phenylacetic acid methyl ester in Example 9, ethyl [3-methoxy-4-(2-methoxyethoxy)phenyl]acetate was prepared from 4-hydroxy-3- methoxyphenylacetic acid ethyl ester. 4-(lH-Indol-4-ylamino)-5-[3-methoxy-4-(2-methoxyethoxy)phenyl] nicotinonitrile 159 was then prepared following procedures analogous to those described for preparing 4-(lH-indol-4-ylamino)-5-[4-methoxy-3-(2-methoxyethoxy)phenyl]-nicotinonitrile 153 (Example 9). MS: 415.2 (M+H), HPLC retention time: 7.9 min( Compounds in Table 5 were prepared following procedures described for preparing compound 153 from 4-chloro-5-[3-methoxy-4-(2-methoxyethoxy)phenyl] nicotinonitrile. Table 5 (Table Removed) Example 12: Preparation of methoxyethoxy)phenyl] nicotinonitrile 164 4-(lH-indol-4-ylamino)-5-[3-(2- Following procedures analogous to those described in Example 9, 4-(lH-indol-4-ylamino)-5-[3-(2-methoxyethoxy)phenyl|nicotinonitrile 164 was prepared from 3-hydroxyphenylacetic acid. MS: 385.2 (M+H), HPLC retention time: 7.10 min.245°C. A mixture of 4-hydroxy-5-iodonicotinonitrile (57.5 g, 234 mmol) and POCl3 (200 mL) was heated at 100°C for 2 hours, cooled to room temperature and evaporated to remove excess POCl3. The residue was cooled in an ice-water bath, adjusted to pH 8-9 with aqueous 10 N NaOH and extracted with ethyl acetate. The combined organics were washed with water and brine, dried over magnesium sulfate and concentrated. The resulting solid residue was washed with a minimum amount of methanol and methylene chloride to give 46.5 g (75%) of 4-chloro-5-iodotiicotinonitrile as a tan solid. Melting range: 120-122°C. A mixture of 4-chloro-5-iodonicotinonitrile (5.0 g, 18.9 mmol) and 5-amino-4-methylindole (3.0 g, 20.8 mmol) in EtOH (100 mL) was heated at reflux for 3 days, cooled to r.t. and diluted with saturated aq. Na2SO4 (300 mL). The precipitated solids were collected by filtration, washed with water and dried to give 5.3 g (75%) of 5-iodo-4-[(4-methyl-lH-indol-5-yl)amino]nicotinonitrile as a grey solid. Melting range: 192-194°C; MS (M+H+): 375.1. To a mixture of 5-iodo-4-[(4-methyl-lH-indol-5-yl)amino]nicotinonitrile (200 mg, 0.53 mmol), 2-benzofuranboronic acid (173 mg, 1.07 mmol) and Pd(PPh3)4 (31 mg, 0.027 mmol) in DME (4.0 mL) was added 2.0 M aqueous Na2CO3 (0.8 mL). The resulting mixture was heated at 80°C for 2 h, cooled to r.t. and filtered. The filtrate was concentrated and purified by HPLC to give 35 mg of 5-(l-benzofuran-2-yl)-4-[(4-methyl-lH-indol-5-yl)amino]nicotinonitrile 222 as a yellow solid. MS: 365.2 (M+H); HPLC retention time: 11.4 min.(a). Following procedures analogous to those described for the preparation of 5-(1 -benzofuran-2-yl)-4-[(4-methyl-1 H-indol-5-yl)a:mino]nicotinonitrile 222, compounds in Table 13 were prepared. Table 13 (Table Removed) Example 27: Preparation of 5-{5-[(dimethylamino)methylJ-l-benzothien-2-yl}-4-(lH-indol-4-yIamino)nicotinonitrile 224 Following procedures analogous to those described in Example 25, 5-(5-formyl-l-benzothien-2-yl)-4-(lH-indol-4-ylamiiio)nicotinonitrile 223 was prepared from 5-iodo-4-[(lH-indol-4-yl)amino] nicotinonitrile, MS: 395.1 (M+H); melting range: 206-208 °C (decom.). To 5-(5-formyl-l-benzothien-2-y])-4-(lH-indol-4-ylamino)nicotmonitrile 223 (166 mg, 0.38 mmol) in THF (7 mL) was added dimethylamine in THF (2.0 M, 0.58 mL, 1.15 mmol) followed by acetic acid (126 mg, 2.09 mmol). The resulting mixture was stirred at r.t. for 1 h and additional dimethylamine (1.2 mL, 2.30 mmol) was added. After stirring at r.t. for an additional hour, Na(OAc)3BH (242 mg, 1.15 mmol) was added. The reaction mixture was stirred at r.t. for 2 h and was partitioned between diluted HC1 and EtOAc. The combined aqueous extracts were basified with aqueous NaHCO3 and extracted with EtOAc. The combined organics were dried over Na2SO4, concentrated and purified by flash column chromatography to give 115 mg (65%) of 5- {5-[(dimethylamino)methyl]-1 -benzothien-2-yl} -4-( 1 H-indol-4- ylamino)nicotinonitrile 224 as a pale yellow solid. MS: 424.2 (M+H); HPLC retention time: 2.1 min. (a). Following procedures analogous to those described for the preparation of 5-(1 -benzofuran-2-yl)-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile 224, compounds in Table 14 were prepared. Table 14 (Table Removed) Example 28: Preparation of 5-(4-{[(2S)-2-amino-3-phenyIpropyl]oxy}phenyl)-4-(lH-indol-4-ylamino)nicotinonitrile 226 Following procedures analogous to those described in Example 25, 5-(4-hydroxyphenyl)-4-(lH-indol-4-ylamino)nicotinonitrile 225 was prepared from 5-iodo-4-[(lH-mdol-4-yl)amino]nicotinonitrile. MS: 327.1 (M+H); melting range: 235-237 °C. To a suspension of 5-(4-hydroxyphenyl)-4-(lH-indol-4- ylamino)nicotinonitrile 225 (100 mg, 0.31 mmol), tert-butyl (lS)-l-benzyl-2-hydroxyethylcarbamate (77 mg, 0.31 mmol), and Ph3P (97 mg, 0.37 mmol) in THF (2.0 mL) was added diethyl azodicarboxylate (64 mg, 0.37 mmol) via a syringe over 6 min. The resulting mixture was stirred at r.t. for 21 h and treated with concentrated HC1 (~200 mg). After heating at 60°C for one h, the reaction mixture was partitioned between saturated NaHCO3 and CH2C12. The combined organics were dried over Na2SO4, concentrated and purified by silica gel flash column chromatography (eluting with 4% MeOH/CH2Cl2) to give 42 mg (30%) of 5-(4-{[(2S)-2-amino-3-phenylpropyl]oxy}phenyl)-4-(lH-indol-4-ylamino)nicotinonitrile 226 as a white solid. MS: 460.4 (M+H); melting range: 83-85 °C. Following procedures analogous to those described for the preparation of 5- (4-{[(2S)-2-amino-3-phenylpropyl]oxy}phenyl)-4-(lH-indol-4-ylamino)nicotinonitrile 226, 5-(4-{[(2R)-2-amino-3-phenylpropyl]oxy}phenyl)-4-(lH-indol-4- ylamino)nicotinonitrile 458 was prepared. HPLC retention time: 6.2 min. (g); MS: 460.2 (M+H); melting point: 95-96 °C; and HRMS: 460.21519. Example 29: Preparation of 4-[(4-niethyl-lH-indol-5-yl)amino]-5-[5-(piperidin-l-ylmethyl)-l-benzothien-2-yl]nicotinonitrile 228 and 5-[5-(hydroxymethyl)-l-benzothien-2-yl]-4-[(4-methyl-lH-indol-5-yl)amino]nicotinonitrile 229 Following procedures analogous to i:hose described in Example 25, 5-(5-formyl-1 -benzothien-2-yl)-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile 227 was prepared from 5-iodo-4-[(4-methyl-lH-indol-5-yl)amino]nicotinonitrile. MS: 409.2 (M+H); melting range: 185-187 °C. Sodium cyanoborohydride (8.0 mg, 0.13 mmol) was added in portions to a stirred mixture of 5-(5-formyl-l-bem:othien-2-yl)-4-[(4-methyl-lH-indol-5-yl)amino]nicotinonitrile 227 (40 mg, 0.098 mmol), piperidine (10 mg, 0.12 mmol) and acetic acid (7.0 mg, 0.12 mmol) in EtOH (3.0 mL). The resulting mixture was stirred at r.t. overnight and diluted with CH2C12 (30 mL). Silica gel and potassium bicarbonate (20 mg) were added and the mixture was concentrated to give a solid residue which was purified by silica gel flash column chromatography (eluting with 3% MeOH in CH2C12) to give 26 mg (57%) of 4-[(4-methyl-l H-indol-5-yl)amino]-5-[5-(piperidin-l-ylmethyl)-l-benzothien-2-yl]nicotinonitrile 228 as an off-white solid (MS: 478.3 (M+H); melting range: 180-182 °C; HPLC retention time: 7.1 min.), and 7 mg (18%) of 5-[5-(hydroxymethyl)-l-benzothien-2-yl]-4-[(4-methyl-lH-indol-5- yl)amino]nicotinonitrile 229 as an off-white solid (MS: 411.3 (M+H); melting range: 174-175 °C, HPLC retention time: 8.6 min.(a)). Following procedures analogous to those described for the preparation of 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[5-(piperidiii-1 -ylmethyl)-1 -benzothien-2-yl]nicotinonitrile 228, the following compounds were prepared: 4-[(4-Methyl-lH-indol-5-yl)amino]-5-{5-[(4-methylpiperazin-l-yl)methyl]-2-thienyl}nicotinonitrile 464. HPLC retention time: 4.9 min. (g); MS: 443.4 (M+H); melting point: 255 °C (decom.); and HRMS: 443.20223; and 4-[(4-Methyl-lH-indol-5-yl)amino]-'i-{5-[(4-methylpiperazin-l-yl)methyl]-2-furyl}nicotinonitrile 468. HPLC retention time: 5.2 min. (g); MS: 427.3 (M+H); melting point: 245 °C (decom.); and HRMS: 427.22449. Example 30: Preparation of 4-chIoro-5-iodo-l-oxy-nicotinonitrile To a solution of 4-chloro-5-iodo-nicotinonitrile (529 mg, 2.0 mmol) in TFA (5 mL) was added H2O2 (30wt% in HiO, 5 ml,). The reaction mixture was stirred at room temperature overnight, heated to 50 °C for 8 h, and concentrated. To the residue was added saturated aqueous NaHCO3 (10 mL) followed by extraction with EtOAc/THF. The organic layers were combined, washed with H2O, dried over Na2SO4, filtered, and concentrated. The residue was purified by a flash chromatography (CH2C12-THF = 10:1) to give 202 mg (36%) of 4-chloro-5-iodo-l-oxy-nicotinonitrile as a pale-yellow solid. Example 31: Preparation of 4-fluoro-5-[3-methoxy-4-(2-methoxyethoxy)phenyl] nicotinonitrile 4-Chloro-5-(3,4-dimethoxyphenyl)nicotinonitrile (2.0 g, 7.3 mmol) was dissolved in DMF (70 mL) and treated with CsF (2.2 g, 14.6 mmol). After the resulting solution was heated at 80 °C for 2 h, additional CsF (1 g, 7 mmol) was added and the heating was continued overnight. The crude product was purified by chromatography (EtOAc/Hex) to give 300 mg of 4-fluoro-5-[3-methoxy-4-(2-methoxyethoxy)phenyl]nicotinonitrile. Example 32: Preparation of 5-amino-6-methylindole 3-Methyl-4-nitroaniline was treated with iodine and silver sulfate to give 2- iodo-5-methyl-4-nitroaniline. Treatment of the nitroaniline with 2- (trimethylsilyl)acetylene under the typical Sonogashira conditions gave 5-methyl-4-nitro-2-[(trimethylsilyl)ethynyl]aniline, which was treated with a base in an aqueous methanolic solution to give 2-ethynyl-5-methyl-4-nitroaniline. A subsequent base-induced cyclization at an elevated temperature gave 5-nitro-6-methylindole, which was treated under a high pressure hydrogenatiori condition to provide 5-amino-6~ methylindole. Example 33: Preparation of 5-amino-4-fluoroindole Treatment of l-(4-fluoro-2,3-dihydro-indol-l-yl)-ethanone, prepared from 4-fluoroindole (See e.g.. EP 0645385A1), with concentrated H2SO4 and fuming HNO3 in glacial acetic acid gave l-(4-fluoro-5-nitro-2,3-dihydro-indol-l-yl)-ethanone. Deprotection of the acetyl group with NaaS in aqueous ethanol provided 4-fiuoro-5-nitro-2,3-dihydro-1H-indole, which was treated with 2,3-dicyano-5,6-dichloro-parabenzoquinone (DDQ) to provide 4-fluoro-5-nitroindole. A subsequent hydrogenation over Pd/C gave 5-amino-4-fiuoroindole. Example 34: Preparation of 5-amino-4-methoxyindole Treatment of l-(4-fluoro-5-nitro-2,3-dihydro-indol-l-yl)-ethanone with Claisen's alkali in CH3OH gave 4-methoxy-5-nii:ro-2,3-dihydro-1H-indole, which was treated with DDQ followed by a hydrogenation over Pd/C to produce 5-amino-4-methoxyindole. Example 35: Preparation of 5-amino-2,4-dimelhylindole Addition of MeMgBr to 2-methyl-5-nitroindole followed by hydrogenation over Pd/C provided 5-amino-2,4-dimethylindole. Example 36: Preparation of 5-amino-4-ethylindole Addition of EtMgBr to 5-nitroindole followed by hydrogenation over Pd/C provided 5-amino-4-ethylindole. Example 37: Preparation of 5-amino-7-chloro-4-methylindole 5-Chloro-2-methyl-4-nitroaniline was treated with acetic anhydride in the presence of 4-dimethylaminopyridine (DMAP) in CH2Cl2 to provide N-(5-chloro-2-methyl-4-nitrophenyl)acetamide, which was reacted with vinyl magnesium bromide at —40 °C to room temperature to give N-(7-chloro-4-methyl-lH-indol-5-yl)acetamide. Deprotection of the acetyl group by heating in an aqueous HC1 solution at the reflux temperature provided 5-amino-7-chloro-4-methylindole. Example 38: Preparation of diisopropyl 2-chloro-4-(2-(4-methylpiperazin-l-yl)ethoxy)phenylboronate 4-Bromo-3-chlorophenol was reacted with 1-methyl-4-(2-hydroxyemyl)piperazme under the Mitsunobu conditions to provide l-[2-(4-bromo-3-chlorophenoxy)ethyl]-4-methyl-piperazine. 1 -[2-(4-Bromo-3-chlorophenoxy)ethyl]-4-methyl-piperazine was reacted with n-BuLi at 0 °C in the presence of triisopropyl borate to give diisopropyl 2-chloro-4-(2-(4-methylpiperazin-l-yl)ethoxy)phenylboronate upon warming to room temperature. Example 39: Preparation of tributyl (5-(2-chloroethoxy)benzofuran-2-yl) stannane 5-Methoxybenzofuran was treated with 2,4,5-collidine and Lil at 170 °C to provide benzofuran-5-ol, which was reacted with 2-chloroethyl-p-toluenesulfonate and Cs2CO3 to give 5-(2-chloroethoxy)-l-benzofuran. Treatment of 5-(2-chloroethoxy)-l-benzofuran with n-BuLi for 16 h followed by the addition of tributyltin chloride at -50 °C gave tributyl (5-(2-chloroethoxy)benzofuran-2-yl) stannane upon warming to room temperature. Example 40: Preparation of diisopropyl 4-(3-chloropropoxy)phenyIboronate 4-Bromophenol was reacted with 2-chloropropyl-p-toluenesulfonate and Cs2CO3 to give l-bromo-4-(3-chloropropoxy)benzene. Treatment of l-bromo-4-(3-chloropropoxy)benzene with n-BuLi at 0 °C in the presence of triisopropyl borate gave diisopropyl 4-(3-chloropropoxy)phenylboronate upon warming to room temperature. Example 41: Preparation of diisopropyl 4-(2-chloroethoxy)-3-methoxyphenylboronate 4-Bromo-2-methoxyphenol was reacted with 2-chloroethyl-p-toluenesulfonate and CS2CO3 at 50 °C for 4 h to give l-bromo-4-(2-chloroethoxy)-3-methoxybenzene. Treatment of l-bromo-4-(2-chloroethoxy)-3-methoxybenzene with n-BuLi at 0 °C in the presence of triisopropyl borate gave diisopropyl 4-(2-chloroethoxy)-3-methoxyphenylboronate upon warming to room temperature. Example 42: Preparation of 4-((4-(tributylstaiinyl)pyridm-2-yl)methyl)morpholine 4-Chloro-2-picolene (10.00 g, 78.74 mmol) in 2-butanone (100 ml) was treated with sodium iodide (50.00 g, 335.82 mmol) and hydriodic acid (12 ml, 57%) and the resulting mixture was heated at the reflux temperature for 18 h. The reaction was cooled to room temperature and the solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was dried over MgSO4 and concentrated to give a dark brown syrup, which was purified by column chromatography (25% ethyl acetate in hexanes) to give 4-iodo-2-picolene as an orange syrup which later crystallized to a red solid (12.3 g, 71% yield). 4-Iodo-2-picolene (10.00 g, 45.66 mmol) in dry carbon tetrachloride (200 ml) was treated with NBS (9.75 g, 54.78 rnmol) and benzoyl peroxide (550 mg, 2.27 mmol) under nitrogen and the resulting mixture was heated at reflux for 24 h. After cooled to room temperature, the reaction mixture was filtered and the solid was washed with dichloromethane, which was combined with the filtrate. The combined organic solution was concentrated to give the crude product, which was purified by column chromatography (20% ethyl acetate in hexanes) to give 2-(bromomethyl)-4-iodopyridine as a yellow solid (4.00 g). 2-(Bromomethyl)-4-iodopyridine (500 mg, 1.68 mmol) in 1,2-dimethoxyethane (15 ml) was treated with morpholine (1.00 g, 11.48 mmol) and sodium iodide (13 mg, 0.09 mmol) and the resulting solution was heated at 90 °C for 5 h. After cooled to room temperature, the reaction mixture was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic layer was dried over MgSO4 and concentrated to give 4-[(4-iodo-2-pyridinyl)methyl]morpholine as a brown solid (315 mg, 62% yield). Treatment of 4-[(4-iodo-2-pyridinyl)methyl]morprioline with n-BuLi at 0°C and tributyltin chloride provided 4-((4-(tributylstannyl)pyridin-2- yl)methyl)morpholine. Example 43: Preparation of 2-(3,4-bis(2-methoxyethoxy)phenyl)-4,4,5,5-tetra methyl-1,3,2-dioxaborolane Step 1: Preparation of 1.2-bis(2-methoxyethoxy)benzene Ortho-catechol (4.75 g, 43 mmol), 2-bromo-l-methoxyethane (15 g, 108 mmol), and potassium carbonate (18 g, 129 mmol) were stirred in 200 mL DMF at 80 °C overnight. The suspension was partitioned between water and EtOAc. The organic layer was washed with water 4 times, dried over magnesium sulfate, and concentrated to give 9.9 g of l,2-bis(2-methoxyethoxy)benzene. Step 2: Preparation of 4-bromo-l,2-bis(2-methoxyethoxy)benzene l,2-Bis(2-methoxyethoxy)benzene (8.1 g, 31.9 mmol) and N-bromosuccinimide (6.2 g, 35 mmol) were stirred in 50 mL DMF at room temperature overnight. The reaction was diluted with 200 mL EtOAc and washed with IN NaOH and water. The organic layer was dried over magnesium sulfate and concentrated to give 9.7 g (92%) of 4-bromo-l,2-bis(2-methoxyethoxy)benzene. Step 3: 2-(3,4-bis(2-methoxyethoxy)phenyl)-4,4,5,5-tetramethyl-L3.2-dioxaborolane 4-Bromo-l,2-bis(2-methoxyethoxy)benzene (4 g, 12 mmol), bis(pinacolato)diboron (3.5 g, 13.8 mmol), KOAc (3.5 g, 36 mmol), and Pd(dppfhCl2 (490 mg, 0.6 mmol) were mixed in 50 mL DMSO and the resulting suspension was heated at 80 °C overnight. The reaction was diluted with EtOAc and washed 4 times with water. The organic layer was concentrated to provide the crude product, which was purified by silica gel chromatography (EtOAc/Hex) to give 4.8 g of 2-(3,4-bis(2-methoxyethoxy)phenyl)-4,4,5,5-tetramethyl-l,3-2-dioxaborolane. Example 44: Preparation of 2-[4-(2-methoxyethoxy)phenylj-4,4,5,5-tetramethyl-1,3,2-dioxaborolane To a solution of 4-(4,4,5,5-tetramethyl-l,3,2-dioxaboralan-2-yl)phenol (1 g, 4.5 mmol), 2-methoxyethanol (450 mg , 5.9 mmol), and triphenylphosphine (1.6 g, 5.9 mmol) in THF (35 mL) was added dropwise diethyl azodicarboxylate (2.7 ml, 5.9 mmol, 40% in toluene) at 0-5 °C. The resulting mixture was stirred at room temperature for 18 h and partitioned between ethyl acetate and water. The organic phase was dried over Na2SO4 filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (ethyl acetate /hexane, 5% to 20%) to provide 989 mg (79%) of 2-[4-(2-methoxyethoxy)phenyl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane as a white solid. Following procedures analogous to those described above, the following boronic esters were prepared: 2-[3-(2-memoxyethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, 2-[4-(4-chlorobutoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaboro lane, and2-[3-(4-chlorobutoxy)phenyl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane. Example 45: Preparation of l-benzofuran-5-carbaldehyde To a solution of 1-benzofuran-5-carbonitrile (5.0 g, 34.9 mmol) in under nitrogen at -15 to -20 °C was added DIBAL-H (41.9 mL, 41.9 mmol, IM/heptane), maintaining the reaction temperature below -15 °C, and the reaction mixture was stirred at -15 to -20 °C for additional 10 min. The reaction mixture was then quenched via dropwise addition of aqueous 2N HC1, maintaining the temperature below room temperature. The organic layer was separated, washed with water, dried over sodium sulfate, and concentrated to give 4.0 g (78%) of l-benzofuran-5-carbaldehyde as a yellow oil. Example 46: Preparation of 2-(tributylstannyl)-l-benzofuran-5-carbaldehyde To a solution of N-methylpiperazine (0.75 g, 7.5 mmol) in hexane (15 mL) at 0 °C under nitrogen was added dropwise a solution of n-BuLi (3 mL, 7.43 mmol, 2.5M/hexanes), and the reaction mixture was stirred at 0 °C for 40 min. 1-Benzofuran-5-carbaldehyde (1.0 g, 6.8 mmol) was added dropwise to the reaction mixture at 0 °C and the resulting mixture was stirred at 0 °C for 15 min. After addition of tetramethylethylenediamine (TMEDA) (1.7 g, 14.96 mmol), a solution of n-BuLi (6,0 mL, 14.86 mmol, 2.5M/hexanes) was added dropwise to the reaction mixture at 0°C and the reaction mixture was allowed to warm up to room temperature and stirred for a total of 18 h. After the reaction mixture was cooled to 0 °C and THF (30 mL) was added, the reaction mixture was cooled to -50 °C, tributyltin chloride (4.87 g, 14.96 mmol) was added dropwise, and the reaction mixture was stirred at -50 °C for 15 min. and at room temperature for 5-6 h. The reaction mixture was quenched with saturated aqueous NaHCOs and extracted into diethyl ether. The organic layer was dried over sodium sulfate and concentrated and the crude product was purified by column chromatography (ethyl acetate/hexane, 2 %) to give 1.0 g (34%) of 2-(tributylstannyl)-1 -benzofuran-5-carbaldehyde as a yellow oil. Example 47: Preparation of dimethyl 5-(piperidin-l-ylmethyl)benzofuran-2-ylboronate 1-Benzofuran-5-carbaldehyde was treated with piperidine and sodium triacetoxyborohydride under the standard reductive animation protocol to provide l-(5-benzofuranylmethyl)piperidine. Treatment of l-(5-benzofuranylmethyl)piperidine with butyl lithium and trimethylborate at low temperature provided dimethyl 5-(piperidin-1-ylmethyl)benzofuran-2-ylboronate. Example 48: Preparation of 5-(5-formyl-l-benzofuran-2-yI)-4-[(4-methyl-lH-indol-5-yl)aminoJ nicotinonitrile 465 A mixture of 5-iodo-4[(4-methyl-lH-indol-5-yl)amino]nicotinonitrile (2.5 g, 6.7 mmol), 2-(tributylstannyl)-l-benzofuran-5-carbaldehyde (4.35 g, 10 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.38 g, 0.34 mmol) in DMF (25 mL) was heated at 120 °C for 1 h. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and water, resulting in a suspension. The insoluble material was removed by filtration and the residue was washed thoroughly with ethyl acetate. The organic layer (from filtrate) was washed with water twice and brine, dried over sodium sulfate, and concentrated and the residue was purified by column chromatography (ethyl acetate/hexane, 1:1) to give 2.0 g (76%) of 5-(5-formyl-l-benzofuran-2-yl)-4-[(4-methyl-lH-indol-5-yl)amino]nicotinomtrile as a yellow solid. HPLC retention time: 10.7 min.(h); MS: 393.2 (M + H); melting point: 235-237 °C; and HRMS: 393.13484. Following procedures analogous to those described for the preparation of 5-(5-formyl-l-benzofuran-2-yl)-4-[(4-methyl-lH-indol-5-yl)amino]nicotinonitrile 465, compounds in Table 15 were prepared. Table 15 (Table Removed) Example 49: Preparation of 4-[(4-methyI-lH-indol-5-yl)amino]-5-{5-[(4-methylpiperazin-l-yI)methyl]-l-benzofuran-2--yl}nicotinonitrile462 To a solution of 5-(5-formyl-l-bem:oruran-2-yl)-4-[(4-methyl-lH-indol-5-yl)amino]nicotinonitrile (800 mg, 2.04 mmol) in a mixture of CH2Cl2 (40 mL) and NMP (5 mL) at room temperature under nitrogen was added N-methylpiperazine (613 mg, 6.12 mmol) followed by glacial acetic acid (674 mg, 11.22 mmol) and the reaction mixture was stirred at room temperature for 1 h. Sodium triacetoxyborohydride (2.38 g, 11.22 mmol) was added to the reaction mixture and the reaction was stirred at room temperature for 5 h. The reaction mixture was partitioned between CH2Cl2 and aqueous IN HC1. The aqueous layer was washed with CH2Cl2 and treated with aqueous IN NaOH whereupon solids precipitated. The solids were collected and dissolved in CH2Cl2. The solution was washed with water thrice and brine, dried over sodium sulfate, and concentrated and the residue was purified by column chromatography (MeOH/CH2Cl2, 6% to 7.5%) to give 560 mg (58%) of 4-[(4-methyl- 1 H-indol-5-yl)amino]-5- {5-[(4-methylpiperazin-1 -yl)methyl]-1 -benzofuran-2-yl}nicotinonitrile as a yellow solid. HPLC retention time: 5.9 min.(g); melting range: 162-165 °C (decom.); and HRMS: 477.24093. Example 50: Preparation of 5-(5-{[4-(hydroxymethyl)piperidin-l-yl]methyl}-l-benzofuran-2-yl)-4-[(4-methyl-lH-indol-5-yl)amino]nicotinonitrile 392 and 5-[5-(hydroxymethyl)-l-benzofuran-2-yl]-4-[(4-methyl-lH-indol-5-yl)amino]nicotinonitrile 481 An alternative procedure for preparing 5-(5-{[4-(hydroxymethyl)piperidin-1 -yl]methyl}-1 -benzofuran-2-yl)-4-[(4-methyl-1 H-indol-5-yl)amino]nicotmonitrile 392 is described below (compare Example 27). To a suspension of 5-(5-formyl-l-benzofuran-2-yl)-4-[(4-methyl-lH-indol-5-yl)amino]nicotinonitrile (200 mg, 0.51 mmol) in a mixture of CH2Cl2 (10 mL) and NMP (1 mL) at room temperature under nitrogen was added 4-(hydroxymethyl)piperidine (176 mg, 1.53 mmol) followed by glacial acetic acid (153 mg, 2.55 mmol) and the reaction mixture was stirred at room temperature for 0.5 h. Sodium triacetoxyborohydride (540 mg, 2.55 mmol) was added in portions at 0 °C and the resulting mixture was stirred at room temperature overnight. The reaction mixture was partitioned between CH2Cl2 and saturated aqueous sodium bicarbonate, and the aqueous layer was extracted with CH2Cl2. The combined organic phases were washed with water and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (MeOH/CH2Cl2, 3% to 20%) to give 128 mg (51%) of 5-(5-{[4-(hydroxymethyl)piperidin-l-yl]methyl}-l-benzofuran-2-yl)-4-[(4-methyl-lH-indol-5-yl)amino]nicotinonitrile 392 as a yellow solid and 23.8 mg of 5-[5-(hydroxymethyl)-l-benzofuran-2-yl]-4-[(4-methyl-lH-indol-5-yl)amino]nicotinonitrile 481 as a yellow solid. Compound 392: HPLC retention time: 6.4 min.(g); melting range: 196-199 °C; and HRMS: 395.15023. Compound 481: HPLC retention time: 8.9 min.(g); MS: 395.3 (M + H); melting range: 232-234 °C; and HRMS: 395.15023. Following procedures analogous to those described for the preparation of 5-(5- {[4-(hydroxymethyl)piperidin-1 -yl]methyl} -1 -benzofuran-2-yl)-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile 392 and 5-[5-(hydroxymethyl)-l-benzofuran-2-yl]-4- [(4-methyl-lH-indol-5-yl)amino]nicotinonitrile 481, the compounds in Table 16 were prepared. Table 16 (Table Removed) Example 51: Preparation of the trifluoroacetic salt of 4-[(4-methyl-lH-indol-5-yl)amino]-5-[5-(piperazin-l-ylmethyl)-l-benzofuran-2-yl]nicotinonitrile 540 A mixture of tert-butyl 4-[(2-{5-cyano-4-[(4-methyl-lH-indol-5-yl)amino]pyridin-3-yl} -1 -benzofuran-5-yl)methyl]piperazine-1 -carboxylate (63 mg, 0.11 mmol) in 10% trifluoroacetic acid/CH2Cl2 was stirred at room temperature for 4 h, concentrated in vacuo, and the residue was purified by preparative HPLC (column: Prodigy ODS3, 4.6 x 150 mm, from Phenomenex (Torrance, CA); mobile phase A: 0.02% trifluoroacetic acid (TFA) in water; mobile phase B: 0.02% TFA in CH3CN, 10-95% B in 25 minutes (min.); flow rate: 1.0 mL/min; column temperature: 40°C; detection wavelength: 254 and 215 nm.) to provide 46 mg (50%) of the trifluoroacetic salt of 4-[(4-methyl-lH-indol-5-yl)amino]-5-[5-(piperazin-l-ylmethyl)-l-benzofuran-2-yl]nicotinonitrile 540 as an orange solid. HPLC' retention time: 5.8 min.(8); MS: 463.3 (M + H); melting point: 113-115 °C; and HRMS: 463.2234. Example 52: Preparation of 5-(3,4-dimethoxyphenyl)-4-[(4-methyl-lH-indol-7-yl)amino]nicotinonitrile 530 A solution of 5-(3,4-dimethoxyphenyl)-4-chloronicotinonitrile (120 mg, 0.44 mmol) and 4-methyl-7-aminoindole (77.8 mg, 0.52 mmol) in ethanol (2.5 mL) was heated at the reflux temperature for 24 h and cooled to room temperature. The reaction mixture was treated with aqueous NH4OH and concentrated in vacuo, and the residue was purified by flash column chroma!ography (ethyl acetate/CH2Cl2 5% to 25%) to provide a 48 mg (29%) of 5-(3,4-dimethoxyphenyl)-4-[(4-methyl-lH-indol-7-yl)amino]nicotinonitrile 530 as an off white solid. HPLC retention time: 9.0 min.(8); MS: 385.3 (M + H); and HRMS: 385.1659. Following procedures analogous to those described for the preparation of 5-(3,4-dimethoxyphenyl)-4-[(4-methyl-lH-indol-7-yl)amino]nicotinonitrile 530, 5-(3,4-dimethoxyphenyl)-4-(lH-indol-7-ylamino)nicotinonitrile 544 was prepared. HPLC retention time: 8.6 min.(g); HRMS: 371.1498; melting range: 205-207 °C. Example 53: Preparation of 5-(2-formyl-l-methyl-lH-imidazol-5-yl)-4-[(4-methyl-lH-indol-5-yl)amino]nicotinonitrile 537 A mixture of 5-iodo-4[(4-memyl-lH-indol-5-yl)amino]nicotinonitrile (250 mg, 0.67 mmol), l-methyl-5-(tributylstannyl)-lH-imidazole-2-carbaldehyde (see e.g.. U.S. Patent No. 6,521,618) (401 mg, 1.0 mmol), dichlorobis(triphenylphosphine)palladium(II) (24 mg, 0.034 mmol), and triethylamine (74.9 mg, 0.74 mmol) in dioxane (6 mL) was heated at the reflux temperature for 22 h, cooled to room temperature, and concentrated in vacuo. The residue was suspended in CH2C12 and filtered and the solid was washed with CH2Cl2. The combined filtrate and washings were concentrated in vacuo and the residue was purified by column chromatography (ethyl acetate /CH2C12, 20% to 90%; MeOH/ ethyl acetate, 5%) to provide 103 mg (43%) of 5-(2-formyl-1 -methyl- lH-imidazol-5-yl)-4-[(4-methyl-lH-indol-5-yl)amino]nicotinonitrile 537 as a dark yellow solid. MS: 355.2 (M + H); melting range: 200-202 °C; and HRMS: 357.1458. Following procedures analogous to those described for the preparation of 5-(2-formyl-1 -methyl-1 H-imidazol-5-yl)-4-[(4-mei:hyl-1 H-indol-5-l)amino]nicotinonitrile 537, compounds in Table 17 were prepared. Table 17 (Table Removed) Example 54: Preparation of 4-[(4-methyl-lH-indol-5-yl)amino]-5-(l,3-thiazol-2-yl)nicotinonitrile 541 A mixture of 5-iodo-4[(4-methyl-lH-indol-5-yl)amino]nicotinonitrile (120 mg, 0.32 mmol), 2-(tributylstannyl)-l,3-thiazole (340 mg, 0.91 mmol), dichlorobis(triphenylphosphine)palladium(II) (28 mg, 0.04 mmol), and triethylamine (36 mg, 0.35 mmol) in dioxane (4 mL) was heated at reflux for 24 h. 4-[(4-Methyl-1H- indol-5-yl)amino]-5-(l,3-thiazol-2-yl)nicotinonitrile was obtained following the work- up and purification procedures as described for the preparation of 5-(2-formyl-l- methyl-lH-imidazol-5-yl)-4-[(4-methyl-lH-indol-5-yl)amino]nicotinonitrile 541. HPLC retention time: 10.1 min.(g); MS: 332.2 (M + H); melting range: 245-247 °C; and HRMS: 332.0964. Following procedures analogous to those described for the preparation of 5-(2-formyl-l-methyl-lH-imidazol-5-yl)-4-[(4-methyl-lH-indol-5- yl)amino]nicotinonitrile 541, 4-[(4-methyl-l H-indol-5-yl)amino]-5-(l,3-thiazol-4-yl)nicotinonitrile 543 was prepared. HPLC retention time: 7.7 min.(g); MS: 332.2 (M + H); melting range: 245-247 °C; and HRMS: 332.0966. Example 55: Preparation of 5-[4-(2-metfaoxyethoxy)phenyIj-4-[(4-methyl-lH-indol-5-yl)amino]nicotinonitrile 482 A mixture of 5-iodo-4[(4-methyl-lH-indol-5-yl)amino]nicotinonitrile (100 mg, 0.27 mmol), 2-[4-(2-methoxyethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (98 mg, 0.35 mmol), and tetrakis(triphenylphosphine)palladium(0) (16 mg, 0.014 mmol) in DME (6 mL) and saturated aqueous NaHCOs (4 mL) was heated at 95 °C for 3 h, cooled to room temperature, and treated with water. The precipitate was filtered, washed with water, dried in vacuo, and purified by flash column chromatography (MeOH/ CH2C12, 2% to 4%) to provide 75 mg (70%) of 5-[4-(2-methoxyethoxy)phenyl]-4-[(4-methyl-lH-indol-.'5-yl)amino]nicotinonitrile as a tan solid. HPLC retention time: 8.2 min.(g); MS: 399.3 (M + H); melting range: 208-210 °C; andHRMS: 399.18056. Example 56: Preparation of 5-[3-(2-methoxyethoxy)phenyl]-4-[(4-methyl-lH-indol-5-yl)amino]nicotinonitrile 483 A mixture of 5-iodo-4[(4-memyl-lH-indol-5-yl)amino]nicotinonitrile (100 mg, 0.27 mmol), 2-[3-(2-methoxyethoxy)phenyl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (98 mg, 0.35 mmol) and tetrakis(triphenylphosphine)palladium(0) (16 mg, 0.014 mmol) in DME (6 mL) and saturated aqueous NaHCOs (4 mL) was heated at 95 °C for 2 h, cooled to room temperature and partitioned between dichloromethane and water. The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo, and the residue was purified by flash column chromatography (MeOH/ CH2Cl2, 1% to 5%) to provide 71 mg (66%) of 5-[3-(2:-methoxyethoxy)phenyl]-4-[(4-methyl-lH-indol-5-yl)amino]nicotinonitrile as a tan solid. HPLC retention time: 8.3 min.(8>; MS: 399.3 (M + H); melting range: 158-160 °C; and HRMS: 399.18291. Following procedures analogous to those described for the preparation of 5-[3-(2-methoxyethoxy)phenyl]-4-[(4-methyl-lH-indol-5-yl)amino]nicotinonitrile 483, 5-[4-(4-chlorobutoxy)phenyl]-4-[(4-memyl-1 H-indol-5-yl)amino]nicotinonitrile 490 and 5-[3-(4-chlorobutoxy)phenyl]-4-[(4-methyl-lH-indol-5-yl)amino]nicotinonitrile 501 were prepared. Compound 490: HPLC retention time: 11.1 min.(g); MS: 431.3 (M+H); melting point: 157-159 °C; and HRMS: 431.16279; and compound 501: HPLC retention time: 11.2 min.(g); MS: 431.3 (M+H); melting point: 151-153 °C; and HRMS: 431.16345. Example 57: Preparation of 4-[(4-methyl-lH-indol-5-yl)amino]-5-{5-[(4-methylpiperazin-l-yl)methyl)-3-furyl}nicotinonitrile 503 To a solution of l-[4-bromo-2-furyi) methyl]-4-methylpiperazine (see e.g., J. Med. Chem., 49, 7868, (2006)) (145 mg, 0.56 mmol), and triisopropylborate (132 mg, 0.16 mL, 0.7 mmol) in THF was added dropwise n-BuLi (0.3 ml, 0.76 mmol, 2.5M/hexane) at -78 °C and the reaction mixture was stirred at -78 °C for 3 h and warmed to room temperature in 1 h. A few drops of water were added and the mixture was concentrated in vacuo. To the residue was added 5-iodo-4[(4-methyl-lH-indol-5- yl)amino]nicotinonitrile (100 mg, 0.27 mmol), [M'- bis(diphenylphosphino)ferrocene]dichloropalladium(II)-CH2Cl2 ((dppfhPdCh, 12 mg, 0.014 mmol), DME (6 mL) and saturated aqueous Na2CO3 (4 mL) and the resulting mixture was heated at 85 °C for 1.5 h and cooled to room temperature. The mixture was partitioned between dichloromethane and water, and the organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (MeOH/ CH2C12, 5% to 20%) to provide 68 mg (57%) of 4-[(4-methyl-lH-indol-5-yl)amino]-5-{5-[(4-methylpiperazin-l-yl)methyl]-3-furyl}nicotinonitrile as a light tan solid. HPLC retention time: 4.8 min. (g); Melting point: 129 °C (decom.); and HRMS: 427.22597. Example 58: Preparation of 4-[(7-chloro-4-methyl-lH-indol-5-yl)amino]-5-(5-formyl-l-benzofuran-2-yl)nicotinonitrile 532 To a stirred solution of 4-[(7-cmoro-4-methyl-lH-indol-5-yl)amino]-5- iodonicotinonitrile (405 mg, 1 mmol) in DMF (7 mL) was added 2-(tributylstannyl)-l- benzofuran-5-carbaldehyde (609 mg, 1.4 mmol) and tetrakis(triphenylphosphine)palladium(0) (110 mg, 0.1 mmol) under nitrogen atmosphere, the reaction mixture was heated at 110 °C for 1.5 h and cooled to room temperature and ethyl acetate was added to the resulting mixture. The organic phase was washed with water, saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated and the residue was purified by flash column chromatography (ethyl acetate/hexane) to give 4-[(7-chloro-4-methyl-lH-indol-5-yl)amino]-5-(5- formyl-l-benzofuran-2-yl)nicotinonitrile as a yellow solid (351 mg, 82%). HPLC retention time: 12.4 min.(8); and MS: 427.3 (M + H). Example 59: Preparation of 4-[(7-chloro-4-methyI-lH-indol-5-yl)amino]-5-{5-[(4-methylpiperazin-l-yl)methyl]-l-benzofuran-2-yl}nicotinonitrile 529 To a stirred solution of 4-[(7-chloro-4-methyl-lH-indol-5-yl)amino]-5-(5-formyl-l-benzofuran-2-yl)nicotinonitrile (106 rag, 0.25 mmol) in THF (3 mL) and EtOH (1 mL) was added 1-methylpiperazine (75 mg, 0.75 mmol) and acetic acid (75 mg, 1.2 mmol) and the reaction mixture was stirred at room temperature for 1 h. Sodium triacetoxyborohydride (159 mg, 0.75 mmol) was added to the reaction mixture and the solution was stirred at room temperature overnight, and concentrated. Aqueous IN HC1 was added and the aqueous phase was extracted with ethyl acetate, basified to pH of 10 by adding sodium carbonate, and extracted with ethyl acetate. The combined organic phases were washed with water and brine, dried over magnesium sulfate, and concentrated to give 4-[(7-chloro-4-methyl-lH-indol-5-yl)amino]-5-{5-[(4-methylpiperazin-l-yl)methyl]-l-benzofuran-2-yl}nicotinonitrile as a yellow solid (68 mg, 53%). HPLC retention time: 7.0 min.rl-1H-indol-5-yl)amino]nicotinonitrile, 5- {5-[(dimethylamino)methyl]-1 -benzofiiran-2-yl} -4-[(4-methyl- lH-indol-5-yl)amino]nicotinonitrile, 5-(5-{[(2-hydroxyethyl)amino]methyl}-l-benzofuran-2-yl)-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile, 5-(5- {[(3-hydroxypropyl)arnino]methyl} -1 -benzofuran-2-yl)-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile, 5-(5-{[(2,3-dihydroxypropyl)amino]methyl}-l-benzofuran-2-yl)-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile, 5-(5- {[(2,3-dihydroxypropyl)(methyl)amino]methyl} -1 -benzofuran-2-yl)-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile, 5-{5-[(cyclohexylamino)methyl]-l-benzofuran-2-yl}-4-[(4-methyl-1H-indol-5- yl)amino]nicotinonitrile, 4-[(4-methyl-1H-indol-5-yl)amino]-5-[5-(morpholin-4-ylmethyl)-1-benzoftiran- 2-yl]nicotinonitri le, 4-[(4-methyl-1H-indol-5-yl)amino]-5-[5-(pyrrolidin-l-ylmethyl)-l-benzofuran- 2-yl]nicotinonitrile, 4-[(4-methyl- 1H-indol-5-yl)amino]-5-(5- {[(2-pyrrolidin-1 -ylethyl)amino]methyl} -1 -benzofuran-2-yl)nicotinonitrile, 4-[(4-methyl-1H-indol-5-yl)amino]-5-[5-({[(l-methylpiperidin-4-yl)methyl]amino}methyl)-l-benzofuran-2-yl]nicotinonitrile, 5-(5- {[4-(hydroxymethyl)piperidin- l-yl]methyl} -1 -benzofuran-2-yl)-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile, 4-[(4-methyl- 1H-indol-5-yl)amino]-5- {.5-[(4-pyrrolidin-1 -ylpiperidin-1 -yl)methyl]-l-benzofuran-2-yl }nicotinomtrile, 5-[5-( 1,4'-bipiperidin-1 '-ylmethyl)- l-betizofuran-2-yl]-4-[(4-methyl- 1H-indol-5-yl)amino]nicotinonitrile, 4-[(4-methyl-1H-indol-5-yl)amino]-5-{5-[(4-morpholin-4-ylpiperidin-l-yl)methyl]-1-benzofuran-2-yl} nicotinon itrile, 5-[5-( {4-[2-(dimethylamino)ethyl]piperazin-1-yl} methyl)-1-benzofuran-2-yl]-4-[(4-methyl-1H-indol-5-yl)amino]nicottnonitrile, 4-[(4-methyl-1H-indol-5-yl)amino]-5-{5-[(4-pyridin-2-ylpiperazin-l-yl)methyl]-l-benzofuran-2-yl}nicotinonitrile, 4-[(4-methyl-1H-indol-5-yl)amino]-5-(5- {[(pyridin-2-ylmethyl)amino]methyl} -1 -benzofuran-2-yl)nicotinonitrile, 4-[(4-methyl-1H-indol-5-yl)amino]-5-(5-{[(pyridin-3-ylmethyl)amino]methyl}-1 -benzofiiran-2-yl)nicotinonitrile, 4-[(4-methyl-1H-indol-5-yl)amino]-5-(5-{[(pyridin-4-ylmethyl)amino]methyl}-1 -benzofuran-2-yl)nicotinonitrile, 4-[(4-methyl-1H-indol-5-yl)amino]-5-[5-(morpholin-4-ylmethyl)-2-furyl]nicotinonitrile, 4-[(4-methyl-1H-indol-5-yl)amino]-5-[5-(piperidin-1 -ylmethyl)-2-furyljnicotinonitrile, 5-[5-(l,4'-bipiperidin-l'-ylmethyl)-2-fury]]-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile, 4-[(4-methyl-1H-indol-5-yl)amino]-5-{5-[(4-pyrrolidin-l-ylpiperidin-l-yl)methyl]-2-furyl}nicotinonitrile, 4-[(4-methyl-1H-indol-5-yl)amino]-5-{5-|(4-morpholin-4-ylpiperidin-l-yl)methyl] -2-furyl} nicotinonitrile, 5-{5-[(diethylamino)methyl]-2-furyl}-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile, 5-{5-[(dibutylamino)methyl]-2-furyl}-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile, 5-{5-[(benzylamino)methyl]-2-fliryl}-4-[(4-methyl-l^-indol-5-yl)ammo]mcotinonitrile, 4-[(4-methyl-1H-indol-5-yl)amino]-5-(5-{[(3-phenylpropyl)amino]methyl}-2-furyl)nicotinonitrile, 4-[(4-methyl-1H-indol-5-yl)amino]-5-[5-(pyrrolidin-l-ylmethyl)-2-furyljnicotinonitrile, 4-[(4-methyl-1H-indol-5-yl)amino]-5-[5-(thiomorpholin-4-ylmethyl)-2-furyljnicotinonitrile, 5-(3,4-dimethoxyphenyl)-4-[(6-methyl-1H-indol-5-yl)amino]nicotinonitrile, 5-( 1 -benzofuran-2-yl)-4-[(6-methyl-1H- indol-5-yl)amino]nicotinonitrile, 5-(4-{2-[(2-hydroxyethyl)amino]ethoxyjphenyl)-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile, 5-(4-(2-[(3-hydroxypropyl)amino]ethoxy}phenyl)-4-[(4-methyl-1H-indol-5-yl)amino] nicotinonitrile, 5-(4- {2-[(2-ethoxyethyl)amino]ethoxy} phenyl)-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile, 5-[4-(2- {[2-(dimethylamino)ethyl]amino } ethoxy)phenyl]-4-[(4-methyl-1H-indol-5-yl)arnino]nicotinonitrile, 4-[(4-methyl-1H-indol-5-yl)amino]-5-[4-(2-pyrrolidin-1-ylethoxy)phenyl]nicotinonitrile, 5- {4-[2-(benzylamino)ethoxy]phenyl} -4--[(4-methyl- 1H-indol-5-yl)amino]nicotinonitrile, 4-[(4-methyl-1H-indol-5-yl)amino]-5-(4- {2-[(l -methylpiperidin-4-yl)amino]ethoxy}phenyl)nicotinonitrile, 4-[(4-methyl-1H-indol-5-yl)amino]-5-[4-(2-{[(l-methylpiperidin-4-yl)methyl]amino}ethoxy)phenyl]nicotinonitrile, 5-(4-{2-[4-(hydroxymethyl)piperidin-l-yl]ethoxy}phenyl)-4-[(4-methyl-1H-indol-5-yl)aminoJnicotinonitrile, 4-[(4-methyl- 1H-indol-5-yl)amino]-5- {4--[2-(4-pyrrolidin- 1-ylpiperidin-1 -yl)ethoxy]phenyl} nicotinonitrile, 4-[(4-methyl- 1H-indol-5-yl)amino] -5- {4 -[2-(4-morpholin-4-ylpiperidin-1 -yl)ethoxy]phenyl}nicotinonitrile, 5- (4-[2-(4-ethylpiperazin-1 -yl)ethoxy]phenyl} -4-[(4-methyl-1H-indol-5-yl)amino] nicotinonitrile, 5- {4-[2-(4-methyl-1,4-diazepan-1 -yl)ethoxy]phenyl} -4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile, 5-(4-{2-[4-(2-hydroxyethyl)piperazin-l-yf]ethoxy}phenyl)-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile, 5-[4-(2- {4-[2-(dimethylamino)ethyl]piperazin-1 -yl} ethoxy)phenyl]-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile, 5-[4-(2-{[3-(1H-imidazol-l-yl)propyl]ammo}ethoxy)phenyl]-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile, 4-[(4-methyl- 1H-indol-5-yl)amino]-5- (4-[2-(4-pyridin-2-ylpiperazin-1 -yl)ethoxy]phenyl}nicotinonitrile, 4-[(4-methyl-1H-indol-5-yl)amino]-5-{4-[2-(4-pyridin-4-ylpiperazin-l-yl)ethoxy]phenyl}nicotinonitrile, 4-[(4-methyl-1H-indol-5-yl)amino]-5-(4-{2-[(pyridin-2-ylmethyl)amino]ethoxy}phenyl)nicotinonitrile, 4-[(4-methyl-1H-indol-5-yl)amino]-5-(4-{2-[(pyridin-3-ylmethyl)amino] ethoxy} phenyl)nicotinonitiile, 4-[(4-methyl-1H-indol-5-yl)aminoJ-5-(4-(2-[(pyridin-4-ylmethyl)amino]ethoxy}phenyl)nicotinonitrile, 4-[(4-methyl- 1H-indol-5-yl)amino]-5- {4-[2- (4-phenylpiperidin-1 - yl)ethoxy]phenyl}nicotinonitrile, 5-(5- {[4-(dimethylamino)piperidin-1 -yljmethyl} -2-furyl)-4-[(4-methyl- IH- . indol-5-yl)amino]nicotinonitrile, 5-{5-[(4-isopropylpiperazin-l-yl)methyl]-2-l:uryl}-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile, 4-[(4-methyl- 1H-indol-5-yl)amino]-5- {5-[2-(4-methylpiperazin-1 -yl)ethoxy]-1 -benzofuran-2-yl} nicotinonitrile, 5-(3,4-dimethoxyphenyl)-4- {[2-(4-methy Ipiperazin-1 -yl)ethyl]amino} nicotinonitrile, 5-(3,4-dimethoxyphenyl)-4- {[3 -(4-methy Ipiperazin-1 -yl)propyl]amino}nicotinonitrile, 4-({[trans-4-(aminomethyl)cyclohexyl]methyl}amino)-5-(3,4-dimethoxyphenyl)nicotinonitrile, 4-{[(trans-4-ammocyclohexyl)methyl]amino}-5-(3,4-dimethoxyphenyl)nicotinonitrile, 4-({[cis-3-(aminomethyl)cyclohexyl]methyl}amino)-5-(3,4-dimethoxyphenyl)nicotinonitrile, 5-(3,4-dimethoxyphenyl)-4-[(2-piperidin-4-ylethyl)amino]nicotinonitrile, 5-(3,4-dimethoxyphenyl)-4-[(piperidin-4-ylmethyl)amino]nicotinonitrile, 4-[(cis-4-aminocyclohexyl)amino]-5-(3,4-dimethoxyphenyl)nicotinonitrile, 5-(3,4-dimethoxyphenyl)-4- {[2-( 1 -methylpiperidin-4-yl)ethyl]amino} nicotinonitrile, 5-(3,4-dimethoxyphenyl)-4- {[(1 -methylpiperidin-4-yl)rnethyl]amino}nicotinonitrile, 4-[(4-methyl-1H-indol-5-yl)amino]-5-{4-[(4-methylpiperazin-l-yl)methyl]phenyl} nicotinonitrile, 4-[(4-methyl-1H-indol-5-yl)amino]-5-[4-(pyrrolidin-l-ylmethyl)phenyl]nicottnonitrile, 4-[(4-methyl-1H-indol-5-yl)amino]-5-[4-(morpholin-4-ylmethyl)phenyl]nicotinonitrile, 5- {4-[(dimethylamino)methyl]phenyl} -4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile, 4-[(4-methyl-1H-indol-5-yl)amino]-2'-(morpholin-4-ylmethyl)-3,4'-bipyridine-5-carbonitrile, 4-[(4-methyl-1H-indol-5-yl)amino]-5- {3 -[(4-methylpiperazin-1 -yl)methyl]phenyl} nicotinonitrile, 4-[(4-methyl-1H-indol-5-yl)amino]-5-[3-(pyrrolidin-l-ylmethyl)phenyl]nicotinonitrile, 4-[(4-methyl-1H-indol-5-yl)amino]-5-[;5-(morpholin-4-ylmethyl)phenyl]nicotinonitrile, 5- {3-[(dimethylamino)methyl]phenyl} -4-[(4-methyl- lH-indol-5-yl)amino]nicotinonitrile, 5-(4-{[(2R)-2-amino-3-phenylpropyl]oxy}phenyl)-4-(1H-indol-4-ylamino)nicotinonitrile, 5- {2-fluoro-4-[(4-methylpiperazin-1 -yl}methyl]phenyl}-4-[(4-methyl- 1H-indol-5-yl)amino]nicotinonitrile, 5-[4-(3-cWoropropoxy)phenyl]-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile, 4-[(4-methyl- 1H-indol-5-yl)amino] -5-[ 5-(piperidin-1 -ylmethyl)-1 -benzofuran-2-yl]nicotinonitrile, 4-[(4-methyl- 1H-indol-5-yl)amino]-5- { 5-[(4-methylpiperazin-1 -yl)methyl] -1 -benzofiiran-2-yl} nicotinonitrile, 5-(5-formyl-2-thienyl)-4-[(4-methyl-l/i-indol-5-yl)amino]nicotinonitrile, 4-[(4-methyl-1H-indol-5-yl)amino]-5- { 5-[(4-methylpiperazin-1 -yl)methyl]-2~ thienyl}nicotinonitrile, 5-(5-formyl-l-ben2:ofiu-an-2-yl)-4-[(4-methyl-1H-iiidol-5-yl)amino]nicotinonitrile, 5-(3-methyl-l-benzofuran-2-yl)-4-[(4-niethyl-1H-indol-5-yl)amino]nicotinonitrile, 4-[(4-methyl-1H-indol-5-yl)amino]-3,4l-bipyridine-5-carbonitrile, 4-[(4-methyl-1H-indol-5-yl)amino]-5-{5-[(4-methylpiperazin-l-yl)methyl]-2-fiiryl} nicotinonitrile, 2'-chloro-4-[(4-methyl-1H-indol-5-yl)amino]-3,4'-bipyridine-5-carbonitrile, 5- {2-chloro-4-[2-(4-methylpiperazin-1 -yl)ethoxy]phenyl} -4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile, 2'-chloro-4-[(4-methyl-1H-indol-5-yl)amino]-3,3'-bipyridine-5-carbonitrile, 4-[(4-methyl-1H-indol-5-yl)amino]-5-{4-[3-(4-methylpiperazin-l-yl)propoxy]phenyl} nicotinonitrile, 4-[(4-methyl-1H-indol-5-yl)amino]-5-[4-(3-morpholin-4-ylpropoxy)phenyl]nicotinonitrile, 4-[(4-methyl- 1H-indol-5-yl)amino]-5-[4-( 3-piperidin-1 -ylpropoxy)phenyl]nicotinonitrile, 5- {4-[3-(dimethylamino)propoxy]phenyl} -4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile, 5-[3,4-bis(2-methoxyethoxy)phenyl]-4-[(4-methyl-1H-indol-5-yl)ajtnino]nicotinonitrile, 5-[3-methoxy-4-(2-methoxyethoxy)phenyl]-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile, 5-[5-(hydroxymethyl)-1 -benzofuran-2-yl] -4-[(4-methyl- 1H-indol-5-yl)amino]nicotinonitrile, 5-[4-(2-methoxyethoxy)phenyl]-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile, 5-[3-(2-methoxyethoxy)phenyl]-4-[(4-meihyl-1H-indol-5- yl)amino]nicotinonitrile, 5-(5-formyl-1 -benzofuran-2-yl)-4-( 1H-inclol-5-ylamino)nicotinonitrile, 4-(1H-indol-5-ylamino)-5- {5-[(4-methylpiperazin- l-yl)methyl]-1 -benzoftiran-2-yl} nicotinonitrile, 5- (5-[(4-cyclopentylpiperazin-1 -yl)methyl]-2-furyl} -4-[(4-methyl-1H-mdol-5-yl)amino]nicotinonitrile, 5- (5-[( 1,1 -dioxidothiomorpholin-4-yl)meithyl]-2-furyl} -4-[(4-methyl- IH-indol-5-yl)amino]nicotinonitrile, 5-(3,4-dimethoxyphenyl)-4-(1H-pyrrolo[2.,3-b]pyridin-5-ylamino)nicotinonitrile, 5-(5-formyl-2-furyl)-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile, 5-[4-(4-chlorobutoxy)phenyl]-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile, 4-[(4-methyl-1H-indol-5-yl)amino]-5-{4-[4-(4-methylpiperazin-1-yl)butoxy]phenyl}nicotinonitrile, 4-[(4-chloro-1H-pyrrolo[2,3-b]pyridin-:5-yl)amino]-5-[3-methoxy-4-(2-methoxyethoxy)phenyl]nicotinonitrile, 5-[4-(2-chloroethoxy)phenyl]-4-[(6-methyl-lH-indol-5-yl)amino]nicotinonitrile, 5-(5-formyl-1 -benzofuran-2-yl)-4-[(6-methyl- lH-indol-5-yl)amino]nicotinonitrile, 4-[(6-methyl-1H-indol-5-yl)amino]-5- {4-[2-(4-methylpiperazin-1 -yl)ethoxy]phenyl} nicotinonitrile, 4-[(6-methyl-1H-indol-5-yl)amino]-5-{5-[(4-methylpiperazin-1-yl)methyl]-1-benzofuran-2-yl} nicotinonitrile, 4-[(7-chloro-4-methyl-1H-indol-5-yl)amino]-5-(3,4-dimethoxyphenyl)nicotinonitrile, 5-[5-(hydroxymethyl)-l -benzofuran-2-yl]-4-[(6-methyl- lH-indol-5-yl)amino]nicotinonitrile, 5-{5-[(diethylamino)methyl]-l-benzofuran-2-yl}-4-[(6-methyl-1H-indol-5-yl)amino]nicotinonitrile, 5-[3-(4-chlorobutoxy)phenyl]-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile, 4-[(4-methyl-1H-indol-5-yl)amino]-5- {3- [4-(4-methylpiperazin-1 -yl)butoxy]phenyl} nicotinonitrile, 4-[(4-methyl-1H-indol-5-yl)amino]-5-{5-[(4-methylpiperazin-l-yl)methyl]-3-furyl} nicotinonitrile, 4-[(6-methyl-1H-indol-5-yl)amino]-5-[4-(2-piperidin-1-ylethoxy)phenyl]nicotinonitrile, 5- {4-[2-(4-hydroxypiperidin-1 -yl)ethoxy]phenyl} -4-[(6-methyl- 1H-indol-5-yl)amino] nicotinonitrile, 4-[(6-methyl- 1H-indol-5-yl)amino]-5- {4- "2-(4-pyrrolidin- 1-ylpiperidin-1 -yl)ethoxy]phenyl} nicotinonitrile, 4-[(4-methyl-1H-indol-5-yl)amino] -6'-morpholin-4-yl-3,3 '-bipyridine-5-carbonitrile, 4-[(4-methyl- 1H-indol-5-yl)amino]-6'-piperidin-1 -yl-3,3'-bipyridine-5-carbonitrile, 4-[(4-methyl-1H-indol-5-yl)amino]-5-pyiimidin-5-ylmcotinonitrile, 4-[(4-methyl- 1H-indol-5-yl)amino]-5-(2- piperidin-1 -ylpyrimidin-5-yl)nicotinonitrile, 4-[(4-methyl-lH-indol-5-yl)amino]-5-(2-morpholin-4-ylpyrimidin-5-yl)nicotinonitrile, 4-[(4-methyl-1H-indol-5-yl)amino]-5-(2-pyrrolidin-1-ylpyrimidin-5-yl)nicotinonitrile, 5-[2-(dimethylamino)pyrimidin-5-yl]-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile, 5-( 1 -benzothien-2-yl)-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile, 5-[4-(2-chloroethoxy)phenyl]-4-(1H-indol-5-ylamino)nicotinonitrile, 5-(5-fortnyl-3-thienyl)-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile, 5-(4-formyl-2-furyl)-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile, 4-[(4-methyl-1H-indol-5-yl)amino]-5-{5-[(4-methylpiperazin-l-yl)methyl]-3-thienyl} nicotinonitrile, 4-[(4-methyl-lH-indol-5-yl)amino]-3,3'-bipyridine-5-carbonitrile, 4-(1H-indol-5-ylamino)-5-{4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl}nicotinonitrile, 4-[(4-methyl-1H-indol-5-yl)amino]-5-{5-[(4-methylpiperazin-l-yl)methyl]-l-benzothien-2-yl}nicotinonitrile, 4-[(4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)amino]-5-(3,4-dimethoxyphenyl)nicotinonitrile, 4-[(trans-4-aminocyclohexyl)amino] -5-(3,4-dimethoxyphenyl)nicotinonitrile, 1 -butyl-3-(4- {5-cyano-4-[(4-methyl-1H-indol-5-yl)amino]pyridin-3-yl}phenyl)urea, methyl (4- {5-cyano-4-[(4-methyl- 1H-indol-5-yl)amino]pyridin-3- yl} phenyl)carbamate, benzyl (4-{5-cyano-4-[(4-methyl-1H-indol-5-yl)amino]pyridin-3-yl}-2- fluorophenyl)carbamate, 4-methoxybenzyl (4-{5-cyano-4-[(4-methyl-1H-indol-5-yl)amino]pyridin-3-yl) -2-fluorophenyl)carbamate, 4-[(7-chloro-4-methyl-1H-indol-5-yl)amino]-5-{5-[(4-methylpiperazin-l-yl)methyl]-1 -benzofuran-2-yl} nicotinonttrile, 5-(3,4-dimethoxyphenyl)-4-[(4-methyl-1H-indol-7-yl)amino]nicotinonitrile, 5-(l-benzofuran-2-yl)-4-[(7-chloro-4-methyl-1H-indol-5-yl)amino]nicotinonitrile, 4-[(7-chloro-4-methyl-1H-indol-5-yl)amino]-5-(5-formyl-l-benzofuran-2-yl)nicotinonitrile, 5-[4-(2-chloroethoxy)phenyl]-4-[(7-chloro-4-methyl-1H-indol-5-yl)amino]nicotinonitrile, 4-[(7-chloro-4-methyl-1H-indol-5-yl)amino]-5-{4-[2-(dimethylamino)ethoxy]phenyl} nicotine nitrile, 4-[(7-chloro-4-methyl-1H-indol-5-yl)amino]-5-{4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl}nicotinonitrile, tert-butyl 4-[(2- {5-cyano-4-[(4-methyl-1H-indol-5-yl)amino]pyridin-3-yl} -1 -benzofuran-5-yl)methyl]piperazine-1 -carboxylate, 5-(2-formyl-1 -methyl- 1H-imidazol-5-yl) -4-[(4-methyl- lH-indol-5-yl)amino]nicotinonitrile, 4-[(4-methyl-1H-indol-5-yl)amino]-5-(5-{[4-(methylsulfonyl)piperazin-l- yljmethyl} -1 -benzofuran-2-yl)nicotinoni trile, 4-[(4-methyl- lH-indol-5-yl)amino]-5- {1 --methyl-2-[(4-methylpiperazin-1 - yl)methyl]- 1H-imidazol-5-yl} nicotinonitrile, 4-[(4-methyl-1H-indol-5-yl)amino]-5-[5-(piperazin-l-ylmethyl)-l-benzofuran- 2-yl]nicotinoni trile, 4-[(4-methyl- 1H-indol-5-yl)amino]-5-( 1,3-thiazol-2-yl)nicotinonitrile, 5-(l-methyl-1H-imidazol-2-yl)-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile, 4-[(4-methyl-1H-indol-5-yl)amino]-5-(l,3-thiazol-4-yl)nicotinonitrile, 5-(3,4-dimethoxyphenyl)-4-(1H-indol-7-ylammo)nicotinonitrile, 5-(3,4-dimethoxyphenyl)-4-[(4-methoxy-1H-indol-5-yl)amino]nicotinonitrile, 5-(3,4-dimethoxyphenyl)-4-[(4-fluoro-1H-indol-5-yl)amino]nicotinonitrile, 4-[(7-chloro-4-methyI-1H-indol-5-yl)arnino]-5-[5-(piperazin-1 -ylmethyl)-1 -benzofuran-2-ylJnicotinonitrile, tert-butyl 4-[(2-{4-[(7-chloro-4-methyl-1H-indol-5-yl)amino]-5-cyanopyridin-3-yl} -1 -benzoftiran-5-yl)methyl]piperazine-1 -carboxylate, 5-(3,4-dimethoxyphenyl)-4-[(2,4-dimet.byl-1H-indol-5-yl)amino]nicotinonitrile, 5- {2-[(dimethylamino)methyl]phenyl} -4-[(4-methyl- lH-indol-5-yl)amino]nicotinonitrile, 5-(5-formyl-2-methoxyphenyl)-4-[(4-msthyl-1H-indol-5-yl)amino]nicotinonitrile, 5- {2-methoxy-5-[(4-methylpiperazin-1 -yl)methyl]phenyl} -4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile, 5-{5-[(4-ethylpiperazin-l-yl)methyl]-l-benzofiiran-2-yl}-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile, 4-[(4-methyl-1H-indol-5-yl)amino]-5-{5-[(4-methyl-4-oxidopiperazin-l-yl)methyl]-1 -benzofuran-2-yl} nicotinonitrile, 5-(3,4-dimethoxyphenyl)-4-[( 1,4-dimethyl- 1H-indol-5-yl)amino]nicotinonitrile, 3-{5-cyano-4-[(4-methyl-1H-indol-5-yl)amino]pyridin-3-yl}benzoic acid, 5-(2-methoxyphenyl)-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile, 5-(3-methoxyphenyl)-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile, 5-(4-methoxyphenyl)-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile, 4-[(4-methyl-1H-indol-5-yl)amino]-5-phenylnicotinonitrile, 4-[(4-methyl-1H-indol-5-yl)amino]-5-(2-thienyl)nicotinonitrile, 4-[(4-methyl-1H-indol-5-yl)amino]-5-(3-thienyl)nicotinonitrile, 5-(3-fiaryl)-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile, 5-( 1 -methyl- lH-imidazol-5-yl)-4-[(4-me thyl- 1H-indol-5-yl)amino]nicotinonitrile, 4'-[(4-methyl-1H-indol-5-yi)amino]-2,3'-bipyridine-5'-carbonitrile, 1 -(4- { 5-cyano-4-[(4-methy 1-1H-indol-5-yl)amino]pyridin-3-yl} phenyl)-3 - cyclopropylurea, l-(4-{5-cyano-4-[(4-methyl-1H-indol-5-yl)amino]pyridin-3-yl}phenyl)-3-methylurea, 3-(4- {5-cyano-4-[(4-methyl-1H-indol-5-yl)amino]pyridin-3 -yl }phenyl)-1,1-dimethylurea, N-(4- (5-cyano-4-[(4-methyl- 1H-indol-5-yl)amino]pyridin-3-yl}phenyl)morpholine-4-carboxamide, 4-[(4-methyl-1H-indol-5-yl)amino]-5-(4-nitroph.enyl)nicotinoiiitrile, 5-(4-aminophenyl)-4-[(4-methyl- IH-indo l-5-yl)amino]nicotinonitrile, 5-(3-aminophenyl)-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile, 5-(2-aminophenyl)-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile, 5-[4-(dimethylamino)phenyl] -4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile, 5-[3-(dimethylamino)phenyl]-4-[(4-meth34-1H-indol-5-yl)amino]mcotinonitrile, N-(4- (5-cyano-4-[(4-methyl- 1H-indol-5-yl)amino]pyridin-3-yl} phenyl)acetamide, N-(2- { 5-cyano-4-[(4-methyl-1 H-indol- 5-yl)amino]pyridin-3-yl} phenyl)acetamide, N-(3-{5-cyano-4-[(4-methyl-1H-indol-5-yl)amino]pyridin-3-yl}phenyl)acetamide, N-(4-{5-cyano-4-[(4-methyl-1H-indol-5-yl)amino]pyridin-3-yl}phenyl)-2-methylpropanamide, 4- (5-cyano-4-[(4-methyl- 1H-indol-5-yl)arnino]pyridin-3-yl} -N-methylbenzamide, 4-[(4-methyl-1H-indol-5-yl)amino]-5-(l-naphthyl)nicotinonitrile, 4-[(4-methyl-lH-indol-5-yl)amino]-5-(2-naphthyl)nicotinonitrile, 4-[(4-methyl-1H-indol-5-yl)amino]-5-(l-methyl-1H-pyrazol-5-yl)nicotinonitrile, 4-[(4-methyl-1H-indol-5-yl)amino]-5-(1H-pyrazol-4-yl)nicotinonitrile, 5-(l-benzothiophen-3-yl)-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile, 5-( 1 -methyl- 1H-indol-2-yl)-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile, 5-(1H-indol-5-yl)-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile, 5-(1H-indol-6-yl)-4-[(4-methyl-1H-indoi-5-yl)amino]nicotinonitrile, 4-[(4-m ethyl-1H-indol-5-yl)amino ] -5-quinolin-3 -ylnicotinonitrile, 4-[(4-methyl-1H-indol-5-yl)amino]-5-quinolin-8-ylnicotinonitrile, 5-( 1-benzofuran-5-yl)-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile, 4-(4-methyl-1H-mdol-5-ylamino)-5-(quinolin-5-yl)nicotinonitrile, 5-(dibenzo[b,d]thiophen-3-yl)-4-(4-methyl-1H-indol-5-ylamino)nicotinonitrile, 5-(benzo[b]thiophen-5-yl)-4-(4-methyl-1H-indol-5-ylamino)nicotinonitrile, 5-(1H-indol-4-yl)-4-(4-methyl-1H-indol-5-ylamino)nicotinonitrile, 4-[(2,4-dimethyl-1H-indol-5-yl)amino]-5-{5-[(4-methylpiperazin-l-yl)inethyl]-1 -benzofuran-2-yl} nicotinonitrile, 4-[(2,4-dimethyl- 1H-indol-5-yl)amino]-5--[5-(piperazin-1 -ylmethyl)-1 -benzofuran-2-yl]nicotinonitrile, 4-[(4-methyl-1H-indol-5-yl)amino]-5- {6-[(4-methylpiperazin-l -yl)methyl]-l -benzofuran-2-yl) nicotinonitrile, 4-[(4-methyl- 1H-indol-5-yl)amino]-5-[6-(piperazin-1 -ylmethyl)-1 -benzofuran-2-yl]nicotinonitrile, 4-[(4-methyl-1H-hidol-5-yl)amino]-5-{4-[(piperazin-l-yl)methyl]phenyl} nicotinonitrile, 4-[(2,4-dimethyl-1H-indol-5-yl)amino]-5- {4-[(4-methylpiperazin-1 -yl)methyl]phenyl} nicotinonitrile, 4-(2,4-dimethyl-1H-indol-5-ylamino)-5- {3-[2-(4-methylpiperazin-1 -yl)ethoxy]phenyl}nicotinonitrile, 5-{4-[2-(dimethylamino)ethoxy]-3-methoxyphenyl}-4-[(2,4-dimethyl-1H-indol-5-yl)amino]nicotinomtrile, 4-[(2,4-dimethyl-lH-indol-5-yl)amino]-5-(4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl} nicotinonitrile, 4-[(4-methyl- 1H-indol-5-yl)amino]-5- {4-[ 2-(piperazin-1 -yl)ethoxy]phenyl} nicotinonitrile, 4-(4-methyl- 1H-indol-5-ylamino)-2'-((4-methylpiperazin-1 -yl)methyl)-3,4'-bipyridine-5-carbonitrile, 4-(4-methyl- 1H-indol-5-ylamino)-2'-((piperazin-1 -yl)methyl)-3,4'-bipyridine-5-carbonitrile, 4'-(4-methyl-1H-indol-5-ylamino)-5-((4--methylpiperazin-l-yl)methyl)-2,3'-bipyridine-5'-carbonitrile, 4'-(4-methyl-1H-indol-5-ylamino)-5-(mc>rpholinomethyl)-2,3'-bipyridine-5'-carbonitrile, - 4'-(4-methyl-1H-indol-5-ylamino)-5-((piperazin-l-yl)metbyl)-2,3'-bipyridine-5'-carbonitrile, 4'-(4-methyl-1H-indol-5-ylamino)-6-((4-methylpiperazin-l-yl)methyl)-2,3'-bipyridine-5'-carbonitrile, 4'-(4-methyl-1H-indol-5-ylamino)-6-(morpholinomethyl)-2,3'-bipyridine-5'-carbonitrile, 4'-(4-methyl-1H-indol-5-ylamino)-6-((piperazin-1-yl)methyl)-2,3'-bipyridine-5'-carbonitrile, 4'-(4-methyl-1H-indol-5-ylamino)-4-(moq3holinomethyl)-2,3'-bipyridine-5l-carbonitrile, 4'-(4-methyl-1H-indol-5-ylamino)-4-((4-methylpiperazin-l-yl)methyl)-2,3'-bipyridine-5'-carbonitrile, 4'-(4-methyl-1H-indol-5-ylamino)-4-((piperazin-l-yl)methyl)-2,3'-bipyridme-5'-carbonitrile, 4-(4-methyl- 1H-indol-5-ylamino)-5 '-((4-methylpiperazin-1 -yl)methyl)-3,3 '-bipyridine-5-carbonitrile, 4-(4-methyl-1H-indol-5-ylamino)-5'-((piperazin-l-yl)methyl)-3,3'-bipyridine-5-carbonitrile, 4-(4-methyl-1H-indol-5-ylamino)-5'-(moipholinomethyl)-3,3'-bipyridine-5-carbonitrile, 4-(4-methyl- 1H-indol-5-ylamino)-6'-((4-rnethylpiperazin-1 -yl)methyl)-3,3'-bipyridine-5-carbonitrile, 4-(4-methyl-1H-indol-5-ylamino)-6'-((piperazin-l-yl)methyl)-3,3'-bipyridine-5-carbonitrile, 4-(4-methyl-1H-indol-5-ylamino)-6'-(morpholinomethyl)-3,3'-bipyridine-5-carbonitrile, 4-(4-methyl-1H-indol-5-ylamino)-5-(3-(piperazin-l-ylmethyl)phenyl)nicotinonitrile, 4-(4-methyl-1H-indol-5-ylamino)-5-(4-(piperazin-1-ylmethyl)phenyl)nicotinonitrile, 4-({[cw-4-(aminomethyl)cyclohexyl]medhyl}amino)-5-(3,4-dimethoxyphenyl)nicotinonitrile, and 5-(3,4-dimemoxyphenyl)-4-(1H-indol-5-ylamino)nicotinonitrile 1-oxide. 21. The compound of any one of claims 1-20, wherein the compound is in the form of an enantiomer. 22. A pharmaceutical composition comprising the compound of any one of claims 1-21 and a pharmaceutically acceptable currier or excipient. 23. A method of treating or inhibiting a pathological condition or disorder mediated by a protein kinase in a mammal, the method comprising providing to a mammal an effective amount of the compound of any one of claims 1-21 or a pharmaceutically acceptable salt, hydrate, or ester thereof. 24. The method of claim 23, wherein the protein kinase is protein kinase C. 25. The method of claim 23 or 24, wherein the pathological condition or disorder is an inflammatory disease or an autoimmune disease selected from asthma, colitis, multiple sclerosis, psoriasis, arthritis, rheumatoid arthritis, osteoarthritis, and joint inflammation. 26. A compound as claimed in any one of claims 1 to 21 or a pharmaceutically acceptable salt, hydrate, or ester thereof for use as a medicament. 27. Use of a compound as claimed in any one of claims 1 to 21 or a pharmaceutically acceptable salt, hydrate, or ester thereof in the preparation of a medicament for the treatment or inhibition of a pathological condition or disorder mediated by a protein kinase in a mammal. 28. Substituted 3-cyanopyridines as protein kinase inhibitors, a composition containing the same and its application substantially such as herein before described.