MX2008015805A - Substituted cyanopyridines as protein kinase inhibitors. - Google Patents

Abstract

The present teachings provide compounds of formula (I) and their pharmaceutically acceptable salts, hydrates, and esters, wherein R1, R2, and X are as defined herein. The present teachings also provide methods of making the compounds of formula (I), and methods of treating autoimmune and inflammatory diseases by administering a therapeutically effective amount of a compound or compounds of formula (I) to a mammal including a human.

Description

CYANOPYRIDINS SUBSTITUTED AS PROTEIN INHIBITORS KINASE Field Current teachings relate to substituted 3-cyanopyridines (also known as nicotinonitriles) that are capable of inhibiting protein kinases. Current teachings are also related to methods for the preparation of substituted cyanopyridines and their methods of use. For example, the compounds of the present teachings may 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 an adenosine triphosphate (ATP) to an amino acid residue (eg, tyrosine, serine, threonine or histidine) on a protein. The 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, for example, 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. ct 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 the sequence and structural homology. PKC is divided into three groups and includes the classical, novel, and atypical isoforms. The theta isoform (PKC0) is a member of the novel class independently of calcium from PKC (Baicer, G. et al. (1993), J. Biol. Qhem., 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 stem 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 PKC9 plays an essential role in signaling mediated by the T cell receptor (TCR) (Tan, S.L. et al. (2003), Biochem. J., 376: 545-52). Specifically, it has been observed that inhibiting PKC0 signal transduction, as demonstrated by two lines of independent PKC9 transgenic mice, 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 has also been shown that deficient PKC0 mice show impaired lung inflammation and hypersensitivity of the airways (AHR) in a TH2-dependent murine asthma model, without defects in viral clearance and Th-dependent cytotoxic T cell functions. 1 (Berg-Brown, NN et al. (2004), J. Exp. Med., 199: 743-52; Marsland, BJ et al. (2004), J. Exp. Med., 200: 181-9 ). The response of impaired Th2 cells results in reduced levels of interleukin-4 (IL-4) and immunoglobulin E (IgE), which contributes to AHR and inflammatory pathophysiology.

There is also evidence that PKC9 participates in the response mediated by the IgE receptor (FceRI) of stem cells (Liu, Y. et al., (2001), J. Leukoc, Biol, 69: 831-840). In human cultured stem cells (HCMC), PKC kinase activity has been shown to localize rapidly (in less than five minutes) to the membrane after FceRI crosslinking (Kimata, M. et al. (1999), Biochem. Biophys. Res. Commun., 257 (3): 895-900). A recent study examining Vitro activation of bone marrow stem cells (BMMC) derived from deficient PKC9 and intact type mice shows that after FceRI cross-linking, BMMC from PKC9 deficient mice produce reduced levels of interleukin-6 ( IL-6), tumor necrosis factor-alpha (TNFa), and interleukin-13 (IL-13) compared to BMMC from wild-type mice, suggesting a potential role for PKC9 in the production of cytokine from stem cells in addition to the activation of T cells (Ciarletta, AB 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 consisting of MAP (MAPK) kinases (e.g., erk) and MAPK kinases (MAPKK) (eg, mek and its substrates). Members of the raf family of residues phosphorylate kinases in mek. Cyclin dependent kinases (cdks) include cdc2 / cyclin B, cdk2 / cyclin A, cdk2 / cyclin E and cdk4 / cyclin D, and others, are serine / threonine kinases that regulate mammary cell division, additional serine / threonine kinases they include protein kinases A and B. These kinases, known as PKA or protein kinase-dependent cyclic AMP and PKB (Akt), play key roles in signal transduction pathways.

Tyrosine kinases (TK) are divided into two classes: the transmembrane growth factor receptor TK (RTK) and non-transmembrane TK. Growth factors, such as epidermal growth factor (EGF), linked to the extracellular domain of the RTK partner on the cell surface that activates RTK, initiate a cascade of signal transduction that controls a wide variety of cellular responses. In addition to EGF, there are several other RTKs that include FGFR (the receptor for fibroblast growth factor (FGF)); flk-1 (also known as KDR), and e 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 stimulation factor receptor, nerve growth factor receptor and insulin-like growth factor receptor. In addition, to the RTK there is another TK family called the cytoplasmic protein and the non-receptor TK. The TK cytoplasmic protein has intrinsic kinase activity, is present in the cytoplasm and the nucleus, and participates in various signaling pathways. There is a large number of non-receptor TKs including Abl, Jak, Fak, Syk, Zap-70 and Csk, the Src family of kinases (SFK) which include Src, Lck, Lyn, Fyn and others.

Certain derivatives of pyridine and pyrimidine have been registered as kinase inhibitors. These compounds differ in the location and nature of the substituents in various positions when the compounds of the present teachings were compared.

Brief description of the invention Current teachings relate to substituted 3-cyanopyridines of formula I: I and its 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 the formula I (which includes their pharmaceutically acceptable salts, hydrates, and esters) and a pharmaceutically acceptable carrier or excipient. One aspect of the present teachings relates to methods for preparing the compounds of formula I and their pharmaceutically acceptable salts, hydrates, and esters. The present teachings also provide methods for using the compounds of formula I and their pharmaceutically acceptable salts, hydrates, and esters. In some embodiments, the present teachings provide methods for treating autoimmune and inflammatory diseases, such as asthma, colitis, multiple sclerosis, psoriasis, arthritis, rheumatoid arthritis, osteoarthritis, and joint inflammation, which includes administering a therapeutically effective amount of one or more compounds of the formula I (or their pharmaceutically acceptable salts, hydrates, or esters) to a mammal including a human.

Detailed description The present teachings provide the compounds of formula I: I and its pharmaceutically acceptable salts, hydrates, and esters, wherein: X is selected from a) -NR3-Y-, b) -OY-, c) -S (0) mY-, d) -S (0) mNR3-Y-, e) -NR3S (0) mY-, f) -C (0) NR3-Y-, g) -C (S) NR3-Y-, h) -NR3C (0) -Y-, i) -NR3C (S) -Y-, j) -C (0) 0-Y-, k) -OC (0) -Y-, and I) a covalent bond; And, in each occurrence, a) divalent d.10 alkyl group is selected independently, b) a divalent C2-io alkenyl group, c) a divalent C2-io alkynyl group, d) a divalent C1-10 haloalkyl group, and e) a covalent bond; R is a phenyl group optionally substituted with 1-4 Y-R4 groups; R2 is a C6-14 aryl group or a 5-14 member heteroaryl group, wherein each group is optionally substituted with 1-4 independently selected groups of -Y-R4 and -O-Y-R4; R3 is selected from a) H, b) an alkyl group Ci.i0, c) a C2-io alkenyl group, d) a C2-io alkynyl group, and e) a C1-10 haloalkyl group; R4, in each occurrence, is independently selected from a) halogen, b) -CN, c) -N02, d) oxo, e) -OY-R5, f) -NR6-Y-R7, g) -N (0) ) R6-Y-R7, h) -S (0) mY-R5, i) -S (0) mO-Y-R5, j) -S (0) mNR6-Y-R7, k) -C (0) ) -Y-R5, I) -C (0) 0-Y-R5, m) -C (0) NR6-Y-R7, n) -C (S) NR6-Y-R7, o) an alkyl group C1-10, p) a C2-io alkenyl group, q) a C2-io alkynyl group, r) a C1-10 haloalkyl group, s) a C3-14 cycloalkyl group, t) an aryl group C6-i4, or ) a cycloheteroalkyl group of 3-14 members, and v) a 5-14 membered heteroaryl group, wherein each of o) - v) is optionally substituted with 1-4 Y-R8 groups; R5, in each occurrence, is independently selected from a) H, b) -C (0) R9, c) -C (0) OR9, d) a CMO alkyl group, e) a C2-10 alkenyl group, f) a C2-0 alkynyl group, g) a haloalkyl group C,. ^, h) a C3-4 cycloalkyl group, i) a C6-14 aryl group, j) a cycloheteroalkyl group of 3-14 members, and k) a group heteroaryl of 5-14 members, wherein each of d) -k) is optionally substituted with 1-4 groups Y-R8; R6 and R7, in each occurrence, are independently selected from a) H, b) -OY-R9, c) -S (0) mY-R9, d) -S (0) mO-Y-R9, e) - C (0) -Y-R 9, f) -C (0) 0-Y-R 9, g) -C (O) NR 10 -YR 1, h) -C (S) NR 0-Y-R 11, i) a C1-10 alkyl group, j) a C2-io alkenyl group, k) a C2-io alkynyl group, I) a C4 o haloalkyl group, m) a C3-14 cycloalkyl group, n) a C6 aryl group. 14, o) a cycloheteroalkyl group of 3-14 members, and p) a 5-14 membered heteroaryl group, wherein each of i) -p) is optionally substituted with 1-4 Y-R8 groups; R8, in each occurrence, is independently selected from a) halogen, b) -CN, c) -N02, d) oxo, e) -OY-R9, f) -NR 0-Y-R11, g) -N ( O) R0-Y-R11, h) -S (0) mY-R9, i) -S (0) mO-Y-R9, j) -S (O) mNR10-Y-R11, k) -C (0) -Y-R9, I) -C (0) 0-Y-R9, m) -C (0) NR10-Y-R11, n) -C (S) NR10-Y-R11, o) a alkyl group Ci.i0, p) a C2-io alkenyl group, q) a C2-i0 alkynyl group, r) a haloalkyl group CMO, s) a C3-4 cycloalkyl group, t) an aryl group C6.14, ) a cycloheteroalkyl group of 3-14 members, and v) a heteroaryl group of 5-14 members, wherein each of o) - v) is optionally substituted with 1-4 Y-R12 groups; R9, in each occurrence, is independently selected from a) H, b) -C (0) -alkyl d. 10, c) -C (0) OH, d) -C (0) 0-C1-10 alkyl, e) a C1-10 alkyl group, f) a C2.10 alkenyl group, g) a C2 alkynyl group. 0, h) a C1-O haloalkyl group,) a C3-14 cycloalkyl group, j) an aryl group C6.i4, k) a cycloheteroalkyl group of 3-14 members, and I) a heteroaryl group of 5-14. members, wherein each of the C-0 alkyl group, the C2-10 alkenyl group, the C2 alkynyl group. 0, the haloalkyl group CMO, the cycloalkyl group C3. 14, the aryl group C6.i4, the cycloheteroalkyl group of 3-14 members, and the 5-14 membered heteroaryl group is optionally substituted with 1-4 Y-R12 groups; R10 and R11, in each occurrence, are independently selected from a) H, b) -OH, c) -SH, d) -NH2, e) -NH-C1-10 alkyl, f) -N (C1-10 alkyl) ) 2, g) -S (0) m-alkyl Ci-10, h) -S (0) 2OH, i) -S (0) m-O-C 1-10 alkyl, j) -C (0) -alkyl CMO , k) -C (0) OH, I) -C (0) -O-Cmo-alkyl, m) -C (0) NH 2, n) -C (0) NH-C 1-10 alkyl, o) -C (0) ) N (C1-10 alkyl) 2, p) -C (S) NH2, q) -C (S) NH-alkyl Ci.i0, r) -C (S) N (CMO alkyl) 2, S) a C1-10 alkyl group, t) a C2-10 alkenyl group, u) a C2.10 alkynyl group v) a CMO alkoxy group, w) a C10 haloalkyl group, x) a C3-C4 cycloalkyl group, and) a group aryl C6-i4, z) a cycloheteroalkyl group of 3-14 members, and aa) a 5-14 membered heteroaryl group, wherein each of the C1-10 alkyl group, the C2.io alkenyl group, the C2.i0 alkynyl group, the C10 alkoxy group, the C1.10 haloalkyl group, the C3-14 cycloalkyl group) the C6-14 aryl group, the 3-14 membered cycloheteroalkyl, and the 5-14 membered heteroaryl group is optionally substituted with 1-4 -Y-R12 groups; R12, in each occurrence, is independently selected from a) halogen, b) -CN, c) -N02, d) oxo, e) -OH, f) -NH2, g) -NH (C1-10 alkyl), ) -N (C 1-10 alkyl) 2l i) -SH, j) -S (0) m-C 1-10 alkyl, k) -S (0) 2OH, I) -S (0) m-O-C 1-6 alkyl 10, m) -C (0) -C 1-10 alkyl, n) -C (0) OH, o) -C (0) -C 1-10 alkyl, p) -C (0) NH 2, q) -C (0) NH-C 1-10 alkyl, r) -C (0) N (C 1-10 alkyl) 2, s) -C (S) NH 2, t) -C (S) NH-C 1-10 alkyl, ) -C (S) N (alkyl? 1-10) 2, v) a C1- 0 alkyl group, w) a C2-10 alkenyl group, x) a C2.10 alkynyl group, and) a C1- 0 group alkoxy, z) a C1-10 haloalkyl group, aa) a C3-i4 cycloalkyl group, ab) a C6-14 aryl group, ac) a cycloheteroalkyl group of 3-14 members, and ad) a 5-14 heteroaryl group members; Y m is 0, 1, or 2.

In some embodiments, the pyridine ring can be oxidized at the nitrogen atom to provide the corresponding N-oxide having the formula G: 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 modalities, X can be -NH-.

In certain modalities, R1 can be selected from: where R4 is as defined here. In particular modalities, R4, in each occurrence, can be independently selected from -F, -Cl, -Br, -CN, -N02, -OY-R5, -C (0) -Y-R5, -C (0) 0-Y-R5, -NR6-Y-R7, and a C1-6 alkyl group. For example, R4, in each occurrence, can be independently selected from -F, -Cl, -Br, -O-C1-3alkyl, -O-phenyl, and a C1-3alkyl group.

In some embodiments, R 2 may be selected from a phenyl group, a C 8-14 aryl group, and a 5-14 member heteroaryl group, wherein each of these groups may be optionally substituted with 1-4 groups independently selected from - Y-R4 and -OY-R4, where Y and R4 are as defined herein. For example, R 2 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, a group indolyl, 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 -OY-R4, where Y and R4 are as defined here.

In certain modalities, R2 can wherein D1, D2, and D3 can independently be H, a group -Y-R4, or a group -O- Y-R4, wherein Y and R4 are as defined herein.

For example, at least one of D1, D2, and D3 can be a group -Y-R4 or a group -OY-R4, wherein Y, at each occurrence, can independently be a divalent C1-4 alkyl group or a covalent bond, and R4, in each occurrence, can be independently selected from a halogen, -CN, -N02, -OY-R5, -NR6-Y-R7, -S (0) 2-Y-R5, -S ( 0) 2NR6-Y-R7, -C (0) -Y-R5, -C (0) 0-Y-R5, -C (0) NR6-Y-R7, a C1-10 alkyl group, a haloalkyl group C1-10l, a C3-14 cycloalkyl group, a C6-i4 aryl group, a cycloheteroalkyl group of 3-14 members, and a heteroaryl group of 5-14 members, wherein each of the C1-10 alkyl group, the group C1-O haloalkyl, the C3-14 cycloalkyl group, the C6-I4 aryl group, the 3-14 membered cycloheteroalkyl group, and the 5-14 membered heteroaryl group may be optionally substituted with 1-4 -Y-R8 groups , where Y, R5, R6, R7, and R8 are as defined herein.

In certain embodiments, at least one of D1, D2, and D3 can be a group -O- (CH2) n -R4, wherein n, in each occurrence, can independently be 0, 1, 2, 3, or 4 , and R4, in each occurrence, can be independently selected from F, Cl, Br, -N02, -OY-R5, -NR6-Y-R7, S (0) 2-Y-R5, -S (0) 2NR6 -Y-R7, -C (0) NR6-Y-R7, a C1-10 alkyl group, a C3 cycloalkyl group. 4, an aryl group C6.i4, a cycloheteroalkyl group of 3-14 members, and a heteroaryl group of 5-14 members, wherein each of the alkyl group Ci.i0, the cycloalkyl group C3.14, the aryl group C6 -i4, the cycloheteroalkyl group of 3-14 members, and the 5-14 member heteroaryl group can be optionally substituted with 1-4 Y-R8 groups, wherein Y, R5, R6, R7, and R8 are as define here In particular embodiments, at least one of D1, D2, and D3 can be -0- (CH2) nNR6-Y-R7 or a cycloheteroalkyl group of 3-14 members -0- (CH2) n, wherein the cycloheteroalkyl group of 3-14 members can be optionally substituted with 1-4 groups - Y-R8, where Y, R6, R7, and R8 are as defined herein, and n, in each occurrence, can be independently 0, 1, 2, 3, or 4.

In some embodiments, at least one of D1, D2, and D3 can be - (CH2),, NR6-Y-R7 or a cycloheteroalkyl group of 3-14 members- (CH2) n, wherein the cycloheteroalkyl group of 3 -14 members can be optionally substituted with 1-4 groups -Y-R8, Y, R6, R7, and R8 are as defined herein, and n, in each occurrence, can be independently 0, 1, 2, 3, or 4 .

In embodiments wherein at least one of D1, D2, and D3 can be a group - 0- (CH2) NNR6-Y-R7 or a group - (CH2) NNR6-Y-R7, the group -0- (CH2) ) NNR6-Y-R7 and the group - (CH2) NNR6-Y-R7 can be -0- (CH2) NNH-Y-R7 or -0- (CH2) NN (CH3) -Y-R7, and - ( CH2) NNH-Y-R7 or - (CH2) NN (CH3) -Y-R7, respectively, wherein Y, in each occurrence, can independently be an alkyl group Ci. divalent or a covalent bond, and R7, in each occurrence, can be independently selected from -OY-R9, -C (0) -Y-R9, -C (0) 0-Y-R9, -C (O) NR10 -Y-R11, a C04 alkyl group, a C3-14 cycloalkyl group, a C6.i4 aryl group, a 3-14 membered cycloheteroalkyl group, and a 5-14 membered heteroaryl group, wherein each of the alkyl group Ci.i0, the C3-14 cycloalkyl group, the C6-i aryl group, the 3-14 membered cycloheteroalkyl group, and the 5-14 membered heteroaryl group can optionally be substituted with 1-4 -Y-R12 groups, wherein Y and R12 are as defined herein, for example, the cycloalkyl group C3-i4, the aryl group C6-i4l the cycloheteroalkyl group of 3-14 members, and the heteroaryl group of 5-14 members 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 R 2 are as defined herein.

In embodiments wherein at least one of D1, D2, and D3 may be a cycloheteroalkyl group of 3-14 members-0- (CH2) not a cycloheteroalkyl group of 3-14 members- (CH2) n, the cycloheteroalkyl group of 3-14 members 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-R groups, where Y and R are as defined herein. For example, Y, in each occurrence, can independently be a divalent C -4 alkyl group or a covalent bond, and R8, in each occurrence, can independently be an oxo group, -OY-R9, -NR10-Y-R11, -S (0) m, -Y-R9, -C (0) 0-Y-R9, a C1-10 alkyl group, a C3-14 cycloalkyl group, a C6-I4 aryl group, a cycloheteroalkyl group of 3- 14 members, and a heteroaryl group of 5-14 members, wherein each of the C-10 alkyl group, the C 3-14 cycloalkyl group, the C 6 aryl group, the 3-14 member cycloheteroalkyl group, and the 5-14 member heteroaryl group can be optionally substituted with 1 - 4 groups -Y-R12, where Y and R12 are as defined herein. For example, the cycloalkyl group C3-i4, the aryl group C6-i4, the cycloheteroalkyl group of 3-14 members, 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 to be optionally substituted with 1-4 groups -Y-R12, wherein Y and R12 are as defined herein.

Alternatively or concurrently, at least one of D, D2, and D3 can be selected from halogen, -CN -N02, -S (0) 2-Y-R5, -S (0) 2NR6-Y-R7, -C (0) 0-Y-R5, -C (0) NR6-Y-R7, a C1-10 alkyl group, and a C1-10 haloalkyl group, wherein Y3 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, where n, in each occurrence, can independently be 0, 1, 2, 3, or 4, and R4, in each occurrence, can be independently selected from F, Cl, Br, -N02, -OY-R5, -NR6-Y-R7, -S (0) 2-Y-R5, -S (0) 2NR6 -Y-R7, -C (0) NR6-Y-R7, a C1-10 alkyl group, a C3.14 cycloalkyl group, a C6 aryl group. 4, a cycloheteroalkyl group of 3-14 members, and a 5-14 membered heteroaryl group, wherein each of the C1_0 alkyl group, the C3-14 cycloalkyl group, the C6.i aryl group, the cycloheteroalkyl group of 3-14 members, and the 5-14 membered heteroaryl group may be optionally substituted with 1-4 Y-R8 groups, wherein Y, R5, R6, R7, and R8 are as defined herein.

In certain embodiments, at least two of D, D2, and D3 can independently be a group -0-CH3 or a group -0- (CH2) n-0-Y-R5, wherein Y and R5 are as defined here, and n, in each occurrence, can be independently 0, 1, 2, 3, or 4. In certain embodiments, two of D1, D2, and D3 can be -0-CH3 groups. In other embodiments, two of D1, D2, and D3 may be groups -0- (CH2) n-0-Y-R5 or alternatively, a group -0-CH3 and a group -0- (CH2) n-0- Y-R5, where Y and R5 are as defined here, and n, in each occurrence, can be independently 0, 1, 2, 3, or 4.

In certain embodiments, at least one of D1, D2, and D3 can be -0-CH3, and at least one of D1, D2, and D3 can be a group -0- (CH2) nNR6-Y-R7 or a -O- (CH2) n-cycloheteroalkyl group of 3-14 members, wherein the cycloheteroalkyl group of 3-14 members may be optionally substituted with 1-4 Y-R8 groups, wherein Y, R6, R7, and R8 are as defined here, and n, in each occurrence, can be independently 0, 1, 2, 3, or 4.

In some modalities, one of D1, D2, and D3 may be wherein R, in each occurrence, can be independently selected from -OY-R9, -NR10-Y-R11, a C6-14 aryl group, and a 5-14 membered heteroaryl group, wherein each of the C6 aryl group .14 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, can be independently 0, 1, 2, 3, or 4.

In certain embodiments, at least one of D1, D2, and D3 may be a C6.14 aryl group or a 5-14 member heteroaryl group, wherein each of these groups may be optionally substituted with 1-4 groups - Y-R8, where Y and R8. They are as defined here. 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 one of these groups it can be optionally substituted with 1-4 Y-R groups, where Y and R are as defined herein. In particular embodiments, Y, in each occurrence, can independently be a C 1-4 alkyl group or a covalent bond, and R 8 can be independently selected from a halogen, -CN, -N02, -OY-R9, -NR10-Y- R11, -C (0) -Y-R9, -C (O) NR10-Y-R11, -S (0) 2-Y-R9, -S (O) 2NR 0-Y-R11, and a cycloheteroalkyl group 3-14 membered optionally substituted with a C1-4 alkyl group, wherein Y, R9. R10, and R1 are as defined herein.

In other embodiments, R2 may be a C8-io bicyclic aryl group or a 5-14 member heteroaryl group, wherein each of these groups may be optionally substituted with 1-4 groups independently selected from -Y-R4 groups and groups- OY-R4, where Y and R4 are as defined here.

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 benzodioxolyl 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 group - (CH2) n -R4 and a group -0- (CH2) n -R4, wherein n, in each occurrence, can be independently 0, 1, 2, 3, or 4, and R4, in each occurrence, can be independently -NR6-Y-R7 or a 3-14 membered cycloheteroalkyl group optionally substituted with 1-4 groups- Y-R8, where Y, R6, R7 and R8 are as defined herein.

For example, R4 can be -0- (CH2) nNH-Y-R7, -0- (CH2) nN (CH3) -Y-R7, - (CH2) nNH- Y-R7, or - (CH2) nN ( CH3) -Y-R7, wherein Y, in each occurrence, can independently be a divalent alkyl group or a covalent bond, and R7, in each occurrence, can be independently selected from -OY-R9, -C (0) - Y-R9, -C (0) 0-Y-R9, -C (O) NR10-Y-R11, a C1-10 alkyl group, a C3-14 cycloalkyl group, a C6-14 aryl group, a cycloheteroalkyl group of 3-14 members, and a 5-14 membered heteroaryl group, wherein each of the C-10 alkyl group, the C3-i4 cycloalkyl group, the C6-i4 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 modalities, R7 can be a group C3-14 cycloalkyl a C6-14 aryl group, a cycloheteroalkyl group of 3-14 members, or a 5-14 member 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 groups -Y-R12, where Y and R12 are as defined here.

Alternatively, R4 can be a 3-14 membered -0- (CH2) n-cycloheteroalkyl group or a 3-14 membered - (CH2) n-cycloheteroalkyl group, wherein the 3-14 membered cycloheteroalkyl group can be selected of 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 , where Y and R8 are as defined here. For example, Y, in each occurrence, can independently be a divalent C1-4 alkyl group or a covalent bond, and R8, in each occurrence, can independently be an oxo group, -OY-R9, -NR10-Y-R11, -S (0) mY-R9, -C (0) 0-Y-R9, a d.10 alkyl group, a C3-14 cycloalkyl group, a C6.14 aryl group, a cycloheteroalkyl group of 3-14 members, and a 5-14 membered heteroaryl group, wherein each of the Ci-10 alkyl group, the C3-14 cycloalkyl group, the C6-i4 aryl group, the 3-14 membered cycloheteroalkyl group, and the 5-membered heteroaryl group. -14 members can optionally be substituted with 1-4 groups -Y-R12, wherein Y and R12 are as defined herein. For example, R8 can be a C3.14 cycloalkyl group, a C6-i aryl group, a 3-14 membered cycloheteroalkyl group, and a 5-14 membered heteroaryl group selected from a cyclopentyl group, a cyclohexyl group, a group phenyl, 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 it may be optionally substituted with 1-4 Y-R12 groups, wherein Y and R12 are as defined herein.

It should be understood that the present teachings may exclude certain embodiments of the compounds within the genus of the compounds identified by the formula I. For example, when R1 is a 3-chloro-4-fluorophenyl group, the current teachings can exclude compounds wherein R2 is a 2 - [(1 H-imidazol-5-methylmethyl) phenol group.

The compounds of the present teachings include the compounds presented in Table 1 below.

Table 1 Compound Name of the compound 101 4 - [(3-chlorophenyl) amino] -5- (3,4-dimethoxyphenyl) nicotinonitrile 102 5- (3,4-dimethoxyphenyl) -4 - [(3-fluorophenyl) amino] nicotinonitrile 103 4-anilino-5 - (3,4-dimethoxyphenyl) nicotinonitrile 104 4 - [(2,5-difluorophenyl) amino] -5- (3,4-dimethoxyphenyl) nicotinonitrile 105 5- (3,4-dimethoxyphenyl) -4 - [(3, 4-dimethoxyphenyl) amino] nicotinonitrile 4 - [(4-chloro-2-fluorophenyl) amino] -5- (3,4-106 dimethoxyphenyl) nicotinonitrile 4 - [(3-chloro-4-fluorophenyl) amino] -5- (3,4- 107 dimethoxyphenyl) nicotinonitrile Compound Name of the compound 108 4 - [(4-chlorophenyl) amino] -5- (3,4-dimethoxyphenol) nicotinonitrile 109 5- (3,4-dimethoxyphenyl) -4 - [(2,4-dimethylphenyl) amino] nicotinonitrile 110 5- (3,4-dimethoxyphenyl) -4 - [(4-methoxyphenyl) amino] nicotinonitrile 4 - [(3-chloro-4-methoxyphenyl) amino] -5- (3,4-dimethoxyphenyl) nicotinonitrile 112 5- (3,4-dimethoxy-phenyl) -4 - [(4-phenoxyphenyl) amino] nicotinonitrile 113 4 - [(2,5-dichlorophenyl) amino] -5- (3,4-dimethoxy-phenyl) n-trinononitrile 5- (3,4-dimethoxy-phenyl) -4 - [( 4-methoxy-2-114-methylen) amine] n-trichloride 115 4 - [(3,4-dichlorophenyl) amino] -5- (3,4-d) Methoxyphenyl) nicotynonitrile 116 4 - [(5-Chloro-2-methoxyphenyl) amino] -5- (3,4-d- methoxy-phenyl) n-trinononitrile 117 4-. { [3- (benzyloxy) phenyl] amino} -5- (3,4-dimethoxy) phenyl) nicotinonitrile 118 5- (3,4-d¡methoxy-phenyl) -4 - [(4-methyloxy) amino] n-phenylnonitrile 119 5- (3,4-d¡methoxyphenol) -4 - [(3,4,5-tr ~ methoxyphenyl) amino] nicotinonitrile 120 5- (3,4-dimethoxyphenyl) -4 - [(3-phenoxyphenyl) amino] nicotinonitrile 4 - [(2-chloro-5-methoxyphenyl) amino] -5- (3,4- 121 di methoxyphenol) ) Nicotinonitrile 4- (. {3-chloro-4 - [(3-cyanobenzyl) oxy] phenyl} amino) -5- (3,4- 122-dimethoxyphenyl) nicotinonitrile 4- ( { 3-Chloro-4 - [(3-methylbenzyl) oxy] phenyl}. Amino) -5- (3,4- 124 dimethoxyphenol) nicotunomethyl 4 - [(3-chloro-4-) { [3- (dimethylamino) benzyl] oxy} phenyl) amino] -5- (3,4- 125-dimethoxyphenol) n-trichnonitrile 126 4 - [(2,4-Dichlorophenyl) amino] -5- (3,4-dimethoxyphenyl) nicotinonitrile N- (3 { [3-cyano-5- (3,4-dimethoxyphenyl) pyridine- 4-121] amino] phenyl) acetamide N- (3 { [3-cyano-5- (3,4-dimethoxyphenyl) pyridin-4-yl] amino} phenyl) -N-128 methylacetamide Compound Name of the compound N- (3 { [3-cyano-5- (3,4-dimethoxy-phenyl) pyridin-4-yl-yl] amino] phenyl) methanesulfonamide 130 - [4- (dimethylamino) phenyl] -4 - [(3-methoxy-phenyl) amino] nicotinonitrile 131 5- [4- (dimethylammono) phenyl] -4 - [(3-fluorophenyl) amino] n-trichnonthi acid 4- (. {3-cyano-5- [4- ( dimethylamino) phenyl] pyridin-4-yl.}. amino) benzoic acid 133 4 - [(4-cyanophenyl) amino] -5- [4- (dimethylamino) phenyl] nicotinonitrile 4 - [(3,4-d-fluorophenyl) ) amino] -5- [4- (4- (dimethylamino) phenyl] nicotinonitrile 135 4 - [(3-bromophenyl) amino] -5- (3,4-d¡methoxyphenol) n-trinononitrile 4- . { [3- (benzyloxy) -4-chlorophenyl] amino} -5- (3,4- 136-dimethoxy-phenyl) -nicotonnonyl 4 - [(2,4-dichloro-5-methoxy-phenyl) -amino] -5- (3,4- 137-dimethoxy-phenyl) nicotonitrile 4 - [(2,4-dichloro-5-ethoxy-phenyl) amino] -5- (3,4- 138 dimethoxy-phenyl) n-tr Nonitrile 4 - [(2,4-dichloro-5-propoxyphenyl) amino] -5- (3,4- 139 dimethoxyphenol) nichotonomethyl 4 - [(5-butoxy-2,4- dichlorophenol) amino] -5- (3,4- 140 dimethoxyphenyl) nicotinonitrile 4-. { [2,4-dichloro-5- (2-hydroxyethoxy) pheny] amino} -5- (3,4- 141 dimethoxyphenyl) nichotonomethyl 4-. { [4- (benzyloxy) -3-chlorophenyl] amino} -5- (3- 142 nitrophenyl) nicotinonitrile 4-. { [3-chloro-4- (pyridin-2-ylmethoxy) phenyl] amino} -5- (3- 143 n -triphenyl) n-trinonitrile 144 4 - [(3-chloro-4-fluorophenyl) amino] -5- (3-nitrophenol) nicotinonitrile 5- (3-aminophenyl) )-4-. { [4- (benzyloxy) -3-145 chlorophenol] amino} nichotonitrile 146 4 - [(3-chloro-4-fluorophenyl) amino] -5- (2-nitrophenol) nicotinonitrile 147 5- (2-aminophenyl) -4 - [(3-chloro-4-fluorophenyl) amino] n-trinonomethyl 4 - [(2,4-dichloro-5-methoxy) l) amino] -5- [4-methoxy-3- (2-methoxy-4-oxy) phenyl] -nicotinonitrile 4 - [(2,4-dichloro-5-methoxy-phenyl)] amino] -5- [3-methoxy-4- (2-methoxyethoxy) phenyl] n-trinonitrile 5- [3- (2-chloroethoxy) phenyl] -4 - [(2,4-dichloro -5- 150 methoxyphenyl) amino] nicotinone Compound Name of the compound 4 - [(2,4-dichloro-5-methoxyphenyl) amino] -5- [3- (2-pyrrolidn-1-ylethoxy) phenyl] n-trichloride 152 5- [4- (dimethylamino) pheny] -4 - [(3-nitrophenol) amino] nicotinonitrile 153 5- (3-methoxyphenyl) -4 - [(3-nitrophenol) amine] nitrotonitrile 154 5- (3-methoxyphenyl) -4 - [(3-methoxyphenyl) amino] nicotinone 155 4 - [(3-fluorophenyl) amino] -5- (3-methoxy-phenyl) n-trinonitrile 156 4-. { [3-cyano-5- (3-methoxyphenyl) pyridin-4-yl] amino} benzoic acid 157 4 - [(4-cyanophenyl) amino] -5- (3-methoxyphenyl) nicotinonitrile 158 4 - [(3,4-d.fluorophenyl) amino] -5- (3-methoxyphenyl) nicotonitrile 159 5- (3,4-dimethoxyphenyl) -4 - [(3-hydroxyphenyl) amino] n-trichonitrile 5- (3,4-dimethoxyphenyl) -4-. { [3- (2-hydroxyethoxy) phenyl] amine} nichotonitrile 4 - [(3- {[[(2S) -2-amino-3-phenyl] -propyl] -oxi.} - phenyl) amino] -5- (3,4- 161-dimethoxy-phenyl) n-trichloromethyl 4 - [(2-chloro-5-hydroxyphenyl) amino] -5- (5-formyl-1-benzoten-2-l, 162 n) n cotonnonitrile 4 - [(2-chloro-5-hydroxyphenyl) amino] -5- [5- (piperidin-1-ylmethyl) -1- 163 benzothien-2-yl] n¡coton Trilo 4-. { [2-chloro-5- (2-hydroxyethoxy) phenyl] amino} -5- [5- (piperidin-1-164methyl) -1-benzoten-2-yl] nicotinonitrile 4 - [(4-amino-2,3-dimethyphenyl) amino] -5- [5- (piperidn-1-ylmethyl) -1- 165 benzoten-2-yl] n-cyclopentyl 4 - [(4-amino-3-methylphenyl) amino] -5- [5- (piperidn-1-methylmet) -1- 166 benzothien-2 -il] nicotinone Compound Name of the compound 4 - [(2-Chloro-5-methoxyphenyl) amino] -5- [5- (piperidin-1-methyl] -1- 167 benzofuran-2-yl] n-phenyl-nitrile 4 - [( 2-Chloro-5-methylphenyl) amino] -5- [5- (piperidin-1-ylmethyl) -1- 168 benzofuran-2-yl] nicotunomethyl 4 - [(5-hydroxy-2- phenoxyphenyl) amino] -5- [5- (piperidin-1-methylmethyl) -1- 169 benzofuran-2-yl] nicotinonitrile 4-. { [3- (aminomethyl) benzyl] amino} -5- (3,4- 170-dimethoxyphenyl) n-trichlorotyl 4 - [(2,4-dichloro-5-hydroxyphenyl) amino] -5- [5- (piperidin-1-methylmethyl) -1 - 171 benzofuran-2-yl] nicotinonitrile 4 - [(4-methoxy-2-methylphenyl) amino] -5- [5- (piperidn-1-ylmetl) -1- 172 benzofuran-2-yl] nicotinone The pharmaceutically acceptable salts of the compounds of the formula I, which may have an acidic functional group, may be formed using organic and inorganic bases. 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; ammonium salts and organic amine salts, such as those formed with morpholine, thiomorpholine, piperidine, pyrrolidine, a mono, di or tri-lower alkylamine (for example, ethyl-tert-butyl-, diethyl-, diisopropyl-, triethyl-, tributyl- or dimethylpropylamine), or mono-, di-, or trihydroxy-lower alkylamine (for example, mono-, di- or triethanolamine). Specific non-limiting examples of inorganic bases include NaHCO3, Na2CO3, KHCO3, K2CO3, Cs2CO3, LiOH, NaOH, KOH, NaH2P0, Na2HP04, and Na3P04. Internal salts can also be formed. Similarly, when a compound described herein contains a basic functional group, the salts can be formed using organic and inorganic acids. For example, the salts can be formed from the following acids: acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, dichloroacetic, ethanesulfonic, formic, fumaric, gluconic, glutamic, hipuric, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic , malonic, mandelic, methanesulfonic, mucic, naphthalenesulfonic, nitric, oxalic, pamoic, pantothenic, phosphoric, italic, propionic, succinic, sulfuric, tartaric, and toluenesulfonic, as well as other known pharmaceutically acceptable acids.

The esters of the compounds of the formula I can include various pharmaceutically acceptable esters known in the art which can be metabolized in the free acid form (e.g., a free carboxylic acid form) in a mammal. Examples of such esters include alkyl esters (for example, from 1 to 10 carbon atoms), cycloalkyl esters (for example, from 3-10 carbon atoms), aryl esters (for example, from 6-14 carbon atoms, which includes 6-10 carbon atoms), and heterocyclic analogues of these (for example, 3-14 atoms in the ring, 1-3 which can be selected from oxygen, nitrogen, and sulfur heteroatoms), wherein the alcohol residue may include additional substituents. In some embodiments, esters of the compounds described herein may be C-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 propyl cyclolesters, methyl cyclopropyl esters, butyl cyclolesters, pentyl cyclolesters, 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 described herein. As used herein, "prodrug" refers to a functional group that produces, generates or releases a compound of the present teachings when administered to a mammalian subject. Prodrugs can be prepared by modifying the functional groups present in the compounds in such a way that the modifications are cloned, by routine or in vivo manipulation, of the parent compounds. Examples of prodrugs include compounds as described herein that contain one or more molecular functional groups attached to a hydroxyl, amino, sulfhydryl, or carboxyl group of the compound, and that when administered to a mammalian subject, it is divated in vivo to form the free hydroxyl group, amino, sulfhydryl, or carboxyl, respectively. Examples of prodrugs may include acetate, formate, and benzoate derived from alcohol and amine functional groups in the compounds of the present teachings. The preparation and use of prodrugs is discusses 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, whose full descriptions are incorporated herein as a reference for all purposes.

The present teachings also provide pharmaceutical compositions that include at least one compound described herein and one or more pharmaceutically acceptable carriers, excipients, or diluents. Examples of such carriers are well known to those skilled in the art and can be prepared according to pharmaceutically acceptable methods, 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), whose entire description is incorporated here as a reference 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 interact adversely with the active ingredient. Accordingly, pharmaceutically acceptable carriers are those that are compatible with the other ingredients in the formulation and are biologically acceptable. The complementary active ingredients can also be incorporated by the pharmaceutical compositions.

The compounds of the present teachings may 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 improving the condition and / or symptoms thereof. Current teachings in accordance therewith include a method for providing a mammal with a pharmaceutical composition that includes a compound of the present teachings in combination or association with a pharmaceutically acceptable carrier. The 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 amount that elicits a biologically desirable activity or effect.

Current teachings also include use of the compounds described 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 may include anti-inflammatory diseases and autoimmune diseases such as asthma, colitis, multiple sclerosis, psoriasis, arthritis, rheumatoid arthritis, osteoarthritis, and joint inflammation. Accordingly, the present teachings additionally provide methods for treating these pathological conditions and disorders using the compounds described herein. In some modalities, methods include identifying a mammal having a pathological condition or disorder mediated by a protein kinase such as PKC and PKC9, and providing the mammal with 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 described herein in combination or in association with a pharmaceutically acceptable carrier.

The present teachings additionally include the use of the compounds described herein as active therapeutic substances for the prevention and / or inhibition of the pathological condition or disorder listed above. Accordingly, the present teachings additionally provide methods for preventing and / or inhibiting these pathological conditions and disorders using the compounds described herein. In some embodiments, methods include identifying a mammal having a pathological condition or disorder mediated by a protein kinase such as PKC and PKC6, and providing the mammal with 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 described herein in combination or in association with a pharmaceutically acceptable carrier.

The compounds of the present teachings can be administered orally or parenterally, alone or in combination with conventional pharmaceutical carriers. Applicable solid carriers may include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, binders, compression aids, binders or tablet disintegrating agents, or encapsulating materials. The compounds can be formulated in the conventional manner, for example, in a manner similar to that used for known anti-inflammatory agents. Oral formulations that contain a Active compound described herein may include any conventionally used oral form, which includes tablets, capsules, mouth forms, troches, lozenges and oral fluids, suspensions or solutions. In the powders, the carrier can be a finely divided solid, which is a mixture 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 desired shape and size. The powders and tablets may contain up to 99% of the active compound.

The capsules may contain mixtures of active compounds with inert fillers and / or diluents such as pharmaceutically acceptable starches (e.g., corn starch, potato or tapioca), sugars, artificial sweetening agents, powdered celluloses (e.g., crystalline cellulose and microcrystalline), flours, jellies, gums, and the like.

Useful tablet formulations can be made by conventional compression, wet granulation or dry granulation methods and use pharmaceutically acceptable diluents, bonding agents, lubricants, disintegrants, surface modifying agents (including surfactants), suspending or stabilizing agents, which includes magnesium stearate, stearic acid, sodium lauryl sulfate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, microcrystalline cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, polyvinyl pyrrolidone, alginic acid, gum acacia, gum xanthan, sodium citrate, silicate complexes, calcium carbonate, glycine, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, low melting waxes, and ion exchange resins. Preferred agents that modify the surface include anionic and nonionic agents that modify the surface. Examples of representative surface modifying agents include poloxamer 188, benzalkonium chloride, calcium stearate, ketostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, colloidal silicon dioxide, phosphates, sodium dodecylsulfate, magnesium aluminum silicate, and triethanolamine. . The oral formulations herein may utilize time-release formulations or standard delay to alter the absorption of the active compounds. The oral formulation may also comprise a compound as described herein in water or fruit juice, which contains the solubilizers appropriate or emulsifiers as needed.

Liquid carriers can be 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 may contain other pharmaceutically suitable 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, for example, cellulose derivatives such as a solution of sodium carboxymethylcellulose), alcohols (including monohydric alcohols and polyhydric alcohols, for example, glycols) and their derivatives, and oils (for example, 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 compositions of sterile liquid form 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 used by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. Compositions for oral administration may be in 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 subdivided into unit doses containing appropriate amounts of the active compound. The unit dosage forms can be packaged compositions, for example, packaged powders, flasks, ampoules, pre-filled syringes or sachets containing liquids. Alternatively, the unit dosage form can be a capsule or tablet itself, or this may be the appropriate number of any such compositions in packaged form. Such unit dosage form may contain from about 1 mg / kg of the active compound to about 500 mg / kg of the active compound, and may be given in a single dose or in two or more doses. Such doses may be administered in any useful way by targeting the active compounds for bloodstream receptors, 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 which include the pharmaceutically acceptable salts thereof, in lotions, creams, foams, patches, suspensions, solutions, and suppositories (rectal and vaginal).

When administered for the treatment or inhibition of a particular disease state or disorder, it is understood that an effective dosage may vary depending on many factors such as the particular compound used, the mode of administration, and the severity of the condition to be treated. , as well as the various physical factors related to the individual to be 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 alleviate the symptoms of the disease and its complications. The dosage to be used in the treatment of a specific individual can typically be subjectively determined by the attending physician. The variables involved include the specific condition and its condition as well as the patient's size, age and response pattern.

In some cases, for example those in which the lung is the target organ, it may be desirable to administer a compound directly into the patient's airways, using devices such as metered-dose inhalers, inhaled-operated inhalers, dry powder inhalers multi-dose, pumps, pressure-driven nebulized aerosol 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 may include, by way of illustration, one or more of the compounds of the present teachings dissolved, partially dissolved, or suspended in one or more pharmaceutically acceptable solvents and can be administered by, for example, pumps or a nebulized aerosol dispenser operated by pressure. The solvents may be, for example, isotonic saline or bacteriostatic water. The solid composition can be, by way of illustration, a powder preparation that includes one or more of the 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 punches a capsule that encapsulates the solid composition and releases the solid composition by inhalation. The aerosol composition may include, by way of illustration, one or more of the compounds of the present teachings, propellants, surfactants, and co-solvents, and may be administered by, for example, a measured device. The propellants can be a chlorofluorocarbon (CFC), a hydrofluoroalkane (HFA), or other propellants that are physiologically and environmentally acceptable.

The 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 a suitable mixture with water with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures of these 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 may include sterile aqueous solutions or sterile dispersions and powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In preferred embodiments, the shape is sterile and its viscosity allows it to flow through a syringe. The form is preferably stable under the conditions of processing 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 (for example, glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

The compounds described herein can be administered transdermally, i.e., administered through the surface of the body and the internal coatings of the body passages include epithelial and mucosal tissues. Such administration can be carried out using the compounds of the present teachings which include the pharmaceutically acceptable salts, hydrates, and esters thereof, in lotions, creams, foams, patches, suspensions, solutions, and suppositories (rectal and vaginal). Topical formulations that release active compounds through the epidermis may be useful for the localized treatment of inflammation and arthritis.

Transdermal administration can be accompanied through the use of transdermal patches containing an active compound and a carrier that can be inert to the active compound, which can be non-toxic to the skin, and can allow the supply of the active compound for systemic absorption into the bloodstream 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 liquid viscous or semi-solid emulsions of the oil-in-water or water-in-oil type. The Pastes are comprised of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the active compound may also be suitable. A variety of occlusive devices can be used to deliver the active compound into the bloodstream, such as a semi-permeable membrane that covers 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.

The 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 boiling point of the suppository, and glycerin. Water-soluble suppository bases, such as polyethylene glycols of various molecular weights, can also be used.

The lipid formulations or nanocapsules can be used to introduce the compounds of the present teachings into the host cells in vitro or in vivo. Lipid formulations and nanocapsules can be prepared by the methods known in the art.

To increase the effectiveness of the compounds of the present teachings, it may be desirable to combine a compound with other effective agents in the treatment of the target disease. For anti-inflammatory diseases, other active compounds (ie, other active ingredients or agents) are effective in their treatment, and particularly in the treatment of asthma and arthritis, they can be administered with active compounds of the present teachings. The other agents can be administered at the same time or different times than the compounds described herein.

Throughout the description, wherein the compositions are described as having, including, or comprising specific components, or wherein the processes are described as having, including, or comprising the specific process steps, it contemplates that the 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 process stages.

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 may be any one of the recited elements or components and You can select from a group consisting of two or more of the elements recited or components. The use of the term "includes" should generally be understood as open and does not limit unless otherwise specified.

The use of the singular here includes the plural (and vice versa) unless otherwise specified. In addition, where the use of the term "approximately" is earlier a quantitative value, the current teachings also include the specific quantitative value itself, unless otherwise specified.

It must be understood that the order of the stages or the order to develop certain actions is not important as long as the current teachings remain operable. Moreover, two or more stages or actions can be conducted simultaneously.

As used herein, a "compound" refers to the compound itself and its pharmaceutically acceptable salts, hydrates and esters, unless otherwise understood in the context of the description or is expressly limited to a 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 fluorine, chlorine, bromine, and iodine.

As used herein, "oxo" refers to a double bond oxygen (ie, = 0).

As used herein, as a functional group or part of a functional group, "alkyl" refers to a straight or branched chain saturated hydrocarbon group. In some embodiments, an alkyl group may have from 1 to 10 carbon atoms (eg, from 1 to 6 carbon atoms). Examples of alkyl groups include methyl (Me), ethyl (Et), propyl (for example, n-propyl and isopropyl), butyl (for example, n-butyl, isobutyl, s-butyl, t-butyl), pentyl groups ( for example, n-pentyl, isopentyl, neopentyl), and the like. In some embodiments, the alkyl groups can be substituted with up to four independently selected groups -Y-R4, -Y-R8 or R12, wherein Y, R4, R8 and R2 are as described herein. A lower alkyl group typically has up to 6 carbon atoms, that is, 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 here, as a functional group or part of a functional group, "alkenyl" refers to a straight or branched chain alkyl group having one or more carbon-carbon double bonds. In some embodiments, an alkenyl group may have from 2 to 10 carbon atoms, (for example, 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 groups -Y-R8 or R 2, wherein Y, R8, and R12 are as described herein.

As used herein, as a functional group or part of a functional group, "alkynyl" refers to a straight or branched chain alkyl group having one or more triple carbon-carbon bonds. In some embodiments, an alkynyl group may have from 2 to 10 carbon atoms (eg, from 2 to 6 carbon atoms). Examples of alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, and the like. The one or more triple carbon-carbon bonds can be internal (such as in 2-butyne) or terminal (such as in 1-butyne). In some embodiments, the alkynyl groups can be substituted with up to four independently selected groups -Y-R8 or R12, wherein Y, R8, and R12 are as described herein.

As used herein, "alkoxy" refers to an -O-alkyl group. In some embodiments, an alkoxy group may have from 1 to 10 carbon atoms (eg, from 1 to 6 carbon atoms). Examples of alkoxy groups include methoxy, ethoxy, propoxy groups (e.g., n-propoxy and isopropoxy), t-butoxy, and the like.

As used herein, "alkyltium" refers to a -S-alkyl group. Examples of alkylthio groups include methylthio, ethylthio, propylthio groups (for example, n-propylthio and isopropylthio), t-butylthio, and the like.

As used herein, "haloalkyl" refers to an alkyl group having one or more halogen substituents. In some embodiments, a haloalkyl group may have from 1 to 10 carbon atoms (eg, from 1 to 6 carbon atoms). Examples of haloalkyl groups include CF3, C2F5, CHF2, CH2F, CCI3, CHCI2, CH2CI, C2CI5, and the like. Perhaloalkyl groups, that is, alkyl groups in which all hydrogen atoms are replaced with halogen atoms (eg, CF3 and C2F5), are included within the definition of "haloalkyl".

As used herein, "cycloalkyl" refers to a non-aromatic carbocyclic group that includes cyclic alkyl, alkenyl, and alkynyl groups. A cycloalkyl group may be monocyclic (for example, cyclohexyl) or polycyclic (for example, containing fused, bridged and / or spiro ring systems), wherein the carbon atoms are located inside or outside the ring system. A cycloalkyl group, as a whole, may have from 3 to 1 ring atoms (e.g., from 3 to 8 carbon atoms for in 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 bonded to the defined chemical structure.

Examples of cycloalkyl groups include cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, cyclohexylethyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbomyl, norpinyl, norcaryl, adamantyl, and spiro [4.5] decanyl groups, as well as their homologs , isomers, and the like. In some embodiments, cycloalkyl groups can be substituted with up to four independently selected groups -Y-R4, -Y-R8 or R12, wherein Y, R4, R8, and R12 are as described herein. For example, cycloalkyl groups may include the 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 bonds or triples A cycloheteroalkyl group, as a whole, may have, for example, from 3 to 14 ring atoms and contains from 1 to 5 heteroatoms in the ring (for example, from 3-7 ring atoms for a monocyclic cycloheteroalkyl group and from 7 to 14 atoms in the ring for a polycyclic cycloheteroalkyl group). One or more N or S atoms in a cycloheteroalkyl ring can be oxidized (e.g., N-oxide morpholine, S-thiomorpholine oxide, S S-thiomorpholine dioxide). In some embodiments, the nitrogen atoms of the cycloheteroalkyl groups may be a substituent, for example, a group-Y-R8 or a group R12, wherein Y, R8, and R12 as described herein. The Cistroheteroalkyl groups may also contain one or more oxo groups, such as piperidone, oxazolidinone, pyrimidine-2,4 (1 H, 3 H) -dione, pyridin-2 (1 H) -one, and the like. Examples of cycloheteroalkyl groups include, among others, morpholine, thiomorpholine, pyran, imidazolidine, imidazoline, oxazolidine, pyrazolidine, pyrazoline, pyrrolidine, pyrroline, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, and the like. In some embodiments, the cycloheteroalkyl groups can optionally be substituted with up to four groups independently selected from groups -Y-R4, -Y-R8 or R12, wherein 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 link in common with) together At least one aromatic monocyclic hydrocarbon ring is fused to one or more cycloalkyl and / or cycloheteroalkyl rings. An aryl group may have from 6 to 14 carbon atoms in its ring system, which may include multiple fused rings. In some embodiments, a polycyclic aryl group may have from 8 to 14 carbon atoms. Any suitable ring position of the aryl group can be covalently bound to the defined chemical structure. Examples of aryl groups having only carbocyclic aromatic rings include phenyl, 1 -naphthyl (bicyclic), 2-naphthyl (bicyclic), anthracenyl (tricyclic), phenanthrenyl (tricyclic) and similar 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 cyclopentane derivatives (i.e., an indanyl group, which is a cycloalkyl group). , 6-bicyclic / aromatic ring system), cyclohexane (ie, a tetrahydro naphthyl group, which is a 6,6-bicyclic cycloalkyl / aromatic ring system), imidazoline (ie, a benzimidazolinyl group, which is a cycloheteroalkyl 5,6-bicyclic / aromatic ring system), and pyran (ie, 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, the aryl groups optionally contain up to four independently selected groups R4, -Y-R4, -O-Y-R4, -Y-R8, or R12, wherein Y, R4, R8, and R12 are as described herein.

As used herein, "heteroaryl" refers to 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 wherein at least one of the rings present in the ring system is aromatic and contains at least 1 ring hetero atom When more than one ring hetero atom is 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, may have, for example, from 5 to 14 ring atoms and contain 1 -5 ring heteroatoms. The heteroaryl group can be attached to the chemical structure defined at any heteroatom or carbon atom resulting in a stable structure. Generally, heteroaryl rings do not contain O-O, S-S, or S-0 bonds. However, one or more N or S atoms in a heteroaryl group can be oxidized (for example, pyridine N-oxide, thiophene S-oxide, thiophene S, S-dioxide). Examples of heteroaryl groups include, for example, the 5-membered and 5- membered monocyclic ring and 5- membered monocyclic ring systems shown below: wherein T is O, S, NH N-Y-R4, N-Y-R8, or NR12; and Y, R4, R8, and R2 are as described herein. Examples of such heteroaryl rings include pyrrolyl, furyl, thienyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazolyl, tetrazolyl, pyrazolyl, midazolyl, isothiazolyl, thiazolyl, thiazolyl, isoxazolyl, 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, isobenzofuilo, naphthyridinyl, phthalazinyl, pteridinyl, purinyl, oxazolopyridinyl , thiazolopyridinyl, imidazopyridinyl, furopyridinyl, thienopyridinyl, pyridopyrimidinyl, pyridopyrazinyl, pyridopyridazinyl, thienothiazolyl, thienoxazolyl, thienoimidazolyl, and the like. Examples of additional 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 groups R4, -Y-R4, -O-Y-R4, -Y-R8, or R12, wherein Y, R4, R8, and R12 are as described herein.

The compounds of the present teachings may include a "divalent group" defined herein as a linking group capable of forming a covalent bond with two of other functional groups. For example, the compounds described herein may include a divalent C-10 alkyl group, such as, for example, a methylene group.

In various places in the present specification, the substituents of the compounds are described in the groups or in the ranges. It is specifically intended that the description includes each and all individual subcombinations of the members of such groups and ranges. For example, the term "Ci-10 alkyl" is specifically intended to individually describe Ci, C2, C3, C4, C5, C6, C7, C8, C9, Cio, C1-C10, C Cg, C Ce, Ci- C7, C- | -C6, C5, C4, C1-C3, Cr C2, C2- C10, C2- Cg, C2-Cg, C2-C7, C2-C6, C2- C5, C2"C, C2 C3, C3- C10, C3- Cg, C3-C8, C3-C7, C3- C6, C3-C5, C3-C4, C4-C10, C4-C9, C4-C8, C4-C7, C4-C6, C-C5, C5-C10, C5-C9, CS-CB, C5-G7, C5-C6, Ce-C10, C6- Cg, C6-C8, C6-C7, C7-C10, C7-C9, C7-C8, C8-C0, C8-C9, and C8-C0. By way of other examples, the. The term "5-14 membered heteroaryl group" is specifically intended to individually discover 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 -1, 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 atoms in the ring; and the phrase "optionally substituted with 1-4 substituents" is specifically intended to individually discover a chemical group which may 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.

The compounds described herein may contain an asymmetric atom (also referred to as a chiral center), and some of the compounds may contain one or more asymmetric atoms or centers, which may thus arise as optical isomers (enantiomers) and diastereomers. The present teachings and the compounds described herein include such optical isomers (enantiomers) and diastereomers (geometric isomers), as well as the enantiomerically pure, racemic, and resolved stereoisomers, as well as other mixtures of the stereoisomers R and S and pharmaceutically acceptable salts of these. The optical isomers can be obtained in pure form by standard procedures known to those skilled in the art, including diastereomeric salt formation, kinetic resolution, and asymmetric synthesis. The present teachings also encompass the cis and trans isomers of compounds containing alkenyl functional groups (eg, alkenes and mines). 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 methods known to those skilled in the art, and include column chromatography, thin layer chromatography, and high performance liquid chromatography.

Through the specification, the structures may or may not be presented with chemical names. When any question arises as a nomenclature, the structure prevails.

One aspect of the present teachings relates to methods for preparing the compounds described herein. The compounds of the present teachings can be prepared according to the methods referred to in the schemes below, of starting materials described below, the compounds known in the literature, or easily prepare the intermediates, by employing standard synthetic methods and procedures known to those skilled in the art. experts in the art. The standard synthetic methods and procedures for the preparation of organic molecules and transformations of the functional group and manipulations can be easily obtained from the relevant scientific literature or from standard texts in the field. It will be appreciated that where typical process conditions (i.e., reaction temperature, times, molar ratios of reactors, solvents, pressures, etc.) are given, other process conditions may also be used unless another is said. thing. Optimal reaction conditions can vary with particular reactors or the solvent is 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 vary for the purpose to optimize the formation of the compounds described herein.

The processes described here 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 (eg, 1H or 13C), infrared spectroscopy, spectrophotometry (eg, UV-visible), or mass spectrometry, and / or by chromatography such as high performance liquid chromatography (HPLC) or thin layer chromatography.

The preparation of the compounds may involve the protection and deprotection of several chemical groups. The need for protection and deprotection and the selection of appropriate protection groups can be easily determined by one skilled in the art. The chemistry of protection groups can be found, for example, in Greene, et al., Protective Groups in Synthesis Organ, 4th Ed., Wiley & Sons, 2006, whose entire description is incorporated here as a reference for all purposes.

The reactions of the processes described herein can be carried out in suitable solvents that can be easily selected by one skilled in the art of organic synthesis. Suitable solvents are typically not substantially reactive with the reactants, intermediates, and / or products at temperatures at which the reactions are carried out, i.e. temperatures that can vary the freezing temperature of the solvent at the boiling point of the solvent . A given reaction can be carried out in a 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 describes an exemplary synthetic route for the preparation of an intermediate of the compounds of formula I.

Scheme 1 The acetic acid ester i is converted to 3-oxo-butyronitrile ii by reaction with the acetonitrile anion prepared by the reaction of acetonitrile (CH 3 CN) with a strong base such as n-butyl lithium (n-BuLi) in a solvent such as THF. The reaction of oxo-butyronitrile ii with dimethylformamide-dimethyl acetal (DMF-DMA) in a solvent such as DMF at high temperature (eg, 122 ° C) results in the formation of the intermediate bisdimethylaminomethylene iii which is converted to 4-hydroxy iv nicotinonitrile by reaction with ammonium (NH3) or ammonium acetate (NH4OAc) in a solvent such as refluxing ethanol. The reaction of hydroxy pyridine with phosphorous oxychloride reflux (POCI3) 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 the conversion of the acetic acid vi to the corresponding acid chloride by reaction with a chlorinating agent such as thionyl chloride (SOCI2) followed by the reaction of the tert-butylcyanoacetate anion prepared by the 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 leads to the deprotection of the ester and the decarboxylation to give 3-oxo- butyronitrile ii by reaction with an acid such as trifluoroacetic acid (TFA).

Scheme 2 Alternatively, as shown in Scheme 3 below, the bisdimethylamine methylene intermediate iii obtained by the reaction of 3-oxobutyronitrile ii with DMF-DMA can be reacted with refluxing 3,4-dimethoxybenzylamine in a solvent such as toluene to give 1- (3,4-dimethoxybenzyl) -4-oxo-l, 4-dihydro-pyridine-3-carbonitrile viii. The reaction of viii with excess LiCl in POCI3 reflux results in removal of the dimethoxybenzyl group and conversion to the corresponding 4-chloro-nicotinonitrile v.

Scheme 3 Scheme 4 below describes an exemplary synthetic route for the preparation of the compounds of formula I.

Scheme 4 X = link To prepare the compounds of the formula I wherein X is -NR3- (CH2) n-, - NR3 (CO) -, -O-, or-S-, where n = 0-10, at C-5 substitution 4-chloro-3-cyanopyridine v can be reacted with R 1 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 an elevated temperature of 60-180 ° C, optionally in the presence of pyridine hydrochloride (Pir.HCl); 2) using an alkyl 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 (DaveFos) or tributylphosphine, in the presence of a base such as potassium phosphate (K3P04) 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 (Cs2C03) in a solvent such as acetonitrile (CH3CN) or DMF at elevated temperatures of 80-150 ° C.

When X is a covalent bond, the compounds of the formula I can be prepared by a C-5 coupling reaction substituted 4-chloro-3-cyanopyridine v with a boronic acid of the formula R 1 B (OH) 2, or boronic ester of the formula R1B (OR) 2, wherein R is an alkyl group (for example, an alkyl group lower), mediated by a palladium catalyst such as tetrakis (triphenylphosphino) -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 (NaHC03 aq.) or aqueous sodium carbonate (Na2C03 aq), optionally in the presence of a phosphino ligand such as triphenyl phosphino (Ph3P). Alternatively, 4-chloro-3-cyanopyridine v can be treated with a stannane R1SnR3, wherein R is an alkyl group (eg, a lower alkyl group), to produce the compounds of formula I.

With reference to scheme 5 below, additional compounds of formula I wherein R 2 is substituted with a group R 4 selected from an aryl group, a heteroaryl group, an alkenyl group and an alkynyl group (formula Ib) can be prepared from the compounds of the formula I wherein R2 is substituted with a starting group (LG) such as bromide (Br), iodide (I), chloride (Cl) or trifluoromethane sulfonate (OTf) (formula la) as described in Scheme 5 ahead.

Scheme 5 alkynyl More specifically, the compounds of the formula Ib wherein R 4 is an aryl group or a heteroaryl group can be prepared by treating the compounds of the formula la with a boronic acid (RB (OH) 2), a boronic ester (R 4B (OR) 2, wherein R is a lower alkyl group) or with an organic stannous 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 NaHC03 aq. or Na2C03 ac, optionally in the presence of a phosphino ligand such as Ph3P.

Similarly, compounds of the formula Ib wherein R 4 is an alkenyl group or an alkynyl group can be prepared by treating the compounds of the formula la with an alkene or alkyne of the formula R -H or with a boronic acid or ester of or a organic stannane reagent in the presence of a palladium catalyst (e.g., (Ph3P) 4Pd, dichlorobis (triphenylphosphino) 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-tolylphosphino and a base (eg, potassium carbonate (K2C03) or Na2C03), optionally with the addition of an organic base such as TEA. A catalytic amount of copper iodide (I) can optionally be used for this coupling reaction.

Scheme 6 describes a synthetic route for preparing additional compounds of formula I wherein R2 and R4 are aryl or heteroaryl groups and R4 is further substituted with an amide (formula Id).

Scheme 6 Compounds of the formula I in which R2 is substituted by an aryl or heteroaryl group is replaced by a carboxylic acid (formula le) can be treated with an amine of the formula NHR10R11 in the presence of a catalyst (for example, benzotriazole hexafluorophosphate -1-ioxytris (dimethylamino) phosphonium (BOP)) and an organic amine (eg, TEA, DIEA, or pyridine) in a solvent such as MeOH or EtOH at room temperature at elevated temperatures of 50-80 ° C to provide the compounds of the formula Id as described.

Additional compounds of the formula I wherein R2 is substituted with -O- Y-NR6R7 (formula If) can be prepared as described in Scheme 7 below, by treating the compounds of the formula I wherein R2 is substituted with - O-Y-LG (formula le), wherein LG is Cl, Br, methanesulfonyl (mesyl, OMs), or p-toluenesulfonyl (tosyl, OTs), with an amine of the formula NHR6R7 in a solvent such as EtOH, DME or DMF optionally in the presence of Nal or a base such as K2C03.

Scheme 7 LG = C1, Bf, OMs, OTs As described in Scheme 8, the compounds of the formula I wherein R2 is substituted by -CH2-NR6YR7 (formula Ih), can be prepared by treating the compounds of the formula I wherein R2 contain an aldehyde functionality (formula Ig ), with an amine of the formula HNR6YR7 in the presence of a reducing agent (for example, sodium triacetoxyborohydride (Na (OAc) 3BH) or sodium cyanoborohydride) in a solvent such as dichloromethane (CHaCl2) or THF with the addition optimum of DMF or NMP and preferably in the presence of acetic acid. The compounds of the formula I wherein R2 are substituted by -CH2-OH (formula II) can be formed as a by-product b of their reductive amination reaction.

Scheme 8 Di Ii As described in Scheme 9, the compounds of the formula I wherein R2 is substituted by -OYR5 (formula Ik) can be prepared by treating the compounds of the formula I wherein R2 contains a hydroxyl functionality (formula Ij), with an alcohol of the formula R5YOH under Mitsunobu conditions. This reaction can be conducted in a solvent such as THF in the presence of Ph3P and diethyl azodicarboxylate or di-t-butyl azodicarboxylate.

Scheme 9 Ij Isonubo Ik Additional compounds of formula 1 wherein X is not a bond can be prepared as shown in Scheme 10, Scheme 11, and Scheme 12 below.

Scheme 10 T A mixture of 3-aminobut-2-enenitrile ix is heated in acid (eg, aqueous HCl) to produce acetoacetonitrile x. Acetoacetonitrile x is treated with t-butoxybis (dimethylamino) methane and DMF-DMA at an elevated temperature to produce 5- (dimethylamino) -2 - [(dimethylamino) methylene] -3-oxopent-4-enenitrile xi, which is then treated with ammonium acetate in EtOH under reflux to produce 4-hydroxynicotinonitrile xii. (An alternate synthesis of 4-hydroxynicotinonitrile is 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 produce 4-hydroxy-5-iodonotinonitrile xiii, which is then treated with POCI3 at a temperature elevated to produce 4-chloro-5-iodonicotinonitrile xiv. The intermediate xiv can then be treated with R1XH, where X is not a bond (eg, R1NH2, R1OH, R SH, etc.) to produce the 4-5 substituted-iodo-nicotinonitrile xv. Further treatment with a boronic acid RB (OH) 2, boronic acid ester R2B (OR) 2 or stannane R2SnR3 (wherein R, in each case, is a lower alkyl group) produces the 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 (wherein R, in each case, is a lower alkyl group), followed by a reaction with R1XH to provide the compounds of formula I.

Scheme 11 As described in scheme 11, the 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. The addition of a boronic acid, ester or organotin (wherein R in each case is a lower alkyl group) under the conditions noted previously provides the compounds of formula G.

Scheme 12 v xvi I As shown in Scheme 12, treatment of compounds of formula v with CsF in a solvent such as DMF provides a 4-fluoro analog. The subsequent displacement of the 4-fluoro group with R1XH in a solvent such as DMSO provides the compounds of formula I.

The aspects of the current teachings can be further understood in clarity with the following examples, which should not be constructed as the limiting scope of the current teachings in any way.

More specifically, the following examples illustrate various synthetic routes that can be used to prepare the compounds of formula I. The HPLC conditions used in the examples are listed as the following: Example 1: Preparation of 4 - [(3-chlorophenyl) amino] -5- (3,4-dimethoxyphenyl) nicotinitrile 101 A solution of 3,4-dimethoxyphenylacetic acid (50 mM) in methanol (MeOH, 100 mL) with concentrated sulfuric acid (H2SO4, 1 mL) or concentrated hydrochloric acid (HCl) is heated at reflux overnight. Concentration to dry on a rotary evaporator and high vacuum pump overnight yields methyl ester of 3,4-dimethoxy-phenyl) acetic acid as an oil which is used directly in the next step.

To a 1.0 L three-necked round bottom flask is added 50 mL of THF and the reaction mixture is cooled to -78 ° C. Butyl lithium (BuLi, 1.6 M, 14.4 mL, 23 mmol) is added in the form of drops maintaining the temperature in front of -70 ° C. Acetonitrile (1.3 mL, 25 mmol) in 30 mL of THF is added as drops to the bottle while stirring and cooling. After 2 hours (h) of stirring, (3,4-dimethoxyphenyl) acetic acid methyl ester (2.3 g, 11 mmol) is added to the resulting white colloidal mixture in the flask. The reaction mixture is stirred for an additional 2 h, followed by the addition of saturated ammonium chloride solution (NH 4 Cl, 75 mL) at -78 ° C. The organic layer is separated, dried with sodium sulfate (Na 2 SO 4), it is filtered to remove the dry agent and evaporated to dry to give the crude product. This crude product is purified by column chromatography on silica gel, eluting with 30-70% ethyl acetate (EtOAc) in hexanes to produce 4- (3,4-dimethoxyphenyl) -3-oxo-butyronitrile in the form of a solidified 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_) DMF-DMA (13.5 ml_, 101 mmol) is added and the solution is heated at 122 ° C overnight. Concentration in a rotary evaporator under high vacuum gives an orange-red solid. This solid is dissolved in EtOH (100 mL) and excess NH4Ac is added and the reaction mixture is heated at 85 ° C for 1 h. The reaction mixture is allowed to cool to room temperature (room temperature) for 1 h then the solids are collected by filtration and washed with EtOH (cold) to give 5- (34-dimelhoxyphenyl) -4-hydroxynicotinonitrile (4.1 g, 69%) as a brown solid. The filtrate is concentrated on a rotary evaporator and the residue is purified on silica gel with 0-25% MeOH in methylene chloride 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 POCI3 (25 mL) is heated at 125 ° C for 1.5 h, then cooled to room temperature and poured into a ice / 3N sodium hydroxide / ethyl acetate mixture. The mixture is stirred and the layers separated. The organic layer is 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 solution of 4-chloro-5- (3,4-dimethoxyphenyl) nicotinonitrile (55 mg, 0.2 mmol), 3-chloroaniline (25 mg, 0.2 mmol) and Pir.HCl (23 mg, 0.2 mmol) in EtOEtOH (2 mL) is heated at reflux for 8 hours, then cooled to room temperature and concentrated. The residue is purified by reverse phase HPLC to give 5- (3,4-dimethoxyphenyl) -4 - [(3-chlorophenyl) amino] nicotinonitrile 101 (3.4 mg). MS: 367 [M + H].

Following procedures analogous to those described for the preparation of compound 101 and using the appropriate aniline in the last step, the compounds are prepared in Table 2. The HPLC retention times provided in Table 2 as well as in Examples 2- 22 ahead are obtained using conditions as designated below: (a) Instrument - Agilent 1100; column: Keystone Aquasil C18, from Thermo Fisher Scientific, Inc. (Waltham, MA); mobile phase A: 10 mM NH4OAc in 95% water / 5% CH3CN; mobile phase B: 10 mM NH4OAc in 5% water / 95% CH3CN; Flow rate: 0.800 ml / min .; column temperature: 40 ° C; (b) Column YMC C18, 4.6 x 500 mm, 5 microns, from YMC (Kyoto, Japan); mobile phase A: 90% water + 10% MeOH + 0.02% H3P04; mobile phase B: 90% MeOH + 10% water + 0.02% H3P04; 1-100% of B in 2 min., Up to 10 min. 100% B, then 100-1% B in 1 min; (c) Column: Prodigy ODS3, 4.6 x 150mm, from Fenomenex (Torrance, CA); mobile phase A: 0.02% TFA in water; mobile phase B: 0.02% TFA in CH3CN; 10-95% B in 20 min .; flow rate: 1.0 mL / min .; column temperature: 40 ° C; detection wavelength: 215 nm; Y (d) Column: Aquasil C18, 50 x 2.1 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 acetonitrile, 0-100% B in 2.5 min., flow index: 0.8 mlJmin; column temperature: 40 ° C; Detection wavelength: 254 nm.

Table 2 HPLC Time Compound Observation Time Compound Name Retention time n [M + H] (min.) 5- (3,4-dimethoxyphenyl) -4 - [(3- 102 2.12 (a) 350 fluorophenyl) amine] Nitrogen-4-anilino-5- (3,4- 103 N / A 332 dimethoxy-phenyl) nicotinonyl 4 - [(2,5-difluorophenyl) ami no] -5- (3,4- 104 1.95 (a) 368 dimethoxyphenyl) nicotinonetria 5- (3,4-dimethoxy-phenyl) -4 - [(3,4-105 1.60 (a) 392 dimethox Phenyl) amino] nicotinonitrile 4 - [(4-chloro-2-fluorophenyl) amino] -5- 106 2.06 (a) 384 (3,4-dimethoxyphenyl) nicotonitrile HPLC Mon Time Observed Compound Name of the compound of o Retention m / e (min.) [M + H] 4 - [(3-chloro-4-fluorophenol) amino] -5- (3.4- 107 2.00 (a) 384 dimethoxyphenyl) ) Nicotinone 4 - [(4-chlorophenyl) amino] -5- (3,4- 108 1.95 (a) 366 dimethoxyphenyl) nicotinonitrile 5- (3,4-dimethoxyphenyl) -4- [ (2,4-dimethyl 109 2.24 (a) 360 phenyl) amino) nicotonnonitrile 5- (3,4-dimethoxyphenyl) -4 - [(4-1 10 2.09 (a) 362 methoxyphenyl) amino] nicotinone 4 - [(3-chloro-4-methoxyphenyl) amino] -5- 1 1 1. 2.17 (a) 396 (3,4-dimethoxy-phenyl) nicotunomethyl 5- (3,4-dimethoxyphenyl) -4 - [(4-1 12 2.41 (a) 424 phenoxyphenyl) amino] nichinonitrile 4 - [(2,5-dichlorophenyl) amino] -5- (3,4- 1 13 2.35 (a) 400 dimethoxyfeni) nicotonitrile 5- (3,4-dimethoxy-phenyl) -4 - [(4-methoxy-2-1 14 1.85 (a) 376 methyl phenyl) amino] n-trichonitrile 4 - [(3,4-dichlorophenyl) amino] -5- (3,4-1) 15 2.36 (a) 400-dimethoxyphenyl) nicotinonitrile 4 - [(5-chloro-2-methoxyphenyl) amino] -5- 1 16 2.12 (a) 396 (3,4-dimethoxy-phenyl) nicotinonitrite 4- { [3- (benzyloxy) phenyl] amino} -5- (3,4- 1 17 2.36 (a) 438 dimethoxyphenyl) nicotine nitrogen HPLC Mon Time Observed Compound Name of the compound of o Retention m / e (min.) [M + H] 5- (3,4-dimethoxyphenyl) -4 - [(4- 118 1.94 (a) 346 methylphenyl) amino] n-phenylnitrile 5- (3,4-dimethoxyphenyl) -4 - [(3,4,5- 119 1.77 (a) 422 trimethoxy-phenyl) amino] n-phenyl-phenyl-5- (3,4- dimethoxyphene) -4 - [(3- 120 2.38 (a) 424 phenoxyphenyl) amino] nicotinonitrile 4 - [(2-chloro-5-methoxyphenyl) amino] -5- 121 2.78 (a) 396 ( 3,4-dimethoxyphenyl) nicotonomethyl 4- (. {3-chloro-4 - [(3-cyanobenzyl) oxy] phenyl}. 122 amino) -5- ( 3,4- 2.35 (a) 497 dimethoxyphenyl) nitrotonitrile 4-. { [3-chloro-4- (thien-2- (yl) ethoxy) phenyl] amino} -5- (3,4- 2.37 (a) 478-dimethoxyphenyl) nicotonitrile 4- (. {3-chloro-4 - [(3-methylbenzyl) oxy] phenyl}. 124 amino) -5 - (3,4- N / A 487 dimethoxyphenyl) nicotonitrile 4 - [(3-chloro-4. {[3- [3- (dimethylamino) benzyl] oxy] phenyl) amino] - 2.28 (a) 515 5- (3,4-D-methoxyphenyl) nicotinonitrile 4 - [(2,4-dichlorophenyl) amino] -5- (3,4- 126 2.16 (a) 400 dimethoxyphenyl) nicotinonitrile N- (3- { [3-cyano-5- (3,4- 127 dimethoxyphenyl) pyridine-4- 1.84 (a) 389.2 [mu] l] amino} phenyl) acetamide N- (3 - { [3-cyano-5- (3,4-dimethoxyphenyl) pyridin-4-N] amino.} Phenyl) - 2.76 (a) 402.7 N-methylacetamide N- (3- { [3 -cyano-5- (3,4- 129-dimethoxyphenyl) pyridin-4- 1.86 (a) 425.1 il] amino.}. phenyl) methanesulfonamide 5- [4- (dimethylamino) phenyl] -4 - [(3- 130 3.0 (b) 345.4 methoxyphenyl) amino] nicotinonitrile 5- [4- (dimethylamino) phenyl] -4 - [(3- 131 3.4 (b) 333.4 fluorophenyl) amino] nicotinonitrile 4- (. {3-cyano-5- [ 4-356.8 [M-132 (dimethylamino) phenyl] pyridine-4- 3.0 (b) H] il.}. Amino) benzoic acid 4 - [(4-cyanophenyl) amino] -5- [4- 133 3.3 (b ) 340.2 (dimethylamino) phenyl] nicotinonitrile 4 - [(3,4-difluorophenyl) amino] -5- [4- 134 3.2 (b) 351.2 (dimethylamino) phenyl] nicotinonitrileExample 2: Preparation of 4 - [(3-bromophenyl) amino] -5- (3,4-dimethoxyphenyl) nicotinonitrile 135 A mixture of 4-chloro-5- (3,4-dimethoxyphenol) nicotin Trilo (0.5 g, 1.82 mmol), 3-bromoaniline (0.313 g, 1.82 mmol), and 0.05 g of Pir.HCl in 8 mL of EtOEtOH is heated at reflux for 8 hours. The solid is collected and dissolved in a mixture of saturated sodium bicarbonate (NaHCO 3) and CH 2 Cl 2. The layers are separated and the organic layer is dried with MgSO 4 and filtered through a Magnasol® pad. The solvent is removed and the residue recrystallized from iso-propanol / hexane to give 0.43 g of 4 - [(3-bromophenyl) amino] -5- (3,4-dimethoxyphenyl) nicotinonitrile 135. HPLC retention time ( a): 2.72 min; MS: 410.2 m / e (M + H).

Example 3: Preparation of 4-. { [3- (benzyloxy) -4-chlorophenyl] amino} -5- (3,4-dimethoxyphenyl) nicotinonitrile 136 This compound is prepared from 4-chloro-5- (3,4-dimethoxyphenyl) nicotinonitrile and 3-benzyloxy-4-chloroaniline using procedures analogous to those described in Example 2. HPLC retention time (a): 2.90 min; MS: 470.2 m / e (M + H).

Example 4: Preparation of 4 - [(2,4-dichloro-5-methoxyphenyl) amino] -5- (3,4-dimethoxyphenyl) nicotinonitrile 137 A mixture of 4-chloro-5- (3,4-dimethoxyphenyl) nicotinonitrile (0.5 g, 1.82 mmol), 2,4-dichloro-5-methoxyaniline (0.402 g, 2.1 mmol), Pd2 (dba) 3 (0.167 g) , 0.18 mmol), 2-dicyclohexylphosino-2 '- (N, N-dimethylamino) biphenyl (0.22 g, 0.56 mmol), and K3P04 (0.58 g, 2.73 mmol) in 10 mL of DME is heated at reflux for 45 minutes. The hot mixture is filtered and the solids are washed with ether. The filtrates are combined washed with saturated NaHCO3, dried (MgSO4), and filtered through a Magnesol® pad. The solvent is removed and the residue is chromatographed on silica gel. The product is eluted with CH2Cl2-ether and then recrystallized from iso-propanol / hexane to give 0.21 g of 4 - [(2,4-dichloro-5-methoxyphenyl) amino] -5- (3,4-dimethoxyphenyl) nicotinonitrile 137. HPLC retention time (a): 0.86 min; MS: 430.2 m / e (M + H).

Following procedures analogous to those described for the preparation of compound 137 and using the appropriate aniline, the compounds in Table 3 are prepared.

Table 3 Example 5: Preparation of 4-. { [4- (benzyloxy) -3-chlorophenyl] amino} -5- (3- nitrophenyl) nicotinonitrile 142 3-Nitrophenylacetic acid (9.5 g, 52 mmol) and SOCI2 (20 mL) are stirred overnight at room temperature, then evaporated to dryness. In a separate bottle NaH (60% dispersion in acetic acid, 5.5 g, 1.4 mmol) is suspended in THF (100 mL). The mixture is cooled to 0 ° C and tert-butylcyanoacetate (8.8 g, 62 mmol) is added. After 15 minutes, a solution of 3-nitrophenylacetyl chloride from the above in THF is added dropwise. The ice bath is removed and the mixture is allowed to warm to room temperature and is stirred for 4 hours. The reaction mixture is quenched by the addition of saline, and extracted with ethyl acetate (EtOAc, 2 x 200 mL). The combined organic extracts are dried over MgSO4 and concentrated. He tere-butyl ester of 2-cyano-4- (3-nitrophenyl) -3-oxo-butyric acid is used in the next step without further purification.

To a solution of tere-butyl ester of 2-cyano-4- (3-nitro-phenyl) -3-oxo-butyric acid (9.5 g, 31 mmol) in toluene (40 mL) is added TFA (4 mL). and the solution is heated at reflux for 2 hours, then the solvent is evaporated in vacuo. The residue is purified by flash chromatography on silica gel to give 4- (3-nitrophenyl) -3-oxo-butyronitrile (4.0 g, 37% over 2 steps).

Following procedures analogous to those described in Example 1, 4- (3-nitrophenyl) -3-oxo-butyronitrile is converted to 4-hydroxy-5- (3-nitrophenyl) nicotinonitrile, which is then converted to 4-chloro- 5- (3-nitrophenyl) nicotinonitrile. A solution of 4-chloro-5- (3-nitrophenyl) nicotinonitrile (2.1 g, 8.1 mmol) and 4-benzyloxy-3-chloroaniline (1.89 g, 8.1 mmol) in 50 mL of EtOEtOH is heated at reflux for 6.5 hours. The mixture is cooled and diluted with 450 ml of ether. A solution of HCl in 10 ml of ether is added. The solid is collected by filtration and washed with ether. The solid is suspended in saturated NaHCO 3 and the mixture is stirred with EtOAc until the solids dissolve. The organic layer is dried (MgSO4) and filtered through a Magnesol® pad. The solvent is removed and the residue is recrystallized from EtOH giving 2.15 g of 4-. { [4- (benzyloxy) -3-chlorophenyl] amino} -5- (3-nitrophenyl) nicotinonitrile 142. HPLC retention time <a): 3.06 min; MS: 456.8 m / e (M + H).

Following procedures analogous to those described for the preparation of compound 142 and using the appropriate aniline, the compounds in Table 4 are prepared.

Table 4 Example 6: Preparation of 5- (3-aminophenyl) -4-. { [4- (benzyloxy) -3-chlorophenyl] amino} nicotinonitrile 145 A mixture of 4-. { [4- (benzyloxy) -3-chlorophenyl] amino} -5- (3-nitrophenyl) nicotinonitrile 142 (2.0 g, 4.38 mmol), iron (1.47 g, 26.3 mmol), and acetic acid (AcOH, 1.58 g, 26.3 mmol) in 90 mL of MeOH is stirred at reflux for 3 hours. hours. The hot mixture is filtered, and the collected solids are washed with hot THF. The combined organic solutions are concentrated and then redissolved in a mixture of hot THF-ethyl acetate. The suspension is filtered and washed with saline / saturated NaHC03. The organic layer is dried (MgSO) and filtered through a Magnesol® pad. The solvent is removed giving 1.81 g of 5- (3-aminophenyl) -4-. { [4- (benzyloxy) -3- chlorophenyl] amino} Nicotonicnontrile 145. HPLC retention time (a): 2.74 min; MS: 426.8 m / e (M + H).

Example 7: Preparation of 4 - [(3-chloro-4-fluorophenyl) amino] -5- (2-nitrophenyl) nicotinonitrile 146 4- Chloro-5- (2-nitrophenyl) nicotinonitrile is prepared from 2-nitrophenylacetic acid using procedures analogous to those described for the preparation of 4-chloro-5- (3-nitrophenyl) nicotinonitrile in Examples 5. MS: 260.1 m / e (M + H).

A mixture of 4-chloro-5- (2-nitrophenyl) nicotinonitrile (4 g, 15.41 mmol), Pir.HCl (0.89 g, 7.7 mmol), and 3-chloro-4-fluoroaniline (2.8 g, 19.26 mmol) in 15 ml of diglyme is heated at 130 ° C for 27 hours. The mixture is cooled and eternal HCl is added and the solids are collected. The solid is stirred with saturated NaHCO 3 and CH 2 Cl 2 until dissolved. The solution is washed with saline, dried (MgSO4), and filtered through a Magnesol® pad and concentrated. The residue is chromatographed on silica gel to give 2.3 g of 4 - [(3-chloro-4-fluorophenyl) amino] -5- (2-nitrophenyl) nicotinonitrile 146. HPLC retention time (a): 3.58 min; MS: 369.1 m / e (M + H).

Example 8: Preparation of 5- (2-aminophenyl) -4 - [(3-chloro-4-fluorophenyl) amino] nicotinonitrile 147 5- (2-Aminophenyl) -4 - [(3-chloro-4-fluorophenyl) amino] nicotinonitrile 147 is prepared by reducing 4 - [(3-chloro-4-fluorophenyl) amino] -5- (2-nitrophenyl) Nicotinonitrile 146 as described above in Examples 6. HPLC retention time (a): 2.06 min; MS: 339.2 m / e (M + H).

Example 9: Preparation of 4 - [(2,4-dichloro-5-methoxyphenyl) amino] -5- [4-methoxy-3- (2-methoxyethoxy) phenyl] nicotinonitrile To a stirred solution of 3-hydroxy-4-methoxyphenylacetic acid (24.84 g, 136 mmol) in 0.2 L of MeOH is added 1 mL of H2SO4 and heated at reflux overnight. The methanol is evaporated in vacuo and the residue is poured into saturated NaHCO 3 solution and extracted with EtOAc (3 x 150 mL). The combined organic extracts then they are washed with saline, dried over anhydrous MgSO4, filtered, and concentrated in vacuo to yield 23.94 g (90% methyl ester of (3-hydroxy-4-methoxy-phenyl) -acetic acid as a yellow oil. .

To a stirred solution of 3-hydroxy-4-methoxyphenylacetic acid methyl ester (5 g, 25.48 mmol), tetrabutylammonium iodide (0.941 g, 2.5 mmol), and 2-bromoethylmethyl ether (4.6 ml_, 50.9 mmol) in 150 ml_ of acetone are added cesium carbonate (17.4 g). The mixture is stirred for 21.5 hours at reflux. The mixture is concentrated and the residue is extracted from water with EtOAc. The combined organic extracts are then dried over anhydrous sodium sulfate (Na 2 SO 4), filtered, and concentrated in vacuo to yield 8.15 g of yellow oil. The oil is purified by flash chromatography on silica gel using 10-50% EtOAc in hexane as the eluent. Fractions containing combined fractions are concentrated to give 5.33 g (821) of [4-methoxy-3- (2-methoxyethoxy) phenyl] acetic acid methyl ester as a light yellow oil.

To a 250 ml three-necked round bottom flask, add 10 mL of anhydrous THF and cool to -78 ° C. Add n-Butyl lithium (2.5 M in hexane), 8.06 mL, 12.9 mmol) to the flask and stirred for 5 minutes. Anhydrous acetonitrile (0.696 mL, 13.3 mmol) in 5 mL of anhydrous THF is added dropwise to the flask with stirring and cooled to -78 ° C. After 1 hour of stirring, methyl ester of [4-methoxy] acid -3- (2-methoxyethoxy) phenyl] acetic acid (1.095 g, 4.3 mmol) in 10 mL of anhydrous THF is added dropwise to the white colloidal mixture resulting in the flask. The reaction mixture is stirred for a further 2 hours, followed by the addition of saturated NH4CI solution at -78 ° C. The solution is warmed to room temperature, diluted with 100 mL water and extracted with EtOAc (3x100 mL). . The organic layer is separated, washed with saline, dried with anhydrous MgSO4, filtered, and concentrated in vacuo. The crude product is purified by chromatography on silica gel eluting with 30-60% EtOAc in hexanes to yield 769.4 mg (681) of 4- [4-methoxy-3- (2-methoxy-ethoxy) -phenyl] -3- oxo-butyronitrile 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 anhydrous DMF was added DMF / DMA (20.2 mL, 152 mmol ) and the solution is heated at 100 ° C for 15 hours. The reaction is concentrated in vacuo and then the crude material is stirred with 3,4-dimethoxy-benzylamine (0.687 mL, 41.4 mmol) in 20 ml_ of anhydrous toluene under reflux for 2 hours. The reaction is cooled, concentrated in vacuo, and purified on chromatography on silica gel eluting with 50-100% EtOAc / hexane to yield 8.5 g (55%) of 1- (3,4-dimethoxybenzyl) -5- [4-methoxy-3- (2-methoxyethoxy) phenyl] -4-oxo-1,4-dihydro-pyridine-3-carbonitrile as a yellow / orange foam.

A solution of 1- (3,4-dimethoxybenzyl) -5- [4-methoxy-3- (2-methoxyethoxy) phenyl] -4-oxo-1,4-dihydro-pyridine-3-carbonitrile (300 mg, 0.666 mmol) and lithium chloride (LiCl, 254 mg, 6 mmol) in 2.5 mL. POCI3 is heated to reflux for 2.5 hours. The excess of POCI3 is removed by concentrating in vacuo and then the residue is co-evaporated with toluene. The residue is dissolved in 100 mL EtOAc and washed with 1 N NaOH cooled with ice. The organic layer is separated, dried over anhydrous MgSO4, filtered, concentrated in vacuo, and the resulting solid is triturated with isopropyl alcohol to yield 165.6 mg of 4-chloro-5- [4-methoxy-3- (2- methoxyethoxy) phenyl] nicotinonitrile as a whitish solid (78%).

To a stirred solution of 4-chloro-5- [4-methoxy-3- (2-methoxyethoxy) phenyljnicotinonitrile (100 mg, 0.313 mmol), 2,4-dichloro-5-methoxyaniline (90 mg, 0.47 mmol), 2 -dicyclohexylphosphino-2 '- (N, N-dimethylamino) biphenyl (37 mg, 0.094 mmol), and K3P04 (99.8 mg, 0.47 mmol) in 4 mL of ethylene glycol dimethyl ether anhydrous is added Pd2 (dba) 3 (28.7 mg , 0.031 mmol). The mixture is heated at 90 ° C for 2 hours, then cooled, filtered through celite®, concentrated in vacuo, and purified by trituration with ether / hexane to yield 19 mg (13%) of 4- [ (2,4-dichloro-5-methoxyphenyl) amino] -5- [4-methoxy-3- (2-methoxyethoxy) phenyl] nicotinonitrile 148. HPLC retention time (c): 11.99 min; MS [M + H]: 474.1.

Example 10: Preparation of 4- (2,4-dichloro-5-methoxy-phenylamino) -5- [3-methoxy-4- (2-methoxy-ethoxy) -phenyl] -nicotinonitrile 149 To a stirred solution of ethyl homovanilate (16.2 g, 77.05 mmol), tetrabutylammonium iodide (TBAI, 1.42 g, 3.85 mmol), and 2-bromoethylmethyl ether (10.4 mL, 115.5 mmol) in 250 mL of acetone is added cesium carbonate. (Cs2CO3, 40.16 g, 123.2 mmol). The mixture is stirred for 21.5 hours at reflux. The mixture is concentrated and the residue is extracted from water with EtOAc. The combined organic extracts are then dried over Na 2 SO 4, filtered, and concentrated in vacuo to yield 27 g of yellow oil. He The oil is purified by flash chromatography using silica gel and 10-60% EtOAc / hexane. The combined fractions are concentrated to give 20.67 g (100%) of ethyl ester of [3-methoxy-4- (2-methoxyethoxy) phenyl] acetic acid as a colorless oil.

To a 500 mL three-necked round bottom flask is added 100 mL of THF was anhydrous and cooled to -78 ° C. N-Butyl lithium (1.6 M in hexane, 69.8 mL, 11.8 mmol) was added to the flask and then stirred for 5 minutes. The anhydrous CH3CN (6.02 mL, 15.3 mmol) in 50 mL of anhydrous THF is added dropwise to the flask with stirring and cooled to -78 ° C. After 1 hour of stirring, ethyl ester of acid [3- methoxy-4- (2-methoxyethoxy) phenyl] acetic acid (10 g, 37.2 mmol) in 60 mL of anhydrous THF is added dropwise to the resulting white colloidal mixture in the flask. The reaction mixture is stirred for an additional 2 hours, followed by the addition of saturated aqueous NH4Cl solution at -78 ° C. The solution is warmed to room temperature, diluted with 200 mL of water and extracted with EtOAc ( 3x200 mL). The organic layer is separated, washed with saline, dried with anhydrous MgSO 4, filtered, and concentrated in vacuo. The crude is purified by chromatography on silica gel eluting with 20-80% EtOAc in hexanes to yield 7.39 mg (75%) of 4- [3-methoxy-4- (2-methoxyethoxy) phenyl] -3-oxo- butyronitrile as a yellow solid.

To a stirred solution of 4- [3-methoxy-4- (2-methoxyethoxy) phenyl] -3-oxo-butyronitrile (7.22 g, 27.4 mmol) in 16 mL anhydrous DMF is added DMF-DMA (16 mL, 120.6 mmol) and the solution is heated at 100 ° C for 15 hours. The reaction is concentrated in vacuo and then the crude material is stirred with 3,4-dimethoxybenzylamine (4.95 mL, 32.8 mmol) in 20 mL of anhydrous toluene under reflux for 2 hours. The reaction is cooled, concentrated in vacuo, and purified by chromatography on silica gel eluting with 50-100% EtOAc / hexane to yield 8.26 g (67%) of 1- (3,4-dimethoxy-benzyl) - 5- [3-methoxy-4- (2-methoxy-ethoxy) -phenyl] -4-oxo-1,4-dihydro-pyridine-3-carbonitrile as a yellow solid.

A solution of 1- (3,4-dimethoxybenzyl) -5- [3-methoxy-4- (2-methoxyethoxy) phenyl] -4-oxo-1,4-dihydro-pyridine-3-carbonitrile (8.13 g, mmol) and LiCl (6.8 g, 162.4 mmol) in 65 mL of POCI3 is heated to reflux for 2.5 h. The excess of POCI3 is ved by concentrating in vacuo and then the residue is coevaporated with toluene. The residue is dissolved in 100 mL of ethyl acetate and washed with ice-cold 1 N aqueous NaOH. The organic layer is separated, dried over anhydrous MgSO4, filtered, concentrated in vacuo, and the solid The resulting mixture is triturated with isopropyl alcohol to yield 4.49 g of 4-chloro-5- [3-methoxy-4- (2-methoxyethoxy) phenyl] nicotinonitrile as a whitish solid (78%).

Following procedures analogous to those described for the preparation of compound 148 in Example 9, 4- (2,4-dichloro-5-methoxyphenylamino) -5- [3-methoxy-4- (2-methoxyethoxy) phenyl] nicotinonitrile 149 it is prepared as a whitish solid, with a yield of 27 mg (18%). MS: 474.1 m / z; HPLC retention time (c): 12.0 min.

Example 11: Preparation of 5- [3- (2-chloroethoxy) phenyl] -4 - [(2,4-dichloro-5-methoxyphenyl) amino] nicotinonitrile 150 and 4 - [(2,4-dichloro-5-methoxyphenyl) amino] -5- [3- (2-pyrrolidin-1-ylethoxy) phenyl] nicotinonitrile 151 To a stirred solution of methyl ester of 3-hydroxyphenylacetic acid (22.6 g, 136 mmol) and 2-chloroethyl p-toluenesulfonate (40 g) in 0.9 L acetone is added Cs2CO3 (88.8 g) and refluxed for 3 hours. hours. The mixture is then cooled, filtered, and concentrated in vacuo. The residue is purified by chromatography on silica gel eluting with 0-7% EtOAc in hexanes to give [3- (2-chloroethoxy) phenyl] acetic acid methyl ester as a colorless oil, 28.9 g (90%).

To a 1.0 L three-necked round bottom flask was added 150 mL of anhydrous THF and cooled to -78 ° C. N-Butyl lithium (2.5 M in hexane, 52.5 mL, 131 mmol) was added dropwise. to the bottle and its contents. Anhydrous CH3CN (7.2 mL, 138 mmol) in 150 mL of anhydrous THF is added dropwise to the flask with stirring and cooling. After stirring for 1 hour, 15 g of [3- (2-chloroethoxy) phenyl] -acetic acid methyl ester (66 mmol) in 20 mL of anhydrous THF is added dropwise to the resulting white colloidal mixture. in the jar. The reaction mixture is stirred for an additional 2 hours, followed by the addition of 4: 1 mixture of MeOH: AcOH at -78 ° C. The solution is diluted with 500 mL of water and extracted with EtOAc (4x150 mL). The organic layer is separated, dried with anhydrous MgSO 4, filtered, and concentrated in vacuo. The residual AcOH is ved by concentrating in vacuo with toluene. The residue is passed through silica gel with CH2Cl2 yielding 4- [3- (2-chloroethoxy) phenyl] -3-oxo-butyronitrile as an off-white solid, 16 g (99%).

To a stirred solution of 4- [3- (2-chloroethoxy) phenyl] -3-oxo-butyronitrile (16 g, 67 mmol) in 100 mL of anhydrous DMF is added DMF-DMA (17.6 g, 19.74 mL, 148 mmol ), triethylamine (9.4 mL, 67 mmol), and the solution is heated at 100 ° C for 2.5 hours. The reaction is concentrated in vacuo then dissolved in CH2CI2 and passed through Magnesol®. The crude material is then stirred with 3,4-dimethoxybenzylamine (1 mL, 74 mmol) in 100 mL of anhydrous toluene under reflux for 2 hours. The reaction is cooled, concentrated in vacuo, and purified by chromatography on silica gel eluting with EtOAc to yield 1.8 g (41%) of 5- [3- (2-chloroethoxy) phenyl] -1- (3, 4-dimethoxybenzyl) -4-oxo-1,4-dihydro-pyridine-3-carbonitrile as a whitish solid.

A solution of 5- [3- (2-chloroethoxy) phenyl] -1- (3,4-dimethoxybenzyl) -4-oxo-1,4-dihydro-pyridine-3-carbonitrile 52 (2.5 g, 5.9 mmol) and LiCl (2.3 g, 53 mmol) in 22 mL of POCI3 is heated at reflux for 2.5 hours. The excess of POCI3 is removed by concentrating in vacuo. The residue is dissolved in 100 mL CH2CI2 and washed with 3 N NaOH cooled with ice. The organic layer is separated, dried over anhydrous MgSO4, filtered, concentrated in vacuo, and purified by chromatography on silica gel eluting with 30% EtOAc in hexanes to yield 1.3 g of 4-chloro-5- [3 - (2-chloroethoxy) phenyl] nicotinonitrile as a whitish solid (75%).

To a stirred solution of 4-chloro-5- [3- (2-chloroethoxy) phenyl] nicotinonitrile (200 mg, 0. 68 mmol), 2,4-dichloro-5-methoxyaniline (196 mg, 1 mmol), 2-dicyclohexylphosphino 2 '(N, N-dimethylamino) biphenyl (80 mg, 0.20 mmol), and K3P0 (216 mg, 1 mmol ) Pd2 (dba) 3 (62 mg, 0.07 mmol) is added in 4 mL of ethylene glycol dimethyl ether anhydrous. The mixture is heated at 90 ° C for 2 hours then cooled, filtered through celite®, concentrated in vacuo, and purified by chromatography on silica gel eluting with 5-50% MeOH in CH 2 Cl 2 to give 160 mg of 5- [3- (2-chloroethoxy) phenyl] -4 - [(2,4-dichloro-5-methoxyphenyl) amino] nicotinonitrile 150 as a solid (52%). HPLC retention time (c): 14.29 min; MS: 448 [M + H].

A stirred solution of 5- [3- (2-chloroethoxy) phenyl] -4 - [(2,4-dichloro-5-methoxyphenyl) amino] nicotinonitrile 150 (138 mg, 0.31 mmol), pyrrolidine (66 mg, 0.93 mmol ) in 2.5 mL EtOH is heated at 105 ° C for 7 hours. The reaction is cooled then poured into 25 mL of water and cooled to 0 ° C. The solid is filtered and dried under vacuum at 50 ° C overnight to produce 32 mg of 4 - [(2,4-dichloro- 5-methoxyphenyl) amino] -5- [3- (2- pyrrolidin-1-ylethoxy) phenyl] nicotinonitrile 151 as a brown solid (21%). HPLC retention time (c): 6.21 min .; MS: 481 [M + H].

Example 12: Preparation of 5- [4- (dimethylamino) phenyl] -4 - [(3-nitrophenyl) amino] nicotinonitrile 152 4-Chloro-5- [4- (dimethylamino) phenyl] nicotinonitrile is prepared from 4- (dimethylamino) phenylacetic acid using procedures analogous to those described for the preparation of 4-chloro-5- (3-nitrophenyl) nicotinonitrile in Example 5. The resulting 4-chloro-5- [4- (dimethylamino) phenyl] nicotinonitrile is reacted with 3-nitroaniline following analogous procedures to those described for the preparation of compound 137 in Example 5 to produce 5- [4- (dimethylamino) phenyl] -4 - [(3-nitrophenyl) amino] nicotinonitrile 152.

Compound 152 is analyzed by HPLC under the following conditions: Column YMC C18, 4.6 x 500 mm, 5 microns; Mobile phase A: 90% water + 10% MeOH + 0.02% H3P04; Mobile phase B: 90% MeOH + 10% water + 0.02% H3P04; 1-100% of B in 2 min., Up to 10 min. 100% B, then 100-1% B in 1 min. HPLC retention time (c): 3.4 min; MS: 357.8 m / e (M-H).

Using procedures analogous to those described for the preparation of compound 147, compounds 153-158 in Table 5 are prepared starting from 3-methoxyphenylacetic acid.

Table 5 Example 13: Preparation of 5- (3,4-dimethoxyphenyl) -4 - [(3-hydroxyphenyl) amino] nicotinonitrile 159 This compound is prepared by heating 4-chloro-5- (3,4-dimethoxyphenyl) nicotinonitrile with 3-aminophenol in ethanol in a sealed bottle at 90 ° C. HPLC retention time (c): 6.4 min .; MS: 348.1 m / e (M-H).

Example 14: Preparation of 5- (3,4-dimethoxyphenyl) -4-. { [3- (2-hydroxyethoxy) phenyl] amino} nicotinonitrile 160 To a mixture of 5- (3,4-dimethoxyphenyl) -4 - [(3-hydroxyphenyl) amino] nicotinonitrile 159 (100 mg, 0.29 mmol) and 2-bromoethanol (55 mg , 0.44 mmol) in DMF (2 ml_) is added cesium carbonate (143 mg, 0.44 mmol). The resulting mixture is heated at 100 ° C overnight, cooled to room temperature and purified by reverse phase HPLC (eluting with a gradient of 95% to 5% water / acetonitrile containing 1% TFA) to give 20 mg (12%) of 5- (3,4-dimethoxyphenyl) -4-. { [3- (2-hydroxyethoxy) phenyl] amino} nicotinonitrile 160 as a cream solid. HPLC retention time (c): 6.5 min .; MS: 392.1 m / e (M + H).URA Example 15: Preparation of 4 - [(3. {[[(2S) -2-amino-3-phenylpropM] -oxi.]. Phenyl) amino] -5- (3,4-dimethoxyphenyl) nicotinonitrile 161 To a mixture of 5- (3,4-dimethoxyphenyl) -4 - [(3-hydroxyphenyl) amino] nicotinonitrile 159 (100 mg, 0.29 mmol) and tert-butyl (1 S) -1-benzyl-2-hydroxyethylcarbamate ( 73 mg, 0.35 mmol), triphenylphosphine (91 mg, 0.35 mmol) in THF (1.0 mL) is added diethylazodicarboxylate (61 mg, 0.35 mmol) at room temperature. The reaction mixture is stirred at room temperature overnight. Additional triphenylphosphine (91 mg, 0.35 mmol) and diethylazodicarboxylate (61 mg, 0.35 mmol) are added. After stirring at room temperature for a further 24 hours, the resulting mixture is treated with TFA (0.4 mL) at 70 ° C overnight and purified by reverse phase HPLC (eluted with a 95% to 5% water gradient). / acetonitrile containing 1% TFA) to give 15 mg (11%) of 4 - [(3- {[[(2S) -2-amino-3-phenylpropyl] -oxi.}. -phenyl) amino ] -5- (3,4-dimethoxyphenyl) nicotinonitrile 161 as a cream solid. HPLC retention time (c): 6.8 min .; MS: 481.3 m / e (M + H).

Example 16: Preparation of 4 - [(2-chloro-5-hydroxyphenyl) amino] -5- (5-formyl-1-benzothien-2-yl) nicotinonitrile 162 A mixture of 3-aminobut-3-enenitrile (100 g, 1.22 mol) and HCl conc. (125 mL) in water (125 mL) is heated at 80 ° C for 2 hours, cooled to room temperature and filtered to remove the solid. The filtrate is extracted with ethyl acetate and the combined extracts are dried over sodium sulfate, filtered and concentrated to give a semi-solid residue which is distilled under vacuum to give 77.4 g (76%) of acetoacetonitrile (73-77). ° C / 3-5 mmHg).

A mixture of acetoacetonitrile (41 g, 493 mmol), t-butoxybis (dimethylamine) methane (86 g, 493 mmol) and?,? - dimethylformamide dimethyl acetal (263 ml_, 1.97 mol) is heated to 100 °. C overnight and evaporate to remove volatiles. The residue is trited with hexanes / ether (1: 1) and the solids are collected by filtration and washed with hexanes / ether (1: 1) and a minimum amount of ethyl acetate to give 64.3 g (67%) of - (dimethylamino) -2 - [(dimethylamino) methylene] -3-oxopent-4-enenitrile as a light yellow solid, which is used in the next step without further purification.

A mixture of 5- (dimethylamino) -2 - [(dimethylamino) methylene] -3-oxopent-4-enenitrile (64.3 g, 333 mmol) and ammonium acetate (126 g, 1.66 mol) in ethanol (1.8 L) was added. heat to reflux for 60 hours and concentrate to remove the solvent. The resulting semi-solid residue is diluted with ethyl acetate, filtered and washed with ethyl acetate followed by CH2Cl2. The filtrate is evaporated at a reduced volume. The precipitated solids are collected by filtration, washed with ethyl acetate and a minimum amount of ethanol to produce 4-hydroxynicotinonitrile. The evaporation and crystallization process is repeated to obtain more solid 4-hydroxynicotinonitrile from the mother liquor. The combined whitish solids provide 20.9 g (53%). P.f. 234-236 ° C.

An alternate synthesis of 4-hydroxynicotinonitrile is reported in the literature. Broekman, F.W. et al., Recueil des Travaux Chimiques des Pays-Bas, 81: 792-6 (1962).

A mixture of 4-hydroxynicotinonitrile (45.7 g, 381 mmol), iodine (96.6 g, 381 mmol) and NaOH (19.8 g, 825 mmol) in water (600 mL) is heated at 85 ° C overnight, cooled to room temperature and diluted with water. The precipitate is collected by filtration and washed with water to give 57.5 g (61%) of 4-hydroxy-5-iodonotinonitrile as a tan solid, mp > 245 ° C.

A mixture of 4-hydroxy-5-iodonicotinonitrile (57.5 g, 234 mmol) and POCI3 (200 mL) is heated at 100 ° C for 2 hours, cooled to room temperature and evaporated to remove excess POCI3. The residue is cooled in an ice water bath, adjusted to pH 8-9 with 10 N aqueous NaOH and extracted with EtOAc. The combined organics are washed with water and saline, dried over MgSO4, filtered and concentrate The resulting solid residue is washed with a minimum amount of MeOH and CH2Cl2 to give 46.5 g (75%) of 4-chloro-5-iodonotinonitrile as a tan solid, mp 120-122 ° C.

A mixture of 4-chloro-5-iodonotinonitrile (2.0 g, 7.6 mmol) and 2-chloro-5-hydroxyaniline (1.09 g, 7.6 mmol) in EtOH (20 mL) is heated at 90 ° C in a sealed flask during the overnight, it is poured into aqueous NaHC03 and filtered. The crude solid is washed with water and dried to provide 3.0 g (quantitative yield) of 4 - [(2-chloro-5-hydroxyphenyl) amino] -5-iodonotinonitrile as a brown solid, which is used for the next step without additional purification. MS (M + H): 372.1.

A mixture of 4 - [(2-chloro-5-hydroxyphenyl) amino] -5-iodonotinonitrile (500 mg, 1.35 mmol), 2- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan- 2-yl) benzo [b] thiophene-5-carbaldehyde (389 mg, 1.35 mmol) and Pd (PPh3) 4 (78 mg, 0.070 mmol) in DME (10 mL) and NaHCO 3 (aq, 2M, 1.4 mL) were heat at 80 ° C overnight, cool to room temperature and concentrate at a reduced volume. The residue is partitioned between EtOAc and water. The combined organics are dried over Na 2 SO 4, filtered, concentrated and purified by column chromatography on silica gel to give 160 mg (30%) of 4 - [(2-chloro-5-hydroxyphenyl) amino] -5- (5-formyl-1-benzothien-2-yl) nicotinonitrile 162 as a yellow solid, MS (M + H): 406.2; HPLC retention time (c): 11.7 min ..

Example 17: Preparation of 4 - [(2-chloro-5-hydroxy-phenyl) amino] -5- [5- (piperidin-1-ylmethyl) -1-benzothien-2-yl] nicotinonitrile 163 To a mixture of 4 - [(2-chloro-5-hydroxyphenyl) amino] -5- (5-formyl-1-benzothien-2-yl) nicotinonitrile 162 (130 mg, 0.32 mmol) and piperidine (82 mg, 0.96) mmol) in THF (5.0 mL) was added AcOH (106 mg, 1.76 mmol). The resulting mixture is stirred at room temperature for one hour and sodium triacetoxyborohydride (203 mg, 0.96 mmol) is added. After stirring at room temperature overnight, the reaction mixture is concentrated and purified by column chromatography on silica gel to give 105 mg (69%) of the title compound as a pale yellow solid. HPLC retention time (c): 7.8 min .; MS: 475.1 m / e (M + H).

Compound 164 in Table 6 is prepared following procedures analogous to those described for the preparation of compound 160 in Example 14. Compounds 165 and 166 are prepared by coupling intermediate 66 with the appropriate aniline then treating with 2- (4 , 4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) benzo [b] thiophene-5-carbaldehyde following the procedures analogous to those described for the preparation of compound 162 described in Example 16, followed by reductive amination following the procedures of compound 163, Example 17.

Table 6 Example 18: Preparation of 4-chloro-5-iodo-1-oxy-nicotinonitrile To a solution of 4-chloro-5-iodo-nicotinonitrile (529 mg, 2.0 mmol) in TFA (5 mL) is added H202 (30% by weight in H20, 5 mL). The reaction mixture is stirred at room temperature overnight, heated at 50 ° C for 8 h, and concentrated. To the residue is added saturated aqueous NaHCO3 (10 mL) followed by extraction with EtOAc / THF. The organic extracts are washed with water, dried over Na 2 SO 4, filtered, and concentrated. The residue is purified by flash chromatography (CH2Cl2-THF = 10: 1) to give 202 mg (36%) of 4-chloro-5-iodo-1-oxy-nicotinonitrile as a pale yellow solid.

Example 19: Preparation of 4-fluoro-5- [3-methoxy-4- (2-methoxyethoxy) phenyl] nicotinonitrile 4-Chloro-5- (3,4-dimethoxyphenyl) nicotinonitrile (7.3 mmol, 2.0 g) is dissolved in 70 ml_ DMF and treated with CsF (14.6 mmol, 2.2 g). After heating for 2 h at 80 ° C, an additional 7 mmol (1 g) of CsF is added and heating is continued overnight. The suspension is evaporated on silica gel and the product is purified by chromatography (EtOAc / Hex) to give 300 mg of 4-fluoro-5- [3-methoxy-4- (2-methoxyethoxy) phenyl] nicotinonitrile.

Example 20: Preparation of 1-benzofuran-5-carbaldehyde To a solution of 1-benzofuran-5-carbonitrile (5.0 g, 34.9 mmol) in CH2Cl2 under nitrogen at -15 to -20 ° C is added DIBAL-H (41.9 ml_, 41.9 mmol, 1 M / heptane) and the temperature it stays below -15 ° C. After the addition is complete, the reaction mixture is stirred at -15 to -20 ° C for an additional 10 min. The reaction mixture is quenched by the dropwise addition of aqueous 2N HCl. The organic layer is separated and washed with water, dried over sodium sulfate, and concentrated to give 4.0 g (78%) of 1-benzofuran-5-carbaldehyde as a yellow oil.

Example 21: Preparation of dimethyl 5- (piperidin-1-methylmethyl) benzofuran-2-ylboronate 1-Benzofuran-5-carbaldehyde is treated with piperidine and sodium triacetoxyborohydride under standard reductive amination procedures to provide 1- (5-benzofuranoylmethyl) piperidine. Treatment of 1- (5-benzofuranoylmethyl) piperidine with butyl lithium and trimethyl borate at low temperature affording dimethyl 5- (piperidin-1-ylmethyl) benzofuran-2-ylboronate. Compounds 167-169, 171, and 172 in Table 7 are provided following procedures analogous to those described in Scheme 10 when coupling with dimethyl 5- (piperidin-1-ylmethyl) benzofuran-2-ylboronate.

Table 7 Example 22: Preparation of 4-. { [3- (aminomethyl) benzyl] amino} -5- (3,4-dimethoxyphenyl) nicotinonitrile 170 A mixture of 4-chloro-5- (3,4-dimethoxyphenyl) nicotinonitrile (74 mg, 0.27 mmol), 1,3-phenylenedimethanamine (54 mg, 0.40 mmol) and triethylamine (40 mg, 0.40 mmol) in 3 mL of DMF is heated at 60 ° C overnight. After cooling to room temperature, the reaction is concentrated to dryness and the residue is dissolved in 3 mL DMSO, filtered, and purified by preparative HPLC to give 4-. { [3- (aminomethyl) benzyl] amino} -5- (3,4-dimethoxyphenyl) nicotinonitrile. HPLC retention time (d): 1.33 min; MS: 375.2 m / e (M + H).

Example 23: Pharmacological Test Evaluation of the representative compounds of the present teachings in various standard pharmacological test procedures indicates that the compounds are inhibitors of PKC0. Based on the activity shown in the standard pharmacological test procedures, the compounds of the current teachings both are useful as anti-inflammatory agents.

A radioactive kinase assay for the inhibition of the active quinase (KD) domain of PKCQ This assay is based on the phosphorylation of a biotinylated substrate by a kinase radiolabel used ATP (ATP? P33). The substrate is a biotinylated peptide with a biotin-F sequence ARKGSLRQ-C (0) NH2. The enzyme purifies the full-length recombinant active kinase domain PKC theta (amino acids 362-706). The assay buffer is composed of 100mM Hepes, pH7.5, 2mM MgCl2, 20mM ß-glycerophosphate and 0.008% TritonX 100. A reaction mixture of ATP, ATP and P33 (PerkinElmer). DTT, and the enzyme is prepared in the assay buffer and added to a 96-well polypropylene dish. The compound (diluted in DIVISO in a separate 96-well polypropylene dish) is added to the reaction mixture and incubated at room temperature. Following the incubation, the peptide substrate is added to the reaction mixture to initiate the enzymatic reaction. The reaction is terminated with the addition of a stop solution (100mM EDTA, 0.2% TritonXlOO, and 20mM NaHPCX) and transferred from the assay dish to a streptavidin wash covered with 96-well belt (PerkinElmer). The belt is incubated at room temperature, washed in PBS with 0.1% TritonX 100, and counted in the 1450 Microbeta Trilux (Wallac, Version 2.60). The counts are recorded for each well as correct counts per minute (CCPM). The counts are considered correct because they are adjusted according to a P33 normalization protocol, which is correct for the efficiency and background differences between the instrument's detectors (software version 4.40.01).

A radioactive kinase assay for the inhibition of full length inhibitors (FL) P C0 This assay differs from what was previously described in that the enzyme used purifies recombinant full length PKC theta (Panvera, P2996).

IMAP PKCQ trial The materials used include the following: human full-length KCO enzyme (Panvera Cat # P2996); peptide substrate: 5FAM-RFARKGSLRQKNV-OH (Molecular Devices, RP7032); ATP (Sigma Cat # A2383); DTT (Pierce, 20291); 5x kinase reaction buffer (Molecular Devices, R7209); 5x A-binding buffer (Molecular Devices, R7282), 5x B-binding buffer (Molecular Devices, R7209); IMAP globules (Molecular Devices, R7284); and plates of 384 wells (Maízing Costar, 3710).

The reaction buffer is prepared by diluting the 5x mother-reaction buffer and adding the DTT to obtain a 3.0 mM concentrate. The joint damper is prepared by diluting the union shock absorber A 5x. A masterbatch solution is prepared using a 90% dilution of reaction buffer containing 2x ATP (12uM) and 2x peptide (200nm). The compounds are diluted in DMSO at 20x of the maximum concentrate for the IC50 measurement. The master mix solution of 27 μ? for each curve IC50 is added to the first column in a plate of 384 wells and 3 μ? 20x of the compound in DMSO is added to each well. The final concentrate of the compound is 2x and 10% DMSO. The DMSO is added to the rest of the master mix to increase the concentrate to 10%. 10 μ? of the master mix containing 10% DMSO is added to the rest of the wells in the plate except the second column. 20 μ? from the first column to the second column. The compounds are serially diluted 2: 1 of the starting ratio of the second column. A 2x (2 nM) PKC0 solution is made in the reaction buffer. 10 μ? of the PKCO solution is added to each well to achieve this final concentration: PKCO - 1 nM; ATP - 6 μ ?; peptide - 100 nM; DMSO - 5%. The samples are incubated for 25 minutes at room temperature. The binding reagent is prepared by diluting the beads in the assay buffer 1x to 800: 1. 50 μ? of the binding reagent is added to each well and incubated for 20 minutes. FP is measured using Envision2100 (PerkinElmer Life Sciences). Wells without ATP and wells without enzymes are used as controls.

The result obtained is summarized in Table 21 below. The data presented represent the average value when testing one or more samples. Table 8 IC50 number PKC9 KD IC50 PKC9 FL IC50 PKC9 IMAP Compound (MU) (μ?) (UM) 101 6.87 N / AN / A 104 0.60 N / AN / A 105 10.60 N / AN / A 106 0.84 N / AN / A 107 2.91 N / AN / A 108 2.77 N / AN / A 109 0.81 N / AN / A 110 1.16 N / AN / A 111 1.41 N / AN / A 113 3.60 N / AN / A 114 0.40 N / AN / A 1 15 4.26 0.38 N / A 1 16 3.20 N / AN / A 117 13.80 N / AN / A 1 18 4.44 N / AN / A 1 19 1 1.70 N / A 1.95 122 1036 N / AN / A 123 38.00 N / AN / A 126 0.34 N / AN / A 127 N / AN / A 0.57 128 N / AN / A 35 129 N / AN / A 36 130 N / AN / A 0.80 131 N / AN / A 0.71 133 N / AN / A 30.0 134 N / AN / A 2.03 135 5.0 N / AN / A 137 0.19 0.16 0.18 138 N / A 0.32 N / A 139 N / A 8.00 N / A 140 N / A 9.75 N / A 141 N / A 0.16 0.10 142 214 N / AN / A 144 158 N / AN / A 146 3.85 N / AN / A 148 N / A 0.52 N / A 149 N / A 7.09 N / A 150 N / A 0.50 N / A 151 N / A 7.10 N / A 152 N / AN / A 7.84 153 N / A AN / A 9.63 154 N / AN / A 1.73 155 N / AN / A 1.57 156 N / AN / A 46.4 157 N / AN / A > 95 158 N / AN / A 2.40 159 N / AN / A 0.31 160 N / AN / A 5.21 161 N / AN / A 0.82 162 N / AN / A 0.03 163 N / AN / A 0.03 164 N / AN / A 0.06 165 N / AN / A 0.65 166 N / AN / A 1.06 167 N / AN / A 0.73 168 N / AN / A 2.04 169 N / AN / A 0.65 170 N / AN / A 11.90 171 N / AN / A 0.27 172 N / AN / A 0.16 Variations, modifications, and other implementations of what is described herein will be apparent to those skilled in the art without departing from the spirit and essential features of current teachings. Accordingly, the scope of the present invention is not defined by the preceding illustrative description but by the following claims, and all changes within the meaning and range of equivalence of the claims are intended to be encompassed therein.

Claims (5)

CLAIMS A compound of formula I or formula G: or a pharmaceutically acceptable salt, hydrate, or ester thereof, wherein: X is selected from a) -NR3-Y-, b) -OY-, c) -S (0) mY-, d) -S (0) mNR3-Y-, e) -NR3S (0) mY-, f) -C (0) NR3-Y-, g) -C (S) NR3-Y-, h) -NR3C (0) -Y-, i) -NR3C (S) -Y-, j) -C (0) 0-Y-, k) -OC (0) -Y-, and I) a covalent bond; And, at each occurrence, a) a divalent C1.10 alkyl group, b) a divalent C2-i0 alkenyl group, c) a divalent C2-io alkynyl group, d) a divalent C0 haloalkyl group, is selected independently from a) and e) a covalent bond; R1 is a phenyl group optionally substituted with 1-4 Y-R4 groups; R2 is a C6-I4 aryl group or a 5-14 membered heteroaryl group, wherein each group is optionally substituted with 1-4 independently selected groups of -Y-R4 or -O-Y-R4; R3 is selected from a) H, b) a Ci- 0 alkyl group, c) a C2.i0 alkenyl group, d) a C2-io alkynyl group, and e) a C1- 0 haloalkyl group; R4, in each occurrence, is independently selected from a) halogen, b) -NC, c) -NOz, d) oxo, e) -OY-R5, f) -NR6-Y-R7, g) -N (0) ) R6-Y-R7, h) - S (0) mY-R5, i) -S (0) mO-Y-R5, j) -S (0) mNR6-Y-R7, k) -C (0) -Y-R5, I) -C (0) 0-Y-R5, m) -C (0) NR6-Y-R7, n) -C (S) NR6-Y-R7, o) a C1-10 alkyl group, p) a C2 alkenyl group -io, q) a C2.io alkynyl group, r) a C1-10 haloalkyl group, s) a C3-14 cycloalkyl group, t) a C6-14 aryl group, u) a cycloheteroalkyl group of 3-14 members, and v) a 5-14 membered heteroaryl group, wherein each of o) - v) is optionally substituted with 1-4 Y-R8 groups; in each occurrence, it is independently selected from a) H, b) -C (0) R9, c) -C (0) OR9, d) a C1-10 alkyl group, e) a C2-io alkenyl group, f) a C2-io alkynyl group, g) a C1.10 haloalkyl group, h) a C3-4 cycloalkyl group, i) a C6-i4 aryl group, j) a cycloheteroalkyl group of 3-14 members, and k) a heteroaryl group of 5-14 members, wherein each of d) -k) is optionally substituted with 1-4 groups Y-R8; / R7, in each occurrence, are independently selected from a) H, b) -O- Y-R9, c) -S (0) mY-R9, d) -S (0) mO-Y-R9, e) -C (0) -Y-R9, f) -C (0) 0-Y- R9, g) -C (O) NR 0-Y-R11, h) -C (S) NR10-Y-R11, i) a C1-10 alkyl group, j) a C2-i0 alkenyl group, k) a C2-i0 alkynyl group, I) a CMO haloalkyl group, m) a C3.14 cycloalkyl group, n) a C6 aryl group. i4, o) a cycloheteroalkyl group of 3-14 members, and p) a 5-14 membered heteroaryl group, wherein each of i) -p) is optionally substituted with 1-4-Y-R8 groups; R8, in each occurrence, is independently selected from a) halogen, b) -NC, c) -N02, d) oxo, e) -OY-R9, f) -NR10-Y-R11, g) -N (O ) R10-Y-R11, h) -S (0) mY-R9, i) -S (0) mO-Y-R9, j) -S (O) mNR10-Y-R11, k) -C (0) ) -Y-R9, I) -C (0) 0-Y-R9, m) -C (O) NR10-Y-R11, n) -C (S) NR10-Y-R11, o) an alkyl group Ci.i0, p) a C2-i0 alkenyl group, q) a C2-0 alkynyl group, r) a C1-10 haloalkyl group, s) a C3-14 cycloalkyl group, t) an aryl group C6-i4, ) a cycloheteroalkyl group of 3-14 members, and v) a 5-14 membered heteroaryl group, wherein each of o) - v) is optionally substituted with 1-4 Y-R12 groups; in each occurrence, it is independently selected from a) H, b) -C (O) -C1-10 alkyl, c) -C (0) OH, d) -C (0) 0-C1-10 alkyl, e) a C1-10 alkyl group, f) a C2-io alkenyl group, g) a C2-i0 alkynyl group, h) a C1-10 haloalkyl group, i) a C3-14 cycloalkyl group, j) a C6 aryl group, 14, k) a cycloheteroalkyl group of 3-14 members, and I) a 5-14 membered heteroaryl group, wherein each of the Ci-10 alkyl group, the C2-io alkenyl group, the C2-io alkynyl group, the haloalkyl group Ci-10, the cycloalkyl group C3-14, the aryl group C6-i, the cycloheteroalkyl group of 3-14 members, and the heteroaryl group of 5-14 members is optionally substituted with 1-4 groups -Y- R12; and R11, in each occurrence, are independently selected from a) H, b) -OH, c) -SH, d) -NH2, e) -NH-C1-10 alkyl, f) -N (C1-10 alkyl) 2, g) -S (0) m- C1-10 alkyl, h) -S (0) 2OH, i) -S (0) m-O-C 1-10 alkyl, j) -C (0) -C 1-10 alkyl, k) -C (0) OH, I) -C (0) -C 1-10 alkyl, m) -C ( 0) NH2, n) -C (0) NH-alkyl d. 10, o) -C (0) N (C 1-10 alkyl) 2, P) -C (S) NH 2, q) -C (S) NH-C 1-10 alkyl, r) -C (S) N ( C1-10 alkyl) 2, s) a C1_0 alkyl group, t) a C2-0 alkenyl group, u) a C2-10 alkynyl group, v) a C -10 alkoxy group, w) a haloalkyl group Ci. 10, x) a C3-1 cycloalkyl group, and) a C6-14 aryl group, z) a cycloheteroalkyl group of 3-14 members, and aa) a 5-14 membered heteroaryl group, wherein each of the alkyl group Ci_10, the C2-10 alkenyl group, the C2-10 alkynyl group, the C1-10 alkoxy group, the C10 haloalkyl group, the C3.14 cycloalkyl group, the C6-14 aryl group, the cycloheteroalkyl group of 3- 14 members, and the heteroaryl group of 5-14 members is optionally substituted with 1-4 groups -Y-R12; in each occurrence, it is independently selected from a) halogen, b) -CN, c) -N02, d) oxo, e) -OH, f) -NH2, g) -NH (C1-10 alkyl), h) - N (Ci-10 alkyl) 2,) -SH, j) -S (0) m-C 1-10 alkyl, k) -S (0) 2OH, I) -S (0) m-Oalkyl C ,. 10, m) -C (0) -C 1-10 alkyl, n) -C (0) OH, o) -C (0) -C 1-10 alkyl, p) -C (0) NH 2, q) -C (0) NH-C 1-10 alkyl, r) -C (0) N (C 1-10 alkyl) 2, s) -C (S) NH 2, t) -C (S) NH-C-10 alkyl, ) -C (S) N (C1-10 alkyl) 2l v) a C1-10 alkyl group, w) a C2-10 alkenyl group, x) a C2-10 alkynyl group, and) a C1-10 alkoxy group, z) a C1-10 haloalkyl group, aa) a C3-4 cycloalkyl group, ab) a aryl group C6-i, ac) a cycloheteroalkyl group of 3-14 members, and ad) a heteroaryl group of 5-14 members; Y m is 0, 1, or 2; since when R1 is a 3-chloro-4-fluorophenyl group, R2 is not a 2- [(1 H-imidazol-5-ylmethyl) amino] phenyl group. The compound of claim 1 or a pharmaceutically acceptable salt, hydrate, or ester thereof, wherein X is selected from -NH-, -N (CH3) -, -NH- CH2-, -NH-CH2CH2-, -NH -CH2CH2CH2-, -O-, and a covalent bond. The compound of claim 1 or 2 or a pharmaceutically acceptable salt, hydrate, or ester thereof, wherein R1 is selected from: The compound of any one of claims 1-3 or a pharmaceutically acceptable salt, hydrate, or ester thereof, wherein R4, at each occurrence, is independently selected from -F, -Cl, -Br, -CN, -N02 , - OY-R5, -C (0) -Y-R5, -C (0) 0-Y-R5, -NR6-Y-R7, and a C1-6 alkyl group. The compound of any one of claims 1-4 or a pharmaceutically acceptable salt, hydrate, or ester thereof, wherein R2 is selected from a phenyl group, a C8.14 aryl group and a 5-14 member heteroaryl group, wherein each group is optionally substituted with 1-4 independently selected groups of -Y-R4 and -OY-R4. The compound of any one of claims 1-5 or a pharmaceutically acceptable salt, hydrate, or ester thereof, wherein R2 is: wherein D1, D2, and D3 independently are H, a group -Y-R4, or a group -O-Y-R4. The compound of claim 6 or a pharmaceutically acceptable salt, hydrate, or ester thereof, wherein at least one of D1, D2, and D3 is a group -Y-R4 or a group -OY-R4, wherein Y, in each occurrence, independently it is a divalent C1-4 alkyl group or a covalent bond, and R4, in each occurrence, is independently selected from a halogen, -CN, N02, ^ OY-R5, -NR6-Y- R7, - S (0) 2-Y-R5, -S (0) 2NR6-Y-R7, -C (0) -Y-R5, -C (0) 0-Y-R5, -C (0) NR6-Y - R7, a C1-O alkyl group, a haloalkyl group Ci.i0, a C3-14 cycloalkyl group, a C6-1 aryl group, a 3-14 membered cycloheteroalkyl group, and a 5-14 membered heteroaryl group, wherein 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 it is optionally substituted with 1-4 Y-R8 groups. The compound of claim 7 or a pharmaceutically acceptable salt, hydrate, or ester thereof, wherein the group -Y-R4 and the group -OY-R4 are selected from -0- (CH2) nNR6-Y-R7, - (CH2) nNR6-Y-R7, a -0- (CH2) n-cycloheteroalkyl group of 3-14 members, and a - (CH2) n-cycloheteroalkyl group of 3-14 members, wherein each of the cycloheteroalkyl group from 3-14 members is optionally substituted with 1-4 Y-R groups, and n, in each occurrence, independently is 0, 1, 2, 3, or 4. The compound of claim 8 or a pharmaceutically acceptable salt, hydrate, or ester thereof, wherein the cycloheteroalkyl group of 3-14 members of the group -0- (CH2) n-cycloheteroalkyl of 3-14 members and the group - (CH2) 3-14 membered n-cycloheteroalkyl is selected from a pyrrolidinyl group, a morpholinyl group, a piperazinyl group, a piperidinyl group, an azepanyl group, a diazepanyl group, and a thiomorpholinyl group. The compound of claim 7 or a pharmaceutically acceptable salt, hydrate, or ester thereof, wherein the group -Y-R4 and the group -O-Y-R4 are wherein R, in each occurrence, is independently selected from -OY-R9, -NR10-Y-R11, an aryl group C6-i4, and a heteroaryl group of 5-14 members, wherein the aryl group C6-1 and the 5-14 membered heteroaryl group is optionally substituted with 1-4 Y-R12 groups, and n, at each occurrence, independently is 0, 1, 2, 3, or 4. The compound of any one of claims 7-10 or a pharmaceutically acceptable salt, hydrate, or ester thereof, wherein at least one of D, D2, and D3 is selected from a halogen, -CN, -N02, - S (0) 2-Y-R5, -S (0) 2NR6-Y-R7, -C (0) 0-Y-R5, -C (0) NR6-Y-R7, a CMO alkyl group, and a haloalkyl group d.i0. The compound of any one of claims 7-1 1 or a pharmaceutically acceptable salt, hydrate, or ester thereof, wherein at least one of D1, P2, and D3 is a C6-aryl group or a heteroaryl group of -14 members, where each group is optionally substituted with 1-4 groups Y-R8. The compound of claim 12 or a pharmaceutically acceptable salt, hydrate, or ester thereof, wherein at least one of D1, D2, and D3 is 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 group is optionally substituted with 1-4 Y-R8 groups, and, at each occurrence, is independently a C -4 alkyl group or a covalent bond, and R8 , in each occurrence, is independently selected from halogen, -CN, -N02, -OY-R9, -NR10-Y-R11, -C (0) -Y-R9, -C (O) NR 0-Y-R11 , -S (0) 2-Y-R9, -S (0) 2NR1 ° -Y-R11, and a cycloheteroalkyl group of 3-14 members optionally substituted with a C1-4 alkyl group. The compound of any one of claims 1-5 or a pharmaceutically acceptable salt, hydrate, or ester thereof, wherein R2 is a C8-14 bicyclic aryl group or a 5-14 membered heteroaryl group, wherein each of the bicyclic aryl group C8-i4 and the 5-14 membered heteroaryl group is optionally substituted with 1-4 independently selected groups of -Y-R4 and -OY-R4. The compound of claim 14 or a pharmaceutically acceptable salt, hydrate, or ester thereof, wherein R2 is selected from a pyridyl group, a pyrimidyl group, a pyrazinyl group, a furyl group, a thienyl group, a thiazolyl group, a oxazolyl group, a benzofuranoyl group, a benzothienyl group, an indolyl group, a benzodioxinyl group, a benzodioxolyl group, a benzodioxanolo group, a dibenzofuranoyl 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 group is optionally substituted with 1-4 groups independently selected from - (CH2) n-R4 and -0- (CH2) n-R4, where n, in each occurrence, independently is 0, 1, 2, 3, or 4, and R4, in each occurrence, independently is -NR6- Y-R7 or a cyclohec group 3-4 membered teroalkyl optionally substituted with a group -Y-R8. A compound of claim 1 selected from the following compounds: 4- [(3-chlorophenyl) amino] -5- (3,4-dimethoxyphenyl) nicotinonitrile, 5- (3,4-dimethoxyphenyl) -4 - [(3-fluoro phenyl) amino] nicotinonitrile, 4-anilino-5 - (3,4-dimethoxyphenyl) nicotinonitrile, 4- [(2,5-difluorophenyl) amino] -5- (3,4-dimethoxyphenyl) nicotinonitrile, 5- (3,4-dimethoxyphenyl) -4 - [(3, 4-dimethoxyphenyl) amino] nicotinonitrile, 4 - [(4-chloro-2-fluorophenyl) amino] -5- (3,4-dimethoxyphenyl) nicotinonitrile, 4 - [(3-chloro-4-fluorophenyl) amino] -5 - (3,4-dimethoxyphenyl) nicotinonitrile, 4- [(4-chlorophenyl) amino] -5- (3,4-dimethoxyphenyl) nicotinonitrile, 5- (3,4-dimethoxyphenyl) -4 - [(2,4- dimethylphenyl) amino] nicotinonitrile, 5- (3,4-dimethoxyphenyl) -4 - [(4-methoxyphenyl) amino] nicotinonitrile, 4- [(3-chloro-4-methoxyphenyl) amino] -5- (3,4- dimethoxyphenyl) nicotinonitrile, 5- (3,4-dimethoxyphenyl) -4 - [(4-phenoxy phenyl) amino] nicotinonitrile4- [(2,5-Dichlorophenyl) amino] -5- (3,4-dimethoxyphenyl) nicotinonitrile, 5- (3,4-dimethoxyphenyl) -4 - [(4-methoxy-2-methylphenyl) amino] nicotinonitrile , 4 - [(3,4-dichlorophenyl) amino] -5- (3,4-dimethoxyphenyl) nicotinonitrile, 4 - [(5-chloro-2-methoxyphenyl) amino] -5- (3,4-dimethoxyphenyl) nicotinonitrile , 4- . { [3- (benzyloxy) phenyl] amino} -5- (3,4-dimethoxyphenyl) nicotinonitrile, 5- (3,4-dimethoxyphenyl) -4 - [(4-methyl phenyl) amino] nicotinonitrile, 5- (3,4-dimethoxyphenyl) -4 - [(3 , 4,5-trimethoxyphenyl) amino] nicotinonitrile, 5- (3,4-dimethoxyphenyl) -4 - [(3-phenoxy phenyl) amino] nicotinonitrile, 4 - [(2-chloro-5-methoxyphenyl) amino] -5- (3,4-dimethoxyphenyl) nicotinonitrile, 4- (. {3-chloro-4 - [(3-cyanobenzyl) oxy] phenyl} amino) -5- (3,4-dimethoxyphenyl) nicotinonitrile, 4- ( { 3-chloro-4 - [(3-methylbenzyl) oxy] phenyl.}. Amino) -5- (3,4-dimethoxyphenyl) nicotinonitrile, 4 - [(3-chloro-4-. { . [3- (dimethylamino) benzyl] oxy} phenyl) amino] -5- (3,4-dimethoxyphenyl) nicotonitrile, 4- [(2,4-dichlorophenyl) amino] -5- (3,4 -methoxyphenyl) nicotinonitrile, N- (3 { [3-cyano-5- (3,4-dimethoxyphenyl) pyridin-4-yl] amino.} phenyl) acetamide, N- (3- { [ 3-cyano-5- (3,4-dimethoxyphenyl) pyridin-4-yl] amino.}. Phenyl) -N-methylacetamide, N- (3 { [3-cyano-5- (3,4- dimethoxyphenyl) pyridin-4-yl] amino.}. phenyl) methanesulforiamide, 5- [4- (dimethylamino) phenyl] -4 - [(3-methoxyphenyl) amino] nicotinonitrile, 5- [4- (dimethylamino) phenyl] -4 - [(3-fluorophenyl) amino] nicotinonitrile, 4- ( {. 3-cyano-5- [4- (dimethylamino) phenyl] pyridin-4-yl} amino) benzoic acid, 4 - [(4-cyanophenyl) amino] -5- [4- (dimethylamino) phenyl] nicotinonitrile, 4 - [(3,4-difluorophenyl) amino] -5- [4- (dimethylamino) phenyl] nicotinonitrile, 4 - [(3-bromophenyl) amino] -5- (3,4-dimethoxyphenol) nicotinone Trilo, 4-. { [3- (benzyloxy) -4-chlorophenyl] amino} -5- (3,4-dimethoxyphenyl) nicotinonitrile, 4 - [(2,4-dichloro-5-methoxyphenyl) amino] -5- (3,4-dimethoxyphenyl) nicotinonitrile, 4 - [(2,4-dichloro- 5-ethoxyphenyl) amino] -5- (3,4-dimethoxyphenyl) nicotinonitrile, 4 - [(2,4-dichloro-5-propoxyphenyl) amino] -5- (3,4-dimethoxyphenyl) nicotinonitrile, 4 - [( 5-butoxy-2,4-dichlorophenyl) amino] -5- (3,4-dimethoxyphenyl) nicotinonitrile, 4-. { [2,4-dichloro-5- (2-hydroxyethoxy) phenyl] amino} -5- (3,4-dimethoxyphenyl) nicotinonitri 4-. { [4- (benzyloxy) -3-chlorophenyl] amino} -5- (3-nitro phenyl) nicotinonitrile, 4-. { [3-chloro-4- (pindin-2-ylmethoxy) phenyl] amino} -5- (3-nitrophenyl) nicotinonitrile, 4- [(3-chloro-4-fluorophenyl) amino] -5- (3-nitrophenyl) nicotinonitrile, 5- (3-aminophenyl) -4-. { [4- (benzyloxy) -3-chlorophenyl] amino} nicotinonitrile, 4- [(3-chloro-4-fluorophenyl) amino] -5- (2-nitrophenyl) nicotinonitrile, 5- (2-aminophenyl) -4 - [(3-chloro-4-fluorophenyl) amino] nicotinonitrile, 4 - [(2,4-Dichloro-5-methoxyphenyl) amino] -5- [4-methoxy-3- (2-methoxy ethoxy) phenyl] nicotinonitrile, 4- [(2,4-dichloro-5-methoxyphenyl) amino] -5- [3-methoxy-4- (2-methoxyethoxy) phenyl] nicotinonitrile, 5- [3- (2-chloroethoxy) phenyl] -4 - [(2,4-dichloro-5-methoxyphenyl) amino] nicotinonitrile, 4- [(2,4-dichloro-5-methoxyphenyl) amino] -5- [3- (2-pyrrolidin-

1-ylethoxy) phenyl] nicotinonitrile, 5- [4- (dimethylamino) phenyl] -4 - [(3-nitrophenyl) amino] nicotinonitrile, 5- (3-methoxyphenyl) -4 - [(3-nitrophenyl) amino] nicotinonitrile, 5- (3-methoxyphenyl) -4 - [(3-methoxyphenyl) amino] nicotinonitide, 4 - [(3-fluorophenyl) amino] -5- (3-methoxyphenyl) nicotinonitrile, 4-. { [3-cyano-5- (3-methoxyphenyl) pyridin-4-yl] amino} benzoic acid, 4 - [(4-cyanophenyl) amino] -5- (3-methoxyphenyl) nicotinonitrile, 4- [(3,4-difluorophenyl) amino] -5- (3-methoxyphenyl) nicotinonitrile, 5- (3, 4-dimethoxyphenyl) -4 - [(3-hydroxy phenyl) amino] nicotinonitrile, 5- (3,4-dimethoxyphenyl) -4-. { [3- (2-hydroxyethoxy) phenyl] airiino} nicotinonitin, 4 - [(3- {[[(2S) -

2-amino-

3-phenylpropyl] -oxy}. phenyl) amino] -5- (3,4-dimethoxyphenyl) nicotinonitrile, 4 - [( 2-chloro-5-hydroxyphenyl) amino] -5- (5-formyl-1-benzo-thien-2-yl) -nicotinonitrile, 4 - [(2-chloro-5-hydroxy-phenyl) amino] -5- [5- (piperidin-1-N-methyl) -1-benzothien-2-yl-nicotinonitrile,

4-. { [2-chloro-

5- (2-hydroxyethoxy) pheny] amino} -5- [5- (piperidin-1-yl methyl) -1-benzothien-2-yl-nicotinonitrile, 4 - [(4-amino-2,3-dimethylphenyl) amino] -5- [5- ( piperidin-1-ylmethyl) -1-benzothien-2-yl] nicotinonitrile, 4 - [(4-arnino-3-rnenylphenol) arnino] -5- [5- (p -peridin-1-ylmethyl) - 1-benzothien-2-yl] nicotinonitrile, 4 - [(2-chloro-5-methoxyphenyl) amino] -5- [5- (piperidn-1-methylmet) -1-benzofuran -2-yl] n-phenylnitrile, 4 - [(2-chloro-5-methylphenyl) arnino] -5- [5- (piperidin-1-methyl] -1-benzofuran-2-yl ] Nicotinonitrile, 4 - [(5-hydroxy-2-phenoxyphenol) amino] -5- [5- (piperidn-1-methylmethyl) -1-benzofuran-2-yl ] nicotonnonitrile, 4-. { [3- (amnomethyl) benzyl] amino} -5- (3,4-dimethoxyphenyl) nicotinonitrile, 4 - [(2,4-dichloro-5-hydroxyphenyl) amino] -5- [5- (p.peridin-1-methyl) -1-benzofuran-2-yl] nicotinonitrile, and 4 - [(4-methoxy-2-methylphenyl) amino] -5- [5- (piperdin-1-ylmethyl) -1-benzofuran-2- L] nicotinonitrile. The compound of any one of claims 1-16 or a pharmaceutically acceptable salt, hydrate, or ester thereof, wherein the compound is in the form of an enantiomer. A pharmaceutical composition comprising the compound of any one of claims 1-17 and a pharmaceutically acceptable carrier or excipient. A method for treating or inhibiting a pathological condition or disorder mediated by a protein kinase in a mammal, the method comprising providing the mammal with an effective amount of the compound of any one of claims 1-17 or a pharmaceutically acceptable salt, hydrate, or ester of this. The method of claim 19, wherein the quinaza mprotein is protein kinase C. The method of claim 19 or 20, 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. A compound as claimed in any one of claims 1-17 or a pharmaceutically acceptable salt, hydrate, or ester thereof for use as a medicament. Use of a compound as claimed in any one of claims 1-17 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.