TW200815356A - 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

200815356 IX. Description of the invention: [Rhyme ^ Minghujin ^^ ^ 彳 彳 $ 员 员 】 】 】 】 】 】 】 】 】 】 】 】 】 】 】 】 】 】 相关 相关 相关 相关 相关 相关 相关 相关 相关 相关 相关 相关 相关 相关 相关 相关 相关 相关The patent application priority of the copending application is hereby incorporated by reference. FIELD OF THE INVENTION The present invention relates to substituted cyanide bites (also known as acid nitriles) capable of inhibiting protein kinases. The invention also relates to the manufacture of the substituted cyanide. The side of the pyridine and its use. For example, the compounds of the invention are useful in the treatment of autoimmune and inflammatory diseases such as asthma and arthritis. [Previously, the winter is good, the background of the protein kinase is the catalytic transfer of the phosphate group from adenine nucleoside triphosphate (ATp) to the amino acid residues on the protein (for example, tyrosine, serine, threonine or group) An enzyme of amino acids. Modulation of these protein kinases essentially controls a variety of cellular events including proliferation and migration. Many diseases include various inflammatory and autoimmune diseases such as asthma, colitis, multiple sclerosis, cowhide stagnation, rheumatoid arthritis, osteoarthritis and joint inflammation. Leading cell abnormalities are related. See, for example, Salek-Ardakami, S. et al. (2〇〇4), /· /mm·. /%}, 173(10): 6440~47; Marsland, B• et al. (2004), J· and φ·, 200(2): 181~89; Tan, S· et al. (2〇〇6) J. Immunology 5 176 · 2872-79 ; Salek-Ardakami, S. et al. ^ J. Immunology j 175(11) * 7635-41 ; Anderson, 5 200815356 Κ· et al. (2006),, 39(6) : 469~78; Healy, Α· et al. (2006), /·/mm, 177(3): 1886~93; Sun, Ζ· et al. (2000), 404: 402~7; and Pfeifhofer, C. et al. (2003), /·five x/7., 197(11): 1525~35. 5 A class of serine/threonine kinases is a family of this protein kinase C (PKC). Such kinases are composed of 10 members with sequence and structural similarities. The protein kinase C (PKC) can be split into three classes including traditional, novel and atypical isomers. Its 0 isomer (PKC0) is a class of novel calcium-dependent PKC (Baier, G. et al. (1993), J. C/zem., 268: 10 4997~5004). PKC 0 is highly expressed in T cells (Mischak, H. et al. (1993), 1 Grab, 326: 51-5), while others are expressed in mast cells (Liu, Y. et al. (2001), J. You (9) moxibustion (10), 〇//, 69: 831~40), endothelial cells (Mattila, P. et al. (1994), 55: 1253~60), and skeletal muscles (Baier, G· et al. 1994), £W·J·, 225: 15 195~203). PKC0 has been shown to play an important role in T cell receptor (TCR)-mediated signaling (Tan, S. L. et al. (2003), Injury ockm. /., 376 · 545~52). Specifically, inhibition of PKC 0 signaling by two independent PKC0 knockout mouse strains has led to defects in T cell activation and interleukin-2 (IL-2) formation (Sun, Z. et al. (2000) , 404: 402~20 7 ; Pfeifhofer, C. et al. (2003), J. MW·, 197: 1525~35). PKC0-deficient mice have been shown to have impaired pulmonary inflammation and tracheal overreaction (AHR) in the Th2-dependent murine asthmatic pattern, with no evidence of viral clearance and Thl-dependent cytotoxic T cell function (Berg-Brown) , NN et al. (2004), /· and φ·, 199: 743~52; Marsland, BJ· et al. 6 200815356 (2004), /· and Φ·She Wen, 200: 181~9). The damage of the Th2-cell response results in a decrease in the concentrations of interleukin-4 (IL-4) and immunoglobulin E (IgE) to produce a pathophysiological response to AHR and inflammation. Evidence also suggests that PKC (9 is also involved in the igE receptor (FceRI)-mediated 5-way response of mast cells (Liu, Y. et al. (2001), 乂, 69: 831-840). In human mast cells (HCMC) Among them, it has been shown that the kinase activity of PKC is rapidly distributed (less than 5 minutes) to the cell membrane after FceRI cross-linking (Kimata, Μ· et al. (1999), Biochem Biophys Res Commun., 25 Ί (2>) · 895-900). In vitro activity assays for bone marrow fat 10 large cells (BMMCs) derived from wild-type and PKC 0-deficient mice recently showed that BMMC from PKC 0 -deficient mice were cross-linked with FceRI and from wild The BMMC of mice can reduce the concentration of interleukin-6 (IL-6), α-tumor necrosis factor (TNFα) and interleukin-13 (IL-13), while PKC0 is considered to be a mast cell other than activated tau cells. The production of cytokines has an important role (ciarleUa, 15 Α·Β· et al. (2005), American International Thoracic Society 2005 Symposium Wall Report). Other serine/threonine kinases including mitogen-activated proteins Kinase (ΜΑΡΚ) pathways * ΜΡΑ kinase (ΜΑρκ) (eg, erk) and ΜΑρκ kinase (ΜΑΡΚΚΧ For example, mek and its matrix are composed of a member of the raf family of phosphorylated residues on the melon. The serine/sulphonic acid kinase that regulates cell division is a cyclin-dependent kinase (cdk), including cdc2/cyclin b, cdk2/peripherin A, cdk2/cyclin E*cdk4/cyclin D, and other. Other silk amine/threonine kinases include protein kinases VIII and 6. These are known as PKA or cyclic ΑΜΡβ-dependent proteins; chymase and PKB (Akt) kinases play an important role in signaling pathways. 7 200815356 Taurine kinases (TKs) can be divided into two classes: non-transmembrane TKs and transmembrane growth factor receptor TKs (RTKs). For example, the growth factor of epidermal growth factor (EGF) binds to the extracellular functional site of the partner RTK that activates RTK on its cell surface, and initiates a sequence of signaling actions that control various cellular responses. 5 In addition to EFG, several other RTKs include FGFR (fibroblast growth factor (FGF) receptor); flk-1 (also known as KDR) and vascular endothelial growth factor (VEGF) receptors; and PDGFR (platelet-derived growth factor (PDGF) receptor). Other RTKs include tie-1 and tie-2, colony stimulating factor receptors, nerve growth factor receptors, and insulin-like growth factor receptors. In addition to 10 RTKs, there is another family of TKs called cytoplasmic proteins or non-receptor TKs. Cytoplasmic protein TKs have primitive kinase activity that is present in the cytoplasm and nucleus and participates in a variety of nicknames. There are a number of non-receptor Tks including Abi, Jak, Fak, Syk, Zap-70 and Csk, as well as Src kinase families (SFKs) & Src, Lck, Lyn and others. 15 Certain pyridine and pyrimidine derivatives have been used as kinase inhibitors. These compounds have different properties compared to the compounds of the invention and substituent substitutions at different positions. SUMMARY OF THE INVENTION The present invention relates to substituted 3·cyanopyrenes of formula I: XR1

8 200815356 Salts, hydrates and esters acceptable for use in pharmaceutically acceptable forms, wherein R1, R2 and χ are as defined herein. The present invention is also directed to the inclusion of one or more pharmaceutically effective amounts of the compounds in the form of pharmaceutically acceptable salts, including pharmaceutically acceptable salts, hydrates and S, and pharmaceutically acceptable carriers or excipients. Pharmaceutical composition. The present invention provides for the treatment of autoimmune and bipolar diseases such as the preparation of a compound of formula I and its pharmaceutically acceptable salts, hydrates and noodles. A method of asthma, colitis, multiple sclerosis, psoriasis, arthritis, rheumatoid arthritis, osteoarthritis, and joint inflammation, comprising a therapeutically effective amount of a phantom compound (or a pharmaceutically acceptable surface thereof, Hydrates or esters are administered to mammals such as humans. C 10,000 Packing Mode 3 DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention provides a compound of formula I: XR1

And pharmaceutically acceptable salts, hydrates and esters thereof, wherein: X#€i(a) .NR3.Y^(b) ^Y..(c) .S(0)mY . (d) S( 〇)mNR -Y-, (4) _NR3SdY, (1) _c(〇)nr3_y, (8) C(S)NR _Y-, (h) _NR3c(〇)_Y•, (1) _nr3c(s)_y, (1), c(0)〇 -Y-, (k) ac(〇)-y-, and (1) a covalent bond; Y when present appears laterally selected from (8) bivalent Ci~ig alkyl, (b) divalent 9 200815356 C2~10 alkenyl (C) a divalent C2-10 alkynyl group, (d) a divalent C^ohaloalkyl group, and (e) a covalent bond; the R system is optionally substituted by 1 to 4 -Υ-R4 groups. Phenyl; R-based C6-M aryl or 5- to 14-membered heteroaryl, these groups being optionally substituted by 1 to 45 independently selected from the group consisting of -Y-R4 and -0-Y-R4; Selected from (4) η, (b) q, alkyl, (4) C21 nonenyl, (4) C2 to 10 alkynyl', and (e) (^~10 haloalkyl; R when present is independently selected from (4) H, (b) -CN , (c) _N〇2, (4) _-, (e) -〇-Y-R5, (1)-NR6-Y-R7, (g) -N(0)R6_Y_R7, (8) 10 -S (m5, (i) _S(〇)m〇-Y-R5, (1)-S(0)mNR6-Y-R7, (k) -C(0)_Y-R5, (1) -C(0)0-Y-R5, ( m) _c(〇)NR6-Y-R7, (8)-C(S) NR -YR, (o) alkyl And (8) c2~1() alkenyl, (q) c2~10 alkynyl, (r) cycloalkyl and (v) 5 to 14 membered heteroaryl, wherein (0) to (v) are respectively selectively 15 It is substituted by 1~4 -Y-R8 groups; R is independently selected from (a) Η, (b) -C(〇)R9, (c) _C(0)0r9, (d) Ci~ Alkyl group, (e) C2~1() fluorenyl group, (f) C2~10 alkynyl group, (g) Cwo haloalkyl group, (h) C3~14 cycloalkyl group, (1) C6-14 aryl group, (1) 3~14 a heterocycloalkyl group and (k) 5 to 14 membered heteroaryl groups, wherein (d) to (k) are each optionally substituted with 1 to 4 -Y-R8 groups; R6 and R7 when present Independently selected from (8)H, (b) -OH, (c) -S(0)mY-R9 ^ (d) -S(0)m0-Y-R9 > (e) -C(0)-Y-R9 > (f) .C(0)〇-Y-R9, (g) -qCONR^Y-R11, (h) -C(S)NR10-Y-RU, (1) Ci i〇haloalkyl, (1)C2~ 10 dilute base, (k) C2~10 fast radical, (1) Cl~10 halogenated base, (m) 10 200815356 C3~14 cycloalkyl, (n) C6~14 aryl, (ο) 3~14 a heterocycloalkyl group and (p) 5 to 14 membered heteroaryl groups, wherein (1) to (p) are each optionally substituted with 1 to 4 -Y-R8 groups; R8, when present, is independently selected from (a) ) Η, (b) -CN (c) -N02, (d) 5 oxo_, (e) -OY-R9, (f) - NR10-Y-RU, (g) -N(O)R10-Y-Rn, (h) -S( 0)mY-R9 ^ (i) -S(0)m0-Y-R9 > (j) -S(O)mNR10-Y-Rn ^ (k) -C(0)-Y-R9 > ( 1) -C(0)0-Y-R9 ^ (m) -C(O)NR10-Y-Rn > (n) -C(S)NR1G-Y_RU, (o) Cwo alkyl, (p) C2~1() alkenyl, (q) C2~10 alkynyl, (r) Cu haloalkyl, (s) C3~14 cycloalkyl, (1) C6-14 aryl, (u) 3~14 10 a cycloalkyl group and (v) a 5 to 14 membered heteroaryl group, wherein (o) to (v) are each optionally substituted by 1 to 4 -Y-R12 groups; R9, when present, is independently selected from (a) Η, (b) -C^CO-Cwo alkyl, (4) -C(0)0H, (d) -CXCOO-Cu alkyl, (e) Cu alkyl, (1) C2~10 alkenyl, (g) C2~10 alkynyl, (8) 匕~(1)haloalkyl, (1)C3~14 cycloalkyl, (j) 15 C6-14 aryl, (k) 3 to 14 membered heterocycloalkyl, and (1) 5 to 14 membered heteroaryl Wherein the C 1 to 10 haloalkyl group, the C 2-10 fine group, the C 2 to 10 fast group, the C 1 to 10 alkyl group, the C 3 ～14 cycloalkyl group, the C 6 1-4 aryl group, the 3 to 14 member heterocyclic ring The alkyl group and the 5 to 14 membered heteroaryl groups are each optionally substituted by 1 to 4 -Y-R12 groups; R10 and R11, when present, are independently selected from (a) Η, (b) -OH, (c) -SH, 20 (d)_NH2, (e) -NH-Cw. Alkyl, (f) - fluorene ((^~1() alkyl) 2, (g) -SODh-Cwo alkyl, (h) -S(0)20H, (i) -SCCOmO-Cwo alkyl, G) -QCO-Cl alkyl, (k) -C(0)0H, (1) -QCOO-Chg alkyl, (m) C(0)NH2, (n) -C^CONH-Cuo alkyl, (o) alkyl) 2, (p) -C(S)NH2, (q). Alkyl, (r) -C(S)N (Cwo 11 200815356 alkyl) 2, (8) Ci~ίο, (t) C2~1G dilute, (U) C2~10 fast radical, (V) Ci~ 〇 alkoxy, (W) Cu haloalkyl, (4) C 3 14 cycloalkyl, (y) C 6 14 aryl, (z) 3 to 14 membered heterocycloalkyl, and (aa) 5 to 14 An aryl group, wherein the Cwo alkyl group, C 2 ～10 dilute group, C 2 ～10 fast group, Cl 10 10 alkoxy group, Cl 10 10 halo group, C 3 ～ 14 5 cycloalkyl group, C 6 ～14 aryl group, 3 The 14-membered heterocycloalkyl group and the 5 to 14-membered heteroaryl group are each optionally substituted by 1 to 4 -Y-R12 groups; R12, when present, is independently selected from (a) halogen, (b) -CN , (c) -N02, (d) oxo, (e) -OH, (f) -NH2, (g) · ΝΗ ((^~1() alkyl), (h) -NCCu alkyl) 2 (i) -SH, (j) -SCCOm-Cwo alkyl, (k) -S(0)20H, (1) 10 -SCCOmO-Cwo alkyl, (m) -C^CO-Cu. Alkyl, (n) -C(0)0H, (o) QCOO-Cwo alkyl, (p) -C(0)NH2, (q) -C(0) NH-Cwoalkyl, (r) Base) 2, (s) -C(S)NH2, (t) -C^S^H-Cwo alkyl, (u) alkyl) 2, (v) Cwo alkyl, (w) C2~1G ene Base, (x) C 〗 〖i 〇 fast radical, (y) Ci~i 〇 alkoxy, (z) Ci~i 〇 halogen, (aa) C3 η η 15 cycloalkyl, (ab) C6 ～14 aryl, (ac) 3 to 14 membered heterocycloalkyl, and (ad) 5 to 14 membered heteroaryl; and m is 0, 1, or 2. In some embodiments, the pyridine ring can be oxidized on the nitrogen atom to a corresponding N-oxide having the formula:

Wherein R1, R2 and X are as defined herein. 12 200815356 In some embodiments, x can be selected from the group consisting of -nr3-Y-, -ο-Υ-, and a covalent bond. For example, X can be selected from the group consisting of -ΝΗ-, -N(CH3)-, -NH-CH2-, -NH_CH2CH2-, -NH-CH2CH2CH2-, -0-, and a covalent bond. In a particular embodiment, X can be -ΝΗ-. 5 In some embodiments, R1 can be selected from:

Where R4 is as defined herein. In a particular embodiment, R4, when present, can be independently selected from the group consisting of -F, -α, -Br, _CN, _N02, -0-Y-R5, -C(0)-Y-R5, -C(0) 0-Y_R5, _NR6-Y-R6, and Ci~6 alkyl. For example, R4 when independently taken up may be independently selected from the group consisting of -F, -a, -Br, -O-Cw alkyl, phenyl, and Cm alkyl. In some embodiments, R2 may be selected from the group consisting of phenyl, C8-14 aryl, and 5 to 14 beta heteroaryl, each of which is independently selected from 1 to 4 independently selected from _γ_R4 and -0-Y. Substituted by a radical -R4 wherein gamma and r4 are as defined herein. For example, 15 may be selected from the group consisting of phenyl, indolyl, sulfhydryl, σ-picolinyl, fluorenyl, fluorenyl, fluorenyl, fluorenyl, fluorenyl, benzopyrene Benzyl, U-radyl, benzodioxinyl, benzodioxanyl, benzodioxanyl, 13 200815356 dibenzofuranyl, dibenzothiophenyl, benzofluorenyl, Mdanyl, indenyl, isothiazolyl, hydrazine, pyrazolyl, tetrahydroindenyl, oxime, fluorenyl, naphthyl, sigma, and sigma These radicals are selected 5 to 5 independently from _y_r4 and Y_R4, where 丫 and Han 4 are defined herein. In some embodiments, R2 can be: D2

Wherein D, D and !) 3 are independent H, -Y-R4 or -〇_Y_R4 groups, wherein γ and R4 are as defined herein.

For example, at least one of D1, D2 and D3 is a -Y-R4 or -0-Y-R4 group, wherein Y is an independent divalent Cw alkyl group or a covalent bond when present, and r4 is independent when present. Selected from _, -CN, _n〇2, _〇_y_r5, _nr6_y _r7, S(0)2-YR, -S(0)2NR6-Y-R7, -C(0)-Y-R5, _c (0)0-Y-R5, C(〇)NR-Yr' alkyl, haloalkyl, ~i4 cycloalkyl, ~μ15 aryl, 3~14 member heterocycloalkyl and 5~14 member An aryl group, wherein a Cl 10 alkyl group, a Cl 10 alkyl group, a C 3 14 cycloalkyl group, a c 6 14 aryl group, a 3 14 membered heterocycloalkyl group, and a 5 14 membered heteroaryl group are selectively Substituted by 丨~々, where Y, R, R6, R7 and chemistry 8 are as defined herein. In some embodiments, at least one of Di, D2, and D3 is _〇_ 2〇(C4H2)n_R4, wherein n may be independently 0, 1, 2, 3, or 4 when present, and when R field appears Independently selected from F, Cl, Br, -Ν〇2, -0-Y-R5, NR YR, S(0Hr5, -S(〇)2NR6-Y-R7, -C(0)NR6_Y-R7, 14 200815356

Ci~ίο alkyl, C3~h cycloalkyl, C6~14 aryl, 3~14 member heterocycloalkyl and 5~14 member heteroaryl, wherein c 1~10 alkyl, C3~14 cycloalkyl , C6~14 aryl, 3~14 membered heterocycloalkyl and 5~14 membered heteroaryl are each optionally substituted by 丨~4-Y-R8, wherein γ, r5, R6, R> Defined here. In a specific embodiment, at least one of Di, D2 and D3 is -〇_(CH2)nNR6-Y-R7 or -〇_(CH2)n-3~14 membered heterocycloalkyl, wherein the 3~ The 14-membered heterocyclic group may be optionally substituted by 1 to 4 _Y_R8, wherein γ, R6, R7 and R8 are as defined herein, and n may independently be 〇, 1, 2, 3 or 4 when present. In some embodiments, at least one of D1, D2, and D3 is -(CH2)n, 6-Y-R7 or _(CH2)n-3~14 membered heterocycloalkyl, wherein the 3 to 14 members are heterozygous. The cycloalkyl group may be optionally substituted by 1 to 4 _Y_R8, γ, R6, R7*R8 are as defined herein, and η may independently be 〇, 1, 2, 3 or 4 when present. In a specific embodiment, when at least one of Di, D2 and D3 is _〇_(CH2)nN 15 R -Y-R7 or _(CH2)nNR6-Y R7 group, the _〇_(cH2)nNR6 -Y-R7 with

The _(CH2)nNR6-Y-R7 group can be _〇<CH2^nh_y r7 or _〇_(CH2)nN(CH3)-Y-R7 and or _ 丄 丄) -YR, where γ When present, it may be an independent divalent Gy alkyl group or a covalent bond, and R may be independently selected from the group consisting of _〇_Y_R9, _c(〇)_Y_R9, Cl~1〇 alkyl, ～14 ring alkyl, 20-C(0)〇-Y-R9-C(〇)NR10-Y-Rn C6~14 aryl, 3~14 membered heterocycloalkyl and 5~14 membered heteroaryl, wherein Cl~10 alkyl The C3~143⁄4 alkyl group, the C6~M aryl group, the 3~14 membered heterocycloalkyl group, and the 5~14 membered heteroaryl group are optionally substituted by one _Y_Rl2, wherein γ and r12 are as defined herein. For example, 'the c3~i4 loop wire, secret, 3~14 member miscellaneous 15 200815356 cycloalkyl and 5~μ μ # — berylyl group may be selected from cyclopentyl, cyclohexyl, phenyl, dimethylmorphinyl, Piperidinyl, piperidinyl, azepanyl P~y) ~ azepanyl, thiomorphinyl, fluorenyl, taste thiol and °. These groups are optionally substituted by 1 to 4 -Υ-R12, respectively, wherein Y and R 2 are as defined herein. . /, in the case of the body K, when at least one of Dl, D2, and D3 is · 〇 γ Η 2) η _ _ _ _ _ _ _ _ _ _ _ (CH2) n _ 3 ~ 14 members of the Wei Wei group, the 3 ~ 14 members of the miscellaneous = burn The base may be selected from the group consisting of silk, ", base, thiol, aza 10 15 20 s ' soil-azacycloheptyl and thiomorpholinyl, these groups are selectively 1 to 4 Substituted, wherein R8 is as defined herein. For example, when it is out; it can be an independent divalent C1 group or a covalent bond, and R can be an independent oxygen s, _0々_r9, _nr10_y_r11, -s(〇)mmc__Y_R9, Ci~ when it appears.歳基, ^ Weiji, c (four) square base, 3 to two members heterocyclic base and 5 to 14 member heteroaryl, wherein the c (four) burnt earth C3 ~ 14% alkyl, C6 ~ H aryl, 3 ~ 14 members The heterocycloalkyl group and the 5 to 14 membered heteroaryl are each optionally substituted by 4 (4) 2, wherein γ^2 is as defined herein. For example, the C3-14 cycloalkyl group, the C6-14 aryl group, the 3-14 membered heterocycloalkyl group and the 5-14 membered heteroaryl group may be selected from the group consisting of a cyclopentyl group, a cyclohexyl group, a phenyl group, and a phenyl group. Subtractive, (tetra)yl, ketone, azetidinyl, diazepine, thiophenanthyl, fluorenyl, indole and K group, these groups are selectively W-Y-, respectively Substituted by β, where γ and Rl2 are defined for this. Alternatively or simultaneously, at least one iy, he is selected from the group consisting of dentate, _CN, -n〇2, _S(0)2_Y_R5, _s(0)2Nr6_y_r7, c(9)〇Y R5, seven (9) 16 200815356 NR-YR, alkane And a Ci i〇 haloalkyl group, wherein y, r5, r^〇R7 are as defined herein. In a specific embodiment, at least two of D1, 〇2, and 〇3 are _〇_(CH2)n-R4, wherein n may be independently 0, 1, 2, 3, or 4, and 5 R4 when present. When present, it can be independently selected from F, Cl, Br, 〇2, .〇_y_r5, -nr6-y-r7 >>S(〇)2.Y.R5. -S(〇)2NR6-Y .R7. -C(0)NR6-Y-R7 >

Cl 〜1 alkyl, C 3 ～14 cycloalkyl, Cw aryl, 3 to 14 membered heterocycloalkyl and 5 14 membered heteroaryl 'wherein Ci, alkyl, Gw cycloalkyl, [(a) 4 aryl, The 3 to 14 membered heterocycloalkyl group and the 5 to 14 membered heteroaryl group are each optionally substituted by 1 to 4 10-Y-R8, wherein Y, R5, R6, R7 and R8 are as defined herein. In some embodiments, D!, D2, and at least two are independent -0-CH3 or -0-(CH2)n-ray-R5 groups, wherein ^r5 is as defined herein, and η when present Independently 〇i, 2, 3 or 4. In some embodiments, 'D, D, and D are in the middle of the work. In other embodiments, 15 D, D, and D are two of _〇_(CH2)n 〇 Y R5 or ο. %with

-0-(CH2)n_〇m, where y*r5 is as defined herein, and η can be independently 0, 1, 2, 3 or 4 when present. In some embodiments, at least one! The ^^ mouth is thought to be ^, and at least one of Dl, D2, and D3 is (CH2)nNR6-Y-R7 or _〇_ 2〇(CH2)n_3~14 member heterocycloalkyl, of which 3 to 14 members The heterocyclic group may be optionally substituted by 4 -Y-RV, wherein Y, R6, R> R8^b^_, and η may independently be 〇, 1, 2, 3 or 4 when present. In some embodiments, one of iy, D2, and D3 is 17 200815356 R8 or R8, wherein R8, when present, is independently selected from the group consisting of _0-Y-R9, _NRHLY-R11, 〇6-14 aryl, and 5~ a 14-membered heteroaryl group, wherein the c6-14 aryl group and the 5-14 membered heteroaryl group are optionally substituted by 1 to 4 -y_Ri2, wherein γ, R9, Ri〇, Ru and Ri2 5 are The definition, and η, when present, can be independently 〇, 1, 2, 3 or 4. In certain embodiments, at least one of D1, D2, and D3 is a C6-14 aryl or a 5-14 membered heteroaryl group, each of which is optionally substituted with 4 -Y_R8, wherein Y and R8 are Defined here. For example, at least one of Di, D2 and D3 is selected from the group consisting of a benzothienyl group, a benzofuranyl group, a furyl group, a pyridyl group, a pyrimidine 10 group, a fluorenyl group and a thienyl group, and these groups are each selectively _Y_R8 Substituted, wherein γ and R8 are as defined herein. In a specific embodiment, Y may be an independent Ci~4 alkyl or a covalent bond when present, and R8 may be independently selected from the group consisting of halogen, _CN, -Ν02, -OY-R9, _NR10-Y-Rn, -c(o)-Y-R9, -C(0)nri〇_y_r1i, .S(〇)2-y.r9, 15 -S(C〇2m'Y-Rii and optionally Ci~4 a 3 to 14 membered heterocycloalkyl group substituted by an alkyl group, wherein Y, R9, R1 and Ru are as defined herein. In other specific embodiments, ^ is ^(4)bicyclic aryl or 5 to 14 member Aryl, these groups are each optionally substituted by i to 4 groups independently selected from _¥_" and -0-Y-R4, wherein 丫 and 4 are as defined herein. 20 In a particular embodiment R2 is selected from the group consisting of benzothienyl, benzofuranyl, furyl, acridine, pyrimidinyl, fluorenyl, thienyl 'imidazolylisoxyl, thiazolyl, oxazolyl, fluorenyl, benzene And bismuthyl, 18 200815356 benzodioxanyl and dibenzofuranyl, these groups are each selectively selected from -(CH2)n-R4 and -〇-(CH2)n- Substituted by the base of R4, where n can be independently 0, 1, 2, 3 or 4 when present, and R4 appears It may be independently -NR6-Y-R7 or a 3- to 4-membered heterocycloalkyl group optionally substituted with ~4 _Y-R8, wherein Y, R6, R7 and R8 are as defined herein. (CH2)nNH-Y-R7 or _(CH2)nN(CH3)_Y_R7, where γ can be = independent bivalent Cl~4 filament or covalent bond when it appears, and independent when the r7# appears 10 15 20 k from -OYR, -C(〇)_y_r9, _c(〇)〇Y r9, _c(〇) pulse i〇_Y_Rn,

Cw-forming group, c3~14 ring-alkyl group, C614 aryl group, 3~14 member heterocyclic alkyl group, and heteroaryl group, wherein the Cl~1G alkyl group, c3~14 ring alkyl group, (:6~14fang) The base, the =12 member heteroarm group and the 5~14 member heteroaryl group are each selectively substituted by four YRs, wherein in the case of R12, R7 is selected from the group consisting of μ.衣 soil, hexyl, phenyl, pyrrolidinyl, morpholine, thiophenanthyl, kouchenkou I, Μ thiophenanyl, naphthyl, 4 heterocycloheptyl, aryl, 3 The base and the base of the Wei group, c6 ~ 14 are by ===:5~14, which are selected respectively or H. wherein 12 is defined here. XI R is -〇_(CH2)n_3 Beta-heterocycloalkyl, complex .... beryllyl or crane) -3 to 14 mouth base, (four) /, 5 (9) hiding base can be selected from (10) burnt base, and 琉 琳 丨 丨 丨 丨 、 、, 二Azacycloheptyl wherein Y and R8 are optionally substituted by 1 to 4 -Y-R8 for this / soil knife 1, not Kappa as defined herein. The valence of Cu4 alkyl or —~ appears as a cleavable double 4 bond' can be an independent oxy group when the state appears, 19 200815356 -O-Y-R9, his ίο alkyl group, C3 π R mR9, . ~14 decyl, C6~14 aryl, 3~14 member heterocyclic succinimide, beta heteroaryl, rehydra 兮^j alkyl and 5~14 member heterocyclic sputum. The alkyl group, the Q 14 ring-containing group U group, and the 3~Η group are substituted, and the 1 2 member heteroaryl group is selectively defined by 1 to 4 groups, ring groups and π, respectively. For example, R8 may be selected from the group consisting of cyclopentazepine, squamous green, sputum, yl, and base. Alkyl, fluorenyl and —I heterocycloheptyl, thiophenanyl.喃 基 、, 味 10 and 5 to 14 members of the hetero- 2,14-cycloalkyl, C6-14 aryl, 3 to 14-membered heterocycloalkyl, yl, these groups are selectively 1 to 4 H12, respectively Substituted, wherein Y and R12 are as defined herein. It will be understood that the present invention excludes certain specific embodiments of the compounds within the class of the compounds of formula I. For example, when R1 is 3-chloro-4-fluorophenyl, the present invention can exclude a compound wherein R2 is 2-[(1Η-imidazolyl-5-ylmethyl)amino]phenyl. The compounds of the invention include the compounds listed in Table 1. 15 Table 1 Compound ----- Compound name 101 4-[(3-Phenylphenyl)amino]-5-(3,4-dioxanoxyphenyl)nicotinic acid nitrile 102 5_(3,4-II Methoxyphenyl)-4-[(3-phenylphenyl)amino]nicotinic acid nitrile 103 ------- 4-anilino-5-(3,4-dimethoxyphenyl)nicotinic acid Nitrile 104 4_[(2,5-difluorophenyl)amino]_5_(3,4-dimethoxyphenyl)nicotinic acid nitrile 105 5_(3,4-dioxanylphenyl) bucket [(3, 4-Dimethoxyphenyl)amino]nicotinic acid nitrile 106--- 4_[(4-Gas-2-fluorophenyl)amino]-5-(3,4-dimethoxyphenyl)nicotinic acid Nitrile 107 — 4-[(3-Isohydrofluorophenyl)amino]>5-(3,4-dimethoxyphenyl)nicotinic acid nitrile 20 200815356 Compound Compound name 108 4-[(4-Chlorophenyl) Amino]-5-(3,4-dioxaxyphenyl)nicotinic acid nitrile 109 5-(3,4-Dimethoxyphenyl)_4-[(2,4-didecylphenyl)amino Niacin nitrile 110 5-(3,4-dimethoxyphenyl)-4_[(4-anthoxyphenyl)amino]nicotinic acid nitrile 111 4-[(3-chloroicylmethoxyphenyl)amine 5-(3,4-dimethoxyphenyl)nicotinic acid nitrile 112 5-(3,4-diindolylphenyl)-4-[(4-phenoxyphenyl)amino]in acid Guess 113 4-[(2,5-Dichlorophenyl)amino]-5-(3,4-dimethoxyphenyl)nicotinic acid nitrile 114 5-(3,4-dioxanylphenyl)- 4-[(4-decyloxy-2-oxo) Amino acid] is an acid-chat 115 4-[(3,4-dichlorophenyl)amino]-5-(3,4-dioxaxyphenyl)nicotinic acid nitrile 116 4-[(5-chloro 2-methoxyphenyl)amino]-5-(3,4-dimethoxyphenyl)nicotinic acid nitrile 117 4-{[3-(hydroxy)phenyl]amino}-5-( 3,4-Dimethoxyphenyl)nicotinic acid nitrile 118 5-(3,4-Dioxaxyphenyl)-4-[(4-nonylphenyl)amino]nicotinic acid nitrile 119 5-(3 , 4-methoxyphene M-[(3,4,5-trimethoxyphenyl)amino]nicotinic acid nitrile 120 5-(3,4-dimethoxyphenyl)-4-[(3- Phenoxyphenyl)amino]nicotinic acid nitrile 121 4-[(2-Gas-5-anthoxyphenyl)amino]-5-(3,4-dioxanoxyphenyl)nicotinic acid nitrile 122 4- ({3-Chloro-4-[(3-cyano)oxy]phenyl}amino)-5-(3,4-dimethoxyphenyl)nicotinonitrile 124 4-({3_氯4-[(3-indolyl)oxy]phenyl}amino)-5-(3,4-dimethoxyphenyl)nicotinic acid nitrile 125 4_[(3_氯冬{[3-( Dimethylamino)benzyl]oxy}phenyl)amino]_5_(3,4-dimethoxyphenyl) Nicotinic nitrile 126 4-[(2,4-dichlorophenyl)amino]- 5-(3,4-Dioxaxyphenyl)nicotinic acid nitrile 127 (3-{[3-muryl-5-(3,4-dioxyloxyphenyl) 0-decyl-4-yl] Amino}phenyl)benzamine 128 N(3-{[3-nitro-5-(3,4-dimethoxyphenyl)indole ratio sigma-4-yl]amino}phenyl -N-methylacetamide 129 N-(3-{[3-cyano-5-(3,4-dioxanylphenyl)pyridin-4-yl]amino}phenyl)methylsulfonate Amine 130 5-[4-(dimethylamino)phenyl H-[(3-methoxybenzene; &)amino]nicotinic acid nitrile 21 200815356 Compound Compound name 131 5-[4-(dimethylamino) Phenyl]-4-[(3-fluorophenyl)amino]nicotinic acid nitrile 132 4-({3-cyano-5-[4-(dimethylamino)phenyl]acridine-4_ 133 4-[(4-cyanophenyl)amino]-5-[4·(didecylamino)phenyl]nicotinic acid nitrile 134 4-[(3,4-difluoro) Phenyl)amino]-5-[4-(dimethylamino)phenyl]nicotinic acid nitrile 135 4-[(3->odorophenyl)amino]-5-(3,4-dimethyl Oxyphenyl) in S complex 136 4_{[3-(τ oxy)-4-chlorophenyl] cumenyl}-5-(3,4-dimethoxyphenyl) in acid guess 137 4· [(2,4-Dichloro-5-methoxyphenyl)amino]-5-(3,4-dimethoxyphenyl) in acid guess 138 4_[(2,4_二气-5-B Milk phenyl)amino]-5-(3,4-dimethoxyphenyl) in acid guess 139 4_[(2,4-dichloro-5-propoxyphenyl)amino]-5-(3 , 4-dimethoxyphenyl) in the acid guess 140 4-[(5-butoxy-2,4-dichlorophenyl)amino]-5-(3,4-dimethoxyphenyl) Acid nitrile 141 4-{[2,4-dichloro-5-(2-hydroxyethoxy)phenyl]amino}-5-(3 ,4-dioxaxyphenyl)nicotinic acid nitrile 142 4-{[4-(oxy)-3-phenylphenyl]amino}_5-(3-stone phenyl) in acid guess 143 4- {[3-Chloro-2-ylindoleoxy)phenyl]amino}-5-(3_石肖phenyl) in acid 144 4-[(3- gas-4-ranylphenyl)amine 5-[3-nitrophenyl) to acid 145 5-(3-aminophenyl)-4-{[4-(oxy)-3-chlorophenyl]amino} Nicotinic nitrile 146 4-[(3-Chloro-4-fluorophenyl)amino]-5·(2-石 肖phenyl) in acid guess 147 5-(2-aminophenyl)-4-[(3-gas- 4- disordered phenyl)amino group] in acid guess 148 4-[(2,4-dichlorophosphoniophenyl)amino]-5-[4.methoxy-3-(2-methoxyethoxy) Phenyl] nicotinic nitrile 149 4-[(2,4-di-rham-5-methyllacylphenyl)amino]-5-[3·methyllacyl-4-(2-methyllactyloxy) Phenyl] nicotinonitrile 150 5-[3-(2-chloroethoxy)phenyl]_4-[(2,4-dichloro-5-fluorenylphenyl)amino]nicotinic acid nitrile 151 4 -[(2,4-dichloro-5-indolylphenyl)amino]-5-[3-(2-pyrrolidin-1-ylethoxy)phenyl]nicotinic acid nitrile 22 200815356 Compound Name 152 5-[4·(Dimethylamino)phenyl]-4-[(3- surephenyl)amino]nicotinic acid nitrile 153 5-(3-methoxyphenyl)-4_[(3- Nitphenyl)amino]nicotinic acid nitrile 154 5-(3-methoxyphenyl)·4_[(3-methoxybenzene) Amino] Nicotinic Acid Nitrile 155 4-[(3-Phenylphenyl)amino]-5-(3-methoxyphenyl) in Acid Guess 156 4-{[3-Cyano-5-(3-曱Phenoxyphenylpyridin-4-ylamino}benzoic acid 157 4_[(4-murophenyl)amino]-5-(3-methoxyphenyl) in acid guess 158 4-[(3 ,4-difluorophenyl)amino]-5-(3-methoxyphenyl)nicotinic acid nitrile 159 5-(3,4-dioxanoxyphenyl)-4-[(3-hydroxyphenyl) Amino] nicotinonitrile 160 5-(3,4-dimethoxyphenyl) bucket {[3-(2-ethoxy)phenyl]amino} Nicotinic nitrile 161 4-[(3-{ [(2S)-2-Amino-3-phenylpropyl]oxy}phenyl)amino]-5-(3,4-dimethoxyphenyl)nicotinic acid nitrile 162 4-[(2- Chloro-5-sayphenyl)amino]-5-(5-methylindol-1-benzoquinone sept-2-yl) in acid guess 163 4-[(2-gas-5-phenylene) Amino]-5-[5-(B.-decyl-1-ylmethyl)-1-benzoquinone sept-2-yl] in acid nitrile 164 4-{[2- gas-5-(2 -Ethyl lactyl) benzyl]aminomethyl)-1-benzoquino-propen-2-yl]-acid 165 4-[(4-amino-2,3-«-mercaptobenzene Amino]-5-[5-(5-(decyl-1-ylindenyl)-1_benzoquinone-s-phen-2-yl]-acids 166 4-[(4-amino-3) -Methylphenyl)hydanto]-5-[5-(orally decyl-1-ylmethyl)-1-phenylindole 0 thiophene-2_yl]nicotinic acid nitrile 167 4-[(2· -5-methoxyphenyl)amino]-5-[5-(piperidin-1-ylmethyl)-1-benzofuran-2-yl] Nicotinic nitrile 168 4-[(2-rat- 5-methylphenyl)amino]-5-[5-(°Bottom-l-ylindenyl)-1-benzoquinone-2-yl] Nicotinic nitrile 169 4-[(5- Alkyl-2-phenoxyphenyl)amino]-5-[5-(. Chen. Ding·1 -ylmethyl)-1 -benzobenzopyran-2-yl]nicotinic acid nitrile 170 4-{[3-(aminoindenyl)]]yl}-5-(3,4-di Methoxyphenyl)nicotinic acid nitrile 171 4-[(2,4-dioxa-5-3⁄4phenyl)amino]1 -ylmethyl)-1 -benzoheptan-2-yl] Nicotinic nitrile 172 4-[(4-Methoxy-2-methylphenyl)amino]-5-[5-(piperidin-1-ylmethyl)-1-benzofuran-2-yl]-acid 23 200815356 Organic and inorganic bases can be utilized to form pharmaceutically acceptable salts of the formula, which can have an acidic group. Mono- and polyanion salts can be used depending on the number of available acidic hydrogens to be protonated. Suitable salts with bases include metal salts such as metal or alkaline earth metal salts such as sodium, potassium or magnesium salts; ammonium salts and 5-alcohol salts such as morpholine; thiomorpholine; piperidine; pyrrolidine; a di- or tri-lower alkylamine (eg, ethyl-tert-butyl, diethyl, diisopropyl, triethyl, tributyl or dimethylpropylamine), or a mono-, di- or trihydroxy lower alkane Formed by a base amine (eg, mono-, di- or diethanolamine). Specific non-limiting examples of inorganic tests include NaHC03, Na2C03, KHC03, K2C03, Cs2C03, 10 LiOH, NaOH, KOH, NaH2P〇4, Na2HP04, and Na3P04. Internal salts can also be formed. Similarly, when the compounds disclosed herein contain a test group, the organic and inorganic acids can be used to form salts thereof. For example, salts can be formed from the following acids: acetic acid, benzenesulfonic acid, benzoic acid, camphoric acid, citric acid, diacetic acid, ethanesulfonic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, 15 hippuric acid, hydrobromic acid, hydrochloric acid, 2-hydroxyethanesulfonic acid (isethi〇nic), lactic acid, maleic acid, malonic acid, mandelic acid, manic acid, mucic acid (mucic), naphthalenesulfonic acid, nitric acid, oxalic acid, pamodioic acid (pam〇ic), pantothenic acid, samaric acid, S-acid, propionic acid, crotonic acid, sulfuric acid, tartaric acid and toluenesulfonic acid, and others Known as a pharmaceutically acceptable acid. The esters of the compounds of formula I include various pharmaceutically acceptable vinegars which are conventionally known in the art of being metabolized to free acids (e.g., free carboxylic acids) in mammals. Examples of such esters include alkyl esters (e.g., having from 1 to 10 carbon atoms); cycloalkyl esters (e.g., having from 3 to 1 carbon atoms); aryl esters (e.g., having from 6 to 14) a carbon atom comprising 6 to 10 carbon atoms), and a heterocyclic analog thereof (for example, having 24 to 1515 atoms having 24 to 14 ring atoms, wherein the alcohol residue may include other substituted nitrogen and sulfur heteroatoms In the specific embodiment, the 1~10 alkyl ester, such as methyl ester, ethyl ester, propionate, isopropyl ester, butyl ester, li , /, Japan, tributyl acrylate, amyl ester, isoprene and hexyl; C3, cycloalkyl §, such as cyclopropyl acetonate, cyclopropylmethyl hydrazine, % butyl ester, cyclopentyl ester and Link base and toluene. - Day, or aryl _, such as phenyl ke, Ben Mao Ming also provides a precursor drug disclosed in ^ + , here. Here, "precursor," means that 10 == can be produced, produced or released in the body of the animal (4) = Γ using conventional procedures or (4) from the original compound broken 15 20 = 修 from the compound in the compound Manufacture of the prodrug. The second to include the compounds described herein which contain - or a plurality of molecular groups attached to the amino group, the amine group, the sulfur-reading group, and are administered to the mammal in the body (four) Whereas, free earth, fe-based, sulfhydryl or county are formed respectively. Examples of the prodrug include the acetate, formate and benzoate derivatives of the alcohol and the functional group of the present invention. Manufacturing and use are disclosed in τ. Higuchi and V. stella, “4_#. 麟象转,, ACS Seminar Series, Volume 14, and the recording of ❹何翁, B. R〇che, ed., American Medical Association and pergamGn Published, 1987, the entire disclosure of which is incorporated herein by reference. The invention also provides a pharmaceutical composition comprising at least one of the compounds described herein and one or more pharmaceutically acceptable face, supernatant or diluent. Examples of such carriers are known to those skilled in the art and can be made according to the hobby procedures accepted by 25 200815356, for example, in effect, attack/Qin Cunxue and practice, 20th edition, Alfonso R· Gennar〇, Lippinc〇tt Furu (10) &

Wilkins, Baltimore, MA (2 〇〇〇), the entire disclosure of which is incorporated herein by reference. As used herein, "pharmaceutically acceptable, refers to a substance that can be applied to a drug without a detrimental effect on the active ingredient from the point of view of toxicity and agent 5. Therefore, the pharmaceutically acceptable carrier can be combined with other ingredients in the formulation. Compatible and biologically acceptable. The pharmaceutical composition may also incorporate an auxiliary active ingredient. The compounds of the invention may be used to treat pathological 10 symptoms or diseases in a mammal, such as a human. Here, "treatment, Means partial or complete alleviation and/or amelioration of the disease and/or its symptoms. The invention thus includes methods of providing a pharmaceutical composition comprising a compound of the invention in combination or synergistically with a pharmaceutically acceptable carrier. The compounds of the invention may be administered alone or in combination with other therapeutically effective compounds or in the treatment of a pathological condition or disease. The term "effectively therapeutic" as used herein refers to a substance that induces an amount of desired biological activity or effect. The invention also encompasses the use of a compound herein as an active therapeutic substance for the treatment of a pathological condition or disease mediated by a protein kinase such as protein kinase C (PKC) and its 6>isomer (PKC(R)). The pathological symptoms or diseases include 20 inflammatory diseases and autoimmune diseases such as asthma, colitis, multiple sclerosis, psoriasis, arthritis, rheumatoid arthritis, osteoarthritis and joint inflammation. Accordingly, the present invention further provides methods of treating these pathological conditions and diseases using the compounds described herein. In some embodiments, the method comprises determining whether a mammal has a pathological condition or disease mediated by a protein kinase such as pKc 26 200815356 and PKC0, and providing an effective amount of a compound described herein to the mammal. In some embodiments, the method comprises administering to a mammal a pharmaceutical composition comprising a compound described herein and in combination or synergistically with a pharmaceutically acceptable carrier. 5 The present invention further encompasses the use of a compound described herein as an active therapeutic substance for preventing and/or inhibiting the above mentioned pathological symptoms or diseases. Thus, the present invention further provides methods of using the compounds described herein for preventing and/or inhibiting these pathological conditions and diseases. In some embodiments, the method comprises identifying whether a mammal has a inflammatory condition or disease mediated by a protein kinase such as 10 PKC and PKC0, and providing an effective amount of a compound described herein to the mammal . In some embodiments, the method comprises administering to a mammal a pharmaceutical composition comprising a compound described herein and in combination or synergistically a pharmaceutically acceptable carrier. The compounds of the present invention can be administered orally or parenterally, either alone or in combination with the pharmaceutically active uploading agent. Useful solid carriers containing one or more of them are also used as flavoring agents, lubricants, solubilizers, suspending agents, fillers, surfactants, compression aids, binders or lozenge breakers, or coatings. material. The compound can be formulated by a conventional method, for example, in a similar manner to a conventional anti-fire agent. Oral formulations containing the active compounds disclosed herein include any of the conventional oral dosage forms including lozenges, capsules, buccal tablets, throat lozenges, lozenges and oral solutions, suspensions or solutions. In the case of a powder, the carrier may be a fine powder solid in which the powdery active compound is mixed. In the case of a tablet, the active compound is mixed in a suitable ratio with a carrier having the properties to be compressed and compressed into a desired opening y shape and size. The powders and lozenges contain up to 99% of active compound. 27 200815356 The mixture in capsules contains the active compound and inert fillers and/or diluents such as pharmaceutically acceptable starches (for example, corn, potato or tapioca starch); sugars; artificial sweeteners; powdered cellulose (for example, crystallization) And microcrystalline cellulose); flour; gel; gum and the like. 5 The manufacture of useful lozenge formulations can be carried out by conventional tableting, wet granulation or dry granulation methods, as well as the use of pharmaceutically acceptable diluents, binders, lubricants, decomposers, surface modifiers (including Surfactant), suspension or stabilizing agent, including magnesium stearate, stearic acid, sodium lauryl sulfate, talc, sugar, lactose, dextrin, starch, gel, cellulose, methyl cellulose, Micro 10 crystal cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, polyvinylpyrrolidone, alginic acid, gum arabic, santillac gum, sodium citrate, citrate double salt, acid Glycine, sucrose, sorbitol, saponin, calcium sulphate, kaolin, mannitol, sodium chloride, low melting wax and ion exchange resin. Preferred surface modifiers include nonionic and anionic surface modifiers. Representative examples of 15 surface modifiers include poloxamer 188, benzalkonium chloride, calcium stearate, cetyl stearyl alcohol, cetomacrogol, Emulsifying wax, sorbitol ester, cerium oxide colloid, phosphate, sodium lauryl sulfate, aluminum magnesium citrate and triethanolamine. Oral formulations herein can utilize standard extended release or sustained release formulations to alter the absorption of the active compound. The oral formulation also contains the compound described herein in water or fruit juice, which contains a suitable amount of co-solvent or emulsifier. Liquid carriers can be used in the preparation of solutions, suspensions, emulsions, syrups, elixirs and inhalants. The compounds described herein can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent or a mixture of the two, or a pharmaceutically acceptable oil or fat. The liquid carrier may contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, pigments, viscosity regulators, stabilizers, and osmotic pressures. Conditioner. Examples of liquid carriers for oral and parenteral administration include water (particularly water containing the above additives, such as cellulose derivatives such as sodium thioglycolate solution); alcohol (including monohydric alcohols and polyhydric alcohols such as Alcohols) and their derivatives, as well as oils (for example, coconut oil and peanut oil). For parenteral administration, the carrier can be an oil such as ethyl oleate and isopropyl myristate. Sterilized liquid carriers are used to sterilize the liquid composition for administration to the intestines 10 times. The liquid carrier used to pressurize the composition can be a halogenated hydroxy or other pharmaceutically acceptable push spray. The liquid pharmaceutical composition of the sterile solution or suspension can be used, for example, in intramuscular, intraperitoneal or subcutaneous injection. The sterile solution can also be administered intravenously. The composition for oral administration can be in a liquid or solid state. 15 The pharmaceutical composition is preferably formulated in a unit dosage form such as a lozenge, capsule, powder, solution, suspension, emulsion, granule or suppository. In such a form, the pharmaceutical composition can be subdivided into unit dosages containing appropriate quantities of the active compound. The unit dosage form can be a packaged composition, such as a packaged powder, a glass vial, an injection, a prefilled syringe, or a liquid containing drug pack. Alternatively, the unit dosage form 20 can be a capsule or lozenge itself, or it can be any suitable number of such compositions in the package. Such unit dosage forms can contain from about 1 mg/kg to about 500 mg/kg of active compound, and can be in a single dose or in two or more doses. This dose can be administered by any means that directs the active ingredient into the recipient's bloodstream, including orally, via implantation, parenteral (including intravenous, 29 200815356 intraperitoneal and subcutaneous injections), rectal, vaginal and meridian The skin is administered. Such administration may utilize the compounds of the present invention which are formulated into emulsions, creams, foams, patches, suspensions, solutions and suppositories (rectal and vaginal) including pharmaceutically acceptable salts thereof. When used to treat or inhibit the administration of a particular disease state or disorder, 5 it is understood that the effective dose depends on a number of factors, such as the particular compound utilized, the mode of administration, and the severity of the condition being treated, and the individual being treated Various physical factors related. When applied to a therapeutic, the compound of the invention is provided in an amount sufficient to heal or at least partially alleviate the symptoms of the disease and its complications. The dosage used to treat a particular individual must generally be determined by the attending physician. The difference between them is related to the specific disease and its state as well as the patient's weight, age and response. In some instances, such as in the case of organs marked with lungs, it is preferred to utilize devices such as metered dose inhalers, breath operated inhalers, multi-dose dry powder inhalers, pumps, squeeze-start spray applicators The aerosol delivery device and the gasification spray directly dose the compound into the patient's trachea. For intranasal or tracheal inhalation administration, the compounds of the present invention can be formulated into a liquid composition, a solid composition, or an aerosol composition. The liquid composition illustrated by the illustration includes one or more compounds of the invention dissolved, partially dissolved or suspended in one or more pharmaceutically acceptable solvents, and the administration thereof is utilized in Example 20, such as a pump or squeeze start spray. Medicament. The solvent is, for example, isotonic saline or sterilized water. The solid composition illustrated by the illustration is a powder formulation containing one or more compounds of the invention in admixture with lactose or other inert powders for use in the trachea, and the encapsulating solid composition by, for example, an aerosol applicator or disrupting or piercing The capsule is used to deliver a solid composition by inhalation to a device of 30 200815356. The illustrated aerosol composition contains one or more compounds of the invention, a push spray, a surfactant, and a cosolvent, and is administered by a metered device. The push spray is chlorofluorocarbon (CFC), hydrofluorocarbon (HFA), or other push sprays that are physiologically and environmentally acceptable. 5 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 may be prepared in water suitable for mixing surfactants such as hydroxypropylcellulose. The dispersion can also be prepared from glycerin, liquid polyethylene glycol and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations usually contain 10 preservatives which inhibit the growth of microorganisms. Pharmaceutical dosage forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for use in sterile preparations or dispersions. In a preferred embodiment, the dosage form is sterilized and its viscosity allows it to flow through a needle. The dosage form is preferably in a stable state under the conditions of manufacture and storage 15 and can be preserved in a state not contaminated by, for example, bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils. The compounds described herein can be administered by transdermal administration, i.e., through the inner surface of the skin surface and body passages, including epithelial and mucosal tissues. Such administration may utilize 20 of the compounds of the present invention in the form of emulsions, creams, foams, patches, suspensions, solutions and suppositories (rectal and vaginal) including pharmaceutically acceptable salts, hydrates and esters thereof. Topical formulations for delivery of the active compounds via the epidermis are useful for the topical treatment of inflammation and arthritis. Transdermal administration can be in any form such as milk by containing the active compound and inert to the compound, without maternal to 31 200815356 skin and delivering the active compound through the skin to the systemic bloodstream. Creams and ointments, ointments, gels and closures. The creams and ointments are viscous or semi-solid emulsions of oil-in-water or water-in-oil. The ointment contains an adsorptive powder dispersed in petroleum or a hydrophilic petroleum containing an active compound. The active compound can be released into the bloodstream using a variety of occlusive devices, for example, a semipermeable membrane coated with or without a carrier active compound or a container containing the active compound matrix. Other closure devices are known in the literature. The compounds described herein can be administered intrarectally or intravaginally using conventional suppositories. The suppository formulations can be prepared from conventional materials including cocoa butter and glycerin with or without other modifications to the suppository. It is also possible to use a water-soluble test substance 'e.g., polyethylene glycol of various molecular weights. The compounds of the invention may be introduced into host cells in vitro or in vivo using a monthly mussel formulation or nanoparticle. 15 lipid formulations and nanoparticles can be prepared by methods well known in the art. Compounds effective to treat other drugs of the underlying disease may be used in combination to increase the effectiveness of the compounds of the invention. For inflammatory diseases, the active compounds of the invention may be administered in combination with other active compounds (i.e., other active ingredients or drugs) effective for use in the treatment, particularly in the treatment of asthma and arthritis. The 20 other drugs may be the same or different dosing times as the compounds described herein. The composition described in the entire patent specification has, contains or contains a specific component' or the process thereof has, contains or contains a specific process step, and the composition of the invention consists essentially of or consists of the component, And the process of the present invention also consists essentially of or consists of the process steps described. 32 200815356 In this patent application, when an element or component is included and/or selected from the list of listed elements or ingredients, it is understood that the element or component can be any one of the elements or ingredients and can be selected from two or more A group of elements or components. Unless expressly stated otherwise, the words "including" are used in the contin Otherwise, the word "about" before the quantitative value of the present invention also includes its specific quantitative value. It should be understood that the order of the steps and the specific actions performed without affecting the present invention are not important. Or a plurality of steps or actions. Unless otherwise stated in the specification or has been designated as - a specific chemical & 'the compound itself or its pharmaceutically acceptable salt vinegar, otherwise "compound," The compound itself and its doctors are subject to salts, hydrates and esters. On the table can be connected here 15 "halogen, or ordinal, refers to fluorine, chlorine, and iron. This thiol refers to the oxygen of a double bond (ie, = 〇). Here at the base _ partial base, The purpose of m is -4 chain or saturation reduction. In some specific implementations, the transfer may have 1 magic 20 :: for example, from 1 to 6 carbon atoms. Examples of alkyl groups include methyl dimethy), propyl ( For example, n-propyl and isopropyl); butyl (eg isobutyl, symmetric butyl, tert-butyl); pentyl (eg, n-di-yl-neopentyl), etc. _中,烧', independently selected from _Y-R4, _Y-R^Rl2& I is backed up to four or more substituents, wherein Y, R4, R8 are as defined herein. - Lower grade base - There are up to 6 carbon atoms 33 200815356, ie one to six carbon atoms. Examples of lower alkyl groups include mercapto, ethyl, propyl (for example, n-propyl and isopropyl), and butyl (for example, n-Butyl, isobutyl, symmetrical butyl, tert-butyl). "Alkenyl," in the group or part of a group, refers to a straight chain having one or more carbon 5-carbon double bonds or Branched alkyl. In some embodiments, an alkenyl group can have from 2 to 10 carbon atoms (e.g., from 2 to 6 carbon atoms). Examples of the alkenyl group include a vinyl group, a propenyl group, a butenyl group, a pentenyl group, a hexenyl group, a butadienyl group, a pentadienyl group, a hexadienyl group and the like. The one or more carbon-carbon double bonds may be on the inside (e.g., 2-butene) or on the end (e.g., i-butene). In some embodiments 10, the alkenyl group can be substituted with up to four groups independently selected from -Υ-R8 or wherein Y, R8 and R12 are as defined herein. "Alkynyl" as used herein in the group or part of a group refers to a straight or branched alkyl group having one or more carbon-carbon triple bonds. In some embodiments, the alkenyl group may have from 2 to 10 carbon atoms (for example, from 2 to 6 carbon atoms). The 15 examples of alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, etc. The one or more carbon-carbon triple bonds may be used. On the inside (for example 2-butyne) or at the end (for example 1-butyne). In some embodiments, the alkynyl group can be substituted with up to four groups independently selected from -γ-R8 or R12, wherein Y R8 and R12 are as defined herein. Alkoxy group here means -0-alkyl. In some embodiments, the calcined base 20 can have from 1 to 10 carbon atoms (e.g., from 1 to 6 carbon atoms). Examples of the alkoxy group include a methoxy group, an ethoxy group, a propoxy group (e.g., n-propoxy group and isopropoxy group), a third butoxy group and the like. Here, "alkylthio" refers to -S-alkyl. Examples of the alkylthio group include a methylthio group, an ethylthio group, a propylthio group (for example, n-propylthio group and isopropylthio group), and a third butylthio group 34 200815356

"Haloalkyl" as used herein refers to an alkyl group having one or more halo substituents. In some embodiments, the lialkyl group can have from 1 to 10 carbon atoms (eg, from 1 to 6 carbon atoms) Examples of haloalkyl groups include CF3, C2F5, CHF2, 5CH2F, CC13, CHC12, CH2Ch C2C15, etc. The perhalogenated alkyl group is also within the definition of "haloalkyl", and all of its hydrogen atoms are replaced by halogen atoms. (e.g., CF3 and C2F5). Here, "cycloalkyl" refers to a non-aromatic carbocyclic group including a cyclized alkyl group, an alkenyl group, and an alkynyl group. The cycloalkyl group may be a single ring (for example, cyclohexyl group) or more. A ring (for example, having 10 fused, bridged, and/or helical systems) wherein the carbon atom is internal or external to the ring system. The cycloalkyl group as a whole may have from 3 to 14 ring atoms (eg, monocyclic naphthenes) The base is from 3 to 8 carbon atoms and the polycyclic cycloalkyl group is from 7 to 14 carbon atoms. Any cycloalkyl group at the appropriate ring position can be covalently bonded to a defined chemical structure. Examples of cycloalkyl groups Including cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, cyclohexylethyl, cycloheptane , cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, n〇rcaryl, Adamantyl and helical [4·5]decyl, and analogs, isomers, etc. In some embodiments, the cycloalkyl group can be as high as four independent from -Y Substituting -R4, -Y-R8 or R12, wherein Y, R4, R> Rl2 are as defined herein. For example, a cycloalkyl group may include a substitution of one or more oxy groups. Here "hetero atom" Refers to atoms of any element other than carbon or hydrogen, such as nitrogen, oxygen, sulfur, 粦, and lithix. 35 200815356 "Heterocyclic alkyl," meaning at least one selected from the group consisting of 〇, 5 10 15 20 A hetero atom and a non-aromatic alkyl group optionally containing one or more double or triple bonds. The heterowei group may have, for example, 3 to 14 ring atoms and 5 to 15 ring hetero atoms (for example, 'monocyclic heterocyclic ring is from 2 ring atoms and polycyclic heterocyclic fluorenyl groups are from 7 to 14 rings atom). One or = N or S atoms in the heterocyclic ring can be oxidized (e.g., oxidized sulfonate, & sulphur oxide s, s-dio-oxidized sulphur). In some embodiments, the nitrogen atom of the heterocycloalkyl group can carry a substituent such as _y_r8*r12, wherein Y, r8 and ru are as defined herein. The heterocyclic group may also contain - or a plurality of oxy groups, such as mother. Ketone, ten sit diketone, shot_2, 4 (10), Kun Erqi kiss and other chat. Examples of heterocyclic leukoxyl groups include, among others, morphine, thiophene, pyran, imidaz〇lidine, sedative, and pyridinium torazolidine. Than the saliva " than a little bite, mouth than 〇 琳 琳, tetrachlorine, tetrahydro porphin, brigade bite, piperazine (piperazine). In some embodiments, a heterocycloalkyl group can be optionally substituted with up to four groups independently selected from _y_r4, _y_rS or R12, wherein γ, r4, r>ri2 are as defined herein. - "Aryl," means an aromatic monocyclic hydrocarbon ring system or a plurality (tetra) of two or more aromatic hydrocarbon rings which are fused to each other (i.e., have a -co-into-aromatic monocyclic hydrocarbon ring to be fused To - or a ring county and / / Wei-based ring. The aryl group may have 6 to 14 germanium atoms in the ring system, which may include multiple fusion %. In some specific examples, a polycyclic aryl group It may have from 8 to 14 carbon atoms. Any suitable ring position (tetra) group may be attached to a chemical structure by a covalent ship. Examples of the aryl group having an aromatic hydrocarbon ring include a phenyl group, a 1-naphthyl group (double %) , 2-nyl (double %), fluorenyl (tricyclic), phenanthryl (tricyclic), and the like. 36 200815356 At least one aromatic carbocyclic ring is fused to one or more cycloalkyl groups and/or Examples of polycyclic ring systems of heterocycloalkyl rings include, among other things, ring calcination (i.e., a dichlorobenzyl group, which is a 5,6.bicyclic cycloalkyl/aromatic ring system); cyclohexene (i.e., Tetrachlorocainyl, which is a 6,6-bicyclic cycloalkyl/aromatic ring system); imidazoline (ie, benzoxazolidinyl, which is a 5,6-bicycloheterocycloalkyl/aromatic ring) System), and whispering (ie, color base, its a benzo derivative of a 6,6,-bicyclic heterocycloalkyl/aromatic ring system. Other examples of aryl include benzodioxanyl, benzodioxolyl, benzodiazepine Oryl, porphyrinyl, etc. In some specific examples, the aryl group may optionally contain up to four groups independently selected from 10 R4, -Y-R4, -OH, _Yf or Ru, wherein γ , r4, core R12 is as defined herein. Here, "heteroaryl" means an aromatic monocyclic ring system or ring containing at least one ring hetero atom selected from the group consisting of oxygen (〇), nitrogen (N) and sulfur (s). At least one ring in the system is aromatic and a polycyclic system containing at least one ring hetero atom. When more than one ring hetero 15 is present, it may be the same or different. The polycyclic heteroaryl includes two or more fused to each other. a heteroaryl ring and a monocyclic heteroaryl ring fused to one or more aromatic carbocyclic, non-aromatic carbocyclic and/or non-aromatic heterocycloalkyl rings. The heteroaryl group as a whole may have, for example, 5 to 14 Ring atoms and containing 1 to 5 ring heteroatoms. The heteroaryl group can be attached to a defined chemical structure at any heteroatom or carbon atom to form a stable 20 构造 structure. The heteroaryl ring does not contain a 0-0, SS or S-0 bond. However, one or more atoms in the heteroaryl group can be oxidized (eg, oxidized pyridine, thiophene oxidized, S, s-double oxidized) Examples of heteroaryl groups include, for example, the following single ring and 5 to 6 double ring systems: 37 200815356

Wherein T is Ο, s, NH, N-Y-R4, Ν-Υ-R8 or NR12; and Υ, R4, R8 and R12 are as described herein. Examples of such heteroaryl rings include pyrrolyl, furyl, porphinyl, fluorenyl, sulfonyl 12, fluorenyl, sigma, succinyl, tetrazolyl, pyrazolyl, imidazole , isothiazolyl, thiazolyl, thiadiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, fluorenyl, isodecyl, benzofuranyl, benzothienyl, quinolyl , 2-methyl quinolyl, isoquinolinyl, 若 若 琳 啥, 啥 琳 基, benzotrisyl, benzo-salt, benzothiazolyl, benzisothiazolyl, benzo Isoxazolyl, benzoxadiazole 10, benzoxazolyl, cinnolinyl, 1 Η-carbazolyl, 2 Η-carbazolyl, fluorenyl, isobenzofuranyl, Naphthyridinyl, hydrazine, pteridinyl, fluorenyl, oxazoline pyridyl, thiazolidine, sulphonyl, fluoropyridyl, thienopyridyl, pyridinyl, pyridyl. The ratio of morphine, σ, 哈, σ, 嗔, 嗔, ϋ, ϋ, σ, σ, σ, σ, 哇, 哇, Further examples of the heteroaryl group include 4,5,6,7-tetradecyl, tetrahydroindenyl, benzoxanthene sigma, benzofluorenyl fluorenyl and the like. In some embodiments, the heteroaryl group can be substituted with up to four groups independently selected from the group consisting of r4, -Y-R4, _〇_y_r4, -Y-R8 or R12, wherein 丫, 厌4, han8 And "2 is as defined herein. The compound of the invention contains a "divalent group" as described herein as a linker to two other groups 38 200815356 (tetra)-co-(iv). For example, the compounds described herein contain a double The valence c^o alkyl group is, for example, a mesyl group. The substituents of the compound are disclosed in a plurality of places in a group or in a specific range. Specifically, it includes each individual of the group and the members in the range. Sub-combination. For example, "Cl~Wiki" is a (4) indeed revealing Cl, c2, C3, C4, C5, C6, C7, C8, C9, Ci, Ch〇, Ci~9, Ci~8, c, ~7, cv6, Cl~5, Cl~4, Cl~3, Ci~2, C2, c2~9, Cm, Cw, c2~6, C2~5, C2~4, c2~3, c3, , c3 to 9, c3 to 8, c3 to 7, Cw, C3 to 4, c4 to 10, c4 to 9, c4 to 8, C4 to 7, c4 to 6, c4 to 5, c5 to i, c5 ~9, 10 15 20 c5~8, C5~7, C5~6, C6M ❶ 'c(4), c", c6~7, Cw, Cm, c7~8, C8~10, C8~^c9 By other examples, "5 to 14 membered heteroaryl groups" are specifically disclosed to have 5, 6, 7, 8, 9, , Η, a, 13, 14, 5 to 14, 5 to 13, 5~12, 5~U, 5~10, 5~9, $~8, 5~7, 5~6, 6~14, 6~13, 6~12, 6~11, 6~10, 6~ 9, 6 to 8, 6 to 7, 7 to 14, 7 to 13, 7 to 12, 7 to U, 7 to 1 , 7 to 9, 7 to 8, 8 to 14, 8 to 13, 8 to 12 , 8~1 Bu 8~10, 8~9, 9~14, 9~13, 9~12, 9~U, 9~10, 10~14, 10~13, 10~12, UMi, U~14 , u~13, u~12, i2~i4, 12~13 and 13~14 heteroaryl groups of ring atoms, and the words "selectively substituted by four substituents" are specifically disclosed Containing hydrazine, hydrazine, 2, 3, 4, 0 to 4, 0 to 3, 0 to 2, 〇~1, 卜4, u, 卜2, 2~4, 2~3 and 3~4 substituents. The compounds described herein may contain an asymmetric atom (also known as the center of the palm), and some compounds may contain one or more asymmetric atoms or centers which may thus form optical isomers (mirroromers) and Non-image isomer. This 39 200815 356 of the invention disclosed herein and non-mirrored optical isomers (mirrible isomers of pure stereoisomers, ',) and other mixed stereoisomers of the genomic isomers and their pharmaceuticals Acceptable salts; obtain 'purified two:: the technocrats of this technology can be resolved by conventional standard process energy analytical methods and asymmetric abundance including non-image mirror salt formation methods, olefins and imines) The invention also includes alkenyl-containing groups (e.g., including all possible and trans isomers). It is also understood that the present invention can be obtained by a conventional method, a mixture thereof, a method of obtaining a purified product by the method of the present invention, a film color =: Γ, and a tube layer method and a directional solution Phase chromatography. In the full text patent description 蚩. : Any naming occurs - a method by which the compounds shown herein can be prepared according to the following ttr. The compounds of the invention, which are known in the literature, are prepared using commercially available starting materials. Alternatively, the compounds of the present invention are prepared by standard methods of synthesis and familiar procedures. The standard synthesis method and procedure for the preparation of the organic transformation and the use of the basics can be easily obtained from the relevant textbooks of the relevant sciences and syllabuses. It will be understood that although the process is general or better, Conditions (ie, reaction temperature, time, reaction: molar tb, _, diligent, etc.), but other process conditions may be used unless otherwise ambiguous. The optimal reaction conditions may depend on the specific agent or solvent used. However, those skilled in the art can arbitrarily determine the condition by conventional maximum order. Those skilled in the art of organic synthesis will understand that the nature and sequence of the illustrated 5 steps may be optimized for the formation of the compound. 40 200815356 is different. The process described herein can be monitored according to any suitable method known in the art. For example, the formation of products can be monitored by spectroscopy, such as nuclear magnetic spectroscopy (eg, 1H or infrared spectroscopy, Spectroscopic spectroscopy (for example, ultraviolet visible light), or mass spectrometry and/or chromatography (such as high performance liquid chromatography (HPLC) or thin film chromatography). And the chemical and deprotective effects of various chemical groups. "This technology can (4) determine the protection and deprotection required and select the appropriate protective group. The chemical of the protective group can be referred to, for example, sputum plus 10, etc. The protection of socks is poor, Wiley & Sons Publishing Company, 4th edition, 4th edition, the full disclosure of which is incorporated herein by reference. The skilled artisan can easily choose the appropriate one. The solvent is used to carry out the process reactions described herein. Suitable solvents are generally inert to the reactants, intermediates and/or products at the reaction temperature, i.e., from the freezing temperature of the solvent 15 to the boiling temperature of the solvent. A known reaction can be carried out in a solvent or a mixture of more than one solvent. A solvent suitable for a particular reaction step can be selected depending on the particular reaction step. The following method 1 describes an example of an intermediate for the preparation of a compound of formula I. Sexual synthesis pathway. 20 Method 1

41 200815356 The acetate i is converted to 3-oxo by reaction with an acetonitrile anion prepared by reacting acetonitrile (ch3CN) with a strong base such as n-butyllithium (n-BuLi) in a solvent such as THF. Nitrile ii. In the solvent (such as i22 ° C) in a solvent such as DMF, oxobutyronitrile ii and dimercaptoacetamide-diacetal (DMF-DMA) can form a didimethylamino group. The olefin intermediate iii, which is converted to 4-hydroxynicotinic acid nitrile iv by reaction with ammonia (NH3) or ammonium acetate (nh4OAc) under reflux of a solvent such as ethanol. Hydroxypyridine can be converted to 4-chloro-acid nitrile v by reaction with oxygenated phosphorus (POCU) for 2 to 6 hours with or without catalyst DMF. Method 2 below is an alternative procedure for the preparation of 3-oxobutyronitrile ii. This alternative method 10 involves converting acetic acid vi to the corresponding chlorinated acid by reaction with a chlorinating agent such as cerium chloride (S0C12) followed by using a third butyl cyanoacetate with a solvent such as THF. The reaction of the anion of the third butyl cyanoacetate prepared by the reaction of sodium hydride (NaH) produces 2-cyano-3_oxobutyric acid tert-butyl ester vii, which undergoes the deprotection of the ester and The decarboxylation of an acid such as trifluoroacetic acid (TFA) 15 produces 3-oxobutyronitrile ii. Method 2

Alternatively, as described in the following Process 3, the bisdimethylaminomethene intermediate Ic obtained by the reaction of 3-oxobutyronitrile and DMF-DMA can be used in a 20 reflux solvent such as toluene and 3, 4 - Dioxobenzylamine is reacted to give 1-(3,4-methoxycarbonyl)-4-oxo-1,4-dihydrocarbonitrile viii. The dimethoxybenzyl group was removed by reacting viii with excess LiCl in reflux p〇ci3 and converted to the 4-gas-terminal acid nitrile v to 42 200815356. Method 3

Viii The following Method 4 is an exemplary synthetic route for the preparation of compounds of Formula I. 5 Method 4

A compound of formula I wherein X is _NR3(CH2)n_, -NR3(C0)-, -0_ is prepared by reacting C_5 substituted 'chloro-3-3-cyanoacridinium with R^XH under one of the following reaction conditions. Or -s· ' n=0 〜1〇: (1) The presence of pyridine hydrochloride (Pyr HC1) 10 at a temperature of 60 to 180 ° C in a solvent such as ethanol (EtOH), propanol, butanol, 2-ethyl lactate Intoxication (EtEtOH), 2, oxime or 2-butoxyethanol; (2) in a solvent such as tetrahydrofuran (THF) or dimethylformamide (DMF) at a temperature of 60 to 120 ° C Bases such as sodium hydride (NaH); (3) 80 to 150 in the presence of a base such as potassium phosphate (Κ3Ρ04) or third potassium hydride. (Using a palladium catalyst 15 such as tris(dibenzylidene)acetone dipalladium (Pd2(dba)3) and a phosphine ligand such as 2-biscyclohexylphosphine-2'-(Ν,Ν·dimethylamino) at a high temperature Biphenyl (DavePhos) or tributylphosphine; (4) at 43 200815356 80~150 ° C for use in solvents such as DMF, N-methyl-2-u than slightly bite steel (NMP) or EtEtOH organic Such as triethylamine (tea), u ratio or diisopropylethylamine (DIEA); (5) inorganic test in a solvent such as acetonitrile (CH3CH) or DMF at a temperature of 80 to 150 ° C Barium carbonate (cS2c〇3). 5 When X is a covalent bond, a solvent such as dimethoxyethane (DME) and an aqueous solution of sodium hydrogencarbonate in the presence of a phosphine ligand such as triphenylphosphine (PhJ) is selectively present ( Use a catalyst such as tetrakis(triphenylphosphine)palladium(〇) [(PhJhPd] or palladium acetate (II) (Pd (0Ac)2) in a mixture of NaHC〇3) or sodium carbonate aqueous solution (aq·NafO3). Preparation of Formula I by C-5 Substituting C-5 for Substitution of 4-Chloro-3-cyanopyrrole v with a Side Acid of Formula 10(R) 2 or a Deesterified Ester of Formula R/BCOR) 2 a compound 'wherein R is a calcinyl group (for example, a lower alkyl group). Alternatively, the treatment of 4-chloro-cyanide with a tin-fired R^SnR3 Further, a compound of the formula I is produced, wherein r is an alkyl group (for example, a lower alkyl group). Referring to the following method 5, R2 may be removed from a group (LG) 15 such as bromine (Br) or iodine (I). a compound of formula I (formula 1b) wherein R2 is selected from aryl, heteroaryl, Substituted by an alkenyl group and an alkynyl group of R4.

More specifically, a solvent such as DME and aq. NaHC03 or aq. Method for treating a compound of formula 1a (wherein R is a lower alkyl group) with boric acid (R4B (〇H) 2), 44 200815356 vinegar vinegar (r4b(〇r) 2), or with an organostannane reagent (for example, R4SnBu3) A compound of formula lb is prepared wherein R4 is aryl or heteroaryl. Similarly, there is a palladium catalyst (for example, (Ph3P)4Pd, dichlorobis(triphenylphosphine) 5 (Π) or Pd(〇Ac) 2) in a solvent such as DMF, NMP, dioxane or DME. A compound such as Ph3p or o-tolylphosphine and a base (for example, potassium carbonate (k2C03) or Na2CO3) is optionally added with an organic base such as tea and an alkene or alkyne of the formula R4-H or a boronic acid or boron ester or organotin. Alkane Reagent Treatment The compound of formula lb wherein R4 is an alkenyl or alkynyl group is prepared by the method of a compound. A catalytic amount of 10 copper iodide (I) can be selectively used in this coupling reaction. Method 6 describes a synthetic route for the preparation of other compounds of formula I (Formula Id) wherein R2 and R4 are aryl or heteroaryl and R4 is further substituted with a captanamine. Method 6

15 The presence of a catalyst (for example, benzotriazol-1-yloxytris(dimethylamino)phosphine hexafluorophosphate (BOP)) and an organic amine (for example, TEA, DIEA or pyridine) at room temperature to 50~ The compound of the formula Id is produced by treating a compound of the formula I (Formula Ic) wherein R2 is substituted with a carboxylic acid-substituted aryl or heteroaryl group in a solvent such as MeOH or EtOH at a temperature of 80 ° C, such as MeOH or EtOH. 20 According to the following method 7, there is Nal or a test such as K2C03 under solvent

Treatment of amines with NHR6R7 in EtOH, DME or DMF with R2 substituted by -〇γ-LG, LG of Cl, Br, fluorite (mesyl, 〇Ms) or p-toluene 45 200815356 sulfonyl ( Tosy OTs) a compound of formula I (formula (8) to prepare another compound (formula If) wherein R2 is substituted by -0-Y-NR6R7. Method 7 XR1 XR1

LG=C1, Br, OMs, OTs 5 As described in Method 8, there is a solvent such as di-methane (a solvent such as triethylphosphonium hydride (Na(0Ac)3BH) or sodium cyanoborohydride). CH2C12) or THF to prepare a compound of formula I (Formula Ih) by treatment with a compound of formula I (Formula Ig) wherein R2 contains an aldehyde functional group, preferably with the presence of acetic acid, optionally with DMF or NMP, with an amine of formula HNR6YR7 , wherein R2 is taken from -CH2-NR6R7 for 10 generations. The by-product formed in this reductive amination reaction is a compound of the formula I wherein R2 is replaced by -CH2-OH (formula). Method 8

The compound of formula I (formula Ik) is prepared as described in method 9, by treating the compound of formula I (formula Ij) wherein R2 contains a hydroxy functional group with an alcohol of formula I5 r5y〇H under a Mitsunobu reaction condition, wherein R2 is replaced by _〇YR5. This reaction is carried out in a solvent such as THF in the presence of Ph3P and diethyl azodicarboxylate or ditributyl azodicarboxylate. Method 9 46 200815356 XR1 XR1

Other formula compounds can be prepared as shown in the following Process 10, Process 11 and Process 12, wherein X is not a bond. Method 10

The mixture of 3-aminobut-2-enenitrile ix is heated in an acid (e.g., aqueous hydrochloric acid) to yield acetonitrile acetonitrile X. Treatment of acetonitrile acetonitrile X with tributoxy bis(dimethylamino)methane and DMF-DMA at elevated temperature to give 5-(dimethylamino)-2-[(dimethylamino)methylene ]-3-oxopentane dilute nitrile xi, which is then treated with ammonium acetate in refluxing EtOH to give 4-hydroxynicotinonitrile xii. (Reported in the literature - 4-based on acid-based alternative synthesis: Broekman, F. W. ^ A 5 Recueil des Travaux Chimiques des Pays-Bas 5 81 * 792~796 (1962)). Mixing 4- via acid nitrile xii, angstrom and NaOH in water overnight to produce 4-3⁄4 base-5-angstrom acid, which is then treated with P0C13 at a temperature of 15 to produce 4-chloro-5 - Iodonicotinonitrile xiv. 4-substituted 5-iodonicotinonitrile xv is then produced as RiH, where X is not a bond (e.g., 1143⁄4, WOH, WSH, etc.) at 47 200815356 intermediate intermediate xiv. It is further treated with the salt of the formula I, R2B(OH)2, boronate R2B(OR)2 or stannane R2SnR3, which is a lower alkyl group in each case. Alternatively, the intermediate xiv may be treated with boric acid R2B(OH)2, borate R2B(OR)2 or stannane R2SnR3 (which in each case is a lower alkyl group) followed by reaction with 111:^11 Produce a formula compound. Method 11

If not in the method 11, the 4-chloro-5-iodo-1-oxo is produced by treating 4-chloro-5-iodonicotinonitrile xiv with oxidizing agent of preferably 10 hydrogen peroxide in trifluoroacetic acid at a temperature of 〇5CTC. Nicotinic acid nitrile xiv. The ruler 411 is added under the foregoing conditions to produce a compound of the formula χν. The compound of formula I is produced by adding boric acid, an ester or an organotin (which is a lower alkyl group in each case) under the foregoing conditions.

N xvi

CN R^H

4-fluoro group to give a compound of formula i. As shown in Method 12, the 4-fluoro analog xvi is produced by treating the compound of formula ν with CsF in a solvent such as DMF. Subsequent to the replacement of r1 纽 in a solvent such as DMs, the aspect of the invention can be further understood from the following examples, but no ISI should be used under any conditions. The present invention is limited only to this range. 48 200815356 More specifically, the following examples illustrate various synthetic routes that can be used to prepare compounds of formula. Example 1: Preparation of 4-[(3-phenylphenyl)amino]-5-(3,4-dioxanoxyphenyl)nicotinic acid nitrile 101 5 Methanol (MeOH, 100 mL) with concentrated sulfuric acid (h2S) A solution of 4,1 ml) or concentrated hydrochloric acid (HC1) in 3,4-dioxyloxyphenylacetic acid (5 mM molecule) was heated under reflux overnight. Concentrate on a rotary evaporation tray to dryness and then under high vacuum to obtain the oily (3,4-dimethoxyphenyl) decyl acetate directly used in the next step. 10 50 ml of THF was placed in a 升·0 liter three-necked round bottom flask and the reaction mixture was cooled to -78 °C. Butyllithium (1.6 moles, 14.4 milliliters, 23 millimoles) was added dropwise at a temperature below -70 °C. Acetonitrile (1.3 ml, 25 mmol) in 3 mL of THF was added dropwise to the flask with stirring and then cooled. After stirring for 2 hours, (3,4-dioxanoxyphenyl)acetic acid decyl ester (2.3 g, u 15 mmol) was added to form a white gum mixture in the flask. The reaction mixture was stirred for a further two hours, then a saturated aqueous solution of ammonium chloride (75 mL) was added at -78 °C. The organic layer was separated, dried over sodium sulfate, filtered and evaporated to dryness. The crude product was purified by hydrazine column chromatography eluting with 30 to 70% ethyl acetate in hexane to yield 18 g (75%) of EtOAc (yield: 4-(3,4-) Dimethoxyphenyl)_3_oxobutyronitrile. Add DMF-DMA (13. 5 ml, 1 〇 1 mmol) to 4-(3,4-dioxanoxyphenyl)-3.oxodidine (5 g, in dmf (12 ml), The solution was then heated overnight at 122 C. Concentrate on a rotary evaporator under high vacuum to obtain an orange-red solid. This solid was dissolved in Et 〇H (i 〇〇 49 200815356 mL) and excess NH 4 〇Ac was added and then the mixture was heated at 85 ° C for 1 hour. The reaction mixture was allowed to cool at room temperature for a few hours (to room temperature) and then the solid was collected by filtration and washed with EtOH (ice cold) to give 5-(3,4-dimethoxyphenyl)-4-hydroxynicotinic acid nitrile ( 4.1 g, 69%) of a brown solid. The filtrate was concentrated on a rotary steaming 5-disc and the residue was purified on a chlorinated gel of 0 to 25% MeOH in dichloromethane (CH2C12) to give an additional amount of 5-(3,4-dimethoxy) Phenyl)-4- is based on an acid nitrile. A solution of 5_(3,4-dimethoxyphenyl)-4-hydroxypentanoic acid nitrile (4 g, 15.7 mmol) in POCIX 25 ml) was heated at 125 ° C for 1.5 hours, then cooled to room temperature and Pour into ice cube / 3 equivalents of sodium hydroxide / ethyl acetate mixture. The mixture was stirred and the layers were separated. The organic layer was dried over magnesium sulfate (MgSO.sub.4) filtered and concentrated to give 4-chloro-5-(3,4-dimethoxyphenyl) as acid acid nitrile (3.9 g, 91%). . 4-Chloro-5_(3,4-dimethoxyphenyl) in EtOEtOH (2 ml) in acid 15 nitrile (55 mg, 〇·2 mmol), 3-chloroaniline (25 mg, 0.2 mM) A solution of moth) and pyridine hydrochloride (23 mg, 0.2 mmol) was heated under reflux for 8 h then cooled to rt and concentrated. The residue was purified by reverse EtOAc to give 5-(3,4-dimethoxyphenyl)-4-[(3-chlorophenyl)amino] nicotinic acid nitrile 101 (3 4 mg). MS ·· 367[Μ+Η]. 20 The following procedure is similar to the procedure for preparing the compound of Example 1 and the compound of Table 2 is prepared using the appropriate aniline in the final step. The retention times of HPLC provided in Table 2 and Examples 2-22 utilize the following conditions: (8) Instrumentation Agilent 1100; Column: Keystone Aquasil C18, taken from Thermo Fisher Technologies, Inc. (Waltham, MA); Mobile Phase a: 50 200815356 10 mg of NH4OAc in 95% water / 5% CH3CN; mobile phase B: 10 mg of NH4OAc in 5% water / 95% CH3CN; flow rate: 0.800 ml / min; column temperature: 40 ° C; b) Column – YMC C18 from YMC (Kyoto City), 5 4.6x500 mm, 5 μm; mobile phase A: 90% water + 10% MeOH + 0.02% H3P〇4; mobile phase B: 90 % MeOH + 10% water + 0.02% H3P〇4; 1~ 100% B in 2 minutes up to 10 minutes 1% B, then 100~1% B in 1 minute; (c) Column one taken from Phenomenex Company (Torrance, Calif.) 10 Prodigy ODS3, 4.6 x 150 mm; mobile phase A: 0.02% TFA in water; mobile phase B: 0.02% TFA in CH3CN; 10 to 95% B in 20 minutes; flow rate: 1·0 ML/min; column temperature: 4 (TC; detection wavelength: 215 nm; and (4) pipe column taken from Thermosil C18, 50 from Thermo Fisher Technologies, Waltham, MA Χ2·1 mm; mobile phase A: 0.1% citric acid in water; mobile phase B: 0.1% formic acid in acetonitrile, 〇~i〇〇〇/oB in 2.5 minutes; flow rate: 0.8 ml/min; column temperature: 40 ° C; Detection wavelength: 254 nm 0 51 200815356 Table 2 Compound compound name HPLC retention time (minutes) Observable ion m/e [M+H] 102 5-(3,4-dioxanylphenyl) -4-[(3-Fluorophenyl)amino]nicotinic acid nitrile 2.12 (8) 350 103 4-anilino-5-(3,4-dimethoxyphenyl) in acid guess N/A 332 104 Φ[( 2,5-difluorophenyl)amino]-5-(3,4-dimethoxybenzoic acid nitrile 1.95 (8) 368 105 5·(3,4-dioxaphenyl)-4-[(3 , 4-dimethoxybenzoylamino]nicotinic acid nitrile 1.60 (8) 392 106 4-[(4-chloro-2-fluorophenyl)amino]-5-(3,4-dimethoxyphenyl) Acid nitrile 2.06 (8) 384 107 4-[(3-chloro-4-fluorophenyl)amino]-5-(3,4-dimethoxyphenyl) to acid nitrile 2.00 (8) 384 108 4·[(4- Chlorophenyl)amino]-5-(3,4-dimethoxyphenyl)nicotinic acid nitrile 1.95 (8) 366 109 5-(3,4-Dimethoxyphenyl)-4-[(2,4- Dimercaptophenyl)amino]nicotinonitrile 2.24 (8) 360 110 5-(3,4-Dimethoxyphenyl)-4-[(4-methoxyphenyl)amino]nicotinic acid nitrile 2.09 (a ) 362 111 4-[(3-Chloro-4_methoxyphenyl)amino]-5·(3,4-dimethoxyphenyl) Nicotinic nitrile 2· 17(8) 396 112 5-(3,4-dioxine Phenyl)-4-[(4-phenoxyphenyl)amino]in acid guess 2.41(a) 424 113 4-[(2,5-dichlorophenyl)amino]5-(3,4 _Dimethoxyphenyl)nicotinic acid nitrile 2.35 (8) 400 114 5-(3,4-Dioxaxyphenyl)-4-[(4-decyloxy-2-methoxyphenyl)amino]nicotinic acid Nitrile 1.85 (8) 376 115 4-[(3,4-Diphenyl)amino]_5-(3,4-dimethoxyphenyl)nicotinic acid nitrile 2.36 (8) 400 116 4-[(5-Chloro-2 -Methoxyphenyl)amino]-5-(3,4-dimethoxyphenyl) Nicotinic Acid 2.12 (8) 396 117 4-{[3-(Benzyloxy)phenyl]amino}-5- (3,4-Dioxaxyphenyl) Nicotinonitrile 2.36 (8) 438 118 5-(3,4-Dimethoxyphenyl)-4-[(4-methylphenyl)amino] (8) 346 119 5-(3,4-dimethoxyphenyl)-4-[(3,4,5-trimethoxyphenyl)amino] Nicotinic nitrile 177(4) 422 120 5-(3,4-dioxin Oxyphenyl)-4-[(3-phenoxyphenyl)amino]nicotinic acid nitrile 2.38 (8) 424 121 4-[(2·chloro-5-methoxyphenyl)amino]-5-(3, 4-Dimethoxyphenyl) Niacin nitrile 2.78 (8) 396 52 200815356

Compound compound name HPLC retention time (min 4) Observable ion m/e 497 122 4_({3·chloro-4_[(3-cyanobenzyl)oxy]phenyl}amino)-5-(3,4 · Dimethoxyphenyl) Nicotinonitrile —— 2.35(a) 123 4-{[3-Chloro-4-(thiophen-2-ylindoleoxy)phenyl]amino}-5_( 3,4-dioxaxyphenyl)nicotinic acid nitrile-2.37(a) 478 124 4-({3-chloro-4-[(3-methylphenyl)oxy]phenyl}amino)-5- (3,4-dioxanylphenyl)nicotinic acid nitrile N/A 487 4-[(3-chloro-4-{[3-(dimethylamino)]]yl}oxy}phenyl)amino] _5_(3,4-dimethoxyphenyl) in acid nitrile----------- 125 2.28(a) 515 126 4-[(2,4-dichlorophenyl)amino]_5_ (3,4-Dimethoxyphenyl)nicotinic acid nitrile 2.16(a) —--- 400 127 N-(3-{[3_Cyano-5_(3,4-dimethoxyphenyl)π ratio淀-4-yl]amino}phenyl)acetamide 1.84(8) 389.2 128 Ν-(3-{[3_cyano_5_(3,4·dioxaphenyl) σ ratio _4_ Amino]phenyl}-indole-methylacetamide 2.76(a) ^-402.7 129 ~^(3-{[3-cyano-5-(3,4-dioxanylphenyl)pyridine 4-yl]amino}phenyl)methanesulfonamide 1.86 (8) 425.1 130 5-[4-(dimethylamino)phenyl]-4-[(3·anoxyphenyl)amino]nicotinic acid Nitrile — 3,) ----- 345.4 131 5-[4-(Didecylamino)phenyl]-4-[(3-fluorophenyl)amino]in acid nitrile 3,) 333.4 132 ~4Η:{3-cyano-5-[4 -(diammonium)phenyl]piperidin-4-yl}amino)benzoic acid 3,) 356.8 340.2 133 4-[(4-cyanophenyl)amino]-5-[4-(dioxin) Amino)phenyl]in acid nitrile 3,) 134 4_[(3,4-difluorophenyl)amino]]5-[4·(dimethylamino)phenyl]nicotinic acid nitrile 3,) --- - 351.2 ^~~~---J Example 2: Preparation of 4-[(3-bromophenyl)amino]-5-(3,4-dimethoxyphenyl) terminal acid 135 8 ml of EtOEtOH 4-chloro-5-(3,4-dimethoxyphenyl) terminal acid guess 5 (〇·5 g, 1.82 mmol), 3-bromoaniline (0.313 g, 1.82 mmol) and 〇〇 A solution of 5 g of pyridine hydrochloride (23 mg, 0.2 mmol) was heated under reflux for 8 hours. The solid was collected and then dissolved in a mixture of sodium hydrogencarbonate (NaHC〇3) and dichloromethane (CH^l2). The layers were separated and the organic layer was dried with MgSO4 and filtered through a pad of Magnasol®. The solvent was removed and then 0.4 gram of 4-[(3-bromophenyl)amino]-5-(3,4-dimethoxyphenyl) fumes were produced from isopropanol / hexane followed by crystal 53 200815356 residue. Acid nitrile 135. HPLC retention time (4): 2.72 minutes; MS: 410.2 m/e (M+H). Example 3: Preparation of 4-{[3-(benzyloxy)-4-chlorophenyl]amino}-5-(3,4-dimethoxy-5phenyl)nicotinic acid nitrile 136 was similarly described in Example 2 The procedure was prepared from 4-ox-5-(3,4-dimethoxyphenyl)nicotinonitrile and 3-benzyloxy-4-chloroaniline. HPLC retention time (4): 2.90 minutes; MS: 470.2 m/e (M+H). Example 4: Preparation of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-5-(3,4-dimethoxyphenyl-10-yl)nicotinic acid nitrile 137 10 mL of DME 4-chloro-5-(3,4-dimethoxyphenyl)nicotinic acid nitrile (〇·5 g, 1.82 mmol), 2,4-dichloro-5-nonanoaniline (0.402 g, 2.1 m) Molar), Pd2(dba)3 (0.167 g, 0.18 mmol), 2-biscyclohexylphosphine-2,-(N,N-dimethylamino)biphenyl (0.22 g, 0.56 mmol) And a mixture of Κ3ΡΟ4 (0·58 g, 2.73 15 mmol) was heated under reflux for 45 minutes. The hot mixture was filtered and the solid was washed with ether. The combined filtrate was washed with saturated NaHC03, dried (MgS 4) and filtered through a pad of Magnasol®. The solvent was removed and the residue was chromatographed on a silica gel. The product was eluted with CH2C12-ether and then recrystallized from isopropanol / hexane to give 0.21 g of 4-[(2,4-dichloro-5- methoxyphenyl)amine 20-based]_5_(3,4· Dimethoxyphenyl) to acid nitrile 137. HPLC residence time (4): 〇·86 min; MS: 430.2 m/e (M+H). The compounds of Table 3 were prepared according to procedures similar to those for the preparation of compounds 137 using the appropriate aniline. 54 200815356 Table 3 Compound 138 139 Compound name HPLC retention time (minutes) Observable ion m/e [M+H1 melting point (°C) Appearance 4: [2 士云多_5-ethoxyphenyl)amino]- 5-(3,4___Oxygen table) End acid guess 444.1 125 ～126 White solid flupropoxyphenyl)amino]-5-(3,4-I-oxygen i·) final acid nitrile 2.35 (8) 458.1 N/A light yellow foam 140 oxy-2,4-dichlorophenyl)amino]_5_(3,4-dioxaxyphenyl)nicotinic acid nitrile 2.47(a) 472.1 N/A light brown foam 141 Dichloro-5-(2-ethoxy)phenyl]amino}-5-(3,4-dimethoxyphenyl)nicotinic acid nitrile 2.35(8) 460.1 N/A ash Gr solids Example 5: Preparation 4 -{[4-(Benzyloxy)-3-phenylphenyl]amino}-5-(3-nitrophenyl)nicotinic acid nitrile 142 5 3-nitrophenylacetic acid (9·5 g, 52 m Mol) and SOC 12 (20 mL) were stirred at room temperature overnight and then evaporated to dryness. NaH (60% dispersion in oil, 5.5 g, 1.4 mmol) was suspended in THF (100 mL) in a separate flask. The mixture was cooled to (TC and then tert-butyl cyanoacetate (8·8 g, 623⁄4 mol) was added. After 15 minutes, the above-mentioned 3 gas 10 nitridinyl hydrazine was added dropwise. The solution was removed, and the mixture was returned to room temperature and then mixed for 4 hours. The reaction mixture was cooled by adding brine, and then extracted with ethyl acetate (EtOAc, 2×200 mL). The combined organic extracts were then concentrated. The unpurified tert-butyl 2-cyano-4-(3-nitrophenyl)-3-oxobutanoate was used in the next step without further purification. Add TFA (4 ml) to a solution of 2-cyano-4-(3-nitrophenyl)-3-oxobutanoic acid tert-butyl ester in toluene (4 mL) (9·5 g, 31 mmol) The solution was heated under reflux for 2 hours, then the solvent was evaporated in vacuo. The residue was purified by flash chromatography eluting to afford 4-(3-nitrophenyloxybutyronitrile), 37% 2 steps). 55 200815356 4_(3 _N-phenylphenyl)_3 oxobutyronitrile was converted to 4-hydroxy-5-(3-nitrophenyl)nicotinonitrile according to the following procedure similar to Example 1, which was then converted Into 'chlorine 5-(3-nitrophenyl) to acid nitrile. 50 liters of 4-chloro-5-(3-nitrophenyl)nicotinic acid nitrile (2.15 g, 8.1*mol) and 4- in EtOEtOH Benzyloxy-3-phenylaniline (1.89 g, 8.1 mmol) was heated under reflux for 6.5 hours. The mixture was cooled and diluted with 45 mL of ether. 10 mL of a solution of hydrochloric acid in hydrochloric acid was added. The solid was collected and washed with ether. The solid was suspended in saturated NaHC03 and EtOAc was stirred and evaporated to dryness. The organic layer was dried (M.sup.4) and then filtered through a pad of 10 Magnasol® to remove solvent and recrystallize from Et. 2·15 g of 4_{[4_(oxy group)_3_gasphenyl]amino nitrophenyl) was obtained as the acid nitrile 142. HPLC residence time (4): 3.06 min; MS: 456.8 m/e (Μ+Η). The compounds of Table 4 were prepared according to procedures similar to those for the preparation of the 142 compound using the appropriate aniline. 15 Table 4 Compound compound name HPLC retention time (minutes) Observable ion m/e [M+H] Melting point CC) Appearance 143 4_{[3_gas·4-(° ratio bit-2·ylmethoxy) Phenyl]amino}-5-(3-decaphenyl) to acid nitrile 2.74 (8) 458.1 183~185 brown solid 144 4_[(3_chloroidyl 1 phenyl)amino]_5_(3_nitrophenyl) Niacin nitrile 2.84(8) 369 165 175 175 brown solid Example 6: Preparation of 5-(3-aminophenyl)-4-{丨4-(hydroxy)-3chlorophenyl]amino} Nicotinic nitrile 145 4-{[4-(Benzyloxy)-3-chlorophenyl]amine 20-yl}-5-(3-nitrophenyl)nicotinic acid nitrile 142 (2.0 g, 4.38 mmol) in 90 mL MeOH A mixture of iron (1.47 56 200815356 g, 26.3 mmol) and acetic acid (AcOH, 1.58 g, 26.3 mmol) was stirred under reflux for 3 hours. The hot mixture was filtered and the collected solid was washed with THF. The combined organic solution was concentrated and then redissolved in a hot THF-ethyl acetate mixture. The suspension was filtered and washed with brine/saturated NaHC03 5 . The organic layer was dried (MgS04) and then filtered through a pad of Magnaso. The solvent was removed to give 1.81 g of 5-(3-aminophenyl)-4-{[4-(benzyloxy)-3-chlorophenyl]amino} nicotinic nitrile 145. HPLC retention time (4): 2.74 minutes; MS: 426.8 m/e (M+H). Example 7: Preparation of 4-indole (3-chloro-4-fluorophenyl)amino]-5-(2-nitrophenyl)nicotinic acid nitrile 10 146 4-chloro-5-(3) was prepared analogously to Example 5. Procedure for the preparation of 4-chloro-5-(2-nitrophenyl) from acid acid nitrile from 2-triphenylacetic acid. MS: 260.1 m/e (M+H). In 15 ml of diglyme, 4-chloro-5-(2-nitrophenyl) 15 nicotinonitrile (4 g, 15.41 mmol), acridine hydrochloride (〇·89 g, 7.7) Mixture of millimolar) and 3-chloro-4-fluoroaniline (2.8 g, 19.26 mmol) at 13 Torr. Heat under the arm for 27 hours. The mixture was cooled and the acid hydrochloride was added and the solid was collected. The solid was stirred with saturated NaHCCh and (33⁄4⁄4) until it was dissolved. The solution was washed with brine, dried (MgSO.sub.4) and then filtered and concentrated on 20 to give 2.3 g of 4-[(3-chloro-4). -Fluorophenyl)amino]5-(2-stone phenyl) in acid nitrile 146. HPLC retention time (4): 3.58 min; MS: 369.1 m/e (Μ+Η) 〇 Example 8: Preparation 5- ( 2-Aminophenyl)-4_[(3-chloro-4-fluorophenyl)amino] Nicotinic nitrile 147 57 200815356 by reduction of 4_[(3_chloro_4_gasphenyl) as described in Example 6. Amino]_5_(2_nitrophenyl) was prepared in acid nitrile H6. 5-(2.Aminophenyl)·4_[(3_气_4_ phenyl)amino] is acid nitrile Μ 7. Muscle C residence time (4): 2 〇 6 minutes; (4): 339 2 _ (M+H) 〇 5 Example 9· Preparation 4_[(2,4-dichloro-5-methoxyphenyl)amine-based 5_[4_methoxy -3-(2-methoxyethoxy)phenyl] Add 1 liter of 〇4〇4 to 酸·2 liters of Me〇HR 3 hydroxy-4-yloxyphenylacetic acid (24.84 g, 136 mils) The stirred solution was then heated to reflux overnight. The residue was poured into EtOAc (3.times.50 mL). The extract was dried over anhydrous MgS(R) 4, filtered and concentrated in vacuo to give &lt;RTI ID=0.0&gt;&gt; 1.7 g) Add 150 ml of methyl 3-hydroxy-4-methoxyphenyl-15-acetate (5 g, 25.48 mmol), tetrabutylammonium iodide (0.941 g, 2.5 mmol) and A stirred solution of 2-bromoethyl methyl ether (4.6 mL, 50.9 mmol). The mixture was stirred at reflux for 21.5 hours. The mixture was concentrated and then the residue was extracted from water with EtOAc (NaJOJ) The combined organic extracts were dried, filtered, and concentrated in vacuo to give EtOAc EtOAc EtOAc. A fractionation product containing the combined product afforded 5.33 g (82%) of a pale yellow oil of [4-methoxy-3-(2-methoxyethoxy)phenyl]acetate. A 250 ml three-necked round bottom flask was added and then cooled to -78 ° C at 58 200815356. n-Butyllithium (2.5 g in hexane, 8.06 ml, 12.9) The flask was added to the flask and stirred for 5 minutes, and anhydrous acetonitrile (0.696 ml, 13.3 mmol) in 5 ml of anhydrous THF was added dropwise with stirring and then cooled to -78 °C. After stirring for 1 hour, methyl [4-5 methoxy-3-(2-methoxyethoxy)phenyl]acetate (1.095 g, 4.3 mmol) in 10 mL of dry THF was added dropwise. A white gum mixture was obtained in the flask. The reaction mixture was further stirred for 2 hours, then a saturated NH.sub.4Cl solution was added at -78. The solution was returned to room temperature, diluted with water (100 mL) andEtOAcEtOAc. The organic layer was separated, washed with brine, dried over anhydrous Mg.sub.4, filtered, 10 and concentrated in vacuo. The crude product was purified by silica gel chromatography eluting with 30 to 60% of EtOAc in hexane to yield 76. <RTIgt; 3-oxobutyronitrile. Add DMF/DMA (20.2 mL, 152 mmol) to 4-[4-methoxy-3-(2-methoxyethoxy)phenyl]-3-oxobutyronitrile 15 in 20 mL of dry DMF A stirred solution of (9·91 g, 34.5 mmol) was then heated at 100 ° C for 15 hours. The reaction solution was concentrated in vacuo and the crude product was stirred with 3? The reaction was cooled, dried in vacuo and purified EtOAc EtOAc EtOAc -5^ 2〇曱-oxy-3_(2-decyloxy)phenyl]-4-oxo-1,4-dihydropyridine-3-methyst yellow/orange bubble. 1-(3,4-Dioxaxybenzyl)-5-[4-methoxy-3-(2-methoxyethoxy)phenyl]_4_oxo' in 20.5 ml of P0Cl3 The solution of dihydropyridinium nitrile (3 (nine) pg, 0.6663⁄4 mol) and lithium chloride (UC1, 254 mg, 6 mmol) in 59 200815356 was heated under reflux for 2 · 5 hours. Excess P0C13 was removed from the vacuum and the residue was co-evaporated with toluene. The residue was taken up in 100 mL EtOAc and washed with ice-cooled 1N NaCI. The organic layer was separated, dried over anhydrous EtOAc EtOAc (EtOAc) Ethoxy)phenyl]nicotinic acid nitrile as an off-white solid (78%). Add Pd2(dba)3 (28.7 mg, 〇·〇31 mmol) to 4 mL of anhydrous ethylene glycol dimethyl ether 4-chloro-5-[4-methoxy-3-(2-methoxy) Oxy)phenyl]in acid nitrile (100 mg, 0.313 mmol), 2,4-dichloro-5-methoxyaniline (90 mM, 0.47 mmol), 2-bicyclohexylphosphine- A scrambled solution of 2'-(N,N-dimethylamino)biphenyl (37 mg, 0.094 mmol) and Κ3Ρ04 (99·8 mg, 0.47 mmol). The mixture was heated to 90 °C for 2 hours, then cooled, filtered through Celite®, concentrated in vacuo, and purified by diethyl ether/hexane to yield 19 mg (13%) of 4-[(2,4- Gas-5-methoxyphenyl)amino]-5-[4-decyloxy-15-H2-decyloxyethoxy)phenyl] in acid nitrile 148c HPLC retention time (4): 1199 min; MS [M+H ] : 474.1. Example 10: Preparation of 4-(2,4-dichloro-5-methoxyanilino)-5-[3-methoxy-4-(2-methoxyethoxy)phenyl]-acid nitrile 149 Cs2C03, 40.16 g, 123.2 mmol.) Add 250 ml of 20 g of ethyl vanillate (16.2 g, 77.05 mmol), tetrabutylammonium iodide (TBAI ' 1.42 g, 3.85 mmol) Agitated solution of 2-bromoethyl methyl ether (ι〇·4 ml '115.5 house Moule). The mixture was stirred at reflux for 2 Torr. 5 hours. The mixture was concentrated and the residue was extracted from water with EtOAc. The combined organic extracts were dried over Na2S04, filtered, and concentrated in vacuo to give &lt The oil was purified by flash chromatography using hydrazine and hydrazine ~ 60% EtOAc / hexanes. The combined fractions were concentrated to give 2 g of 67 g (100%) of &lt;&quot;&gt;&gt; 5 100 ml of anhydrous THF was placed in a 500 ml three-necked round bottom flask and cooled to -78C. n-Butyl (1.6 g in hexane, 69.8 ml, 111.8 mmol) was added to the flask and stirred for 5 minutes. Under stirring, anhydrous CH3CN (6.02 mL, 115.3 mmol) in 50 mL of dry THF was added dropwise to the flask and then cooled to _78. After stirring for a few hours, [3-methoxy-4-(2-oxoethoxy)phenyl]acetate (10 g, 37.2 mmol) in 6 mL of dry THF was added dropwise. A white gelatinous mixture in the flask was obtained. The reaction mixture was further stirred for 2 hours, then a saturated aqueous solution of NH.sub.4Cl. The solution was allowed to come to room temperature, diluted with EtOAc (EtOAc) The organic layer was separated, washed with brine, dried over EtOAc EtOAc EtOAc. The crude product was purified by chromatography on silica gel eluting with 20 to 80% EtOAc in hexane to yield 7.39 mg (75%) of 4-[3-methoxy-4-(2-methoxyethoxy)benzene. a yellow solid of _3_oxobutyronitrile. Add DMF-DMA (16 ml, 120.6 mmol) to 16 mL of anhydrous 20 DMF of 4-[3-decyloxy-4_(2-methoxyethoxy)phenyl]_3_oxobutyronitrile (7.22) Gram, 27.4 mmol) of the stirred solution and then the solution was at 1 Torr. (: heating for 15 hours. Concentrate the reaction solution in vacuo and then stir the crude product with 3,4-dimethoxybenzylamine in 2 ml of anhydrous toluene for 2 hours under reflux. Cool the reaction, dry in vacuo, and Purification by chromatography with 5〇~1〇〇〇/() Et〇Ac/hexane elution 61 200815356 yielded 8.26 g (67%) 1-(3,4-dioxabenzyl) a yellow solid of _5-[3_methoxy-4-(2-oximeoxyethoxy)phenyl H-oxo-M-dihydroacridinyl carbonitrile. 65 ml of p〇ci3 in 1-( 3,4-Dioxaxybenzyl)-5_[3_methoxy-5ice(2-oximeoxyethoxy)phenyl]oxo-indoline is more than biting winter nitrile (813 g, 18 mmol) The solution of the ear and LiCl (6.8 g, 162.4 mmol) was heated under reflux for 2.5 hours. The excess p〇αα was removed by concentration in vacuo, and the residue was co-evaporated with toluene. The residue was dissolved in It was washed with 1 ml of ethyl acetate and then with ice-cold 1 NaOH solution. The organic layer was separated, dried on anhydrous MgSO.sub.4, dried, evaporated and evaporated. 4.49 mg 4-gas-5-[3-decyloxy-4-(2-methoxyethoxy) ) Phenyl]nicotinic acid nitrile as an off-white solid (78%). </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Anhydrous anilide methoxy 15 methoxyethoxy) phenyl] as an off-white solid in acid nitrile 149. MS: 474·1 m/z; HPLC retention time (4): 12.0 min. Example 11: Preparation 5_[3- (2-chloroethoxy)phenyl]-4-[(2,4-dichloro-5-methoxyphenyl)amino] Nicotinic nitrile 150 and 4-[(2,4-dichloro-5) -Methoxyphenyl)aminobenz-5_[3_(2_pyrrolidin-1-ylethoxy)phenyl]nicotinic acid nitrile 151 20 Add Cs2C03 (88.8 g) to 0.9 liter of acetone 3-phenyl A stirred solution of methyl acetate (22.6 g '136 mmol) and 2-chloroethyl-p-toluene (40 g) was then heated under reflux for 3 hours. The mixture was cooled, filtered and concentrated in vacuo. The residue was purified by EtOAc (EtOAc) elut elut elut elut elut elut elut Methyl acetate. 150 ml of anhydrous THF was added to a 1.0 liter three-necked round bottom and cooled to -78 ° C. 2.5 g of hexane, 52. 5 ml, i3i house Moule) was added dropwise to the flask and its contents. Under stirring, 5 ml of anhydrous CH3CN in anhydrous THF (7.2 ml, 138 mmol) was added. The flask was added dropwise. After stirring for 1 hour, 20 ml of anhydrous tHi 15 g of [3-(2-chloroethoxy)phenyl]acetic acid decyl ester (66 mmol) was added dropwise to obtain a white gum mixture in the flask. The reaction mixture was stirred for a further 2 hours then a 4:1 MeOH : AcOH mixture was then taken at -78 C. The solution was diluted with EtOAc (4×l 50 mL). The organic layer was separated, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residual AcOH was removed by concentration in a vacuum with toluene. The residue was passed through a solution of CH2C12 containing EtOAc to yield 16 g (yield: 99%) of 4-[3-(2-chloroethoxy)phenyl]-3-oxobutyronitrile as an off-white solid. 15 Add DMF-DMA (17.6 g, 19.74 ml, 148 mmol), triethylamine (9.4 ml, 67 mmol) to 100 mL of dry DMF 4-[3·(2-chloroethoxy)benzene A stirred solution of 3-oxobutyronitrile (16 g, 67 mmol) was then heated at 100 ° C for 2.5 hours. The reaction solution was concentrated in vacuo and then dissolved in CH: 2C12 and passed through Magnesol®. The crude product was stirred with 3,4-dioxazolidine (11 mL, 74 mmol) in 20 mL of dry tolu. The reaction was cooled, concentrated in vacuo and purified EtOAc elut elut elut elut elut elut Dimethoxybenzyl)-4-oxo-1,4-dihydroacridine-3-carbonitrile as an off-white solid. 63 200815356 22-ml P〇Cl3 in 5-[3-(2·chloroethoxy)phenyl]-H3,4-dimethoxyoxy]_4_oxo-deca-4_dihydroindole A solution of 52 (25 g, 59 mmol) and LiCl (2.3 g, 53 mmol) was heated under reflux for 25 hours. Excess PQC13 was removed by concentration in a vacuum. The residue was dissolved in 100 liters of 5 liters (3⁄4⁄4⁄4) and then washed with ice-cooled 3 equivalents of Na 〇H. The organic layer was separated, dried over anhydrous MgSO4, and concentrated in vacuo. The AC-eluting layer was purified to yield 1.3 g of 4-chloro-5-[3_(2-chloroethoxy)phenyl]nicotinic acid nitrile as an off-white solid (75%). ) 3 (62 mg, 〇·07 mmol) was added to 4 mL of anhydrous ethylene dihydric alcohol dioxime in 4-chloro-5-[3-(2'chloroethoxy)phenyl]-acid nitrile (2 〇〇mg, 〇·68*mol), 2,4·dichloro-5-methoxyaniline (196 mg, 1 mmol), 2_dicyclohexylphosphine-2'-(N,N-dimethylamine a solution of biphenyl (8 mg, 〇 2 〇 mmol) and Κ 3 Ρ〇 4 (216 * g, 1 mmol). The mixture was heated to 9 Torr for 2 hours, then cooled, passed through Cdite ® Filtration, concentration in vacuo, and purification with 15% to 50% MeOH in CH.sub.2Cl.sub. Solid (52%) of 2,4-dichloro-5-methoxyphenyl)amino]nicotinic acid nitrile 150. HPLC retention time (4): 14.29 min; MS: 448 [M+H]. 5-[3-(2-chloroethoxy)phenyl]·4-[(2,4-dichloro 20 -5-methoxyphenyl)amino] nicotinic acid nitrile 150 (138 mg, in EtOH) A stirred solution of 0.31 mmol (mole) and pyrrolidine (66 mg, 0.93 mmol) was heated to 10 ° C for 7 hours. The reaction solution was cooled and poured into 25 ml of water and cooled to dryness. And drying in a vacuum at 50 ° C overnight to yield 32 mg of 4-[(2, 'dichloro-5-methoxyphenyl)amino]-5-[3-(2-n ratio 嘻 -1- -1 Ethyl ethoxy)phenyl]on acid 64 200815356 Nitrile 151 as a brown solid (21%). HPLC retention time (c): 6.21 min; MS: 481 [M+H]. Example 12: Preparation 5-[4- (Diammonium)phenyl]_4_[(3-nitrophenyl)amino]nicotinic acid nitrile 152 5 According to similar example 5 for the preparation of 4-chloro-5-(3-nitrophenyl)nicotinonitrile of

The procedure was carried out to produce 4-chloro-5-[4^dimethylamino)phenyl]nicotinic acid nitrile from 4-(dimethylamino)phenylacetic acid. The synthesized 4-chloro-5-[4-(dimethylamino)phenyl;]nicotinic acid nitrile was reacted with 3-nitroaniline according to the procedure described in Example 5 for the preparation of compound 137 to give 5-[4. -(Dimethylamino)phenyl]_4-[(3-nitrophenyl)amino] nicotinonitrile nitrile 152. 10 Compound 152 was analyzed by HPLC under the following conditions: column YMC C18 ' 4.6 x 500 mm, 5 μm; mobile phase a: 90% water + 10% MeOH + 0.02% H3P 〇4; mobile phase B: 90% MeOH + 10 % water +0.02% H3PO4; 1~100% B in 2 minutes up to 10 minutes 1〇〇% b, then 1〇〇~1% B in 1 minute. HPLC retention time (4): 3.4 minutes; MS: 357.8 15 m/e (M-H) ° Compounds 153 to 158 in Table 5 were prepared from 3-methoxyphenylacetic acid according to a procedure similar to the preparation of compound 147. 65 200815356 Table 5 Compound compound name HPLC retention time (minutes) Observable ion m/e [M+H] 153 5-(3-methoxyphenyl)-4_[(3_nitrophenyl)amino] Acid nitrile 3.4(6) 346.8 154 5-(3-indolylphenyl)-4-[(3-methoxyphenyl)amino]nicotinic acid nitrile 3.2(6) 332.3 155 4-[(3-phenyl)amino group ]-5_(3-indolylphenyl)nicotinic acid nitrile 3.3(c) 320·1[Μ·Η] 156 4_ {[3-cyano-5-(3-methoxyphenyl) ° pyridine-4 -] Amino}benzoic acid 3.1 (6) 346.3 157 4-[(4-cyanophenyl)amino]_5_(3-indolyloxyphenyl)nicotinic acid nitrile 3.3(6) 327.4 158 4-[(3,4-difluoro Phenyl)amino]-5-(3-methoxyphenyl)nicotinic acid nitrile 3.4(6) 335.8 [Μ-Η] Example 13: Preparation of 5-(3,4-dioxanoxyphenyl)-4-[( 3-hydroxyphenyl)amino]nicotinic acid nitrile 159 5 by heating 4-chloro-5(3,4-dimethoxyphenyl)nicotinonitrile and 3-amine in ethanol in a sealed glass vial of 9CTC This compound is prepared by the method of phenol. HPLC residence time (4): 6.4 min; MS: 348.1 m/e (M-H). Example 14: Preparation of 5-(3,4-dimethoxyphenyl)-4-{[3·(2-hydroxyethoxy)phenyl]amino} Nicotinic nitrile 160 10 Barium carbonate (143 mg, 0.44) Milliol) Add 5-(3,4-dimethoxyphenyl)-4-[(3-phenyl)amino) to DMF (2 ml) to acid nitrile 159 (100 mg, 0·29 mmol) A mixture of 2-) bromoethanol (55 mg, 0.44 mmol). The obtained mixture was heated overnight at 100 ° C, cooled to room temperature and then purified by reverse-phase HPLC (eluting with 95% to 5% water/acetonitrile containing 1% TFA) 15 to obtain 20 mg (12%) A milky solid of 5-(3,4-dimethoxyphenyl)-4-{[3-(2-ethoxy)phenyl]amino} nicotinonitrile nitrile 160. HPLC retention time (4): 6.5 min; MS: 392.1 m/e (M+H). 66 200815356 Example 15: Preparation of 4-[(3-{[(2S)_2-amino-3-phenyl)oxy}phenyl)amino]-5-(3,4-dioxaphenyl) Nicotinic nitrile 161 Add 5-(3,4-dimethoxyphenyl)-4-[ azo azodicarboxylate (61 mg, 0.35 mmol) to THF (1.0 mL) at room temperature. (3-hydroxyphenyl)amino] 5 nicotinonitrile nitrile 159 (100 mg, 0.29 mmol), tert-butyl (1SH-nodal 2-hydroxyethyl carbamate (73 mg, 0·) 35 mM) and triphenylphosphine (91 mg '0.353⁄4 mol). The reaction mixture was disturbed overnight at room temperature. More triphenylphosphine (91 mg, 0.35 mmol) and azo were added. Diethyl dicarboxylate (61 mg, 0.35 mmol). After additional stirring at room temperature for 24 hours, the mixture obtained was taken from &lt;RTI ID=0.0&gt;&gt; Purification by HPLC (elution with 95% to 5% water/acetonitrile with 1% TFA) afforded 15 mg (11%) of 4-[(3-{[(2S)-2-amino-3-benzene Milky solid of propyl]oxy}phenyl)amino]-5-(3,4-dimethoxyphenyl)nicotinic acid nitrile 161. HPLC retention time (4): 6.8 min; MS: 481·3 m /e (M+H). 16 · Preparation of 4-indole (2-chloro-5-hydroxyphenyl)amino]-5-(5-methylindol-1-benzothiophen-2-yl)nicotinonitrile 162 Water (125 ml a mixture of 3-aminobut-3-enenitrile (1 g, 1.22 mol) and concentrated hydrochloric acid (125 ml) was heated at 80 ° C for 2 hours, cooled to room temperature and then filtered to remove solids. The filtrate was extracted with ethyl acetate and the combined extracts were dried over sodium sulfate, filtered and concentrated to give a semi-solid residue which was distilled in vacuo to afford 77.4 g (76%) of acetonitrile (73) ~77 ° C / 3 to 5 mm Hg). Ethyl acetonitrile (41 g, 493 mmol), Ternoxy bis (dimethylamino) methane (86 g, 493 mmol) and a mixture of n,N-dimethylformamide dimethyl acetal 67 200815356 (2633⁄4 liters 'L97 mol) was heated overnight under the c.c. and then evaporated to remove volatiles. The residue was then obtained by filtration = solid and washed with hexane/diethyl ether (1: hydrazine and a minimum amount of ethyl acetate) to obtain 64.3 g (67%) of 5-(dimethylamino)_2_[(dimethyl Amino)methylene]oxol-4-ennitrile/fire-page solid, not in one It was used in the next step under the step of purification. 5-(dimethylamino)_2_[(dimethylamino)methylene]_3-oxopen-4-enenitrile (64.3 g) in ethanol (1.8 L) A mixture of 333 mmoles and ammonium acetate (126 g, 1.66 moles) was heated under reflux for 6 hours and then concentrated to remove the solvent. The semi-solid residue obtained was diluted with ethyl acetate, filtered and washed with ethyl acetate then CH2 C12. Evaporate the filtrate to a smaller volume. The precipitated solid was collected by filtration, washed with ethyl acetate and a minimum of ethanol to give 4-hydroxynicotinonitrile. This evaporation and crystallization process was repeated to obtain more 4-hydroxyl nicotinonitrile solids from the mother liquor. It produced 2 〇 9 g (53%) of a combined grayish 15-color solid. The temperature of 234~236 ° C. An alternative synthesis of 4-hydroxynicotinonitrile is described in the literature. BYoekman, W. et al., Recueil des Tmvaux Chimiques des Paj^-5〇y, 81: 792~6 (1962). A mixture of 4-hydroxynicotinonitrile (45.7 g, 381 mmol), 20 峨 (96. 6 g, 381 mmol) and NaOH (19.8 g, 825 mmol) in water (600 mL) Heat at 85 ° C overnight, cool to room temperature and dilute with water. The precipitate was collected by filtration and washed with water to give 57.5 g (yield: 61%) of 4-hydroxy-5-iodonicotinonitrile as a brown solid, m.p. A mixture of 4-hydroxy-5-iodonicotinonitrile (57.5 g, 234 mmol) and p〇ci3 (200 200815356 ml) was heated at 100 ° C for 2 hours, cooled to room temperature and then evaporated to remove excess P0C13. . The residue was cooled in an ice-water bath, adjusted to pH 8 to 9 with 10N EtOAc. The combined organics were washed with water and brine, dried over MgSO4, filtered and concentrated. The solid residue obtained was washed with a minimum of MeOH 5 and CH.sub.2Cl.sub.2 to afford 46.5 g (75%) of 4-chloro-5-iodonicotinic acid as a brown solid, m. (:. EtOH (20 ml) in 4-chloro-5-iodonicotinonitrile (2.0 g, 7.6 mmol) and 2-chloro-5-hydroxyaniline (1·〇9 g, 7·6 mmol) The mixture of the ears was heated overnight in a 9 CTC sealed glass vial, poured into a NaHC03 solution and then filtered. The unpurified solid was washed with 10 water and dried to give 3.0 g (quantitative yield) 4-[(2-chloro-5-) A brown solid of phenyl)amino]-5-ylidene acid acetonitrile, which was used in the next step without further purification. MS (M+H): 372.1. DME (10 ml) and NaHC03 ( Solution, 2 mol, 1.4 ml) 4-[(2-chloro-5-hydroxyphenyl)amino]_5_峨nicotinic acid nitrile (5 mg, 1.35 mmol 15 ears), 2_( 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophene-5-methyl (389 mg, 1.35 mmol) and A mixture of Pd(PPh3)4 (78 mg, 0.070 mmol) was heated overnight at 80 ° C, cooled to room temperature and then concentrated to a smaller volume. The residue was partitioned between Et EtOAc and water. The bound organics were dried over Na 2 S 〇 4, filtered, concentrated and purified by silica gel column chromatography to afford 160 mg (30%) 4-[(2-chloro-5-hydroxy) Amino]-5-(5-methylindole-based small benzophenan-2-yl)nicotin nitrile 162 as a yellow solid, MS (M+H): 406.2 · ' HPLC retention time (4): 11/ 7 minutes. Example 17: Preparation 4_[(2_Chloro-5-hydroxyphenyl)amino]_5_[5-(Bistidinylmethyl)-1_benzothiophene-2-yl] Nicotinic Nitrile 163 69 200815356 AcOH (106 4: gram ' 1.76 moules) into the thf (5.0 ml) 4-[(2-chloro-5-phenyl)amino]-5-(5-anthracene Small benzoxanthyl) is a mixture of 162 (130 Zucker '0.32 house Moule) and ^chen. (82 mg, 〇 · 96 mmol). The obtained mixture is stirred at room temperature. Then, triethylsulfonium sulfonate (203 mg, 0.96 mmol) was added. After stirring at room temperature overnight, the reaction mixture was concentrated and purified by a silica gel column to give 1053⁄4 g (69%). The title compound was observed as a pale solid. hplc retention time (4)··················································· Compound 162. Compound 162 was prepared by coupling intermediate 66 with the appropriate aniline followed by similar Example 16. The procedure is treated with 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophene-5-formaldehyde, followed by an example π compound Reductive amination of 163 produced compounds 165 and 166. Table 6 Compound compound name HPLC residence time (minutes) Observable ion m/e [M+H] 164 7.6(c) 519.3 165 Price -1- 5.4(6) 468.4 166 (secret 1 - 5.4 5.4(c) 454.3 [ MH] 15 Example 18 Preparation of 4-chloro-5-iodo q-oxynicotinic acid nitrile H2〇2 (3 〇 wt% in water, 5 ml) was added to TFA (5 ml) 4-chloro-5_ A solution of niobonic nitrile (529 g, 2 mmol). The reaction mixture was stirred overnight at room temperature, heated to 50 ° C for 8 hours, then concentrated. Saturated 70 200815356

The residue was added to a solution of NaHCO.sub.3 (10 mL). The organic extract was washed with water, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (CH2C12-THF = 10·············· 5 Example 19: Preparation of 4-fluoro-5-[3-methoxy-4-(2-methoxyethoxy)phenyl]nicotinic acid nitrile 4-chloro-5-(3,4 methoxyl Nicotinic nicotinamide (7.3 mmol, 2.0 g) was dissolved in 70 mL of DMF and then treated with CsF (14.6 mmol, 2.2 g). After heating at 80 °C for 2 hours, another 7 mM (1 gram) of CsF was added and the heat was maintained overnight. The suspension was evaporated on celite and the product was purified by chromatography 10 (EtOAc/Hex) to afford 300 mg of 4-fluoro-5-[3-methoxy-4-(2-methoxyethoxy) )phenyl]nicotinic acid nitrile. Example 20: Preparation of 1-benzofuran-5-furfural DIBAL-H (41.9 ml, 41.9 mmol, 1 mol/hexane) was added to the -15 to -20 C nitrogen CHfl2 1- Benzofurancarbonitrile (5·〇I5 g '34.9 mmol) then maintains the temperature below. After the addition was completed, the reaction mixture was further stirred at -15 to -20 ° C for an additional 1 minute. The reaction mixture was cooled by dropwise addition of 2 equivalents of HCl solution. The organic layer was separated and washed with water, dried over sodium sulfate, and then evaporated to afford EtOAc (EtOAc) 20 Example 21: Preparation of 5-(piperidinyl-1-ylmethyl)benzofuran-2ylboronic acid dinonyl ester under standard reductive amination procedure with BTS and triethyl oxy-sodium treatment 1- Benzofuran-5-formaldehyde gives 丨_(5-benzofuranylfluorenyl) piperidine. Treatment of bis(5-benzofuranyl fluorenyl) ruthenium with butyl lithium and tridecyl borate at low temperature to produce Η 咬 -1- 基 基 ) ) ) ) 71 2008 2008 2008 2008 2008 2008 2008 2008 2008 2008 Dimethyl ester. The compounds 167 to 169, 171 and 172 in Table 7 were produced by a coupling reaction with dimethyl 5-(piperidin-1-ylmethyl)benzofuran-2-ylborate according to the procedure described in a similar method. . Table 7 Compound Compound Name HPLC Retention Time (Functional Touch) Observable Ion m/e [M+H] 167 4_[(2_Chloro-5-methoxyphenyl)amino]-5-[5-(Piperidine -1-ylmethyl) benzofuran-2-yl]nicotinic acid nitrile 1.99 (d) 473.4 168 4-[(2-chloro-5-methylphenyl)amino]-5-[5-( Travelling bite-1-ylindenyl)_1-benzopyrene-2-tabler]acid nitrile 2.02(d) 457.3 169 4-[(5-pyributyrylphenyl)amino]_5_[5 -(Big -1-ylmethyl)-1 -benzoindole 4 -2-yl]in acid nitrile 1.94(d) 517.3 171 4-[(2,4-dichlorohydroxyphenyl)amino]- 5_[5_(5 ( 小 小 ) · · · · · ] ] ] ] ] 8.3 8.3 8.3 8.3 8.3 (c) 493.3 172 七 [(4_甲基基_2-曱phenyl)amino]_5- [5_(Brigade bite)_基基)_1_Benzene 弁 夫 夫 _ _ _ 7.2 7.2 7.2 (c) 453.4 5 Example 22 · Preparation of 4-{[3-(aminomethyl)benzyl Aminobutyric 5-(3,4-dimethoxyphenyl)nicotinic acid nitrile 170 4-L-5-(3,4-dimethoxyphenyl)nicotinic acid nitrile (74 mg' in 3 ml of DMF A mixture of 0.27 mmol, 1,3-xylylenediamine (54 mg, 〇·4 〇 mmol) and 10 diethylamine (40 mg, 0.40 mmol) to 6 (rc heated overnight). After cooling to room temperature, concentrate the reaction mixture To dryness, the residue was dissolved in 3 mL of DMSO, filtered and purified by preparative HpLC to afford 4-{[3-(aminomethyl) benzyl] yl}}_5_(3,4-dimethoxybenzene Base) Final acid guess. HPLC retention time (4): 1.33 minutes; MS: 375.2 m/e (M+H). 15 Example 23 · Pharmacological test The representativeness of the invention was evaluated in a number of standard pharmacological test procedures. The compounds of the present invention can inhibit ρκ(9). The compounds of the present invention can be effectively used as anti-inflammatory agents according to the activities shown in the standard pharmacological test 72 200815356. Inhibition of PKC 6» active kinase function Zone (KD) radioactive kinase assay This assay is based on the phosphorylation of a biotinylated matrix by ATP (ATP 7 P33) 5 kinase using a biotin•FARKGSLRQ-C(o) A biotin-labeled peptide of the sequence of Li 2, which is a purified recombinant active kinase domain of full-length PKC 0 (amino acid 362-706). The detection buffer is composed of 1 〇〇 molecule Hepes, pH 7.5, 2 Mm molecule MgCl2, 20 mg molecule/5-glycerophosphate and 〇.008% 10 TritonX 10 . A reaction mixture of ATP, ATPr P33 (Perkin Elmer), DTT and enzyme was prepared in assay buffer and added to a 96-well polypropylene plate. The compound (diluted in DMSO in an additional 96-well polypropylene plate) was added to the reaction mixture and then incubated at room temperature. In the culture, the peptide matrix is added to the reaction mixture to initiate the enzyme reaction. The reaction was terminated by the addition of a stop solution (1 〇〇 15 mol EDTA, 〇 2% Triton X 100 and 20 mg NaHP04) and then transferred from the assay plate to the washed streptavidin coated 96-well flat bottom micro Orifice plate (PerkinElmer). Flat-bottomed scintiplates were incubated at room temperature, washed with PBS containing 0.1% Triton X 100, and then counted in a 1450 Microbeta Trilux (Wallac, version 2.60). The count value of each well was recorded by correcting 20 numbers per minute (&lt;:^1) 1^). Since it is adjusted according to the P33 standardization protocol, the count is considered corrected, which corrects the efficiency and background differences between the instrument detectors (software version 4.40.01). Full-length (FL) PKC (Radiokinase Assay for Inhibition of 9 Inhibitors This assay differs from the above in the use of purified recombinant full-length PKC 0 73 200815356 (Panvera, P2996). PKC0 IMAP assay involves the use of the following materials : Human PKC0 full-length enzyme (panvera

Cat# P2996); matrix peptide: 5FAM-RFARKGSLRQKNV-OH 5 (Molecular Devices, rP7〇32); ATp (sigma classification number a 2383); DTT (Pierce, 20291); 5x kinase reaction buffer (Molecular Devices, Inc.) , r72〇9); imap beads (Molecular Devices, R7284); and 384-well plates (Corning Costar, 3710) 〇10 Reaction buffer preparation by diluting 5x stock reaction buffer followed by DTT The concentration of 3.0 mg of the molecule. Binding buffer was prepared by diluting binding buffer A. The main mixed solution was prepared by diluting with 2 x ATP (12 micromoles) and 9% by weight of the peptide (200 nm) reaction buffer. The compound was diluted in DMSO to 2 (the highest concentration) for the IC5 oxime assay. Each 1 (: 5 升 15 curve of 27 microliters of the main mixed solution was added to the first column and each well in a 384-well plate. 3 microliters of 20x compound in DMSO. The final concentration of the compound was 2x 10% DMSO. Add DMSO to the remaining main mixed solution to increase the concentration to 10%. Add 10 μl of the main mixed solution containing 10% DMSO. On the plate, except for the remaining holes of the column, transfer 2 〇 microliters from the first column to the 20th column. Sequence dilution is started from the second column at a ratio of 2: 1. Prepared in the reaction buffer. 2x (2 ng) PKC0 solution. Add 1 〇 microliter of ppk6> solution to each well to reach the final concentration · PKC0-丨Nike molecule; ATP-6 micromolecule; peptide-1 〇〇Nike molecule DMSO - 5%. The sample was incubated for 25 minutes at room temperature. The binding reagent was prepared by diluting the beads 74 200815356 in lx binding buffer to 800: 1. Add 50 μl of binding reagent to each well. Then incubated for 20 minutes. The FP was measured using Envision 2100 (PerkinElmer Life Sciences). The wells without enzymes were used as controls. The results obtained are summarized in Table 8. The data shown in Figure 5 represents the average value when one or more samples are determined.

Compound number IC5OPKC0 KD (micromolecule) IC5OPKC0 FL (micromolecule) IC5OPKC0 IMAP (micromolecule) 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 115 4.26 0.38 N/A 116 3.20 N/AN/A 117 13.80 N/AN/A 118 4.44 N/AN/A 119 11.70 N/A 1.95 122 1036 N/AN/A 75 200815356 Compound number IC5OPKC0 KD (micromolecule) IC5OPKC0 FL ( Micromolecules IC5OPKC0 IMAP (micromolecule) 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 76 200815356 Compound number IC5OPKC0 KD (micrograms IC5OPKC0 FL (micromolecule) IC5OPKC0 IMAP (micromolecule) 153 N/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 &gt;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 Those skilled in the art will appreciate the variations, modifications, and other methods of operation described herein without departing from the spirit and scope of the invention. Therefore, the scope of the present invention is not to be construed as being limited by the scope of the invention, and the scope of the claims and the scope of the claims. t schema simple description 3 (none) [main component symbol description] (none) 78

Claims (2)

200815356 X. Patent application scope: 1. A compound of formula I or formula: IV 5 and pharmaceutically acceptable salts, hydrates and esters thereof, wherein: X is selected from the group consisting of (a) -NR3_Y-, (b) -0-Y-, (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) -0C(0)-Y-, and (1) a covalent bond; ίο Y when present is independently selected from (a) a bivalent Cho alkyl group, (b) a bivalent C2-10 alkenyl group, (c) a bivalent C2 10 alkynyl group, (d) a bivalent Cwo Haloalkyl, and (e) - covalent bond; R1 is a phenyl group optionally substituted by 1 to 4 -Y-R4 groups; R2 is a C6-14 aryl group or a 5 to 14 membered heteroaryl group, These groups are optionally substituted by 15 1 to 4 independently selected from the group consisting of -Y-R4 and -0-Y-R4; R3 is selected from the group consisting of (a) hydrazine, (b) Cl alkyl group, (c) C2~ 1G alkenyl, (d) C2~1G alkynyl, and (e) C 1~10 haloalkyl; R4, when present, is independently selected from (a) hydrazine, (b) -CN, (c) -N02, (d) oxo-, (e) -OY-R5, (f) -NR6_Y-R7, (g), N(0)R6-Y-R7, 20 (h) -S(0)mY-R5 &gt; (i) -S(0)m0-Y-R5 &gt; G) -S(0)mNR6-Y-R7 ^ (k) -C(0)-Y-R5,(1) -C(0)0 -Y-R5 (M) -C (0) NR6-Y-R7, (n) -C (S) NR6-Y-R7, (o) ◦ alkyl, (p) Cw. Alkenyl, (q) 79 200815356 C2~1 0 alkynyl, (r) C 1~10 haloalkyl, (s) C3-14 cycloalkyl, (1) C6-14 aryl, (8) 3 to 14 heterocycloalkyl And (v) 5 to 14 membered heteroaryl groups, wherein (〇) to (v) are each optionally substituted by 1 to 4 -Y-R8 groups; R5, when present, is independently selected from (a) Η, (b) -C(0)R9, (c) 5 -C(0)0R9, (d) Cu alkyl, (8) C2~π)alkenyl, (f) C2~1() alkynyl, (g) Cwo haloalkyl, (h) C3-14 cycloalkyl, (1) C6-14 aryl, (1) 3 to 14 membered heterocycloalkyl, and (k) 5 to 14 membered heteroaryl, wherein (d) to (k) are respectively Optionally substituted by 1 to 4 -Y-R8 groups; R6 and R7, when present, are independently selected from (a) Η, (b) -OY-R9, (c) 10 -S(0)m_Y- R9, (d) -S(0)m0-Y_R9, (e) -C(0)-Y-R9, (f) -C(0)0-Y-R9 ^ (g) -C(O)NR10 -Y-Rn ^ (h) -C(S)NR10-Y-Rn &gt; (i) Heart. Haloalkyl, (1) C2~10 alkenyl, (k) C2~10 alkynyl, (1) Cu haloalkyl, (m) C3-14 cycloalkyl, (n) C6-14 aryl, (o) 3 ~14 membered heterocycloalkyl and (p) 5 to 14 membered heteroaryl, wherein (i) to (p) are each optionally substituted by 1 to 4 -Y-R8 groups; R8 when present Independently selected from (8) Η, (b) -CN, (c) -N02, (d) oxo- ^ (e) -OY-R9 &gt; (f) -NR10-Y-Rn &gt; (g) -N(O ) R10-Y-Rn &gt; (h) -S(0)mY-R9, (i) -S(0)m0-Y-R9, (1) AOkNR^Y-R11, (k) -C(0)- Y-R9 &gt; (1) -C(0)0-Y-R9 &gt; (m) -C(O)NR10-Y-Rn &gt; 20 (n) -CXS^R^-Y-R11,( 0) Cw. Alkyl, (p) Cm nonenyl, (q) C2~10 fast radical, (r) Cl~10 haloalkyl, (S) C3~14 cycloalkyl, (1) C6~14 aryl, (u) 3 ~14 membered heterocycloalkyl and (V) 5 to 14 membered heteroaryl, wherein (〇) to (v) are each optionally substituted by 1 to 4 -Y-R12 groups; R9 is independent when present Selected from (a) H, (b) -C^CO-Cwo alkane 80 200815356 base, (c) -C(0)0H, (d) -CXCOO-Cl alkyl, (e) Cwo alkyl, (f C2~10 dilute base, (g) C2~10 fast group, (h) Cl~10 haloalkyl group, (1) C3~14 cycloalkyl group, (1) c6~14 aryl group, (k) 3~14 member heterocycloalkyl group And (1) 5 to 14 membered heteroaryl groups, wherein the haloalkyl group, c2 10 10 alkenyl group, c 2 10 10 alkynyl group, 5 Cwo haloalkyl group, C 3 14 cycloalkyl group, C 6 14 aryl group, 3 The 14-membered heterocycloalkyl group and the 5-14 membered heteroaryl group are each optionally substituted by 1 to 4 -Y-R12 groups; R10 and R11 are independently selected from (a) Η, (b) when present. -OH, (c) _SH, (d)-NH2, (e) -NH-Cwo alkyl, (f) -Nfwo alkyl) 2, 10 (g) -SODVCwo alkyl, (h) -S (0 20H, (i) -SCCOmO-Cu alkyl, (1)-C^CO-Cw. Alkyl, (k) -C(0)0H, (1) -C^COO-Cwo alkyl, (m) _C(0)NH2, (n) -CCCONH-Cwo alkyl, (o) -C^ CO^Cw. Alkyl)2, (p) -C(S)NH2, (q) -C(S)NH-Ch〇alkyl, (r) -C(S)N (Cualkyl)2, (s) Cu Alkyl, (t) C2 to 10 15 alkenyl, (u) C2 to 10 alkynyl, (v) Cho alkoxy, (w) Cuo haloalkyl, (8) C3 to 14 cycloalkyl, (y) C6~ a 14 aryl group, a (8) 3 to 14 membered heterocycloalkyl group, and (aa) a 5 to 14 membered heteroaryl group, wherein the Cho alkyl group, the C 2 ～10 alkenyl group, the C 2 ～10 benzyl group, the C 1-10 alkyl group, the Cl group ～10 haloalkyl, C3-14 ring alkyl, C6-14 aryl, 3 to 14 membered heterocycloalkyl and 5 to 14 membered heteroaryl are each optionally 20 to 1 to 4 -Y-R12 groups Substituted; R12, when present, is independently selected from the group consisting of (a) halogen, (b) -CN, (c) -N02, (d) oxo_, (e) _0H, (f), NH2, (g) -NHCCw. Alkyl), (h) -Nfwoalkyl)2, (i) -SH, G) ^(Ok-Cwoalkyl, (k)-S(0)20H, (1)-SWmO-Cualkyl, (m) -C(0)-Choalkyl, 81 200815356 (n) -C(0)0H, (〇) -C^COO-Cw. alkyl, (p) -C(0)NH2, (q -C(O) NH-Cu alkyl, (r) -CXSWCCw◦alkyl)2, (s) -C(S)NH2, (t) -C^S^H-Cualkyl' (u) &lt;(3) Ν((^~10 alkyl) 2, (7) Cwo alkyl, (w) C2~1G alkenyl, (8) C2~1G alkynyl, (y) 5 Cuo alkoxy, (z) Cwo halogen a group, (aa) C3~14 cycloalkyl, (ab) C6-14 aryl, (ac) 3 to 14 membered heterocycloalkyl, and (ad) 5 to 14 membered heteroaryl; and m is 0, 1 Or 2; if R1 is 3-chloro-4-fluorophenyl, R2 is not 2-[(1Η-imidazole-5-yl10-methyl)amino]phenyl. 2. As claimed in the first item Or a pharmaceutically acceptable salt, hydrate or ester thereof, wherein X is selected from the group consisting of -NH-, -N(CH3)-, -NH-CH2-, -NH-CH2CH2-, -NH-CH2CH2CH2. And - Ο- and a covalent bond. 15 3. The compound of claim 1 or a pharmaceutically acceptable salt, hydrate or ester thereof, wherein R1 is selected from the group consisting of: R4 R4, 82 200815356 4. A compound according to claim 1 or a pharmaceutically acceptable salt, hydrate or ester thereof, wherein R4, when present, is independently selected from the group consisting of _F, -α, -CN, _N〇2 , _〇_Y_r5, _c(〇)_y_r5, c(〇)〇γ r5 -NR6-Y_r6, and Cl~6 alkyl. 5. The compound of claim 1 or a pharmaceutically acceptable salt, hydrate or ester thereof, wherein R2 is selected from the group consisting of phenyl, Gw aryl and 5 to 14 membered heteroaryl, these groups are selected respectively It is optionally substituted with 4 groups independently selected from -Y-R4 and -0-Y-R4. 6. A compound of claim 1 or a pharmaceutically acceptable salt, hydrate or ester thereof, wherein R2 is: Wherein D1, D2 and D3 are independent η, -Y-R4 or _〇_Y_R4 groups. The compound of claim 6 or a pharmaceutically acceptable salt, hydrate or ester thereof, wherein at least one of Di, D2 and D3 is -Y_R4 or -〇-Y_R4, wherein Y is independent when present Bivalent (^~4 alkyl or a covalent bond, and R4 when independently present is selected from the group consisting of halogen, -CN_N〇2, -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, alkyl, C^H)haloalkyl a c3-1414 cycloalkyl group, a c6-14 aryl group, a 3 to 14 membered heterocycloalkyl group, and a 5 to 14 membered heteroaryl group, wherein the Cl~1〇 alkyl group, the Ci i〇_alkyl group, and the c3~i4 ring The alkyl group, the C6-H aryl group, the 3- to 14-membered heterocycloalkyl group, and the 5- to 14-membered heteroaryl group are each optionally substituted with 1 to 4 -Υ-R8. 83 200815356 8. The compound of claim 7 or a pharmaceutically acceptable salt, hydrate or ester thereof, wherein the _Y_R4 or _〇_Y_R4 group is selected from the group consisting of _〇_(CH2)nNR6-Y- R7, -(CH2)nNR6_Y_R7, _〇_(CH2)n_3~14 membered heterocycloalkyl and -(CH2)n-3~14 membered heterocycloalkyl, wherein the 3 to 14 membered heterocycloalkyl group may be selected It is replaced by 1 to 4 _y_r8, and 11 can be independently 〇, 1, 2, 3 or 4 when it appears. 9. The compound of claim 8 or a pharmaceutically acceptable salt, hydrate or ester thereof, wherein the -〇-(CH2)n_3~14 membered heterocycloalkyl group and the -(CH2)n- 3 to 14 membered heterocycloalkyl 3~μ member heterocycloalkyl selected from pyrrolidinyl, morpholinyl, piperidinyl, piperidinyl, azepanyl, azacycloheptyl And thioline. The compound of claim 7 or a pharmaceutically acceptable salt, hydrate or ester thereof, wherein the _Y-r4 and _〇_Y_R4 groups are R8 or R8, wherein R8 is present Independently selected from -〇_Y_R9, -NR1G-Y_RU, C6~H aryl and 5- to 14-membered heteroaryl, wherein the (:6~14 aryl group and the 5~14 member heteroaryl group are optionally 1 ～4-Υ-R12 substituted, and η may be independently 〇, 1, 2, 3 or 4 when present. II. A compound of claim 7 or a pharmaceutically acceptable salt or hydrate thereof Or an ester, wherein at least one of D^D2 and D3 is selected from the group consisting of halogen, -CN, ·Ν02, _S(0)2-Y-R5, -S(0)2NR6-Y-R7, ·&lt;:(0 ) 0-Υ·Ι15, -C(0)NR6-Y-R7, Ci~ι〇烧基, and Ci~ι〇烧烧基. 84 200815356 12. A compound according to claim 7 or a pharmaceutical thereof Acceptable salts, hydrates or esters, wherein at least one of D1, D2 and D3 is a C6-14 aryl group or a 5-14 membered heteroaryl group, these groups are selectively 1 to 4 -Y-R8 respectively Substitute. 5 13. The compound of claim 12 or a pharmaceutically acceptable salt thereof, a compound or ester wherein at least one of D1, D2 and D3 is selected from the group consisting of a benzo sigma group, a benzofuranyl group, a fluorenyl group, a σ ratio sigma group, a benzyl group, a sigma base group and a thienyl group. The groups are each optionally substituted by 1 to 4 -Y-R8, which may be an independent alkyl group or a covalent bond when present, and 10 R8 may be independently selected from halogen, -CN, -N02, when present. -0-Y-R9, -NR10-Y-Rn, -C(0)-Y-R9, -C(O)NR10_Y_Rn, -S(0)2-Y-R9, -S(0)2NR1G-Y -Ru and a 3 to 14 membered heterocycloalkyl group optionally substituted by a Cm alkyl group. 14. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, a hydrate or an ester thereof, wherein R2 is a C8-14 bicyclic aryl group or a 5 to 14 membered heteroaryl group, wherein the C8-14 bicyclic aryl group and the 5~14 membered heteroaryl group are each selectively selected from 1 to 4 independently selected from -Y-R4 and - A compound of the formula 0-Y-R4. 15. A compound according to claim 14 or a pharmaceutically acceptable salt, hydrate or ester thereof, wherein the R2 is selected from the group consisting of pyridyl, pyrimidinyl and pyridinium 20 Base, fluorenyl, fluorenyl, σ thiol, 4-saltyl, benzofuranyl, benzo Benzyl, fluorenyl, benzodioxyl, benzodioxyl, benzodioxanyl, dibenzofuranyl, dibenzothiophenyl, benzofluorenyl, indanyl, anthracene Base, iso-σ-saltyl, thalmyl, 11-indenyl, tetrahydronaphthyl, iso-4-salt, fluorenyl, naphthyl, sigma-based and sigma-based, 85 200815356 The ground is replaced by 1 to 4 groups independently selected from _(CH2)n-R4 and -0-(CH2)n-R4, wherein η can be independently 0, 1, 2, 3 or 4 when present, and R4, when present, may be independently -NR6-Y-R7 or a 3 to 14 membered heterocycloalkyl group optionally substituted with -Y-R8. 5. 16. A compound according to claim 1 which is selected from the group consisting of 4-[(3-chlorophenyl)amino]-5-(3,4-dimethoxyphenyl) Nicotinic nitrile; 5-(3,4-dimethoxyphenyl)-4-[(3-fluorophenyl)amino] nicotinic acid nitrile; 4-anilino-5-(3,4-dimethoxy Phenyl) nicotinonitrile; 10 4-[(2,5-difluorophenyl)amino]-5-(3,4-dimethoxyphenyl) in acid nitrile; 5- (3,4-di Methoxyphenyl)-4·[(3,4-dimethoxyphenyl)amino] nicotinic acid nitrile; 4-[(4-chloro-2-fluorophenyl)amino]-5-(3, 4-Dimethoxyphenyl)nicotinic acid 15 nitrile; 4-[(3-chloro-4-fluorophenyl)amino]-5-(3,4-dimethoxyphenyl)nicotinic acid nitrile; 4- [(4-Chlorophenyl)amino]-5-(3,4-dimethyllactylphenyl) is acidated, 5-(3,4-dimethoxyphenyl)-4-[(2,4) -didecylphenyl)amino]nicotinic acid 20 nitrile; 5-(3,4-dimethoxyphenyl)-4-[(4-methoxyphenyl)amino] nicotinic acid nitrile; 4- [ (3-chloro-4-indolylphenyl)amino]-5·(3,4-dimethoxyphenyl)nicotinic acid nitrile; 5-(3,4-dimethylthiophenyl)-4-[ (4-Phenoxyphenyl)amino] is an acid guess, 86 200815356 4- [(2,5-Dichlorophenyl)amino]-5-(3,4-dimethoxyphenyl)nicotinonitrile ; 5- (3, 4-Dioxaxyphenyl)-4-[(4-decyloxy-2-methoxyphenyl)amino] Nicotinic nitrile; 5 4-[(3,4-Dichlorophenyl)amino] -5-(3,4-dimethoxyphenyl)nicotinic acid nitrile; 4-[(5-chloro-2-methoxyphenyl)amino]-5-(3,4-dimethoxyphenyl) Nicotinic acid nitrile; 4-{[3-(benzyloxy)phenyl]aminodibu 5-(3,4-dimethoxyphenyl)nicotinic acid 10 nitrile; 5-(3,4-dimethoxybenzene 4-((4-methylphenyl)amino] nicotinic acid nitrile; 5-(3,4-dimethoxyphenyl)-4-[(3,4,5-trimethoxyphenyl) Amino] nicotinonitrile; 5-(3,4-dimethoxyphenyl)-4-[(3 phenoxyphenyl)amino] nicotinic nitrile; 15 4-[(2-chloro-5-) Methoxyphenyl)amino]-5-(3,4-dimethoxyphenyl)nicotinic acid nitrile; 4-({3-chloro-4-[(3-cyano)oxy]phenyl} Amino)-5-(3,4-dimethoxyphenyl)nicotinic acid nitrile; 4-({3-chloro-4-[(3-methylbenzyl)oxy]phenyl}amino)-5 -(3,4-di20-methoxyphenyl)nicotinic acid nitrile; 4·[(3-chloro-4-{[3-(dimethylamino)benzyl]oxy}phenyl)amino]- 5-(3,4-dimethoxyphenyl)nicotinic acid nitrile; 4-[(2,4-dichlorophenyl)amino]-5-(3,4-dimethoxyphenyl)nicotinonitrile ; 87 200815356 N-(3-{|&gt;Cyano·5·(3,4-dioxaphenyl)n-4-yl Amino] phenyl) acetamidine; Ν·(3·{[3-cyano·5-(3,4-dimethoxyphenyl) η than -4-yl]amino} phenyl )-Ν-methylacetamide; Ν-(3-{[3-cyano-5-(3,4-dioxaphenyl)π-pyridin-4-yl]amino}phenyl) Sulfonamide; 5-[4.(dimethylamino)phenyl]-4-[(3-indolylphenyl)amino] nicotinic acid nitrile; 5-[4-(-methyl-hydroxyl)benzene 4-[(3-fluorophenyl)amino]in acid nitrile; 4-({3-cyano-5-[4-(dimethylamino)phenyl]pyridinyl-4-yl "amino" benzoic acid; 4-[(4-cyanophenyl)amino]_5-[4-(didecylamino)phenyl]nicotinic acid nitrile; 4-[(3,4-difluorobenzene) Amino]_5-[4-(didecylamino)phenyl]nicotinic acid nitrile; 4-[(3-bromophenyl)amino]-5-(3,4-dimethoxyphenyl) Acid nitrile 4-UM 节oxy)_4_chlorophenyl]amino}·5·(3,4·dimethoxyphenyl) Nicotinic nitrile; 4-[(2,4_二气_5_methoxybenzene) Amino]_5_(3,4-dimethoxyphenyl) nicotinonitrile; 4-[(2,4-dioxa-5-ethoxyphenyl)amino]_5_(3,4-dimethyl Oxyphenyl) nicotinonitrile; 4-[(2'4-y-5-propoxyphenyl)amino]-5-(3,4-dioxanylphenyl) nicotinonitrile; 4-[ (5-butoxy-2,4·dichlorophenyl)amino]-5-(3,4-dimethoxybenzene 88 200815356 base) nicotinonitrile; 4-{[2,4-dichloro- 5-(2-hydroxyethoxy)phenyl]aminodipyridinium (3,4-dimethoxyphenyl)nicotinonitrile; 4-{[4-(benzyloxy)-3-chlorophenyl] Aminobutyric 5-(3-nitrophenyl)nicotinic acid 5 nitrile; 4·{[3_chloro-4 tetrapyridin-2-ylmethoxy)phenyl]amino} each (3_ phenyl Nicotinic acid nitrile; 4-[(3-Ga-4-fluorobenzyl)amino]_5_(3_nitrophenyl) is acidated; 5-(3-aminophenyl)-4-{[4- (benzyloxy)-3-chlorophenyl]aminoindolenicotinic acid 10 nitrile; 4-[(3- gas-4-fluorophenyl)amino]-5-(2-nitrophenyl)nicotinic acid nitrile ; 5-(2-Amine-4-yl)-4-[(3-chloro-4-fluorophenyl)amino]in acid nitrile; 4-[(2,4-chloro-5-indole phenyl) Amino]-5-[4-methoxy-3-(2-methoxyethoxy)phenyl] Acid nitrile; 15 4-[(2,4-dichloro-5-fluorenyloxy)amino]-5-[3-decyloxy-4-(2-methoxyethoxy)phenyl] Acid nitrile; 5-[3_(2-glyoxy)phenyl]_4_[(2,4-dioxa-5-methoxyphenyl)amino] is an acid guess; 4- [(2,4_ Dichloro-5-indolylphenyl)amino]-5-[3-(2-n-rhododec-1-yl-2-ethoxy)phenyl]nicotinic acid nitrile; 5_[4-(dimethylamine) Phenyl]-4-[(3-nitrophenyl)amino] nicotinic acid nitrile; 5-(3-methoxyphenyl)-4-[(3-nitrophenyl)amino] ; 5_(3-indolylphenyl)-4-[(3-methoxyphenyl)amino] nicotinic acid nitrile; 4-[(3-fluorophenyl)amino]-5-(3_oxime Phenyl)nicotinic acid nitrile; 200815356 4-{[3-cyano-5-(3-methoxyphenylcarbidin-4-yl)amino}benzoic acid; 4-[(4-phenylphenyl)amine 4-[(3-methoxyphenyl)-acid-supply, 4-[(3,4-difluorophenyl)amino]-5-(3-methoxyphenyl)nicotinic acid nitrile; 5- (3,4-Dimethoxyphenyl)-4-[(3-hydroxyphenyl)amino] nicotinic acid nitrile; 5 5-(3,4-Dimethoxyphenyl)-4-{[3- (2-hydroxyethoxy)phenyl]amino} Nicotinic nitrile; 4-[(3_{[(2S)-2_Amino-3-phenylphenyl)oxy}phenyl)amino] 5-(3-(2-chloro-5-hydroxyphenyl)amino group ]-5-(5-Mercapto-1-benzothiophene 10 -2-yl) in acid gamma, 4-[(2-chloro-5-hydroxyphenyl)amino]-5-[5-( Piperidin-1-ylmethyl)-1-benzothiophen-2-yl]nicotinic acid nitrile; 4-{[2-chloro-5-(2-hydroxyethoxy)phenyl]amino}-5 -[5-(piperidin-1-ylmethyl)-1-benzophenen-2-yl] is an acid guess, 15 4-[(4-amino-2,3-dimethylphenyl) Amino]-5-[5-(唆唆-1 -ylindenyl)-1_benzoquinone-s-phen-2-yl]-acidic acid, 4-[(4-amino-3-methylbenzene) Amino]1-ylmethyl)-1-benzoquinone sept-2-yl] is an acid guess, 4_[(2_--5-methoxyphenyl)amino]-5-[5 -(piperidin-1-ylindole 20-yl)-1-phenylindole-2-yl]-acid guess, 4-[(2-a-5-methylphenyl)amino]-5-[ 5-(11 辰11-1-ylmethyl)-1-benzobenzopyran-2-yl] is an acid guess, 4-[(5-yl-2-yloxyphenyl)amino] 5-[5-(ϋϋ定-1 -ylmethyl)-1-benzoquinone-2-yl]in acid guess, 90 200815356 4-{[3-(Aminomethyl)benzyl]amine }-5-(3,4-Dimethoxyphenyl)nicotinic acid nitrile; 4-[(2,4-dichloro-5-phenyl)amino]_5-[5-(派唆小基甲Base)_1-benzofuran-2-yl]nicotinic acid nitrile; 5 4_[(4-methoxy-2-tolyl)amino]-5-[5- (Piperidinylmethyl)-1-benzofuran-2-yl]nicotinic acid nitrile. The compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt, hydrate or ester thereof, wherein the compound is in the form of a mirror image isomer. A pharmaceutical composition comprising a compound according to any one of the claims of the patent application and a pharmaceutically acceptable carrier or excipient. A compound or a pharmaceutically acceptable salt, hydrate or ester thereof according to any one of the above-mentioned items of the invention. 15 2〇I, such as the compound of any of the first to seventh aspects of the patent scope, or a pharmaceutically acceptable salt, hydrate or ester thereof, for preparing or inhibiting protein kinase-mediated pathology in a mammal Use of drugs for sexual symptoms or diseases. 21. The use of claim 2G, wherein the protein kinase is protein kinase C. 〇22· The use of the second or the second paragraph of the patent application, wherein the pathological symptom or disease is selected from the group consisting of asthma, colitis, multiple sclerosis, psoriasis, arthritis, rheumatoid arthritis, osteoarthritis Inflammatory and autoimmune diseases that are inflammatory with joints. 91 200815356 VII. Designated representative map: (1) The representative representative of the case is: (). (None) (2) A brief description of the symbol of the representative figure: 8. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: CN 4