CA2709314A1 - 5-alkyl/alkenyl-3-cyanopyridines as kinase inhibitors - Google Patents

Abstract

Described herein are compounds of formula I: wherein G is and pharmaceutically acceptable salts thereof, wherein J, X, R1, R2, R11, R12' and p are as defined herein. Also provided herein are methods of making the compounds of formula I, and methods of using these compounds for inhibiting or treating a pathological condition or disorder linked to or mediated by a protein kinase in a mammal.

Description

TECHNICAL FIELD

[0001] This invention relates to 3-cyanopyridine compounds which are useful as kinase inhibitors.

BACKGROUND
[0002] Protein kinases are enzymes that catalyze the transfer of a phosphate group from adenosine triphosphate (ATP) to an amino acid residue, such as tyrosine, serine, threonine or histidine, on a protein. Regulation of these protein kinases is essential for the control of a wide variety of cellular events including proliferation and migration.
A large number of diseases are associated with abnormal cellular events that are mediated by these kinases, for example, various inflammatory diseases and autoimmune diseases such as asthma, psoriasis, rheumatoid arthritis, inflammatory bowel disease, and joint inflammation. See, e.g., Salek-Ardakami, S., et al., J.
Immunology, (2004), 173(10), 6440-47; Marsland, B., et al., J. Exp.
Med.,(2004), 200(2), 181-89; Tan, S, et al., J. Immunology, (2006), 176, 2872-79; Salek-Ardakami, S., et al., J. Immunology, (2005), 175(11), 7635-41; Anderson, K., et al., Autoimmunity, (2006), 39(6), 469-78;. Healy, A., et al., J. Immunology, (2006), 177(3), 1886-93; Sun, Z., et a/., Nature, (2000), 404, 402-7; and Pfeifhofer, C., et al., J. Exp.
Med., (2003), 197(11), 1525-35.

[0003] One class of serine/threonine kinases is the protein kinase C (PKC) family. This group of kinases consists of 10 members that share sequence and structural homology. The PKCs are divided into 3 groups and include the classic, the novel, and the atypical isoforms. The theta isoform (PKCO) is a member of the novel calcium-independent class of PKCs (Baier, G. et al., J. Biol. Chem., (1993), 268:
4997-5004). PKCO is highly expressed in T cells (Mischak, H. et al. , FEBS
Lett., (1993), 326: 51-5), with some expression reported in mast cells (Liu, Y. et al. (2001), J. Leukoc. Biol., 69: 831-40), endothelial cells (Mattila, P. et al., Life Sci., (1994), 55:

1253-60), and skeletal muscles (Baier, G. at aL, Eur. J. Biochem., (1994), 225: 195-203). It has been shown that PKC6 plays an essential role in T cell receptor (TCR)-mediated signaling (Tan, S.L. et a!., Biochem. J., (2003), 376: 545-52).
Specifically, it has been observed that inhibiting PKCO signal transduction, as demonstrated with two independent PKC6 knockout mouse lines, will result in defects in T cell activation and interleukin-2 (IL-2) production (Sun, Z. et al., Nature, (2000), 404: 402-7;
Pfeifhofer, C. et al., J. Exp. Med., (2003), 197: 1525-35). It also has been shown that PKCO-deficient mice show impaired pulmonary inflammation and airway hyperresponsiveness (AHR) in a Th2-dependent murine asthma model, with no defects in viral clearance and Th1-dependent cytotoxic T cell function (Berg-Brown, N.N. at a/., J. Exp. Med., (2004), 199: 743-52; Marsland, B.J. et al., J. Exp.
Med., (2004), 200: 181-9). The impaired Th2 cell responses result in reduced levels of interleukin-4 (IL-4) and immunoglobulin E (IgE), contributing to the AHR and inflammatory pathophysiology.

[0004] Evidence also exists that PKCB participates in the IgE receptor (FceRl)-mediated response of mast cells (Liu, Y. et al., J. Leukoc. Blot., (2001), 69: 831-840). In human-cultured mast cells (HCMC), it has been demonstrated that PKCO kinase activity rapidly localizes (in less than five minutes) to the membrane following FceRI
cross-linking' (Kimata, M. et aL, Biochem. Biophys. Res. Commun., (1999), 257(3):
895-900). A recent study examining in vitro activation of bone marrow mast cells (BMMCs) derived from wild-type and PKCB-deficient mice shows that upon FceRI
cross-linking, BMMCs from PKCB-deficient mice produced reduced levels of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNFa), and interleukin-13 (IL-13) in comparision with BMMCs from wild-type mice, suggesting a potential role for PKCB in mast cell cytokine production in addition to T cell activation (Ciarletta, A.B. et al., poster presentation at the 2005 American Thorasic Society International Conference, (2005)).

[0005] Other serine/threonine kinases include those of the mitogen-activated protein kinase (MAPK) pathway which consists of the MAP kinases (MAPK) (e.g., erk) and the MAPK kinases (MAPKK) (e.g., mek and their substrates). Members of the raf family of kinases phosphorylate residues on mek. The cyclin-dependent kinases (cdks), including cdc2/cyclin B, cdk2/cyclin A, cdk2/cyclin E and cdk4/cyclin D, and others, are serine/threonine kinases that regulate mammalian cell division. Additional serine/threonine kinases include the protein kinases A and B. These kinases, known as PKA or cyclic AMP-dependent protein kinase and PKB (Akt), play key roles in signal transduction pathways.

[0006] Tyrosine kinases (TKs) are divided into two classes: the non-transmembrane TKs and transmembrane growth factor receptor TKs (RTKs). Growth factors, such as epidermal growth factor (EGF), bind to the extracellular domain of their partner RTK
on the cell surface which activates the RTK, initiating a signal transduction cascade that controls a wide variety of cellular responses. In addition to EGF, there are several other RTKs including FGFR (the receptor for fibroblast growth factor (FGF));
fik-1 (also known as KDR), and fit-1 (the receptors for vascular endothelial growth factor (VEGF)); and PDGFR (the receptor for platelet derived growth factor (PDGF)).
Other RTKs include tie-1 and tie-2, colony stimulating factor receptor, the nerve growth factor receptor, and the insulin-like growth factor receptor. In addition to the RTKs there is another family of TKs termed the cytoplasmic protein or non-receptor TKs. The cytoplasmic protein TKs have intrinsic kinase activity, are present in the cytoplasm and nucleus, and participate in diverse signaling pathways. There are a large number of non-receptor TKs including Abl, Jak, Fak, Syk, Zap-70 and Csk, and the Src family of kinases (SFKs) which include Src, Lck, Lyn, Fyn and others.

SUMMARY

[0007] One aspect of the present invention is directed to compounds of formula 1:

G\ X

(1) or a pharmaceutically acceptable salt thereof, wherein:
X is -0- or -N(R10)-; wherein R10 is H or CH3;
G is R12' N
(R11)P ,,,,, wherein:
R" is, independently at each occurrence, selected from halo, -0-R12", C1.4 alkyl, -CF3 and -N(R12" )-R12";

R12'is, independently at each occurrence, H or CH3;

R12" is, independently at each occurrence, H or CH3; and p is 0, 1 or 2;

J is (i) -Q-(A1)q ;

R12 R12 R1~2 fQ)m-(A1)Q
(ii)(Q)m-(A1)q- (iii) '~nR 12 (iv) R12 or _j_CE (Y)m (v) , wherein:

Q is, independently at each occurrence, C1.4 alkylene;

A' is (i) a C6.10 aryl, (ii) a 5- to 10-membered hetero,3aryl, (iii) 3- to 10-membered hetero,_3cyclyl or (iv) a 5- to 8-membered cycloalkyl, wherein each of (i)-(iv) is optionally substituted with 1 or 2 substituents independently selected from halo, -O-R13, C,4 alkyl, C14 haloalkyl, formyl, -S-R13, -Q-O-R13, -Q-N(R13)-R13, -C(O)-O-R13, -C(O)-R13, -O-C(O)-R13, -C(O)-N(R13)-R13, -N(R13)-C(O)-R'3, -S(O)2-N(R13)-R13, -N(R13)-S(O)2-R13, -O-Q-O-R13, -O-Q-N(R13)-R13, -N(R13)-Q-O-R13, -N(R13)-Q-N(R13)-R13, O-C(O)-N(R13)-R13, -N(R13)-C(O)-O-R13, -S(O)2-R13, -SO2NH(NH)NH2, -SO2NH(NH)NR73R13or wherein 2 substituents together on the same carbon atom form an oxo group;

R12 is, independently at each occurrence, H or CH3;
m and q are independently 0 or 1;

E is N or C(R12'); wherein:

when E is N, Y is absent, -C(O)-, -C(O)-O-, -C(O)-N(R 13)_ or -S(0)2-; and when E is C(R12), y is -0-, -C(O), -C(O)-0-, -0-C(O)-, -C(O)-N(R13)-, -0-C(O)-N(R13)-, -N(R13)-C(O)-, -N(R13)-C(O}O-, -N(R13}C(O)-N(R13)-, -S-, -S(O)-, -S(0)2-, -S(0)2-N(R13)- or -N(R13YS(0)2-;

R13 is, independently at each occurrence, selected from (i) an electron pair, (ii) H, (iii) C1.6 alkyl, (iv) C6.1o aryl, (v) 5- to 10-membered heteroaryl, (vi) 3- to 10-membered hetero1 cyclyl or (vii) two R13 together on the same carbon atom form a 4- to 8-membered ring containing 1-3 heteroatoms, wherein each of (iii)-(vi) is optionally substituted with 1-2 R14; and R 14 is, independently at each occurrence, (i) H, (ii) oxo when two R14 together on the same carbon atom are bound to an oxygen atom, iii) C1.6 alkyl, (iv) C3..8 cycloalkyl, (v) C6.10 aryl, (vi) 5- to 10-membered heteroaryl, (vii) 3- to 10-membered heterol.3cyclyl, wherein each of (iii)-(vii) is optionally substituted with 1-2 C1.6 alkyl;

R' is C1.4 alkyl, C2.4 alkenyl or -(L),-(A2-A3), wherein:

L is -(T)r(Q),r, -(Q), -(T) t, or -(T)r(Q),r(T)r, wherein:

T is, independently at each occurrence, -0-, -C(O)-, -C(O)-0-, -O-C(O)-, C(O)-N(R73)-, -O-C(O)-N(R13)-, -N(R13)-, -N(R13)-C(O)-, -N[C(O)R13]-, -N(R13)-C(O)-0-, -N(R13)-C(O)-N(R13)-, -S-, _S(O)_, -S(O)r, -S(O)rN(R'3)- or -N(R'3)_S(0)r;

t is, independently at each occurrence, 0 or 1;
u is, independently at each occurrence, 0 or 1;
r is, independently at each occurrence, 0 or 1;

A2 is (i) absent, (ii) C1-6 alkylene, (iii) a C6_10 arylene, (iv) 5- to 10-membered heteroarylene, (v) 3- to 10-membered heterol.3cyclylene or (vi) C3.6 cycloalkylene, wherein each of (ii)-(vi) is optionally substituted with 1 or 2 substituents independently selected from halo, -0-R13, C1.4 alkyl, C1-4 haloalkyl, -S-R13, -N(R13)R13, -Q-O-R13, -Q-N(R13)-R13, -C(O)-O-R13, -O-C(O)-R13, -C(O)-N(R13)R13, -N(R13)-C(O)-R13, -S(0)2-N(R13)-R13, -N(R13)-S(0)2R13, -O-Q-O-R13, -O-Q-N(R13)-R13, -N(Rt3)-Q-O-R13, -N(R73)-Q-N(R13)-R13, -0-C(O)-N(R13)-R13, -N(R13)-C(O)-O-R13, -S(0)2-R 13, -OS(O)2-OR13 -C(O)-R13 and oxo when ,2 substituents together on the same carbon atom are bound to an oxygen atom; and A3 is (i) H, (ii) halo, (iii) -O-R14, (iv) R13, (v) -CHO, (vi) -S(O)-O-R13, (vii) -N(R13)R13 (viii) C6-C10 aryl, (ix) 5- or 6-membered heteroaryl, (x) 3- to 10-membered heterol_3cyclyl or (xi) C3.6 cycloalkyl, wherein each of (viii)-(xi is optionally substituted with 1 or 2 substituents independently selected from halo, -O-R13, C1.4 alkyl, C1.4 haloalkyl, -S-R13, -N(R13)R13, -Q-O-R13, -Q-N(R13)-R13, -C(O)-O-R13, -O-C(O)-R13, -C(O)-N(R'3)-R13, -N(R13)-C(O)-R'3, S(O)z-N(R13)-R13, -N(R13)-S(O)2-R13, -O-Q-O-R13, -O-Q-N(R'3)-R'3, -N(R13)-Q-O-R13, -N(R13)-Q-N(R13)-R13, -O-C(O)-N(R13)-R13, -N(R13)-C(O)-O-R13, -S(O)2-R13, -C(O)-R13 and oxo when 2 substituents together on the same carbon atom are bound to an oxygen atom;

and R2 is H, C1.4 alkyl or -CF3.

[0008] Another aspect of the present invention is directed to compositions comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0009] Another aspect of the present invention is directed to a method of using compounds of the present invention for inhibiting or treating a pathological condition or disorder linked to or mediated by a protein kinase, for example protein kinase C, in a mammal, The method comprises administering to the mammal (e.g., a human), a therapeutically effective amount of the compound of formula I or a pharmaceutically acceptable salt thereof. One embodiment of the invention is wherein the method is used to reduce symptoms of a pathological condition or disorder, for example in the treatment of inflammation in a mammal.

[0010] Another aspect of the present invention is directed to methods of making the compounds of formula I and pharmaceutically acceptable salts thereof.

[0011] Another aspect of the present invention is directed to intermediate compounds useful for making the compounds of formula 1.

DETAILED DESCRIPTION

Definitions [0012] Except where otherwise indicated, the terms below have the following meanings everywhere in this specification and in the appended claims:

[0013] As used herein, the terms "include", "includes", "including" and the like are intended to be open-ended unless otherwise specified, i.e., e.g., "including" means "including but not limited to" in the absence of an express limitation.

[0014] As used herein, alone or as part of another group, "halo" or "halogen"
refers to fluoro, chloro, bromo and/or iodo.

[0015] As used herein, alone or as part of another group, "alkyl" refers to a straight-chain or branched saturated hydrocarbyl group having from 1 to 8 carbon atoms. In some embodiments, an alkyl group can have from 1 to 6 carbon atoms. In some embodiments, an alkyl group can have from 1 to 4 carbon atoms. Examples of C1_4 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl. Examples of C,{ alkyl groups include the aforementioned C14 alkyl groups as well as pentyl, isopentyl, neopentyl, hexyl and the like. Additional examples of alkyl groups include heptyl, octyl and the like.

[0016] As used herein, alone or as part of another group, "alkylene" refers to a diradical of a straight-chain or branched saturated hydrocarbon group having from 1 to 6 carbon atoms. In some embodiments, an alkylene group can have from 1 to 4 carbon atoms. In some embodiments, an alkylene group can have from 1 to 2 carbon atoms. Examples of C1_2 alkylene groups include methylene and ethylene.
Examples of C1_4 alkylene groups include the aforementioned C1_2 alkylene groups as well as trimethylene (1,3-propanediyl), propylene (1,2-propanediyl), tetramethylene (1,4-butanediyl), butylene (1,2-butanediyl), 1,3-butanediyl, 2-methyl-1,3-propanediyl and the like. Examples of Cj.6 alkylene groups include the aforementioned C14 alkylene groups as well as pentamethylene (1,5-pentanediyl), pentylene (1,2-pentanediyl), hexamethylene (1,6-hexanediyl), hexylene (1,2-hexanediyl), 2,3-dimethyl-1,4-butanediyl and the like. In some embodiments, an alkylene group is an a,w-diradical. Examples of a,u.-diradical alkylene groups include methylene, ethylene, trimethylene, tetramethylene, pentamethylene and hexamethylene.

[0017] As used herein, alone or as part of another group, "alkoxy" or "alkyloxy" refers to an -0-alkyl group having from 1 to 8 carbon atoms. In some embodiments, an alkoxy group can have from 1 to 6 carbon atoms. In some embodiments, an alkoxy group can have from I to 4 carbon atoms. Examples of C1.4 alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy and the like.
Examples of C1.6 alkoxy groups include the aforementioned C14 alkoxy groups as well as pentyloxy, isopentyloxy, neopentyloxy, hexyloxy and the like. Additional examples of alkoxy groups include heptyloxy, octyloxy and the like.

[0018] As used herein, alone or as part of another group, "cycloalkyl" refers to a monocyclic, saturated cyclic hydrocarbyl group having from 3 to 8 ring carbon atoms.
In some embodiments ("C3.5 cycloalkyl"), a cycloalkyl group can have from 3 to 6 ring carbon atoms. In some embodiments ("C5$ cycloalkyl"), a cycloalkyl group can have from 5 to 6 ring carbon atoms. Examples of Cm cycloalkyl groups include cyclopentyl and cyclohexyl. Examples of Cm cycloalkyl groups include the aforementioned C5.5 cycloalkyl groups as well as cyclopropyl and cyclobutyl.
Examples of C3..8 cycloalkyl groups include the aforementioned CM cycloalkyl groups as well as cycloheptyl and cyclooctyl.

[0019] As used herein, alone or as part of another group, "haloalkyl" refers to a C14alkyl group as defined above wherein one or more of the alkyl group's hydrogen atoms has been replaced with a halogen atom. For each replacement, the halogen atom is independently selected from -F, -Cl, -Br and -I. In some embodiments, a haloalkyl group can be an alkyl group in which one of the alkyl group's hydrogen atoms has been replaced with a halogen atom. Examples of such haloalkyl groups include -CH2F, -CH2CI, -CH2CH2Br, -CH2CH2I, -CH2CH2CH2F, -CH2CH2CH2CI, -CH2CH2CH2CH2Br, -CH2CH2CH2CH21, -CH2CH2CH2CH2CH2Br, -CH2CH2CH2CH2CH2I, -CH2CH(Br)CH3, -CH2CH(CI)CH2CH3 and -CH(F)(CH2)3CH3.
In some embodiments, a haloalkyl group can be an alkyl group in which one to three of the alkyl group's hydrogen atoms has been replaced with a halogen atom.
Examples of such haloalkyl groups include the aforementioned haloalkyl groups as well as -CCI3, -CF3 and -CH2CF3. Other examples of haloalkyl groups include -CF2(CH2)8CHCI2.

[0020] In some embodiments ("perhaloalkyl"), "haloalkyl" can refer to a C14 alkyl group wherein all of the hydrogen atoms are each independently replaced with fluoro or chloro. In some embodiments, all of the hydrogen atoms are each replaced with fluoro. In some embodiments, all of the hydrogen atoms are each replaced with chloro. Examples of perhaloalkyl groups include -CF3, -CF2CF3, -CF2CF2CF3, -CCI3, -CFCI2, -CF2CI and the like.

[0021] As used herein, alone or as part of another group, "aryl" refers to a radical of an aromatic monocyclic or bicyclic ring system having from 6 to 10 ring carbon atoms.
Examples of such aryl groups include phenyl, 1-naphthyl and 2-naphthyl.

[0022] As used herein, alone or as part of another group, "heteroaryl" refers to a radical or diradical of a 5- to 10-membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each heteroatom independently selected from N, 0 and S.
Examples of such heteroaryl groups include pyrrolyl, furanyl (furyl), thiophenyl (thienyl), pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl (pyridyl), pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolyl, benzofuranyl, benzothiophenyl (benzothienyl), indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl and the like. As the foregoing examples illustrate, in some embodiments a heteroaryl group can be monocyclic ("monocyclic heteroaryl"), and in some embodiments a heteroaryl group can be bicyclic ("bicyclic heteroaryl"). In some embodiments ("hetero,.2aryl"), heteroaryl can refer to a heteroaryl group having 1 or 2 ring heteroatoms and otherwise as defined above. In some embodiments ("monocyclic hetero,_2aryl"), heteroaryl can refer to a monocyclic heteroaryl group having 1 or 2 ring heteroatoms and otherwise as defined above. In some embodiments ("bicyclic hetero,.2aryl"), heteroaryl can refer to a bicyclic heteroaryl group having 1 or 2 ring heteroatoms and otherwise as defined above.

[0023] As used herein, alone or as part of another group, "heterocyclyl"
refers to a radical or diradical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each heteroatom independently selected from N, 0 and S. In some embodiments ("hetero1. cyclyl"), a heterocyclyl group can have ring atoms selected from carbon atoms and 1 to 3 heteroatoms, and otherwise defined as above. In some embodiments ("hetero,.2cyclyl"), a heterocyclyl group can have ring atoms selected from carbon atoms and 1 or 2 heteroatoms, and otherwise defined as above. Examples of hetero,.2cyclyl groups include pyrrolidinyl, dihydropyrrolyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyridinyl, dihydropyridinyl, piperazinyl, tetrahydropyranyl, dioxanyl, morpholinyl, azepanyl, diazepanyl, diazepinyl, oxepanyl, dioxepanyl, oxazepanyl, oxazepinyl and the like. Examples of hetero,_3cyclyl groups include the aforementioned hetero1.2cyclyl groups as well as oxiranyl, aziridinyl, oxetanyl, azetidinyl, triazolidinyl, oxadiazolidinyl, triazinanyl and the like.
Additional examples of heterocyclyl groups include decahydroisoquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydrolsochromenyl, decahydronaphthyridinyl; and bridged heterocyclyl groups such as 2,5-diazabicyclohexane and 2-oxa-5-azabicyclo [2.2.1]heptane, and the like. Hetero14cyclyl groups or hetero,_2cyclyl groups may also include groups where the heterocyclyl moiety is fused to another ring which may be saturated, unsaturated or an aromatic ring. Examples of such fused rings include, but are not limited to, phthalimide and tetrahydroisoquinoline.

[0024] As used herein, alone or as part of another term, "pharmaceutically acceptable"
refers to a substance that is acceptable for use in pharmaceutical applications from a toxicological perspective.

[0025] Abbreviations, as used herein, are generally known In the art. Examples of such abbreviations include, but are not limited to: t-butyl (tertiary butyl), LG
(leaving group), PG (protecting group), CDI (1,1'-carbonyldiimidazole), DCE (1,2-dichioroethane), DCM (dichloromethane), DMF (dimethylformamide), DMF-DMA
(dimethylformamide dimethyl acetal), DMSO (dimethylsulfoxide), EDCI (ethyl (dimethylaminopropyl)carbodiimide), EtOAc (ethyl acetate), HOAc (acetic acid), HPLC (high performance Liquid Chromatography), rt (retention time), TBAF
(tetrabutylammonium fluoride), TEA (triethylamine), TFA (trifluoroacetic acid), THE
(tetrahydrofuran) and TMS (trimethylsilyl).

[0026] Compounds of formula I include:

G R12' R1-J CN (R11) N

wherein G is or a pharmaceutically acceptable salt thereof.

[0027] In some embodiments of the compound of formula I, or pharmaceutically acceptable salt thereof, X is -0- or -N(R10)-. In some embodiments, X is -N(R10)-. In further embodiments, R10 is H or CH3. In some embodiments, X is -NH-.

[0028] In some embodiments of the compound of formula I, or pharmaceutically acceptable salt thereof, R2 is H, C14 alkyl or -CF3. In some embodiments, R2 is H. In some embodiments, R2 is methyl, ethyl, propyl or isopropyl. In some embodiments, R2 is methyl.

[0029] In some embodiments of the compound of formula I, or pharmaceutically acceptable salt thereof, G is R1r R1r R 12' N N N
(R11)p~ (R11)P~

[0030] R" is an optional substituent at any indolyl ring carbon position. In some embodiments of the compound of formula I, or pharmaceutically acceptable salt thereof, R" is, independently at each occurrence, selected from halo, -O-R12", alkyl, -CF3 and -N(R12')-R72". In some embodiments, R" is, independently at each occurrence, halo or C1.4 alkyl. In further embodiments, R" is, independently at each occurrence, chloro or methyl.

[0031] In some embodiments of the compound of formula 1, or pharmaceutically acceptable salt thereof, G is indol-4-yl, indol-5-yl, 2-methylindol-5-yl, 4-methylindol-5-yl, 2,4-dimethylindol-5-yl, 4,7-dimethylindol-5-yl, 4-methyl-7-chloroindol-5-yl or indol-6-yl.
In further embodiments, G is indol-5-yl or 4-methylindol-5-yl.

[0032] In some embodiments of the compound of formula I, or pharmaceutically acceptable salt thereof, R12' and R12" is, each independently, H or CH3.

[0033] In some embodiments of the compound of formula I, or pharmaceutically acceptable salt thereof, J is -4(A')d-. In some embodiments of J, q is 0. In some embodiments of J,gis1.

[003.4] In some embodiments of the compound of formula 1, or pharmaceutically acceptable salt thereof, J may be a cis or trans alkene. In some embodiments, J is R12 R12 Rig Q)m (A' "`~~(Q),~ (A')y- or " R12 . In some embodiments of the compound of formula I, or pharmaceutically acceptable salt thereof, J is a trans alkene.
In some R12 - (Q)m-(A1)v embodiments, J is '''R 12 . In some embodiments of J, R72 is H. In some embodiments of J, m is 0. In some embodiments of J, q is 0 or 1.

[0035] In some embodiments of the compound of formula I,.or.pharmaceutically acceptable salt thereof, J is R12 . In some embodiments of J, R12 is H. In some embodiments of J, m is 0. In some embodiments of J, q is 0 or 1.

[0036] In some embodiments of the compound of formula I, or pharmaceutically acceptable ~-salt thereof, J is - //E-mm . In some embodiments of J, E is N.' In some embodiments of J, m is 0 or 1.

[0037] In some embodiments of the compound of formula I, or pharmaceutically acceptable salt thereof, A' is optionally substituted C6.10 arylene. In further embodiments, A' is optionally substituted phenylene. In some embodiments, A' is optionally substituted 5- to 10-membered heterol4arylene. In further embodiments, A' is optionally substituted pyridinyl, thiazolyl furanyl or thienyl.

[0038] In some embodiments of the compound of formula I, or pharmaceutically acceptable salt thereof, Q is methylene, ethylene, trimethylene or tetramethylene. In some embodiments, Q is methylene, ethylene or propylene.

[0039] In some embodiments of the compound of formula I, or pharmaceutically acceptable salt thereof, R' is -(L)r(A2-A). In further embodiments of R', r is 0 and R' is -(A2-A3).
[0040] In some embodiments of the compound of formula I, or pharmaceutically acceptable salt thereof, L is -(T)~(Q)u- or -(Q)u(T)t-. In some embodiments, t is 0. In further embodiments, t is 0 and u is 0 or 1. In some embodiments, t is 1. In further embodiments, t is 1 and u is 0 or 1. In some embodiments, u is 0, t is 0 and L
is a covalent bond. In some embodiments, T is -0- or -N(R13)-. In some embodiments, Q is methylene, ethylene or propylene. In further embodiments, Q is methylene.

[0041] In some embodiments of the compound of formula I, or pharmaceutically acceptable R1,2 salt thereof, J is R12 , R12 is H; m is 0; R2 is H; X is -(NR'0)- and A' is optionally substituted C61 arylene or optionally substituted 5- to 10-membered heterol.3arylene.

[0042] In some embodiments of the compound of formula 1, or pharmaceutically acceptable salt thereof, J may be a trans alkene, wherein J is ' R12 ; R12 is H, m is 0, R2 is H; X is -(NR10)-, A' is phenylene, pyridinyl, thiazolyl, or furanyl, each of which is optionally substituted. In some embodiments, A' is optionally substituted phenylene. In other embodiments, A' is optionally substituted 5- to 10-membered heterol-3arylene. In further embodiments, A' is optionally substituted pyridinyl, thiazolyl furanyl or thienyl. In further embodiments, A' is optionally substituted phenylene, T is -0-, u is I and A3 is 3- to 7-membered heterol-3cycyl. In further embodiments of the compound of formula I, or pharmaceutically acceptable salt thereof, R1 is -(L),-(A2-A3), wherein L is -(TN(Q)u- or -(Q)õ (TN-. In further embodiments, t is 0, u is 1, L is -Q- and Q is methylene.

[0043] In some embodiments of the compound of formula I, or pharmaceutically acceptable salt thereof, J is J(ii) or J(iii) and -(Q)m (A')q R, is:

(131) -A3, wherein m, q and r are 0 and A2 is absent and A3 is as defined in claim 1; or (B2) -A'-A2-A3, wherein m is 0, q is 1, and r is 0 and wherein A' and A3 are as defined in claim 1 and A2 is C1-6 alkylene; or (B3) -A2-A3, wherein m, q and r are 0 and A2 and A3 are as defined in claim 1;
or (B4) -A'-T-A3, wherein m is 0, q is 1, A2 is absent, r is 1 and L is -T- and A', T
and A3 are as defined in claim 1; or (B5) -A'-T-A2-A3, wherein m is 0, q and r are 1 and L is -T- and A', T, A2 and are as defined in claim 1; or (B6) -A'-Q-T-A2-A3, wherein m is 0, q and r are 1 and L is-Q-T- and A', T, A2 and A3 are as defined in claim 1; or (B7) A'-Q-A2-A3, wherein m is 0, q and r are 1 and L is -Q- and A', Q, A2 and are as defined in claim 1.

[0044] In further embodiments of the compound of formula I, or pharmaceutically acceptable salt thereof, wherein J is J(ii) or J(iii) and:

(Cl) (Q)m (A')q-R, is 131 and A3 is optionally substituted C6-C10 aryl, 5- or membered heteroaryl, 3- to 10-membered heterol-3cyclyl or C3.8 cycloalkyl;
or (C2) -(Q).-(A')q-R, is B2 and A' is optionally substituted C6-C10 aryl or optionally substituted 5- to 10- membered heterol-3aryl, and A3 is -N(R13)R13 or optionally substituted 3- to 10-membered hetero,4cyclyl wherein at least one heteroatom is a nitrogen atom and A3 is joined via the nitrogen atom to A2.
(C3) -(Q)m(A')q-R, is B3 and -(A2-A3) is:

N
NNN N
La N
N N ~
V N..-ON \N~ N
'CH3 ~N-/ or OH l N--15- ~/

or (C4) -(Q),(A')q R, is B4 and A' is optionally substituted C6-to aryl or optionally substituted 5- to 10-membered hetero13aryl and A3 is optionally substituted 3- to 10-membered hetero13cyclyl and T is -0-, -NH-, -C(O)-, or -C(O)-NH- or -S(0)2-; or (C5) -(Q),(A')gR, is B5 and A2 is alkylene and A' is optionally substituted C6.,o aryl or optionally substituted 5- to 10-membered hetero,.3aryl and A3 is optionally substituted 3- to 10-membered heterol3cyclyl and T is -0-, -C(O)-, or -C(O)-NH- or -S(0)2-; or (C6) -(Q).(A')gR, is B6 and A' is optionally substituted C6_,0 aryl or optionally substituted 5- to 10-membered hetero13aryl and A2 is alkylene or is absent, T is -0-, -NH-, -C(O)-, -C(O)-NH- or -S(0)2- and A3 is -N(R13)R13 or optionally substituted 3- to 10-membered heterol3cyclyl; or (C7) -(Q)m (A')q-R, is B7 and A' is optionally substituted 06.70 aryl or optionally substituted 5- to 10-membered heterol.3aryl and wherein -(A2-A) or -A3 when A2 is absent is:

Na AINa =N

OLOH 'NaN N No N ON O N

-CH3 E ON or OH l N~

[0045] In some embodiments of the compound of formula I, or pharmaceutically acceptable salt thereof, A2 is optionally substituted phenylene. In some embodiments, A2 is morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, azetidinyl, thiomorpholinyl, thiomorpholinyl-1, 1 -dioxide, 1,3-dioxoisoindolyl, oxopiperazinyl, 1,4-diazepanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 1,2,3,4-tetrahydroisoquinolinyl and indolinyl, wherein A2 is optionally substituted. In some embodiments, A2 is optionally substituted 3-to 10-membered hetero1.2cyclyl. In some embodiments, A2 is optionally substituted piperidinyl, piperazinyl or pyrrolidinyl. In some embodiments, A2 is optionally substituted C3..8 cycloalkyl. In some embodiments, A2 is optionally substituted cyclohexyl.

[0046] In some embodiments of the compound of formula I, or pharmaceutically acceptable salt thereof, A2 is absent.

[0047] In some embodiments of the compound of formula I, or pharmaceutically acceptable salt thereof, A3 is H.

[0048] In some embodiments of the compound of formula I, or pharmaceutically acceptable salt thereof, A3, when present, is -NR 13R73, 5- to 10-membered heteroarylene or 3- to 10-membered heterol.3cyclylene, and wherein each A3 contains a nitrogen atom, joined via the nitrogen atom to A2, when present, or when A2 is absent, joined via the nitrogen atom to an adjacent atom.

[0049] In some embodiments of the compound of formula I, or pharmaceutically acceptable salt thereof, -(A2-A3) is Na ~" ~`~N~N
N
UN N aN") aN

N,CH3 N"" , ~/N~/\ or -OH N-`

[0050] Examples of compounds of formula I, or a pharmaceutically acceptable salt thereof, are as described herein throughout the specification, some of which are:
5-{(E)-2-[2-methoxy-4-(piperazin-1-ylmethyl)phenyl]vinyl)-4-[(4-methyl-1 H-indol-5-yl)amino]
nicotinonitrile;

4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[3-({[2-(1-methylpyrrolidin-2-yl)ethyl]amino}methyl) phenyl]ethenyl)pyridine-3-carbonitrile;

5-[(1 E)-4-(4-aminopiperidin-l-yl)but-l-en-l-yl]-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile;
4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[2-(2-piperazin-1-ylethoxy)phenyl]vinyl}
nicotinonitrile;

5-[(E)-2-(6-bromopyridin-2-yl)vinyl]-4-[(4-methyl-1 H-indol-5-yl)aminolnicotinonitrile;
5-[(E)-2-(6-chloropyridin-2-yl)vinyl]-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile;

4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[6-(piperazin-l-ylmethyl)pyridin-2-yl]vinyl}
nicotinonitrile;

5-[(E)-2-(5-bromopyridin-3-yl)ethenyl]-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile;
4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[6-(thiomorpholin-4-ylmethyl)pyridin-2-yl]ethenyl}
pyridine-3-ca rbon it ri l e ;

5-[(E)-2-{6-[(4-cyclopentylpiperazin-1-yl)methyl]pyridin-2-yl}ethenyl]-4-[(4-methyl-1 H-indol-5-yl )a m i n o] pyrid i n e-3-ca rbo n i trt l e;

5-[(E)-2-(6-{[4-(1-methylethyl)piperazin-1-yl]methyl}pyridin-2-yl)ethe nyl]-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile;

5-[(E)-2-{6-[(4-methyl-1,4-d iazepan-1-yl)methyl]pyridin-2-yl)ethenyl]-4-[(4-methyl-1 H-indol-5-yl) amino]pyridine-3-carbonitrile;

4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[6-({[3-(2-oxopyrrolidin-1-yl)propyl]amino}methyl) pyrid in-2-yl]ethe nyl}pyridin e-3-carbon itrile;

5-{(E)-2-[6-({[2-(dimethylamino)ethyl]amino}methyl)pyridin-2-yl]ethenyl}-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile;

4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[6-({[2-(1-methylpyrrolidin-2-yl)ethyl]amino}methyl) pyridin-2-yl]ethenyl}pyridine-3-carbonitrile;

5-[(E)-2-(6-{[(2-azepan-1-ylethyl)amino]methyl}pyridin-2-yl)ethenyl}4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile;

5-[(E)-2-{3-[(4-cyclopentylpiperazin-1 -yl)methyl]phenyl}ethenyl]-4-[(4-methyl-1 H-indol-5-yl) amino]pyridine-3-carbonitrile;

4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{3-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}vinyl]
nicotinonitrile;

6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{3-[(4-methylpiperazin-1 -yl)sulfonyl]phenyl}
ethenyl]pyridine-3-carbonitrile;

4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}vinyl]
nicotinonitrile;

5-[(E)-2-(3-{[4-(dimethylamino)piperidin-l -yl]methyl}phenyl)ethenyl]-6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile;

5-{(E)-2-[3-({[2-(dimethylamino)ethyl]amino}methyl)phenyl]ethenyl}-6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile;

4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{5-[(4-methylpiperazin-l -yl)methyl]pyridin-2-yl}vinyl]
nicotinonitrile;

4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{2-[(4-methylpiperazin-1-yl)methyl]-1,3-thiazol-4-yl}vinyl]nicotinonitnle;

4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{6-[(4-methylpiperazin-1-yl)methyl]pyridin-2-yl}vinyl]
nicotinonitrile;

4-[(4-methyl-1 H-indol-5-y1)amino]-5-{(E)-2-[4-(2-pyrrolidin-1-ylethoxy)phenyl]vinyl}
nicotinonitrile;

6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{5-[(4-methylpiperazin-l -yl)methyl]pyridin-2-yl}vinyl]nicotinonitrile;

4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{3-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}vinyl]
nicotinonitrile;

4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{3-[(4-methylpiperazin-1 -yl)methyl]phenyl}vinyl]
nicotinonitrile;

4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{5-[(4-methylpiperazin-1-yl)methyl]-3-furyl}vinyl]
nicotinonitrile;

5-[(E)-2-{2-methoxy-5-[(4-methylpiperazin-l-yl)methyl]phenyl}vinyl]-4-[(4-methyl-1 H-indol-5-yl) amino]nicotinonitrile;

4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{4-[(4-pyrrolidin-1-ylpiperidin-1-yl)methyl]phenyl}
vinyl]nicotinonitrile;

5-{(E)-2-[4-(1,4'-bipiperidin-l'-ylmethyl )phenyl]ethenyl}-4-[(4-methyl-1 H-indol-5-yl)amino]
pyridine-3-carbonitrile;

6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{4-[(4-methylpiperazin-1-yl)methyl]phenyl) ethenyl]pyridine-3-carbonitrile;

5-{(E)-2-[5-(1,4'-bipiperidin-l'-ylmethyl )pyridin-2-yl]ethenyl}-4-[(4-methyl-l H-indol-5-yl)amino]
pyridine-3-carbonitrile;

5-[(E)-2-(5-{[4-(dimethylamino)piperidin-1-yl]methyl}pyridin-2-yl)ethenyl]-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile;

5-[(E)-2-{5-[(4-methyl-1,4-diazepan-1-yl)methyl]pyridin-2-yl}ethenyl]-4-[(4-methyl-1 H-indol-5-yl) amino]pyridine-3-carbonitrile;

5-[(E)-2-(6-{[4-(2-hydroxyethyl)piperazin-1-yl]methyl}pyridin-2-yl)ethenyl]-4-[(4-methyl-1 H-indol-5-yl )amino]pyridine-3-carbon itrile;

5-{(E)-2-[6-(1,4'-bipiperidin-I'-ylmethyl)pyridin-2-yi]ethenyl}-4-[(4-methyl-1 H-indol-5-yl)amino]
pyrid i ne-3-carbonitrile;

4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{6-[(4-pyrrolidin-1-ylpiperidin-1-yl)methyl]pyridin-2-yi}ethenyl]pyrid ine-3-carbonitrile;

5-[(E)-2-(6-{[4-(dimethylamino)pipeddin-1-yl]methyl}pyridin-2-yl)ethenyl]-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile;

6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{4-[(4-pyrrolid in-1-ylpiperidi -yipip)methyl]
phenyl)ethenyl]pyridine-3-carbonitrile;

5-{(E)2-[4-({[2-(dimethylamino)ethyl]amino}methyl)phenyl]ethenyl}-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile;

4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{3-[(4-pyrrolidin-1-ylpiperidin-1-yl)methyl]phenyl}
ethenyl]pyridine-3-carbonitrile;

4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(4-([(2-pyrrolidin-1-ylethyl)amino]methyl}phenyl) ethenyl]pyrid ine-3-carbonitrile;

6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{5-[(4-morpholin-4-ylpiperidin-1-yl)methyl]
pyrid in-2-yl}ethenyl]pyridine-3-carbonitrile;

5-{(E)-2-[5-(1,4'-bipiperidin-l'-ylmethyl)pyridin-2-yl]ethenyl}-6-methyl-4-[(4-methyl-1 H-indol-5-yl )ami no]pyridine-3-carbonitrile;

5-[(E)-2-(3-{[4-(dimethylamino)piperidin-1-yl]methyl}phenyl)vinyl]-4-[(4-methyl-1 H-indol-5-yl) amino]nicotinonitrile; or 5-{(E)-2-[3-(1,4'-bipiperidin-1'-ylmethyl)phenyl]vinyl}-4-[(4-methyl-1 H-indol-5-yl)amino]
nicotinonitrile.

[0051] Pharmaceutically acceptable salts of the compounds of formula I having an acidic moiety can be formed using organic and/or inorganic bases. Both mono and polyanionic salts are contemplated, depending on the number of acidic hydrogens available for deprotonation. Suitable salts formed with bases include metal salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium and magnesium salts; ammonia salts and organic amine salts, such as those formed with morpholine, thiomorpholine, piperidine, pyrrolidine, a mono-, di- or tri-(C,.,, alkyl)amine (e.g., ethyl-tert-butyl-, diethyl-, diisopropyl-, triethyl-, tributyl- or dimethylpropyl-amine), or a mono-, di-, or tri-hydroxy (C1.6 alkyl)amine (e.g., mono-, di- or tri-ethanolamine). Examples of inorganic bases useful for forming such pharmaceutically acceptable salts include NaHCO3, Na2CO3, KHCO3, K2CO3, Cs2CO3, LiOH, NaOH, KOH, NaH2PO4, Na2HPO4 and Na3PO4. Similarly, pharmaceutically acceptable salts of the compounds of formula I having a basic moiety can be formed using organic and/or inorganic acids. Both mono and polycationic salts are contemplated, depending on the number of lone-pair electrons available for donation. For example, suitable salts can be formed from the following acids: acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, dichloroacetic, ethenesulfonic, formic, fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, malonic, mandelic, methanesulfonic, mucic, naphthalenesulfonic, nitric, oxalic, palmitic, pantothenic, phosphoric, phthalic, propionic, succinic, sulfuric, tartaric, and toluenesulfonic.

[0052] Esters of the compounds of formula I can include various pharmaceutically acceptable esters known in the art that can be metabolized into the free acid form (e.g., a free carboxylic acid form) in a mammal. Examples of such esters include alkyl esters (e.g., of 1 to 10 carbon atoms), cycloalkyl esters (e.g., of 3-10 carbon atoms), aryl esters (e.g., of 6-14 carbon atoms, including of 6-10 carbon atoms), and heterocyclic analogues thereof (e.g., of 3-14 ring atoms, 1-3 of which can be selected from oxygen, nitrogen, and sulfur heteroatoms), wherein the alcohol residue can include further substituents. In some embodiments, esters of the compounds disclosed herein can be C,_10 alkyl esters, such as methyl esters, ethyl esters, propyl esters, isopropyl esters, butyl esters, isobutyl esters, t-butyl esters, pentyl esters, isopentyl esters, neopentyl esters, and hexyl esters; C3.1o cycloalkyl esters, such as cyclopropyl esters, cyclopropylmethyl esters, cyclobutyl esters, cyclopentyl esters, and cyclohexyl esters; or aryl esters, such as phenyl esters, benzyl esters, and tolyl esters.

[0053] The compounds of this invention may contain one or more asymmetric centers. They may occur as racemates and racemic mixtures, single enantiomers, individual diastereomers and diastereomeric mixtures. Enantiomers may occur in enantiomeric excess of more than 50%, for example, an enantiomeric excess of at least 60%, 70%, 80%, 85%, 90%, 95%, or 98%. Some compounds may have an enantiomeric excess of at least 99%. All such isomeric forms of these compounds are expressly included in the present invention. The syntheses described herein may also employ racemates, enantiomers or diastereomers as starting materials or intermediates.
Single enantiomers can be obtained by asymmetric synthesis, synthesis from optically pure precursors or by resolution of the racemates. Resolution of the racemates can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example a chiral HPLC column. Similarly, diastereomeric products resulting from such syntheses may be separated by chromatographic or crystallization methods, or by other methods known in the art. Each of the asymmetric carbon atoms, when present in the compounds of this invention, may be in one of two configurations (R or S), both of which are within the scope of the present invention. The compounds may also occur in cis- or trans- or E- or Z-double bond isomeric forms. The compounds may also be represented in multiple tautomeric forms. All such isomeric and tautomeric forms of such compounds are expressly included in the present invention.
Crystalline forms of the compounds described herein are expressly included in the present invention.

[0054] Another aspect of the present invention relates to compositions comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. A further embodiment of the invention relates to compositions comprising a compound of formula 1, wherein:

R12Q)m-(A1)4 J is R12 ;R12isH; mis0;

R2 is H; X is -(NR1 )-, A' is phenylene, pyridinyl, thiazolyl, or furanyl, each of which is optionally substitued and R' is -(L),-(A2-A3), wherein L is -(TN(Q)u- or -(Q)u(T)r.
[0055] Compositions can include at least one compound of formula I, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients, or diluents. Suitable excipients are those that do not adversely interact with the active ingredient are compatible with the other ingredients in the formulation and are biologically acceptable. Examples of such excipients are well known to those skilled in the art, e.g., as described in Handbook of Pharmaceutical Excipients, 5th edtion, eds. R.C. Rowe, P.J. Sheskey and S.C. Owen, Pharmaceutical Press:
London, UK (2003), the entire disclosure of which is incorporated by reference herein. Examples of such compositions are well known to those skilled in the art and can be prepared in accordance with acceptable pharmaceutical procedures, such as, e.g., those described in Remington: The Science and Practice of Pharmacy, 20th edition, ed. A.R. Gennaro, Lippincott Williams & Wilkins: Baltimore, MD
(2000), the entire disclosure of which is incorporated by reference herein. Supplementary active ingredients can also be incorporated into the pharmaceutical compositions.

[0056] Throughout the description, where compositions are described as having, including, or comprising specific components, or where processes are described as having, including, or comprising specific process steps, it is contemplated that compositions of the present teachings also consist essentially of, or consist of, the recited components, and that the processes of the present teachings also consist essentially of, or consist of, the recited processing steps.

[0057] It should be understood that the order of steps or order for performing certain actions is immaterial so long as the present teachings remain operable. Moreover, two or more steps or actions may be conducted simultaneously.

Processes are provided for preparing a compound of formula I, wherein J is J(ii) or J(iii) as defined herein, the process comprising reacting a compound of formula 15 R1z\

~Rh1~ N
P\ \
X0.

Z CN

[0058] wherein R2, R", R12' and p are as defined herein and Z is I or Br; in the presence of a Pd catalyst; with a compound of formula R'-J-B(OR)2, wherein J and R' are as defined herein, and each R is, independently at each occurrence, H or C1-C6 alkyl; or two R groups together in -B(OR)2, with R comprising C1-C6 alkylene, form a ring comprising boron, oxygen and carbon atoms. In some embodiments, the -B(OR)2 o A\o moiety may be [0059] An example of such a reaction is shown below:

R'7 R+\
N N
(R11)p / I (R11)D\ \
3 _ X Pd catalyst R12 X'"
I/Br CN R12 R1'(g1)a CN

RR N
R2 15 R'(A1)Q B(OR)2 16 [0060] Another example of such a reaction is shown below:

N
(R11)P\
~ I- R1 X
N
L I/Br CN (R++~\ \

( n ~O R2 N~ R13 Xi'-p -- - R13 N CN
Pd(PPh3)2CI2, Cs2CO3 where -NR 13R13 is equivalent to (A2-A3) as defined for Formula I.

[0061] Processes are also provided for preparing a compound of formula I, wherein J is J(iii), the process comprising reacting a compound of formula 15 R1 z N
(R1+) Z CN
R2 *N

wherein R2, R", R12' and p are as defined herein and Z is I or Br; in the presence of a Pd catalyst; with a compound of formula R'-(A1)Q(Q)m\--, wherein q is 1, m is and R1 is as defined herein. .

[0062] Processes are also provided for preparing a compound of formula I, wherein J is J(iii) as defined herein, comprising reacting a compound of formula 36 R12\
(R )p N
X , LIE9 CN
RZ N

wherein R2, R", R12'and p are as defined herein; in the presence of a palladium catalyst; with a compound of formula R'A'Br or R'A1I, wherein R' and A'-is as defined herein. A further embodiment of the process comprises reacting a compound of formula 15 R,r\
(R>>) N
Z CN

in the presence of a palladium catalyst, with a vinyl reagent, to give a compound of formula 36. The vinyl reagent may be any reagent that transfers a vinyl moiety to an aryl or heteroaryl ring. In some embodiments, the vinyl reagent may be tributyl(vinyl)tin, vinyl boronic acid pinacol ester, vinyl boronic acid dibutyl ester or potassium vinyl trifluoroborate.

[0063] Processes are also provided for processes for preparing a compound of formula I
wherein J is J(iii), the process comprising first reacting a compound of formula 38 R1 \
(R11) N
X.I -K,Q1A1 / CN

RZ IN

wherein K is OH; Q is methylene and A1, R", R12', p, X and R2 are as defined herein; with an alcohol-activating agent to form an electrophile; followed by reacting the electrophile with an amine R13R13NH. In one embodiment of the invention, the alcohol activating agent may comprise a base and an alkyl or aryl sulfonyl chloride.
In one embodiment of the invention, the base may be a tertiary amine. In a further embodiment, the tertiary amine may be triethylamine or diisopropylethylamine.
In one embodiment of the invention, the alkyl or aryl sulfonyl chloride may be p-toluenesulfonyl chloride or methanesulfonyl chloride.

[0064] Processes are also provided for preparing a compound of formula I
wherein J is J(iii), the process comprising reacting a compound of formula 41 R12\
N
(R11~
X' W~A1 CN

wherein W is CHO; A', R", R1z, p, X and R2 are as' defined herein; with an amine R13R13NH, in the presence of a reducing agent. Various reducing agents known in the art may be used. In some embodiments, the reducing agent may be sodium cyanoborohydride or sodium triacetoxyborohydride.

[0065] The teachings of the present invention also provide for processes for preparing compounds herein, comprising reacting a compound of formula E

CI

E
with a compound of formula C
\ NR1r I
i HX/~/ (R71)P
C, wherein R', J, R2, X, R", R12 and p are as defined herein.
[0066] The compound of Formula 15 is made by utilizing the reaction:

R1r` R12;
N N
(R11)p\ I (R11~\ I
CI
I/Br, ' CN HX - x, 1/Br CN
R2 N solvent, heat [0067] The following Schemes and description provide further illustrative examples.

[0068] Several intermediates serve important roles in the syntheses of compounds of Formula I. One example of such an intermediate is compound 6, the synthesis of which is outlined in Scheme 1.

[0069] Scheme 1:

Me2N O
NH4OAc CN
~CN-.- ~CN e2N
NHZ O M/ CN
O N

O CI
12/NaOH I I CN POC13 I CN
N N
H

[0070] The synthesis of compound 6 begins with 3-aminobut-2-enenitrile I
which. is heated in acid (e.g., aqueous HCI) to yield acetoacetonitrile 2. Acetoacetonitrile 2 is treated with t-butoxybis(dimethylamino)methane and DMF-DMA at an elevated temperature to yield 5-(dimethylamino)-2-[(dimethylamino)methylene]-3-oxopent-4-enenitrile 3, which is then treated with ammonium acetate in EtOH at reflux to produce 4-hydroxynicotinonitrile 4. (An alternate synthesis of 4-hydroxynicotinonitrile is reported in the literature: Broekman, F. W. et al., Recueil des Travaux Chimiques des Pays-Bas, 81: 792-796 (1962)). A mixture of 4-hydroxynicotinonitrile 4, iodine and NaOH
in water is heated overnight to yield 4-hydroxy-5-iodonicotinonitrile 5, which is then treated with POCI3 at an elevated temperature to yield 4-chloro-5-iodonicotinonitrile 6. The analogous 4-bromo-5-iodonicotinonitrile may be prepared in two steps from compound 4 using bromine in acetic acid followed by treatment with POCI3.

[0071 ] Scheme 2:

o c1 0 0 1) CDI
COON ICI Z 0H :xi a (Z=I) 9a (Z=I) 10 (Z=I) 8b (Z--BY) 9b (Z=Br) 11 (Z--Br) CI a) UHMDS, THE CI CI
I/Br I CN b) CH31 I/Br \ I CN + I/Br / I CN
N N
or 11 12 13 [0072] Another intermediate in the syntheses of compounds of Formula I is 10/11. A useful synthesis of 10/11 is illustrated in scheme 2. The 6-alkyl-4(1 H}pyridone-3-carboxylic acids 7 can be iodinated at C-5 using the method reported in W09948892 to prepare 5-iodo-6-methyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (8a where R2 is Me).
The carboxylic acid group is converted to the primary amide 9a by reaction with N,N-carbonyldiimidazole followed by treatment with aqueous ammonium hydroxide.
Heating of the amide 9a In phosphorus oxychloride, optionally in the presence of a catalytic amount of DMF, results in dehydration of the amide with concomitant chlorination at C-4 to give the key 4-chloro-5-iodo intermediate 10. The analogous 5-bromo-4-chloro intermediates can. be prepared by bromination of 7 at C-5 with bromine in acetic acid containing an optional amount of pyridine to give 8b.
The subsequent steps to generate the C-5 bromo analogs 9b and 11 are the same as described above.

[0073] In certain circumstances, one C-6 alkyl group can be transformed into another group.
Specifically, as illustrated in scheme 2, the C-6 methyl group of 10/11 can be deprotonated with a strong base such as LHMDS and be quenched with a carbon electrophile such as Mel to give 12 or 13. The ratio of 12:13 can be controlled by adjusting the equivalents of base and electrophile used. Those skilled in the art can envision various related transformations to yield larger and more diverse alkyl groups.

[0074] Scheme 3:

R' z R1r R12\
N D N N
. \
(Rtt~\ \ (Rtt)p\ (R11)p CI
1/Br CN HX -'- X Pd catalyst R12 X"

UBr CN 1 CN
R2 N solvent, heat I R12 Rt(A )y or 11 base (optional) R2 N .(A1') R1 R2 N
R1 -B(OR)2 16 [0075] Treatment of compound 10 or 11 with various aryl compounds of formula 14 in a suitable solvent such as ethanol or ethoxyethanol at an elevated temperature leads to compound 15. When appropriate, this reaction may be performed in the presence of a base such as potassium carbonate, sodium bicarbonate, or triethylamine.
Compound 15 may be further elaborated by well documented procedures such as Suzuki or Stille couplings as shown to ultimately give compounds of the invention, such as 16.

[0076] Scheme 4:

O HNR13Rt3 N .
LG-t LG
1 T = " ~O R73 ( " ~O

B O
R' Z 18 B
N
(R11);' R1z R'T \
N N
I/Br CN n (R )D~ (R11)p\
R2 N R13 X~ - X~'-D
1s 13 CN :x_2_N
Pd(PPh3)2CI2, Cs2CO3 N
-NR13R13 = (A2-A3) or (L)r(A2-A3) [0077] An example of a procedure for the synthesis of compound 20 is illustrated in Scheme 4. An alkyne of formula 17 is hydroborated under conditions well known to those skilled in the art (Tetrahedron Letters, 46(50), 8777-8780; 2005) to provide boronic esters of formula 18. This reaction can be performed neat or in a solvent such as dichloroethane and related solvents at temperatures ranging from 0 C to 100 C, preferably approximately 20 C. The leaving group (LG) is displaced by nucleophiles such as primary and secondary amines in a suitable solvent such as DMF or DMSO.
Leaving groups are selected from Cl, Br, o-tosyl, and the like. The displacement generally occurs at room temperature, but elevated temperatures and reduced temperatures are necessary and beneficial under particular circumstances.
Intermediate 19 is treated with intermediate 15 and an appropriate catalyst such as Pd(PPh3)2CI2 or Pd(PPh3)4 under basic conditions at an elevated temperature to provide compounds of formula 20. It should be understood that analogous procedures utilizing the related tin reagents (Stille coupling) may also be employed to obtain compound 20. Moreover, it is not necessary to isolate each intermediate illustrated in scheme 4. In specific circumstances intermediate 18 is subjected to the Suzuki conditions in the presence of an amine nucleophile to obtain compound without the isolation of intermediate 19.

[0078] In cases where compound 18 is treated under Suzuki conditions in the presence of both a secondary amine and a carbonate base, compound 21 may be formed as a mixture with compound 20. The ratio of 20:21 can be influenced by the choice of solvent, temperature, and base. In some circumstances, compound 21 may be obtained as the major product of the reaction. The formation of compound 21 may be minimized by treatment of compound 18 with excess secondary amine at room temperature prior to treatment with the carbonate base and palladium catalyst necessary for the subsequent Suzuki coupling. This will be made more clear in the specific examples that follow this general description.

[0079] Scheme 5:

R1 \
(R")p N
X
R13 IBr CN
)NNH m N-N R2 N 15 K . PG/ O
18 p B Pd(PPtyhG2, Cs2CO3 R'\ 23 0 R1 \
N N
R13 (R11)P\ \ I R13 (R"1oO
PG-~N, 1 X deprotedion HN~/~ X
CN -~N~ CN

or R19C02H I EDC
R1\ R1\

R73 (R11) \ ( R73 (R11A\
I
0 q N !-X' 0=S'NIC X OYN~ 1 RisN CN R13 CN
26 R2 N ff~ ~~~n 27 R2 N

R13 = R13 or (A2-A3) or (L)r(A2-A) Scheme 6:

N
(R11)P ' X
I NH UBr CN
( n\ O PG~228 N R2 I N 15 i 18 B p PGA - B Pd(PPh3)2CI2 C52C03 R12' 29 R1z N N
(R11)p\l\ I (R11)p, X --~
deprotection ///```~~~ X
PG- NN n / CPI HNN CN

or R13CO2H / EDC
R1 ; R1r N
N
(R11)vim \ I ' (R11)v' \
O x' 0 x O::::~S-N N / \ CN -N N ^ CN
R13 m I R13 / {{ \

R13 = R13 or (A2-A3) or (L),-(A2-A%

[0080] In particular circumstances, compounds can be prepared by the routes illustrated in Schemes 5 and 6. Similar to the previously shown route, compound 18 is treated with an appropriately protected diamine to give boronic ester 23 / 29.
Preferred protecting groups include, but are not limited to, Boc and Cbz. The boronic ester 23 /
29 is coupled under the previously discussed conditions to give compound 24 /
30.
Deprotection, frequently utilizing TFA and dichloromethane at room temperature, gives compound 25 / 31. Compound 25 / 31 may be further derivatized to compounds 26 / 27 / 32 / 33 via sulfonylation and amidation chemistry that is well known in the art.

[0081] Scheme 7:

R72\ R1 \
N N
(R11)p\ (R11)p\ \
x x I/Br I CN Et Nol)3, Pd(OAc)2 R1.A I CN

[0082] In addition to the routes described above, a Heck reaction (Scheme 7) may be utilized to synthesize various compounds. As such, compounds of formula 35 may be prepared by a Heck reaction with an appropriate alkene coupling partner such as 34 (where A' is aryl or heteroaryl). The reaction may be conducted under conditions well known to those skilled in the art. An especially useful set of conditions is the treatment of an aryl halide 15 with an alkene of formula 34 in the presence of Pd(OAc)2 and tri(ortho-tolyl)phosphine in a solvent such as DMF at an elevated-temperature, preferably 70-120 C. Generally, excess base such as triethyl amine (preferably 3 equivalents) is utilized for this transformation.

[0083] Scheme 8:

4z~,SnBu3 RrA:Br/I Pd(PPh3)2CI11 2 R'. A'"
Cul 34a A` HNR7R8 R13 \~,SnBu3 R13 OHC' Br/1 NaBH(OAc)3 R13 N~A,Br/1 Pd(PPh3 R13 NA1,,/
Cul 34b A` R5-LG \\,SnBu3 5 1 HO' Br/I base RS 01A,Br/1 Pd(PCul~12 R 0_A
34c HNR7R8 R -Iz,SnBu3 i 1 H02C'A'Br/I EDC or DCC R13N~A~ Br/I Pd(PPh3)2CI2 R13NYA~
Cut 0 34d 0 -NR13R13 = -NR13R13 or (A2-A3) or (L)r-(A243) [0084] The appropriate alkene coupling partner, 34, may be obtained commercially or may be readily synthesized via Stille couplings of an aryl or heteroaryl halide with a vinyl tin reagent. The synthesis of several especially useful compounds of formula 34a-d are illustrated in Scheme 8. The synthesis of additional coupling partners can be easily envisioned by those skilled in the art.

[0085] Scheme 9:

R12= R12' R12 N N N
(R1t)p\ (Rh1)p\ I (R )p\

X ~SnBu3 X~ R1'AlBr/1 x~'-1/Br , CN Pd(PPh3)2CI2 \ CN P(o-tol R,=A~ CN
Cul, base Pd(OAch R2 N R2 N Et3N R2 N

[0086] The alkene and the aryl halide coupling partners may be transposed as illustrated in Scheme 9. As such, compound 15 is subjected to Stille coupling conditions with a vinyl tin to give compound 36. This reaction generally requires the use of a palladium catalyst such as Pd(PPh3)2CI2, an additive such as Cul, and a base such as NaHCO3 or K2CO3. The reaction is conducted at an elevated temperature in a suitable solvent such as DMF. The unsubstituted vinyl derivative thus obtained (36) is treated under standard Heck coupling conditions with an aryl or heteroaryl halide to give compounds of formula 37. Generally the Heck reaction is conducted in the presence of a catalytic amount of Pd(OAc)2 and tri(ortho-tolyl)phosphine in a solvent such as DMF or DMSO. An excess of base, usually a tertiary amine such as Et3N or Hunig's base is generally required for the reaction to proceed. The reaction is generally conducted at an elevated temperature, preferably 800 C to 120 C.

[0087] Scheme 10:

RlZ\ R1 \
N N
\ I.
(Rn)a" ( R
1) MsCI ! Et3N
x 2) R13R13NH R13 X
HO~A' I-tz CN -~ Rt3N~A1 / I CN

38 R1z\ 43 R12' \
N
N
(R,1)a~ (RI

R73-LG Xi'--HO'A1 CN - R13 .A1 CN
base p /
R2 N Rz N

R1Z\ R1 \
N N
(R,1)v~ (Rõ)p\
~'- . -0,A' CN - Al CN
base O

LG 40 R' r R13 N, R13 45 R1 \
N N
R11 i~ R11 0-9 ( ~`\ \ R13R13NH ( )Px NaBH(OAc_ XOHC'A / CN A1/ I CN

R2 N R13 Nr,R13 R2 N

RI Z R1\
N N
R11 R,1 ( )c\ \ R13R13NH ( )off x EDC x HO2C'A1 CN OA1 TCN
R2 I N R13N'R13 R2 N

-NR13R13 = -NR13R13 or (A2-A3) or (L)r(A2-A3) -OR13 = (A2-A3) or (L)r(A2-A3) [0088] The various intermediates (38-42) illustrated in Scheme 10 can be prepared by routes illustrated in schemes 1-9. These intermediates can be subjected as shown to conditions well known in the art to form compounds 43-47. These conditions include such standard transformations as nucleophilic displacements, reductive aminations, amidations, sulfonylations, alkylations, acylations and the like.

[0089] Scheme 11:
R12\ R12' R12' N N
N
(R11\. \ \ I (R11)pN i I (RP

X Pd(OAc)2 G'N ) a2 X HN )a2 X"' I/Br. TPPTS
)a2 I .CN \ CN
R2 N PCr-N ~~-B(ORh 2 \V\~ R N R2 N

[0090] As shown in Scheme 11, cyclic alkenyl boronic acids (48) can also be coupled to core 15 giving structure 49. This coupling can be conducted under standard Suzuki conditions or, preferably, utilizing a less well-known ligand, triphenyiphosphine trisulfonic acid trisodium salt (TPPTS) in conjuction with Pd(OAc)2. Generally the reaction is performed in a solvent such as DME, DMF, or dioxane containing a base such as sodium bicarbonate. Reactions are typically heated to 70-90 C for 2-24h.
The requisite cyclic boronic acids are commercially available or can be synthesized according to methods known in the art (Tetrahedron Letters, 41(19), 3705-3708;
2000). Deprotection of the cyclic amine (typically with TFA/DCM when PG = Boc) results in secondary amine 50.

[0091] . Scheme 12:

R17 Rt \
N N
(Rtt)p O (Rtt)P\
R'CO2H
HN )a2 X~ _ EDC õ Rt~N )a2 X
CN CN

~aBH(OM)3 RtSO2Cl R1 base R12' N
O O (Rtt)P\ A2p3 (Rtt~\ \

R' N )a2 Xi'- `N )a2 X~
CN / CN

[0092] Compound 50 may be further manipulated as shown via acylations, sulfonylations, reductive aminations and the like as Illustrated in Scheme 12. In particular examples, compound 50 can be acylated with a Boc-protected amino acid followed by deprotection to give compound 54 as illustrated in Scheme 13.

[0093] Scheme 13:

R17 Rt\
t1) N 1) BocHN 4C02H (R P\ I EDC (L)r 0II (R11) P. I
HN )at X 2) TFA H2N\(L) N )at X
CN CN

[0094] Scheme 14:

Rt\ R12' N N
(Rtt)v \ I (Rtt)v \
.14 12 ~~
x-' R X H2/Pd R112 R1~(A / CN R1~(At)q I \ CN
Rte R12 16 Rt\ RR' Z
Rt\
N N. N
(R
(Rtt)v0191 tt)v~ (R)vX1~(At~ Xi x _ R H2/Pd IBr % CNR CN R1(Al)q I .~ CN
R2 N 'Pd", ligand, Cul R2 N R2 N
15 base 56 57 [0095] Shown in Scheme 14 are two methods for the synthesis of compounds of the invention substituted with alkanes at the C5-position. Such alkane derivatives may be synthesized by palladium catalyzed reduction of compound 16 (prepared by any of the aforementioned routes) to give alkane 55. Any of the various methods of reduction known in the art may be utilized to affect this transformation. Of particular utility is the use of 10% palladium on activated carbon under a 10-30 psi atmosphere of hydrogen performed in a mixture of ethanol and toluene at 10-20 C. In a similar manner, alkynes such as 56 may be catalytically reduced to the corresponding alkanes utilizing methods well known in the art. The requisite alkynes are made by palladium catalyzed couplings of terminal acetylenes and compound 15.

[0096] Scheme 15:

R1z R12 N N
(Rtt)p\ \ (R11)a0-2 XR1~(A1)q~BF3K R1 ( A1)q Xi UBr \ CN -i . CN

XPhos / Pd(dppf)2CN2 I
R2 N base / DME /heat R2 N

[0097] An alternative preparation of alkane derivatives involves the use of transition metal catalyzed carbon-carbon bond formation. One particularly useful reaction has been reported by Molander (Organic Letters (2007), 9(8), 1597-1600). As such, compound 15 may be heated with an alkyl tetrafluoroborate salt and a suitable catalyst / ligand system such as XPhos and Pd(dppf)2CI2 in the presence of a suitable base such as sodium bicarbonate to give compounds of formula 58.

[0098] Scheme 16:

AvgCO2Et V~CN a , ~O CN DMF-DMA
~

0 Bredenck's 0 A CN Reagent A' CN NH4OAc/HOAc I I I
61 NMe2 Me2N NMe2 62 R1;
N
OH CI (R")phi A' CN SOCI2 CN HX/-A

R1 \ 64 N
(Ril X/
A' CN
N

[0099] Scheme 16 illustrates an alternative synthesis of 5-alkyl cyanopyridines. A 3-aryl-propanoic ester 59 is treated with the anion of acetonitrile in a solvent such as THE to give ketone 60. The ketone is treated sequentially with DMF-DMA followed by Brederick's reagent to give bis-vinylogous amide 62. 62 can be treated with ammonia in acetic acid to give the 4-hydroxypyridine 63. This compound can be chlorinated with POCI3 and transformed to 65 by the aforementioned routes.

[00100] Scheme 17:
R12*
R12' N
N (R11)p (R11) P\ ~ = R12 X
CI R12 Cl ~.- Al IIBr \ CN Pd, base R2 CN HX R,C q/ CN
i 12 R12 solvent, heat R12 2 10111 A1B(OR)2 = 66 16 R12 ?A~
CsF OAF c R12' N
R12 F ~R11)P~

Al / \ CN HX

[00101] An alternative preparation of compound 16 is illustrated in scheme 17.
The 4-chloro,5-iodo/bromo core (10 or 11) is first treated under Suzuki conditions or Heck conditions as previously described to give compounds of formula 66. Treatment of 66 with an indolyl nucleophile in an appropriate solvent such as DMF, DMSO, ethanol, or ethoxyethanol at elevated temperatures (600 to 1500 C) leads to compounds of formula 16. In certain cases, the indolyl nucleophile proves to be unreactive in the displacement of the 4-CI in compound 66. In these cases, compound 66 may be treated with an anhydrous fluoride source such as CsF in DMF
to give the more reactive 4-F pyridine 67. Subsequent treatment of 67 with an indolyl nucleophile in an appropriate solvent such as DMF, DMSO,. ethanol, or ethoxyethanol at elevated temperatures (60 to 150 C) leads to compounds of formula 16.

[00102] Scheme 18=
R12' N
(R11) \
P
X
I/Br CN
0\
/BH
O )n / B O R2 N
n N )m CP2ZrHCI /N Pd(PPh3)2CI2, Cs2CO3 R12= R1r N N
(R11)P\ \ I (Rt1)P\
1.) deprotect )n X~ ' 2.) electrophile ), X~ -PG- N CN R1_N CN
M m [00103] Scheme 18 illustrates a further synthesis of compounds of the present invention.
Alkynes such as 68 may be hydroborated by conditions well known in the art to give the alkenyl boronic ester 69. This boronic ester undergoes a Pd catalyzed coupling reaction as previously described to give compound 70. Useful protecting groups include Boc, Cbz, and the like. Deprotection of the amine gives the corresponding secondary amine. The addition of various electrophiles utilizing conditions well known by those skilled in the art may give compounds of the invention such as compound 71.

[00104] Another aspect relates to methods of reducing an increased activity of an enzyme in a mammal, wherein the enzyme is a protein kinase, and wherein the method comprises administering to the mammal an effective amount of the compound of formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the protein kinase Is protein kinase C. In further embodiments, the protein kinase C is a theta isoform.

[00105] Compounds of Formula I can be useful for treating a pathological condition or disorder in a mammal, for example, a human. As used herein, "treating" refers to partially or completely alleviating and/or ameliorating the condition and/or symptoms thereof. One embodiment of the present invention relates to the use of the compounds disclosed herein for treating a pathological condition or disorder mediated by a protein kinase such as protein kinase C (PKC) and protein kinase C
theta isoform (PKCO). One aspect relates to the the use of the compounds disclosed herein for treating or preventing inflammation, in a mammal. Another aspect relates to the use of the compounds disclosed herein for treating asthma, colitis, multiple sclerosis, psoriasis, rheumatoid arthritis, inflammatory bowel disease, joint inflammation, organ transplant and graft rejection in a mammal, for example, in a human. The present teachings further include use of the compounds disclosed herein as active therapeutic substances for the prevention and/or inhibition of the pathological condition or disorder listed above.

[00106] In some embodiments, the methods include identifying a mammal having a pathological condition or disorder linked to a protein kinase such as PKC and PKCe, and providing to the mammal an effective amount of a compound as described herein. The present teachings accordingly include a method of providing to a mammal a pharmaceutical composition that includes a compound of the present teachings in combination or association with a pharmaceutically acceptable carrier.
Compounds of the present teachings can be administered alone or in combination with other therapeutically effective compounds or therapies for the treatment of a pathological condition or disorder. As used herein, "therapeutically effective" refers to a substance or an amount that elicits a desirable biological activity or effect.

[00107] Compounds of the present teachings can be administered orally or parenterally, neat or in combination with conventional pharmaceutical carriers. Applicable solid carriers can include one or more substances which can also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents, or encapsulating materials. The compounds can be formulated in conventional manner, for example, in a manner similar to that used for known antiinflammatory agents. Oral formulations containing an active compound disclosed herein can include any conventionally used oral form, including tablets, capsules, buccal forms, troches, lozenges and oral liquids, suspensions or solutions.
In powders, the carrier can be a finely divided solid, which is an admixture with a finely divided active compound. In tablets, an active compound can be mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets may contain'up to 99% of the active compound.

[00108] Capsules can contain mixtures of active compound(s) with inert filler(s) and/or diluent(s) such as the pharmaceutically acceptable starches (e.g., corn, potato or tapioca starch), sugars, artificial sweetening agents, powdered celluloses (e.g., crystalline and microcrystalline celluloses), flours, gelatins, gums, and the like.

[00109] Useful tablet formulations can be made by conventional compression, wet granulation or dry granulation methods and utilize pharmaceutically acceptable diluents, binding agents, lubricants, disintegrants, surface modifying agents (including surfactants), suspending or stabilizing agents, including magnesium stearate, stearic acid, sodium laUryl sulfate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, microcrystalline cellulose, sodium carboxymethyl cellulose, carboxymethylcellulose calcium, polyvinylpyrrolidine, alginic acid, acacia gum, xanthan gum, sodium citrate, complex silicates, calcium carbonate, glycine, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, low melting waxes, and ion exchange resins. Preferred surface modifying agents include nonionic and anionic surface modifying agents. Representative examples of surface modifying agents include poloxamer 188, benzalkonium chloride, calcium stearate, cetostearl alcohol, cetomacrogol emulsifying wax, sorbitan esters, colloidal silicon dioxide, phosphates, sodium dodecylsulfate, magnesium aluminum silicate, and triethanolamine. Oral formulations herein can utilize standard delay or time-release formulations to alter the absorption of the active compound(s).
The oral formulation can also comprise a compound as described herein in water or fruit juice, containing appropriate solubilizers or emulsifiers as needed.

[00110] Liquid carriers can be used in preparing solutions, suspensions, emulsions, syrups, elixirs, and for inhaled delivery. A compound described herein can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, or a mixture of both, or pharmaceutically acceptable oils or fats.
The liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers, and osmo-regulators.
Examples of liquid carriers for oral and parenteral administration include water (particularly containing additives as described above, e.g., cellulose derivatives such as a sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g., glycols) and their derivatives, and oils (e.g., fractionated coconut oil and arachis oil). For parenteral administration, the carrier can be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration. The liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellants.

[00111] Liquid pharmaceutical compositions, which are sterile solutions or suspensions, can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection.
Sterile solutions can also be administered intravenously. Compositions for oral administration can be in either liquid or solid form.

[00112] Preferably the pharmaceutical composition is in unit dosage form, for example, as tablets, capsules, powders, solutions, suspensions, emulsions, granules, or suppositories. In such form, the pharmaceutical composition can be sub-divided in unit dose(s) containing appropriate quantities of the active compound. The unit dosage forms can be packaged compositions, for example, packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids. Alternatively, the unit dosage form can be a capsule or tablet Itself, or it can be the appropriate number of any such compositions in package form. Such unit dosage form may contain from about 1 mg/kg of active compound to about 500 mg/kg of active compound, and can be given in a single dose or in two or more doses. Such doses can be administered in any manner useful in directing the active compound(s) to the recipient's bloodstream, including orally, via implants, parenterally (including intravenous, intraperitoneal and subcutaneous injections), rectally, vaginally, and transdermally.
Such administrations can be carried out using the compounds of the present teachings including pharmaceutically acceptable salts thereof, in lotions, creams, foams, patches, suspensions, solutions, and suppositories (rectal and vaginal).

[00113] When administered for the treatment or inhibition of a particular disease state or disorder, it is understood that an effective dosage can vary depending upon many factors such as the particular compound utilized, the mode of administration, and severity of the condition being. treated, as well as the various physical factors related to the individual being treated. In therapeutic applications, a compound of the present teachings can be provided to a patient already suffering from a disease in an amount sufficient to cure or at least partially ameliorate the symptoms of the disease and its complications. The dosage to be used in the treatment of a specific individual typically must be subjectively determined by the attending physician. The variables involved include the specific condition and its state as well as the size, age and response pattern of the patient.

[00114] In some cases, for example those in which the lung is the targeted organ, it may be desirable to administer a compound directly to the airways of the patient, using devices such as metered dose inhalers, breath-operated inhalers, multidose dry-powder inhalers, pumps, squeeze-actuated nebulized spray dispensers, aerosol dispensers, and aerosol nebulizers. For administration by intranasal or intrabronchial inhalation, the compounds of the present teachings can be formulated into a liquid composition, a solid composition, or an aerosol composition. The liquid composition can include, by way of illustration, one or more compounds of the present teachings dissolved, partially dissolved, or suspended in one or more pharmaceutically acceptable solvents and can be administered by, for example, a pump or a squeeze-actuated nebulized spray dispenser. The solvents can be, for example, isotonic saline or bacteriostatic water. The solid composition can be, by way of illustration, a powder preparation including one or more compounds of the present teachings intermixed with lactose or other inert powders that are acceptable for intrabronchial use, and can be administered by, for example, an aerosol dispenser or a device that breaks or punctures a capsule encasing the solid composition and delivers the solid composition for inhalation. The aerosol composition can include, by way of illustration, one or more compounds of the present teachings, propellants, surfactants, and co-solvents, and can be administered by, for example, a metered device. The propellants can be a chlorofluorocarbon (CFC), a hydrofluoroalkane (HFA), or other propellants that are physiologically and environmentally acceptable.

[00115] Compounds described herein can be administered parenterally or intraperitoneally.
Solutions or suspensions of these active compounds or pharmaceutically acceptable salts, hydrates, or esters thereof can be prepared in water suitably mixed with a surfactant such as hydroxyl-propylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations typically contain a preservative to inhibit the growth of microorganisms.

[00116] The pharmaceutical forms suitable for injection can include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In preferred embodiments, the form is sterile and its viscosity permits it to flow through a syringe. The form preferably is stable under the conditions of manufacture and storage and can be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

[00117] Compounds described herein can be administered transdermally, i.e., administered across the surface of the body and the inner linings of bodily passages including epithelial and mucosal tissues. Such administration can be carried out using the compounds of the present teachings including pharmaceutically acceptable salts, hydrates, and esters thereof, in lotions, creams, foams, patches, suspensions, solutions, and suppositories (rectal and vaginal). Topical formulations that deliver active compound(s) through the epidermis can be useful for localized treatment of inflammation and arthritis.

[00118] Transdermal administration can be accomplished through the use of a transdermal patch containing an active compound and a carrier that can be inert to the active compound, can be non-toxic to the skin, and can allow delivery of the active compound for systemic absorption into the blood stream via the skin. The carrier can take any number of forms such as creams and ointments, pastes, gels, and occlusive devices. The creams and ointments can be viscous liquid or semisolid emulsions of either the oil-in-water or water-in-oil type. Pastes comprised of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the active compound can also be suitable. A variety of occlusive devices can be used to release the active compound into the blood stream, such as a semi-permeable membrane covering a reservoir containing the active compound with or without a carrier, or a matrix containing the active compound. Other occlusive devices are known in the literature.

[00119] Compounds described herein can be administered rectally or vaginally in the form of a conventional suppository. Suppository formulations can be made from traditional materials, including cocoa butter, with or without the addition of waxes to alter the suppository's melting point, and glycerin. Water-soluble suppository bases, such as polyethylene glycols of various molecular weights, can also be used.

[00120] Lipid formulations or nanocapsules can be used to introduce compounds of the present teachings into host cells either in vitro or in vivo. Lipid formulations and nanocapsules can be prepared by methods known in the art.

[00121] To increase the effectiveness of compounds of the present teachings, it can be desirable to combine a compound with other agents effective in the treatment of the target disease. For inflammatory diseases, other active compounds (i.e., other active ingredients or agents) effective in their treatment, and particularly in the treatment of asthma and arthritis, can be administered with active compounds of the present teachings. The other agents can be administered at the same time or at different times than the compounds disclosed herein.

[00122] General experimental conditions:

[00123] Method A (abbreviated as [a] in experimental section): Prodigy ODS3, 0.46 x 15 cm column, 1.0 mUmin, 20min gradient of acetonitrile in water/trifluoroacetic acid.
[00124] Method B (abbreviated as [b] in experimental section): Prodigy ODS3, 0.46 x 15 cm column, 1.0 mUmin, 20 min Gradient MeOH in H2O/TFA.

[00125] Method C (abbreviated as [c] in experimental section): Prodigy ODS3, 0.46 x 15 cm column, 1.0 mUmin, 20 min Gradient ACN in ammonium hydroxide.

[00126] Method D (abbreviated as [d] in experimental section): Thermo Aquasil 2.1mm, 0.8 mUmin, 2.5 min gradient of acetonitrile in water/formic acid.

[00127] Method E (abbreviated as [e] in experimental section): Prodigy ODS3, 0.46 x 15 cm column, 1.0 mUmin, 10 min gradient of acetonitrile in water/trifluoroacetic acid.
[00128] The following examples are presented to illustrate certain embodiments of the present invention, but should not be construed as limiting the scope of this invention.

N
H ~

N
[00129] Preparation of 4-hydroxynicotinonitrile:

A mixture of acetoacetonitrile (41 g, 493 mmol), t-butoxybis(dimethyl amino)methane (86 g, 493 mmol) and DMF-DMA (263 mL, 1.97 mol) was heated at 100 C overnight and evaporated to remove the volatiles. The residue was triturated with hexanes/ether (1:1) and the solids were collected by filtration and washed with hexanes/ether (1:1) and a minimum amount of EtOAc to give 64.3 g (67%) of 5-(dimethylamino)-2-[(dimethylamino)methylene]-3-oxopent-4-enenitrile as a light yellow solid, which was used for the next step without further purification.

[00130] A mixture of 5-(dimethylamino)-2-[(dimethylamino)methylene]-3-oxopent-4-enenitrile (64.3 g, 333 mmol) and ammonium acetate (126 g, 1.66 mol) in EtOH (1.8 L) was heated at reflux for 60 h and concentrated to remove solvent. The resultant semi-solid residue was diluted with EtOAc, filtered and washed with EtOAc followed by CH2CI2. The filtrate was evaporated to a reduced volume. The precipitated solids were collected by filtration, washed with' EtOAc and a minimum amount of EtOH. The process of evaporation and crystallization was repeated to obtain more solid product from the mother liquor. The combined off-white solids provided 20.9 g of 4-hydroxynicotinonitrile (53%), m.p. 234-236 C.

OH
N

[00131] Preparation of 4-hydroxy-5-iodonicotinonitrile:

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

a / N

[00132] Preparation of 4-chloro-5-iodonicotinonitrile:

A mixture of 4-hydroxy-5-iodonicotinonitrile (57.5 g, 234 mmol) and POCI3 (200 mL) was heated at 100 C for 2 hours, cooled to room temperature and evaporated to remove excess POCI3. The residue was cooled in an ice-water bath, adjusted to pH 8-9 with aqueous 10 N
NaOH and extracted with ethyl acetate. The combined organics were washed with water and brine, dried over magnesium sulfate and concentrated. The resulting solid residue was washed with a minimum amount of methanol and methylene chloride to give 46.5 g (75%) of 4-chloro-5-iodonicotinonitrile as a tan solid, mp 120-122 C.

NH
HV
N

[00133] Preparation of 5-iodo-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile:

A mixture of 4-chloro-5-iodonicotinonitrile (5.0 g, 18.9 mmol) and 5-amino-4-methylindole (3.0 g, 20.8 mmol) in EtOH (100 ml-) was heated at reflux for 3 days, cooled to r.t and diluted with saturated aq. Na2SO4 (300 mL). The precipitated solids were collected by filtration, washed with water and dried to give 5.3 g (75%) of 5-iodo-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile as a grey solid. mp 192-194 C; MS (M+H*): 375.1.

[00134] Preparation of 6-methyl-4(1 H)-pyridone-3-carboxylic acid:
6-Methyl-4(1H)-pyrdone-3-carboxylic acid was prepared from 4-hydroxy-6-methyl-2-pyrone according to the route in J. Org. Chem., (1972), 37, 1145.

OH
[00135] Preparation of 5-iodo-6-methyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid:
6-Methyl-4(1H)-pyridone-3-carboxylic acid was converted to 5-iodo-6-methyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid 5-iodo-6-methyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid by the published route: see W09948892 step a of Example 82.

O O
NF' [00136] Preparation of 5-iodo-6-methyl-4-oxo-1,4-dihydropyridine-3-carboxamide:

A mixture of 5-iodo-6-methyl-4-oxo-1,4-dihydropyndine-3-carboxylic acid (5.0 g, 17.9 mmol) and 1,1'-carbonyldiimidazole (CDI) (6.39 g, 39.4 mmol) in 60 mL of DMF was heated at 60-70 C for 3 h. The reaction mixture was cooled on an ice-bath and poured into cooled 29%
aqueous ammonium hydroxide (84 mL). After stirring at 0-5 C for 3 h, the mixture was poured onto ice and the pH was adjusted to 5-6. The solids were collected by filtration, then washed with water followed by diethyl ether to provide 3.30 g (66%) of 5-iodo-6-methyl-4-oxo-1,4-dihydropyridine-3-carboxamide as a white solid, mp 296-298 C; MS 277.1 (M-H)-.

a / N

[00137] Preparation of 4-chloro-5-iodo-6-methylnicotinonitrile:

A mixture of 5-iodo-6-methyl-4-oxo-1,4-dihydropyridine-3-carboxamide (3.0 g, 10.8 mmol) and phosphorus oxychloride (16.6 g, 108 mmol) was heated at 60-70 C for 30 min.
The temperature was slowly increased to 90 C and a drop of DMF was added. Heating was continued for 2 h resulting in a dark brown solution. The volatiles were removed in vacuo and the residue was slurried with ice. Aqueous sodium bicarbonate was slowly added. The solids were collected by filtration, washing with aqueous sodium bicarbonate and water to provide 2.85 g (95%) of 4-chloro-5-iodo-6-methylnicotinonitrile as a light yellow solid, mp 120-122 C;
MS 279.1 (M+H).

NH

HV \
N

[00138] Preparation of 5-iodo-6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile:
5-iodo-6-methyl-4-oxo-1,4-dihydropyridine-3-carboxamide (4.0 g, 14.4 mmol) and 5-amino-4-methylindole (2.7 g, 18.7 mmol) were heated to a vigorous reflux in 100 mL
EtOH. After heating for 4 days, the reaction was cooled and the grey solid was filtered to give 3.4 g of 5-iodo-6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile, mp 222-223 C;
MS 389.2 (M+H).

H
H \

[00139] Preparation of 4-[(4-methyl-1H-indol-5-yl)amino]-5-[(1 E)-3-(4-phenylpiperazin-1-yl)prop-1-en-l-yl]nicotinonitrile:

A mixture of 5-iodo-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile (90 mg, 0.24 mmol), 1-phenylpiperazine (117 mg, 0.72 mmol), trans-2-chloromethylvinylboronic acid (58 mg, 0.48 mmol), cesium carbonate (157 mg, 0.48 mmol) and Pd(PPh3)2CI2 (8.4 mg, 0.012 mmol) in 3 mL of DMSO was heated at 900C for 16 h, cooled to room temperature, diluted with water and extracted into EtOAc. The organic layer was washed with water and the crude material was purified by silica gel chromatography, eluting with McOH/ DCM to give 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(1E)-3-(4-phenylpiperazin-1-yl)prop-1-en-1-yl]nicotinonitrile as a solid; MS 449.4 (M+H); HPLC: rt = 6.4 min [a].

NH
H
N
N

[00140] Preparation of 5-[(IE)-3-aminoprop-1-en-1-yl]-4-[(4-methyl-IH-indol-5-yl) amino]nicotinonitrile:

A mixture of 5-iodo-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile (100 mg, 0.27 mmol), 7N
ammonia in MeOH (2.7 mmol), trans-2-chloromethylvinylboronic acid (62 mg, 0.53 mmol), cesium carbonate (173 mg, 0.53 mmol) and Pd(PPh3)2CI2 (9.4 mg, 0.014 mmol) in 2 mL of DMSO was heated at 75 for 16 h, cooled to room temperature, diluted with EtOAc and washed with water. The organic extracts were concentrated and the crude product was purified by silica gel chromatography with a MeOH / DCM / EtOAc gradient to give 5-[(1 E)-3-aminoprop-1-en-1-yl]-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile. The HCI salt of 5-[(1 E)-3-aminoprop-1-en-1-yl]-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile was made by treatment with HCI/dioxane; MS 304.2 (M+H); HPLC: rt = 2.8 min [c].

NH
HNCI
N

[00141] Preparation of 4-[(4-methyl-IH-indol-5-yl)amino]-5-[(IE)-3-(4-methylpiperazin-1-yl)prop-I -en-1 -yl]nicotinonitrile:

A mixture of 5-iodo-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile (100 mg, 0.27 mmol), 1-methylpiperazine (80 mg, 0.80 mmol), trans-2-chloromethylvinylboronic acid (64 mg, 0.53 mmol), cesium carbonate (173 mg, 0.53 mmol) and Pd(PPh3)2CI2 (9.5 mg, 0.014 mmol) in 3 mL of DMSO was heated at 90 C for 16 h, cooled to room temperature, and filtered. The filtrate was concentrated and purified by HPLC to give 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(1E)-3-(4-methylpiperazin-1-yl)prop-1-en-l-yl]nicotinonitrile. The HCI salt of 4-[(4-methyl-lH-indol-5-yl)amino]-5-[(1E)-3-(4-methylpiperazin-1-yl)prop-l-en-l-yl]nicotinonitrile was made by treatment with HCI/ dioxane; MS 387.3 (M+H); HPLC: rt = 7.4 min [b].

[00142] Preparation of compounds in Table 1:

Compounds were prepared from 5-iodo-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile, the corresponding amine and trans-2-chloromethylvinylboronic acid via the procedure used to prepare 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(1 E)-3-(4-methylpiperazin-1-yl)prop-1 -en-1-yl]
nicotinonitrile.

Table 1 Name MS (M+H) HPLC rt 1-[(4-methyl-1H-indol-5-yI)amino]-5-[(1E)-3-morpholin-4- 374.3 .1 min[a]
I ro-1-en-1- I nicotinonitrile [(1E)-3-(3,4-dihydroisoquinolin-2(1H)-yl)prop-1-en-1 -yl]- 120.4 6.1 min[a]
1-[(4-methyl-1 H-indol-5- I amino icotinonitrile ert-butyl {1-[(2E)-3-{5-cyano-4-[(4-methyl-1 H-indol-5-I)amino]pyridine-3-yl}prop-2-en-1-yl]pipendin-4- 187.5 6.6 min[a]
I carbamate ert-butyl 4-[(2E)-3-{5-cyano-4-[(4-methyl-1 H-indol-5-I)amino]pyridine-3-yl}prop-2-en-1-yl]piperazine-1- 173.4 .6 min[a]
arbox late -[(4-methyl-lH-indol-5-yl)amino]-5-[(1E)-3-piperidin-l- 3724 1.8 min[a]
I rol-en-l- nicotinonitrile N

[00143] Preparation of 5-[(1E)-3-(4-aminopiperidin-1-yl)prop-l-en-l-yl]-4-[(4-methyl-lH-lndol-5-yl)amino]nicotinonitrile:

A solution of tert-butyl{l-[(2E)-3-{5-cyano-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-yl}prop-2-en-1-yl]piperidin-4-yl}carbamate (64 mg, 0.13 mmol) in 10% trifluoroacetic acid/ DCM was stirred for 1 h at room temperature. The reaction was quenched with NaOH until the reaction solution was neutral pH. The product was extracted into DCM/ MeOH. The extracts were concentrated and the crude product was purified by silica gel chromatography using a DCM/
MeOH gradient to give 5-[(1 E)-3-(4-aminopiperidin-1-yl)prop-1-en-l-yl]-4-[(4-methyl-1 H-indol-5-yl)aminol]nicotinonitrile; MS 387.3 (M+H); HPLC: rt = 2.9 min[a].

NH
HL) [00144] Preparation of 4-[(4-methyl-lH-indol-5-yl)amino]-5-[(IE)-3-piperazin-1-ylprop-1-en-l -yl]nicotinonitrile:

4-[(4-methyl-1 H-indo-5-yl)amino]-5-[(1 E)-3-piperazin-1 -ylprop-l-en-1 -yl]nicotinonitrile was prepared from tert-butyl 4-[(2E)-3-{5-cyano-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-yl}prop-2-en-l-yljpipenzine-1-carboxylate via the route used to prepare 5-[(1E)-3-(4-aminopiperidin-1-yl)prop-l-en-1-yl]-4-[(4-methyl-1 H-indol-5-yl)aminol]nicotinonitrile; MS 373.3 (M+H); HPLC: rt = 3.7 min[a].

fNH
VN / ,N

[00145] Preparation of 4-[(4-methyl-1H-indol-5-yl)amino]-5-[(1E)-3-(4-methylpiperazin-1-yl)but-1-en-1-yl]nicotinonitrile:

A mixture of 5-iodo-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile (100 mg, 0.27 mmol), 1-methylpiperazine (80 mg, 0.80 mmol), (E)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-enyl 4-methylbenzenesulfonate (187 mg, 0.53 mmol), cesium carbonate (173 mg, 0.53 mmol) and Pd(PPh3)4 (16 mg, 0.014 mmol) in 3 mL of DMSO was heated at 70 for 16 h, cooled to room temperature, and filtered. The filtrate was concentrated and purified by HPLC to give 4-[(4-methyl-1 H-indo-5-yl)amino]-5-[(1 E)-3-(4-methylpiperazin-1-yl)but-l-en-l-yl]nicotinonitrile.
The HCI salt of 4-[(4-methyl-lH-indo-5-yl)amino]-5-[(1E)-3-(4-methylpiperazin-1-yl)but-1-en-1-yl]nicotinonitrile was generated by addition of HCI/ dioxane; MS 401.4 (M+H);
HPLC: rt = 5.1 min[b].

I'NH
HN)a N

~NH
~
H

[00146] Preparation of 5-[(1E)-buta-1,3-dien-yI]-4-[(4-methyl-1H-indol-5-yI)amino]
nicotinonitrile and (3E)-4-(5-cyano-4-[(4-methyl-1 H-indol-5-yl)amino]
pyridine-3y1}but-3-en-1-yl indoline-l-carboxylate:

A mixture of 5-iodo-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile (100 mg, 0.27 mmol), indoline (95 mg, 0.80 mmol), (E)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-enyl 4-methylbenzenesulfonate (187 mg, 0.53 mmol), cesium carbonate (173 mg, 0.53 mmol) and Pd(PPh3)4 (16 mg, 0.014 mmol) in 3 mL of DMSO was heated at 700 for 16 h, cooled to room temperature, diluted with EtOAc and washed with water. The crude material was purified by silica gel chromatography with an EtOAc/ hexane gradient to give 5-[(1E)-buta-1,3-dienyl]-4-[(4-methyl-1 H-in do-5-yl)amino]n icoti non itrile and (3E)-4-{5-cyano-4-[(4-methyl-1 H-indo-5-yl)amino]pyridin-3-yl}but-3-en-1-yl indoline-1-carboxylate. The HCI salt of (3E)-4-{5-cyano-4-[(4-methyl-1 H-indo-5-yl)amino]pyridin-3-yl}but-3-en-1-yl indoline-1-carboxylate was generated by addition of HCI/ dioxane.

[00147] 5-[(1 E)-buta-1,3-dienyl]-4-[(4-methyl-1 H-indo.5.yl)amino]nicotinonitrile:
MS 301.2 (M+H); HPLC: rt = 7.9 min[a]

[00148] (3E)-4-{5-cyano-4-[(4-methyl-1H-indo-5-yl)amino]pyridin-3-yl}but-3-en-1-yl Indoline-1-carboxylate (HCI salt):

MS 464.3 (M+H); HPLC: rt = 10.4 min.[a].
Na tJl ~O IN

[00149] Preparation of 4-[(4-methyl-lH-indol-5-yl)amino]-5-[(1E)-4-morpholin-4-ylbut-1-en-1-yl]nicotinonitrile and (3E)-4-{5-cyano-4-[(4-methyl-1H-indol-5-yl)amino]
pyridine-3yl}but-3-en-1-yl morpholine-4-carboxylate:

A mixture of 5-iodo-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile (150 mg, 0.40 mmol), morpholine (104 mg, 1.2 mmol), (E)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-enyl 4-methylbenzenesulfonate (281 mg, 0.80 mmol), cesium carbonate (261 mg, 0.80 mmol) and Pd(PPh3)4 (23 mg, 0.02 mmol) in 4 mL of DMSO was heated at 70 for 16 h, cooled to room temperature, diluted with EtOAc and washed with water. The crude extracts were purified by silica gel chromatography with a MeOH/ DCM gradient to give (3E)-4-(5-cyano-4-[(4-methyl-1 H-indo-5-yl)amino]pyridin-3-yl}but-3-en-1-yl morpholine-4-carboxylate and 4-[(4-methyl-1 H-indo-5-yl)amino]-5-[(1 E)-4-morpholin-4-ylbut-1-en-l-yl]nicotinonitrile. The HCI salt of both products were generated using HCI/ dioxane:

[00150] 4-[(4-methyl-1 H-indo-5-yl)amino]-5-[(1 E)-4-morpholin-4-ylbut-1-en-1-yl]nicotinonitrile:

MS 386.2 (M-H); HPLC: rt = 5.4 min [b]

[00151] (3E)-4-{5-cyano-4-[(4-methyl-lH-indo-5-yl)amino]pyridin-3-yl)but-3-en-l-yl morpholine-4-carboxylate:

MS 432.2 (M+H); HPLC: rt = 7.8 min [a]

[00152] Preparation of compounds in Table 2:

These compounds were prepared from 5-iodo-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile, the corresponding amine and (E)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-enyl 4-methylbenzenesulfonate via the procedure used to prepare 4-[(4-methyl-1 H-indo-5-yl)amino]-5-[(1 E)-4-morpholin-4-ylbut-l-en-1-yl]nicotinonitrile.

[00153] Table 2:

Name MS (M+H) HPLC rt 1-[(4-methyl-1 H-indol-5-yl)amino]-5-[(IE)-4-(4-phenyl 163.4 5 .9 min[a]
i erazine-i- I but-l-en-1- I nicotinonitrile -[(4-methyl-1H-indol-5-yI)aminoj-5-[(1E)-4-pyrrolidin- 372.3 1.8 min[a]
1 - 1 but-l-en-i- I nicotinonitrile (3E)-4-(5cyano-4-[(4-methyl-1 H-indol-5-yl)amino]
yridin-3-yl}but-3-en-1-yl]thiomorpholine-4-carboxylate 180.3 1.6 min[a]
1,1-dioxide NH

H
N

[00154] Preparation of 4-[(4-methyl-1H-indol-5-yl)amino]-5-[(1E)-4-piperidin-1-ylbut-l-en-l -yl]nicotinonitrile:

A mixture of piperidine (104 mg, 1.2 mmol) and (E)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-enyl 4-methylbenzenesulfonate (200 mg, 0.57 mmol) in 2 mL of DMSO
was stirred for 16 h at room temperature. 5-iodo-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile (108 mg, 0.29 mmol), cesium carbonate (186 mg, 0.57 mmol) and Pd(PPh3)4 (17 mg, 0.015 mmol) were added to the same pot. After heating the reaction to 70 for 16 h, the reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated and purified by HPLC
to give 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(1 E)-4-piperidin-1-ylbut- 1-en-l-yl]nicotinonitri le as its TFA salt; MS 386.4 (M+H); HPLC rt = 4.8 min[a].

[00155] Preparation of compounds in Table 3:

The compounds in Table 3 were prepared from 5-iodo-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile, the corresponding amine and (E)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-enyl 4-methylbenzenesulfonate via the procedure used to prepare 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(1 E)-4-piperidin-1-ylbut-l-en-1-yl]nicotinonitrile.

[00156] Table 3:

Name MS (M+H) HPLC rt -[(4-methyl-lH-indol-5-yl)amino]-54(1E)-4-thiomorpholin-4- 04.2 1.8 min[a]
Ibut-l-en-1- I nicotinonitrile -[(lE)-4-(4-acetylpiperazin-1-yl)but-1-en-l-yl]-4-[(4-methyl- 129.4 1.2 min[a]
1H-indol-5- I amino nicotinonitrile -[(4-methyl-1H-indol-5-yI)amino]-5-((1E)-4-[4-(methyl 65.4 1 8 min[a]
ulfon I i erazin-1- I but-l-en-1- I nicotinonitrile Name MS (M+H) HPLC rt ert-butyl-4-[(3E)-4-{5-cyano-4-[(4-methyl-1H-indol-5-yl) 487.4 1.6 min[a]
mino ridin-3- I but-3-en-1- I i erazine-l-carbox ate ert-butyl-{1-[(3E)-4-{5-cyano-4-((4-methyl-lH-indol-5-yl) 01.4 .6 min[a]
mino ridin-3- but-3-en-1- I i eridin-4- carbamate [(1E)-4-aminobut-l-en-1-yl]-4-[(4-methyl-lH-indol-5-yl) 318.3 .2 min[b]
mino nicotinonitrile -[(4-methyl-1H-indol-5-yl)amino]-5-{(1E)-4-[(2-morpholin-4- 131.4 1.9 min[a]
lath I amino but-l-en-1- I nicotinonitrile -[(4-methyl-l H-indol-5-yl)amino]-5-{(1 E)-3-[(2-morpholin-4- 117.2 1.22 min[d]
leth I amino ro 1-en-1- I nicotinonitrile -[(4-methyl-1 H-indol-5-yl)amino]-5-[(1 E)-4-(4-phenyl 162.3 1.56 min[d]
i eridin-1- I but-l-en-1- I nicotinonitrile (1E)-4-[4-(dimethylamino)piperidin-1-yl]but-1-en-1-yl)-4- 429.3 1.09 min[d]
[(4-methyl-1 H-indol-5- I amino nicotinonitrile [(1 E)-4-(4-hydroxypiperidin-1-yl)but-1 -en-1 -yl]-4-((4-methyl 102.2 1.25 min[d]
1 H-indol-5- I amino nicotinonitrile -[(4-methyl-1H-indol-5-yl)amino]-5-[(1E)-4-(4-morpholin-4- 471.3 1.12 min[d]
I i eridin-1- I but-l-en-1- I nicotinonitrile -[(1E)-4-(isopropylamino)but-l-en-1-yl]-4-[(4-methyl-l H- 360.4 .9 min[a]
indol-5- I amino nicotinonitrile [(1 E)-4-(cyclohexylamino)but-l-en-1-yl]-4-[(4-methyl-l H- 100.4 .0 min[a]
ndol-5- I amino nicotinonitrile -[(4-methyl-1 H-indol-5-yl)amino]-5-[(1E)-4-(piperidin-4- 101.4 .3 min[a]
lamino but-l-en-1- I nicotinonitrile [(1E)-4-(2,5-diazabicyclo[2.2.1]hept-2-yl)but-1-en-1-yl]-4- 399.2 .24 min[d]
[(4-methyl-1 H-indol-5- I amino nicotinonitrile [(1E)-4-(dimethylamino)but-l-en-1-yl]-4-[(4-methyl-1 H- 346.4 .4 min[b]
ndol-5- I amino nicotinonitrile -[(4-methyl-1 H-indol-5-yl)amino]-5-{(1 E)-4-[(1- 115.5 3.3 min[a]
eth I i eridin-4- I amino but-l-en-1- I nicotinonitrile [(1E)-4-(4-hydroxy-4-phenylpiperidin-1-yl)but-l-en-1-yl]-4- 478.5 3.3 min[a]
[(4-methyl-1 H-indol-5- I amino nicotinonitrile (1 E)-4-[(trans-4-hydroxycyclohexyl)amino]but 1-en-l-yl)- 16.4 5.0 min[a]
4+4-methyl-1 H-indol-5- I amino nicotinonitrile -{(1E)-4-[4-(hydroxymethyl)piperidin-1-yl]but-l-en-l-yl)-4- 116.3 1.1 min[a]
[(4-methyl-1 H-indol-5- I amino nicotinonitrile -{(1 E)4-[(3R)-3-hydroxypyrro l id i n-1-y l]but-l -en-1-yl)-4-[(4-88.3 3.8 min[a]
eth l-1H-indol-5- I mino nicotnonitrile (lE)-4-((3S)-3-hydroxypyrrolidin-1-yl]but-l-en-1-yl)-4-((4- 388.3 3.8 min[a]
meth l-1H-indol-5- I mino nicotinonitrile [(1E)-4-(4-methoxypiperidin-1-yl)but-l-en-1-yl]4-[(4- 16.3 1.8 min[a]
eth l-1H-indol-5- I mino nicotinonitrile -{(1 E)-4-[(3R)-3-hydroxypiperdin-l-yl]but-l-en-l-yl)-4-[(4- 102.2 1.33 min[d]
eth l-1H-indol-5- I amino nicotinonitrile (lE)-4-[(3S)-3-hydroxypiperidin-l-yl]but-l-en-1-yl)-4-[(4- 102.2 1.33 min[d]
methyl-1 H-indol-5- I mino nicotinonitrile -[(4-methyl-1 H-indol-5-yl)amino]-5-[(1 E)-4-(3-oxopiperazin- 101.2 1.7 min[b]
1 - I but-1-en-1- I nicotinonitrile -[(4-methyl-1 H-lndol-5-yl)amino]-5-{(1E)-4-[4-(pyrrolidin-l- 183.5 5.5 min [a]
(carbon i eridin-l- but-1-en-1- I nicotinonitrile [00157] Preparation of compounds in Table 4:

The appropriate boc-protected amine (0.53 mmol) and (E)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-enyl 4-methylbenzenesulfonate (186 mg, 0.53 mmol) were stirred in 1 mL of DMSO for 16 h at room temperature. 5-iodo-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile (100 mg, 0.27 mmol), cesium carbonate (173 mg, 0.53 mmol) and Pd(PPh3)4 (16 mg, 0.014 mmol) were added to the same pot and heated at 70 C
for 16 h. The reaction mixture was cooled to room temperature, diluted with EtOAc and washed with water to give the corresponding Boc protected intermediate. The crude organic extracts were concentrated and treated with 10% trifluoroacetic acid/ DCM for 2 hr at room temperature.
Concentration and purification by HPLC gave the desired product as its TFA
salt.

[00158] Table 4:

Amine Name MSH) HPLC rt (R)-tert-butyl pyrrolidin-3- (1E)-4-[(3R)-3-aminopyrrolidin-1-yl]
Icarbamate but- l-en-l-yl}-4-[(4-methyl-lH-indol-5- 387.2 1.04 min[d]
I amino nicotinonitrile (R)-tert-butyl pyrrolidin-3- (3E)-4-(5-cyano-4-[(4-methyl-1H-indol-Icarbamate yl)amino]pyridin-3-yl}but-3-en-1-yl 131.2 1.37 min[d].
3R 3-amino rrolidine-l-carbo late (S)-tert-butyl pyrrolidin-3- (1E)-4-[(3S)-3-aminopyrrolidin-1-yl]
Icarbamate but- l-en-l-yl}-4-[(4-methyl-1H-indol-5- 387.2 1.05 min[d]
I amino nicotinonitrile ert-butyl azetidin-3-yl [(1 E)-4-(3-aminoazetidin-1-yl)but-1-arbamate n-1-yI)-4-[(4-methyI-1 H-indol-5- 373.3 1.25 min[d]
I amino nicotinonitrile ert-butyl 1,4-diazepane-1 [(1 E)-4-(1,4-diazepan-1-yl)but-l-en-1-rboxylate Ij-4-[(4-methyl-1H-indol-5-yl)amino 101.2 1.06 min[d]
nicotinonitrile ert-butyl methyl(piperidin (1E)-4-[4-(methylamino)piperidin-l--yl)carbamate l]but-l-en-1-yl}-4-[(4-methyl-1H-indol- 15.3 1.08 min[d]
- I amino nicotinonitrile (R) tert-butyl piperidin-3 (1E)-4-[(3R)-3-aminopiperidin-1-yl]
Icarbamate ut-1-en-1-yl}-4-[(4-methyl-1H-indol-5- 01.2 1.26 min[d]
I amino nicotinonitrile (S) tert-butyl piperidin-3 (1E)-4-[(3S)-3-aminopiperidin-1-yl]
Icarbamate ut-l-en-1-yl}-4-[(4-methyl-lH-indol-5- 01.2 .24 min[d]
I amino nicotinonitrile ert-butyl piperidin-4 -((1E)-4-[4-(aminomethyl)piperidin-1-Imethylcarbamate l]but-1-en-l-yl}-4-[(4-methyl-lH-indol- 115.3 1.09 min[d]
I amino nicotinonitrile NH

HO H

[00159] Preparation of 4-[(4-methyl-IH-indol-5-yl)amino]-5-[(1E)-4-piperazin-l-ylbut-l-en-l-yl]nicotinonitrile:

A solution of tert-butyl 4-[(3E)-4-{5-cyano-4-[(4-methyl-1 H-indol-5-yl)amino]-pyridin-3-yl}-but-3-en-1-yl]piperazine-1-carboxylate (54 mg, 0.11 mmol) in 10% trifluoroacetic acid/ DCM was stirred for 1 h at room temperature. The reaction mixture was concentrated and purified by HPLC to give 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(1 E)-4-piperazin-l-ylbut-1 -en-1 -yl]
nicotinonitrile as its TFA salt; HRMS 387.2 (M+H); HPLC it = 2.8 min[a].

NH
HN~
N
N~

[00160] Preparation of 5-[(1 E)-4-(4-aminopiperidin-l -yl)but-1-en-l -yl]-4-[(4-methyl-I H-lndol-5-yl)amino]nicotinonitrile:

Tert-butyl-{1-[(3E)-4-{5-cyano-4-[(4-methyl-1 H-indol-5-yl)amino]-pyridin-3-yl}-but-3-en-l-yl]
piperidin-4-yl}carbamate was used to prepare 5-[(1E)-4-(4-aminopiperidin-1-yl)but-1-en-1 -yl]-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile via the route used to prepare 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(1E)-4-piperazin-1-ylbut-1-en-l-yl]nlcotinonitrile; HRMS
401.2 (M+H);
HPLC it = 2.3 min[a].

~OH
H
S~ H C7C ~O N

[00161] Preparation of N-{1-[(3E)-4-{5-cyano-4-[(4-methyl-1H-indol-5--yl)amino] pyridin-3-yl}but-3-en-1-yl]piperidin-4-yl}methanesulfonamide:
5-[(1 E)-4-(4-amino piperidin-1-yl)but-1-en-1-yl]-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile (75 mg, 0.10 mmol), methanesulfonyl chloride (15 mg, 0.13 mmol) and triethylamine (41 mg.
0.40 mmol) in 1 mL of DMF were stirred at room temperature for 1 h. The reaction mixture was filtered and the filtrate was purified by HPLC to give N-{1[(3E)-4-{5-cyano-4-[(4-methyl-1H-indol-5-yl)amino]pyridin-3-yl}but-3-en-1-yl]piperidin-4-yl}methanesulfonamide as its TFA
salt; HRMS 479.2 (M+H); HPLC rt = 4.6 min[a].

[00162] Preparation of compounds in Table 5:

These analogs were prepared using 5-[(1 E)-4-(4-aminopiperidin-l-yl)but-1-en-1-yl]-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile and the appropriate sulfonyl chloride or acid chloride via the procedure used for N-{1 [(3E)-4-{5-cyano-4-[(4-methyl-1 H-indol-5-yl)amino]pyridin-3-yI}but-3-en-1-yl]piperidin-4-yl}methanesulfonamide.

[00163] Table 5:

Name MS HPLC rt (M+H) -{1-[(3E)-4-{5-cyano-4-[(4-methyl-1H-indol-5-yl)amino]pyridin-3 07.2 1.45 min[d]
I but-3-en-1- I i eridin-4- ro ane-2-sulfonamide -{1-[(3E)-4-{5-cyano-4-[(4-methyl-1H-indol-5-yl)amino]pyridin-3 93.4 .9 min[a]
I but-3-en-1- I i eridin-4- I ethanesulfonamide -{1-[(3E)-4-{5-cyano-4-[(4-methyl-1H-indol-5-yl)amino]pyridin-3 541.4 .3 min[a]
I but-3-en-1- I i eridin-4- I benzenesulfonamide -{1-[(3E)-4-{5-cyano-4-[(4-methyl-1 H-indol-5-yl)amino]pyridin-3 143.5 .1 min[a]
I but-3-en-1- I i eridin-4- I acetamide o,õ

[00164] Preparation of 5-{(1E)-4-[4-(ethylsulfonyl)piperazin-1-yl]but-1-en-l-yl}-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile:

4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(1 E)-4-piperazin-1-ylbut-l-en-1-yl]nicotinonitrile (75 mg, 0.12 mmol), ethanesulfonyl chloride (21 mg, 0.16 mmol) and triethylamine (36 mg, 0.36 mmol) in 1 mL of DMF was stirred at room temperature for 1 h. The reaction mixture was filtered and the filtrate was purified by HPLC to give 5-{(1 E)-4-[4-(ethylsulfonyl)piperazin-1-yl]but-1-en-1-yl}4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile, as its TFA salt; HRMS
479.2227 (M+H);
HPLC: rt = 4.8 min[a].

[00165] Preparation of compounds in Table 6:

The analogs in Table 6 were prepared using 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(1 E)-4-piperazin-1-ylbut-1-en-1-yl]nicotinonitrile and the appropriate electrophile via the procedure used for 5-{(1 E)-4-[4-(ethylsulfonyl)piperazin-1-yl]but-1-en-1-yl}4-[(4-methyl-1 H-indol-5-yl) amino]nicotinonitrile.

[00166] Table 6:

Name MS (M+H) HPLC rt I-[(4-methyl-1H-indol-5-yl)amino]-5-{(1E)-4-[4-(phenylsulfonyl) 527.2 .2 min.[a]
i erazin-l- I but-l-en-1- I nicotinonittile (1 E)-4-[4-(2,2-dimethylpropanoyl)piperazin-l-yl]but-l-en-1- 71 2 .4 min[a]
I - 4-meth l-1H-indol-5- amino nicotinonitrile -{(1E)-4-[4-(isopropylsulfonyl)piperazin-1-yl]but-1-en-l-yl}-4- 193.2 1.42 min[d]
[(4-methyl-1 H-indol-5- I amino nicotinonitrile o IN"6 [00167] Preparation of 5-[(IE)-4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)but-1-en-1-yi]-4-[(4-methyl-1 H-indol-5 yl)amino]nicotinonitrile:

A mixture of 5-iodo-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile (153 mg, 0.41 mmol), (E)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-enyl)isoindoline-1,3-dione (200 mg, 0.61 mmol), sodium bicarbonate (0.40 mL, sat.) and Pd(PPh3)4 (23.5 mg, 0.02 mmol) in 2 mL of DME was heated at 800 for 16 h. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated and purified by HPLC to give 5-[(1E)-4-(1,3-dioxo-1,3-d1hydro-2H-isoindol-2-yl)but-1-en-1-yI]-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile as a solid; HRMS 448.1768 (M+H); HPLC rt = 9.2 min [a].

NH
DIJIIN~
0 W~
N

[00168] Preparation of tert-butyl 4-[(3E)-4-{5-cyano-2-methyl-4-[(4-methyl-1 H-indol-5-yl) amino] pyridin-3-yl}but-3-en-1-yl]piperazine-1-carboxylate:

A mixture of tert-butyl piperazine-1-carboxylate (193 mg, 1.04 mmol) and (E)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-enyl 4-methylbenzenesulfonate (183 mg, 0.52 mmol) in 1 mL of DMSO was stirred for 16 h at room temperature. 5-iodo-6-methyl-4-[(4-methyl-1 H-indol-5-yl)amin o]nicoti non itrile (100 mg, 0.26 mmol), cesium carbonate (170 mg, 0.52 mmol) and Pd(PPh3)4 (15 mg, 0.013 mmol) were added to the same pot and the resulting suspension was heated at 70 for 16 h. After cooling to room temperature, the reaction was diluted with EtOAc and washed with water. The organic extracts were concentrated and purified by silica gel chromatography with a MeOH/ DCM gradient to give tert-butyl 4-[(3E)-4-{5-cyano-2-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]pyridin-3-yl}but-3-en-1-yl]piperazine-1-carboxylate as a solid; MS 501.5 (M+H); HPLC: rt = 6.5 min[a].

NH
H
OY N
N N

[00169] Preparation of tert-butyl(1-[(3E)-4{5-cyano-2-methyl-4-[(4-methyl-1H-indol-5-yl) amino] pyridin-3-yl}but-3-en-1-yl]piperidin-4-yl}carbamate:
5-iodo-6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile, tert-butylpiperidin-4-yl carbamate and (E)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-enyl-4-methyl benzenesulfonate were used to prepare tert-butyl {1-[(3E)-4-{5-cyano-2-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]pyridin-3-yl}but-3-en-1-yl]piperidin-4-yl}carbamate via the same method used for preparing tert-butyl 4-[(3E)-4-{5-cyano-2-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]
pyridin-3-yl}but-3-en-1-yl]piperazine-1-carboxylate, above; MS 515.5 (M+H);
HPLC: rt = 6.4 min [a].

NH
H
HO

[00170] Preparation of 6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-[(1E)-4-piperazin-1-ylbut-l -en-l-yl] nicotinonitri le:

A solution of tert-butyl 4-[(3E)-4-{5-cyano-2-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]pyridin-3-yl)but-3-en-1-yl]piperazine-1-carboxylate (402 mg, 0.80 mmol) in 10%
trifluoroacetic acid/
DCM was stirred for 1 h at room temperature. The reaction was concentrated and the residue was purified by HPLC-to give 6-methyl-4-[(4-methyl-lH-indol-5-yl)amino]-5-[(1E)-4-piperazin-1-ylbut-1-en-1-yl]nicotinonitrile as its TFA salt; MS 401.4 (M+H); HPLC: rt =
4.8 min [b].

NN
MN
N

[00171] Preparation of 5-[(1E)-4-(4-aminopiperidin-1-yl)but-1-en-1-yl]-6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile:

Tert-butyl {1-[(3E)-4-{5-cyano-2-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]pyridin-3-yl}but-3-en-1-yl]piperidin-4-yl}carbamate was used to prepare 5-[(1E)-4-(4-aminopiperidin-l-yl)but-l-en-1-yl]-6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile via the route used to prepare 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(1 E)-4-piperazin-1-ylbut-1-en-1-yi]nicotinonitrile, above. The title compound was isolated as its TFA salt; HRMS 415.2610 (M+H);
HPLC: rt =
5.6 min [b].

NFI
o , ~N'~-~~ Ift \ N
I N / \

[00172] Preparation of 6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-{(1E)-4-[4-(methylsulfonyl)piperazin-1-yl]but-1-en-1-yl}nicotinonitrile:
A solution of 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(1 E)-4-piperazin-1-ylbut-1-en-1-yl]nicotinonitrile (106 mg, 0.27 mmol), methane sulfonyl chloride (42 mg, 0.37 mmol) and triethylamine (109 mg, 1.08 mmol) in I mL DMF was stirred for I h at room temperature. The reaction was filtered and the filtrate was purified by HPLC to give 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(1 E)-4-[4-(methylsulfonyl)piperazin-1 -yl]but-1-en-1 -yl}nicotinonitrile as its TFA salt; MS 479.4 (M+H); HPLC: rt = 5.1 min [a].

NH

1H~
3~ L H
d~ Il k, A N
O

[00173] Preparation of N-(1-[(3E)-4-{5-cyano-2-methyl-4-[(4-methyl-1H-indol-5-yl)amino]
pyridin-3-yl}but-3-en-1-yl]piperidin-4-yl}methanesulfonamide:
A solution of 5-[(1 E)-4-(4-aminopiperidin-1-yl)but-1-en-1-yl]-6-methyl-4-[(4-methyl-1 H-indol-5-yl) amino]nicotinonitrile (92 mg, 0.22 mmol), methane sulfonyl chloride (36 mg, 0.31 mmol) and triethylamine (89 mg, 0.88 mmol) in 1 mL DMF was stirred for 1 h at room temperature.
The reaction was filtered and the filtrate was purified by HPLC to give N-(1-[(3E)-4-{5-cyano-2-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]pyridin-3-yl}but-3-en-1-yl]piperidin-4-yl}methane sulfonamide as its TFA salt; MS 493.5 (M+H); HPLC: it = 4.8 min [a].

[00174] Preparation of (E)-2-(5-chloropent-1-enyl)-4,4,5,5-tetramethyl-1,3,2-dioxa borolane:

A mixture of 5-chloro-1-pentyne (500 mg, 4.9 mmol), 4,4,5-tetramethyl-1,3,2-dioxaborolane (947 mg, 7.4 mmol), bis(cyclopentadienyl)-zirconium(IV) chloride hydride (191 mg, 0.74 mmol) and triethylamine (49.5 mg, 0.49 mmol) were stirred neat at room temperature for 24 hr. The reaction was dissolved in DCM, filtered through a pad of silica gel and washed with DCM. The eluent was removed to give 824 mg of (E)-2-(5-chloropent-1-enyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane as a clear yellow liquid; MS 231.2 (M+H); HPLC: rt = 18.2 min [a].

NH

r / N
v I N

N) / N

[00175] Preparation of 4-[(4-methyl-1H-indol-5-yl)amino]-5-[(1E)-5-morpholin-4-ylpent-1-en-1-yl]nicotinonitrile and (4E)-5-(5-cyano-(4-methyl-1H-indol-5-yl) amino]
pyridin-3-yl}pent-4-en-1-yl morpholine-4-carboxylate:

A mixture of morpholine (148 mg, 1.7 mmol) and (E)-2-(5-chloropent-1-enyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (131 mg, 0.61 mmol) in 1 mL of DMSO was stirred for 16 hr at room temperature. 5-iodo-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile (108 mg, 0.29 mmol), cesium carbonate (186 mg, 0.57 mmol) and Pd(PPh3)4 (16 mg, 0.014 mmol) were added and the reaction mixture was heated at 700 for 16 h. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated and purified by HPLC to give 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(1 E)-5-morpholin-4-ylpent-1-en-1-yl]nicotinonitrile and (4E)-5-{5-cyano-(4-methyl-1 H-indol-5-yl)amino]pyridin-3-yl}pent-4-en-1-ylmorpholine-4-carboxylate.
[00176] 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(1 E)-5-morpholin-4-ylpent-1-en-1-yl]
nicotinonitrile: (TFA salt):

HRMS 402.2288 (M+H); HPLC: rt = 6.1 min [b]

[00177] (4E)-5-{5-cyano-(4-methyl-IH-indol-5-yl)amino]pyridin-3-yl}pent-4-en-1-yl mo rph of i ne-4-ca rboxyl ate:

HRMS 446.2187 (M+H); HPLC rt = 11.9 min[b].

[00178] Preparation of compounds in Table 7A:

These analogs were prepared using 5-iodo-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile, (E)-2-(5-chloropent-l-enyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, and the appropriate amine via the procedure used for, 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(l E)-5-morpholin-4-yl pent- 1 -en- 1 -yl]n icotinon itri le.

Table 7A

Name MS (M+H) HPLC rt -[(4-methyl-1H-indol-5-yl)aminoj-54(1E)-5-(4-methyl 115.2608 5.9 min[b]
i erazin-1- I ent-1-en-1- I nicotinonitdle -[(4-methyl-1H-indol-5-yl)amino]-54(1E)-5-pyrrolidin-1- 386.2344 .5 min[bj I ent-1-en-1- 1 nicotinonitrile -[(4-methyl-1H-indol-5-y1)amino]-54(1E)-5-piperidin-1 - 100.4 .1 min[a]
I ent-l-en-1- I nicotinonitrile ert-butyl4-[(4E)-5-{5-cyano-4-((4-methyl-1 H-indol-5-I)amino]pyridin-3-yl}pent-4-en-1-yl]piperazine-1- 01.5 .7 min[a]
arboxylate ert-butyl{1-[(4E)-5-{5-cyano-4-[(4-methyl-1 H-indol-5-I)amino]pyddin-3-yl}pent-4-en-1-yljpiperidin-4- 15.5 .7 min[a]
I rbamate [(1E)-5-(4-hydroxypiperidin-1-yl)pent-1-en-1-yl)-4-[(4- 16.4 .4 min[a]
ethyl-1 H-indol-5-I mino nicotinonitrile NH
HN
fN
HNJ

[00179] Preparation 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(1 E)-5-piperazin-1-ylpent-1-en-1-yl]nicotinonitrile:

A solution of tert-butyl 4-[(4E)-5-{5-cyano-4-[(4-methyl-1 H-indol-5-yl)amino]pyridin-3-yl}pent-4-en-l-yl]piperazine-1-carboxylate (91 mg, 0.18 mmol) in 10% trifluoroacetic acid/ DCM was stirred for 1 h at room temperature. The reaction was filtered and the filtrate was concentrated and purified by HPLC to give the title compound as its TFA salt; HRMS 401.2456 (M+H);
HPLC: rt = 7.3 min [b].

NH
H~/J I nY

[00180] Preparation of 5-[(1E)-5-(4-aminopiperidin-l-yl)pent-1-en-l-yl]-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile:

Tert-butyl{1-[(4E)-5-{5-cyano-4-[(4-methyl-1 H-indol-5-yl)amino]pyridin-3-yl}pent-4-en-1-yl]
piperidin-4-yl}carbamate was used to prepare 5-[(1 E)-5-(4-aminopiperidin-1-yl)pent-l-en-l-yl]-4-[(4-methyl-1 H-indol-5-yl) amino]nicotinonitrile via the route used to prepare 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(1 E)-5-piperazin-1-ylpent-l-en-l-yl]nicotinonitrile:
HRMS 415.2605 (M+H);
HPLC: rt = 6.9 min [b].

H

[00181] Preparation of tert-butyl 5-cyano-4-[(4-methyl-1H-indol-5-yl)amino]-3',6'-dihydro-3,4'-bipyridi ne-I'(2'H)-carboxylate:

A mixture of 5-iodo-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile (1.5 g, 4.0 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yi)-5,6-dihydropyndine-1(2H)-carboxylate (1.85 g, 6 mmol), Pd(OAc)2 (62.7 mg; 0.28 mmol), triphenylphosphine trisulfonic acid (340 mg; 0.6 mmol) and sodium bicarbonate (saturated aq., 4 mL) in 50 mL of dimethoxyethane was heated at 90 C for 16 h, cooled to room temperature, diluted with EtOAc and washed with water. The crude organic extract was concentrated and the residue was purified by silica gel chromatography with a hexane/ EtOAc gradient to give 640 mg of tert-butyl 5-cyano-4-[(4-methyl-1 H-indol-5-yl)amino]-3',6'-dihydro-3,4'-bipyridine-1'(2'H)-carboxylate as a solid; MS
430.3 (M+H); HPLC: rt = 9.8 min [a].

Ni N
. I ~

[00182] Preparation of 4-[(4-methyl-1 H-indol-5-yl)amino]-1',2',3',6'-tetrahydro-3,4'-bipyridine-5-carbonitrile:

Tert-butyl-5-cyano-4-[(4-methyl-1 H-indol-5-yl)amino]-3',6'-dihydro-3,4'-bipyridine-1'(2'H)-carboxylate (100 mg, 0.23 mmol) was treated with 10% trifluoroacetic acid/ DCM
to give 96 mg of 4-[(4-methyl-1 H-indol-5-yl)amino]-1',2',3',6'-tetrahydro-3,4'-bipyridine-5-carbonitrile as its TFA salt upon concentration; MS 330.2 (M+H); HPLC: rt = 3.7 min [a].

NH
0,1/

N

[00183] Preparation of 4-[(4-methyl-1 H-indol-5-yl)amino]-1'-(methylsulfonyl)-l',2',3',6'-tetrahydro-3,4'-bi pyrid ine-5-carbon itrile:

A mixture of 4-[(4-methyl-1 H-indol-5-yl)amino]-1',2',3',6'-tetrahydro-3,4'-bipyridine-5-carbonitrile (100 mg, 0.23 mmol), methane sulfonyl chloride (28.7 mg, 0.25 mmol), and triethylamine (68.7 mg, 0.68 mmol) in 1 mL of DMF was stirred at room temperature for 10 min. The reaction was filtered and the filtrate was purified by HPLC to give 4-[(4-methyl-1 H-indol-5-yl)amino]-1'-(methylsulfonyl)-l',2',3',6'-tetrahydro-3,4'-bipyridine-5-carbonitrile as a solid; MS 408.3 (M+H); HPLC: rt = 6.7 min [a].

[00184] Preparation of compounds in Table 7B:

These compounds were prepared from 4-[(4-methyl-1 H-indol-5-yl)amino]-1',2',3',6'-tetrahydro-3,4'-bipyridine-5-carbonitrile, the corresponding electrophile and triethylamine in DMF via the procedure used to prepare 4-[(4-methyl-1 H-indol-5-yl)amino]-1'-(methylsulfonyl)-l',2',3',6'-tetrahydro-3,4'-bipyridine-5-ca rbonitrile.

[00185] Table 713:

MS
Electrophile Name (M+H) HPLC rt Benzenesulfonyl -[(4-methyl-1 H-indol-5-yl)amino]-1'-(phenyl chloride ulfonyl)-1',2',3',6'-tetrahydro-3,4'-bipyridine-5- 70.2 .3 min[a]
arbonitrile Acetyl chloride 1~ acetyl-4-[(4-methyl-lH-indol-5-yl)amino} 72.1 .8 min[a]
,3 6 tetrah dro-3,4 bi ridine-5-carbonitrile [a]
-cyano-N-ethyl-4-[(4-methyl-1 H-indol-5-yl) Ethyl isocyanate mino]-3',6'-dihydro-3,4'-bipyridine-l'(2'H)- 01.2 .2 min[a]
arboxamide Ethyl thyl 5-cyano-4-[(4-methyl-1 H-indol-5-yl)amino] 02.2 1.6 min[a]
hloroformate 3',6'-dih dro-3,4'-bi ridine-1' 2'H rbo late ~ I H /N

=Ewa [00186] Preparation of I'-benzyl-4-[(4-methyl-1H-indol-5-yl)amino]-1',2',3',6'-tetrahydro-3,4'-bipyrid ine-5-carbonitrile:

A mixture of 4-[(4-methyl-1 H-indol-5-yl)amino]-1',2',3',6'-tetrahydro-3,4'-bipyridine-5-carbonitrile (100mg, 0.23 mmol), benzaldehyde (31.8 mg, 0.30 mmol), and sodium triacetoxyborohydride (195 mg, 0.92 mmol) in 1 mL of DCE was stirred at room temperature for 1 h. The reaction was filtered and the filtrate was purified by HPLC to give 1'-benzyl-4-[(4-methyl-1 H-indol-5-yl)amino]-1',2',3',6'-tetrahydro-3,4'-bipyridine-5-carbonitrile as its TFA salt;
MS 420.3 (M+H); HPLC: rt = 5.7 min [a].

[00187] Preparation of compounds In Table 8:

4-[(4-methyl-1 H-indol-5-yl)amino]-1',2',3',6'-tetrahydro-3,4'-bipyridine-5-carbonitrile was used to prepare these analogs via the same route used to prepare 1'-benzyl-4-[(4-methyl-1 H-indol-5-yl)amino]-1',2',3',6'-tetrahydro-3,4'-bipyridin e-5-carbonitrile.

[00188] Table 8:

Name MS (M+H) HPLC rt 1'-methyl-4-[(4-methyl-1H-indol-5-yl)amino]- 344.3 3 .8 min[a]
1',2',3',6'-tetrah dro-3,4'-bi ridine-5-carbonitrile -[(4-methyl-1H-indol-5-yl)amino]-1'-(2-phenylethyl)- 134.5 .2 min[a]
1 ',2',3',6'-tetrah dro-3,4'-bi ridine-5-carbonitrile 1'-(2-fluorobenzyl)-4-[(4-methyl-1 H-indol-5-yl) amino]-1',2',3',6'-tetrahydro-3,4'-bipyridine-5- 138.3 5.6 min[a]
arbonitle 1'-(3-fluorobenzyl)-4-[(4-methyl-1 H-indol-5-yl) mino]-1',2',3',6'-tetrahydro-3,4'-bipyridine-5- 38.3 5.9 min[a]
arbonitrile 1'-(4-fluorobenzyl)-4-[(4-methyl-1 H-indol-5-yl) mino]- 1',2',3',6'-tetrahydro-3,4'-bipyridi ne-5- 38.3 5.9 min[a]
arbonitrile -[(4-methyl-1 H-indol-5-yl)amino]-1'-(piperidin-4-yl ethyl)-1',2',3',6'-tetrahydro-3,4'-bipyridine-5- 27.4 3.8 min[b]
arbonitrile NH

~ I \

[00189] Preparation of 4-[(4-methyl-lH-indol-5-yl)amino]-1'-[(1-methylpiperidin-4-yl) carbonyl]-1',2', 3',6'-tetrahyd ro-3,4'-bipyrid ine-5-carbonitrile:

A mixture of 4-[(4-methyl-1 H-indol-5-yl)amino]-1',2',3',6'-tetrahydro-3,4'-bipyridine-5-carbonitrile (100mg, 0.23 mmol), 1-methylpiperidine-4-carboxylic acid (54 mg, 0.30 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (88 mg, 0.46 mmol), and triethylamine (69.7 mg; 0.69 mmol) in 2 mL of DMF was stirred at room temperature for 1 h.
The reaction was filtered and the filtrate was purified by HPLC to give 4-[(4-methyl-1 H-indol-5-yl)amino]-1'-[(1-methylpiperidin-4-yl)carbonyl]-1',2',3',6'-tetrahydro-3,4'-bipyridine-5-carbonitrile as its TFA salt; MS 455.4 (M+H); HPLC: rt = 4.2 min [a].

H ~6NH

[00190] Preparation of 4-[(4-methyl-lH-indol-5-yl)amino]-5-[(1E)-3-pyrrolidin-1-ylprop-1-en-l-yl]nicotinonitrile:

(E)-3-Chloroprop-l-enylboronic acid (67 mg, 0.53 mmol), 5-iodo-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile (0.27 mmol, 100 mg), pyrolidine (57 mg, 0.80 mmol), palladium bis(triphenylphosphine) dichloride (9.0 mg, 0.013 mmol) and cesium carbonate (172 mg, 0.53 mmol) were heated in 3 mL DME at 900 C overnight. The reaction mixture was partitioned between DCM/MeOH and water. The organic layer was washed twice with water and concentrated onto silica gel. Elution with 10% MeOH/DCM (ammonia modifier) gave 28 mg of 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(1 E)-3-pyrrolidin-1-ylprop-l-en-l-yl]nicotinonitrile; MS
358.3 (M+H); HPLC: it = 5.8 min [b].

Ni H I~

[00191] Preparation of 5-[(1E)-3-(4-hydroxypiperidin-l-yl)prop-1-en-1-yl]-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile:

The title compound was synthesized from 5-iodo-4-[(4-methyl-1H-indol-5-yl) amino]nicotinonitrile and 4-hydroxypiperidine according to the procedure described for 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(1 E)-3-pyrrolidin-l -ylprop-l-en-l-yl]nicotinonitrile; MS 388.4 (M+H); HPLC: rt = 3.9 min [a].

Ni o N

HN~, [00192] Preparation of 4-[(4-methyl-IH-indol-5-yl)amino]-1'-(piperidin-4-ylcarbonyl)-I',2', 3', 6'-tetrahydro-3,4'-bi py rid i ne-5-carbon itril e:

4-[(4-methyl-1 H-indol-5-yl)amino]-1',2',3',6'-tetrahydro-3,4'-bipyridine-5-carbonitrile (70 mg, 0.12 mmol), 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (37 mg, 0.16 mmol), triethyl amine (36 mg, 0.36 mmol), and EDC (46 mg, 0.24 mmol) were stirred in 5 mL of DCM. After 30 minutes, the reaction was treated with TFA (2 ml-) and stirred for 1h. The reaction mixture was concentrated and the residue was purified by HPLC to give 4-[(4-methyl-1 H-indol-5-yl)amino]-1'-(piperidin-4-ylcarbonyl)-1',2',3',6'-tetrahydro-3,4'-bipyridine-5-carbonitrile; MS
387.1 (M+H); HPLC: rt = 1.2 min [a].

[00193] Preparation of compounds in Table 9:

The compounds in Table 9 were prepared from 4-[(4-methyl-1 H-indol-5-yl)amino]-1',2',3',6'-tetrahydro-3,4'-bipyridine-5-carbonitrile and the appropriate Boc-protected amino acid by the method described for 4-[(4-methyl-1 H-indol-5-yl)amino]-1'-(piperidin-4-ylcarbonyl)-1',2',3',6'-te t ra h yd ro-3 , 4'-b i pyri d i n e- 5-ca rb o n i t ri l e:

[00194] Table 9:

Compound name MS (M+H) HPLCrt [method]
1'-glycyl-4-[(4-methyl-1 H-indol-5-yl)amino]- 387.1 1.2 min [d]
1',2',3',6'-tetrahydro-3,4'-bipyridi ne-5-carbonitrile Compound name MS (M+H) HPLCrt [method]
1'-(2-methylalanyl)-4-[(4-methyl-1 H-indol-5- 415.1 1.3 min [d]
yl)ami no]-1',2',3',6'-tetrahydro-3,4'-bipyridine-5-carbonitrile 1'-b-aIanyl-4-[(4-methyl-1 H-indol-5-yl)amino]- 401.2 1.2 min [d]
1',2',3',6'-tetrahydro-3,4'-bipyridine-5-carbonitrile 4-[(4-methyl-1 H-indol-5-yI)amino]-1'-D-valyl- 429.3 1.4 min [d]
1',2',3',6'-tetrahydro-3,4'-b ipyridine-5-carbonitrile 44(4-methyl-1 H-indol-5-yI)amino]-1'-L-valyl- 429.1 1.4 min [d]
1',2',3',6'-tetrahydro-3,4'-b ipyridine-5-carbonitrile 4-[(4-methyl-1 H-indol-5-yl)amino]-1'-D-prolyl- 427.1 1.3 min [d]
1',2',3',6'-tetrahydro-3,4'-b ipyridine-5-carbonitrile 4-[(4-methyl-1H-indol-5-yl)amino]-1'-L-prolyl- 427.1 1.3 min [d]
1',2',3',6'-tetrahydro-3,4'-b ipyndine-5-carbonitrile 4-[(4-methyl-1H-indol-5-yl)amino]-1'-(pyrrolidin- 427.1 1.3 min [d]
3-ylca rbonyl)-1',2',3',6'-tetrahydro-3,4'-bi ridine-5-carbonitrile M )(5NH

N

[00195) Preparation of 4-[(4-methyl-1H-indol-5-ylamino)]-5-vinylnicotinonitrile:

A mixture of 5-iodo-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile (300 mg, 0.80 mmol), tributyl(vinyl)tin (350 L, 1.20 mmol), Cul (5 mg) and (Ph3P)2PdCl2 (15 mg) in 8 mL of DMF
was heated at 80 C for 30 min. After cooling to room temperature the reaction mixture was partitioned between saturated aqueous sodium bicarbonate and ethyl acetate.
The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo.
The residue was triturated with ethyl acetate to give 128 mg (58%) of 4-[(4-methyl-1 H-indol-5-ylamino)]-5-vinylnicotinonitrile as a light tan solid; MS 275.2 (M+H); HPLC: 95.5% at 215 nm, 6.2 min [a].

NH
H I

[00196] Preparation of 4-[(4-methyl-1H-indol-5-yl)amino]-5{(E)-2-[4-(2-pyrrolidin-1-yl ethoxy)phenyl]vinyl}nicotinonitrile:

4-[(4-methyl-1H-indol-5-ylamino)]-5-vinylnicotinonitrile (60 mg, 0.22 mmol), 1-(2-(4-bromophenoxy)ethyl)pyrolidine (70 mg, 0.26 mmol), tri(ortho-tolyl)phosphine (10 mg, 0.033 mmol), and palladium acetate (4 mg, 0.016 mmol) were heated to 120 C in a mixture of 2 mL
DMF and 92 uL (0.66 mmol) of triethyl amine. After heating for 1h, the reaction was cooled and filtered. The filtrate was concentrated and the product was purified by preparative HPLC
(ACN/water) to give 50 mg of 4[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[4-(2-pyrrolidin-1-ylethoxy)phenyl]vinyl}nicotinonitrile as its TFA salt; MS 464.4 (M+H); HPLC:
rt = 6.0 min [a].

N
Q,~

[00197] Preparation of 5{(E)-2-[4-(2-chloroethoxy)phenyl]vinyl}-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile:

4-[(4-methyl-1 H-indol-5-ylamino)]-5-vinylnicotinonitrile (100 mg, 0.36 mmol), 1-bromo-4-(2-chloroethoxy)benzene (103 mg, 0.44 mmol), tri(ortho-tolyl)phosphine (16 mg, 0.054 mmol), and palladium acetate (6 mg, 0.027 mmol) were heated to 120 C in a mixture of 2 mL DMF
and 100 uL (0.72 mmol) of triethyl amine. After heating for 1 h, the reaction was cooled and diluted with EtOAc/methanol and washed twice with water. The organic layer was concentrated onto silica gel and purified by chromatography (EtOAc/hex) to give 66 mg of 5-{(E)-2-[4-(2-chloroethoxy)phenyl]vinyl}-4-[(4-methyl-1 H-indol-5-yl)a mino]nicoti non itrile; MS
429.3 (M+H); HPLC rt = 10.7 min [a].

NH
H
N

[00198] Preparation of 4-[(4-methyl-IH-indol-5-yl)amino]-5-[(IE)-3-phenylprop-l-en-l-yl]
nicotinonitrile:

5-iodo-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile (200 mg, 0.53 mmol), (E)-3-phenyl prop-1-enylboronic acid (121 mg, 0.75 mmol), and tetrakis(triphenylphosphine) palladium (50 mg) was heated to 80 C in 5 mL of DMF and 0.5 mL of saturated aqueous sodium bicarbonate.
After heating overnight, the reaction was filtered and the filtrate was purified by preparative HPLC (acetonitrile/water) to give 100 mg of 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(1 E)-3-phenylprop-1-en-1-yl]nicotinonitrile; MS 365.3 (M+H); HPLC: rt = 10.0 min [a].

Ni [00199] Preparation of 4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-(4-[2-(4-methyl piperazin-1-yl)ethoxy]phenyl}vinyl]nicotinonitrile:
5-{(E)-2-[4-(2-chloroethoxy) phenyl]vinyl}-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile (75 mg, 0.18 mmol), N-methyl piperazine (54 mg,. 0.54 mmol), and Nal (8 mg, 0.05 mmol) were heated in 3 mL DME at 100 C for 48h. The reaction was concentrated, dissolved in DMF, and purified by preparative HPLC (acetonitrile/water) to give 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}vinyl]nicotinonitrile as its bis-TFA salt.
The free base was generated by addition of excess polymer-bound ammonium carbonate to a solution of the title compound in DCM/methanol: MS 493.4 (M+H); HPLC: rt = 5.8 min [a].

Ni N

[00200] Preparation of 4-[(4-methyl-1 H-indol-5-yl)amino]-5-(3-phenylpropyl) nicotinonitrile:

4-[(4-methyl-1H-indol-5-yl)amino]-5-[(1E)-3-phenylprop- 1-en-l-yl]nicotinonitrile (80 mg) was treated with 15 mg of 10% Pd on activated carbon and shaken in 10 mL EtOH
under 30 PSI of hydrogen. After 2h the reaction mixture was filtered and the filtrate was concentrated and purified by HPLC to give 35 mg of 4-[(4-methyl-1H-indol-5-yl)amino]-5-(3-phenyl propyl)nicotinonitrile; MS 367.3 (M+H); HPLC: rt = 9.8 min [a].

NH
H
N
~ J~ \ f N
f NA
NH
HN /

[00201] Preparation 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[3-(4-methylpiperazin-1-yl) propyl]nicotinonitrile and 4-[(4-methyl-1 H-indol-5-yl)amIno]-5-propyl nicotinonitrile:

4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(1 E)-3-(4-methylpiperazin-1-yl) prop-1-ens1-yl]
nicotinonitrile (154 mg, 0.40 mmol) and palladium (15 mg, 10% on C; wet) in 30 mL of EtOH
was stirred rapidly under H2 at 1 atm for 1 hr at room temperature. The reaction was filtered and the two products were isolated from the filtrate via HPLC purification.

[00202] 4-[(4-methyl-1H-indol-5-yl)amino]-5-[3-(4-methylpiperazin-1-yl)propyl]
nicotinonitrile:

MS 389.4 (M+H); HPLC: rt = 2.7 min [a]

[00203] 4-[(4-methyl-1H-indol-5-yl)amino]-5-propylnicotinonitrile:
MS 291.2 (M+H); HPLC: rt = 1.59 min[c].

fNi N
N

[00204] Preparation 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[4-(4-methylpiperazin-1-yl) butyl]nicotinonitrile:

4-[(4-methyl-1 H-indo-5-yl)amino]-5-[(1 E)-3-(4-methylpiperazin-1-yl)but-1 -en-1 -yl]nicotinonitrile (92 mg, 0.23 mmol) and palladium (9 mg, 10%; wet) in 20 mL of EtOH was stirred rapidly .under H2 at 1 atm for 1 hr at room temperature. The palladium was filtered and the filtrate was purified by HPLC to give 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[4-(4-methylpiperazin-l-yl)butyl]nlcotinonitrile as a solid; MS 403.4 (M+H); HPLC rt = 4.6 min [b].

NH

HM H
N

[00205] Preparation 4-[(4-methyl-1 H-indol-5-yl)amino]-5-(4-piperazin-l-ylbutyl) nicotinonitrile:

Tert-Butyl-4-[(3E)-4-{5-cyano-4-[(4-methyl-1 H-indol-5-yl)amino]-pyridin-3-yl}-but-3-en-1-yl]
piperazine-1-carboxylate (194 mg, 0.40 mmol) and palladium (20 mg, 10%; wet) in 20 mL of EtOH was stirred rapidly under H2 at 1 atm for 16 hr at room temperature.
Additional palladium (20 mg, 10%; wet) was added and the reaction was shaken under 30 psi H2 for 6 hr. The palladium and solvent were removed to give tert-butyl 4-(4-(5-cyano-4-(4-methyl-1 H-indol-5-ylamino)pyridin-3-yl)butyl) piperazine-1-carboxylate. 10% Trifluoracetic acid/
DCM (5.5 ml-) was added to the crude tert-butyl 4-(4-(5-cyano-4-(4-methyl-1 H-indol-5-ylamino)pyridin-3-yl)butyl)piperazine-1-carboxylate. After stirring for 3 hr at room temperature, the reaction was concentrated and the residue was purified by HPLC to give 4-[(4-methyl-1 H-indol-5-yl)amino]-5-(4-piperazin-1-ylbutyl)nicotinonitrile as its TFA salt; HRMS 389.2454 (M+H);
HPLC: rt = 4.2 min [b].

NH

[00206] Preparation 5-[4-(4-aminopiperidin-1-yl)butyl]-4-[(4-methyl-IH-indol-5-yl)amino]
nicotinonitrile:

Tert-butyl-{1-[(3E)-4-{5-cyano-4-[(4-methyl-1 H-indol-5-yl)amino]-pyrid in-3-yl}-but-3-en-1=y1]
piperidin-4-yl}carbamate (200 mg, 0.40 mmol) and palladium (20 mg, 10%; wet) in 20 mL of EtOH was stirred rapidly under H2 at 1 atm for 16 hr at room temperature. The solvent and palladium were removed to give tert-butyl 1-(4-(5-cyano-4-(4-methyl-1 H-indol-ylamino)pyridin-3-yl)butyl)piperidin-4-ylcarbamate. 10% Trifluoracetic acid/
DCM (5.5 mL) was added to the crude tert-butyl 1-(4-(5-cyano-4-(4-methyl-1 H-indol-5-ylamino)pyridin-3-yl)butyl)piperidin-4-yicarbamate. After stirring for 2 hr at room temperature the reaction was concentrated and the residue was purified by HPLC to give 5-[4-(4-aminopiperidin-1-yl)butyl]-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile as its TFA salt; HRMS
403.2612 (M+H); HPLC:
rt = 5.3 min [b].

f N
J I ~

[00207] Preparation 5-benzyl-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile:
5-iodo-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile (150 mg, 0.40 mmol), potassium benzyltrifluoroborate (158 mg, 0.80 mmol), 2-d icyclohexylphosphino-2',4',6=triisopropyI
biphenyl (38 mg, 0.08 mmol), cesium carbonate (391 mg, 1.2 mmol) and palladium acetate (18 mg, 0.08 mmol) in 2.2 mL of 10: 1 THF/ water was heated at 80 C for 32 hr, cooled to room temperature, diluted with DCM and washed with water. The crude material was purified by silica gel chromatography with a MeOH/ DCM gradient to give 5-benzyl-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile as a solid; MS 339.2 (M+H); HPLC: rt = 1.88 min [c]. 4-methyl-1,5-dihydropyrido[4,3-b]pyrrolo[2,3-f]indole-6-carbonitrile was isolated as a by product of this reaction; MS 245.2 (M-H).

v ~N

[00208] Preparation of 5-(3,4-dimethoxyphenyl)-3-oxopentanonitrile:

To 65 mL of THE at -78C was added 2.5 M n-butyllithium in hexane (44 mL, 110 mmol). To this solution was added a solution of acetonitrile (4.92 g, 120 mmol) in 120 mL of THE during min. After sirring for 15 min at -78 C the solution was treated with a solution of ethyl 3-(3,4-dimethoxyphenyl)propanoate (11.9 g, 50 mmol) in 15 mL of THE over 5 min.
The solution was stirred at -78 C for 30 min, quenched with HOAc (7.2 mL, 125 mmol), and partitioned between Et2O and water. The organic layer was washed with brine, dried and concentrated to give 5-(3,4-dimethoxyphenyl)-3-oxopentanonitrile as a white solid (11.4 g, 97%).

[00209] Preparation of 2-(dimethylaminomethylene)- 5-(3,4-dimethoxyphenyl)-3-oxopentanonitrile:

A solution of 5-(3,4-dimethoxyphenyl)-3-oxopentanonitrile (4.67 g, 20 mmol) and dimethyl formamide dimethyl acetal (3.1 mL, 22 mmol) was stirred at 25 C for 20 min and concentrated under high vacuum to give 2-(dimethylaminomethylene)-5-(3,4-dimethoxyphenyl)-3-oxopentanonitrile as an oil.

[00210] Preparation of 5-(3,4-dimethoxybenzyl)-4-hydroxynicotinonitrile:

A solution of 2-(dimethylaminomethylene)- 5-(3,4-dimethoxyphenyl)-3-oxopentanonitrile (3.46 g, 12.0 mmol), t butoxybis(dimethylamino)methane (3.72 mL, 18 mmol), and 6.0 mL of toluene was heated at reflux for 30 min and concentrated under high vacuum to give 2,4-bis(dimethylaminomethylene)- 5-(3,4-dimethoxyphenyl)-3-oxopentanonitrile as a syrup.

A solution of 2,4-bis(dimethylaminomethylene)- 5-(3,4-dimethoxyphenyl)-3-oxopentanonitrile (4.6 -g, 12 mmol) in 36 mL of HOAc at 0 C was gassed with ammonia. The resulting suspension was heated at. 65 C for 30 min and concentrated to dryness. The residue was partitioned between EtOAc. and water. The EtOAc layer was washed with water, dried and concentrated to give a sticky solid. Recrystallization from EtOH gave 1.96 g of 5-(3,4-dimethoxybenzyl)-4-hydroxynicotinonitrile as a tan solid, mp 228-235 C; MS
269.1 (M-H)'.

I
[00211] Preparation of 4-chloro-5-(3,4-dimethoxybenzyl)nicotinonitrile:

To a stirred suspension of 5-(3,4-dimethoxybenzyl)-4-hydroxynicotinonitrile (1.24 g, 4.6 mmol) and 46 mL of thionyl chloride at 25 C was added 0.07 mL of DMF. The resulting solution was stirred for 3 h and concentrated to dryness under high vacuum. A solution of the residue in 5:1 DCM-toluene was passed through a pad of Magnesol. The filtrate was concentrated to give 4-chloro-5-(3,4-dimethoxybenzyl)nicotinonitrile as a light amber solid (1.14 g, 86%).

H
N
H

o' [00212] Preparation of 5-(3,4-dimethoxybenzyl)-4-(1H-indol-5-ylamino)nicotinonitrile:

A stirred solution of 4-chloro-5-(3,4-dimethoxybenzyl)nicotinonitrile (144 mg, 0.50 mmol), 5-aminoindole (99 mg, 0.75 mmol), pyridine hydrochloride ( 58 mg, 0.50 mmol), and 1.5 mL of i-PrOH was heated at reflux for 1.5 h and concentrated to dryness. The residue was stirred' in dilute aq NaHCO3, and the resulting solid was filtered, washed with water, and dried.
Crystallization from EtOAc-hexane gave 5-(3,4-dimethoxybenzyl)-4-(1 H-indol-5-ylamino) nicotinonitrile as a tan solid (50 mg, 26%), mp 108-115 C; MS 385.2 (M+H).

NH

[00213] Preparation of 5-(3,4-dimethoxybenzyl)-4-(1H-indol-4-ylamino)nicotinonitrile:

A stirred solution of 4-chloro-5-(3,4-dimethoxybenzyl)nicotinonitrile (144 mg, 0.50 mmol), 4-aminoindole (99 mg, 0.75 mmol), pyridine hydrochloride (58 mg, 0.50 mmol), and 1.5 mL of t amyl alcohol was heated at reflux for 24 h. The cooled mixture was stirred in dilute NaHCO3 and hexane, and the resulting solid was filtered, washed with water, and dried.
Chromatography of the residue on silica gel with DCM-EtOAc-MeOH gave 5-(3,4-dimethoxybenzyl)-4-(1 H-indol-4-ylamino)nicotinonitrile as an amber solid (82 mg, 43%); R, (25:25:1 DCM-EtOAc-MeOH) 0.50; MS 385.1 (M+H).

er CH
H

[00214] Preparation of 5-bromo-6-methyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid:
To 6-methyl-4(1H)-pyridone-3-carboxylic acid (1.54 g, 10.06 mmol) and 800 L
of pyridine in 30 mL of acetic acid at 100 C was slowly added 720 L of bromine in 5 mL of acetic acid. The reaction mixture was kept at 100 C for 2 h then cooled to room temperature.
The solids were collected by filtration and washed with methanol to provide 850 mg (36%) of 5-bromo-6-methyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid as a white solid; MS 232.0 (M+H).

0 0 .
V NK

[00215] Preparation of 5-bromo-6-methyl-4-oxo-1,4-dihydropyridine-3-carboxamide:

A mixture of 5-bromo-6-methyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (8.0 g, 34.5 mmol) and 1,1'-carbonyldiimidazole (12.2 g, 75.3 mmol) in 120 mL of DMF was heated at 65-75 C
for 3 h. The reaction mixture was cooled on an ice-bath and poured into cooled 29% aqueous ammonium hydroxide (84 mL). After stirring at 0-5 C for 1.5 h, the mixture was poured onto ice and the pH was adjusted to 5-6 with 1 N hydrochloric acid. The solids were collected by filtration, then washed with water followed by diethyl ether to provide 7.25 g (91 %) of 5-bromo-6-methyl-4-oxo-1,4-dihydropyridine-3-carboxamide as a white solid; MS 228.9(M-H) N

[00216] Preparation of 5-bromo-4-chloro-6-methylnicotinonitrile:

A mixture of 5-bromo-6-methyl-4-oxo-1,4-dihydropyridine-3-carboxamide (7.12 g, 30.8 mmol) and 1 drop of DMF in 30 mL of phosphorus oxychloride was heated at reflux for 2 h. The volatiles were removed in vacuo and the residue was slurried with ice.
Saturated aqueous sodium bicarbonate was slowly added until the mixture had a basic pH. The solids were collected by filtration, washing with aqueous sodium bicarbonate and water to provide 5.50 g (77%) of 5-bromo-4-chloro-6-methylnicotinonitrile as a tan solid; MS 231.0 (M+H).

NH

HV ~
N
Br ~

[00217] Preparation of 5-bromo-4-(1 H-indol-5-ylamino)-6-methylnicotinonitrile:

A mixture of 5-bromo-4-chloro-6-methylnicotinonitrile (1.0 g, 4.31 mmol) and 5-aminoindole (830 mg, 6.29 mmol) in 10 mL of ethanol was heated at reflux for 2 h. The resulting mixture was cooled slightly and filtered, washing with ethanol and diethyl ether. The solid was stirred with saturated aqueous sodium bicarbonate for 30 min then the aqueous mixture was extracted with ethyl acetate. The layers were separated and the organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was triturated with diethyl ether to give 852 mg (60%) of 5-bromo-4-(1 H-indol-5-ylamino)-6-methylnicotinonitrile as a light tan solid; MS 327.2 (M+H); HPLC: 99.9% at 215 nm, 8.6 min [a].

N
B~I I ~~

[00218] Preparation of 5-bromo-6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]
nicotinonitrile:

Mixture of 5-bromo-4-chloro-6-methylnicotinonitrile (2.00 g, 8.63 mmol) and 5-amino-4-methylindole (1.82 mg, 12.47 mmol) in 20 mL of ethanol was heated at reflux overnight. The resulting mixture was cooled slightly and filtered washing with ethanol. The solid was stirred with saturated aqueous sodium bicarbonate then the aqueous mixture was extracted with ethyl acetate. The layers were separated and the organic layer was washed with saturated aqueous sodium bicarbonate dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was triturated with diethyl ether to give 1.21 g (41%) of 5-bromo-6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile as an off-white solid; MS 341.2 (M+H);
HPLC: 99.2% at 215 nm, 9.5 min [a].

H

[00219] Preparation of 5-bromo-4-(1 H-indol-6-ylamino)-6-methylnicotinonitrile:

A mixture of 5-bromo-4-chloro-6-methylnicotinonitrile (500 mg, 2.15 mmol) and 6-aminoindole (415 mg, 3.14 mmol) in 5 mL of ethanol was heated at reflux for 2 h. The resulting mixture was cooled slightly and filtered washing with ethanol. The residue was poured into saturated aqueous sodium bicarbonate and the aqueous mixture was extracted with ethyl acetate. The layers were separated and the organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was triturated with diethyl ether to give 253 g (36%) of 5-bromo-4-(1 H-indol-6-ylamino)-6-methylnicotinonitrile as an off-white solid;
MS 327.1 (M+H);
HPLC: 99.7% at 215 nm, rt = 9.1 min [a].

o~
N /--\
O
\ ~Nl [00220] Preparation of tert-butyl 4-[(6-bromopyridin-3-yl)methyl]piperazine-1-carboxylate:

To a 0 C solution of 6-bromopyridine-3-carbaldehyde (2.06 g, 11.08 mmol) and tert-butyl piperazine-l-carboxylate (2.94g, 15.81 mmol) in 40 mL of dichloromethane and 2 mL of 1-methyl-2-pyrrolidin one was added sodium triacetoxyborohydride (3.12 g, 14.72 mmol). After min, 400 L of acetic acid was added and the reaction mixture was allowed to stir at room temperature overnight. Additional amounts of both tert-butyl piperazine-1-carboxylate (1.0 g) and sodium triacetoxyborohydride (0.98 g) were added and the reaction mixture was stirred at room temperature for 3 h then partitioned between dichioromethane and saturated aqueous sodium bicarbonate. The layers were separated and the organic layer was washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated in vacuo. Trituration of the residue with hexane gave 1.80 g (46%) of tert-butyl 4-[(6-bromopyndln-3-yl)methyl]piperazine-1-carboxylate as off-white crystals; MS
356.2 (M+H).
oYn- J
o [00221] Preparation of tert-butyl 4-[(6-vinylpyridin-3-yl)methyl]piperazine-1-carboxylate:

A mixture of tert-butyl 4-[(6-bromopyridin-3-yl)methyl]piperazine-1-carboxylate (1.52 g, 4.25 mmol), tributyl(vinyl)tin (1.84 mL, 6.30 mmol), Cul (50 mg) and (Ph3P)2PdCl2 (150 mg) in 20 mL of toluene was heated at reflux overnight. After cooling to room temperature the reaction mixture was partitioned between saturated aqueous potassium carbonate and dichloromethane. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography eluting with a gradient of 3:1 hexane:ethyl acetate to 100% ethyl acetate to give 1.04 g (81 %) of tert-butyl 4-[(6-vinylpyridin-3-yl)methyl]piperazine-1-carboxylate as a light yellow oil;
MS 304.3 (M+H).

( ! NN
OYN---I-I
O

[00222] Preparation of tert-butyl 4-({6-[(E)-2(S-cyano-4-[(4-methyl-I H-indol-5-yl) amino]pyridin-3-yl}vinyl]pyridin-3-yl}methyl)piperazine-1-carboxylate:

A mixture of 5-iodo-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile (240 mg, 0.64 mmol), tert-butyl 4-[(6-vinylpyridin-3-yl)methyl]piperazine-1-carboxylate (318 mg, 1.05 mmol), palladium(II)acetate (25 mg), tri(ortho-tolyl)phosphine (12 mg) and 600 L of triethylamine in 6 mL of DMF was heated at 90-105 C for 3 h. After cooling to room temperature the reaction mixture was partitioned between saturated aqueous sodium bicarbonate and dichloromethane.
The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography eluting with a gradient of 1:1 hexane:ethyl acetate to all ethyl acetate to 20% methanol in ethyl acetate to give 149 mg (42%) of tert butyl 4-({6-[(E)-2-{5-cyano-4-[(4-methyl-1 H-indol-5-yl)amino]pyridin-3-yl)vinyl]pyridin-3-yl}methyl)piperazine-l-carboxylate as a yellow solid; MS
550.5 (M+H) HPLC
97.2% at 215 nm, rt = 7.1 min [a].

NH
HN 7~N

[00223] Preparation of 4-[(4-methyl-1 H-indol-5-yl)amino]-5{(E)-2-[5-(piperazin-1-yl methyl)pyridin-2-yl]vinyl}nicotinonitrile:
To a solution of tert-butyl 4-({6-[(E)-2-{5-cyano-4-[(4-methyl-1 H-indol-5-yl)amino]pyridin-3-yl}vinyl]pyridin-3-yl}methyl)piperazine-1-carboxylate (143 mg, 0.26 mmol) in 4 mL of dichloromethane was added 400 L of TFA. Black solids formed and the mixture was stirred. at room temperature for 3.5 h. The solvent was decanted off and the residue was stirred with saturated aqueous sodium bicarbonate. The solids were collected by filtration, washing with water, ethyl acetate and diethyl ether, then heated with dichloromethane and the resulting precipitate was filtered. The filtrate was concentrated and purified . by flash column chromatography eluting with a gradient of 10% methanol in dichloromethane to 2% ammonium hydroxide in 30% methanol in dichloromethane to give 12 mg (9%) of 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[5-(piperazin-1-ylmethyl)pyridin-2-yl]vinyl}nicotinonitrile as a tan solid; MS
450.3 (M+H);'H NMR (400 MHz, DMSO-d6) 8 2.33 (s, 3H), 2.56 (m, 4H), 3.09 (m, 4H), 3.60 (s, 2H), 6.51 (s, 1 H), 6.92 (d, J = 8 Hz, 1 H), 7.23-7.36 (m, 3H), 7.68-7.74 (m, 2H), 7.83 (d, J =
16 Hz, 1 H), 8.30 (s, 1 H), 8.45-8.55 (m, 2H), 8.61 (s, 1 H), 8.93 (s, 1 H), 11.14 (s, 1 H).

/ I a N

[00224] Preparation of 4-chloro-5-[(E)-2-phenylvinyl]nicotinonitrile:

A mixture of 4-chloro-5-iodonicotinonitrile (2.00 g, 7.56 mmol), trans 2-phenylvinylboronic acid (1.27 g, 8.57 mmol) and (Ph3P)4Pd (90 mg) in 30 mL of 1,2-dimethoxyethane and 15 mL of saturated aqueous sodium bicarbonate was heated at 90-100 C for 1 h. After cooling to room temperature the reaction mixture was partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue triturated with ethyl acetate to give 225 mg (12%) of 4-chloro-5-[(E)-2-phenylvinyl]nicotinonitrile as a white solid; MS 241.1 (M+H);
HPLC 97.0% at 215 nm, 16.5 min [a]. Concentration of the filtrate and trituration with ethyl acetate provided an additional 996 mg (55%) of 4-chloro-5-[(E)-2-phenylvinyl]nicotinonitrile. HN) H

[00225] Preparation of 4-(1 H-indol-6-ylamino)-5-[(E)-2-phenylvinyl]nicotinonitrile:

A mixture of 4-chloro-5-[(E)-2-phenylvinyl]nicotinonitrile (134 mg, 0.56 mmol) and 6-aminoindole (100 mg, 0.76 mmol) in 3 mL of ethanol was heated at reflux overnight. The resulting mixture was cooled to room temperature and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The layers were separated and the organic layer was dried over magnesium sulfate; filtered and concentrated in vacuo. The residue was triturated with ethyl acetate and the solid was collected by filtration washing with diethyl ether to give 110 mg (59%) of 4-(1 H-indol-6-ylamino)-5-[(E)-2-phenylvinyl]nicotinonitrile as a pale yellow solid; MS 337.2 (M+H); HPLC: 97.3% at 215 nm, rt = 10.0 min [a].

\ I / HIT' [00226] Preparation of 4-(1 H-indol-5-ylamino)-6-methyl-5-[(E)-2-phenylvinyl]
nicotinonitrile:

A mixture of 5-bromo-4-(1 H-indol-5-ylamino)-6-methylnicotinonitrile (130 mg, 0.40 mmol), trans 2-phenylvinylboronic acid (110 mg, 0.74 mmol) and (Ph3P)4Pd (50 mg) in 10 mL of 1,2-dimethoxyethane and 5 mL of saturated aqueous sodium bicarbonate was heated at 100 C for 2 h. After cooling to room temperature the reaction mixture was partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography eluting with a gradient of 4:1 hexane:ethyl acetate to 1:1 hexane:ethyl acetate to give 49 mg (35%) of 4-(1 H-indol-5-ylamino)-6-methyl-5-[(E)-2-phenylvi nyl]nicoti non itri le as a light yellow solid; MS 351.3 (M+H); HPLC:
94.7% at 215 nm, it = 9.5 min [a].

H
H -~ I

[00227] Preparation of 4-(1 H-indol-5-ylamino)-5-iodonicotinonitrile:

The title compound was prepared from 5-aminoindole and 4-chloro-5-iodonicotinonitrile by the procedure described for 5-iodo-4-[(4-methyl-1 H-i ndol-5-yl)amino] nicoti non itrile: MS 377 (M+H);
HPLC: rt = 9.3 min [a].

NH
H /
N

[00228] Preparation of 4-(1 H-indol-5-ylamino)-5-[(E)-2-phenylvinyl]nicotinonitrile:

The title compound was prepared from 4-(1 H-indol-5-ylamino)-5-iodonicotinonitrile and trans 2-phenylvinylboronic acid via the procedure used to prepare 4-(1H-indol-5-ylamino)-6-methyl-5-[(E)-2-phenylvinyl]nicotinonitrile; MS 337.3 (M+H); HPLC: 99.8% at 215 nm, rt = 9.3 min [a].
[00229] Preparation of 4-(1 H-indol-6-ylamino)-6-methyl-5-[(E)-2-phenylvinyl]
nicotinonitrile:

A mixture of 5-bromo-4-(1H-indol-6-ylamino)-6-methylnicotinonitrile (190 mg, 0.58 mmol), trans 2-phenylvinylboronic acid (130 mg, 0.88 mmol) and (Ph3P)4Pd (50 mg) in 10 mL of 1,2-dimethoxyethane and 5 mL of saturated aqueous sodium bicarbonate was heated at 100 C for 2 h. After cooling to room temperature the reaction mixture was partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography eluting with a gradient of 4:1 hexane:ethyl acetate to 1:1 hexane:ethyl acetate to give 146 mg (72%) of 4-(1 H-indol-6-ylamino}6-methyl-5-[(E)-2-phenylvinyl]nicoti non itrile as a pale yellow solid; MS 351.3 (M+H); HPLC:

95.2% at 215 nm, rt = 9.7 min [a].

I\
[00230] Preparation of 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-phenylvinyl]
nicotinonitrile:

The title compound was prepared from 5-bromo-6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile and trans 2-phenylvinylboronic acid via the procedure used to prepare 4-(1 H-indol-6-ylamino)-6-methyl-5-[(E)-2-phenylvinyl]nicotinonitrile; MS
365.3 (M+H); HPLC:
94.8% at 215 nm, rt = 9.6 min [a].

\o Imo, \ I / ~,N

[00231] Preparation of 5-[(E)-2-(3-methoxyphenyl)vinyl]-6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile:

The title compound was prepared from 5-bromo-6-methyl-4-[(4-methyl-1 H-indol-5-yl) amino]nicotinonitrile and trans 2-(3-methoxyphenyl) vinylboronic acid via the procedure used to prepare 4-(1 H-indol-6-ylamino)-6-methyl-5-[(E)-2-phenylvinyl]nicotinonitrile; MS 395.2 (M+H); HPLC: 98.1% at 215 nm, rt = 9.8 min [a].

NH

N

[00232] Preparation of 5-[(E)-2-(4-methoxyphenyl)vinyl]-6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile:

The title compound was prepared from 5-bromo-6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile and trans 2-(4-methoxyphenyl) vinylboronic acid via the procedure used to prepare 4-(1 H-indol-6-ylamino)-6-methyl-5-[(E)-2-phenylvinyl]nicotinonitrile; MS 395.2 (M+H); HPLC: 98.0% at 215 nm, rt = 9.5 min [a].

h 0 [00233] Preparation of 2,5-dimethyl-4-nitroacetanilide:

2,5-Dimethylaniline in dichioromethane was treated with acetyl chloride. ' The reaction mixture was evaporated to a solid residue. The residue was dissolved in a mixture of acetic acid and sulfuric acid. To the cooled mixture (-10 C) was added a mixture of nitric acid and sulfuric acid. The resulting acidic solution was poured on to ice. The precipitate was filtered and washed with water. The solid was recrystallized twice from ethanol. The crystalline 2,5-dimethyl-4-nitroacetanilide was dried under high vacuum.

H
O /

[00234] Preparation of N -acetyl-5-a min o-4,7 -dimethylindole:

A solution of 2,5-dimethyl-4-nitroacetanilide in THE was added to vinyl magnesium bromide in THE at -30 C and the resulting mixture was allowed to warm to room temperature. The reaction mixture was poured into a saturated solution of ammonium chloride.
The aqueous phase was extracted with ethyl acetate. An analytical sample of N-acetyl-5-amino-4,7-dimethylindole was prepared by silica gel chromatography (chloroform).

[00235] Preparation of 5-amino-4,7-dimethylindole:

A solution of N-acetyl-5-amino-4,7-dimethylindole in THE was mixed with 1N
HCI. The resulting solution was heated at reflux for 72 h. The reaction mixture was allowed to cool to room temperature and then basified with ammonia solution. The aqueous phase was extracted with dichioromethane. The combined extracts were dried (magnesium sulfate) and concentrated. The concentrated residue was purified by silica gel chromatography (hexanes-ethyl acetate, 4:1) to afford 5-amino-4,7-dimethylindole.

NH
HV \
N

[00236] Preparation of 4-[(4,7-dimethyl-lH-indol-5-yl)amino]-5-iodonicotinonitrile:

A mixture of 4-chloro-5-iodonicotinonitrile (630 mg, 2.39 mmol) and 5-amino-4,7-dimethylindole (350 mg, 2.18 mmol) in 10 mL of ethanol was heated in a sealed tube at 95 C
for 16 h. The resulting mixture was cooled to room temperature. The precipitate was filtered and dried in vacuo (450 mg, 53 %). An analytical sample was obtained by prep HPLC
purification (column: Phenomenex Gemini 5 m C18 100 x 30 mm; eluent: aq acetonitrile containing 0.02 % trifluoroacetic acid) followed by basification with ammonia solution to give 4.5 mg of 4-[(4,7-dimethyl-1 H-indol-5-yl)amino]-5-iodonicotinonitrile as a grey solid; MS 389.1 (M+H).

fNH

\ I / / N

[00237] Preparation of 4-[(4,7-dlmethyl-1 H-indol-5-yl)amino]-5-[(E)-2-phenylvinyl]
nicotinonitrile:

A mixture of 4-[(4,7-dimethyl-1 H-indol-5-yl)amino]-5-iodonicotinonitrile (96 mg, 0.24 mmol), (E)-2-phenylvinylboronic acid (90 mg, 0.61mmol), tetrakis(triphenylphosphine)palladium (10.7 mg), and saturated sodium bicarbonate (5 mL) in DME (5 mL) was heated at reflux 14 h. The reaction mixture was allowed to cool to room temperature. The reaction mixture was extracted (ethyl acetate, 3 x 20 ml-) and the organic extracts were combined, dried (magnesium sulfate), and concentrated. The residue, weighing 60 mg, was purified by prep HPLC
(column:
Phenomenex Gemini 5 C18 100 x 30 mm; eluent: aq acetonitrile containing 0.02 %
trifluoroacetic acid) followed by basification with ammonia solution giving 10.0 mg (11%) of 4-[(4,7-dimethyl-lH-indol-5-yl)amino]-5-[(E)-2-phenylvinyl]nicotinonitrile as a yellow solid; MS
365.2 (M+H), HPLC: rt = 10.2 min [a].

H
HN J
N
i [00238] Preparation of 5-iodo-4-(2-methyl-1H-indol-5-ylamino)-6-methylnicotinonitrile:
A mixture of 4-chloro-5-iodo-6-methylnicotinonitrile (1.0 g, 3.6 mmol) and 5-amino-2-methylindole (735 mg, 5.0 mmol) in 8 mL of ethanol was heated at reflux 3 h.
The resulting mixture was cooled to room temperature, diluted with saturated aqueous sodium bicarbonate, filtered and washed with ethanol, water to give 781 mg (56%) of 5-iodo-4-(2-methyl-1 H-indol-5-ylamino)-6-methylnicotinonitrile as a light yellow solid; MS 389.1 (M+H);
HPLC: rt = 9.5 min [a].

N

[00239]. Preparation of 6-methyl-4-[(2-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-phenylvinyl]
nicotinonitrile:

A mixture of 5-iodo-4-(2-methyl-1 H-indol-5-ylamino)-6-methylnicotinonitrile (194 mg, 0.5 mmol), trans-2-phenylvinylboronic acid (110 mg, 0.75 mmol) and (Ph3P)4Pd (57mg) in 5 mL of 1,2-dimethoxyethane and 1 mL of 2 M aqueous sodium bicarbonate was heated at reflux for 5 h. After cooling to room temperature the reaction mixture was partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography eluting with a gradient of 4:1 hexane:ethyl acetate to 3:1 hexane:ethyl acetate to give 170 mg (93%) of 6-methyl-4-[(2-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-phenyl vinyl]nicotinonitrile as a light yellow solid; MS 365.4 (M+H); HPLC: rt = 9.9 min [a].

[00240] Preparation of 4-(1 H-indol-4-ylamino)-5-[(E)-2-phenylvinyl]nicotinonitrile:

A mixture of 4-chloro-5-[(E)-2-phenylvinyl]nicotinonitrile (135 mg, 0.56 mmol) and 4-aminoindole (105 mg, 0.79 mmol) in 4 mL of ethanol was heated at reflux overnight. The resulting mixture was cooled slightly and filtered, washing with diethyl ether. The solid was stirred with saturated aqueous sodium bicarbonate for 20 min, then the suspension was extracted with ethyl acetate. The layers were separated and the organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was triturated with diethyl ether and the solid was collected by filtration washing with diethyl ether to give 45 mg (23%) of 4-(1 H-indol-4-ylamino)-5-[(E)-2-phenylvinyl]nicotinonitrile as a yellow solid; MS 337.2 (M+H);
HPLC: 98.8% at 215 nm, rt = 9.7 min [a].

N

[00241] Preparation of 5-bromo-4-(1H-indol-4-ylamino)-6-methylnicotinonitrile:

A mixture of 5-bromo-4-chloro-6-methylnicotinonitrile (530 mg, 2.29 mmol) and 4-aminoindole (440 mg, 3.33 mmol) in 5 mL of ethanol was heated at reflux for 6.5 h. The resulting mixture was cooled slightly and filtered washing with diethyl ether. The solid was partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The layers were separated and the organic layer was washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was triturated with diethyl ether to give 448 mg- (60%) of 5-bromo-4-(1 H-indol-4-ylamino)-6-methylnicotinonitrile as a light tan solid;
MS 327.1 (M+H); HPLC: 98.3% at 215 nm, rt = 9.3 min [a].

I\h`

[00242] Preparation of 4-(1 H-indol-4ylamino)-6-methyl-5-[(E)-2-phenylvinyl]
nicotinonitrile:

A mixture of 5-bromo-4-(1H-indol-4-ylamino)-6-methylnicotinonitrile (190 mg, 0.58 mmol), trans 2-phenylvinylboronic acid (130 mg, 0.88 mmol) and (Ph3P)4Pd (50 mg) in 10 mL of 1,2-dimethoxyethane and 5 mL of saturated aqueous sodium bicarbonate was heated at 100 C for 1.25 h. After cooling to room temperature the reaction mixture was partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography eluting with a gradient of 4:1 hexane:ethyl acetate to 1:1 hexane:ethyl acetate to give 155 mg (76%) of 4-(1 H-indol-4-ylamino)-6-methyl-5-[(E)-2-phenylvinyl]nicotinonitrile as a yellow solid; MS
351.2 (M+H); HPLC: 99.2% at 215 nm, rt = 9.4 min [a].

a N

[00243] Preparation of 4-chloro-5-vinylnicotinonitrile:

A mixture of 4-chloro-5-iodonicotinonitrile (1.42 g, 5.37 mmol), tributyl(vinyl)tin (1.8 mL, 6.17 mmol), Cul (25 mg) and (Ph3P)2PdCl2 (70 mg) in 10 mL of toluene and 2 mL of DMF was heated at 80 C for 2.5 h. After cooling to room temperature the reaction mixture was partitioned between saturated aqueous sodium bicarbonate and ethyl acetate.
The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo.
The residue was triturated with diethyl ether and hexane to give 390 mg (44%) of 4-chloro-5-vinylnicotinonitrile as a pale yellow solid. The filtrate was concentrated and purified by flash column chromatography eluting with a gradient of 6:1 hexane:ethyl acetate to 2:1 hexane:ethyl acetate to give 233 mg (26%) of 4-chloro-5-vinylnicotinonitrile as a pale yellow solid; MS 165.0 (M+H);
HPLC: 98.5% at 215 nm, rt = 11.4 min [a].

NH

[00244] Preparation of 4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-(4-methyl phenyl) vinyl]nicotinonitrile:

To a reaction mixture of 5-iodo-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile (75 mg, 0.2 mmol), trans-2-(4-methylphenyl) vinylboronic acid (65 mg, 0.4 mmol) and Pd(PPh3)4 (23 mg, 0.02 mmol) in 1.0 mL of 1,2-dimethoxyethane was added 0.5 mL of saturated aq NaHCO3 solution. The reaction mixture was heated at reflux for 3 h then diluted with ethyl acetate. The organic layer was washed with H2O, brine and dried over Na2SO4. After filtration and concentration, the residue was purified by silica gel chromatography eluting with hexane-ethyl acetate (1:1 to 100% ethyl acetate), providing 70 mg (96%) of 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(4-methylphenyl)vinyl]nicotinonitrile as a yellow solid; MS
365.4 (M+H);
HPLC: 92% at 215 nm, rt = 10.4 min [a].

NH

[00245] Preparation of 5-[(E)-2-(4-methoxyphenyl)vinyl]-4-[(4-methyl-1H-indol-5- yl) amino] n icoti nonitri le:

The title compound was prepared from 5-iodo-4-[(4-methyl-1 H-indol-5-yl)amin o]nicoti non itri le and trans-2-(4-methoxy phenyl)vinylboronic acid via the procedure used to prepare 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(4-methylphenyl)vinyl]-nicotinonitrile;
MS 381.4 (M+H);
HPLC: rt = 9.6 min [a].

NH
/ t-tv N

[00246] Preparation of 5-[(E)-2-biphenyl-4-ylvinyl]-4-[(4-methyl-1 H-indol-5-yl)amino]-nicotinonitrile:

The title compound was prepared from 5-iodo-4-[(4-methyl-1 H-indol-5-yl)amin o]nicoti non itri le and trans-2-(4-biphenyl)vinylboronic acid via the procedure used to prepare 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)=2-(4-methylphenyl)vinyl]-nicotinonitrile; MS 427.4 (M+H); HPLC: 99%
at 215 nm, rt = 9.6 min [a].

NH
F

F

[00247] Preparation of 4-[(4-methyl-1H-indol-5-yi)amino]-5-{(E)-2-[4-(trifluoromethyl)-phenyl]vinyl}nicotinonitrile:

The title compound was prepared from 5-iodo-4-[(4-methyl-1 H-indol-5-yl)amin o]nicoti non itrile and trans-2-(4-trifluoromethylphenyl)vinylboronic acid via the procedure used to prepare 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(4-methylphenyl)vinyl]nicotinonitrile;
MS 419.2 (M+H);
HPLC: 98% at 215 nm, rt = 11.5 min [a].

NH
Cl iN

[00248] Preparation of 5-[(E)-2-(4-chlorophenyl)vinyl]-4-[(4-methyl-1H-indol-5-yl)amino]-nicotinonitrile:

The title compound was prepared from 5-iodo-4-[(4-methyl-1 H-indol-5-yl)a min o]nicoti non itrile and trans-2-(4-chlorophenyl)vinylboronic acid via the procedure used to prepare 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(4-methyl phenyl)vinyl]-nicotinonitrile; MS
385.2 (M+H); HPLC: rt = 10.8 min [a].

J w IN

[00249] Preparation of 4-[(4-methyl-1H-indol-5-yl)amino]-5-[(Z)-2-phenylvinyl]-nicotinonitrile:

The title compound was prepared from 5-iodo-4-[(4-methyl-1 H-indol-5-yl)amino]nicoti non itrile and cis-2-phenylvinylboronic acid via the procedure used to prepare 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(4-methylphenyl)vinyl]nicotinonitrile; MS 351.3 (M+H);
HPLC: 94% at 215 nm, rt = 8.9 min [a].

NB

[00250] Preparation of 5-[(E)-2-(3-methoxyphenyl)vinyl]-4-[(4-methyl-1H-indol-5-yl) amino]nicotinonitrile:

The title compound was prepared from 5-iodo-4-[(4-methyl-1 H-indol-5-yl)a min o]nicotinon itri le and Frans-2-(3-methoxyphenyl)vinylboronic acid via the procedure used to prepare 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(4-methyl. phenyl)vinyl]-nicotinonitrile; MS 381.2 (M+H);
HPLC 94% at 215 nm, rt = 10.6 min [a].

F
I Fib [00251] Preparation of 5-[(E)-2-(4-fluorophenyl)vinyl]-4-[(4-methyl-1H-indol-5-yl)amino]-nicotinonitrile:

The title compound was prepared from 5-lodo-4-[(4-methyl-1 H-indol-5-yl)a mi no]nicoti non itrile and trans-2-(4-fluorophenyl)vinylboronic acid via the procedure used to prepare 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(4-methylphenyl)vinyl]-nicotinonitrile; MS
369.3 (M+H); HPLC: rt = 10.1 min [a].

[00252] Preparation of 5-bromo-4-chloro-6-ethylnicotinonitrile:

To a -78 C solution of 5-bromo-4-chloro-6-methylnicotinonitrile (392 mg, 1.7 mmol) in anhydrous tetrahydrofuran (8.0 ml-) was slowly added lithium bis(trimethylsilyl)amide (3.8 mL, 3.8 mmol). The resulting slurry was stirred at -78 C for 1 h under N2.
lodomethane (483 mg, 3.4 mmol) was added and the reaction mixture was stirred at -78 C then gradually warmed to room temperature overnight. The reaction was quenched with 1.0 M citric acid solution and H2O, then extracted with ethyl acetate three times. The combined organic layers were washed with H2O and brine then dried over Na2SO4. After filtration and concentration, the residue was purified by silica gel column chromatography, eluting with dichloromethane, providing 74 mg (18%) of 5-bromo-4-chloro-6-ethylnicotinonitrile as a yellow solid containing a small amount of 5-bromo-4-chloro-6-isopropylnicotinonitrile (<10%); MS 245 (M+H).

J nit Br ( \

NH
I

[00253] Preparation of 5-bromo-6-ethyl-4-(4-methyl-1 H-indol-5-ylamino)nicotinonitrile, 6-ethyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-phenylvinyl]-nicotinonitrile, and of 6-isopropyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-phenylvinyl]-nicotinonitrile:

5-Bromo-4-chloro -6-ethylnicotinonitrile (71 mg, 0.29 mmol) contaminated with a small amount of the corresponding isopropyl derivative was combined with 5-amino-4-methyl indole (42 mg, 0.29 mmol) in anhydrous ethanol (1.0 ml-) and heated at reflux for 48 h. After cooling to room temperature, the reaction mixture was added to 10 mL of H2O and filtered. The solid residue was washed with H2O and diethyl ether then dried in vacuo to provide a quantitative amount of crude 5-brom6-6-ethyl-4-(4-methyl-1H-indol-5-ylamino)nicotinonitrile as a dark solid which was used directly without further purification; MS 355 (M+H). The product was contaminated with small amounts of the corresponding isopropyl derivative.

(00254] The mixture thus obtained was treated with trans-2-phenylvinylboronic acid via the procedure used to prepare 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(4-methylphenyl)vinyl]-nicotinonitrile. Two products were isolated, 6-ethyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-phenylvinyl]-nicotinonitri le and 6-isopropyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-phenyl vinyl]-nicotinonitrile.

[00255] 6-ethyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-phenylvinyl]-nicotinonitrile:
MS 379.3 (M+H); HPLC: rt = 10.4 min [a].

[00256] 6-isopropyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-phenylvinyl]-nicotinonitrile:

MS 393.3 (M+H); HPLC: rt = 11.1 min [a].

[00257] Preparation of 5-[(E)-2-(4-bromophenyl)vinyl]-4-[(4-methyl-1 H-indol-5-yl) amino]-nicotinonitrile:

To a reaction mixture of 5-iodo-4[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile (75 mg, 0.2 mmol), 4-bromostyrene (48 mg, 0.26 mmol), Pd(AcO)2 (14 mg, 0.06 mmol) and tri(ortho-tolyl)phosphine (3 mg, 0.01 mmol) in 1.0 mL of DMF was added triethylamine (42 L, 0.3 mmol). The reaction mixture was heated to 100 C for 2.5 h, then concentrated.
The residue was purified by silica gel chromatography eluting with CH2CIrTHF (9:1), providing 52 mg (61 %) of 5-[(E)-2-(4-bromophenyl)vinyl]-4-[(4-methyl-1 H-indol-5-yl)amino]-nicotinonitrile as a yellow solid; MS 429.2 (M+H); HPLC: rt = 11.7 min [a].

ra [00258] Preparation of 5-[(E)-2-(2-methoxyphenyl)vinyl]-4-[(4-methyl-1H-indol-5-yl) amino]nicotinonitrile:

The title compound was prepared from 5-iodo-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile and 2-methoxystyrene via the procedure used to prepare 5-[(E)-2-(4-bromophenyl)vinyl]-4-[(4-methyl-1 H-indol-5-yl)amino]-nicotinonitrile; MS 381.2 (M+H); HPLC: rt = 10.6 min [a].

[00259] Preparation of 5-[(E)-2-(3,4-dimethoxyphenyl)vinyl]-4-[(4-methyl-1 H-indol-5- yl) amino]nicotinonitrile:

The title compound was prepared from 5-iodo-4-[(4-methyl-1 H-indol-5-yl)amino]nicoti non itrile and 3,4-dimethoxystyrene via the procedure used to prepare 5-[(E)-2-(4-bromophenyl)vinyl]-4-[(4-methyl-1 H-indol-5-yl)amino]-nicotinonitrile; MS 411.3 (M+H); HPLC: rt =
9.7 min[a].

H. /
~N
/ -[00260] Preparation of 4-[(2,4-dimethyl-1H-indol-5-yl)amino]-5-Iodonicotinonitrile:

To a reaction mixture of 5-amino-2,4-dimethylindole (800 mg, 5.0 mmol) and 4-chloro-5-iodonicotinonitrile (1.056 g, 4.0 mmol) in 15 mL of anhydrous ethanol was added triethylamine (0.78 mL, 5.6 mmol). The reaction mixture was heated at reflux for 40 h and subsequently concentrated to remove half of the solvent. To the residue was added saturated NaHCO3 solution and H2O. The suspension was filtered and the solid was washed with H2O several times and dried in vacuo to give 1.45 g of crude 4-[(2,4-dimethyl-1 H-indol-5-yl)amino]-5-iodonicotinonitrile. The product was further purified by preparative HPLC, providing 1.28 g (66%) of 4-[(2,4-dimethyl-1 H-indol-5-yl)amino]-5-iodonicotinonitrile as a dark solid; MS 389.1 (M+H).

NH

[00261] Preparation of 4-[(2,4-dimethyl-1H-indol-5-yl)amino]-5-[(E)-2-{5-[(4-methyl-piperazin-1-yl)methyl]pyridin-2-yl}vinyl]nicotinonitrile:

The title compound was prepared from 4-[(2,4-dimethyl-1 H-indol-5-yl)amino]-5-iodonicotinonitrile and 1-methyl-4-[(6-vinylpyridin-3-yl)methyl]piperazine via the procedure used to prepare 5-[(E)-2-(4-bromophenyl)vinyl]-4-[(4-methyl-1 H-indol-5-yl)amino]-nicotinonitrile; MS 478.5 (M+H); HPLC: rt = 5.5 min [a].

[00262] Preparation of 5-[(E)-2-(4-formylphenyl)vinyl]-4-[(4-methyl-1 H-indol-5-yl)amino]
nicotinonitrile:

5-[(E)-2-(4-formylphenyl)vinyl]-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile was prepared from 5-iodo-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile and 4-vinylbenzaldehyde via the procedure used to prepare 5-[(E)-2-(4-bromophenyl)vinyl]-4-[(4-methyl-1 H-indol-5-yl)amino]-nicotinonitrile; MS 379.0 (M+H).

5-[(E)-2-(4-formylphenyl)vinyl]-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile was also prepared by an alternative method as follows. To a reaction mixture of 4-[(E)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethenyl] benzaldehyde (1.0 g, 3.9 mmol), 5-iodo-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile (1.73 g, 4.8 mmol) and Pd(PPh3)4 (266 mg, 0.23 mmol) in 1,2-dimethoxyethane (50 ml-) at room temperature was added saturated NaHCO3 solution (26 mL). The reaction mixture was heated to 100 C for 3.5 h, then stirred at room temperature overnight, quenched with H2O, extracted with a mixture of THF-EtOAc (1:2) three times. The extracts were combined and washed with H2O and brine. Drying, filtration and evaporation gave a brown solid, which was purified by silica gel chromatography (hexane-EtOAc, 10:1 to 2:1), providing 2.6 g (72%) the title compound as a yellow solid. 'HNMR(300 MHz, DMSO) 2.34 (s, 3H), 6.53 (s, 1H), 6.95 (d, 1H, J = 8.0 Hz), 7.26 (d, 111, J = 8.0 Hz), 7.36(m, 2H), 7.61 (m, 2H), 7.84 (m, 1 H), 7.96 (d, 1 H, J = 8.0 Hz), 8.16 (s, 1 H), 8.29 (s, 1 H), 8.62 (s, 1 H), 8.93 (s, 1 H), 9.98 (s, 1 H), 11.16 (s, 1 H); MS 379.2 (M+H). .

:):5-N
[00263] Preparation of 4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-{4-[(4-methylpiperazin-1- yl)methyl]phenyl}vinyl]nicotinonitrile:

To a reaction mixture of 5-[(E)-2-(4-formylphenyl)vinyl]-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile (75 mg, 0.2 mmol) and 1-methylpiperazine (100 mg, 1.0 mmol) in 3 mL
of CH2CI2 was added 0.5 mL of 1-methyl-2-pyrrolidinone plus two drops of glacial HOAc. The resulting mixture was stirred at room temperature for 40 min. To this was added NaBH(OAc)3 (212 mg, 1.0 mmol) in portions over a period of 20 min. The reaction mixture was stirred at room temperature for 16 h and then concentrated. The residue was purified by preparative HPLC, providing 10 mg (11%) of 4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}vinyl]nicotinonitrile as a yellow solid; MS
369.3 (M+H);
HPLC 98% at 215 nm, rt = 12.4 min[b].

r---j 11"~', ICI

[00264] ' Preparation of tert-butyl 4{4-[(E)-2(5-cyano-4-[(4-methyl-1 H-indol-5-yl)amino]
pyridin-3-yl}vinyl]benzyl}piperazine-1-carboxylate:
The title compound was prepared from 5-[(E)-2-(4-formylphenyl)vinyl]-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile and 1-Boc-piperazine via the procedure used to prepare 4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}vinyl]nicotinonitrile; MS
549.5 (M+H); HPLC: it = 7.8 min [a].

NH
H / HIv ( [00265] Preparation of 4-[(E)-2-(5-cyano-44(4-methyl-1H-indol-5-yl)amino]pyridin-3-yl}
. vinyl]benzoic acid:

The title compound was prepared from 5-iodo-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile and 4-vinylbenzoic acid via the procedure used to prepare 5-[(E)-2-(4-bromophenyl)vinyl]-4-[(4-methyl-1 H-indol-5-yl)amino]-nicotinonitrile; MS 395.3 (M+H); HPLC: 97% at 215 nm, rt =
8.0 min [a].

o I

[00266] Preparation of 4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-(4-[(4-methylpiperazin-1-yl)carbonyl]phenyl)vinyl]nicotinonitrile:
To a reaction . mixture of 4-[(E)-2-{5-cyano-4-[(4-methyl-1 H-indol-5-yl)amino]pyridin-3-yl}vinyl]benzoic acid (70 mg, 0.18 mmol) and PyBOP (120 mg, 0.23 mmol) in 4 mL
of CH2CI2 was added diisopropylethylamine (63 pL, 0.36 mmol) followed by 1-methylpiperazine (23 mg, 0.023 mmol). The resulting mixture was stirred at room temperature for 16 h and subsequently concentrated. The residue was purified by preparative HPLC providing 65 mg (77%) of 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}vinyl]
nicotinonitrile as a dark yellow solid; MS 477.4 (M+H); HPLC: 92% at 215 nm, rt = 5.4 min [a].
N

[00267] Preparation of 4-(1H-indoi-4-ylamino)-5-iodonicotinonitrile:

4-(1 H-indol-4-ylamino)-5-iodonicotinonitrile was prepared by the procedure described for. 5-iodo-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile; MS: 361 [M+H].

r [00268] Preparation of 4-(1 H-indol-4-ylamino)-5-iodo-6-methylnicotinonitrile:

4-(1 H-indol-4-ylamino)-5-iodo-6-methylnicotinonitrile was prepared by the procedure described for 5-iodo-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile; MS: 375 [M+H].

[00269] Preparation of 1-methyl-4-[(2-vinylpyridin-4-yl)methyl]piperazine:

A mixture of 1-[(2-bromo-4-pyridinyl)methyl]-4-methylpiperazine (1.0 g, 3.7 mmol), tributyl(vinyl)tin (1.78, 5.6 mmol), and Pd(PPh3)4 (218.3 mg, 0.19 mmol) in 17 mL of toluene was heated at reflux for 19 h. The mixture was cooled to room temperature and partitioned between dichioromethane and aqueous saturated sodium bicarbonate. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluting with a gradient of 2% methanol in dichloromethane to 8%
methanol in dichloromethane to provide 688 mg (86%) of 1-methyl-4-[(2-vinylpyridin-4-yl)methyl]piperazine as a yellow oil; MS 218.3 (M+H).

S
[00270] Preparation of 1-methyl-4-[(4-vinyl-1,3-thiazol-2-yl)methyl]piperazine:

Following the procedure to prepare 1-methyl-4-[(2-vinylpyridin-4-yl)methyl]piperazine, 1-methyl-4-[(4-vinyl-1,3-thiazol-2-yl)methyl] piperazine was prepared via the reaction of 1-[(4-bromo-1,3-thiazol-2-yl)methyl]-4-methylpiperazine with tributylvinyltin; MS
224.2 (M+H).

te' [00271] Preparation of 4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-{4-[(4-methylpiperazin-1-yl)methyl]pyridin-2-yl}vinyl]nicotinonitrile:

A mixture of 5-iodo-4-[(4-methyl-lH-indol-5-yl)amino]nicotinonitrile (150 mg, 0.40 mmol), 1-methyl-4-[(2-vinylpyridin-4-yl)methyl]piperazine (113.0 mg, 0.52 mmol), Pd(OAc)2 (18 mg, 0.08 mmol) and tri(ortho-tolyl)phosphine (6.1 mg, 0.02 mmol) in 3.5 mL of DMF and 1.0 mL of TEA
was heated at 95 C for 2 h. The mixture was cooled to room temperature, and partitioned between dichloromethane and aqueous saturated sodium bicarbonate. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography, eluting with a gradient of 2% methanol in dichloromethane to 20%
methanol in dichloromethane to provide 84.0 mg (45%) of 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{4-[(4-methylpiperazin-i-yl)methyl]pyridin-2-yl}vinyl]nicotinonitrile as a light tan solid; MS
464.3 (M+H); HPLC: 99.4% at 215 nm, rt = 4.6 min [a].

[00272] Preparation of 4-[(4-methyl-lH-indol-5-yl)amino]-5-[(E)-2-{2-[(4-methylpipe razin-1-yl)methyl]-1,3-thiazol-4-yl}vinyl]nicotinonitrile:
Following the procedure to prepare 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{4-[(4-methylpiperazin-l-yl)methyl]pyridin-2-yl}vinyl]nicotinonitrile, 4-[(4-methyl-lH-indol-5-yl)amino]-5-[(E)-2-{2-[(4-methylpiperazin-1-yl)methyl]-1,3-thiazol-4-yl}vinyl]nicotinonitrile was prepared via the reaction of 5-iodo-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile with 1-methyl-4-[(4-vinyl-1,3-thiazol-2-yl)methyl]piperazine; MS 470.3 (M+H), HPLC: 98.5% at 215 nm, rt = 5.4 min [a].

H

NH

[00273] Preparation of 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-pyridin-2-ylvinyl]
nicotinonitrile:

A mixture of 5-iodo-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile (150 mg, 0.40 mmol), 2-vinylpyridine (54.6 mg, 0.52 mmol), Pd(OAc)2 (18 mg, 0.08 mmol) and tri-o-tolylhosphine (6.1 mg, 0.02 mmol) in 2.5 mL of DMF and 0.50 mL of TEA was heated at 95 C for 3 h.
The mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by column chromatography, eluting with 20% to 50% ethyl acetate in hexane, ethyl acetate and 2% methanol in ethyl acetate to provide 74.1 mg (53%) of 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-pyridin-2-ylvinyl]nicotinonitrile as a yellow solid; MS
352.2 (M+H), Analysis for C22HõNS-0.7H2O-0.14 CH2CI2; Calcd: C, 70.74; H, 5.01; N, 18.63, Found: C, 70.38; H, 4.78; N, 18.61.

N =
B

I
H

[00274] Preparation of 5-bromo-4-oxo-1,4-dihydropyridine-3-carbonitrile:

To a solution of 1,4-dihydro-4-oxonicotinonitrile (1.2 g, 9.99 mmol) in 30 mL
of acetic acid was added dropwise a solution of bromine (1.92 g, 11.99 mmol) in 5.5 mL of acetic acid at 90 C
over a period of 3 h. The resulting reaction mixture was further stirred at 90 C for 3 h. After cooling to room temperature, the mixture was concentrated in vacuo. The solid residue was triturated with ethanol to give 1.0 g (52%) of 5-bromo-4-oxo-1,4-dihydropyridine-3-carbonitrile as a light brown solid; MS 199.0, 201.0 (M+H).

a N
i [00275] Preparation of 5-bromo-4-chloronicotinonitrile:

A mixture of 5-bromo-4-oxo-1,4-dihydropyridine-3-carbonitrile (1.75 g, 8.79 mmol) in POCI3 was heated at reflux for 3 h. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was cooled in an ice bath and treated with aqueous saturated sodium bicarbonate. The aqueous suspension was extracted with dichloromethane.
The combined extracts were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography, eluting with a gradient of 10% dichloromethane/hexane to 60% dichloromethane/hexane to give 1.5 g (86%) of 5-bromo-4-chloronicotinonitrile as a white solid; MS 217.0, 219.0 (M+H).

(XNH
N
Br /~

[00276] Preparation of 5-bromo-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile:

A mixture of 5-bromo-4-chloronicotinonitrile (1.40 g, 6.43 mmol), 5-amino-4-methylindole (0.94 g, 6.43 mmol) in 15 mL of ethanol was heated at reflux overnight, then cooled to room temperature. The precipitate was filtered and washed with ethanol twice and diethyl ether once, then air-dried. The resultant HCI salt was suspended in methanol, treated with conc.
aqueous ammonium hydroxide and concentrated in vacuo to dryness. The solid residue was washed with water and diethyl ether to give 1.3 g (62%) of 5-bromo-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile as a pale gray solid; MS 327.1, 329.1 (M+H).

ter NH

[00277] Preparation of 5-[(E)-2-(4-butylphenyl)vinyl]-4-[(4-methyl-f H-indol-5-yl)amino]
nicotinonitrile:

A mixture of 5-bromo-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile (130 mg, 0.40 mmol), 2-[2-(4-butylphenyl)vinyl]-4,4,5,5-tetramethyl-1.,3,2-dioxaborolane (171,7 mg, 0.60 mmol) and Pd(PPh3)4 and 2.5 mL of aqueous saturated sodium bicarbonate in 5 mL of DME
was heated at reflux for 4 h. The mixture was cooled to room temperature and partitioned between dichioromethane and water. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography, eluting with a gradient of 10% ethyl acetate in hexane to 50% ethyl acetate in hexane to provide 95 mg (59%) of 5-[(E)-2-(4-butylphenyl)vinyl]-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile as a pale yellow solid; MS 407.3 (M+H), HPLC: 96.2% at 215 nm rt = 12.5 min [a].

HN
N/ NH
N

(00278]. Preparation of 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-pyridin-4-ylvinyl]
nicotinonitrile:

Following the procedure to prepare 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{4-[(4-methylpiperazin-1-yl)methyl]pyridin-2-yl}vinyl]nicotinonitrile, 4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-pyridin-4-ylvinyl]nicotinonitrile was prepared via the reaction of 5-iodo-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile with 4-vinylpyridine; MS 352.3 (M+H), HPLC: 91.4% at 215 nm, rt = 4.9 min [a].

NH
~ Hh \
N

[00279] Preparation of 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-phenylvinyl]
nicotinonitrile:

A mixture of 5-iodo-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitnle (100 mg, 0.267 mmol, trans-2-phenylvinylboronic acid (44 mg, 0.294 mmol), tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.013 mmol) in 4 mL of 1,2-dimethoxyethane and 3 mL of saturated aqueous sodium bicarbonate was heated at 95 C overnight. The reaction was diluted with EtOAc, washed with water, dried over MgSO4 and concentrated to give dark residue. The residue was purified by preparative TLC to give 13 mg (14%) of 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-phenylvinyl]nicotinonitrile as a yellow solid, mp 203-205 C; MS 351.2 (M+H).

NH
/ I I \

[00280] Preparation of 5-[(E)-2-{5-[(dimethylamino)methyl] pyridin-2-yl)vinyl]-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile:

A mixture of 5-iodo-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile (150 mg, 0.40 mmol), N,N-dimethyl-1-(6-vinylpyridin-3-yl)methanamine (78 mg, 0.48 mmol), palladium(II) acetate (18 mg, 0.08 mmol) and tri(ortho-tolyl)phosphine (6 mg, 0.02 mmol) in 2 mL of anhydrous N,N-dimethylform amide and 0.5 mL of triethylamine was heated at 100 C for 2 h, cooled to room temperature, diluted with dichloromethane, washed with water, dried over MgSO4 and concentrated to give dark residue. The crude product was purified by column chromatography, eluting with 5-10% gradient methanol in dichloromethane, to give 97 mg (59%) of 5-[(E)-2-{5-[(dimethylamino)methyl]pyridin-2-yl}vinyl]-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile as a tan solid, mp 234-236 C; MS 409.3 (M+H).

[00281] Preparation of 1-methyl-4-[(6-vinylpyridin-3-yl)methyl]piperazine:
1-[(6-bromo-3-pyridinyl)methyl]-4-methylpiperazine was prepared from 6-bromo-3-pyridine carboxaldehyde and 1-methylpiperazine via the procedure used to prepare 2-iodo-5[(4-methylpiperazin-1-yl)methyl]phenol . A mixture of 1-[(6-bromo-3-pyridinyl)methyl]-4-methyl piperazine (2.0 g, 7.40 mmol), tributylvinyltin (3.24 mL, 11.10 mmol), trans-dichlorobis (triphenylphosphine)palladium(ll) (260 mg, 0.37 mmol) and copper iodide (71 mg, 0.37 mmol) in 40 mL of toluene was heated at reflux overnight. The reaction mixture was cooled, diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate, filtered, dried over MgSO4 and concentrated to give dark brown residue. The residue was purified by column chromatography (0 to 5% gradient methanol in dichloromethane) to give 1.03 g (64%) of 1-methyl-4-[(6-vinylpyridin-3-yl)methyl]piperazine as a light brown syrup; MS
218.3 (M+H).

h N
ff [00282] Preparation of 4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-(5-[(4-methylpipe razin-1-yl)methyl]pyridin-2-yl}vinyl]nicotinonitrile:

The title compound was prepared from 5-iodo-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile and 1-methyl-4-[(6-vinylpyridin-3-yl)methyl]piperazine via the procedure used to prepare 5-[(E)-2-{5-[(dimethylamino)methyl]pyridin-2-yl}vinyl]-4-[(4-methyl-1 H-indol-5-yI)amino]nicotinonitrile, mp 193-196 C; MS 464.4 (M+H).

[00283] Preparation of 1-methyl-4-[(6-vinylpyridin-2-yl)methyl]piperazine:

The title compound was prepared analogously to 1-methyl-4-[(6-vinylpyridin-3-yl)methyl]piperazine beginning with 6-bromopicolinaldehyde; MS 218.3 (M+H).

[00284] Preparation of 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(6-[(4-methyl piperazin-1-yl)methyl]pyridin-2-yl}vinyl]nicotinonitrile:
The title compound was prepared from 5-iodo-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile and 1-methyl-4[(6-vinylpyridin-2-yl)methyl]piperazine via the procedure used to prepare 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{6-[(4-methylpiperazin-1-yl)methyl]pyridin-2-yl}vinyl]
nicotinonitrile; MS 464.3 (M+H).

MI

J ~ ~N

[00285] Preparation of 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{5-[(4-methylpiperazin-1-yl)methyl]pyridin-2-yl}vinyl]nicotinonitrile:
The title compound was prepared from 5-bromo-6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile and 1-methyl-4-[(6-vinylpyridin-3-yl)methyl]piperazine via the procedure used to prepare 5-[(E)-2-{5-[(dimethylamino)methyl]pyridin-2-yl}vinyl]-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile; MS 479.4 (M+H).

nB
[00286] Preparation of 4-(1H-indol-5-ylamino)-5-[(E)-2-(5-[(4-methylpiperazin-yl)methyl]pyridin-2- yl}vinyl]nicotinonitrile:

The title compound was prepared from 4-(1H-indol-5-ylamino)-5-iodonicotinonitrile and 1-methyl-4-[(6-vinylpyridin-3-yl)methyl]piperazine via the procedure used to prepare 5-[(E)-2-{5-[(dimethylamino)methyl]pyridin-2-yl}vinyl]-4-[(4-methyl-lH-indol-5-yl)amino]nicotinonitrile; MS
450.3 (M+H).

NH

[00287] Preparation of 5-[(E)-2-{2-methoxy-4-[(4-methylpiperazin-1-yl)methyl]
phenyl) vinyl]-4-[(4- methyl-1 H-indol-5-yl)amino]nicotinonitrile:

A mixture of 4-[(4-methyl-1 H-indol-5-ylamino)]-5-vinylnicotinonitrile (200 mg, 0.73 mmol), 1-(4-iodo-3-methoxybenzyl)-4-methylpiperazine (210 mg, 0.61 mmol), palladium(II) acetate (27 mg, 0.12 mmol) and tri-o-toluenephosphine (9 mg, 0.03 mmol) and 0.5 mL of triethylamine in 2 mL
of anhydrous N,N-dimethylformamide was heated at 120 C for 4 h. The reaction was cooled to room temperature, diluted with dichioromethane, washed with saturated aqueous sodium bicarbonate, dried over MgSO4 and concentrated to give dark residue. The crude product was purified by HPLC (ACN in H,O/TFA) to give 86 mg (29%) of 5-((E)-2-{2-methoxy-4-[(4-methylpiperazin-1-yl)methyl]phenyl)vinyl]-4-[(4- methyl-1 H-indol-5-yl)amino]nicotinonitrile as a yellow solid; MS 493.3 (M+H); HPLC: 90.4% at 215 nm, it = 7.2 min [a].

MM"
[00288] Preparation of 2-iodo-5-[(4-methylpiperazin-1-yl)methyl]phenol:
3-Hydroxy-4-iodobenzaldehyde (2.0, g, 8.06 mmol) and 1-methylpiperazine (4.0 g, 40.34 mmol) were dissolved in THE (100 mL). Upon cooling to 0 C, sodium triacetoxyborohydride (8.6 g, 40.34 mmol) was added to the reaction solution along with catalytic amount of HOAc.
The mixture was slowly warmed to room temperature and stirred overnight. The suspension was filtered, and the filtrate was diluted with dichioromethane, washed with saturated aqueous sodium bicarbonate, dried over MgSO4 and concentrated to give a light color syrup. The syrup was purified by column chromatography, eluting with 10-15% gradient methanol in dichloromethane, to give 2.36 g (88%) of 2-iodo-5-[(4-methylpiperazin-1-yl)methyl]phenol as a white solid; MS 333.2 (M+H).

[00289] Preparation of 3-iodo-4-methoxybenzaldehyde:

A mixture of p-anisaldehyde (1.00 g, 7.34 mmol), iodine (932 mg, 3.67 mmol) and selectfluor (1.56 g, 4.40 mmol) in 75 mL of methanol was heated at 50 C for 21 h. The reaction was cooled and diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate, dried over MgSO4 and concentrated to give a brown residue. The residue was purified by column chromatography, eluting with 20-40% gradient EtOAc in hexanes, to give 690 mg (36%) of 3-iodo-4-methoxybenzaldehyde as a yellow solid; MS 263.1 (M+H).

[00290] Preparation of 1-(3-iodo-4-methoxybenzyl)-4-methylpiperazine:

The title compound was prepared from 3-iodo-4-methoxybenzaldehyde and 1-methylpiperazine via the procedure used to prepare 2-iodo-5-[(4-methylpiperazin-1-yl)methyl]phenol; MS 347.2 (M+H).

o [00291] Preparation of tert-butyl 4-(3-iodo-4-methoxybenzyl)piperazine-1-carboxylate:
3-iodo-4-methoxybenzaldehyde (300 mg, 1.14 mmol) and tert-butyl 1-piperazinecarboxylate (1.06 g, 5.70 mmol) was dissolved in THE (15 mL). Upon cooling to 0 C, sodium triacetoxyborohydride (1.21 g, 5.71 mmol) was added to the reaction solution along with a catalytic amount of HOAc. The mixture was slowly warmed to room temperature and was stirred overnight. The suspension was filtered and the filtrate was diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate, dried over MgSO4 and concentrated to give a light color syrup. The residue was purified by column chromatography, eluting with a 0-5% gradient methanol in dichloromethane to give 420 mg (85%) of tert-butyl 4-(3-iodo-4-methoxybenzyl)piperazine-l-carboxylate as a colorless gum; MS 433.3 (M+H).

[00292] Preparation of 4-iodo-3-methoxybenzaldehyde:

A mixture of 3-hydroxy-4-iodobenzaldehyde (1.8 g, 7.26 mmol), iodomethane (3.2 g, 22.54 mmol) and potassium carbonate (1.51 g, 10.93 mmol) in 80 mL of acetone was heated at reflux for 2 h. The reaction was cooled and filtered. After the removal of the solvent from the filtrate, the residue was re-dissolved in EtOAc and washed with saturated aqueous sodium bicarbonate, dried over MgSO4 and concentrated to give off-white solid. The solid was eluted through silica gel with 50% EtOAc in hexanes to give 1.85 g (97%) of 4-iodo-3-methoxybenzaldehyde as a white solid; MS 263.0 (M+H).

o~11 [00293] Preparation of 1-(44odo-3-methoxybenzyl)-4-methylpiperazine:

The title compound was prepared from 4-iodo-3-methoxybenzaldehyde and 1-methylpiperazine via the procedure used to prepare 2-iodo-5-[(4-methylpiperazin-l-yl)methyl]phenol; MS 347.1 (M+H).

\I/o o-1 [00294] Preparation of tert-butyl 4-(4-odo-3-methoxybenzyl)piperazine-1-carboxylate:
The title compound was prepared from 4-iodo-3-methoxybenzaldehyde and tert-butyl 1-piperazinecarboxylate via the procedure used to prepare tert-butyl 4-(3-iodo-4-methoxybenzyl)piperazine-l-carboxylate; MS 433.2 (M+H).

N
NH NJ

[00295] Preparation of 5-((E)-2-[2-methoxy-4-(piperazin-1-ylmethyl)phenyl]vinyl}-4-[(4-methyl-1 H-indol- 5-yl)amino]nicotinonitrile:

The title compound was prepared from 4-[(4-methyl-1 H-indol-5-ylamino)]-5-vinylnicotinonitrile and tert-butyl 4-(4-iodo-3-methoxybenzyl)piperazine-l-carboxylate via the procedure used to prepare 5-[(E)-2-{2-methoxy-4-[(4-methylpiperazin-1-yl)methyl]phenyl}vinyl]-4-[(4- methyl-1 H-indol-5-yl)amino]nicotinonitrile. The Boc group was removed with DCM/TFA; MS
479.5 (M+H), HPLC: rt = 2.50 min [d].

NH

[00296] Preparation of 4-[(2,4-dimethyl-lH-indol-5-yl)amino]-5-[(E)-2-phenylvinyl]-nicotinonitrile:

The title compound was prepared from 4-[(2,4-dimethyl-1 H-indol-5-yl)amino]-5-iodonicotinonitrile and styrene via the procedure used to prepare 5-[(E)-2-(4-bromophenyl)vinyl]-4-[(4-methyl-1H-indol-5-yl)amino]-nicotinonitrile; MS 365.3 (M+H); HPLC rt = 10.2 min[a].

[00297] Preparation of 4-[(2-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-phenylvinyl]
nicotinonitrile:

A mixture of 4-chloro-5-[(E)-2-phenylvinyl]nicotinonitrile (134 mg, 0.56 mmol) and 5-amino-2-methylindole (110 mg, 0.75 mmol) in 5 mL of ethanol was heated at reflux for 4.5 h. The resulting mixture was cooled slightly and filtered. The solid was washed with ethanol and ethyl acetate then partitioned between saturated aqueous sodium bicarbonate and ethyl acetate.
The layers were separated and the organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was triturated with diethyl ether and the solid was collected by filtration washing with diethyl ether to give 52 mg (27%) of 4-[(2-methyl-1 H-indol-=
5-yl)amino]-5-[(E)-2-phenylvinyl]nicotinonitrile as a light tan solid; MS
351.3 (M+H); HPLC: rt 10.1 min[a].

H
N
Nf ~ I / N.

[00298] Preparation of 4-[(4-methyl-lH-indol-5-yl)amino]-5-(2-{5-[(4-methyl piperazin-l-yl)methyl]pyridin-2-yl}ethyl)nicotinonitrile:
A mixture of 4-[(4-methyl-lH-indol-5-yl)amino]-5[(E)-2(-{5-[(4-methylpiperazin-l-yl)methyl]
pyridine-2-yl}vinyl]nicotinonitrile (100 mg, 0.216 mmol) and 20 mg of Pd/C
(10% wt.) in 10 mL
of methanol was shaken under hydrogen (50 psi) overnight. The reaction was filtered through celite. The filtrate was concentrated to dryness and the resultant solid was purified by HPLC, gradient ACN in H2O/TFA, to give 30 mg (30%) of 4-[(4-methyl-1 H-indol-5-yl)amino]-5-(2-{5-[(4-methylpiperazin-1-yl)methyl]pyridin-2-yl}ethyl)nicotinonitrile as an off-white solid; MS 466.3 (M+H); HPLC: 95.5% at 215 nm, rt = 4.2 min [a].

NH
--'N

[00299] Preparation of 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-vinylnicotinonitrile:
A mixture of 5-iodo-6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile (250 mg, 0.64 mmol), tributyl(vinyl)stannane (307 mg, 0.97 mmol), copper iodide (6 mg, 0.032 mmol) and Pd(PPh3)2CI2 (18 mg, 0.026 mmol) in 7 mL of DMF was heated at 80 C for 5 h.
The reaction was cooled to room temperature and the DMF was removed in vacuo. Sodium bicarbonate was added and the product was extracted into EtOAc. The organic layer was dried with magnesium sulfate and the solvent was removed to give 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-vinylnicotinonitrile as a solid; MS 289.2 (M+H); HPLC: rt = 6.2 min [a].

[00300] Preparation of 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[4-(2-pyrrolidin-1-ylethoxy)phenyl]vinyl}nicotinonitrile:
A mixture of 6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-vinylnicotinonitrile (75 mg, 0.26 mmol), 1-(2-(4-bromophenoxy)ethyl)pyrrolidine (84 mg, 0.31 mmol), tri(ortho-tolyl)phosphine (11.9 mg, 0.039 mmol), palladium acetate (4.1 mg, 0.018 mmol) and triethylamine (79 mg, 0.78 mmol) in 3 mL of DMF was heated at 120 C for 2 h. An additional 0.039 mmol of tri(ortho-tolyl)phosphine and 0.018 mmol of palladium acetate were added and the reaction was flushed with N2 and heated for an additional 1 h. The reaction was filtered and the filtrate was purified by HPLC to give 6-methyl-4-[(4-methyl-lH-indol-5-yl)amino]-5-{(E)-2-[4-(2-pyrrolidin-1-ylethoxy)phenyl]vinyl}nicotinonitrile as its TFA salt; MS 478.4 (M+H); HPLC:
rt = 5.8 min [a].

[00301] Preparation of 5-{(E)-2-[2-(2-chloroethoxy)phenyl]vinyl}-4-[(4-methyl-lH-indol-5-yl)amino]nicotinonitrile:

A mixture of 4-[(4-methyl-1 H-indol-5-ylamino)]-5-vinylnicotinonitrile (373 mg, 1.36 mmol), 1-bromo-2-(2-chloroethoxy)benzene (387 mg, 1.63 mmol), tri(ortho-tolyl)phosphine (61 mg, 0.20 mmol), palladium acetate (22 mg, 0.10 mmol) and triethylamine (412 mg, 4.08 mmol) in 20 mL
of DMF was heated at 120 C for 2 h. The reaction was diluted with EtOAc and washed with water. The crude material was purified by silica gel chromatography with a EtOAc/ hexane gradient. The product was further purified by HPLC to give 5-{(E)-2-[2-(2-chloroethoxy)phenyl]vinyl}-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile as a solid; MS 429.2 (M+H); HPLC: rt = 15.2 min [a].

ci H
O

N

[00302] Preparation of 5-{(E)-2-[3-(2-chloroethoxy)phenyl]vinyl}-4-[(4-methyl-lH-indol-5-yl)amino]nicotinonitrile:

A mixture of 4-[(4-methyl-1 H-indol-5-ylamino)]-5-vinylnicotinonitrile (450 mg, 1.64 mmol), 1-bromo-3-(2-chloroethoxy)benzene (466 mg, 1.97 mmol), tri(ortho-tolyl)phosphine (76 mg, 0.25 mmol), palladium acetate (29 mg, 0.13 mmol) and triethylamine (497 mg, 4.92 mmol) in 20 mL
.of DMF was heated at 120 C for 2 h. The reaction was diluted with EtOAc and washed with water. The organic extract was concentrated and the crude material was purified by silica gel chromatography with an EtOAc / hexane gradient to give 5-{(E)-2-[3-(2-chloroethoxy)phenyl]vinyl)-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile as a solid; MS 429.1 (M+H); HPLC: rt = 11.1 min [a].

H
\ Hiv ~
N

[00303] Preparation of 4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-{2-[2-(4-methyl piperazin-1-yl)ethoxy]phenyl}vinyl]nicotinonitrile:
A mixture of 5-{(E)-2-[2-(2-chloroethoxy)phenyl]vinyl}-4-[(4-methyl-1 H-indol-5-yl)amino]
nicotinonitrile (75 mg, 0.18 mmol), 1-methyl piperazine (108 mg, 1.08 mmol) and sodium iodide (1.4 mg, 0.01 mmol) in 2 mL of DME was heated at 100 C overnight in a sealed vial.
The reaction was concentrated and the crude material was purified by HPLC to give 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{2-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}vinyl]
nicotinonitrile as a solid; MS 493.4 (M+H); HPLC: rt = 6.8 min [a].

~ H \
HNJ~\/O

[00304] Preparation 4-[(4-methyl-1 H-indol-5-yl)amino]-5-((E)-2-[2-(2-piperazin-1-yl ethoxy)phenyl]vinyl}nicotinonitrile:

A mixture of 5-{(E)-2-[2-(2-chloroethoxy) phenyl]vinyl}-4-[(4-methyl-1 H-indol-5-yl)amino]
nicotinonitrile (90 mg, 0.21 mmol), tert-butyl piperazine-1-carboxylate (234 mg, 1.26 mmol) and sodium iodide (1.5 mg, 0.01 mmol) in 2 mL of DME was heated at 100 C
overnight in a sealed vial to give (E)-tert-butyl 4-(2-(2-(2-(5-cyano-4-(4-methyl-1 H-indol-5-ylamino)pyridin-3-yl)vinyl) phenoxy) ethyl)piperazine-1-carboxylate.

The crude intermediate, (E)-tert-butyl 4-(2-(2-(2-(5-cyano-4-(4-methyl-1 H-indol-5-ylamino)pyridin-3-yl)vinyl)phenoxy)ethyl)piperazine-1-carboxylate, was treated with 2.2 mL of 10% trifluoroacetic acid/ DCM and stirred at room temperature for 1 h. The reaction was concentrated and the residue was purified by HPLC to give 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[2-(2-piperazin-1-ylethoxy)phenyl]vinyl}nicotinonitrile as its TFA
salt; MS 479.4 (M+H);
HPLC: rt = 6.3 min [a].

H
N~"' X
N
N~/~ I N

[00305] Preparation of 4-[(4-methyl-1H-indol-5-yl)amino]-5-((E)-2-[2-(2-pyrrolidin-1-ylethoxy)phenyl]vinyl}nicotinonitrile:
A mixture of 5-{(E)-2-[2-(2-chloroethoxy)phenyl]vinyl}-4-[(4-methyl-1 H-indol-5-yl)amino]
nicotinonitrile (75 mg, 0.18 mmol), pyrrolidine (77 mg, 1.08 mmol) and sodium iodide (1.4 mg, 0.01 mmol) in 2 mL of DME was heated at 100 C overnight in a sealed vial. The reaction was concentrated and the crude material was purified by HPLC to give 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[2-(2-pyrrolidin-1-ylethoxy)phenyl]vinyl}nicotinonitrile as its TFA salt; MS
464.3 (M+H); HPLC: rt = 7.0 min [a].

NH
NCO .., I

N
I n [00306] Preparation of 4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-(3-[2-(4-methyl piperazin-1 yl)ethoxy]phenyl)vinyl]nicotinonitrile:

A mixture of 5-{(E)-2-[3-(2-chloroethoxy)phenyl]vinyl}-4-[(4-methyl-1 H-indol-5-yl)amino]
nicotinonitrile (75 mg, 0.18 mmol), 1-methyl-piperazine (108 mg, 1.08 mmol) and sodium iodide (1.4 mg, 0.01 mmol) in 2 mL of DME was heated at 100 C overnight in a sealed vial.
The reaction was concentrated and the crude material was purified by HPLC to give 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{3-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}vinyl]
nicotinonitrile as its TFA salt; MS 493.3 (M+H); HPLC: it = 6.2 min [a].
f H

N

[00307] Preparation of 4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[3-(2-pyrrolidin-1-yl ethoxy)phenyl]vinyl}nicotinonitrile:

A mixture of 5-{(E)-2-[3-(2-chloroethoxy)phenyl]vinyl}-4-[(4-methyl-1 H-indol-5-yl)amino]
nicotinonitrile (75 mg, 0.18 mmol), pyrrolidine (77 mg, 1.08 mmol) and sodium iodide (1.4 mg, 0.01 mmol) in 2 mL of DME was heated at 100 C overnight in a sealed vial. The reaction was concentrated and the crude material was purified by HPLC to give 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[3-(2-pyrrolidin-1-ylethoxy)phenyl]vinyl}nicotinonitrile as its TFA salt; MS
464.3 (M+H); HPLC: it = 6.6 min [a].

NH
N

[00308] Preparation of 4-[(4-methyl-IH-indol-5-yl)amino]-5-[(E)-2-piperidin-4-ylvinyl]
nicotinonitrile:

A mixture of 5-iodo-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile (250 mg, 0.67 mmol), (E)-tert-butyl 4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)piperidine-l-carboxylate (452 mg, 1.34 mmol), cesium carbonate (437 mg, 1.34 mmol) and Pd(PPh3)4 (39.3 mg, 0.034 mmol) in 3 mL of DMSO was heated at 90 C for 16 h. The reaction mixture was cooled to room temperature and purified by HPLC. After purification both (E)-tert-butyl 4-(2-(5-cyano-4-(4-methyl-1 H-indol-5-ylamino)pyridin-3-yl)vinyl)piperidine-1-carboxylate and 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-piperidin-4-ylvinyl]nicotinonitrile were observed due to the TFA buffer in the HPLC solvents. The mixture was diluted with DCM and treated with 0.70 mL of trifluoroacetic acid. Upon full conversion to 4-[(4-methyl-1 H-indol-5-yl)aminoj-5-[(E)-2-piperidin-4-ylvinyl]nicotinonitrile, the product was purified by HPLC to give 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-piperidin-4-ylvinyl]nicotinonitrile as a solid;
HPLC: 96.2% at 215 nm, it = 4.3 min [a]; MS = 358 (M+H).

ci [00309] Preparation of 4-[(7-chloro-4-methyl-1H-indol-5-yl)amino]-5-iodonicotinonitrile:
A mixture of 4-chloro-5-iodonicotinonitrile (142 mg, 0.54 mmol) and 5-amino-7-chloro-4-methylindole (71 mg, 0.39 mmol) in 5 mL of ethanol was heated in a sealed tube at 95 C for 72 h. The resulting mixture was cooled to room temperature. The reaction was diluted with ethyl acetate and washed with sodium bicarbonate solution. The organic phase was dried over magnesium sulfate. Flash column chromatography (ethyl acetate-hxanes 2 :
1) afforded 35 mg (15 %) of 4-[(7-chloro-4-methyl-1 H-indol-5-yl)amino]-5-iodonicotinonitrile; MS 409.1 (M+H).

NH

[00310] Preparation of 4-[(7-chloro-4-methyl-lH-indol-5 yl)amino]-5-[(E)-2-phenylvinyl]
nicotinonitrile:

A mixture of 4-[(7-chloro-4-methyl-1 H-indol-5-yl)amino]-5-iodonicotinonitrile (120mg, 0.29 mmol), trans-2-phenylvinylboronic acid (65 mg, 0.44 mmol), Pd(PPh3)2C12 (103mg, 0.015mmol) and saturated aqueous NaHCO3 (2.5 ml-) in 3 mL DME was heated at 95 C for 4 h.
The resulting mixture was cooled to room temperature, diluted with saturated aqueous sodium bicarbonate, and extracted into DCM. The organic layer was washed with brine and concentrated. The crude product was purified by column chromatography, eluting with hexanes and ethyl acetate(4:1), to give 51 mg(54%) of 4-[(7-chloro-4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-phenylvinyl]nicotinonitrile as a yellow solid; MS
385.2(M+H); HPLC: 99.4%
at 215 nm, rt = 10.9 min [a].

NH
_N

[00311] Preparation of 4-[(7-chloro-4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-(3-methoxy phenyl)vinyl]nicotinonitrile:

A mixture of 4-[(7-chloro-4-methyl-1 H-indol-5-yl)amino]-5-iodonicotinonitrile (120 mg, 0.29 mmol), trans-2-(3-methoxyphenyl)vinylboronic acid (115 mg, 0.44 mmol), Pd(PPh3)4 (170 mg, 0.015 mmol) and saturated aqueous NaHCO3(2 ml-) in 3 mL DME was heated at 95 C
for 4 h.
The resulting mixture was cooled to room temperature, diluted with saturated aqueous sodium bicarbonate, and extracted into DCM. The organic layer was washed with brine and concentrated. The crude product was purified by column chromatography, eluting with hexanes and ethyl acetate (1:1), to give 41 mg (34%) of 4-[(7-chloro-4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(3-methoxyphenyl)vinyl]nicotinonitrile as a yellow solid;
MS 415.5(M+H);
HPLC: 91.4% at 215 nm, rt = 10.8 min [a].

~- rx 1W a [00312] Preparation of 4-{(7-chloro-4-methyl-1H-indol-6-yl)amino]-5-[(E)-2-pyridine-2-yl vinyl))nicotinonitrile:

A mixture of 4-[(7-chloro-4-methyl-1 H-indol-5-yl)amino]-5-iodonicotinonitrile (120 mg, 0.29 mmol), 2-vinylpyridine (61 mg, 0.58 mmol), tri(ortho-tolyl)phosphine (2.7 mg, 0.0087 mmol), Pd(OAc)2 (13.2 mg, 0.058 mmol) and Et3N (2 ml-) in 5 mL DMF was heated at 140 C for overnight. The resulting mixture was cooled to room temperature, diluted with saturated aqueous sodium bicarbonate, and extracted into DCM. The organic layer was washed by brine and concentrated. The crude product was purified by column chromatography, eluting with hexanes and ethyl acetate (1:1), to give 52 mg (45%) of 4-{(7-chloro-4-methyl-1h-indol-6-yl)amino]-5-[(e)-2-pyridine-2-ylvinyl))nicotinonitrile as a yellow solid; MS
386.5 (M+H); HPLC:
99.8% at 215 nm, rt = 7.3 min [a].

[00313] Preparation of 4-iodo-3-methylbenzaldehyde:

To a solution of 4-iodo-3-methylbenzonitrile (2.43 g, 10 mmol) in CH2CI2 (70 ml) at -15 to -20 C
under nitrogen was added DIBAL-H (12 mL, 12 mmol, 1 M/heptane) such that the temperature was less than or equal to -15 C. After addition was complete, the reaction mixture was stirred an additional 10 min at -15 to -20 C. The reaction mixture was then quenched via dropwise addition of aqueous 2N HCI such that the temperature was less than or equal to room temperature. The organic layer was separated and washed with water, dried over sodium sulfate and concentrated to give 2.13 g (87%) of 4-iodo-3-methylbenzaldehyde as yellow oil.
[00314] Preparation of 1-(44odo-3-methylbenzyl)-4-methylpiperazine:

To a solution of 4-iodo-3-methylbenzaldehyde (1.47 g, 6 mmol) in a mixture of THE (60 ml-) and EtOH (15 mL) at room temperature under nitrogen was added N-methylpiperazine (1.80 g, 18 mmol) followed by glacial acetic acid (1.80 g, 30 mmol). The reaction mixture was stirred at room temperature for 1h. Sodium triacetoxyborohydride (6.36 g, 30 mmol) was added to the reaction mixture and the reaction was stirred at room temperature for 5 h. The reaction mixture was partitioned between EtOAc and aqueous I IN HCI. The aqueous layer was washed with EtOAc and treated with aqueous 1N NaOH whereupon solids precipitated. The solids were collected, dissolved in EtOAc, washed with water (thrice), then brine. The organic layer was dried over sodium sulfate, concentrated and the residue was purified by column chromatography eluting with a gradient of 50% EtOAc/hexane to 70% EtOAc/hexane to give 0.94 g (48%) of 1-(4-iodo-3-methylbenzyl)-4-methylpiperazine as a solid; MS
331.1 (M+H);
HPLC: 98.4% at 215 nm, rt = 11.4 min [a].

HN)Q'-[00315] Preparation of 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2{2-methyl-4-[(4-methylpiperazin-1-yl)methyl]phenyl}vinyl]nicotinonitrile:
A mixture of 4-[(4-methyl-1 H-indol-5-ylamino)}5-vinylnicotinonitrile (150 mg, 0.55 mmol), 1-(4-iodo-3-methylbenzyl)-4-methylpiperazine (165 mg, 0.5 mmol), 11 mg of tri(ortho-tolyl)phosphine and Pd(OAc)2 (22mg) in 3 mL of DMF and 1 mL of Et3N was heated at 120 C for 3 h. After cooling to room temperature the reaction mixture was partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography, eluting with a gradient of ethyl acetate to 4% CH3OH in ethyl acetate to give 201 mg (84%) of 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{2-methyl-4-[(4-methylpiperazin-1-yl)methyl]phenyl}vinyl]nicotinonitrile as a yellow solid; MS
477.3 (M+H);
HPLC: 90.8% at 215 nm, rt = 6.1 min [a].

[00316] Preparation of 4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-pyrazin-2-yl vinyl]
nicotinonitrile:

A mixture of 5-iodo-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile (120 mg, 0.321 mmol), Pd(OAc)2 (14.4 mg, 0.064 mmol), P(o-Tol)3 (3.0 mg, 0.01 mmol) and 2-vinylpyrazine (70.2 L, 0.642 mmol) in DMF (5 ml-) and Et3N (2 ml-) was stirred under nitrogen at 120 C for 4 hours.
The reaction was cooled to room temperature and concentrated in vacuo. The residue was suspended in EtOAc (5 ml-) and filtered. The filter cake was washed with EtOAc (3 x 5 ml-) and dried at 60 C in vacuo to provide 52.2 mg (46%) of 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-pyrazin-2-ylvinyl]nicotinonitrile as a yellow solid. 1H NMR (400 MHz, DMSO-d6) S 2.33 (s, 3H), 6.51 (bs, 1H), 6.93 (d, J = 8.0 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 7.31-7.36 (m, 2H), 7.96 (d, J = 16.0 Hz, 1 H), 8.32 (s, 1 H), 8.51 (s, 1 H), 8.63 (m, 2H), 8.93 (s, 1 H), 9.01 (s, 1 H), 11.14 (s, 111); MS 353.2 (M+H).

N H
ILI
~~N \
N~ N / \ N

[00317] Preparation of 4-[(4-methyl-lH-indol-5-yl)amino]-5-[(E)-2-(lH-1,2,4-triazol-1-yl) vinyl]nicotinonitrile:

The procedure for 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-pyrazin-2-ylvinyl]nicotinonitrile was followed using 1-vinyl-1,2,4-triazole (110 mg, 0.642 mmol). The crude residue was purified by HPLC to provide 6.4 mg (6%) of 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(1 H-1,2,4-triazol-1-yl)vinyl]nicotinonitrile as a tan solid. 1H NMR (400 MHz, DMSO-d6) 82.33 (s, 3H), 6.51 (bs, 1 H), 6.91 (d, J = 8.0 Hz, 1 H), 7.23 (d, J = 8.0 Hz, 1 H), 7.35 (bs, 1 H), 7.43 (d, J =
16 Hz, 1 H), 7.92 (d, J = 16.0 Hz, 1 H), 8.20 (s, 1 H), 8.30 (s, 1 H), 8.50 (s, 1 H), 8.89 (m, 2H), 11.14 (s, 1 H); MS 342.1 (M+H).

[00318] Preparation of 4-(1 H-indol-5-yloxy)-5-iodonicotinonitrile:

A mixture of 4-chloro-5-iodonicotinonitrile (3.327 g, 12.58 mmol), 5-hydroxyindole (2.01g, 15.11 mmol) and 2.63 g of potassium carbonate in 50 mL of acetonitrile was heated at reflux for 3 h. The reaction mixture was cooled and poured into water. The solid was collected by filtration and dissolved in ethyl acetate, and washed with saturated aqueous sodium bicarbonate. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Trituration with ethyl acetate gave 960 mg (21%) of 4-(1 H-indol-5-yloxy)-5-iodonicotinonitrile as a light tan solid. The filtrate was concentrated and the residue was recrystallized from. ethyl acetate to give 510 mg (11%) of 4-(1 H-indol-5-yloxy)-5-iodonicotinonitrile as an off-white solid, MS 362.0 (M+H)+; HPLC: 97.1% at 215 nm, rt = 14.1 min. Prodigy ODS3, 0.46 x 15 cm column: 1.0 mUmin, 20 min gradient of acetonitrile in water/TFA.

[00319] Preparation of 4-(1 H-indol-5-yloxy)-5-[(E)-2-phenylvinyl]nicotinonitrile:

A mixture of 4-(1 H-indol-5-yloxy)-5-iodonicotinonitrile (200 mg, 0.55 mmol), trans 2-phenylvinyl boronic acid (164 mg, 1.11 mmol) and 35 mg of (Ph3P)4Pd in 10 mL of dimethoxyethane and 5 mL of saturated aqueous sodium bicarbonate was heated at reflux for 1.5 h. The reaction mixture was cooled and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by flash column chromatography eluting with a gradient of 5:1 to 1:1 hexane:ethyl acetate gave 59 mg (32%) of 4-(1 H-indol-5-yloxy)-5-[(E)-2-=
phenylvinyl]nicotinonitrile as a light tan solid, MS 338.2 (M+H)+; HPLC: 98.7%
at 215 nm, rt 16.5 min. Prodigy ODS3, 0.46 x 15 cm column: 1.0 mUmin, 20 min gradient of acetonitrile in watedTFA.

[00320] Preparation of 5-iodo-4-[(4-methyl-1 H-indol-5-yl)oxy]nicotinonitrile:

4-Methyl-1 H-indol-5-ol (0.664 g, 4.51 mmol), 4-chloro-5-iodonicotinonitrile (1.084 g, 4.1 mmol), and potassium carbonate (0.850 g, 6.15 mmol) were heated to 1000 C in 20 mL
acetonitrile for 2 h. The reaction was poured over water (75 ml-) and the precipitate was filtered and washed with water to give 1.45 g of the title compound. HPLC: 98.5% at 215 nm, rt =14.5 min [a]; MS:
376 [M+H].

NM

[00321] Preparation of 4-[(4-methyl-1H-indol-5-yl)oxy]-5-[(E)-2-phenylvinyl]
nicotinonitrile:

5-lodo-4-(4-methyl-1 H-indol-5-yloxy)nicotinonitrile (100 mg, 0.267 mmol), (E)-4,4,5,5-tetramethyl-2-styryl-1,3,2-dioxaborolane (73.6 mg, 0.320 mmol), and Pd(PPh3)2CI2 (22 mg, 0.03 mmol) were stirred in 3 mL DME and 0.5 mL of saturated aqueous NaHCO3.
The reaction was heated to 80 C overnight. The residue after concentration was dissolved in 2 mL DMSO. The mixture was filtered and the filtrate was purified by HPLC to give 40 mg of the title compound. MS: 352.1 (M+H); HPLC 99.6%, rt =17.1 min [a].

/ NH

I/
N

[00322] Preparation of 4-(1 H-indol-4-yloxy)-5-iodonicotinonitrile:

4-Hydroxy indole (1.14 g, 8.6 mmol), 4-chloro-5-iodonicotinonitrile (2.06 g, 7.8 mmol), and potassium carbonate (1.6 g, 11.7 mmol) were heated to 1000 C in 30 mL
acetonitrile. After 1.5 h the reaction was cooled and quenched with 3 equivalents of acetic acid. The reaction was concentrated and re-dissolved in DCM/MeOH and subsequently evaporated onto silica gel.
The desired product was purified by column chromatography (10% to 40% EtOAc in Hex) to give 1.85 g of material. This product was further purified by recrystallization from EtOH/water =
to give 850 mg of pure 4-(1 H-indol-4-yloxy)-5-iodonicotinonitrile. HPLC:
95.9% at 215 nm, rt 14.0 min [a]; MS: 362.1 [M+H].

/ NM
\ I / \ /jN

[00323] Preparation of 4-(1H-indol-4-yloxy)-5-[(E)-2-phenylvinyl]nicotinonitrile:

4-(1 H-Indol-4-yloxy)-5-iodonicotinonitrile (0.41 mmol, 150 mg), (E)-4,4,5,5-tetramethyl-2-styryl-1,3,2-dioxaborolane (142 mg, 0.62 mmol), Pd(PPh3)2CI2 (44 mg, 0.06 mmol), and sodium bicarbonate (0.3 mL of a saturated aqueous solution) were heated to 80 C for 4 h in 3 mL of DMSO. The reaction was filtered and the filtrate was purified by HPLC to give 60 mg of the title compound as a white solid. HPLC: rt =16.4 min [a]; HRMS: calculated 338.12879; found 338.1286.

Ni N

[00324] Preparation of 5-[(E)-2-(6-bromopyridin-2-yl)vinyl]-4-[(4-methyl-lH-indol-5-yl) amino] nicotinonitrile :

4-[(4-methyl-1 H-indol-5-yl)amino]-5-vinylnicotinonitrile (60 mg, 0.22 mmol), 2,6-dibromopyridine (62 mg, 0.26 mmol), Pd(OAc)2 (5 mg, 0.022 mmol), P(o-Tol)3 (13 mg, 0.044 mmol), and triethyl amine (66 mg, 0.66 mmol) were heated to 90 C for 3 h in 2 mL DMF. The temperature was increased to 100 C and the reaction was heated overnight. LCMS
indicated the reaction was complete. A significant amount of the double addition product (E)-5-(2-(6'-bromo-2,2'-bipyridin-6-yl)vinyl)-4-(4-methyl-1 H-indol-5-ylamino)nicotinonitrile was observed (20-30%). The reaction was filtered and the product was isolated by preparative HPLC giving 18 mg of the desired (monoaddition) product. HPLC: 92.1%, rt = 9.7 min [a];
HRMS:
calculated 430.06618, found 430.06591.

\
I / N

[00325] Preparation of 5-{(E)-2-[3,4-bis(2-methoxyethoxy)phenyl]vinyl}-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile:

4-[(4-methyl-1H-indol-5-yl)amino]-5-vinylnicotinonitrile (75 mg, 0.27 mmol), 4-bromo-1,2-bis(2-methoxyethoxy)benzene (167 mg, 0.54 mmol), Pd(OAc)2 (6 mg, 0.03 mmol), P(o-Tol)3 (12 mg, 0.04 mmol), and triethylamine (83 mg, 0.83 mmol) were dissolved in 2 mL DMF
and heated to 70 C for 3 h. The temperature was increased to 1000 C and the reaction was heated overnight. The reaction was filtered and the filtrate was purified by HPLC to give 65 mg of the title compound. HPLC: 93.2%, rt = 9.2 min [a]; HRMS: calculated 499.23398, found 499.23254.

[00326] Preparation of 1-(4-ethynylbenzyl)pyrrolidine:

4-Ethynylbenzaldehyde (.5 g, 3.84 mmol) and pyrrolidine (0.328 g, 4.61 mmol) were stirred in 40 mL 1,2-dichloroethane. Sodium triacetoxyborohydride (1.629 g, 7.68 mmol) was added and the reaction was stirred over the weekend. The reaction was quenched with water (20 mL) and HOAc (2 eq) and stirred until bubbling ceased. The product was partitioned between dichloromethane and aqueous NaHCO3. The product was extracted 2x into dichloromethane and dried over MgSO4. The solution was concentrated to give 600 mg of a yellow oil. MS:
186.1 (M+H).

[00327] Preparation of 4-(4-methyl-1 H-Indol-5-ylamino)-5-((4-(pyrrolldin-1-ylmethyl) phenyl)ethynyl)nicotinonitrile:

5-lodo-4-(4-methyl-1H-indol-5-ylamino)nicotinonitri le (250 mg, 0.67 mmol), 1-(4-ethynylbenzyl)pyrrolidine (136 mg, 0.375 mmol), Pd(PPh3)2CI2 (47 mg, 0.067 mmol), Cul (13 mg, 0.067 mmol), and triethylamine (270 mg, 2.67 mmol) were stirred at room temperature in 4 mL DMF. After 3 h the reaction was treated with a small amount of TFA (-50 uL), filtered, and the filtrate was purified by HPLC. The residue (TFA salt) was treated with HCI/dioxane to make the HCI salt. Evaporation from ethanol gave a yellow solid, which was treated with 1 mL
of EtOH and sonicated. The cloudy suspension was filtered and the filter cake was dried to give 22 mg of pure product. HPLC: 96.8%, rt = 7.2 min [a]; MS: 432.3 (M+H).

NH
N

[00328] Preparation of 4-[(4-methyl-1H-indol-5-yl)amino]-5-{2-[4-(pyrrolidin-1-ylmethyl)phenyl]ethyl}nicotinonitrile:
4-(4-Methyl-1H-indol-5-ylamino)-5-((4-(pyrrolidin-1-ylmethyl)phenyl)ethynyl)nicotinonitrile (85 mg, 0.197 mmol) (hydrochloride salt) was dissolved in 10 mL ethanol and treated with 1 eq. of Et3N. The reaction was treated with 25 mg of Pd/C and shaken under hydrogen (30 psi) for 2 h. The reaction was filtered, concentrated, and purified by HPLC to give 30 mg of the title compound as its free base. HPLC: 97.0%, rt = 5.3 min [a]; HRMS: calculated 436.24957, found 436.25152.

N

[00329] Preparation of 5-[(E)-2-(6-chloropyridin-2-yl)vinyl]-4-[(4-methyl-1H-indol-5-yl) amino]nicotinonitrile:

2-Bromo-6-chloropyridine (.66 mmol, 126 mg), 4-[(4-methyl-1 H-indol-5-yl)amino]-5-vinylnicotinonitrile (.55 mmol, 150 mg), Pd(OAc)2 (0.055 mmol, 12 mg), triethylamine (1.6 mmol, 160 mg), and P(o-Tol)3 (0.11 mmol, 33 mg) were heated to 100 C in 5 mL
DMF
overnight. An additional 50 mg of 2-bromo-6-chloropyridine was added and the heating was continued for 2 h. The reaction was filtered and the filtrate was purified by reverse-phase chromatography (acetonitrile/water). The product fractions were concentrated the material was treated with 10 mL ethanol and heated gently for a few minutes. After cooling to room temperature and filtering, 65 mg of the title compound was obtained as a yellow solid. HPLC:
91.4%, rt = 9.2 min; HRMS: calculated 386.11670; found 386.11.598.

Ni H

tJ' [00330] Preparation of 5-{(E)-2-[4-(dimethylamino)phenyl]vinyl)-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile:

Following the procedure to prepare 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{4-[(4-methylpiperazin-1-yl)methyl]pyridin-2-yl} vinyl]nicotinonitrile , the title compound was prepared via the reaction of 5-iodo-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile with N,N-dimethyl-4-vinylaniline. MS 394.1 (M+H)+, HPLC purity 94.2% at 215 nm, it = 8.6 min [a].

HN

NH
I / N

[00331] Preparation of 4-[(4-methyl-lH-indol-5-yl)amino]-5-[(E)-2-{3-[(4-methylpiperazin-1-yl)methyl]phenyl}vinyl]nlcotinonitrile:
A mixture of 4-[(4-methyl-1 H-indol-5-yl)amino]-5-vinylnicotinonitrile (100 mg, 0.36 mmol), 1-(3-bromobenzyl)-4-methylpiperazine (116.3 mg, 0.43 mmol), Pd(OAc)2 (16.2 mg, 0.072 mmol) and P(o-Tol)3 (7.7 mg, 0.025 mmol) in 3.0 mL of DMF and 0.75 mL of TEA
was heated 120 C for 2.5 h. The mixture was cooled to room temperature, and was partitioned between dichloromethane and aqueous saturated sodium bicarbonate. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography, eluting with a gradient of 2% methanol in dichloromethane to 12% methanol in dichloromethane to provide 64.8 mg (39%) of 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{3-[(4-methylpiperazin-1-yl)methyl]phenyl}vinyl]nicotinonitrile as an off white solid, MS 463.3 (M+H)+, HPLC purity 95.5% at 215 nm, rt = 5.9 min [a].

&.NH
O N

[00332] Preparation of 4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-{5-[(4-methylpiperazin-1-yl)methyl]-3-furyl}vinyl]nicotinonitrile:
Following the procedure to prepare 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{3-[(4-methylpiperazin-1-yl)methyl]phenyl}vinyl]nicotinonitrile, 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{5-[(4-methylpiperazin-1-yl)methyl]-3-furyl}vinyl]nicotinonitrile was prepared via the reaction of 4-[(4-methyl-1 H-indol-5-yl)amino]-5-vinylnicotinonitrile with 1-[(4-bromo-2-furyl)methyl]-4-methylpiperazine . MS 453.2 (M+H)+, HPLC purity 96.3% at 215 nm, rt=5.2 min [a].

N

[00333] Preparation of 5-[(E)-2-(3-[(diethylamino)methyl]phenyl}vinyl]-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile:

Following the procedure to prepare 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{3-[(4-methylpiperazin-1-yl)methyl]phenyl}vinyl]nicotinonitrile, 5-[(E)-2-{3-[(diethylamino)methyl]
phenyl}vinyl]-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile was prepared via the reaction of u 4-[(4-methyl-1 H-indol-5-yl)amino]-5-vinylnicotinonitrile with N-(3-bromobenzyl)-N,N-diethyl amine. MS (ESI) m/z 436.1 (M+H)+, HPLC purity 91.1% at 215 nm, rt = 6.0 min [a].

MN
a~'NH
tJ'~
[00334] Preparation of 5-[(E)-2{4-[(diethylamino)methyl]phenyl}vinyl]-4-[(4-methyl-lH-indol-5-yl)amino]nicotinonitrile:
Following the procedure to prepare 4[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{3-[(4-methylpiperazin-1-yl)methyl]phenyl}vinyl]nicotinonitrile, 4-[(4-methyl-1 H-indol-5-yl) amino]-5-[(E)-2-{3-[(4-methylpiperazin-1-yl)methyl]phenyl}vinyl]nicotinonitrile was prepared via the reaction of 4-[(4-methyl-1 H-indol-5-yl)amino]-5-vinylnicotinonitrile with N-(4-bromobenzyl)-N,N-diethylamine. MS (ESI) m/z 436.1 (M+H)+, HPLC purity 90.4% at 215 nm, rt =
5.9 min [a].
N

[00335] Preparation of 5-[(E)-2-(4-[(dimethylamino)methyl]phenyl}vinyl]-4-[(4-methyl-I H-indol-5-yl)amino]nicotinonitrile:

Following the procedure to prepare 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{3-[(4-methylpiperazin-1-yl)methyl]phenyl}vinyl]nicotinonitrile, 5-[(E)-2-{4-[(dimethylamino)methyl]
phenyl}vinyl]- 4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile was prepared via the reaction of 4-[(4-methyl-1 H-indol-5-yl)amino]-5-vinylnicotinonitrile with 1-(4-bromophenyl)-N,N-dimethylmethanamine. MS (ESI) m/z 408.2; (M+H)+, HPLC, it = 5.4 min [a).

i N

[00336] Preparation of 5-[(E)-2-(4-ethoxyphenyl)vinyl]-44(4-methyl-1H-indol-5-yl) amino]nicotinonitrile:

Following the procedure to prepare 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{3-[(4-methylpiperazin-l-yl)methyl]phenyl}vinyl]nicotinonitrile, 5-[(E)-2-(4-ethoxyphenyl)vinyl]-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile was prepared via the reaction of 4-[(4-methyl-1 H-indol-5-yl)amino]-5-vinylnicotinonitrile with 4-iodophenetole. MS (ESI) m/z 395.2 (M+H)+, HPLC rt = 10.6 min [a].

Hv X.NH

[00337] Preparation of 4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-(4-propoxyphenyl) vinyl]nicotinonitrile:

Following the procedure to prepare 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{3-[(4-methylpiperazin-1-yl)methyl] phenyl}vinyl]nicotinonitrile, 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(4-propoxyphenyl)vinyl]nicotinonitrile was prepared via the reaction of 4-[(4-methyl-1 H-indol-5-yl)amino]-5-vinylnicotinonitrle with 4-n-propoxy-l-bromobenzene. MS
(ESI) m/z 409.2 (M+H)+, HPLC purity 99.3% at 215 nm, rt = 11.6 min [a].

NH

[00338] Preparation of 4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[4-(piperidin-1-ylmethyl)phenyl]vinyl}nicotinonitrile:
A reaction mixture of 5-[(E)-2-(4-formylphenyl)vinyl]-4-[(4-methyl-1 H-indol-5-yl)amino]
nicotinonitrile (70 mg, 0.185 mmol) and piperidine (79 mg, 0.926 mmol) in 3.0 mL of dichloromethane and 0.5 mL of 1-methyl-2-pyrrolidinone was stirred at room temperature for 30 minutes. To this was added NaBH(OAc)3 (196 mg, 0.926 mmol) over 10 min. The reaction mixture was stirred at room temperature for 20 h then concentrated. The residue was purified by HPLC (A: 0.1 %NH4OH in H2O; B: 0.1 %NH4OH in acetonitrile) providing 17 mg (20%) of 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[4-(piperidin-1-ylmethyl)phenyl]vinyl} nicotinonitrile as a pale yellow solid. MS 448.2 (M+H); HPLC 98% at 215 nm, rt = 6.0 min [a].

Ni N

[00339] Preparation of 4-[(4-methyl-1H-indol-5-yl)amino]-5-((E)-2-[4-(pyrrolidin-1-yl methyl)phenyl]vinyl}nicotinonitrile:

The title compound was prepared from 5-[(E)2-(4-formylphenyl)vinyl]-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile and pyrrolidine via the procedure used to prepare 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[4-(piperidin-1-ylmethyl)phenyl]vinyl}nicotinonitrile. MS 434.2 (M+H);
HPLC 99.1 % at 215 nm, rt = 5.7 min [a].

NH

I ' I \

[00340] Preparation of 5-{(E)-2-[4-(azetidin-1-ylmethyl)phenyl]vinyl)-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile:

The title compound was prepared from 5-[(E)-2-(4-formylphenyl)vinyl]-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile and azetidine via the procedure used to prepare 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[4-(piperidin-1-ylmethyl)phenyl]vinyl)nicotinonitrile. MS
420.2 (M+H);
HPLC 98.3% at 215 nm, rt = 5.8 min [a].

SNH

[00341] Preparation of 4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)=2-(4-[(4-pyridin-2-yI
piperazin-1-yl)methyl]phenyl}vinyl]nicotinonitrile:
The title compound was prepared from 5-[(E)-2-(4-formylphenyl)vinyl]-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile and 1-(2-pyridyl)piperazine via the procedure used to prepare 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[4-(piperidin-1-ylmethyl)phenyl]vinyl}
nicotinonitrile. MS
526.3 (M+H); HPLC 96.8% at 215 nm, rt = 5.8 min [a].

/ I H
H / 'N

[00342] Preparation of tert-butyl-3-({4-[(E)-2-{5-cyano-4-[(4-methyl-1H-indol-5-yI) amino] pyridin-3-yi}vinyl]benzyl}amino)azetidine-1-carboxylate: The title compound was prepared from 5-[(E)-2-(4-formylphenyl)vinyl]-4-[(4-methyl-1 H-indol-5-yl)amino] nicotinonitrile and tert-butyl 4-amino-l-azetidinecarboxylate via the procedure used to prepare 4-[(4-methyl-lH-indol-5-yl)amino]-5-{(E)-2-[4-(piperidin-1-=
ylmethyl)phenyl]vinyl}nicotinonitrile. MS 535.3 (M+H); HPLC 97.5% at 215 nm, rt 7.3 min [a].

NA
HN~ ~ I / / IN

[00343] Preparation of 4-[(4-methyl-1H-indol-5-yl)amino]-5-((E)-2-[4-(piperazin-1-ylmethyl)phenyl]vinyl}nicotinonitrile:
ter- Butyl-4-{4-[(E)-2-{5-cyano-4-[(4-methyl-1 H-indol-5-yl)amino]pyridin-3-yl}vinyl]benzyl) piperazine-l-carboxylate was prepared from 5-[(E)-2-(4-formylphenyl)vinyl]-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile and ter-butyl 1-piperazinecarboxylate via the procedure used to prepare ' 4-[(4-methyl-lH-indol-5-yl)amino]-5{(E)-2-[4-(piperidin-1 -ylmethyl)phenyl]vinyl}
nicotinonitrile. MS 549.3.

A solution of tert-butyl 4-{4-[(E)-2-{5-cyano-4-[(4-methyl-1 H-indol-5-yl)amino]pyridin-3-yl)vinyl]benzyl}piperazine-1-carboxylate (40 mg, 0.07 mmol) in 2.0 mL of dichloromethane was treated with trifluoroacetic acid (0.4 mL). The reaction mixture was stirred at room temperature for 3 h and subsequently concentrated. The residue was purified by preparative HPLC (A:
0.02%TFA in H2O; B: acetonitrile) providing 34 mg (83%) of 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[4-(piperazin-1-ylmethyl) phenyl] vinyl}nicotinonitrile. MS (M+H) 449.3; HPLC 96.7% at 215 nm, rt = 5.2 min [a].

NH
N

[00344] Preparation of 5-[2-(4-methoxyphenyl)ethyl]-4-[(4-methyl-1H-indol-5-yl)amino]
nicotinonitrile:

A solution of 5-[(E)-2-(4-methoxyphenyl)vinyl]-4-[(4-methyl-lH-indol-5-yl)amino]nicotinonitrile (20 mg, 0.05 mmol) in CH3OH (4 ml-) was hydrogenated over 10% Pd/C (10 mg) at 50 psi of H2 pressure at room temperature for 12 h then filtered through a pad of Celite under N2. The filtrate was concentrated and the residue was dried in vacuo to give 20 mg (99%) of 5-[2-(4-methoxyphenyl)ethyl]-4-[(4-methyl-1 H-indol-5-yl)amino] nicotinonitrile as a yellow solid. MS
383.2 (M+H); HPLC 84% at 215 nm, rt = 9.3 min [a].

NH

[00345] Preparation of 5-(2-biphenyl-4-ylethyl)-4-[(4-methyl-1H-indol-5-yl)amino]
nicotinonitrile:

The title compound was prepared from 5-[(E)-2-biphenyl-4-ylvinyl]-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile via the procedure used to prepare 5-[2-(4-methoxyphenyl)ethyl]-4-[(4-=
methyl-1 H-indol-5-yl)amino]nicotinonitrile. MS 429.3 (M+H); HPLC 87.4 % at 215 nm, rt 11.6 min [a].

Ni -iN

[00346] Preparation of 4-[(4-methyl-1 H-indol-5-yl)amino]-5-(2-phenylethyl) nicotinonitrile:

The title compound was prepared from 4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-phenylvinyl]nicotinonitrile via the procedure used to prepare 5-[2-(4-methoxyphenyl)ethyl]-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile. MS 353.2 (M+H); HPLC 96.6% at 215 nm, rt =
8.9 min [a].

N

[00347] Preparation of 6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-(2-phenylethyl) nicotinonitrile:

The title compound was prepared from 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-phenylvinyl]nicotinonitrile via the procedure used to prepare 5-[2-(4-methoxyphenyl)ethyl]-4-=
[(4-methyl-1 H-indol-5-yl)amino] nicotinonitrile. MS 367.2 (M+H); HPLC 97.7%
at 215 nm, rt 9.0 min [a].

Ni N ~ I

[00348] Preparation of 4-[(4-methyl-1H-indol-5-yl)amino]-5-(2{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}ethyl)nicotinonitrile:

The title compound was prepared from 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{4-[(4-methylpiperazin-1-yl)carbonyl]phenylvinyl]nicotinonitrile via the procedure used to prepare 5-[2-(4-methoxyphenyl)ethyl]-4-[(4-methyl-1 H-indol-5-yl)amino] nicotinonitrile.
MS 479.2 (M+H);
HPLC 95% at 215 nm, rt =.4.9 min [a].

S ~` ~

[00349] Preparation of 4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-(4-methyl-1,3-thiazol-5-yl)vinyl]nicotinonitrile:

The procedure for 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-pyrazin-2-ylvinyl]nicotinonitrile was followed using 4-methyl-5-vinylthiazole (70.2 uL, 0.642 mmol). The crude residue was purified by HPLC to provide 3.3 mg (3%) of the title compound as a tan solid.
MS 372.2 (M+H). HPLC rt = 7.5 min [a].

N-H
/I

[00350] Preparation of 5-[(1 E)-3-(1 H4midazol-1-yl)prop-1-en-1-yl]-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile:

The procedure for 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-pyrazin-2-ylvinyl]nicotinonitrile was followed using 1-allylimidazole (69 uL, 0.642 mmol). The crude residue was purified by HPLC to provide 11.2 mg (10%) of the title compound as a tan solid. 'H NMR
(400 MHz, DMSO-d6) 2.30 (s, 3H), 4.72 (d, J = 4 Hz, 2H), 6.36 (m, 1 H), 6.52 (bs, 1 H), 6.85 (d, J = 16 Hz, 1 H), 6.91. (m, 2H), 7.24 (m, 2H), 7.36 (bs, 1 H), 7.71 (bs, 1 H), 8.27 (s, 1 H), 8.34 (s, 1 H), 8.68 (s, 1 H), 11.16 (s, 1 H); MS 355.2 (M+H).

M
.- ~

N

[00351] Preparation of 5-[(E)-2-cyclohexylvinyl]-4-[(4-methyl-1H-indol-5-yl)amino]
nicotinonitrile:

The procedure for 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-pyrazin-2-ylvinyl]nicotinonitrile was followed using vinylcyclohexane (88 uL, 0.642 mmol). The crude residue was purified by HPLC to provide 3.0 mg (3%) of the title compound as a tan solid. MS 357.2 (M+H). HPLC rt = 11.1 min [a].

o [00352] Preparation of 1-(3-iodo-4-methylbenzoyl)-4-methylpiperazine:

A mixture of 3-iodo-4-methylbenzoic acid (5.24 g, 20.0 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (4.22 g, 22 mmol) and DIEA (10.5 mL, 60 mmol) in dichloromethane (100 ml-) was stirred for 10 minutes, after which N-methylpiperazine (2.44 mL, 22 mmol) was added. The reaction was stirred for 18 h before being washed with water (3 x 50 mL), 0.1 N aq. NaOH (2 x 50 ml-) and brine (2 x 50 mL). The solution was dried with anhydrous MgSO4, filtred and concentrated in vacuo. The residue was purified by flash chromatography using 100:10:1 DCM/MeOH/aq. NH4OH to provide 3.54 g (52%) of the title compound as a white solid. 'H NMR (400 MHz, CDCI3) 2.32-2.45 (m, 10H), 3.45 (m, 2 H), 3.76 (m, 2H), 7.26 (bs, 2H), 7.86 (s, 1 H); MS 345.0 (M+H).

[00353] Preparation of 1-(3-iodo-4-methylbenzyl)-4-methylpiperazine:

To a THE solution (5 mL) of 1-(3-iodo-4-methylbenzoyl)-4-methylpiperazine (300 mg, 0.87 mmol) at room temperature was added 1 M BH3-THF (2.6 mL, 2.6 mmol). The solution was heated to reflux for one hour. After cooling to room temperature, ethanol (2 ml-) was added carefully. The solution was concentrated in vacuo and the residue purified by flash chromatography with 1:1 EtOAc/hexane to provide 172 mg (62%) of the title compound as a white solid. 'H NMR (400 MHz, CDCI3) 2.41 (s, 3H), 2.46-2.50 (m, 2 H), 2.63 (s, 3H), 2.74-2.83 (m, 4 H), 3.06-3.10 (m, 2 H), 3.49 (s, 2H), 7.25 (bs, 2H), 7.76 (s, 1H);
MS 331.0 (M+H).
[00354] Preparation of 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{2-methyl-5-[(4-methylpiperazin-1-yl)carbonyl]phenyl}vinyl]nicotinonitrile:
A mixture ' of 4-[(4-methyl-1 H-indol-5-yl)amino]-5-vinylnicotinonitrile (151 mg, 0.55 mmol), Pd(OAc)2 (22.5 mg, 0.1 mmol), P(o-Tol)3 (22.5 mg, 0.035 mmol), 1-(3-iodo-4-methylbenzoyl)-4-methylpiperazine (172 mg, 0.5 mmol), triethylamine (0.7 ml-) and DMF (2.5 ml-) was heated to 120 C for 3 hours. The cooled solution was diluted with EtOAc (100 mL), washed with water (3 x 20 mL), dried over anhydrous MgSO4i filtered and concentrated in vacuo. The residue was purified by flash chromatography using 100:10:1 dichloromethane/methanol/aq.

NH4OH to provide 117 mg (48%) of the title compound as a white solid. 1H NMR
(400 MHz, DMSO-d6) 2.18 (s, 3H), 2.33 (s, 3H), 2.47 (s, 3H), 3.34 (m, 8H), 6.54 (bs, 1 H), 6.94 (d, J = 8 Hz, 1 H), 7.20 (m, 3H), 7.40 (m, 3H), 7.86 (s, 1 H), 8.28 (s, 1 H), 8.64 (s, 1 H), 8.92 (s, 1 H), 11.20 (s, 1 H); MS 491.4 (M+H).

[00355] Preparation of 4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-(2-methyl-5-[(4-methylpiperazin-l-yl)methyl]phenyl}vinyl]nicotinonitrile:
The procedure for 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(2-methyl-5-[(4-methylpiperazin-1-yl)carbonyl]phenyl}vinyl]nicotinonitrile was followed using 1-(3-iodo-4-methyl benzyl)-4-methylpiperazine (165 mg, 0.5 mmol). Flash chromatography provided 83.5 mg (35%) of the title compound as an amber glass. 1H NMR (400 MHz, DMSO-d6) 2.27 (s, 3H), 2.33 (s, 3H), 2.40 (s, 3H), 3.33 (m, 8H), 3.43 (bs, 2H), 6.53 (m, 1 H), 6.95 (d, J = 8 Hz, 1 H), 7.14 (m, 3H), 7.25 (d, J = 8 Hz, 1 H), 7.31 (d, J = 4 Hz, 1 H), 7.36 (m, 1 H), 7.56 (s, 1 H), 8.29 (s, 1 H), 8.60 (s, 1 H), 8.86 (s, 1 H), 11.16 (s, 1 H); MS 477.4 (M+H).

NH
VI

[00356] Preparation of 5-isopropenyl-4-[(4-methyl-lH-indol-5-yl)amino]
nicotinonitrile:
A mixture of 5-iodo-4-[(4-methyl-1 H-i ndol-5-yl)a mino]n icoti non itrile (351 mg, 0.94 mmol), Pd(PPh3)4 (37 mg, 0.03 mmol) and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (201 mg, 1.13 mmol) in 1,2-dimethoxyethane (5 ml-) and saturated NaHCO3 (5 ml-) was heated to 80 C for 20 h.. The resulting mixture was cooled to room temperature. The reaction was diluted with ethyl acetate (30 mL) and washed with sodium bicarbonate solution (30 mL) and brine (30 mL) sequentially. The organic phase was dried over magnesium sulfate and filtered through magnesol. Flash column chromatography on silica gel (ethyl acetate-hexanes 1:1) afforded 231 mg (85 %) of the title compound; MS 289.2 (M+H). HPLC rt =
6.8 min [a].
NI/\

[00357] Preparation of 5-(2-{2-methoxy-4-[(4-methylpiperazin-1-yl)methyl]phenyl) ethyl)-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile:

4-[(4-Methyl-1 H-indol-5-yl)amino]-5-vinylnicotinonitrile (300 mg, 1.094 mmol) was dissolved in a mixture of DMF (3 ml) and triethylamine (0.75 ml) and subsequently treated with 1-(4-iodo-3-methoxybenzyl)-4-methylpiperazine (380 mg, 1.098 mmol), Pd(OAc)2 (50 mg, 0.223 mmol) and P(o-Tol)3 (17 mg, 0.056 mmol). The reaction mixture was stirred at 120 C
under nitrogen for 4 hr. Upon cooling to room temperature, the reaction was diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate, dried over MgSO4 and concentrated to give a dark residue. The residue was redissolved in methanol (20 ml) and treated with Pd/C
(10% wt., 40 mg). The reaction was shaken under hydrogen gas (45 psi) for 18 hr. The resulting crude compound was purified by HPLC to give 12.5 mg (2.3%) of 5-(2-{2-methoxy-4-[(4-methylpiperazin-1-yl)methyl]phenyl)ethyl)-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile as a light tan solid. MS 495.2 (M+H); HPLC rt = 3.1, min [e].

(00358] Preparation of 1-acetyl-4-[(6-bromopyridin-2-yl)methyl]piperazine:
6-Bromopyridine-2-carboxaldehyde (2.0 g, 10.75 mmol) and 1-acetylpiperazine (6.9 g, 53.75 mmol) were dissolved in THE (120 ml). Upon cooling to 0 C, sodium triacetoxyborohydride (11.39 g, 53.74 mmol) was added to the reaction solution with a catalytic amount of HOAc.
The mixture was slowly warmed to room temperature and was stirred at room temperature overnight. The suspension was filtered, and the filtrate was diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate, dried over MgSO4 and concentrated to give a light color syrup. The syrup was purified by column chromatography, eluting with 10-15% gradient of methanol in dichloromethane, to give 2.36 g (88%) of 1-acetyl-4-[(6-bromopyridin-2-yl)methyl]piperazine as a light color syrup. MS 298.1 (M+H);
HPLC rt = 3.6 min [a].

[00359] Preparation of 1-acetyl-4-[(6-vinylpyridin-2-yl)methyl]piperazine:
1-acetyl-4-[(6-bromopyridin-2-yl)methyl]piperazine (500 mg, 1.677 mmol) and tributylvinyltin (0.98 ml, 3.356 mmol) were dissolved in anhydrous toluene (10 ml). The solution was treated with Pd(PPh3)2CI2 (59 mg, 0.084 mmol) and Cul (16 mg, 0.084 mmol) and was heated to reflux overnight. Upon cooling, the reaction was filtered and the filtrate was partitioned between dichloromethane and saturated aqueous sodium bicarbonate then dried over MgSO4 and concentrated to give a yellow syrup. The crude compound was purified by column chromatography, eluting with 5-15% gradient methanol in dichloromethane, to give 163 mg (40%) of 1-acetyl-4-[(6-vinylpyridin-2-yl)methyl]piperazine as a brown syrup.
MS 246.2 (M+H);
HPLC rt = 10.5 min [a].

NH

ry ~ / N

[00360] Preparation of 5-[(E)-2{6-[(4-acetylpiperazin-1-yl)methyl]pyridin-2-yl} vinyl]-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile:
5-lodo-4-[(4-methyl-lH-indol-5-yl)amino]nicotinonitrile (164 mg, 0.438 mmol) was dissolved in a mixture of DMF (2 ml) and triethylamine (0.5 ml) and treated with 1-acetyl-4-[(6-vinylpyridin-2-yl)methyl]piperazine (129 mg, 0.526 mmol), Pd(OAc)2 (20 mg, 0.089 mmol) and P(o-Tol)3 (7.0 mg, 0.023 mmol). The reaction mixture was stirred at 100 C under nitrogen for 2 hr. The reaction was cooled to room temperature and diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate, dried over MgSO4 and concentrated to give a dark residue. The resulting crude compound was purified by column chromatography, eluting with 5-10% gradient methanol in dichloromethane, to give 100 mg (46%) of 5-[(E)-2-{6-[(4-acetylpiperazin-1-yl)methyl]pyridin-2-yl}vinyl]-4-[(4-methyl-1 H-indol-5-yl)amino] nicotinonitrile as a yellow solid. MS 492.4 (M+H); HPLC it = 5.1 min [a].

,NH
N

O

[00361] Preparation of 5-[(E)-2-{2-methoxy-5-[(4-methylpiperazin-1-yl)methyl]
phenyl}vinyl]-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile:

4-[(4-Methyl-1 H-indol-5-yl)amino]-5-vinylnicotinonitrile (100 mg, 0.36 mmol) was dissolved in a mixture of DMF (2 ml) and triethylamine (0.5 ml). 1-(3-lodo-4-methoxybenzyl)-4-methylpiperazine (151 mg, 0.44 mmol), Pd(OAc)2 (16 mg, 0.07 mmol) and P(o-Tol)3 (6.0 mg, 0.02 mmol) were added and the reaction mixture was stirred at 120 C under nitrogen for 8 hr.
Upon cooling to room temperature, the reaction was diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate, dried over MgSO4 and concentrated to give a dark residue. The resulting crude compound was purified by HPLC to give 78 mg (43%) of 5-[(E)-2-{2-methoxy-5-[(4-methylpiperazin-1-yl)methyl]phenyl}vinyl]-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile as a yellow solid. MS 493.4 (M+H); HPLC rt = 5.7 min [a].
L u \ I / N
O

[00362] Preparation of 5-((E)-2-[2-methoxy-5-(piperazin-1 ylmethyl) phenyl]vinyl}-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile:

4-[(4-Methyl-1 H-indol-5-yl)amino]-5-vinylnicotinonitrile (200 mg, 0.73 mmol) was dissolved in a mixture of DMF (2 ml) and triethylamine (0.5 ml). Teri Butyl 4-(3-iodo-4-methoxybenzyl)piperazine-1-carboxylate (380 mg, 0.88 mmol), Pd(OAc)2 (33 mg, 0.15 mmol) and P(o-Tol)3 (11 mg, 0.04 mmol). The reaction mixture was stirred at 120 C
under nitrogen for 8 hr then cooled to room temperature and diluted with dichloromethane. The solution was washed with saturated aqueous sodium bicarbonate, dried over MgSO4 and concentrated to give a dark residue. The residue was redissolved in dichloromethane and trifluoroacetic acid (ratio 4:1) and stirred at room temperature for 2 hr. The reaction was quenched with saturated aqueous sodium bicarbonate, dried over MgSO4 and concentrated to give a dark syrup. The resulting crude compound was purified by HPLC to give 12 mg (3.4%) of 5-{(E)-2-[2-methoxy-5-(piperazin-1-ylmethyl)phenyl]vinyl}-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile as a yellow solid. MS 479.4 (M+H); HPLC rt = 5.4 min [a].

o~
a o`1 [00363] Preparation of 3-bromo-2-methoxybenzaldehyde:
3-Bromo-2-hydroxybenzaldehyde (5.0 g, 24.87 mmol) was dissolved in acetone (200 ml) and treated with iodomethane (5.3 g, 37.34 mmol) and potassium carbonate (5.2 g, 37.63 mmol).
The mixture was heated to 60 C for 2 hr then cooled to room temperature and filtered. The filtrate was concentrated to dryness and re-dissolved in ethyl acetate. The solution was washed with saturated aqueous sodium bicarbonate and dried over MgSO4. After concentration, the residue was passed through a layer of silica gel, which was eluted with 50%
ethyl acetate in hexanes. The eluent was concentrated to give 2.0 g (93%) of 3-bromo-2-methoxybenzaldehyde as a colorless syrup. MS 215.0 (M+H); HPLC rt = 13.8 min [a].

ar [00364] Preparation of 1-(3-bromo-2-methoxybenzyl)-4-methylpiperazine:
3-Bromo-2-methoxybenzaldehyde (1.00 g, 4.65 mmol) and 1-methylpiperazine (2.33 g, 23.26 mmol) were dissolved in THE (40 ml) and treated with sodium triacetoxyborohydride (4.93 g, 23.26 mmol) and acetic acid (a few drops). After stirring overnight at room temperature, the reaction was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic extract was dried over MgSO4, concentrated, and purified by column chromatography (5%-15% gradient methanol in dichloromethane) to give 500 mg (36%0) of.1-(3-bromo-2-methoxybenzyl)-4-methylpiperazine as a colorless syrup. MS 299.0 (M+H); HPLC
rt = 5.7 min [a].

[00365] Preparation of 5-[(E)-2-{2-methoxy-3-[(4-methylpiperazin-1-yl)methyl]
phenyl}vinyl]-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile:

4-[(4-Methyl-1 H-ind ol-5-yl)amino]-5-vinyin icoti non itrile (100 mg, 0.36 mmol) was dissolved in a mixture of DMF (2 ml) and triethylamine (0.5 ml). The solution was treated with 1-(3-bromo-2-methoxybenzyl)-4-methylpiperazine (132 mg, 0.44 mmol), Pd(OAc)2 (16 mg, 0.07 mmol) and P(o-Tol)3 (6.0 mg, 0.02 mmol) and heated to 120 C under nitrogen for 8 h. The reaction was cooled to room temperature and diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate, dried over MgSO4 and concentrated to give a dark residue.
The resulting crude compound was purified by HPLC to give 58 mg (32%) of 5-[(E)-2-{2-methoxy-3-[(4-methylpiperazin-1-yl)methyl]phenyl}vinyl]-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile as a light yellow solid. MS 493.2 (M+H); HPLC rt = 5.7 min [a].

o [00366] Preparation of tert-butyl 4-(3-iodo-2-methoxybenzyl)piperazine-l-carboxylate:
3-Bromo-2-methoxybenzaldehyde (1.50 g, 6.98 mmol) and 1-Boc-piperazine (6.50 g, 34.90 mmol) were dissolved in THE (60 ml) and treated with sodium triacetoxyborohydride (7.39 g, 34.87 mmol) and acetic acid (a few drops). The reaction was stirred at room temperature overnight then partitioned between dichloromethane and saturated aqueous sodium bicarbonate and dried over MgSO4. The solution was concentrated to dryness and the residue was purified by column chromatography (0%-10% gradient methanol in dichloromethane) to give 1.8 g (67%) of tert-butyl 4-(3-iodo-2-methoxybenzyl)piperazine-1-carboxylate as a colorless syrup. MS 385.1 (M+H); HPLC rt = 8.7 min [a].

)6NH
tl I ~N
`v ~v ~ v y ~v [00367] Preparation of 5-{(E)-2-[2-methoxy-3-(piperazin-l-ylmethyl)phenyl]vinyl}-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile:

4-[(4-Methyl-1 H-indol-5-yl)amino]-5-vinylnicotinonitrile (200 mg, 0.73 mmol) was dissolved in a mixture of DMF (2 ml) and triethylamine (0.5 ml) and treated with tert-butyl 4-(3-iodo-2-methoxybenzyl)piperaziine-1-carboxylate (339 mg, 0.88 mmol), Pd(OAc)2 (33 mg, 0.15 mmol) and P(o-Tol)3 (11 mg, 0.04 mmol). The reaction mixture was stirred at 120 C
under nitrogen for 8 h then cooled and diluted with dichloromethane. The solution was washed with saturated aqueous sodium bicarbonate, dried over MgSO4 and concentrated to give a dark residue. The residue was redissolved in dichloromethane and trifluoroacetic acid (ratio 4:1) and stirred at room temperature for 2 h. The reaction was quenched with saturated aqueous sodium bicarbonate, dried over MgSO4 and concentrated to give a dark syrup. The resulting crude compound was purified by HPLC to give 39 mg (11%) of 5-{(E)-2-[2-methoxy-3-(piperazin-1-ylmethyl)phenyl]vinyl}-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile as a light yellow solid.
MS 479.2 (M+H); HPLC rt = 5.5 min [a].

NH
N
N

[00368] Preparation of 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{6-[(4-methyl piperazin-1-yl)methyl]pyridin-2-yl}vinyl]nicotinonitrile:
5-Bromo-6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile (200 mg, 0.586 mmol) was dissolved in a mixture of DMF (2 ml) and triethylamine (0.5 ml). The reaction was treated with 1-methyl-4-[(6-vinylpyridin-2-yl)methyl]piperazine (153 mg, 0.704 mmol), Pd(OAc)2 (26 mg, 0.116 mmol) and P(o-Tol)3 (9.0 mg, 0.030 mmol). The reaction mixture was stirred at 100 C
under nitrogen for 8 h. Upon cooling to room temperature, the reaction was diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate, dried over MgSO4 and concentrated to give a dark residue. The resulting crude compound was purified by HPLC to give 89 mg (32%) of 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{6-[(4-methylpiperazin-1 -yl) methyl]pyridin-2-yl}vinyl]nicotinonitrile as a light purple solid. MS 478.3 (M+H); HPLC rt = 5.0 min [a].

[00369] Preparation of 1-(3-bromo-5-methoxybenzyl)-4-methylpiperazine:
4-Bromo-2-hydroxybenzaldehyde (1.0 g, 4.65 mmol) and 1-methylpiperazine (2.33 g, 23.26 mmol) were dissolved in THE (40 ml) and treated with sodium triacetoxyborohydride (4.93 g, 23.26 mmol) and acetic acid (a few drops). The reaction was stirred at room temperature overnight then partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The solution was dried over MgSO4, concentrated, and purified by column chromatography (5% methanol in dichloromethane) to give 870 mg (63%) of 1-(3-bromo-5-methoxybenzyl)-4-methylpiperazine as a colorless syrup. MS 299.1 (M+H); HPLC
it = 5.1 min [a).

NH

[00370] Preparation of 5-[(E)-2-{3-methoxy-4-[(4-methylpiperazin-1-yl)methyl]phenyl}
vinyl]-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile:

4-[(4-methyl-1 H-indol-5-yl)amino]-5-vinylnicotinonitrile (100 mg, 0.36 mmol) was dissolved in a mixture of DMF (2 ml) and triethylamine (0.5 ml) and treated with 1-(3-bromo-5-methoxybenzyl)-4-methylpiperazine (132 mg, 0.44 mmol), Pd(OAc)2 (16 mg, 0.07 mmol) and P(o-Tol)3 (6.0 mg, 0.02 mmol). The reaction mixture was stirred at 120 C under nitrogen for 8 h. The reaction was cooled to room temperature, diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate, dried over MgSO4 and concentrated to give a dark residue. The resulting crude compound was purified by HPLC to give 55 mg (31 %) of 5-[(E)-2-{3-methoxy-4-[(4-methylpiperazin-1-yl)methyl]phenyl}vinyl]-4-[(4-methyl-1 H-indol-5-yl)amino]
nicotinonitrile as a light yellow solid. MS 493.3 (M+H); HPLC rt = 5.3 min [a].

I AO

[00371] Preparation of tert-butyl 4-(3-bromo-5-methoxybenzyl)piperazine-1-carboxylate: .

4-Bromo-2-hydroxybenzaldehyde (1.50 g, 6.98 mmol) and 1-Boc-piperazine (6.50 g, 34.90 mmol) were dissolved in THE (60 ml) and treated with sodium triacetoxyborohydride (7.39 g, 34.87 mmol) and acetic acid (a few drops). The reaction was stirred overnight at room temperature then partitioned between dichioromethane and saturated aqueous sodium bicarbonate. After drying over MgSO4, the solution was concentrated and purified by column chromatography (0%-6% gradient methanol in dichloromethane). to give 2.4 g (89%) of tert-butyl 4-(3-bromo-5-methoxybenzyl)piperazine-1-carboxylate as a white solid. MS
385.1 (M+H); HPLC rt = 12.2 min [a].

Ni ` r 1 [00372] Preparation of 5-{(E)-2-[3-methoxy-4-(piperazin-1-ylmethyl)phenyl]vinyl}-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile:

4-[(4-Methyl-1 H-indol-5-yl)amino]-5-vinylnicotinonitrile (200 mg, 0.73 mmol) was dissolved in a mixture of DMF (2 ml) and triethylamine (0.5 ml) and treated with tent-butyl 4-(3-bromo-5-methoxybenzyl)piperazine-1-carboxylate (562 mg, 1.46 mmol), Pd(OAc)2 (33 mg, 0.15 mmol) and P(o-Tol)3 (11mg, 0.04 mmol). The reaction mixture was stirred at 120 C
under nitrogen for 8 h. The reaction was cooled to room temperature and diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate, dried over MgSO4 and concentrated to give a dark residue. The residue was redissolved in dichloromethane and trifluoroacetic acid (ratio 4:1) and stirred at room temperature for 2 h. After quenching with saturated aqueous sodium bicarbonate, the organic layer was dried over MgSO4 and concentrated to give a dark syrup. The resulting crude compound was purified by HPLC to give 32 mg (9.2%) of 5-{(E)-2-[3-methoxy-4-(piperazin-1-ylmethyl)phenyl]vinyl}-4-[(4-methyl-1 H-indol-5-yl)amino]
nicotinonitrile as a light yellow solid. MS 479.3 (M+H); HPLC rt = 5.0 min [a].
CH

[00373] Preparation of (6-vinylpyridin-2-yl)methanol:

(6-Bromopyridine-2-yl)methanol (5.00 g, 26.59 mmol) and tributylvinyltin (15.5 ml, 53.09 mmol) were dissolved in anhydrous toluene (100 ml) and treated with Pd(PPh3)4 (1.54 g, 1.33 mmol).
The reaction mixture was heated to reflux for 8 h then cooled to room temperature and filtered.
The filtrate was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic layer was dried over MgSO4 and concentrated to give a yellow residue. The crude compound was purified by column chromatography (5-10%
gradient methanol indichloromethane) to give 2.06g (57%) of (6-vinylpyridin-2-yl)methanol as a yellow syrup. MS 136.1 (M+H).

[00374] Preparation of 5-{(E)-2-[6-(hydroxymethyl)pyridin-2-yl]vinyl}-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile:

5-lodo-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile (2.0 g, 5.34 mmol) was dissolved in a mixture of DMF (24 ml) and triethylamine (6 ml) and treated with (6-vinylpyridin-2-yl)methanol (866 mg, 6.41 mmol), Pd(OAc)2 (240 mg, 1.07 mmol) and P(o-Tol)3 (82 mg, 0.27 mmol). The reaction mixture was stirred at 110 C under nitrogen for 5 h then cooled to room temperature and diluted with dichloromethane. The resulting solution was washed twice with saturated aqueous sodium bicarbonate. A precipitate formed during the 2nd wash and was collected by filtration and washed with dichloromethane and water giving 1.6 g (78%) of 5-{(E)-2-[6-(hydroxyl methyl)pyridin-2-yl]vinyl}-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile as a yellow solid. MS 382.1 (M+H); HPLC rt = 5.9 min [a].

Ni H

fJ' [00375] Preparation of 4-[(4-methyl-1H-indol-5-yl)amino]-5-((E)-2-[6-(piperidin-1-ylmethyl)pyridin-2-yl]vinyl)nicotinonitrile:
A solution of 5-{(E)-2-[6-(hydroxymethyl)pyridin-2-yl]vinyl)-4-[(4-methyl-1 H-indol-5-yl) amino] nicotinonitrile (100 mg, 0.262 mmol) in a mixture of THE (5 ml) and DMF
(2.5 ml) was treated with triethylamine (183 pL, 1.313 mmol). The resulting solution was stirred under nitrogen at room temperature for 10 min then treated dropwise with methanesulfonyl chloride (61 pL, 0.788 mmol). The reaction was stirred overnight at room temperature then treated with piperidine (104 NL, 1.050 mmol). After allowing the reaction to continue stirring overnight, the solvent was removed and the residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic layer was dried over MgSO4 and concentrated to give a dark syrup. The resulting residue was purified by HPLC to give 29 mg (25%) of 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[6-(piperidin-1-ylmethyl)pyridin-2-yl]vinyl}nicotinonitrile as a light yellow solid. MS 449.2 (M+H); HPLC rt = 5.8 min [a].

NH

[00376] Preparation of 4-[(4-methyl-1H-indol-5-yl)amino]-5-((E)-2-[64pyrrolidin-1-ylmethyl)pyridin-2-yl]vinyl}nicotinonitrile:

The title compound was prepared from 5-{(E)-2-[6-(hydroxymethyl)pyridin-2-yl]vinyl}-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile (200 mg, 0.524 mmol) and pyrrolidine by the procedure utilized for 4-[(4-methyl-lH-indol-5-yl)amino]-5-{(E)-2-[6-(piperidin-l-ylmethyl) pyridin-2-yl]vinyl}nicotinonitrile. MS 435.2 (M+H); HPLC rt = 5.6 min [a].

Ni [00377] Preparation of 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[6-(piperazin-1-yl methyl)pyridin-2-yl]vinyl}nicotinonitrile:

5-{(E)-2-[6-(hydroxymethyl)pyridin-2-yl]vinyl)-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile (200 mg, 0.524 mmol) was dissolved in a solvent mixture of THE (10 ml) and DMF
(5 ml) and treated with triethylamine (366 pL, 2.626 mmol).. The solution was stirred under nitrogen at room temperature for 10 min then treated dropwise with methanesulfonyl chloride (122 pL, 1.577 mmol). The reaction was allowed to stir at room temperature for 2 h then treated with 1-Boc-piperazine (390 mg, 2.094 mmol). The reaction was allowed to stir for 8 h at room temperature. The solvent was removed and the residue was partitioned between CH2CI2 and saturated aqueous sodium bicarbonate. The organic layer was dried over MgSO4 and concentrated to give a dark syrup. The syrup was redissolved in dichioromethane and trifluoroacetic acid (ratio 4:1) and stirred at room temperature for 2 h. The reaction was quenched with saturated aqueous sodium bicarbonate, dried over MgSO4 and concentrated to give a dark residue. The resulting crude material was purified by HPLC to give 48 mg (20%) of 4-[(4-methyl-lH-indol-5-yl)amino]-5-{(E)-2-[6-(piperazin-1-ylmethyl)pyridin-2-yl]vinyl) nicotinonitrile as a light yellow solid. MS 450.2 (M+H); HPLC rt = 5.0 min [a].

[00378] Preparation of (6-vinylpyridin-3-yl)methanol:

(6-Bromopyridine-3-yl)methanol (1.00 g, 5.313 mmol) and tributylvinyltin (3.10 ml, 10.617 mmol) were dissolved in anhydrous toluene (20 ml) and treated with Pd(PPh3)4 (308 mg, 0.266 mmol). The reaction mixture was heated to reflux for 3 h then cooled to room temperature and filtered. The filtrate was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic layer was dried over MgSO4 and concentrated to give a yellow residue. The crude compound was purified by column chromatography (3-8%
gradient methanol in dichloromethane) to give 516 mg (31%) of (6-vinylpyridin-3-yl)methanol as a yellow syrup. MS 136.1 (M+H).

[00379] Preparation of 5-{(E)-2-[5-(hydroxymethyl)pyridin-2-yl]vinyl}-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile:

5-iodo-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile (1.0 g, 2.67 mmol) was dissolved in a mixture of DMF (12 ml) and triethylamine (3 ml) and treated with (6-vinylpyridin-3-yl)methanol (433 mg, 3.20 mmol), Pd(OAc)2 (120 mg, 0.54 mmol) and P(o-Tol)3 (41 mg, 0.14 mmol). The reaction mixture was stirred at 110 C under nitrogen for 5 h. The reaction was cooled to room temperature and diluted with dichloromethane then washed twice with saturated aqueous sodium bicarbonate. A precipitate formed during the 2nd wash and was collected by filtration and washed with dichloromethane and water giving 610 mg (60%) of 5-{(E)-2-[5-(hydroxymethyl)pyridin-2-yl]vinyl}-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile as a yellow solid. MS 382.1 (M+H); HPLC rt = 5.3 min [a].

N

N M
NM
l0l [00380] Preparation of 4-[(E)-2-{5-cyano-4-[(4-methyl-1H-indol-5-yl)amino]pyridin-3-yl}
vinyl]-N-phenylpiperidine-1-carboxamide:
A mixture of 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-piperidin-4-ylvinyl]nicotinonitrile as its TFA salt (61 mg, 0.13 mmol), phenyl isocyanate (20 mg, 0.17 mmol), and triethylamine (39 mg, 0.39 mmol) in 1 mL of DMF was stirred at room temperature for 45 min. The mixture was purified by H PLC to give 4-[(E)-2-{5-cyano-4-[(4-methyl-1H-indol-5-yl)amino]pyridin-3-yl}vinyl]-N-phenylpiperidine-1-carboxamide. MS 477.2 (M+H); HPLC rt = 1.92 min [d].

[00381] Preparation of compounds in Table 10:

The compounds in Table, 10 were prepared from 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-piperidin-4-ylvinyl]nicotinonitrile, the corresponding electrophile and triethylamine via the procedure used to prepare 4-[(E)-2-{5-cyano-4-[(4-methyl-1 H-indol-5-yl)amino]pyridin-3-yl}vinyl]-N-phenylpiperidine-1-carboxamide.

Table 10:

HPLC MS r.t.
-[(4-methyl-lH-indol-5-yl)amino]-5-{(E)-2-[1- 98.2 .05 min. [d]
hen Isulfon i endin-4- 1 vin I nicotinonitrile 5-[(E)-2-(1-benzoylpiperidin-4-yl)vinyl]-4-[(4-methyl-1H- 62.2 1.93 min. [d]
indol-5- I amino nicotinonitrile -[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[1-(3-phenyl 90.3 .04 min. [d]
ro ano I i eridin-4- I vin I nicotinonitrile -[(E)-2-{5-cyano-4-[(4-methyl-1 H-indol-5-yl)amino] 43.2 1.81 min. [d]
ridin-3- I vin I -N- ro I i eridine-l-carboxamide (E)-2-[l-(isopropylsulfonyl)piperidin-4-yl]vinyl}-4-[(4- 64.2 1.89 min. [d]
meth l-1H-indol-5- I amino nicotinonitrile Ni Y llO
O / N

[00382] Preparation of tert-butyl 4-[(E)-2-(5-cyano-4-[(4-methyl-1H-indol-5-yl) amino]pyridin-3-yl)vinyl]piperidine-1-carboxylate:
A mixture of 5-iodo-4-(4-methyl-1 H-indol-5-ylamino)nicotinonitrile (843 mg, 2.26 mmol), (E)-tert-butyl 4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)piperidine-1-carboxylate (1.14 g, 3.38 mmol), cesium carbonate (1.47 g, 4.52 mmol) and Pd(PPh3)4 (130 mg, 0.11 mmol) in 9 mL of DMSO was heated to 90 C for 16 h. The reaction mixture was cooled to room temperature and filtered. The filtrate was purified by HPLC to give (E)-tert-butyl 4-(2-(5-cyano-4-(4-methyl-1 H-indol-5-ylamino)pyridin-3-yl)vinyl) piperidine-1-carboxylate.
MS 458.2 (M+H);
HPLC rt = 10.6 min [a].

NM
N

[00383] Preparation of 5-[(E)-2-(2-chloropyridin-3-yl)vinyl]-4-[(4-methyl-lH-indol-5-yl) amino]nicotinonitrile:

A mixture of 5-iodo-4-(4-methyl-1 H-indol-5-ylamino)nicotinonitrile (240 mg, 0.65 mmol), 2-chloro-3-vinylpyridine (75 mg, 0.54 mmol), P(o-Tol)3 (25 mg, 0.08 mmol), Pd(OAc)2 (9 mg, 0.04 mmol) and triethylamine (164 mg, 1.63 mmol) in 15 mL of DMF was heated to overnight. The reaction was cooled to room temperature and filtered. The filtrate was purified by HPLC to give 5-[(E)-2-(2-chloropyridin-3-yl)vinyl]-4-[(4-methyl-1 H-indol-5-yl)amino]
nicotinonitrile as a solid. MS 386.1 (M+H); HPLC rt = 8.4 min [a].

NNN' N

[00384] Preparation of 5-[(E)-2-(2-chloropyridin-4-yl)vinyl]-4-[(4-methyl-lH-indol-5-yl) amino]nicotinonitrile:

A mixture of 4-[(4-methyl-1 H-indol-5-yl)amino]-5-vinylnicotinonitrile (100 mg, 0.36 mmol), 4-bromo-2-chloropyridine (90 mg, 0.47 mmol), P(o-Tol)3 (22 mg, 0.072 mmol), Pd(OAc)2 (16 mg, 0.072 mmol) and triethylamine (145 mg, 1.44 mmol) in 2 mL of DMF was heated to overnight. The reaction was cooled to room temperature and filtered. The filtrate was purified by HPLC to give 5-[(E)-2-(2-chloropyridin-4-yl)vinyl]-4-[(4-methyl-1 H-indol-5-yl)amino]
nicotinonitrile as a solid. MS 386.1 (M+H); HPLC it = 8.8 min [a].

N
N~ =/ ~ J

[00385] Preparation of 5-[(E)-2-(6-chloropyridin-3-yl)vinyl]-4-[(4-methyl-lH-indol-5-yl) amino] n icotinon itri le:

A mixture of 4-[(4-methyl-1 H-indol-5-yl)amino]-5-vinylnicotinonitrile (200 mg, 0.73 mmol), 5-bromo-2-chloropyridine (155 mg, 0.80 mmol), P(o-Tol)3 (22 mg, 0.072 mmol), Pd(OAc)2 (16 mg, 0.072 mmol) and triethylamine (295 mg, 2.92 mmol) in 7 mL of DMF was heated to 120 C
overnight. The reaction was cooled to room temperature and filtered. The filtrate was purified by HPLC to give 5-[(E)-2-(6-chloropyridin-3-yl)vinyl]-4-[(4-methyl-1H-indol-5-yl) amino]
nicotinonitrile as a solid. MS 386.1 (M+H); HPLC: it = 8.8 min [a].

NH

[00386] Preparation of 4-[1H-indol-5-yl(methyl)amino]-5-[(E)-2-phenylvinyl]
nicotinonitrile:

A solution of 4-chloro-5-[(E)-2-phenylvinyl]nicotinonitrile (100 mg, 0.41 mmol) and N-methyl-1 H-indol-5-amine (48 mg, 0.33 mmol) in ethanol (5 ml-) was heated to 90 C
for 72 h. The mixture was cooled to room temperature, diluted with saturated aqueous sodium bicarbonate and extracted with dichloromethane. The organic layer was washed with brine and concentrated in vacuo. The residue was purified by column chromatography with 4:1 hexane/ethyl acetate to provide 18 mg (13%) of the title compound as a yellow solid. MS
351.2 (M+H); HPLC rt = 12.5 min [a].

N

[00387] Preparation of 4-[(7-chloro-4-methyl-lH-indol-5-yl)amino]-5-[(E)-2-pyridin-4-yl vinyl]nicotinonitrile:

A mixture of 4-[(7-chloro-4-methyl-1 H-indol-5-yl)amino]-5-iodonicotinonitrile (120 mg, 0.29 mmol), 4-vinylpyridine (63 mg, 0.59 mmol), Pd(OAc)2 (13 mg, 0.059 mMol), P(o-Tol)3, and Et3N (2 ml-) In DMF (5 ml-) was heated to 95 C overnight. The resulting mixture was cooled to room temperature, diluted with saturated aqueous sodium bicarbonate and extracted with dichloromethane. The combined organic extracts were washed with brine and concentrated in vacuo. The residue was purified by column chromatography (4:1 hexane/ethyl acetate) to provide 38 mg (31%) of the title compound as a yellow solid. MS 386.1 (M+H);
HPLC it = 5.4 min [a].

&NH

"
[00388] Preparation of 4-[(7-chloro-4-methyl-1H-indol-5-yl)amino]-5-iodo-6-methyl nicotinonitrile:

A solution of 7-chloro-4-methly-1H-indol-5-amine (537 mg, 3.0 mmol) and 4-chloro-5-iodo-6-methylnicotinonitrile (1.0 g, 6.0 mmol) in EtOH (10 ml-) was heated to reflux for 72 h. The reaction mixture was cooled to room temperature and filtered. The filter cake was washed with EtOH and dried in vacuo to provide 610 mg (82%) of the title compound as yellow solid.
MS 423.3 (M+H).

[00389] Preparation of 4-[(7-chloro-4-methyl-1H4ndol-5-yl)amino]-5-[(E)-2-pyridin-4-yl vinyl]nicotinonitrile:

A mixture of 4-[(7-chloro-4-methyl-1 H-indol-5-yl)amino]-5-iodo-6-methylnicotinonitrile (130 mg, 0.28 mmol), 2-vinyl-pyridine (49 mg, 0.59 mmol), Pd(OAc)2 (11 mg, 0.014 mmol), P(o-Tol)3 (2.8 mg, 0.0084 mmol) and Et3N (2 ml-) in DMF (5 ml-) was heated to 95 C
overnight. The resulting mixture was cooled to room temperature, diluted with saturated aqueous sodium bicarbonate, extracted with dichloromethane. The organic layer was washed with brine and concentrated in vacuo. The crude product was purified by column chromatography (4:1 hexane/ethyl acetate) to provide 36 mg (30%) of the title compound as a yellow solid. MS
400.2 (M+H); HPLC 96.1 % at 215 nm, rt = 6.8 min [a].

nri \` a N
NJ

L __j [00390] Preparation of 4-[(7-chloro-4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{5-[(4-methylpiperazin-1-yl)methyl]pyridin-2-yl}vinyl]nicotinonitrile:
A mixture of 4-[(7-chloro-4-methyl-1H-indol-5-yl)-amino]-5-iodonicotinonitdle (120 mg, 0.29 mmol), 1-methyl-4[(6-vinylpyridin-3-yl)methyl]piperazine (128 mg, 0.59 mmol), Pd(OAc)2 (13 mg, 0.059 mmol), P(o-Tol)3, and Et3N (2 mL) in DMF (5 mL) was heated to 95 C
overnight.
The resulting mixture was cooled to room temperature, diluted with saturated aqueous sodium bicarbonate, and extracted with dichloromethane. The organic layer was washed with brine and concentrated in vacuo. The crude product was purified by column chromatography with (4:1 hexane/ethyl acetate) to provide 60 mg (41 %) of the title compound as a yellow solid. MS
499.1 (M+H); HPLC 93.6% at 215 nm, rt = 5.2 min [a].

N

[00391] Preparation of 4-[(7-chloro-4-methyl-1H-indol-5-yl)amino]-6-methyl-5-[(E)-2-phenylvinyl]nicotinonitrile:

A mixture of 4-[(7-chloro-4-methyl-1 H-indol-5-yl)amino]-5-iodo-6-methylnicotinonitrile (130 mg, 0.28 mmol), [(E)-2-phenylvinyl]boronic acid (68 mg, 0.59 mmol), Pd(PPh3)2CI
(11 mg, 0.014mmol), NaHCO3 (saturated aqueous, 3 ml) and DME (3ml) was heated at 95 C
overnight. The resulting mixture was cooled to room temperature, diluted with saturated aqueous sodium bicarbonate, and extracted with DCM. The organic layer was washed with brine and concentrated. The crude product was purified by column chromatography (eluting with 4:1 hexanes/ethyl acetate) to give 36mg (30%) of 4-[(7-chloro-4-methyl-1 H-indol-5-yl)amino]-6-methyl-5-[(E)-2-phenylvinyl]nicotinonitrile as a yellow solid. MS
399.2(M+H);
HPLC 96.2% at 215 nm, rt = 5.7 min [a].

Ni \~ I
N ` / \ oN
\ w~. `1~' . \ a [00392] Preparation of 4-[(7-chloro-4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{6-[(4-methylpiperazin-1-yl)methyl]pyridin-2-yi}vinyl]nicotinonitrile:
A mixture of 4-[(7-chloro-4-methyl-1H-indol-5-yl)-amino]-5-iodonicotinonitrile (130 mg, 0.28 mmol), 1-methyl-4-(6-vinyl-pyridin-2-ylmethyl)-piperazine (128 mg, 0.59 mmol), Pd(OAc)2 (11 mg, 0.014 mmol), P(o-Tol)3 (2.8 mg, 0.0084 mmol) and Et3N (2 mL) in DMF (5 mL) was heated to 950 C overnight. The resulting mixture was cooled to room temperature, diluted with saturated aqueous sodium bicarbonate and extracted with dichioromethane. The combined organic layers were washed with brine and concentrated in vacuo. The residue was purified by column chromatography (4:1 hexenelethyl acetate) to provide 40 mg (27%) of the title compound as a yellow solid. MS 270.2 (M+H); rt = 10.5 min [a].

N

(CH [00393] Preparation of 5-[(E)-2-(4-{[4-(2-hydroxyethyl)piperazin-1-yl]methyl}
phenyl)vinyl]-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile:

A mixture of 5-[(E)-2-(4-formylphenyl)ethenyl]-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile (130 mg, 0.34 mmol), 2-piperazine-1-yl-ethanol (88 mg, 0.68 mmol), NaBH(AcO)3 (358 mg, 1.7 mmol) in THE (5 mL) was stirred at room temperature overnight.
The resulting mixture was diluted with saturated aqueous sodium bicarbonate and extracted with dichloromethane. The combined organic layers were washed with brine and concentrated in vacuo. The crude product was purified by HPLC to provide 71 mg (42%) of the title compound as a yellow solid; MS 493.2 (M+H).

[00394] Preparation of compounds in Table 11:

The compounds in Table 11 were prepared from 5-[(E)-2-(4-formylphenyl)ethenyl]-4-[(4-methyl-lH-indol-5-yl)amino]pyridine-3-carbonitrile and the appropriate amine via the procedure described for 5-[(E)-2-(4-{[4-(2-hydroxyethyl)piperazin-1-yl]methyl)phenyl)vinyl]-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile.

Compound name MS HPLC rt 5-[(E)-2-{4-[(4-hydroxypipendin-1-yl)methyl]phenyl} 464.2 (M+H) 5.4 min [a]
vinyl]-4-[(4-methyl-1 H-indol-5- I amino nicotinonitrile 5-{(E)-2-[4-({[3-(dimethylamino)propyl]amino}methyl) 465.2 (M+H) 4.6 min [a]
phenyl]vinyl}-4-[(4-methyl-1 H-indol-5-yl)amino]
nicotinonitrile 4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-{4-[(4- 517.2 (M+H) 4.7 min [a]
pyrrol idi n-1-ylpi peridi n-1-yl) methyl]phenyl}
vin I nicotinonitdle 4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[4- 466.1 (M+H) 6.1 min [a]
thiomo holin-4- meth I hen I vin I nicotinonitrile 5-{(E)-2-[4-(1,4'-bipipeddin-l'-ylmethyl)phenyl]ethenyl}- 531.3 (M+H) 4.7 min [a]
4+4-methyl-1 H-indot-5- amino 'dine-3-carbonitrile 5-[(E)-2-(4-{[(3-ethoxypropyl)amino]methyl}phenyl) 466.3 (M+H) 6.4 min [a]
ethenyl]-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile 5-[(E)-2-(4-[(3-hydroxypyrrolidin-1-yl)methyl]phenyl) 450.2 (M+H) 5.5 min [a]
etheny1]-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile N-{4-[(E)-2-{5-cyano-4-[(4-methyl-1H-indol-5-yl)amino] 267.2 NA
pyridin-3-yl}ethenyl]benzyl}-N-(2-piperidin-l- (M+2H) eth I acetamide 5-[(E)-2-(4-{[4-(1-methylethyl)piperazin-1-yl]methyl} 246.1 5.6 min [a]
phenyl)ethenyl]-4-[(4-methyl-1 H-indol-5- (M+2H) yl)amino]pyridine-3-carbonitrile N-{4-[(E)-2-{5-cyano-4-[(4-methyl-1H-indol-5-yl)amino] 260.2 NA
pyridin-3-yl}ethenyl]benzyl}-N-(2-pyrrolidin-l- (M+2H) eth acetamide 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(4-{[(2- 485.3 (M+H) 4.9 min [a]
pyridin-3-ylethyl )amino]methyl}phenyl )ethenyl]pyddine-3-carbonitrile 4-[(4-methyl-lH-indol-5-yl)amino]-5-[(E)-2-(4-[[(2- 485.3 (M+H) 5.9 min [a]
pyridin-2-ylethyl)amino]methyl}phenyl )ethenyl]pyridine-3-carbonitrile 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(4-{[(3- 507.1 (M+H) 4.9 min [a]
morpholin-4-ylpropyl )amino]methyl}phenyl) ethen I ridine-3-carbonitrile 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{4-[(4- 533.3 (M+H) 4.6 min [a]
morpholin-4-ylpiperidin-1-yl)methyl]phenyl)ethenyl]
ridine-3-carbonitrile 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(4-{[(2- 493.3 (M+H) 4.6 min [a]
morpholin-4-ylethyl)am ino]methyl}phenyl) ethen I ridine-3-carbonitrile 5-[(E)-2-{4-[(4-cyclopentylpiperazin-l-yl)methyl]phenyt) 517.3 (M+H) 6.1 min ethenylJ-4-[(4-methyl-1 H-indol-5-yl)amino]pyndine-3- [a]
carbonitrile 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[4- 450.3 (M+H) 5.4 min (morpholin-4-ylmethyl)phenyl]ethenyl}pyridine-3- [a]
carbonitrile H
\ / \ N

[00395] Preparation of 5-[(E)-2-(4-formylphenyl)ethenyl]-6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile:

A mixture of 5-iodo-6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile (6.3 g, 16.2 mmol), 4-[(E)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl]benzaldehyde (3.5 g, 13.5 mmol), Pd(PPh3)4 (779 mg, 0.81 mmol), DME (150 mM) and saturated aqueous NaHCO3 (100 ml-) was stirred at 100 C overnight. The resulting mixture was cooled to room temperature, diluted with saturated aqueous sodium bicarbonate and extracted with dichloromethane. The combined organic layers were washed with brine and concentrated in vacuo. The residue was purified by chromatergraphy (1:2 ethyl acetate/hexane) to provide 3.8 g (71%) of the title compound as a yellow solid. MS 393.20 (M+H).

NH

[00396] Preparation of 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-pyridin-2-yI
vinyl ]nicotinonitrile:

A mixture of 5-iodo-6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile (194 mg, 2.5 mmol), 2-vinylpyridine (63 mg, 0.6 mmol), P(o-Tol)3 (15 mg), triethylamine (0.7 ml-) and Pd(OAc)2 (22 mg) in 2.5 mL of DMF was heated at 90 C for 3 h. After cooling to room temperature, the reaction mixture was partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography eluting with a gradient of hexane/ethyl acetate to give 162 mg (89%) of the desired product as a light yellow solid. MS 366.2 (M+H); HPLC: 98.2% at 215 nm, 5.6 min [a].

[00397] Preparation of 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-pyridin-4-yl vinyl] nicotinonitri le:

The title compound was prepared from 5-iodo-6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile and 4-vinylpyridine via the procedure used to prepare 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-pyridin-2-ylvinyl]nicotinonitrile to give 33 mg (18%) of the desired product as tan solid. MS 366.1 (M+H); HPLC: 4.0 min. [a].

NH
N

[00398] Preparation of 5-[(E)-2-(2-methoxyphenyl)vinyl]-6-methyl-4-[(4-methyl-lH-indol-5-yl)amino] nicotinonitrile:

The title compound was prepared from 5-iodo-6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile and 2-vinylanisole via the procedure used to prepare 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-pyridin-2-ylvinyl]nicotinonitrile to give 71 mg (36%) of the desired product as tan solid. MS 395.2 (M+H); HPLC: rt = 9.7 min [a].

\ NH
N

[00399] Preparation of 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-pyridin-3-yl vinyl]nicotinonitrile:

The title compound was prepared from 5-iodo-6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile and 3-vinylpyridine via the procedure used to prepare 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-pyridin-2-ylvinyl]nicotinonitrile to give 31 mg (17%) of the desired product as tan solid. MS 366.2 (M+H); HPLC: 91.0% at 215 nm, 4.6 min [a].

NH

[00400] Preparation of 5-[(E)-2-(3,4-dimethoxyphenyl)vinyl]-6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino] nicotinonitrile:

The title compound was prepared from 5-iodo-6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile and 3,4-dimethoxystyrene via the procedure used to prepare 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-pyridin-2-ylvinyl]nicotinonitrile to give 82 mg (38%) of the desired product as tan solid. MS 425.3 (M+H); HPLC: 95.7% at 215 nm, rt = 9.1 min [a].
NH
/

[00401] Preparation of 6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-pyrazin-2-yl vinyl]nicotinonitrile:

The title compound was prepared from 5-iodo-6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile and 2-vinylpyrazine via the procedure used to prepare 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-pyridin-2-ylvinyl]nicotinonitrile to give 164 mg (90%) of the desired product as yellow solid. MS 367.4 (M+H); HPLC: 97.4% at 215 nm, rt = 6.5 min [a].

rl [00402] Preparation of 6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-(4-methyl-1,3-thiazol-5-yl)vinyl]nicotinonitrile:

The title compound was prepared from 5-iodo-6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile and 4-methyl-5-vinylthiazole via the procedure used to prepare 6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-pyridin-2-ylvinyl]nicotinonitrile to give 28 mg (15%) of the desired product as yellow solid. MS 386.2 (M+H); HPLC: rt = 5.6 min [a].

o [00403] Preparation of 1-(4-iodo-3-methylbenzoyl)-4-methylpiperazine:

To a stirred solution of 4-iodo-3-methylbenzoic acid (1.57 g, 6 mmol) in DMF
(18 ml-) was added PyBOP (3.75 g, 7.2 mmol) at 0 C followed by Hunig's base (1.94 g, 15 mmol) and Iw methylpiperazine (1.21 g, 12 mmol). The solution was stirred at room temperature overnight.
After removal of the volatile material, the reaction mixture was partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacua. The residue was purified by flash column chromatography eluting with a gradient of hexane/ethyl acetate to give 2.01 g (98%) of the desired product as a light yellow oil. MS 345.0 (M+H); HPLC: 94.4% at 215 nm, rt = 6.8 min [a].

O N~

[00404] Preparation of 1-[(4-ethenyl-3-methylphenyl)carbonyl]-4-methyl piperazine:

A mixture of 1-(4-iodo-3-methylbenzoyl)-4-methylpiperazine (840 mg, 2.4 mmol), tributylvinyltin (1.17 g, 3.7 mmol), and Pd(PPh3)4 (230 mg) in 10 mL of DMF was heated at 115 C for 3 h.
After cooling to room temperature, the reaction mixture was partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography eluting with a gradient of hexane/ethyl acetate to give 524 mg (88%) of the desired product as a light yellow oil. MS 245.2 (M+H); HPLC: 94.4% at 215 nm, rt = 6.0 min [a].

f -11H
O

I N

[00405] Preparation of 4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-{2-methyl-4-[(4-methylpiperazln-1-yl)carbonyl]phenyl}vinyl]nlcotinonitrile:
The title compound was prepared from 4-[(4-methyl-1 H-indol-5-yl)amino]-5-vinylnicotinonitrile and 1-(4-iodo-3-methylbenzoyl)-4-methylpiperazine via the procedure used to prepare 6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-pyridin-2-ylvinyl]nicotinonitrile to give 123 mg (50%) of the desired product as yellow solid. MS 491.2 (M+H); HPLC: 94.8% at 215 nm, rt =
5.4 min [a].

[00406] Preparation of 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(2-methyl-4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}ethenyl]pyridine-3-carbonitrile:

The title compound was prepared from 5-iodo-6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile and 1-[(4-ethenyl-3-methylphenyl)carbonyl]-4-methylpiperazine via the procedure used to prepare 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-pyridin-2-ylvinyl]nicotinonitrile to give 36 mg (15%) of the desired product as off-white solid. MS 505.4 (M+H); HPLC: 91.3% at 215 nm, rt = 5.4 min [a].

E r]

[00407] Preparation of 3-[(trimethylsilyl)ethynyl]benzaldehyde:

3-Bromobenzaldehyde (5 g, 27.0 mmol) was dissolved in 50 mL THE and treated with TMS-acetylene (29.7 mmol, 2.9 g) and Et3N (81 mmol, 8.2 g). After stirring briefly, Pd(PPh3)4 (1.351 mmol, 1.6 g) was added and the reaction was stirred under N2 at room temperature overnight.
Subsequently, another 2 equivalents of TMS-acetylene (60 mmol, 6.0 g) was added followed by Cul (100 mg) and Et3N (81 mmol, 8.2 g). The reaction was heated to 60 C
overnight then evaporated onto silica gel and purified by chromatography (0 to 20% EtOAc in hexanes) to give 2.4 g of the title compound as a yellow oil. MS: 202 [M+].

[00408] Preparation of 1-[3-[(trimethylsilyl)ethynyl]benzyl)pyrrolidine:
3-[(Trimethylsilyl)ethynyl]benzaldehyde (1.0 g, 4.9 mmol) was stirred in 30 mL
DCM.
Pyrrolidine (0.613 mL, 7.41 mmol) was added followed by 1 drop of HOAc. After stirring 5 minutes, NaBH(OAc)3 (2.1 g, 9.9 mmol) was added and the reaction was stirred for 1h. Two equivalents of HOAc were added (-0.6 mL) and, after stirring for 1/2 h, the reaction was partitioned between DCM and dilute NaHCO3. The aqueous layer was extracted 1 x with DCM
and the combined organic layers were dried over MgSO4, filtered and concentrated to give 1.1 g of the title compound as an oil. MS: 258.2 [M+H].

I ~^a [00409] Preparation of 1-(2-chloroethoxy)-4-ethynylbenzene:

A mixture of 4-[(trimethylsilyl)ethynyl]phenol (700 mg, 3.68 mmol) (Mohamed Ahmed et al., Tetrahedron, 2004, 60, 9977), 2-chloroethyl 4-methylbenzenesulfonate (863 mg, 3.68 mmol), and cesium carbonate (1198 mg, 3.68 mmol) was stirred in 20 mL DMF at room temperature for 24 h. The reaction was poured over water and extracted with EtOAc. The organic phase was washed once with water then dried over MgSO4, filtered, and concentrated.
The product was purified by chromatography (5% to 25% EtOAc/Hex) to give 460 mg of the title compound.
(Note that the TMS group fell off during the workup).

S

[00410] Preparation of 1-(2-chloroethoxy)-2-ethynylbenzene:

The title compound was prepared from 2-[(trimethylsilyl)ethynyl]phenol (Kabalka et. al., Tetrahedron, 2006, 62, 857) according to the procedure outlined for 1-(2-chloroethoxy)-4-ethynylbenzene.

[00411] Preparation of 1-[2-(4-ethynylphenoxy)ethyl]pyrrolidine:

A mixture of 1-(2-chloroethoxy)-4-ethynylbenzene (0.45 g, 2.491 mmol), sodium iodide (0.075 g, 0.498 mmol), and pyrrolidine (0.532 g, 7.47 mmol) was heated to 100 C in 5 mL DME in a sealed vial. After heating overnight the reaction was diluted with EtOAc then twice washed with water. The organic layer was dried over MgSO4, filtered and concentrated to give 0.50 g of the title compound. MS: 216.1 [M+H].

G~

[00412] Preparation of 1-[2-(3-ethynylphenoxy)ethyl]pyrrolidilne:

The title compound was prepared from 1-(2-chloroethoxy)-3-ethynylbenzene according to the procedure used for 1-[2-(4-ethynylphenoxy)ethyl]pyrrolidine. MS: 216.1 [M+H].

[00413] Preparation of 1-[2-(2-ethynylphenoxy)ethyl]pyrrolidine:

The title compound was prepared from 1-(2-chloroethoxy)-2-ethynylbenzene according to the procedure used for 1-[2-(4-ethynylphenoxy)ethyl]pyrrolidine. MS: 216.1 [M+H].

o\ \
N

[00414] Preparation of 4-[(4-Methyl-lH-indol-5-yl)amino]-5-([3-(2-pyrrolidin-1-ylethoxy) phenyl]ethynyl}nicotinonitrile:

A mixture of 5-lodo-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile (94 mg, 0.25 mmol), 1-[2-(3-ethynylphenoxy)ethyl]pyrrolidine (59 mg, 0.28 mmol), Pd(PPh3)2CI2 (17 mg, 0.025 mmol), Cul (5 mg, 0.025 mmol), and Et3N (101 mg, 1.0 mmol) was stirred in 2.5 mL DMF
at room temperature for 3h. The reaction was filtered and the filtrate was purified by HPLC giving 72 mg of the title compound. MS (ESI) m/z 463.2; HPLC 97.6% at 215 nm, rt = 9.9 min [A].

NH

[00415] Preparation of 4-[(4-methyl-1H-indol-5-yl)amino]-5-([3-(pyrrolidin-1-ylmethyl) phenyl] ethynyl}pyridine-3-carbonitrile:

A mixture of 1-{3-[(trimethylsilyl)ethynyl]benzyl}pyrrolidine (250 mg, 0.97 mmol), 5-iodo-4-(4-methyl-1 H-indol-5-ylamino)nicotinonitrile (280 mg, 0.75 mmol), Pd(PPh3)2CI2 (52 mg, 0.075 mmol), Et3N (151 mg, 1.5 mmol), and Cul (14 mg, 0.075 mmol) was stirred in 7 mL DMF at room temperature. TBAF (1 M in THF, 0.97 mmol) was added and the reaction was stirred at room temperature for 1h. The reaction mixture was filtered and the filtrated was purified by HPLC to give 240 mg of the title compound. Trituration with EtOAc gave 70 mg of product.
HPLC: 90.1% at 215 nm, rt = 7.3 min [a]; HRMS:, calcd for C28H25N5+H, 432.21827, found 432.2183.

NH
= HN iN

/ O I
u N

[00416] Preparation Of 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{[2-(2-pyrrolidin-1-ylethoxy) phenyl]ethynyl}pyridine-3-carbonitrile:
A mixture of 1-[2-(2-ethynylphenoxy)ethyl]pyrrolidine (127 mg, 0.59 mmol), 5-iodo-4-(4-methyl-1 H-indol-5-ylamino)nicotinonitrile (200 mg, 0.54 mmol), Pd(PPh3)2CI2 (37 mg, 0.053 mmol), Cul (10 mg, 0.053 mmol), and Et3N (160 mg, 1.6 mmol) was stirred at room temperature in 5 mL DMF. After 3h the reaction was acidified with TFA (-50 uL) and filtered.
The filtrate was purified by preparative HPLC to give the TFA salt of the title compound.
Treatment with HCI/dioxane and trituration with EtOH gave 140 mg (56%) of the title compound as its HCI salt.
HRMS: 462.2286 (M+H); HPLC rt = 8.2 min [a].

N
NgN H
No HN

[00417] Preparation Of 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{[4-(2-pyrrolidin-1-ylethoxy) phenyl]ethynyl}pyridine-3-carbonitrile:

The title compound was prepared from 5-iodo-4-(4-methyl-1 H-indol-5-ylamino)nicotinonitrile and 1-[2-(4-ethynylphenoxy)ethyl]pyrrolidine according to the procedure utilized for 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{[2-(2-pyrrolidin-1-ylethoxy)phenyl]ethynyl}pyridine-3-carbonitrile. MS (ESI): 462.2 (M+H); HPLC rt = 1.77 min [d].

I
HN
N
N

[00418] Preparation Of 4-[(1,4-dimethyl-1H-indol-5-yl)amino]-5-iodonicotinonitrile:
4-Chloro-5-iodonicotinonitrile (300 mg, 1.13 mmol) and 1,4-dimethyl-1 H-indol-5-amine (218 mg, 1.36 mmol) were dissolved in ethanol (3 ml). The reaction mixture was heated at reflux overnight then cooled to room temperature and poured into saturated aqueous sodium bicarbonate. The precipitate formed was filtered and washed with water and methanol to give 401 mg (91 %) of the title compound as a brown solid, MS 389.2 (M+H).

N~
O,SO^/O I

O
[00419] Preparation of 2-[(6-vinylpyridin-2-yl)methoxy]ethyl sulfate:

A solution of (6-vinylpyridin-2-yl)methanol (200 mg, 1.48 mmol) in anhydrous DMF (2.5 ml) was cooled to -45 C, followed by the addition of sodium hydride (95% wt., 45 mg, 1.78 mmol) in portions. The temperature was kept under -20 C during the addition. It was warmed to 0 C
and stirred at this temperature for 1 hr. The solution was then cooled to -45 C, followed by the addition of 1,3,2-dioxathiolane-2,2-dioxide (226 mg, 1.78 mmol). The reaction mixture was slowly warmed to room temperature and stirred overnight. The solvent was removed, and the residue was purified by HPLC to give 130 mg (34%) of the title compound as an off-white solid, MS 258.0 (M). HPLC: 92.7% at 215 nm, rt = 3.6 min [a].

[00420] Preparation of 3-[(E)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethenyl]
benzaldehyde:

To a solution of 3-bromobenzaldehyde (5.0 g, 27 mmol), Pd(OAc)2 (360 mg, 1.6 mmol) and 1,10-phenanthroline (320 mg, 1.61 mmol) in anhydrous CH3CN (100 ml) at room temperature was added triethylamine (7.6 ml, 54.5 mmol) followed by the addition of vinylboronic acid pinacolester (5.6 ml, 33 mmol). The reaction mixture was heated to 65 C for 3 days, diluted with diethyl ether (700 ml), then washed successively with 10% HCI, H2O and brine. Drying, filtration and evaporation gave a brown oil, which was purified by silica gel chromatography (CH2CH2), providing 1.65 g (24%) of the title compound as a dark-yellow oil.
1H NMR (300 MHZ, DMSO) 1.32 (s, 12H), 6.27 (d, 1 H, J = 12 Hz), 7.43 (d, 1 H, J = 12 Hz), 7.51 (t, 1 H, J =
6.0 Hz), 7.73 (d, 1 H, J = 6.0 Hz), 7.81 (d, 1 H, J = 6.0 hz), 7.97 (s, 1 H), 10.03 (s, 1 H); MS 259.2 (M+ H).
ro N

[00421] Preparation Of 4-Benzyl-2-Vinylmorpholine:

A solution of allylpalladium chloride dimer (126 mg, 0.34 mmol), BINAP (920 mg, 1.4 mmol) in dichloromethane (150 ml-) was maintained at room temperature for 1 h. To the clear red solution was added 2-(benzylamino)ethanol (4.42 g, 28.1 mmol), (Z)-but-2-ene-1,4-diyl diacetate (5.47 g, 31.8 mmol) and potassium fluoride (3.80 g, 65 mmol) sequentially. The resulting yellow slurry was maintained at 40 C for 24 h before filtration.
The filtrate was concentrated and chromatographed. The fraction containing product was concentrated. The residue was dissolved in ethyl ether (20 mL) and added to a solution of camphorsulphonic acid (3.5 g) in ethyl ether (500 mL). The precipitate was collected. The solid was basified with sodium bicarbonate solution. The organic portion was dried (magnesium sulfate) and concentrated to provide a solid (2.5 g); HPLC: 94.6%, rt = 4.7 min [A].

[00422] Preparation of 1-methyl-4-[(5-vinylpyridin-2-yl)methyl]piperazine:

A mixture of 1-[(5-bromo-2-pyndinyl)methyl]-4-methylpiperazine (1.4 g, 5.07 mmol) (US2002026052 al), vinyl tributyltin (2.31 g, 2.2 ml, 7.6 mmol) and Pd(PPh3)4 (293 mg, 0.25 mmol) in 23 ml of toluene was heated at reflux for 3 h, cooled to room temperature and partitioned between ethyl acetate and aqueous saturated sodium bicarbonate.
The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo.
The residue was purified by column chromatography, eluting with a gradient of 5% methanol in dichloromethane to 15% methanol in dichloromethane to 15% methanol in dichloromethane containing 1% of conc. aq. ammonium hydroxide to give 883.2 mg (80%) of 1-methyl-4-[(5-vinylpyridin-2-yl)methyl]piperazine as deep yellow oil, MS (ESI) m/z 218.1 (M+H)+.

[00423] Preparation of 1-(3-bromo-4-ethylbenzyl)-4-methylpiperazine:

To a solution of 3-bromo-4-ethylbenzaldehyde (3.89 g, 18.3 mmol) (WO
2003099776 Al) and N-methyl-piperazine (9.2 g, 91.5 mmol) in 40 ml of dichloromethane at room temperature under nitrogen was added glacial acetic acid (2.2 g, 2.1 ml, 36.6 mmol). the reaction mixture was stirred at room temperature for 1 h. sodium_triacetoxyborohydride (19.4 g, 91.5 mmol) was added to the reaction mixture in portions. The resulting mixture was stirred at room temperature overnight, then partitioned between dichloromethane and aqueous saturated sodium bicarbonate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. the residue was purified by column chromatography, eluting with a gradient of 2% methanol in dichioromethane to 7% methanol in dichioromethane to give 4.2 g (77%) of 1-(3-bromo-4-ethylbenzyl)-4-methylpiperazine as a yellow oil, MS (ESI) 297.1, 299.1 [00424] Preparation of 1-[(2-bromo-1,3-thiazol-4-yl)methyl]-4-methylpiperazine:

To a solution of 2-bromo-4-formylthiazole (1.0 g, 5.2 mmol), N-methyl-piperazine (2.6 g, 2.9 ml, 26 mmol) in 15 ml of dichloromethane at room temperature under nitrogen was added glacial acetic acid (629.4 mg, 0.6 ml, 10.4 mmol). The reaction mixture was stirred at room temperature for 1 h. Sodium triacetoxyborohydride (5.5 g, 26 mmol) was added to the reaction mixture in portions. The resulting mixture was stirred at room temperature overnight, then partitioned between dichloromethane and aqueous saturated sodium bicarbonate.
The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo.
The residue was purified by column chromatography, eluting with a gradient of 2% methanol in dichloromethane to 10% methanol in dichloromethane to give 940 mg (66%) of 1-[(2-bromo-1,3-thiazol-4-yl)methyl]-4-methylpiperazine as a white solid, MS (ESI) 276.2, 278.2 S
F

[00425] Preparation of 1-[(2-ethenyl-1,3-thiazol-4-yl)methyl]-4-methylpiperazine:

A mixture of 1-[(2-bromo-1,3-thiazol-4-yl)methyl]-4-methylpiperazine (749.5 mg, 2.71 mmol), vinyl tributyltin (1.30 g, 1.19 ml, 4.1 mmol) and Pd(Ph3)4 (156.6 mg, 0.14 mmol) in 14 ml of toluene was heated at reflux for 6 h, cooled to room temperature and partitioned between ethyl acetate and aqueous saturated sodium bicarbonate. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography, eluting with a gradient of 5% methanol in dichloromethane to 10%
methanol in dichloromethane to 10% methanol in dichloromethane containing 1%
of conc. aq.
ammonium hydroxide to give 354 mg (59%) of 1-[(2-ethenyl-1,3-thiazol-4-yl)methyl]-4-methylpiperazineas deep yellow oil, MS (ESI) m/z 224.1 (M+H)+.

/"`ter [00426] Preparation of 1-[(5-bromopyridin-3-yl)methyl]-4-methylpiperazine:

To a solution of 5-bromo-3-pyridine-carboxyaldehyde (1.5 g, 8.1 mmol), N-methyl-piperazine (4.03 g, 4.5 ml, 40.3 mmol) in 20 ml of dichloromethane at room temperature under nitrogen was added glacial acetic acid (966.8 mg, 0.92 ml, 16.1 mmol). The reaction mixture was stirred at room temperature for 1 h. Sodium triacetoxyborohyd ride (8.54 g, 40.3 mmol) was added to the reaction mixture in portions. The resulting mixture was stirred at room temperature overnight, then partitioned between dichloromethane and aqueous saturated sodium bicarbonate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography, eluting with a gradient of 10% methanol in ethyl acetate to 20% methanol in ethyl acetate to 20% methanol in ethyl acetate containing 1 % of conc. aq. ammonium hydroxide to give 2.1 g (95%) of 1-[(5-bromopyridin-3-yl)methyl]-4-methylpiperazine as a yellowish solid, MS (ESI) 270.1, 272.1.

[00427] Preparation of 1-methyl-4-[(5-vinylpyridin-3-yl)methyl]piperazine:

A mixture of 1-[(5-bromopyridin-3-yl)methyl]-4-methylpiperazine (1.32 g, 4.89 mmol), vinyl tributyltin (2.34 g, 2.16 mL, 7.3 mmol) and Pd(PPh3)4 (282.5 mg, 0.25 mmol) in 25 mL of toluene was heated at reflux for 3 h, cooled to room temperature and partitioned between ethyl acetate and aqueous saturated sodium bicarbonate. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography, eluting with a gradient of 5% methanol in dichloromethane to 15%
methanol in dichloromethane to 15% methanol in dichloromethane containing 1%
of conc. aq.
ammonium hydroxide to give 872 mg (82%) of 1-methyl-4-[(5-vinylpyridin-3-yl)methyl]piperazine as yellow oil, MS (ESI) m/z 218.1 (M+H)+.

N
HN

[00428] Preparation of N-((1H-indol-3-yl)methyl)-N-methyl-l-phenylmethanamine:

To a THE solution (10 ml-) containing indole (586 mg, 5.0 mmol) and N-(methoxymethyl)-N-(trimethylsilylmethyl)benzyla mine was added trifluoroacetic acid (1.0 mL).
The reaction was stirred at room temperature overnight and was quenched with saturated aqueous NaHCO3 (3 mL). The solvent was removed under vacuum and the residue partitioned between EtOAc (5 ml-) and water (3 mL). The water was removed and the organic layer dried over anhydrous MgSO4 and concentrated under vacuum to a residue. The title compound was isolated from the by-products N-((1H-indol-3-yl)methyl)-N-benzyl-1-(trimethylsilyl)methanamine and N-benzyl-1-(3-((benzyl((trimethylsilyl)methyl)amino)methyl)-1 H-indol-1-yl)-N-methylmethanamine by preparative HPLC. MS 251.1 (M+H); HPLC rt = 8.1 min [a].

INH
HN

[00429] Preparation of 1-(1 H-indol-3-yl)-N-methylmethanamine dihydrochloride:

A methanol solution (10 ml-) of N-((1 H-indol-3-yl)methyl)-N-methyl-1-phenylmethanamine (100 mg, 0.4 mmol) was treated with 10% Pd/C and was stirred under hydrogen supplied by a rubber balloon. After stirring overnight, the mixture was filtered through magnesium silicate and the filtrate concentrated under vacuum. The residue was dissolved in 1:1 THF/Et20 and HCI gas bubbled into the solution. The resulting red solid was filtered and triturated with Et2O.
The solid was dried under vacuum at 60 C overnight to provide the title compound (80 mg, 86%). MS 161.1 (M+H); HPLC rt = 4.0 min [a].

[00430] Preparation of 1-{2-[(5-bromopyridin-3-yl)oxy]ethyl}-4-methyl-piperazine:

To a THE (50 ml) solution of 5-bromo-pyridin-3-ol (500 mg, 2.87 mmol) cooled in a ice bath for 30 min was added 1,1'-(azodicarbonyl)-dipiperidine (1.1 ml, 4.31 mmol), tri-n-butylphosphine (1.06 ml, 4.31 mmol) and 2-(4-methyl-piperazine-1-yl)-ethanol with stirring.
The ice bath was removed after 30 min. The reaction was stirred at room temperature overnight.
The resulting mixture was added to saturated NaHCO3 and ethyl acetate. The organic layer was washed with brine and concentrated in vacuo. The residue was purified by chromatography eluting with MeOH:DCM(1:10) to afford 450 mg (52%) of the title compound as a yellow solid.
MS: (M+H) 300.19.

,Ilk [00431] Preparation of 3-bromo-5-(2-pyrrolidin-1-yl-ethoxy)pyridine:

The title compound was prepared from 2-pyrrolidin-1-yl-ethanol and 5-bromo-pyridin-3-ol via the procedure used to prepare 1-{2-[(5-bromopyridin-3-yl)oxy]ethyl}-4-methyl-piperazine to afford 506 mg (65%) of the title compound as a yellow solid. MS: (M+H) 271.15.

[00432] Preparation of 3-[(5-bromopyridin-3-yl)oxy]-N,N-dimethylpropan-1-amine:

The title compound was prepared from 3-dimethylamino-propan-l-ol and 5-bromo-pyridin-3-ol via the procedure used to prepare 1-{2-[(5-bromopyridin-3-yl)oxy]ethyl}-4-methyl-piperazine to afford 450 mg (61%) of the title compound as a yellow solid. MS: (M+H) 259.1.

[00433] Preparation of 1-(2-[(5-bromopyridin-3-yl)oxy]ethyl}azepane:

The title compound was prepared from 2-azepan-1-yl-ethanol and 5-bromo-pyridin-3-ol via the procedure used to prepare 1-(2-[(5-bromopyridin-3-yl)oxy]ethyl}-4-methyl-piperazine to afford 510 mg (59%) of the title compound as a yellow solid. MS: (M+H) 299.1.

.[00434] Preparation of 3-bromo-5-(3-piperidin-1-ylpropoxy)pyridine:

The title compound was prepared from 3-piperidin-1-yl-propan-l-ol and 5-bromo-pyridin-3-ol via the procedure used to prepare 1-{2-[(5-bromopyridin-3-yl)oxy]ethyl}-4-methyl-piperazine to afford 880 mg (64%) of the title compound as a yellow solid. MS: (M+H) 299.1.

o [00435] Preparation of 4-[(E)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethenyl]
benzaldehyde:

To a solution of 4-bromobenzaldehyde (10.0 g, 54 mmol), Pd(OAc)2 (720 mg, 3.2 mmol) and 1,10-phenanthroline (624 mg, 3.1 mmol) in anhydrous CH3CN (160 ml) at room temperature was added triethylamine (15 ml, 107.5 mmol) followed by the addition of vinylboronic acid pinacolester (11 ml, 64.8 mmol). The reaction mixture was heated to 65 C for 3 days, diluted with diethyl ether (1400 ml), washed successively with 10% HCI, H2O and brine.
Drying, filtration and evaporation gave a brown oil, which was purified by silica gel chromatography (CH2CI2), providing 7.0 g (50%) of the title compound as a yellow solid. 'H
NMR (300 mHz, DMSO) 1.24 (s, 12H), 6.35 (d, 1 H, J = 12 Hz), 7.38 (d, 1 H, J = 12 Hz), 7.82 (t, 2H), 7.89 (s, 1 H), 7.91(s, 1 H), 10.00 (s, 1 H); MS 259.2 (M+H).

a NH
[00436] Preparation of 4-[(6-chloro-1H-Ind ol-5-yl)amino]-5-iodopyridine-3-carbonitrile:

4-Chloro-5-iodonicotinonitrile (490 mg, 1.9 mmol) and 6-chloro-1H-indol-5-amine (320 mg, 1.9 mmol) was heated at reflux in 3. mL of EtOH for 16 h. The reaction was cooled to RT and the precipitate was collected by filtration. The filter cake was dried under reduced pressure to afford 164 mg of the title compound. HPLC rt = 11.3 min [a]; m/e 394.9 (M+H);
HRMS:
calculated 394.9555 found 394.9553 (M+H).

Br O=S=O
(N) N
[00437] Preparation of 1-[(3-bromobenzyl)sulfonyl]-4-methylpiperazine:

A mixture of sodium 3-bromo-benzenemethanesulfonate (1.31 g, 4.8 mmol), POCI3 (10 mL) and PCIS (2.0 g, 9.6 mmol) was heated to 85 C for 2 h. The resulting reaction mixture was cooled to rt and poured onto ice. The mixture was partitioned between dichioromethane and water. The organic layer was dried (MgSO4) and concentrated. A portion of the residue (0.27 g) was immediately dissolved in THE (10 ml-) and the solution was treated with methylpiperazine (100mg, 1 mmol). Upon completion, the reaction was quenched with sat sodium bicarbonate and dried (MgSO4). Silica gel flash column chromatography with ethyl acetate and hexanes afforded desired product (195 mg, 20 %). HPLC rt = 6.2 min [a]; MS We 333.0 (M+H).

[00438] Preparation of 1-(3-bromobenzylsulfonyl)pyrrolidine:

The title compound was prepared via the route described for 1-[(3-bromobenzyl)sulfonyl]-4-methylpiperazine.

` N
N `N Br [00439] Preparation of 1-[(6-bromopyridin-3-yl)methyl]-N,N-dimethylpiperidin-4-amine:
A mixture of 6-bromo-3-pridinecarboxaldehyde (930 mg, 5.0 mmol) and 4-dimethylaminopiperidine (2.56 g, 20 mmol) in THE (40 mL) was stirred at room temperature for 1h. To this was added NaBH(OAc)3 (4.24 g, 20 mmol). The reaction mixture was stirred at room temperature for 20 h, diluted with ethyl acetate (100' mL), washed with saturated NaHCO3 solution, H2O, brine and dried (Na2SO4). Filtration and evaporation gave 780 mg (52%) of the title compound. MS 298.1 (M+H).

N
N
JCO'o N

[00440] Preparation of N,N-dimethyl-1-[(6-vinylpyridin-3-yl)methyl]piperidin-4-amine:

A mixture of 1-[(6-bromopyridin-3-yl)methyl]-N,N-dimethylpiperidin-4-amine (596 mg, 2.0 mmol), tributyl(vinyl)tin (1.268 g, 4.0 mmol) and Pd(PPh3)4 (116 mg, 0.1 mmol) in toluene (8 ml) was refluxed for 3.5 h, cooled to room temperature, diluted with ethyl acetate (50 mL), washed with saturated NaHCO3 solution, H2O, brine and dried (Na2SO4)=
Filtration and evaporation gave a brown oil, which was purified by silica gel chromatography (CH2CI2-CH3OH, 0% to 30% CH3OH), providing 256 mg (52%) of the title compound as a sticky yellow oil. MS 246.2 (M+H).

NH
I I

HN 'N
I i rO
N
GN

[00441] Preparation of 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{2-[2-(2-pyrrolidin-l -yl ethoxy)phenyl]ethyl}pyridine-3-carbonitrile:
4-[(4-Methyl-1 H-indol-5-yl)amino]-5-([2-(2-pyrrolidin-1-ylethoxy)phenyl]ethynyl}pyridine-3-carbonitrile (100 mg, 0.22 mmol) and 10% Pd/C (15.mg) was treated with 10 mL
of 1:1 EtOH/toluene (10 ml-) and shaken under an atmosphere of 30 psi hydrogen for 3 days. The reaction mixture was filtered and the filtrate was concentrated and purified by HPLC to give 30 mg of the title compound. HPLC rt = 6.7 min [a]; HRMS: 466.2605 (M+H).

[00442] Table 12:

The following compounds were prepared from the indicated starting material following the procedure outlined for 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{2-[2-(2-pyrrolidin-1-ylethoxy) phenyl]ethyl}pyridine-3-carbonitrile.

Compound Name Starting material. MS HPLC
(ESI) rt 4-[(4-methyl-1 H-indol-5-yl)amino]- 4-[(4-Methyl-1 H-indol-5-yl)amino]-5-{[3-(2- 466.3 1.51 5-{2-[3-(2-pyrrolidin-1-ylethoxy) pyrrolidin-1-ylethoxy)phenyl]ethynyl} (M+H) min phenyl]ethyl)pyridine-3-carbonitdie nicotinonitrile (D) 4-[(4-methyl-1H-indol-5-yl)amino]- 4-[(4-methyl-1H-indol-5-yl)amino]-5-{[3-436.3 5.5 5-{2-[3-(pyrrolidin-1-ylmethyl) (pyrrolidin-1-ylmethyl)phenyl]ethynyl) (M+H) min phenyl]ethyi)pyridine-3-carbonitrile pyridine-3-carbonitnle (A) 4-[(4-methyl-1 H-indol-5-yl)amino]- 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{[4-(2- 466.3 1.48 5-{2-[4-(2-pyrrolidin-1-ylethoxy) pyrrolidin-1-ylethoxy)phenyl]ethynyl} (M+H) min hen I eth I ridine-3-carbonitnle ridine-3-carbonitrile (D) H rN

[00443] Preparation of tert-butyl 5-cyano-2-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-3',6'-dihydro-3,4'-bi pyrid ine-1'(2'H)-carboxylate:

A mixture of 5-iodo-6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile (200 mg, 0.52 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)piperidine-l -carboxylate (191 mg, 0.62 mmol), Pd(PPh3)4 (72 mg, 0.62 mmol) and NaHCO3 (aq. sat., 2 ml-) in 5 mL of DME
was heated to 100 C for 16 h. The reaction was diluted with ethyl acetate and washed with water. The solvents were removed and the residue was purified by chromatography using an ethyl acetate/ hexane gradient. Impurities were further removed by HPLC to give the title compound as a solid; MS 444.5 (M+H), HPLC rt = 9.8 min [a].

H
FA HN ~

[00444] Preparation of 2-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-1',2',3',6'-tetrahydro-3,4'-bipyridine-5-carbonitrile:

A solution of tert-butyl 5-cyano-2-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-3',6'-dihydro-3,4'-bipyridine-1'(2'H)-carboxylate (500 mg, 1.12 mmol) in 20% trifluoroacetic acid/ DCM (6 ml-) was stirred at room temperature for 16 h. All solvents were removed in vacuo.
Impurities were removed by HPLC purification to give the title compound as its TFA salt; MS
344.2 (M+H), HPLC rt = 3.8 min [b].

NH
O
0Is.N HN
iN
N

[00445] Preparation of 5-{(E)-2-[1-(isopropylsulfonyl)piperidin-4-yl]vinyl}-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile:

A mixture of 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-pip eridin-4-ylvinyl]nicotinonitrile (61 mg, 0.13 mmol), propane-2-sulfonyl chloride (17 mg, 0.17 mmol), and triethylamine (39 mg; 0.39 mmol) was stirred at room temperature for 45 min. The reaction mixture was purified by HPLC
to give 11.5 mg (19%) of the title compound as a solid; MS 464.2 (M+H), HPLC
rt = 1.89 min [d].

NH
H
N~"' N N

N

[00446] Preparation of 4-[(4-methyl-IH-indol-5-yl)amino]-5-[(E)-2-{6-[(2-piperidin-1-yl ethyl)amino]pyridin-3-yl}ethenyl]pyridine-3-carbonitrile:
A mixture of 5-[(E)-2-(6-chloropyridin-3-yl)vinyl]-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile (100 mg, 0.26 mmol), 2-(piperidin-1-yl)ethanamine (66 mg, 0.52 mmol), BINAP
(16 mg, 0.026 mmol), Pd2dba3 (24 mg, 0.026 mmol), and potassium tertbutoxide (IM in THF, 1.04 mmol) was heated in THF at 65 C under N2 and anhydrous conditions for 5 hr. The reaction was cooled to room temperature and the solvents were removed. The residue was redissolved in DMSO for purification by HPLC to give 17 mg (14% yield) of the title compound as a solid; MS 478.3 (M+H), HPLC rt = 1.48 min [d].

NH

/

N

[00447] Preparation of I'-(N,N-dimethylglycyl)-4-[(4-methyl-1H-indol-5-yl)amino]-1',2',3', 6'-tetrahydro-3,4'-bipyridine-5-carbonitrile:

The TFA salt of 4-[(4-methyl-1 H-indol-5-yl)amino]-1',2',3',6'-tetrahydro-3,4'-bipyridine-5-carbonitrile (80 mg, 0.18 mmol) was dissolved in 2:1 DCM/ methanol (3 ml-) and treated with triethylamine (54 mg, 0.54 mmol). 2-(Dimethylamino)acetic acid (56 mg, 0.54 mmol) was added followed by 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (172 mg, 0.90 mmol). The reaction was stirred at room temperature for 36 h. The solvents were removed and the residue was redissolved in DMSO for purification by HPLC to give the title compound as a solid; MS 415.2 (M+H), HPLC rt = 4.6 min [a].

TH

[00448] Preparation of 4-[(4-methyl-1H-indol-5-yl)amino]-1'-[(1-methylpiperidin-4-yl) methyl]-1',2',3',6'-tetrahydro-3,4'-bipyridine-5-carbonitrile:
The TFA salt of 4-[(4-methyl-1 H-indol-5-yl)amino]-1',2',3',6'-tetrahydro-3,4'-bipyridine-5-carbonitrile (120 mg, 0.27 mmol) was combined with 1-methylpiperidine-4-carbaldehyde (41 mg, 0.33 mmol), sodium triacetoxyborohydride (171 mg, 0.81 mmol) and triethylamine (33 mg, 0.33 mmol) in 3 mL of.DCE and stirred at room temperature for 16 h. The solvents were removed and the residue was redissolved in DMSO for purification by HPLC to give the title compound as its TFA salt; MS 441.2 (M+H), HPLC rt = 4.9 min [a].

NH

QflH,N

[00449] Preparation of 1'-benzyl-2-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-1',2',3',6'-tetrahydro-3,4'-bipyridine-5-carbonitrile:
The TFA salt of 2-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-1',2',3',6'-tetrahydro-3,4'-bipyridine-5-carbonitrile (100 mg, 0.22 mmol) was combined with benzaldehyde (28 mg, 0.26 mmol), sodium triacetoxyborohydride (140 mg, 0.66 mmol) and triethylamine (89 mg, 0.88 mmol) in 3 mL of DCE and stirred at room temperature for 2 h. The solvents were removed and the residue was redissolved in DMSO for purification by HPLC to give the title compound as its TFA salt; MS 434.2 (M+H), HPLC rt = 6.1 min [a].

fl I \ / N

[00450] Preparation of 2-methyl-4-[(4-methyl-1 H-indol-5-yQarnino]-I'-[(I -methyl piperidi n-4-yl)methyl]-1',2',3',6'-tetrahydro-3,4'-bipyridi ne-5-carbonitrile:

The TFA salt of 2-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-1',2',3',6'-tetrahydro-3,4'-bipyridine-5-carbonitrile (100 mg, 0.22 mmol) was combined with 1-methylpiperidine-4-carbaldehyde (61 mg, 0.48 mmol), sodium triacetoxyborohydride (140 mg, 0.66 mmol) and triethylamine (89 mg, 0.88 mmol) in 3 mL of DCE and stirred at room temperature for 16 h. The solvents were removed and the residue was redissolved in DMSO for purification by HPLC to give the title compound as its TFA salt; MS 455.2 (M+H), HPLC rt = 4.7 min [a].

NH
o N
I~

[00451] Preparation of 2-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-1'-(methylsulfonyl)-1',2', 3',6'-tetrahydro-3,4'-bi pyrid ine-5-carbonitrile:

The TFA salt of 2-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-1',2',3',6'-tetrahydro-3,4'-bipyridine-5-carbonitrile (100 mg, 0.22 mmol) was combined with methanesulfonyl chloride (30 mg, 0.26 mmol) and triethylamine (89 mg, 0.88 mmol) in 1 mL of DMF and stirred at room temperature for 2 h. The reaction was purified by HPLC to give the title compound as its TFA salt; MS
422.2 (M+H), HPLC rt = 7.6 min [a].

[00452] Preparation of 4-(1H-indol-5-ylamino)-5-[(E)-2-pyridin-2-ylethenyl]pyridine-3-carbonitrile :

A mixture of 4-(1 H-indol-5-ylamino)-5-iodonicotinonitrile (200 mg, 0.55 mmol), 2-vinylpyridine (0.120 mL, 1.11 mmol), palladium(II)acetate (30 mg), tri(o-tolyl)phosphine (19 mg) and 0.500 mL of triethylamine in 5 mL of DMF was heated at 100 C for 30 min. After cooling to room temperature, the reaction mixture was partitioned between saturated aqueous sodium bicarbonate and dichloromethane. The organic layer was further extracted with ethyl acetate and the organic layers were combined, washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography eluting with a gradient of 3:1 hexane : ethyl acetate to all ethyl acetate.
Trituration with diethyl ether provided 19.8 mg (11 %) of 4-(1H-indol-5-ylamino)-5-[(E)-2-pyridin-2-ylethenyl]pyridine-3-carbonitrile as a pale yellow solid: MS 338.1 (M+H), HPLC 98.0%, rt = 5.9 min [a].

~6H

HO HN 'N

N II
N

[00453] Preparation of 5{(E)-2-[5-(hydroxymethyl)pyridin-2-yll]ethenyl}-6-methyl-4-[(4-methyl-1 H-indol- 5-yl)amino]pyridine-3-carbonitrile:
5-lodo-6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile (3.0 g, 7.73 mmol) was dissolved in a mixture of DMF (40 ml) and triethylamine (10 ml) and subsequently treated with (6-vinylpyridin-3-yl)methanol (1.15 g, 8.51 mmol), Pd(OAc)2 (347 mg, 1.55 mmol) and P(o-Tol)3 (118 mg, 0.39 mmol). After stirring at 110 C under nitrogen for 5 hr, the reaction was cooled and diluted with dichloromethane and washed one time with saturated aqueous sodium bicarbonate. A precipitate formed during a 2"d wash with saturated aqueous sodium bicarbonate. The precipitate was collected by filtration and washed with dichloromethane then water giving 2.08 g (68%) of the title compound as a tan solid, MS 396.3 (M+H); 93.9% at 215 nm, rt = 5.5 min [a].

NH
N I ~*O ~6 HO H iN
N

N

[00454] Preparation of 5{(E)-2-[6-(hydroxymethyl)pyridin-2-yl]ethenyl}-6-methyl-4-[(4-methyl-I H-indol- 5-yl)amino]pyridine-3-carbonitrile:
5-lodo-6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile (3.0 g, 7.73 mmol) was dissolved in a mixture of DMF (40 ml) and triethylamine (10 ml), followed by the addition of (6-vinylpyridin-2-yl)methanol (1.05 g, 7.77 mmol), Pd(OAc)2 (347 mg, 1.55 mmol) and P(o-Tol)3 (118 mg, 0.39 mmol). The reaction mixture was stirred at 110 C under nitrogen for 5 hr then cooled and diluted with dichloromethane. The organic layer was washed one time with saturated aqueous sodium bicarbonate. During a 2"d wash with saturated aqueous sodium bicarbonate, a precipitate formed and was collected by filtration. The solid was washed with dichloromethane then water giving 2.31 g (76%) of the title compound as a tan solid, MS 396.3 (M+H); 94.7% at 215 nm, rt = 6.3 min [a].

[00455] Preparation of 4-[(4-methyl-IH-indol-5-yl)amino]-5-{(E)-2-[5-piperidin-1-yl ethyl)pyridin-2- yl]ethenyl}pyridine-3-carbonitrile:

To the solution of 5-{(E)-2-[5-(hydroxymethyl)pyridin-2-yl]vinyl}-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile (100 mg, 0.262 mmol) in solvent mixture THE (5 ml) and DMF (2.5 ml) was added triethylamine (183 NL, 1.313 mmol). The solution was stirred under nitrogen at rt for min. Methanesulfonyl chloride (61 pL, 0.788 mmol) was added dropwise into the reaction mixture. After stirring under nitrogen at rt for 8 hours, piperidine (104 pL, 1.050 mmol) was added and the reaction was stirred overnight. The solvent was removed and the residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate.
The organic layer was dried over MgSO4 and concentrated to give dark syrup. The resulting crude compound was purified by HPLC to give 32 mg (27%) of the title compound as a yellow solid, MS 449.3 (M+H); 92.2% at 215 nm, 5.3 min [A].

[00456] Preparation of 4-[(4-methyl-IH-indol-5-yl)amino]-5-{(E)-2-[5-(pyrrolidin-1-yl methyl)pyridin-2- yl]ethenyl}pyridine-3-carbonitrile:

The title compound was prepared from 5-{(E)-2-[5-(hydroxymethyl)pyridin-2-yl]vinyl}-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile and pyrrolidine via the procedure used to prepare 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E}2-[5-(piperidin-l-ylmethyl)pyridin-2-yl]ethenyl}pyridine-3-carbonitrile, MS 435.3 (M+H); 90.3% at 215 nm, rt = 5.0 min [a].

N
H
N

F

[00457] Preparation of 4-[(4-methyl-1 H-indol-5-yl)amino]-5{(E)-2-[5-(morpholin-4-yl methyl)pyridin-2- yl]ethenyl}pyridine-3-carbonitrile:

The title compound was prepared from 5-{(E)-2-[5-(hydroxymethyl)pyridin-2-yl]vinyl}-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile and morpholine via the procedure used to prepare 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[5-(piperidin-1-ylmethyl)pyridin-2-yl]ethenyl)pyridine-3-carbonitrile, MS 451.3 (M+H); 91.8% at 215 nm, rt = 4.9 min [a].

NH
[00458] Preparation of 4-[(4-methyl-1H-indol-5-yl)amino]-5{(E)-2-[5-(thiomorpholin-4-ylmethyl)pyridin- 2-yl]ethenyl)pyridine-3-carbonitrile:

The title compound was prepared from 5-{(E)-2-[5-(hydroxymethyl)pyridin-2-yl]vinyl}-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile and thiomorpholine via the procedure used to prepare 4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[5-(piperidin-1-ylmethyl)pyridin-2-yl]ethenyl}
pyridine-3-carbonitrile, MS 467.2 (M+H); 95.2% at 215 nm, rt = 5.4 min [a].

NH

[00459] Preparation of 5-[(E)-2{5-[(4-hydroxypiperidin-1-yl)methyl]pyridin-2-yl}ethenyl]
-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile:

The title compound was prepared from 5{(E)-2-[5-(hydroxymethyl)pyridin-2-yl]vinyl}-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile and 4-hydroxypiperidine via the procedure used to prepare 4-[(4-methyl-1 H-indol-5-yl)amino]-5{(E)-2-[5-(piperidin-1-ylmethyl)pyridin-2-yl]ethenyl}
pyridine-3-carbonitrile, MS 465.3 (M+H); HPLC rt = 4.7 min [a].

NH

[00460] Preparation of 5-[(E)-2-(5{[4-(2-hydroxyethyl)piperazin-1-yl]methyl}pyridin-2-yl) ethenyl]-44(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile:

The title compound was prepared from 5-((E)-2-[5-(hydroxymethyl)pyridin-2-yl]vinyl}-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile and 4-(2-hydroxyethyl)piperazine via the procedure used to prepare 4-[(4-methyl-1 H-indol-5-yl)amino]-5{(E)-2-[5-(piperidin-1-ylmethyl)pyridin-2-yl]ethenyl}pyridine-3-carbonitrile, MS 494.3 (M+H); 90.7% at 215 nm, rt = 4.7 min [a].

NH
l I /

H I / N

[00461] Preparation of 4-[(4-methyl-lH-indol-5-yl)amino]-5-[(E)-2-(5-([(2-morpholin-4-ylethyl)amino]methyl}pyridin-2-yl)ethenyl]pyridine-3-carbonitrile:
The title compound was prepared from 5-{(E)-2-[5-(hydroxymethyl)pyridin-2-yl]vinyl}-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile and 4-(2-aminoethyl)morpholine via the procedure used to prepare 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[5-(piperidin-1-ylmethyl)pyridin-2-yl]ethenyl}pyridine-3-carbonitrile, MS 494.3 (M+H); HPLC: 90.8% at 215 nm, rt = 4.4 min [a].

. ~NH
rl F OI-Ij H ( / jN

[00462] Preparation of 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(5-{[(3-morpholin-4-ylpropyl)amino]methyl}pyridin-2-yl)ethenyl]pyridine-3-carbonitrile:
The title compound was prepared from 5-{(E)-2-[5-(hydroxymethyl)pyridin-2-yl]vinyl}-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile and 4-(3-aminopropyl)morpholine via the procedure used to prepare 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[5-(piperidin-1-ylmethyl)pyridin-2-yl]ethenyl}pyridine-3-carbonitrile, MS 508.3 (M+H); HPLC: 98.2% at 215 nm, rt = 4.6 min [a].

N
H

N
F

[00463] Preparation of 4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-{5-[(4-morpholin-4-ylpiperidin-1-yl)methyl]pyridin-2-yl}ethenyl]pyridine-3-carbonitrile:
The title compound was prepared from 5-{(E)-2-[5-(hydroxymethyl)pyridin-2-yl]vinyl}-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile and 4-morpholinopiperidine via the procedure used to prepare 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[5-(piperidin-1-ylmethyl)pyridin-2-yl]
ethenyl}pyridine-3-carbonitrile, MS 534.3 (M+H); HPLC: 98.1% at 215 nm, rt =
4.6 min [a].

dNH

[00464] Preparation of 5-{(E)-2-[5-(1,4'-bipiperidin-1'-ylmethyl)pyridin-2-yl]ethenyl}-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile:

The title compound was prepared from 5-{(E)-2-[5-(hydroxymethyl)pyridin-2-yl]vinyl}-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile and 4-piperidinopiperidine via the procedure used to prepare 4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[5-(piperidin-1-ylmethyl)pyridin-2-yl]ethenyl}
pyridine-3-carbonitrile, MS 532.4 (M+H); HPLC: 97.7% at 2,15 nm, rt = 4.8 min [a].

NH
f I F \

[00465] Preparation of 4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-{5-[(4-pyrrolidin-1-yl piperidin-1-yl)methyl]pyridin-2-yl)ethenyl]pyridine-3-carbonitrile:
The title compound was prepared from 5-{(E)-2-[5-(hydroxymethyl)pyridin-2-yl]vinyl}-4-[(4-methyl-1 H-indol-5=yl)amino]nicotinonitrile and 4-pyrrolidinopiperidine via the procedure used to prepare 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[5-(piperidin-1-ylmethyl)pyridin-2-yl]ethenyl}
pyridine-3-carbonitrile, MS 518.3 (M+H); HPLC: 97.4% at 215 nm, rt = 4.6 min [a].

NH
r NI I/~ N

[00466] Preparation of 5-[(E)-2-(5-[(4-cyclopentylpiperazin-1-yl)methyl]pyridin-2-yl}
ethenyl]-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile:

The title compound was prepared from 5-{(E)-2-[5-(hydroxymethyl)pyridin-2-yl]vinyl}-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile and 1-cyclopentylpiperazine via the procedure used to prepare 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[5-(piperidin-1-ylmethyl)pyridin-2-yl]
ethenyl}pyridine-3-carbonitrile, MS 518.3 (M+H); HPLC: 97.1% at 215 nm, rt =
5.8 min [a].

NH
I N / I R4 \
N ) / N

[00467] Preparation of 5-[(E)-2-(5-{[4-(1-methylethyl)piperazin-1-yl]methyl}pyridin-2-yl)ethenyl]-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile:

The title compound was prepared from 5-{(E)-2-[5-(hydroxymethyl)pyridin-2-yl]vinyl}-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile and 1-isopropylpiperazine via the procedure used to prepare 4-[(4-methyl-1 H-indol-5-yl)amino)-5-{(E)-2-[5-(piperidin-1-ylmethyl)pyridin-2-yl]ethenyl) pyridine-3-carbonitrile, MS 492.3 (M+H); HPLC: 96.6% at 215 nm, rt = 5.4 min [a].

NH
Nr) / N

[00468] Preparation of 5-[(E)-2-(5-{[4-(dimethylamino)piperidin-1-yl]methyl}pyridin-2-yl) ethenyl]-44(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile:

The title compound was prepared from 5-{(E)-2-[5-(hydroxymethyl)pyridin-2-yl]vinyl)-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile and 4-dimethylaminopiperidine via the procedure used to prepare 4[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[5-(piperidin-l-ylmethyl)pyridin-2-yl]ethenyl}pyridine-3-carbonitrile, MS 492.3 (M+H); HPLC: 96.3% at 215 nm, rt = 4.5 min [a].

NH
JN
N~\(i J

[00469] Preparation of 5-[(E)-2-{5-[(4-methyl-1,4-diazepan-1-yl)methyl]pyridin-2-yl}
ethenyl]-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile:

The title compound was prepared from 5-{(E)-2-[5-(hydroxymethyl)pyridin-2-yl]vinyl}-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile and 1-methylhomopiperazine via the procedure used to prepare 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[5-(piperidin-1-ylmethyl)pyridin-2-yl]
ethenyl}pyridine-3-carbonitrile, MS 478.3 (M+H); HPLC: 96.3% at 215 nm, rt =
4.5 min [a].

U

H JJN

[00470] Preparation of 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[5-({[3-(2-oxo pyrrolidin-1-yl)propyl]amino}methyl)pyridin-2-yl]ethenyl}pyridine-3-carbonitrile:
The title compound was prepared from 5-{(E)-2-[5-(hydroxymethyl)pyridin-2-yl]vinyl}-4-[(4-methyl-l H-indol-5-yl)amino]nicotinonitrile and 1-(3-aminopropyl)-2-pyrrolidinone via the procedure used to prepare 4-[(4-methyl-lH-indol-5-yl)amino]-5-{(E)-2-[5-(piperidin-1-ylmethyl) pyridin-2-yl]ethenyl}pyridine-3-carbonitrile, MS 506.3 (M+H); HPLC: 98.8% at 215 nm, rt = 5.6 min [a].

NH
H N

[00471] Preparation of 5-{(E)-2-[5-({[2-(dimethylamino)ethyl]amino}methyl)pyridin-2-yl]ethenyl}-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile:

The title compound was prepared from 5-{(E)-2-[5-(hydroxymethyl)pyridin-2-yl]vinyl}-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile and N,N-dimethylethylenediamine via the procedure used to prepare 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[5-(piperidin-l-ylmethyl)pyridin-2-yl]ethenyl}pyridine-3-carbonitrile, MS 452.1 (M+H); HPLC: 90.9% at 215 nm, rt = 5.4 min [a].

H
N
~\ Ili \ ~v I v~~~\/x\
H~

[00472] Preparation of 5-{(E)-2-[5-(([3-(dimethylamino)propyl]amino)methyl)pyridin-2-yl]ethenyl}-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile:

The title compound was prepared from 5-{(E)-2-[5-(hydroxymethyl)pyridin-2-yl]vinyl}-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile and 3-(dimethylamino)propylamine via the procedure used to prepare 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[5-(piperidin-1-ylmethyl)pyridin-2-yl]ethenyl}pyridine-3-carbonitrile, MS 466.3 (M+H); HPLC: rt = 1.31 min [d].

N
N

[00473] Preparation of 5-[(E)-2-(5-{[(2-ethoxyethyl)amino]methyl}pyridin-2-yl)ethenyl]-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile:

The title compound was prepared from 5-{(E)-2-[5-(hydroxymethyl)pyridin-2-yl]vinyl}-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile and 2-ethoxyethylamine via the procedure used to prepare 4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[5-(piperidin-l-ylmethyl)pyridin-2-yl]ethenyl}
pyridine-3-carbonitrile, MS 453.1 (M+H); HPLC: rt = 6.5 min [a].

H ~ I r ~N

[00474] Preparation of 5-[(E)-2-(5-{[(3-ethoxypropyl)amino]methyl}pyridin-2-yl)ethenyl]-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile:

The title compound was prepared from 5-{(E)-2-[5-(hydroxymethyl)pyridin-2-yl]vinyl}-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile and 3-ethoxypropylamine via the procedure used to prepare 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[5-(piperidin-1-ylmethyl)pyridin-2-yl]ethenyl}
pyridine-3-carbonitrile, MS 467.1 (M+H); HPLC: 94.0% at 215 nm, rt = 6.7 min [a].

rH
[00475] Preparation of 5-[(E)-2-(5-{[(2-methoxyethyl)amino]methyl}pyridin-2-yl)ethenyl]-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile:

The title compound was prepared from 5-{(E)-2-[5-(hydroxymethyl)pyridin-2-yl]vinyl}-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile and 2-methoxyethylamine via the procedure used to prepare 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[5-(piperidin-1-ylmethyl)pyridin-2-yl]ethenyl) pyridine-3-carbonitrile, MS 439.1 (M+H); HPLC: 97.2% at 215 nm, rt = 6.1 min [a].

[00476] Preparation of 4-[(4-methyl-1h-indol-5-yl)amino]-5-((e)-2-[6-(morpholin-4-yl methyl)pyridin-2-yl]ethenyl}pyridine-3-carbonitrile:
To a solution of 5-{(E)-2-[6-(hydroxymethyl)pyridin-2-yl]vinyl}-4-[(4-methyl-1 H-indol-5-yl) amino]nicotinonitrile (100 mg, 0.262 mmol) in a solvent mixture of THE (5 ml) and DMF (2.5 ml) was added triethylamine (183 pL, 1.313 mmol). The solution was stirred under nitrogen at room temperature for 10 min. Methanesulfonyl chloride (61 pL, 0.788 mmol) was added dropwise into the reaction mixture. The reaction was stirred under nitrogen at room temperature for 8 hours, followed by the addition of morpholine (100 pL, 1.147 mmol). The reaction was stirred overnight. The solvent was evaporated and the residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic solution was dried over MgSO4 and concentrated to give a dark syrup. The resulting crude compound was purified by HPLC to give 61 mg (52%) of the title compound as a yellow solid, MS 451.1 (M+H); HPLC: 96.7% at 215 nm, rt = 6.3 min [a].

NH
N

[00477] Preparation of 4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[6-(thiomorpholin-4-yl methyl)pyridin-2-yl]ethenyl}pyridine-3-carbonitrile:
The title compound was prepared from 5-{(E)-2-[6-(hydroxymethyl)pyridin-2-yl]vinyl}-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonit(le and thiomorpholine via the procedure used to prepare 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[6-(morpholin-4-ylmethyl)pyridin-2-yl]
ethenyl}pyridine-3-carbonitrile, MS 467.1 (M+H); HPLC: 97.9% at 215 nm, rt =
6.8 min [a].

NH
HO

[00478] Preparation of 5-[(E)-2-{6-[(4-hydroxypiperidin-1-yl)methyl]pyridin-2-yl}ethenyl]
-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile:

The title compound was prepared from 5-{(E)-2-[6-(hydroxymethyl)pyridin-2-yl]vinyl}-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile and 4-hydroxypiperidine via the procedure used to prepare 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[6-(morpholin-4-ylmethyl)pyridin-2-yl]
ethenyl}pyridine-3-carbonitrile, MS 465.1 (M+H); HPLC: 97.0% at 215 nm, rt =
6.2 min [a].

NH
HO ~ ~
N
[00479] Preparation of 5-[(E)-2-(6{[4-(2-hydroxyethyl)piperazin-1-yl]methyl}pyridin-2-yl)ethenyl]-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile:

The title compound was prepared from 5-{(E)-2-[6-(hydroxymethyl)pyridin-2-yl]vinyl}-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile and 4-(2-hydroxyethyl)piperazine via the procedure used to prepare 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[6-(morpholin-4-ylmethyl)pyridin-2-yl]ethenyl}pyridine-3-carbonitrile, MS 494.1 (M+H); HPLC: 94.3% at 215 nm, rt = 5.8 min [a].

H I //N

[00480] Preparation of 4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-(6{[(2-morpholin-4-ylethyl)amino]methyl}pyridin-2-yl)ethenyl]pyridine-3-carbonitrile:
The title compound was prepared from 5{(E)-2-[6-(hydroxymethyl)pyridin-2-yl]vinyl}-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile and 4-(2-aminoethyl)morpholine via the procedure used to prepare 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[6-(morpholin-4-ylmethyl)pyridin-2-yl]ethenyl}pyridine-3-carbonitrile, MS 494.1 (M+H); HPLC: 95.7% at 215 nm, rt = 6.1 min [a].

tit HN

[00481] Preparation of 4-[(4-methyl-IH-indol-5-yl)amino]-5-[(E)-2-(6-([(3-morpholin-4-ylpropyl)amino]methyl}pyridin-2-yl)ethenyl]pyridine-3-carbonitrile:
The title compound was prepared from 5-{(E)-2-[6-(hydroxymethyl)pyridin-2-yl]vinyl)-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile and 4-(3-aminopropyl)morpholine via the procedure used to prepare 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[6-(morpholin-4-ylmethyl)pyridin-2-yl]ethenyl}pyridine-3-carbonitrile, MS 508.2 (M+H); HPLC: 97.1% at 215 nm, rt = 4.5 min [a].

NH
N`~~

[00482] Preparation of 4-[(4-methyl-1 H-Indol-5-yl)amino]-5-[(E)-2-{6-[(4-morpholin-4-ylpiperidin-1-yl)methyl]pyridin-2-yl}ethenyl]pyridine-3-carbonitrile:
The title compound was prepared from 5-{(E)-2-[6-(hydroxymethyl)pyridin-2-yl]vinyl}-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile and 4-morpholinopiperidine via the procedure used to prepare 4-[(4-methyl-lH-indol-5-yl)amino]-5-{(E)-2-[6-(morpholin-4-ylmethyl)pyridin-2-yl]ethenyl}pyridine-3-carbonitrile, MS 534.2 (M+H); HPLC: 96.1% at 215 nm, rt = 4.5 min [a].

NH
C)N

[00483] Preparation of 5-{(E)-2-[6-(1,4'-bipiperidin-1'-ylmethyl)pyridin-2-yl]ethenyl}-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile:

The title compound was prepared from 5-{(E)-2-[6-(hydroxymethyl)pyridin-2-yl]vinyl}-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile and 4-piperidinopiperidine via the procedure used to prepare 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[6-(morpholin-4-ylmethyl)pyridin-2-yl]
ethenyl}pyridine-3-carbonitrile, MS 266.6 (M+2H); HPLC: 92.6% at 215 nm, it =
4.6 min [a].

Nx CN I{1i T ~.

N I / \

[00484] Preparation of 4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-{6-[(4-pyrrolidin-1-yl piperidin-1-yl)methyl]pyridin-2-yl}ethenyl]pyridine-3-carbonitrile:
The title compound was prepared from 5-{(E)-2-[6-(hydroxymethyl)pyridin-2-yl]vinyl}-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile and 4-pyrrolidinopiperidine via the procedure used to prepare 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[6-(morpholin-4-ylmethyl)pyridin-2-yl]
ethenyl}pyridine-3-carbonitrile, MS 518.2 (M+H); HPLC: 91.8% at 215 nm, rt =
4.5 min [a].

WO 2009/076602' PCT/US2008/086594 Nil H
ON. N

[00485] Preparation of 5-[(E)-2-{6-[(4-cyclopentylplperazin-1-yl)methyl]pyridin-2-yl}ethenyl]-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile:

The title compound was prepared from 5-{(E)-2-[6-(hydroxymethyl)pyridin-2-yl]vinyl}-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile and 1-cyclopentylpiperazine via the procedure used to prepare 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[6-(morpholin-4-ylmethyl)pyridin-2-yl]
ethenyl}pyridine-3-carbonitrile, MS 259.6 (M+2H); HPLC: 96.1% at 215 nm, rt =
6.3 min [a].

~NH
l HK'~~/
N

[00486] Preparation of 5-[(E)-2-(6-{[4-(1-methylethyl)piperazin-1-yl]methyl}pyridin-2-yl) ethenyl]-44(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile:

The title compound was prepared from 5-{(E)-2-[6-(hydroxymethyl)pyridin-2-yl]vinyl}-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile and 1-isopropylpiperazine via the procedure used to prepare 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[6-(morpholin-4-ylmethyl)pyridin-2-yl]
ethenyl}pyridine-3-carbonitrile, MS 246.6 (M+2H); HPLC: rt = 4.3 min [a].

NH
/N / H \

[00487] Preparation of 5-[(E)-2-(6{[4{dimethylamino)piperidin-1-yl]methyl}pyridin-2-yl) ethenyl]-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile:

The title compound was prepared from 5-{(E)-2-[6-(hydroxymethyl)pyridin-2-yl]vinyl}-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile and 4-dimethylaminopiperidine via the procedure used to prepare 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[6-(morpholin-4-ylmethyl)pyridin-2-yl]ethenyl}pyridine-3-carbonitrile, MS 492.2 (M+H); HPLC: 92.6% at 215 nm, rt = 5.3 min [a].

NH

[00488] Preparation of 5-[(E)-2{6-[(4-methyl-1,4-diazepan-1-yl)methyl]pyridin-2-yl}
ethenyl]-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile:

The title compound was prepared from 5-{(E)-2-[6-(hydroxymethyl)pyridin-2-yl]vinyl}-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile and 1-methylhomopiperazine via the procedure used to prepare 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[6-(morpholin-4-ylmethyl)pyridin-2-yl]
ethenyl}pyridine-3-carbonitrile, MS 478.2 (M+H); HPLC: 92.2% at 215 nm, rt =
5.3 min [a].

NH

[00489] Preparation of 4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[6-({[3-(2-oxo pyrrolidin-1-yl)propyl]amino}methyl)pyridin-2-yl]ethenyl}pyridine-3-carbonitrile:
The title compound was prepared from 5-{(E)-2-[6-(hydroxymethyl)pyridin-2-yl]vinyl}-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile and 1-(3-aminopropyl)-2-pyrrolidinone via the procedure used to prepare 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[6-(morpholin-4-yl methyl)pyridin-2-yl]ethenyl}pyridine-3-carbonitrile, MS 506.2 (M+H); HPLC:
99.5% at 215 nm, rt = 6.3 min [a].

NH
\N/\/H I / N

[00490] Preparation of 5-{(E)-2-[6-(([2-(dimethylamino)ethyl]amino)methyl)pyridin-2-yl]
ethenyl}-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile:

The title compound was prepared from 5-{(E)-2-[6-(hydroxymethyl)pyridin-2-yl]vinyl}-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile and N,N-dimethylethylenediamine via the procedure used to prepare 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[6-(morpholin-4-ylmethyl)pyridin-2-yl]ethenyl}pyridine-3-carbonitrile, MS 452.2 (M+H); HPLC: 90.5% at 215 nm, rt = 5.3 min [a].

rtt H N

[00491] Preparation of 5-{(E)-2-[6-({[3-(dimethylamino)propyl]amino}methyl)pyridin--2-yl]ethenyl}-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile The title compound was prepared from 5-{(E)-2-[6-(hydroxymethyl)pyridin-2-yl]vinyl}-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile and 3-(dimethylamino)propylamine via the procedure used to prepare 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[6-(morpholin-4-ylmethyl)pyridin-2-yl]ethenyl}pyridine-3-carbonitrile, MS 466.2 (M+H); HPLC: 94.6% at 215 nm, rt = 5.3 min [a].

NH
H )::
5~
H N

[00492] Preparation of 5-[(E)-2-(6-{[(2-ethoxyethyl)amino]methyl}pyridin-2-yl)ethenyl]-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile:

The title compound was prepared from 5-{(E)-2-[6-(hydroxymethyl)pyridin-2-yl]vinyl}-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile and 2-ethoxyethylamine via the procedure used to prepare 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[6-(morpholin-4-ylmethyl)pyridin-2-yl]
ethenyl}pyridine-3-carbonitrile, MS 453.2 (M+H); HPLC: 97.8% at 215 nm, rt =
6.5 min [a].

Ott N

[00493] Preparation of 5-[(E)-2-(6-{[(3-ethoxypropyl)amino]methyl}pyridin-2-yl)ethenyl]-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile:

The title compound was prepared from 5-{(E)-2-[6-(hydroxymethyl)pyridin-2-yl]vinyl)-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile and 3-ethoxypropylamine via the procedure used to prepare 4-[(4-methyl-1 H-indol-5-yl)amino]5-{(E)-2-[6-(morpholin-4-ylmethyl)pyridin-2-yl]
ethenyl}pyridine-3-carbonitrile, MS 467.2 (M+H).

NH
cT v [00494] Preparation of 5-[(E)-2-(6-{[(2-methoxyethyl)amino]methyl}pyridin-2-yl)ethenyl]-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile:

The title compound was prepared from 5-{(E)-2-[6-(hydroxymethyl)pyridin-2-yl]vinyl}-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile and 2-methoxyethylamine via the procedure used to prepare 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[6-(morpholin-4-ylmethyl)pyridin-2-yl]
ethenyl}pyridine-3-carbonitrile, MS 439.2 (M+H); HPLC: 96.0% at 215 nm, rt =
6.2 min [a].

[00495] Preparation of 4-[(1,4-dimethyl-1H-indol-5-yl)amino]-5-[(E)-2-phenylethenyl]
pyrid ine-3-carbon itrile:

4-[(1,4-Dimethyl-1 H-indol-5-yl)amino]-5-iodonicotinonitrile (100 mg, 0.258 mmol) and 2-vinylphenylboronic acid (46 mg, 0.311 mmol) were dissolved in anhydrous DME (5 ml), followed by the addition of Pd(PPh3)4 (15 mg, 0.013 mmol) and saturated aqueous sodium bicarbonate (4 ml). The reaction mixture was heated at 100 C overnight, then cooled to room temperature and diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate, dried over MgSO4 and concentrated to give a yellow residue. The crude compound was purified by HPLC to give 31 mg (33%) of 4-[(1,4-dimethyl-lH-indol-5-yl)amino]-5-iodonicotinonitrile as a yellow syrup, MS 365.1 (M+H); HPLC: 96.9% at 215 nm, rt = 11.2 min [a].

MNH
a:'D

[00496] Preparation of 5-[(E)-2-{6-[(dimethylamino)methyl]pyridin-2-yl}ethenyl]-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile:

The title compound was prepared from 5-{(E)-2-[6-(hydroxymethyl)pyridin-2-yl]vinyl}-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile and dimethylamine via the procedure used to prepare 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[6-(morpholin-4-ylmethyl)pyridin-2-yl]
ethenyl}pyridine-3-carbonitrile, MS 409.3 (M+H); HPLC: rt = 5.0 min [a].

NH
ter ~

[00497] Preparation of 4-[(4-methyl-1 H-indol-5-yl)amino]-5-((E)-2-[6-(([2i1 -methyl pyrrolidin-2-yl)ethyl]amino)methyl)pyridin-2-yl]ethenyl}pyridine-3-carbonitrile:
The title compound was prepared from 5-{(E)-2-[6-(hydroxymethyl)pyridin-2-yl]vinyl}-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile and 2-(2-aminoethyl)-1-methylpyrrolidine via the procedure used to prepare 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[6-(morpholin-4-yl methyl)pyridin-2-yl]ethenyl}pyridine-3-carbonitrile, MS 492.4 (M+H); HPLC:
94.2% at 215 nm, rt = 4.4 min [a].

H N ~ ~, \

[00498] Preparation of 5-[(E)-2-(6-[(3-hydroxypyrrolidin-1-yl)methyl]pyridin-2-yl}
ethenyl]-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile:

The title compound was prepared from 5-{(E)-2-[6-(hydroxymethyl)pyridin-2-yl]vinyl}-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile and 3-pyrrolidinol via the procedure used to prepare 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[6-(morpholin-4-ylmethyl)pyridin-2-yl]ethenyl}
pyridine-3-carbonitrile, MS 451.3 (M+H); HPLC: 96.3% at 215 nm, rt = 5.1 min [a].

NH
f~'' FIAi H N
[00499] Preparation of 5-[(E)-2-(6-{[(2-azepan-1-ylethyl)amino]methyl}pyridin-2-yl) ethenyl]-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile:

The title compound was prepared from 5-{(E)-2-[6-(hydroxymethyl)pyridin-2-yl]vinyl}-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile and N-2-aminoethyl homopiperidine via the procedure used to prepare 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[6-(morpholin-4-yI
methyl)pyridin-2-yl]ethenyl}pyridine-3-carbonitrile, MS 506.4 (M+H); HPLC:
92.6% at 215 nm, rt = 5.1 min [a].

NH
uN
T N
\ / I \
N

[00500] Preparation of 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(6-{[(2-pyridin-2-yl ethyl)amino]methyl}pyridin-2-yl)ethenyl]pyridine-3-carbonitrile:
The title compound was prepared from 5-{(E)-2-[6-(hydroxymethyl)pyridin-2-yl]vinyl}-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile and 2-(2-aminoethyl)pyridine via the procedure used to prepare 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[6-(morpholin-4-ylmethyl)pyridin-2-yI]ethenyl}pyridine-3-carbonitrile, MS 486.3 (M+H); HPLC: 93.5% at 215 nm, rt = 5.5 min [a].

tvN
/H \
H

[00501] Preparation of 4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-(6-([(2-pyridin-3-ylethyl)amino]Methyl)pyridin-2-yl)ethenyl]pyridine-3-carbonitrile:
The title compound was prepared from 5-{(E)-2-[6-(hydroxymethyl)pyridin-2-yl]vinyl}-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile and 3-(2-aminoethyl)pyridine via the procedure used to prepare 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[6-(morpholin-4-ylmethyl)pyridin-2-yl]ethenyl}pyridine-3-carbonitrile, MS 486.3 (M+H); HPLC: 95.6% at 215 nm, rt = 4.6 min [a].

H I /'N

[00502] Preparation of 4-[(4-methyl-IH-indol-5-yl)amino]-5-[(E)-2-(6-([(2-pyridin-4-ylethyl)amino]methyl)pyridin-2-yl)ethenyl]pyridine-3-carbonitrile:
The title compound was prepared from 5-{(E)-2-[6-(hydroxymethyl)pyridin-2-yl]vinyl}-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile and 4-(2-aminoethyl)pyridine via the procedure used to prepare 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[6-(morpholin-4-ylmethyl)pyridin-2-yl]
ethenyl}pyridine-3-carbonitrile, MS 486.3 (M+H); HPLC: 97.7% at 215 nm, rt =
4.3 min [a].

H N

[00503] Preparation of 4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[5-({[2-(1-methyl pyrrolidin-2-yl)ethyl]amino}methyl)pyridin-2-yl]ethenyl}pyridine-3-carbonitrile:
The title compound was prepared from 5-{(E)-2-[5-(hydroxymethyl)pyridin-2-yl]vinyl}-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile and 2-(2-aminoethyl)-1-methylpyrrolidine via the procedure used to prepare 4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[5-(piperidin-1-yl methyl)pyridin-2-yl]ethenyl}pyridine-3-carbonitrile, MS 492.4 (M+H); HPLC:
90.3% at 215 nm, rt = 4.1 min [a].

H N

[00504] Preparation of 5.[(E)-2-{5-[(3-hydroxypyrrolidin-1-yl)methyl]pyridin-2-yl}
ethenyl]-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile:

The title compound was prepared from 5-{(E)-2-[5-(hydroxymethyl)pyridin-2-yl]vinyl}-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile and 3-pyrrolidinol via the procedure used to prepare 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[5-(piperidin-l-ylmethyl)pyridin-2-yl]ethenyl}pyridine-3-carbonitrile, MS 451.3 (M+H); HPLC: 94.5% at 215 nm, rt = 4.7 min [a].

NH

[00505] Preparation of 5-[(E)-2-(5-{[(2-azepan-1-ylethyl)amino]methyl}pyridin-2-yl) ethenyl]-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile:

The title compound was prepared from 5-{(E)-2-[5-(hydroxymethyl)pyridin-2-yl]vinyl}-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile and N-2-aminoethyl homopiperidine via the procedure used to prepare 4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[5-(piperidin-1-yl methyl)pyridin-2-yl]ethenyl}pyridine-3-carbonitdle, MS 506.4 (M+H); HPLC:
95.3% at 215 nm, rt =4.6min[a].

NH
H N

[00506] Preparation of 4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-(5-{[(2-pyridin-2-yl ethyl)amino]methyl}pyridin-2-yl)ethenyl]pyridine-3-carbonitrile:
The title compound was prepared from 5-{(E)-2-[5-(hydroxymethyl)pyridin-2-yl]vinyl}-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile and 2-(2-aminoethyl)pyridine via the procedure used to prepare 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[5-(piperidin-1-ylmethyl)pyridin-2-yl]
ethenyl}pyridine-3-carbonitrile, MS 486.3 (M+H); HPLC: 92% at 215 nm, rt = 5.4 min [a].

H I / /.N

[00507] Preparation of 4-[(4-methyl-1h-indol-5-yl)amino]-5-[(e)-2-(5-([(2-pyridin-3-yl ethyl)amino] methyl}pyridin-2-yl)ethenyl]pyridine-3-carbonitrile:

The title compound was prepared from 5-{(E)-2-[5-(hydroxymethyl)pyridin-2-yl]vinyl}-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile and 3-(2-aminoethyl)pyridine via the procedure used to prepare 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[5-(piperidin-1-ylmethyl)pyridin-2-yl]
ethenyl}pyridine-3-carbonitrile, MS 486.2 (M+H); HPLC: 97.2% at 254nm, rt =
1.39 min [d].

NH
H

[00508] Preparation of 4-[(4-methyl-1h-indol-5-yl)amino]-5-[(e)-2-(5-([(2-pyridin-4-yl ethyl)amino]methyl}pyridin-2-yl)ethenyl]pyridine-3-carbonitrile:
The title compound was prepared from 5-{(E)-2-[5-(hydroxymethyl)pyridin-2-yl]vinyl}-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile and 4-(2-aminoethyl)pyridine via the procedure used to prepare 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[5-(piperidin-1-ylmethyl)pyridin-2-yl]
ethenyl}pyridine-3-carbonitrile, MS 486.3 (M+H); HPLC: 99.6% at 215 nm, rt =
4.7 min [a].
TABLE 13:

The following compounds were synthesized from 5-{(E)-2-[6-(hydroxymethyl)pyridin-2-yl]ethenyl}-6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile and the corresponding amines via the procedure used to prepare 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[6-(morpholin-4-ylmethyl)pyridin-2-yl]ethenyl}pyridine-3-carbonitrile:
(HPLC method A) Chemical Name M+H HPLC results 6-methyl-4-[(4-methyl-I H-indol-5-yl)amino]-5-{(E)- 96.8% at 215 rim, 6.3 2-[6-(pipendin-1-ylmethyl)pyrdin-2-yljethenyl) 463.4 ridine-3-carbonitrile min.
6-methyl-4-[(4-methyl-1 H-indol-5-yt)amino]-5-{(E)- 98.6% at 215 nm, 5.7 -[6-(pyrrolidin-1-ylmethyl)pyridin-2-yI]ethenyl} 449.3 ridine-3-carbonitrile min.
6-methyl-4-[(4-methyl-1 H-indol-5-yl)aminoj-5-{(E)- 98.8% at 215 nm, 5.4 2-[6-(morpholin-4-ylmethyl)pyridin-2-yl]ethenyl) 465.3 ridine-3-carbonitrile min.
6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)- 99.1% at 215 nm, 5.8 2-[6-(thiomorpholin-4-ylmethyl)pyridin-2-yl]ethenyl} 481.3 ridine-3-carbonitrile min.
5-[(E)-2-{6-[(4-hydroxypiperidin-1-yl)methyl]pyndin- 99,3% at 215 nm, 5.4 2-yl}ethenylj-6-methyl-4-[(4-methyl-lH-indol-5-yl) 479.4 amino ridine-3-carbonitrile min.
5-[(E)-2-(6-{[4-(2-hydroxyethyl)piperazin-1-yl] 97.7% at 215 rim, 4.7 methyl}pyridin-2-yl)ethenylj-6-methyl-4-[(4-methyl- 508.4 1 H-indol-5- I amino 'dine-3-carbonitnle min.
6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(6-{[(2-morpholin-4-ylethyl)amino]methyl}pyndin- 508.4 97% at 215 nm, 4.4 min.
2- ethen I ridine-3-carbonitnle 6-methyl-4-[(4-methyl-I H-indol-5-yl)aminoj-5-[(E)- 98.5% at 215 nm, 3.9 2-(6-{[(3-morpholin-4-ylpropyl)amino]methyl} 522.4 ridin-2- I ethen I ridine-3-carbonitrile min.
6-methyl-4-[(4-methyl-1H-indol-5-yl)aminoj-5-[(E)- 98.6% at 215 rim, 3.9 2-{6-[(4-morpholin-4-ylpiperidin-1-yl)methyljpyridin- 548.4 min.
2- ethen t ridine-3-carbonitrile 5-{(E)-2-[6-(1,4'-bipipendin-1'-ylmethyl)pyridin-2- 98.6% at 215 nm, 4.0 ]ehhenyl)-6-methyl-4-[(4-methyl-1H-indol-5- 546.4 I amino ridine-3-carbonitrile min.
6-methyl-4-[(4-methyl-I H-indol-5-yl)aminol-5-[(E)- 98.6% at 215 nm, 3.9 2-{6-[(4-pyrrolidin-1-ylpiperidin-1-yl)methyljpyridin- 532.4 min.
2- ethen I rdine-3-carbonitrile 5-[(E)-2-{6-[(4-cyclopentylpiperazin-1-yl)methylj 98.4% at 215 nm, 5.4 pyridin-2-yl}ethenyl]-6-methyl-4-[(4-methyl-1 H- 532.4 min.
indol-5- I amino ridine-3-carbonitnle 6-methyl-5-[(E)-2-(6-{[4-(1-methylethyl)piperazin-l- 95.2% at 215 nm, 3.8 yi]methyl}pyridin-2-yl)ethenyl]-4-[(4-methyl-1 H- 506.4 min.
indol-5- I amino ridine-3-carbonitrite 6-methyl-5-[(E)-2-{6-[(4-methyl-1,4-diazepan-1- 93.3% at 215 nm, 4.1 yl)methyl]pyridin-2-yl}ethenyl]-4-[(4-methyl-1 H- 492.4 indol-5- I amino ridine-3-carbonitrite min.
5-{(E)-2-[6-({[3-(dimethylamino)propyl]amino} 96.6% at 215 nm, 4.4 methyl)pyridin-2-yl]ethenyl}-6-methyl-4-[(4-methyl- 480.4 min.
1 H-indol-5-I amino dine-3-carbonitrle 5- E -2- 6 2-ethox eth amino meth I ridin-2- 467.3 97.3% at 215 nm, 5.7 Chemical Name M+H HPLC results )ethenyl]-6-methyl-4-[(4-methyl-1 H-indol-5-yl) min.
amino ridine-3-carbonitrile 5-[(E)-2-(6-{[(3-ethoxypropyl)amino]methyl}pyridin- 96.7% at 215 nm, 6.0 2-yl)ethenyl]-6-methyl-4-[(4-methyl-1H-indol-5-yl) 481.4 min.
amino ridine-3-carbonitrile 5-[(E)-2-{6-[(dimethylamino)methyl]pyridin-2-yl} 98.9% at 215 nm, 5.2 ethenyl}6-methyl-4-[(4-methyl-1 H-indol-5- 423.3 amino ridine-3-carbonitrile min.
6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[6-(([2-(1-methytpyrrolidin-2-yl)ethyl]amino} 506.4 96.9% at 215 rim, 4.5 min.
meth I ddin-2- I ethen I ridine-3-carbonitrile 5-[(E)-2-{6-[(3-hydroxypyrrolidin-1-yl)methyl] 93.6% at 215 rim, 5.5 pyridin-2-yl}ethenyl]-6-methyl-4-[(4-methyl-1 H- 465.4 indol-5- I amino ridine-3-carbonitrile min.
5-[(E)-2-(6-{[(2-azepan-1-ylethyl)amino]methyl}
pyridin-2-yl)ethenyl]-6-methyl-4-[(4-methyl-l H- 520.4 97.7% at 215 nm, 5.4 min.
indol-5- I amino ridine-3-carbonitrle 6-methyl-4-[(4-methyl-lH-indol-5-yl)amino]-5-[(E)- 98.3% at 215 nm, 5.6 2-(6-{[(2-pyridin-2-ylethyl)amino]methyl}pyridin-2- 500.4 min.
yl)ethenyllpyddine-3-carbonitdle 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino)-5-[(E)-2-(6-{[(2-pyridin-3-ylethyl)amino]methyl}pyridin-2- 500.4 98% at 215 nm, 4.9 min.
yl)ethenyllpyridine-3-carbonitrile 6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)- 95.3% at 215 nm, 4.8 2-(6-{[(2-pyridin-4-ylethyl)amino]methyl}pyridin-2- 500.4 min.
yt)ethenyl]pyHdine-3--arbonitrile Table 14:

The following compounds were synthesized from 5-{(E)-2-[5-(hydroxymethyl)pyridin-2-yl]
ethenyl}-6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile and the corresponding amines via the procedure used to prepare 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[5-(piperidin-1-ylmethyl)pyridin-2-yl]ethenyl}pyridine-3-carbonitrile:
(HPLC method A) MS HPLC results Chemical Name (M+H) 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5- 98.0% at 215 nm, 4.6 {(E)-2-[5-(pyrrolidin-1-ylmethyl)pyridin-2- 449.3 min.
yllethenyl)pyddine-3-carbonitrile 6-methyl-4-[(4-methyl-lH-indol-5-yl)amino)-5- 98.8% at 215 nm, 4.9 {(E)-2-[5-(piperidin-1- ylmethyl)pyndin-2-yl] 463.4 min.
ethen I ridine-3-carbonitrile 6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5- 99.3% at 215 nm, 4.4 {(E)-2-[5-(morpholin-4-ylmethyl)pyndin-2-yl] 465.3 min.
ethen I ridine-3-carbonitrile 11 6-methyl-4-[(4-methyl-lH-indol-5-yl)aminoJ-5- 481 3 96.6% at 215 nm, 5.0 E -2- 5- thiomo holin-4- meth I ridin-2- min.

MS HPLC results Chemical Name (M+H) yllethenyl)pyridine-3-carbonitrile 5-[(E)-2-{5-[(4-hydroxypipendin-1-yl)methyl] 97.0% at 215 nm, 4.4 pyridin-2-yl)ethenylj-6-methyl-4-[(4-methyl- 479.3 min.
1 H-indol-5- I amino 'dine-3-carbonitrle 5-[(E)-2-(5-{[4-(2-hydroxyethyl)piperazin-1- 97.4% at 215 nm, 4.4 11]methyl}pyridin-2-yl)vinyl]-6-methyl-4-[(4- 508.4 methyl-1 H-indol-5- I amino nicotinonitrile min.
6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(5-([(2-morpholin-4-ylethyl)amino] 508.3 97.8% at 215 nm, 4.3 methyl}pyridin-2-yl)ethenyl]pyridine-3- min.
carbonitnle 6-methyl-4-[(4-methyl-1 H-indol-5-yl)aminoj-5-((E)-2-(5-([(3-morpholin-4-ylpropyl)amino] 522 4 95.3% at 215 nm, 4.2 methyl}pyridin-2-yl)ethenyljpyridine-3- min.
carbonitrile 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(5-[(4-morpholin-4-ylpipendin-1-yl) 548.4 97.4% at 215 nm, 4.2 methyljpyndin-2-yl}ethenyl]pyridine-3- min.
carbonitnle 5-{(E)-2-[5-(1,4'-bipiperidin-l'-ylmethyl)pyndin- 97.8% at 215 nm, 3.8 2-yl]ethenyl}-6-methyl-4-[(4-methyl-1 H-indol- 546.4 5- amino idine-3-carbonitrile min.
6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{5-[(4-pyrrolidin-1-ylpiperidin-1-yl) 532.5 97.3% at 215 nm, 3.8 methyl]pyridin-2-yl}ethenyl]pyridine-3- min.
carbonitnle 5-[(E)-2-(5-[(4-cyclopentylpiperazi n-1-yl) methyl]pyridin-2-yl)ethenyl]-6-methyl-4-[(4- 532.4 96.3% at 215 nm, 5.2 methyl-1H-indol-5-yl)amino]pyndine-3- min.
carbonitrile 5-[(E)-2-{5-[(4-isopropylpiperazin-1-yl) 94.6% at 215 nm, 4.5 methyllpyridin-2-yl}vinyl]-6-methyl-4-[(4- 506.4 meth l-1 H-indol-5- I amino nicotinonitrile min.
6-methyl-5-[(E)-2-{5-[(4-methyl-1,4-diazepan-1-yl)methyl]pyridin-2-yl}vinyl]-4-[(4-methyl-l H- 492.4 97.7% at 215 nm, 4.4 min.
indol-5- I amino nicotinonitrile 5-{(E)-2-[5-({[3-(dimethylamino)propyl]amino} 99.1 % at 215 nm, 4.2 methyl)pyridin-2-yl]vinyl}-6-methyl-4-[(4- 532.4 methyl-1 H-indol-5- I amino nicotinonitrile min.
5-[(E)-2-(5-{[(2-ethoxyethyl)amino]methyl} 92.2% at 215 nm, 5.8 pyndin-2-yl)vinyl]-6-methyl-4-[(4-methyl-1 H- 467.4 min.
indol-5- I amino nicotnonitrile 5-[(E)-2-(5-{[(3-ethoxypropyl)amino]methyl} 92.3% at 215 nm, 6.0 pyndin-2-yl)vinyl]-6-methyl-4-[(4-methyl-1 H- 481.4 indol-5- I amino]nicotinonitrile min.
5-[(E)-2-{5-[(dimethylamino)methyl]pyridin-2- 96.5% at 215 nm, 5.1 yl}vinyl]-6-methyl-4-[(4-methyl-1H-indol-5- 423.4 min.
yi)aminolnicotinonitdle 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5- 92.2% at 215 nm, 4.4 {(E)-2-[5-({[2-(1 -meth I rrolidin-2- I eth l 506.5 min.

MS HPLC results Chemical Name (M+H) amino meth ridin-2- vin nicotinonitrile 5-[(E)-2-{5-[(3-hydroxypyrrolidin-1-yl)methyl] 95.5% at 215 nm, 5.1 pyridin-2-yl}vinyl]-6-methyl-4-[(4-methyl-1 H- 465.4 min.
indol-5- I amino nicotinonitrile 5-[(E)-2-(5-{[(2-azepan-1-ylethyl)amino] 98.7% at 215 nm, 4.3 methyl}pyridin-2-yl]vinyl]-6-methyl-4-[(4- 520.5 methyl-1 H-indol-5- I amino nicotinonitdle min.
6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5- 99.8% at 215 nm, 4.7 [(E)-2-(5-{[(2-pyridin-2-ylethyl)amino]methyl} 500.4 ridin-2- I vin I nicotinonitrile min.
6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5- 89.5% at 215 nm, 4.7 [(E)-2-(5-{[(2-pyridin-3-ylethyl)amino]methyl} 500.4 min.
ridin-2- I vin I nicotinonitrile 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5- 99.2% at 215 nm, 3.7 [(E)-2-(5-([(2-pyridin-4-ylethyl)amino]methyl} 500.4 ridin-2- I vin I nicotinonitrile min.
HO

r'~ / FIN
N

[00509] Preparation of 5-[2-(6{[4-(2-hydroxyethyl)piperazin-1-yl]methyl}pyridin-2-yl) ethyl]-4-[(4-methyl-1 h-indol-5-yl)amino]nicotinonitrile:

To a solution of 5-{(E)-2-[6-(hydroxymethyl)pyridin-2-yl]vinyl}-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile (200 mg, 0.52 mmol) in a solvent mixture THE (5 ml) and DMF (2.5 ml) was added triethylamine (370 pL, 2.65 mmol). The solution was stirred under nitrogen at room temperature for 10 min. Methanesulfonyl chloride (122 NL, 1.58 mmol) was added dropwise into the reaction mixture. The reaction was stirred under nitrogen at room temperature for 8 hours, followed by the addition of 4-(2-hydroxyethyl)piperazine (200 pL, 2.29 mmol). The reaction was stirred overnight. The solvent was evaporated and the residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic solution was dried over MgSO4 and concentrated to give dark syrup. The resulting crude compound was purified by HPLC to give 61 mg (52%) of alkene compound as a yellow solid.
The alkene was then subjected to hydrogenation (H2(g), 45 psi) with Pd/C (10% wt., 20 mg) in methanol (10 ml) overnight. The solution was filtered through celite and the filtrate was purified by HPLC

to give 20 mg (7.7%) of the title compound as an off-white solid, MS 496.2 (M+H); HPLC:
99.4% at 215 nm, rt = 4.5 min [a].

NH
N
n I \

[00510] Preparation of 5-(2-[6-(1,4'-bipiperidin-1'-ylmethyl)pyridin-2-yl]ethyl}-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile:

The title compound was prepared from 5-{(E)-2-[6-(hydroxymethyl)pyridin-2-yl]vinyl}-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile and 4-piperidinopiperidine via the procedure used to prepare 5-[2-(6-{[4-(2-hydroxyethyl)piperazin-1-yl]methyl}pyridin-2-yl)ethyl]-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile, MS 534.3 (M+H); HPLC: 99.5% at 215 nm, rt =
4.0 min [a].

Nli 01"-ON N

[00511] Preparation of 4-[(4-methyl-I h-indol-5-yl)amino]-5-(2-{6-[(4-pyrrolidin-1-yl piperidin-1-yl)methyl]pyridin-2-yl}ethyl)nicotinonitrile:
The title compound was prepared from 5-{(E)-2-[6-(hydroxymethyl)pyridin-2-yl]vinyl}-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile and 4-pyrrolidinopiperidine via the procedure used to prepare 5-[2-(6-{[4-(2-hydroxyethyl)piperazin-1-yl]methyl}pyridin-2-yl)ethyl]-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile, MS 520.2 (M+H); HPLC: it = 3.7 min [a].

xx /N~ f / FtJ ~

[00512] Preparation of 5-[2-(6-{[4-(dimethylamino)piperidin-1-yl]methyl}pyridin-2-yl) ethyl]-4-[(4-methyl-1 h-indol-5-yl)amino]nicotinonitrile:

The title compound was prepared from 5-{(E)-2-[6-(hydroxymethyl)pyridin-2-yl]vinyl}-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile and 4-dimethylaminopiperidine via the procedure used to prepare 5-[2-(6-{[4-(2-hydroxyethyl)piperazin-l-yl]methyl)pyridin-2-yl)ethyl]-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile, MS 494.1 (M+H); HPLC: 99.4% at 215 nm, rt = 4.2 min [a].

HO

[00513] Preparation of 5-(2-[6-(hydroxymethyl)pyridin-2-yl]ethyl}-4-[(4-methyl-1h-indol-5-yl)amino]nicotinonitrile:

To the solution of 5-{(E)-2-[6-(hydroxymethyl)pyridin-2-yl]vinyl}-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile (800 mg, 2.10 mmol) in methanol (30 ml) was added Pd/C (10% wt., 30 mg). The reaction mixture was then subjected to hydrogenation (H2 gas, 45 psi) overnight. The solution was filtered through celite and purified by HPLC to give 516 mg (64%) of the title compound as an off-white solid, MS 384.0 (M+H); HPLC: 94.5% at 215 nm, rt =
5.2 min [a].

o O o N

[00514] Preparation of 2-({6-[(E)-2-{5-cyano-4-[(4-methyl-1H-indol-5-yl)amino]pyridin-3-yl) vinyl]pyridin-2-yl)methoxy)ethyl sulfate:.

5-lodo-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile (90 mg, 0.24 mmol) was dissolved in a mixture of DMF (2 ml) and triethylamine (0.5 ml) and treated with 2-[(6-vinylpyridin-2-yl)methoxy]ethyl sulfate (68 mg, 0.26 mmol), Pd(OAc)2 (11 mg, 0.049 mmol) and P(o-Tol)3 (4 mg, 0.013 mmol). The reaction mixture was stirred at 110 C under nitrogen for 5 hr. Upon cooling, the reaction was diluted with dichloromethane and washed one time with saturated aqueous sodium bicarbonate. The solvent was removed, and the residue was purified by HPLC to give 20 mg (17%) of the title compound as a yellow solid, MS 504.2 (M); HPLC:
95.0% at 215 nm, rt = 6.7 min [a].

NH
N
o~
[00515] Preparation of 5-[(E)-2-(3-formylphenyl)ethenyl]-44(4-methyl-1H-indol-5-yl) amino] pyridine-3-carbonitrile: , To a reaction mixture of 3-[(E)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ethenyl]benzaldehyde (1.19 g, 4.61 mmol), 5-iodo-4-[(4-methyl-1 H-indol-5-yl)amino]
nicotinonitrile (1.33 g, 3.55 mmol) and Pd(PPh3)4 (410 mg, 0.355 mmol) in 1,2-dimethoxyethane (16 ml-) at room temperature was added saturated NaHCO3 solution (8 mL).

The reaction mixture was heated to 100 C for 3.5 h, then stirred at room temperature overnight, quenched with H2O and extracted with a mixture of THF-EtOAc (1:2) three times.
The extracts were combined and washed with H2O and brine. Drying, filtration and evaporation gave a brown solid, which was purified by silica gel chromatography (hexane-EtOAc, 10:1 to 2:1), providing the title compound in quantitative yield as a yellow solid.
'HNMR(300 MHz, DMSO) 2.34 (s, 3H), 6.53 (s, 1 H), 6.95 (d, J = 6.0 Hz, 1 H), 7.31 (m, 3H), 7.60 (m, 2H), 7.82 (s, 1 H), 7.95 (d, J = 6.0 Hz, 1 H), 8.17 (s, 1 H), 8.29 (s, 1 H), 8.62 (s, 1 H), 8.93 (s, 1 H), 10.03 (s, I H), 11.16 (s, 1 H); MS 379.2 (M+H).

[00516] Preparation of 4-[(4-methyl-lH-indol-5-yl)amino]-5-{(E)-2-[3-(piperidin-1-yl methyl)phenyl] ethenyl)pyridine-3-carbonitri le:

A mixture of 5-[(E)-2-(3-formylphenyl)ethenyl]-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile (76 mg, 0.2 mmol) and piperidine (68 mg, 0.8 mmol) in THE (2.0 ml-) was stirred at room temperature for 30 minutes. To this was added NaBH(OAc)3 (170 mg, 0.8 mmol). The reaction mixture was stirred at room temperature for 20 h then concentrated.
The residue was purified by HPLC providing 47 mg (53%) of the title compound as a pale yellow solid. MS
448.4 (M+H); HPLC: 99.1 % at 215 nm, rt = 6.0 min [a].

[00517] Preparation of 5-[(E)-2-(3-formylphenyl)ethenyl]-6-methyl-4-[(4-methyl-1 H-indol -5-yl)amino]pyridine-3-carbonitrile:

The title compound was prepared from 3-[(E)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethenyl]benzaldehyde and 5-iodo-6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile via the procedure used to prepare 5-[(E)-2-(3-formylphenyl)ethenyl]-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile. The crude was purified by silica gel chromatography (CH2CI2-THF and CH2CI2-CH3OH, gradient), providing the title compound in quantitative yield as a yellow solid.'HNMR(300 MHz, DMSO) 2.31 (s, 3H), 2.51 (s, 3H), 6.49 (s, 1 H), 6.90 (d, J = 9.0 Hz, 1H), 7.01 (d, J = 12.0 Hz, 1H), 7.30 (m, 2H), 7.57 (m, 2H), 7.82 (d, J =
6.0 Hz, 1H), 7.96 (d, J = 6.0 Hz, 1 H), 8.16 (d, J = 12.0 Hz, 2H), 8.46 (s, 1 H), 10.03 (s, 1 H), 11.10 (s, 1 H); MS
393.1 (M+H).

NH
H~ - N

[00518] Preparation of 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[3-(piperidin-1-ylmethyl)phenyl]ethenyl}pyridine-3-carbonitrile:
The title compound was prepared from 5-[(E)-2-(3-formylphenyl)ethenyl]-6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile and piperidine via the procedure used to prepare- 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[3-(piperidin-1-ylmethyl)phenyl]ethenyl}
pyridine-3-carbonitrile. MS 462.3 (M+H); HPLC: 90.8% at 215 nm, it = 5.9 min [a].

TABLE 15:

[00519] The compounds in table 15 were prepared from either 5-[(E)-2-(3-formylphenyl)ethenyl]-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile or 5-[(E)-2-(3-formylphenyl)ethenyl]-6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile and the appropriate amine via the procedure described for 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[3-(piperidin-1-ylmethyl)phenyl]ethenyl}pyridine-3-carbonitrile and 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[3-(piperidin-1-ylmethyl)phenyl]ethenyl}pyridine -3-carbonitrile.

MS HPLC rt Compound name (M+H) method 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(3-{[(2-morpholin-4-ylethyl)amino]methyl)phenyl)ethenyl]pyridine-3- 5.2 carbonitrile 493.3 [a]
4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{3-[(4-morpholin-4-ylpiperidin-1-yl)methyl]phenyl}ethenyl]pyridine-3- 4.7 carbonitnle 533.0 [a]
4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{3-[(4-pyrrolidin- 4.7 1- i eridin-1- I meth I hen I ethen I ridine-3- 517.1 [a]

MS HPLC rt Compound name (M+H) method carbonitrile 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[3-(([2-(1-methylpyrrolidin-2-yl)ethyl]amino}methyl)phenyl] ethenyl} 4.8 ridine-3-carbonitrle 491.3 [a]
4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[3-(([3-(2-oxo pyr rolidin-l-yl)propyl]amino}methyl)phenyl]ethenyl)pyridine 6.3 3-carbonitrile 505.3 [a]
4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[3-(morpholin-4- 5.6 meth hen 1 ethen I ndine-3-carbonitrile 450.2 [a]
4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[3-(pyrrolidin-1-yl 5.8 meth I hen ethen I idine-3-carbonitrile 434.3 a 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[3-(thiomorpholin 6.0 -4- lmeth I hen I ethen I ridine-3-carbonitrile 466.3 [a]
5-[(E)-2-(3-{[(2-methoxyethyl)amino]methyl)phenyl)ethenyl]- 6.3 4+4-methyl-1 H-indol-5- I amino ndine-3-carbonitrile 438.2 a 5-[(E)-2-(3-{[4-(1-methylethyl)piperazin-1-yl]methyl} phenyl) ethenyl]-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3- 5.9 carbonitrile 491.4 [a]
5-[(E)-2-(3-{[4-(2-hydroxyethyl)piperazin-1-yl]methyl}phenyl) ethenyl]-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3- 5.5 carbonitrle 493.4 [a]
5-[(E)-2-(3-{[4-(2-hydroxyethyl)piperazin-1-yl]methyl}phenyl) ethenyl]-6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine- 5.4 3-carbonitrile 507.3 [a]
5-[(E)-2-(3-{[4-(d i methylam i no)piperid i n-1-yl] methyl}phenyl ) ethenyl]-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3- 5.2 carbonitrle 491.2 [a]
5-[(E)-2-(3-{[4-(dimethylamino)pipendin-l -yl]methyl}phenyl) ethenyl]-6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine- 5.6 3-carbonitrile 505.3 [a]
5-[(E)-2-(4-{[4-(dimethylamino)pipeddi n-1-yl]methyl}phenyl) ethenyl]-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3- 4.6 carbonitrle 491.4 [a]
5-[(E)-2-(3-[(4-cyclopentylpi perazin-l -yl)methyl]phenyl}
ethenyl]-4-[(4-methyl-1H-indol-5-yl)amino]pyridine-3- 259.2 6.5 carbonitrile (2M+H) [a]
5-[(E)-2-{3-[(4-hydroxypiperidin-1-yl)methyl]phenyl)ethenyl]- 5.6 4-[(4-methyl-1 H-indol-5-I amino 'dine-3-carbonitrile 464.4 [a]
5-[(E)-2-{3-[(4-hydroxypi pendin-1-yl)methyl]phenyl}ethe nyl]-6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3- 5.4 carbonitrile 478.3 [a]
5-[(E)-2-{3-[(4-methyl-1,4-diazepan-1-yl)methyl]phenyl}
ethenyl]-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3- 5.2 carbonitrile 477.2 a 5-{(E)-2-[3-({[2-(dimethylamino)ethyl]amino}methyl) phenyl]ethenyl}-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3- 4.7 carbonitrile 451.3 [a]

MS HPLC rt Compound name (M+H) method 5-{(E)-2-[3-({[2-(dimethylamino)ethyl]amino}methyl) phenyl]
ethenyl}-6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino] 5.3 ridine-3-carbonitrle 465.3 a 5-{(E)-2-[3-({[3-(dimethylamino)propyl]amino}methyl) phenyl]ethenyl)-6-methyl-4-[(4-methyl-1 H-indol-5- 5.3 yl)amino]pyridine-3-carbonitrile 479.3 [a]
5-{(E)-2-[3-(1,4'-bipipendin-l'-ylmethyl)phenyl]ethenyl}-6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]pyndine-3- 4.7 carbonitrle 545.3 [a]
6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(3-{[(3-morpholin-4-ylpropyl)amino]methyl)phenyl)vinyl] 5.2 nicotinonitrile 521.2 [a]
6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(3-[(4-methylpiperazin-1-yl)methyl]phenyl)ethenyl]pyndine-3- 5.5 carbonitrile 477.3 [a]
6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{3-[(4-morpholin-4-ylpiperidin-1 -yl)methyl]phenyl)ethenyl]pyridine- 5.7 3-carbonitrile 547.3 [a]
6-methyl-4-[(4-methyl-1 H-i nd of-5-yl )amino]-5-[(E)-2-{3-[(4-pyrrolidin-l-ylpiperidin-l-yl)methyl]phenyl}ethenyl]pyridine- 4.8 3-carbonitrile 531.3 [a]
6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[3- 5.4 (morph olin-4- (meth I hen I ethen I ridine-3-carbonitrile 464.2 [a]
6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[3- 5.8 rrolidin-l -lmeth hen I ethen I ridine-3-carbonitrle 448.3 [a]
6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[3-(thiomorpholin-4-ylmethyl)phenyl]ethenyl}pyridine-3- 5.9 carbonitrile 480.3 [a]
6-methyl-5-[(E)-2-(3-{[4-(1-methylethyl)piperazin-1-yl]
methyl}phenyl)ethenylj-4-[(4-methyl-1 H-indol-5-yl)amino] 5.8 ridine-3-carbonitrile 505.4 [a]
6-methyl-5-[(E)-2-{3-[(4-methyl-1,4-diazepan-1-yl)methyl]
phenyl}ethenyl]-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3- 5.6 carbonitrle 491.3 [a]
6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(3-{[(2-pyrrolidin-1 -ylethyl)amino]methyl}phenyl)ethenyl]pyridine-3- 4.8 carbonitrile 491.3 [a]
5-[(E)-2-{3-[(di methylamino)methyl]phenyl}ethenyl]-6-methyl-4-[(4-methyl-l H- indol-5-yl)amino]pyndine-3- 5.5 carbonitrile 422.3 [a]
5-[(E)-2-{3-[(3-hyd roxypyrrolidin-1-yi)methyl]phenyl}
ethenyl]-6-methyl-4-[(4- methyl-1 H-indol-5- 5.4 yl)aminolpyddine-3-carbonitrile 464.2 [a]
5-[(E)-2-{3-[(diethylamino)methyl]phenyl}ethenyl]-6-methyl- 7.5 4-1(4-methyl-1 H- indol-5- I amino ridine-3-carbonitrile 450.2 [a]

[00520] The compounds in the following table were prepared from 5-[(E)-2-(4-formylphenyl)ethenyl]-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile and the appropriate amine via the procedure described for 5-[(E)-2-(4-{[4-(2-hydroxyethyl)piperazin-1-yl]methyl}phenyl)vinyl]-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile.

MS HPLC rt Compound name M+H method 5-[(E)-2-(4-([(2-ethoxyethyl )a mi no]methyl}phenyl ) ethenyl]-4-[(4-methyl-l H- indol-5-yl)amino]pyridine-3- 7.2 carbonitrile 438.1 [a]
5-[(E)-2-(4-{[(2-ethoxyethyl)ami no]methyl}phenyl) ethenyl]-4-[(4-methyl-1 H-indol- 5-yl)amino]pyridine-3- 6.7 carbonitrile 452.1 [a]
4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[4-({[2-(1-methylpyrrolidin-2- yl)ethyl]amino)methyl)phenyl] 5.3 ethen I ridine-3-carbonitrile 491.1 [a]
5-[(E)-2-(4-{[(2-azepan-1-ylethyl)amino]methyl}phenyl) ethenyl]-4-[(4-methyl-1 H- indol-5-yl)amino]pyridine-3- 6.8 carbonitrile 505.2 [a]
H

[00521] Preparation of 5-[(E)-2-{4-[(azetidin-3-ylamino)methyl]phenyl}ethenyl]-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile:

The title compound was prepared from tert-butyl 3-({4-[(E)-2-{5-cyano-4-[(4-methyl-1 H-indol-5-yl)amino]pyridin-3-yl}vinyl]benzyl}amino)azetidine-l-carboxylate via the procedure used to prepare 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[4-(piperazin-1 -ylmethyl)phenyl]vinyl}
nicotinonitrile. MS 435.2 (M+H); HPLC: 63.3% at 215 nm, rt = 4.5 min [a].

[00522] Preparation of 6-ethyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-(2-phenylethyl) pyridine-3- carbonitrile:

The title compound was prepared from 6-ethyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-phenylvinyl]nicoti non itrile via the procedure used to prepare 5-[2-(4-methoxyphenyl)ethyl]-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile. MS 381.2 (M+H). HPLC: rt =
9.8 min [a].

NH
O / I HN
S CN

N
[00523] Preparation of 3-[(E)-2-{5-cyano-44(4-methyl-1H-indol-5-yl)amino]pyridin-3-yl) vinyl]benzenesulfonamide:

4-[(4-Methyl-1 H-indol-5-yl)amino]-5-vinylnicotinonitrile (98 mg, 0.36 mmol), bromobenzenesulfonamide (93 mg, 0.39 mmol), Pd(OAc)2 (5.2 mg, 0.023 mmol), P(o-ToI)3 (7.6 mg, 0.063 mmol), and triethylamine (726 mg, 7.2 mmol) were dissolved in 3 mL DMF and heated to 90 C for 16 h. The reaction was cooled to room temperature and partitioned between chloroform and saturated sodium bicarbonate. The organic portion was dried (magnesium sulfate) and concentrated. The residue was dissolved in DMSO and purified by HPLC to give 11 mg of the title compound. HPLC: rt = 7.4 min [a]; We 430.0 (M+H); HRMS:
calculated 430.1332 found 430.1328 (M+H).

H
N HN
N
S' ~= I / C N
O I
N

[00524] Preparation of 4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-(3-{[(4-methyl piperazin-1-yl)sulfonyl]methyl}phenyl)ethenyl]pyridine-3-carbonitrile:
4-[(4-methyl-1H-indol-5-yl)amino]-5-vinylnicotinonitrile (89 mg, 0.32 mmol),1-[(3-bromobenzyl)sulfonyl]-4-methylpiperazine (125 mg, 0.38 mmol), Pd(OAc)2 (8.0 mg, 0.036 mmol), P(o-Tol)3 (32 mg, 0.11 mmol), and triethylamine (726 mg, 7.2 mmol) were dissolved in 3 mL DMF and heated to 90 C for 16 h. The reaction was cooled to room temperature and partitioned between chloroform and saturated sodium bicarbonate. The organic portion was dried (magnesium sulfate) and concentrated. The residue was dissolved in DMSO
and purified by HPLC to give 101 mg of the title compound. HPLC: 94.2%, it = 6.8 min [a]; m/e 527.3 (M+H); HRMS: calculated 527.2224 found 527.2221 (M+H).

~OH
OS HN I JN ,o iN CN
N
[00525] Preparation of 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(4-{[(4-methyl piperazin-1-yl)sulfonyl]methyl}phenyl)ethenyl]pyridine-3-carbonitrile:
4-[(4-Methyl-1H-indol-5-yl)amino]-5-vinylnicotinonitrile (84 mg, 0.31 mmol), 1-(4-bromobenzylsulfonyl)-4-methylpiperazine (54 mg, 0.16 mmol), Pd(OAc)2 (5.0 mg, 0.022 mmol), P(o-Tol)3 (17 mg, 0.056 mmol), and triethylamine (726 mg, 7.2 mmol) were dissolved in 3 mL DMF and heated to 90 C for 16 h. The reaction was cooled to room temperature and partitioned between chloroform and saturated sodium bicarbonate. The organic portion was dried (magnesium sulfate) and concentrated. The residue was dissolved in DMSO
and purified by HPLC to give 24 mg of the title compound. HPLC: it = 6.7 min [a];
We 527.3 (M+H); HRMS: calculated 527.2224 found 523.2215 (M+H).

~
CN
~NO

[00526] Preparation of 4-[(4-methyl-IH-Ind ol-5-yl)amino]-5-[(E)-2-{3-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}vinyl]nicotinonitrile:
4-[(4-Methyl-1H-indol-5-yl)amino]-5-vinylnicotinonitrile (65 mg, 0.24 mmol), 1-(3-bromophenylsulfonyl)-4-methylpiperazine (76 mg, 0.24 mmol), Pd(OAc)2 (5.0 mg, 0.022 mmol), P(o-Tol)3 (11 mg, 0.036 mmol), and triethylamine (726 mg, 7.2 mmol) were dissolved in 2 mL DMF and heated to 90 C for 16 h. The reaction was cooled to room temperature and partitioned between chloroform and saturated sodium bicarbonate. The organic portion was dried (magnesium sulfate) and concentrated. The residue was dissolved in DMSO
and purified by HPLC to give 101 mg of the title compound. HPLC: 98.9%, rt = 7.1 min [a]; m/e 513.2 (M+H); HRMS: calculated 513.2067 found 513.2065 (M+H).

NH
I HN
0S'1CN
N
[00527] Preparation of 4-[(4-methyl-IH-indol-5-yl)amino]-5-[(E)-2-{3-[(pyrrolidin-1-yl sulfonyl)methyl]phenyl}ethenyl]pyridine-3-carbonitrile:
4-[(4-Methyl-1H-indol-5-yl)amino]-5-vinylnicotinonitrile (66 mg, 0.24 mmol), 1-(3-bromobenzylsulfonyl)pyrrolidine (108 mg, 0.36 mmol), Pd(OAc)2 (8.4 mg, 0.037 mmol), P(o-Tol)3 (24 mg, 0.079 mmol), and triethylamine (726 mg, 7.2 mmol) were dissolved in 2 mL DMF
and heated to 90 C for 16 h. The reaction was cooled to room temperature and partitioned between chloroform and saturated sodium bicarbonate. The organic portion was dried (magnesium sulfate) and concentrated. The residue was dissolved in DMSO and purified by HPLC to give 101 mg of the title compound. HPLC: 93.0%, rt = 10.1 min [a]; We 498.3 (M+H);
HRMS: calculated 498.1958 found 498.1957 (M+H).

H
NONS
i, HN
\ I / \ CN
N

[00528] Preparation of 4-[(4-methyl-1H-Ind ol-5-yl)amino]-5-[(E)-2-{4-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}ethenyl]pyridine-3-carbonitrile:
4-[(4-Methyl-1 H-indol-5-yl)amino]-5-vinylnicotinonitrile (50 mg, 0.18 mmol), 1-(4-bromophenylsulfonyl)-4-methylpiperazine (58 mg, 0.18 mmol), Pd(OAc)2 (3.5 mg, 0.016 mmol), P(o-Tol)3 (11.2 mg, 0.037 mmol), and triethylamine (726 mg, 7.2 mmol) were dissolved in 5 mL DMF and heated to 90 C for 16 h. The reaction was cooled to room temperature and partitioned between chloroform and saturated sodium bicarbonate. The organic portion was dried (magnesium sulfate) and concentrated. The residue was dissolved in DMSO
and purified by HPLC to give 36 mg of the title compound. HPLC: 93.3%, rt = 6.4 min [a]; We 513.3 (M+H); HRMS: calculated 513.2067 found 513.2070 (M+H).

~611 N S~ HN
Go cN
N

[00529] Preparation of 4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-{4-[(pyrrolidin-1-yl sulfonyl)methyl]phenyl}vinyl]nicotinonitrile:
4-[(4-Methyl-1H-indol-5-yl)amino]-5-vinylnicotinonitrile (96 mg, 0.35 mmol), 1-(4-bromobenzylsulfonyl)pyrrolidine (111 mg, 0.37 mmol), Pd(OAc)2 (7.1 mg, 0.032 mmol), P(o-Tol)3 (8.6 mg, 0.028 mmol), and triethylamine (726 mg, 7.2 mmol) were dissolved in 2 mL DMF
and heated to 900 C for 16 h. The reaction was cooled to room temperature and partitioned between chloroform and saturated sodium bicarbonate. The organic portion was dried (magnesium sulfate) and concentrated. The residue was dissolved in DMSO and purified by HPLC to give 14 mg of the title compound. HPLC: 96.1%, rt = 9.6 min [a]; We 498.2 (M+H);
HRMS: calculated 498.1958 found 498.1960 (M+H).

NHN ~OH
N 3 \ I / \ CN
N

[00530] Preparation of 4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[3-(pyrrolidin-1-yl sulfonyl) phenyl]vinyl}nicotinonitrile:
4-[(4-methyl-1H-indol-5-yl)amino]-5-vinylnicotinonitrile (65 mg, 0.24 mmol), 1-(3-bromophenylsulfonyl)pyrrolidine (69 mg, 0.24 mmol), Pd(OAc)2 (6 mg, 0.027 mmol), P(o-Tol)3 (11 mg, 0.036 mmol), and triethylamine (726 mg, 7.2 mmol) were dissolved in 2 mL DMF and heated to 90 C for 16 h. The reaction was cooled to room temperature and partitioned between chloroform and saturated sodium bicarbonate. The organic portion was dried (magnesium sulfate) and concentrated. The residue was dissolved in DMSO and purified by HPLC to give 47 mg of the title compound. HPLC: 96.4%, rt = 10.6 min [a]; m/e 484.2 (M+H);
HRMS: calculated 484.1804 found 484.1802 (M+H).

HN-N NH

N OAS I HN
CC
N
N

[00531] Preparation of 4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[4-(2H-tetrazol-5-yl) phenyl]vinyl}nicotinonitrile:

4-[(4-Methyl-1 H-indol-5-yl)amino]-5-vinylnicotinonitrile (61 mg, 0.22 mmol), 5-(4-bromophenyl)-2H-tetrazole (J. Med Chem. 1991, 1135) (50 mg, 0.22 mmol), Pd(OAc)2 (11 mg, 0.05 mmol), P(o-Tol)3 (15 mg, 0.05 mmol), and triethylamine (363 mg, 3.6 mmol) were dissolved in 2 mL
DMF and heated to 90 C for 16 h. The reaction was cooled to room temperature and partitioned between chloroform and saturated sodium bicarbonate. The organic portion was dried (magnesium sulfate) and concentrated. The residue was dissolved in DMSO
and purified by HPLC to give 6 mg of the title compound. HPLC: rt = 8.0 min [a];
We 419.2 (M+H);
HRMS: calculated 419.1727 found 419.1731 (M+H).

NH
N.P
OS HN
CN
N

[00532] Preparation of 4-[(4-methyl-I H-indol-5-yl)amino]-5-((E)-2-[4-(pyrrolidin-1-yl sulfonyl)phenyl]ethenyl)pyridine-3-carbonitrile:
4-[(4-Methyl-1 H-indol-5-yl)amino]-5-vinylnicoti non itri le (50 mg, 0.18 mmol), 1-(4-bromophenylsulfonyl)-4-methylpiperazine (58 mg, 0.18 mmol), Pd(OAc)2 (3.5 mg, 0.016 mmol), P(o-Tol)3 (11.2 mg, 0.037 mmol), and triethylamine (726 mg, 7.2 mmol) were dissolved in 5 mL DMF and heated to 90 C for 16 h. The reaction was cooled to room temperature and partitioned between chloroform and saturated sodium bicarbonate. The organic portion was dried (magnesium sulfate) and concentrated. The residue was dissolved in DMSO
and purified by HPLC to give 28 mg of the title compound. HPLC: 97.4%, rt = 9.9 min [a]; We 484.2 (M+H); HRMS: calculated 484.1802 found 484.1801 (M+H).

CI H
N
I HN
=N
N

[00533] Preparation of 4-[(6-chloro-1 H-indol-5-yl)amino]-5-[(E)-2-phenylethenyl]
pyridine-3-carbonitrile:

4-[(6-Chloro-1 H-indol-5-yl)amino]-5-iodopyridine-3-carbonitrile (53 mg, 0.13 mmol), (E)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl-2-yl)styrene (37 mg, 0.16 mmol), Pd(PPh3)4 (8.3 mg, 0.072 mmol), and saturated sodium bicarbonate (1 mL) was heated at reflux in 5 mL DME for 2 h. The reaction was cooled to room temperature and partitioned between ethyl acetate and saturated sodium bicarbonate. The organic portion was dried (magnesium sulfate) and concentrated. The residue was dissolved in DMSO and purified by HPLC to give 35 mg of the title compound. HPLC: 91.5%, rt = 10.3 min [a]; m/e 371.2 (M+H); HRMS:
calculated 371.1058 found 371.1058 (M+H).

NH
H2N, it OS HN \
N CN
I i N
[00534] Preparation of 4-[(E)-2-{5-cyano-4-[(4-methyl-lH-indol-5-yl)amino]pyridin-3-yl) vinyl]benzenesulfonamide:

4-[(4-Methyl-1 H-indol-5-yl)amino]-5-vinylnicotinonitrile (70 mg, 0.26 mmol), bromobenzenesulfonamide CL-4999 (70 mg, 0.30 mmol), Pd(OAc)2 (7.2 mg, 0.032 mmol), P(o-Tol)3 (11.2 mg, 0.037 mmol), and triethylamine (726 mg, 7.2 mmol) were dissolved in 2 mL
DMF and heated to 900 C for 16 h. The reaction was cooled to room temperature and partitioned between chloroform and saturated sodium bicarbonate. The organic portion was dried (magnesium sulfate) and concentrated. The residue was dissolved in DMSO
and purified by HPLC to give 22 mg of the title compound. HPLC: 97.7%, rt =. 7.5 min [a]; We 430.1 (M+H); HRMS: calculated 430.1330 found 430.1332 (M+H).

NH
N,#
/~H O /
OS HN \
CN

N
[00535] Preparation of 4-[(E)-2-{5-cyano-4-[(4-methyl-1H-indol-5-yl)amino]pyridin-3-yl) vinyl]-N-isobutylbenzenesulfonamide:

4-[(4-Methyl-1 H-indol-5-yl)amino]-5-vinylnicotinonitrile (90 mg, 0.33 mmol), 4-bromo-N-isobutylbenzenesulfonamide (93 mg, 0.32 mmol), Pd(OAc)2 (7.2 mg, 0.032 mmol), P(o-Tol)3 (9.7 mg, 0.037 mmol), and triethylamine (726 mg, 7.2 mmol) were dissolved in 2 mL DMF and heated to 900 C for 16 h.' The reaction was cooled to room temperature and partitioned between chloroform and saturated sodium bicarbonate. The organic portion was dried (magnesium sulfate) and concentrated. The residue was dissolved in DMSO and purified by HPLC to give 5 mg of the title compound. HPLC: rt = 10.5 min [a]; m/e 486.2 (M+H); HRMS:
calculated 486.1958 found 486.1959 (M+H).

NH

N CN
N
[00536] Preparation of 5-[(E)-2-(4-benzylmorpholin-2-yl)ethenyl]-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile:

4-[(4-methyl-lH-indol-5-yl)amino]-5-iodonicotinonitnle (2.1 g, 5.7 mmol), 4-benzyl-2-vinylmorpholine (1.2 mg, 5.7 mmol), Pd(OAc)2 (65 mg, 0.28 mmol), P(o-Tol)3 (96 mg, 0.31 mmol), and triethylamine (5.4 g, 54 mmol) were dissolved in 30 mL DMF and heated to 120 C
for 2 h. The reaction was cooled to room temperature and partitioned between ethyl acetate and saturated sodium bicarbonate. The organic portion was dried (magnesium sulfate) and concentrated. A portion of the residue was dissolved in DMSO and purified by HPLC to give 11 mg of the title compound. HPLC: 92.0%, rt = 5.4 min [a]; m/e 450.3 (M+H);
HRMS:
calculated 450.2288 found 450.2289 (M+H).

NH
HN
% CN
O I N

[00537] Preparation of 5-{(E)-2-[3-(1,4'-bipiperidin-l'-ylsulfonyl)phenyl]vinyl}-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile:

4-[(4-methyl- I H-indol-5-yl)amino]-5-vinylnicotinonitrile (107 mg, 0.39 mmol), 1'-(3-bromophenylsulfonyl)-1,4'-bipiperidine (151 mg, 0.39 mmol), Pd(OAc)2 (7.0 mg, 0.031 mmol), P(o-Tol)3 (14 mg, 0.046 mmol), and triethylamine (726 mg, 7.2 mmol) were dissolved in 2 mL
DMF and heated to 900 -C for 16 h. The reaction was cooled to room temperature and partitioned between chloroform and saturated sodium bicarbonate. The organic portion was dried (magnesium sulfate) and concentrated. The residue was dissolved in DMSO
and purified by HPLC to give 13.1 mg of the title compound. HPLC: rt = 7.6 min [a]; We 581.5 (M+H); HRMS: calculated 581.2693 found 581.2693 (M+H).

H O NH
H2N N, ei ~S HN
NH
CN
N

[00538] Preparation of N-carbamimidoyl-4-[(E)-2{5-cyano-44(4-methyl-1H-indol-5-yl) amino]pyridin-3 yl}vinyl]benzenesulfonamide:

4-[(4-methyl-1 H-indol-5-yl)amino]-5-vinylnicotinonitrile (90 mg, 0.33 mmol), 4-bromo-N-carbamimidoylbenzenesulfonamide (70 mg, 0.25 mmol), Pd(OAc)2 (6.0 mg, 0.027 mmol), P(o-Tol)3 (12 mg, 0.039 mmol), and triethylamine (726 mg, 7.2 mmol) were dissolved in 2 mL DMF
and heated to 90 C for 16 h. The reaction was cooled to room temperature and partitioned between chloroform and saturated sodium bicarbonate. The organic portion was dried (magnesium sulfate) and concentrated. The residue was dissolved in DMSO and purified by HPLC to give 2.8 mg of the title compound. HPLC: 93.5%, rt = 7.3 min [a]; m/e 472.3 (M+H);
HRMS: calculated 472.1550 found 472.1550 (M+H).m/e 204.1 (M+H) N

[00539] Preparation of 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(2-methyl-4-[(4-methylpiperazin-1-yl)methyl]phenyl}ethenyl]pyridine-3-carbonitrile:

The title compound was prepared from 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-vinylnicotinonitrile and 1-(4-iodo-3-methylbenzyl)-4-methylpiperazine via the procedure to prepare 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]5-[(E)-2-pyridin-2-ylvinyl]nicotinonitrile to give 202 mg (83%) of the desired product as a tan solid, MS (ESI) m/z 491.3;
HPLC: 98.0% at 215 nm, rt = 5.5 min [a].

NH
N

[00540] Preparation of 6-methyl-4-[(4-methyl-lH-indol-5-yl)amino]-5-(2-pyridin-2-yI
ethyl)pyridine-3-carbonitrile:

The title compound was prepared by the procedure described for the preparation 'of 4-[(4-methyl-1 H-indol-5-yl)amino]-5-(2-{6-[(4-pyrrolidin-l-ylpiperidin-1-yl)methyl]pyridin-2-yl}ethyl) nicotinonitrile and was isolated as a tan solid (80 mg, 79%). MS 368.2 (M+H);
HPLC: 91.6%
at 216 nm, rt = 5.6 min [a].

}I
N

6a N ( ~ N

[00541] Preparation of 6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-(2-{2-methyl-4-[(4-methylpiperazin-1 yI)methyl]phenyl}ethyl)nicotinonitrile:

The title compound was prepared by the procedure described for the preparation of 4-[(4-methyl-1 H-indol-5-yl)amino]-5-(2-{6-[(4-pyrrolidin-1-ylpiperidin-1-yl)methyl]pyridin-2-yl}ethyl) nicotinonitrile and was isolated as a tan solid (91 mg, 60%). MS 493.5 (M+H);
HPLC: 91.4%
at 216 nm, rt = 5.4 min [a].

N
H
N

F

[00542] Preparation of 5-[(E)-2-{5-[(diethylamino)methyl]pyridin-2-yl}ethenyl]-4-[(4-methyl-I H-indol-5-yl)amino]pyridine-3-carbonitrile:

The title compound was prepared by the procedure described for the preparation of 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[5-(piperidin-1-ylmethyl)pyridin-2-yl]ethenyl)pyridine-3-carbonitrile and was isolated as a yellow solid (29 mg, 25%). MS 437.3 (M+H);
HPLC: 96.6%
at 216 nm, rt = 6.2 min [a].

NH

[00543] Preparation of 5-[(E)-2-(6-([4-(dimethylamino)piperidin-1-yl]methyl}pyridin-2-yi) ethenyl]-6-methyl-4-[(4-rnethyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile:

The title compound was prepared by the procedure for the preparation of 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[5-(piperidin-1-ylmethyl)pyridin-2-yl]ethenyl}pyridine-3-carbonitrile and was isolated as a yellow solid (16 mg, 14%). MS 506.4 (M+H); : 93.5% at 216 nm, rt =. 4.8 min [a].

NH

[00544] Preparation of 5-[(E)-2-(6-[(diethylamino)methyl]pyridin-2-yl}ethenyl]-6-methyl-4-[(4-methyl-1 H-indol-5 yl)amino]pyridine-3-carbonitrile:

The title compound was prepared by the procedure described for the preparation of 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[5-(piperidin-1-ylmethyl)pyridin-2-yl]ethenyl}pyridine-3-carbonitrile and was isolated as a yellow solid (58 mg, 50%). MS 451.2 (M+H);
HPLC: 99.2%
at 216 nm, rt = 5.5 min [a].

NH
N
F

[00545] Preparation of 5-[(E)-2-(6-[(diethylamino)methyl]pyridin-2-yl}ethenyl]-4-[(4-methyl-1 H-indol-5- yl)amino]pyridine-3-carbonitrile:

The title compound was prepared by the procedure for the preparation of 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[5-(piperidin-1-ylmethyl)pyridin-2-yl]ethenyl}pyridine-3-carbonitrile and was isolated as a yellow solid (78 mg, 69%). MS 437.2 (M+H); HPLC: 98.9%
at 216 nm, rt = 5.8 min [a].

N

HN

[00546] Preparation of 4-[(1-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-phenylethenyl]
pyridine-3-carbonitrile:

A mixture of 4-chloro-5-[(E)-2-phenylvinyl]nicotinonitrile (120 mg, 0.5 mmol), 1-methyl-1 H-indol-5-amine (Ian T. Forbes et al, J. Med. Chem 1993, 36, 1104) (73.1 mg, 0.5 mmol) in 3 mL
of ethanol was heated at reflux for 17 h, then cooled to room temperature. The precipitate was filtered, washed with ethanol and diethyl ether. After drying in vacuo, 155.6 mg (81%) of 4-[(1-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-phenylethenyi]pyridine-3-carbonitrile was obtained as a yellow solid, MS (ESI) m/z 351.2 (M+H)+; HPLC: rt = 10.3 min [a].

NH
/I HA \

[00547] Preparation of 4-[(4-methyl-lH-indol-5-yl)amino]-5-[(E)-2-(2-methylphenyl) ethenyl]pyridine-3-carbonitrile:

A mixture of 4-[(4-methyl-1 H-indol-5-yl)amino]-5-vinylnicotinonitrile (120 mg, 0.44 mmol, 2-iodotoluene (122.5 mg, 0.53 mmol), Pd(OAc)2 (19.7 mg, 0.088 mmol) and tri-o-tolylphosphine (8.5 mg, 0.028 mmol) in 0.6 mL of triethylamine and 2.5 mL of DMF was heated at 120 C for 2 h, then cooled to room temperature and concentrated in vacuo. The residue was purified by column chromatography, eluting with a gradient of 5% ethyl acetate in dichloromethane to 15% ethyl acetate in dichloromethane to provide 83.0 mg (52%) of 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(2-methylphenyl)ethenyl]pyridine-3-carbonitrile as a yellow solid, MS (ESI) m/z 365.2; HPLC: rt = 14.8 min [b].

HN

\ NH
/N

[00548] Preparation of 4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-{2-[(4-methylpiperazin-1-yl)methyl]phenyl)ethenyl]pyridine-3-carbonitrile:
A mixture of 4-[(4-methyl-1 H-indol-5-yl)amino]-5-vinylnicotinonitrile (150 mg, 0.54 mmol, 1-(2-bromobenzyl)-4-methylpiperazine (218.0 mg, 0.81 mmol), Pd(OAc)2 (49.4 mg, 0.22 mmol) and tri-o-tolylphosphine (32.8 mg, 0.108 mmol) in 0.6 mL of triethylamine and 2.5 mL of DMF was heated at 120 C for 4 h, then cooled to room temperature and concentrated in vacuo. The residue was purified by column chromatography, eluting with a gradient of 5%
methanol in dichloromethane to 20% methanol in dichloromethane to provide 17.4 mg (7%) of 4-[(4-methyl-1 H-indol-5-yl)amino}-5-[(E)-2-{2-[(4-methylpiperazin-1-yl)methyl]phenyl}ethenyl]
pyridine-3-carbonitrile as a yellow solid, MS (ESI) m/z 463.2; HPLC: rt = 6.5 min [a].

HN

NH

[00549] Preparation of 4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-{3-[(4-methylpipe razin-1-yl)methyl]phenyl)vinyl]nicotinonitrile:
A mixture of 4-[(4-methyl-1 H-indol-5-yl)amino]-5-vinylnicotinonitrile (100 mg, 0.36 mmol), 1-(3-bromobenzyl)-4-methylpiperazine (116.3 mg, 0.43 mmol), Pd(OAc)2 (16.2 mg, 0.072 mmol) and tri-o-tolylphosphine (7.7 mg, 0.025 mmol) in 0.75 mL of triethylamine and 3.0 mL of DMF
was heated at 120 C for 2.5 h, then cooled to room temperature and partitioned between dichloromethane and aqueous saturated sodium bicarbonate. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography, eluting with a gradient of 2% methanol in dichioromethane to 12% methanol in dichioromethane to provide 64.8 mg (39%) of 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{3-[(4-methylpiperazin-1-yl)methyl]phenyl}vinyl]nicotinonitrile as an off white solid, MS (ESI) m/z 463.3; HPLC rt = 5.9 min [a].

~N / S fNH
FN H
/

[00550] Preparation of 4-[(4-methyl-lH-indol-5-yl)amino]-5-[(E)-2-{4{(4-methylpiperazin-1-yl)methyl]-1,3-thiazol-2-yl}ethenyl]pyridine-3-carbonitrile:
A mixture of 5-iodo-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile (297.0 mg, 0.79 mmol), 1-[(2-ethenyl-1,3-thiazol-4-yl)methyl]-4-methylpiperazine (120.0 mg, 0.53 mmol), Pd(OAc)2 (47.6 mg, 0.22 mmol) and tri-o-tolyl phosphine (22.6 mg, 0..074 mmol) in 1.0 mL of triethylamine and 3.5 mL of DMF was heated at 120 C for 3 h, then cooled to room temperature and partitioned between dichloromethane and aqueous saturated sodium bicarbonate.
The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo.
The residue was purified by column chromatography, eluting with a gradient of 5% methanol in dichioromethane to 20% methanol in dichloromethane to provide .103 mg (41%) of 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{4-[(4-methylpiperazin-1-yl)methyl]-1,3-thiazol-2-yl) ethenyl]pyridine-3-carbonitrile as a yellow solid, MS (ESI) mlz 470.1; HPLC:
rt = 5.1 min [a].
\N~ -^
N HN

N
N

[00551] Preparation of 4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-{5-[(4-methylpiperazin-1-yl)methyl]pyridin-3-yl}ethenyl]pyridine-3-carbonitrile:

Following the procedure used to prepare 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{4-[(4-methylpiperazin-1-yl)methyl]-1,3-thiazol-2-yl}ethenyl]pyridine-3-carbonitrile, 25.0 mg (10%) of 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{5-[(4-methylpiperazin-1-yl)methyl]pyridin-3-yl}
ethenyl]pyridine-3-carbonitrile was prepared as a yellow solid via the reaction of 5-iodo-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile with 1-methyl-4-[(5-vinylpyridin-3-yl)methyl]
piperazine, MS (ESI) m/z 464.2; HPLC: rt = 4.4 min [a].

NN' F ~N --'' ~ \ I NH

[00552] Preparation of 4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-{6-[(4-methylpiperazin-1-yl)methyl]pyridin-3-yl}ethenyl]pyridine-3-carbonitrile:
Following the procedure used to prepare 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{4-[(4-methylpiperazin-1-yl)methyl]-1,3-thiazol-2-yl}ethenyl]pyridine-3-carbonitrile, 41.2 mg (16%) of 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{6-[(4-methylpiperazin-l-yl)methyl]pyridin-3-yl}
ethenyl]pyridine-3-carbonitrile was prepared as a yellow solid via the reaction of 5-iodo-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile with 1-methyl-4-[(5-vinylpyridin-2-yl) methyl]
piperazine, MS (ESI) m/z 464.3; HPLC: it = 10.5 min [b].

NH
H
N\ jN
H F

[00553] Preparation of 4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-pyridin-3-ylethenyl]
pyridine-3-carbonitrile:

A mixture of 5-iodo-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile (150.0 mg, 0.40 mmol), 3-vinylpyridine (54.6 mg, 0.52 mmol), Pd(OAc)2 (18 mg, 0.08 mmol) and tri-o-tolyl phosphine (8.5 mg, 0..028 mmol) in 0.70 mL of triethylamine and 2.5 mL of DMF was heated at 120 C for 3 h, then cooled to room temperature and partitioned between dichloromethane and aqueous saturated sodium bicarbonate. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography, eluting with a gradient of 2% methanol in ethyl acetate to 6%
methanol in ethyl acetate to provide 14.3 mg (10%) of 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-pyridin-3-ylethenyl]pyridine-3-carbonitrile as a deep yellow solid, MS (ESI) m/z 352.1;
HPLC: rt = 5.6 min [a].

NH
/ HN \

[00554] Preparation of 5-[(E)-2-(2-ethylphenyl)ethenyl]-4-[(4-methyl-1 H-indol-5-yi) amino]pyridine-3-carbonitrile:

Following the procedure used to prepare 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(.E)-2-(2-methylphenyl)ethenyl]pyridine-3-carbonitrile, 76.1 mg (46%) of 5-[(E)-2-(2-ethylphenyl) ethenyl]-4-[(4-methyl-1 H-indol-5-yl)a m ino]pyrid ine-3-carbon itrile was prepared as a yellow solid via the reaction of 4-[(4-methyl-1 H-indol-5-yl)amino]-5-vinylnicotinonitrile with 2-ethyliodobenzene, MS (ESI) m/z 379.2; HPLC: rt = 11 min [a].

N NH

HN
N

[00555] Preparation of 5-[(E)-2-{2-ethyl-5-[(4-methylpiperazin-1-yl)methyl]phenyl}
ethenyl]-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile:

A mixture of 4-[(4-methyl-1 H-indol-5-yl)amino]-5-vinylnicotinonitrile (150.9 mg, 0.55 mmol), 1-(3-bromo-4-ethylbenzyl)-4-methylpiperazine (150 mg, 0.50 mmol), Pd(OAc)2 (22.5 mg, 0.1 mmol) and tri-o-tolylphosphine (10.7 mg, 0.035 mmol) in 0.7 mL of triethylamine and 2.5 ml of DMF was heated at 120 C for 4 h. The resulting mixture was cooled to room temperature, partitioned between dichloromethane and aqueous saturated sodium bicarbonate.
The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography, eluting with a gradient of 5% methanol in ethyl acetate to 20% methanol in ethyl acetate to 20% methanol In ethyl acetate containing 0.5%
of conc. aq.
ammonium hydroxide. Repurification by preparative TLC, developing with 15%
methanol in dichloromethane provided 97.8 mg (39%) of 5-[(E)-2-{2-ethyl-5-[(4-methylpiperazin-1-yl)methyl]phenyl}ethenyl]-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile as a yellow solid, MS (ESI) m/z 491.1; HPLC: rt = 6.7 min [a].

N

[00556] Preparation of 5-[(E)-2-(2-ethyl-5-[(4-methylpiperazin-1-yl)methyl]phenyl}
ethenyl]-6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile:

Following the procedure used to prepare 5-[(E)-2-{2-ethyl-5-[(4-methylpiperazin-1-yl)methyl]phenyl}ethenyl]-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile, 88.7 mg (35%) of 5-[(E)-2-{2-ethyl-5-[(4-methylpiperazin-1-yl)methyl]phenyl}ethenyl]-6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile was prepared as an off-white solid via the reaction of 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-vinylnicotinonitrile with 1-(3-bromo-4-ethylbenzyl)-4-methylpiperazine, MS (ESI) m/z 505.1; HPLC: rt = 10.6 min [b].

HO

[00557] Preparation of 5-{(E)-2-[2-(hydroxymethyl)-1,3-thiazol-4-yl]ethenyl}-4-[(4-methyl -1H-indol-5- yi)amino]pyridine-3-carbonitrile:

A mixture of 4-[(4-methyl-lH-indol-5-yl)amino]-5-vinylnicotinonitrile 65 mmol), (4-bromo-1,3-thiazol-2-yl)methanol ( Simeon, F. G. et al J. Med. Chem., 2007, 50, 3256) (1.63 g, 8.40 mmol), Pd(OAc)2 (491.7 mg, 2.19 mmol) and tri-o-tolylphosphine (333.3 mg, 1.09 mmol) in 5 mL of triethylamine and 19 mL of DMF was heated at 120 C for 18 h. The resulting mixture was cooled to room temperature and partitioned between dichloromethane and aqueous saturated sodium bicarbonate. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography, eluting with a gradient of 50% ethyl acetate in hexane to 100%
ethyl acetate to 1% methanol in ethyl acetate to provide 582.3 mg (41%) of 5-{(E)-2-[2-(hydroxymethylr1,3-thiazol-4-yl]ethenyl}-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile as a deep yellow solid, MS (ESI) m/z 388.1; HPLC: rt = 7.7 min [a].

NH
HN
N\ ~N
N

[00558] Preparation of 5-[(E)-2-(5-bromopyridin-3-yl)ethenyl]-4-[(4-methyl-lH-indol-5-yl) amino]pyridine-3-carbonitrile:

To a DMF solution (11 ml-) of 4-[(4-methyl-1 H-indol-5-yl)amino]-5-vinylnicotinonitrile (300 mg, 1.1 mmol) was added 3,5-dibromopyridine (379 mg, 1.6 mmol), Pd(OAc)2 (25 mg, 0.11 mmol), P(o-Tol)3 (34 mg, 0.11 mmol) and Et3N (0.061 mL, 4.4 mmol). The solution was heated at 120 C overnight. After cooling to room temperature, water (100 ml-) was added to the rapidly stirred solution. The resulting precipitate was collected by vacuum filtration and purified by flash chromatography with 100:5:0.5 CH2CI2/MeOH/saturated aqueous NH4OH to provide the title compound (188 mg, 40%) as a white solid. MS 430.0 (M+H);
HPLC: it = 9.4 min [a].

NH
~ I

HN \
N~ I / iN
N

[00559] Preparation of 5-[(E)-2-(5-methoxypyridin-3-yl)egthenyl]-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile:

The procedure for the preparation of 5-[(E)-2-(5-bromopyridin-3-yl)ethenyl]-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile was followed using 3-bromo-5-methoxypyridine. The title compound was isolated as a yellow solid (170 mg, 41%). MS 382.1 (M+H);
HPLC: 6.7 min [a].

H
~OTN
p NH

O YN
~ HN 4 N

[00560] Preparation of tert-butyl [2-({5-[(E)-2-{5-cyano-4-[(4-methyl-1H-indol-5-yl)amino]
pyridin-3-yl}ethenyl]pyridin-3-yl}oxy)ethyl]carbamate:

The procedure for the preparation of 5-[(E)-2-(5-bromopyridin-3-yl)ethenyl]-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile was followed using tert-butyl {2-[(5-bromopyridin-3-yl)oxy]ethyl}carbonate. The title compound was isolated as a yellow solid (450 mg, 81 %). MS
511.2 (M+H); HPLC: rt = 8.9 min [a].

NH
O
HN
N / \ N
N

[00561] Preparation of 5-{(E)-2-[5-(2-aminoethoxy)pyridin-3-yl)ethenyl}-4-[(4-methyl-1H-indol-5-yl)amino]pyridine-3-carbonitrile:
Tert-butyl [2-({5-[(E)-2-{5-cyano-4-[(4-methyl-1 H-indol-5-yl)amino]pyridin-3-yl}ethenyl]pyridin-3-yl}oxy)ethyl]carba mate (255 mg, 0.50 mmol) was added to a CH2CI2 solution containing 10%
TFA (10 mL). After 2 hours at room temperature, saturated aqueous NaHCO3 (2 ml-) was added and the solvent removed under vacuum. The residue was suspended in MeOH
and filtered. The filtrate was condensed to a gum and triturated with Et20. The solid was dried under vacuum at 60 C overnight to provide the title compound (200 mg, 98%) as a light red solid. MS 411.1 (M+H); HPLC: rt = 4.3 min [a].

N
P
HN

HN
N N
N

[00562] Preparation of 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-245-(2-[(1 -methyl piperidin-4-yl)amino]ethoxy}pyridin-3-yl)ethenyl]pyridine-3-carbonitrile:

To a CH2CI2 solution (5 mL) of 5-{(E)-2-[5-(2-aminoethoxy)pyridin-3-yl]ethenyl}-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile (200 mg, 0.49 mmol) was added NaBH(OAc)3 (156 mg, 0.74 mmol), AcOH (0:043 mL) and N-methyl4-piperidone (0.070 mL, 0.58 mmol). The reaction was stirred at room temperature overnight. The solvent was removed under vacuum, and the residue partitioned between EtOAc (5 mL) and water (3 mL). The organic layer was dried over anhydrous MgSO4, filtered, and concentrated under vacuum. The residue was dissolved in DMSO and the title compound (3.0 mg, 2%) purified by preparative HPLC. MS
508.2 (M+H); HPLC: rt = 6.5 min [a].

Y
N
HN`
1` ^ N

HN \
N~ I iN
N

[00563] Preparation of 5-{(E)-2-[5-(2-{[1-(1-methylethyl)piperidin-4-yl]amino}ethoxy) pyridin-3-yl]ethenyl}-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile:
The procedure for the preparation of 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(5-{2-[(1-methylpiperidin-4-yl)amino]ethoxy}pyridin-3-yl)ethenyl]pyridine-3-carbonitrile was followed using N-iso-propyl-4-piperidone. The title compound (16 mg, 6%) was purified by preparative HPLC. MS 536.3 (M+H); HPLC: it = 6.9 min [a].

N
HN
NH
O
HN
N
N

N

[00564] Preparation of 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(5{2-1(1 -propyl piperidin-4-yl)amino]ethoxy}pyridin-3-yl)ethenyl]pyridine-3-carbonitrile:

The procedure for the preparation of 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(5-{2-[(1-methylpipendin-4-yl)amino]ethoxy}pyridin-3-yl)ethenyl]pyridine-3-carbonitrile was followed using N-propyl-4-piperidone. The title compound (19 mg, 7%) was purified by preparative HPLC. MS 536.3 (M+H); HPLC: rt = 6.9 min [a].

N
HN
NH

N
N~

N

[00565] Preparation of 4-[(4-methyl-1H-indol-5-yl)amino]-5{(E)-2-[5-(2{[1-(2-methyl propyl)piperidin-4-yl]amino}ethoxy)pyridin-3-yl]ethenyl}pyridine-3-carbonitrile:
The procedure for the preparation of 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(5-{2-[(1-methylpiperidin-4-yl)amino]ethoxy}pyridin-3-yl)ethenyl]pyridine-3-carbonitrile was followed using N-iso-butyl-4-piperidone. The title compound (6 mg, 2%) was purified by preparative HPLC. MS 550.3 (M+H); HPLC: rt= 7.4 min [a].

HN
NH
O
HN
N
N~

N

[00566] Preparation of 5-[(E)-2-(5-{2-[(1-ethylpiperidin-3-yl)amino]ethoxy}pyridin-3-yl) ethenyl]-44(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile:

The procedure for the preparation of 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(5-{2-[(1-methylpiperidin-4-yl)amino]ethoxy}pyridin-3-yl)ethenyl]pyridine-3-carbonitrile was followed using 1-ethyl-3-piperidone hydrochloride and N, N-di-iso-propylethylamine. The title compound (3 mg, 1%) was purified by preparative HPLC. MS 522.2 (M+H); HPLC: rt = 6.2 min [a].

HN
NH
HN
N` N
N

[00567] Preparation of 5-[(E)-2-(5-{2-[(2,2-dimethylpropyl)amino]ethoxy}pyridin-3-yl) vinyl]-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile:

The procedure for the preparation of 4-[(4-methyl-lH-indol-5-yl)amino]-5-[(E)-2-(5-{2-[(1-methylpipendin-4-yl)amino]ethoxy}pyridin-3-yl)ethenyl]pyridine-3-carbonitrile was followed using trimethylacetaldehyde. The title compound (3 mg, 1%) was purified by preparative HPLC. MS 481.2 (M+H); HPLC: rt = 5.9 min [a].

\^'N
N
o HN
N~ iN
N

[00568] Preparation of 5-[(E)-2-(5{2-[bis(3,3-dimethylbutyl)amino]ethoxy}pyridin-3-yI
vinyl]-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile:

The procedure for the preparation of 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(5-{2-[(1-methylpiperidin-4-yl)amino]ethoxy}pyridin-3-yl)ethenyl]pyridine-3-carbonitrile was followed using 3,3-dimethylbutyraldehyde. The title compound (4 mg, 2%) was purified by preparative HPLC. MS 579.3 (M+H); HPLC: 8.9 min [a].

N
HN
iN
i N
[00569] Preparation of 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[4-(pyrrolidin-1-ylsulfonyl)phenyl]ethenyl}pyridine-3-carbonitrile:

To a DMF solution (3 ml-) was added 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-vinylnicotinonitrile (58 mg, 0.20 mmol), Pd(OAc)2 (5 mg, 0.02 mmol), P(o-Tol)3 (6 mg, 0.02 mmol), Et3N (0.11 mL, 0.8 mmol), and 1-[(4-bromophenyl)sulfonyl]pyrrolidine (87 mg, 0.3 mmol). The solution was heated at 100 C overnight. The solution was cooled and filtered and the filtrate was purified by preparative HPLC to give the title compound (44 mg, 44 %).
MS 498.1 (M+H); HPLC: rt = 9.3 min [a].

N NH
LN, ~o ~ HN
N
/ I \
N ", [00570] Preparation of 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{4-[(4-methyl piperazin-1-yl)sulfonyl]phenyl}ethenyl]pyridine-3-carbonitrile:
The procedure for the preparation of 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[4-(pyrrolidin-1-ylsulfonyl)phenyl]ethenyl}pyridine-3-carbonitrile was followed using 1-[(4-bromo) sulfonyl]-4-methylpiperazine. The title compound (41 mg, 39%) was purified by preparative HPLC. MS 527.2 (M+H); HPLC: rt = 6.1 min [a].

N

HN
rN' I N

[00571] Preparation of 6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2{3-[(4-methyl piperazin-1-yl)sulfonyl]phenyl}ethenyl]pyridine-3-carbonitrile:
The procedure for the preparation of 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[4-(pyrrolidin-1-ylsulfonyl)phenyl]ethenyl}pyridine-3-carbonitrile was followed using 1-[(3-bromophenyl)sulfonyl]-4-methylpiperazine. The title compound (44 mg, 42%) was purified by preparative HPLC. MS 527.2 (M+H); HPLC: rt = 6.1 min [a].

iNH
HN
ps \ I / \ N
IN
[00572] Preparation of 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5{(E)-2-[3-(piperidin-1-ylsulfonyl)phenyl]ethenyl}pyridine-3-carbonitrile:
The procedure for the preparation of 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[4-(pyrrolidin-1-ylsulfonyl)phenyl]ethenyl}pyridine-3-carbonitrile was followed using 1-[(3-bromo phenyl)sulfonyl]piperidine. The title compound (42 mg, 41%) was purified by preparative HPLC. MS 512.2 (M+H); HPLC: rt = 11.1 min [a].

NH
HN

ICY' N

[00573] Preparation of 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[3-(pyrrolidin-1-ylsulfonyl)phenyl]ethenyl}pyridine-3-carbonitrile:

The procedure for the preparation of 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[4-(pyrrolidin-1-ylsulfonyl)phenyl]ethenyl}pyridine-3-carbonitrile was followed using 1-[(3-bromophenyl)sulfonyl]pyrrolidine. The title compound (42 mg, 41%) was purified by preparative HPLC. MS 498.1 (M+H); HPLC: rt = 10.3 min [a].

I O NH
,/ I
N, oS H14 N
N

[00574] Preparation of 4-[(4-methyl-1 H-indol-5=y1)amino]-5-{(E)-2-[4-(N,N-dimethyl benzenesulfonyl)phenyl]ethenyl}pyridine-3-carbonitrile:
The procedure for the preparation of 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[4-(pyrrolidin-1-ylsulfonyl)phenyl]ethenyl}pyridine-3-carbonitrile was followed using 4-[(4-methyl-1 H-indol-5-yl)amino]-5-vinylnicotinonitrile and 4-bromo-N,N-dimethylbenzenesulfonamide.
The title compound (19 mg, 21%) was purified by preparative HPLC. MS 458.0 (M+H);
HPLC: rt = 9.4 min [a].

NH
OS HN
\ ~N
i N

[00575] Preparation of 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[4-(N,N-diethyl benzenesulfonyl)phenyl]ethenyl}pyridine-3-carbonitrile:
The procedure for the preparation of 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[4-(pyrrolidin-1-ylsulfonyl)phenyl]ethenyl}pyridine-3-carbonitrile was followed using 4-[(4-methyl-1 H-indol-5-yl)amino]-5-vinylnicotinonitrile and 4-bromo-N,N-diethylbenzenesulfonamide. The title compound (19 mg, 20%) was purified by preparative HPLC. MS 486.1 (M+H);
HPLC: rt = 10.7 min [a].

N
N,O
OS HN \
N
N

[00576] Preparation of 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[4-(N,N-dipropyl benzenesulfonyl)phenyl]ethenyl}pyridine-3-carbonitrile:
The procedure for the preparation of 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[4-(pyrrolidin-1-ylsulfonyl)phenyl]ethenyl}pyridine-3-carbonitrile was followed using 4-[(4-methyl-1 H-indol-5-yl)amino]-5-vinylnicotinonitrile and 4-bromo-N,N-dipropylbenzenesulfonamide. The title compound (45 mg, 44%) was purified by preparative HPLC. MS 514.1 (M+H);
HPLC: rt =
12.2 min [a].

NH
ONio OAS HN \
N
N

[00577] Preparation of 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[4-(piperidin-1-yl sulfonyl)phenyl]ethenyl}pyridine-3-carbonitrile:
The procedure for the preparation of 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[4-(pyrrolidin-1-ylsulfonyl)phenyl]ethenyl}pyridine-3-carbonitnle was followed using 4-[(4-methyl-1H-indol-5-yl)amino]-5-vinylnicotinonitrile and 1-[(4-bromophenyl)sulfonyl]piperidine. The title compound (43 mg, 44%) was purified by preparative HPLC. MS 498.0 (M+H); HPLC:
rt 11.3 min [a].

NH

N
N~SO I i N

[00578] Preparation of 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[3-piperidin-1-yl sulfonyl) phenyl]ethenyl}pyridine-3-carbonitrile:

The procedure for the preparation of 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[4-(pyrrolidin-1-ylsulfonyl)phenyl]ethenyl}pyridine-3-carbonitrile was followed using 4-[(4-methyl-1H-indol-5-yl)amino]-5-vinylnicotinonitrile and 1-[(3-bromophenyl)sulfonyl]piperidine. The title =
compound (37 mg, 37%) was purified by preparative HPLC. MS 498.0 (M+H); HPLC:
rt 11.0 min [a].

Y NH

YI US HN
IYN` #

LN
[00579] Preparation of 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[4-(N,N-di-iso-propyl benzenesulfonyl)phenyl]ethenyl}pyridine-3-carbonitrile:

The procedure for the preparation of 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[4-(pyrrolidin-1-ylsulfonyl)phenyl]ethenyl}pyridine-3-carbonitrile was followed using 4-[(4-methyl-1 H-indol-5-yl)amino]-5-vinyinicotinonitrile and 4-bromo-N,N-di-iso-propylbenzenesulfonamide.
The title compound (32 mg, 31%) was purified by preparative HPLC. MS 514.1 (M+H);
HPLC: rt = 12.0 min [a].

N
N / HN
\ N
N

[00580] Preparation of 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-(2-(4-[(4-methyl piperazin-1- yl)methyl]phenyl}ethyl)pyridine-3-carbonitrile:

To pressure vessel containing a solution of EtOH (10 mL), THE (5 mL) and 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}ethenyl]
pyridine-3-carbonitrile (150 mg, 0.31 mmol) was added 10% Pd on carbon (50 mg). The pressure vessel was charged with hydrogen (40 psi) and shaken overnight. The pressure was relieved and the solution filtered through magnesium silicate. The filtrate was concentrated under vacuum and the title compound (61 mg, 41%) was purified by preparative HPLC. MS 479.3 (M+H); HPLC:rt = 5.4 min [a].

NH
HN
\ I iN
N
[00581] Preparation of 6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-[2-(4-methyl phenyl)ethyl]pyridine- 3-carbonitrile:

The procedure for the preparation of 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-(2-{4-[(4-methylpiperazin-1-yl)methyl]phenyl)ethyl)pyridine-3-carbonitrile was followed.
The title compound (19 mg, 16%) was purified by preparative HPLC. MS 381.2 (M+H); HPLC:
rt = 10.9 min [a].

/ N / N
HN
HN
N
N

[00582] Preparation of 5-[(E)-2-(4-{[(1H-indol-3-ylmethyl)(methyl) amino]methyl}phenyl) ethenyl]-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile:

To a 1:1 THF/MeOH solution (5 ml-) of 5-[(E)-2-(4-formylphenyl)ethenyl]-4-[(4-methyl-1H-indol-5-yl)amino]pyridine-3-carbonitrile (76 mg, 0.20 mmol) and 1 -(1 H-indol-3-yl)N-methylmethanamine dihydrochloride. (70 mg, 0.3 mmol) was added N,N-diisopropylethyla mine (0.11 mL, 0.6 mmol) and NaBH(OAc)3 (212 mg, 1.0 mmol).
The solution was stirred at room temperature overnight. The solvent was removed under vacuum and the residue was purified by preparative HPLC to provide the title compound (45 mg, 45%) MS 523.1 (M+H); HPLC: rt = 7.5 min [a].

[00583] Preparation of 5-[(E)-2-(4-formylphenyl)ethenyl]-6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile:

The title compound was prepared from 4-[(E)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethenyl]benzaldehyde and 5-iodo-6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile via the procedure used to prepare 5-[(E)-2-(3-formylphenyl)ethenyl]-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile. The crude was purified by silica gel chromatography (CH2CI2-THF and CH2CI2-CH3OH, gradient), providing 3.8 g (71%) of the title compound as a yellow, solid. 1HNMR(300 MHz, DMSO) 2.30 (s, 3H), 6.49 (s, 1H), 6.89 (d, 1H, J = 8.0 Hz), 7.25 (m, 2H), 7.57 (m, 3H), 7.85 (m, 3H), 8.18 (s, 1H), 8.47 (s, 114), 10.00 (s, 1H), 11.10 (s, 1H); MS
393.1 (M+H).

xx [00584] Preparation of 4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-(4-{[(2-pyridin-4-yl ethyl) amino]methyl}phenyl)ethenyfpyridine-3-carbonitrile:

A reaction. mixture of 5-[(E)-2-(4 formylphenyl)ethenyl]-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3- carbonitrile (130 mg, 0.34 mmol), 3-pyridin-4-yl-propylamine (83 mg, 0.68 mmol) in THE (2.0 ml-) was stirred at room temperature for 30 minutes. To this was added NaBH(OAc)3 (358 mg, 1.7 mmol). The reaction mixture was stirred at room temperature for 20 h, concentrated. The residue was purified by HPLC-MS (A: 0.1%NH4OH in H2O; B:

0.1 %NH4OH in acetonitrile), providing 35 mg (22%) of the title compound as a pale-yellow solid. MS 485.3 (M+H); HPLC: 97.01% at 215 nm, rt = 6.0 min [a].

H~6 [00585] Preparation of 5-[(E)-2-{4-[(4-cyclopentylpiperazin-1-yl)methyl]phenyl}ethenyl]-6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile:

A reaction mixture of 5-[(E)-2-(4-formylphenyl)ethenyl]-6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile (132 mg, 0.34 mmol), 4-pyrrolidin-1-yl-piperidine (104 mg, 0.68 mmol) in THE (2.0 ml-) was stirred at room temperature for 30 minutes. To this was added NaBH(OAc)3 (358 mg, 1.7 mmol). The reaction mixture was stirred at room temperature for 20 h, concentrated. The residue was purified by HPLC-MS (A: 0.1%NH4OH in H,O; B:
0.1%NH4OH in acetonitrile), providing 35 mg (19%) of the title compound as a pale-yellow solid. MS 531.3 (M+H); HPLC: 94.2% at 215 nm, rt = 6.0 min [a].

Table 17:

The compounds in table 17 were prepared from either 5-[(E)-2-(4-formylphenyl)ethenyl]-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3- carbonitrile or 5-[(E)-2-(4-formylphenyl)ethenyl]-6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile and the appropriate amine via the procedure described for and 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(4-{[(2-pyridin-4-yl ethyl)amino]methyl}phenyl)ethenyl]pyridine-3-carbonitrile and 5-[(E)-2-{4-[(4-cyclopentyl piperazin-1-yl)methyl]phenyl}ethenyl]-6-methyl-4-[(4-methyl-1 H-indol-5-yl )amino]pyridine-3-carbonitrile Compound name MS HPLC rt 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(4-{[(2- 246.2 piperidin-1-ylethyl)amino]methyl)phenyl)ethenyl] (M+H) 5.4 min pyridine-3-carbonitrile [A]

4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(4-{[(2-pyrrolidin-1-ylethyl)amino]methyl)phenyl)ethenyl] 477.4 5.2 min pyridine-3-carbonitrile (M+H) [A]
4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[4-({[3-(4-methylpiperazin-l-yl)propyl]amino}methyl)phenyl] 520.5 4.8 min ethen I ridine-3-carbonitrile (M+H) [A]
5-[(E)-2-(3-{[4-(dimethylamino)piperidin-1-yl] methyl}
phenyl)vinyl]-4-[(4-methyl-1H-indol-5-yl)amino] 491.2 5.2 min nicotinonitrile (M+H) A
5-[(E)-2-(3-{[4-(dimethylami no)piperidin-l -yl]methyl}
phenyl)ethenyl]-6-methyl-4-[(4-methyl-1 H-indol-5- 505.4 4.4 min amino ridine-3-carbonitrile (M+H) A
5-[(E)-2-(4-{[(3-ethoxypropyl )amino]methyl}phenyl) ethenyl}6-methyl-4-[(4-methyl-1H-indol-5-yl)amino] 480.4 6.2 min pyridine-3-carbonitrile M+H [A]
5-[(E)-2-(4-{[4-(2-hydroxyethyl)piperazin-1-yl]methyl} 507.3 phenyl)ethenyl]-6-methyl-4-[(4-methyl-1 H-indol-5-yl) (M+H) 7.2 min amino ridine-3-carbonitrile A
5-[(E)-2-(4-[(3-hydroxypyrrolidin-1-yl)methyl] phenyl) ethenyl]-6-methyl-4-[(4-methyl-lH-indol-5-yl)amino] 464.4 5.6 min pyridine-3-carbonitrile (M+H) [A]
5-[(E}2-{4-[(4-hydroxypiperidi n-1-yl)methyl]phenyl}
ethenyl]-6-methyl-4-[(4-methyl-I H-indol-5-yl)amino] 478.3 5.1 min pyridine-3-carbonitrile M+H A
5-[(E)-2-{4-[(4-methyl-1,4-diazepan-1-yl)methyl]
phenyl}ethenyl]-4-[(4-methyl-1 H-indol-5-yl)amino] 477.3 4.6 min pyridine-3-carbonitrile (M+H) [A]
5-[(E)-2-{4-[(diethylamino)methyl]phenyl}ethenyl]-6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3- 450.2 5.6 min carbonitrile (M+H) [A]
5-{(E)-2-[3-(1,4'-bipiperidin-1'-ylmethyl)phenyl]vinyl)-4- 531.3 5.3 min f(4-methyl-1 H-indol-5- I amino nicotinonitdle (M+H) [A]
5-{(E)-2-[4-({[(1-ethylpyrrol idin-2-yl)methyl]amino}
methyl)phenyl]ethenyl}-4-[(4-methyl-1H-indol-5- 491.4 5.1 min yl)aminolpyridine-3-carbonitrile (M+H) [A]
5-{(E)-2-[4-({[(1 -ethylpyrrol idi n-2-yl)methyl]am i no}
methyl)phenyl]ethenyl}-6-methyl-4-[(4-methyl-1 H- 505.3 6.1 min indol-5- I amino ridine-3-carbonitrile (M+H) [A]
5-{(E)-2-[4-({[2-(dimethylami no)ethyl]amino}methyl) phenyl]ethenyl}-4-[(4-methyl-I H-indol-5- 226.1 5.1 min yl)amino]pyridine-3-carbonitrile (M+2H) [A]
5-{(E)-2-[4-({[2-(dimethylamino)ethyl]am ino}methyl) phenyl]ethenyl}-6-methyl-4-[(4-methyl-1 H-indol-5- 465.3 4.8 min A
yl)aminolpyddine-3-carbonitrile (M+H) 5-{(E)-2-[4-({[3-(dimethylamino)propyl]amino} methyl) phenyl]ethenyl}-6-methyl-4-[(4-methyl-1H-indol-5-yl) 479.4 4.9 min A
amino ridine-3-carbonitrile (M+H) 5-{(E)=2-[4-(1,4'-bipiperidin-l'-ylmethyl)phenyl]ethenyl}
-6-methyl-4-[(4-methyl-lH-indol-5-yl)amino]pyridine-3- 545.3 4.0 min carbonitrile (M+H) A
6-methyl-4-[(4-methyl-lH-indol-5-yl)amino]-5-[(E)-2-(4- 507.1 6.5 min 2-mo holin-4- leth I amino meth I hen I )vinyl] (M+H) [A]

nicotinonitrile 6-methyl-4-[(4-methyl-1 H-indol-5-yl )amino]-5-[(E)-2-(4-{[(2-piperidin-1-ylethyI)amino]methyl}phenyl)ethenyl] 253.2 5.1 min pyridine-3-carbonitrile (M+2H) A
6-methyl-4-[(4-methyl-1 H-indol-5-yl )amino]-5-[(E)-2-(4-{[(2-pyndin-2-ylethyI)amino]methyl}phenyl)ethenyl] 499.1 5.1 min pyridine-3-carbonitrile M+H [A]
6-methyl-4-[(4-methyl-1 H-i ndol-5-yl )amino]-5-[(E)-2-(4-{[(2-pyridin-3-ylethyI)amino]methyl}phenyl)ethenyl] 499.1 4.7min pyridine-3-carbonitrile (M+H) [A]
6-methyl-4-[(4-methyl-1 H-i ndo I-5-yl )amino]-5-[(E)-2-(4-{[(2-pyridin-4-ylethyI)amino]methyl)phenyl)ethenyl] 480.1 5.7 min pyridine-3-carbonitrile M+H [A]
6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(4-{[(2-pyrrolidin-1-ylethyl)amino]methyl}phenyl)vinyl] 491.6 4.3 min nicotinonitrile (M+H) A]
6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(4-{[(3-morpholin-4-ylpropyl)amino]methyl}phenyl) 521.3 5.9 min ethen I ridine-3-carbonitrile M+H A
6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}ethenyl] 239.1 5.1 min ridine-3-carbonitrile (M+2H) A
6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{4-[(4-pyrrolidin-1-ylpipe(din-1-yl)methyl]phenyl)ethenyl] 531.4 4.2 min pyridine-3-carbonitrile (M+H) [A]
6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[4-({[3-(4-methylpiperazin-1-yl)propyl]amino}methyl) 520.5 4.6 min hen I ethen I ridine-3-carbonitrile (M+H) A
6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[4-(morpholin-4-ylmethyl)phenyl]ethenyl}pyridine-3- 232.6 5.2 min carbonitrile (M+2H) [A]
6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[4-(piperidin-1-ylmethyl)phenyl]ethenyl}pyridine-3- 462.2 5.9 min A
carbonitrile (M+H) 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[4-(pyrrolidin-1-ylmethyl)phenyl]ethenyl}pyridine-3- 448.2 6.0 min carbonitrile (M+H) A
6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[4-(thiomorpholin-4-ylmethyl)phenyl]ethenyl}pyridine-3- 480.1 5.7 min carbonitrile (M+H) [A]
6-methyl-5-[(E)-2-(4-{(4-(1-methylethyl )pi pe razin-1-yl]methyl}phenyl)ethenyl]-4-[(4-methyl-1H-indol-5-yl) 505.3 5.9 min amino ridine-3-carbonitrile (M+H) [A]
6-methyl-5-[(E)-2-{4-[(4-methyl-1,4-diazepan-1-yl) methyl]phenyl}ethenyl]-4-[(4-methyl-1 H-indol-5-yl) 491.3 4.3 min amino ridine-3-carbonitrile (M+H) A
5-[(E)-2-(3-{[(3-ethoxypropyl)amino]methyl}phenyl) ethenyl]-4-[(4-methyl-1H-indol-5-yl)amino]pyridine-3- 466.3 6.7min carbonitrile (M+H) [A]
5-[(E)-2-(3-{[(2-ethoxyethyl)amino]methyl}phenyl) 452.3 6.4min ethen I -4- 4-meth l-1H-indol-5- amino ridine-3- (M+H) [A]

carbonitrile 5-[(E)-2-{3-[(dimethylamino)methyl]phenyl}ethenyl]-4- 408.1 6.2min 4-meth -IH-indol-5- I amino ridine-3-carbonitnle (M+2H) [A]
5-[(E)-2-(3-{[(2-azepan-1-ylethyl)amino]methyl}phenyl) ethenyl]-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3- 505.2 6.1 min carbonitrile (M+H) [A]
5-[(E)-2-(3-{[(3-ethoxypropyl)amino]methyl}phenyl) ethenyl]-6-methyl-4-[(4-methyl-1 H-indol-5- 480.2 6.9min I amino ridine-3-carbonitrile (M+H) A
5-[(E)-2-(4-{[(2-azepan-1-ylethyl)amino]methyl}phenyl) ethenyl]-6-methyl-4-[(4-methyl-1H-indol-5-yl)amino] 519.4 5.4 pyridine-3-carbonitrile (M+H) [A]
6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[4-({[2-(2-methylpyrrolidin-1-yl)ethyl]amino}methyl) 505.3 4.9min hen I ethen ridine-3-carbonitrile (M+H) [A]
6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[3-({[3-(4-methylpiperazin-1-yl)propyl]amino}methyl) 534.6 5.1 min hen I ethen ridine-3-carbonitrile (M+H) [A]
6-methyl-4-[(4-methyl-1 H-indol-5-yl )amino]-5-[(E)-2-{4-[(4-morpholin-4-ylpiperidin-1-yl)methyl]phenyl) 534.6 6.0min ethen I ridine-3-carbonitrile (M+H) [A]
(E)-4-(4-methyl-I H-indol-5-ylamino)-5-(3-[(2- 491.3 i(pipeddin-1-yl)ethylamino)methyllstMI)nicotinonitdle (M+H) 5.1 min [A]

i N
F ~ I J

[00586] Preparation of 4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-(5-[2-(4-methyl piperazin-1-yl)ethoxy]pyridin-3-yl}ethenyl]pyridine-3-carbonitrile:
A DMF (5 ml) solution of 4-[(4-methyl-1H-indol-5-yl)amino]-5-vinylnicotinonitrile (50 mg, 0.5 mmol), 1-{2-[(5-bromopyridin-3-yl)oxy]ethyl}-4-methyl-piperazine (173 mg, 0.6 mmol), Pd(OAc)2 (23 mg, 0.01 mmol), P(o-tolyl)3 and Et3N(5 ml) was heated at 115 C
overnight. The reaction mixture was cooled to room temperature, diluted with saturated NaHCO3 and extracted with ethyl acetate. The organic layer was washed with brine and concentrated in vacuo. The residue was purified by preparative HPLC to afford 50 mg (21%) of the title compound as a yellow solid. MS: (M+H) 494.3, HPLC: rt = 4.9 min [a].

NH
\ - HN \
N
[00587] Preparation of 6-methyl-4-[(4-methyl-1 H-indoi-5-yl)amino]-5-[(E)-2-{5-[2-(4-methylpiperazin-1-yl)ethoxy]pyridin-3-yl}ethenyl]pyridine-3-carbonitrile:

The title compound was prepared from 1-{2-[(5-bromopyridin-3-yl)oxy]ethyl}-4-methyl-piperazine and 6-methyl-4-(4-methyl-1H-indol-5-ylamino}5-vinyl-nicotinonitrile via' the procedure used to prepare 4-[(4-methyl-l H-indol-5-yl)amino]-5-[(E)-2-{5-[2-(4-methylpiperazin-1-yl)ethoxy]pyridin-3-yl)ethenyl]pyridine-3-carbonitrile to afford 48 mg(18%) of the title compound as a yellow solid. MS: (M+H) 508.4. HPLC: 92.5% at 215 nm, rt = 4.1 min [a].

NH
F

[00588] Preparation of 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-((E)-2.[5.(2-pyrrolidin-1 ylethoxy)pyridin-3-yl]ethenyl}pyridine-3-carbonitrile:

The title compound was prepared from 3-bromo-5-(2-pyrrolidin-1-yl-ethoxy)pyridine and 6-methyl-4-(4-methyl-1H-indol-5-ylamino)-5-vinyl-nicotinonitrile via the procedure used to prepare 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{5-[2-(4-methylpiperazin-1-yl)ethoxy]pyridin-3-yI}ethenyl]pyridine-3-carbonitrile to afford 31 mg (12%) of the title compound as a yellow solid. MS: (M+H) 479.4. HPLC: rt = 4.9 min [a].

t3I
N
~ IA

[00589] Preparation of 5-[(E)-2-{5-[3-(dimethylamino)propoxy]pyridin-3-yl}ethenyl]-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile:

The title compound was prepared from 3-[(5-bromopyridin-3-yl)oxy]-N,N-dimethylpropan-l-amine and 6-methyl-4-(4-methyl-1H-indol-5-ylamino)-5-vinyl-nicotinonitrile via the procedure used to prepare 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{5-[2-(4-methylpiperazin-1-yl)ethoxy]pyridin-3-yl}ethenyl]pyridine-3-carbonitrile to afford 31 mg (12%) of the title compound as a yellow solid. MS: (M+H) 453.3. HPLC: rt = 4.7 min [a].

N
01\1 F

[00590] Preparation of 5-((E)-2-[5-(2-azepan-1-ylethoxy)pyridin-3-yl]ethenyl}-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile:

The title compound was prepared from 1-{2-[(5-bromopyridin-3-yl)oxy]ethyl}azepane and 6-methyl-4-(4-methyl-1H-indol-5-ylamino)-5-vinyl-nicotinonitrile via the procedure used to prepare 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{5-[2-(4-methylpiperazin-l-yl)ethoxy]pyridin-3-yl}ethenyl]pyridine-3-carbonitrile to afford 31 mg(12%) of the title compound as a yellow solid. MS: (M+H) 493.4. HPLC: rt = 6.1 min [a].

NH
\ ^ ^ /N

[00591] Preparation of 4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[5-(3-piperidin-1-yl propoxy) pyridin-3-yl]ethenyl}pyridine-3-carbonitrile:

The title compound was prepared from 3-bromo-5-(3-piperidin-1-ylpropoxy)pyridine and 6-methyl-4-(4-methyl-1H-indol-5-ylamino)-5-vinyl-nicotinonitrile via the procedure used to prepare 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{5-[2-(4-methylpiperazin-1-yl)ethoxy]pyridin-3-yl}ethenyl]pyridine-3-carbonitrile to afford 45 mg(18%) of the title compound as a yellow solid. MS: (M+H) 493.4. HPLC: rt = 4.8 min [a].

N
S` HN
N-N
J

N
[00592] Preparation of 6-Methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-(4-{[(4-methyl piperazin-1- yl)sulfonyl]methyl}phenyl)ethenyl]pyridine-3-carbonitrile:

The procedure for the preparation of 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[4-(pyrrolidin-1-ylsulfonyl)phenyl]ethenyl}pyridine-3-carbonitrile was followed using 1-[(4-bromobenzyl)sulfonyl]-4-methylpiperazine. The title compound (19 mg, 23%) was purified by preparative HPLC. MS 541.6 (M+H); HPLC: rt = 6.2 min [a].

N
N ~*' N SO ' HN
Oi / I \
N

[00593] Preparation of 6-Methyl-4-[(4-methyl-lH-indol-5-yl)amino]-5-[(E)-2-(3-([(4-methyl piperazin-1 - yl)sulfonyl]methyl}phenyl)ethenyl]pyridine-3-carbonitrile:

The procedure for the preparation of 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[4-(pyrrolidin-1-ylsulfonyl)phenyl]ethenyl}pyridine-3-carbonitrile was followed using 1-[(3-bromobenzyl)sulfonyl]-4-methylpiperazine. The title compound (25 mg, 31%) was purified by preparative HPLC. MS 541.6 (M+H); HPLC: rt = 6.4 min [a].

NH
ONOS '( HN \
~N
/ I \

N
[00594] Preparation of 6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-{4-[piperidin-1-ylsulfonyl]phenyl}ethenyl]pyridine-3-carbonitrile:

The procedure for the preparation of 6-methyl-4-[(4-methyl-lH-indol-5-yl)amino]-5-{(E)-2-[4-(pyrrolidin-1-ylsulfonyl)phenyl]ethenyl}pyridine-3-carbonitrile was followed using 1-[(4-bromophenyl)sulfonyl]piperidine. The title compound (24 mg, 31%) was purified by preparative HPLC eluting with CH3CN (containing 0.01% NH4OH)/water (containing 0.01%
NH4OH). MS 512.6 (M+H); HPLC: rt = 10.7 min [a].

o / I NH
OS I HN
N
N

[00595] Preparation of 6-Methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[4-(N,N-dimethylbenzenesulfonyl)phenyl]ethenyl}pyridine-3-carbonitrile:
The procedure for the preparation of 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[4-(pyrrolidin-1-ylsulfonyl)phenyl]ethenyl}pyridine-3-carbonitrile was followed using 4-bromo-N,N-dimethylbenzenesulfonamide. The title compound (20 mg, 28%) was purified by preparative HPLC. MS 472.5 (M+H); HPLC: rt = 9.2 min [a].

NH
f OS HN
N
N

[00596] Preparation of 6-Methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[4-(N,N-diethylbenzenesulfonyl)phenyl]ethenyl}pyridine-3-carbonitrile:
The procedure for the preparation of 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[4-(pyrrolidin-1-ylsulfonyl)phenyl]ethenyl}pyridine-3-carbonitrile was followed using 4-bromo-N,N-diethylbenzenesulfonamide. The title compound (41 mg, 55%) was purified by preparative HPLC. MS 500.6 (M+H); HPLC: rt = 10.5 min [a].

~6H
I HN
N CN
N
[00597] Preparation of (E)-5-[2-(6-formylpyridin-2-yl)vinyl]-4-(4-methyl-1 H-indol-5-yl amino)nicotinonitrile:

A mixture of 5-{(E)-2-[6-(hydroxymethyl)pyridin-2-yl]vinyl)-4-[(4-methyl-1 H-indol-5-I)amino]nicotinonitrile (38 mg, 0.1 mmol) and Dess-Martin periodinane (52 mg, 0.12 mmol) in CH2CI2 (1.0 ml-) was stirred overnight at room temperature, concentrated. The residue was purified by preparative HPLC providing 14 mg (37%) of the title compound as a yellow solid.
'HNMR(300 MHz, DMSO) 0 2.33 (s, 3H), 6.50 (s, 1 H), 6.94 (d, 1 H, J = 6.9 Hz), 7.24 (d, 1 H, J
= 6.6 Hz), 7.35 (m, 2H), 7.80 (d, 1 H, J = 6.0 Hz),- 7.88 (d, 1 H, J = 12 Hz), 8.02 (m, 2H), 8.33 (s, 1 H); 8.65 (s, 1 H), 8.97 (s, 1 H); 9.96 (s, 1 H), 11.14 (s, 1 H); MS 380.1 (M+H).

~NH
/=N H, NI
N~ N / \ N
N

[00598] Preparation of 4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-(1H-1,2,4-triazol-1- yl) vinyl]nicotinonitrile:

The procedure for 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-pyrazin-2-ylvinyl]nicotinonitrile was followed using 1-vinyl-1,2,4-triazole. The crude residue was purified by HPLC to provide 6.4 mg (6%) of the title compound as a tan solid. MS 342.2 (M+H); HPLC: rt =
6.1 min [a].

I
o [00599] Preparation of 4-[(4-methyl-1 h-indol-5-yl)amino]-5-[(e)-2-(4{[4-(methylsulfonyl) piperazin-l- yl]methyl}phenyl)ethenyl]pyridine-3-carbonitrile:

To a 0 C mixture of 5-[(E)-2-(4-formylphenyl)ethenyl]-4-[(4-methyl-1 H-indol-5-yl)amino]
pyridine-3-carbonitrile (100 mg, 0.26 mmol) and 1-methylsulfonylpiperazine (100 mg, 0.61 mmol) in 4 mL of dichloromethane and 1 mL of 1-methyl-2-pyrrolidinone was added sodium triacetoxyborohydride (320 mg, 1.51 mmol). After stirring at 0 C for 10 min, 2 drops of acetic acid were added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between aqueous sodium bicarbonate and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography eluting with a gradient of 1:1 hexane:ethyl acetate to ethyl acetate to 10% methanol in ethyl acetate. The fractions containing the desired product were combined, concentrated in vacuo and the residue triturated with diethyl ether to provide 64 mg (47%) of 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(4-{[4-(methylsulfonyl)piperazin-1-yl]methyl}phenyl)ethenyl]pyridine-3-carbonitrile as a pale yellow solid, MS 527.3 (M+H), HPLC: rt = 6.5 min [a].

NH
HN
r'NCN
"NJ IN

[00600] Preparation of 4-[(4-methyl-lH-indol-5-yl)amino]-5-[(4-methylpiperazin-1-yl) methyl]pyridine-3-carbonitrile:

A mixture of 5-iodo-4-[(4-methyl-1 H-indol-5-yl)amino]nicotinonitrile (374.2 mg, 1.0 mmol), potassium 1-methyl-4-trifluoroboratomethylpiperazine (242.1 mg, 1.1 mmol), Pd(OAc)2 (11.2 mg, 0.05 mmol), XPhos (47.76 mg, 0.1 mmol) and cesium carbonate (1.14 g, 3.5 mmol) in 4.0 mL of THE/H20 (10:1) was heated at 80 C for 24 h. Additional potassium 1-methyl-4-trifluoroboratomethylpiperazine (242.1 mg, 1.1 mmol), Pd(OAc)2 (11.2 mg, 0.05 mmol) and XPhos (47.76 mg, 0.1 mmol) were added. The resulting mixture was headed at 80 C for an.
additional 18 h, then cooled to room temperature and partitioned between dichloromethane and water. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography, eluting with a gradient of 5% methanol in dichloromethane to 20% methanol in dichloromethane.
Repurification by preparative HPLC (NH3 condition) provided 15.2 mg (4%) of 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(4-methylpiperazin-1-yl)methyl]pyridine-3-carbonitrile as a white solid, MS
(ESI) m/z 361.3; HPLC: rt = 3.6 min [a].

I H

[00601] Preparation of 4-[(4-methyl-1H-indol-5-yl)amino]-5-((E)-2-[2-(pyrrolidin-1-yl methyl)-1,3-thiazol-4-yl]ethenyl}pyridine-3-carbonitrile:
A solution of 5-{(E)-2-[2-(hydroxymethyl)-1,3-thiazol-4-yl]ethenyl}-4-[(4-methyl-lH-indol-5-yl)amino]pyridine-3-carbonitrile (100 mg, 0.26 mmol) in 1.5 ml- of DMF was cooled to -30 C, then triethylamine (52.6 mg, 72.2 NL, 0.52 mmol) followed by mesyl chloride (35.5 mg, 24 NL, 0.31 mmol) was added dropwise. The resulting mixture was warmed to 0 C slowly over 60 min. Water (7.5 ml-) was added and extracted with dichloromethane. The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to give the mesylate intermediate. To the crude compound was added 1 mL of DMF, triethylamine (52.6 mg, 72.2 pL, 0.52 mL) and pyrrolidine (37 'mg, 43 pL, 0.52 mmol), the mixture was stirred at room temperature for 3 h then concentrated in vacuo. The residue was purified by preparative HPLC (TFA condition) to provide 39 mg (34%) of 4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[2-(pyrrolidin-1-ylmethyl)-1,3-thiazol-4-yl]ethenyl}pyridine-3-carbonitrile as a deep yellow solid, MS (ESI) m/z 441.2; HPLC: rt = 5.2 min [a].

N

[00602] Preparation of (E)-4-(4-methyl-1 H-indol-5-ylamino)-5-{2-[2-(piperidin-1-yl methyl)thiazol-4-yl]vinyl}nicotinonitrile:
The title compound was prepared according to the procedure described for 4-[(4-methyl-lH-indol-5-yl)amino]-5-{(E)-2-[2-(pynrolidin-1-ylmethyl)-1,3-thiazol-4-yl]ethenyl}pyridine-3-carbonitrile. MS (ESI) mlz 455.2; HPLC: rt = 5.3 min [a].

PKCe IMAP ASSAY

[00603] The materials used include the following: human PKCB full length enzyme (Panvera Cat# P2996); substrate peptide: 5FAM-RFARKGSLRQKNV-OH (Molecular Devices, RP7032);
ATP (Sigma Cat # A2383); DTT (Pierce, 20291); 5x kinase reaction buffer (Molecular Devices, R7209); 5x binding buffer A (Molecular Devices, R7282), 5x binding buffer B
(Molecular Devices, R7209); IMAP Beads (Molecular Devices, R7284); and 384-well plates (Corning Costar, 3710).

[00604] The reaction buffer was prepared by diluting the 5x stock reaction buffer and adding DTT to obtain a concentration of 3.0 mM. The binding buffer was prepared by diluting the 5x binding buffer A. A master mix solution was prepared using a 90% dilution of the reaction buffer containing 2x ATP (12 uM) and 2x peptide (200 nm). Compounds were diluted in DMSO to 20x of the maximum concentration for the IC50 measurement. 27 pl of the master mix solution for each IC50 curve was added to the first column in a 384-well plate and 3 pl of 20x compound in DMSO was added to each well. The final concentration of compound was 2x and 10% DMSO. DMSO was added to the rest of the master mix to increase the concentration to 10%. 10 pl of the master mix containing 10% DMSO was added to the rest of the wells on the plate except the 2nd column. 20 pl was transferred from the first column to the 2nd column. The compounds were serially diluted in 2:1 ratio starting from the 2nd column. A 2x (2 nM) PKCO solution was made in the reaction buffer. 10 pI of the PKCB
solution was added to every well to achieve these final concentrations: PKCB -1 nM; ATP - 6 NM; peptide - 100 nM; DMSO - 5%. Samples were incubated for 25 minutes at room temperature. The binding reagent was prepared by diluting the beads in 1x binding buffer to 800:1. 50 pI of the binding reagent was added to every well and incubated for 20 minutes. FP
was measured using Envision2100 (PerkinElmer Life Sciences). Wells with no ATP
and wells with no enzyme were used as controls.

[00605] The results obtained are summarized in the table below.
PKC Theta Compound Name Mean IC50 (nM) 4-[(4-methyl-1 H-indol-5-yl)aminoJ-5-{(1 E)-3-[(2-mo holin-4- eth I amino ro1-en-1- I nicotinonitrile 396.8 N-{1-[(3E)-4-{5-cyano-4-[(4-methyl-1 H-indol-5-yl)amino]
pyridin-3-yl}but-3-en-1 -yl]piperidin-4-yl}propane-2-sulfonamide 22.2 5-{(1 E)-4-[4-(isopropylsulfonyl)piperazin-1 -yl]but-1 -en-1-I - 4-meth -1H-indol-5- I amino nicotinonitrile 10.6 N-{ 1-[(3E)-4-{5-cyano-4-[(4-methyl-1 H-indol-5-yl)amino]
pyridin-3-yl}but-3-en-1-yl]piperid in-4-yl}ethane sulfonamide 21.8 N-{1-[(3E)-4-{5-cyano-4-[(4-methyl-1 H-indol-5-yl)amino]
pyridin-3-yl)but-3-en-1-yl]piperid in-4-yl}benzene sulfonamide 22.7 5-{(1 E)-4-[(3R)-3-aminopyrrolidin-1-yl]but-1-en-1 -yl}-4-4-meth l-1H-indol-5- I amino nicotinonitrile 3.5 (3E)-4-{5-cyano-4-[(4-methyl-1 H-indol-5-yl )amino]
pyridin-3-yl}but-3-en-1-yl (3R)-3-aminopyrrolidine-1-carboxlate 3.2 5-{(1 E)-4-[(3S)-3-aminopyrrolidin-1-yl]but-l-en-l-yl}-4-4-meth l-1H-indol-5- I amino nicotinonitrile 1.3 5-[(1 E)-4-(3-aminoazetidin-1-yl)but-l-en-1-yl]-4-[(4-meth l-1H-indol-5- amino nicotinonitrile 8.9 5-[(1 E)-4-(1,4-diazepan-1-yl)but-1 -en-1 -yl]-4-[(4-methyl-1H-indol-5- mino nicotinonitrile 3.6 5-{(1 E)-4-[4-(methylamino)piperidin-l -yl]but-1-en-1-yl}-4- 4-meth l-lH-indol-5- I amino nicotinonitrile 9.3 5-{(1 E)-4-[(3R)-3-aminopiperidin-1-yl]but-1 -en-l -yl)-4-4-meth -1H-indol-5- I amino nicotinonitrile 3.6 5-((1 E)-4-[(3S)-3-aminopiperidin-1-yl]but-1-en-1-yl}-4-4-meth l-1H-indol-5- amino nicotinonitrile 6.8 5-{(l E)-4-[4-(aminomethyl )piperidin-l -yl]but-1-en-1-yl)-4- 4-meth -1H-indol-5- I amino nicotinonitrile 5.7 5-[(1 E)-4-(2, 5-d iazabicyclo[2.2.1 ] hept-2-yl yl]-4-[(4-methyl-1 -4- 4-meth l-1H-indol-5-Iamino nicotinonitrile 3.8 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(1 E)-4-(4-phenyl i eridin-l- I but-l-en-1- I nicotinonitrile 19.2 5-{(1 E)-4-[4-(dimethylamino)piperidin-1 -yl]but-1 -en-1-I - 4-meth -1H-indol-5- I amino nicotinonitrile 4.9 5-[(1 E)-4-(4-hydroxypiperidin-1-yi)but-l-en-1-yl]-4-[(4-meth l-1H-indol-5- I amino nicotinonitrile 6 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(1 E)-4-(4-mor holin-4- i eridin-l- I but-l-en-1- I nicotinonitrile 50.7 1'-g tycyl-4-[(4-methyl-1 H-indol-5-yl)amino]-I',2',3',6'-tetrah dro-3,4'-bi ridine-5-carbonitrile 10.6 1'-(2-methylalanyl)-4-[(4-methyl-1 H-indol-5-yl)amino]-1',2' 3',6'-tetrah dro-3 4'-bi ridine-5-carbonitrile 32.9 1'-b-alanyl-4-[(4-methyl-1 H-indol-5-yl )amino]-1',2',3',6'-tetrah dro-3,4'-bi ridine-5-carbonitnle 23.5 4-[(4-methyl-1 H-indol-5-yl)amino]-1'-D-valyl-l',2',3',6'-tetrah dro-3,4'-bi ridine-5-carbonitrile 34 4-[(4-methyl-1 H-i n d o l-5-y l) a m i n o]-1'-L-v a lyl-1', 2' , 3', 6'-tetrah dro-3,4'-bi ridine-5-carbonitrile 23.2 4-[(4-methyl-1 H-indol-5-yl)amino]-1'-D-prolyl-l',2',3',6'-tetrah dro-3,4'-bi ridine-5-carbonitrile 32.9 4-[(4-methyl-1 H-indol-5-yl)amino]-1'-L-prolyl-l',2',3',6'-tetrah ro-3,4'-bi ridine-5-carbonitdle 23.7 4-[(4-methyl-1 H-indol-5-yl)amino]-1'-(pyrrolidin-3-yl carbonyl)-1 ',2',3',6'-tetrahydro-3,4'-bi pyrid ine-5-carbonitrile 22.4 5-{(1 E)-4-[(3R)-3-hydroxypiperidin-l -yl]but-l -en-1-yl}-4-4-meth -1H-indol-5- amino nicotinonitrile 71.3 5-((l E)-4-[ (3 S )-3-hydroxypiperidin -1-yl ]but-1-e n-I
-yl [(4-methyl-1 H-indol-5- I amino nicotinonitrile 116.5 5-[(E)-2-(4-formylphenyl)vinyl]-4-[(4-methyl-1 H-indol-5-lamino nicotinonitrile 58.2 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{4-[(4-methyl piperazin-1 - meth 1 hen Ivin I nicotinonitrile 3.6 5-[(E)-2-(4-fluorophenyl)vinyl]-4-[(4-methyl-1 H-indol-5-I amino nicotinonitrile 23.9 4-[(2,4-dimethyl-1 H-indol-5-yl)amino]-5-[(E)-2-{5-[(4-methylpiperazin-1 -yl)methyl] pyridin-2-yl}vinyl]
nicotinonitrile 24.1 5-benz l-4- 4-meth l-1H-indol-5- I amino nicotinonitrile 49.5 6-ethyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-hen Ivin I nicotinonitrile 1,368.5 6-isopropyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-hen Ivin I nicotinonitrile 19,414.6 5-{(E)-2-[2-methoxy-4-(pi perazin-1-ylmethyl )phenyl vin I - 4-meth -lH-indol-5-Iamino nicotinonitrile 0.5 6-methyl-4-[(4-methyl-1 H! indol-5-yl)amino]-5-{(E)-2-[4-2- rrolidin-1- lethox hen vin I nicotinonitrile 56.5 5-(2-{2-methoxy-4-[(4-methylpiperazin- l-yl)methyl]
phenyl}ethyl)-4-[(4-methyl-1 H-i ndol-5-yl )amino]
nicotinonitrile 24.8 4-[(4-methyl-1 H-indol-5-yl)amino]-5-(2-{4-[(4-methyl i erazin-1- I carbon I hen I ethnicotinonitrle 20.1 4-[(4-methyl-1 H-indol-5-yl)oxy]-5-[(E)-2-phenylvinyl]
nicotinonitrile 10,543 4-[(E)-2-{5-cyano-4-[(4-methyl-1 H-indol-5-yl)amino]
ridin-3- l vin I -N-hen i eridine-l-carboxamide 3.8 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[1-(phenyl sulfon i eridin-4- I vin I nicotinonitrle 25.8 5-[(E)-2-(1-benzoylpipendin-4-yl)vinyl]-4-[(4-methyl-1 H -indol-5- Iamino nicotinonitrile 2.4 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[1-(3-phenyl propanoyl)pipeHdin-4-yllvinyl)nicotinonitHle 33.1 4-[(E)-2-(5-cyano-4-[(4-methyl-1 H-indol-5-yl)amino]
ridin-3- I vin I -N- ro I i endine-1-carboxamide 5.7 5-{(E)-2-[1-(isopropylsulfonyl)piperidin-4-yljvinyl}-4-[(4-meth l-1H-indol-5- amino nicotinonitrile 7.2 5-{(E)-2-[4-(dimethyla mino)phenyl]vinyl}-4-[(4-methyl-1H-indol-5- amino nicotinonitrile 24.1 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{6-[(2-piperidin-1-ylethyl)amino]pyridin-3-yl}ethenyl]pyridine-3-carbonitrile 16.8 5-{(E)-2-[5-(([3-(d i m et h yl a m i n o) p ro p yl ] a m i n o}m e t h y l) pyridin-2-yl)ethenyl}-4-[(4-methyl-1 H-indol-5-yl) amino ridine-3-carbonitrile 4.7 5-[(E)-2-(6-{[(3-ethoxypro pyl )a mi no]methyl}pyndi n-2-yl)ethenyl]-4-[(4-methyl-1 H-indol-5-yl)amino]pyddine-3-carbonitrile NA
4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(5-{[(2-pyridin-3-ylethyl)amino]methyl}pyridin-2-yl)ethenyl]
pyridine-3-carbonitrile 6.3 5-[(E)-2-(3-{[4-(1-methylethyl)piperazin-1-yl]methyl}
phenyl)ethenylj-4-[(4-methyl-1 H-indol-5-yl)aminol pyridine-3-carbonitrile 5.5 4-[(4-methyl-1 H-indol-5-yl)aminoj-5-{(E)-2-[3-(morpholin-4-ylmethyl)phenyl]ethenyl}pyridine-3-carbonitrile 1.2 4-[(4-methyl-1 H-indol-5-yl)aminoj-5-[(E)-2-(3-{[(2-morpholin-4-ylethyl)amino]methyl} phenyl)ethenyl]
p ridine-3-carbonitnle 3.9 5-[(E)-2-(3-{[4-(dimethylamino)piperid in-l -yl]methyl}
phenyl)ethenyl]-4-[(4-methyl-1 H-indol-5-yl)amino]
pyridine-3-carbonitrile 1.5 5-[(E)-2-{3-[(4-methyl-1,4-diazepan-1-yl )methyl] phen yl}
ethenyl]-4-[(4-methyl-1f -indol-5-yl)amino]pyridine-3-carbonitrile 2.3 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[3-({[2-(1-methyl pyrrol idin-2-yl)ethyl]amino}methyl)phenylj ethen 1 ridine-3-carbonitrile 0.6 5-{(E)-2-[3-({[2-(dimethylamino)ethyl]amino}methyl) phenylJethenyl}-4-[(4-methyl-1 H-indol-5-yl)amino]
ridine-3-carbonitrile 2.7 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[3-({[3-(2-oxopyrrolidin-1-yl)propyl]amino}methyl) phenyl]ethenyl) pyridine-3-carbonitnle 6.7 5-[(E)-2-(3{[(2-methoxyethyl)amino]methyl}phenyl ) ethenyl]-4-[(4-methyl-lH-indol-5-yl)amino] pyridine-3-carbonitrile 4.9 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[3-(piperidin-1-yimethyl)phenyl]ethenyl}pyridine-3-carbonitrile 24.2 5-{(E)-2-[3-(1,4'-bipiperidin-l'-ylmethyl)phenyl]ethenyl}-6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile 6.8 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{3-[(4-pyrrolidin-1-ylpiperidin-1-yl)methyl]phenyl}ethenyl]
pyridine-3-carbonitnle 36 5-[(E)-2-(3-{[4-(2-hyd roxyethyl )p i perazi n-1-yl]methyl}
phenyl )ethenyl]-6-methyl-4-[(4-methyl-1 H-indol-5-Iamino 'dine-3-carbonitdle 8.4 5-[(E)-2-(3-{[4-(dimethylamino)piperidin-1-yi]methyl}
phenyl)ethenyt]-6-methyl-4-[(4-methyl-1 H-indol-5-lamino ridine-3-carbonitrile 4 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{3-[(4-morpholin-4-yl piperidin-1-yi )methyl]phenyl}ethenyl]
ridine-3-carbonitnle 15.8 6-methyl-5-[(E)-2-{3-[(4-methyl-1,4-diazepan-1-yl) methyl]phenyl}ethenyl]-4-[(4-methyl-1/ -indol-5-yl) amino idine-3-carbonitrile 5.8 5-{(E)-2-[3-({[3-(dimethylamino)propyl]amino}methyl ) phenyl]ethenyl}-6-methyl-4-[(4-methyl-1 H-indol-5-lamino ridine-3-carbonitnle 2.4 5-{(E)-2-[3-({[2-(dimethylamino)ethyl]amino}methyl) phenyl]ethenyl}-6-methyl-4-[(4-methyl-1 H-indol-5-lamino ridine-3-carbonitnle 4.4 6-methyl-5-[(E)-2-{5-[(4-methyl-1,4-diazepan-1-yl) methyl]pyridin-2-yl}vinylJ-4-[(4-methyl-1 H-indol-5-yl) amino nicotinonitrile 15 5-{(E)-2-[5-({[3-(dimethylamino)propyl]amino}methyl ) pyridin-2-yljvinyl)-6-methyl-4-[(4-methyl-1 H-indol-5-yl) amino nicotinonitrile 4.8 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[5-({[2-(1-meth yl pyrrol id i n-2-yl)ethyl jam ino}methyl )pyrid i n-2- I vin I nicotinonitrile 9.9 5-[(E)-2-(5-{[(2-azepan-1-ylethyl)amino]methyl}pynd i n-2-yl)vinyl]-6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]
nicotinonitrile 15 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(5-{[(2-pyridin-2-ylethyl )amino]methyl}pyndi n-2-yl)vinyl]
nicotinonitrile 14.5 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(5-. {[(2-pyndin-4-ylethyl)amino]methyl}pyridin-2-yl)vinyl) nicotinonitrile 8.8 4-[(4-methyl-1 H-indol-5-yl)aminoj-1'-[(1-methylpiperidin-4-yl)methyl]-1',2',3',6'-tetrahydro-3,4'-bipyridine-5-carbonitrile 22.3 6-methyl-4-[(4-methyl-1 H-indol-5-yl)aminoj-5-[(E)-2-(3-{[(3-morpholin-4-ylpropyl)amino] methyl}
hen I vin I nicotinonitrile 10.4 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(3-{[(2-pyrrolidin-1-ylethyl)amino]methyl}phenyl) ethen ridine-3-carbonitrile 4.4 5-[(E -2-{3-[(dimethylamino)methyl]phenyl}ethenyl]-6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile 23 5-[(E)-2-{3-[(3-hydroxypyrrolidin-1-yl)methyl]phenyl}
ethenyl]-6-methyl-4-[(4-methyl-1 H-indol-5-yl )amino]
ridine-3-carbonitnle 10.2 6-ethyl-4-[(4-methyl-l H-indol-5-yl)amino]-5-(2-phenyl ethI ridine-3-carbonitrile NA
4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(4-methyl piperazin-1 - meth I ridine-3-carbonitrile NA
5-(3,4-dimethoxybenzyl)-4-(1 H-indol-5-ylamino) nicotinonitrile 671.1 5-(3,4-dimethoxybenzyl)-4-(1 H-indol-4-ylamino) nicotinonitrile 580.5 4-[(4-methyl-1 H-indol-5-yl)aminoj-5-[(E)-2-phenylvinylj nicotinonitrile 10.7 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(1 E)-3-pyrrolidin-1-I ro 1-en-1- I nicotinonitrile 151.1 4-[(4-methyl-1 H-indol-5-yl)aminoj-5-[(1 E)-3-(4-phenyl piperazin-1 - I ro -1-en-1- I nicotinonitrile 113.5 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(1 E)-3-(4-methyl i erazin-1- I ro-1-en-1- I nicotinonitrile 31.1 tent butyl 5-cyano-4-[(4-methyl-lH-indol-5-yl)amino]-3',6'-dih dro-3,4'-bi ndine-1' 2' rbox ate 42.5 4-[(4-methyl-1 H-indol-5-yl)ami no]-5-[(1 E)-3-morphol i n-4- I ro 1-en-1- nicotinonitrile 50.6 5-[(1 E)-3-(3,4-dihydroisoquinolin-2(1 H)yl)prop-l-en-1-I -4- 4-meth l-1H-indol-5- I amino nicotinonitrile 35 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(l E)-4-(4-methyl i erazin-l- but-1-en-1- I nicotinonitrile 2.2 5-[(i E)-3-aminoprop-l-en-1-yl]-4-[(4-methyl-1 H-indol-5-lamino nicotinonitrile 8.5 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(1 E)-4-(4-phenyl i erazin-1- but-l-en-1- I nicotinonitrile 67.7 5-[(1 E)-buta-1,3-dien-l-yl]-4-[(4-methyl-1 H-indol-5-yl) amino nicotinonitrile 19.6 (3E)-4-{5-cyano-4-[(4-methyl-1 H-indol-5-yl )amino]
ridin-3- I but-3-en-1- l indoline-1-carbo late 5.2 (3E)-4-{5-cyano-4-[(4-methyl-1 H-indol-5-yl)amino]
pyridin-3-y1}but-3-en-l-yl thiomorpholine-4-carboxylate 1,1-dioxide 30.7 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(l E)-4-morpholin-4- lbut-1-en-1- 1 nicotinonitrile 16.2 (3E)-4-(5-cyano-4-[(4-methyl-1 H-indol-5-yl)amino]
ridin-3- I but-3-en-1- l mo holine-4-carbox late 7.6 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(1 E)-4-pyrrolidin-1 -Ibut-l-en-1- (nicotinonitrile 28.7 tent-butyl {1-[(2E)-3-(5-cyano-4-[(4-methyl-1H-indol-5-yl)amino]pyddin-3-yl}prop-2-en-1 yl]piperidin-4-yl}
carbamate 244.3 tert-butyl 4-[(2E)-3-{5-cyano-4-[(4-methyl-1 H-indol-5-yl)amino]pyridin-3-yl}prop-2-en-1-yl]piperazine-1-carbo late 181.5 5-[(1 E)-3-(4-aminopiperidin-1-yl)prop-1-en-1-yl]-4-[(4-meth l-1H-indol-5- I amino nicotinonitri le 3.6 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(1 ylprop-1 ro 1-en-1- nicotinonitrile 12.4 4-[(4-methyl-1 H-indol-5-yl)amino]-1',2',3',6'-tetrahydro-3 4'-bi ridine-5-carbonitrile 143.2 4-[(4-methyl-1 H-indol-5-yl)amino]-1'-(methylsulfonyl) 1',2',3',6'-tetrah ro-3,4'-bi ridine-5-carbonitrile 9.3 4-[(4-methyl-1 H-indol-5-yl)amino]-1'-(phenylsulfonyl)-1',2',3',6'-tetrah dro-3,4'-bi ridine-5-carbonitrile 6.4 1'-acetyl-4-[(4-methyl-1 H-i ndol-5-yl)amino]-1',2',3',6'-tetrah dro-3,4'-bi ridine-5-carbonitrile 49.5 5-cyano-N-ethyl-4-[(4-methyl-1 H-indol-5-yl)amino]-3',6'-dih dro-3,4'-bi ridine-l' 2' -carboxamide 54.3 4-[(4-methyl-1 H-indol-5-yl)amino]-l'-[(1-methylpiperidin-4-yl)carbonyl]-1',2',3',6'-tetrahydro-3,4'-bipyridine-5-carbonitrile 45.1 1'-benzyl-4-[(4-methyl-1 H-indol-5-yl)amino]-1',2',3',6'-tetrah dro-3,4'-bi ridine-5-carbonitrile 6.4 ethyl 5-cyano-4-[(4-methyl-1 H-indol-5-yl)amino]-3',6'-dih dro-3 4'-bi ridine-1' 2' -carbo late 19.5 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(1 E)-4-piperidin-1-lbut-1-en-1- I nicotinonitrile 35.2 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(1 E)-4-thiomo holin-4- lbut-1-en-I- I nicotinonitnle 13.6 5-[(1 E)-4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)but-1-en-1- I -4- 4-meth l-1H-indol-5- I amino nicotinonitrile 6.3 1'-methyl-4-[(4-methyl-1 H-indol-5-yl )amino]-1',2',3',6'-tetrah dro-3,4'-bi ridine-5-carbonitnle 253.4 5-[(1 E)-4-(4-acetyl pi perazi n-1-yl )but-1 -en-1 -yl]-4-[(4-meth l-1H-indol-5- amino nicotinonitrile 37.8 4-[(4-methyl-1 H-i ndol-5-yl )amino]-5-{(1 E)-4-[4-(methyl sulfon i erazin-1- I but-l-en-1- I nicotinonitrile 12 tent butyl 4-[(3E)-4-{5-cyano-4-[(4-methyl-lH? indol-5-yl)amino]pyridin-3-yl}but-3-en-1-yl] piperazine-l -carboxlate 34.7 tert-butyl {1-[(3E)-4-(5-cyano-4-[(4-methyl-1 H-indol-5-yl) amino]pyridin-3-yl}but-3-en-1-yl]pipeddin-4-yl) carbamate 21.5 4-[(4-methyl-1 H:indol-5-yl)amino]-5-[(1 E)-5-(4-methyl piperazin-1-yi)pent-l-en-1-yllnicotinonitdle 6.4 4-[(4-methyl-1 H-indol-5-yl)amino)-5-[(1 E)-5-morpholin-4- I ent-1-en-1- I nicotinonitrile 34.2 (4E)-5-{5-cyano-4-[(4-methyl-1 H-indol-5-yl )amino]
ridin-3- ent-4-en-1- l mo holine-4-carbox late 21.3 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(1 E)-5-pyrrolidin-l-I ent-l-en-1- I nicotinonitrile 14.9 5-[(1 E)-4-aminobut-l-en-1-yl]-4-[(4-methyl-1 H-indol-5-I amino nicotinonitrile 5 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[3-(4-methyl piperazin-1 - ronicotinonitrile 63.7 4-[(4-methyl-1 H-indol-5-yl)aminoj-5-[4-(4-methyl piperazin-1 - I bu I nicotinonitrile 26.9 5-[(1 E)-4-(4-aminopi peridin-1-yl)but-1-en-l -yl]-4-[(4-meth l-1H-indol-5- amino nicotinonitrile 0.9 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(1 E)-4-piperazin-1-Ibut-l-en-1- I nicotinonitrile 4 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(1 E)-4-[(2-mor holin-4- eth Iamino but-1-en-1- I nicotinonitrile 45.7 5-[(E)-2-{5-[(d imethylamino)methyl]pyridin-2-yl}vinyl]-4-4-meth l-1H-indol-5- I amino nicotinonitnle 8 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{5-[(4-methyl piperazin-I - I meth I ndin-2- I vin I nicotinonitrile 1.9 5-{(1 E)-4-[4-(ethylsulfonyl)piperazin-1-yl)but-1 -en-1 -yl)-4- 4-meth -1H-indol-5- I amino nicotinonitrile 12.1 4-[(4-methyl-1 H-indol-5-yl)aminoj-5-{(1 E)-4-[4-(phenyl sulfon I i erazin-l- I but-l-en-1- I nicotinonitrile 50.7 5-{(1 E)-4-[4-(2,2-dimethylpropanoyl)piperazin-1-yl]but-1-en-1-yl}-4-[(4-methyl-1 Hindol-5-yl)amino]
nicotinonitrile 51.3 N-{1 -[(3E)-4-{5-cyano-4-[(4-methyl-1 H-indol-5-yl)amino]
pyridin-3-yl)b u t-3-e n- l -yl] pi pe ri d i n-4-yl}m etha n e sulfonamide 16.4 N-{1-[(3E)-4-{5-cyano-4-[(4-methyl-1 Hindol-5-yl)amino]
ridin-3- I but-3-en-1- I i eridin-4- I acetamide 30.9 5-[(1 E)-4-(isopropylamino)but-l-en-l-yl]-4-[(4-methyl-1H-indol-5- mind nicotinonitrile 104.8 5-[(1 E)-4-(cyclohexylamino)but-l-en-1-yl]-4-[(4-methyl-1H-indol-5- amino nicotinonitrile 56.3 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(1 E)-4-(piperidin-4-lamino but-1-en-1- nicotinonitrile 10.1 4-[(4-methyl-1 H-indol-5-yl)amino]-1'-(piperidin-4-yl carbonyl)-l',7,3',6'-tetrahydro-3,4'-bipyridine-5-carbonitrile 12 tert-butyl 4-[(3E)-4-{5-cyano-2-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]pyridi n-3-yl}but-3-en-1-yl]pi perazine-1-carboxlate 443.9 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(1 E)-5-piperidin-1-I ent-1-en-1- (nicotinonitrile 18.7 tent butyl 4-[(4E)-5-(5-cyano-4-[(4-methyl-1 Hindol-5-yl) amino]pyridin-3-yl}pent-4-en-1-yl]piperazi ne-1-carboxlate 203.4 tent butyl {1-[(4E)-5-{5-cyano-4-[(4-methyl-1H-indol-5-yl)amino]pyridi n-3-yl}pent-4-en-1-yl]piperidin-4-yl}
carbamate 24.7 tent butyl {1-[(3E)-4-{5-cyano-2-methyl-4-[(4-methyl-1H-indol-5-yl)ami no] pyrid i n-3-yl}but-3-en-1-yl]pi peridi n-4-I carbamate 170.6 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(1 ylprop-1 ro1-en-1- nicotinonitrile 189.1 6-methyl-4-[(4-methyl-1 14indol-5-yl)amino]-5-[(1 E)-4-i erazin-1- lbut-1-en-1- (nicotinonitrile 16.9 4-[(4-methyl-1 H-indol-5-yl)amino]-5-(4-piperazin-1-yl bu I nicotinonitrile 4.7 5-[4-(4-aminopiperidin-1-yl)butyl]-4-[(4-methyl-1 H-indol-5- lamino nicotinonitrile 5.2 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(1 E)-5-piperazin-1 -I ent-l-en-i- (nicotinonitrile 2.8 5-[(1 E)-5-(4-aminopiperidin-1 -yl)p e n t-1-e n-1-yl ]-4-[ (4-meth l-1H-indol-5- I amino nicotinonitrile 5.2 5-[(1 E)-4-(4-aminopiperidin-1-yl )but-1-en-1 -yl]-6-meth l-4- 4-meth I-1H-indol-5- I amino nicotinonitrile 45.5 5-[(1 E)-4-(dimethylamino)but-1-en-1-yl]-4-[(4-methyl-IH-indol-5- lamino nicotinonitrile 38.7 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(1 E)-4-[(1-methyl pipeddin-4-yl)aminolbut-l-en-1-yl)nicotinonitrile 13.1 5-{(1 E)-4-[(trans-4-hydroxycyclohexyl)amino]but-1-en-1- I - 4-meth -1H-indol-5- I amino nicotinonitrile 35.8 5-[(1 E)-5-(4-hydroxypiperidin-1-yl)pent-1-en-l-ylj-4-[(4-meth l-IH-indol-5- I amino nicotinonitrile 10.5 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(1 E)-4-[4-(methylsulfonyl)piperazin-1-yl]but-1-en-1 -yl}
nicotinonitrile 30 N-(1-[(3E)-4-{5-cyano-2-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]pyridin-3-yl}but-3-en-1-yl]piperidin-4-yl}
methanesulfonamide 57.3 5-[(1 E)-4-(4-hyd roxy-4-p h e nyl pi pe rid i n- l -yl )but-1-e n-1-I -4- 4-meth l-1H-indol-5- 1 amino nicotinonitrile 44.2 4-[(E)-2-{5-cyano-4-[(4-methyl-1 H-indol-5-yl)amino]
ridin-3- vin I benzoic acid 63.4 5-[(1 E)-3-(4-hydroxypiperidin-l-yl)prop-1-en-l-yl]-4-[(4-meth l-1H-indol-5- amino nicotinonitrile 143.2 tert butyl 4-({6-[(E)-2-{5-cyano-4-[(4-methyl-1H-indol-5-yl)amino]pyridin-3-yl}vinyl]pyridin-3-yl}methyl ) piperazine-l-carboxylate 72.3 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[5-(piperazin-1- lmeth I ridin-2- vin I nicotinonitrile 5.2 tert-butyl 4-(4-[(E)-2-(5-cyano-4-[(4-methyl-1 H-indol-5-yl )amino]pyridin-3-yl}vinyl]benzyl}piperazine-1-carbo late 44 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{4-[(4-methyl piperazin-1-yl)carbonyl]phenyl}vi nyl]
nicotinonitrile 28.4 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(4-methyl hen I vin I nicotinonitrile 35.2 5-[(E)-2-(4-methoxyphenyl)vinylj-4-[(4-methyl-1 H-indol-5- (amino nicotinonitrile 13.1 5-[(E)-2-biphenyl-4-ylvinyl]-4-[(4-methyl-1 H-indol-5-Iamino nicotinonitrile 57.2 4-[(2,4-dimethyl-1 H-indol-5-yl)amino]-5-[(E)-2-phenyl vin nicotinonitrile 70.1 4-[(4-methyl-1 H-indol-5-yl)aminoj-5-{(E)-2-[4-trifluorometh hen vin I icotinonitnle 115.2 5-[(E)-2-(4-chlorophenyl)vinyl]-4-[(4-methyl-1 H-indol-5-lamino nicotinonitrile 42.9 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(Z)-2-phenylvinyl]
nicotinonitrile 79 5-{(1 E)-4-[(3R)-3-hydroxypyrrolidin-1-yl]but-1 -en-1 -yl}-4- 4-meth l-1H-indol-5- I amino nicotinonitrile 13.7 5-{(1 E)-4-[(3S)-3-hydroxypyrrolidin-1-yl]but-l-en-1-yl)-4- 4-meth l-1H-indol-5- I amino nicotinonitrile 23.9 5-{(1 E)-4-[4-(hydroxymethyl )pipeadin-1-yl]but-l yi)-4-1(4-methyl-lH-indol-5-yl)amino]nicotinonitdle nitrile 39.4 5-[(1 E)-4-(4-methoxypiperidi n-1-yl)but-1-en-1-yl]-4-[(4-meth l-1H-indol-5- I amino nicotinonitrile 41.6 4-[(4-methyl-1 H-indol-5-yl)amino]-1'-(2-phenylethyl)-1',2' 3' 6'-tetrah dro-3,4'-bi ridine-5-carbonitrile 16.8 1'-(2-fluorobenzyl)-4-[(4-methyl-1 H-indol-5-yl)amino]-1',2',3',6'-tetrah dro-3,4'-bi ridine-5-carbonitrile 6.9 1'-(3-fluorobenzyl)-4-[(4-methyl-1 H-indol-5-yl)amino]-1',2' 3' 6'-tetrah ro-3,4'-bi ridine-5-carbonitrile 3.7 1'-(4-fluorobenzyl)-4-[(4-methyl-1 H-indol-5-yl)amino]-1',2',3',6'-tetrah dro-3,4'-bi ridine-5-carbonitrile 7.3 4-[(4-methyl-1 H-ind of-5-yl )amino]-5-{(1 E)-4-[4-(pyrrolidin-1-ylcarbonyl)piperidin-1-yl]but-1-en-1-I nicotinonitrile 18.2 5-[(E)-2-(3-methoxyphenyl)vinyIJ-4-[(4-methyl-1 H-indol-5- (amino nicotinonitrile 7 5-[(E)-2-(4-bromophenyl)vinyl]-4-[(4-methyl-1 H-indol-5-I amino nicotinonitrile 58.3 5-[(E)-2-(2-methoxyphenyl)vinyl]-4-[(4-methyl-1I -indol-5- Iamino nicotinonitdle 8.2 5-[(E)-2-(3,4-d i methoxyphe nyl )vi nyl]-4-[(4-methyl-1 H -indol-5- Iamino nicotinonitrile 8.1 4-(1 H-indol-5-ylamino)-5-[(E)-2-phenylvinyl]
nicotinonitrile 12.9 4- 4-meth l-1H-indol-5-Iamino -5-vin nicotinonitrile 22.4 4-(1 H-indol-5-ylamino)-6-methyl-5-[(E)-2-phenyl vin nicotinonitrile 96.6 4-[(4-methyl-1 H-indol-5-yl)amino]-1'-(piperidin-4-ylmethyl)-1',2',3',6'-tetrahydro-3,4'-bi pyridine-5-carbonitrile 6.1 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(1 E)-4-(3-oxo piperazin-I - I but-1-en-1- I nicotinonitrile 11 5-[(E)-2-(3-methoxyphenyl)vinyl]-6-methyl-4-[(4-methyl-1H-indol-5- mino nicotinonitdle 16.4 4-[(4-methyl-1 H-indol-5-yl)aminoJ-5-[(E)-2-{4-[(4-methylpiperazin-1-yl)methyl] pyridin-2-yl}vinyl]
nicotinonitrile 13.6 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{2-[(4-methylpiperazin-1-yl)methyl]-1,3-thiazol-4-yl}vinyl]
nicotinonitrile 2.4 4-[(4-methyl-1 H-indol-5-yl)amino]-5-(2-{5-[(4-methylpiperazin-1-yl)methyl]pyridin-2-yl}ethyl) nicotinonitrile 12.3 4[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{6-[(4-methylpiperazin-1-yl)methyl] pyridin-2-yl}vinyl]
nicotinonitrile 1.1 4-(1 H-indol-6-ylamino)-6-methyl-5-[(E)-2-phenylvinyl]
nicotinonitrile 4,221.5 4-(l H-indol-6-ylamino)-5-[(E)-2-hen lvin I nicotinonitrile 1,395 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[4-(2-rrolidin-1 - ethox hen vin I nicotinonitrile 9 5-{(E)-2-[4-(2-ch loroethoxy)phe nyl]vi nyl }-4-[(4-methyl-IH-indol-5- amino nicotinonitrile 25 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(1 E)-3-phenylprop-1-en-1- I nicotinonitrile 17.8 6-methyl-4-[(4-methyl-1 H-indol-5-yi)amino]-5-[(E)-2-{5-[(4-methylpiperazin-1-yl)methyl] pyridin-2-yi}vinyl]
nicotinonitrile 10.5 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-hen Ivin I nicotinonitrile 9 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-pyridin-2-Ivin I nicotinonitrile 5 5-[(E)-2-(4-butylphenyl)vinyl]-4-[(4-methyl-1 H-indol-5-lamino nicotinonitrile 77.6 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-pyridin-4-Ivin I nicotinonitrle 6.6 6-methyl-4-[(2-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-hen lvin I nicotinonitrile 714.6 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-vinyl nicotinonitrile 111.1 4-[(4,7-dimethyl-1I -indol-5-yl)amino]-5-[(E)-2-phenyl vin I nicotinonitrile 33.6 4-[(7-chloro-4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-hen Ivin I nicotinonitrile 77.5 4-[(7-chloro-4-methyl-1 H-indol-5-yl )amino]-5-((E)-2-(3-methox hen Ivin I nicotinonitrile 26.3 4-[(7-chloro-4-methyl-1 H-i ndol-5-yi )amino]-54(E)-2-ridin-2-Ivin I nicotinonitrile 28.6 4-[(2-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-phenyl vin I nicotinonitrile 362.2 5-[(E)-2-(4-methoxyphenyl)vinylJ-6-methyl-4-[(4-methyl-1H-indol-5- amino nicotinonitdle 58.2 4-[(4-methyl-1 H-indol-5-yl)amino]-5-(3-phenyl propyl)nicotinonitrile 31.8 4-[(4-methyl-1 H-indol-5-yl)ami no]-5-[(E)-2-{4-[2-(4-meth i erazin-1- I ethox hen Ivin I nicotinonitrile 3.6 4-(1 H-indol-5-ylamino)-5-[(E)-2-{5-[(4-methylpiperazin-1- Imethndin-2- I vin I nicotinonitrile 16.5 4-(1 H-indol-4-ylamino)-5-[(E)-2-phenylvinyl]
nicotinonitrile 12.9 4-(1 H-indol-4-ylamino)-6-methyl-5-[(E)-2-phenylvinyl]
nicotinonitrile 25.3 5-[(E)-2-{2-methoxy-4-[(4-methylpiperazin-1-yi)methyl]
phenyl}vinyl]-4-[(4-methyl-l -indol-5-yl)amino]
nicotinonitrile 8.8 5-{(E)-2-[2-(2-chloroethoxy)phenyllvinyl}-4-[(4-methyl-1H-indol-5- amino nicotinonitrile 5.1 5-{(E)-2-[3-(2-chloroethoxy)phenyl]vi nyl}-4-[(4-methyl-1H-indol-5- mino nicotinonitrile 8.6 4-[(4-methyl-1 H-indol-5-yl)ami no]-5-[(E)-2-(2-[2-(4-meth ierazin-l- etho hen I vin I nicotinonitrile 7.6 4-[1 H-indol-5-yl(methyl)amino]-5-[(E)-2-phenylvinyl]
nicotinonitrile 438.2 4-[(4-methyl-1 H-indol-5-yl)amino)-5-[(E)-2-{2-methyl-4-[(4-methylpiperazin-1-yl)methyl]phenyl}vinyl]
nicotinonitrile 5.3 4-[(4-methyl-1 H-indol-5-yl)aminoj-5-{(E)-2-[2-(2-ierazin-1- letho hen I vin I nicotinonitrile 0.6 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[2-(2-rrolidin-l- lethox hen vin I nicotinonitrile 12.9 4-[(4-methyl-1 H-indol-5-yl)ami no]-5-[(E)-2-pi perid i n-4-Ivin I nicotinonitrile 6.1 4-[(4-methyl-1 H-ind ol-5-yl)ami no]-5-[(E)-2-{3-[2-(4-meth ierazin-1- I ethox hen Ivin I nicotinonitrile 4.7 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[3-(2-rrolidin-1- etho hen vin I nicotinonitrile 4.7 5-[2-(4-methoxyphenyl)ethyl]-4-[(4-methyl-1 H-indol-5-Iamino nicotinonitrile 18.3 5-(2-biphenyl-4-ylethyl)-4-[(4-methyl-1 H-indol-5-yl) amino nicotinonitrile 82.1 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{3-[(4-methyl piperazin-1 meth I hen Ivin I nicotinonitrile 1.4 4[(4-methyl-1 H-indol-5-yl)amino]-5-(2-phenyl ethyl) nicotinonitrile 34.2 4-[(7-chloro-4-methyl-1 H-indol-5-yl)aminoj-5-[(E)-2-ridin-4- Ivin I nicotinonitrile 71.6 4-[(7-chloro-4-methyl-1 H-indol-5-yl)aminoj-6-methyl-5--2- ridin-2-Ivin nicotinonitrile 74 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-ridin-2-vin I nicotinonitrile 6.3 4-[(7-chloro-4-methyl-1 H-i ndol-5-yl )amino]-5-[(E)-2-{5-[(4-methylpiperazin-1-yl)methyl]pyridin-2-yl}vinyl]
nicotinonitrile 16.3 4-[(4-methyl-1 H-indol-5-yl)ami no]-5-[(E)-2-(1 H-1,2,4-triazol-1- vin nicotinonitrile 11 4-[(4-methyl-1 H-i ndol-5-yl )amino]-5-[(E)-2-(4-methyl-1,3-thiazol-5- vin I nicotinonitrile 4.1 5-[(1 E)-3-(1 H-i midazol-1-yI )prop-1 -en-1 -yl]-4-[(4 meth l-1H-indol-5- I amino nicotinonitrile 19.5 5-[(E)-2-cyclohexylvinyl]-4-[(4-methyl-1 H-indol-5-lamino nicotinonitrile 26 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-ridin-4-vin I nicotinonitrile 12.3 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{5-[(4-methyl 2.9 piperazin-1-yl)methyl]-3-furyi)vinyiInicotinonitrile 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{2-methyl-5-[(4-methylpiperazin-l -yl)carbonyl]phenyl}vinyl]
nicotinonitrile 27.8 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{2-methyl-5-[(4-methylpiperazin-l -yl )methyl]phenyl}vinyl]
nicotinonitrile 16.1 4-[(7-chloro-4-methyl-1 H-indol-5-yl)amino]-6-methyl-5-2-hen Ivin I nicotinonitrile 282.6 4-[(7-chloro-4-methyl-1 H-i ndol-5-yl )amino]-5-[(E)-2-{6-[(4-methylpiperazin-1-yl)methyl]pyridin-2-yl}vinyl]
nicotinonitrile 4.8 5-[(E)-2-{6-[(4-acetylpiperazin-1-yl )methyl]pyridin-2-yl}
vinyl]-4-[(4-methyl-1 H-indol-5- I amino nicotinonitrile 1.6 5-[(E)-2-{2-methoxy-5-[(4-methylpiperazin-1-yl)methyl]
phenyl}vinyl]-4-[(4-methyl-1 H-indol-5-yl)amino]
nicotinonitrile 4.9 5-{(E)-2-[2-methoxy-5-(piperazin-1-ylmethyl)phenyl]
vinyl)-4-[(4-methyl-1 H-indol-5-I amino nicotinonitrile 1.2 5-[(E)-2-(2-methoxyphenyl)vinyl]-6-methyl-4-[(4-methyl-1H-indol-5- mino nicotinonitrile 8.2 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-ridin-3- Ivin I nicotinonitrile 12.1 5-[(E)-2-(3, 4-d i methoxyph enyl )vi nyl]-6-methyl-4-[(4-meth l-1H-indol-5- I amino nicotinonitrile 25.3 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-razin-2-Ivin I nicotinonitrile 7.9 test butyl 4-[(E)-2-(5-cyano-4-[(4-methyl-lH-indol-5-lamino ridin-3- I vin I i eridine-l-carbo late 48.2 4-(1 H-indol-4- ox -5- -2-hen Ivin I nicotinonitrile 324.8 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(4-meth l-1,3-thiazol-5- I vin nicotinonitrile 3.2 4-[(4-methyl-1 H-indol-5-yl)amino]-5-((E)-2-[4-(piperidin-1- lmeth hen Ivin I nicotinonitrile 4.1 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[4-(pyrrolidin-1- (meth hen Ivin I nicotinonitrile 3.6 5-[(E)-2-(2-chloropyndin-3-yl)vinyl]-4-[(4-methyl-1 H -indol-5- (amino nicotinonitrile 4.2 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{2-methyl-4-[(4-methyl piperazin-1-yl)carbonyl]phenyl}vinyl]
nicotinonitrile 23.4 5-[(E)-2-(4-{[4-(2-hydroxyethyl)piperazin-1-yl]
methyl}phenyl)vinyl]-4-[(4-methyl-1 H-indol-5-yl ) amino nicotinonitrile 4.7 5-[(E)-2-{4-[(4-hydroxypipendin-1 -yl)methyl]
phenyl}vinyl]-4-[(4-methyl-1 H-indol-5-yl)amino]
nicotinonitrile 5.5 5-{(E)-2-[4-(([3-(dimethylamino)propyl]amino}methyl) phenyl]vinyl}-4-[(4-methyl-1H indol-5-yl)amino]
nicotinonitrile 1.2 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[4-thiomor holin-4- lmeth I hen I vin I nicotinonitrile 46.2 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(4-[(4-pyrrolidin-1 -ylpiperidin-l -yl)methyl]phenyl}vinyl]
nicotinonitrile 1.6 5-[(E)-2-{2-methoxy-3-[(4-methylpi perazin-l -yl) methyl]phenyl}vinyl]-4-[(4-methyl-1 H-indol-5-1amino nicotinonitrile 5.8 5-{(E)-2-[2-methoxy-3-(piperazin-1-ylmethyl)phenyl]
vinyl}-4-[(4-methyl-1 H-indol-5- I amino nicotinonitrile 7.3 6-methyl-4-{(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{6-[(4-methylpiperazin-1 -yl)methyl] pyridin-2-yl}vinyl]
nicotinonitrile 3 5-[(E)-2-{3-methoxy-4-[(4-methylpiperazin-1-yl )methyl]
phenyl}vinyl]-4-[(4-methyl-1 H-indol-5-yl)amino]
nicotinonitrile 2.3 5-{(E)-2-[3-methoxy-4-(piperazin-1-ylmethyl)phenyl]
vinyl}-4-[(4.-methyl-1 H-indol-5- I amino nicotinonitrile 2.2 5-isopropenyl-4-[(4-methyl-1 H-indol-5=yl)amino]
nicotinonitrile 7.5 5-[(E)-2-{3-[(diethylamino)methyl]phenyl}vinyl]-4-[(4-meth l-1H-indol-5- I amino nicotinonitrile 2.9 5-[(E)-2-{4-[(d iethylami n o)methyl] phen yl}vinyl]-4-[(4-meth l-1H-indol-5- amino nicotinonitrile 14.8 5-[(E)-2-(6-bromopynd in-2-yl)vinyl]-4-[(4-methyl-1 H-indol-5- (amino nicotinonitrile 0.7 5-{(E)-2-[3,4-bis(2-methoxyethoxy)phenyljvinyl)-4-[(4-meth l-1H-indol-5- amino nicotinonitrle .31.8 5-[(E)-2-(4-formylphenyl)ethenyl]-4-[(4-methyl-1 H-indol-5- (amino ridine-3-carbonitrile 58.2 5-{(E)-2-[4-(1,4'-bipiperidin-1'-ylmethyl)phenyl]ethenyl}-4- 4-meth -1H-indol-5- I amino ridine-3-carbonitrle 3.2 5-[(E)-2-(4-{[(3-ethoxypropyl)aminojmethyl}phenyl) ethenyl]-4-[(4-methyl-1H-indol-5-yl)amino] pyridine-3-carbonitrile 3.6 5-[(E)-2-(2-chloropyndin-4-yl)vinyl]-4-[(4-methyl-1 H -indol-5- (amino nicotinonitrile 7.2 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[4-(piperazin-1- lmeth hen I vin I icotinonitrile 2.6 5-{(E)-2-[4-(azetidin-l -yl methyl)phenyl]vinyl}-4-[(4-meth l-1H-indol-5- I amino nicotinonitrile 3.3 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-(2-hen eth I nicotinonitrle 40.7 5-[(E)-2-{4-[(d i methylam ino)methyl] phe nyl}vinyl]-4-[(4-meth l-1H-indol-5- (amino nicotinonitrile 10.5 5-[(E -2-(4-ethoxyphenyl)vinyl]-4-[(4-methyl-1H-indol-5-lamino nicotinonitrile 14.2 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{4-[(4-pyridin-2-ylpiperazin-1-yl)methyl]phenyl}vinyl]
nicotinonitrile 37.8 Pert-butyl 3-({4-[(E)-2-{5-cyano-4-[(4-methyl-1 H-indol-5-yl)am ino]pyridin-3-yl}vinyl]benzyl}amino)azetidi ne-1-carboxlate 61.1 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(4-propoxy hen I vin I nicotinonitrile 66.4 5-[(E)-2-(6-chloropyndin-3-yl)vinyl]-4-[(4-methyl-1 H -indol-5- Iamino nicotinonitrile 2.2 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{2-[4-(pyrrolidin-1-Imeth 1 hen I eth I nicotinonitrile 13.4 5-[(E)-2-(6-chloropyndin-2-yl)vinyl]-4-[(4-methyl-1 H -indol-5- (amino nicotinonitrile 0.4 5-((E)-2-[6-(hydroxymethyl)pyridin-2-yl]vi nyl}-4-[(4-meth l-1H-indol-5- amino nicotinonitrile 1.5 4-[(4-methyl-1 H-indol-5-yl)aminoj-5-{(E)-2-[6-(pipeddin-1- lmeth I ridin-2- 1 in nicotinonitrile 4.3 4-[(4-methyl-1 H-indol-5-yl)aminoj-5-{(E)-2-[6-(pyrrolid in-1- lmeth I ridin-2- I vin I nicotinonitrile 1.6 4-[(4-methyl-1 H-indol-5-yl)aminoj-5-{(E)-2-[6-(piperazin-1- (meth I ridin-2- I vin nicotinonitrile 0.3 5-{(E)-2-[5-(hydroxymethyl)pyridin-2-yl]vinyl}-4-[(4-meth l-1H-indol-5- I amino nicotinonitrile 6.1 5-[(E)-2-{4-[(3-hydroxypyrrolidi n-1-yl)methyl]phenyl}
ethenyl]-4-[(4-methyl-1 H-indol-5-yl)amino]pyndine-3-carbonitrile 6.3 N-{4-[(E)-2-(5-cyano-4-1(4-methyl-1 H-indol-5-yl)aminoJ
pyridin-3-yl}ethenyljbenzyl}-N-(2-piperid in-1-leth I acetamide 2.4 5-[(E)-2-(4-{[4-(1 -methylethyl )pi perazi n-1-yl]m ethyl}
phenyl)ethenylj-4-[(4-methyl-1 H-indol-5-yl)aminoj ridine-3-carbonitrile 3 N-{4-[(E)-2-{5-cyano-4-[(4-methyl-1 H-indol-5-yl)aminoj pyridin-3-yl}ethenyl]benzyl}-N-(2-pyrrolidin-1-ylethyl ) acetamide 2.2 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(4-{[(2-pyridin-3-ylethyl)amino]methyl}phenyl)ethenyl]pyridine-3-carbonitrile 0 2.9 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(4-{[(2-pyridin-2-ylethyl)amino] methyl}phenyl)ethenyl]pyridine-3-carbonitrile 10 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(4-{[(3-morpholin-4-ylpropyl)amino]methyl}phenyl ) ethen I ridine-3-carbonitrile 0.9 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(4-[(4-morpholin-4-ylpiperidin-1-yl)methyl]phenyl}ethenyl]
pyridine-3-carbonitnle 3.4 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(4-{[(2-morpholi n-4-ylethyl)amino]methyl}phenyl) ethen I ridine-3-carbonitrile 22.1 5-[(E)-2-{4-[(4-cyclopentyl pipe razin-1-yl)methyl]phenyl}
ethenyl]-4-[(4-methyl-l H-indol-5-yl)amino]pyridine-3-carbonitrile 3.4 5-[(E)-2-(4-formylphenyl)eth enyl]-6-methyl-4-[(4-methyl-1H-indol-5- amino ridine-3-carbonitrile NA
4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[4-(morpholin-4-ylmethyl)phenyl]ethenyl}pyridine-3-carbonitrile 39.7 5-[(E)-2-{4-[(azetidin-3-ylamino)methyl]phenyl}ethenyl]-4- 4-meth l-1H-indol-5- I amino ridine-3-carbonitrile 1.5 6-methyl-4-[(4-methyl-1 H-indol-S-yl)amino]-5-[(E)-2-{2-methyl-4-[(4-methyl piperazin-1-yl)carbonyl]phenyl}
ethen I ridine-3-carbonitrile 22.2 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{4-[(4-methylpipe razin-1-yl)methyl] phenyl}ethenyl]pyridine-3-carbonitrile 7.1 5-[(E)-2-{4-[(4-hydroxypipe ridin-1-yl )methyl] phenyl}
ethenyl]-6-methyl-4-[(4-methyl-1 H-indol-5-lamino ridine-3-carbonitrile 11.7 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[4-(piperidin-1-ylmethyl)phenyl]ethenyl}pyndine-3-carbonitrile 17.4 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[4-(pyrrolidi n-1-ylmethyl )phenyl]ethenyl}pyridin a-3-carbonitrile 34.7 5-[(E)-2-{4-[(diethylamino)methyl]phenyl}ethenyl]-6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile 8.6 6-methyl-5-[(E)-2-{4-[(4-methyl-1,4-diazepan-1-yl) methyl]phenyl)ethenyl]-4-[(4-methyl-1 H-indol-5-Iamino ridine-3-carbonitrile 13.9 5-[(E)-2-(4-benzyl morpholin-2-yl)ethenyl]-4-[(4-methyl-IH-indol-5- amino ridine-3-carbonitrile 57.3 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{2-[(4-methyl piperazin-1-yl)methyl]phenyl}ethenyl]pyridine-3-carbonitrile 9.9 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{5-[(4-methyl piperazin-1-yl)methyl]pyridin-3-yl}ethenyl]pyndine-3-carbonitrile 16.3 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{4-[(4-methyl piperazin-1-yl)methyl]-1,3-thiazol-2-yl}ethenyl]pyridine-3-carbonitrile 14.8 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{6-[(4-methylpiperazin-1-yl)methyl]pyridin-3-yl}ethenyl]
pyridine-3-carbonitrile 6.6 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[5-(piperidin-1- lmeth I ndin-2- ethen I ridine-3-carbonitrile 14.2 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[5-(pyrrolidin-1- lmeth I idin-2= I ethen I ridine-3-carbonitrile 19.4 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[5-(morphol in-4-ylmethyl)pyridin-2-yl]ethenyl}pyridine-3-carbonitrile 56.4 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[5-(th iomorpholin-4-ylmethyl )pyridin-2-yl]ethenyl}pyridine-3-carbonitrile 38.5 5-[(E)-2-{5-[(4-hyd roxypiperid in-1-yl )methyl]pyridi n-2-yl}ethenyl]-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile 30.3 5-[(E)-2-(5-{[4-(2-hydroxyethyl)piperazin-1-yl]methyl}
pyridin-2-yl)ethenyl]-4-[(4-methyl-1 H-indol-5-yl)amino]
ridine-3-carbonitrile 6.2 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(5-{[(2-morpholin-4-ylethyl)amino]methyl)pyridin-2-yl)ethenyl]
pyridine-3-carbonitrile 15.3 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[4-(morpholin-4-ylmethyl)phenyl]ethenyl}pyridine-3-carbonitrile 43.4 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(4-{[(2-pyndin-2-ylethyl)ami no]methyl}phenyl) ethen I ridine-3-carbonitrile 34.1 5-[(E)-2-{4-[(4-cyclopentyl piperazin-1-yl)methyl]phenyl}
ethenyl]-6-methyl-4-[(4-methyl-1H' indol-5-yl)amino]
ridine-3-carbonitrle 32 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[4-(thiomorpholin-4-ylmethyl)phenyl]ethenyl}pyridine-3-carbonitrile 187 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(4-{[(2-pyridin-4-ylethyl)amino]methyl}phenyl) ethenyl]
pyridine-3-carbonitnle 178.3 6-methyl-5-[(E)-2-(4-{[4-(1-methylethyl)piperazin-l -yl]methyl}phenyl)ethenyl]-4-[(4-methyl-1 H-indol-5-amino ridine-3-carbonitrle 12.1 5-[(E)-2-(5-bromopyridin-3-yl)ethenyl]-4-[(4-methyl-1 H-indol-5- 1 amino ridine-3-carbonitrile 0.8 tent butyl [2-((5-[(E)-2-{5-cyano-4-[(4-methyl-lH-indol-5-yl)amino]pyridin-3-yl}ethenyl]pyndin-3-yl}oxy)ethyl]
carbamate 21.3 5-[(E)-2-(5-methoxypyridin-3-yl)ethenyl]-4-[(4-methyl-1H-indol-5- amino ridine-3-carbonitrle 5.5 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{2-methyl-4-[(4-methyl pi perazi n-1-yl )methyl] phe nyl}
ethen I ridine-3-carbonitrile 9.4 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(2-methyl phenyl)ethenyllpyridine-3-carbonitHle 15.5 5-[(E)-2-(2-ethylphenyl)ethenyl]-4-[(4-methyl-1 H-indol-5- Iamino ridine-3-carbonitnle 58 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(5-{[(3-morpholin-4-ylpropyl)a mi no]methyl}pyrid in-2-yl)ethenyl]
pyridine-3-carbonitrile 5.1 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{5-[(4-morpholin-4-ylpiperid in-1-yl)methyl]pyridin-2-yl}
ethen I ridine-3-carbonitrile 5 5-{(E)-2-[5-(1,4'-bipiperidin-l'-ylmethyl)pyridin-2-yl]
ethenyl}-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile 2.7 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{5-[(4-pyrrolidin-1-ylpiperidin-1-yl)methyl]pyddin-2-yl}
ethen I ridine-3-carbonitrile 2.3 5-[(E)-2-{5-[(4-cyclopentyl piperazin-1-yl )methyl]pyrid in-2-yl}ethenyl]-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitnle 2.4 5-[(E)-2-(5-{[4-(1-methylethyl )piperazin-1-yl]
methyl}pyridin-2-yl)ethenyl]-4-[(4-methyl-1 H-indol-5-lamino ridine-3-carbonitnle 7.4 5-[(E)-2-(5-{[4-(dimethylamino)piperid in-1-yl]methyl}
pyridin-2-yl)ethenyl]-4-[(4-methyl-1 H-indol-5-yl)amino]
pyridine-3-carbonitrile 2.8 5-[(E)-2-{5-[(4-methyl-1,4-diazepan-1-yl )methyl]pyridin-2-yl}ethenyl]-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile 3 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[5-({[3-(2-oxopyrrolidi n-1-yl)propyl]amino}methyl)pyridin-2-I ethen ridine-3-carbonitrile 4.4 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(4-{[(3-morpholin-4-ylpropyl)amino] methyl}phenyl ethen I ridine-3-carbonitrile 32 5-{(E)-2-[4-(1,4'-bipiperidin-1'-ylmethyl)phenyl]ethenyl}-6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile 6.9 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{4-[(4-morphol i n-4-yl pi perid in-1-yl )methyl] phenyl}ethe nyl]
pyridine-3-carbonitnle 18 5-{(E)-2-[4-({[(1-ethylpyrrolidin-2-yl)methyl]ami no}
methyl)phenyl]ethenyl}-6-methyl-4-[(4-methyl-1 H-indol-5- (amino ridine-3-carbonitrile 43.2 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-(2-pyridin-2- leth I ridine-3-carbonitrile 11.5 5-{(E)-2-[5-(2-ami noethoxy)pyridin-3-yl]ethenyl}-4-[(4-meth l-1H-indol-5- amino ridine-3-carbonitrile 156.3 5-[(E)-2-{2-ethyl-5-[(4-methylpi perazin-1-yl)methyl]
phenyl}ethenyl]-4-[(4-methyl-1 H-indol-5-yl)amino]
pyridine-3-carbonitnle 18 5-[(E)-2-{2-ethyl-5-[(4-methylpi perazin-1-yl)methyl]
phenyl}ethe nyl]-6-methyl-4-[(4-methyl-1 H-i ndol-5-lamino ridine-3-carbonitrile 14.5 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E}2-pyridin-3-lethen I ridine-3-carbonitnle 7.6 5-{(E)-2-[5-({[2-(d i m et hyl a m i no)eth yl] a m i n o) me thyl ) pyridin-2-yljethenyl}-4-[(4-methyl-1 H-indol-5-yi)amino]
pyridine-3-carbonitnle 1.7 5-[(E)-2-(5-{[(2-ethoxyethyl)amino]methyl}pyridin-2-yl) ethenyl]-4-[(4-methyl-11 -indol-5-yl)amino]pyridine-3-carbonitrile 3.2 5-[(E)-2-(5-{[(3-ethoxypropyl)amino]methyl}pyridi n-2-yl) ethenyl]-4-[(4-methyl-1H'-indol-5-yl)amino]pyridin a-3-carbonitrile 2.1 5-[(E)-2-(5-{[(2-methoxyethyl)amino]methyl}pyridin-2-yl ) ethenyl]-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile 3.1 4-[(1,4-dimethyl-1 H-indol-5-yl)amino]-5-[(E)-2-phenyl ethen I ridine-3-carbonitnle 192.4 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[6-(morphol in-4-ylmethyl )pyridin-2-yl]ethenyl}pyridi ne-3-carbonitrile 1.5 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[6-(th iomorpholin-4-ylmethyl )pyridin-2-yl]ethenyl}pyridine-3-carbonitrile 0.8 5-[(E)-2-{6-1(4-hydroxypipendin-1-yl)methyl]pyndin-2-yl}
ethenyl]-4-[(4-methyl-1I -indol-5-yl)amino]pyridine-3-carbonitrile 2 5-[(E)-2-(6-{[4-(2-hydroxyethyl)piperazin-1-yl]methyl}
pyridin-2-yl)ethenyl]-4-[(4-methyl-1 H-indol-5-yl) amino idine-3-carbonitdle 0.7 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(6-{[(2-morpholin-4-ylethyl)amino]methyl}pyridin-2-yl ) ethen I ridine-3-carbonitrile 1.3 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(6-{[(3-morpholin-4-ylpropyl)aminojmethyl}pyridin-2-yl) ethen I ridine-3-carbonitrile 2.9 4-[(4-methyl-1 H-i ndol-5-yl)ami no]-5-[(E)-2-{6-[(4-morpholin-4-ylpiperidin-1-yl)methyl]pyrid in-2-yl}
ethen I ridine-3-carbonitrile 1.9 5-{(E)-2-[6-(1,4'-bipiperidin-l'-ylmethyl)pyridin-2-yl]
ethenyl}-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile 0.4 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{6-[(4-pyrrolidin-1-ylpiperidin-1-yl )methyl]pyridin-2-yl) ethen I ridine-3-carbonitrile 0.8 5-[(E)-2-{6-[(4-cyclopentylpiperazin-1-yl )methyl]pyridin-2-yl}ethenyl]-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile 0.5 5-[(E)-2-(4-[(4-methyl-1,4-diaze pan-1-yl )methyl]
phenyl}ethe nyl]-4-[(4-methyl-1 H-i ndol-5-yl )a mi noj pyridine-3-carbonitrile 2.7 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(4-{[(2-pyridin-4-ylethyl)amino]methyl}phenyl)ethenyljpyridine-3-carbonitrile 1.7 5-[(E)-2-(6-{[4-(1-methylethyl)pi perazin-1-yl]methyl}
pyridin-2-yl)ethenyl]-4-[(4-methyl-1 H-indol-5-yl)amino]
ridine-3-carbonitrle 0.6 5-[(E)-2-(6-{[4-(dimethylamino)piperid in-l -yl]methyl}
pyridin-2-yl)ethenyl]-4-[(4-methyl-1 H-indol-5-yl )amino]
pyridine-3-carbonitrile 0.8 5-[(E)-2-{6-[(4-methyl-1,4-diazepan-1-yl)methyl]pyridin-2-yI}ethenyl]-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile 0.8 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[6-({[3-(2-oxopyrrolidin-1-yl )propyl]amino}methyl)pyridin-2-yl]
ethen I ridine-3-carbonitrile 0.5 5-{(E)-2-[6-({[2-(dimethylamino)ethyl]amino}methyl) pyridin-2-yl]ethenyl}-4-[(4-methyl-1 H-indol-5-yl )amino]
ridine-3-carbonitrile 0.4 5-{(E)-2-[6-({[3-(dimethylamino)propyl]amino}methyl) -2-yl]ethenyl}-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile 2 5-[(E)-2-(6-{[(2-ethoxyethyl)amino]methyl}pyridin-2-yl) ethenyl]-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile 1.9 5-[(E)-2-(6-{[(2-methoxyethyl)amino]methyl}pyrid in-2-yl ) ethenyl]-4-1(4-methyl-1 H-indol-5-yl)amino]pyridina-3-carbonitrile 4.2 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{5-[2-(4-methyl piperazin-1-yl)ethoxy]pyridin-3-yl}ethenyl]
pyridine-3-carbonitrle 6.7 5-[(E)-2-(4-{[4-(2-hydroxyethyl )piperazin-1-yl]methyl}
phenyl)ethenyl]-6-methyl-4-[(4-methyl-1 H-indol-5-lamino ridine-3-carbonitrle 10 5-[(E)-2-(3-formylphenyl)ethenyl]-4-[(4-methyl-1 H-indol-5- lamino ridine-3-carbonitrile NA
6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{5-[2-(4-methylpiperazin-1-yl)ethoxy]pyridin-3-yl}ethenyl]
ridine-3-carbonitrile 26.7 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-((E)-2-{4-[(4-pyrrolidin-1-ylpiperidin-1-yl)methyl]phenyl}ethenyl]
ridine-3-carbonitrile 3.9 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5--{(E)-2-[5-(2-pyrrolidin-1-ylethoxy)pyridin-3-yl]ethenyl}pyridine-3-carbonitrile 17 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(4-{[(2-piperidin-1-ylethyl)amino]methyl}phenyl) ethenyl]
pyridine-3-carbonitrle 6 4-[(6-chloro-1 H-indol-5-yl)amino]-5-[(E)-2-phenyl ethen I ridine-3-carbonitrile 65 5-[(E)-2- (6-[(dimethylamino)methyl]pyrid in-2-yl}ethenyl]-4- 4-meth. l-1H-indol-5- I amino ridine-3-carbonitrile 2.9 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[6-({[2-(1-methylpyrrolidin-2-yl)ethyl]amino}methyl)pyndin-2-yi]
ethen I ridine-3-carbonitrile 0.7 5-[(E)-2-{6-[(3-hydroxypyrrol idin-1-yl)methyl]pyridin-2-yl}ethenyl]-4-[(4-methyl-1 H-indol-5-yl)amino]pyridi ne-3-carbonitrile 2.3 5-[(E)-2-(6-{[(2-azepan-1-ylethyl )am i no]methyl}pyrid i n-2-yl)ethenyl]-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile 0.3 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(6-{[(2-pyridin-2-ylethyl)amino]methyl}pyridin-2-yl)ethenyl]
pyridine-3-carbonitrile 1.8 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(6-{[(2-pyridin-3-ylethyl)amino]methyl}pyridin-2-yl)ethenyl]
ridine-3-carbonitrile 1.7 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(6-{[(2-pyridin-4-ylethyl)amino]methyl}pyrid in-2-yl)ethenyl]
ridine-3-carbonitnle 2.1 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[5-({[2-(1-methyl pyrrolidin-2-yl)ethyl]amino}methyl)pyridin-2-Iethen I ridine-3-carbonitrile 3.1 5-[(E)-2-{5-[(3-hydroxypyrrolidin-1-yl)methyl]pyndin-2-yl)ethenyl]-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile 11.6 5-[(E)-2-(5-{[(2-azepa n-1-yleth yl )ami no]methyl}pyrid i n-2-yl)ethenyl]-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile 2.7 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(5-{[(2-pyridin-2-ylethyl)amino]methyl}pyridin-2-yl)ethenyl]
ridine-3-carbonitnle 10.4 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(5-{[(2-pyrid i n-4-yl ethyl)amino] methyl}pyrid i n-2-yl)ethenyl]
pyridine-3-carbonitrile 5.6 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[4-(pyrrolidin-1- Isulfon I hen ethen I ridine-3-carbonitrile 6 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E -2-{4-[(4-methyl piperazin-1-yl)sulfonyl]phenyl}ethenyl]pyridine-3-carbonitrile 22.6 5-{(E)-2-[4-({[2-(dimethylamino)ethyl]amino}methyl) phenyl]ethenyl}-4-[(4-methyl-1 H-indol-5-yl)amino]
ridine-3-carbonitrile 3.7 5-[(E)-2-{5-[3-(dimethylamino)propoxy]pyridin-3-yl}
ethenyl]-4-[(4-methyl-1 H-i ndol-5-yl)amino]pyridin a-3-carbonitrile 11.6 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[3-(piperidin-1- lmeth I hen I ethen I ridine-3-carbonitrile 4.9 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[3-(pyrrolidin-1- lmeth I hen I ethen I ridine-3-carbonitrile 2.9 5-[(E)-2-(3-{[4-(2-hyd roxyethyl)piperazin-1-yl]methyl}
phenyl )ethenyl]-4-[(4-methyl-1 H-indol-5-yl)amino]
ridine-3-carbonitrile 1.5 4-[(4-methyl-1 H-indol-5-yl)ami no]-5-[(E)-2-{3-[(4-pyrrolidin-1-ylpiperidin-1-yl)methyl]phenyl)ethenyl]
pyridine-3-carbonitrile 1.0 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{3-[(4-morpholin-4-ylpi peridin-1-yl)methyl]phenyl}ethenyl]
ridine-3-carbonitnle 3.8 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[3-(thiomorpholin-4-ylmethyl)phenyl]ethenyl}pyridine-3-carbonitrile 18.6 5-[(E)-2-{3-[(4-cyclopentyl piperazin-1-yl)methyl]
phenyl)ethenyl]-4-[(4-methyl-1 H-indol-5-lamino ridine-3-carbonitnle 0.8 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(4-{[(2-pyrrolidin-l-ylethyl)amino]methyl)phenyl) ethen 1 ridine-3-carbonitrile 2.2 5-[(E)-2-(3-formylphe nyl)ethenyl]-6-methyl-4-[(4-methyl-1H-indol-5- amino ridine-3-carbonitrile NA
5-{(E)-2-[5-(hyd roxymethyl )pyrid in-2-yl]ethenyl}-6-methyl-4-[(4-methyl-1 H-i ndol-5-yl )am ino]pyridine-3-carbonitrile 17.8 5-{(E)-2-[6-(hydroxymethyl )pyndin-2-yl]ethenyl}-6-methyl-4-[(4-methyl-1 H-indol-5-yl )amino]pyndine-3-carbonitrile 5.9 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[6-(pipedd in-l -ylmethyl)pyridin-2-yl]ethenyl}pyridine-3-carbonitrile 20.7 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-((E)-2-[6-(pyrrolidin-1-ylmethyl)pyndin-2-yl]ethenyl}pyridine-3-carbonitrile 24.5 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[6-(morpholin-4-ylmethyl)pyridin-2-yl]ethenyl}pyridi ne-3-carbonitrile . 8.6 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[6-(th iomorpholin-4-ylmethyl)pyridin-2-yl]ethenyl}pyridine-3-carbonitrile 6.6 5-[(E)-2-{6-[(4-hydroxypiperidin-l -yl)methyl] pyrdi n-2-yl}ethenyl]-6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]
ridine-3-carbonitrile 14.5 5-[(E)-2-(6-{[4-(2-hydroxyethyl )piperazin-1-ylmethyl}
pyridin-2-yi)ethenyl]-6-methyl-4-[(4-methyl-1 H-indol-5-lamino ridine-3-carbonitrile 7.3 6-methyl-4-[(4-methyl-1 l+indol-5-yl)amino]-5-[(E)-2-(6-{[(2-morpholin-4-ylethyl)amino]methyl)pyrid in-2-yl) ethen I ridine-3-carbonitrile 24.6 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(6-{[(3-morpholin-4-ylpropyl)amino]methyl}pyridin-2-yl) ethen I ridine-3-carbonitrile 37.8 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{6-[(4-morpholin-4-ylpiperidi n-1-yl)methyl] pyridin-2-yl}
ethen I ridine-3-carbonitrile 13.5 5-{(E)-2-[6-(1,4'-bipipeddin-1'-ylmethyl)pyridin-2-yl]
ethenyl}-6-methyl-4-[(4-methyl-1 H-indol-5-yl) amino =dine-3-carbonitrile 8.4 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{6-[(4-pyrrolidin-1-ylpiperidin-1-yl)methyl]pyridin-2-yl}
etheny I ridine-3-carbonitrile 3.4 5-[(E)-2-{6-[(4-cyclopentylpiperazin-1-yl)methyl] pyrid in-2-yl}ethenyl]-6-methyl-4-[(4-methyl-1 H-indol-5-yl) amino ridine-3-carbonitrile 5.3 4-[(1-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-phenyl ethen I ridine-3-carbonitrile 4,699.4 6-methyl-5-[(E)-2-(6-{[4-(1-methylethyl)piperazin-1-yl]
methyl}pyridin-2-yl)ethenyl]-4-[(4-methyl-1 H-indol-5-lamino idine-3-carbonitrile . 6.2 6-methyl-5-[(E)-2-{6-[(4-methyl-1,4-diazepan-1-yl) methyl]pyridin-2-yl)ethenyl]-4-[(4-methyl-1 H-indol-5-lamino ridine-3-carbonitrle 5.6 5-{(E)-2-[6-({[3-(dimethylamino)propyl]amino}methyl) pyridin-2-yl)ethenyl)-6-methyl-4-[(4-methyl-1 H-indol-5-lamino ridine-3-carbonitrile 4.2 5-[(E)-2-(6-{[(2-ethoxyethyl)am ino]methyl}pyridin-2-yl) ethenyl]-6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]
pyridine-3-carbonitnle 17.4 5-[(E)-2-(6-{[(3-ethoxypropyl)ami nojmethyl}pyridin-2-yl) ethenyl]-6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]
ridine-3-carbonitrle 5.5 5-[(E)-2-{6-[(dimethylamino)methyl]pyrid in-2-yl}ethenyl]-6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile 19.4 6-methyl-4-[(4-methyl-1 1+indol-5-yl)amino]-5-{(E)-2-[6-({[2-(1-methyl pyrrolidin-2-yl)ethyl]amino}methyl )pyridin-2- I ethen I ridine-3-carbonitrile 4.1 5-[(E)-2-{6-[(3-hydroxypyrrol idin-1-yl)methyl]pyrid in-2-yl}ethenyl]-6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]
pyridine-3-carbonitrle 11.1 5-[(E)-2-(6-{[(2-azepan-1-ylethyl)amino]methyl}pyrid i n-2-yl)ethenyl]-6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]
pyridine-3-carbonitrile 1.8 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(6-{[(2-pyridi n-2-ylethyl )ami no]methyl}pyridin-2-yl)ethenyl]
pyridine-3-carbonitrile 15.2 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(6-{[(2-pyridin-3-ylethyl )amino]methyl}pyridin-2-yI)ethenyl) ridine-3-carbonitnle 16 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(6-{[(2-pyridin-4-ylethyl)ami no]methyl}pyridin-2-yl)ethenyl]
ridine-3-carbonitrile 12.6 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[4-(([3-(4-methylpiperazin-1-yl)propyljamino}methyl) phenyllethenyl)pyridine-3-carbonitrile 6.5 5-{(E)-2-[5-(2-azepan-1-ylethoxy)pyridin-3-yl]ethenyl}-4-4-meth l-1H-indol-5- (amino idine-3-carbonitrile 11.5 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[4-({[3-(4-methylpiperazin-1-yl)propyl]amino}methyl) phenyljethenyl)pyridine-3-carbonitrile 12.3 5-{(E)-2-[4-({[2-(dimethylamino)ethyl]amino}methyl) phenyl]ethenyl}-6-methyl-4-[(4-methyl-1 H-indol-5-yl) amino ridine-3-carbonitrile 24.6 4-[(4-methyl-1 H-indol-5-yl)aminoj-5-[(E)-2-(4-{[(2-pi perid i n-1-ylethyl )ami no]methyl}phenyl )eth enyl]
ridine-3-carbonitnle 7.5 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[5-(3-piperidin-1-ylpropoxy)pyridin-3-yl]ethenyl}pyridine-3-carbonitrile 16.4 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(5-{2-[(1-methylpiperidi n-4-yl)amino]ethoxy}pyridin-3-yl) ethen ridine-3-carbonitrile 41.2 5-{(E)-2-[5-(2-{[1-(1-methylethyl)piperidin-4-yl]amino}
ethoxy)pyridin-3-yl]ethenyl}-4-[(4-methyl-l H-indol-5-lamino ridine-3-carbonitrle 10.7 4-[(4-methyl-1 H-indol-5-yl)aminoj-5-[(E)-2-(5-{2-[(1-propylpiperidin-4-yl)amino]ethoxy}pyrid in-3-yl )ethenyl]
ridine-3-carbonitrile 15.1 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[5-(2-{[1-(2-methylpropyl)piperid in-4-yl]amino)ethoxy)pyndin-3-yl]
ethen I 'dine-3-carbonitrile 25.9 5-[(E)-2-{3-[(4-hydroxypiperidin-1-yl )methyl]phenyl) ethenyl]-4-[(4-methyl-1 H-i ndol-5-yl)amino]pyridine-3-carbonitrile 2.9 4-[(4-methyl-1 H-indol-5-yl)aminoj-5-[(E)-2-(3-{[(4-methylpiperazin-1-yl)sulfonyl]methyl}phenyl)ethenyl]
ridine-3-carbonitrile 6.2 5-[(E)-2-(4-[(3-hydroxypyrrolidin-1-yl)methyl]phenyl}
ethenyl]-6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]
pyridine-3-carbonitnle 18.7 5-{(E)-2-[4-({[3-(dimethylamino)propyl]amino}methyl) phe nyl]ethenyl}-6-methyl-4-[(4-methyl-1 H-i ndol-5-lamino ridine-3-carbonitrle 8.2 5-{(E)-2-[4-({[(1-ethylpyrrolidin-2-yl)methyl]amino}
methyl)phenyl]ethenyl)-4-[(4-methyl-1 H-indol-5-lamino 'dine-3-carbonitrile 14.9 5-[(E)-2-(4-{[(3-ethoxypropyl)ami no]methyl}phenyl) ethenyl]-6-methyl-4-[(4-methyl-1 H-indol-5-Iamino ridine-3-carbonitrle 27.9 4-[(4-methyl-1 H-indol-5-yl)aminoj-5-[(E)-2-{3-[(pyrrol id in-1-ylsulfonyl )methyl] phe nyl}ethenyl]pydd i ne-3-carbonitrile 24.5 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(4-{[(4-methyl piperazin-1-yl)sulfonyl]methyl}phenyl) ethen I ridine-3-carbonitrile 7.9 5-[(E)-2-(5-{2-[(1-ethyl piperidi n-3-yl )a m i no]ethoxy}
pyridin-3-yl)ethenyl]-4-[(4-methyl-1 H-indol-5-lamino ridine-3-carbonitrile 18.2 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[5-.(piperidin-1-ylmethyl)pyridin-2-yl]ethenyl}pyridine-3-carbonitrile 11.4 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[5-(pyrrolidi n-1-ylmethyl )pyrid in-2-yl]ethenyl}pyridine-3-carbonitrile 20.2 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino)-5-{(E)-2-[5-(morpholin-4-ylmethyl)pyridin-2-yl]ethenyl}pyridi ne-3-carbonitrile 42.3 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[5-(th iomorpholin-4-ylmethyl)pyridin-2-yl]ethenyl}pyddine-3-carbonitrle 76.5 5-[(E)-2-{5-[(4-hydroxypiperidin-1-yl)methyl]pyndi n-2-yl}ethenyl]-6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]
ridine-3-carbonitdle 33.6 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(5-{[(2-morpholin-4-ylethyl)amino]methyl}pyrid in-2-yl) ethen I ridine-3-carbonitrile 21.1 6-methyl-4-[(4-methyl-114indol-5-yl)amino]-5-[(E)-2-(5-{[(3-morpholin-4-ylpropyl)amino]methyl}pyridin-2-yl) ethen I ridine-3-carbonitrile 15.8 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(5-[ (4-mo rphol i n-4-yl pi pe rid i n-1-yl) me th yl] pyrid i n-2-yl) ethen I ridine-3-carbonitrile 10.8 5-{(E)-2-[5-(1,4'-bipiperidin-1'-ylmethyl)pyrdin-2-yl]ethenyl}-6-methyl-4-[(4-methyl-1 H-indol-5-yl) amino ridine-3-carbonitrile 11.9 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{5-[(4-pyrrolidin-1-ylpipeddin-1-yl)methyl]pyridi n-2-yl}
ethen I ridine-3-carbonitrile 12.1 5-[(E)-2- (5-[(4-cyclopentyl piperazin-1-yl)methyl]pyridin-2-yl}ethenyl]-6-methyl-4-[(4-methyl-1 H-indol-5-yl) amino ridine-3-carbonitdle 18.2 5-{(E)-2-[3-(1,4'-bipipendin-l'-ylsu Ifonyl)phenyl]vinyl}-4-4-meth -1H-indol-5- amino nicotinonitrile 1.3 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-(2-{2-meth l-4- 4-meth I i erazin-1- 46.7 I meth I hen I eth I nicotinonitrile 1'-(N,N-dimethylglycyl)-4-[(4-methyl-1 H-indol-5-yl)amino]-1',2',3',6'-tetrahydro-3,4'-bipyridine-5-carbonitrile 53.5 4-[(E)-2-{5-cyano-4-[(4-methyl-1 H-indol-5-yl)amino]
ridin-3- vin I -N-isobu Ibenzenesulfonamide 120.7 5-[(E)-2-(5-{2-[(2,2-di methylpropyl )amino]ethoxy}
pyridin-3-yl)vinyl]-4-[(4-methyl-1 H-indol-5-yl)amino]
nicotinonitrile 46.1 5-[(E)-2-(5-{2-[bis(3,3-dimethylbutyl)amino]ethoxy}
pyridin-3-yl)vinyl]-4-[(4-methyl-1 H-indol-5-yl)amino]
nicotinonitrile 344.6 5-[(E)-2-(5-{[4-(2-hydroxyethyl )piperazin-1-yI]methyl}
pyridin-2-yl)vinyl]-6-methyl-4-[(4-methyl-1 H-indol-5-amino nicotinonitrile 11.9 5-[(E)-2-{5-[(4-isopropylpiperazin-1-yl)methyl]pyndin-2-yl}vinyl]-6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]
nicotinonitrile 8.2 5-[(E -2-(5-{[(2-ethoxyethyl)amino]methyl}pyridin-2-yl)vinyl]-6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]
nicotinonitrile 25.8 5-[(E)-2-(5-{[(3-ethoxypropyl )amino]methyl}pyridin-2-yI)vinyl]-6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]
nicotinonitrile 23.9 5-[(E)-2-{5-[(d imethylamino)methyl]pyddin-2-yl}vinyl]6-meth l-4- 4-meth l-1H-indol-5- I amino nicotinonitrile 21.3 5-[(E)-2-{5-[(3-hydroxypyrrolidin-1-yl)methyl]pyddin-2-yl}vinyl]-6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]
nicotinonitrile 40.6 6-methyl-4-[(4-methyl-11-indol-5-yl)amino]-5-[(E)-2-(5-{[(2-pyridi n-3-ylethyl )a mi no]methyl}pyridin-2-yl)vinyl]
nicotinonitrile 21.9 5-[2-(6-{[4-(2-hyd roxyethyl )pi perazi n-1-yl] methyl}
pyridin-2-yl)ethyl]-4-[(4-methyl-1 H-indol-5-yl)amino]
nicotinonitrile 27.8 4-[(4-methyl-1 H-indol-5-yl)amino]-5-(2-{6-[(4-pyrrolid in-1- I i eridin-l- Imeth I ridin-2- I eth I nicotinonitrle 22 tent butyl 5-cyano-2-methyl-4-[(4-methyl-lH-indol-5-yl)amino]-3',6'-d ihydro-3,4'-bipyridine-1'(2'H)-carboxlate 111.8 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-((E)-2-(4-{[(2-morpholin-4-ylethyl )amino]methyl}phenyl) vin I nicotinonitrle 13.1 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(4-{[(2-pyrrolidin-1-ylethyl)amino]methyl}phenyl) vin I nicotinonitrile 3.7 N-carbamimidoyl-4-[(E)-2-{5-cyano-4-[(4-methyl-1 H -indol-5- Iamino ridin-3- 1 vin Ibenzenesulfonamide 15.6 4-[(E)-2-{5-cyano-4-[(4-methyl-1 H-indol-5-yl)amino]
ridin-3- I vin Ibenzenesulfonamide 5.4 2-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-1',2',3',6'-tetrah dro-3 4'-bi ridine-5-carbonitdle 557.2 1'-benzyl-2-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-I',2',3',6'-tetrah dro-3 4'-bi ridine-5-carbonitrile 8.4 2-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-1'-[(1-methylpiperidin-4-yl)methyl]-1',2',3',6'-tetrahydro-3,4'-bi ridine-5-carbonitrile 117.3 2-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-1-(methylsulfonyl)-1',2',3',6'-tetrahydro-3,4'-bipyridine-5-carbonitrile 19.8 5-{2-[6-(1,4'-bipiperidin-l'-ylmethyl)pyridin-2-yl]ethyl}-4-4-meth l-1H-indol-5- amino nicotinonitrile 15.8 5-[2-(6-{[4-(dimethylamino)piperidi n-1-yl]methyl}pyridin-2-yl)ethyl]-4-((4-methyl-1 H-indol-5-yl)amino]
nicotinonitrile 5.8 5-{2-[6-(hyd roxymethyl)pyridin-2-yl]ethyl)-4-[(4-methyl-1H-indol-5- mino nicotinonitnle NA
3-[(E)-2-{5-cyano-4-[(4-methyl-1 H-indol-5-yl)amino]
ridin-3- vin I benzenesulfonamide 2.7 4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{4-[(pyrrolidin-1-ylsulfonyl)methyl] phenyl}vinyl]
nicotinonitrile 7 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[3-(pyrrolidin-1- lsulfon I hen in I icotinonitrile 6 4-[(4-methyl-1 H-indol-5-yl)amino)-5-[(E)-2-{3-[(4-methyl piperazin-1 - sulfon I hen I vin I nicotinonitnle 0.5 2-({6-[(E)-2-{5-cyano-4-[(4-methyl-1 H-indol-5-yl) amino]pyddin-3-yl}vinyl]pyridin-2-yl}methoxy)ethyl sulfate 12.5 4-[(4-methyl-1 H-indol-5-yl)aminoj-5-{(E)-2-[4-(2H-tetrazol-5- I hen I in I nicotinonitrile 131.6 5-{(E)-2-[3-(1,4'-bipiperidin-1'-ylmethyl)phenyl]vinyl}-4-4-meth l-1H-indol-5- amino niootinonitrile 3.1 5-[(E)-2-(4-{[4-(dimethylamino)pipedd in-1-yl]methyl}
phenyl)ethenyl]-4-[(4-methyl-1 H-indol-5-lamino ridine-3-carbonitnle 1.3 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[3-(morphol in-4-ylmethyl)phenyl]ethenyl}pyridine-3-carbonitrile 27.6 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{3-[(4-methylpiperazin-1-yl)methyl]phenyl}ethenyl]pyridine-3-carbonitrile 6.1 5-[(E)-2-(3-[(4-hydroxypipendin-1-yl)methyl]phenyl}
ethenylj-6-methyl-4-[(4-methyl-1 H-indol-5-yl )amino]
pyridine-3-carbonitrile 15.8 4-(1 H-indol-5-ylamino)-5-[(E)-2-pyridin-2-ylethenyl]
pyridine-3-carbonitnle 23.9 6-methyl-5-[(E)-2-(3-{[4-(1-methylethyl)piperazin-l-yl]methyl}phenyl)ethenyl]-4-[(4-methyl-1 H-indol-5-yi) amino ridine-3-carbonitrile 9 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[3-(pyrrolidi n-1-ylmethyl)phenyl]ethenyl}pyridine-3-carbonitrile 14 6-methyl-4-[(4-methyl-114-indol-5-yl)amino]-5-{(E)-2-[3-(th iomorpholin-4-ylmethyl)phenyl]ethenyl}pyridine-3-carbonitrile 7.1 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[4-(pyrrolidin-1-ylsulfonyl )phenyl]ethenyl}pyridine-3-carbonitrile 20.5 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{4-[(4-methylpiperazi n-1-yl)sulfonyl]phenyl}ethenyl]
ridine-3-carbonitrile 9.3 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-{3-[(4-methylpiperazin-1-yl )sulfonyl]phenyl}ethenyl]
ridine-3-carbonitrile 0.4 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[3-(pipendin-1-ylsulfonyl)phenyl]ethenyl}pyridine-3-carbonitrile 4.8 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[3-(pyrrolidi n-1-ylsulfonyl )phenyl]ethenyl}pyridine-3-carbonitrile 2.4 5-{(E)-2-[2-(hydroxymethyl)-1,3-thiazol-4-yl]ethenyl}-4-4-meth l-1H-indol-5- amino ridine-3-carbonitrile 6.7 5-[(E)-2-(4-{[(1 H-indol-3-ylmethyl)(methyl)amino]
methyl}phenyl)ethenyl]-4-[(4-methyl-1 H-indol-5-lamino ridine-3-carbonitrile 2.5 5-[(E)-2-{3-[(d iethylamino)methyl]phenyl)ethenyl]-6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile 19.9 5-[(E)-2-(4-{[(2-methoxyethyl)amino]methyl}
phenyl )ethenyl]-4-[(4-methyl-1 H-indol-5-yl)amino]
ridine-3-carbonitrile 5.2 5-[(E)-2-(4-([(2-ethoxyethyl)amino]methyl}phenyl) ethenyl]-4-[(4-methyl-1H-indol-5-yl)amino] pyridine-3-carbonitrile 6.3 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[4-({[2-(1-methyl pyrrol idi n-2-yl )ethyl]a mi no}methyl )phenyl]
ethen I 'dine-3-carbonitrile 0.9 5-[(E)-2-(4-{[(2-azepan-1-ylethyl )amino]methyl}phenyl).
ethenyl]-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile 2.0 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-(2-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}ethyl)pyridine-3-carbonitrile 11.1 6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-[2-(4-meth Then eth I ridine-3-carbonitrile 23.8 4-[(E)-2-{5-cyano-4-[(4-methyl-1 H-indol-5-yl)amino]
ridin-3- ethen I N N-dimeth lbenzenesulfonamide 11.0 4-[(E)-2-{5-cyano-4-[(4-methyl-1 H-indol-5-yl)amino]
ridin-3- I ethen I N,N-dieth benzenesulfonamide 8.7 4-[(E)-2-(5-cyano-4-[(4-methyl-1 H-indol-5-yl)amino]
ridin-3- I ethen I N N-di rolbenzenesulfonamide 354 4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[4-(piperidin-1-Isulfon I hen ethen I ridine-3-carbonitrle 11.5 4-[(4-methyl-1 H-indol-5-yl)amino]-5-((E)-2-[3-(piperidin-1-Isulfon I hen I ethen I ridine-3-carbonitrile 3.0 5-[(E)-2-{5-[(d iethylamino)methyljpyridin-2-yl}ethenyl]-4-4-meth l-1H-indol-5- I amino 'dine-3-carbonitrile 15.8 5-[(E)-2-(6-{[4-(dimethylamino)piperid in-1-yl]methyl}
pyridin-2-yl)ethenyl]-6-methyl-4-[(4-methyl-1 H-indol-5-lamino idine-3-carbonitnle 7.0 5-[(E)-2-{6-[(diethylamino)methyl]pyridin-2-yl}ethenyl]-6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile 66.3 5-[(E)-2-{6-[(diethylamino)methyljpyridin-2-yl}ethenyl]-4-4-meth l-1H-indol-5- I amino 'dine-3-carbonitrile 3.1 4-[(E)-2-{5-cyano-4-[(4-methyl-1 H-indol-5-yl)amino]
pyridin-3-yl}ethenyl}-N,N-bis(1-methylethyl) benzenesulfonamide 405 5-[(E)-2-(3-{[(2-azepan-1-ylethyl)ami no]methyl}
phenyl)ethenyl]-4-[(4-methyl-1 H-indol-5-yl)amino]
pyridine-3-carbonitrile 2.3 5-[(E)-2-(3-{[(3-ethoxypropyl)amino]methyl}
phenyl)ethenyl]-4-[(4-methyl-1 H-indol-5-yl)amino]
pyridine-3-carbonitrile 4.6 5-[(E)-2-(3-{[(2-ethoxyethyl)amino]methyl}phenyl) ethenyl]-4-[(4-methyl-1 H-i ndol-5-yl)amino]pyridin a-3-carbonitrile 4.6 5-[(E)-2-{3-[(dimethylamino)methyl]phenyl}ethenyl]-4-4-meth l-1H-indol-5- I mino ridine-3-carbonitrle NA
6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(4-{[(4-methylpiperazin-1-yl)sulfonyl]methyl}phenyl) ethen I ridine-3-carbonitrile NA
6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(3-{[(4-methylpiperazin-1-yl )sulfonyl]methyl}phenyl) ethen I ridine-3-carbonitrile NA
6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[4-(piperid in-1-ylsu lfonyl)phenyl]ethenyl}pyridine-3-carbonitrile NA
4-[(E)-2-{5-cyano-2-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]pyridin-3-yl}ethenyl]-N,N-dimethyl benzenesulfonamide NA
4-[(E)-2-{5-cyano-2-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]pyridin-3-yl}ethenyl]-N,N-diethyl benzenesulfonamide NA

4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(4-{[4-(methylsu lfonyl)pi perazin-1-yl]methyl}phenyl)ethenyl]
pyridine-3-carbonitrile NA
6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[3-({[3-(4-methylpiperazin-1-yl)propyl]amino}methyl) hen I ethen I ridine-3-carbonitrile NA
5-[(E)-2-(4-{[(2-azepan-1-ylethyl )amino]methyl}phenyl) ethenyl]-6-methyl-4-[(4-methyl-1 H-indol-5-yl )amino]
ridine-3-carbonitrile NA
5-[(E)-2-(3-{[(3-ethoxypropyl)ami no]methyl}phenyl) ethenyl]-6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]
ridine-3-carbonitrile NA
6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[4-({[2-(2-methylpyrrolidin-1-yl)ethyl]amino}methyl) phenyl]ethenyl)pyridine-3-carbonitrile NA
4-[(4-methyl-1 H-indol-5-yl)amino]-5-{(E)-2-[2-(pyrrolidin-1-ylmethyl)-1,3-thiazol-4-yl]ethe nyl}pyridine-3-carbonitrile NA
6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]-5-[(E)-2-(4-{[(2-pyridin-3-ylethyl)ami no]methyl}phenyl) ethen I ridine-3-carbonitrile 12.8 'NA' indicates data has not been measured [00606] Many variations of the present invention not illustrated herein will occur to those skilled in the art. The present invention is not limited to the embodiments illustrated and described herein, but encompasses all the subject matter within the scope of the appended claims.

Claims (38)

1. A compound of formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
X is -O- or -N(R10)-; wherein R10 is H or CH3;
G is ; wherein:

R11 is, independently at each occurrence, selected from halo, -O-R12", C1-4 alkyl, -CF3 and -N(R12")-R12";

R12'is, independently at each occurrence, H or CH3;

R 12" is, independently at each occurrence, H or CH3; and p is 0, 1 or 2;

J is (i) -Q-(A1)q-;

; wherein:

Q is, independently at each occurrence, C1-4 alkylene;

A1 is (i) a C6-10 aryl, (ii) a 5- to 10-membered hetero1-3aryl, (iii) 3- to 10-membered hetero1-3cyclyl or (iv) a 5- to 8-membered cycloalkyl, wherein each of (i)-(iv) is optionally substituted with 1 or 2 substituents independently selected from halo, -O-R13, C1-4 alkyl, C1-4 haloalkyl, formyl, -S-R13, -Q-O-R13, -Q-N(R13)-R13, -C(O)-O-R13, -C(O)-R13, -O-C(O)-R13, -C(O)-N(R13)-R13, -N(R13)-C(O)-R13, -S(O)2-N(R13)-R13, -N(R13)-S(O)2-R13, -O-Q-O-R13, -O-Q-N(R13)-R13, -N(R13)-Q-O-R13, -N(R13)-Q-N(R13)-R13, -O-C(O)-N(R13)-R13, -N(R13)-C(O)-O-R13, -S(O)2-R13, -SO2NH(NH)NH2, -SO2NH(NH)NR13R13 or wherein 2 substituents together on the same carbon atom form an oxo group;

R12 is, independently at each occurrence, H or CH3;
m and q are independently 0 or 1;

E is N or C(R12'); wherein:

when E is N, .gamma. is absent, -C(O)-, -C(O)-O-, -C(O)-N(R 13)- or -S(O)2-;
and when E is C(R12), .gamma. is -O-, -C(O), -C(O)-0-, -O-C(O)-, -C(O)-N(R13)-, -O-C(O)-N(R13)-, -N(R13)-C(O)-, -N(R13)-C(O)-O-, -N(R13)-C(O)-N(R13)-, -S-, -S(O)-, -S(O)2-, -S(O)2-N(R13)- or -N(R13)-S(O)2-;

R13 is, independently at each occurrence, selected from (i) an, electron pair, (ii) H, (iii) C1-6 alkyl, (iv) C6-10 aryl, (v) 5- to 10-membered heteroaryl, (vi) 3- to 10-membered hetero1-3cyclyl or (vii) two R13 together on the same carbon atom form a 4- to 8-membered ring containing 1-3 heteroatoms, wherein each of (iii)-(vi) is optionally substituted with 1-2 R14; and R14 is, independently at each occurrence, (i) H, (ii) oxo when two R14 together on the same carbon atom are bound to an oxygen atom, iii) C1-6 alkyl, (iv) C3-8 cycloalkyl, (v) C6-10 aryl, (vi) 5- to 10-membered heteroaryl, (vii) 3- to 10-membered heterol-3cyclyl, wherein each of (iii)-(vii) is optionally substituted with 1-2 C1-6 alkyl;

R1 is C1-4 alkyl, C2-4 alkenyl or -(L)r-(A2-A3), wherein:

L is -(T)t-(Q)u-, -(Q)u-(T)t, or -(T)r-(Q)u-(T)t-, wherein:

T is, independently at each occurrence, -O-, -C(O)-, -C(O)-O-, -O-C(O)-, -C(O)-N(R13)-, -O-C(O)-N(R13)-, -N(R13)-, -N(R13)-C(O), -N[C(O)R13]-, -N(R13)-C(O)-O-, -N(R13)-C(O)-N(R13)-, -S-, -S(O)-, -S(O)2-, -S(O)2-N(R13)- or -N(R13)-S(O)2-;

t is, independently at each occurrence, 0 or 1;
u is, independently at each occurrence, 0 or 1;
r is, independently at each occurrence, 0 or 1;

A2 is (i) absent, (ii) C1-6 alkylene, (iii) a C6-10 arylene, (iv) 5- to 10-membered heteroarylene, (v) 3- to 10-membered hetero1-3cyclylene or (vi) C3-8 cycloalkylene, wherein each of (ii)-(vi) is optionally substituted with 1 or 2 substituents independently selected from halo, -O-R13, C14 alkyl, CI-4 haloalkyl, -S-R13, -N(R13)R13, -Q-O-R13, -Q-N(R13)-R13, -C(O)-O-R13, -O-C(O)-R13, -C(O)-N(R13)-R13, -N(R13)-C(O)R13, -S(O)2-N(R13)-R13, -N(R13)-S(O)2-R13, -O-Q-O-R13, -O-Q-N(R13)-R13, -N(R13)-Q-O-R13, -N(R13)-Q-N(R13)-R13, -O-C(O)-N(R13)-R13, -N(R13)-C(O)-O-R13, -S(O)2-R13, -OS(O)2-OR13,-C(O)-R13 and oxo when 2 substituents together on the same carbon atom are bound to an oxygen atom; and A3 is (i) H, (ii) halo, (iii) -O-R14 (iv) R13, (v) -CHO, (vi) -S(O)-O-R13, (vii) -N(R13)R13 (viii) C6-C10 aryl, (ix) 5- or 6-membered heteroaryl, (x) 3- to 10-membered hetero1-3cyclyl or (xi) C3-8 cycloalkyl, wherein each of (viii)-(xi is optionally substituted with 1 or 2 substituents independently selected from halo, -O-R13, C1-4 alkyl, C1-4 haloalkyl, -S-R13, -N(R13)R13, -Q-O-R13, -Q-N(R13)-R13, -C(O)-O-R13, -O-C(O)-R13, -C(O)-N(R13)-R13, -N(R13)-C(O)-R13, -S(O)2-N(R13)-R13, -N(R13)-S(O)2-R13, -O-Q-O-R13, -O-Q-N(R13)-R13, -N(R13)-Q-O-R13, -N(R13)-Q-N(R13)-R13, -O-C(O)-N(R13)-R13, -N(R13)-C(O)-O-R13, -S(O)2-R13, -C(O)-R13 and oxo when 2 substituents together on the same carbon atom are bound to an oxygen atom;

and R2 is H, C1-4 alkyl or -CF3.

2. The compound of claim 1, wherein X is -N(R10)- and R10 is H.

3. The compound of claims 1 or 2, wherein R2 is H or methyl.

4. The compound of claims 1 or 2, wherein G is

5. The compound of any of claims 1-4, wherein R12' is H.

6. The compound of any of claims 1-5, wherein each R11 is, independently at each occurrence, chloro or methyl.

7. The compound of any of claims 1-6, wherein G is indol-4-yl, indol-5-yl, 2-methylindol-5-yl, 4-methylindol-5-yl, 2,4-dimethylindol-5-yl, 4,7-dimethylindol-5-yl, 4-methyl-7-chloroindol-5-yl or indol-6-yl.

8. The compound of any of claims 1-7, wherein J is -Q-(A1)q-.

9. The compound of any of claims 1-7, wherein J is ; and wherein q = 1.

10. The compound of any of claims 1-9, wherein R12 is H.

11. The compound of any of claims 1-10 wherein A1, where present, is optionally substituted C6-10 arylene or optionally substituted 5- to 10-membered hetero1-3arylene.

12. The compound of claim 9, wherein:

J is ; R12 is H; m is 0;

R2 is H; X is -(NR10)- and A1 is optionally substituted C6-10 arylene or optionally substituted 5- to 10-membered hetero1-3arylene.

13. The compound of any of claims 1-12, wherein Q, where present, is methylene, ethylene or trimethylene.

14. The compound of claim 1, wherein J is ; and wherein E = N.

15. The compound of claim 12, wherein:

J is ; each R12 is H; m is 0;

R2 is H; X is -(NR10)-; A1 is phenylene, pyridinyl, thiazolyl, or furanyl, each of which is optionally substituted; and R1 is -(L)r-(A2-A3), wherein L is -(T)t(Q)u- or -(Q)u(T)t-.

16. The compound of claim 15, wherein t is 0, u is 1 and L is -Q-, wherein Q
is methylene.

17. The compound of any of claims 1-16, wherein A1, where present, is phenylene, pyridinyl, thiazolyl or furanyl, each of which is optionally substituted.

18. The compound of claim 15, wherein A1 is optionally substituted phenylene, T is -O-, u is 1 and A3 is 3- to 7-membered hetero1-3cycyl.

19. The compound of any of claims 1-18, wherein A2 is absent.

20. The compound of any of claims 1-18, wherein A2, where present, is morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, azetidinyl, thiomorpholinyl, thiomorpholinyl-1,1-dioxide, 1,3-dioxoisoindolyl, oxopiperazinyl, 1,4-diazepanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 1,2,3,4-tetrahydroisoquinolinyl, indolinyl or cyclohexyl, wherein A2 is optionally substituted.

21. The compound of any of claims 1-18, wherein A2 may be present or absent and -(A2-A3), where present, is:

22. A compound of any of claims 1-21, wherein A3, when present, is -NR13R13, 5-to 10-membered heteroarylene or 3- to 10-membered hetero1-3cyclylene, and wherein A3 contains a nitrogen atom, joined via the nitrogen atom to A2, when present, or when A2 is absent, joined via the nitrogen atom to an adjacent atom.

23. A compound according to claim 1 wherein J is J(ii) or J(iii) and -(Q),(A1)q-R1 is:
(B1) -A3, wherein m, q and r are 0 and A2 is absent and A3 is as defined in claim 1; or (B2) -A1-A2-A3, wherein m is 0, q is 1, and r is 0 and wherein A1 and A3 are as defined in claim 1 and A2 is C1-6 alkylene; or (B3) -A2-A3, wherein m, q and r are 0 and A2 and A3 are as defined in claim 1;
or (B4) -A1-T-A3, wherein m is 0, q is 1, A2 is absent, r is 1 and L is -T- and A1, T
and A3 are as defined in claim 1; or (B5) -A1-T-A2-A3, wherein m is 0, q and r are 1 and L is -T- and A1, T, A2 and are as defined in claim 1; or (B6) -A1-Q-T-A2-A3, wherein m is 0, q and r are 1 and L is-Q-T- and A1, T, A2 and A3 are as defined in claim 1; or (B7) A1-Q-A2-A3, wherein m is 0, q and r are 1 and L is -Q- and A1, Q, A2 and are as defined in claim 1.

24. A compound according to claim 23 wherein J is J(ii) or J(iii) and:

(Cl) (Q)m (A1)q-R1 is B1 and A3 is optionally substituted C6-C10 aryl, 5- or 6-membered heteroaryl, 3- to 10-membered hetero1-3cyclyl or C3-8 cycloalkyl;
or (C2) -(Q)m-(A1)q-R1 is B2 and A1 is optionally substituted C6-C10 aryl or optionally substituted 5- to 10- membered hetero1-3aryl, and A3 is -N(R13)R13 or optionally substituted 3- to 10-membered hetero1-3cyclyl wherein at least one heteroatom is a nitrogen atom and A3 is joined via the nitrogen atom to A2.
(C3) -(Q)m-(A1)q-R1 is B3 and -(A2-A3) is:
or (C4) -(Q)m-(A1)q-R1 is B4 and A1 is optionally substituted C6-10 aryl or optionally substituted 5- to 10-membered hetero1-3aryl and A3 is optionally substituted 3- to 10-membered hetero1-3cyclyl and T is -O-, -NH-, -C(O)-, or -C(O)-NH- or -S(O)2- ; or (C5) -(Q)m-(A1)q-R1 is B5 and A2 is alkylene and A1 is optionally substituted aryl or optionally substituted 5- to 10-membered hetero1-3aryl and A3 is optionally substituted 3- to 10-membered hetero1-3cyclyl and T is -O-, -C(O), or -C(O)-NH- or -S(O)2-; or (C6) -(Q)m-(A1)q-R1 is B6 and A1 is optionally substituted C6-10 aryl or optionally substituted 5- to 10-membered hetero1-3aryl and A2 is alkylene or is absent, T is -O-, -NH-, -C(O)-, -C(O)-NH- or -S(O)2- and A3 is -N(R13)R13 or optionally substituted 3- to 10-membered hetero1-3cyclyl; or (C7) -(Q)m-(A1)q-R1 is B7 and A1 is optionally substituted C6-10 aryl or optionally substituted 5- to 10-membered hetero,-3aryl and wherein -(A2-A3) or -A3 when A2 is absent is:

25. A compound, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

4-[(4-methyl-1H-indol-5-yl)amino]-5-{(1E)-3-[(2-morpholin-4-ylethyl)amino]prop-1-en-1-yl}
nicotinonitrile;

N-{1-[(3E)-4-{5-cyano-4-[(4-methyl-1H-indol-5-yl)amino]pyridin-3-yl}but-3-en-1-yl]piperidin-4-yl}
propane-2-sulfonamide;

5-{(1E)-4-[4-(isopropylsulfonyl)piperazin-1-yl]but-1-en-1-yl}-4-[(4-methyl-1H-indol-5-yl) amino]nicotinonitrile;

N-{1-[(3E)-4-{5-cyano-4-[(4-methyl-1H-indol-5-yl)amino]pyridin-3-yl}but-3-en-1-yl]piperidin-4-yl}
ethanesulfonamide;

N-{1-[(3E)-4-{5-cyano-4-[(4-methyl-1H-indol-5-yl)amino]pyridin-3-yl}but-3-en-1-yl]piperidin-4-yl}
benzenesulfonamide;

5-{(1E)-4-[(3R)-3-aminopyrrolidin-1-yl]but-1-en-1-yl}-4-[(4-methyl-1H-indol-5-yl)amino]
nicotinonitrile;

(3E)-4-{5-cyano-4-[(4-methyl-1H-indol-5-yl)amino]pyridin-3-yl}but-3-en-1-yl (3R)-3-amino pyrrolidine-1-carboxylate;

5-{(1E)-4-[(3S)-3-aminopyrrolidin-1-yl]but-1-en-1-yl}-4-[(4-methyl-1H-indol-5-yl)amino]
nicotinonitrile;

5-[(1E)-4-(3-aminoazetidin-1-yl)but-1-en-1-yl]-4-[(4-methyl-1H-indol-5-yl)amino] nicotinonitrile;
5-[(1E)-4-(1,4-diazepan-1-yl)but-1-en-1-yl]-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile;
5-((1E)-4-[4-(methylamino)piperidin-1-yl]but-1-en-1-yl}-4-[(4-methyl-1H-indol-5-yl)amino]
nicotinonitrile;

5-{(1E)-4-[(3R)-3-aminopiperidin-1-yl]but-1-en-1-yl}-4-[(4-methyl-1H-indol-5-yl)amino]
nicotinonitrile;

5-{(1E)-4-[(3S)-3-aminopiperidin-1-yl]but-1-en-1-yl}-4-[(4-methyl-1H-indol-5-yl)amino]
nicotinonitrile;

5-{(1E)-4-[4-(aminomethyl)piperidin-1-yl]but-1-en-1-yl}-4-[(4-methyl-1H-indol-5-yl)amino]
nicotinonitrile;

5-[(1E)-4-(2,5-diazabicyclo[2.2.1]hept-2-yl)but-1-en-1-yl]-4-[(4-methyl-1H-indol-5-yl)amino]
nicotinonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-[(1E)-4-(4-phenylpiperidin-1-yl)but-1-en-1-yl] nicotinonitrile;
5-{(1E)-4-[4-(dimethylamino)piperidin-1-yl]but-1-en-1-yl}-4-[(4-methyl-1H-indol-5-yl)amino]
nicotinonitrile;

5-[(1E)-4-(4-hydroxypiperidin-1-yl)but-1-en-1-yl]-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile;
4-[(4-methyl-1H-indol-5-yl)amino]-5-[(1E)-4-(4-morpholin-4-ylpiperidin-1-yl)but-1-en-1-yl]
nicotinonitrile;

1'-glycyl-4-[(4-methyl-1H-indol-5-yl)amino]-1',2',3',6'-tetrahydro-3,4'-bipyridine-5-carbonitrile;
1'-(2-methylalanyl)-4-[(4-methyl-1H-indol-5-yl)amino]-1',2',3',6'-tetrahydro-3,4'-bipyridine-5-carbonitrile;

1'-.beta.-alanyl-4-[(4-methyl-1H-indol-5-yl)amino]-1',2',3',6'-tetrahydro-3,4'-bipyridine-5-carbonitrile;
4-[(4-methyl-1H-indol-5-yl)amino]-1'-D-valyl-1',2',3',6'-tetrahydro-3,4'-bipyridine-5-carbonitrile;
4-[(4-methyl-1H-indol-5-yl)amino]-1'-1-valyl-1',2',3',6'-tetrahydro-3,4'-bipyridine-5-carbonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-1'-D-prolyl-1',2',3',6'-tetrahydro-3,4'-bipyridine-5-carbonitrile;
4-[(4-methyl-1H-indol-5-yl)amino]-1'-L-prolyl-1',2',3',6'-tetrahydro-3,4'-bipyridine-5-carbonitrile;
4-[(4-methyl-1H-indol-5-yl)amino]-1'-(pyrrolidin-3-ylcarbonyl)-1',2',3',6'-tetrahydro-3,4'-bipyridine-5-carbonitrile;

5-{(1E)-4-[(3R)-3-hydroxypiperidin-1-yl]but-1-en-1-yl}-4-[(4-methyl-1H-indol-5-yl)amino]
nicotinonitrile;

5-{(1E)-4-[(3S)-3-hydroxypiperidin-1-yl]but-1-en-1-yl}-4-[(4-methyl-1H-indol-5-yl)amino]
nicotinonitrile;

5-[(E)-2-(4-formylphenyl)vinyl]-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile;
4-[(4-methyl-1H-indol-5-yl)amino)-5-[(E)-2-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}
vinyl]nicotinonitrile;

5-[(E)-2-(4-fluorophenyl)vinyl]-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile;
4-[(2,4-dimethyl-1H-indol-5-yl)amino]-5-[(E)-2-{5-[(4-methylpiperazin-1-yl)methyl]pyridin-2-yl}
vinyl]nicotinonitrile;

5-benzyl-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile;
6-ethyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-phenylvinyl]nicotinonitrile;
6-isopropyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-phenylvinyl]nicotinonitrile;
5-{(E)-2-[2-methoxy-4-(piperazin-1-ylmethyl)phenyl]vinyl}-4-[(4-methyl-1H-indol-5-yl)amino]
nicotinonitrile;

6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[4-(2-pyrrolidin-1-ylethoxy)phenyl]
vinyl}nicotinonitrile;

5-(2-{2-methoxy-4-[(4-methylpiperazin-1-yl)methyl]phenyl}ethyl)-4-[(4-methyl-1H-indol-5-yl) amino]nicotinonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-(2-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}ethyl) nicotinonitrile;

4-[(4-methyl-1H-indol-5-yl)oxy]-5-[(E)-2-phenylvinyl]nicotinonitrile;
4-[(E)-2-{5-cyano-4-[(4-methyl-1H-indol-5-yl)amino]pyridin-3-yl}vinyl]-N-phenylpiperidine-1-carboxamide;

4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[1-(phenylsulfonyl)piperidin-4-yl]vinyl} nicotinonitrile;
5-[(E)-2-(1-benzoylpiperidin-4-yl)vinyl]-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[1-(3-phenylpropanoyl)piperidin-4-yl]vinyl}
nicotinonitrile;

4-[(E)-2-(5-cyano-4-[(4-methyl-1H-indol-5-yl)amino]pyridin-3-yl}vinyl]-N-propylpiperidine-1-carboxamide;

5-{(E)-2-[1-(isopropylsulfonyl)piperidin-4-yl]vinyl}-4-[(4-methyl-1H-indol-5-yl)amino]
nicotinonitrile;

5-{(E)-2-[4-(dimethylamino)phenyl]vinyl}-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile;
4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-{6-[(2-piperidin-1-ylethyl)amino]pyridin-3-yl}ethenyl]
pyridine-3-carbonitrile;

5-{(E)-2-[5-({[3-(dimethylamino)propyl]amino}methyl)pyridin-2-yl]ethenyl}-4-[(4-methyl-1H-indol-5-yl)amino]pyridine-3-carbonitrile;

5-[(E)-2-(6-{[(3-ethoxypropyl)amino]methyl}pyridin-2-yl)ethenyl]-4-[(4-methyl-1H-indol-5-yl) amino]pyridine-3-carbonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-(5-{[(2-pyridin-3-ylethyl)amino]methyl}pyridin-2-yl)ethenyl]pyridine-3-carbonitrile;

5-{(E)-2-[3-(1,4'-bipiperidin-1'-ylmethyl)phenyl]ethenyl}-4-[(4-methyl-1H-indol-5-yl)amino]
pyridine-3-carbonitrile;

5-[(E)-2-(3-{[4-(1-methylethyl)piperazin-1-yl]methyl}phenyl)ethenyl]-4-[(4-methyl-1H-indol-5-yl) amino]pyridine-3-carbonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[3-(morpholin-4-ylmethyl)phenyl]ethenyl} pyridine-3-carbonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-(3-{[(2-morpholin-4-ylethyl)amino]methyl}phenyl) ethenyl]pyridine-3-carbonitrile;

5-[(E)-2-(3-{[4-(dimethylamino)piperidin-1-yl]methyl}phenyl)ethenyl]-4-[(4-methyl-1H-indol-5-yl)amino]pyridine-3-carbonitrile;

5-[(E)-2-{3-[(4-methyl-1,4-diazepan-1-yl)methyl]phenyl}ethenyl]-4-[(4-methyl-1H-indol-5-yl)amino]pyridine-3-carbonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[3-({[2-(1-methylpyrrolidin-2-yl)ethyl]amino}
methyl)phenyl]ethenyl}pyridine-3-carbonitrile;
5-{(E)-2-[3-({[2-(dimethylamino)ethyl]amino}methyl)phenyl]ethenyl}-4-[(4-methyl-1H-indol-5-yl)amino]pyridine-3-carbonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[3-({[3-(2-oxopyrrolidin-1-yl)propyl]amino}
methyl)phenyl]ethenyl}pyridine-3-carbonitrile;

5-[(E)-2-(3-{[(2-methoxyethyl)amino]methyl}phenyl)ethenyl]-4-[(4-methyl-1H-indol-5-yI)amino]pyridine-3-carbonitrile;

6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[3-(piperidin-1-ylmethyl)phenyl] ethenyl}
pyridine-3-carbonitrile;

5-{(E)-2-[3-(1,4'-bipiperidin-1'-ylmethyl)phenyl]ethenyl}-6-methyl-4-[(4-methyl-1H-indol-5-yl) amino]pyridine-3-carbonitrile;

6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-{3-[(4-pyrrolidin-1-ylpiperidin-1-yl)methyl]
phenyl}ethenyl]pyridine-3-carbonitrile;

5-[(E)-2-(3-{[4-(2-hydroxyethyl)piperazin-1-yl]methyl}phenyl)ethenyl]-6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]pyridine-3-carbonitrile;

5-[(E)-2-(3-{[4-(dimethylamino)piperidin-1-yl]methyl}phenyl)ethenyl]-6-methyl-4-[(4-methyl-1H-indol-5-yl )amino]pyridine-3-carbonitrile;

6-methyl-4-[(4-methyl-1H-indol-5-yl )amino]-5-[(E)-2-{3-[(4-morpholin-4-ylpiperidin-1-yl)methyl]
phenyl}ethenyl]pyridine-3-carbonitrile;

6-methyl-5-[(E)-2-{3-[(4-methyl-1,4-diazepan-1-yl)methyl]phenyl}ethenyl]-4-[(4-methyl-1H-indol-5-yl)amino]pyridine-3-carbonitrile;

5-{(E)-2-[3-({[3-(di methylamino)propyl]amino}methyl)phenyl]ethenyl}-6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]pyridine-3-carbonitrile;

5-{(E)-2-[3-({[2-(dimethylamino)ethyl]amino}methyl)phenyl]ethenyl}-6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]pyridine-3-carbonitrile;

6-methyl-5-[(E)-2-{5-[(4-methyl-1,4-diazepan-1-yl)methyl]pyridin-2-yl}vinyl]-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile;

5-{(E)-2-[5-({[3-(dimethylamino)propyl]amino}methyl)pyridin-2-yl]vinyl}-6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile;

6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[5-({[2-(1-methylpyrrolidin-2-yl) ethyl]amino}
methyl)pyridin-2-yl]vinyl}nicotinonitrile;

5-[(E)-2-(5-{[(2-azepan-1-ylethyl)amino]methyl}pyridin-2-yl)vinyl]-6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile;

6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E}2-(5-{[(2-pyridin-2-ylethyl)amino]methyl}
pyridin-2-yl)vinyl]nicotinonitrile;

6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-(5-{[(2-pyridin-4-ylethyl)amino]methyl}
pyridin-2-yl)vinyl]nicotinonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-1'-[(1-methylpiperidin-4-yl)methyl]-1',2',3',6'-tetrahydro-3,4'-bipyridine-5-carbonitrile;

6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-(3-{[(3-morpholin-4-ylpropyl)amino] methyl}
phenyl)vinyl]nicotinonitrile;

6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-(3-{[(2-pyrrolidin-1-ylethyl)amino] methyl}
phenyl)ethenyl]pyridine-3-carbonitrile;

5-[(E)-2-{3-[(dimethylamino)methyl]phenyl}ethenyl}-6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]
pyridine-3-carbonitrile;

5-[(E)-2-{3-[(3-hydroxypyrrolidin-1-yl)methyl]phenyl}ethenyl]-6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]pyridine-3-carbonitrile;

6-ethyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-(2-phenylethyl)pyridine-3-carbonitrile;
4-[(4-methyl-1H-indol-5-yl)amino]-5-[(4-methylpiperazin-1-yl)methyl]pyridine-3-carbonitrile;
5-(3,4-dimethoxybenzyl)-4-(1H-indol-5-ylamino)nicotinonitrile;
5-(3,4-dimethoxybenzyl)-4-(1H-indol-4-ylamino)nicotinonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-phenylvinyl]nicotinonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-[(1E)-3-pyrrolidin-1-ylprop-1-en-1-yl]nicotinonitrile;
4-[(4-methyl-1H-indol-5-yl)amino]-5-[(1E)-3-(4-phenylpiperazin-1-yl)prop-1-en-1-yl]
nicotinonitrile;

4-[(4methyl-1H-indol-5-yl)amino]-5-[(1E)-3-(4-methylpiperazin-1-yl)prop-1-en-1-yl]
nicotinonitrile;

tert-butyl 5-cyano-4-[(4-methyl-1H-indol-5-yl)amino]-3',6'-dihydro-3,4'-bipyridine-1'(2'H)-carboxylate;

4-[(4-methyl-1H-indol-5-yl)amino]-5-[(1E)-3-morpholin-4-ylprop-1-en-1-yl]nicotinonitrile;

5-[(1E)-3-(3,4-dihydroisoquinolin-2(1H)-yl)prop-1-en-1-yl]-4-[(4-methyl-1H-indol-5-yl) amino]
nicotinonitrile;

4-[(4methyl-1H-indol-5-yl)amino]-5-[(1E)-4-(4-methylpiperazin-1-yl)but-1-en-1-yl] nicotinonitrile;
5-[(1E)-3-aminoprop-1-en-1-yl]-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile;
4-[(4-methyl-1H-indol-5-yl)amino]-5-[(1E)-4-(4-phenylpiperazin-1-yl)but-1-en-1-yl] nicotinonitrile;
5-[(1E)-buta-1,3-dien-1-yl]-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile;

(3E)-4-{5-cyano-4-[(4-methyl-1H-indol-5-yl)amino]pyridin-3-yl}but-3-en-1-yl indoline-1-carboxylate;

(3E)-4-{5-cyano-4-[(4-methyl-1H-indol-5-yl)amino]pyridin-3-yl}but-3-en-1-yl thiomorpholine-4-carboxylate 1,1-dioxide;

4-[(4-methyl-1H-indol-5-yl)amino]-5-[(1E)-4-morpholin-4-ylbut-1-en-1-yl]nicotinonitrile;
(3E)-4-{5-cyano-4-[(4-methyl-1H-indol-5-yl)amino]pyridin-3-yl}but-3-en-1-yl morpholine-4-carboxylate;

4-[(4-methyl-1H-indol-5-yl)amino]-5-[(1E)-4-pyrrolidin-1-ylbut-1-en-1-yl]nicotinonitrile;
tert-butyl {1-[(2E)-3-{5-cyano-4-[(4-methyl-1H-indol-5-yl)amino]pyridin-3-yl)prop-2-en-1-yl]
piperidin-4-yl}carbamate;

tert-butyl 4-[(2E)-3-{5-cyano-4-[(4-methyl-1H-indol-5-yl)amino]pyridin-3-yl}prop-2-en-1-yl]
piperazine-1-carboxylate;

5-[(1E)-3-(4-aminopiperidin-1-yl)prop-1-en-1-yl]-4-[(4-methyl-1H-indol-5-yl)amino] nicotinonitrile;
4-[(4-methyl-1H-indol-5-yl)amino]-5-[(1E)-3-piperazin-1-ylprop-1-en-1-yl]nicotinonitrile;
4-[(4-methyl-1H-indol-5-yl)amino]-1',2',3',6'-tetrahydro-3,4'-bipyridine-5-carbonitrile;
4-[(4-methyl-1H-indol-5-yl)amino]-1'-(methylsulfonyl)-1',2',3,6'-tetrahydro-3,4'-bipyridine-5-carbonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-1'-(phenylsulfonyl)-1',2',3',6'-tetrahydro-3,4'-bipyridine-5-carbonitrile;

1'-acetyl-4-[(4-methyl-1H-indol-5-yl)amino]-1',2',3',6'-tetrahydro-3,4'-bipyridine-5-carbonitrile;
5-cyano-N-ethyl-4-[(4-methyl-1H-indol-5-yl)amino]-3',6'-dihydro-3,4'-bipyridine-1'(2'H)-carboxamide;

4-[(4-methyl-1H-indol-5-yl)amino]-1'-[(1-methylpiperidin-4-yl)carbonyl]-1',2',3',6'-tetrahydro-3,4'-bipyridine-5-carbonitrile;

1'-benzyl-4-[(4-methyl-1H-indol-5-yl)amino]-1',2',3',6'-tetrahydro-3,4'-bipyridine-5-carbonitrile;
ethyl 5-cyano-4-[(4-methyl-1H-indol-5-yl)amino]-3',6'-dihydro-3,4'-bipyridine-1'(2'H)-carboxylate;
4-[(4-methyl-1H-indol-5-yl)amino]-5-[(1E)-4-piperidin-1-ylbut-1-en-1-yl]nicotinonitrile;
4-[(4-methyl-1H-indol-5-yl)amino]-5-[(1E)-4-thiomorpholin-4-ylbut-1-en-1-yl]nicotinonitrile;

5-[(1E)-4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)but-1-en-1-yl]-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile;

1'-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-1',2',3',6'-tetrahydro-3,4'-bipyridine-5-carbonitrile;
5-[(1E)-4-(4-acetylpiperazin-1-yl)but-1-en-1-yl]-4-[(4-methyl-1H-indol-5-yl)amino] nicotinonitrile;
4-[(4-methyl-1H-indol-5-yl)amino]-5-((1E)-4-[4-(methylsulfonyl)piperazin-1-yl]but-1-en-1-yl}
nicotinonitrile;

tert-butyl 4-[(3E)-4-(5-cyano-4-[(4-methyl-1H-indol-5-yl)amino]pyridin-3-yl}but-3-en-1-yl]
piperazine-1-carboxylate;

tert-butyl {1-[(3E)-4-{5-cyano-4-[(4-methyl-1H-indol-5-yl)amino]pyridin-3-yl}but-3-en-1-yl]
piperidin-4-yl}carbamate;

4-[(4-methyl-1H-indol-5-yl)amino]-5-[(1E)-5-(4-methylpiperazin-1-yl)pent-1-en-1-yl]
nicotinonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-[(1E)-5-morpholin-4-ylpent-1-en-1-yl]nicotinonitrile;
(4E)-5-{5-cyano-4-[(4-methyl-1H-indol-5-yl)amino]pyridin-3-yl}pent-4-en-1-yl morpholine-4-carboxylate;

4-[(4-methyl-1H-indol-5-yl)amino]-5-[(1E)-5-pyrrolidin-1-ylpent-1-en-1-yl]nicotinonitrile;
5-[(1E)-4-aminobut-1-en-1-yl]-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile;
4-[(4-methyl-1H-indol-5-yl)amino]-5-[3-(4-methylpiperazin-1-yl)propyl]nicotinonitrile;
4-[(4-methyl-1H-indol-5-yl)amino]-5-[4-(4-methylpiperazin-1-yl)butyl]nicotinonitrile;
5-[(1E)-4-(4-aminopiperidin-1-yl)but-1-en-1-yl]-4-[(4-methyl-1H-indol-5-yl)amino] nicotinonitrile;
4-[(4-methyl-1H-indol-5-yl)amino]-5-[(1E)-4-piperazin-1-ylbut-1-en-1-yl]nicotinonitrile;
4-[(4-methyl-1H-indol-5-yl)amino]-5-{(1E)-4-[(2-morpholin-4-ylethyl)amino]but-1-en-1-yl}
nicotinonitrile;

5-[(E)-2-{5-[(dimethylamino)methyl]pyridin-2-yl}vinyl]-4-[(4-methyl-1H-indol-5-yl)amino]
nicotinonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-{5-[(4-methylpiperazin-1-yl)methyl]pyridin-2-yl}vinyl]nicotinonitrile;

5-{(1E)-4-[4-(ethylsulfonyl)piperazin-1-yl]but-1-en-1-yl}-4-[(4-methyl-1H-indol-5-yl)amino]
nicotinonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-{(1E)-4-[4-(phenylsulfonyl)piperazin-1-yl]but-1-en-1-yl}
nicotinonitrile;

5-{(1E)-4-[4-(2,2-dimethylpropanoyl)piperazin-1-yl]but-1-en-1-yl}-4-[(4-methyl-1H-indol-5-yl) amino]nicotinonitrile;

N-{1-[(3E)-4-(5-cyano-4-[(4-methyl-1H-indol-5-yl)amino]pyridin-3-yl}but-3-en-1-yl]piperidin-4-yl}
methanesulfonamide;

N-(1-[(3E)-4-(5-cyano-4-[(4-methyl-1H-indol-5-yl)amino]pyridin-3-yl}but-3-en-1-yl]piperidin-4-yl) acetamide;

5-[(1E)-4-(isopropylamino)but-1-en-1-yl]-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile;
5-[(1E)-4-(cyclohexylamino)but-1-en-1-yl]-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile;
4-[(4-methyl-1H-indol-5-yl)amino]-5-[(1E)-4-(piperidin-4-ylamino)but-1-en-1-yl] nicotinonitrile;
4-[(4-methyl-1H-indol-5-yl)amino]-1'-(piperidin-4-ylcarbonyl)-1',2',3',6'-tetrahydro-3,4'-bipyridine-5-carbonitrile;

tert-butyl 4-[(3E)-4-{5-cyano-2-methyl-4-[(4-methyl-1H-indol-5-yl)amino]pyridin-3-yl}but-3-en-1-yl]piperazine-1-carboxylate;

4-[(4-methyl-1H-indol-5-yl)amino]-5-[(1E)-5-piperidin-1-ylpent-1-en-1-yl]nicotinonitrile;
tert-butyl 4-[(4E)-5-{5-cyano-4-[(4-methyl-1H-indol-5-yl)amino]pyridin-3-yl}pent-4-en-1-yl]
piperazine-1-carboxylate;

tert-butyl {1-[(4E)-5-{5-cyano-4-[(4-methyl-1H-indol-5-yl)amino]pyridin-3-yl}pent-4-en-1-yl]
piperidin-4-yl}carbamate;

tert-butyl {1-[(3E)-4-{5-cyano-2-methyl-4-[(4-methyl-1H-indol-5-yl)amino]pyridin-3-yl}but-3-en-1-yl]piperidin-4-yl}carbamate;

4-[(4-methyl-1H-indol-5-yl)amino]-5-[(1E)-3-piperidin-1-ylprop-1-en-1-yl]nicotinonitrile;
6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-[(1E)-4-piperazin-1-ylbut-1-en-1-yl]nicotinonitrile;
4-[(4-methyl-1H-indol-5-yl)amino]-5-(4-piperazin-1-ylbutyl)nicotinonitrile;
5-[4-(4-aminopiperidin-1-yl)butyl]-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile;
4-[(4-methyl-1H-indol-5-yl)amino]-5-[(1E)-5-piperazin-1-ylpent-1-en-1-yl]nicotinonitrile;

5-[(1E)-5-(4-aminopiperidin-1-yl)pent-1-en-1-yl]-4-[(4-methyl-1H-indol-5-yl)amino] nicotinonitrile;
5-[(1E)-4-(4-aminopiperidin-1-yl)but-1-en-1-yl]-6-methyl-4-[(4-methyl-1H-indol-5-yl) amino]nicotinonitrile;

5-[(1E)-4-(dimethylamino)but-1-en-1-yl]-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-{(1E)-4-[(1-methylpiperidin-4-yl)amino]but-1-en-1-yl}
nicotinonitrile;

5-((1E)-4-[(trans-4-hydroxycyclohexyl)amino]but-1-en-1-yl}-4-[(4-methyl-1H-indol-5-yl) amino]nicotinonitrile;

5-[(1E)-5-(4-hydroxypiperidin-1-yl)pent-1-en-1-yl]-4-[(4-methyl-1H-indol-5-yl)amino]
nicotinonitrile;

6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-{(1E)-4-[4-(methylsulfonyl)piperazin-1-yl]but-1-en-1-yl}nicotinonitrile;

N-{1-[(3E)-4-{5-cyano-2-methyl-4-[(4-methyl-1H-indol-5-yl)amino]pyridin-3-yl}but-3-en-1-yl]
piperidin-4-yl}methanesulfonamide;

5-[(1E)-4-(4-hydroxy-4-phenylpiperidin-1-yl)but-1-en-1-yl]-4-[(4-methyl-1H-indol-5-yl) amino]nicotinonitrile;

4-[(E)-2-{5-cyano-4-[(4-methyl-1H-indol-5-yl)amino]pyridin-3-yl}vinyl]benzoic acid;
5-[(1E)-3-(4-hydroxypiperidin-1-yl)prop-1-en-1-yl]-4-[(4-methyl-1H-indol-5-yl)amino]
nicotinonitrile;

tert-butyl 4-({6-[(E)-2-{5-cyano-4-[(4-methyl-1H-indol-5-yl)amino]pyridin-3-yl}vinyl]pyridin-3-yl}
methyl)piperazine-1-carboxylate;

4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[5-(piperazin-1-ylmethyl)pyridin-2-yl]vinyl}
nicotinonitrile;

tert-butyl 4-{4-[(E)-2-{5-cyano-4[(4-methyl-1H-indol-5-yl)amino]pyridin-3-yl}vinyl]benzyl}
piperazine-1-carboxylate;

4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}
vinyl]nicotinonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-(4-methylphenyl)vinyl]nicotinonitrile;
5-[(E)-2-(4-methoxyphenyl)vinyl]-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile;
5-[(E)-2-biphenyl-4-ylvinyl]-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile;

4-[(2,4-dimethyl-1H-indol-5-yl)amino]-5-[(E)-2-phenylvinyl]nicotinonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[4-(trifluoromethyl)phenyl]vinyl}nicotinonitrile;
5-[(E)-2-(4-chlorophenyl)vinyl]-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile;
4-[(4-methyl-1H-indol-5-yl)amino]-5-[(Z)-2-phenylvinyl]nicotinonitrile;

5-{(1E)-4-[(3R)-3-hydroxypyrrolidin-1-yl]but-1-en-1-yl}-4-[(4-methyl-1H-indol-5-yl)amino]
nicotinonitrile;

5-{(1E)-4-[(3S)-3-hydroxypyrrolidin-1-yl]but-1-en-1-yl}-4-[(4-methyl-1H-indol-5-yl) amino]
nicotinonitrile;

5-{(1E)-4-[4-(hydroxymethyl)piperidin-1-yl]but-1-en-1-yl}-4-[(4-methyl-1H-indol-5-yl)amino]
nicotinonitrile;

5-[(1E)-4-(4-methoxypiperidin-1-yl)but-1-en-1-yl]-4-[(4-methyl-1H-indol-5-yl)amino]
nicotinonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-1'-(2-phenylethyl)-1',2',3',6'-tetrahydro-3,4'-bipyridine-5-carbonitrile;

1'-(2-fluorobenzyl)-4-[(4-methyl-1H-indol-5-yl)amino]-1',2',3',6'-tetrahydro-3,4'-bipyridine-5-carbonitrile;

1'-(3-fluorobenzyl)-4-[(4-methyl-1H-indol-5-yl)amino]-1',2',3',6'-tetrahydro-3,4'-bipyridine-5-carbonitrile;

1'-(4-fluorobenzyl)-4-[(4-methyl-1H-indol-5-yl)amino]-1',2',3',6'-tetrahydro-3,4'-bipyridine-5-carbonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-{(1E)-4-[4-(pyrrolidin-1-ylcarbonyl)piperidin-1-yl]but-1-en-1-yl}nicotinonitrile;

5-[(E)-2-(3-methoxyphenyl)vinyl]-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile;
5-[(E)-2-(4-bromophenyl)vinyl]-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile;
5-[(E)-2-(2-methoxyphenyl)vinyl]-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile;
5-[(E)-2-(3,4-dimethoxyphenyl)vinyl]-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile;
4-(1H-indol-5-ylamino)-5-[(E)-2-phenylvinyl]nicotinonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-vinylnicotinonitrile;

4-(1H-indol-5-ylamino)-6-methyl-5-[(E)-2-phenylvinyl]nicotinonitrile;

4-[(4-methyl-1H-indol-5-yl)amino}-1'-(piperidin-4-ylmethyl}1',2',3',6'-tetrahydro-3,4'-bipyridine-5-carbonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-[(1E)-4-(3-oxopiperazin-1-yl)but-1-en-1-yl] nicotinonitrile;
5-[(E)-2-(3-methoxyphenyl)vinyl]-6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-{4-[(4-methylpiperazin-1-yl)methyl]pyridin-2-yl}
vinyl]nicotinonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-{2-[(4-methylpiperazin-1-yl)methyl]-1,3-thiazol-4-yl}
vinyl]nicotinonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-(2-{5-[(4-methylpiperazin-1-yl)methyl]pyridin-2-yl}
ethyl)nicotinonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-{6-[(4-methylpiperazin-1-yl)methyl]pyridin-2-yl}
vinyl]nicotinonitrile;

4-(1H-indol-6-ylamino)-6-methyl-5-[(E)-2-phenylvinyl]nicotinonitrile;
4-(1H-indol-6-ylamino)-5-[(E)-2-phenylvinyl]nicotinonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[4-(2-pyrrolidin-1-ylethoxy)phenyl]vinyl} nicotinonitrile;
5-{(E)-2-[4-(2-chloroethoxy)phenyl]vinyl}-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile;
4-[(4-methyl-1H-indol-5-yl)amino]-5-[(1E}-3-phenylprop-1-en-1-yl]nicotinonitrile;
6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-{5-[(4-methylpiperazin-1-yl)methyl]pyridin-2-yl}vinyl]nicotinonitrile;

6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-phenylvinyl]nicotinonitrile;
4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-pyridin-2-ylvinyl]nicotinonitrile;
5-[(E)-2-(4-butylphenyl)vinyl]-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile;
4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-pyridin-4-ylvinyl]nicotinonitrile;
6-methyl-4-[(2-methyl-1H-indol-5-yl)amino]-5-[(E)-2-phenylvinyl]nicotinonitrile;
6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-vinylnicotinonitrile;
4-[(4,7-dimethyl-1H-indol-5-yl)amino]-5-[(E)-2-phenylvinyl]nicotinonitrile;
4-[(7-chloro-4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-phenylvinyl]nicotinonitrile;
4-[(7-chloro-4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-(3-methoxyphenyl)vinyl]nicotinonitrile;
4-[(7-chloro-4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-pyridin-2-ylvinyl]nicotinonitrile;
4-[(2-methyl-1H-indol-5-yl)amino]-5-[(E)-2-phenylvinyl]nicotinonitrile;
5-[(E)-2-(4-methoxyphenyl)vinyl]-6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-(3-phenylpropyl)nicotinonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-{4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}
vinyl]nicotinonitrile;

4-(1H-indol-5-ylamino)-5-[(E)-2-{5-[(4-methylpiperazin-1-yl)methyl]pyridin-2-yl}vinyl]
nicotinonitrile;

4-(1H-indol-4-ylamino}5-[(E)-2-phenylvinyl]nicotinonitrile;

4-(1H-indol-4-ylamino}6-methyl-5-[(E)-2-phenylvinyl]nicotinonitrile;
5-[(E)-2-{2-methoxy-4-[(4-methylpiperazin-1-yl)methyl]phenyl}vinyl]-4-[(4-methyl-1H-indol-5-yl) amino]nicotinonitrile;

5-{(E)-2-[2-(2-chloroethoxy)phenyl]vinyl}-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile;
5-{(E)-2-[3-(2-chloroethoxy)phenyl]vinyl}-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile;
4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-{2-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}
vinyl]nicotinonitrile;

4-[1H-indol-5-yl(methyl)amino]-5-[(E)-2-phenylvinyl]nicotinonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-{2-methyl-4-[(4-methylpiperazin-1-yl)methyl]
phenyl}vinyl]nicotinonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[2-(2-piperazin-1-ylethoxy)phenyl]vinyl} nicotinonitrile;
4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[2-(2-pyrrolidin-1-ylethoxy)phenyl]vinyl} nicotinonitrile;
4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-piperidin-4-ylvinyl]nicotinonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-{3-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}
vinyl]nicotinonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[3-(2-pyrrolidin-1-ylethoxy)phenyl]vinyl)nicotinonitrile;
5-[2-(4-methoxyphenyl)ethyl]-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile;

5-(2-biphenyl-4-ylethyl)-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-{3-[(4-methylpiperazin-1-yl)methyl]phenyl}
vinyl]nicotinonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-(2-phenylethyl)nicotinonitrile;
4-[(7-chloro-4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-pyridin-4-ylvinyl]nicotinonitrile;

4-[(7-chloro-4-methyl-1H-indol-5-yl)amino]-6-methyl-5-[(E)-2-pyridin-2-ylvinyl] nicotinonitrile;
6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-pyridin-2-ylvinyl]nicotinonitrile;
4-[(7-chloro-4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-{5-[(4-methylpiperazin-1-yl)methyl]pyridin-2-yl}vinyl]nicotinonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-(1H-1,2,4-triazol-1-yl)vinyl]nicotinonitrile;
4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-(4-methyl-1,3-thiazol-5-yl)vinyl]nicotinonitrile;
5-[(1E)-3-(1H-imidazol-1-yl)prop-1-en-1-yl]-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile;
5-[(E)-2-cyclohexylvinyl]-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile;
6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-pyridin-4-ylvinyl]nicotinonitrile;
4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-{5-[(4-methylpiperazin-1-yl)methyl]-3-furyl}vinyl]
nicotinonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-{2-methyl-5-[(4-methylpiperazin-1-yl)carbonyl] phenyl) vinyl]nicotinonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-{2-methyl-5-[(4-methylpiperazin-1-yl)methyl]phenyl}
vinyl]nicotinonitrile;

4-[(7-chloro-4-methyl-1H-indol-5-yl)amino]-6-methyl-5-[(E)-2-phenylvinyl]nicotinonitrile;
4-[(7-chloro-4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-{6-[(4-methylpiperazin-1-yl)methyl] pyridin-2-yl}vinyl]nicotinonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}vinyl]
nicotinonitrile;

5-[(E)-2-{6-[(4-acetylpiperazin-1-yl)methyl]pyridin-2-yl}vinyl]-4-[(4-methyl-1H-indol-5-yl) amino]
nicotinonitrile;

5-[(E)-2-{2-methoxy-5-[(4-methylpiperazin-1-yl)methyl]phenyl}vinyl]-4-[(4-methyl-1H-indol-5-yl) amino]nicotinonitrile;

5-{(E)-2-[2-methoxy-5-(piperazin-1-ylmethyl)phenyl]vinyl}-4-[(4-methyl-1H-indol-5-yl) amino]nicotinonitrile;

5-[(E)-2-(2-methoxyphenyl)vinyl]-6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile;
6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-pyridin-3-ylvinyl]nicotinonitrile;
5-[(E)-2-(3,4-dimethoxyphenyl)vinyl]-6-methyl-4-[(4-methyl-1H-indol-5-yl)amino] nicotinonitrile;

6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-pyrazin-2-ylvinyl]nicotinonitrile;
tert-butyl 4-[(E)-2-(5-cyano-4-[(4-methyl-1H-indol-5-yl)amino]pyridin-3-yl}vinyl]piperidine-1-carboxylate;

4-(1H-indol-4-yloxy)-5-[(E)-2-phenylvinyl]nicotinonitrile;

6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-(4-methyl-1,3-thiazol-5-yl)vinyl]
nicotinonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[4-(piperidin-1-ylmethyl)phenyl]vinyl} nicotinonitrile;
4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[4-(pyrrolidin-1-ylmethyl)phenyl]vinyl} nicotinonitrile;
5-[(E)-2-(2-chloropyridin-3-yl)vinyl]-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-{2-methyl-4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}
vinyl]nicotinonitrile;

5-[(E)-2-(4-{[4-(2-hydroxyethyl)piperazin-1-yl]methyl)phenyl)vinyl]-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile;

5-[(E)-2-{4-[(4-hydroxypiperidin-1-yl)methyl]phenyl}vinyl]-4-[(4-methyl-1H-indol-5-yl)amino]
nicotinonitrile;

5-{(E)-2-[4-({[3-(dimethylamino)propyl]amino}methyl)phenyl]vinyl}-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[4-(thiomorpholin-4-ylmethyl)phenyl]vinyl}
nicotinonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-{4-[(4-pyrrolidin-1-ylpiperidin-1-yl)methyl]
phenyl)vinyl]nicotinonitrile;

5-[(E)-2-{2-methoxy-3-[(4-methylpiperazin-1-yl)methyl]phenyl}vinyl]-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile;

5-{(E)-2-[2-methoxy-3-(piperazin-1-ylmethyl)phenyl]vinyl}-4-[(4-methyl-1H-indol-5-yl) amino]nicotinonitrile;

6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-{6-[(4-methylpiperazin-1-yl)methyl]pyridin-2-yl}vinyl]nicotinonitrile;

5-[(E)-2-{3-methoxy-4-[(4-methylpiperazin-1-yl)methyl]phenyl}vinyl]-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile;

5-((E)-2-[3-methoxy-4-(piperazin-1-ylmethyl)phenyl]vinyl}-4-[(4-methyl-1H-indol-5-yl) amino]nicotinonitrile;

5-isopropenyl-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile;
5-[(E)-2-{3-[(diethylamino)methyl]phenyl}vinyl]-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile;
5-[(E)-2-{4-[(diethylamino)methyl]phenyl}vinyl]-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile;
5-[(E)-2-(6-bromopyridin-2-yl)vinyl]-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile;
5-{(E)-2-[3,4-bis(2-methoxyethoxy)phenyl]vinyl)-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile;
5-[(E)-2-(4-formylphenyl)ethenyl]-4-[(4-methyl-1H-indol-5-yl)amino]pyridine-3-carbonitrile;
5-{(E)-2-[4-(1,4'-bipiperidin-1'-ylmethyl)phenyl]ethenyl}-4-[(4-methyl-1H-indol-5-yl)amino]
pyridine-3-carbonitrile;

5-[(E)-2-(4-{[(3-ethoxypropyl)amino]methyl}phenyl)ethenyl]-4-[(4-methyl-1H-indol-5-yl) amino]pyridine-3-carbonitrile;

5-[(E)-2-(2-chloropyridin-4-yl)vinyl]-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile;
4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[4-(piperazin-1-ylmethyl)phenyl]vinyl}nicotinonitrile;
5-{(E)-2-[4-(azetidin-1-ylmethyl)phenyl]vinyl}-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile;
6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-(2-phenylethyl)nicotinonitrile;
5-[(E)-2-{4-[(dimethylamino)methyl]phenyl}vinyl]-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile;
5-[(E)-2-(4-ethoxyphenyl)vinyl]-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-{4-[(4-pyridin-2-ylpiperazin-1-yl)methyl]phenyl}
vinyl]nicotinonitrile;

tert-butyl3-({4-[(E)-2-{5-cyano-4-[(4-methyl-1H-indol-5-yl)amino]pyridin-3-yl}vinyl]benzyl amino)azetidine-1-carboxylate;

4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-(4-propoxyphenyl)vinyl]nicotinonitrile;
5-[(E)-2-(6-chloropyridin-3-yl)vinyl}-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile;
4-[(4-methyl-1H-indol-5-yl)amino]-5-{2-[4-(pyrrolidin-1-ylmethyl)phenyl]ethyl}nicotinonitrile;
5-[(E)-2-(6-chloropyridin-2-yl)vinyl]-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile;
5-{(E)-2-[6-(hydroxymethyl)pyridin-2-yl]vinyl}-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile;
4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[6-(piperidin-1-ylmethyl)pyridin-2-yl]vinyl}
nicotinonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[6-(pyrrolidin-1-ylmethyl)pyridin-2-yl]vinyl}
nicotinonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[6-(piperazin-1-ylmethyl)pyridin-2-yl]vinyl}
nicotinonitrile;

5-{(E)-2-[5-(hydroxymethyl)pyridin-2-yl]vinyl}-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile;
5-[(E)-2-{4-[(3-hydroxypyrrolidin-1-yl)methyl]phenyl}ethenyl]-4-[(4-methyl-1H-indol-5-yl)amino]
pyridine-3-carbonitrile;

N{4-[(E)-2-{5-cyano-4-[(4-methyl-1H-indol-5-yl)amino]pyridin-3-yl}ethenyl]benzyl}-N-(2-piperidin-1-ylethyl)acetamide;

5-[(E)-2-(4-{[4-(1-methylethyl)piperazin-1-yl]methyl}phenyl)ethenyl]-4-[(4-methyl-1H-indol-5-yl) amino]pyridine-3-carbonitrile;

N{4-[(E)-2-{5-cyano-4-[(4-methyl-1H-indol-5-yl)amino]pyridin-3-yl}ethenyl]benzyl}-N-(2-pyrrolidin-1-ylethyl)acetamide;

4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-(4-{[(2-pyridin-3-ylethyl)amino]methyl}phenyl) ethenyl]pyridine-3-carbonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-(4-{[(2-pyridin-2-ylethyl)amino]methyl}phenyl) ethenyl]pyridine-3-carbonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-(4-{[(3-morpholin-4-ylpropyl)amino]methyl}phenyl) ethenyl]pyridine-3-carbonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-{4-[(4-morpholin-4-ylpiperidin-1-yl)methyl]
phenyl}ethenyl]pyridine-3-carbonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-(4-{[(2-morpholin-4-ylethyl)amino]methyl}
phenyl)ethenyl]pyridine-3-carbonitrile;

5-[(E)-2-{4-[(4-cyclopentylpiperazin-1-yl)methyl]phenyl}ethenyl]-4-[(4-methyl-1H-indol-5-yl) amino]pyridine-3-carbonitrile;

5-[(E)-2-(4-formylphenyl)ethenyl]-6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]pyridine-3-carbonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[4-(morpholin-4-ylmethyl)phenyl]ethenyl} pyridine-3-carbonitrile;

5-[(E)-2-{4-[(azetidin-3-ylamino)methyl]phenyl}ethenyl]-4-[(4methyl-1H-indol-5-yl)amino]
pyridine-3-carbonitrile;

6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-{2-methyl-4-[(4-methylpiperazin-1-yl) carbonyl]phenyl)ethenyl]pyridine-3-carbonitrile;

6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-{4-[(4-methylpiperazin-1-yl) methyl]
phenyl}ethenyl]pyridine-3-carbonitrile;

5-[(E)-2-{4-[(4-hydroxypiperidin-1-yl)methyl]phenyl}ethenyl]-6-methyl-4-[(4-methyl-1H-indol-5-yl) amino]pyridine-3-carbonitrile;

6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[4-(piperidin-1-ylmethyl)phenyl]
ethenyl}pyridine-3-carbonitrile;

6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[4-(pyrrolidin-1-ylmethyl)phenyl]
ethenyl}pyridine-3-carbonitrile;

5-[(E)-2-{4-[(diethylamino)methyl]phenyl}ethenyl]-6methyl-4-[(4-methyl-1H-indol-5-yl)amino]
pyridine-3-carbonitrile;

6-methyl-5-[(E)-2-{4-[(4-methyl-1,4-diazepan-1-yl)methyl]phenyl}ethenyl]-4-[(4-methyl-1H-indol-5-yl)amino]pyridine-3-carbonitrile;

5-[(E)-2-(4-benzylmorpholin-2-yl)ethenyl]-4-[(4-methyl-1H-indol-5-yl)amino]pyridine-3-carbonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-{2-[(4-methylpiperazin-1-yl)methyl]phenyl}
ethenyl]pyridine-3-carbonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-{5-[(4-methylpiperazin-1-yl)methyl]pyridin-3-yl}ethenyl]pyridine-3-carbonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-{4-[(4-methylpiperazin-1-yl)methyl]-1,3-thiazol-2-yl}ethenyl]pyridine-3-carbonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-{6-[(4-methylpiperazin-1-yl)methyl]pyridin-3-yl}ethenyl]pyridine-3-carbonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[5-(piperidin-1-ylmethyl)pyridin-2-yl]ethenyl}pyridine-3-carbonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[5-(pyrrolidin-1-ylmethyl)pyridin-2-yl]ethenyl}pyridine-3-carbonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[5-(morpholin-4-ylmethyl)pyridin-2-yl]ethenyl}
pyridine-3-carbonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[5-(thiomorpholin-4-ylmethyl)pyridin-2-yl]
ethenyl}pyridine-3-carbonitrile;

5-[(E)-2-{5-[(4-hydroxypiperidin-1-yl)methyl]pyridin-2-yl}ethenyl]-4-[(4-methyl-1H-indol-5-yl) amino]pyridine-3-carbonitrile;

5-[(E)-2-(5-{[4-(2-hydroxyethyl)piperazin-1-yl]methyl}pyridin-2-yl)ethenyl]-4-[(4-methyl-1H-indol-5-yl)amino]pyridine-3-carbonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-(5-{[(2-morpholin-4-ylethyl)amino]methyl}pyridin-2-yl)ethenyl]pyridine-3-carbonitrile;

6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[4-(morpholin-4-ylmethyl)phenyl]
ethenyl}pyridine-3-carbonitrile;

6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-(4-{[(2-pyridin-2-ylethyl)amino]methyl}
phenyl)ethenyl]pyridine-3-carbonitrile;

5-[(E)-2-{4-[(4-cyclopentylpiperazin-1-yl)methyl]phenyl}ethenyl]-6-methyl-4-[(4-methyl-1H-indol-5-yl )amino]pyridine-3-carbonitrile;

6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[4-(thiomorpholin-4-ylmethyl)phenyl]
ethenyl}pyridine-3-carbonitrile;

6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-(4-{[(2-pyridin-4-ylethyl)amino]methyl}
phenyl)ethenyl]pyridine-3-carbonitrile;

6-methyl-5-[(E)-2-(4-{[4-(1-methylethyl)piperazin-1-yl]methyl}phenyl)ethenyl]-4-[(4-methyl-1H-indol-5-yl)amino]pyridine-3-carbonitrile;

5-[(E)-2-(5-bromopyridin-3-yl)ethenyl]-4[(4-methyl-1H-indol-5-yl]amino]pyridine-3-carbonitrile;
tert-butyl[2-({5-[(E)-2-{5-cyano-4-[(4-methyl-1H-indol-5-yl)amino]pyridin-3-yl}ethenyl]pyridin-3-yl}oxy)ethyl]carbamate;

5-[(E)-2-(5-methoxypyridin-3-yl)ethenyl]-4-[(4-methyl-1H-indol-5-yl)amino]pyridine-3-carbonitrile;
6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-{2-methyl-4-[(4-methylpiperazin-1-yl)methyl]
phenyl}ethenyl]pyridine-3-carbonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-(2-methylphenyl)ethenyl]pyridine-3-carbonitrile;
5-[(E)-2-(2-ethylphenyl)ethenyl]-4-[(4-methyl-1H-indol-5-yl)amino]pyridine-3-carbonitrile;
4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-(5-{[(3-morpholin-4-ylpropyl)amino]methyl}pyridin-2-yl)ethenyl]pyridine-3-carbonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-{5-[(4-morpholin-4-yl)piperidin-1-yl)methyl]pyridin-2-yl}ethenyl]pyridine-3-carbonitrile;

5-{(E)-2-[5-(1,4'-bipiperidin-1'-ylmethyl)pyridin-2-yl]ethenyl}-4-[(4-methyl-1H-indol-5-yl)amino]
pyridine-3-carbonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-{5-[(4-pyrrolidin-1-ylpiperidin-1-yl)methyl]pyridin-2-yl}ethenyl]pyridine-3-carbonitrile;

5-[(E)-2-{5-[(4-cyclopentylpiperazin-1-yl)methyl]pyridin-2-yl}ethenyl]-4-[(4-methyl-1H-indol-5-yl)amino]pyridine-3-carbonitrile;

5-[(E)-2-(5-{[4-(1-methylethyl)piperazin-1-yl]methyl}pyridin-2-yl)ethenyl]-4-[(4-methyl-1H-indol-5-yl)amino]pyridine-3-carbonitrile;

5-[(E)-2-(5-{[4-(dimethylamino)piperidin-1-yl]methyl}pyridin-2-yl)ethenyl]-4-[(4-methyl-1H-indol-5-yl)amino]pyridine-3-carbonitrile; .

5-[(E)-2-{5-[(4-methyl-1,4-diazepan-1-yl)methyl]pyridin-2-yl}ethenyl]-4-[(4-methyl-1H-indol-5-yl)amino]pyridine-3-carbonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[5-({[3-(2-oxopyrrolidin-1-yl)propyl]amino}
methyl)pyridin-2-yl]ethenyl}pyridine-3-carbonitrile;
6-methyl-4-[(4-methyl-1H-indol-5-yl)a mino]-5-[(E)-2-(4-{[(3-morpholin-4-ylpropyl)amino]
methyl}phenyl)ethenyl]pyridine-3-carbonitrile;
5-{(E)-2-[4-(1,4'-bipiperidin-1'-ylmethyl)phenyl]ethenyl}-6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]pyridine-3-carbonitrile;

6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-{4-[(4-morpholin-4-ylpiperidin-1-yl)methyl]
phenyl}ethenyl]pyridine-3-carbonitrile;

5-{(E)-2-[4-({[(1-ethylpyrrolidin-2-yl)methyl]amino}methyl)phenyl]ethenyl}-6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]pyridine-3-carbonitrile;

6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-(2-pyridin-2-ylethyl)pyridine-3-carbonitrile;
5-{(E)-2-[5-(2-aminoethoxy)pyridin-3-yl]ethenyl}-4-[(4-methyl-1H-indol-5-yl)amino]pyridine-3-carbonitrile;

5-[(E)-2-{2-ethyl-5-[(4-methylpiperazin-1-yl)methyl]phenyl}ethenyl]-4-[(4-methyl-1H-indol-5-yl)amino]pyridine-3-carbonitrile;

5-[(E)-2-{2-ethyl-5-[(4-methylpiperazin-1-yl)methyl]phenyl}ethenyl]-6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]pyridine-3-carbonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-pyridin-3-ylethenyl]pyridine-3-carbonitrile;
5-{(E)-2-[5-({[2-(dimethylamino)ethyl]amino}methyl)pyridin-2-yl]ethenyl}-4-[(4-methyl-1H-indol-5-yl)amino]pyridine-3-carbonitrile;

5-[(E)-2-(5-{[(2-ethoxyethyl)amino]methyl}pyridin-2-yl)ethenyl]-4-[(4-methyl-1H-indol-5-yl) amino]pyridine-3-carbonitrile;

5-[(E)-2-(5-{[(3-ethoxypropyl)amino]methyl}pyridin-2-yl)ethenyl]-4-[(4-methyl-1H-indol-5-yl) amino]pyridine-3-carbonitrile;

5-[(E)-2-(5-{[(2-methoxyethyl)amino]methyl}pyridin-2-yl)ethenyl]-4-[(4-methyl-1H-indol-5-yl)amino]pyridine-3-carbonitrile;

4-[(1,4-dimethyl-1H-indol-5-yl)amino]-5-[(E)-2-phenylethenyl]pyridine-3-carbonitrile;
4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[6-(morpholin-4-ylmethyl)pyridin-2-yl]ethenyl}
pyridine-3-carbonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[6-(thiomorpholin-4-ylmethyl)pyridin-2-yl]
ethenyl}pyridine-3-carbonitrile;

5-[(E)-2-{6-[(4-hydroxypiperidin-1-yl)methyl]pyridin-2-yl}ethenyl]-4-[(4-methyl-1H-indol-5-yl) amino]pyridine-3-carbonitrile;

5-[(E)-2-(6-{[4-(2-hydroxyethyl)piperazin-1-yl]methyl)pyridin-2-yl)ethenyl]-4-[(4-methyl-1H-indol-5-yl)amino]pyridine-3-carbonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-(6-{[(2-morpholin-4-ylethyl)amino]methyl}pyridin-2-yl)ethenyl]pyridine-3-carbonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-(6-{[(3-morpholin-4-ylpropyl)amino]methyl}pyridin-2-yl)ethenyl]pyridine-3-carbonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-{6-[(4-morpholin-4-ylpiperidin-1-yl)methyl]pyridin-2-yl}ethenyl]pyridine-3-carbonitrile;

5-{(E)-2-[6-(1,4'-bipiperidin-1'-ylmethyl)pyridin-2-yl]ethenyl}-4-[(4-methyl-1H-indol-5-yl)amino]
pyridine-3-carbonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-{6-[(4-pyrrolidin-1-ylpiperidin-1-yl)methyl]pyridin-2-yl}ethenyl]pyridine-3-carbonitrile;

5-[(E)-2-{6-[(4-cyclopentylpiperazin-1-yl)methyl]pyridin-2-yl}ethenyl]-4-[(4-methyl-1H-indol-5-yl)amino]pyridine-3-carbonitrile;

5-[(E)-2-{4-[(4-methyl-1,4-diazepan-1-yl)methyl]phenyl}ethenyl]-4-[(4-methyl-1H-indol-5-yl)amino]pyridine-3-carbonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-(4-{[(2-pyridin-4-ylethyl)amino]methyl}phenyl) ethenyl]pyridine-3-carbonitrile;

5-[(E)-2-(6-{[4-(1-methylethyl)piperazin-1-yl]methyl}pyridin-2-yl)ethenyl]-4-[(4-methyl-1H-indol-5-yl)amino]pyridine-3-carbonitrile;

5-[(E)-2-(6-{[4-(dimethylamino)piperidin-1-yl]methyl}pyridin-2-yl)ethenyl]-4-[(4-methyl-1H-indol-5-yl)amino]pyridine-3-carbonitrile;

5-[(E)-2-{6-[(4-methyl-1,4-diazepan-1-yl)methyl]pyridin-2-yl}ethenyl]-4-[(4-methyl-1H-indol-5-yl)amino]pyridine-3-carbonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[6-({[3-(2-oxopyrrolidin-1-yl)propyl]amino}
methyl)pyridin-2-yl]ethenyl}pyridine-3-carbonitrile;
5-{(E)-2-[6-({[2-(dimethylamino)ethyl]amino}methyl)pyridin-2-yl]ethenyl}-4-[(4-methyl-1H-indol-5-yl)amino]pyridine-3-carbonitrile;

5-{(E)-2-[6-({[3-(dimethylamino)propyl]amino}methyl)pyridin-2-yl]ethenyl}-4-[(4-methyl-1H-indol-5-yl)amino]pyridine-3-carbonitrile;

5-[(E)-2-(6-{[(2-ethoxyethyl)amino]methyl}pyridin-2-yl)ethenyl]-4-[(4-methyl-1H-indol-5-yl)amino]
pyridine-3-carbonitrile;

5-[(E)-2-(6-{[(2-methoxyethyl)amino]methyl}pyridin-2-yl)ethenyl]-4-[(4-methyl-1H-indol-5-yl) amino]pyridine-3-carbonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-{5-[2-(4-methylpiperazin-1-yl)ethoxy]pyridin-3-yl}
ethenyl]pyridine-3-carbonitrile;

5-[(E)-2-(4-{[4-(2-hydroxyethyl)piperazin-1-yl]methyl}phenyl)ethenyl]-6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]pyridine-3-carbonitrile;

5-[(E)-2-(3-formylphenyl)ethenyl]-4-[(4-methyl-1H-indol-5-yl)amino]pyridine-3-carbonitrile;
6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-{5-[2-(4-methylpiperazin-1-yl)ethoxy]pyridin-3-yl}ethenyl]pyridine-3-carbonitrile;

6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-{4-[(4-pyrrolidin-1-ylpiperidin-1-yl)methyl]
phenyl}ethenyl]pyridine-3-carbonitrile;

6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[5-(2-pyrrolidin-1-ylethoxy)pyridin-3-yl]ethenyl}pyridine-3-carbonitrile;

6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-(4-{[(2-piperidin-1-ylethyl)amino]
methyl}phenyl)ethenyl]pyridine-3-carbonitrile;

4-[(6-chloro-1H-indol-5-yl)amino]-5-[(E)-2-phenylethenyl]pyridine-3-carbonitrile;
5-[(E)-2-{6-[(dimethylamino)methyl]pyridin-2-yl}ethenyl]-4-[(4-methyl-1H-indol-5-yl) amino]pyridine-3-carbonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[6-({[2-(1-methylpyrrolidin-2-yl)ethyl]amino}
methyl)pyridin-2-yl]ethenyl}pyridine-3-carbonitrile;
5-[(E)-2-{6-[(3-hydroxypyrrolidin-1-yl)methyl]pyridin-2-yl}ethenyl]-4-[(4-methyl-1H-indol-5-yl)amino]pyridine-3-carbonitrile;

5-[(E)-2-(6-{[(2-azepan-1-ylethyl)amino]methyl}pyridin-2-yl)ethenyl]-4-[(4-methyl-1H-indol-5-yl)amino]pyridine-3-carbonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-(6-{[(2-pyridin-2-ylethyl)amino]methyl}pyridin-2-yl)ethenyl]pyridine-3-carbonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-(6-{[(2-pyridin-3-ylethyl)amino]methyl}pyridin-2-yl)ethenyl]pyridine-3-carbonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-(6-{[(2-pyridin-4-ylethyl)amino]methyl}pyridin-2-yl)ethenyl]pyridine-3-carbonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[5-({[2-(1-methylpyrrolidin-2-yl)ethyl]amino}
methyl)pyridin-2-yl]ethenyl}pyridine-3-carbonitrile;
5-[(E)-2-{5-[(3-hydroxypyrrolidin-1-yl)methyl]pyridin-2-yl}ethenyl]-4-[(4-methyl-1H-indol-5-yl)amino]pyridine-3-carbonitrile;

5-[(E)-2-(5-{[(2-azepan-1-ylethyl)amino]methyl}pyridin-2-yl)ethenyl]-4-[(4-methyl-1H-indol-5-yl)amino]pyridine-3-carbonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-(5-{[(2-pyridin-2-ylethyl)amino]methyl}pyridin-2-yl)ethenyl]pyridine-3-carbonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-(5-{[(2-pyridin-4-ylethyl)amino]methyl}pyridin-2-yl)ethenyl]pyridine-3-carbonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[4-(pyrrolidin-1-ylsulfonyl)phenyl]ethenyl}pyridine-3-carbonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-{4-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}
ethenyl]pyridine-3-carbonitrile;

5-{(E)-2-[4-({[2-(dimethylamino)ethyl]amino}methyl)phenyl]ethenyl}-4-[(4-methyl-1H-indol-5-yl)amino]pyridine-3-carbonitrile;

5-[(E)-2-{5-[3-(dimethylamino)propoxy]pyridin-3-yl}ethenyl]-4-[(4-methyl-1H-indol-5-yl)amino]
pyridine-3-carbonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[3-(piperidin-1-ylmethyl)phenyl]ethenyl}pyridine-3-carbonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[3-(pyrrolidin-1-ylmethyl)phenyl]ethenyl}pyridine-3-carbonitrile;

5-[(E)-2-(3-{[4-(2-hydroxyethyl)piperazin-1-yl]methyl}phenyl)ethenyl]-4-[(4-methyl-1H-indol-5-yl)amino]pyridine-3-carbonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-{3-[(4-pyrrolidin-1-ylpiperidin-1-yl)methyl]
phenyl}ethenyl]pyridine-3-carbonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-{3-[(4-morpholin-4-ylpiperidin-1-yl)methyl]
phenyl}ethenyl]pyridine-3-carbonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[3-(thiomorpholin-4-ylmethyl)phenyl]ethenyl}pyridine-3-carbonitrile;

5-[(E)-2-{3-[(4-cyclopentylpiperazin-1-yl)methyl]phenyl}ethenyl]-4-[(4-methyl-1H-indol-5-yl) amino]pyridine-3-carbonitdle;

4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-(4-{[(2-pyrrolidin-1-ylethyl)amino]methyl}phenyl) ethenyl]pyridine-3-carbonitrile;

5-[(E)-2-(3-formylphenyl)ethenyl]-6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]pyridine-3-carbonitrile;

5-{(E)-2-[5-(hydroxymethyl)pyridin-2-yl]ethenyl}-6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]
pyridine-3-carbonitrile;

5-{(E)-2-[6-(hydroxymethyl)pyridin-2-yl]ethenyl}-6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]
pyridine-3-carbonitrile;

6-methyl-4-[(4-methyl-1H+indol-5-yl)amino]-5-{(E)-2-[6-(piperidin-1-ylmethyl)pyridin-2-yl]
ethenyl}pyridine-3-carbonitrile;

6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[6-(pyrrolidin-1-ylmethyl)pyridin-2-yl]
ethenyl}pyridine-3-carbonitrile;

6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[6-(morpholin-4-ylmethyl)pyridin-2-yl]
ethenyl}pyridine-3-carbonitrile;

6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[6-(thiomorpholin-4-ylmethyl)pyridin-2-yl]
ethenyl}pyridine-3-carbonitrile;

5-[(E)-2-{6-[(4-hydroxypiperidin-1-yl)methyl]pyridin-2-yl}ethenyl]-6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]pyridine-3-carbonitrile;

5-[(E)-2-(6-{[4-(2-hydroxyethyl)piperazin-1-yl]methyl}pyridin-2-yl)ethenyl]-6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]pyridine-3-carbonitrile;

6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-(6-{[(2-morpholin-4-ylethyl)amino]methyl}
pyridin-2-yl)ethenyl]pyridine-3-carbonitrile;

6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-(6-{[(3-morpholin-4-ylpropyl)amino]methyl) pyridin-2-yl)ethenyl]pyridine-3-carbonitrile;

6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-{6-[(4-morpholin-4-ylpiperidin-1-yl)methyl]
pyridin-2-yl}ethenyl]pyridine-3-carbonitrile;

5-{(E)-2-[6-(1,4'-bipiperidin-1'-ylmethyl)pyridin-2-yl]ethenyl}-6-methyl-4-[(4-methyl-1H-indol-5-yl) amino]pyridine-3-carbonitrile;

6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-{6-[(4-pyrrolidin-1-ylpiperidin-1-yl)methyl]
pyridin-2-yl}ethenyl]pyridine-3-carbonitrile;

5-[(E)-2-{6-[(4-cyclopentylpiperazin-1-yl)methyl]pyridin-2-yl}ethenyl]-6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]pyridine-3-carbonitrile;

4-[(1-methyl-1H-indol-5-yl)amino]-5-[(E)-2-phenylethenyl]pyridine-3-carbonitrile;
6-methyl-5-[(E)-2-(6-{[4-(1-methylethyl)piperazin-1-yl]methyl}pyridin-2-yl)ethenyl]-4-[(4-methyl-1H-indol-5-yl)amino]pyridine-3-carbonitrile;

6-methyl-5-[(E)-2-{6-[(4-methyl-1,4-diazepan-1-yl)methyl]pyridin-2-yl)ethenyl]-4-[(4-methyl-1H -indol-5-yl)amino]pyridine-3-carbonitrile;

5-{(E)-2-[6-({[3-(dimethylamino)propyl]amino}methyl)pyridin-2-yl]ethenyl}-6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]pyridine-3-carbonitrile;

5-[(E)-2-(6-{[(2-ethoxyethyl)amino]methyl}pyridin-2-yl)ethenyl]-6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]pyridine-3-carbonitrile;

5-[(E)-2-(6-{[(3-ethoxypropyl)amino]methyl}pyridin-2-yl)ethenyl]-6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]pyridine-3-carbonitrile;

5-[(E)-2-{6-[(dimethylamino)methyl]pyridin-2-yl)ethenyl]-6-methyl-4-[(4-methyl-1H-indol-5-yl) amino]pyridine-3-carbonitrile;

6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[6-({[2-(1-methylpyrrolidin-2-yl)ethyl]amino}
methyl)pyridin-2-yl]ethenyl}pyridine-3-carbonitrile;
5-[(E)-2-{6-[(3-hydroxypyrrolidin-1-yl)methyl]pyridin-2-yl}ethenyl]-6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]pyridine-3-carbonitrile;

5-[(E)-2-(6-{[(2-azepan-1-ylethyl)amino]methyl}pyridin-2-yl)ethenyl]-6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]pyridine-3-carbonitrile;

6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-(6-{[(2-pyridin-2-ylethyl)amino]methyl}
pyridin-2-yl)ethenyl]pyridine-3-carbonitrile;

6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-(6-{[(2-pyridin-3-ylethyl)amino]methyl}
pyridin-2-yl)ethenyl]pyridine-3-carbonitrile;

6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-(6-{[(2-pyridin-4-ylethyl)amino]methyl}
pyridin-2-yl)ethenyl]pyridine-3-carbonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[4-({[3-(4-methylpiperazin-1-yl)propyl]amino}
methyl)phenyl]ethenyl}pyridine-3-carbonitrile;

5-{(E)-2-[5-(2-azepan-1-ylethoxy)pyridin-3-yl]ethenyl}-4-[(4-methyl-1H-indol-5-yl)amino]pyridine-3-carbonitrile 6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[4-({[3-(4-methylpiperazin-1-yl)propyl]amino}
methyl)phenyl]ethenyl}pyridine-3-carbonitrile;

5-{(E)-2-[4-({[2-(dimethylamino)ethyl]amino}methyl)phenyl]ethenyl}-6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]pyridine-3-carbonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-(4-{[(2-piperidin-1-ylethyl)amino]methyl}phenyl) ethenyl]pyridine-3-carbonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[5-(3-piperidin-1-ylpropoxy)pyridin-3-yl]ethenyl}
pyridine-3-carbonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-(5-{2-[(1-methylpiperidin-4-yl)amino]ethoxy}pyridin-3-yl)ethenyl]pyridine-3-carbonitrile;

5-{(E)-2-[5-(2-{[1-(1-methylethyl)piperidin-4-yl]amino}ethoxy)pyridin-3-yl]ethenyl}-4-[(4-methyl-1H-indol-5-yl)amino]pyridine-3-carbonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-(5-{2-[(1-propylpiperidin-4-yl)amino]ethoxy}pyridin-3-yl)ethenyl]pyridine-3-carbonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[5-(2-{[1-(2-methylpropyl)piperidin-4-yl]amino}ethoxy) pyridin-3-yl]ethenyl}pyridine-3-carbonitrile;

5-[(E)-2-{3-[(4-hydroxypiperidin-1-yl)methyl]phenyl}ethenyl]-4-[(4-methyl-1H-indol-5-yl)amino]
pyridine-3-carbonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-(3-{[(4-methylpiperazin-1-yl)sulfonyl]methyl}phenyl) ethenyl]pyridine-3-carbonitrile;

5-[(E)-2-{4-[(3-hydroxypyrrolidin-1-yl)methyl]phenyl}ethenyl]-6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]pyridine-3-carbonitrile;

5-{(E)-2-[4-({[3-(dimethylamino)propyl]amino}methyl)phenyl]ethenyl}-6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]pyridine-3-carbonitrile;

5-{(E)-2-[4-({[(1-ethylpyrrolidin-2-yl)methyl]amino}methyl)phenyl]ethenyl}-4-[(4-methyl-1H-indol-5-yl)amino]pyridine-3-carbonitrile;

5-[(E)-2-(4-{[(3-ethoxypropyl)amino]methyl)phenyl)ethenyl]-6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]pyridine-3-carbonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-{3-[(pyrrolidin-1-ylsulfonyl)methyl]phenyl}ethenyl]
pyridine-3-carbonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-(4-{[(4-methylpiperazin-1-yl)sulfonyl]methyl}phenyl) ethenyl]pyridine-3-carbonitrile;

5-[(E)-2-(5-{2-[(1-ethylpiperidin-3-yl)amino]ethoxy}pyridin-3-yl)ethenyl]-4-[(4-methyl-1H-indol-5-yl)amino]pyridine-3-carbonitrile;

6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[5-(piperidin-1-ylmethyl)pyridin-2-yl]ethenyl}
pyridine-3-carbonitrile;

6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[5-(pyrrolidin-1-ylmethyl)pyridin-2-yl]ethenyl}
pyridine-3-carbonitrile;

6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[5-(morpholin-4-ylmethyl)pyridin-2-yl]
ethenyl}pyridine-3-carbonitrile;

6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[5-(thiomorpholin-4-ylmethyl)pyridin-2-yl]
ethenyl}pyridine-3-carbonitrile;

5-[(E)-2-{5-[(4-hydroxypiperidin-1-yl)methyl]pyridin-2-yl}ethenyl]-6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]pyridine-3-carbonitrile;

6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-(5-{[(2-morpholin-4-ylethyl)amino]
methyl}pyridin-2-yl)ethenyl]pyridine-3-carbonitrile;

6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-(5-{[(3-morpholin-4-ylpropyl)amino]
methyl)pyridin-2-yl )ethenyl]pyridine-3-carbonitrile;

6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-{5-[(4-morpholin-4-ylpiperidin-1-yl)methyl]
pyridin-2-yl}ethenyl]pyridine-3-carbonitrile;

5-{(E)-2-[5-(1,4'-bipiperidin-1'-ylmethyl)pyridin-2-yl]ethenyl}-6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]pyridine-3-carbonitrile;

6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-{5-[(4-pyrrolidin-1-ylpiperidin-1-yl)methyl]
pyridin-2-yl}ethenyl]pyridine-3-carbonitrile;

5-[(E)-2-{5-[(4-cyclopentylpiperazin-1-yl)methyl]pyridin-2-yl}ethenyl]-6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]pyridine-3-carbonitrile;

5-{(E)-2-[3-(1,4'-bipiperidin-1'-ylsulfonyl)phenyl]vinyl}-4-[(4-methyl-1H-indol-5-yl)amino]
nicotinonitrile;

6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-(2-{2-methyl-4-[(4-methylpiperazin-1-yl)methyl]
phenyl}ethyl)nicotinonitrile;

1'-(N,N-dimethylglycyl)-4-[(4-methyl-1H-indol-5-yl)amino]-1',2',3',6'-tetrahydro-3,4'-bipyridine-5-carbonitrile;

4-[(E)-2-{5-cyano-4-[(4-methyl-1H-indol-5-yl)amino]pyridin-3-yl}vinyl]-N-isobutyl benzenesulfonamide;

5-[(E)-2-(5-{2-[(2,2-dimethylpropyl)amino]ethoxy}pyridin-3-yl)vinyl]-4-[(4-methyl-1H-indol-5-yl) amino] nicotinonitrile;

5-[(E)-2-(5-{2-[bis(3,3-dimethylbutyl)amino]ethoxy}pyridin-3-yl)vinyl]-4-[(4-methyl-1H-indol-5-yl) amino]nicotinonitrile;

5-[(E)-2-(5-{[4-(2-hydroxyethyl)piperazin-1-yl]methyl}pyridin-2-yl)vinyl]-6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile;

5-[(E)-2-{5-[(4-isopropyl piperazin-1-yl)methyl]pyridin-2-yl}vinyl]-6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile;

5-[(E)-2-(5-{[(2-ethoxyethyl)amino]methyl}pyridin-2-yl)vinyl]-6-methyl-4-[(4-methyl-1H-indol-5-yl) amino] nicotinonitrile;

5-[(E)-2-(5-{[(3-ethoxypropyl)amino]methyl}pyridin-2-yl)vinyl]-6-methyl-4-[(4-methyl-1H-indol-5-yl) amino]nicotinonitrile;

5-[(E)-2-{5-[(dimethylamino)methyl]pyridin-2-yl}vinyl]-6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]
nicotinonitrile;

5-[(E)-2-{5-[(3-hydroxypyrrolidin-1-yl)methyl]pyridin-2-yl}vinyl]-6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile;

6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]5-[(E)-2-(5-{[(2-pyridin-3-ylethyl)amino]methyl}
pyridin-2-yl)vinyl]nicotinonitrile;

5-[2-(6-{[4-(2-hydroxyethyl)piperazin-1-yl]methyl}pyridin-2-yl)ethyl]-4-[(4-methyl-1H-indol-5-yl) amino]nicotinonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-(2-{6-[(4-pyrrolidin-1-ylpiperidin-1-yl)methyl]pyridin-2-yl}
ethyl)nicotinonitrile;

tert-butyl 5-cyano-2-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-3',6'-dihydro-3,4'-bipyridine-1'(2'H)-carboxylate;

6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-(4-{[(2-morpholin-4-ylethyl)amino]methyl}
phenyl)vinyl]nicotinonitrile;

6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-(4-{[(2-pyrrolidin-1-ylethyl)amino]methyl}
phenyl)vinyl]nicotinonitrile;

N-carbamimidoyl-4-[(E)-2-{5-cyano-4-[(4-methyl-1H-indol-5-yl)amino]pyridin-3-yl}vinyl]
benzenesulfonamide;

4-[(E)-2-{5-cyano-4-[(4-methyl-1H-indol-5-yl)amino]pyridin-3-yl}vinyl]benzenesulfonamide;

2-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-1',2',3',6'-tetrahydro-3,4'-bipyridine-5-carbonitrile;
1'-benzyl-2-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-1',2',3',6'-tetrahydro-3,4'-bipyridine-5-carbonitrile;

2-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-1'-[(1-methylpiperidin-4-yl)methyl]-1',2',3',6'-tetrahydro-3,4'-bipyridine-5-carbonitrile;

2-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-1'-(methylsulfonyl)-1',2',3',6'-tetrahydro-3,4'-bipyridine-5-carbonitrile;

5-{2-[6-(1,4'-bipiperidin-1'-ylmethyl)pyridin-2-yl]ethyl}-4-[(4-methyl-1H-indol-5-yl)amino]
nicotinonitrile;

5-[2-(6-{[4-(dimethylamino)piperidin-1-yl]methyl}pyridin-2-yl)ethyl]-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile;

5-{2-[6-(hydroxymethyl)pyridin-2-yl]ethyl}-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile;
3-[(E)-2-(5-cyano-4-[(4-methyl-1H-indol-5-yl)amino]pyridin-3-yl}vinyl]benzenesulfonamide;
4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-{4-[(pyrrolidin-1-ylsulfonyl)methyl]phenyl}vinyl]
nicotinonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[3-(pyrrolidin-1-y1sulfonyl)phenyl]vinyl}nicotinonitrile;
4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-{3-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}
vinyl]nicotinonitrile;

2-({6-[(E)-2-{5-cyano-4-[(4-methyl-1H-indol-5-yl)amino]pyridin-3-yl}vinyl]pyridin-2-yl}methoxy)ethyl sulfate;

4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[4-(2H-tetrazol-5-yl)phenyl]vinyl}nicotinonitrile;
5-{(E)-2-[3-(1,4'-bipiperidin-1'-ylmethyl)phenyl]vinyl}-4-[(4-methyl-1H-indol-5-yl)amino]
nicotinonitrile;

5-[(E)-2-(4-{[4-(dimethylamino)piperidin-1-yl]methyl}phenyl)ethenyl]-4-[(4-methyl-1H-indol-5-yl) amino]pyridine-3-carbonitrile;

6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[3-(morpholin-4-ylmethyl)phenyl]
ethenyl}pyridine-3-carbonitrile;

6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-{3-[(4-methylpiperazin-1-yl)methyl]phenyl}
ethenyl]pyridine-3-carbonitrile;

5-[(E)-2-{3-[(4-hydroxypiperidin-1-yl)methyl]phenyl}ethenyl]-6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]pyridine-3-carbonitrile;

4-(1H-indol-5-ylamino)-5-[(E)-2-pyridin-2-ylethenyl]pyridine-3-carbonitrile;
6-methyl-5-[(E)-2-(3-{[4-(1-methylethyl)piperazin-1-yl]methyl}phenyl)ethenyl]-4-[(4-methyl-1H-indol-5-yl)amino]pyridine-3-carbonitrile;

6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[3-(pyrrolidin-1-ylmethyl)phenyl]ethenyl}
pyridine-3-carbonitrile;

6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[3-(thiomorpholin-4-ylmethyl)phenyl]
ethenyl}pyridine-3-carbonitrile;

6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[4-(pyrrolidin-1-ylsulfonyl)phenyl]
ethenyl}pyridine-3-carbonitrile;

6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-{4-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}
ethenyl]pyridine-3-carbonitrile;

6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-{3-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}
ethenyl]pyridine-3-carbonitrile;

6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[3-(piperidin-1-ylsulfonyl)phenyl]ethenyl}
pyridine-3-carbonitrile;

6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[3-(pyrrolidin-1-ylsulfonyl)phenyl]ethenyl) pyridine-3-carbonitrile;

5-{(E)-2-[2-(hydroxymethyl)-1,3-thiazol-4-yl]ethenyl}-4-[(4-methyl-1H-indol-5-yl)amino]pyridine-3-carbonitrile;

5-[(E)-2-(4-{[(1H-indol-3-ylmethyl)(methyl)amino]methyl}phenyl)ethenyl]-4-[(4-methyl-1H-indol-5-yl)amino]pyridine-3-carbonitrile;

5-[(E)-2-{3-[(diethylamino)methyl]phenyl}ethenyl]-6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]
pyridine-3-carbonitrile;

5-[(E)-2-(4-{[(2-methoxyethyl)amino]methyl}phenyl)ethenyl]-4-[(4-methyl-1H-indol-5-yl)amino]
pyridine-3-carbonitrile;

5-[(E)-2-(4-{[(2-ethoxyethyl)amino]methyl}phenyl)ethenyl]-4-[(4-methyl-1H-indol-5-yl)amino]
pyridine-3-carbonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[4-({[2-(1-methylpyrrolidin-2-yl)ethyl]amino}methyl) phenyl]ethenyl}pyridine-3-carbonitrile;

5-[(E)-2-(4-{[(2-azepan-1-ylethyl)amino]methyl}phenyl)ethenyl]-4-[(4-methyl-1H-indol-5-yl)amino]
pyridine-3-carbonitrile;

6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-(2-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}ethyl) pyridine-3-carbonitrile;

6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-[2-(4-methylphenyl)ethyl]pyridine-3-carbonitrile;
4-[(E)-2-(5-cyano-4-[(4-methyl-1H-indol-5-yl)amino]pyridin-3-yl}ethenyl]-N,N-dimethyl benzenesulfonamide;

4-[(E)-2-{5-cyano-4-[(4-methyl-1H-indol-5-yl)amino]pyridin-3-yl}ethenyl]-N,N-diethyl benzenesulfonamide;

4-[(E)-2-{5-cyano-4-[(4-methyl-1H-indol-5-yl)amino]pyridin-3-yl}ethenyl]-N,N-dipropyl benzenesulfonamide;

4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[4-(piperidin-1-ylsulfonyl)phenyl]ethenyl)pyridine-3-carbonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[3-(piperidin-1-ylsulfonyl)phenyl]ethenyl}pyridine-3-carbonitrile;

5-[(E)-2-{5-[(diethylamino)methyl]pyridin-2-yl}ethenyl]-4-[(4-methyl-1H-indol-5-yl)amino]pyridine-3-carbonitrile;

5-[(E)-2-(6-{[4-(dimethylamino)piperidin-1-yl]methyl}pyridin-2-yl)ethenyl]-6-methyl-4-[(4-methyl-1 H-indol-5-yl)amino]pyridine-3-carbonitrile;

5-[(E)-2-{6-[(diethylamino)methyl]pyridin-2-yl}ethenyl]6-methyl-4-[(4-methyl-1H-indol-5-yl) amino]pyridine-3-carbonitrile;

5-[(E)-2-{6-[(diethylamino)methyl]pyridin-2-yl}ethenyl]-4-[(4-methyl-1H-indol-5-yl)amino]
pyridine-3-carbonitrile;

4-[(E)-2-{5-cyano-4-[(4-methyl-1H-indol-5-yl)amino]pyridin-3-yl}ethenyl]-N,N-bis(1-methyl, ethyl)benzenesulfonamide;

5-[(E)-2-(3-{[(2-azepan-1-ylethyl)amino]methyl}phenyl)ethenyl]-4-[(4-methyl-1H-indol-5-yl)amino]
pyridine-3-carbonitrile;

5-[(E)-2-(3-{[(3-ethoxypropyl)amino]methyl}phenyl)ethenyl]-4-[(4-methyl-1H-indol-5-yl)amino]
pyridine-3-carbonitrile;

5-[(E)-2-(3-{[(2-ethoxyethyl)amino]methyl}phenyl)ethenyl]-4-[(4-methyl-1H-indol-5-yl)amino]
pyridine-3-carbonitrile;

5-[(E)-2-{3-[(dimethylamino)methyl]phenyl}ethenyl]-4-[(4-methyl-1H-indol-5-yl)amino]pyridine-3-carbonitrile;

6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-(4-{[(4-methylpiperazin-1-yl)sulfonyl]methyl}
phenyl)ethenyl]pyridine-3-carbonitrile;

6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-(3-{[(4-methylpiperazin-1-yl)sulfonyl]
methyl}phenyl)ethenyl]pyridine-3-carbonitrile;

6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[4-(piperidin-1-ylsulfonyl)phenyl]ethenyl}p yridine-3-carbonitrile;

4-[(E)-2-{5-cyano-2-methyl-4-[(4-methyl-1H-indol-5-yl)amino]pyridin-3-yl}ethenyl]-N,N-dimethyl benzenesulfonamide;

4-[(E)-2-{5-cyano-2-methyl-4-[(4-methyl-1H-indol-5-yl)amino]pyridin-3-yl}ethenyl]-N,N-diethyl benzenesulfonamide;

4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-(4-{[4-(methylsulfonyl)piperazin-l-yl]methyl}phenyl) ethenyl]pyridine-3-carbonitrile;

6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[3-({[3-(4-methylpiperazin-1-yl)propyl]a mino) methyl)phenyl]ethenyl}pyridine-3-carbonitrile;
5-[(E)-2-(4-{[(2-azepan-1-ylethyl)amino]methyl}phenyl)ethenyl]-6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]pyridine-3-carbonitrile;

5-[(E)-2-(3-{[(3-ethoxypropyl)amino]methyl}phenyl)ethenyl]-6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]pyridine-3-carbonitrile;

6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[4-({[2-(2-methylpyrrolidin-1-yl)ethyl]amino) methyl)phenyl]ethenyl}pyridine-3-carbonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-{(E)-2-[2-(pyrrolidin-1-ylmethyl)-1,3-thiazol-4-yl]
thenyl}pyridine-3-carbonitrile;

6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-(4-{[(2-pyridin-3-ylethyl)amino]methyl}
phenyl)ethenyl]pyridine-3-carbonitrile;

6-ethyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-{4-[(4-methylpiperazin-1-yl)methyl]
phenyl}ethenyl]pyridine-3-carbonitrile;

6-ethyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-{3-[(4-methylpiperazin-1-yl)methyl]phenyl) ethenyl]pyridine-3-carbonitrile;

6-ethyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}
ethyl]pyridine-3-carbonitrile;

6-ethyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-{3-[(4-methylpiperazin-1-yl)methyl]phenyl) ethyl]pyridine-3-carbonitrile;

5-[(E)-2-{4-[(dimethylamino)methyl]phenyl}ethenyl]-6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]
yridine-3-carbonitrile;

5-[(E)-2-(4-{[4-(dimethylamino)piperidin-1-yl]methyl}phenyl)ethenyl]-6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]pyridine-3-carbonitrile;

5-[(E)-2-(5-{[4-(dimethylamino)piperidin-1-yl]methyl}pyridin-2-yl)ethenyl]-6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]pyridine-3-carbonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-{5-[(4-methylpiperazin-1-yl)methyl]-3-thienyl) vinyl]nicotinonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-{5-[(4-methylpiperazin-1-yl)methyl]-2-thienyl) vinyl]nicotinonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-{5-[(4-methylpiperazin-1-yl)methyl]-2-furyl}
vinyl]nicotinonitrile;

6-methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-{2-[(4-methylpiperazin-1-yl)methyl]-1,3-thiazol-4-yl}vinyl]nicotinonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-{2-[(1,4'-bipiperidin-1'-ylmethyl)methyl]-1,3-thiazol-4-yl}vinyl]nicotinonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-{2-[(4-pyrrolidin-1-ylpiperidin-1-yl)methyl]-1,3-thiazol-4-yl}vinyl]nicotinonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-{2-[(4-(dimethylamino)piperidin-1-yl)methyl]-1,3-thiazol-4-yl}vinyl]nicotinonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-{2-[(4-(dimethylamino)methyl]-1,3-thiazol-4-yl}vinyl]
nicotinonitrile;

6-Methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-(4-{[pyrrolidin-1-ylsulfonyl]methyl} phenyl) ethenyl]pyridine-3-carbonitrile;

6-Methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-(3-{[pyrrolidin-1-ylsulfonyl]methyl} phenyl) ethenyl]pyridine-3-carbonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)2-(4-{[piperidin-1-ylsulfonyl]methyl}phenyl) ethenyl]pyridine-3-carbonitrile;

4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-(3-{[piperidin-1-ylsulfonyl]methyl}phenyl) ethenyl]pyridine-3-carbonitrile;

6-Methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-(4-{[piperidin-1-ylsulfonyl]methyl) phenyl)ethenyl]pyridine-3-carbonitrile; or 6-Methyl-4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-(3-{[piperidin-1-ylsulfonyl]methyl}phenyl) ethenyl]pyridine-3-carbonitrile.

26. A compound of any of claims 1-25 or a pharmaceutically acceptable salt thereof for use in the reduction of an increased activity of protein kinase enzyme in a mammal.

27. A composition comprising a compound of any of claims 1-25, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

28. A use of an effective amount of the compound of any of claims 1-25, or a pharmaceutically acceptable salt thereof in the reduction of an increased activity of an enzyme in a mammal, wherein the enzyme is a protein kinase.

29. A use of an effective amount of the compound of any of claims 1-25, or a pharmaceutically acceptable salt thereof in the treatment of inflammation, asthma, colitis, multiple sclerosis, psoriasis, rheumatoid arthritis, inflammatory bowel disease, joint inflammation, organ transplant and graft rejection, in a mammal.

30. A process for preparing a compound of formula I, wherein J is J(ii) or J(iii) as defined in claim 1, the process comprising reacting a compound of formula 15 wherein R2, R11, R12'and p are as defined in claim 1 and Z is I or Br;
in the presence of a Pd catalyst;

with a compound of formula R1-J-B(OR)2, wherein J and R1 are as defined in claim 1, and each R is, independently at each occurrence, H or C1-C6 alkyl; or two R groups together in -B(OR)2, with R comprising C1-C6 alkylene, form a ring comprising boron, oxygen and carbon atoms.

31. A process for preparing a compound of formula I, wherein J is J(iii) as defined in claim 1, the process comprising reacting a compound of formula 15 wherein R2, R11, R12' and p are as defined in claim 1 and Z is I or Br;
in the presence of a Pd catalyst;

with a compound of formula , wherein q is 1; m is 0 and R1 is as defined in claim 1.

32. A process for preparing a compound of formula I, wherein J is J(iii) as defined in claim 1, comprising reacting a compound of formula 36 wherein R2, R11, R12'and p are as defined in claim 1;
in the presence of a palladium catalyst;

with a compound of formula R1-A1-Br or R1-A1-I, wherein R1 and A1 are as defined in claim 1.

33. The process of claim 32, wherein the compound of formula 36 is produced by a process comprising reacting a compound of formula 15 in the presence of a palladium catalyst, with a vinyl reagent.

34. A process for preparing a compound of formula I wherein J is J(iii) as defined in claim 1, the process comprising first reacting a compound of formula 38 wherein K is OH; Q is methylene;
and A1, R11, R12, p, X and R2 are as defined in claim 1;
with an alcohol-activating agent to form an electrophile, followed by reacting the electrophile with an amine R13R13NH, wherein R13is as defined in claim 1, and wherein the alcohol activating agent comprises a base and an alkyl or aryl sulfonyl chloride.

35. A process for preparing a compound of formula I wherein J is J(iii) as defined in claim 1, the process comprising reacting a compound of formula 41 wherein W is CHO, and A1, R11, R12', p, X and R2 are as defined in claim 1;
with an amine R13R13NH wherein R13 is as defined in claim 1;
in the presence of a reducing agent.

36. A process for making a compound according to any of claims 1-25 comprising reacting a compound of formula E

with a compound of formula C

wherein R1, J, R2, X, R11, R12' and p are as defined in claim 1.

37. A use of an effective amount of the compound of any of claims 1-25, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the reduction of an increased activity of an enzyme in a mammal, wherein the enzyme is a protein kinase.

38. A use of an effective amount of the compound of any of claims 1-25, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of inflammation, asthma, colitis, multiple sclerosis, psoriasis, rheumatoid arthritis, inflammatory bowel disease, joint inflammation, organ transplant and graft rejection, in a mammal.