1. Field of the Invention
This invention relates to 3-cyanoquinoline, 3-cyano-1,6-naphthyridine and 3-cyano-1,7-naphthyridine containing compounds as well as their pharmaceutically acceptable salts. The compounds of the present invention inhibit the activity of protein kinases that are required for cell growth and differentiation. The compounds of this invention are therefore useful for the treatment of certain diseases that result from activity of these protein kinases. The compounds of this invention are anti-cancer agents and are useful for the treatment of cancer in mammals. In addition, the compounds of this invention are useful for the treatment of polycystic kidney disease in mammals. The compounds of this invention may also be used in the treatment of osteoporosis. This invention also relates to the manufacture of said compounds, their use for the treatment of cancer, polycystic kidney disease and osteoporosis, and the pharmaceutical preparations containing them.
2. Description of the Prior Art
Protein kinases are enzymes that catalyze the transfer of a phosphate group from 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. Specific protein kinases have been implicated in diverse conditions including cancer [Traxler P. M., Exp. Opin. Ther. Patents, 8, 1599 (1998); Bridges, A. J., Emerging Drugs, 3, 279 (1998)], restenosis [Mattsson, E., Trends Cardiovas. Med. 5, 200 (1995); Shaw, Trends Pharmacol. Sci. 16, 401 (1995)], atherosclerosis [Raines, E. W., Bioessays, 18, 271 (1996)], angiogenesis [Shawver, L. K., Drug Discovery Today, 2, 50 (1997); Folkman, J., Nature Medicine, 1, 27 (1995)] and osteoporosis [Boyce, J. Clin. Invest., 90, 1622 (1992).
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 including proliferation and migration. The overexpession of EGF and also of members of the epidermal growth factor receptor (ECFr) family, which includes EGF-r, erbB-2, erbB-3 and erbB-4, is implicated in the development and progression of cancer [Rusch, V., Cytokine Growth Factor Rev., 7, 133 (1996), Davies, D. E., Biochem. Pharmacol., 51, 1101 (1996) and Modjtahedi, E., Int. J. Oncol., 4, 277 (1994)]. Specifically, over expression of the receptor kinase product of the erbB-2 oncogene has been associated with human breast and ovarian cancers [Slamon, D. J., Science, 244, 707 (1989) and Slamon, D. J. Science, 235, 177 (1987)]. Upregulation of EGFr kinase activity has been associated with epidermoid tumors [Reiss, M., Cancer Res., 51, 6254 (1991)], breast tumors [Macias, A., Anticancer Res., 7, 459 (1987)], and tumors involving other major organs [Gullick, W. J., Brit. Med. Bull., 47, 87 (1991)].
It is also known that deregulation of EGF receptors is a factor in the growth of epithelial cysts in the disease described as polycystic kidney disease [Du, J., Amer. J. Physiol., 269 (2 Pt 1), 487 (1995); Nauta, J., Pediatric Res., 37(6), 755 (1995); Gattone, V. H., Developmental Biology, 169(2), 504 (1995); Wilson, P. D., Eur. J. Cell Biol., 61(1), 131, (1993)]. Compounds which inhibit the catalytic function of the EGF receptors, may consequently be useful for the treatment of this disease.
In addition to EGFr, there are several other RTKs including FGFr, the receptor for fibroblast growth factor (FGF); flk-1, also known as KDR, and flt-1, the receptors for vascular endothelial growth factor (VEGF); and PDGFr, the receptor for platelet derived growth factor (PDGF). The formation of new blood vessels, a process known as angiogenesis, is essential for tumor growth. Two natural angiogenesis inhibitors, angiostatin and endostatin, dramatically inhibited the growth of a variety of solid tumors. [O""Reilly, M. S., Cell, 79, 315 (1994)]; O""Reilly, M. S., Nature Medicine, 2, 689 (1996); O""Reilly, M. S., Cell, 88, 277 (1997)]. Since FCF and VEGF are known to stimulate angiogenesis, inhibition of the kinase activity of their receptors should block the angiogenic effects of these growth factors. In addition, the receptor tyrosine kinases tie-1 and tie-2 also play a key role in angiogenesis [Sato, T. N., Nature, 376, 70 (1995)]. Compounds that inhibit the kinase activity of FGFr, flk-1, flt-1, tie-1 or, tie-2 may inhibit tumor growth by their effect on angiogenesis.
PDGF is a potent growth factor and chemoattractant for smooth muscle cells (SMCs) and the renarrowing of coronary arteries following angioplasty is due in part to the enhanced proliferation of SMCs in response to increased levels of PDGF. Therefore, compounds that inhibit the kinase activity of PDGFr may be useful in the treatment of restenosis. In addition, since PDGF and PDGFr are overexpessed in several types of human gliomas, small molecules capable of suppessing PDGFr activity, have potential utility as anticancer therapeutics [Nister, M., J. Biol. Clem. 266, 16755 (1991); Strawn, L. M., J. Biol. Chem. 269, 21215 (1994)].
Other RTKs that could potentially be inhibited by compounds of this invention include colony stimulating factor receptor, the nerve growth factor receptors (trkA, trkB and trkC), the insulin receptor, the insulin-like growth factor receptor, the hepatocyte growth factor receptor and the erythiopoietin-producing hepatic cell receptor (EPH).
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. However, the major family of cytoplasmic protein TKs is the Src family which consists of at least eight members (Src, Fyn, Lyn, Yes, Lck, Fgr, Hck and Blk) that participate in a variety of signaling pathways [Schwartzberg, P. L., Oncogene, 17, 1463 (1998)]. The prototypical member of this tyrosine kinase family is Src, which is involved in proliferation and migration responses in many cell types. Src activity has been shown to be elevated in breast, colon (xcx9c90%), pancreatic ( greater than 90%) and liver ( greater than 90%) tumors. Greatly increased Src activity is also associated with metastasis ( greater than 90%) and poor prognosis. Antisense Src message impedes growth of colon tumor cells in nude mice [Staley, C. A., Cell Growth Differentiation, 8, 269 (1997)], suggesting that Src inhibitors should slow tumor growth. In addition to its role in cell proliferation, Src also acts in stress response pathways, including the hypoxia response. Nude mice studies with colon tumor cells expressing antisense Src message have reduced vascularization [Ellis, L. M., J. Biol. Chem., 273, 1052 (1998)], which suggests that Src inhibitors would be anti-angiogenic as well as anti-proliferative.
In addition to its role in cancer, Src also appears to play a role in osteoporosis. Mice genetically engineered to be deficient in Src production were found to exhibit osteopetiosis, the failure to resorb bone [Soriano, P., Cell, 64, 693 (1991); Boyce, B. F., J. Clin., Invest., 90, 1622 (1992)]. This defect was characterized by a lack of osteoclast activity. Since osteoclasts normally express high levels of Src, inhibition of Src kinase activity may be useful in the treatment of osteoporosis [Missbach, M., Bone, 24, 437 (1999)].
Two members of the cytoplasmic protein TKs, lck and ZAP-70 are predominately expressed on T-cells and natural killer (NK) cells. Inhibitors of these kinases can suppress the immune system and therefore have possible therapeutic potential to treat autoimmune diseases such as rheumatoid arthritis, sepsis, and transplant rejection [Myers, M., Current Pharm. Design, 3, 473 (1997)].
Besides TKs, there are additional kinases including those that phosphorylate serine and/or threonine residues on proteins. A major pathway in the cellular signal transduction cascade is the mitogen-activated protein kinase (MAPK) pathway which consists of the MAP kinase kinases (MAPKK), including mek, and their substrates, the MAP kinases (MAPK), including erk [Seger, R., FASEB, 9, 726 (1995)]. When activated by phosphorylation on two serine residues by upstream kinases, such as members of the raf family, mek catalyzes the phosphorylation of threonine and tyrosine residues on erk. The activated erk then phosphorylates and activates both transcription factors in the nucleus and other cellular targets. Over-expression and/or over-activation of mek or erk is associated with various human cancers [Sivaraman, V. S., J. Clin. Invest., 99, 1478 (1997)].
As mentioned above, members of the raf family of kinases phosphorylate serine residues on mek. There are three serine/threonine kinase members of the raf family known as a-raf, b-raf and c-raf. While mutations in the raf genes are rare in human cancers, c-raf is activated by the ras oncogene which is mutated in a wide number of human tumors. Therefore inhibition of the kinase activity of c-raf may provide a way to prevent ras medicated tumor growth [Campbell, S. L., Oncogene, 17, 1395 (1998)].
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. Increased activity or activation of these kinases is associated with the development of human tumors [Garrett, M. D., Current Opin. Genetics Devel., 9, 104 (1999); Webster, K. R., Exp. Opin. Invest. Drugs, 7, 865 (1998)]. Additional serine/threonine kinases include the protein kinases A, B, and C. These kinases, are known as PKA or cyclic AMP-dependent protein kinase, PKB or Akt, and PKC, and all three play key roles in signal transduction pathways responsible for oncogenesis [Glazer, R. I., Current Pharm. Design, 4(3), 277 (1998)]. Compounds capable of inhibiting the kinase activity of mek, erk, raf, cdc2/cyclin B, cdk2/cyclin A, cdk2/cyclin E, cdk4/cyclin D, PKA, Akt or PKC may be useful in the treatment of diseases characterized by abnormal cellular proliferation, such as cancer.
The serine/threonine kinase UL97 is a virion-associated protein kinase which is required for the replication of human cytomegalovirus [Wolf, D. G., Arch. Virology 143(6), 1223 (1998) and He, Z., J. Virology, 71, 405(1997)]. Compounds capable of inhibiting the kinase activity of UL97 may be useful antiviral therapeutics. Since certain bacteria require the action of a histidine kinase for proliferation [Loomis, W. F., J. Cell Sci. 110, 1141 (1997)], compounds capable of inhibiting such histidine kinase activity may be useful antibacterial agents.
Some 3-cyanoquinoline derivatives are inhibitors of tyrosine kinases and are described in the application WO9843960 (U.S. Pat. No. 6,002,008). These 3-cyanoquinolines may be substituted at carbon-5 through carbon-8 with an unsubstituted phenyl, alkene or alkyne group. A 3-cyanoquinoline with a 4-(2-methylanilino) substituent having gasitic (H+/K+)-ATPase inhibitory activity at high concentrations has been described [Ife, R., J. Med. Chem., 35(18) 3413 (1992)].
Some 3-cyanoquinolines are claimed as inhibitors of tumor necrosis factor (TNF) or phosphodiesterase IV. The application WO982007 claims 3-cyanoquinolines that may be unsubstituted at carbon-2 and substituted at carbon-4 with an aryloxy, cycloalkoxy, heteroaryloxy or anilino group. However these compounds must contain at carbon-8 a hydroxy, thioalkyl, alkoxy of 1 to 6 carbon atoms or cycloalkoxy group optionally substituted with one or more halogens. These compounds must also contain at carbon-5 an imidazole, oxazole, or thiazole ring attached to the quinoline ring at carbon-2 and this hereroaryl ring must be fused to a 6-membered aromatic ring that may contain 1 or 2 nitrogen atoms in the ring. The application WO9857936 also claims 3-cyanoquinolines as inhibitors of tumor necrosis factor (TNF) or phosphodiesterase IV. These compounds may be unsubstituted at carbon-2 but must contain at carbon-8 a hydroxy, thioalkyl, alkoxy of 1 to 6 carbon atoms or cycloalkoxy group optionally substituted with one or more halogens. These compounds must contain at carbon-5 an aryl or heteroaryl ring that may be substituted. In addition these compounds may contain a aryloxy, cycloalkoxy, or heteroaryloxy group at carbon-4. However when an amino group is present at carbon-4 the amino group must be substituted by an alkylcarbonyl, alkoxycarbonyl, arylsulfonyl, heteroarylsulfonyl, heterocyclosulfonyl, arylcarbonyl, heteroarylcarbonyl, heterocyclocarbonyl or alkylsulfonyl group.
The applications WO9744036 and WO9744322 claim additional 3-cyanoquinolines as inhibitors of tumor necrosis factor (TNF) of phosphodiesterase IV but these applications do not claim the substituents at carbon-5 through carbon-8 of the 3-cyanoquinolines claimed herein.
The applications WO9404526 and WO9404527 claim 3-cyanoquinolines as pesticides. These 3-cyanoquinolines may be unsubstituted at carbon-2, but differ from the compounds claimed herein that they must contain at carbon-4 a group of formula xe2x80x94Y(CH2)2-phenyl, xe2x80x94Y(CH2)2-pyridine or xe2x80x94Y(CH2)2-pyridazine, where Y is O, CH2, NH or N-alkyl. These applications also do not claim the substituents at carbon-5 through carbon-8 of the 3-cyanoquinolines claimed herein.
A series of patent applications, WO9719927, WO9602509, and WO9532948 claim 3-cyanoquinolines as neurokinin inhibitors. However these compounds must contain at carbon-4 of the quinoline a group of the formula C(X)NRR wherein X is O, S or Nxe2x80x94CN and in addition carbon-2 of the quinoline can not be unsubstituted.
Several patents and patent applications claim 3-cyanoquinolines as inhibitors of leukotriene biosynthesis. While some of these, including U.S. Pat. No. 5,232,916, U.S. Pat. No. 5,104,882, EP349062 and DE19532714, claim compounds with the substituents at carbon-4 and at carbon-5 through carbon-8 of the cyanoquinoline claimed herein, all of the compounds must contain a substituent at carbon-2.
Several patent applications claim 3-cyanoquinolines as angiotensin II antagonists. EP499415 claims 3-cyanoquinolines, unsubstituted at carbon-2 and substituted at carbon-4 with a group of the formula NRCH2Ph, wherein R is H or lower, alkyl and Ph is phenyl which must be substituted by a tetrazole, C(O)NHtetrazole or other specified groups. This application does not claim the substituents at carbon-5 through carbon-8 of the 3-cyanoquinolines claimed herein. A series of patent applications EP527534, EP156442 and CB2264710 claim 3-cyanoquinolines, unsubstituted at carbon-2 and substituted at carbon-4 with a group of the formula OCH2Ph, but these applications do not claim the substituents at carbon-5 through carbons-8 of the 3-cyanoquinolines claimed herein.
U.S. Pat. No. 5,480,883 describes a series of compounds including quinolines as tyrosine kinase inhibitors. These quinoline compounds are unsubstituted at carbon-3. Patent application WO9609294 describes quinazolines and quinolines substituted at carbon-4 by anilino, phenoxy and thiophenoxy groups as tyrosine kinase inhibitors, however the quinoline compounds are unsubstituted at carbon-3. U.S. Pat. No. 5,650,415 describes quinolines substituted at carbon-4 by a benzylamino or benzylthio group as tyrosine kinase inhibitors. These quinolines however must contain an ethyl ester group at carbon-3. Additional quinoline compounds substituted with an ethyl ester at carbon-3 and an anilino group at carbon-4 are claimed in U.S. Pat. No. 4,343,804 as antisecretory and antiulcer compounds.
Patent application WO9813350 describes 3-fluoroquinolines, quinolines, 1,6-naphthyridines and 1,7-naphthyridines substituted at carbon-4 by anilino, phenoxy and thiophenoxy groups as tyrosine kinase inhibitors, but does not include the 3-cyano group contained in the quinoline, 1,6-naphthyridine and 1,7-naphthyridine compounds of the present invention.
Several patents and patent applications disclose quinazolines with anilino groups it carbon-4 and substituted at carbons-5 to 8 with a phenyl, naphthyl, alkene, alkyne or a 5-6 membered heteroaryl group as kinase inhibitors. U.S. Pat. No. 5,814,630 describes quinazolines substituted at carbon-7 with a phenyl, naphthyl or 5-6 membered heteroaromatic ring. U.S. Pat. No. 5,866,572 describes 4-anilinoquinazolines substituted at carbon-6 with a phenyl, naphthyl or 5-6 membered heteroaryl group that may be directly attached to the quinoline or attached via a carbonyl, alkyl or hydroxymethylene linker. U.S. Pat. No. 5,955,464 describes 4-anilinoquinazolines substituted at carbon-6 by a nitrogen containing heteroaryl group that is linked to the quinazoline via a nitrogen atom. The application EP837063 describes quinazolines that are substituted at carbons-5 to 8 with one or more optionally substituted 5- or 6-membered heteroaryl, or phenyl rings either directly attached to the quinazoline or attached via an alkene or alkyne linker.
Additionally, the application WO98024134 describes quinazolines and quinolines, as kinase inhibitors, unsubstituted at carbon-3, that are substituted at carbons-5 to 8 with one or more optionally substituted 5- or 6-membered heteroalyl or phenyl rings. Patent applications WO9802437 and WO9935146 further describe ring systems, including quinolines, 1,6-naphthyridines and 1.7-naphthyridines with anilino groups at carbon-4 and substituted at carbons-5 to 8 with one or more optionally substituted 5- or 6-membered heteroaryl or phenyl rings, as kinase inhibitors and which do not disclose the 3-cyano group of the present invention.
The compounds of the present invention are 3-cyanoquinolines with a suitably substituted heteroaryl, bicyclic heteroaryl, aryl, alkene or alkyne group at carbon-5, carbon-6, carbon-7, or carbon-8. Alternative names for 3-cyanoquinolines include 3-quinolinecarbonitriles and quinoline-3-carbonitriles. Also included in the present invention, are 3-cyano-1,6-naphthyridines with a suitably substituted heteroaryl, bicyclic heteroaryl, alkene or alklyne group at carbon-5, carbon-7, or carbon-8 and 3-cyano-1,7-naphthyridines with a suitably substituted heteroaryl, bicyclic heteroaryl, aryl, alkene or alkyne group at carbon-5, carbon-6, or carbon-8. The compounds of the present invention inhibit the activity of protein kinases that are required for cell growth and differentiation and are therefore useful for the treatment of certain diseases that result from activity of these protein kinases. The compounds of this invention are anti-cancer agents and are useful for the treatment of cancer in mammals. Further, the compounds of this invention are useful for the treatment of polycystic kidney disease in mammals.
In accordance with the present invention there is provided compounds represented by Formula (I): 
wherein:
X is xe2x80x94NHxe2x80x94, xe2x80x94NR5xe2x80x94, xe2x80x94Oxe2x80x94, or xe2x80x94S(O)mxe2x80x94;
n is an integer of 0 or 1;
m is an integer of 0 to 2;
q is an integer of 0 to 5;
p is an integer of 2 to 5;
s is an integer of 0 to 5;
r is an integer of 0 to 5;
J is halogen;
A is xe2x80x94(C(R9)2)rxe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)(C(R9)2)rxe2x80x94, xe2x80x94(C(R9)2)rC(O)xe2x80x94, -cycloalkyl- or is absent;
T and Z are each independently carbon or N, provided that both T and Z are not simultaneously N;
R1 is selected from a cycloalkyl ring of 3 to 10 carbon atoms, optionally substituted with one or more independently selected alkyl groups of 1 to 6 carbon atoms; aryl of 6 to 12 carbon atoms optionally substituted with 1 to 4 substituents which may be the same or different independently selected from xe2x80x94H, xe2x80x94J, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94OH, xe2x80x94SH, xe2x80x94CN, xe2x80x94N3, xe2x80x94COOH, xe2x80x94CONH2, xe2x80x94NHC(O)NH2, xe2x80x94C(O)H, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94R5, xe2x80x94OR5, xe2x80x94NHR5, xe2x80x94Q, xe2x80x94S(O)mR5, xe2x80x94NHSO2R5, xe2x80x94R6OH, xe2x80x94R6OR5, xe2x80x94R6NH2, xe2x80x94R6NHR5, xe2x80x94R6Q, xe2x80x94R6SH, xe2x80x94R6S(O)mR5, xe2x80x94NHR7OH, xe2x80x94NHR7OR5, xe2x80x94N(R5)R7OH, xe2x80x94N(R5)R7OR5, xe2x80x94NHR7NH2, xe2x80x94NHR7NHR5, xe2x80x94NHR7Q, xe2x80x94N(R5)R7NH2, xe2x80x94N(R5)R7NHR5, xe2x80x94N(R5)R7Q, xe2x80x94OR7OH, xe2x80x94OR7OR5, xe2x80x94OR7NH2, xe2x80x94OR7NHR5, xe2x80x94OR7Q, xe2x80x94OC(O)R5, xe2x80x94NHC(O)R5, xe2x80x94NHC(O)NHR5, xe2x80x94OR6C(O)R5, xe2x80x94NHR6C(O)R5, xe2x80x94C(O)R5, xe2x80x94C(O)OR5, xe2x80x94C(O)NHR5, xe2x80x94C(O)Q, xe2x80x94R6C(O)H, xe2x80x94R6C(O)R5, xe2x80x94R6C(O)OH, xe2x80x94R6C(O)OR5, xe2x80x94R6C(O)NH2, xe2x80x94R6C(O)NHR5, xe2x80x94R6C(O)Q, xe2x80x94R6OC(O)R5, xe2x80x94R6OC(O)NH2, xe2x80x94R6OC(O)NHR5, xe2x80x94R6OC(O)Q and YR8 groups wherein Y is independently selected from xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94OC(O)xe2x80x94, xe2x80x94C(O)NHxe2x80x94, xe2x80x94NHC(O)xe2x80x94, xe2x80x94NHSO2xe2x80x94, xe2x80x94SO2NHxe2x80x94, xe2x80x94C(OH)Hxe2x80x94, xe2x80x94O(C(R9)2)qxe2x80x94, xe2x80x94S(O)m(C(R9)2)qxe2x80x94, xe2x80x94NH(C(R9)2)qxe2x80x94, xe2x80x94NR10(C(R9)2)qxe2x80x94, xe2x80x94(C(R9)2)q(C(R9)2)qxe2x80x94, xe2x80x94(C(R9)2)qOxe2x80x94, xe2x80x94(C(R9)2)qS(O)mxe2x80x94, xe2x80x94(C(R9)2)qNHxe2x80x94, xe2x80x94(C(R9)2)qNR10, xe2x80x94Cxe2x89xa1Cxe2x80x94, cis and trans xe2x80x94CHxe2x95x90CHxe2x80x94 and cycloalkyl of 3 to 10 carbon atoms;
a heteroaryl ring having 5 or 6 atoms containing 1 to 4 heteoatoms or particularly 1 or 2 heteroatoms which may be the same or different, selected from N, O and S wherein the heteroaryl ring may be optionally substituted with 1 to 4 substituents which may be the same or different selected from xe2x80x94H, xe2x80x94J, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94OH, xe2x80x94SH, xe2x80x94CN, xe2x80x94N3, xe2x80x94COOH, xe2x80x94CONH2, xe2x80x94NHC(O)NH2, xe2x80x94C(O)H, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94R5, xe2x80x94OR5, xe2x80x94NHR5, xe2x80x94Q, xe2x80x94S(O)mR5, xe2x80x94NHSO2R5, xe2x80x94R6OH, xe2x80x94R6OR5, xe2x80x94R6NH2, xe2x80x94R6NHR5, xe2x80x94R6Q, xe2x80x94R6SH, xe2x80x94R6S(O)mR5, xe2x80x94NHR7OH, xe2x80x94NHR7OR5, xe2x80x94N(R5)R7OH, xe2x80x94N(R5)R7OR5, xe2x80x94NHR7NH2, xe2x80x94NHR7NHR5, xe2x80x94NHR7Q, xe2x80x94N(R5)R7NH2, xe2x80x94N(R5)R7NHR5, xe2x80x94N(R5)R7Q, xe2x80x94OR7OH, xe2x80x94R7OR5, xe2x80x94OR7NH2, xe2x80x94OR7NHR5, xe2x80x94OR7Q, xe2x80x94OC(O)R5, xe2x80x94NHC(O)R5, xe2x80x94NHC(O)NHR5, xe2x80x94R6C(O)R5, xe2x80x94NHR6C(O)R5, xe2x80x94C(O)R5, xe2x80x94C(O)OR5, xe2x80x94C(O)NHR5, xe2x80x94C(O)Q, xe2x80x94R6C(O)H, xe2x80x94R6C(O)R5, xe2x80x94R6C(O)OH, xe2x80x94R6C(O)OR5, xe2x80x94R6C(O)NH2, xe2x80x94R6C(O)NHR5, xe2x80x94R6C(O)Q, xe2x80x94R6OC(O)R5, xe2x80x94R6OC(O)NH2, xe2x80x94R6OC(O)NHR5, xe2x80x94R6OC(O)Q and YR8 groups wherein Y is independently selected from xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94OC(O)xe2x80x94, xe2x80x94C(O)NHxe2x80x94, xe2x80x94NHC(O)xe2x80x94, xe2x80x94NHSO2xe2x80x94, xe2x80x94SO2NHxe2x80x94, xe2x80x94C(OH)Hxe2x80x94, xe2x80x94O(C(R9)2)qxe2x80x94, xe2x80x94S(O)m(C(R9)2)qxe2x80x94, xe2x80x94NH(C(R9)2)qxe2x80x94, xe2x80x94NR10(C(R9)2)qxe2x80x94, xe2x80x94(C(R9)2)qxe2x80x94, xe2x80x94(C(R9)2)qOxe2x80x94, xe2x80x94(C(R9)2)qS(O)mxe2x80x94, xe2x80x94(C(R9)2)qNHxe2x80x94, xe2x80x94(C(R9)2)qNR10xe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, cis and trans xe2x80x94CHxe2x95x90CHxe2x80x94 and cycloalkyl of 3 to 10 carbon atoms;
a bicyclic heteroaryl ring system having 8 to 20 atoms containing 1 to 4 heteroatoms which may be the same or different selected from N, O and S wherein the bicyclic heteroaryl ring system may be optionally substituted with 1 to 4 substituents which may be the same or different selected from xe2x80x94H, xe2x80x94J, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94OH, xe2x80x94SH xe2x80x94CN, xe2x80x94N3, xe2x80x94COOH, xe2x80x94CONH2, xe2x80x94NHC(O)NH2, xe2x80x94C(O)H, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94R5, xe2x80x94OR5, xe2x80x94NHR5, xe2x80x94Q, xe2x80x94S(O)mR5, xe2x80x94NHSO2R5, xe2x80x94R6OH, xe2x80x94R6OR5, xe2x80x94R6NH2, xe2x80x94R6NHR5, xe2x80x94R6Q, xe2x80x94R6SH, xe2x80x94R6S(O)mR5, xe2x80x94NHR7OH, xe2x80x94NHR7OR5, xe2x80x94N(R5)R7OH, xe2x80x94N(R5)R7OR5, xe2x80x94NHR7NH2, xe2x80x94NHR7NHR5, xe2x80x94NHR7Q, xe2x80x94N(R5)R7NH2, xe2x80x94N(R5)R7NHR5, xe2x80x94N(R5)R7Q, xe2x80x94OR7OH, xe2x80x94OR7OR5, xe2x80x94OR7NH2, xe2x80x94OR7NHR5, xe2x80x94OR7Q, xe2x80x94OC(O)R5, xe2x80x94NHC(O)R5, xe2x80x94NHC(O)NHR5, xe2x80x94OR6C(O)R5, xe2x80x94NHR6C(O)R5, xe2x80x94C(O)R5, xe2x80x94C(O)OR5, xe2x80x94C(O)NHR5, xe2x80x94C(O)Q, xe2x80x94R6C(O)H, xe2x80x94R6C(O)R5, xe2x80x94R6C(O)OH, xe2x80x94R6C(O)OR5, xe2x80x94R6C(O)NH2, xe2x80x94R6C(O)NHR5, xe2x80x94R6C(O)Q, xe2x80x94R6OC(O)R5, xe2x80x94R6OC(O)NH2, xe2x80x94R6OC(O)NHR5, xe2x80x94R6OC(O)Q and YR8 groups wherein Y is independently selected from xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94OC(O)xe2x80x94, xe2x80x94C(O)NHxe2x80x94, xe2x80x94NHC(O)xe2x80x94, xe2x80x94NHSO2xe2x80x94, xe2x80x94SO2NHxe2x80x94, xe2x80x94C(OH)Hxe2x80x94, xe2x80x94O(C(R9)2)qxe2x80x94, xe2x80x94S(O)m(C(R9)2)qxe2x80x94, NH(C(R9)2)q, xe2x80x94NR10(C(R9)2)q, xe2x80x94(C(R9)2)qxe2x80x94, xe2x80x94(C(R9)2)qOxe2x80x94, xe2x80x94(C(R9)2)qS(O)mxe2x80x94, xe2x80x94(C(R9)2)qNHxe2x80x94, xe2x80x94(C(R9)2)qNR10xe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, cis and trans xe2x80x94CHxe2x95x90CHxe2x80x94 and cycloalkyl of 3 to 10 carbon atoms; and a moiety of the formula 
E is xe2x80x94NHxe2x80x94, xe2x80x94NR5xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94S(O)mxe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94CHR5xe2x80x94 or xe2x80x94CR5R5xe2x80x94;
Q is xe2x80x94NR5R5 and further provided that when each R5 is independently selected from alkyl and alkenyl, R5R5 may optionally be taken together with the nitrogen atom to which they are attached forming a heterocyclyl ring of 3 to 8 atoms, optionally containing 1 or 2 additional heteroatoms which may be the same or different selected from N, O and S;
R1a, R1b, R1c, R1d and R1e are each, independently selected from xe2x80x94H, xe2x80x94J, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94OH, xe2x80x94SH, xe2x80x94CN, xe2x80x94N3, xe2x80x94COOH, xe2x80x94CONH2, xe2x80x94NHC(O)NH2, xe2x80x94C(O)H, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94R5, xe2x80x94OR5, xe2x80x94NHR5, xe2x80x94Q, xe2x80x94S(O)mR5, xe2x80x94NHSO2R5, xe2x80x94R6OHxe2x80x94, xe2x80x94R6OR5, xe2x80x94R6NH2, xe2x80x94R6NHR5, xe2x80x94R6Q, xe2x80x94R6SH, xe2x80x94R6S(O)mR5, xe2x80x94NHR7OH, xe2x80x94NHR7OR5, xe2x80x94N(R5)R7OH, xe2x80x94N(R5)R7OR5, xe2x80x94NHR7NH2, xe2x80x94NHR7NHR5, xe2x80x94NHR7Q, xe2x80x94N(R5)R7NH2, xe2x80x94N(R5)R7NHR5, xe2x80x94N(R5)R7Q, xe2x80x94OR7OH, xe2x80x94OR7OR5, xe2x80x94OR7NH2, xe2x80x94OR7NHR5, xe2x80x94OR7Q, xe2x80x94OC(O)R5, xe2x80x94NHC(O)R5, xe2x80x94NHC(O)NHR5, xe2x80x94OR6C(O)R5, xe2x80x94NHR6C(O)R5, xe2x80x94C(O)R5, xe2x80x94C(O)OR5, xe2x80x94C(O)NHR5, xe2x80x94C(O)Q, xe2x80x94R6C(O)H, xe2x80x94R6C(O)R5, xe2x80x94R6C(O)OH, xe2x80x94R6C(O)OR5, xe2x80x94R6C(O)NH2, xe2x80x94R6C(O)NHR5, xe2x80x94R6C(O)Q, xe2x80x94R6OC(O)R5, xe2x80x94R6OC(O)NH2, xe2x80x94R6OC(O)NHR5, -aryl, xe2x80x94CH2aryl, xe2x80x94NHaryl, xe2x80x94Oaryl, xe2x80x94S(O)maryl, xe2x80x94R11, xe2x80x94OR11, xe2x80x94NHR11 and xe2x80x94R6OC(O)Q;
R2a, R2b, and R2c, are each, independently selected from xe2x80x94H, -aryl, xe2x80x94CH2aryl, xe2x80x94Oaryl, xe2x80x94S(O)m, xe2x80x94J, xe2x80x94NO2, xe2x80x94OH, xe2x80x94SH, xe2x80x94CN, xe2x80x94N3, xe2x80x94COOH, xe2x80x94CONH2, xe2x80x94NHC(O)NH2, xe2x80x94C(O)H, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94R5, xe2x80x94OR5, xe2x80x94S(O)mR5, xe2x80x94NHSO2R5, xe2x80x94R11, xe2x80x94OR11, xe2x80x94R6OH, xe2x80x94R6OR5, xe2x80x94R6SH, xe2x80x94R6S(O)mR5, xe2x80x94OR7OH, xe2x80x94OR7OR5, xe2x80x94OC(O)R5, xe2x80x94NHC(O)R5, xe2x80x94NHC(O)NHR5, xe2x80x94OR6C(O)R5, xe2x80x94NHR6C(O)R5, xe2x80x94C(O)R5, xe2x80x94C(O)OR5, xe2x80x94C(O)NHR5, xe2x80x94C(O)Q, xe2x80x94R6C(O)H, xe2x80x94R6C(O)R5, xe2x80x94R6C(O)OH, xe2x80x94R6C(O)OR5, xe2x80x94R6C(O)NH2, xe2x80x94R6C(O)NHR5, xe2x80x94R6C(O)Q, xe2x80x94R6OC(O)R5, xe2x80x94R6OC(O)NH2, xe2x80x94R6OC(O)NHR5, xe2x80x94R6OC(O)Q, xe2x80x94Gxe2x80x94(C(R9)2)pR12, xe2x80x94(C(R9)2)qR12, 
G is xe2x80x94NHxe2x80x94, xe2x80x94NR10xe2x80x94, xe2x80x94Oxe2x80x94 of xe2x80x94S(O)mxe2x80x94;
R3 is selected from alkenyl of 2 to 6 carbon atoms, optionally substituted with one or more of xe2x80x94R10, xe2x80x94(C(R9)2)sR12, xe2x80x94CHO, 1,3-dioxolane, xe2x80x94NO2, xe2x80x94CN, xe2x80x94CO2H, xe2x80x94CONH2, xe2x80x94CO2R10, xe2x80x94CONHR10, xe2x80x94COR10, xe2x80x94(C(R9)2)qOH, xe2x80x94(C(R9)2)qOR10, xe2x80x94(C(R9)2)qNHR10, xe2x80x94(C(R9)2)qJ, xe2x80x94(C(R9)2)qNH2, xe2x80x94(C(R9)2)rH, xe2x80x94G(C(R9)2)pOR10, xe2x80x94G(C(R9)2)pR12, and xe2x80x94G(C(R9)2)pOH; alkynyl of 2 to 6 carbon atoms, optionally substituted with one or more of xe2x80x94R10, xe2x80x94(C(R9)2)sR12, xe2x80x94CHO, 1,3-dioxolane, xe2x80x94NO2, xe2x80x94CN, xe2x80x94CO2H, xe2x80x94CONH2, xe2x80x94CO2R10, xe2x80x94CONHR10, xe2x80x94COR10xe2x80x94(C(R9)2)qOH, xe2x80x94(C(R9)2)qOR10, xe2x80x94(C(R9)2)qNHR10, xe2x80x94(C(R9)2)qJ, xe2x80x94(C(R9)2)qNH2, xe2x80x94(C(R9)2)rH, xe2x80x94G(C(R9)2)qOR10, xe2x80x94G(C(R9)2)pR12, and xe2x80x94G(C(R9)2)pOH; aryl of 6 to 12 carbon atoms optionally substituted with 1 to 4 substituents which may be the same or different selected from xe2x80x94R10, xe2x80x94(C(R9)2)sR12, xe2x80x94CHO, 1,3-dioxolane, xe2x80x94NO2, xe2x80x94CN, xe2x80x94CO2Hxe2x80x94, xe2x80x94CONH2, xe2x80x94CO2R10, xe2x80x94CONHR10, xe2x80x94COR10, xe2x80x94(C(R9)2)qOH, xe2x80x94(C(R9)2)qOR10, xe2x80x94(C(R9)2)qNHR10, xe2x80x94(C(R9)2)qJ, xe2x80x94(C(R9)2)qNH2, xe2x80x94(C(R9)2)rH, xe2x80x94G(C(R9)2)pOR10, xe2x80x94G(C(R9)2)pR12, and xe2x80x94G(C(R9)2)pOH; a heteroaryl ring having 5 or 6 atoms containing 1 to 4 heteoatoms or particularly 1 or 2 heteroatoms which may be the same or different, selected from N, O and S where the heteroaryl ring may be optionally substituted with to 4 substituents which may be the same or different selected from R10, xe2x80x94(C(R9)2)sR12, xe2x80x94CHO, 1,3-dioxolane, xe2x80x94NO2, xe2x80x94CN, xe2x80x94CO2H, xe2x80x94CONH2, xe2x80x94CO2R10, xe2x80x94CONHR10, xe2x80x94COR10, xe2x80x94(C(R9)2)qOH, xe2x80x94(C(R9)2)qOR10, xe2x80x94(C(R9)2)qNHR10, xe2x80x94(C(R9)2)qJ, xe2x80x94(C(R9)2)qNH2, xe2x80x94(C(R9)2)qH, xe2x80x94G(C(R9)2)pOR10, xe2x80x94G(C(R9)2)pR12 and xe2x80x94G(C(R9)2)pOH; a bicyclic heteroaryl ring system having 8 to 20 atoms containing 1 to 4 heteroatoms which may be the same or different selected from N, O and S wherein the bicyclic heteroaryl ring system may be optionally substituted with 1 to 4 substituents which may be the same or different selected from xe2x80x94R10, xe2x80x94(C(R9)2)sR12, xe2x80x94CHO, 1,3-dioxolane, xe2x80x94NO2, xe2x80x94CN, xe2x80x94CO2H, xe2x80x94CONH2, xe2x80x94CO2R10, xe2x80x94CONHR10, xe2x80x94COR10, xe2x80x94(C(R9)2)qOH, xe2x80x94(C(R9)2)qOR10, xe2x80x94(C(R9)2)qNHR10, xe2x80x94(C(R9)2)qJ, xe2x80x94(C(R9)2)qNH2, xe2x80x94(C(R9)2)rH, xe2x80x94G(C(R9)2)pOR10, xe2x80x94G(C(R9)2)pR12, and xe2x80x94G(C(R9)2)pOH;
R4 is selected from xe2x80x94(C(R9)2)rH, optionally substituted with one or more of xe2x80x94R10, xe2x80x94(C(R9)2)sR12, xe2x80x94CHO, 1,3-dioxolane, xe2x80x94NO2, xe2x80x94CN, xe2x80x94CO2H, xe2x80x94CONH2, xe2x80x94CO2R10, xe2x80x94CONHR10, xe2x80x94COR10, xe2x80x94(C(R9)2)qOH, xe2x80x94(C(R9)2)qOR10, xe2x80x94(C(R9)2)qNHR10, xe2x80x94(C(R9)2)qJ, xe2x80x94(C(R9)2)qNH2, xe2x80x94(C(R9)2)rH, xe2x80x94G(C(R9)2)pOR10, xe2x80x94G(C(R9)2)pR12, and xe2x80x94G(C(R9)2)pOH;
alkenyl of 2 to 6 carbon atoms, optionally substituted with one or more of xe2x80x94R10, xe2x80x94(C(R9)2)sR12, xe2x80x94CHO, 1,3-dioxolane, xe2x80x94NO2, xe2x80x94CN, xe2x80x94CO2H, xe2x80x94CONH2, xe2x80x94CO2R10, xe2x80x94CONHR10, xe2x80x94COR10, xe2x80x94(C(R9)2)qOH, xe2x80x94(C(R9)2)qOR10, xe2x80x94(C(R9)2)qNHR10, xe2x80x94(C(R9)2)qJ, xe2x80x94(C(R9)2)qNH2, xe2x80x94(C(R9)2)rH, xe2x80x94G(C(R9)2)pOR10, xe2x80x94G(C(R9)2)pR12, and xe2x80x94G(C(R9)2)pOH;
alkynyl of 2 to 6 carbon atoms, optionally substituted with one or more of xe2x80x94R10, xe2x80x94(C(R9)2)sR12, xe2x80x94CHO, 1,3-dioxolane, xe2x80x94NO2, xe2x80x94CN, xe2x80x94CO2H, xe2x80x94CONH2, xe2x80x94CO2R10, xe2x80x94CONHR10, xe2x80x94COR10, xe2x80x94(C(R9)2)qOH, xe2x80x94(C(R9)2)qOR10, xe2x80x94(C(R9)2)qNHR10, xe2x80x94(C(R9)2)qJ, xe2x80x94(C(R9)2)qNH2, xe2x80x94(C(R9)2)rH, xe2x80x94G(C(R9)2)pOR10, xe2x80x94G(C(R9)2)pR12, and xe2x80x94Q(C(R9)2)pOH;
aryl of 6 to 12 carbon atoms optionally substituted wit 1 to 4 substituents which may be the same or different selected from xe2x80x94R10, xe2x80x94(C(R9)2)sR12, xe2x80x94CHO, 1,3-dioxolane, xe2x80x94NO2, xe2x80x94CN, xe2x80x94CO2H, xe2x80x94CONH2, xe2x80x94CO2R10, xe2x80x94CONHR10, xe2x80x94COR10, xe2x80x94(C(R9)2)qOH, xe2x80x94(C(R9)2)qOR10, xe2x80x94(C(R9)2)qNHR10, xe2x80x94(C(R9)2)qJ, xe2x80x94(C(R9)2)qNH2, xe2x80x94(C(R9)2)rH, xe2x80x94G(C(R9)2)pOR10, xe2x80x94G(C(R9)2)pR12, and xe2x80x94G(C(R9)2)pOH; a heteroaryl ring having 5 or 6 atoms containing 1 to 4 heteroatoms or particularly 1 or 2 heteroatoms which may be the same or different, selected from N, O and S wherein the heteroaryl ring may be optionally substituted with 1 to 4 substituents which may be the same or different selected from xe2x80x94R10, xe2x80x94(C(R9)2)sR12, xe2x80x94CHO, 1,3-dioxolane, xe2x80x94NO2, xe2x80x94CN, xe2x80x94CO2H, xe2x80x94CONH2, xe2x80x94CO2R10, xe2x80x94CONHR10, xe2x80x94COR11, xe2x80x94(C(R9)2)qOH, xe2x80x94(C(R9)2)qOR10, xe2x80x94(C(R9)2)qNHR10, xe2x80x94(C(R9)2)qJ, xe2x80x94(C(R9)2)QNH2, xe2x80x94(C(R9)2)rH, xe2x80x94G(C(R9)2)pOR10, xe2x80x94G(C(R9)2)PR12, and xe2x80x94G(C(R9)2)pOH; a bicyclic heteroaryl ring system having 8 to 20 atoms containing 1 to 4 heteroatoms which may be the same or different selected from N, O and S wherein the bicyclic heteroaryl ring system may be optionally substituted with 1 to 4 substituents which may be the same or different selected from xe2x80x94R10, xe2x80x94(C(R9)2)sR12, xe2x80x94CHO, 1,3-dioxolane, xe2x80x94NO2, xe2x80x94CN, xe2x80x94CO2H, xe2x80x94CONH2, xe2x80x94CO2R10, xe2x80x94CONHR10, xe2x80x94COR10, xe2x80x94(C(R9)2)qOH, xe2x80x94(C(R9)2)qOR10, xe2x80x94(C(R9)2)qNHR10, xe2x80x94(C(R9)2)qJ, xe2x80x94(C(R9)2)qNH2, xe2x80x94(C(R9)2)rH, xe2x80x94G(C(R9)2)pOR10, xe2x80x94G(C(R9)2)pR12, and xe2x80x94G(C(R9)2)pOH;
R5 is a monovalent group independently selected from alkyl of 1 to 12 carbon atoms, preferred is 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, and alkynyl of 2 to 6 carbon atoms;
R6 is a divalent group selected from alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, and alkynyl of 2 to 6 carbon atoms;
R7 is a divalent alkyl group of 2 to 6 carbon atoms;
R8 is a cycloalkyl ring of 3 to 10 carbon atoms that may optionally be substituted with one or more alkyl groups of 1 to 6 carbon atoms; aryl of 6 to 12 carbon atoms optionally substituted with 1 to 4 substituents which may be the same or different selected from xe2x80x94H, -aryl, xe2x80x94CH2aryl, xe2x80x94NHaryl, xe2x80x94Oaryl, xe2x80x94S(O)maryl, xe2x80x94J, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94OH, xe2x80x94SH, xe2x80x94CN, xe2x80x94N3, xe2x80x94COOH, xe2x80x94CONH2, xe2x80x94NHC(O)NH2, xe2x80x94C(O)H, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94R5, xe2x80x94OR5, xe2x80x94NHR5, xe2x80x94Q, xe2x80x94S(O)mR5, xe2x80x94NHSO2R5, xe2x80x94R11, xe2x80x94OR11, xe2x80x94NHR11, xe2x80x94R6OH, xe2x80x94R6OR5, xe2x80x94R6NH2, xe2x80x94R6NHR5, xe2x80x94R6Q, xe2x80x94R6SH, xe2x80x94R6S(O)mR5, xe2x80x94NHR7OH, xe2x80x94NHR7OR5, xe2x80x94N(R5)R7OH, xe2x80x94R6R12, xe2x80x94N(R5)R7OR5, xe2x80x94NHR7NH2, xe2x80x94NHR7NHR5, xe2x80x94NHR7Q, xe2x80x94N(R5)R7NH2, xe2x80x94N(R5)R7NHR5, xe2x80x94N(R5)R7Q, xe2x80x94OR7OH, xe2x80x94OR7OR5, xe2x80x94OR7NH2, xe2x80x94OR7NHR5, xe2x80x94OR7Q, xe2x80x94OC(O)R5, xe2x80x94NHC(O)R5, xe2x80x94NHC(O)NHR5, xe2x80x94OR6C(O)R5, xe2x80x94NHR6C(O)R5, xe2x80x94C(O)R5, xe2x80x94C(O)OR5, xe2x80x94C(O)NHR5, xe2x80x94C(O)Q, xe2x80x94R6C(O)H, xe2x80x94R6C(O)R5, xe2x80x94R6C(O)OH, xe2x80x94R6C(O)OR5, xe2x80x94R6C(O)NH2, xe2x80x94R6C(O)NHR5, xe2x80x94R6C(O)Q, xe2x80x94R6C(O)R5, xe2x80x94R6C(O)NH2, xe2x80x94R6OC(O)NHR5 and xe2x80x94R6OC(O)Q; a heteroaryl ring having 5 or 6 atoms containing 1 to 4 heteroatoms or particularly 1 or 2 heteroatoms which may be the same or different, selected from N, O and S wherein the heteroaryl ring may be optionally substituted with 1 to 4 substituents which may be the same or different selected from xe2x80x94H, -aryl, xe2x80x94CH2aryl, xe2x80x94NHary, xe2x80x94Oaryl, xe2x80x94S(O)maryl, xe2x80x94J, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94OH, xe2x80x94SH, xe2x80x94CN, xe2x80x94N3, xe2x80x94COOH, xe2x80x94CONH2, xe2x80x94NHC(O)NH2, xe2x80x94C(O)H, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94R5, xe2x80x94OR5, xe2x80x94NHR5, xe2x80x94Q, xe2x80x94S(O)mR5, xe2x80x94NHSO2R5, xe2x80x94R11, xe2x80x94OR11, xe2x80x94NHR11, xe2x80x94R6OH, xe2x80x94R6OR5, xe2x80x94R6NH2, xe2x80x94R6NHR5, xe2x80x94R6Q, xe2x80x94R6SH, xe2x80x94R6S(O)mR5, xe2x80x94NHR7OH, xe2x80x94NHR7R5, xe2x80x94N(R5)R7OH, xe2x80x94N(R5)R7OR5, xe2x80x94NHR7NH2, xe2x80x94NHR7NHR5, xe2x80x94NHR7Q, xe2x80x94N(R5)R7NH2, xe2x80x94N(R5)R7NHR5, xe2x80x94N(R5)R7Q, xe2x80x94OR7OH, xe2x80x94OR7OR5, xe2x80x94OR7NH2, xe2x80x94OR7NHR5, xe2x80x94OR7Q, xe2x80x94OC(O)R5, xe2x80x94NHC(O)R5, xe2x80x94R6R12, xe2x80x94NHC(O)NHR5, xe2x80x94OR6C(O)R5, xe2x80x94NHR6C(O)R5, xe2x80x94C(O)R5, xe2x80x94C(O)OR5, xe2x80x94C(O)NHR5, xe2x80x94C(O)Q, xe2x80x94R6C(O)H, xe2x80x94R6C(O)R5, xe2x80x94R6C(O)OH, xe2x80x94R6C(O)OR5, xe2x80x94R6C(O)NH2, xe2x80x94R6C(O)NHR5, xe2x80x94R6C(O)Q, xe2x80x94R6C(O)R5, xe2x80x94R6OC(O)NH2, xe2x80x94R6C(O)NHR5 and xe2x80x94R6OC(O)Q; a bicyclic heteroaryl ring system having 8 to 20 atoms containing 1 to 4 heteroatoms which may be the same or different selected from N, O and S wherein the bicyclic heteroaryl ring system may be optionally substituted with 1 to 4 substituents which may be the same or different selected from xe2x80x94H, -aryl, xe2x80x94CH2aryl, xe2x80x94NHaryl, xe2x80x94Oaryl, xe2x80x94S(O)maryl, xe2x80x94J, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94OH, xe2x80x94SH, xe2x80x94CN, xe2x80x94N3, xe2x80x94COOH, xe2x80x94CONH2, xe2x80x94NHC(O)NH2, xe2x80x94C(O)H, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94R5, xe2x80x94OR5, xe2x80x94NHR5, xe2x80x94Q, xe2x80x94S(O)mR5, xe2x80x94NHSO2R5, xe2x80x94R11, xe2x80x94OR11, xe2x80x94NHR11, xe2x80x94R6OH, xe2x80x94R6OR5, xe2x80x94R6NH2, xe2x80x94R6NHR5, xe2x80x94R6Q, xe2x80x94R6SH, xe2x80x94R6R12, xe2x80x94R6S(O)mR5, xe2x80x94NHR7OH, xe2x80x94NHR7OR5, xe2x80x94N(R5)R7OH, xe2x80x94N(R5)R7OR5, xe2x80x94NHR7NH2, xe2x80x94NHR7NHR5, xe2x80x94NHR7Q, xe2x80x94N(R5)R7NH2, xe2x80x94N(R5)R7NHR5, xe2x80x94N(R5)R7Q, xe2x80x94OR7OH, xe2x80x94OR7OR5, xe2x80x94OR7NH2, xe2x80x94OR7NHR5, xe2x80x94OR7Q, xe2x80x94OC(O)R5, xe2x80x94NHC(O)R5, xe2x80x94NHC(O)NHR5, xe2x80x94OR6C(O)R5, xe2x80x94NHR6C(O)R5, xe2x80x94C(O)R5, xe2x80x94C(O)OR5, xe2x80x94C(O)NHR5, xe2x80x94C(O)Q, xe2x80x94R6C(O)H, xe2x80x94R6C(O)R5, xe2x80x94R6C(O)OH, xe2x80x94R6C(O)OR5, xe2x80x94R6C(O)NH2, xe2x80x94R6C(O)NHR5, xe2x80x94R6C(O)Q, xe2x80x94R6OC(O)R5, xe2x80x94R6OC(O)NH2, xe2x80x94R6OC(O)NHR5 and xe2x80x94R6OC(O)Q;
R9 is independently xe2x80x94H, xe2x80x94F or xe2x80x94R5;
R10 is an alkyl group of 1 to 12 carbon atoms, preferred is 1 to 6 carbon atoms;
R11 is a cycloalkyl group of 3 to 10 carbon atoms;
R12 is xe2x80x94N(O)nR13R14 or xe2x80x94N+(R10R13R14)Jxe2x88x92;
provided that when R12 is N(O)nR13R14 and n is 1, R13 or R14 are not H;
R13 and R14 are independently selected from a group consisting of xe2x80x94H, xe2x80x94R5, xe2x80x94R11, xe2x80x94(C(R9)2)qaryl-R15, xe2x80x94(C(R9)2)qheteroaryl-R15, xe2x80x94(C(R9)2)qheterocyclyl-R15, xe2x80x94(C(R9)2)pOR16, xe2x80x94(C(R9)2)pNR16R17, xe2x80x94(C(R9)2)pS(O)mR16, xe2x80x94(C(R9)2)pCO2R16, xe2x80x94(C(R9)2)pC(O)NHR16and xe2x80x94(C(R9)2)pC(O)R15; further provided that R3 and R14 may optionally be taken together with the nitrogen to which they are attached forming a heterocyclyl, heteroaryl or bicyclyl heteroaryl ring optionally substituted on either nitrogen or carbon by one or more selected from the group, xe2x80x94R5, xe2x80x94R11, xe2x80x94(C(R9)2)qarylR15, xe2x80x94(C(R9)2)qheteroarylR15, xe2x80x94(C(R9)2)qheterocyclylR15, xe2x80x94(C(R9)2)qCO2R16, xe2x80x94(C(R9)2)qC(O)NHR16, and xe2x80x94(C(R9)2)qC(O)R15; or optionally substituted on carbon by xe2x80x94F, xe2x80x94(C(R7)2)qOR16, xe2x80x94(C(R7)2)qNR16R17, and xe2x80x94(C(R9)2)qS(O)mR16; or optionally substituted on nitrogen by xe2x80x94(C(R9)2)pOR16, xe2x80x94(C(R9)2)pNR16R17, and xe2x80x94(C(R9)2)pS(O)mR16;
R15 is independently selected from a group consisting of xe2x80x94H, xe2x80x94R5, xe2x80x94R11, xe2x80x94(C(R9)2)qaryl, xe2x80x94(C(R9)2)qheteroalyl, xe2x80x94(C(R9)2)qhetetocyclyl, xe2x80x94(C(R9)2)qOH, xe2x80x94(C(R9)2)qOR10, xe2x80x94(C(R9)2)qNH2, xe2x80x94(C(R9)2)qNHR10, xe2x80x94(C(R9)2)qS(O)mR10, xe2x80x94(C(R9)2)qCO2R10, xe2x80x94(C(R9)2)qCONHR10, xe2x80x94(C(R9)2)qCONR10R10, xe2x80x94(C(R9)2)qCOR10, (C(R9)2)qCO2H, and xe2x80x94(C(R9)2)qCONH2;
R16 and R17 are independently selected from n group consisting of xe2x80x94H, xe2x80x94R5, xe2x80x94R11, xe2x80x94(C(R9)2)qaryl, xe2x80x94(C(R9)2)qheteroaryl, xe2x80x94(C(R9)2)qheterocyclyl, xe2x80x94(C(R9)2)pOH, xe2x80x94(C(R9)2)pOR10, xe2x80x94(C(R9)2)pNH2, xe2x80x94(C(R9)2)pNHR2, xe2x80x94(C(R9)2)pNR10R10, xe2x80x94(C(R9)2)pS(O)mR10, xe2x80x94(C(R9)2)pCO2R10, xe2x80x94(C(R9)2)pCONHR10, xe2x80x94(C(R9)2)pCONR10R10, xe2x80x94(C(R9)2)pCOR10, xe2x80x94(C(R9)2)pCO2H, and xe2x80x94(C(R9)2)pCONH2;
R18 is independently selected from the group consisting of xe2x80x94H, -aryl, xe2x80x94R5, xe2x80x94R6NH2, xe2x80x94R6NHR5 and xe2x80x94R6Q;
provided that, when T and Z are carbon, A is absent, r is 0 and R4 is xe2x80x94(C(R9)2)rH, then,
a. R3 is not unsubstituted thiophene, furan, thiazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, pyridine, phenyl, alkenyl or alkynyl; or
b. R3 is not monosubstituted by xe2x80x94R10, xe2x80x94(C(R9)2)qOH, or xe2x80x94(C(R9)2)qOR10 when R3 is thiophene, furan, thiazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole or pyridine; and
c. R13 and R14 are not alkyl of 1 to 6 carbon atoms when R3 is thiophene, furan, thiazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole or pyridine when R3 is substituted by xe2x80x94(C(R9)2)sR12 and R12 is xe2x80x94NR13R14;
further provided that, when T and Z are carbon, A is absent and R4 is phenyl, then,
a. R4 is not substituted by xe2x80x94NO2, xe2x80x94CN, xe2x80x94CO2H, xe2x80x94CONH2, xe2x80x94CO2R10, xe2x80x94CONHR10, xe2x80x94(C(R9)2)qOH, xe2x80x94(C(R9)2)qOR10, xe2x80x94(C(R9)2)qNHR10, xe2x80x94(C(R9)2)qJ or xe2x80x94(C(R9)2)qNH2 or unsubstituted when R3 is thiophene, furan, thiazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole or pyridine; and
b. R13 and R14 are not independently alkyl of 1 to 3 carbon atoms when R3 is thiophene, furan, thiazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole or pyridine, wherein R4 is substituted by xe2x80x94(C(R9)2)sR12 and s is 0 and R12 is xe2x80x94NR13R14;
additionally provided that, when T and Z are carbon, then,
a. carbon-8 is not substituted by xe2x80x94OH, xe2x80x94OR10, xe2x80x94SR10, or xe2x80x94OR11 when carbon-5 is substituted by an imidazole, oxazole or thiazole ring that is fused to a 6-membered aryl or heteroaryl ring heaving 0 to 2 nitrogen atoms and wherein the fused bicyclic heteroaryl ring is attached to carbon-5 of Formula (I) via carbon-2 of the imidazole, oxazole or thiazole ring; and
b. carbon-8 is not substituted by xe2x80x94OH, xe2x80x94OR10, xe2x80x94SR10, or xe2x80x94OR11 when X is xe2x80x94Oxe2x80x94 and carbon-5 is substituted by aryl or heteroaryl;
further provided that when either T or Z are N, then R2c is absent; or a pharmaceutically acceptable salt thereof.
Among the preferred groups of compounds of Formula (I) of this invention including pharmaceutically acceptable salts thereof are those in the subgroups below, wherein the other variables of Formula (I) in the subgroups are as defined above wherein:
a) X is xe2x80x94NHxe2x80x94, xe2x80x94NR5xe2x80x94 and xe2x80x94Oxe2x80x94;
b) T and Z are carbon;
c) T is N and Z is carbon;
d) T is carbon and Z is N;
e) T and Z are carbon, n is 0 and X is xe2x80x94NHxe2x80x94;
f) T is carbon and Z, is N, n is 0 and X is xe2x80x94NHxe2x80x94;
g) T is N and Z is carbon, n is 0 and X is xe2x80x94NHxe2x80x94;
h) T and Z are carbon, n is 0, X is xe2x80x94NHxe2x80x94 and R1 is aryl;
i) T is carbon and Z is N, n is 0, X is xe2x80x94NHxe2x80x94 and R1 is aryl;
j) T is N and Z is carbon, n is 0, X is xe2x80x94NHxe2x80x94 and R1 is aryl;
Among the additionally preferred groups of compounds of Formula (I) of this invention including pharmaceutically acceptable salts thereof are those in the subgroups below, wherein the other valuables of Formula (I) in the subgroups are as defined above wherein:
a) 3-cyanoquinolines, 3-cyano-1,6-naphthyridines and 3-cyano-1,7-naphthyridines of Formula (I) wherein:
X is xe2x80x94NHxe2x80x94;
n is 0;
R1 is a phenyl ring optionally substituted with 1 to 4 substituents which may be the same or different independently selected from xe2x80x94H, xe2x80x94J, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94OH, xe2x80x94SH, xe2x80x94CN, xe2x80x94N3, xe2x80x94COOH, xe2x80x94CONH2, xe2x80x94NHC(O)NH2, xe2x80x94C(O)H, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94R5, xe2x80x94OR5, xe2x80x94NHR5, xe2x80x94Q, xe2x80x94S(O)mR5, xe2x80x94NHSO2R5, xe2x80x94R6OH, xe2x80x94R6OR5, xe2x80x94R6NH2, xe2x80x94R6NHR5, xe2x80x94R6Q, xe2x80x94R6SH, xe2x80x94R6S(O)mR5, xe2x80x94NHR7OH, xe2x80x94NHR7OR5, xe2x80x94N(R5)R7OH, xe2x80x94N(R5)R7OR5, xe2x80x94NHR7NH2, xe2x80x94NHR7NHR5, xe2x80x94NHR7Q, xe2x80x94N(R5)R7NH2, xe2x80x94N(R5)R7NHR5, xe2x80x94N(R5)R7Q, xe2x80x94OR7OH, xe2x80x94OR7OR5, xe2x80x94OR7NH2, xe2x80x94OR7NHR5, xe2x80x94OR7Q, xe2x80x94OC(O)R5, xe2x80x94NHC(O)R5, xe2x80x94NHC(O)NHR5, xe2x80x94OR6C(O)R5, xe2x80x94NHR6C(O)R5, xe2x80x94C(O)R5, xe2x80x94C(O)OR5, xe2x80x94C(O)NHR5, xe2x80x94C(O)Q, xe2x80x94R6C(O)H, xe2x80x94R6C(O)R5, xe2x80x94R6C(O)OH, xe2x80x94R6C(O)OR5, xe2x80x94R6C(O)NH2, xe2x80x94R6C(O)NHR5, xe2x80x94R6C(O)Q, xe2x80x94R6OC(O)R5, xe2x80x94R6OC(O)NH2, xe2x80x94R6OC(O)NHR5, xe2x80x94R6OC(O)Q and YR8 groups wherein Y is independently selected from xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94OC(O)xe2x80x94, xe2x80x94C(O)NHxe2x80x94, xe2x80x94NHC(O)xe2x80x94, xe2x80x94NHSO2xe2x80x94, xe2x80x94SO2N Hxe2x80x94, xe2x80x94C(OH)Hxe2x80x94, xe2x80x94O(C(R9)2)qxe2x80x94, xe2x80x94S(O)m(C(R9)2)qxe2x80x94, xe2x80x94NH(C(R9)2)q, xe2x80x94NR10(C(R9)2)q, xe2x80x94(C(R9)2)qxe2x80x94, xe2x80x94(C(R9)2)qO, xe2x80x94(C(R9)2)qS(O)mxe2x80x94, xe2x80x94(C(R9)2)qNHxe2x80x94, xe2x80x94(C(R9)2)(NR10xe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, cis and trans xe2x80x94CHxe2x95x90CHxe2x80x94 and cycloalkyl of 3 to 10 carbon atoms; or a pharmaceutically acceptable salt thereof.
b) 3-cyanoquinolines, of Formula (I) wherein:
T and Z are carbon;
X is xe2x80x94NHxe2x80x94;
n is 0;
R1 is a phenyl ring optionally substituted with 1 to 4 substituents which may be the same or different independently selected form xe2x80x94H, xe2x80x94J, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94OH, xe2x80x94SH, xe2x80x94CN, xe2x80x94N3, xe2x80x94COOH, xe2x80x94CONH2, xe2x80x94NHC(O)NH2, xe2x80x94C(O)H, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94R5, xe2x80x94OR5, xe2x80x94NHR5, xe2x80x94Q, xe2x80x94S(O)mR5, xe2x80x94NHSO2R5, xe2x80x94R6OH, xe2x80x94R6OR5, xe2x80x94R6NH2, xe2x80x94R6NHR5, xe2x80x94R6Q, xe2x80x94R6SH, xe2x80x94R6S(O)mR5, xe2x80x94NHR7OH, xe2x80x94NHR7OR5, xe2x80x94N(R5)R7OH, xe2x80x94N(R5)R7OR5, xe2x80x94NHR7NH2, xe2x80x94NHR7NHR5, xe2x80x94NHR7Q, xe2x80x94N(R5)R7NH2, xe2x80x94N(R5)R7NHR5, xe2x80x94N(R5)R7Q, xe2x80x94OR7OH, xe2x80x94OR7OR5, xe2x80x94OR7NH2, xe2x80x94OR7NHR5, xe2x80x94OR7Q, xe2x80x94OC(O)R5, xe2x80x94NHC(O)R5, xe2x80x94NHC(O)NHR5, xe2x80x94OR6C(O)R5, xe2x80x94NHR6C(O)R5, xe2x80x94C(O)R5, xe2x80x94C(O)OR5, xe2x80x94C(O)NHR5, xe2x80x94C(O)Q, xe2x80x94R6C(O)H, xe2x80x94R6C(O)R5, xe2x80x94R6C(O)OH, xe2x80x94R6C(O)OR5, xe2x80x94R6C(O)NH2, xe2x80x94R6C(O)NHR5, xe2x80x94R6C(O)Q, xe2x80x94R6OC(O)R5, xe2x80x94R6OC(O)NH2, xe2x80x94R6OC(O)NHR5, xe2x80x94R6OC(O)Q and YR8 groups wherein Y is independently selected from xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94OC(O)xe2x80x94, xe2x80x94C(O)NHxe2x80x94, xe2x80x94NHC(O)xe2x80x94, xe2x80x94NHSO2xe2x80x94, xe2x80x94SO2NHxe2x80x94, xe2x80x94C(OH)Hxe2x80x94, xe2x80x94O(C(R9)2)qxe2x80x94, xe2x80x94S(O)m(C(R9)2)q, xe2x80x94NH(C(R9)2)q, xe2x80x94NR10(C(R9)2)q, xe2x80x94(C(R9)2)qxe2x80x94, xe2x80x94(C(R9)2)qOxe2x80x94, xe2x80x94(C(R9)qS(O)m, xe2x80x94(CR9)2)qNHxe2x80x94, xe2x80x94(C(R9)2)qNR10, xe2x80x94Cxe2x89xa1Cxe2x80x94, cis and trans xe2x80x94CH∇CHxe2x80x94 and cycloalkyl of 3 to 10 carbon atoms;
or a pharmaceutically acceptable salt thereof.
c) 3-cyanoquinolines, 3-cyano-1,6-naphthyridines and 3-cyano-1,7-naphthyridines of Formula (I) wherein:
X is xe2x80x94NHxe2x80x94;
n is 0;
A is absent;
R1 is a phenyl ring optionally substituted with 1 to 4 substituents which may be the same or different independently selected from xe2x80x94H, xe2x80x94J, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94OH, xe2x80x94SH, xe2x80x94CN, xe2x80x94N3, xe2x80x94COOH, xe2x80x94CONH2, xe2x80x94NHC(O)NH2, xe2x80x94C(O)H, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94R5, xe2x80x94OR5, xe2x80x94NHR5, xe2x80x94Q, xe2x80x94S(O)mR5, xe2x80x94NHSO2R5, xe2x80x94R6OH, xe2x80x94R6OR5, xe2x80x94R6NH2, xe2x80x94R6NHR5, xe2x80x94R6Q, xe2x80x94R6SH, xe2x80x94R6S(O)mR5, xe2x80x94NHR7OH, xe2x80x94NHR7OR5, xe2x80x94N(R5)R7OH, xe2x80x94N(R5)R7OR5, xe2x80x94NHR7NH2, xe2x80x94NHR7NHR5, xe2x80x94NHR7Q, xe2x80x94N(R5)R7NH2, xe2x80x94N(R5)R7NHR5, xe2x80x94N(R5)R7Q, xe2x80x94OR7OH, xe2x80x94OR7OR5, xe2x80x94OR7NH2, xe2x80x94OR7NHR5, xe2x80x94OR7Q, xe2x80x94OC(O)R5, xe2x80x94NHC(O)R5, xe2x80x94NHC(O)NHR5, xe2x80x94OR6C(O)R5, xe2x80x94NHR6C(O)R5, xe2x80x94C(O)R5, xe2x80x94C(O)OR5, xe2x80x94C(O)NHR5, xe2x80x94C(O)Q, xe2x80x94R6C(O)H, xe2x80x94R6C(O)R5, xe2x80x94R6C(O)OH, xe2x80x94R6C(O)OR6, xe2x80x94R6C(O)NH2, xe2x80x94R6C(O)NHR5, xe2x80x94R6C(O)Q, xe2x80x94R6OC(O)R5, xe2x80x94R6OC(O)NH2, xe2x80x94R6OC(O)NHR5, xe2x80x94R6OC(O)Q and YR8 groups wherein Y is independently selected from xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94OC(O)xe2x80x94, xe2x80x94C(O)NHxe2x80x94, xe2x80x94NHC(O)xe2x80x94, xe2x80x94NHSO2xe2x80x94, xe2x80x94SO2NHxe2x80x94, xe2x80x94C(OH)Hxe2x80x94, xe2x80x94O(C(R9)2)q, xe2x80x94S(O)m(C(R9)2)qxe2x80x94, xe2x80x94NH(C(R9)2)q, xe2x80x94NR10(C(R9)2)q, xe2x80x94(C(R9)2)qxe2x80x94, xe2x80x94(C(R9)2)qOxe2x80x94, xe2x80x94(C(R9)2)qS(O)mxe2x80x94, xe2x80x94(C(R9)2)qNHxe2x80x94, xe2x80x94(C(R9)2)qNR10xe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, cis and trans xe2x80x94CHxe2x95x90CHxe2x80x94 and cycloalkyl of 3 to 10 carbon atoms;
or pharmaceutically acceptable salt thereof.
d) 3-cyanoquinolines of Formula (I) wherein:
X is xe2x80x94NHxe2x80x94;
T and Z are carbon;
n is 0;
A is absent;
R1 is a phenyl ring optionally substituted with 1 to 4 substituents which may be the same or different independently selected from xe2x80x94H, xe2x80x94J, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94OH, xe2x80x94SH, xe2x80x94CN, xe2x80x94N3, xe2x80x94COOH, xe2x80x94CONH2, xe2x80x94NHC(O)NH2, xe2x80x94C(O)H, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94R5, xe2x80x94OR5, xe2x80x94NHR5, xe2x80x94Q, xe2x80x94S(O)mR5, xe2x80x94NHSO2R5, xe2x80x94R6OH, xe2x80x94R6OR5, xe2x80x94R6NH2, xe2x80x94R6NHR5, xe2x80x94R6Q, xe2x80x94R6SH, xe2x80x94R6S(O)mR5, xe2x80x94NHR7OH, xe2x80x94NHR7OR5, xe2x80x94N(R5)R7OH, xe2x80x94N(R5)R7OR5, xe2x80x94NHR7NH2, xe2x80x94NHR7NHR5, xe2x80x94NHR7Q, xe2x80x94N(R5)R7NH2, xe2x80x94N(R5)R7NHR5, xe2x80x94N(R5)R7Q, xe2x80x94OR7OH, xe2x80x94OR7OR5, xe2x80x94OR7NH2, xe2x80x94OR7NHR5, xe2x80x94OR7Q, xe2x80x94OC(O)R5, xe2x80x94NHC(O)R5, xe2x80x94NHC(O)NHR5, xe2x80x94OR6C(O)R5, xe2x80x94NHR6C(O)R5, xe2x80x94C(O)R5, xe2x80x94C(O)OR5, xe2x80x94C(O)NHR5, xe2x80x94C(O)Q, xe2x80x94R6C(O)H, xe2x80x94R6C(O)R5, xe2x80x94R6C(O)OH, R6C(O)OR5, xe2x80x94R6C(O)NH2, xe2x80x94R6C(O)NHR5, R6C(O)Q, xe2x80x94R6OC(O)R5, xe2x80x94R6OC(O)NH2, xe2x80x94R6OC(O)NHR5, xe2x80x94R6OC(O)Q and YR8 groups wherein Y is independently selected from xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94OC(O)xe2x80x94, xe2x80x94C(O)NHxe2x80x94, xe2x80x94NHC(O)xe2x80x94, xe2x80x94NHSO2xe2x80x94, xe2x80x94SO2NHxe2x80x94, xe2x80x94C(OH)Hxe2x80x94, xe2x80x94O(C(R9)2)qxe2x80x94, xe2x80x94S(O)m(C(R9)2)qxe2x80x94, xe2x80x94NH(C(R9)2)q, xe2x80x94NR10(C(R9)2)q, xe2x80x94(C(R9)2)qxe2x80x94, xe2x80x94(CR9)2)qOxe2x80x94, xe2x80x94(C(R9)2)qS(O)mxe2x80x94, xe2x80x94(C(R9)2)qNHxe2x80x94, xe2x80x94(C(R9)2)qNR10xe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, cis and trans xe2x80x94CHxe2x95x90CHxe2x80x94 and cycloalkyl of 3 to 10 carbon atoms;
or pharmaceutically acceptable salt thereof.
e) 3-cyanoquinolines of Formula (I) wherein:
T and Z are carbon;
X is xe2x80x94NHxe2x80x94;
n is 0;
R1 is a phenyl ring substituted with 1 to 4 substituents which may be the same or different independently selected from xe2x80x94H, xe2x80x94J, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94OH, xe2x80x94SH, xe2x80x94CN, xe2x80x94N3, xe2x80x94COOH, xe2x80x94CONH2, xe2x80x94NHC(O)NH2, xe2x80x94C(O)H, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94R5, xe2x80x94OR5, xe2x80x94NHR5, xe2x80x94Q, xe2x80x94S(O)mR5, xe2x80x94NHSO2R5, xe2x80x94R6OH, xe2x80x94R6OR5, xe2x80x94R6NH2, xe2x80x94R6NHR5, xe2x80x94R6Q, xe2x80x94R6SH, xe2x80x94R6S(O)mR5, xe2x80x94NHR7OH, xe2x80x94NHR7OR5, xe2x80x94N(R5)R7OH, xe2x80x94N(R5)R7OR5, xe2x80x94NHR7NH2, xe2x80x94NHR7NHR5, xe2x80x94NHR7Q, xe2x80x94N(R5)R7NH2, xe2x80x94N(R5)R7NHR5, xe2x80x94N(R5)R7Q, xe2x80x94OR7OH, xe2x80x94OR7OR5, xe2x80x94OR7NH2, xe2x80x94OR7NHR5, xe2x80x94OR7Q, xe2x80x94OC(O)R5, xe2x80x94NHC(O)R5, xe2x80x94NHC(O)NHR5, xe2x80x94OR6C(O)R5, xe2x80x94NHR6C(O)R5, xe2x80x94C(O)R5, xe2x80x94C(O)OR5, xe2x80x94C(O)NHR5, xe2x80x94C(O)Q, xe2x80x94R6C(O)H, xe2x80x94R6C(O)R5, xe2x80x94R6C(O)OH, xe2x80x94R6C(O)OR5, xe2x80x94R6C(O)NH2, xe2x80x94R6C(O)NHR5, xe2x80x94R6C(O)Q, xe2x80x94R6OC(O)R5, xe2x80x94R6OC(O)NH2; xe2x80x94R6OC(O)NHR5, xe2x80x94R6OC(O)Q and YR8 groups wherein Y is independently selected from xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94OC(O)xe2x80x94, xe2x80x94C(O)NHxe2x80x94, xe2x80x94NHC(O)xe2x80x94, xe2x80x94NHSO2xe2x80x94, xe2x80x94SO2NHxe2x80x94, xe2x80x94C(OH)Hxe2x80x94, xe2x80x94O(C(R9)2)qxe2x80x94, xe2x80x94S(O)m(C(R9)2)qxe2x80x94, xe2x80x94NH(C(R9)2)qxe2x80x94, xe2x80x94NR10(C(R9)2)qxe2x80x94, xe2x80x94(C(R9)2)qxe2x80x94, xe2x80x94(C(R9)2)qOxe2x80x94, xe2x80x94(C(R9)2)qS(O)mxe2x80x94, xe2x80x94(C(R9)2)qNHxe2x80x94, xe2x80x94(C(R9)2)qNR10xe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, cis and trans xe2x80x94CHxe2x95x90CHxe2x80x94 and cycloalkyl of 3 to 10 carbon atoms;
A is absent;
R4 is (C(R9)2)rH;
r is 0;
or a pharmaceutically acceptable salt thereof.
Among the broadly preferred groups of compounds of Formula (I) of this invention including pharmaceutically acceptable salts thereof are those in the subgroups below, wherein the other variables of Formula (I) in the subgroups are as defined above wherein:
a) 3-cyanoquinolines of Formula (I) wherein:
T and Z are carbon;
R2a and R2b are hydrogen;
R2c is selected from xe2x80x94H, xe2x80x94J, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94R5, xe2x80x94OR5, xe2x80x94OR11, xe2x80x94OR7OH, xe2x80x94OR7OR5 and xe2x80x94S(O)mR5;
X is xe2x80x94NHxe2x80x94;
n is 0;
R1 is phenyl optionally substituted with 1 to 4 substituents which may he the same or different independently selected from xe2x80x94H, xe2x80x94J, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94OH, xe2x80x94SH, xe2x80x94CN, xe2x80x94N3, xe2x80x94COOH, xe2x80x94CONH2, xe2x80x94NHC(O)NH2, xe2x80x94C(O)H, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94R5, xe2x80x94OR5, xe2x80x94NHR5, xe2x80x94Q, xe2x80x94S(O)mR5, xe2x80x94NHSO2R5, xe2x80x94R6OH, xe2x80x94R6OR5, xe2x80x94R6NH2, xe2x80x94R6NHR5, xe2x80x94R6Q, xe2x80x94R6SH, xe2x80x94R6S(O)mR5, xe2x80x94NHR7OH, xe2x80x94NHR7OR5, xe2x80x94N(R5)R7OH, xe2x80x94N(R5)R7OR5, xe2x80x94NH7NH2, xe2x80x94NHR7NHR5, xe2x80x94NHR7Q, xe2x80x94N(R5)R7NH2, xe2x80x94N(R5)R7NHR5, xe2x80x94N(R5)R7Q, xe2x80x94OR7OH, xe2x80x94OR7OR5, xe2x80x94OR7NH2, xe2x80x94OR7NH5, xe2x80x94OR7Q, xe2x80x94OC(O)R5, xe2x80x94NHC(O)R5, xe2x80x94NHC(O)NHR5, xe2x80x94OR6C(O)R5, xe2x80x94NHR6C(O)R5, xe2x80x94C(O)R5, xe2x80x94C(O)OR5, xe2x80x94C(O)NHR5, xe2x80x94C(O)Q, xe2x80x94R6C(O)H, xe2x80x94R6C(O)R5, xe2x80x94R6C(O)OH, xe2x80x94R6C(O)OR5, xe2x80x94R6C(O)NH2, xe2x80x94R6C(O)NHR5, xe2x80x94R6C(O)Q, xe2x80x94R6OC(O)R5, xe2x80x94R6OC(O)NH2, xe2x80x94R6OC(O)NHR5, xe2x80x94R6OC(O)Q and YR8 groups wherein Y is independently selected from xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94OC(O)xe2x80x94, xe2x80x94C(O)NHxe2x80x94, xe2x80x94NHC(O)xe2x80x94, xe2x80x94NHSO2xe2x80x94, xe2x80x94SO2NHxe2x80x94, xe2x80x94C(OH)H, xe2x80x94O(C(R9)2)qxe2x80x94, xe2x80x94S(O)m(C(R9)2)qxe2x80x94, xe2x80x94NH(C(R9)2)qxe2x80x94, xe2x80x94NHR10(C(R9)2)qxe2x80x94, xe2x80x94(C(R9)2)qxe2x80x94, xe2x80x94(C(R9)2)qOxe2x80x94, xe2x80x94(C(R9)2)qxe2x80x94S(O)mxe2x80x94, xe2x80x94(C(R9)2)qNHxe2x80x94, xe2x80x94(C(R9)2)qNR10xe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, cis and trans xe2x80x94CHxe2x95x90CHxe2x80x94 and cycloalkyl of 3 to 10 carbon atoms;
or a pharmaceutically acceptable salt thereof.
b) 3-cyanoquinolines of Formula (I) wherein:
T and Z are carbon;
R2a and R2b are hydrogen;
R2c is selected from xe2x80x94H, xe2x80x94J, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94R5, xe2x80x94OR5, xe2x80x94OR11, xe2x80x94OR7OH, xe2x80x94OR7OR5 and xe2x80x94S(O)mR5;
X is xe2x80x94NHxe2x80x94;
n is 0;
R1 is phenyl optionally substituted with 1 to 4 substituents which may be the same or different independently selected from xe2x80x94H, xe2x80x94J, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94OH, xe2x80x94SH, xe2x80x94CN, xe2x80x94N3, xe2x80x94COOH, xe2x80x94CONH2, xe2x80x94NHC(O)NH2, xe2x80x94C(O)H, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94R5, xe2x80x94OR5, xe2x80x94NHR5, xe2x80x94Q, xe2x80x94S(O)mR5, xe2x80x94NHSO2R5, xe2x80x94R6OH, xe2x80x94R6OR5, xe2x80x94R6NH2, xe2x80x94R6NHR5, xe2x80x94R6Q, xe2x80x94R6SH, xe2x80x94R6S(O)MR5, xe2x80x94NHR7OH, xe2x80x94NHR7OR5, xe2x80x94N(R5)R7OH, xe2x80x94N(R5)R7OR5, xe2x80x94NHR7NH2, xe2x80x94NHR7NHR5, xe2x80x94NHR7Q, xe2x80x94N(R5)R7NH2, xe2x80x94N(R5)R7NHR5, xe2x80x94N(R5)R7Q, xe2x80x94OR7OH, xe2x80x94OR7OR5, xe2x80x94OR7NH2, xe2x80x94OR7NHR5, xe2x80x94OR7Q, xe2x80x94OC(O)R5, xe2x80x94NHC(O)R5, xe2x80x94NHC(O)NHR5, xe2x80x94OR6C(O)R5, xe2x80x94NHR6C(O)R5, xe2x80x94C(O)R5, xe2x80x94C(O)OR5, xe2x80x94C(O)NHR5, xe2x80x94C(O)Q, xe2x80x94R6C(O)H, xe2x80x94R6C(O)R5, xe2x80x94R6C(O)OH, xe2x80x94R6C(O)OR5, xe2x80x94R6C(O)NH2, xe2x80x94R6C(O)NHR5, xe2x80x94R6C(O)Q, xe2x80x94R6OC(O)R5, xe2x80x94R6OC(O)NH2, xe2x80x94R6OC(O)NHR5, xe2x80x94R6OC(O)Q and YR8 groups wherein Y is independently selected from xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94OC(O)xe2x80x94, xe2x80x94C(O)NHxe2x80x94, xe2x80x94NHC(O)xe2x80x94, xe2x80x94NHSO2xe2x80x94, xe2x80x94SO2NHxe2x80x94, xe2x80x94C(OH)Hxe2x80x94, xe2x80x94O(C(R9)2)qxe2x80x94, xe2x80x94S(O)m(C(R9)2)qxe2x80x94, xe2x80x94NH(C(R9)2)qxe2x80x94, xe2x80x94NR10(C(R9)2)qxe2x80x94, xe2x80x94(C(R9)2)qxe2x80x94, xe2x80x94(C(R9)2)qOxe2x80x94, xe2x80x94(C(R9)2)qS(O)mxe2x80x94, (C(R9)2)qNHxe2x80x94, xe2x80x94(C(R9)2)qNR10xe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, cis and trans xe2x80x94CHxe2x95x90CHxe2x80x94 and cycloalkyl of 3 to 10 carbon atoms;
A is absent;
or a pharmaceutically acceptable salt thereof.
c) 3-cyanoquinolines of Formula (I) wherein:
T and Z are carbon;
R2a and R2b are hydrogen;
R2c is selected from xe2x80x94H, xe2x80x94J, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94R5, xe2x80x94OR5, xe2x80x94OR5, xe2x80x94OR7OH, xe2x80x94OR7OR5 and xe2x80x94S(O)mR5;
X is xe2x80x94NHxe2x80x94;
n is 0;
R1 is phenyl optionally substituted with 1 to 4 substituents which may be the same or different independently selected from xe2x80x94H, xe2x80x94J, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94OH, xe2x80x94SH, xe2x80x94CN, xe2x80x94N3, xe2x80x94COOH, xe2x80x94CONH2, xe2x80x94NHC(O)NH2, xe2x80x94C(O)H, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94R5, xe2x80x94OR5, xe2x80x94NHR5, xe2x80x94Q, xe2x80x94S(O)mR5, xe2x80x94NHSO2R5, xe2x80x94R6OH, xe2x80x94R6OR3, xe2x80x94R6NH2, xe2x80x94R6NHR5, xe2x80x94R6Q, xe2x80x94R6SH, xe2x80x94R6S(O)mR5, xe2x80x94NH7OH, xe2x80x94NHR7OR5, xe2x80x94N(R5)R7OH, xe2x80x94N(R5)R7OR5, xe2x80x94NHR7NH2, xe2x80x94NHR7NHR5, xe2x80x94NHR7Q, xe2x80x94N(R5)R7NH2, xe2x80x94N(R5)R7NHR5, xe2x80x94N(R5)R7Q, xe2x80x94OR7OH, xe2x80x94OR7OR5, xe2x80x94OR7NH2, xe2x80x94OR7NHR5, xe2x80x94OR7Q, xe2x80x94OC(O)R5, xe2x80x94NHC(O)R5, xe2x80x94NHC(O)NHR5, xe2x80x94OR6C(O)R5, xe2x80x94NH6C(O)R5, xe2x80x94C(O)R5, xe2x80x94C(O)OR5, xe2x80x94C(O)NHR5, xe2x80x94C(O)Q, xe2x80x94R6C(O)H, xe2x80x94R6C(O)R5, xe2x80x94R6C(O)OH, xe2x80x94R6C(O)OR5, xe2x80x94R6C(O)NH2, xe2x80x94R6C(O)NHR5, xe2x80x94R6C(O)Q, xe2x80x94R6OC(O)R5, xe2x80x94R6OC(O)NH2, xe2x80x94R6OC(O)NHR5, xe2x80x94R6OC(O)Q and YR8 groups wherein Y is independently selected from xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94OC(O)xe2x80x94, xe2x80x94C(O)NHxe2x80x94, xe2x80x94NHC(O)xe2x80x94, xe2x80x94NHSO2xe2x80x94, xe2x80x94SO2NHxe2x80x94, xe2x80x94C(OH)Hxe2x80x94, xe2x80x94O(C(R9)2)qxe2x80x94, xe2x80x94S(O)m(C(R9)2)qxe2x80x94, xe2x80x94NH(CR9)2)qxe2x80x94, xe2x80x94NR10(C(R9)2)qxe2x80x94, xe2x80x94(C(R9)2)qxe2x80x94, xe2x80x94(C(R9)2)qOxe2x80x94, xe2x80x94(C(R9)2)qS(O)mxe2x80x94, xe2x80x94(C(R9)2)qNH, xe2x80x94(C(R9)2)qNR10xe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, cis and trans xe2x80x94CHxe2x95x90CHxe2x80x94 and cycloalkyl of 3 to 10 carbon atoms;
R4 is xe2x80x94(C(R9)2)rH;
r is 0;
A is absent;
R3 is attached to carbon-7 of Formula (I) and is selected from aryl, heteroaryl, bicyclic heteroaryl, alkenyl, alkynyl wherein each aryl, heteroaryl, bicyclic heteroaryl, alkenyl, and alkynyl is optionally substituted by one or more of xe2x80x94R10, xe2x80x94(C(R9)2)sR12, xe2x80x94CHO, 1,3-dioxolane, xe2x80x94CONH2, xe2x80x94CO2R10, xe2x80x94CONHR10, xe2x80x94COR10, xe2x80x94(C(R9)2)qOH, xe2x80x94(C(R9)2)qOR10, xe2x80x94(C(R9)2)qNHR10, xe2x80x94(C(R9)2)qNH2, G(C(R9)2)pOR10, G(C(R9)2)pOH, and G(C(R9)2)sR12;
or a pharmaceutically acceptable salt thereof.
d) 3-cyanoquinolines of Formula (I) wherein:
T and Z are carbon;
R2a and R2b are hydrogen;
R2c is selected from xe2x80x94H, xe2x80x94J, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94R5, xe2x80x94OR5, xe2x80x94OR11, xe2x80x94OR7OH, xe2x80x94OR7OR5 and xe2x80x94S(O)mR5;
X is xe2x80x94NHxe2x80x94;
n is 0;
R1 is phenyl optionally substituted with 1 to 4 substituents which may be the same or different independently selected from xe2x80x94H, xe2x80x94J, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94OH, xe2x80x94SH, xe2x80x94CN, xe2x80x94N3, xe2x80x94COOH, xe2x80x94CONH2, xe2x80x94NHC(O)NH2, xe2x80x94C(O)H, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94R5, xe2x80x94OR5, xe2x80x94NHR5, xe2x80x94Q, xe2x80x94S(O)mR5, xe2x80x94NHSO2R5, xe2x80x94R6OH, xe2x80x94R6OR5, xe2x80x94R6NH2, xe2x80x94R6NHR5, xe2x80x94R6Q, xe2x80x94R6SH, xe2x80x94R6S(O)mR5, xe2x80x94NHR7OH, xe2x80x94NHR7OR5, xe2x80x94N(R5)R7OH, xe2x80x94N(R5)R7OR5, xe2x80x94NHR7NH2, xe2x80x94NHR7NHR5, xe2x80x94NHR7Q, xe2x80x94N(R5)R7NH2, xe2x80x94N(R5)R7NHR5, xe2x80x94N(R5)R7Q, xe2x80x94OR7OH, xe2x80x94OR7OR5, xe2x80x94OR7NH2, xe2x80x94OR7NHR5, xe2x80x94OR7Q, xe2x80x94OC(O)R5, xe2x80x94NHC(O)R5, xe2x80x94NHC(O)NHR5, xe2x80x94OR6C(O)R5, xe2x80x94NHR6C(O)R5, xe2x80x94C(O)R5, xe2x80x94C(O)OR5, xe2x80x94C(O)NHR5, xe2x80x94C(O)Q, xe2x80x94R6C(O)H, xe2x80x94R6C(O)R5, xe2x80x94R6C(O)OH, xe2x80x94R6C(O)OR5, xe2x80x94R6C(O)NH2, xe2x80x94R6C(O)NHR5, xe2x80x94R6C(O)Q, xe2x80x94R6OC(O)R5, xe2x80x94R6OC(O)NH2, xe2x80x94R6OC(O)NHR5, xe2x80x94R6OC(O)Q and YR8 groups wherein Y is independently selected from xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94OC(O)xe2x80x94, xe2x80x94C(O)NHxe2x80x94, xe2x80x94NHC(O)xe2x80x94, xe2x80x94NHSO2xe2x80x94, xe2x80x94SO2NHxe2x80x94, xe2x80x94C(OH)Hxe2x80x94, xe2x80x94O(C(R9)2)qxe2x80x94, xe2x80x94S(O)m(C(R9)2)qxe2x80x94, xe2x80x94NH(C(R9)2)q, xe2x80x94NR10(C(R9)2)q, xe2x80x94(C(R9)2)qxe2x80x94, xe2x80x94(C(R9)2)qOxe2x80x94, xe2x80x94(C(R9)2)qS(O)mxe2x80x94, xe2x80x94(C(R9)2)qNHxe2x80x94, xe2x80x94(C(R9)2)qNR10xe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, cis and trans xe2x80x94CHxe2x95x90CHxe2x80x94 and cycloalkyl of 3 to 10 carbon atoms;
R4 is xe2x80x94(C(R9)2)rH;
r is 0;
A is absent;
R3 is attached to carbon-6 of Formula (I) and is selected form aryl, heteroaryl, bicyclic heteroaryl, alkenyl, alkynyl wherein each aryl, heteroaryl, bicyclic heteroaryl, alkenyl, and alkynyl is optionally substituted by one or more of xe2x80x94R10, xe2x80x94(C(R9)2)sR12, xe2x80x94CHO, 1,3-dioxolane, xe2x80x94CONH2, xe2x80x94CO2R10, xe2x80x94CONHR10, xe2x80x94COR10, xe2x80x94(C(R9)2)qOH, xe2x80x94(C(R9)2)qOR10, xe2x80x94(C(R9)2)qNHR10, xe2x80x94(C(R9)2)qNH2, G(C(R9)2)pOR10, xe2x80x94G(C(R9)2)pOH, and G(C(R9)2)pR12;
or a pharmaceutically acceptable salt thereof.
Among the more preferred groups of compounds of Formula (I) of this invention including pharmaceutically acceptable salts thereof are those in the subgroups below wherein the other variables of Formula (I) in the subgroups are as defined above wherein:
a) 3-cyanoquinolines of Formula (I) wherein:
T and Z are carbon;
R2a and R2b are hydrogen;
R2c is attached to carbon-6 or carbon-7 of Formula (I) and is selected from xe2x80x94H, xe2x80x94J, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94R5, xe2x80x94OR5, xe2x80x94OR11, xe2x80x94OR7OH, xe2x80x94OR7OR5 and xe2x80x94S(O)mR5;
X is xe2x80x94NHxe2x80x94;
n is 0;
R1 is phenyl optionally substituted with 1 to 4 substituents which may be the same or different independently selected from xe2x80x94H, xe2x80x94J, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94OH, xe2x80x94SH, xe2x80x94CN, xe2x80x94N3, xe2x80x94COOH, xe2x80x94CONH2, xe2x80x94NHC(O)NH2, xe2x80x94C(O)H, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94R5, xe2x80x94OR5, xe2x80x94NHR5, xe2x80x94Q, xe2x80x94S(O)mR5, xe2x80x94NHSO2R5, xe2x80x94R6OH, xe2x80x94R6OR5, xe2x80x94R6NH2, xe2x80x94R6NHR5, xe2x80x94R6Q, xe2x80x94R6SH, xe2x80x94R6S(O)mR5, xe2x80x94NHR7OH, xe2x80x94NHR7OR5, xe2x80x94N(R5)R7OH, xe2x80x94N(R5)R7OR5, xe2x80x94NHR7NH2, xe2x80x94NH7NHR5, xe2x80x94NHR7Q, xe2x80x94N(R5)R7NH2, xe2x80x94N(R5)R7NHR5, xe2x80x94N(R5)R7Q, xe2x80x94OR7OH, xe2x80x94OR7OR5, xe2x80x94OR7NH2, xe2x80x94OR7NHR5, xe2x80x94OR7Q, xe2x80x94OC(O)R5, xe2x80x94NHC(O)R5, xe2x80x94NHC(O)NHR5, xe2x80x94OR6C(O)R5, xe2x80x94NHR6C(O)R5, xe2x80x94C(O)R5, xe2x80x94C(O)OR5, xe2x80x94C(O)NHR5, xe2x80x94C(O)Q, xe2x80x94R6C(O)H, xe2x80x94R6C(O)R5, xe2x80x94R6C(O)OH, xe2x80x94R6C(O)OR5, xe2x80x94R6C(O)NH2, xe2x80x94R6C(O)NHR5, xe2x80x94R6C(O)Q, xe2x80x94R6OC(O)R5, xe2x80x94R6OC(O)NH2, xe2x80x94R6OC(O)NHR5, xe2x80x94R6OC(O)Q and xe2x80x94YR8 groups wherein Y is independently selected from xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94OC(O)xe2x80x94, xe2x80x94C(O)NHxe2x80x94, xe2x80x94NHC(O)xe2x80x94, xe2x80x94NHSO2xe2x80x94, xe2x80x94SO2NHxe2x80x94, xe2x80x94C(OH)Hxe2x80x94, xe2x80x94O(C(R9)2)q, xe2x80x94S(O)m(C(R9)2)qxe2x80x94, xe2x80x94NH(C(R9)2)qxe2x80x94, xe2x80x94NR10(C(R9)2)qxe2x80x94, xe2x80x94(CR9)2)qxe2x80x94, xe2x80x94(C(R9)2)qOxe2x80x94, xe2x80x94(C(R9)2)qS(O)mxe2x80x94, xe2x80x94(C(R9)2)qNHxe2x80x94, xe2x80x94(C(R9)2)qNR10xe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, cis and trans xe2x80x94CHxe2x95x90CHxe2x80x94 and cycloalkyl of 3 to 10 carbon atoms;
R4 is xe2x80x94(C(R9)2)rH;
r is 0;
A is absent;
R3 is attached to carbon-6 or carbon-7 of Formula (I) and is selected from aryl, heteroaryl, bicyclic heteroaryl, alkenyl, alkynyl wherein each aryl, heteroaryl, bicyclic heteroaryl, alkenyl, alkynyl is optionally substituted by one or more of xe2x80x94R10, xe2x80x94(C(R9)2)sR12, xe2x80x94CHO, and 1,3-dioxolane;
or a pharmaceutically acceptable salt thereof.
b) 3-cyanoquinolines of Formula (I) wherein:
T and Z are carbon;
X is xe2x80x94NHxe2x80x94;
n is 0;
R1 is phenyl optionally substituted with 1 to 4 substituents which may be the same or different independently selected from xe2x80x94H, xe2x80x94J, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94OH, xe2x80x94SH, xe2x80x94CN, xe2x80x94N3, xe2x80x94COOH, xe2x80x94CONH2, xe2x80x94NHC(O)NH2, xe2x80x94C(O)H, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94R5, xe2x80x94OR5, xe2x80x94NHR5, xe2x80x94Q, xe2x80x94S(O)mR5, xe2x80x94NHSO2R5, xe2x80x94R6OH, xe2x80x94R6OR5, xe2x80x94R6NH2, xe2x80x94R6NHR5, xe2x80x94R6Q, xe2x80x94R6SH, xe2x80x94R6S(O)mR5, xe2x80x94NHR7OH, xe2x80x94NHR7OR5, xe2x80x94N(R5)R7OH, xe2x80x94N(R5)R7OR5, xe2x80x94NHR7NH2, xe2x80x94NHR7NHR5, xe2x80x94NHR7Q, xe2x80x94N(R5)R7NH2, xe2x80x94N(R5)R7NHR5, xe2x80x94N(R5)R7Q, xe2x80x94OR7OH, xe2x80x94OR7OR5, xe2x80x94OR7NH2, xe2x80x94OR7NHR5, xe2x80x94OR7Q, xe2x80x94OC(O)R5, xe2x80x94NHC(O)R5, xe2x80x94NHC(O)NHR5, xe2x80x94OR6C(O)R5, xe2x80x94NHR6C(O)R5, xe2x80x94C(O)R5, xe2x80x94C(O)OR5, xe2x80x94C(O)NHR5, xe2x80x94C(O)Q, xe2x80x94R6C(O)H, xe2x80x94R6C(O)R5, xe2x80x94R6C(O)OH, xe2x80x94R6C(O)OR5, xe2x80x94R6C(O)NH2, xe2x80x94R6C(O)NHR5, xe2x80x94R6C(O)Q, xe2x80x94R6OC(O)R5, xe2x80x94R6OC(O)NH2, xe2x80x94R6OC(O)NHR5, xe2x80x94R6OC(O)Q and YR8 groups wherein Y is independently selected from xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94OC(O)xe2x80x94, xe2x80x94C(O)NHxe2x80x94, xe2x80x94NHC(O)xe2x80x94, xe2x80x94NHSO2xe2x80x94, xe2x80x94SO2NHxe2x80x94, xe2x80x94C(OH)Hxe2x80x94, xe2x80x94O(C(R9)2)qxe2x80x94, xe2x80x94S(O)m(C(R9)2)qxe2x80x94, xe2x80x94NH(C(R9)2)qxe2x80x94, xe2x80x94NR10(C(R9)2)qxe2x80x94, xe2x80x94(C(R9)2)qxe2x80x94, xe2x80x94(C(R9)2)qOxe2x80x94, xe2x80x94(C(R9)2)qS(O)mxe2x80x94, xe2x80x94(C(R9)2)qNHxe2x80x94, xe2x80x94(C(R9)2)qNR10xe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, cis and trans xe2x80x94CHxe2x95x90CHxe2x80x94 and cycloalkyl of 3 to 10 carbon atoms;
R2a and R2b are H;
R2c is attached to carbon-6 of Formula (I) and is selected from xe2x80x94H, xe2x80x94J, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94R5, xe2x80x94OR5, xe2x80x94OR11, xe2x80x94OR7OH, xe2x80x94OR7OR5 and xe2x80x94S(O)mR5;
R3 is attached to carbon-7 of Formula (I) and is selected from heteroaryl, phenyl, alkenyl of 2 to 6 carbon atoms or alkynyl of 2 to 6 carbon atoms with each heteroaryl, phenyl, alkenyl and alkynyl group further substituted by one or more of the group xe2x80x94(C(R9)2)sR12;
A is absent;
R4 is (C(R9)2)rH;
r is 0;
or a pharmaceutically acceptable salt thereof.
c) 3-cyanoquinolines of Formula (I) wherein:
T and Z are carbon;
X is xe2x80x94NHxe2x80x94;
n is 0;
R1 is phenyl optionally substituted with 1 to 4 substituents which may be the same or different independently selected from xe2x80x94H, xe2x80x94J, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94OH, xe2x80x94SH, xe2x80x94CN, xe2x80x94N3, xe2x80x94COOH, xe2x80x94CONH2, xe2x80x94NHC(O)NH2, xe2x80x94C(O)H, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94R5, xe2x80x94OR5, xe2x80x94NHR5, xe2x80x94Q, xe2x80x94S(O)mR5, xe2x80x94NHSO2R5, xe2x80x94R6OH, xe2x80x94R6OR5, xe2x80x94R6NH2, xe2x80x94R6NHR5, xe2x80x94R6Q, xe2x80x94R6SH, xe2x80x94R6S(O)mR5, xe2x80x94NHR7OH, xe2x80x94NHR7OR5, xe2x80x94N(R5)R7OH, xe2x80x94N(R5)R7OR5, xe2x80x94NHR7NH2, xe2x80x94NHR7NHR5, xe2x80x94NHR7Q, xe2x80x94N(R5)R7NH2, xe2x80x94N(R5)R7NHR5, xe2x80x94N(R5)R7Q, xe2x80x94OR7OH, xe2x80x94OR7OR5, xe2x80x94OR7NH2, xe2x80x94OR7NHR5, xe2x80x94OR7Q, xe2x80x94OC(O)R5, xe2x80x94NHC(O)R5, xe2x80x94NHC(O)NHR5, xe2x80x94OR6C(O)R5, xe2x80x94NR6C(O)R5, xe2x80x94C(O)R5, xe2x80x94C(O)OR5, xe2x80x94C(O)NHR5, xe2x80x94C(O)Q, xe2x80x94R6C(O)H, xe2x80x94R6C(O)R5, xe2x80x94R6C(O)OH, xe2x80x94R6C(O)OR5, xe2x80x94R6C(O)NH2, xe2x80x94R6C(O)NHxe2x80x94R5, xe2x80x94R6C(O)Q, xe2x80x94R6OC(O)R5, xe2x80x94R6OC(O)NH2, xe2x80x94R6OC(O)NHR5, xe2x80x94R6OC(O)Q and xe2x80x94YR8 groups wherein Y is independently selected from xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94OC(O)xe2x80x94, xe2x80x94C(O)NHxe2x80x94, xe2x80x94NHC(O)xe2x80x94, xe2x80x94NHSO2xe2x80x94, xe2x80x94SO2NHxe2x80x94, xe2x80x94C(OH)Hxe2x80x94, xe2x80x94O(C(R9)2)qxe2x80x94, xe2x80x94S(O)m(C(R9)2)qxe2x80x94, xe2x80x94NH(C(R9)2)qxe2x80x94, xe2x80x94NR10(CR9)2)qxe2x80x94, xe2x80x94(C(R9)2)qxe2x80x94, xe2x80x94(C(R9)2)qOxe2x80x94, xe2x80x94(C(R9)2)qS(O)mxe2x80x94, xe2x80x94(C(R9)2)qNHxe2x80x94, xe2x80x94(C(R9)2)qNR1xe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, cis and trans xe2x80x94CHxe2x95x90CHxe2x80x94 cycloalkyl of 3 to 10 carbon atoms;
R2a and R2b are H;
R2c is attached to carbon-7 of Formula (I) and is selected from xe2x80x94H, xe2x80x94J, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94R5, xe2x80x94OR5, xe2x80x94OR11, xe2x80x94OR7OH, xe2x80x94OR7OR5 and xe2x80x94S(O)mR5;
R3 is attached to carbon-6 of Formula (I) and is selected from heteroaryl, phenyl, alkenyl of 2 to 6 carbon atoms or alkynyl of 2 to 6 carbon atoms with each heteroaryl, phenyl, alkenyl and alkynyl group substituted by one or more of the group xe2x80x94(C(R9)2)sR12;
A is absent;
R4 is xe2x80x94(C(R9)2)rH;
r is 0;
or a pharmaceutically acceptable salt thereof.
d) 3-cyanoquinolines of Formula (I) wherein:
X is xe2x80x94NHxe2x80x94;
T and Z are carbon;
n is 0;
R2a and R2b are H;
R2c attached to carbon-6- or carbon-7 of Formula (I) and is selected from xe2x80x94H, xe2x80x94J, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94R5, xe2x80x94OR5, xe2x80x94OR11, xe2x80x94OR7OH, xe2x80x94OR7OR5 and xe2x80x94S(O)mR5;
R1 is phenyl optionally substituted which 1 to 4 substituents which may be the same or different independently selected from xe2x80x94H, xe2x80x94J, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94OH, xe2x80x94SH, xe2x80x94CN, xe2x80x94N3, xe2x80x94COOH, xe2x80x94CONH2, xe2x80x94NHC(O)NH2, xe2x80x94C(O)H, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94R5, xe2x80x94OR5, xe2x80x94NHR5, xe2x80x94Q, xe2x80x94S(O)mR5, xe2x80x94NHSO2R5, xe2x80x94R6OH, xe2x80x94R6OR5, xe2x80x94R6NH2, xe2x80x94R6NHR5, xe2x80x94R6Q, xe2x80x94R6SH, xe2x80x94R6S(O)mR5, xe2x80x94NHR7OH, xe2x80x94NHR7OR5, xe2x80x94N(R5)R7OH, xe2x80x94N(R5)R7OR5, xe2x80x94NHR7NH2, xe2x80x94NHR7NHR5, xe2x80x94NHR7Q, xe2x80x94N(R5)R7NH2, xe2x80x94N(R5)R7NHR5, xe2x80x94N(R7)R7Q, xe2x80x94OR7OH, xe2x80x94OR7OR5, xe2x80x94OR7NH2, xe2x80x94OR7NHR5, xe2x80x94OR7Q, xe2x80x94OC(O)R5, xe2x80x94NHC(O)R5, xe2x80x94NHC(O)NHR5, xe2x80x94OR6C(O)R5, xe2x80x94NHR6C(O)R5, xe2x80x94C(O)R5, xe2x80x94C(O)OR5, xe2x80x94C(O)NR5, xe2x80x94C(O)Q, xe2x80x94R6C(O)H, xe2x80x94R6C(O)R5, xe2x80x94R6C(O)OH, xe2x80x94R6C(O)OR5, xe2x80x94R6C(O)NH2, xe2x80x94R6C(O)NHR5, xe2x80x94R6C(O)Q, xe2x80x94R6OC(O)R5, xe2x80x94R6OC(O)NH2, xe2x80x94R6OC(O)NHR5, xe2x80x94R6OC(O)Q and xe2x80x94YR8 groups wherein Y is independently selected form xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94OC(O)xe2x80x94, xe2x80x94C(O)NHxe2x80x94, xe2x80x94NHC(O)xe2x80x94, xe2x80x94NHSO2xe2x80x94, xe2x80x94SO2NHxe2x80x94, xe2x80x94C(OH)Hxe2x80x94, xe2x80x94O(C(R9)2)qxe2x80x94, xe2x80x94S(O)m(C(R9)2)qxe2x80x94, xe2x80x94NH(C(R9)2)qxe2x80x94, xe2x80x94NR10(C(R9)2)qxe2x80x94, xe2x80x94(C(R9)2)qxe2x80x94, xe2x80x94(C(R9)2)qOxe2x80x94, xe2x80x94(C(R9)2)qS(O)mxe2x80x94, xe2x80x94(C(R9)2)qNHxe2x80x94, xe2x80x94(C(R9)2)qNR10, xe2x80x94Cxe2x89xa1Cxe2x80x94, cis- and trans- xe2x80x94CHxe2x95x90CHxe2x80x94 and cycloalkyl of 3 to 10 carbon atoms;
R3 is attached to carbon-6 or carbon-7 of Formula (I) and is alkenyl of 2 carbon atoms;
A is absent;
or a pharmaceutically acceptable salt thereof.
e) 3-cyanoquinolines of Formula (I) wherein:
X is xe2x80x94NHxe2x80x94;
T and Z are carbon;
n is 0;
R2a and R2b are H;
R2c is attached to carbon-6 or carbon-7 of Formula (I) and is selected from xe2x80x94H, xe2x80x94J, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94R5, xe2x80x94OR5, xe2x80x94OR11, xe2x80x94OR7OH, xe2x80x94OR7OR5 and xe2x80x94S(O)mR5;
R1 is phenyl optionally substituted with 1 to 4 substituents which may be the same or different independently selected from xe2x80x94H, xe2x80x94J, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94OH, xe2x80x94SH, xe2x80x94CN, xe2x80x94N3, xe2x80x94COOH, xe2x80x94CONH2, xe2x80x94NHC(O)NH2, xe2x80x94C(O)H, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94R5, xe2x80x94OR5, xe2x80x94NHR5, xe2x80x94Q, xe2x80x94S(O)mR5, xe2x80x94NHSO2R5, xe2x80x94R6OH, xe2x80x94R6OR5, xe2x80x94R6NH2, xe2x80x94R6NHR5, xe2x80x94R6Q, xe2x80x94R6SH, xe2x80x94R6S(O)mR5, xe2x80x94NHR7OH, xe2x80x94NHR7OR5, xe2x80x94N(R5)R7OH, xe2x80x94N(R5)R7OR5, xe2x80x94NHR7NH2, xe2x80x94NHR7NHR5, xe2x80x94NHR7Q, xe2x80x94N(R5)R7NH2, xe2x80x94N(R5)R7NHR5, xe2x80x94N(R5)R7Q, xe2x80x94OR7OH, xe2x80x94OR7OR5, xe2x80x94OR7NH2, xe2x80x94OR7NHR5, xe2x80x94OR7Q, xe2x80x94OC(O)R5, xe2x80x94NHC(O)R5, xe2x80x94NHC(O)NHR5, xe2x80x94OR6C(O)R5, xe2x80x94NHR6C(O)R5, xe2x80x94C(O)R5, xe2x80x94C(O)OR5, xe2x80x94C(O)NHR5, xe2x80x94C(O)Q, xe2x80x94R6C(O)H, xe2x80x94R6C(O)R5, xe2x80x94R6C(O)OH, xe2x80x94R6C(O)OR5, xe2x80x94R6C(O)NH2, xe2x80x94R6C(O)NHR5, xe2x80x94R6C(O)Q, xe2x80x94R6OC(O)R5, xe2x80x94R6OC(O)NH2, xe2x80x94R6OC(O)NHR5, xe2x80x94R6OC(O)Q and YR8 groups wherein Y is independently selected from xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94OC(O)xe2x80x94, xe2x80x94C(O)NHxe2x80x94, xe2x80x94NHC(O)xe2x80x94, xe2x80x94NHSO2xe2x80x94, xe2x80x94SO2NHxe2x80x94, xe2x80x94C(OH)Hxe2x80x94, xe2x80x94O(C(R9)2)qxe2x80x94, xe2x80x94S(O)m(C(R9)2)qxe2x80x94, xe2x80x94NH(C(R9)2)qxe2x80x94, xe2x80x94NR10(C(R9)2)qxe2x80x94, xe2x80x94(C(R9)2)qxe2x80x94, xe2x80x94(C(R9)2)qOxe2x80x94, xe2x80x94(C(R9)2)qS(O)mxe2x80x94, xe2x80x94(C(R9)2)qNHxe2x80x94, xe2x80x94(C(R9)2)qNR10xe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, cis and trans xe2x80x94CHxe2x95x90CHxe2x80x94 and cycloalkyl of 3 to 10 carbon atoms;
R3 is attached to carbon-6 or carbon-7 of Formula (I) and is alkynyl of 2 carbon atoms;
A is absent;
or a pharmaceutically acceptable salt thereof.
Preferred compounds of the invention or a pharmaceutically acceptable salt thereof are:
4-(4-Chloro-2-fluoroanilino)-7-[5-(4-morpholinylmethyl)-3-thienyl]-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-7-[(E)-2-(4-pyridinyl)ethenyl]-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-7-[(E)-2-(2-pyridinyl)ethenyl]-3-quinolinecarbonitrile,
4-(2,4-Dichloroanilino)-7-[(E)-2-(4-pyridinyl)ethenyl]-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-7-[5-(1,3-dioxolan-2-yl)-2-furyl]-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-7-(5-formyl-2-furyl)-3-quinolinecarbonitrile,
7-[5-(4-Morpholinylmethyl)-3-thienyl]-4-(4-phenoxyanilino)-3-quinolinecarbonitrile,
4-(4-Benzylanilino)-7-[5-(4-morpholinylmethyl)-3-thienyl]-3-quinolinecarbonitrile,
4-(2,4-Dichloroanilino)-7-{5-[2-(4-morpholinyl)ethyl]-2-thienyl}-3-quinolinecarbonitrile,
4-(2,4-Dichloroanilino)-7-{5-[(4-ethyl-1-piperazinyl)methyl]-3-thienyl}-3-quinolinecarbonitrile,
4-(2,4-Dichloroanilino)-7-[5-(4-morpholinyl)-1-pentynyl]-3-quinolinecarbonitrile,
4-(2,4-Dichloroanilino)-7-[(E/Z)-5-(4-morpholinyl)-1-pentynyl]-3-quinolinecarbonitrile,
4-(2,4-Dichloroanilino)-7-[5-(4-morpholinylmethyl)-2-furyl]-3-quinolinecarbonitrile,
4-(2,4-Dichloroanilino)-7-(3-hydroxy-1-propynyl)-3-quinolinecarbonitrile,
4-(2,4-Dichloroanilino)-7-[3-(dimethylamino)-1-propynyl]-3-quinolinecarbonitrile,
4-(2,4-Dichloroanilino)-7-[(E/Z)-6-(4-morpholinyl)-1-hexenyl]-3-quinolinecarbonitrile,
7-[4,5-Bis(4-morpholinylmethyl)-2-thienyl]-4-(2,4-dichloroanilino)-3-quinolinecarbonitrile,
4-(2,4-Dichloroanilino)-7-[5-(2-pyridinyl)-2-thienyl]-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-7-{5-[(4-ethyl-1-piperazinyl)methyl]-3-thienyl}-3-quinolinecarbonitrile,
7-[4,5-Bis(4-morpholinylmethyl)-2-thienyl]-4-(2,4-dichloro-5-methoxyanilino)-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-7-{5-[(E)-3-(4-morpholinyl)-1-propenyl]-2-thienyl}-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-7-{5-[4-(4-morpholinyl)butyl]-2-thienyl}-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-7-[5-(4-morpholinylmethyl)-2-thienyl]-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-7-[5-(4-morpholinylmethyl)-3-thienyl]-3-quinolinecarbonitrile,
4-(2,4-Dichloroanilino)-7-[5-(4-morpholinylmethyl)-3-thienyl]-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-7-[3-(4-morpholinylmethyl)phenyl]-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-7-{4-[2-(4-morpholinyl)ethyl]phenyl}-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-7-{3-[2-(4-morpholinyl)ethyl]phenyl)-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-7-[4-(4-morpholinylmethyl)phenyl]-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-7-{4-[(4-ethyl-1-piperazinyl)methyl]phenyl-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-7-{4-[(4-ethyl-1-piperazinyl)methyl]phenyl}-methoxy-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-7-{4-[2-(4-ethyl-1-piperazinyl)ethyl]phenyl}-3-quinolinecarbonitrile,
4-{3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-[5-(4-morpholinylmethyl)-3-thienyl]-3-quinolinecarbonitrile,
7-[3,4-Bis(4-morpholinylmethyl)phenyl]-4-(2,4-dichloro-5-methoxyanilino)-3-quinolinecarbonitrile,
7-[3,4-Bis(4-morpholinylmethyl)phenyl]-4-(3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-6-methoxy-7-[5-(4-morpholinylmethyl)-3-thienyl]-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)6-methoxy-7-[4-(4-morpholinylmethyl)phenyl]3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-6-methoxy-7-{3-[2-(4-morpholinyl)ethyl]phenyl}-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-6-methoxy-7-[3-(4-morpholinylmethyl]phenyl}-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-6-methoxy-7-{4-[2-(4-morpholinyl)ethyl]phenyl}-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-7-{5-[(4-ethyl-1-piperazinyl)methyl]-2-furyl-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-7-[5-(1,3-dioxolan-2-yl)-3-thienyl]-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-7-(5-formyl-3-thienyl)-3-quinolinecarbonitrile,
4-(2,4-Dichloroanilino)-7-(5-formyl-3-thienyl)-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-6-(5-formyl-3-thienyl)-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-7-{5-[(4-methyl-1-piperazinyl)methyl]-3-thienyl}-3-quinolinecarbonitrile,
(2R)-1-({5-[3-Cyano-4-(2,4-dichloro-5-methoxyanilino)-7-quinolinyl]-2-furyl}methyl)-2-pyrrolidinecarboxamide,
7-[5-(4-Morpholinylmethyl)-3-pyridinyl]-4-(4-phenoxyanilino)-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-7-[5-(4-morpholinylmethyl)-3-pyridinyl]-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-6-[5-(4-morpholinylmethyl)-3-thienyl]-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-7-[5-(1,3-dioxolan-2-yl)-2-thienyl]-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-7-(5-formyl-2-thienyl)-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-7-[5-(4-morpholinylmethyl)-2-furyl]-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-7-[(E)-2-(4-methoxyphenyl)ethenyl]-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-7-{5-[(4-methyl-1-piperazinyl)methyl]-2-thienyl}-3-quinolinecarbonitrile,
7-[5-(4-Morpholinylmethyl)-2-pyridinyl]-4-(4-phenoxyanilino)-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-7-[5-(4-morpholinylmethyl)-2-pyridinyl]-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-7-[5-({[2-(phenylsulfonyl)ethyl]amino}methyl)-2-furyl]-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-6-methoxy-7-(1H-pyrrol-1-yl)-3-quinolinecarbonitrile,
4-(3-Bromoanilino)-6-(2-formyl-1H-pyrrol-1-yl)-3-quinolinecarbonitrile,
4-(3-Chloro-4-fluoro-phenylamino)-7-methoxy-6-(1H-pyrrol-1-yl)-3-quinolinecarbonitrile,
4-{3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-(4-formylphenyl)-3-quinolinecarbonitrile,
4-{3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-[4-(4-morpholinylmethyl)phenyl]-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-7-{1-[2-(4-morpholinyl)ethyl]-1H-imidazol-5-yl}-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-7-[4-(4-morpholinylmethyl)-3-thienyl]-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-7-[2-(4-morpholinylmethyl)-3-thienyl]-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-7-[4-(4-morpholinyl)phenyl]-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-7-[4-(4-morpholinylmethyl)-2-thienyl]-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-7-(5-formyl-1-methyl-1H-pyrrol-2-yl)-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-7-[1-methyl-5-(4-morpholinylmethyl)-1H-pyrrol-2-yl]-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-7-(1-methyl-5-[(4-methyl-1-piperazinyl)methyl]-1H-pyrrol-2-yl}-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-7-[1-methyl-5-({[2-(phenylsufonyl)ethyl]amino}methyl)-1H-pyrrol-2-yl]-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-7-[1-methyl-5-({[2-(methylsulfonyl)ethyl]amino}-methyl)-1H-pyrrol-2-yl]-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-7-[5-({[2-(2-pyridinyl)ethyl]amino}methyl)-2-furyl]-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-7-(5-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}-2-furyl)-3-quinolinecarbonitrile,
7-(5-{[Bis(2-hydroxyethyl)amino]methyl}-2-furyl)-4-(2,4-dichloro-5-methoxyanilino)-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-7-[5-({[2-(methylsulfonyl)ethyl]amino}methyl)-furyl]-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-7-[5-(1-piperidinylmethyl)-2-thienyl]-3-quinolinecarbonitrile,
4-{2-Chloro-4-fluoro-5-methoxyanilino)-7-[5-(4-morpholinylmethyl)-3-thienyl]-3-quinolinecarbonitrile,
4-{2-Chloro-5-methoxy-4-methoxyanilino)-7-[5-(4-morpholinylmethyl)-3-thienyl]-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-7-[6-4-morpholinylmethyl)-3-pyridinyl]-3-quinolinecarbonitrile,
7-[4,5-Bis(4-morpholinylmethyl)-2-thienyl]-4-(2,4-dichloro-5-methoxyanilino)-6-methoxy-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-7-(4-formylphenyl)-3-quinolinecarbonitrile,
(2R)-1-{4-[3-Cyano-4-(2,4-dichloro-5-methoxyanilino)-7-quinolinyl]benzyl}-2-pyrrolidinecarboxamide,
4-(2,4-Dichloro-5-methoxyanilino)-7-[4-({[2-(phenylsulfonyl)ethyl]amino}methyl)phenyl]-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-7-{4-[(dimethylamino)methyl]phenyl}-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-7-{4-[(diethylamino)methyl]phenyl}-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-7-[4-({[2-(methylsufonyl)ethyl]amino}methyl)phenyl]-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-7-{5-[(4-hydroxy-1-piperidinyl)methyl]-2-thienyl}-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-7-[2-(4-methoxyphenyl)ethynyl]-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-7-[2-(2-pyridinyl)ethynyl]-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-7-pyrrol-1-yl-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-7-{(2-[(dimethylamino)methyl]-1H-pyrrol-1-yl}-3-quinolinecarbonitrile,
7-[5-(1,3-Dioxolan-2-yl)-3-thienyl]-4-[3-methyl-4-(2-pyridinylmethoxy)anilino]-3-quinolinecarbonitrile,
4-[3-Methyl-4-(2-pyridinylmethoxy)anilino]-7-[5-(4-morpholinylmethyl)-3-thienyl]-3-quinolinecarbonitrile,
4-[(2,4-Dichloro-5-methoxyanilino]-7-(2-formyl-1-methyl-1H-imidazol-5-yl)quinoline-3-carbonitrile,
4-({3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-7-[4-(1-piperazinylmethyl)phenyl]-3-quinolinecarbonitrile,
4-({3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-7-{4-[(4-isopropyl-1-piperazinyl)methyl]phenyl}-3-quinolinecarbonitrile,
(E)-3-[3-Cyano-4-(2,4-dichloro-1-methoxyanilino)-7-quinolinyl]-2-propenoic acid,
(1-{4-[3-Cyano-4-(2,4-dichloro-5-methoxyanilino)-7-quinolinyl]benzyl}-4-piperidinyl)acetic acid,
4-(2,4-Dichloro-5-methoxyanilino)-7-[4-(hydroxymethyl)phenyl]-3-quinolinecarbonitrile,
7-[4-(Chloromethyl)phenyl]-4-(2,4-dichloro-5-methoxyanilino)-3-quinolinecarbonitrile,
4-[(2,4-Dichloro-5-methoxyphenyl)amino]-7-[4-(1H-1,2,3-triazol-1-methyl)phenyl]-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-7-(1H-pyrrol-2-yl)-3-quinolinecarbonitrile,
4-[(2,4-Dichloro-5-methoxyanilino]-7-[4-(1H-tetraazol-5-yl)phenyl]-3-quinolinecarbonitrile,
4-({3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-7-(5-{[(2-hydroxyethyl)(methyl)amino]methyl}-2-pyridinyl)-3-quinolinecarbonitrile,
Methyl 1-{[6-(4-(3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-3-cyano-7-quinolinyl)-3-pyridinyl]methyl}-4-piperidinecarboxylate,
4-({3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-7-[5-(4-ethyl-1-piperazinyl)-2-pyridinyl]-3-quinolinecarbonitrile,
4-({3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-7-[6-(4-morpholinylmethyl)-3-pyridinyl]-3-quinolinecarbonitrile,
4-({3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-7-[6-(4-thiomorpholinyl)-3-pyridinyl]-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-7-[3-(morpholin-4-ylmethyl)-pyridin-2-yl]-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxylanilino)-7-(3-formyl)-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-7-{3-[(4-methyl-1-piperazinyl)methyl]phenyl}-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-7-(2-formylphenyl)-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-7-[2-(4-morpholinylmethyl)phenyl]-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-7-(1-naphthyl)-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-7-(2-naphthyl)-3-quinolinecarbonitrile,
N-{3-[3-Cyano-4-(2,4-dichloro-5-methoxyanilino)-7-quinolinyl]phenyl}acetamide,
7-(1-Benzofuran-2-yl)-4-(2,4-dichloro-5-methoxyanilino)-3-quinolinecarbonitrile,
7-(1-Benzothien-2-yl)-4-2,4-dichloro-5-methoxyanilino)-3-quinolinecarbonitrile,
4-[3-Cyano-4-(2,4-dichloro-5-methoxyanilino)-7-quinolinyl]benzoic acid,
4-(2,4-Dichloro-5-methoxyanilino)-7-(3-nitrophenyl)-3-quinolinecarbonitrile,
4-{3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-6-methoxy-7-[4-(4-morpholinylmethyl)phenyl]-3-quinolinecarbonitrile,
7-[3,4-Bis(4-morpholinylmethyl)phenyl-4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-6-methoxy-3-quinolinecarbonitrile,
4-{3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-6-methoxy-7-[5-(4-morpholinylmethyl)-3-thienyl]-3-quinolinecarbonitrile,
4-{3-Chloro-4-[(1-methyl-1H-imidazol-2-y)sulfanyl]anilino}-6-methoxy-7-{5-[(4-methyl-1-piperazinyl)methyl]-3-thienyl}-3-quinolinecarbonitrile,
4-{3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-6-methoxy-7-(4-methoxyphenyl)-3-quinolinecarbonitrile,
4-[(2,4-Dichloro-5-methoxyphenyl)amino]-7-[4-(4-morpholinyl)phenyl]-3-quinolinecarbonitrile,
4-({3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-7-[4-(4-morpholinylcarbonyl)phenyl]-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-7-{4-[(2-methoxy)ethoxyl]phenyl}-3-quinolinecarbonitrile,
4-(2-Chloro-5-methoxyanilino)-7-[5-(4-morpholinylmethyl)-3-thienyl]-3-quinolinecarbonitrile,
4-[4-(Benzyloxy)-3-chloroanilino]-7-[3,4-bis(4-morpholinylmethyl)phenyl]-3-quinolinecarbonitrile,
7-[3,4-Bis(4-morpholinylmethyl)phenyl]-4-(2-chloro-5-methoxy-4-methylanilino)-3-quinolinecarbonitrile,
4-{3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-{4-[(4-hydroxy-1-piperidinyl)methyl]phenyl}-3-quinolinecarbonitrile,
4-{3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-{4-[(4-methyl-1-piperazinyl)methyl]phenyl}-3-quinolinecarbonitrile,
4-{3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-[4-(1-piperidinylmethyl)phenyl]-3-quinolinecarbonitrile,
tert-Butyl 4-{4-[4-({3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-3-cyano-7-quinolinyl]benzyl}-1-piperazinecarboxylate,
4-({3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-7-{4-[(4-morpholinyl)methyl]phenyl}-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-7-[(E)-2-phenylethenyl]-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-7-(2-phenylethynyl)-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-7-[2-(4-methylphenyl)ethynyl]-3-quinolinecarbonitrile,
tert-Butyl (E)-3-[3-cyano-4-(2,4-dichloro-5-methoxyanilino)-7-quinolinyl]-2-propenoate,
4-(2,4-Dichloro-5-methoxyanilino)-7-(3-hydroxy-1-propynyl)-3-quinolinecarbonitrile,
Ethyl (1-{4-[3-Cyano-4-(2,4-dichloro-5-methoxyanilino)-7-quinolinyl]benzyl}-4-piperidinyl)acetate,
Ethyl 1-{4-[3-cyano-4-(2,4-dichloro-5-methoxyanilino)-7-quinolinyl]benzyl}-2-piperidinecarboxylate,
4-(2,4-Dichloro-5-methoxyanilino)-7-[3-(4-morpholinyl)-1-propynyl]-3-quinolinecarbonitrile,
1-{4-[3-Cyano-4-(2,4-dichloro-5-methoxyanilino)-7-quinolinyl]benzyl}-2-piperidinecarboxylic acid,
Ethyl 1-(4-{3-cyano-4-[(2,4-dichloro-5-methoxyphenyl)amino]-7-quinolinyl}benzyl)-3-piperidinecarboxylate,
1-(4-{3-Cyano-4-[(2,4-dichloro-5-methoxyphenyl)amino]-7-quinolinyl}benzyl)-3-piperidinecarboxylic acid,
4-[(2,4-Dichloro-5-methoxyphenyl)amino]-7-{4-[(1,1-dioxido-4-thiomorpholinyl)methyl]phenyl}-3-quinolinecarbonitrile,
4-[(2,4-Dichloro-5-methoxyphenyl)amino]-7-{4-[(1-oxido-4-thiomorpholinyl)methyl]phenyl}-3-quinolinecarbonitrile,
7-(3-Chloro-1-propynyl)-4-[(2,4-dichloro-5-methoxyphenyl)amino]-3-quinolinecarbonitrile,
4-[(2,4-Dichloro-5-methoxyphenyl)amino]-7-[4-(4-thiomorpholinylmethyl)phenyl]-3-quinolinecarbonitrile,
4-{3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-[5-(4-morpholinylmethyl)-2-furyl-3-quinolinecarbonitrile,
4-{3-Chloro-4-[(-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-[5-(1-piperidinylmethyl)-2-furyl]-3-quinolinecarbonitrile,
4-{3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-{5-[(4-ethyl-1-piperazinyl)methyl]-2-furyl}-3-quinolinecarbonitrile,
4-{3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-(5-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}-2-furyl)-3-quinolinecarbonitrile,
4-({3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-7-(5-formyl-2-furyl)-3-quinolinecarbonitrile,
4-{3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-{5-[(4-hydroxy-1-piperidinyl)methyl]-2-thienyl}-3-quinolinecarbonitrile,
4-{3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-[5-(1-piperidinylmethyl)-2-thienyl]-3-quinolinecarbonitrile,
4-{3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-(5-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}-2-thienyl)-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-7-[5-(hydroxymethyl)-1-methyl-1H-pyrrol-2-yl]-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-7-(3-formyl-2-thienyl)-3-quinolinecarbonitrile,
tert-Butyl 2-[3-cyano-4-(2,4-dichloro-5-methoxyanilino)-7-quinolinyl]-1H-pyrrole-1-carboxylate,
7-[1,1xe2x80x2-Biphenyl]-4-yl-4-(2,4-dichloro-5-methoxyanilino)-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-6-methoxy-7-[3-(4-morpholinyl)-1-propynyl]-3-quinolinecarbonitrile,
4-(4-Chloro-5-methoxy-2-methylanilino)-7-[5-(4-morpholinylmethyl)-3-thienyl]-3-quinolinecarbonitrile,
7-[4,5-Bis(4-morpholinylmethyl)-2-thienyl]-4-(4-phenoxyanilino)-3-quinolinecarbonitrile,
7-[4,5-Bis(4-morpholinylmethyl)-2-thienyl]-4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-3-quinolinecarbonitrile,
4-{3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-(5-formyl-2-pyridinyl)-3-quinolinecarbonitrile,
4-{3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-{5-[(4-ethyl-1-piperidinyl)methyl]-2-pyridinyl}-3-quinolinecarbonitrile,
4-{3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-{5-[(4-hydroxy-1-piperidinyl)methyl]-2-pyridinyl}-3-quinolinecarbonitrile,
4-{3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-(5-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}-2-pyridinyl)-3-quinolinecarbonitrile,
7-(3-Aminophenyl)-4-[(2,4-dichloro-5-methoxyphenyl)amino]-3-quinolinecarbonitrile,
1-{[6-{4-(3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-3-cyano-7-quinolinyl)-3-pyridinyl)methyl]-2-pyridinyl}-4-piperidinecarboxylic acid,
1-{6-[3-Cyano-4-(2,4-dichloro-5-methoxyphenylamino)-quinolin-7-yl]-pyridin-3-ylmethyl}-piperidine-4-carboxylic acid methyl ester,
1-{6-[3-Cyano-4-(2,4-dichloro-5-methoxyphenylamino)-quinolin-7-yl]-pyridin-3-ylmethyl}-piperidine-4-carboxylic acid,
4-({3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-7-(5-chloro-2-pyridinyl)-3-quinolinecarbonitrile,
4-[(2,4-Dichloro-5-methoxyphenyl)amino]-7-[5-(4-ethyl-1-piperazinyl)-2-pyridinyl]-3-quinolinecarbonitrile,
4-({3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-7-[5-(1-pyridinyl]-3-quinolinecarbonitrile,
4-({3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-6-[5-(4-ethyl-1-piperazinyl)-2-pyridinyl]-3-quinolinecarbonitrile,
4-({3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-6-[5-(4-morpholinylmethyl)-2-pyridinyl]-3-quinolinecarbonitrile,
4-({3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-6-{5-[(4-methyl-1-piperazinyl)methyl]-2-pyridinyl}-3-quinolinecarbonitrile,
4-({3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-6-[6-(4-morpholinyl)-3-pyridinyl-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-7-[6-(4-morpholinyl)-3-pyridinyl-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-7-[2-(4-morpholinyl)-5-pyrimidinyl]-3-quinolinecarbonitrile,
4-{(3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-[5-(4-morpholinylmethyl)-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-7-{5-[(4-methyl-1-piperazinyl)methyl]-2-pyridinyl}-3-quinolinecarbonitrile,
4-{3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-{5-[(4-methyl-1-piperazinyl)methyl]-2-pyridinyl}-3-quinolinecarbonitrile,
4-{3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-[6-(4-morpholinyl]-3-pyridinyl]-3-quinolinecarbonitrile,
4-{3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-[2-(4-morpholinyl]-5-pyrimidinyl]-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-7-{5-[(4-hydroxy-1-piperidinyl)methyl]-3-thienyl}-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-7-{6-[4-(4-morpholinylmethyl)phenoxy]-3-pyridinyl)-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-7-(4-methoxyphenyl)-3-quinolinecarbonitrile,
4-{3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-[6-(4-ethyl-1-piperazinyl)-3-pyridinyl]-3-quinolinecarbonitrile,
4-{3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-[6-(4-methyl-1-piperazinyl)-3-pyridinyl]-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-7-[6-(4-ethyl-1-piperazinyl)-3-pyridinyl]-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-7-[6-(4-methyl-1-piperazinyl)-3-pyridinyl]-3-quinolinecarbonitrile,
4-{3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-[6-(4-morpholinylmethyl)-2-pyridinyl]-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-7-[6-(4-morpholinylmethyl)-2-pyridinyl]-3-quinolinecarbonitrile,
4-{3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-{6-[(4-ethyl-1-piperazinyl)methyl]2-pyridinyl}-3-quinolinecarbonitrile,
4-{3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-{6-[(4-methyl-1-piperazinyl)methyl]-2-pyridinyl}-3-quinolinecarbonitrile,
4-((3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-4-(4-morpholinylmethyl)-2-pyridinyl]-3-quinolinecarbonitrile,
4-[(2,4-Dichloro-5-methoxyphenyl)amino]-7-[4-(4-morpholinylmethyl)-2-pyridinyl]-3-quinolinecarbonitrile,
4-({3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-7-{4-[(4-ethyl-1-piperazinyl)methyl]-2-pyridinyl}-3-quinolinecarbonitrile,
4-({3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-7-{4-[(4-methyl-1-piperazinyl)methyl]-2-pyridinyl}-3-quinolinecarbonitrile,
4-({3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-7-[3-(4-morpholinylmethyl)-2-pyridinyl]-3-quinolinecarbonitrile,
4-({3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-7-{3-[(4-ethyl-1-piperazinyl)methyl]-2-pyridinyl}-3-quinolinecarbonitrile,
4-({3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-7-{3-[(4-methyl-1-piperazinyl)methyl]-2-pyridinyl}-3-quinolinecarbonitrile,
4-({3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-7-{6-[4-(1-pyrrolidinyl)-1-piperidinyl]-3-pyridinyl}-3-quinolinecarbonitrile,
4-({3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-7-[6-(1-piperidinyl)-3-pyridinyl]-3-quinolinecarbonitrile,
4-({3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-7-{6-[(2-methoxyethyl)(methyl)amino]3-pyridinyl}-3-quinolinecarbonitrile,
Ethyl 1-{5-[4-({3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-3-cyano-7-quinolinyl]-2-pyridinyl}-4-piperidinecarboxylate,
4-({3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-7-[6-(4-hydroxy-1-piperidinyl)-3-pyridinyl]-3-quinolinecarbonitrile,
4-({3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-7-{6-[4-(2-hydroxyethyl)-1-piperazinyl]-3-pyridinyl}-3-quinolinecarbonitrile,
4-({3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-7-{6-[(2-hydroxyethyl)(methyl)amino]-3-pyridinyl}-3-quinolinecarbonitrile,
4-({3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-7-(5-{[4-(2-hydroxyethyl)-1-piperazinyl]-methyl}-2-pyridinyl)-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-7-{4-[(4-methyl-1-piperazinyl)methyl]phenyl}-3-quinolinecarbonitrile,
4-({3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-7-(5-thiomorpholinylmethyl)-2-pyridinyl]-3-quinolinecarbonitrile,
4-({3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-7-{6-[(4-ethyl-1-piperazinyl)methyl]-3-pyridinyl}-3-quinolinecarbonitrile,
4-({3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-7-{6-[(4-methyl-1-piperazinyl)methyl]-3-pyridinyl}-3-quinolinecarbonitrile,
4-({3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-7-(6-formyl-3-pyridinyl)-3-quinolinecarbonitrile,
4-({3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-7-{6-[(4-hydroxy-1-piperidinyl)methyl]-3-pyridinyl)-3-quinolinecarbonitrile,
4-({3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-7-[6-(1-piperidinylmethyl)-3-pyridinyl]-3-quinolinecarbonitrile,
4-({3-Chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-7-{6-[(4-isopropyl-1-piperazinyl)methyl]-3-pyridinyl}-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-7-[1-methyl-2-(4-morpholinylmethyl)-1H-imidazol-5-yl]-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-7-{1-methyl-2-[(4-methyl-1-piperazinyl)methyl]-1H-imidazol-5-yl}-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-7-(2-formyl-1-methyl-1H-imidazol-5-yl)-6-methoxy-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-7-[4-({[2-(2-pyridinyl)ethyl]amino}methyl)phenyl]-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-7-(4-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}phenyl)-3-quinolinecarbonitrile,
Methyl 1-{4-[3-cyano-4-(2,4-dichloro-5-methoxyanilino)-7-quinolinyl]benzyl}-4-piperidinecarboxylate,
4-(2,4-Dichloro-5-methoxyanilino)-6-methoxy-7-[1-methyl-2-(4-morpholinylmethyl)-1H-imidazol-5-yl]-3-quinolinecarbonitrile,
4-(2,4-Dichloro-5-methoxyanilino)-6-methoxy-7-{1-methyl-2-[(4-methyl-1-piperazinyl)methyl]-1H-imidazol-5-yl}-3-quinolinecarbonitrile,
4-(2-Chloro-5-methoxy-4-methylanilino)-7-[4-(4-morpholinylmethyl)phenyl]-3-quinolinecarbonitrile,
4-(2-Chloro-4-fluoro-5-methoxyanilino)-7-[(4-(4-morpholinylmethyl)phenyl]-3-quinolinecarbonitrile,
4-(2-Chloro-5-methoxyanilino)-7-[4-(4-morpholinylmethyl)phenyl]-3-quinolinecarbonitrile,
1-{4-[3-Cyano-4-(2,4-dichloro-5-methoxyanilino)-7-quinolinyl]benzyl}-4-piperidinecarboxylic acid,
4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-{4-[(4-methyl-1-piperazinyl)methyl]phenyl}-3-quinolinecarbonitrile,
Additionally, preferred compounds of the invention or a pharmaceutically acceptable salt thereof are:
4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-[4-({[2-(dimethylamino)ethyl]amino}methyl)phenyl]-3-quinolinecarbonitrile,
4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-(4-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}phenyl)-3-quinolinecarbonitrile,
4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-(4-{[(4-pyridinylmethyl)amino]methyl}phenyl)-3-quinolinecarbonitrile,
4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-{4[(dimethylamino)methyl]phenyl}-3-quinolinecarbonitrile,
4-{3-chloro-4-[(1-methyl-1H-imidazol-2-y)sulfanyl]anilino})-7-(4-{[(2-hydroxyethyl)amino]methyl}phenyl)-3-quinolinecarbonitrile,
4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-[4-({[3-(4-morpholinyl)propyl]amino}methyl)phenyl]-3-quinolinecarbonitrile,
4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-{4-[(4-ethyl-1-piperazinyl)methyl]phenyl}-3-quinolinecarbonitrile,
4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-(4-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}phenyl)-3-quinolinecarbonitrile,
4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-{3-[(4-hydroxy-1-piperidinyl)methyl]phenyl}-3-quinolinecarbonitrile,
4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-[3-({[2-dimethylamino)ethyl]amino}methyl)phenyl]-3-quinolinecarbonitrile,
4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-(3-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}phenyl)-3-quinolinecarbonitrile,
4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-(3-{[(4-pyridinylmethyl)amino]methyl}phenyl)-3-quinolinecarbonitrile,
4-{3-chloro-4-(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-{3-[(dimethylamino)methyl]phenyl}-3-quinolinecarbonitrile,
4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-[3-(4-morpholinylmethyl)phenyl]-3-quinolinecarbonitrile,
4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-(3-{[(2-hydroxyethyl)amino]methyl}phenyl)-3-quinolinecarbonitrile,
4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-{3-[(4-methyl-1-piperazinyl)methyl]phenyl}-3-quinolinecarbonitrile,
4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-[3-({[3-(4-morpholinyl)propyl]amino}methyl)phenyl]-3-quinolinecarbonitrile,
4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-[3-(1-piperidinylmethyl)phenyl]3-quinolinecarbonitrile,
4-{3-chloro-4-[(1-methyl-1-imidazol-2-yl)sulfanyl]anilino}-7-{3-[(4-ethyl-1-piperazinyl)methyl]phenyl}-3-quinolinecarbonitrile,
4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-(3-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}phenyl)-3-quinolinecarbonitrile,
4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-{5-[(4-hydroxy-1-piperidinyl)methyl]-2-furyl}-3-quinolinecarbonitrile,
4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-[5-({[2-(dimethylamino)ethyl]amino}methyl)-2-furyl]-3-quinolinecarbonitrile,
4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-(5-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}-2-furyl)-3-quinolinecarbonitrile,
4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-(5-{[(2-hydroxyethyl)amino]methyl-2-furyl)-3-quinolinecarbonitrile,
4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-{5-[(4-methyl-1-piperazinyl)methyl]-2-furyl}-3-quinolinecarbonitrile,
4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-[5-({[3-(4-morpholinyl)propyl]amino}methyl)-2-furyl]-3-quinolinecarbonitrile,
4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-[5-({[2-(dimethylamino)ethyl]amino}methyl)-2-thienyl]-3-quinolinecarbonitrile,
4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-(5-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}-2-thienyl)-3-quinolinecarbonitrile,
4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-(5-{[(2-hydroxyethyl)amino]methyl}-2-thienyl)-3-quinolinecarbonitrile,
4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-[5-({[3-(4-morpholinyl)propyl]amino}methyl)-2-thienyl]-3-quinolinecarbonitrile,
4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-{5-[(4-ethyl-1-piperazinyl)methyl]-2-thienyl}-3-quinolinecarbonitrile,
4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-[5-({[2-(dimethylamino)ethyl]amino}methyl)-2-pyridinyl]-3-quinolinecarbonitrile,
4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-[5-({[3-(4-morpholinyl)propyl]amino}methyl)-2-pyridinyl]-3-quinolinecarbonitrile,
4-(2,4-dimethylanilino)-7-{4-[(4-hydroxy-1-piperidinyl)methyl]phenyl}-3-quinolinecarbonitrile,
7-[4-({[2-(dimethylamino)ethyl]amino}methyl)phenyl]-4-(2,4-dimethylanilino)-3-quinolinecarbonitrile,
4-(2,4-dimethylanilino)-7-(4-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}phenyl)-3-quinolinecarbonitrile,
4-(2,4-dimethylanilino)-7-(4-{[(4-pyridinylmethyl)amino]methyl}phenyl)-3-quinolinecarbonitrile,
4-(2,4-dimethylanilino)-7-[4-({[2-(1H-imidazol-4-yl)ethyl]amino}methyl)phenyl]-3-quinolinecarbonitrile,
4-(2,4-dimethylanilino)-7-[4-(4-morpholinylmethyl)phenyl]-3-quinolinecarbonitrile,
4-(2,4-dimethylanilino)-7-(4-{[(2-hydroxyethyl)amino]methyl}phenyl)-3-quinolinecarbonitrile,
4-(2,4-dimethylanilino)-7-{4-[(4-methyl-1-piperazinyl)methyl]phenyl}-3-quinolinecarbonitrile,
4-(2,4-dimethylanilino)-7-[4-({[3-(4-morpholinyl)propyl]amino}methyl)phenyl]-3-quinolinecarbonitrile,
4-(2,4-dimethylanilino)-7-(4-(1-piperidinylmethyl)phenyl]-3-quinolinecarbonitrile,
4-(2,4-dimethylanilino)-7-{4-[(4-ethyl-1-piperazinyl)methyl]phenyl}-3-quinolinecarbonitrile,
4-(2,4-dimethylanilino)-7-(4-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}phenyl)-3-quinolinecarbonitrile,
4-(2,4-dimethylanilino)-7-{3-[(4-hydroxy-1-piperidinyl)methyl]phenyl}-3-quinolinecarbonitrile,
7-[3-({[2-(dimethylamino)ethyl]amino}methyl)phenyl]-4-(2,4-dimethylanilino)-3-quinolinecarbonitrile,
4-(2,4-dimethylanilino)-7-(3-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}phenyl)-3-quinolinecarbonitrile,
4-(2,4-dimethylanilino)-7-(3-{[(4-pyridinylmethyl)amino]methyl}phenyl)-3-quinolinecarbonitrile,
4-(2,4-dimethylanilino)-7-[3-({[2-(1H-imidazol-4-yl)ethyl]amino}methyl)phenyl]-3-quinolinecarbonitrile,
4-(2,4-dimethylanilino)-7-[3-(4-morpholinylmethyl)phenyl]-3-quinolinecarbonitrile,
4-(2,4-dimethylanilino)-7-(3-{[(2-hydroxyethyl)amino]methyl}phenyl)-3-quinolinecarbonitrile,
4-(2,4-dimethylanilino)-7-{3-[(4-methyl-1-piperazinyl)methyl]phenyl}-3-quinolinecarbonitrile,
4-(2,4-dimethylanilino)-7-[3-({[3-(4-morpholinyl)propyl]amino}methyl)phenyl]-3-quinolinecarbonitrile,
4-(2,4-dimethylanilino)-7-[3-(1-piperidinylmethyl)phenyl]-3-quinolinecarbonitrile,
4-(2,4-dimethylanilino)-7-{3-[(4-ethyl-1-piperazinyl)methyl]phenyl}-3-quinolinecarbonitrile,
4-(2,4-dimethylanilino)-7-(3-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}phenyl)-3-quinolinecarbonitrile,
4-(2,4-dimethylanilino)-7-{5-[(4-hydroxy-1-piperidinyl)methyl]-2-furyl}-3-quinolinecarbonitrile,
7-[5-({[2-(dimethylamino)ethyl]amino}methyl)-2-furyl]-4-(2,4-dimethylanilino)-3-quinolinecarbonitrile,
4-(2,4-dimethylanilino)-7-(5-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}-2-furyl)-3-quinolinecarbonitrile,
4-(2,4-dimethylanilino)-7-(5-{[(4-pyridinylmethyl)amino]methyl}-2-furyl)-3-quinolinecarbonitrile,
4-(2,4-dimethylanilino)-7-[5-({[2-(1H-imidazol-4-yl)ethyl]amino}methyl)-2-furyl]3-quinolinecarbonitrile,
4-(2,4-dimethylanilino)-7-[5-(4-morpholinylmethyl)-2-furyl]-3-quinolinecarbonitrile,
4-(2,4-dimethylanilino)-7-(5-{[(2-hydroxyethyl)amino]methyl}-2-furyl)-3-quinolinecarbonitrile,
4-(2,4-dimethylanilino)-7-{5-[(4-methyl-1-piperazinyl)methyl]-2-furyl}-3-quinolinecarbonitrile,
4-(2,4-dimethylanilino)-7-[5-(1-piperidinylmethyl)-2-furyl]-3-quinolinecarbonitrile,
4-(2,4-dimethylanilino)-7-{5-[(4-ethyl-1-piperazinyl)methyl]-2-furyl}-3-quinolinecarbonitrile,
4-(2,4-dimethylanilino)-7-(5-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}-2-furyl)-3-quinolinecarbonitrile,
4-(2,4-dimethylanilino)-7-{5-[(4-hydroxy-1-piperidinyl)methyl]-2-thienyl}-3-quinolinecarbonitrile,
7-[5-({[2-(dimethylamino)ethyl]amino}methyl)-2-thienyl]-4-(2,4-dimethylanilino)-3-quinolinecarbonitrile,
4-(2,4-dimethylanilino)-7-(5-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl)-2-thienyl}-3-quinolinecarbonitrile,
4-(2,4-dimethylanilino)-7-(5-{[(4-pyridinylmethyl)amino]methyl}-2-thienyl)-3-quinolinecarbonitrile,
4-(2,4-dimethylanilino)-7-[5-({[2-(1H-imidazol-4-yl)ethyl]amino}methyl)-2-thienyl]-3-quinolinecarbonitrile,
4-(2,4-dimethylanilino)-7-[5-(4-morpholinylmethyl)-2-thienyl]-3-quinolinecarbonitrile,
4-(2,4-dimethylanilino)-7-(5-{[(2-hydroxyethyl)amino]methyl}-2-thienyl)-3-quinolinecarbonitrile,
4-(2,4-dimethylanilino)-7-{5-[(4-methyl-1-piperazinyl)methyl]-2-thienyl}-3-quinolinecarbonitrile,
4-(2,4-dimethylanilino)-7-{5-[(4-ethyl-1-piperazinyl)methyl]-2-thienyl}-3-quinolinecarbonitrile,
4-(2,4-dimethylanilino)-7-(5-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}-2-thienyl)-3-quinolinecarbonitrile,
4-(2,4-dimethylanilino)-7-{5-[(4-hydroxy-1-piperidinyl)methyl]-3-thienyl}-3-quinolinecarbonitrile,
7-[5-({[2-(dimethylamino)ethyl]amino}methyl)-3-thienyl]-4-(2,4-dimethylanilino)-3-quinolinecarbonitrile,
4-(2,4-dimethylanilino)-7-(5-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}-3-thienyl)-3-quinolinecarbonitrile,
4-(2,4-dimethylanilino)-7-(5-{[(4-pyridinylmethyl)amino]methyl}-3-thienyl)-3-quinolinecarbonitrile,
4-(2,4-dimethylanilino)-7-[5-{[2-(1H-imidazol-4-yl)ethyl]amino}methyl)-3-thienyl]-3-quinolinecarbonitrile,
4-(2,4-dimethylanilino)-7-[5-(4-morpholinylmethyl)-3-thienyl]-3-quinolinecarbonitrile,
4-(2,4-dimethylanilino)-7-(5-{[(2-hydroxyethyl)amino]methyl}-3-thienyl)-3-quinolinecarbonitrile,
4-(2,4-dimethylanilino)-7-{5-[(4-methyl-1-piperazinyl)methyl]-3-thienyl}-3-quinolinecarbonitrile,
4-(2,4-dimethylanilino)-7-[5-({[3-(4-morpholinyl)propyl]amino}methyl)-3-thienyl]-3-quinolinecarbonitrile,
4-(2,4-dimethylanilino)-7-[5-(1-piperidinylmethyl)-3-thienyl]-3-quinolinecarbonitrile,
4-(2,4-dimethylanilino)-7-{5-[(4-ethyl-1-piperazinyl)methyl]-3-thienyl}-3-quinolinecarbonitrile,
4-(2,4-dimethylanilino)-7-(5-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}-3-thienyl)-3-quinolinecarbonitrile,
4-(4-bromo-2-chloro-6-methylanilino)-7-{5-[(4-hydroxy-1-piperidinyl)methyl]-2-furyl}-3-quinolinecarbonitrile,
4-(4-bromo-2-chloro-6-methylanilino)-7-[5-({[2-(dimethylamino)ethyl]amino}methyl)-2-furyl]-3-quinolinecarbonitrile,
4-(4-bromo-2-chloro-6-methylanilino)-7-(5-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}-2-furyl)-3-quinolinecarbonitrile,
4-(4-bromo-2-chloro-6-methylanilino)-7-(5-{[(4-pyridinylmethyl)amino]methyl}-2-furyl)-3-quinolinecarbonitrile,
4-(4-bromo-2-chloro-6-methylanilino)-7-[5-({[2-(1H-imidazol-4-yl)ethyl]amino}methyl)-2-furyl]-3-quinolinecarbonitrile,
4-(4-bromo-2-chloro-6-methylanilino)-7-[5-(4-morpholinylmethyl)-2-furyl]-3-quinolinecarbonitrile,
4-(4-bromo-2-chloro-6-methylanilino)-7-(5-{[(2-hydroxyethyl)amino]methyl}-2-furyl)-3-quinolinecarbonitrile,
4-(4-bromo-2-chloro-6-methylanilino)-7-{5-[(4-methyl-1-piperazinyl)methyl]-2-furyl}-3-quinolinecarbonitrile,
4-(4-bromo-2-chloro-6-methylanilino)-7-[5-({[3-(4-morpholinyl)propyl]amino}methyl)-2-furyl]-3-quinolinecarbonitrile,
4-(4-bromo-2-chloro-6-methylanilino)-7-[5-(1-piperidinylmethyl)-2-furyl]-3-quinolinecarbonitrile,
4-(4-bromo-2-chloro-6-methylanilino)-7-{5-[(4-ethyl-1-piperazinyl)methyl]-2-furyl}-3-quinolinecarbonitrile,
4-(4-bromo-2-chloro-6-methylanilino)-7-(5-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}-2-furyl)-3-quinolinecarbonitrile,
4-(4-bromo-2-chloro-6-methylanilino)-7-{5-[(4-hydroxy-1-piperidinyl)methyl]-2-thienyl}-3-quinolinecarbonitrile,
4-(4-bromo-2-chloro-6-methylanilino)-7-[5-({[2-(dimethylamino)ethyl]amino}methyl)-2-thienyl]-3-quinolinecarbonitrile,
4-(4-bromo-2-chloro-6-methylanilino)-7-(5-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}-2-thienyl)-3-quinolinecarbonitrile,
4-(4-bromo-2-chloro-6-methylanilino)-7-(5-{[(4-pyridinylmethyl)amino]methyl}-2-thienyl)-3-quinolinecarbonitrile,
4-(4-bromo-2-chloro-6-methylanilino)-7-[5-{[2-(1H-imidazol-4-yl)ethyl]amino}methyl)-2-thienyl]-3-quinolinecarbonitrile,
4-(4-bromo-2-chloro-6-methylanilino)-7-[5-(4-morpholinylmethyl)-2-thienyl]-3-quinolinecarbonitrile,
4-(4-bromo-2-chloro-6-methylanilino)-7-(5-{[(2-hydroxyethyl)amino]methyl}-2-thienyl)-3-quinolinecarbonitrile,
4-(4-bromo-2-chloro-6-methylanilino)-7-{5-[(4-methyl-1-piperazinyl)methyl]-2-thienyl}-3-quinolinecarbonitrile,
4-(4-bromo-2-chloro-6-methylanilino)-7-[5-({[3-(4-morpholinyl)propyl]amino}methyl)-2-thienyl-3-quinolinecarbonitrile,
4-(4-bromo-2-chloro-6-methylanilino)-7-[5-(1-piperidinylmethyl)-2-thienyl]-3-quinolinecarbonitrile,
4-({3-chloro-4xe2x80x2-[(4-hydroxy-1-piperidinyl)methyl]-5-methyl[1,1xe2x80x2-biphenyl]-4-yl)amino)-7-{4-[(4-hydroxy-1-piperidinyl)methyl]phenyl}-3-quinolinecarbonitrile,
4-{[3-chloro-4xe2x80x2-({[2-(dimethylamino)ethyl]amino}methyl)-5-methyl[1,1xe2x80x2-biphenyl]-4-yl]amino}-7-({[2-(dimethylamino)ethyl]amino}methyl)phenyl]-3-quinolinecarbonitrile,
4-[(3-chloro-5-methyl-4xe2x80x2-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}[(1,1xe2x80x2-biphenyl]-4-yl)amino]-7-(4-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}phenyl)-3-quinolinecarbonitrile,
4-{[3-chloro-5-methyl-4xe2x80x2-(4-morpholinylmethyl)[1,1xe2x80x2-biphenyl]-4-yl]amino}-7-[4-morpholinylmethyl)phenyl]-3-quinolinecarbonitrile,
4-[(3-chloro-4xe2x80x2-([(2-hydroxyethyl)amino]methyl}-5-methyl[1,1xe2x80x2-biphenyl]-4-yl)amino]-7-(4-{[(2-hydroxyethyl)amino]methyl}phenyl)-3-quinolinecarbonitrile,
4-({3-chloro-5-methyl-4xe2x80x2-[(4-methyl-1-piperazinyl)methyl][1,1xe2x80x2-biphenyl]-4-yl)amino)-7-{4-[(4-methyl-1-piperazinyl)methyl]phenyl}-3-quinolinecarbonitrile,
4-{[3-chloro-5-methyl-4xe2x80x2-({[3-(4-morpholinyl)propyl]amino}methyl)[1,1xe2x80x2-biphenyl]-4-yl]amino}-7-[4-({[3-(4-morpholinyl)propyl]amino}methyl)phenyl]-3-quinolinecarbonitrile,
4-{[3-chloro-5-methyl-4xe2x80x2-(1-piperidinylmethyl)[1,1xe2x80x2-biphenyl)-4-yl]amino}-7-[4-({[3-(4-morpholinyl)propyl]amino}methyl)phenyl]-3-quinolinecarbonitrile,
4-({3-chloro-4xe2x80x2-[(4-ethyl-1-piperazinyl)methyl]-5-methyl[1,1xe2x80x2-biphenyl]-4-yl}amino]-7-{4-[(4-ethyl-1-piperazinyl)methyl]phenyl}-3-quinolinecarbonitrile,
4-[(3-chloro-4xe2x80x2-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}-5-methyl[1,1xe2x80x2-biphenyl]-4-yl)amino]-7-(4-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}phenyl)-3-quinolinecarbonitrile,
4-({(3-chloro-3xe2x80x2-[(4-hydroxy-1-piperidinyl)methyl]-5-methyl[1,1xe2x80x2-biphenyl]-4-yl}amino)-7-{3-[(4-hydroxy-1-piperidinyl)methyl]phenyl}-3-quinolinecarbonitrile,
4-{[3-chloro-3xe2x80x2-({[2-(dimethylamino)ethyl]amino}methyl)-5-methyl[1,1xe2x80x2-biphenyl]-4-yl]amino}-7-[3-({[2-(dimethylamino)ethyl]amino}methyl)phenyl]-3-quinolinecarbonitrile,
4-[(3-chloro-5-methyl-3xe2x80x2-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}[1,1xe2x80x2-biphenyl]-4-yl)amino]-7-(3-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}phenyl)-3-quinolinecarbonitrile,
4-[(3-chloro-5-methyl-3xe2x80x2-{[(4-pyridinylmethyl)amino]methyl}[1,1xe2x80x2-biphenyl]-4-yl)amino]-7-(3-{[(4-pyridinylmethyl)amino]methyl}phenyl)-3-quinolinecarbonitrile,
4-{[3-chloro-3xe2x80x2-({[2-(1H-imidazol-4-yl)ethyl]amino}methyl)-5-methyl[1,1xe2x80x2biphenyl]-4-yl]amino}-7-[3-({[2-(1H-imidazol-4-yl)ethyl]amino}methyl)phenyl]-3-quinolinecarbonitrile,
4-{[3-chloro-5-methyl-3xe2x80x2-(4-morpholinylmethyl)[1,1xe2x80x2-biphenyl]-4-yl]amino}-7-[3-(4-morpholinylmethyl)phenyl]-3-quinolinecarbonitrile,
4-[(3-chloro-3xe2x80x2-{[(2-hydroxyethyl)amino]methyl}-5-methyl[1,1xe2x80x2-biphenyl]-4-yl)amino]-7-{[(2-hydroxyethyl)amino]methyl}phenyl)-3-quinolinecarbonitrile,
4-({3-chloro-5-methyl-3xe2x80x2-[(4-methyl-1-piperazinyl)methyl][1,1xe2x80x2-biphenyl]-4-yl}amino)-7-{3-[(4-methyl-1-piperazinyl)methyl]phenyl}-3-quinolinecarbonitrile,
4-{[3-chloro-5-methyl-3xe2x80x2-({[3-(4-morpholinyl)propyl]amino}methyl)[1,1xe2x80x2-biphenyl]-4-yl]amino}-7-[3-({[3-(4-morpholinyl)propyl]amino}methyl)phenyl]-3-quinolinecarbonitrile,
4-{[3-chloro-5-methyl-3xe2x80x2-(1-piperidinylmethyl)[1,1xe2x80x2-biphenyl]-4-yl]amino}-7-[3-(1-piperidinylmethyl)phenyl]-3-quinolinecarbonitrile,
4-({3-chloro-3xe2x80x2-[(4-ethyl-1-piperazinyl)methyl]-5-methyl[1,1xe2x80x2-biphenyl]-4-yl}amino)-7-{3-[(4-ethyl-1-piperazinyl)methyl]phenyl}-3-quinolinecarbonitrile,
4-[(3-chloro-3xe2x80x2-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}-5-methyl[1,1xe2x80x2-biphenyl]-4-yl)amino]-7-(3-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}phenyl)-3-quinolinecarbonitrile,
4-(2-chloro-4-[5-({[2-(dimethylamino)ethyl]amino}methyl)-3-thienyl]-6-methylanilino}-7-[5-({[2-(dimethylanilino)ethyl]amino}methyl)-3-thienyl]-3-quinolinecarbonitrile,
4-[2-chloro-6-methyl-4-(5-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}-3-thienyl)anilino]-7-(5-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}-3-thienyl)-3-quinolinecarbonitrile,
4-[2-chloro-6-methyl-4-(5-{[(4-pyridinylmethyl)amino]methyl}-3-thienyl)anilino]7-(5-{[(4-piperidinylmethyl)amino]methyl}-3-thienyl)-3-quinolinecarbonitrile,
4-{2-chloro-4-[5-({[2-(1H-imidazol-4-yl)ethyl]amino}methyl)-3-thienyl]-6-methylanilino-7-[5-({[2-(1H-imidazol-4-yl)ethyl]amino}methyl)-3-thienyl]-3-quinolinecarbonitrile,
4-(2-chloro-6-methyl-4-[5-(4-morpholinylmethyl)-3-thienyl]anilino}-7-[5-(4-morpholinylmethyl)-3-thienyl]-3-quinolinecarbonitrile,
4-(2-chloro-6-methyl-4-{5-[(4-methyl-1-piperazinyl)methyl]-3-thienyl}anilino)-7-{5-[(4-methyl-1-piperazinyl)methyl]-3-thienyl}-3-quinolinecarbonitrile,
4-{2-chloro-6-methyl-4-[5-({[3-(4-morpholinyl)propyl]amino}methyl)-3-thienyl]anilino}-7-[5-({[3-(4-morpholinyl)propyl]amino}methyl)-3-thienyl]-3-quinolinecarbonitrile,
4-{2-chloro-6-methyl-4-[5-(1-piperidinylmethyl)-3-thienyl]anilino}-7-[5-(1-piperidinylmethyl)-3-thienyl]-3-quinolinecarbonitrile,
4-(2-chloro-4-{5-[(4-ethyl-1-piperazinyl)methyl]-3-thienyl}-6-methylanilino)-7-{5-[(4-ethyl-1-piperazinyl)methyl]-3-thienyl}-3-quinolinecarbonitrile,
4-[2-chloro-4-(5-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}-3-thienyl)-6-methylanilino]-7-(5-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}-3-thienyl)-3-quinolinecarbonitrile,
4-[(3-chloro-4-phenoxyphenyl)amino]-7-[4-({[3-(4-morpholinyl)propyl]amino}methyl)phenyl]-3-quinolinecarbonitrile,
4-[(3-chloro-4-phenoxyphenyl)amino]-7-{4-[(4-ethyl-1-piperazinyl)methyl]phenyl}-3-quinolinecarbonitrile,
4-[(3-chloro-4-phenoxyphenyl)amino]-7-(4-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}phenyl)-3-quinolinecarbonitrile,
4-[(3-chloro-4-phenoxyphenyl)amino]-7-[3-({[2-(dimethylamino)ethyl]amino}methyl)phenyl]-3-quinolinecarbonitrile,
4-[(3-chloro-4-phenoxyphenyl)amino]-7-(3-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}phenyl)-3-quinolinecarbonitrile,
4-[(3-chloro-4-phenoxyphenyl)amino]-7-(3-{[(4-pyridinylmethyl)amino]methyl}phenyl)-3-quinolinecarbonitrile,
4-[(3-chloro-4-phenoxyphenyl)amino]-7-[3-({[3-(4-morpholinyl)propyl]amino}methyl)phenyl]-3-quinolinecarbonitrile,
4-[(3-chloro-4-phenoxyphenyl)amino]-7-{3-[(4-ethyl-1-piperazinyl)methyl]phenyl}-3-quinolinecarbonitrile,
4-[(3-chloro-4-phenoxyphenyl)amino]-7-{5-[(4-hydroxy-1-piperidinyl)methyl]-2-furyl}-3-quinolinecarbonitrile,
4-[(3-chloro-4-phenoxyphenyl)amino]-7-[5-({[2-(dimethylamino)ethyl]amino}methyl)-2-furyl]-3-quinolinecarbonitrile,
4-[(3-chloro-4-phenoxyphenyl)amino]-7-(5-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}-2-furyl)-3-quinolinecarbonitrile,
4-[(3-chloro-4-phenoxyphenyl)amino]-7-(5-{[(4-pyridinylmethyl)amino]methyl}-2-furyl)-3-quinolinecarbonitrile,
4-[(3-chloro-4-phenoxyphenyl)amino]-7-[5-({[2-(1H-imidazol-4-yl)ethyl]amino}methyl)-2-furyl]-3-quinolinecarbonitrile,
4-[(3-chloro-4-phenoxyphenyl)amino]-7-5[-(4-morpholinylmethyl)-2-furyl]-3-quinolinecarbonitrile,
4-[(3-chloro-4-phenoxyphenyl)amino]-7-(5-{[(2-hydroxyethyl)amino]methyl}-2-furyl)-3-quinolinecarbonitrile,
4-[(3-chloro-4-phenoxyphenyl)amino]-7-{5-[(4-methyl-1-piperazinyl)methyl]-2-furyl}-3-quinolinecarbonitrile,
4-[(3-chloro-4-phenoxyphenyl)amino]-7-[5-({[3-(4-morpholinyl)propyl]amino}methyl)-2-furyl]-3-quinolinecarbonitrile,
4-[(3-chloro-4-phenoxyphenyl)amino]-7-[5-(1-piperidinylmethyl)-2-furyl]-3-quinolinecarbonitrile,
4-[(3-chloro-4-phenoxyphenyl)amino]-7-{5-[(4-ethyl-1-piperazinyl)methyl]-2-furyl}-3-quinolinecarbonitrile,
4-[(3-chloro-4-phenoxyphenyl)amino]-7-(5-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}-2-furyl)-3-quinolinecarbonitrile,
4-[(3-chloro-4-phenoxyphenyl)amino]-7-[5-({[2-(dimethylamino)ethyl]amino}methyl)-2-thienyl]-3-quinolinecarbonitrile,
4-[(3-chloro-4-phenoxyphenyl)amino]-7-(5-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}-2-thienyl)-3-quinolinecarbonitrile,
4-[(3-chloro-4-phenoxyphenyl)amino]-7-(5-{[(4-pyridinylmethyl)amino]methyl}-2-thienyl)-3-quinolinecarbonitrile,
4-[(3-chloro-4-phenoxyphenyl)amino]-7-[5-(4-morpholinylmethyl)-2-thienyl]-3-quinolinecarbonitrile,
4-[(3-chloro-4-phenoxyphenyl)amino]-7-{5-[(4-methyl-1-piperazinyl)methyl]-2-thienyl}-3-quinolinecarbonitrile,
4-[(3-chloro-4-phenoxyphenyl)amino]-7-{5-[(4-ethyl-1-piperazinyl)methyl]-2-thienyl}-3-quinolinecarbonitrile,
4-[(3-chloro-4-phenoxyphenyl)amino]-7-{5-[(4-hydroxy-1-piperidinyl)methyl]-3-thienyl}-3-quinolinecarbonitrile,
4-[(3-chloro-4-phenoxyphenyl)amino]-7-[5-({[2-(dimethylamino)ethyl]amino}methyl)-3-thienyl]-3-quinolinecarbonitrile,
4-[(3-chloro-4-phenoxyphenyl)amino]-7-(5-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}-3-thienyl)-3-quinolinecarbonitrile,
4-[(3-chloro-4-phenoxyphenyl)amino]-7-(5-{[(4-pyridinylmethyl)amino]methyl}-3-thienyl)-3-quinolinecarbonitrile,
4-[(3-chloro-4-phenoxyphenyl)amino]-7-[5-({[2-(1H-imidazol-4-yl)ethyl]amino}methyl)-3-thienyl]-3-quinolinecarbonitrile,
4-[(3-chloro-4-phenoxyphenyl)amino]-7-[5-(4-morpholinylmethyl)-3-thienyl]-3-quinolinecarbonitrile,
4-[(3-chloro-4-phenoxyphenyl)amino]-7-(5-{[(2-hydroxyethyl)amino]methyl}-3-thienyl)-3-quinolinecarbonitrile,
4-[(3-chloro-4-phenoxyphenyl)amino]-7-{5-[(4-methyl-1-piperazinyl)methyl]-3-thienyl}-3-quinolinecarbonitrile,
4-[(3-chloro-4-phenoxyphenyl)amino]-7-[5-({[3-(4-morpholinyl)propyl]amino}methyl)-3-thienyl]-3-quinolinecarbonitrile,
4-[(3-chloro-4-phenoxyphenyl)amino]-7-[5-(1-piperidinylmethyl)-3-thienyl]-3-quinolinecarbonitrile,
4-[(3-chloro-4-phenoxyphenyl)amino]-7-{5-[(4-ethyl-1-piperazinyl)methyl]-3-thienyl)-3-quinolinecarbonitrile,
4-[(3-chloro-4-phenoxyphenyl)amino]-7-(5-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}-3-thienyl)-3-quinolinecarbonitrile,
4-[(3-chloro-4-phenoxyphenyl)annoy]-7-[5-({[3-(4-morpholinyl)propyl]amino}methyl)-2-pyridinyl]-3-quinolinecarbonitrile,
4-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-{4-[(4-hydroxy-1-piperidinyl)methyl]phenyl}-3-quinolinecarbonitrile,
4-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-(4-{[(4-pyridinylmethyl)amino]methyl}phenyl)-3-quinolinecarbonitrile,
4-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-[4-({[2-(1H-imidazol-4-yl)ethyl]amino}methyl)phenyl]-3-quinolinecarbonitrile,
4-{[3-chloro-4-(phenylfanyl)phenyl]amino}-7-[4-(4-morpholinylmethyl)phenyl]-3-quinolinecarbonitrile,
4-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-(4-{[(2-hydroxyethyl)amino]methyl}phenyl)-3-quinolinecarbonitrile,
4-[3-chloro-4-(phenylsulfanyl)phenyl]amino)-7-{4-[(4-methyl-1-piperazinyl)methyl]phenyl}-3-quinolinecarbonitrile,
4-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-[4-({[3-(4-morpholinyl)propyl]amino}methyl)phenyl]-3-quinolinecarbonitrile,
4-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-{4-[(4-ethyl-1-piperazinyl)methyl]phenyl}-3-quinolinecarbonitrile,
4-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-(4-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}phenyl)-3-quinolinecarbonitrile,
4-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-{3-[(4-hydroxy-1-piperidinyl)methyl]phenyl}-3-quinolinecarbonitrile,
4-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-[3-({[2-(dimethylamino)ethyl]amino}methyl)phenyl]-3-quinolinecarbonitrile,
4-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-(3-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}phenyl)-3-quinolinecarbonitrile,
4-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-(3-{[(2-hydroxyethyl)amino]methyl}phenyl)-3-quinolinecarbonitrile,
4-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-[3-({[3-(4-morpholinyl)propyl]amino}methyl)phenyl]-3-quinolinecarbonitrile,
4-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-(3-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}phenyl)-3-quinolinecarbonitrile,
4-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-{5-[(4-hydroxy-1-piperidinyl)methyl]-2-furyl}-3-quinolinecarbonitrile,
4-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-[5-({[2-(dimethylamino)ethyl]amino}methyl)-2-furyl]-3-quinolinecarbonitrile,
4-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-(5-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}-2-furyl)-3-quinolinecarbonitrile,
4-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-(5-{[(4-pyridinylmethyl)amino]methyl}-2-furyl)-3-quinolinecarbonitrile,
4-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-[5-({[2-(1H-imidazol-4-yl)ethyl]methyl}-2-furyl]-3-quinolinecarbonitrile,
4-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-[5-(4-morpholinylmethyl)-2-furyl]3-quinolinecarbonitrile,
4-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-{5-[(2-hydroxyethyl)amino]methyl}-2-furyl)-3-quinolinecarbonitrile,
4-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-{5-[(4-methyl-1-piperazinyl)methyl]-2-furyl}-3-quinolinecarbonitrile,
4-[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-[5-({[3-(4-morpholinyl)propyl]amino}methyl)-2-furyl]-3-quinolinecarbonitrile,
4-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-{5-[(4-ethyl-1-piperazinyl)methyl]-2-furyl}-3-quinolinecarbonitrile,
4-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-[5-({[2-(dimethylamino)ethyl]amino}methyl)-2-thienyl]-3-quinolinecarbonitrile,
4-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-(5-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}-2-thienyl)-3-quinolinecarbonitrile,
4-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-[5-(4-morpholinylmethyl)-2-thienyl]-3-quinolinecarbonitrile,
4-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-{5-[(4-methyl-1-piperazinyl)methyl]-2-thienyl}-3-quinolinecarbonitrile,
4-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-[5-({[3-(4-morpholinyl)propyl]amino}methyl)-2-thienyl]-3-quinolinecarbonitrile,
4-[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-{5-[(4-ethyl-1-piperazinyl)methyl]-2-thienyl}-3-quinolinecarbonitrile,
4-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-{5-[(4-hydroxy-1-piperidinyl)methyl]-3-thienyl}-3-quinolinecarbonitrile,
4-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-[5-({[2-(dimethylamino)ethyl]amino}methyl)-3-thienyl]-3-quinolinecarbonitrile,
4-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-(5-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}-3-thienyl)-3-quinolinecarbonitrile,
4-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-(5-{[(4-pyridinylmethyl)amino]methyl}-3-thienyl)-3-quinolinecarbonitrile,
4-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-[5-({[2-(1H-imidazol-4-yl)ethyl]amino}methyl)-3-thienyl]-3-quinolinecarbonitrile,
4-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-[5-(4-morpholinylmethyl)-3-thienyl]-3-quinolinecarbonitrile,
4-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-(5-{[(2-hydroxyethyl)amino]methyl}-3-thienyl)-3-quinolinecarbonitrile,
4-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-{5-[(4-methyl-1-piperazinyl)methyl]-3-quinolinecarbonitrile,
4-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-[5-({[3-(4-morpholinyl)propyl]amino}methyl)-3-thienyl]-3-quinolinecarbonitrile,
4-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-[5-(1-piperidinylmethyl)-3-thienyl]-3-quinolinecarbonitrile,
4-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-{5-[(4-ethyl-1-piperazinyl)methyl]-3-thienyl}-3-quinolinecarbonitrile,
4-{[3-chloro-4-(phenylsulfanyl)phenyl]amino}-7-(5-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl-3-thienyl)-3-quinolinecarbonitrile,
4-{[3-chloro-4-(3-furylmethyl)phenyl]amino}-7-{4-[(4-hydroxy-1-piperidinyl)methyl]phenyl}-3-quinolinecarbonitrile,
4-{[3-chloro-4-(3-furylmethyl)phenyl]amino}-7-[4-({[2-(dimethylamino)ethyl]amino}methyl)phenyl]-3-quinolinecarbonitrile,
4-{[3-chloro-4-(3-furylmethyl)phenyl]amino}-7-(4-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}phenyl)-3-quinolinecarbonitrile,
4-{[3-chloro-4-(3-furylmethyl)phenyl]amino}-7-(4-{[(4-pyridinylmethyl)amino]methyl}phenyl)-3-quinolinecarbonitrile,
4-{[3-chloro-4-(3-furylmethyl)phenyl]amino}-7-[4-({[2-(1-imidazol-4-yl)ethyl]amino}methyl)phenyl]-3-quinolinecarbonitrile,
4-{[3-chloro-4-(3-furylmethyl)phenyl]amino}-7-[4-(4-morpholinylmethyl)phenyl]-3-quinolinecarbonitrile,
4-{[3-chloro-4-(3-furylmethyl)phenyl]amino}-7-(4-{[(2-hydroxyethyl)amino]methyl}phenyl)-3-quinolinecarbonitrile,
4-{[3-chloro-4-(3-furylmethyl)phenyl]amino}-7-{4-[(4-methyl-1-piperazinyl)methyl]phenyl}-3-quinolinecarbonitrile,
4-{[3-chloro-4-(3-furylmethyl)phenyl]amino}-7-[4-({[3-(4-morpholinyl)propyl]amino}methyl)phenyl]-3-quinolinecarbonitrile,
4-{[3-chloro-4-(3-furylmethyl)phenyl]amino}-7-[4-(1-piperidinylmethyl)phenyl]-3-quinolinecarbonitrile,
4-{[3-chloro-4-(3-furylmethyl)phenyl]amino}-7-{4-[(4-ethyl-1-piperazinyl)methyl]phenyl}-3-quinolinecarbonitrile,
4-[3-chloro-4-(3-furylmethyl)phenyl]amino}-7-(4-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}phenyl)-3-quinolinecarbonitrile,
4-{[4-(3-furylmethyl)phenyl]amino}-7-(4-{[(4-pyridinylmethyl)amino]methyl}phenyl)-3-quinolinecarbonitrile,
4-{[4-(3-furylmethyl)phenyl]amino}-7-[4-({[2-(1H-imidazol-4-yl)ethyl]amino}methyl)phenyl]-3-quinolinecarbonitrile,
4-{[4-(3-furylmethyl)phenyl]amino}-7-[4-(4-morpholinylmethyl)phenyl]-3-quinolinecarbonitrile,
4-{[4-(3-furylmethyl)phenyl]amino}-7-(4-{[(2-hydroxyethyl)amino]methyl}phenyl)-3-quinolinecarbonitrile,
4-{[4-(3-furylmethyl)phenyl]amino}-7-{4-[(4-methyl-1-piperazinyl)methyl]phenyl}-3-quinolinecarbonitrile,
4-{[4-(3-furylmethyl)phenyl]amino}-7-[4-(1-piperidinylmethyl)phenyl]-3-quinolinecarbonitrile,
7-{4-[(4-ethyl-1-piperazinyl)methyl]phenyl}-4-{[4-(3-furylmethyl)phenyl]amino}-3-quinolinecarbonitrile,
4-{[4-(3-furylmethyl)phenyl]amino}-7-(4-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}phenyl)-3-quinolinecarbonitrile,
4-{[4-(3-furylmethyl)phenyl]amino}-7-{3-[(4-hydroxy-1-piperidinyl)methyl]phenyl}-3-quinolinecarbonitrile,
7-[3-({[2-(dimethylamino)ethyl]amino}methyl)phenyl]-4-{[4-(3-furylmethyl)phenyl]amino}-3-quinolinecarbonitrile,
4-{[4-(3-furylmethyl)phenyl]amino}-7-(3-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}phenyl)-3-quinolinecarbonitrile,
4-{[4-(3-furylmethyl)phenyl]amino}-7-(3-{[(4-pyridinylmethyl)amino]methyl}phenyl)-3-quinolinecarbonitrile,
4-{[4-(3-furylmethyl)phenyl]amino}-7-[3-({[2-(1H-imidazol-4-yl)ethyl]amino}methyl)phenyl]-3-quinolinecarbonitrile,
4-{[4-(3-furylmethyl)phenyl]amino}-7-[3-(4-morpholinylmethyl)phenyl]-3-quinolinecarbonitrile,
4-[4-(3-furylmethyl)phenyl]amino}-7-(3-{[(2-hydroxyethyl)amino]methyl}phenyl)-3-quinolinecarbonitrile,
4-{[4-(3-furylmethyl)phenyl]amino}-7-{3-[(4-methyl-1-piperazinyl)methyl]phenyl}-3-quinolinecarbonitrile,
4-{[4-(3-furylmethyl)phenyl]amino)-7-[3-({[3-(4-morpholinyl)propyl]amino}methyl)phenyl]-3-quinolinecarbonitrile,
7-{3-[(4-ethyl-1-piperazinyl)methyl]phenyl}-4-{[4-(3-furylmethyl)phenyl]amino}-3-quinolinecarbonitrile,
4-{[4-(3-furylmethyl)phenyl]amino}-7-(3-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}phenyl)-3-quinolinecarbonitrile,
4-{[4-(3-furylmethyl)phenyl]amino}-7-{5-[(4-hydroxy-1-piperidinyl)methyl]-2-pyridinyl}-3-quinolinecarbonitrile,
7-[5-({[2-(dimethylamino)ethyl]amino}methyl)-2-pyridinyl]-4-{[4-(3-furylmethyl)phenyl]amino}-3-quinolinecarbonitrile,
4-{[4-(3-furylmethyl)phenyl]amino}-7-{5-[(2-hydroxyethyl)amino]methyl}-2-pyridinyl)-3-quinolinecarbonitrile,
4-{[4-(3-furylmethyl)phenyl]amino}-7-[5-({[3-(4-morpholinyl)propyl]amino}methyl)-2-pyridinyl]-3-quinolinecarbonitrile,
4-{[4-(3-furylmethyl)phenyl]amino}-7-(5-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}-2-pyridinyl)-3-quinolinecarbonitrile,
4-{[4-(3-furylmethyl)phenyl]amino}-7-{5-[(4-hydroxy-1-piperidinyl)methyl]-3-thienyl}-3-quinolinecarbonitrile,
4-{[4-(3-furylmethyl)phenyl]amino}-7-(5-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}-3-thienyl)-3-quinolinecarbonitrile,
4-{[4-(3-furylmethyl)phenyl]amino}-7-(5-{[(4-pyridinylmethyl)amino]methyl}-3-quinolinecarbonitrile,
4-{[4-(3-furylmethyl)phenyl]amino}-7-[5-(4-morpholinylmethyl)-3-thienyl]-3-quinolinecarbonitrile,
4-{[4-(3-furylmethyl)phenyl]amino}-7-(5-{[(2-hydroxyethyl)amino]methyl}-3-thienyl)-3-quinolinecarbonitrile,
4-{[4-(3-furylmethyl)phenyl]amino}-7-{5-[(4-methyl-1-piperazinyl)methyl]-3-thienyl}-3-quinolinecarbonitrile,
4-{[4-(3-furylmethyl)phenyl]amino}-7-[5-({[3-(4-morpholinyl)propyl]amino}methyl)-3-thienyl]-3-quinolinecarbonitrile,
4-{[4-(3-furylmethyl)phenyl]amino}-7-[5-(1-piperidinylmethyl)-3-thienyl]-3-quinolinecarbonitrile,
7-{5-[(4-ethyl-1-piperazinyl)methyl]-3-thienyl}-4-{[4-(3-furylmethyl)phenyl]amino}-3-quinolinecarbonitrile,
4-[4-(3-furylmethyl)phenyl]amino}-7-(5-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}-3-thienyl)-3-quinolinecarbonitrile,
4-(2,4-dichloro-5-methoxyanilino)-7-(4-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}phenyl)-3-quinolinecarbonitrile,
4-(2,4-dichloro-5-methoxyanilino)-7-(4-{[(4-pyridinylmethyl)amino]methyl}phenyl)-3-quinolinecarbonitrile,
4-(2,4-dichloro-5-methoxyanilino)-7-[4-({[2-(1H-imidazol-4-yl)ethyl]amino}methyl)phenyl]-3-quinolinecarbonitrile,
4-(2,4-dichloro-5-methoxyanilino)-7-(4-{[(2-hydroxyethyl)amino]methyl}phenyl)-3-quinolinecarbonitrile,
4-(2,4-dichloro-5-methoxyanilino)-7-[4-({[3-(4-morpholinyl)propyl]amino}methyl)phenyl]-3-quinolinecarbonitrile,
4-(2,4-dichloro-5-methoxyanilino)-7-{5-[(4-hydroxy-1-piperidinyl)methyl]-2-furyl}-3-quinolinecarbonitrile,
4-(2,4-dichloro-5-methoxyanilino)-7-[5-({[2-(dimethylamino)ethyl]amino}methyl)-2-furyl]-3-quinolinecarbonitrile,
4-(2,4-dichloro-5-methoxyanilino)-7-(5-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}2-furyl)-3-quinolinecarbonitrile,
4-(2,4-dichloro-5-methoxyanilino)-7-(5-{[(4-pyridinylmethyl)amino]methyl}-2-furyl)-3-quinolinecarbonitrile,
4-(2,4-dichloro-5-methoxyanilino)-7-[5-({[2-(1H-imidazol-4-yl)ethyl]amino}methyl)-2-furyl-3-quinolinecarbonitrile,
4-(2,4-dichloro-5-methoxylanilino)-7-(5-{[(2-hydroxyethyl)amino]methyl}-2-furyl)-3-quinolinecarbonitrile,
4-(2,4-dichloro-51-methoxyanilino)-7-[5-({[3-(4-morpholinyl)propyl]amino}methyl)-2-furyl]-3-quinolinecarbonitrile,
4-(2,4-dichloro-5-methoxyanilino)-7-[5-(1-piperidinylmethyl)-2-furyl]-3-quinolinecarbonitrile,
4-(2,4-dichloro-5-methoxyanilino)-7-{5-[(4-ethyl-1-piperazinyl)methyl]-2-furyl}-3-quinolinecarbonitrile,
4-(2,4-dichloro-5-methoxyanilino)-7-(5-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}2-thienyl)-3-quinolinecarbonitrile,
4-(2,4-dichloro-5-methoxyanilino)-7-{5-[(4-ethyl-1-piperazinyl)methyl]-2-thienyl}-3-quinolinecarbonitrile,
4-(2,4-dichloro-5-methoxyanilino)-7-(5-({[2-(dimethylamino)ethyl]amino}methyl)-3-thienyl]-3-quinolinecarbonitrile,
4-(2,4-dichloro-5-methoxyanilino)-7-(5-{[(4-pyridinylmethyl)amino]methyl}-3-thienyl)-3-quinolinecarbonitrile,
4-(2,4-dichloro-5-methoxyanilino)-7-[5-({[2-(1H-imidazol-4-yl)ethyl]amino}methyl)-3-thienyl]-3-quinolinecarbonitrile,
4-(2,4-dichloro-5-methoxyanilino)-7-{5-[(4-hydroxy-1-piperidinyl)methyl]-2-pyridinyl}-3-quinolinecarbonitrile,
4-(2,4-dichloro-5-methoxyanilino)-7-[5-({[2-(dimethylamino)ethyl]amino}methyl)-2-pyridinyl]-3-quinolinecarbonitrile,
4-(2,4-dichloro-5-methoxyanilino)-7-(5-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}2-pyridinyl)-3-quinolinecarbonitrile,
4-(2,4-dichloro-5-methoxyanilino)-7-{5-[(2-hydroxyethyl)amino]methyl}-2-pyridinyl)-3-quinolinecarbonitrile,
4-(2,4-dichloro-5-methoxyanilino)-7-[5-({[3-(4-morpholinyl)propyl]amino}methyl)-2-pyridinyl]-3-quinolinecarbonitrile,
4-(2,4-dichloro-5-methoxyanilino)-7-[(5-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}-2-pyridinyl]-3-quinolinecarbonitrile,
7-{4-[(4-hydroxy-1-piperidinyl)methyl]phenyl}-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile,
7-[4-(4-morpholinylmethyl)phenyl]-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile,
7-(4-{[(2-hydroxyethyl)amino]methyl}phenyl)-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile,
7-{4-[(4-methyl-1-piperazinyl)methyl]phenyl}-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile,
7-[4-(1-piperidinylmethyl)phenyl]-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile,
7-{4-[(4-ethyl-1-piperazinyl)methyl]phenyl}-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile,
7-{3-[(4-hydroxy-1-piperidinyl)methyl]phenyl}-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile,
7-[3-({[2-(dimethylamino)ethyl]amino}methyl)phenyl]-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile,
7-(3-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}phenyl)-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile,
7-(3-{[(4-pyridinylmethyl)amino]methyl}phenyl)-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile,
7-[3-({[2-(1H-imidazol-4-yl)ethyl]amino}methyl)phenyl]-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile,
7-[3(4-morpholinylmethyl)phenyl]-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile,
7-(3-{[(2-hydroxyethyl)amino]methyl}phenyl)-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile,
7-{3-[(4-methyl-1-piperazinyl)methyl]phenyl}-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile,
7-[3-({[3-(4-morpholinyl)propyl]amino}methyl)phenyl]-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile,
7-[3-(1-piperidinylmethyl)phenyl]-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile,
7-((3-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}phenyl)-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile,
7-(5-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}-2-furyl)-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile,
7-{5-[(4-hydroxy-1-piperidinyl)methyl]-2-thienyl}-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile,
7-[5-({[2-(1H-imidazol-4-yl)ethyl]amino}methyl)-2-thienyl]-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile,
7-{5-[(4-methyl-1-piperazinyl)methyl]-2-thienyl}-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile,
7-{5-[(4-ethyl-1-piperazinyl)methyl]-2-thienyl}-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile,
7-(5-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}-2-thienyl)-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile,
7-(5-{[(4-pyridinylmethyl)amino]methyl}-3-thienyl)-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile,
7-[5-(4-morpholinylmethyl)-3-thienyl]-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile,
7-(5-{[(2-hydroxyethyl)amino]methyl}-3-thienyl)-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile,
7-{5-[(4-methyl-1-piperazinyl)methyl]-3-thienyl}-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile,
7-{5-[(4-hydroxy-1-piperidinyl)methyl]-2-pyridinyl}-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile,
7-(5-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}-2-pyridinyl)-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile,
7-(5-{[(2-hydroxyethyl)amino]methyl}-2-pyridinyl)-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile,
7-[5-({[3-(4-morpholinyl)propyl]amino}methyl)-2-pyridinyl]-4-(3,4,5-trimethoxyanilino)-3-quinolinecarbonitrile, and
7-[(5-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl)-2-pyridinyl]-4-(3,4,5trimethoxyanilino)-3-quinolinecarbonitrile,
For the compounds of Formula (I) defined above and referred to herein, unless otherwise noted, the following terms are defined:
Halogen, as used herein means chloro, fluoro, bromo and iodo.
Alkyl as used herein means a branched or straight chain having from 1 to 12 carbon atoms and more preferably from 1 to 6 carbon atoms. Exemplary alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobultyl, t-butyl, pentyl and hexyl optionally substituted with phenyl, phenyl optionally substituted with one or more substituents preferably from one to three substituents independently selected from alkyl, alkoxy, perhaloalkyl, halogen, nitro, hydroxy, amino, carboxy, carboxyalkyl, alkylamino and dialklylamino, thioalkyl, alkoxycarbonyl and acyl.
Alkenyl as used herein means a branched or straight chain having from 2 to 12 carbon atoms and more preferably from 2 to 6 carbon atoms, the chain containing at least one carbon-carbon double bond and all possible configurational isomers. Alkenyl, may be used synonymously with the term olefin and includes alkylidenes. Exemplary alkenyl groups include ethenyl, propenyl, 1,4-butadienyl, 3-hexen-1-yl and the like optionally substituted with phenyl, phenyl optionally substituted with one or more substituents preferably from one to three substituents independently selected from alkyl, alkoxy, perhaloalkyl, halogen, nitro, hydroxy, amino, carboxy, carboxyalkyl, alkylamino and dialkylamino, thioalkyl, alkoxycarbonyl and acyl.
An alkynyl group is defined as straight or branched carbon chain of 2 to 6 carbon atoms that contains at least one carbon-carbon triple bond and includes propynyl and the like optionally substituted with phenyl, phenyl optionally substituted with one or more substituents preferably from one to three substituents independently selected from alkyl, alkoxy, perhaloalkyl, halogen, nitro, hydroxy, amino, carboxy, carboxyalkyl, alkylamino and dialkylamino, thioalkyl, alkoxycarbonyl and acyl.
Alkoxy as used herein means an alkyl-Oxe2x80x94 group in which the alkyl group is as previously described. Exemplary alkoxy groups include methoxy, methoxy, n-propoxy, i-propoxy, n-butoxy, t-butoxy and polyethers including xe2x80x94Oxe2x80x94(CH2)2OCH3.
Cycloalkyl as used herein means a simple carbocycle having a saturated ring having from 3 to 10 carbon atoms and more preferably from 3 to 6 carbon atoms optionally substituted with 1 to 3 independently selected alkyl groups of 1 to 12 carbon atoms. Exemplary cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and adamantyl and the like.
Aryl is used herein means a mono or bicyclic aromatic ring having from 6 to 12 carbon atoms. Monocyclic rings preferably have 6 members and bicyclic rings preferably have 8, 9, 10 or 12 membered ring structures. Exemplary aryl groups include phenyl, alpha-naphithyl, beta-naphthyl, indene, and the like independently substituted with one or more substituents and more preferably with 1 to 4 substituents.
Heteroaryl denotes an unsubstituted or optionally substituted monocyclic 5 or 6 membered ring, which contains 1 to 4, or particularly 1 or 2 heteroatoms which may be the same or different. Nitrogen, oxygen and sulfur are the preferred heteroatoms, provided that the heteroaryl does not contain Oxe2x80x94O, Sxe2x80x94S or Sxe2x80x94O bonds. Specific examples include thiophene, furan, pyrrol, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, thiazole, oxazole, isothiazole, isoxazole, 1,3,4-oxadiazole, 1,2,4-oxadiazole, 1,3,4-thiadiazole, pyridine, pyrimidine, pyrazine, pyridazine and 1,3,5-triazine. The heteroaryl ring may be oxidized when a heteroatom is a nitrogen atom to provide the corresponding N-oxide, including pyridine-N-oxide. The heteroaryl ring may be oxidized on a sulfur atom to provide the corresponding sulfoxide or sulfone, including thiophene-1-oxide. The heterocyclic ring may contain a carbonyl group on one of the carbon atoms, such as 1,3,4-oxadiazol-2-one.
Bicyclic heteroaryl as used herein refers to saturated or partially unsaturated bicyclic fused rings having 8 to 20 ring atoms containing 1 to 4 heteroatoms which may be the same or different independently selected from nitrogen, oxygen and sulfur optionally substituted with 1 to 3 independently selected substituents which may be the same or different provided that the bicyclic heteroaryl does not contain Oxe2x80x94O, Sxe2x80x94S or Sxe2x80x94O bonds. Specific examples include: indole, 2,3-dihydroindole, 2-indazole, isoindazole, quinoline, isoquinoline, tetrahydroquinoline, benzofuran, benzothiophene, benzimidazole, benzotriazole, benzothiazole, benzoxazole, benzisoxazole, 1,2-benzopyran, cinnoline, phthalazine, quinazoline, 1,8-naphthyridine, pyrido[3,2-b]pyridine, pyrido[3,4-b]pyridine, pyrido[4,3-b]pyridine, pyrido[2,3-d]pyrimidine, purine, and ptenidine and the like. Either or both rings of the bicyclic ring system may be partially saturated, or fully saturated. The bicyclic group may be oxidized on a nitrogen atom to provide the corresponding N-oxide, such as quinoline-N-oxide. The bicyclic group may be oxidized on a sulfur atom to provide the corresponding sulfoxide or sulfone, such as benzothiophene-1-oxide. The bicyclic ring system may contain a carbonyl group on one of the carbon atoms, such as 2-indanone.
Heterocyclyl means a saturated or partially unsaturated monocyclic radical containing preferably 3 to 8 ring atoms, more preferably 3 to 7 ring atoms and most preferably 5 to 6 ring atoms selected from carbon, nitrogen, oxygen and sulfur with at least 1 and preferably 1 to 4, more preferably 1 to 2 nitrogen, oxygen or sulfur as ring atoms. Specific examples include but are not limited to morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-dioxide, piperidine, piperazine, pyrrolidine, aziridine, oxirane, tetrahydrothiophene, tetrahydrofuran, 1,2-pyran, 1,4-pyran, dioxane, 1,3-dioxolane and tetralhydropyran. The heterocyclyl ring may be oxidized on a tri-substituted nitrogen atom to provide the corresponding N-oxide, such as N-ethylpiperazine-N-oxide, or the heterocyclyl ring may contain a carbonyl group on one of the carbon atoms, such as pyrrolidinone.
Thioalkyl as used herein means an alkyl-Sxe2x80x94 group in which the alkyl group is as previously described. Thioalkyl groups include thiomethyl and the like.
A carboxy group is defined as xe2x80x94C(O)OH, and an alkoxycarbonyl group is defined as xe2x80x94C(O)OR where R is alkyl of 1 to 6 carbon atoms and includes methoxycarbonyl, allyloxycarbonyl and the like.
Carboxyalkyl is defined as HOOC-alkyl of 1 to 12 carbon atoms.
Alkylamino is defined as a nitrogen atom substituted with an alkyl of 1 to 12 carbon atoms.
Dialkylamino is defined as a nitrogen atom disubstituted with an alkyl of 1 to 12 carbon atoms.
An acyl group is defined as a group xe2x80x94C(O)R where R is an alkyl or aryl radical and includes acetyl, trifluoroacetyl, benzoyl and the like.
Phenyl as used herein refers to a 6-membered aromatic ring.
Where terms are used in combination, the definition for each individual part of the combination applies unless defined otherwise. For instance, perhaloalkyl refers to an alkyl group, as defined above and perhalo refers to all hydrogen atoms on the alkyl group being substituted with a halogen as define above. An example is trifluoromethyl.
Some of the compounds of the invention have centers of asymmetry. The compounds may, therefore, exist in at least two and often more stereoisomeric forms. The present invention encompasses all stereoisomers of the compounds whether free from other stereoisomers or admixed with other stereoisomers in any proportion and thus includes, for instance, racemic mixture of enantiomers as well as the diasteieomeric mixture of isomers. The absolute configuration of any compound may be determined by conventional X-ray crystallography. Optically active isomers may be prepared, for example, by resolving racemic derivatives or by asymmetric synthesis. The resolution can be carried out by the methods known to those skilled in the art such as in the presence of a resolving agent, by chromatography, or combinations thereof.
The compounds of Formula (I) may be obtained as inorganic or organic salts using methods known to those skilled in the art (Richard C. Larock, Comprehensive Organic Transformations, VCH publishers 411-415, 1989). It is well known to one skilled in the art that an appropriate salt form is chosen based on physical and chemical stability, flowability, hydroscopicity and solubility.
Pharmaceutically acceptable salts of the compounds of Formula (I) with an acidic moiety may be formed from organic and inorganic bases. For example with alkali metals or alkaline earth metals such as sodium, potassium, lithium, calcium, or magnesium or organic bases and N-tetraalkylammonium salts such as N-tetrabutylammonium salts. Similarly, when a compound of this invention contains a basic moiety, salts may be formed from organic and inorganic acids. For example salts may be formed from acetic, propionic, lactic, citic, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, naphthialenesulfonic, benzenesulfonlic, toluenesulfonic, camphorsulfonic, and similarly known acceptable acids. The compounds can also be used in the form of esters, carbamates and other conventional prodrug forms, which when administered in such form, convert to the active moiety in vivo.
The present invention accordingly provides a pharmaceutical composition which comprises a compound of this invention in combination or association with a pharmaceutically acceptable carrier. In particular, the present invention provides a pharmaceutical composition which comprises an effective amount of a compound of this invention and a pharmaceutically acceptable carrier.
The compounds of this invention are certain substituted 3-cyanoquinolines, 3-cyano-1,6-naphthyridine and 3-cyano-1,7-naphthyridine containing compounds.
The quinoline, 1,6-nphthyridine and 1,7-naphthyridine ring systems will be numbered as indicated in the formulae: 
In addition to the utilities, described herein some of the compounds of this invention are intermediates useful for the preparation of other compounds of this invention.
The compounds of this invention may be prepared from: (a) commercially available starting materials (b) known starting materials which may be prepared as described in literature procedures or (c) new intermediates described in the schemes and experimental procedures herein.
Reactions are performed in a solvent appropriate to the reagents and materials employed and suitable for the transformation being effected. It is understood by those skilled in the art of organic synthesis that the various functionalities present on the molecule must be consistent with the chemical transformations proposed. This may necessitate judgement as to the order of synthetic steps. Appropriate consideration must be made as to the protection of reactive functional groups to prevent undesired side reactions. For example, it may be necessary to protect primary or secondary amino or hydroxyl groups. Suitable protecting groups include, but are not limited to, tert-butoxycarbonyl (BOC), trimethylsilylethanesulfonamide (SES), benzyloxycarbonyl (CBZ) and benzyl (Bn) protecting groups. The BOC protecting group may be removed by treatment with in acid such as trifluoroacetic acid or concentrated hydrochloric acid and the SES protecting group may be removed with a fluoride salt, such as cesium fluoride or tetrabutylammonium fluoride. The CBZ and Bn protection groups may be removed by catalytic hydrogenation. Additional suitable protecting groups for hydroxy substituents include, but are not limited to, t-butyldimethylsilyl (TBDMS), tetrahydropyranyl (THP), or isopropyl (i-Pr) protecting groups. The TBDMS and THP protecting groups may be removed by treatment with an acid such as acetic acid or hydrochloric acid while the i-Pr protecting group may be removed by aluminum trichloride.
Substituents on the starting materials may be incompatible with some of the reaction conditions. Such restrictions to the substituents which are compatible with the reaction conditions will be apparent to one skilled in the salt. Reactions were run under inert atmospheres where appropriate.
The preparation of the compounds and intermediates of this invention encompassed by Formula (I) is described as follows where key intermediates for the preparation of compounds of Formula (I) are compounds of Formulae (II), (III), and (IV) wherein LG is attached to a carbon atom and designates a leaving group preferably Br, I or OTf where OTf designates a trifluoromethanesulfonate (triflate) group. 
As shown in Scheme 1, a 3-bromoaniline 1 where T and Z are carbon atoms and R2a, R2b and R2c are hereinbefore defined and LG is bromo and ethyl(ethoxymethylene)cyano acetate 2 may be heated at temperatures ranging from 60 to 120xc2x0 C. either neat or in an inert solvent which includes toluene and the like followed by cyclization in a 3:1 mixture of diphenyl ether and biphenyl at an optimal temperature of 260xc2x0 C. to provide a mixture of isomers 7-bromo-4-oxo-1,4-dihydroquinoline-3-carbonitrile 3a and 5-bromo-4-oxo-1,4-dihydroquinoline-3-carbonitrile 3b. The isomers may be separated by either recrystallization or chromatography. Heating of 7-bromo-4-oxo-1,4-dihydroquinoline-3-cabonitrile 3a with a chlorinating reagent selected from phosphorus oxychloride and oxalyl chloride either neat or in an inert solvent which includes methylene chloride, provides the corresponding 7-bromo-4-chloro-3-cyanoquinoline 4 where T and Z are carbon atoms and R2a, R2b and R2c are hereinbefore defined and LG is bromo. Reaction of 7-bromo-4-chloro-3-cyanoquinoline 4 with an aniline, phenol, thiophenol, amine, alcohol or thiol reagent 5 having the formula HXxe2x80x94(CH2)nxe2x80x94R1, wherein R1, X and n are hereinbefore defined, gives the 3-cyanoquinolines of Formula (II) where the leaving group LG may be bromo, where T and Z are carbon atoms, X, R1, R2a, R2b and R2c are hereinbefore defined. The condensation may be accelerated by heating the reaction mixture together with a catalytic amount or one equivalent of pyridime hydrochloride or by using organic bases selected from triethylamine, 4-dimethylaminopyridine, and diazabicyclo[5.4.0]undec-7-ene and the like or sodium hydride in an inert solvent, which includes tetrahydrofuan and the like or sodium or potassium alkoxides in the absence of solvent or in an inert solvent. 
The reaction sequence shown in Scheme 1 may be modified by substitution of 3-iodoaniline for 3-bromoaniline 1, where the LG may be iodo in place of bromo with the resulting compounds of Formula (II) now containing a 7-iodo group.
Scheme 2 shows an alternate route for the preparation of compounds of Formula (II). Reaction of 5-bromoanthranilic acid or ester 6 where T and Z are carbon atoms and R2a, R2b and Rc are hereinbefore defined with N,Nxe2x80x2-dimethylformamide dimethyl acetal (DMF-DMA), in the presence or absence of a co-solvent selected from dimethylformamide and toluene gives the corresponding intermediate amidine which may be further reacted with the lithium anion of acetonitrile prepared by using a base which includes n-butyllithium, lithium di-isopropylamine, or the like in an inert solvent, preferably tetrahydrofuran, to give 6-bromo-4-oxo-1,4-dihydroquinoline-3-carbonitrile 7. Heating 6-bromo-4-oxo-1,4-dihydroquinoline-3-carbonitrile 7 with a chlorinating reagent selected from phosphorus oxychloride and oxalyl chloride either neat or in a solvent such as methylene chloride, provides the corresponding 6-bromo-4-chloro-3-cyanoquinoline 8 where T and Z are carbon atoms and R2a, R2b and R2c are hereinbefore defined, which when reacted with an aniline, phenol, thiophenol, amine, alcohol or thiol reagent 5 of the formula HXxe2x80x94(CH2)nxe2x80x94R1, wherein R1, X and n are as previously defined, gives the 3-cyanoquinolines of Formula (II) where the leaving group LG may be bromo. 
Alternatively compounds of Formulae (II), (III) or (IV) containing a triflate (-OTf) leaving group may be prepared as shown in Scheme 3. The phenolic group of an ester of formula 9 where T and Z are carbon atoms and R2a, R2b and R2c are hereinbefore defined is protected with a benzyl group and subsequent nitration provides the 2-nitro derivative 10. Removal of the benzyl group, formation of the triflate and reduction of the nitro group provides the aniline 11 where T and Z are carbon atoms and R2a, R2b and R2c are hereinbefore declined. Further reaction of aniline 11 with N,Nxe2x80x2-dimethylformamide dimethyl acetal (DMF-DMA), in the presence or absence of a co-solvent selected from toluene and N,N-dimethylformamide, gives the corresponding intermediate amidine which is further reacted with the lithium anion of acetonitrile prepared by using a base which includes n-butyllithium, lithium di-isopropylamine, or the like in an inert solvent, preferably tetrahydrofuran, to give quinoline-3-carbonitrile 12. Heating quinoline-3-carbonitrile 12 with a chlorinating reagent selected from phosphorus oxychloride and oxalyl chloride either neat or in it solvent such as methylene chloride, provides the corresponding 4-chloro-3-cyanoquinoline 13 where T and Z are carbon atoms and R2a, R2b and R2c are hereinbefore defined, which when reacted with an aniline, phenol, thiophenol, amine, alcohol or thiol reagent 5 of the formula HXxe2x80x94(CH2)nxe2x80x94R1, wherein R1, X and n are as previously defined, gives the 3-cyanoquinolines of Formula (II) where the leaving group LG is -OTf where T and Z are carbon atoms and R2a, R2b and R2c are hereinbefore defined. 
The compounds of Formulae (III) and (IV) may be prepared by routes analogous to those shown in Schemes 1-3. As shown in Scheme 4 oxidation of a 2-bromopyridine 14, where T is a nitrogen atom, Z is a carbon atom, R2a, R2b are hereinbefore defined and R2c is absent and LG is bromo, using m-chloroperbenzoic acid forms the N-oxide followed by nitration to afford a 2-bromo-4-nitro-pyridine-N-oxide which following subsequent reduction using iron in the presence of ammonium chloride provides a 4-amino-2-bromopyridine 16. Using conditions analogous to those in Scheme 1, a 4-amino-2-bromopyridine 16 and ethyl(ethoxymethylene)cyano acetate 2 are heated at temperatures ranging from 60 to 120xc2x0 C. either neat or in an inert solvent which includes toluene and the like followed by cyclization in a 3:1 mixture of diphenyl ether and biphenyl at an optimal temperature of 260xc2x0 C. to provide a 7-bromo-4-oxo-1,4,-dihydro-1,6-naphthyridine-3-carbonitrile 17 where T is a nitrogen atom, Z is a carbon atom, R2a and R2b are hereinbefore defined. Heating of a 7-bromo-4-oxo-1,4-dihydro-1,6-naphthyridine-3-carbonitrile 17 with a chlorinating agent selected from phosphorus oxychloride and oxalyl chloride either neat or in a solvent such as methylene chloride, provides the corresponding 7-bromo-4-chloro-1,6-naphthyridine-3-carbonitrile 18. Reaction of a 7-bromo-4-chloro-1,6-naphthyridine-3-carbonitrile 18 with an aniline, phenol, thiophenol, amine, alcohol or thiol reagent 5 of the formula HXxe2x80x94(CH2)nxe2x80x94R1, wherein R1, X and n are as previously defined, gives the 3-cyano-1,6-naphthyridines of Formula (III) where the leaving group LG is bromo and where T is a nitrogen atom, Z is a carbon atom, R2a, R2b, X, R1 and n are hereinbefore defined. 
Compounds of Formulae (II), (III) and (IV) may be converted to compounds of Formula (I) of the invention by replacement of the leaving group (LG) of Formulae (II), (III) and (IV) with organometallic reagents and formation of a carbon-carbon bond. The organometallic reagents, which are organoboron and organotin reagents may be prepared as shown in Scheme 5.
Organoboron reagents of formula R4xe2x80x94Axe2x80x94R3xe2x80x94BL1L2 19, wherein R3 is aryl, heteroaryl, and bicyclic heteroaryl, L1 and L2 are suitable ligands independently selected from alkoxy, alkyl and hydroxy and readily obtained by standard procedures, (R. D. Larsenl, Current Opinoion Drug Discovery and Development, 2, No. 6, 651-667(1999). Compounds of formula R4xe2x80x94Axe2x80x94R3xe2x80x94H 20 or R4xe2x80x94Axe2x80x94R3xe2x80x94Br 21 may be converted to the corresponding in organolithium by treatment with a lithium base which include n-BuLi. The organolithium may then be treated with an organoboron reagent of formula Q1xe2x80x94BL1L2 22 where Q1 is defined as a leaving group selected from alkoxy and the like to provide compounds of formula R4xe2x80x94Axe2x80x94R3xe2x80x94BL1L2 19. Organoboron reagents of formula Q1xe2x80x94BL1L2 9 include alkyl borates including tri-isopropyl borate, wherein one of the tri-isopropyl groups functions as the leaving group Q1. Suitable L1 and L2 groups are independently hydroxy, alkyl of 1 to 12 carbon atoms or alkoxy of 1 to 12 carbon atoms. In addition, the ligands L1L2 may be taken together with the boron to which they are attached to form a cyclic boron ester, where L1L2 may be oxyethyleneoxy and the like. Alternatively a compound of formula R4xe2x80x94Axe2x80x94R3xe2x80x94Br 21 may be treated with an organoboron compound such as bis(pinacolato)diboron and the like in the presence of potassium acetate and a palladium catalyst including [1,1xe2x80x2-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane in a solvent selected from dimethyl sulfoxide, N,N-dimethylformamide (DMF), and dioxane and the like to provide the organoboron compound of formula R4xe2x80x94Axe2x80x94R3xe2x80x94BL1L2 19.
Organotin reagents of formula R4xe2x80x94Axe2x80x94R3xe2x80x94SnR3 24 may be readily obtained by standard procedures. Compounds of formula R4xe2x80x94Axe2x80x94R3xe2x80x94H 20 or R4xe2x80x94Axe2x80x94R3xe2x80x94Br 21 may be converted to the corresponding organolithium compound by treatment with a lithium base which includes n-BuLi. The organolithium compound may then be treated with an organotin compound of formula Q1xe2x80x94SnR3 23 which include tri-n-butylstannyl chloride where Q1 is a chloro leaving group to afford organotin reagents of formula R4xe2x80x94Axe2x80x94R3xe2x80x94SnR3 24. Organoboron reagents of formula 19 and organotin reagant of formula 24 may be generated in situ and used without purification. 
Scheme 6 shows a route for the preparation of compounds of Formula (I) from the reaction of compounds of Formulae (II), (III) and (IV) in a solvent selected from tetrahydrofuran, dioxane, and ethylene glycol dimethyl ether and the like at temperatures preferably 60 to 150xc2x0 C. with reagents R4xe2x80x94Axe2x80x94R3xe2x80x94BL1L2 19 or R4xe2x80x94Axe2x80x94R3xe2x80x94SnR3 24 in the presence of catalysts which include tetrakis(triphenylphosphine)palladium(0), palladium(II)chloride, nickel(II)bromide and the like, where A, R3 and R4 are hereinbefore defined. 
Specifically as shown in Scheme 7 compounds of Formula (I) wherein R3 is an alkene may be prepared via reaction of compounds of formula R4xe2x80x94Axe2x80x94CHxe2x95x90CH2 25 with compounds of Formula (II), (III) or (IV) in the presence of triphenylphosphine and a palladium catalyst, which include palladium acetate. Preferred solvents include trialkylamines such as triethylamine, or alternatively N,N-dimethylformamide with an equivalent of a base which include sodium bicarbonate. Similarly, compounds of Formula (I) wherein R3 is an alkyne group may be obtained by reaction of compounds of formula R4xe2x80x94Axe2x80x94Cxe2x89xa1CH 26 with compounds of Formula (II), (III) or (IV) in the presence of triphenylphosphine, copper(I)iodide and a palladium catalyst, which include dichloro bis(triphenylphosphine)palladium(I). 
As shown in Scheme 8, an alternate route to some compounds of Formula (I) involves reaction of compounds of Formulae (II), (III) and (IV) with a stannane reagent 27 where R3 is an aryl, heteroaryl, or bicyclic heteroaryl which include 2-(tributylstannyl)-5-(1,3-dioxolan-2-yl)furan, 2-(1,3-dioxolan-2-yl)-1-methyl-5-(tributylatannyl)imidazole. The stannane reagent 27 may be reacted with compounds of Formulae (II), (III) and (IV) in an inert solvent which includes tetrahydrofuran or dioxane and the like in the presence of a palladium catalyst such as bis(triphenylphosphine)palladium(II)chloride or 1,4-bis(diphenylphosphino)butane palladium(II)chloride to afford an acetal 29. The acetal protecting group may be removed by acid hydrolysis, preferably using aqueous hydrochloric acid with a cosolvent such as tetrahydrofuran, to give the aldehyde 29. Alternatively the aldehyde 29 may be obtained directly by reaction of compounds of Formulae (II), (III) and (IV) with a boronic acid reagent 30 where R3 is aryl, heteroaryl and bicyclic heteroaryl which include 4-formylphenyl boronic acid and the like, to also give aldehyde 29. The boronic acid reagent 30 may be reacted with compounds of Formulae (II), (III) and (IV) in a solvent selected from tetrahydrofuran and dioxane in the presence of a palladium catalyst which includes bis(triphenylphosphine)palladium(II)chloride or 1,4-bis(diphenylphosphino)butane palladium(II)chloride. Aldehyde 29 may be treated with an amine 31 of formula HNR13R14, in a solvent selected from methylene chloride, dioxane and tetrahydrofuan, in the presence of a reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride with the optional addition of a catalyst which includes acetic acid and the like. 
Alternatively compounds of the invention may be prepared by the routes shown in Schemes 9 and 10 where the olganotin reagent R4xe2x80x94Axe2x80x94R3xe2x80x94SnR3 24 or organoboron reagent R4xe2x80x94Axe2x80x94R3xe2x80x94BL1L2 19, may be coupled to cyano compound 32 where T, Z, R2a, R2b and R2c are hereinbefore defined to give intermediate 33 which may then be converted to the 4-chloro intermediate 34 by reaction with a chlorinating reagent selected from phosphorous oxychloride, oxalyl chloride and polymer supported triphenylphosphine and carbon tetrachloride, which when reacted with an aniline, phenol, thiophenol, amine, alcohol or thiol reagent 5 of the formula HXxe2x80x94(CH2)nxe2x80x94R1, wherein R1, X and n are as previously defined, gives compounds of Formula, (I) of the invention 
Referring to Scheme 10, compounds of the formula R4xe2x80x94Axe2x80x94CHxe2x95x90CH2 25 coupled to cyano compound 32 where T, Z, R2a, R 2b and R2c are hereinbefore defined give intermediate 35 which may then be converted to the 4-chloro intermediate 36 by reaction with a chlorinating reagent selected from phosphorous oxychloride, oxalyl chloride and polymer supported triphenylphosphine and carbon tetrachloride, which when reacted with an aniline, phenol, thiophenol, amine, alcohol or thiol reagent 5 of the formula HXxe2x80x94(CH2)nxe2x80x94R1, wherein R1, X and n are as previously defined, to give compounds of Formula (I). 
Additional key intermediates for the preparation of compounds of Formula (I) are compounds of Formulae (V), (VI), and (VII), when in the primary amino group is attached to a carbon atom. 
Compounds of Formula (V) where T and Z are carbon atoms and R2a, R2b and R2c are hereinbefore defined may be prepared as shown in Scheme 11. A 3-nitroaniline 37 where R2a, R2b and R2c are hereinbefore defined and ethyl(ethoxymethylene)cyano acetate 2 are heated at temperatures ranging from 60 to 190xc2x0 C. either neat or in a solvent such as toluene followed by cyclization in a 3:1 mixture of diphenyl ether and biphenyl at all optimal temperature of 260xc2x0 C. to provide a mixture of 7-nitro-4-oxo-1,4-dihydro-3-quinolinecarbonitrile 38a and 5-nitro-4-oxo-1,4-dihydro-3-quinolinecarbonitrile 38b which may be separated by either recrystallization or chromatography. Heating of 7-nitro-4-oxo-1,4-dihydro-3-quinolinecarbonitrile 38a with a chlorinating agent selected from phosphorus oxychloride and oxalyl chloride either neat or in a solvent such as methylene chloride, provides the corresponding 4-chloro-7-nitro-3-cyanoquinoline 39 followed by reaction with an aniline, phenol, thiophenol, amine, alcohol or thiol reagent of formula HXxe2x80x94(CH2)nxe2x80x94R1 5 wherein R1, X and n are hereinbefore defined gives the 4-substituted 7-nitro-3-cyanoquinolines 40 where R2a, R2b, R2c, R1, X and n are hereinbefore defined and T and Z are carbon atoms. The condensation may be accelerated by heating the reaction mixture together with a catalytic amount or one equivalent of pyridine hydrochloride or by using bases such as triethylamine, 4-dimethylaminopyridine, diazabicyclo[5.4.0]undec-7-ene or sodium hydride in an inert solvent, such as tetrahydrofuran, or sodium or potassium alkoxides in an inert solvent, or in the absence of solvent. The nitro group may be reduced with iron and ammonium chloride in methanol and water, or with iron and acetic acid in methanol to give the 3-cyanoquinolines of Formula (V). 
Scheme 12 shows an alternate route for the preparation of compounds of Formula (V). Reaction of a 3-nitroaniline 37 where R2a, R2b and R2c are hereinbefore defined with acetic anhydride (Ac2O) in water gives the corresponding acetamide 41. Reaction of the acetamide 41 with iron and ammonium chloride in methanol and water yields N-(3-aminophenyl)acetamide 42 which may be further reacted with ethyl(ethoxylmethylene)cyano acetate 2 with heating at temperatures ranging from 60 to 120xc2x0 C. either neat or in an inert solvent which includes toluene followed by cyclization in a 3:1 mixture of diphenyl ether and biphenyl at an optimal temperature of 260xc2x0 C. to provide a mixture of N-(3-cyano-4-oxo-1,4-dihydro-7-quinolinyl)acetamide 43a and N-(3-cyano-4-oxo-1,4-dihydro-5-quinolinyl)acetamide 43b which may be separated by either recrystallization or chromatography. Heating of N-(3-cyano-4-oxo-1,4-dihydro-7-quinolinyl)acetamide 43a with a chlorinating agent selected from phosphorus oxychloride and oxalyl chloride either neat or in a solvent which includes methylene chloride, provides the corresponding N-(4-chloro-3-cyano-7-quinolinyl)acetamide 44 followed by reaction with an aniline, phenol, thiophenol, amine, alcohol or thiol reagent of formula 5 HXxe2x80x94(CH2)nxe2x80x94R1, wherein R1, X and n are hereinbefore defined, followed by acid hydrolysis to give the 3-cyanoquinolines of Formula (V). The condensation may be accelerated by heating the reaction mixture together with a catalytic amount or one equivalent of pyridine hydrochloride or by using bases such as triethylamine, 4-dimethylaminopyridine, diazabicyclo[5.4.0]undec-7-ene or sodium hydride in an inert solvent, such as tetrahydrofuran, or sodium or potassium alkoxides in an inert solvent or in the absence of solvent. 
Compounds of Formulae (V), (VI), and (VII) may be converted to compounds of Formula (I) of the invention by additional, routes as shown in Schemes 13, 14, 15 and 16. As outlined in Scheme 13, reaction of the amino group bonded to a carbon atom of Formulae (V), (VI) and (VII) where T, Z, R2a, R2b, R2c, R1, X and n are hereinbefore defined with 2,5-dimethoxytetrahydrofuran 45 where A and R4 are hereinbefore defined, in acetic acid or N,N-dimethylformamide containing 4-chloropyridine hydrochloride at temperatures ranging from 70 to 110xc2x0 C. affords compounds of formula I where R3 is pyrrole and T, Z, R2a, R2b, R2c, R1, X A, R4 and n are hereinbefore defined. 
Specifically as outlined in Scheme 14, reaction of the amino group bonded to a carbon atom of Formulae (V), (VI) and (VII) where T, Z, R2a, R2b, R2c, R1, X and n are hereinbefore defined may be reacted with furfuyl aldehyde 46 catalyzed by acids which include Amberlite IR-120 in 2-ethoxyethanol to give the corresponding pyrrole carboxaldehyde 47 which may be treated with an amine 31 of formula HNR13R14 where R13 and R14 are hereinbefore defined, which may be either a primary or secondary amine, in a solvent selected from methanol, dioxane, tetrahydrofuan and methylene chloride, with the optional addition of a cosolvent which includes N,N-dimethylformamide, in the presence of a reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride with the optional addition of a catalyst such as acetic acid to afford compounds of formula I where R3 is pyrrole, A is absent, R4 is xe2x80x94(C(R9)2)rH and r is 0.
It should be noted that compounds of formula 47 are also compounds of formula I where R3 is pyrrole, A is absent, R4 is xe2x80x94(C(R9)2)rH and r is 0. 
Alternatively, Scheme 15 shows that the pyrrole carboxaldehyde 47 may be reduced to alcohol 48 using a reducing agent such as sodium borohydride. The resulting alcohol 48 may then be converted to pyrrole 49 having a leaving group LG selected from Cl, Br, p-toluelnesulfonate (TsO), methanesufonate (MsO) and trifluoromethanesulfonate (TfO). For example the alcohol may be converted into the corresponding chloride by a reagent such as thionyl chloride or phosphorus oxychloide in the presence of pyridine, or by hydrogen chloride. The leaving group LG may then be displaced by treatment with a primary or secondary amine of formula R13R14NH, 31 where R13 and R14 are hereinbefore defined, which may be either a primary or secondary amine to afford compounds of formula I where R3 is pyrrole, A is absent, R4 is xe2x80x94(C(R9)2)rH and r is 0.
It should be noted that compounds of formula 48 are also compounds of formula I where R3 is pyrrole, A is absent, R4 is xe2x80x94(C(R9)2)rH and r is 0. 
As outlined in Scheme 16, reaction of the amino group bonded to a carbon atom of Formulae (V), (VI) and (VII) where T, Z, R2a, R2b, R2c, R1, X and n are hereinbefore defined, with 2,5-dimethoxytetrahydrofuran 50 in acetic acid or N,N-dimethylformamide containing 4-chloropyridine hydrochloride at temperatures ranging from 70 to 110xc2x0 C. affords pyrrole 51 where T, Z, R2a, R2b, R2c, R1, X, and n are hereinbefore defined. Compounds of formula 51 are also compounds of Formula I where R3 is pyrrole, A is absent, R4 is xe2x80x94(C(R9)2)rH and r is 0. Further reaction of pyrrole 51 with paraformaldehyde and an amine 31 of formula HNR13R14 as the hydrochloride, where R13 and R14 are hereinbefore defined, which may be either a primary or secondary amine, in at solvent selected from methanol, dioxane, tetrahydrofuran and methylene chloride, with the optional addition of a cosolvent which includes N,N-dimethylformamide affords pyrrole compounds of Formula I. 
Scheme 17 shows an alternative route for the conversion of compounds of Formulae (II), (III) and (IV) to compounds of Formula (I) of the invention by initial reaction of compounds of Formulae (II), (III) and (IV), wherein the LG is bromo, with hexabutylditin, also known as bis(tributyltin), in N,N-dimethylformamide in the presence of a base such as triethylamine and a catalyst such as tetrakis(triphenylphosphine)pallidium(0) at elevated temperatures, preferably around 100xc2x0 C. to provide the corresponding tin derivative 52. Reaction of 52 with bromo derivative 21 in a solvent such as N,N-dimethylformamide in the presence of a a catalyst such as dichlorobis(triphenylphosphine)pallidium(II) at elevated temperatures, provides compounds of Formula (I) of the invention wherein R1, R2a, R2b, R2c, R3, R4, n, A, T, X, and Z are hereinbefore defined. 
Scheme 18 shows an alternate route for the preparation of compounds of Formula (I) from 29. The carboxaldehyde group of 29 may be reduced to an alcohol 53 with a reducing agent such as sodium bomohydride. The resulting alcohol 53 may then be converted to 54 which has a leaving group LG selected from Cl, Br, p-toluenesulfonate (TsO), methanesulfonate (MsO) and trifluoromethanesulfonate (TfO). For example the alcohol is converted into the corresponding chloride by a reagent such as thionyl chloride or phosphorus oxychloride in the presence of pyridine, or by hydrogen chloride. The alcohol may also be converted to the chloride with 1-chloro-N,N, 2-trimethylpropenylamine in the presence of pyridine. The leaving group LG may then be displaced by treatment with a primary or secondary amine of formula R13R14NH, 31, where R13 and R14 are hereinbefore defined, which may be either a primary or secondary amine to afford compounds of Formula (I) of the invention wherein R1, R2a, R2b, R2c, R3, R13, R14, n, T, X, and Z are hereinbefore defined, A is absent and R4 is xe2x80x94C((R9)2)rH where r is 0. 
Scheme 19 shows a route for the conversion of compounds of Formulae (II), (III) and (IV) to compounds of Formula (I) of the invention by reaction of compounds of Formulae (II), (III) and (IV), wherein the LG is bromo, with bromo derivative 21 in the presence of hexamethylditin and a catalyst such as tetrakis(triphenylphosphine)pallidium(0) in dioxane at elevated temperatures to provide compounds of Formula (I) of the invention wherein R1, R2a, R2b, R2c, R3, R4, n, A,T, X, and Z are hereinbefore defined. 
Scheme 20 depicts the preparation of compounds of Formula (I) of the invention whereby compounds of Formulae (II), (III) and (IV), wherein the LG is bromo, may be reacted with bromo containing aldehydes of structure 55 in the presence of hexamethylditin and a catalyst such as tetrakis(triphenylphosphine)pallidium(0) in dioxane at elevated temperatures to provide compounds of structure 29. Aldehyde 29 may be treated with an amine 31 of formula HNR13R14 in a solvent selected from methylene chloride, dioxane and tetrahydrofuran in the presence of a reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride with the optional addition of a catalyst which includes acetic acid and the like to provide compounds of Formula (I) of the invention wherein R1, R2a, R2b, R2c, R3, R13, R14, n, T, X, and Z are hereinbefore defined, A is absent and R4 is xe2x80x94C((R9)2)rH where r is 0. 
Evaluation of representative compounds of this invention in several standard pharmacological test procedures indicated that the compounds of this invention possess significant antiproliferative activity and are inhibitors of protein tyrosine kinases. Based on the activity shown in the standard pharmacological test procedures, the compounds of this invention are therefore useful as antineoplastic agents. In particular, these compounds are useful in treating, inhibiting the growth of, or eradicating neoplasms such as those of the breast, kidney, bladder, mouth, larynx, esophagus, stomach, colon, ovary, lung, pancreas, liver, prostate and skin.
In addition to having antineoplastic properties, the compounds of the present invention are expected to be useful in treating a variety of protein tylosine kinase associated disorders including, but not limited to, osteoporosis, osteoarthritis, restenosis, atherosclerosis, fibroplasia, angiofibromas, hemangiomas, diabetes, acute and chronic nephropathies, Kaposi""s sarcoma, atheroma, neovascular glaucoma, neovascularization associated with macular degeneration, rheumatoid arthritis, psoriatic arthritis, transplant rejection, T-cell mediated hypersensitivity diseases, including gluten-sensitive eniteropatily (Celiac disease), contact and delayed-type hypersensitivity, psoriasis, contact dermatitis, protection from ischemic or reperfusion injury such as that incurred during organ transplantation, stroke or myocardial infarction, transplantation tolerance induction, lupus, graft versus host disease, glomerulonephritis, serum sickness, respiratory and skin allergies, autoimmune alopecia, pernicious anemia, Hashimoto""s thyroiditis, autoimmune hyperthyroidism, Addison""s disease, multiple sclerosis, inflammatory bowel disease, acute inflammatory responses (for example acute respiratory distress syndrome), Behcet""s disease, atopic dermatitis, systemic sclerosis and eczema.
The test procedures used and results obtained are shown below.
Inhibitors of Src (partially purified preparation purchased from Upstate Biotechinologies) tyrosine kinase activity are analyzed in an ELISA format. The Boehringer Mannheim Tyrosine Kinase Assay Kit (Catalog number 1-534505) with a cdc2 substrate peptide containing Tyr15 is used for the assay. Horseradish Peroxidase (HRP)-conjugated anti-phosphotyrosine is used to detect phosphorylated peptide via a color reaction. Conditions recommended by the manufacturer are employed.
Reaction conditions: Five micmoliter aliquots of each compound prepared fresh at the time of the assay are added as a solution in 10 mM HEPES pH 7.5, 10% DMSO to the reaction well. Thirty-five microliters of reaction mix containing Src, bluffer and peptide/bovine serum albumin mix are acided to the compound wells and incubated at 30xc2x0 C. for 10 minutes (reaction buffer: 50 mM TrisHCl pH 7.5, 10 nM MgCl2, 0.1 mM ECTA, 0.5 mM Na3VO4). The reaction is started by addition of 10 microliters of ATP, incubated at 30xc2x0 C. for 1 hour, and stopped by addition of 20 microliters of 0.5M EDTA. The reaction mixture with the phosphorylated peptide is then transferred to a streptavidin-coated microtiter plate (provided in the kit) and allowed to bind for 20 minutes. Unbound peptide and reaction mixture is decanted and the plate is washed with PBS six times. HRP-conjugated phosphotyrosine antibody supplied in the kit is incubated with the plate for one hour, then decanted. The plate is again washed with PBS six times. Substrate (provided in the kit) is added and absorbance at 405 nm is measured.
Activity is determined as % inhibition as calculated by the formula: (1xe2x88x92Abs/Abs(max)xc3x97100% inhibition. Where multiple concentrations of the test agent are used, an IC50 (concentration which gives 50%. inhibition) may be determined. The results obtained for representative compounds of this invention are listed in Table 1. Multiple entries for a given compound indicate that it is tested multiple times.
Rat2 fibroblasts stably transformed with a plasmid containing a CMV promotor controlled v-Src/-Hu c-Src fusion gene in which the catalytic domain of human c-Src was inserted in place of the v-Src catalytic domain in the v-Src gene are used for the measurement of src dependent suspension growth. Ultra-low cluster plates (Costar #3474) are seeded with 10,000 cells per well on Day 1. Compound is added in serial two-fold dilutions from 10 micromoar to 0.009 micromolar on Day 2 and MTS reagent (Promega) is added on Day 5 (100 microliters of MTS/medium mix+100 microliters of medium already on the cells and the absorbance is measured at 490 nm. The results are analyzed as follows to yield an IC50 for proliferation (micromolar units) as follows: % inhibition=(Abs490 nm samplexe2x88x92blank)/(Abs490 nm no cmpd controlxe2x88x92blank)xc3x97100%. The results obtained for representative compounds of this invention are listed in Table 1. Multiple entries for a given compound indicate that it was tested multiple times.
Raf-1 (c-Raf) is used to phosphorylate and activate inactive GST-MEK1 which then can phosphorylate and activate inactive p42 GST-MAPK, which subsequently is measured for phosphorylation of the TEY sequence (aa""s 202-204) by a phospho-specific antibody from Sigma (cat. #77439219041) Reagents: Sf9 insect cell lysate containing full length 6his-tagged recombinant human c-Raf. (Specific Activity: xcx9c200 U/ml). Human Non-active Mek-1-GST and human GST-MAP kinase (recombinant proteins produced in E. coli).
Stock Solutions Raf Assay:
Assay Dilution Buffer (ADB): 20 mM MOPS, pH 7.2, 25 mM xcex2-glycerol phosphate, 5 mM EGTA, 1 mM sodium orthovanadate, 1 mM dithiothreitol.
Magnesium/ATP Cocktail: 500 xcexcM cold ATP and 75 mM magnesium chloride in ADB.
Active Kinase: Human Active c-Raf: Use at 0.4 U per assay point.
Non-active GST-MEK1: Use at 0.1 xcexcg per assay point.
Non-active GST-p42 MAP Kinase: Use at 1.0 xcexcg per assay point.
Stock Solutions ELISA:
TBSTxe2x80x94Tris (50 mM, pH 7.5), NaCl (150 mM), Tween-20 (0.05%)
Superblock (Pierce)
Anti-GST Ab (Pharmacia)
Anti-Phospho MAPK (Sigma)
Anti-Mouse Ab/Europium conjugate (Wallac)
Assay Procedure:
First Stage: c-Raf Dependent Activation of GST-MEK and GST-MAPK
Add 20 ml of ADB per assay (i.e. per well of a 96 well plate)
Add 10 ml of 0.5 mM cold ATP and 75 mM magnesium chloride in ADB.
Add 2 ml of c-Raf (0.4 U/assay), in conjunction with 1.6 ml non-active MEK1 (0.4 mg/assay).
Add 4 ml of non-active GST-p42 MAP Kinase (1.0 mg/assay).
Incubate for 60 minutes at 30xc2x0 C. in a shaking incubator.
Transfer this mixture to an anti-GST Ab coated 96 well plate (Nunc Immunosorb plates coated o/n with a-GST, then blocked with Pierce Superblock).
Incubate for 60 minutes at 30xc2x0 C. in a shaking incubator
Wash 3xc3x97 with TBST, add Anti-Phospho MAPK (Sigma) (1:3000)
Incubate for 60 minutes at 30xc2x0 C. in a shaking incubator
Wash 3xc3x97 with TBST, add Anti-Mouse Ab/Europium conjugate (Wallac) (1:500)
Incubate for 60 minutes at 30xc2x0 C. in a shaking incubator
Wash 3xc3x97 with TBST, Read plates in Wallac Victor model Plate Reader.
Collect data analyze in Excel for single point and IC50 determinations.
Single point assayxe2x80x94% inhibition at 10 mg/ml (% Inhibition=1xe2x88x92cpd.treated sample/untreated control). IC50 determinationsxe2x80x94done on compounds from single point assays with  greater than 80% inhibition. Typically Raf-1 assay is run at compound concentrations from 10 xcexcM to 30 nM in half log dilutions. (% inhibition is determined for each compound concentration). The results obtained for representative compounds of this invention are listed in Table 2.
Materials
Cell Lines: Human adenocarcinoma cell line LoVo which is known to be growth inhibited by low nM concentrations of a reference standard inhibitor of Ras and human adenocarcinoma cell line CaCo-2, which is known to be growth resistant to the same reference compound.
Cell Media: RPMI 1640 with 10% Fetal Bovine Serum supplemented with L-glutamine and Pennicilin/Streptomycin.
Compounds: Supplied usually as a 10 mM stock in 100% DMSO.
Normal Saline: 150 mM NaCl
Trichloroacetic Acid (TCA): 50% (w/v) in water
Sulforhodamine B (SRB): 0.4% (w/v) in 1% Acetic Acid
Tris Base: 10 min in water
Methods
Cells are plated at 2000 cells per well for cell line LoVo and 1500 cells for cell line CaCo-2 in 96 well plates. Cells are plated in media (200 xcexcl) and allowed to adhere overnight at 37xc2x0 C. At 24 hours post plating, compounds are added directly at a volume of 0.5 xcexcl. For the qualitative screen (compounds screened at 25 xcexcM) compound is added directly to cells. For the quantitative screen, compound is first diluted in DMSO to generate concentrations of compound or reference standard of: 1, 5, 10 and 25 xcexcM. It is advisable to make the dilutions in an identical 96 well plate so that compounds may be added using a multichannel micropipettor set at 0.5 xcexcl. The cells are then incubated for four days after which the media is removed using a 12 well manifold by first tipping the plate forward at a 45 degree angle and then inserting the manifold in an upright orientation to prevent the tips of the manifold from disturbing cells it the bottom of the plate. 200 xcexcl of normal saline is then added to each well using an 8 well multichannel pipettor, followed by the careful addition of 50 xcexcl of 50% TCA. The plates are then incubated for 2 hours at 4xc2x0 C., after which the supernatant is removed using the same technique as above and the plated washed twice with 200 xcexcl water. The plates are then air dried and 50 xcexcl of SRB stock solution is carefully added so that the entire bottom of each well is covered. This again may be used using an 8 well multichannel pipettor. The SRB is incubated with fixed cells for 15 minutes at room temperature after which the SRB is removed with the manifold as described above and the plates washed twice with 350 xcexcl of 1% acetic acid per well each time. The plates are then air dried after which the bound SRB is released from protein by the addition of 200 xcexcl of Tris base. Resolubilizing the SRB is aided by placing the plates on a rotator for 15-30 minutes. The absorbance of each well is determined at 550 or 562 nm using a microtiter plate reader.
Each compound or dilution thereof is performed in triplicate. Outliers are identified by visual inspection of the data. Each plate should have a xe2x80x9c0xe2x80x9d control (vehicle only).
Qualitative screen: To calculate % inhibition of a compound at 25 xcexcM, the following formula is used: 1-(experimental absorbance @ 25 xcexcM compound/xe2x80x9c0xe2x80x9d control absorbance)xc3x97100=% inhibition at 25 xcexcM. Compounds having  greater than 50% inhibition at 25 xcexcM are placed in the quantitative assay.
Quantitative Assay: A standard curve is constructed by plotting the concentration of compound against the average absorbance calculated at that concentration. A curve is plotted and the concentration at which the curve passes through the 50% the absorbance mark seen in the xe2x80x9c0xe2x80x9d control well is the IC50 calculated for that compound. Multiple entries for a given compound indicate that it was tested multiple times. The results obtained for representative compounds of this invention in Table 2.
Based on the results obtained for representative compounds of this invention, the compounds of this invention are antineoplatic agents which are useful in treating, inhibiting the growth of, or eradicating neoplasms. In particular, the compounds of this invention are useful in treating, inhibiting the growth of, or eradicating neoplasms that either express Src or raf or neoplasms that depend at least in part on the Src or raf pathways. Such neoplasms include those of the breast, kidney, bladder, mouth, larynx, esophagus, stomach, colon, ovary, lung, pancreas, skin, liver, prostate or brain. Based on the results obtained, the compounds of this invention are also useful in the treatment of osteoporosis.
As may be appreciated from the data in Tables 1 and 2, the compounds according to the invention are endowed with valuable biological properties useful in the treatment of certain diseases that are the result of deregulation of protein kinases.
The compounds of this invention may be formulated neat or may be combined with one or more pharmaceutically acceptable carriers for administration. For example, solvents, diluents and the like, and may be administered orally in such forms as tablets, capsules, dispersible powders, granules, or suspensions containing, for example, from about 0.05 to 5% of suspending agent, syrups containing, for example, from about 10 to 50% of sugar, and elixirs containing, for example, from about 20 to 50% ethanol, and the like, or parenterally in the form of sterile injectable solution or suspension containing from about 0.05 to 5% suspending agent in an isotonic medium. Such pharmaceutical preparations may contain, for example, from about 0.05 up to about 90% of the active ingredient in combination with the carrier, more usually between about 5% and 60% by weight.
The effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration and the severity of the condition being treated. However, in general, satisfactory results are obtained when the compounds of the invention are administered at a daily dosage of from about 0.5 to about 1000 mg/kg of animal body weight, optionally given in divided doses two to four times a day, or in sustained release form. For most large mammals the total daily dosage is from about 1 to 1000 mg, preferably from about 2 to 500 mg. Dosage forms suitable for internal use comprise from about 0.5 to 1000 mg of the active compound in intimate admixture with a solid or liquid pharmaceutically acceptable carrier. This dosage regimen may be adjusted to provide the optimal therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation.
The compounds of this invention may be administered orally as well as by intravenous, intramuscular, or subcutaneous routes. Solid carriers include starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, while liquid carriers include sterile water, polyethylene glycols, non-ionic surfactants and edible oils such as corn, peanut and sesame oils, as are appropriate to the nature of the active ingredient and the particular form of administration desired. Adjuvants customarily employed in the preparation of pharmaceutical compositions may be advantageously included, such as flavoring agents, coloring agents, preserving agents, and antioxidants, for example, vitamin E, ascorbic acid, BHT and BHA.
The preferred pharmaceutical compositions from the standpoint of ease of preparation and administration are solid compositions, particularly tablets and hard-filled or liquid-filled capsules. Oral administration of the compounds is preferred.
In some cases it may be desirable to administer the compounds directly to the airways in the form of an aerosol.
The compounds of this invention may also be administered parenterally or intraperitoneally. Solutions or suspensions of these active compounds as a free base or pharmacologically acceptable salt may be prepared in water suitably mixed with a surfactant such as hydroxy-propylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparation contain a preservative to prevent the growth of microorganisms.
The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier may 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.
For the treatment of cancer, the compounds of this invention may be administered in combination with other antitumor substances or with radiation therapy. These other substances or radiation treatments may be given at the same or at different times as the compounds of this invention. These combined therapies may effect synergy and result in improved efficacy. For example, the compounds of this invention may be used in combination with mitotic inhibitors such as taxol or vinblastine, alkylating agents such as cisplatin or cyclophosamide, antimetabolites such as 5-fluorouracil or hydroxyurea, DNA intercalators such as adriamycin or bleomycin, topoisomerase inhibitors such as etoposide or camptothecin, antiangiogenic agents such is angiostatin, and , antiestrogens such is tamoxifen.
As used in accordance with this invention, the term providing an effective amount of a compound means either directly administering such compound, or administering a prodrug, derivative, or analog which will form an effective amount of the compound within the body.
The invention will be more fully described in conjunction with the following specific examples which are not to be construed as limiting the scope of the invention.
USPTO Backgrounds
USPTO Backgrounds