AU2003304497B2 - Substituted quinolines as protein tyrosine kinase enzyme inhibitors - Google Patents

Substituted quinolines as protein tyrosine kinase enzyme inhibitors Download PDF

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AU2003304497B2
AU2003304497B2 AU2003304497A AU2003304497A AU2003304497B2 AU 2003304497 B2 AU2003304497 B2 AU 2003304497B2 AU 2003304497 A AU2003304497 A AU 2003304497A AU 2003304497 A AU2003304497 A AU 2003304497A AU 2003304497 B2 AU2003304497 B2 AU 2003304497B2
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chloro
compound
cyano
ethoxy
anilino
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Sridhar Krishna Rabindran
Hwei-Ru Tsou
Allan Wissner
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Wyeth LLC
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

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Description

WO 2005/034955 PCT/US2003/032612 SUBSTITUTED QUINOLINES AS PROTEIN TYROSINE KINASE ENZYME INHIBITORS BACKGROUND OF THE INVENTION This invention relates to certain substituted 3-cyano quinoline compounds as well as the pharmaceutically acceptable salts thereof. The compounds of the present 5 invention inhibit the HER-2 and epidermal growth factor receptor (EGFR) enzyme thereby inhibiting the abnormal growth of certain cell types. The compounds of this invention are anti-cancer agents and are useful for the treatment of cancer in mammals. This invention also relates to the use of 3-cyano quinolines in the treatment of cancer and the pharmaceutical preparations containing them. 10 Protein tyrosine kinases are a class of enzymes that catalyze the transfer of a phosphate group from ATP to a tyrosine residue located on a protein substrate. Protein tyrosine kinases clearly play a role in normal cell growth. Many of the growth factor receptor proteins function as tyrosine kinases and it is by this process that they effect signaling. The interaction of growth factors with these receptors is a 15 necessary event in normal regulation of cell growth. However, under certain conditions, as a result of either mutation or over expression, these receptors can become deregulated, the result of which is uncontrolled cell proliferation which can lead to tumor growth and ultimately to the disease known as cancer [Walks, A.F., Adv. Cancer Res., 60, 43 (1993) and Parsons, J.T.; Parsons, S.J., Important 20 Advances in Oncology, DeVita, V.T. Ed., J.B. Lippincott Co., Phila., 3 (1993) ]. Among the growth factor receptor kinases and their proto-oncogenes that have been identified and which are targets of the compounds of this invention are the epidermal growth factor receptor kinase (EGF-R kinase, the protein product of the erbB oncogene), and the product produced by the erbB-2 (also referred to as the neu or 25 HER-2) oncogene. Since the phosphorylation event is a necessary signal for cell division to occur and since over expressed or mutated kinases have been associated with cancer, an inhibitor of this event, a protein tyrosine kinase inhibitor, will have therapeutic value for the treatment of cancer and other diseases characterized by uncontrolled or abnormal cell growth. For example, over expression of the receptor 30 kinase product of the erbB-2 oncogene has been associated with human breast and ovarian cancers [Slamon, D. J., et. al., Science, 244, 707 (1989) and Science, 235, -1- WO 2005/034955 PCT/US2003/032612 1146 (1987)]. Deregulation of EGF-R kinase has been associated with epidermoid tumors [Reiss, M., et al., Cancer Res., 51, 6254 (1991)], breast tumors [Macias, A., et. al., Anticancer Res., 7, 459 (1987)], and tumors involving other major organs [Gullick, W. J., Brit. Med. Bull., 47, 87 (1991)]. Because of the importance of the role 5 played by deregulated receptor kinases in the pathogenesis of cancer, many recent studies have dealt with the development of specific PTK inhibitors as potential anti cancer therapeutic agents [some recent reviews: Burke. T. R., Drugs Future, 17, 119 (1992) and Chang, C. J.; Geahlen, R. L., J. Nat. Prod., 55, 1529 (1992)]. The compounds of this invention inhibit the kinase activity of EGF-R and are therefore 10 useful for treating certain disease states, such as cancer, that result, at least in part, from deregulation of this receptor. The HER-2 gene (c-erbB-2, neu) encodes a 185kDa transmembrane tyrosine kinase receptor that has partial homology with other members of the epidermal growth factor receptor family [Shih, C., Padhy, L. C., Murray, M., et al. Transforming 15 genes of carcinomas and neuroblastomas introduced into mouse fibroblasts, Nature, 290, 261-264 (1981)]. It is now known that normal human cells express a small constitutive amount of HER-2 protein on the plasma membrane. The activation of the HER-2 oncogene is believed to follow the binding of a yet unidentified growth factor ligand to the HER-2 receptor complex, which leads to heterodimerization, 20 triggering a cascade of growth signals that culminates in gene activation. More specifically, the epidermal growth factor family can be subdivided into four groups based on their receptor-binding specificities (HER-1, HER-2, HER-3, and HER-4). HER-2 is the preferred heterodimerization partner of all other HER receptors. Over expression of HER-2 has been demonstrated to lead to increased tumorigenicity, 25 tumor invasiveness, increased metastatic potential, and altered sensitivity to hormonal and chemotherapeutic agents in transfection studies in cellular and animal models [Pegram, M. D., Finn, R. S., Arzoo, K., et aL The effect of HER-2/neu over expression on chemotherapeutic drug sensitivity in human breast and ovarian cells Oncogene, 15, 537-547 (1997)]. 30 -2- HER-2 protein over expression has been reported to occur in approximately 30% of invasive human breast cancers, with HER-2 gene amplification detected in 95% or more of the specimens found to over express HER-2 protein, [Gebhardt, F., Zanker, K., Brandt, B. Differential expression of alternatively spliced c-erbB-2 mRNA in primary tumors, lymph node 5 metastases, and bone marrow micro metastases from breast cancer patients Biochem Biophys, Res. Commun., 247, 319-323 (1998)]. U.S. patent 6,288,082 issued September 11, 2001 (the '082 patent) discloses substituted 3-cyano quinoline compounds that inhibit epidermal growth factor receptor 10 (EGFR). The compounds of this application are distinguished from those of the '082 patent in their ability to act as potent HER-2 inhibitors. A reference herein to a patent document or other matter which is given as prior art is not to be taken as an admission that that document or matter was known or that the 15 information it contains was part of the common general knowledge as at the priority date of any of the claims. The invention provides a compound of the formula (E)-N-{4-[3-chloro-4-(2 pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide or 20 a pharmaceutically acceptable salt thereof. In a further embodiment, the invention also provides a method of treating, inhibiting the growth of, or eradicating neoplasms in a mammal in need thereof which comprises administering to said mammal an effective amount of (E)-N-{4-[3-chloro-4-(2 25 pyridinylmethoxy)aniline]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide or a pharmaceutically acceptable salt thereof. In yet a further embodiment, the invention also provides a pharmaceutical composition which includes (E)-N-(4-{3-chloro-4-[(3-fluorobenzyl)oxy]anilino}-3-cyano-7-ethoxy-6 30 quinolinyl)-4-(dimethylamino)-2-butenamide or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier. In yet a further embodiment, the invention also provides the maleate salt of the compound (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4 35 (dimethylamino)-2-butenamide. ream" 3 In yet a further embodiment, the invention also provides a method of treating, inhibiting the growth of, or eradicating neoplasms in a mammal in need thereof which comprises administering to said mammal an effective amount of the maleate salt of the compound (E)-N {4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino) 5 2-butenamide. In yet a further embodiment, the invention also provides a pharmaceutical composition which includes the maleate salt of the compound (E)-N-{4-[3-chloro-4-(2 pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide 10 together with a pharmaceutically acceptable carrier. In yet a further embodiment, the invention also provides a compound having the structure: 15 C I N H N H3C N Fi 3 C 20 25 'rirename> 4 In yet a further embodiment, the invention also provides a method of treating, inhibiting the growth of, or eradicating neoplasms in a mammal in need thereof which comprises administering to said mammal an effective amount of a compound having the structure: 5 C I
CH
3 0 In yet a further embodiment, the invention also provides a pharmaceutical composition 10 wherein the composition includes a compound having the structure: C I H NN CH 3 O together with a pharmaceutically acceptable carrier. 'filcnme' 5 In yet a further embodiment, the invention also provides a compound having the structure: C I H N F13 C,' 5 In yet a further embodiment, the invention also provides a method of treating, inhibiting the growth of, or eradicating neoplasms in a mammal in need thereof which comprises administering to said mammal an effective amount of a compound having the structure: NN CH3CO 10 HOOC CH renamee 6 In yet a further embodiment, the invention also provides a pharmaceutical composition wherein the composition includes a compound having the structure: C I HFN Ha N CH 3 O 5 together with a pharmaceutically acceptable carrier. 10 ""a 6a WO 2005/034955 PCT/US2003/032612 The following experimental details are set forth to aid in an understanding of the invention, and are not intended, and should not be construed, to limit in any way the invention set forth in the claims that follow thereafter. 5 DETAILED DESCRIPTION OF THE INVENTION The compounds of this invention are certain substituted 3-cyano quinolines. Throughout this patent application, the quinoline ring system will be numbered as indicated in the formula below; the numbering for the quinazoline ring system is also shown: 5 4 5 4 6 7N 3 63 7 2 7 N 2 10 8 1 8 1 The pharmaceutically acceptable salts of the compounds of this invention are those derived from such organic and inorganic acids as: acetic, lactic, citric, tartaric, succinic, maleic, malonic, gluconic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, and similarly known acceptable acids. 15 For purposes of this invention "halogen" is F, Cl, Br, or I. As used herein, the term "substituted" includes attaching a methyl group to a ring carbon The compounds of this invention may contain one or more asymmetric carbons atoms; in such cases, the compounds of this invention include the individual 20 diasteromers, the racemates, and the individual R and S entantiomers thereof. Some of the compounds of this invention may contain one or more double bonds; in such cases, the compounds of this invention include each of the possible configurational isomers as well as mixtures of these isomers. -7- WO 2005/034955 PCT/US2003/032612 For purposes of this invention a "neoplasm" is defined as cells selected from the breast, kidney, bladder, mouth, larynx, esophagus, stomach, colon, ovary, pancreas, brain, prostrate and lung having a morphology not found in the majority of 5 the cells of a mammal. In one embodiment, the present invention provides for a method of inhibiting the neoplasm. The method comprises contacting a cell with an amount of a compound effective to decrease or prevent HER-2 function. The cell may be a mammalian cell and more specifically a human cell. The cell may also be a bacterial 10 cell such as for example E co/i. The cell may include but is not limited to, a neuronal cell, an endothelial cell, a glial cell, a microglial cell, a smooth muscle cell, a somatic cell, a bone marrow cell, a liver cell, an intestinal cell, a germ cell, a myocyte, a mononuclear phagocyte, an endothelial cell, a tumor cell, a lymphocyte cell, a mesangial cell, a retinal epithelial cell, a retinal vascular cell, a ganglion cell or a 15 stem cell. The cell may be a normal cell, an activated cell, a neoplastic cell, a diseased cell, or an infected cell. In another embodiment, the present invention provides a method for the treatment or prevention of a neoplasm in a mammal. The present invention accordingly provides to a mammal, a pharmaceutical composition that comprises a 20 compound of this invention in combination or association with a pharmaceutically acceptable carrier. The compound of this invention may be administered alone or in combination with other therapeutically effective compounds or therapies for the treatment or prevention of the neoplasm. The compounds may be provided orally, by intralesional, intraperitoneal, 25 intramuscular or intravenous injection; infusion; liposome-mediated delivery; topical, nasal, anal, vaginal, sublingual, uretheral, transdermal, intrathecal, ocular or otic delivery. In order to obtain consistency in providing the compound of this invention it is preferred that a compound of the invention is in the form of a unit dose. Suitable unit dose forms include tablets, capsules and powders in sachets or vials. Such unit 30 -8- WO 2005/034955 PCT/US2003/032612 dose forms may contain from 0.1 to 300 mg of a compound of the invention and preferably from 2 to 100 mg. Still further preferred unit dosage forms contain 5 to 50 mg of a compound of the present invention. The compounds of the present invention can be administered orally at a dose range of about 0.01 to 100 mg/kg or 5 preferably at a dose range of 0.1 to 10 mg/kg. Such compounds may be administered from 1 to 6 times a day, more usually from 1 to 4 times a day. The effective amount will be known to one of skill in the art; it will also be dependent upon the form of the compound. One of skill in the art could routinely perform empirical activity tests to determine the bioactivity of the compound in bioassays and 10 thus determine what dosage to administer. The compounds of the invention may be formulated with conventional excipients, such as a filler, a disintegrating agent, a binder, a lubricant, a flavoring agent, a color additive, or a carrier. The carrier may be for example a diluent, an aerosol, a topical carrier, an aqueous solution, a nonaqueous solution or a solid 15 carrier. The carrier may be a polymer or a toothpaste. A carrier in this invention encompasses any of the standard pharmaceutically accepted carriers, such as phosphate buffered saline solution, acetate buffered saline solution, water, emulsions such as an oil/water emulsion or a triglyceride emulsion, various types of wetting agents, tablets, coated tablets and capsules. 20 When provided orally or topically, such compounds would be provided to a subject by delivery in different carriers. Typically, such carriers contain excipients such as starch, milk, sugar, certain types of clay, gelatin, stearic acid, talc, vegetable fats or oils, gums, or glycols. The specific carrier would need to be selected based upon the desired method of delivery, for example, phosphate buffered saline (PBS) 25 could be used for intravenous or systemic delivery and vegetable fats, creams, salves, ointments or gels may be used for topical delivery. The compounds of the present invention may be delivered together with suitable diluents, preservatives, solubilizers, emulsifiers, adjuvants and/or carriers useful in treatment or prevention of neoplasm. Such compositions are liquids or 30 lyophilized or otherwise dried formulations and include diluents of various buffer -9- WO 2005/034955 PCT/US2003/032612 content (for example, Tris-HCI, acetate, phosphate), pH and ionic strength, additives such as albumins or gelatin to prevent absorption to surfaces, detergents (for example, TWEEN 20, TWEEN 80, PLURONIC F68, bile acid salts), solubilizing agents (for example, glycerol, polyethylene glycerol), anti-oxidants (for example 5 ascorbic acid, sodium metabisulfate), preservatives (for example, thimerosal, benzyl alcohol, parabens), bulking substances or tonicity modifiers (for example, lactose, mannitol), covalent attachment of polymers such as polyethylene glycol, complexation with metal ions, or incorporation of the compound into or onto particulate preparations of hydrogels or liposomes, micro-emulsions, micelles, 10 unilamellar or multilamellar vesicles, erythrocyte ghosts, or spheroblasts. Such compositions will influence the physical state, solubility, stability, rate of in vivo release, and rate of in vivo clearance of the compound or composition. The choice of compositions will depend on the physical and chemical properties of the compound capable of treating or preventing a neoplasm. 15 The compound of the present invention may be delivered locally via a capsule that allows a sustained release of the compound over a period of time. Controlled or sustained release compositions include formulation in lipophilic depots (for example, fatty acids, waxes, oils). The present invention further provides a compound of the invention for use 20 as an active therapeutic substance for preventing neoplasm. The present invention further provides a method of treating neoplasm in humans, which comprises administering to the infected individual an effective amount of a compound or a pharmaceutical composition of the invention. The compounds of this invention can be prepared as outlined in Flowsheet 1 25 wherein R 1 , R 2 , and R 3 are as described above. The amino group of compound 1 can be protected as an amide group by acetylation using acetic anhydride in a solvent such as acetic acid. The hydroxyl group of 2 can be alkylated with an alkyl bromide, iodide, tosylate, or mesylate using potassium carbonate in a refluxing solvent such as acetone. The nitro group of 3 can be reduced using catalytic 30 -10- WO 2005/034955 PCT/US2003/032612 hydrogenation to give the substituted aniline 4. Heating of 4 with reagent 5 with or without a solvent gives the intermediate 6. Refluxing 6 in a high boiling solvent such as Dowtherm results in cyclization to the hydroxy quinoline 7. This can be chlorinated by heating in phosphorous oxychloride to give the chloro derivative 8. 5 Condensation of 8 with an aniline of formula 9 in a refluxing solvent such as ethanol in the presence of a catalytic amount of acid yields the intermediate 10. The acetate group of 10 can be removed by hydrolysis using acidic or basic conditions followed by neutraliztion to give 11. The intermediate 11 can be acylated with an amino acid chloride 12 (as the hydrochloride salt) to give the compounds of this invention of 10 formula 13. Methods used to prepare the compounds in U.S. patent 6,288,082, WO 9633978 and WO-9633980 can also be used to prepare the compounds of this invention and are hereby incorporated by reference. H2N Ac2O HN R 4 halogen,K 2
CO
3 HN H 2 , Pd/C HN HO NO 2 HOAc HO NO 2 0.....o NO 2 -O NH 2 1 2 3 4 0 O 2 Et HN NC CO 2 Et OH ci EtO 5ON N Dowtherm HN CN POc1 3 HN CN - H 250*C --.- O N -- O N 678 RR R2 R 2 R H2 N RR2HN R 1. 2.7 N HCI, 759C HN R HN CN r KOH, CH 3 0H H 2 N ON N 2. 10% K 2
CO
3 ,MeOH r I cH 3
SO
3 H, EtOH 1 N 01 N cl 0 H 12 HN CN 13 15 -11- WO 2005/034955 PCT/US2003/032612 Flowsheet 1 In addition to the method described herein above, there a number of patent applications that describe methods that are useful for the preparation of the compounds of this invention. Although these methods describe the preparation of 5 certain quinazolines, they are also applicable to the preparation of correspondingly substituted 3-cyanoquinolines and are hereby incorporated by reference. The chemical procedures described in the application WO-9633980 can be used to prepare the 3-cyanoquinoline intermediates used in this invention wherein the substitution at position 6 is an aminoalkylalkoxy group. The chemical procedures 10 described in the application WO-9633978 can be used to prepare the 3 cyanoquinoline intermediates used in this invention wherein the substitution at position 6 is an aminoalkylamino group. Example 1
(E)-N-{
4
-[
4 -(benzyloxy)-3-chloroanilino]-3-cyano-7-ethoxy-6-quinolinyl}-4 15 (dimethylamino)-2-butenamide A 1.74 ml (2.54 g, 0.02 moles) portion of oxalyl chloride was added to 3.31 grams (0.02 moles) of (E)-4-(dimethylamino)-2-butenoic acid hydrochloride in 75 ml of acetonitrile. To this was added a small drop of dimethylformamide. The reaction was heated and stirred in an oil bath at 630 for 20 minutes, giving an orange solution. 20 This solution as concentrated in vacuo without the application of heat to about half its original volume. This solution was cooled in an ice bath and a solution of 4.45 g (0.01 moles) of the 6 -amino- 4
-[
4 -(benzyloxy)-3-chloroanilino]-7-ethoxy-3 quinolinecarbonitrile in 50 ml of N-methyl pyrrolidone was added in a stream. The reaction was cooled and stirred for 2 hours. The reaction was poured onto 100 ml of 25 saturated aqueous sodium bicarbonate in ice. On standing the resulting gum solidified and the solid was filtered. This solid was chromatographed on silica gel. The column was washed with 3 liters of 1:19 methanol-ethyl acetate, then the product was eluted with 3 liters of 1:5:94 triethylamine-methanol-ethyl acetate. -12- WO 2005/034955 PCT/US2003/032612 Concentration of the eluate gave a solid, which was filtered to give 2.96 grams of the title compound. From the filtrate was obtained an additional 1.0 grams of product. Total: 3.96 g. Example 2 5 (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4 (dimethylamino)-2-butenamide A solution of (E)-4-(dimethylamino)-2-butenoic acid hydrochloride in 1.2 L of tetrahydrofuran (THF) and a catalytic amount of dimethylformide (DMF) (1.2 ml) was cooled to 0-5 *C. Oxalyl chloride (0.95 eq) was added dropwise and the mixture was 10 warmed to 25-30 0C and stirred for 2 hours. The orange suspension was checked for complete consumption of oxalyl chloride by HPLC then cooled to 0-5 C. A solution of 111 g of 4-[4-(2-pyridylmethoxy)-3-chloro]amino-6-amino-3-cyano-7 ethoxyquinoline in 1.47 L of 1-methyl-2-pyrrolidinone was added dropwise and the mixture was stirred until 5 1.0% of the starting aniline remained (3-16 hours). The 15 reaction was quenched with water and the mixture was warmed to 40 C. Aqueous sodium hydroxide was added to bring the pH to 10-11. The resulting precipitates were filtered hot and washed with water. The wet solids were heated to reflux (70-75 0C) in acetonitrile:THF (1.5:1) and the solution cooled over 3 hours to room temperature. The product was filtered and washed with acetonitrile:THF. The 20 product was dried (50 *C, 10 mm Hg, 24 hours) to give 80-85% yield. Melting point of maleate salt 178 - 183 C. Example 3 (E)-N-(4-{3-chloro-4-[(3-fluorobenzyl)oxy]anilino}-3-cyano-7-ethoxy-6-quinolinyl)-4 (dimethylamino)-2-butenamide 25 A solution of 108 g (E)-4-(dimethylamino)-2-butenoic acid hydrochloride in 1.1 L of tetrahydrofuran (THF) and a catalytic amount of dimethylformide (DMF) (1.2 ml) was cooled to 0-5 *C. Oxalyl chloride (0.95 eq) was added dropwise and the mixture was warmed to 25-30 0C and stirred for 2 hours. The orange suspension was checked -13- WO 2005/034955 PCT/US2003/032612 for complete consumption of oxalyl chloride by HPLC then cooled to 0-5 0C. A solution of 150 g of 6-amino-4-[3-chloro-4-(3-fluorobenzyloxy)]anilino-3-cyano-7 ethoxy quinoline in 1.5 L of 1-methyl-2-pyrrolidinone was added dropwise and the mixture was stirred until 1.0% of the starting aniline remained (3-16 hours). The 5 reaction was quenched with water and the mixture was warmed to 40 C. Aqueous sodium hydroxide (101 g in 750 ml) was added to bring the pH to 10-11. The resulting precipitates were filtered hot and washed with water. The wet solids were heated to reflux (70-75 0C) in acetonitrile:THF (1.5:1) and the solution was cooled over 3 hours to room temperature. The product was filtered and washed with 10 acetonitrile:THF. The product was dried (50 C, 10 mm Hg, 24 h) and obtained in 80-85% yield. Melting Point 165 - 167 0C Example 4 4-Benzyloxy-3-chloro-nitrobenzene A 15.43 g (0.275 moles) portion of solid (pellets) potassium hydroxide was added to 15 a solution of 43.89 g (0.25 moles) of 3-chloro-4-fluoro nitrobenzene and 32.34 ml (33.79 grams, 0.373 moles) of benzyl alcohol in 220 ml of acetonitrile. The reaction was vigorously stirred with a mechanical stirrer overnight. The resulting solid was filtered. Concentration of the filtrate gave a second crop, which was also filtered. On standing more solid came out of this filtrate. This mixture was treated with ether, 20 and the solid filtered. All solids were washed thoroughly with water, and combined to give 49.71 g of the title compound. Example 5 4-Benzyloxy-3-chloro-phenylamine A mixture of 6.59 g (0.025 moles) of the 4-benzyloxy-3-chloro nitrobenzene (example 25 4), 4.19 g (0.075 moles) of iron powder, and 12.04 g (0.225 moles) of ammonium chloride in 100 ml of ethanol and 25 ml of water was stirred mechanically and refluxed for half an hour. The reaction was allowed to cool and stir for 1 hour. The mixture was filtered and solids were washed with ethanol. The combined filtrates -14- WO 2005/034955 PCT/US2003/032612 were taken to dryness in vacuo. This solid was dissolved in methylene chloride and passed through Magnesol. Removal of the solvent from the filtrate in vacuo gave 5.60 g of title compound. Example 6 5 N-{4-[4-(Benzyloxy)-3-chloroanilino]-3-cyano-7-ethoxy-6-quinolinyl}acetamide A mixture of 4.17 g (0.0149 moles) of the N-(4-chloro-3-cyano-7-ethoxy-6 quinolinyl)acetamide, 4.04 g (0.0173 moles) of 4-benzyloxy-3-chloro-phenylamine (example 5), and 2.0 g (0.017 moles) of pyridine hydrochloride in 85 ml of isopropanol was stirred and refluxed in an oil bath for 30 minutes. The reaction was 10 cooled in an ice bath, and the solid, was collected by filtration and washed with isopropanol, and then with ether yielding 7.26 g of crude product as the hydrochloride salt. This material was purified by chromatography of the free base on silica gel by elution with 1:39 methanol-methylene chloride. Example 7 15 6-Amino-4-[4-(benzyloxy)-3-chloroanilino]-7-ethoxy-3-quinolinecarbonitrile A solution of 298 mg (0.612 mmoles) of the purified N-{4-[4-(benzyloxy)-3 chloroanilino]-3-cyano-7-ethoxy-6-quinolinyl}acetamide (example 6) and 97 mg (1.73 mmoles) of potassium hydroxide in 10 ml of methanol was stirred and refluxed for 60 hours. On cooling a solid formed. This mixture was poured onto ice, and the 20 resulting solid was filtered and washed with water. On drying, 242 mg of the title compound was obtained. Example 8 2-Acetamido-5-nitrophenol To 400 g of 2-amino-5-nitrophenol in a 5-L multi-necked flask equipped with a 25 mechanical stirrer, reflux condenser, nitrogen inlet, 500-mL addition funnel, heating mantle, and a thermocouple attached to a temperature controller was added 1.6 L of acetic acid. The mixture was stirred at 60 0 C as 398 g of acetic anhydride was -15- WO 2005/034955 PCT/US2003/032612 added over 1.5 hours. After 1 hour, another 37 g of acetic anhydride was added. After another 1 hour, the mixture was cooled and diluted with 2 L of water. Solid was collected by filtration and washed with water and heptane. The solid was dried in a vacuum oven to give 509 g of the title compound. 5 Example 9 4-Acetamido-3-ethoxynitrobenzene To 400 g of 2-acetamido-5-nitrophenol in a 12-L, 4-necked flask equipped with a reflux condenser, nitrogen inlet, thermocouple, addition funnel, and mechanical stirrer was added 790 g of potassium carbonate and 2.0 L of dimethylformamide. 10 The mixture vvas stirred at 60 *C as 294 g of ethyl bromide was added over 30 minutes. After 1 hour, an additional 27 g of ethyl bromide was added and the mixture was stirred at 60 LC for another hour. The mixture was cooled to room temperature and poured into 4 L of water. After 30 minutes, the product was collected by filtration and washed with water and heptane. The product was dried in 15 a vacuum oven at 60 *C to give 457 g of the title compound. Example 10 3-(4-Acetamido-3-ethoxyaniline)-2-cyanopropenoic acid ethyl ester A suspension of 4-acetamido-3-ethoxynitrobenzene compound in tetrahydrofuran (10 parts) was reduced to the aniline derivative using 10% Pd/C wet at 50 psi 20 hydrogen and 30 0C for 2 hours. The resulting solution was filtered and concentrated to 2 parts of tetrahydrofuran. The concentrate was diluted with toluene and allowed to react with commercially available ethyl (ethoxymethylene)cyanoacetate at reflux for 16 hours. After reaction completion, the mixture was cooled. The precipitated product was collected by filtration, washed and 25 dried. The product was obtained in 90% yield. -16- WO 2005/034955 PCT/US2003/032612 Example 11 3-Cyano-7-ethoxy-4-hydroxy-6-N-acetyquinoline A solution of 210 g of 3-(4-acetamido-3-ethoxyaniline)-2-cyanopropenoic acid ethyl ester in 12 L of Dowtherm was stirred under nitrogen at 250 "C for 15 to 20 hours. 5 The mixture was cooled to room temperature and solid was collected by filtration. The solid was washed with toluene and mixed with 1.2 L of tetrahydrofuran. The mixture was refluxed for 30 minutes and then cooled to room temperature. The solid was collected and washed with tetrahydrofuran. After drying 179.4 g of the title compound was obtained. 10 Example 12 4-Chloro-3-cyano-7-ethoxy-6-nitro quinoline A stirred mixture of 300 g 3-cyano-7-ethoxy-4-hydroxy-6-N-acetylquinoline in 2.53 L of 1,2-diethoxyethane was heated to 80-85 0C. To this was added 224 ml of 15 phosphorus oxychloride over 30-40 minutes. The mixture was stirred at 80-85 0C for 2-4 hours. The mixture was cooled, filtered over a celite pad and washed with 1,2 diethoxyethane. The filtrates were added over 1.5 hours to a cooled (0-10 0C) potassium carbonate (537 g in 1.5 L water) solution. The resulting yellow mixture was stirred for a minimum of 12 hours. The mixture was filtered and washed with hot 20 water. The solids were dried (50 C, 10 mm Hg, 24 h) to give the title compound in 30-50% yield. The material was used directly in the next step. Example 13 3-Chloro-4-(2-pyridylmethoxy)nitrobenzene 25 A mixture of 160 g of potassium hydroxide and 2-pyridylcarbinol in 8 L acetonitrile was stirred for 20-30 minutes. To this was added 400 g of 3-chloro-4 fluoronitrobenzene and the mixture was stirred at 40 0C for a minimum of 18 hours -17- WO 2005/034955 PCT/US2003/032612 until the reaction was complete. Water was added and the precipitated yellow solids were filtered and washed with water. The product was dried (40-50 0C, 10 mm Hg, 24 h) to the product in 85-95% yield. Example 14 5 3-Chloro-4-(3-fluorobenzyloxy)nitrobenzene This compound was prepared from 3-chloro-4-fluoronitrobenzene and 3-fluorobenzyl alcohol using the method described above in Example 13. Example 15 10 6-Amino-4-(3-chloro-4-(3-fluorobenzyloxy))anilino-3-cyano-7-ethoxy quinoline To a mixture of 400 g of 3-chloro-4-(3-fluorobenzyloxy)nitrobenzene (example 14) and 464 g zinc dust in 4 L of ethanol at 40-50 0C was added aqueous ammonium chloride (152 g in 800 ml water). After stirring a minimum of 2 hours, the reaction mixture was filtered hot through a celite pad and washed with hot ethanol. The 15 filtrate was evaporaed and 1.72 L of 2-methyl THF, water and brine were added. The organic layer was separated and washed with water. The organic layer was evaporated and replaced with 3.8 L of ethanol. 4-Chloro-3-cyano-7-ethoxy-6-N acetylamino-quinoline was added with a catalytic amount of methane sulfonic acid and the mixture was heated at 70-75 0C for a minimum of 2 hours until reaction 20 completion. Concentrated 1.69 L HCI was added at 70-75 0C and held for a minimum of 2 hours until complete hydrolysis. Water was added and the mixture was cooled to 40 C, solid was collected and washed with water. The wet cake was slurried in 5.4 L of methanol, 10% aqueous potassium carbonate (315 g in 2.8 L water) was added and the mixture was stirred for 2.5 hours. The mixture was filtered 25 and washed with 1:1 methanol:water. The product was dried (50 C, 10 mm Hg, 24 hours) to give the title compound in 80-90% yield. -18- WO 2005/034955 PCT/US2003/032612 Example 16 6-Amino-4-(4-(2-pyridylmethoxy)-3-chloro)anilino-3-cyano-7-ethoxyquinoline The above-identified compound was prepared from 3-chloro-4-(2 pyridylmethoxy)nitrobenzene and 4-chloro-3-cyano-7-ethoxy-6-N-acetylamino 5 quinoline using the method described above in Example 15. Example 20 4-Dimethyl-but-2-enoic acid [4-(3-chloro-4-fluoro-phenylamino)-3-cyano-7 ethoxy-quinolin-6-yl]-amide NH C1 H N N NN 0 N 10 Example 21 N-{4-[3-Chloro-4-(1 -methyl-1 H-imidazol-2-ylsulfanyl)-phenylamino]-3-cyano quinolin-6-yl}-acrylamide CH3 o H I: HN: C I 15 H HN N N -19- WO 2005/034955 PCT/US2003/032612 Example 22 6,7-Diethoxy-4-(1 H-indol-6-ylamino)-quinoline-3-carbonitrile NH 5H "e N 5
H
3 %,/O , HC Example 23 4-(2,3-Dihydro-benzo[1 ,4]dioxin-6-ylamino)-6,7-diethoxy-quinoline-3 carbonitrile 10 N 0 N Ho ColN
CH
3 15 Example 24 4-(1 H-Indazol-6-ylamino)-6,7-bis-(2-methoxy-ethoxy)-quinoline-3-carbonitrile N-NH NH
H
3 CCN 20 0 0 N 0
-CH
3 -20- WO 2005/034955 PCT/US2003/032612 Example 25 4-(1 ,4-Dioxo-1 ,2,3,4-tetrahydro-phthalazin-6-ylamino)-6,7-diethoxy-quinoline 3-carbonitrile HN0 HN 50 /NH 0 Cl_ CH N" Example 26 10 6,7-Diethoxy-4-(indan-5-ylamino)-quinoline-3-carbonitrile kNH 0 O N O 15 Example 27 4-(2,4-Dioxo- 1,4-dihyd ro-2H-benzo[d] [1 ,3]oxazin-6-ylamino)-6,7-diethoxy quinoline-3-carbonitrile 0 o 0 HN:& 20 CON 20N 7 6) N CMH, -21- WO 2005/034955 PCT/US2003/032612 Example 28 6,7-Diethoxy-4-(1 -oxo-indan-5-ylamino)-quinoline-3-carbonitrile 011 5 NH H3C O 0 HC Example 29 6,7-Diethoxy-4-(3-oxo-1,3-dihydro-isobenzofuran-5-ylamino)-quinoline-3 10 carbonitrile 0 0 /NH H 3 r' 00/ C o N HC 15 Example 30 4-(1,1 -Dioxo-1 H-1 -benzo[b]thiophen-6-ylamino)-6,7-diethoxy-quinoline-3 carbonitrile 0 /NH 20 H3 N 0 C N
H
3 C -22- WO 2005/034955 PCT/US2003/032612 Example 31 7-Ethoxy-4-(1 H-indazol-6-ylamino)-6-methoxy-quinoline-3-carbonitrile HNN HN- O N
H
3 C0 C!I 0 N
H
3 C Example 32 6-Ethoxy-4-(1 H-indazol-6-ylamino)-7-methoxy-quinoline-3-carbonitrile NH N 10 HC 0C 0 N CH, Example 33 6,7-Diethoxy-4-(1 -methyl-2,5-dioxo-2,3,4,5-tetrahydro-1 H 15 benzo[e][1,4]diazepin-7-ylamino)-quinoline-3-carbonitrile OH, N HN 'NH N j,
H
3 C 0 -23- WO 2005/034955 PCT/US2003/032612 Example 34 4-(1 H-Indazol-6-ylamino)-6-methoxy-7-(3-morpholin-4-y-propoxy)-quinoline 3-carbonitrile N 5 HN NH
H
3 CO Example 35 10 4-({3-chloro-4-[(1 -methyl-1 H-imidazol-2-yl)sulfanyl]phenyl}amino)-7-methoxy 6-nitro-3-quinolinecarbonitrile N HC' cl & NH O N 15 I
H
3 C Example 36 6-amino-4-({3-chloro-4-[(1 -methyl-1 H-imidazol-2-yl)sulfanyl]phenyl}amino)-7 methoxy-3-quinolinecarbonitrile CIH3 20 HN&cH
CH
3 -24- WO 2005/034955 PCT/US2003/032612 Example 37 (2E)-N-[4-({3-chloro-4-[(1 -methyl-1 H-imidazol-2-yl)sulfanyl]phenyl}amino)-3 cyano-7-methoxy-6-quinolinyl]-4-(dimethylamino)-2-butenamide 5 HN(C CHI Example 38 4-{[3-chloro-4-( 1,3-thiazol-2-ylsulfanyl)phenyllamino}-7-methoxy-6-nitro-3 10 quinolinecarbonitrile s N Y OZQNH H~acN I I II HaC 15 Example 39 6-amino-4-{[3-chloro-4-(1,3-thiazol-2-ylsulfanyl)phenyl]amino}-7-methoxy-3 quinolinecarbonitrile Y S N C 20 C NH
H
3 C -25- WO 2005/034955 PCT/US2003/032612 Example 40 (2E)-N-(4-{[3-chloro-4-(1 ,3-thiazol-2-ylsulfanyl)phenyljamino}-3-cyano-7 methoxy-6-q uinolinyl)-4-(dimethylamino)-2-butenamide CH, 5 HCN/cl 0 ~HN'& HNN HC, Example 41 4-[3-chloro-4-( 1 H-imidazol-1 -yl)anilino]-7-methoxy-6-nitro-3-idazol-1 10 yl)anilino]-7-methoxy-6-nitro-3-quinolinecarbonitrile + NN N H 0 I Example 42 15 6-amino-4-[3-chloro-4-(1 H-imidazol-1 -yl)anilino]-7-methoxy-3-4-(1 H-imidazol 1 -yl)anilino]-7-methoxy-3-quinolinecarbonitrile >N HN 20I 0N
H
3 C -26- WO 2005/034955 PCT/US2003/032612 Example 43 (E)-N-{4-[3-chloro-4-(1 H-imidazol-1 -yl)anilino]-3-cyano-7-methoxy-6 quinolinyl}-azol-1 -yl)anilino]-4-(dimethylamino)-2-)anilino-2-butenamide 5 N N HHC C H 10 Example 44 4-{3-chloro-4-[(4-oxo-3,4-dihydro-2-quinazolinyl)sulfanyl]anilino}-7-methoxy 6-hydro-2-quinazolinyl)sulfanyl]anilino}-7-methoxy-6-nitro-3 quinolinecarbonitrile Cl 0 HN& 15 0 N C Example 45 6-amino-4-{3-chloro-4-[(4-oxo-3,4-dihydro-2-quinazolinyl)sulfanyl]anilino}-7 3,4-dihydro-2-quinazolinyl)sulfanyl]anilino}-7-methoxy-3-quinolinecarbonitrile 20 CI HN H H3C H3- NO -27- WO 2005/034955 PCT/US2003/032612 Example 46 (E)-N-(4-{3-chloro-4-[(4-oxo-3,4-dihydro-2-quinazolinyl)sulfanyl]anilino}-3 fany]anilino}-3-cyano-7-methoxy-6-quinolinyl)-4-(dimethylamino)-2 butenamide 5 c
H
3 H O HN"& H3C Ojo N Example 47 10 (E)-N-(4-{4-[acetyl(3-pyridinylmethyl)amino]-3-chloroanilino}-3-cyano-7 methoxy-]-3-chloroanilino}-3-cyano-7-methoxy-6-quinol inyl)-4 (dimethylamino)-2-oanilino}-3-cyano-7-methoxy-6-quinolinyl)-4 (dimethylamino)-2-butenamide NN H3C O HN 15 C IH3 H N) N 0 Example 48 N-{2-chloro-4-[(3-cyano-7-methoxy-6-nitro-4-quinolinyl)amino]phenyl}-N-(3-7 methoxy-6-nitro-4-quinolinyl)amino]phenyl}-N-(3-pyridinylmethyl)acetamide 20 cH N o - HN HOl O C N
H
3 C 0 N -28- WO 2005/034955 PCT/US2003/032612 Example 49 N-{4-[(6-amino-3-cyano-7-methoxy-4-quinolinyl)amino]-2-chlorophenyl}-N-(3methoxy-4-quinolinyl)amino]-2-chlorophenyl}-N-(3-pyridinylmethyl)acetamide 5 HN"& H3C Example 50 N-(4-{[6-(acetylamino)-3-cyano-7-methoxy-4-quinolinyl]amino}-2 chlorophenyl)-N-ano-7-methoxy-4-quinolinyl]amino}-2-chlorophenyl)-N-(3 10 pyridinylmethyl)acetamide
H
3 C N
H
3 O. HN HN C 0 N 15 Example 51 4-{3-chloro-4-[(1-methyl-1 H-imidazol-2-yl)sulfanyl]anilino}-6-methoxy-7-[3-(4 morpholinyl)propoxy]-3-quinolinecarbonitrile OH3 20 HN6T -29 -29- WO 2005/034955 PCT/US2003/032612 Example 52 4-(3-chloro-4-{[5-(trifluoromethyl)-1 ,3,4-thiadiazol-2-yl]aminolanilino)-7 ethoxy-6-nitro-3-quinolinecarbonitrile F 0-c 0 N HC Example 53 10 (E)-N-[4-(3-chloro-4-{[5-(trifluoromethyl)-1 ,3,4-thiadiazol-2-yl]aminolanilino) 3-cyano-7-ethoxy-6-quinolinyl]-4-(dimethylamino)-2-butenamide HN \\Tk F N HSC% N.
4 N.NH , _ N 15CIH 3 0 )O N 15 H3C Example 54 4-[3-chloro-4-(4-pyridinyloxy)aniIi no]-7-ethoxy-6-nitro-3-quinolinecarbonitrile 0~0 0 HN
H
3 C -30- WO 2005/034955 PCT/US2003/032612 Example 55 6-amino-4-[3-chloro-4-(4-pyridinyloxy)anilino]-7-ethoxy-3-quinolinecarbonitrile /N HN
H
2 N N
H
3 C Example 56 (E)-N-{4-[3-chloro-4-(4-pyridinyloxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4 10 (dimethylamino)-2-butenamide HN H3C ", NH C N CH, 0NT HC 15 Example 57 4-{3-chloro-4-[(3-pyridinylmethyl)amino]anilino}-7-methoxy-6-nitro-3 quinolinecarbonitrile HN N HN 20 NO, CN
OCH
3 N -31- WO 2005/034955 PCT/US2003/032612 Example 58 (E)-N-(4-{3-chloro-4-[(4-phenyl-1 ,3-thiazol-2-yl)sulfanyl]anilino}-3-cyano-7 methoxy-6-quinolinyl)-4-(dimethylamino)-2-butenamide CH3I 5 H 3 CN~NN HN \/S HNS N N 0 N Example 59 6-ami no-4-(3-chloro-4-{[5-(trifluoromethyl)-1 ,3,4-thiadiazol-2 yi]aminolanilino)-7-ethoxy-3-quinolinecarbonitrile 10 F F HN_(I NN H 0 Nr
H
3 C 15 Example 60 4-[3-chloro-4-(1 H-imidazol-1 -ylmethyl)anilino]-7-ethoxy-6-nitro-3 quinolinecarbonitrileN 0 HN I 20N H -11 0) N. _32- WO 2005/034955 PCT/US2003/032612 Example 61 6-amino-4-[3-ohloro-4-(1 H-imidazol-1 -ylmethyl)anilino]-7-ethoxy-3 quinolinecarbonitrileN N 5
H
2 N Cr
H
3 C 0 Example 62 (E)-N-{4-[3-chloro-4-(1 H-imidazol-1 -ylmethyl)anilino]-3-cyano-7-ethoxy-6 10 quinolinyl}-4-(dimethylamino)-2-butenamide N IN C
CH
3 MNjo 15 Example 63 4-{3-chloro-4-[(4-methyl-2-pyrimidinyl)sulfanyl]anilino}-7-ethoxy-6-nitro-3 quinolinecarbonitrile 20 0 HN 2 ' CIN J,
H
3 C I _.33- WO 2005/034955 PCT/US2003/032612 Example 64 6-amino-4-{3-chloro-4-[(4-methyl-2-pyrimidinyl)sulfanyl]anilino}-7-ethoxy-3 quinolinecarbonitrile 5 HNa:lN H N
H
3 C or Example 65 (E)-N-(4-{3-chloro-4-[(4-methyl-2-pyrimidinyl)sulfany]anilino}-3-cyano-7 10 ethoxy-6-quinolinyl)-4-(dimethylamino)-2-butenamide
H
3 Ni N Z H I &I CH, HN v 15 Example 66 (E)-N-(4-{3-chloro-4-[(4,6-dimethyl-2-pyrimidinyl)sulfanyl]anilino}-3-cyano-7 ethoxy-6-quinolinyl)-4-(dimethylamino)-2-butenamide N~ CH 3 HAC N HN)kcl 20 CH, HN O H 3 -34- WO 2005/034955 PCT/US2003/032612 Example 67 7-ethoxy-6-nitro-4-[4-[(4-phenyl-1 ,3-thiazol-2-yI)sulfanyl]-3 (trifiuoromethyl)anilino]-3-quinolinecarbonitrile 5F 10 HN S I N Example 69 15 (E)6-N-{-no-7-ethoxy-4-[4-[(4-phenyl-1,-thiazol-2-ylsulfanyl]-3 trifluoromethyl-panl]--qinolqinlin-4-ime tln)2btnmd 10 N HNN
OH
3 Exm0e6 15 (E)-N-{3-cyano-7-ethoxy-4-[4-5-ey-,thao2ylsfnl]3 WO 2005/034955 PCT/US2003/032612 Example 70 (E)-N-(4-{3-chloro-4-[(5-phenyl-1,3-thiazol-2-yl)sulfanyl]anilino}-3-cyano-7 methoxy-6-quinolinyl)-4-(dimethylamino)-2-butenamide 5 S N C1
CH
3 0 HsC H Cf N
H
3 C 10 Example 71 (E)-N-{4-[3-chloro-4-(1,3-thiazol-2-ylsulfanyl)anilino]-3-cyano-7-methoxy-6 quinolinyl}-4-[(2-methoxyethyl)(methyl)amino]-2-butenamide SN S C1 15 CH3O H3C...N H C'¢E'N
H
3 Co (E)-N-{4-[3-chloro-4-(1,3-thiazol-2-ylsulfanyl)anilino]-3-cyano-7-methoxy-6 20 quinolinyl}-4-[(2-methoxyethyl)(methyl)amino]-2-butenamide was prepared by adding dropwise, 3.43 g (18.71 mmol, 1.95 mL) 4-bromocrotonyl chloride in 12 mL THF over 45 minutes to a stirred solution of 4.7 g (10.69 mmol) 6-amino-4-[3-chloro-4-(thiazol -36- WO 2005/034955 PCT/US2003/032612 2-ylsulfanyl)-phenylamino]-7-methoxy-quinolin-3-carbonitrile in 588 mL THF containing 3.73 mL (21.36 mmol) diisopropylethylamine, at 0 'C under nitrogen. The reaction produced a mixture of 4-bromo-(and chloro)-but-2-enoic acid {4-[3-chloro-4 (thiazol-2-ylsulfanyl)-phenylamino]-3-cyano-7-methoxy-quinolin-6-yl}-amide. A 300 5 mL portion of the solution was cooled to 0 *C and 2.38 g (26.7 mmol) (2 methoxyethyl)-methylamine in 11 mL THF was added dropwise. After the reaction had warmed to room temperature, 401 mg (0.5 eq) of sodium iodide was added and the solution was stirred overnight. The solvents were evaporated to leave a red gum, which was partitioned between EtOAc and saturated NaHCO 3 . After standing 10 overnight, the layers were separated and the organic layer was dried and evaporated. Chromatography of the residue on a short column of Kieselgel 60, eluting with EtOAc, then EtOAc/1 5% MeOH, and finally EtOAc/1 5% MeOH/1 % Et 3 N yielded 1.3 g (41%) of the product as a yellow glass; HRMS (ESI) m/z 595.13338 (M)+', A = -2.28 mmu. 15 Example 72 (E)-N-(4-{3-chloro-4-[(4-phenyl-1,3-thiazol-2-yl)sulfanyl]anilino}-3-cyano-7 ethoxy-6-quinolinyl)-4-(dimethylamino)-2-butenamide CI HC- C HN\ / SN HN N 20 HC 0 N -37- WO 2005/034955 PCT/US2003/032612 Example 73 4-{3-chloro-4-[(1-methyl-1 H-imidazol-2-yl)sulfanyl]anilino}-6-methoxy-7-[3 (1 H-1,2,3-triazol-1 -yl)propoxy]-3-quinolinecarbonitrile 5 N,\ N 5cl N NCH3 s HN' H3Cr 0 C :N N O N N%N 10 Example 74 4-{3-chloro-4-[(4,6-dimethyl-2-pyrimidinyl)sulfany]anilino}-7-ethoxy-6-nitro 3-quinolinecarbonitrile S N CH 3 15 0i HN'a ~CI H N
CH
3
H
3 C -O ZO -P -38- WO 2005/034955 PCT/US2003/032612 Example 75 6-amino-4-{3-chloro-4-[(4,6-dimethyl-2-pyrimidinyl)sufanyl]anili no}-7-ethoxy-3 quinolinecarbonitrile 5HN C C'
H
2 N N CH3
H
3 C Example 76 (2E)-N-{4-[3-chloro-4-(2-thienylmethoxy)anilino]-3-cyano-7-ethoxy-6 quinolinyl}-4-(dimethylamino)-2-butenamide N 1/ HN Cl N N 10 -N Representative compounds of this invention were evaluated in several standard pharmacological test procedures that showed that the compounds of this invention possess significant activity as inhibitors of HER-2 and are antiproliferative agents. Based on the activity shown in the standard pharmacological test 15 procedures, the compounds of this invention are therefore useful as antineoplastic agents. The test procedures used and results obtained are shown below. Kinase Assays: example 1, example 2 and example 3 are potent inhibitors of the HER-2 enzyme, example 20 is not. Purified recombinant C-terminal fragment of each enzyme is incubated with ATP in the absence or presence of a range of 20 compound concentrations. Autophosphorylation of the receptors was evaluated with phosphotyrosine antibodies in an ELISA format. In a cell-free autophosphorylation -39- WO 2005/034955 PCT/US2003/032612 assay using the recombinant cytoplasmic domain of HER-2, all three inhibitors reduced enzyme activity by 50% (ICgo) at concentrations between 33-65 nM (Table 1). Table 1 Enzyme IC5o (pg/mL) Compound HER-2 EGFR Example 1 0.036 0.028 Example 2 0.033 0.051 Example 3 0.019 0.019 Example 20 0.58 0.02 5 They also inhibited EGFR under similar assay conditions at 33-92 nM. Cell Proliferation Assays: example 1, example 2, and example 3 repressed the proliferation of a mouse fibroblast cell line transfected with the HER-2 oncogene (3T3/neu) by 50% (ICso) at 3-5 nM (Table 2). This value was substantially lower than 10 that obtained with the isogenic untransfected cells (3T3; IC50 683-906 nM), indicating a high degree of selectivity for this oncogenic pathway. Cells were incubated with various concentrations of compound for 2 days (6 days for BT474 cells). Cell survival was determined using a protein binding dye assay (SRB),(Rubinstein LV, Shoemaker RH, Paull KD, Simon RM, Tosini S, Skehan P, Scudiero DA, Monks A, 15 Boyd MR. Comparison of in vitro anticancer-drug-screening data generated with a tetrazolium assay versus a protein assay against a diverse panel of human tumor cell lines. J. Natl. Cancer Inst. 82(13):1113-8, 1990, Skehan P, Storeng R, Scudiero D, Monks A, McMahon J, Vistica D, Warren JT, Bokesch H, Kenney S, Boyd MR. New colorimetric cytotoxicity assay for anticancer-drug screening. J. Natl. Cancer 20 Inst. 82(13):1107-12, 1990). -40- WO 2005/034955 PCT/US2003/032612 The concentration of drug (nM) which inhibits enzyme activity or cell proliferation by 50% is shown. The three inhibitors also inhibited two other HER-2 overexpressing breast cancer cell lines, SK-Br-3 and BT474 (ICo 2-4 nM), but were much less active on MDA-MB-435 and SW620 cells (a breast cancer and a colon 5 cancer cell line, respectively), that are EGFR- and HER-2-negative. The compounds repressed the epidermal carcinoma cell line, A431, that overexpresses EGFR (IC50 81-120 nM) (Table 2). Table 2 CELL IC50 (pg/mL) EGFR - - - + Her-2 - + +++ +++ COMPOUND 3T3 3T3/NEU A431 SKBr3 BT474 MDA-MB- SW620 435 Example 1 0.38 0.0029 0.062 0.0015 0.0014 0.47 0.24 Example 2 0.39 0.0018 0.045 0.001 0.0013 0.44 0.44 Example 3 0.52 0.0023 0.069 0.0015 0.0024 0.51 0.29 Example 20 0.26 0.0230 0.030 0.0071 0.020 0.34 0.32 Example 21 0.463 0.62 0.01 4.57 1.84 Example 22 0.933 0.123 0.0374 0.365 0.286 Example 23 0.375 0.27 0.281 0.235 0.411 Example 24 >5 1.961 >5 2.045 >5 Example 25 >5 >5 >5 >5 >5 -41- WO 2005/034955 PCT/US2003/032612 Table 2 CELL IC5o (pg/mL) EGFR - - - + Her-2 - + +++ +++ COMPOUND 3T3 3T3/NEU A431 SKBr3 BT474 MDA-MB- SW620 435 Example 26 0.0198 0.342 0.294 0.352 0.294 Example 27 4.616 >5 >5 >5 2.922 Example 28 0.0311 0.0181 0.0281 0.028 0.0244 Example 29 3.301 >5 >5 3.404 1.565 Example 30 0.251 0.257 0.336 0.00328 0.146 Example 31 0.0267 0.0368 0.022 0.0359 0.0212 Example 32 4.801 0.786 2.094 2.626 4.313 Example 33 >5 >5 >5 >5 >5 Example 34 >5 >5 >5 >5 >5 Example 35 4.09 2.88 0.669 1 1.55 Example 36 1.06 3.04 0.011 0.39 3.16 Example 37 0.02 0.02 0.0004 0.43 0.43 Example 38 0.262 0.148 0.124 0.35 0.15 -42- WO 2005/034955 PCT/US2003/032612 Table 2 CELL IC50 (pg/mL) EGFR - - - + Her-2 - + +++ +++ COMPOUND 3T3 3T3/NEU A431 SKBr3 BT474 MDA-MB- SW620 435 Example 39 0.333 0.663 0.236 0.65 0.55 Example 40 0.002 0.017 0.0007 0.33 1.13 Example 41 1.09 1.79 1.48 0.95 1.66 Example 42 0.53 1.63 1.73 1.27 5.99 Example 43 1.46 0.51 0.32 0.57 1.45 Example 44 4.54 2.28 4.54 >5 1.96 Example 45 1.88 1.22 2.15 4.58 4.66 Example 46 0.15 0.34 0.06 >5 >5 Example 47 >5 0.646 >5 1.16 1.64 Example 48 1.79 1.6 0.68 2.61 2.57 Example 49 2.4 >5 3.41 3.76 >5 Example 50 >5 3.68 3.94 >5 >5 -43- WO 2005/034955 PCT/US2003/032612 Table 2 CELL ICso (pg/mL) EGFR - - +++ - + Her-2 - +++ + +++ +++ COMPOUND 3T3 3T3/NEU A431 SKBr3 BT474 MDA-MB- SW620 435 Example 51 0.196 0.775 0.32 2.18 Example 52 1.89 1.79 1.22 1.84 2.54 Example 53 0.89 0.728 0.179 0.95 1.05 Example 54 >5 >5 >5 2.54 >5 Example 55 >5 >5 >5 1.61 >5 Example 56 >5 3.27 1.51 2.06 >5 Example 57 4.03 1.6 0.726 1.87 3.21 Example 58 0.028 0.162 0.005 0.23 0.57 Example 59 >5 >5 0.551 0.91 1.38 Example 60 >5 >5 2.44 >5 >5 Example 61 >5 >5 0.75 >5 >5 Example 62 0.99 0.95 0.045 2.1 3.8 -44- WO 2005/034955 PCT/US2003/032612 Table 2 CELL IC50 (pg/mL) EGFR - - +- Her-2 - + ++ + COMPOUND 3T3 3T3/NEU A431 SKBr3 BT474 MDA-MB- SW620 435 Example 63 1.49 1.2 0.45 1.3 0.9 Example 64 3.03 1.53 >5 1.8 2 Example 65 0.003 0.12 0.001 0.3 0.2 Example 66 0.01 0.24 0.006 0.2 0.32 Example 67 0.68 0.76 0.268 0.4 0.4 Example 68 2.52 >5 0.943 2.5 3.1 Example 69 0.42 0.3 >5 0.3 0.6 Example 70 0.12 0.22 0.01 0.08 0.5 Example 71 0.002 0.03 0.002 0.09 0.4 Example 72 0.02 0.24 0.006 0.18 0.54 Example 73 0.973 1.83 0.104 3.69 -45- WO 2005/034955 PCT/US2003/032612 Table 2 CELL IC50 (pg/mL) EGFR - - - + Her-2 - +++ + +++ +++ COMPOUND 3T3 3T3/NEU A431 SKBr3 BT474 MDA-MB- SW620 435 Example 74 >5 >5 >5 4.1 >5 Example 75 2.12 0.76 0.98 1.3 1.36 Example 76 0.41 0.0039 0.066 0.004 0.003 0.77 0.25 Receptor Phosphorylation: Compounds that repressed the proliferation of a mouse fibroblast cell line transfected with the HER-2 oncogene (3T3/neu) by 50% 5 (IC 50 ) <0.05 pg/ml in Table 2 above were tested for in vitro phosphorylation. For Her-2 and EGFR phosphorylation assays, cells (BT474 and A431, respectively) were incubated with various concentrations of compound for 3 hours at 37 0 C. Protein extracts were analyzed by immunoblotting using phospho-tyrosine antibodies. Blots were quantified by densitometric scanning. Concentration of compound (nM) which 10 inhibits phosphorylation by 50% was determined. Example 1, Example 3 and HKI 272 decreased ligand-independent receptor phosphorylation by 50% (IC 5 o) at 5-23 nM in BT474 cells (Table 3). They also repressed EGF-dependent phosphorylation of EGFR in A431 cells at a comparable dose (ICso 3-7 nM). -46- WO 2005/034955 PCT/US2003/032612 Table 3 IC50 (pg/mL) Compound BT474 A431 Example 1 0.0075 0.0031 Example 2 0.0026 0.0014 Example 3 0.013 0.0042 Example 20 0.080 0.0031 Example 37 < 1 Example 40 10-50 Example 58 50-500 Example 76 0.0015 0.0025 -47- WO 2005/034955 PCT/US2003/032612 IN VIVO: The in vivo antitumor activity of example 3 was evaluated in tumor xenograft models. Tumor cells (grown in tissue culture) or tumor fragments were implanted subcutaneously in female nude mice. Treatment was initiated after tumors had reached a size of 90-200 mg, following random assignment of the 5 animals to different treatment groups (staging). Alternatively (3T3/neu), treatment was initiated the day after tumor implantation, due to the rapid outgrowth of these tumors. Compounds were formulated in 0.5% Methocel-0.4% polysorbate-80 (Tween-80) and administered daily, PO, by gavage. Tumor mass [(L X W 2 ) /2] was determined every 7 days. Statistical significance of compound effects was evaluated 10 using Student's t-test. The activity of example 3 was first evaluated in xenografts of 3T3/neu cells example 3 inhibited tumor growth when administered to animals at 20 mg/kg/day (65% inhibition, day 21), 40 mg/kg/day (97% inhibition), and 80 mg/kg/day (99% inhibition). These results were almost identical to those obtained with example 2 15 treatment (53%, 95%, and 98% inhibition, respectively at 20, 40 and 80 mg/kg/day). In two other independent tests, EXAMPLE 3 treatment produced a statistically significant inhibition of tumor growth (21-33%) at a dose of 10 mg/kg/day. Based on these studies, the minimum efficacious dose (MED) was estimated to be 10 mg/kg/day. This is the smallest dose that produces a sustained, statistically 20 significant (p<0.05) reduction of tumor growth. The effect of example 3 was next studied in xenografts of HER-2-dependent human tumor cell lines. In animals bearing BT474 xenografts, example 3 treatment reduced tumor growth when dosed between 10 mg/kg/day and 40 mg/kg/day. Maximum inhibition was observed on day 21, and ranged from 59% (10/mg/kg/day) 25 to 96% (40 mg/kg/day). For example 2, inhibition ranged from 76% (10 mg/kg/day) to 95% (40 mg/kg/day). Similar results were obtained in two other independent experiments. In animals bearing xenografts of SUM-190 (a second HER-2 dependent breast cancer cell line), example 3 treatment resulted in substantial repression of tumor growth when dosed at 40 mg/kg/day (94% inhibition, day 28). 30 Example 3 was also effective against xenografts of SK-OV-3 (a HER-2-dependent human ovarian carcinoma cell line). Here, example 3 was active between 20 mg/kg/day (86% inhibition, day 35) and 60 mg/kg/day (91 % inhibition). The MED -48- WO 2005/034955 PCT/US2003/032612 in the HER-2 overexpressing human xenograft models was estimated at 10 mg/kg/day, similar to example 2. In these studies, there was no decrease in tumor size below the initial size at the start of dosing. Furthermore, tumors showed evidence of re-growth when treatment was completed, which is consistent with a 5 non-cytotoxic mode of action for example 3. -49-

Claims (10)

1. The compound (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6 quinolinyl}-4-(dimethylamino)-2-butenamide or a pharmaceutically acceptable salt thereof. 10 2. A method of treating, inhibiting the growth of, or eradicating neoplasms in a mammal in need thereof which comprises administering to said mammal an effective amount of (E) N-{4-[3-chloro-4-(2-pyridinylmethoxy)aniline]-3-cyano-7-ethoxy-6-quinolinyl}-4 (dimethylamino)-2-butenamide or a pharmaceutically acceptable salt thereof. 15 3. A pharmaceutical composition which includes (E)-N-(4-{3-chloro-4-[(3 fluorobenzyl)oxy]anilino}-3-cyano-7-ethoxy-6-quinolinyl)-4-(dimethylamino)-2 butenamide or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier. 20 4. The maleate salt of the compound (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3 cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide.
5. A method of treating, inhibiting the growth of, or eradicating neoplasms in a mammal in need thereof which comprises administering to said mammal an effective amount of the 25 maleate salt of the compound (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano
7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide. -6. A pharmaceutical composition which includes the maleate salt of the compound (E)-N 30 {4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4 (dimethylamino)-2-butenamide together with a pharmaceutically acceptable carrier. 35 CApoiwrd\SPEC-770295 doc 50 7. A compound having the structure: CIN N CH 3 0 5
8. A method of treating, inhibiting the growth of, or eradicating neoplasms in a mammal in need thereof which comprises administering to said mammal an effective amount of a compound having the structure: 10 C I HNN CH 3 0 C d3 C .oof\anISPEC-770295.W
9. A pharmaceutical composition wherein the composition includes a compound having the structure: C I H NN HH N CH 3 0 together with a pharmaceutically acceptable carrier. 5
10. A compound having the structure: CI H N MaC N 10 C:\po\wrd\SPEC-770295.doc
11. A method of treating, inhibiting the growth of, or eradicating neoplasms in a mammal in need thereof which comprises administering to said mammal an effective amount of a compound having the structure: C I 0-13 NN CH 3 O 5
12. A pharmaceutical composition wherein the composition includes a compound having the structure: C I NN CH 3 O I-b 10 together with a pharmaceutically acceptable carrier. C:\ponword\SPEC-770295.doC
13. A compound according to claim 1 or 7 substantially as hereinbefore described with reference to any one of the Examples. 5 14. A method according to claims 2 or 8, substantially as hereinbefore described with reference to any one of the Examples.
15. A pharmaceutical composition according to claims 3 or 9, substantially as hereinbefore described with reference to any one of the Examples. 10 C:\ponwovr\SPEC-77295Adc 54
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