USOO7652009B2

(12) United States Patent (10) Patent No.: US 7.652,009 B2 Kim et al. (45) Date of Patent: Jan. 26, 2010

(54) SUBSTITUTED HETEROCYCLES AND 2004.0053908 A1 3/2004 Funahashi et al. METHODS OF USE 2004/0209905 A1 10/2004 Kubo et al. (75) Inventors: Tae-Seong Kim, Thousand Oaks, CA 2004/0242603 A1 12/2004 Fujiwara et al. (US); Steven Bellon, Wellesley, MA 2005.0245547 A1 11/2005 Kim et al. (US); Shon Booker, Thousand Oaks, CA (US); Noel D’Angelo, Thousand Oaks, CA (US); Celia Dominguez, Los Angeles, CA (US); Ingrid Fellows, FOREIGN PATENT DOCUMENTS Fresno, CA (US); Matthew Lee, EP 86O433 A1 8, 1998 Calabasas, CA (US); Longbin Liu, EP 141 104.6 A1 4/2004 Thousand Oaks, CA (US); Elizabeth Rainbeau, Port Hueneme, CA (US); EP 1415987 A1 5, 2004 Aaron C. Siegmund, Ventura, CA (US); EP 1548 008 A1 6, 2005 Andrew Tasker, Simi Valley, CA (US); JP 63-145272 6, 1988 Ning Xi. Thousand Oaks, CA (US); JP 11-158149 6, 1999 Yuan Cheng, Newbury Park, CA (US) WO WO96/23774 8, 1996 WO WO96,293O1 9, 1996 (73) Assignee: Amgem Inc., Thousand Oaks, CA (US) WO WO96,293.05 9, 1996 (*) Notice: Subject to any disclaimer, the term of this WO WO97/03069 1, 1997 patent is extended or adjusted under 35 WO WO97.22596 6, 1997 U.S.C. 154(b) by 486 days. WO WO98/37079 8, 1998 WO WO99,35132 7, 1999 (21) Appl. No.: 11/289,659 WO WO99.54309 10, 1999 (22) Filed: Nov. 29, 2005 WO WO99,61428 12/1999 WO WOOOf 10981 3, 2000 (65) Prior Publication Data WO WOOOf 47212 8, 2000 US 2006/0252777 A1 Nov. 9, 2006 WO WOOO,50405 8, 2000 WO WOOOf 56720 9, 2000 Related U.S. Application Data WO WOOOf 61580 10, 2000 (60) Provisional application No. 60/632,271, filed on Nov. WO WOO1/21594 3, 2001 30, 2004. WO WOO 1/7O673 9, 2001 WO WOO 1/70734 9, 2001 (51) Int. Cl. A6 IK3I/506 (2006.01) CO7D 40/02 (2006.01) C07D 239/22 (2006.01) (Continued) (52) U.S. Cl...... 514/252.04: 514/269: 544/238; 544/242: 544/298; 54.4/319 OTHER PUBLICATIONS (58) Field of Classification Search ...... 544/224, Sathi, Garima. New Quinolines as Potential CNS Agents. Arch. 544/238, 242, 298,319; 546/152: 514/252.04, Pharm. (Weinheim). 316 (1983) 767-772.* 51.4/269 See application file for complete search history. (Continued) (56) References Cited Primary Examiner Kamal A Saeed U.S. PATENT DOCUMENTS Assistant Examiner—Samantha L. Shterengarts 3,755,332 A 8/1973 Wasley et al. (57) ABSTRACT 4,916, 135 A 4, 1990 Effland et al. 5,580,870 A 12/1996 Barker et al. 5,866,572 A 2f1999 Barker et al. Selected compounds are effective for prophylaxis and treat 5,965,563 A 10, 1999 Buzzetti et al. ment of diseases, such as HGF mediated diseases. The inven 6,143,764 A 11/2000 Kubo et al. tion encompasses novel compounds, analogs, prodrugs and 6,265,398 B1 7/2001 Braun et al. pharmaceutically acceptable salts thereof, pharmaceutical 6,313,129 B1 1 1/2001 Uckun et al. compositions and methods for prophylaxis and treatment of 6,358,962 B2 3, 2002 Uckun et al. diseases and other maladies or conditions involving, cancer 6,399,602 B1 6, 2002 Barker et al. and the like. The subject invention also relates to processes for 6,469,013 B2 10/2002 Uckun et al. 6,495,556 B2 12/2002 Uckun et al. making Such compounds as well as to intermediates useful in 6,573.289 B1 6/2003 Tasaka et al. Such processes. 6,897.214 B2 5, 2005 Barker et al. 2003/O165873 A1 9, 2003 Come et al. 25 Claims, No Drawings US 7,652,009 B2 Page 2

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Asano et al., “Silver halide color photographic materials.” Abstract Montesano et al., “Induction of epithelial tubular morphogenesis in 113: 181318 (1990). vitro by fibroblast-derived soluble factors.” Cell, 66:697-711 (1991). Boehm et al., “Antiangiogenic therapy of experimental cancer does Monti et al., IV. Abstract 55:2681. 1 page. not induce acquired drug resistance.” Nature, 390:404–407 (1997). Moszew et al., “Thermal reactions of Y-thiols in pyridine and Bolen et al., "Leukocyte protein tyrosine kinases: Potential targets for quinoline series.” Abstract 77:164418. 1 page. drug discovery.” Annu. Rev. Immunology, 15:371-404 (1997). Nakamura et al., “Partial purification and characterization of Brazhko et al., “Investigations of the biological activity hepatocyte growth factor from serum of hepatectomized rats. 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Comoglio, "Structure, biosynthesis and biochemical prop Omar et al., “Synthesis of some new 4-substituted anilinoquinolines erties of the HGF receptor in normal and malignant cells.” of expected biological activity” Chemical Abstracts Service, Data Hepatocyte Growth Factor-Scatter Factor (HGF-SF) and the C-Met base accession No. 1999-45.8494 Egyptian Journal of Pharmaceuti Receptor, eds. Goldberg and Rosen, Birkhauser Verlag Basel, Swit cal Sciences, Volume Date 1997, 38(4-6), (1998) 1 page. zerland, 131-165 (1993). * cited by examiner US 7,652,009 B2 1. 2 SUBSTITUTED HETEROCYCLES AND Increased VEGF expression could explain the occurrence of METHODS OF USE cerebral edema in patients with glioma. Direct evidence of the role of VEGF as a tumorangiogenesis factor in vivo is shown FIELD OF THE INVENTION in studies in which VEGF expression or VEGF activity was 5 inhibited. This was achieved with anti-VEGF antibodies, This invention is in the field of pharmaceutical agents and with dominant-negative VEGFR-2 mutants which inhibited specifically relates to compounds, compositions, uses and signal transduction, and with antisense-VEGF RNA tech methods for treating cancer. niques. All approaches led to a reduction in the growth of BACKGROUND OF THE INVENTION glioma cell lines or other tumor cell lines in vivo as a result of 10 inhibited tumor angiogenesis. Protein kinases represent a large family of proteins which Angiogenesis is regarded as an absolute prerequisite for play a central role in the regulation of a wide variety of tumors which grow beyond a diameter of about 1-2mm; up to cellular processes, maintaining control over cellular function. this limit, oxygen and nutrients may be Supplied to the tumor A partial list of such kinases includes ab1, Akt, bcr-ab1, Blk, cells by diffusion. Every tumor, regardless of its origin and its Brk, Btk, c-kit, c-Met, c-Src, c-fms, CDK1, CDK2, CDK3. 15 cause, is thus dependent on angiogenesis for its growth after CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, it has reached a certain size. cRaf1, CSF1R, CSK, EGFR, ErbB2, ErbB3, ErbB4, Erk, Three principal mechanisms play an important part in the Fak, fes, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, Fgr. activity of angiogenesis inhibitors against tumors: 1) Inhibi filt-1, Fps, Frk, Fyn, Hck, IGF-1R, INS-R, Jak, KDR, Lck, tion of the growth of vessels, especially capillaries, into avas Lyn, MEK, p38, PDGFR, PIK, PKC, PYK2, ros, tie, tie2, cular resting tumors, with the result that there is no net tumor TRK, Yes, and Zap70. Inhibition of such kinases has become growth owing to the balance that is achieved between cell an important therapeutic target. death and proliferation; 2) Prevention of the migration of Certain diseases are known to be associated with deregu tumor cells owing to the absence of blood flow to and from lated angiogenesis, for example ocular neovascularisation, tumors; and 3) Inhibition of endothelial cell proliferation, Such as retinopathies (including diabetic retinopathy), age 25 thus avoiding the paracrine growth-stimulating effect exerted related macular degeneration, psoriasis, hemangioblastoma, on the surrounding tissue by the endothelial cells which nor hemangioma, arteriosclerosis, inflammatory disease, such as mally line the vessels. See R. Connell and J. Beebe, Exp. a rheumatoid or rheumatic inflammatory disease, especially Opin. Ther. Patents, 11:77-114 (2001). arthritis (including rheumatoid arthritis), or other chronic VEGFs are unique in that they are the only angiogenic inflammatory disorders, such as chronic asthma, arterial or 30 growth factors known to contribute to vascular hyperperme post-transplantational atherosclerosis, endometriosis, and ability and the formation of edema. Indeed, vascular hyper neoplastic diseases, for example so-called solid tumors and permeability and edema that is associated with the expression liquid tumors (such as leukemias). or administration of many other growth factors appears to be At the center of the network regulating the growth and mediated via VEGF production. differentiation of the vascular system and its components, 35 Inflammatory cytokines stimulate VEGF production. both during embryonic development and normal growth, and Hypoxia results in a marked upregulation of VEGF in numer in a wide number of pathological anomalies and diseases, lies ous tissues, hence situations involving infarct, occlusion, the angiogenic factor known as Vascular Endothelial Growth ischemia, anemia, or circulatory impairment typically invoke Factor (VEGF; originally termed Vascular Permeability VEGF/VPF-mediated responses. Vascular hyperpermeabil Factor. VPF), along with its cellular receptors (see G. Breier 40 ity, associated edema, altered transendothelial exchange and et al., Trends in Cell Biology, 6:454-456 (1996)). macromolecular extravasation, which is often accompanied VEGF is a dimeric, disulfide-linked 46-kDa glycoprotein by diapedesis, can result in excessive matrix deposition, aber related to “Platelet-Derived Growth Factor” (PDGF); it is rant stromal proliferation, fibrosis, etc. Hence, VEGF-medi produced by normal cell lines and tumor cell lines; is an ated hyperpermeability can significantly contribute to disor endothelial cell-specific mitogen; shows angiogenic activity 45 in in vivo test systems (e.g. rabbit cornea); is chemotactic for ders with these etiologic features. As such, regulators of endothelial cells and monocytes; and induces plasminogen angiogenesis have become an important therapeutic target. activators in endothelial cells, which are involved in the pro The hepatocyte growth factor receptor (“c-Met') is a teolytic degradation of extracellular matrix during the forma unique receptor tyrosine kinase shown to be overexpressed in tion of capillaries. A number of isoforms of VEGF are known, 50 a variety of malignancies. c-Met typically comprises, in its which show comparable biological activity, but differ in the native form, a 190-kDa heterodimeric (a disulfide-linked type of cells that secrete them and in their heparin-binding 50-kDa C-chain and a 145-kDa 3-chain) membrane-spanning capacity. In addition, there are other members of the VEGF tyrosine kinase protein (Proc. Natl. Acad. Sci. USA, 84.6379 family, such as “Placenta Growth Factor” (PIGF) and VEGF 6383 (1987)). c-Met is mainly expressed in epithelial cells C. 55 and stimulation of c-Met leads to Scattering, angiogenesis, VEGF receptors (VEGFR) are transmembranous receptor proliferation and metastasis. (See Cytokine and Growth Fac tyrosine kinases. They are characterized by an extracellular tor Reviews, 13:41-59 (2002)). domain with seven immunoglobulin-like domains and an The ligand for c-Met is hepatocyte growth factor (also intracellular tyrosine kinase domain. Various types of VEGF known as scatterfactor, HGF and SF). HGF is a heterodimeric receptor are known, e.g. VEGFR-1 (also known as filt-1), 60 protein secreted by cells of mesodermal origin (Nature, 327: VEGFR-2 (also known as KDR), and VEGFR-3. 239-242 (1987); J. Cell Biol. 111:2097-2108 (1990)). A large number of human tumors, especially gliomas and Various biological activities have been described for HGF carcinomas, express high levels of VEGF and its receptors. through interaction with c-met (Hepatocyte Growth Factor This has led to the hypothesis that the VEGF released by Scatter Factor (HGF-SF) and the c-Met Receptor, Goldberg tumor cells stimulates the growth of blood capillaries and the 65 and Rosen, eds., Birkhauser Verlag-Basel, 67-79 (1993). The proliferation of tumor endothelium in a paracrine manner and biological effect of HGF/SF may depend in part on the target through the improved blood Supply, accelerate tumor growth. cell. HGF induces a spectrum of biological activities in epi US 7,652,009 B2 3 4 thelial cells, including mitogenesis, stimulation of cell motil matoid or rheumatic inflammatory disease, especially arthri ity and promotion of matrix invasion (Biochem. BiophyS. tis (including rheumatoid arthritis), or other chronic Res. Comm., 122:1450-1459 (1984); Proc. Natl. Acad. Sci. inflammatory disorders, such as chronic asthma, arterial or U.S.A., 88:415-419 (1991)). It stimulates the motility and post-transplantational atherosclerosis, endometriosis, and invasiveness of carcinoma cells, the former having been 5 neoplastic diseases, for example so-called Solid tumors and implicated in the migration of cells required for metastasis. liquid tumors (such as leukemias). Treatment of malaria and HGF can also act as a “scatter factor', an activity that pro related viral diseases may also be mediated by HGF and motes the dissociation of epithelial and vascular endothelial cMet. cells (Nature, 327:239-242 (1987); J. Cell Biol., 111:2097 Elevated levels of HGF and c-Met have also been observed 2108 (1990); EMBO J., 10:2867-2878 (1991); Proc. Natl. 10 in non-oncological settings, such as hypertension, myocar Acad. Sci. USA, 90:649-653 (1993)). Therefore, HGF is dial infarction and rheumatoid arthritis. It has been observed thought to be important in tumor invasion (Hepatocyte that levels of HGF increase in the plasma of patients with Growth Factor-Scatter Factor (HGF-SF) and the C-Met hepatic failure (Gohda et al., Supra) and in the plasma (Hepa Receptor, Goldberg and Rosen, eds., Birkhauser Verlag tol., 13:734-750 (1991)) or serum (J. Biochem., 109:8-13 Basel, 131-165 (1993)). 15 (1991)) of animals with experimentally induced liver dam HGF and c-Met are expressed at abnormally high levels in age. HGF has also been shown to be a mitogen for certain cell a large variety of solid tumors. High levels of HGF and/or types, including melanocytes, renal tubular cells, kerati c-Met have been observed in liver, breast, pancreas, lung, nocytes, certain endothelial cells and cells of epithelial origin kidney, bladder, ovary, brain, prostate, gallbladder and (Biochem. Biophys. Res. Commun., 176:45-51 (1991); Bio myeloma tumors in addition to many others. The role of chem. Biophys. Res. Commun., 174:831-838 (1991); Bio HGF/c-Met in metastasis has been investigated in mice using chem., 30: 9768-9780 (1991); Proc. Natl. Acad. Sci. USA, cell lines transformed with HGF/c-Met (J. Mol. Med., 88:415-419 (1991)). Both HGF and the c-Met protooncogene 74:505-513 (1996)). Overexpression of the c-Met oncogene have been postulated to play a role in microglial reactions to has also been Suggested to play a role in the pathogenesis and CNS injuries (oncogene, 8:219-222 (1993)). progression of thyroid tumors derived from follicular epithe 25 Metastatic SCC cells overexpress c-Met and have lium (Oncogene, 7:2549-2553 (1992)). HGF is a morphogen enhanced tumoregenesis and metastasis in vivo G. Gong et (Development, 110:1271-1284 (1990); Cell, 66:697–711 al., Oncogene, 23:6199-6208 (2004). C-Met is required for (1991)) and a potentangiogenic factor (J. Cell Biol. 119:629 tumor cell survival N. Shinomiya et al., Cancer Research, 641 (1992)). 64:7962-70 (2004). For a general review see C. Birchmeier Recent work on the relationship between inhibition of 30 et al., Nature Reviews/Molecular Biology 4:915-925 (2003). angiogenesis and the Suppression or reversion of tumor pro In view of the role of HGF and/or c-Met in potentiating or gression shows great promise in the treatment of cancer (Na promoting such diseases or pathological conditions, it would ture, 390:404–407 (1997)), especially the use of multiple be useful to have a means of substantially reducing or inhib angiogenesis inhibitors compared to the effect of a single iting one or more of the biological effects of HGF and its inhibitor. Angiogenesis can be stimulated by HGF, as well as 35 receptor. Thus a compound that reduces the effect of HGF vascular endothelial growth factor (VEGF) and basic fibro would be a useful compound. Compounds of the current blast growth factor (bFGF). invention have not been previously described as inhibitors of Angiogenesis, the process of Sprouting new blood vessels angiogenesis Such as for the treatment of cancer. from existing vasculature and arteriogenesis, the remodeling Kirin Japanese patent application JP11158149, published of Small vessels into larger conduit vessels are both physi 40 28 Nov. 1997, describes substituted phenyl compounds. Kirin ologically important aspects of vascular growth in adult tis publication WO 00/43366 describes substituted phenyl com Sues. These processes of vascular growth are required for pounds. Kirin publication WO 03/000660 describes substi beneficial processes such as tissue repair, wound healing, tuted phenyl compounds. Substituted quinolines are recovery from tissue ischemia and menstrual cycling. They described in U.S. Pat. No. 6,143,764. WO 02/32872 describes are also required for the development of pathological condi 45 substituted quinolines. Patent Application WO 00/47212 tions such as the growth of neoplasias, diabetic retinopathy, describes substituted quinazoline derivatives. Patent Applica rheumatoid arthritis, psoriasis, certain forms of macular tion WO 98/37079 describes substituted N-heterocyclic com degeneration, and certain inflammatory pathologies. The pounds. Kubo et al, Biorg. Med. Chem., 11:5117-33 (2003) inhibition of vascular growth in these contexts has also shown describes phenoxyquinoline derivatives. Patent Application beneficial effects in preclinical animal models. For example, 50 WO 04/46133, published 3 Jun. 2004, describes amino-het inhibition of angiogenesis by blocking vascular endothelial erocycles for treating pain. Patent Application WO growth factor or its receptor has resulted in inhibition of 03/004472, published 16 Jan. 2003, describes pyrazine-2- tumor growth and in retinopathy. Also, the development of carboxamides. JP63145272, published 17 Jun. 1988, pathological pannus tissue in rheumatoid arthritis involves describes 4,5-dihydro-6-(4-substituted phenyl)-3(2H)-py angiogenesis and might be blocked by inhibitors of angiogen 55 ridazinones. Kamel, et al., Egyptian J. of Pharm. Sci., 38:61 CS1S. 69 (1997) describes 4-substituted phenoxyquinolines. Patent The ability to stimulate vascular growth has potential util Application WO 04/18430, published 4 Mar. 2004, describes ity for treatment of ischemia-induced pathologies such as quinoline derivatives. Patent Application WO 02/32872, pub myocardial infarction, coronary artery disease, peripheral lished 25 Apr. 2002, describes urea derivatives. Patent Appli vascular disease, and stroke. The Sprouting of new vessels 60 cation WO 04/37784, published 6 May 2004, describes sub and/or the expansion of Small vessels in ischemic tissues stituted pyrrolidones. Patent Application WO 00/50405 prevents ischemic tissue death and induces tissue repair. Cer published 31 Aug. 2000, describes quinoline-6-carboxam tain diseases are known to be associated with deregulated ides. Patent Application WO 04/083235, published 30 Sep. angiogenesis, for example ocular neovascularization, such as 2004, describes azaheterocyclyl aromatic compounds. retinopathies (including diabetic retinopathy), age-related 65 Compounds of the current invention have not been macular degeneration, psoriasis, hemangioblastoma, heman described as inhibitors of c-Met such as for the treatment of gioma, arteriosclerosis, inflammatory disease, Such as a rheu CaCC. US 7,652,009 B2 5 6 DESCRIPTION OF THE INVENTION wherein R" is selected from cyano, OR, SR, halo, SOR, C(=O)R SONRR, NRC(=O) A class of compounds useful in treating cancer and angio OR2 NRC(=O)NRR, NRC(=O)R, COR, genesis is defined by Formula I C(=O)NRR and NRR: wherein p is 0, 1, 2, or 3; and wherein R is selected from substituted or unsubstituted aryl, whereint is 0, 1 or 2: substituted or unsubstituted heterocyclyl, substituted or wherein each alkyl, aryl, heteroaryl, cycloalkyl, alkenyl, unsubstituted cycloalkyl, substituted or unsubstituted alkynyl, heterocyclyl, and alkoxy moiety of any R, R', R, cycloalkenyl, H. —OH, alkylamino, substituted or unsub 10 stituted alkyl, and substituted or unsubstituted alkenyl and R. R. RandR is optionally substituted with one or more substituted or unsubstituted alkynyl: groups selected from halo, R', NH, OR, COH, wherein R' is (C-C)alkylamino, (C-C)alkyl, (C-C)cycloalkyl, (C- C.)haloalkyl, di(C-C)alkylamino, (C-C)alkylamino 15 (C-C)alkyl, (C-C)hydroxyalkylamino, (C-C)alky lamino-(C-C)alkylamino, phenyl, and heterocyclyl: and pharmaceutically acceptable derivatives thereof. The invention also relates to compounds of Formula I provided the compound is not 6,7-dimethoxy-4-6-methyl 2-(3-thienyl)-3-pyridinyloxy-quinoline, R10 provided W is not thiadiazole-3-yl when A is piperazin-4-yl, X is O, Y is –C(=O)NH , R is 3,5-bis(trifluoromethyl) wherein ring T is selected from phenyl and 5-6-membered 25 phenyl and R' is 6,7-dimethoxyquinolin-4-yl: heteroaryl; wherein Z is selected from Nor CH; wherein R" is one or more substituents selected from Co provided W is not 2,3-dimethylpyridyl when A is pyrid-2-yl alkoxy, Cle-haloalkoxy, C-alkylamino-Cio-alkoxy, or pyrid-3-yl, X is O, Y is a direct bond and R is methyl or aryl-C6-alkoxy, heterocyclyl-C-alkoxy, cycloalkyl H; Co-alkoxy, heterocyclyl-C-(hydroxyalkoxy), provided W is not 2,3-dimethylpyridyl when A is thiazol-2- cycloalkyl-C-(hydroxyalkoxy), aryl-C-(hydroxy 30 alkoxy), C-alkoxyalkoxy, aryloxy-C-alkoxy, het y1, X is O. Y is a direct bond and R is methyl or H: erocyclyloxy-C-alkoxy, cycloalkyloxy-C-alkoxy, provided W is not 2-methylpyridyl when A is thiazol-2-yl or aryloxy, heterocyclyloxy, and cycloalkyloxy; 3-thienyl, X is O, Y is a direct bond and R is H: wherein W is an substituted or unsubstituted aryl or substi 35 provided W is not 2-methylthiopyridyl when A is pyrid-3-yl, tuted or unsubstituted 5-6-membered heteroaryl; X is O, Y is a direct bond and R is H; wherein A is an substituted or unsubstituted 5-7-membered provided W is not 2-methylpyridyl when A is pyrazol-4-yl, nitrogen-containing heterocyclyl; pyrazol-3-yl, isoxazol-5-yl or pyrazol-5-yl, X is O. Y is a wherein X is selected from O, S, NR and CRR: direct bond and R is methyl; whereinY is selected from a direct bond, NR(CR R) , 40 —O(CRR), , —(CRR) , S(=O),(CRR), , provided W is not 2,3-dimethylpyridyl when A is pyrazol-4- —CO. , C(=O)NH- and –C(=O)(CRR) ; y1, X is O. Y is a direct bond and R is H: wherein Y is in either direction; provided W is not 2,3-dimethylpyridyl when A is 6-oxo wherein R is selected from H, alkyl, heterocyclyl, aryl, ary pyrid-3-yl, X is O. Y is a direct bond and R is H: lalkyl, heterocyclylalkyl, cycloalkyl, cycloalkylalkyl, alk enyl, alkynyl, RRN (C=O)—, and R (=O) ; 45 provided W is not 2,3-dimethylpyridyl when A is pyrimidin wherein R is optionally substituted; 2-yl, X is O, Y is a direct bond and R is H; wherein R is selected from H, alkyl, haloalkyl, aryl, hetero provided W is not 2-methylpyridyl when A is pyrimidin-5-yl, cyclyl, arylalkyl, heterocyclylalkyl, cycloalkyl, cycloalky X is O, Y is a direct bond and R is H; lalkyl, hydroxyalkyl, alkoxyalkyl, alkylaminoalkyl, alky 50 provided W is not 2-methylpyridyl when A is pyridyl, X is O, lthioalkyl, alkenyl, alkynyl and R-carbonyl: wherein R and R is each independently selected from H, Y is a direct bond and R is H; alkyl, aryl, heterocyclyl, arylalkyl, heterocyclylalkyl, provided Wis not 2-iodophenyl when A is imidazol-1-yl, X is haloalkyl, cycloalkyl, cycloalkylalkyl, Randalkyl substi O, Y is a direct bond and R is H; tuted with R: 55 provided W is not dimethylphenyl or methylphenyl, when A wherein R is selected from H. alkyl, haloalkyl, hydroxyalkyl, is pyrid-3-yl pyrid-2-yl or isoxazol-5-yl, X is O, Y is a alkoxyalkyl, alkylaminoalkyl, alkylthioalkyl, arylalkyl, direct bond and R is H; heterocyclylalkyl, cycloalkylalkyl, aryl, heterocyclyl alk provided W is not ethoxycarbonylphenyl when A is pyrrol enyl, alkynyl and cycloalkyl, 1-yl, X is O, Y is a direct bond and R is H: wherein R is selected from H, alkyl, haloalkyl, arylalkyl, 60 heterocyclylalkyl, cycloalkylalkyl, aryl, heterocyclyl, provided A is not 3,4-dihydro-2-oxo-1H-quinazolin-3-yl, hydroxyalkyl, alkoxyalkyl, alkylaminoalkyl, alkylthio morpholin-1-yl or 1-imidazolyl when W is phenyl, X is O, alkyl, alkenyl, alkynyl and cycloalkyl; Y is a direct bond and R is H; and wherein R is selected from cyano, —OR, SR, halo, provided A is not 2-amino-3-cyano-pyrid-6-yl, 2-oxo-3-cy SOR, C(=O)R, SONRR, NRC(=O) 65 ano-pyrid-6-yl or 2-thio-3-cyano-pyrid-6-y1 when W is OR, NRC(=O)NRR, NRC(=O)R, COR, phenyl, X is O. Y is a direct bond and R is optionally C(=O)NR'R'' and NRR: substituted phenyl. US 7,652,009 B2 7 8 The invention also relates to compounds of Formula I wherein p is 0, 1, 2, or 3; and whereint is 0, 1 or 2: wherein each alkyl, aryl, heteroaryl, cycloalkyl, alkenyl, I alkynyl, heterocyclyl, and alkoxy moiety of any R, R', R, N An-R R. R. RandR is optionally substituted with one or more groups selected from halo. —NH, -OH, -CO2H. (C- R C.)alkylamino, (C-C)alkyl, (C-C)alkoxy, (C-C)ha na 1. loalkyl, di(C-C)alkylamino, (C-C)alkylamino-(C-C) x^2, alkyl, (C-C)hydroxyalkylamino, (C-C)alkylamino 10 (C-C)alkylamino, phenyl, and heterocyclyl; wherein R is selected from substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or and pharmaceutically acceptable derivatives thereof. unsubstituted cycloalkyl, substituted or unsubstituted The invention also relates to compounds of Formula I or I' cycloalkenyl, H. —OH, alkylamino, substituted or unsub wherein R is selected from H, 6-10 membered aryl, 4-10 stituted alkyl, and substituted or unsubstituted alkenyl and 15 membered heterocyclyl, 4-6 membered cycloalkyl, C substituted or unsubstituted alkynyl: alkyl, C-alkenyl and C2-alkynyl, wherein R is Substituted wherein R' is or unsubstituted; in conjunction with any of the above or below embodiments. The invention also relates to compounds of Formula I or I' wherein R is optionally substituted phenyl; in conjunction with any of the above or below embodiments. The invention also relates to compounds of Formula I or I' wherein R is phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluo rophenyl, 4-methylphenyl, 4-trifluoromethylphenyl or 25 4-(dimethylamino)phenyl; in conjunction with any of the R10 above or below embodiments. The invention also relates to compounds of Formula I or I' wherein R is a substituted or unsubstituted heterocyclyl ring wherein ring T is selected from phenyl and 5-6-membered selected from pyrrolidinyl, piperidinyl, piperazinyl, 2,3-dihy heteroaryl; wherein Z is selected from Nor CH; wherein droindolyl, pyrrolyl, imidazolyl pyrazolyl pyrazinyl, pyri R" is one or more substituents selected from C 30 midinyl, pyridyl, quinolinyl, isoquinolinyl, 2,3-dihydroben alkoxy, C-haloalkoxy, C-alkylamino-Cio-alkoxy, Zofuryl, 2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl, aryl-C-alkoxy, heterocyclyl-C-alkoxy, cycloalkyl isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, furanyl, and Co-alkoxy, heterocyclyl-C-(hydroxyalkoxy), thienyl; in conjunction with any of the above or below cycloalkyl-C-(hydroxyalkoxy), aryl-C-(hydroxy 35 embodiments. alkoxy), C-alkoxyalkoxy, aryloxy-C-alkoxy, het The invention also relates to compounds of Formula I or I' erocyclyloxy-C-alkoxy, cycloalkyloxy-C-alkoxy, wherein R is 3-6 membered cycloalkyl selected from cyclo aryloxy, heterocyclyloxy, and cycloalkyloxy; propyl, cyclobutyl, cyclopenty1 and cyclohexyl, in conjunc wherein A is an substituted or unsubstituted 5-7-membered tion with any of the above or below embodiments. nitrogen-containing heterocyclyl; 40 The invention also relates to compounds of Formula I or I' wherein X is selected from O, S, NR and CRR: wherein R is selected from methyl, ethyl, propyl, butyl, isobu whereinY is selected from a direct bond, NR(CR R) , tyl, tert-butyl, 3.3-dimethylpropyl and pentyl; in conjunction —O(CRR), , —(CRR) , S(=O),(CRR), , with any of the above or below embodiments. —CO. , C(=O)NH- and –C(=O)(CRR) ; The invention also relates to compounds of Formula I or I' wherein Y is oriented in either direction; 45 wherein R is selected from ethenyl and propenyl; in conjunc wherein R is selected from H, alkyl, heterocyclyl, aryl, ary tion with any of the above or below embodiments. lalkyl, heterocyclylalkyl, cycloalkyl, cycloalkylalkyl, alk The invention also relates to compounds of Formula I or I' enyl, alkynyl, RRN (C=O)—, and R (=O) ; wherein R is H; in conjunction with any of the above or below wherein R is optionally substituted; embodiments. wherein R is selected from H, alkyl, haloalkyl, aryl, hetero 50 The invention also relates to compounds of Formula I or I' cyclyl, arylalkyl, heterocyclylalkyl, cycloalkyl, cycloalky wherein A is selected from lalkyl, alkenyl, alkynyl and R-carbonyl: wherein R and R is each independently selected from H. alkyl, aryl, heterocyclyl, arylalkyl, heterocyclylalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, Randalkyl substi 55 tuted with R: wherein R is selected from H, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkylaminoalkyl, alkylthioalkyl, arylalkyl, heterocyclylalkyl, cycloalkylalkyl, aryl, heterocyclyl alk enyl, alkynyl and cycloalkyl, 60 wherein R is selected from cyano, —OR. —SR, halo, O s O / O / SOR, C(=O)R, SONRR, NRC(=O) OR, NRC(=O)NRR, NRC(=O)R, COR°, C(=O)NR'R'' and NRR: 65 X US wherein R is selected from H. halo, NH, OH, -COH, (C-C)alkylamino, (C-C)alkyl, (C-C)alkoxy, and (C- C.)haloalkyl; US 7,652,009 B2 9 10 The invention also relates to compounds of Formula I or I' -continued wherein A is O O R2 N N ) / ) M 5 -N o, 1 s

O O O J and -2.

15 in conjunction with any of the above or below embodiments. wherein A is bound in either direction; wherein R is selected The invention also relates to compounds of Formula I or I' from H. C-alkyl, aryl-C-alkyl, and heterocyclyl-C- wherein A is alkyl; and wherein R* is selected from H and methyl; in conjunction with any of the above or below embodiments. The invention also relates to compounds of Formula I or I' 20 wherein A is selected from 1NO R2 N n N 25 N and in conjunction with any of the above or below embodiments. N R 2 22. N The invention also relates to compounds of Formula I or I' O wherein A is 30

N1 N 2 35 N conjunction with any of the above or below embodiments. The invention also relates to compounds of Formula I or I' wherein A is selected from in conjunction with any of the above or below embodiments. The invention also relates to compounds of Formula I or I' wherein A is O / O / O N N 45

s s and 1 N 1. N 1. N O O 50

1. NN, in conjunction with any of the above or below embodiments. The invention also relates to compounds of Formula I or I'ss in conjunction with any of the above or below embodiments. wherein A is The invention also relates to compounds of Formula I or I' wherein A is

O N O N 60

N N 1. O 1. X-0. O 65 in conjunction with any of the above or below embodiments. in conjunction with any of the above or below embodiments. US 7,652,009 B2 11 12 The invention also relates to compounds of Formula I or I' and wherein R' is selected from Cis-alkoxy, Cis-alky wherein A is lamino-C-alkoxy, 5-6 membered heterocyclyl-C- alkoxy, Cale-cycloalkyl-C-alkoxy, 5-6 membered hetero cyclyl-C-(hydroxyalkoxy), C-6-cycloalkyl-C-s- (hydroxyalkoxy), C2-alkoxy-C-alkoxy, phenyloxy-C- alkoxy, 5-6 membered heterocyclyloxy-C-alkoxy, cycloalkyloxy-C-alkoxy, 5-6 membered heterocyclyloxy, and C-cycloalkyloxy; in conjunction with any of the above or below embodiments. 10 The invention also relates to compounds of Formula I or I' wherein R' is selected from 6,7-dimethoxy-4-quinolinyl, in conjunction with any of the above or below embodiments. 6-methoxy-7-(dimethylaminopropoxy)-4-quinolinyl, The invention also relates to compounds of Formula I or I' 6-methoxy-7-(3-(morpholin-4-yl)propoxy)-4-quinolinyl, wherein A is 6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)-4-quinolinyl, 15 6-methoxy-7-(2-hydroxy-3-(morpholin-4-yl)propoxy)-4- quinolinyl, 6-methoxy-7-(3-(1,2,4-triazol-1-yl)propoxy)-4- R2 quinolinyl, 6-methoxy-7-(3-(4-methylpiperazin-1-yl)pro poxy)-4-quinolinyl, 6-methoxy-7-(3-(piperidin-4-yl) N propoxy)-4-quinolinyl, 6,7-dimethoxy-4-quinazolinyl, and 1N s 6-methoxy-7-(dimethylaminopropoxy)-4-quinazolinyl; in conjunction with any of the above or below embodiments. O The invention also relates to compounds of Formula I or I' wherein R' is selected from 6-methoxy-7-(3-(morpholin-4- yl)propoxy)-4-quinolinyl; in conjunction with any of the in conjunction with any of the above or below embodiments. 25 above or below embodiments. The invention also relates to compounds of Formula I or I' The invention also relates to compounds of Formula I or I' wherein A is wherein R' is 6,7-dimethoxy-4-quinolinyl; in conjunction with any of the above or below embodiments. The invention also relates to compounds of Formula I or I' 30 wherein Y is selected from direct bond, NR(CRR) , O(CR R") , (CR R") - and C(=O)(CR R") ; and wherein p is 0 or 1; in conjunction with any of the above or below embodiments. 35 The invention also relates to compounds of Formula I or I' in conjunction with any of the above or below embodiments. wherein Y is selected from a direct bond, —NH , The invention also relates to compounds of Formula I or I' —NHCH2— and —CH2—, in conjunction with any of the wherein A is above or below embodiments. The invention also relates to compounds of Formula I or I' 40 wherein Y is —CH2—, in conjunction with any of the above or below embodiments. The invention also relates to compounds of Formula I or I' wherein Y is a direct bond; in conjunction with any of the above or below embodiments. 45 The invention also relates to compounds of Formula I or I' in conjunction with any of the above or below embodiments. whereinY is NH ; in conjunction with any of the above or The invention also relates to compounds of Formula I or I' below embodiments. wherein R' is selected from 9-10-membered bicyclic nitro The invention also relates to compounds of Formula I or I' gen-containing heterocyclyl; in conjunction with any of the wherein Y is N(CH)—; in conjunction with any of the above or below embodiments. 50 above or below embodiments. The invention also relates to compounds of Formula I or I' The invention also relates to compounds of Formula I or I' wherein R' is selected from wherein Y is —CH(CH)—; in conjunction with any of the above or below embodiments. 55 The invention also relates to compounds of Formula I or I' wherein R is selected from H. ethyl, isopropyl, (CH) RQ RIQ CCH , ethenyl, and an unsubstituted or Substituted ring 21 N N selected from phenyl, cyclobutyl, cyclopentyl, cyclohexyl, Sa 2 2 2-pyrrolidinyl, 2-pyrrolyl, 5-imidazolyl, 5-pyrazolyl, R10 N N R10 N 2-pyrazinyl, 4-pyrimidinyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 60 8-quinolinyl, 2,3-dihydrobenzofur-7-y1, 2,3-dihydro-1,4- RQ RIQ benzodioxin-5-yl, 1,3-benzodioxol-4-yl 4-isoxazolyl, 21 n N and n N: 3-isothiazolyl, 5-oxazolyl, 4-thiazolyl, 5-thiazolyl 2-furanyl, 3-furanyl, 3-thienyl and 2-thienyl; in conjunction with any of R10 N N R10 N 65 the above or below embodiments. The invention also relates to compounds of Formula I or I' wherein R is selected from H. halo, NH, OH, -COH,

US 7,652,009 B2 17 18 5-Benzyl-3-3-fluoro-4-6-methoxy-7-(3-morpholin-4-yl The invention also relates to compounds of Formula II propoxy)-quinolin-4-yloxy)-phenyl-1-methyl-imidazo wherein Y" is selected from a direct bond, N(CH) , lidine-2,4-dione; —N(CH2CH2CHCCH))— —NHCH —NH(CH) , 3-3-Fluoro-4-6-methoxy-7-(3-morpholin-4-yl-propoxy)- —NHCH (CH)— —NH- and —CH2—, in conjunction quinolin-4-yloxyl-phenyl)-1-phenethyl-imidazolidine-2, 5 with any of the above or below embodiments. 4-dione; The invention also relates to compounds of Formula II 1-4-(6,7-Dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl wherein R'' is methyl; in conjunction with any of the above or 4-(phenyl-propoxy-methyl)-pyrrolidin-2-one; below embodiments. 1-4-(6,7-Dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl The invention also relates to compounds of Formula II 4-(phenyl-propoxy-methyl)-pyrrolidin-2-one; 10 wherein R' is selected from ethyl, isopropyl, isobutyl, (CH) 4-Benzyl-1-3-fluoro-4-6-methoxy-7-(3-morpholin-4-yl CCH , and dimethylamino; in conjunction with any of the propoxy)-quinolin-4-yloxy)-phenyl-pyrrolidin-2-one; above or below embodiments. 4-Benzyl-1-4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro The invention also relates to compounds of Formula II phenyl-pyrrolidin-2-one; wherein R is selected from cyclopropyl, cyclobutyl, cyclo 3-Benzyl-1-3-fluoro-4-6-methoxy-7-(3-morpholin-4-yl 15 pentyl and cyclohexyl, in conjunction with any of the above propoxy)-quinolin-4-yloxy)-phenyl)-imidazolidine-2,4- or below embodiments. dione; and The invention also relates to compounds of Formula II 1-4-(6,7-Dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl wherein R is cyclopropyl or cyclopentyl; in conjunction with 4-phenoxymethyl-pyrrolidin-2-one. any of the above or below embodiments. The invention also relates to compounds of Formula II The invention also relates to compounds of Formula II wherein R' is selected from 1-pyrrolidinyl, 2-pyrrolyl, 5-imi dazolyl, 5-pyrazolyl, 2-pyrazinyl, 4-pyrimidinyl, 2-pyridyl, II 3-pyridyl, 4-pyridyl, 8-quinolinyl, 2,3-dihydrobenzofur-7-yl, 2,3-dihydro-1,4-benzodioxin-5-yl, 1,3-benzodioxol-4-yl, 25 4-isoxazolyl, 3-isothiazolyl, 5-oxazolyl, 4-thiazolyl, 5-thiaz olyl 2-furanyl, 3-furanyl, 3-thienyl and 2-thienyl; in conjunc R ns. tion with any of the above or below embodiments. The invention also relates to compounds of Formula II R10d O O wherein R is selected from phenyl, 2-fluorophenyl, 3-fluo 30 rophenyl, 4-fluorophenyl, 4-methylphenyl, 4-trifluorometh ylphenyl, and 4-(dimethylamino)phenyl; in conjunction with R0c n Z. R9 any of the above or below embodiments. The invention also relates to compounds of Formula II wherein R is H; in conjunction with any of the above or R10b e 35 below embodiments. R10a The invention also relates to compounds of Formula II wherein R is H. methyl or fluoro; in conjunction with any of the above or below embodiments. wherein Y" is selected from a direct bond, —NR'(CH.) The invention also relates to compounds of Formula II and —CH2—, 40 wherein R'' and Rare both H; and wherein R'' and R' wherein p is 0, 1, 2, or 3; wherein R is H or C-alkyl, are independently selected from 4-morpholinopropoxy, 2-hy wherein Z is CH or N: droxy-3-morpholin-4-yl-propoxy, pyrrolidin-1-ylpropoxy, wherein R is selected from H. Co-alkyl, di-C-alkylamino 1-pyrrolidinylethoxy, 4-piperidinyloxypropoxy, (4-meth and an unsubstituted or Substituted ring selected from phe ylpiperazin-1-yl)propoxy, 3-(4-methylpiperazin-1-yl)pro nyl, C-cycloalkyl, pyrrolidinyl, piperidinyl, piperazinyl, 45 poxy, 3-(1,2,4-triazol-1-yl)propoxy, triazinylpropoxy, 3-(pi 2,3-dihydroindolyl pyrrolyl, imidazolyl pyrazolyl, peridin-4-yl)propoxy, dimethylaminoethoxy, pyrazinyl, pyrimidinyl, pyridyl, quinolinyl, isoquinolinyl, dimethylaminopropoxy and methoxy; in conjunction with 2,3-dihydrobenzofuryl, 2,3-dihydro-1,4-benzodioxinyl, any of the above or below embodiments. 1,3-benzodioxolyl, isoxazolyl, isothiazolyl, oxazolyl, thia The invention also relates to compounds of Formula II Zolyl, furanyl, and thienyl: 50 wherein R' is methoxy; in conjunction with any of the wherein R is selected from H, fluoro, chloro and methyl: above or below embodiments. wherein R is selected from H. methyl and fluoro; The invention also relates to compounds of Formula II and wherein R', R', R'' and R' is each independently pharmaceutically acceptable salts thereof selected from Selected from C-alkoxy, C-alkylamino-C-alkoxy, 2-Benzyl-5-3-fluoro-4-6-methoxy-7-(3-morpholin-4-yl 5-6 membered heterocyclyl-C-alkoxy, Cale-cycloalkyl 55 propoxy)-quinolin-4-yloxyl-phenyl-3-methyl-3H-pyri C-alkoxy, 5-6 membered heterocyclyl-C-(hydroxy midin-4-one; alkoxy), C-cycloalkyl-C-(hydroxyalkoxy), C 5-(3-fluoro-4-((6-methoxy-7-(3-(4-morpholinyl)propoxy)- alkoxy-C-alkoxy, phenyloxy-Calkoxy, 5-6 4-quinolinyl)oxy)phenyl)-2-(phenylmethyl)-4(3H)-pyri membered heterocyclyloxy-C-alkoxy, cycloalkyloxy midinone; C-alkoxy, 5-6 membered heterocyclyloxy, and C-cy 60 5-(3-fluoro-4-((7-(((2R)-2-hydroxy-3-(4-morpholinyl)-pro cloalkyloxy; and pyl)oxy)-6-methoxy-4-quinolinyl)oxy)phenyl)-3-methyl 2-(phenylmethyl)-4(3H)-pyrimidinone; wherein R'' is H or methyl: 5-(3-fluoro-4-((6-methoxy-7-((3-(1-pyrrolidinyl)propyl) and pharmaceutically acceptable derivatives thereof. oxy)-4-quinolinyl)oxy)phenyl)-3-methyl-2-(phenylm The invention also relates to compounds of Formula II 65 ethyl)-4(3H)-pyrimidinone; wherein Z is CH; in conjunction with any of the above or 5-4-(6,7-Dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl below embodiments. 2-(4-fluoro-phenylamino)-3-methyl-3H-pyrimidin-4-one;

US 7,652,009 B2 21 22 4-thiazolyl, 5-thiazolyl, 2-furanyl, 3-furanyl, 3-thienyl and and —CH2—, wherein p is 0, 1, 2, or 3; wherein R is Hor 2-thienyl; in conjunction with any of the above or below C-alkyl, embodiments. wherein Z is CH or N: The invention also relates to compounds of Formula IIIa or wherein R is selected from H. Co-alkyl, di-C-alkylamino IIIb wherein R is selected from phenyl, 2-fluorophenyl, and an unsubstituted or Substituted ring selected from phe 3-fluorophenyl, 4-fluorophenyl, 4-methylphenyl, 4-trifluo nyl, C-cycloalkyl, pyrrolidinyl, piperidinyl, piperazinyl, romethylphenyl, and 4-(dimethylamino)phenyl; in conjunc 2,3-dihydroindolyl, pyrrolyl, imidazolyl pyrazolyl, tion with any of the above or below embodiments. pyrazinyl, pyrimidinyl, pyridyl, quinolinyl, isoquinolinyl, The invention also relates to compounds of Formula IIIa or 2,3-dihydrobenzofuryl, 2,3-dihydro-1,4-benzodioxinyl, IIIb wherein R is H; in conjunction with any of the above or 10 1,3-benzodioxolyl, isoxazolyl, isothiazolyl, oxazolyl, thia below embodiments. Zolyl, furanyl, and thienyl: The invention also relates to compounds of Formula IIIa or wherein R is selected from H. fluoro, chloro and methyl: IIIb wherein R is H. methyl or fluoro; in conjunction with wherein R is selected from H. methyl and fluoro; and any of the above or below embodiments. wherein R', R', R'' and R' is each independently The invention also relates to compounds of Formula IIIa or 15 selected from C-alkoxy, C-alkylamino-C-alkoxy, IIIb wherein R'' and R'' are both H; and wherein R'' and 5-6 membered heterocyclyl-C-alkoxy, C-cycloalkyl R'' are independently selected from 4-morpholinopropoxy, C-alkoxy, 5-6 membered heterocyclyl-C-(hydroxy 2-hydroxy-3-morpholin-4-yl-propoxy, pyrrolidin-1-ylpro alkoxy), C-cycloalkyl-C-(hydroxyalkoxy), C poxy, 1-pyrrolidinylethoxy, 4-piperidinyloxypropoxy, alkoxy-C-alkoxy, phenyloxy-Calkoxy, 5-6 (4-methylpiperazin-1-yl)propoxy, 3-(4-methylpiperazin-1- membered heterocyclyloxy-C-alkoxy, cycloalkyloxy yl)propoxy, 3-(1,2,4-triazol-1-yl)propoxy, triazinylpropoxy, C-alkoxy, 5-6 membered heterocyclyloxy, and C-cy 3-(piperidin-4-yl)propoxy, dimethylaminoethoxy, dimethy cloalkyloxy; laminopropoxy and methoxy; in conjunction with any of the and pharmaceutically acceptable derivatives thereof. above or below embodiments. The invention also relates to compounds of Formula IV The invention also relates to compounds of Formula IIIa or 25 wherein Z is CH; in conjunction with any of the above or IIIb wherein R' is methoxy; in conjunction with any of the below embodiments. above or below embodiments. The invention also relates to compounds of Formula IV The invention also relates to compounds of Formula IIIa or wherein Y" is selected from a direct bond, —CO and IIIb and pharmaceutically acceptable salts thereof selected 30 —C(=O)NH ; in conjunction with any of the above or from below embodiments. 5-Benzyl-3-3-fluoro-4-6-methoxy-7-(3-morpholin-4-yl The invention also relates to compounds of Formula IV propoxy)-quinolin-4-yloxy)-phenyl)-imidazolidine-2,4- wherein R' is selected from ethyl, isopropyl, isobutyl, (CH), dione; CCH , and dimethylamino; in conjunction with any of the 5-Benzyl-3-3-fluoro-4-6-methoxy-7-(3-morpholin-4-yl 35 above or below embodiments. propoxy)-quinolin-4-yloxy)-phenyl-1-methyl-imidazo The invention also relates to compounds of Formula IV lidine-2,4-dione; and wherein R is selected from cyclopropyl, cyclobutyl, cyclo 3-3-Fluoro-4-6-methoxy-7-(3-morpholin-4-yl-propoxy)- pentyl and cyclohexyl, in conjunction with any of the above quinolin-4-yloxyl-phenyl)-1-phenethyl-imidazolidine-2, or below embodiments. 4-dione. 40 The invention also relates to compounds of Formula IV The invention also relates to compounds of Formula IV wherein R is cyclopropyl or cyclopentyl; in conjunction with any of the above or below embodiments. The invention also relates to compounds of Formula IV IV wherein R' is selected from 1-pyrrolidinyl, 2-pyrrolyl, 5-imi O dazolyl, 5-pyrazolyl, 2-pyrazinyl, 4-pyrimidinyl, 2-pyridyl, 45 3-pyridyl, 4-pyridyl, 8-quinolinyl, 2,3-dihydrobenzofur-7-yl, R N Y 2,3-dihydro-1,4-benzodioxin-5-yl, 1,3-benzodioxol-4-yl, NR 4-isoxazolyl, 3-isothiazolyl, 5-oxazolyl, 4-thiazolyl, 5-thiaz olyl 2-furanyl, 3-furanyl, 3-thienyl and 2-thienyl; in conjunc R10d O 50 tion with any of the above or below embodiments. The invention also relates to compounds of Formula IV R10 R9 wherein R is selected from phenyl, 2-fluorophenyl, 3-fluo n Z rophenyl, 4-fluorophenyl, 4-methylphenyl, 4-trifluorometh ylphenyl, and 4-(dimethylamino)phenyl; in conjunction with R10b e 55 any of the above or below embodiments. The invention also relates to compounds of Formula IV R10a wherein R is H; in conjunction with any of the above or below embodiments. whereinY" is selected from direct bond, —CO. , —C(=O) The invention also relates to compounds of Formula IV 60 wherein R is H. methyl or fluoro; in conjunction with any of NH NR"(CH.) , —CHO , the above or below embodiments. The invention also relates to compounds of Formula IV ORb wherein R'' and Rare both H; and wherein R'' and R' are independently selected from 4-morpholinopropoxy, 2-hy CH 1 ''n. 65 droxy-3-morpholin-4-yl-propoxy, pyrrolidin-1-ylpropoxy, 1-pyrrolidinylethoxy, 4-piperidinyloxypropoxy, (4-meth ylpiperazin-1-yl)propoxy, 3-(4-methylpiperazin-1-yl)pro US 7,652,009 B2 23 24 poxy, 3-(1,2,4-triazol-1-yl)propoxy, triazinylpropoxy, 3-(pi The invention also relates to compounds of Formula V peridin-4-yl)propoxy, dimethylaminoethoxy, wherein R' is selected from ethyl, isopropyl, isobutyl, (CH), dimethylaminopropoxy and methoxy; in conjunction with CCH , and dimethylamino; in conjunction with any of the any of the above or below embodiments. above or below embodiments. The invention also relates to compounds of Formula IV The invention also relates to compounds of Formula V wherein R' is methoxy; in conjunction with any of the wherein R is selected from cyclopropyl, cyclobutyl, cyclo above or below embodiments. pentyl and cyclohexyl, in conjunction with any of the above The invention also relates to compounds of Formula IV and or below embodiments. pharmaceutically acceptable salts thereof selected from The invention also relates to compounds of Formula V 1-3-Fluoro-4-6-methoxy-7-(3-morpholin-4-yl-propoxy)- 10 wherein R is cyclopropyl or cyclopentyl; in conjunction with quinolin-4-yloxyl-phenyl)-4-(methoxy-phenyl-methyl)- any of the above or below embodiments. pyrrolidin-2-one; The invention also relates to compounds of Formula V 1-4-(6,7-Dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl wherein R' is selected from 1-pyrrolidinyl, 2-pyrrolyl, 5-imi 4-(phenyl-propoxy-methyl)-pyrrolidin-2-one; and dazolyl, 5-pyrazolyl, 2-pyrazinyl, 4-pyrimidinyl, 2-pyridyl, 15 3-pyridyl, 4-pyridyl, 8-quinolinyl, 2,3-dihydrobenzofur-7-yl, 4-Benzyl-1-3-fluoro-4-6-methoxy-7-(3-morpholin-4-yl 2,3-dihydro-1,4-benzodioxin-5-yl, 1,3-benzodioxol-4-yl, propoxy)-quinolin-4-yloxy)-phenyl-pyrrolidin-2-one. 4-isoxazolyl, 3-isothiazolyl, 5-oxazolyl, 4-thiazolyl, 5-thiaz The invention also relates to compounds of Formula V olyl 2-furanyl, 3-furanyl, 3-thienyl and 2-thienyl; in conjunc tion with any of the above or below embodiments. V The invention also relates to compounds of Formula V Y wherein R is selected from phenyl, 2-fluorophenyl, 3-fluo N n R rophenyl, 4-fluorophenyl, 4-methylphenyl, 4-trifluorometh ylphenyl, and 4-(dimethylamino)phenyl; in conjunction with R8 2 N any of the above or below embodiments. 25 The invention also relates to compounds of Formula V wherein R is H; in conjunction with any of the above or R10d O below embodiments. R10 R9 The invention also relates to compounds of Formula V n Z wherein R is H. methyl or fluoro; in conjunction with any of 30 the above or below embodiments. The invention also relates to compounds of Formula V R10b e wherein R'' and R'' are both H; and wherein R'' and R' R10a are independently selected from 4-morpholinopropoxy, 2-hy droxy-3-morpholin-4-yl-propoxy, pyrrolidin-1-ylpropoxy, 35 1-pyrrolidinylethoxy, 4-piperidinyloxypropoxy, (4-meth wherein Y" is a direct bond, NR(CH.) or —CH2—, ylpiperazin-1-yl)propoxy, 3-(4-methylpiperazin-1-yl)pro wherein p is 0, 1, 2, or 3; wherein R is H or Cis-alkyl, poxy, 3-(1,2,4-triazol-1-yl)propoxy, triazinylpropoxy, 3-(pi wherein Z is CH or N: peridin-4-yl)propoxy, dimethylaminoethoxy, wherein R' is selected from H. C-alkyl, di-C-alkylamino dimethylaminopropoxy and methoxy; in conjunction with and an unsubstituted or Substituted ring selected from phe 40 any of the above or below embodiments. nyl, C-cycloalkyl, pyrrolidinyl, piperidinyl, piperazinyl, The invention also relates to compounds of Formula V 2,3-dihydroindolyl pyrrolyl, imidazolyl pyrazolyl, wherein R' is methoxy; in conjunction with any of the pyrazinyl, pyrimidinyl, pyridyl, quinolinyl, isoquinolinyl, above or below embodiments. 2,3-dihydrobenzofuryl, 2,3-dihydro-1,4-benzodioxinyl, The invention also relates to compounds of Formula V and 1,3-benzodioxolyl, isoxazolyl, isothiazolyl, oxazolyl, thia 45 pharmaceutically acceptable salts thereof selected from Zolyl, furanyl, and thienyl: 6-(4-((6.7-bis(methoxy)-4-quinolinyl)oxy)-3-fluorophenyl)- wherein R is selected from H. fluoro, chloro and methyl: N-(2-chlorophenyl)-3-pyridazinamine; and wherein R is selected from H. methyl and fluoro; and 6-(4-((6.7-bis(methoxy)-4-quinolinyl)oxy)-3-fluorophenyl)- wherein R', R', R'' and R' is each independently N-(3-fluorophenyl)-3-pyridazinamine. selected from C-alkoxy, C-alkylamino-C-alkoxy, 50 5-6 membered heterocyclyl-C-alkoxy, Cale-cycloalkyl Indications C-alkoxy, 5-6 membered heterocyclyl-C-(hydroxy alkoxy), C-cycloalkyl-C-(hydroxyalkoxy), C Compounds of the present invention would be useful for, alkoxy-C-alkoxy, phenyloxy-Calkoxy, 5-6 but not limited to, the prevention or treatment of angiogenesis membered heterocyclyloxy-Ca-alkoxy, cycloalkyloxy 55 related diseases. The compounds of the invention have kinase C-alkoxy, 5-6 membered heterocyclyloxy, and C-cy inhibitory activity, such as VEGFR/KDR and/or c-Met cloalkyloxy; inhibitory activity. The compounds of the invention are useful in therapy as antineoplasia agents or to minimize deleterious and pharmaceutically acceptable derivatives thereof. effects of VEGF and/or HGF. The invention also relates to compounds of Formula V 60 Compounds of the invention would be useful for the treat wherein Z is CH; in conjunction with any of the above or ment of neoplasia including cancer and metastasis, including, below embodiments. but not limited to: carcinoma Such as cancer of the bladder, The invention also relates to compounds of Formula V breast, colon, kidney, liver, lung (including Small cell lung wherein Y" is selected from a direct bond, N(CH)—, cancer), esophagus, gall-bladder, ovary, pancreas, stomach, —N(CH2CH2CHCCH))— —NHCH —NH(CH) , 65 cervix, thyroid, prostate, and skin (including squamous cell —NHCH2(CH)— —NH- and —CH2—, in conjunction carcinoma); hematopoietic tumors of lymphoid lineage (in with any of the above or below embodiments. cluding leukemia, acute lymphocitic leukemia, acute lym US 7,652,009 B2 25 26 phoblastic leukemia, B-cell lymphoma, T-cell-lymphoma, fever, rubeosis, neovascular glaucoma and retinopathies Such Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, hairy cell as those associated with diabetic retinopathy or macular lymphoma and Burkett's lymphoma); hematopoietic tumors degeneration. In addition, some of these compounds can be of myeloid lineage (including acute and chronic myelog used as active agents against Solid tumors, malignant ascites, enous leukemias, myelodysplastic syndrome and promyelo hematopoietic cancers and hyperproliferative disorders such cytic leukemia); tumors of mesenchymal origin (including as thyroid hyperplasia (especially Grave's disease), and cysts fibrosarcoma and rhabdomyosarcoma, and other sarcomas, (such as hypervascularity of ovarian stroma, characteristic of e.g. soft tissue and bone); tumors of the central and peripheral polycystic ovarian syndrome (Stein-Leventhal syndrome)) nervous system (including astrocytoma, neuroblastoma, since such diseases require a proliferation of blood vessel glioma and Schwannomas); and other tumors (including 10 melanoma, seminoma, teratocarcinoma, osteosarcoma, cells for growth and/or metastasis. Xenoderoma pigmentosum, keratoctanthoma, thyroid follicu Further, some of these compounds can be used as active lar cancer and Kaposi's sarcoma). agents against burns, chronic lung disease, stroke, polyps, Preferably, the compounds are useful for the treatment of anaphylaxis, chronic and allergic inflammation, ovarian neoplasia selected from lung cancer, colon cancer and breast 15 hyperstimulation syndrome, brain tumor-associated cerebral CaCC. edema, high-altitude, trauma or hypoxia induced cerebral or The compounds also would be useful for treatment of pulmonary edema, ocular and macular edema, ascites, and ophthalmological conditions such as corneal graft rejection, other diseases where vascular hyperpermeability, effusions, ocular neovascularization, retinal neovascularization includ exudates, protein extravasation, or edema is a manifestation ing neovascularization following injury or infection, diabetic of the disease. The compounds will also be useful in treating retinopathy, retrolental fibroplasia and neovascular glau disorders in which protein extravasation leads to the deposi coma; retinal ischemia; vitreous hemorrhage; ulcerative dis tion of fibrin and extracellular matrix, promoting stromal eases such as gastric ulcer, pathological, but non-malignant, proliferation (e.g. fibrosis, cirrhosis and carpal tunnel Syn conditions such as hemangiomas, including infantile hemagi drome). nomas, angiofibroma of the nasopharynx and avascular 25 necrosis of bone; and disorders of the female reproductive The compounds of the present invention are also useful in system such as endometriosis. The compounds are also useful the treatment of ulcers including bacterial, fungal, Mooren for the treatment of edema, and conditions of vascular hyper ulcers and ulcerative colitis. permeability. The compounds of the present invention are also useful in The compounds of the invention are useful in therapy of 30 the treatment of conditions wherein undesired angiogenesis, proliferative diseases. These compounds can be used for the edema, or stromal deposition occurs in viral infections such treatment of an inflammatory rheumatoid or rheumatic dis as Herpes simplex, Herpes Zoster, AIDS, Kaposi's sarcoma, ease, especially of manifestations at the locomotor apparatus, protozoan infections and toxoplasmosis, following trauma, Such as various inflammatory rheumatoid diseases, especially radiation, stroke, endometriosis, ovarian hyperstimulation chronic polyarthritis including rheumatoid arthritis, juvenile 35 syndrome, systemic lupus, sarcoidosis, synovitis, Crohn's arthritis or psoriasis arthropathy; paraneoplastic syndrome or disease, sickle cell anemia, Lyme disease, pemphigoid, Pag tumor-induced inflammatory diseases, turbid effusions, col et's disease, hyperviscosity syndrome, Osler-Weber-Rendu lagenosis, Such as systemic Lupus erythematosus, poly-myo disease, chronic inflammation, chronic occlusive pulmonary sitis, dermatomyositis, systemic sclerodermia or mixed col disease, asthma, and inflammatory rheumatoid or rheumatic lagenosis; postinfectious arthritis (where no living 40 disease. The compounds are also useful in the reduction of pathogenic organism can be foundator in the affected part of subcutaneous fat and for the treatment of obesity. the body), seronegative spondylarthritis, such as spondylitis The compounds of the present invention are also useful in ankylosans; vasculitis, sarcoidosis, or arthrosis; or further any the treatment of ocular conditions such as ocular and macular combinations thereof. An example of an inflammation related edema, ocular neovascular disease, Scleritis, radial kerato disorder is (a) synovial inflammation, for example, synovitis, 45 tomy, uveitis, vitritis, myopia, optic pits, chronic retinal including any of the particular forms of synovitis, in particu detachment, post-laser complications, glaucoma, conjunc lar bursal synovitis and purulent synovitis, as far as it is not tivitis, Stargardt's disease and Eales disease in addition to crystal-induced. Such synovial inflammation may for retinopathy and macular degeneration. example, be consequential to or associated with disease, e.g. The compounds of the present invention are also useful in arthritis, e.g. osteoarthritis, rheumatoid arthritis or arthritis 50 the treatment of cardiovascular conditions such as atheroscle deformans. The present invention is further applicable to the rosis, restenosis, arteriosclerosis, vascular occlusion and systemic treatment of inflammation, e.g. inflammatory dis carotid obstructive disease. eases or conditions, of the joints or locomotor apparatus in the The compounds of the present invention are also useful in region of the tendon insertions and tendon sheaths. Such the treatment of cancer related indications such as Solid inflammation may be, for example, consequential to or asso 55 tumors, sarcomas (especially Ewing's sarcoma and osteosa ciated with disease or further (in a broader sense of the inven rcoma), retinoblastoma, rhabdomyosarcomas, neuroblas tion) with Surgical intervention, including, in particular con toma, hematopoietic malignancies, including leukemia and ditions such as insertion endopathy, myofasciale syndrome lymphoma, tumor-induced pleural or pericardial effusions, and tendomyosis. The present invention is further especially and malignant ascites. applicable to the treatment of inflammation, e.g. inflamma 60 tory disease or condition, of connective tissues including The compounds of the present invention are also useful in dermatomyositis and myositis. the treatment of diabetic conditions such as diabetic retinopa These compounds can be used as active agents against Such thy and microangiopathy. disease states as arthritis, atherosclerosis, psoriasis, heman The compounds of the present invention are also useful in giomas, myocardial angiogenesis, coronary and cerebral col 65 the reduction of blood flow in a tumor in a subject. laterals, ischemic limb angiogenesis, wound healing, peptic The compounds of the present invention are also useful in ulcer Helicobacter related diseases, fractures, cat scratch the reduction of metastasis of a tumor in a subject. US 7,652,009 B2 27 28 The compounds of this invention may also act as inhibitors hepatocyte growth factor from humans (“huHGF) and any of other protein kinases, e.g. tie-2, lck, Src, fgf, c-Met, ron, non-human mammalian species, and in particular rat HGF. ckit and ret, and thus be effective in the treatment of diseases The terms as used herein include mature, pre, pre-pro, and pro associated with other protein kinases. forms, purified from a natural source, chemically synthesized Besides being useful for human treatment, these com or recombinantly produced. Human HGF is encoded by the pounds are also useful for veterinary treatment of companion cDNA sequence published by Miyazawa et al. (1989), supra, animals, exotic animals and farm animals, including mam or Nakamura et al. (1989), supra. The sequences reported by mals, rodents, and the like. More preferred animals include Miyazawa et al. and Nakamura et al. differ in 14 amino acids. horses, dogs, and cats. The reason for the differences is not entirely clear; polymor As used herein, the compounds of the present invention 10 phism or cloning artifacts are among the possibilities. Both include the pharmaceutically acceptable derivatives thereof. sequences are specifically encompassed by the foregoing Where the plural form is used for compounds, salts, and the terms. It will be understood that natural allelic variations exist like, this is taken to mean also a single compound, Salt and the and can occur among individuals, as demonstrated by one or like. more amino acid differences in the amino acid sequence of 15 each individual. The terms “hepatocyte growth factor” and Definitions “HGF specifically include the delta 5 huHGF as disclosed by Seki et al., Supra. Angiogenesis” is defined as any alteration of an existing The terms “HGF receptor” and “c-Met” when used herein vascular bed or the formation of new vasculature which ben refer to a cellular receptor for HGF, which typically includes efits tissue perfasion. This includes the formation of new an extracellular domain, a transmembrane domain and an vessels by sprouting of endothelial cells from existing blood intracellular domain, as well as variants and fragments vessels or the remodeling of existing vessels to alter size, thereof which retain the ability to bind HGF. The terms “HGF maturity, direction or flow properties to improve blood per receptor' and “c-Met include the polypeptide molecule that fusion of tissue. comprises the full-length, native amino acid sequence As used herein, “HGF refers to hepatocyte growth factor/ 25 encoded by the gene variously known as p190.sup.MET. The scatter factor. This includes purified hepatocyte growth fac present definition specifically encompasses soluble forms of tor/scatter factor, fragments of hepatocyte growth factor/scat HGF receptor, and HGF receptor from natural sources, syn ter factor, chemically synthesized fragments of hepatocyte thetically produced in vitro or obtained by genetic manipula growth factor/scatter factor, derivatives or mutated versions tion including methods of recombinant DNA technology. The of hepatocyte growth factor/scatterfactor, and fusion proteins 30 HGF receptor variants or fragments preferably share at least comprising hepatocyte growth factor/scatter factor and about 65% sequence homology, and more preferably at least another protein. “HGF as used herein also includes hepato about 75% sequence homology with any domain of the cyte growth factor/scatter factor isolated from species other human c-Metamino acid sequence published in Rodrigues et than humans. al., Mol. Cell. Biol., 11:2962-2970 (1991); Parket al., Proc. As used herein “c-Met” refers to the receptor for HGF. This 35 Natl. Acad. Sci., 84:6379-6383 (1987); or Ponzetto et al., includes purified receptor, fragments of receptor, chemically Oncogene, 6:553-559 (1991). synthesized fragments of receptor, derivatives or mutated The terms “agonist' and “agonistic' when used herein versions of receptor, and fusion proteins comprising the refer to or describe a molecule which is capable of directly or receptor and another protein. “c-Met as used herein also indirectly, Substantially inducing, promoting or enhancing includes the HGF receptor isolated from a species other than 40 HGF biological activity or HGF receptor activation. humans. The terms "cancer and "cancerous” when used herein As used herein, “HGF refers to hepatocyte growth factor/ refer to or describe the physiological condition in mammals scatter factor. This includes purified hepatocyte growth fac that is typically characterized by unregulated cell growth. tor/scatter factor, fragments of hepatocyte growth factor/scat Examples of cancer include but are not limited to, carcinoma, ter factor, chemically synthesized fragments of hepatocyte 45 lymphoma, sarcoma, blastoma and leukemia. More particular growth factor/scatter factor, derivatives or mutated versions examples of Such cancers include squamous cell carcinoma, of hepatocyte growth factor/scatterfactor, and fusion proteins lung cancer, pancreatic cancer, cervical cancer, bladder can comprising hepatocyte growth factor/scatter factor and cer, hepatoma, breast cancer, colon carcinoma, and head and neck cancer. While the term "cancer as used herein is not another protein. “HGF as used herein also includes hepato 50 cyte growth factor/scatter factor isolated from species other limited to any one specific form of the disease, it is believed than humans. that the methods of the invention will be particularly effective As used herein “c-Met” refers to the receptor for HGF. This for cancers which are found to be accompanied by increased includes purified receptor, fragments of receptor, chemically levels of HGF or expression of c-Met in the mammal. synthesized fragments of receptor, derivatives or mutated 55 The terms “treating.” “treatment, and “therapy” as used versions of receptor, and fusion proteins comprising the herein refer to curative therapy, prophylactic therapy, and receptor and another protein. “c-Met as used herein also preventative therapy. includes the HGF receptor isolated from a species other than The term “mammal’ as used herein refers to any mammal humans. classified as a mammal, including humans, cows, horses, As used herein, the terms “hepatocyte growth factor” and 60 dogs and cats. In a preferred embodiment of the invention, the “HGF refer to a growth factor typically having a structure mammal is a human. with six domains (finger, Kringle 1, Kringle 2, Kringle 3. Given that elevated levels of c-Met and HGF are observed Kringle 4 and serine protease domains). Fragments of HGF in hypertension, arteriosclerosis, myocardial infarction, and constitute HGF with fewer domains and variants of HGF may rheumatoid arthritis, nucleic acid ligands will serve as useful have some of the domains of HGF repeated; both are included 65 therapeutic agents for these diseases. if they still retain their respective ability to binda HGF recep The term “treatment includes therapeutic treatment as tor. The terms “hepatocyte growth factor” and “HGF include well as prophylactic treatment (either preventing the onset of US 7,652,009 B2 29 30 disorders altogether or delaying the onset of a pre-clinically radicals having all hydrogen atoms replaced with fluoro evident stage of disorders in individuals). atoms. Examples include trifluoromethyl and pentafluoroet A “pharmaceutically-acceptable derivative' denotes any hyl. salt, ester of a compound of this invention, or any other The term “hydroxyalkyl embraces linear or branched compound which upon administration to a patient is capable 5 alkyl radicals having one to about ten carbonatoms any one of of providing (directly or indirectly) a compound of this inven which may be substituted with one or more hydroxyl radicals. tion, or a metabolite or residue thereof, characterized by the More preferred hydroxyalkyl radicals are “lower hydroxy ability to inhibit angiogenesis. alkyl radicals having one to six carbon atoms and one or The phrase “therapeutically-effective' is intended to more hydroxyl radicals. Examples of Such radicals include qualify the amount of each agent, which will achieve the goal 10 hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl of improvement in disorder severity and the frequency of and hydroxyhexyl. Even more preferred are lower hydroxy incidence over treatment of each agent by itself, while avoid alkyl radicals having one to three carbon atoms. ing adverse side effects typically associated with alternative The term “alkoxy” embrace linear or branched oxy-con therapies. For example, effective neoplastic therapeutic taining radicals each having alkylportions of one to about ten agents prolong the survivability of the patient, inhibit the 15 carbon atoms. More preferred alkoxy radicals are “lower rapidly-proliferating cell growth associated with the neo alkoxy' radicals having one to six carbonatoms. Examples of plasm, or effect a regression of the neoplasm. Such radicals include methoxy, ethoxy, propoxy, butoxy and The term “H” denotes a single hydrogenatom. This radical tert-butoxy. Even more preferred are lower alkoxy radicals may be attached, for example, to an oxygen atom to form a having one to three carbon atoms. Alkoxy radicals may be hydroxyl radical. further substituted with one or more halo atoms, such as Where the term “alkyl is used, either alone or within other fluoro, chloro or bromo, to provide “haloalkoxy' radicals. terms such as “haloalkyl and “alkylamino', it embraces Even more preferred are lower haloalkoxy radicals having linear or branched radicals having one to about twelve carbon one to three carbon atoms. Examples of such radicals include atoms. More preferred alkyl radicals are “lower alkyl radi fluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoro cals having one to about six carbon atoms. Examples of Such 25 ethoxy, fluoroethoxy and fluoropropoxy. radicals include methyl, ethyl, n-propyl, isopropyl. n-butyl, The term “aryl', alone or in combination, means a carbocy isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, hexyl and the clic aromatic system containing one or two rings wherein like. Even more preferred are lower alkyl radicals having one Such rings may be attached together in a fused manner. The or two carbonatoms. The term “alkylenyl embraces bridging term “aryl” embraces aromatic radicals such as phenyl, naph divalent alkyl radicals such as methylenyl and ethylenyl. The 30 thyl, indenyl, tetrahydronaphthyl, and indanyl. More pre term “lower alkyl substituted with R” does not include an ferred aryl is phenyl. Said “aryl group may have 1 to 3 acetal moiety. substituents such as lower alkyl, hydroxyl, halo, haloalkyl, The term “alkenyl embraces linear or branched radicals nitro, cyano, alkoxy and lower alkylamino. Phenyl Substi having at least one carbon-carbon double bond of two to tuted with —O—CH2—O forms the aryl benzodioxolyl about twelve carbon atoms. More preferred alkenyl radicals 35 substituent. are “lower alkenyl radicals having two to about six carbon The term "heterocyclyl embraces saturated, partially atoms. Most preferred lower alkenyl radicals are radicals saturated and unsaturated heteroatom-containing ring radi having two to about four carbon atoms. Examples of alkenyl cals, where the heteroatoms may be selected from nitrogen, radicals include ethenyl, propenyl, allyl, propenyl, butenyl Sulfur and oxygen. It does not include rings containing and 4-methylbutenyl. The terms “alkenyl' and “lower alk 40 O—O— —O—S— or —S-S portions. Said “hetero enyl', embrace radicals having “cis' and “trans' orientations, cyclyl group may have 1 to 3 Substituents such as hydroxyl, or alternatively, “E” and “Z” orientations. Boc, halo, haloalkyl, cyano, lower alkyl, lower aralkyl, OXo, The term “alkynyl' denotes linear or branched radicals lower alkoxy, amino and lower alkylamino. having at least one carbon-carbon triple bond and having two Examples of Saturated heterocyclic radicals include Satu to about twelve carbon atoms. More preferred alkynyl radi 45 rated 3 to 6-membered heteromonocyclic groups containing 1 cals are “lower alkynyl radicals having two to about six to 4 nitrogen atoms e.g. pyrrolidinyl, imidazolidinyl, pip carbonatoms. Most preferred are lower alkynyl radicals hav eridinyl, pyrrolinyl, piperazinyl; saturated 3 to 6-membered ing two to about four carbon atoms. Examples of Such radi heteromonocyclic group containing 1 to 2 oxygenatoms and cals include propargyl, butynyl, and the like. 1 to 3 nitrogen atoms e.g. morpholinyl: Saturated 3 to The term “halo' means halogens such as fluorine, chlorine, 50 6-membered heteromonocyclic group containing 1 to 2 Sulfur bromine or iodine atoms. atoms and 1 to 3 nitrogen atoms e.g., thiazolidinyl. The term “haloalkyl embraces radicals wherein any one or Examples of partially saturated heterocyclyl radicals include more of the alkyl carbon atoms is substituted with halo as dihydrothienyl, dihydropyranyl, dihydrofuryl and dihy defined above. Specifically embraced are monohaloalkyl, drothiazolyl. dihaloalkyl and polyhaloalkyl radicals including perha 55 Examples of unsaturated heterocyclic radicals, also termed loalkyl. A monohaloalkyl radical, for one example, may have "heteroaryl radicals, include unsaturated 5 to 6 membered either an iodo, bromo, chloro or fluoro atom within the radi heteromonocyclyl group containing 1 to 4 nitrogenatoms, for cal. Dihalo and polyhaloalkyl radicals may have two or more example, pyrrolyl, imidazolyl pyrazolyl 2-pyridyl, 3-py of the same halo atoms or a combination of different halo ridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl radicals. “Lower haloalkyl embraces radicals having 1-6 60 e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triaz carbon atoms. Even more preferred are lower haloalkyl radi olyl; unsaturated 5- to 6-membered heteromonocyclic group cals having one to three carbon atoms. Examples of haloalkyl containing an oxygen atom, for example, pyranyl, 2-furyl, radicals include fluoromethyl, difluoromethyl, trifluorom 3-furyl, etc.; unsaturated 5 to 6-membered heteromonocyclic ethyl, chloromethyl, dichloromethyl, trichloromethyl, pen group containing a Sulfur atom, for example, 2-thienyl, tafluoroethyl, heptafluoropropyl, difluorochloromethyl, 65 3-thienyl, etc.; unsaturated 5- to 6-membered heteromonocy dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichlo clic group containing 1 to 2 oxygenatoms and 1 to 3 nitrogen roethyl and dichloropropyl. “Perfluoroalkyl means alkyl atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl e.g., US 7,652,009 B2 31 32 1,2,4-oxadiazolyl, 1.3,4-oxadiazolyl, 1,2,5-oxadiazolyl); The terms "N-alkylaminocarbonyl and “N,N-dialkylami unsaturated 5 to 6-membered heteromonocyclic group con nocarbonyl denote aminocarbonyl radicals independently taining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for substituted with one or two alkyl radicals, respectively. More example, thiazolyl, thiadiazolyl e.g., 1,2,4-thiadiazolyl, 1.3, preferred are “lower alkylaminocarbonyl having lower alkyl 4-thiadiazolyl, 1,2,5-thiadiazolyl). radicals as described above attached to an aminocarbonyl The term heterocyclyl also embraces radicals where het radical. erocyclic radicals are fused/condensed with aryl radicals: The terms “N-arylaminocarbonyl' and "N-alkyl-N-ary unsaturated condensed heterocyclic group containing 1 to 5 laminocarbonyl denote aminocarbonyl radicals Substituted, nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl, respectively, with one aryl radical, or one alkyl and one aryl benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotria 10 radical. Zolyl, tetraZolopyridazinyl e.g., tetraZolo 1.5-b]pyridazi The terms "heterocyclylalkylenyl and "heterocyclyla nyl; unsaturated condensed heterocyclic group containing 1 lkyl embrace heterocyclic-substituted alkyl radicals. More to 2 oxygen atoms and 1 to 3 nitrogen atoms e.g. benzox preferred heterocyclylalkyl radicals are “5- or 6-membered azolyl, benzoxadiazolyl; unsaturated condensed heterocy heteroarylalkyl radicals having alkyl portions of one to six clic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen 15 carbon atoms and a 5- or 6-membered heteroaryl radical. atoms e.g., benzothiazolyl, benzothiadiazolyl; and Satu Even more preferred are lower heteroarylalkylenyl radicals rated, partially unsaturated and unsaturated condensed het having alkyl portions of one to three carbonatoms. Examples erocyclic group containing 1 to 2 oxygen or Sulfur atoms e.g. include Such radicals as pyridylmethyl and thienylmethyl. benzofuryl, benzothienyl, 2,3-dihydro-benzo 1.4 dioxinyl The term “aralkyl embraces aryl-substituted alkyl radi and dihydrobenzofuryl. Preferred heterocyclic radicals cals. Preferable aralkyl radicals are “lower aralkyl radicals include five to ten membered fused or unfused radicals. More having aryl radicals attached to alkyl radicals having one to preferred examples of heteroaryl radicals include quinolyl, six carbonatoms. Even more preferred are “phenylalkylenyl isoquinolyl, imidazolyl pyridyl, thienyl, thiazolyl, oxazolyl, attached to alkyl portions having one to three carbon atoms. furyl, and pyrazinyl. Other preferred heteroaryl radicals are 5 Examples of such radicals include benzyl, diphenylmethyl or 6-membered heteroaryl, containing one or two heteroat 25 and phenylethyl. The aryl in said aralkyl may be additionally oms selected from Sulfur, nitrogen and oxygen, selected from substituted with halo, alkyl, alkoxy, halkoalkyl and thienyl, furyl, pyrrolyl, indazolyl, pyrazolyl, oxazolyl, triaz haloalkoxy. olyl, imidazolyl pyrazolyl, isoxazolyl, isothiazolyl pyridyl, The term “alkylthio’ embraces radicals containing a linear piperidinyl and pyrazinyl. or branched alkyl radical, of one to ten carbonatoms, attached Particular examples of non-nitrogen containing heteroaryl 30 to a divalent sulfur atom. Even more preferred are lower include pyranyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, benzo alkylthio radicals having one to three carbon atoms. An furyl, benzothienyl, and the like. example of “alkylthio” is methylthio, (CHS ). Particular examples of partially saturated and Saturated The term “haloalkylthio’ embraces radicals containing a heterocyclyl include pyrrolidinyl, imidazolidinyl, piperidi haloalkyl radical, of one to ten carbon atoms, attached to a nyl, pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl, tet 35 divalent sulfur atom. Even more preferred are lower haloalky rahydropyranyl, thiazolidinyl, dihydrothienyl, 2,3-dihydro lthio radicals having one to three carbon atoms. An example benzo 1.4 dioxanyl. indolinyl, isoindolinyl, of “haloalkylthio’ is trifluoromethylthio. dihydrobenzothienyl, dihydrobenzofuryl, isochromanyl, The term “alkylamino' embraces "N-alkylamino” and chromanyl, 1,2-dihydroquinolyl, 1,2,3,4-tetrahydro-iso “N,N-dialkylamino” where amino groups are independently quinolyl, 1.2.3,4-tetrahydro-quinolyl, 2.3.4.4a,9.9a-hexahy 40 substituted with one alkyl radical and with two alkyl radicals, dro-1H-3-aza-fluorenyl, 5,6,7-trihydro-1,2,4-triazolo 3,4-a respectively. More preferred alkylamino radicals are “lower isoquinolyl, 3,4-dihydro-2H-benzo 1.4 oxazinyl, benzo 1.4 alkylamino” radicals having one or two alkyl radicals of one dioxanyl. 2,3-dihydro-1H-12'-benzodisothiazol-6-yl, to six carbon atoms, attached to a nitrogen atom. Even more dihydropyranyl, dihydrofuryl and dihydrothiazolyl, and the preferred are lower alkylamino radicals having one to three like. 45 carbon atoms. Suitable alkylamino radicals may be mono or The term "sulfonyl', whether used alone or linked to other dialkylamino such as N-methylamino, N-ethylamino, N.N- terms such as alkylsulfonyl, denotes respectively divalent dimethylamino, N,N-diethylamino and the like. radicals —SO-. The term “arylamino” denotes amino groups which have The terms “sulfamyl.” “aminosulfonyl and “sulfona 50 been substituted with one or two aryl radicals, such as N-phe midyl. denotes a sulfonyl radical substituted with an amine nylamino. The arylamino radicals may be further substituted radical, forming a sulfonamide (-SONH2). on the aryl ring portion of the radical. The term “alkylaminosulfonyl' includes "N-alkylamino The term "heteroarylamino” denotes amino groups which sulfonyl' where sulfamyl radicals are independently substi have been substituted with one or two heteroaryl radicals, tuted with one or two alkyl radical(s). More preferred alky 55 such as N-thienylamino. The "heteroarylamino” radicals may laminosulfonyl radicals are “lower alkylaminosulfonyl be further substituted on the heteroaryl ring portion of the radicals having one to six carbon atoms. Even more preferred radical. are lower alkylaminosulfonyl radicals having one to three The term “aralkylamino” denotes amino groups which carbon atoms. Examples of Such lower alkylaminosulfonyl have been substituted with one or two aralkyl radicals. More radicals include N-methylaminosulfonyl, and N-ethylamino 60 preferred are phenyl-C-C-alkylamino radicals, such as sulfonyl. N-benzylamino. The aralkylamino radicals may be further The terms “carboxy' or “carboxyl', whether used alone or Substituted on the aryl ring portion. with other terms, such as "carboxyalkyl', denotes —CO.H. The terms "N-alkyl-N-arylamino” and “N-aralkyl-N-alky The term “carbonyl', whether used alone or with other lamino” denote amino groups which have been indepen terms, such as "aminocarbonyl', denotes —(C=O)—. 65 dently substituted with one aralkyl and one alkyl radical, or The term “aminocarbonyl' denotes an amide group of the one aryl and one alkyl radical, respectively, to an amino formula—C(=O)NH2. group. US 7,652,009 B2 33 34 The term “aminoalkyl embraces linear or branched alkyl The term "heteroarylalkoxy” embraces oxy-containing radicals having one to about ten carbon atoms any one of heteroarylalkyl radicals attached through an oxygen atom to which may be substituted with one or more amino radicals. other radicals. More preferred heteroarylalkoxy radicals are More preferred aminoalkyl radicals are “lower aminoalkyl “lower heteroarylalkoxy' radicals having optionally substi radicals having one to six carbon atoms and one or more tuted heteroaryl radicals attached to lower alkoxy radical as amino radicals. Examples of Such radicals include aminom described above. ethyl, aminoethyl, aminopropyl, aminobutyl and amino The term “cycloalkyl includes saturated carbocyclic hexyl. Even more preferred are lower aminoalkyl radicals groups. Preferred cycloalkyl groups include C-C rings. having one to three carbon atoms. More preferred compounds include, cyclopentyl, cyclopro The term “alkylaminoalkyl embraces alkyl radicals sub 10 pyl, and cyclohexyl. stituted with alkylamino radicals. More preferred alkylami The term “cycloalkylalkyl embraces cycloalkyl-substi noalkyl radicals are “lower alkylaminoalkyl radicals having tuted alkyl radicals. Preferable cycloalkylalkyl radicals are alkyl radicals of one to six carbonatoms. Even more preferred “lower cycloalkylalkyl radicals having cycloalkyl radicals are lower alkylaminoalkyl radicals having alkyl radicals of attached to alkyl radicals having one to six carbon atoms. one to three carbon atoms. Suitable alkylaminoalkyl radicals 15 Even more preferred are “5-6-membered cycloalkylalkyl may be mono or dialkyl substituted, such as N-methylami attached to alkyl portions having one to three carbon atoms. nomethyl, N,N-dimethyl-aminoethyl, N,N-diethylaminom Examples of such radicals include cyclohexylmethyl. The ethyl and the like. cycloalkyl in said radicals may be additionally substituted The term “alkylaminoalkoxy” embraces alkoxy radicals with halo, alkyl, alkoxy and hydroxy. substituted with alkylamino radicals. More preferred alky The term “cycloalkenyl' includes carbocyclic groups hav laminoalkoxy radicals are “lower alkylaminoalkoxy' radi ing one or more carbon-carbon double bonds including cals having alkoxy radicals of one to six carbon atoms. Even “cycloalkyldienyl compounds. Preferred cycloalkenyl more preferred are lower alkylaminoalkoxy radicals having groups include C-C rings. More preferred compounds alkyl radicals of one to three carbonatoms. Suitable alkylami include, for example, cyclopentenyl, cyclopentadienyl, noalkoxy radicals may be mono or dialkyl Substituted. Such as 25 cyclohexenyl and cycloheptadienyl. N-methylaminoethoxy, N,N-dimethylaminoethoxy, N,N-di The term "comprising is meant to be open ended, includ ethylaminoethoxy and the like. ing the indicated component but not excluding other ele The term “alkylaminoalkoxyalkoxy” embraces alkoxy mentS. radicals substituted with alkylaminoalkoxy radicals. More The term “Formulas I-V” includes any sub formulas. preferred alkylaminoalkoxyalkoxy radicals are “lower alky 30 The compounds of the invention are endowed with kinase laminoalkoxyalkoxy' radicals having alkoxy radicals of one inhibitory activity, such as KDR and/or c-Met inhibitory to six carbonatoms. Even more preferred are lower alkylami activity. noalkoxyalkoxy radicals having alkyl radicals of one to three The present invention also comprises the use of a com carbon atoms. Suitable alkylaminoalkoxyalkoxy radicals pound of the invention, or pharmaceutically acceptable salt may be mono or dialkyl substituted, such as N-methylami 35 thereof, in the manufacture of a medicament for the treatment nomethoxyethoxy, N-methylaminoethoxyethoxy, N,N-dim either acutely or chronically of an angiogenesis mediated ethylaminoethoxyethoxy, N,N-diethylami disease State, including those described previously. The com nomethoxymethoxy and the like. pounds of the present invention are useful in the manufacture The term “carboxyalkyl embraces linear or branched of an anti-cancer medicament. The compounds of the present alkyl radicals having one to about ten carbonatoms any one of 40 invention are also useful in the manufacture of a medicament which may be substituted with one or more carboxy radicals. to attenuate or prevent disorders through inhibition of KDR More preferred carboxyalkyl radicals are “lower carboxy and/or c-Met. alkyl radicals having one to six carbon atoms and one car The present invention comprises a pharmaceutical compo boxy radical. Examples of Such radicals include carboxym sition comprising a therapeutically-effective amount of a ethyl, carboxypropyl, and the like. Even more preferred are 45 compound of Formulas I-V in association with a least one lower carboxyalkyl radicals having one to three CH2 groups. pharmaceutically-acceptable carrier, adjuvant or diluent. The term “halosulfonyl embraces sulfonyl radicals sub The present invention also comprises a method of treating stituted with a halogen radical. Examples of Such halosulfo angiogenesis related disorders in a Subject having or Suscep nyl radicals include chlorosulfonyl and fluorosulfonyl. tible to Such disorder, the method comprising treating the The term “arylthio’ embraces aryl radicals of six to ten 50 subject with a therapeutically-effective amount of a com carbonatoms, attached to a divalent Sulfur atom. An example pound of Formula I-V. of “arylthio’ is phenylthio. The term “aralkylthio’ embraces aralkyl radicals as Combinations described above, attached to a divalent sulfur atom. More preferred are phenyl-C-C-alkylthio radicals. An example of 55 While the compounds of the invention can be administered “aralkylthio' is benzylthio. as the Sole active pharmaceutical agent, they can also be used The term “aryloxy” embraces optionally substituted aryl in combination with one or more compounds of the invention radicals, as defined above, attached to an oxygen atom. or other agents. When administered as a combination, the Examples of Such radicals include phenoxy. therapeutic agents can be formulated as separate composi The term “aralkoxy' embraces oxy-containing aralkyl 60 tions that are administered at the same time or sequentially at radicals attached through an oxygen atom to other radicals. different times, or the therapeutic agents can be given as a More preferred aralkoxy radicals are “lower aralkoxy' radi single composition. cals having optionally substituted phenyl radicals attached to The phrase “co-therapy' (or “combination-therapy'), in lower alkoxy radical as described above. defining use of a compound of the present invention and The term "heteroaryloxy” embraces optionally substituted 65 another pharmaceutical agent, is intended to embrace admin heteroaryl radicals, as defined above, attached to an oxygen istration of each agent in a sequential manner in a regimen atOm. that will provide beneficial effects of the drug combination, US 7,652,009 B2 35 36 and is intended as well to embrace co-administration of these tives, Chugai DWA-2114R, ITI E09, elmustine, Erbamont agents in a Substantially simultaneous manner, Such as in a FCE-24517, estramustine phosphate sodium, fotemustine, single capsule having a fixed ratio of these active agents or in Unimed G-6-M, Chinoin GYKI-17230, hepsul-fam, ifosfa multiple, separate capsules for each agent. mide, iproplatin, lomustine, mafosfamide, mitolactol, Nip Specifically, the administration of compounds of the pon Kayaku NK-121, NCI NSC-264395, NCI NSC-342215, present invention may be in conjunction with additional oxaliplatin, Upjohn PCNU, prednimustine, Proter PTT-119, therapies known to those skilled in the art in the prevention or ranimustine, semustine, SmithKline SK&F-101772, Yakult treatment of neoplasia, such as with radiation therapy or with Honsha SN-22, spiromus-tine, Tanabe Seiyaku TA-077, tau cytostatic or cytotoxic agents. romustine, temozolomide, teroxirone, tetraplatin and tri If formulated as a fixed dose. Such combination products 10 melamol. employ the compounds of this invention within the accepted A third family of antineoplastic agents which may be used dosage ranges. Compounds of Formula I may also be admin in combination with compounds of the present invention con istered sequentially with known anticancer or cytotoxic sists of antibiotic-type antineoplastic agents. Suitable antibi agents when a combination formulation is inappropriate. The otic-type antineoplastic agents may be selected from but not invention is not limited in the sequence of administration; 15 limited to the group consisting of Taiho. 4181-A, aclarubicin, compounds of the invention may be administered either prior actinomycin D, actinoplanone, Erbamont ADR-456, aeropl to, simultaneous with or after administration of the known ysinin derivative, Ajinomoto AN-201-II, Ajinomoto AN-3, anticancer or cytotoxic agent. Nippon Soda anisomycins, anthracycline, azino-mycin-A, Currently, standard treatment of primary tumors consists bisucaberin, Bristol-Myers BL-6859, Bristol-Myers BMY of surgical excision followed by either radiation or IV admin 25067, Bristol-Myers BMY-25551, Bristol-Myers BMY istered chemotherapy. The typical chemotherapy regime con 26605, Bristol-Myers BMY-27557, Bristol-Myers BMY sists of either DNA alkylating agents, DNA intercalating 28438, bleomycin sulfate, bryostatin-1, Taiho C-1027, agents, CDK inhibitors, or microtubule poisons. The chemo calichemycin, chromoximycin, dactinomycin, daunorubicin, therapy doses used are just below the maximal tolerated dose Kyowa Hakko DC-102, Kyowa Hakko DC-79, Kyowa Hakko and therefore dose limiting toxicities typically include, nau 25 DC-88A, Kyowa Hakko DC89-A1, Kyowa Hakko DC92-B, sea, vomiting, diarrhea, hair loss, neutropenia and the like. ditrisarubicin B, Shionogi DOB-41, doxorubicin, doxorubi There are large numbers of antineoplastic agents available cin-fibrinogen, elsamicin-A, epirubicin, erbStatin, esorubi in commercial use, in clinical evaluation and in pre-clinical cin, esperamicin-A1, esperamicin-Alb, Erbamont FCE development, which would be selected for treatment of neo 21954, Fujisawa FK-973, fostriecin, Fujisawa FR-900482, plasia by combination drug chemotherapy. Such antineoplas 30 glidobactin, gregatin-A, grincamycin, herbimycin, idarubi tic agents fall into several major categories, namely, antibi cin, illudins, kaZusamycin, kesarirhodins, Kyowa Hakko otic-type agents, alkylating agents, antimetabolite agents, KM-5539, Kirin Brewery KRN-8602, Kyowa Hakko hormonal agents, immunological agents, interferon-type KT-5432, Kyowa Hakko KT-5594, Kyowa Hakko KT-6149, agents and a category of miscellaneous agents. American Cyanamid LL-D49194, Meiji Seika ME 2303, A first family of antineoplastic agents which may be used 35 menogaril, mitomycin, mitoxantrone, SmithKline M-TAG, in combination with compounds of the present invention con neoenactin, Nippon Kayaku NK-313, Nippon Kayaku NKT sists of antimetabolite-type/thymidilate synthase inhibitor 01, SRI International NSC-357704, oxalysine, oxaunomycin, antineoplastic agents. Suitable antimetabolite antineoplastic peplomycin, pilatin, pirarubicin, porothramycin, pyrindany agents may be selected from but not limited to the group cin A, Tobishi RA-I, rapamycin, rhizoxin, rodorubicin, Siba consisting of 5-FU-fibrinogen, acanthifolic acid, aminothia 40 nomicin, siwenmycin, Sumitomo SM-5887, Snow Brand diazole, brequinar sodium, carmofur, Ciba-Geigy CGP SN-706, Snow Brand SN-07, Sorangicin-A, sparsomycin, SS 30694, cyclopentyl cytosine, cytarabine phosphate Stearate, Pharmaceutical SS-21020, SS Pharmaceutical SS-7313B, SS cytarabine conjugates, Lilly DATHF, Merrel Dow DDFC, Pharmaceutical SS-9816B, Steffimycin B, Taiho. 4181-2, tali deZaguanine, dideoxycytidine, dideoxyguanosine, didox, somycin, Takeda TAN-868A, terpentecin, thrazine, tric Yoshitomi DMDC, doxifluridine, Wellcome EHNA, 45 rozarin A, Upjohn U-73975, Kyowa Hakko UCN-10028A, Merck & Co. EX-015, fazarabine, floxuridine, fludarabine Fujisawa WF-3405, YoshitomiY-25024 and Zorubicin. phosphate, 5-fluorouracil, N-(2-furanidyl)-5-fluorouracil, A fourth family of antineoplastic agents which may be used Daiichi Seiyaku FO-152, isopropyl pyrrolizine, Lilly in combination with compounds of the present invention con LY-188011, Lilly LY-264618, methobenzaprim, methotrex sists of a miscellaneous family of antineoplastic agents, ate, Wellcome MZPES, norspermidine, NCI NSC-127716, 50 including tubulin interacting agents, topoisomerase II inhibi NCI NSC-264880, NCI NSC-39661, NCI NSC-612567, tors, topoisomerase I inhibitors and hormonal agents, Warner-Lambert PALA, pentostatin, piritrexim, plicamycin, selected from but not limited to the group consisting of Asahi Chemical PL-AC, Takeda TAC-788, thioguanine, tia C-carotene, C-difluoromethyl-arginine, acitretin, Biotec Zoflurin, Erbamont TIF, trimetrexate, tyrosine kinase inhibi AD-5, Kyorin AHC-52, alstonine, amonafide, amphethinile, tors, Taiho UFT and uricytin. 55 amsacrine, Angiostat, ankinomycin, anti-neoplaston A10. A second family of antineoplastic agents which may be antineoplaston A2, antineoplaston A3, antineoplaston A5. used in combination with compounds of the present invention antineoplaston AS2-1, Henkel APD, aphidicolin glycinate, consists of alkylating-type antineoplastic agents. Suitable asparaginase, Avarol, baccharin, batracylin, benfluron, ben alkylating-type antineoplastic agents may be selected from Zotript, Ipsen-Beaufour BIM-23015, bisantrene, Bristol-My but not limited to the group consisting of Shionogi 254-S, 60 ers BMY-40481, Vestar boron-10, bromofosfamide, aldo-phosphamide analogues, altretamine, anaxirone, Boe Wellcome BW-502, Wellcome BW-773, caracemide, carme hiringer Mannheim BBR-2207, bestrabucil, budotitane, thizole hydrochloride, Ajinomoto CDAF, chlorsulfaquinoxa Wakunaga CA-102, carboplatin, carmustine, Chinoin-139, lone, Chemes CHX-2053, Chemex CHX-100, Warner-Lam Chinoin-153, chlorambucil, cisplatin, cyclophosphamide, bert CI-921, Warner-Lambert CI-937, Warner-Lambert American Cyanamid CL-286558, Sanofi CY-233, cyplatate, 65 CI-941, Warner-Lambert CI-958, clanfenur, claviridenone, Degussa D-19-384, Sumimoto DACHP(Myr), diphenyl ICN compound 1259, ICN compound 4711, Contracan, spiromustine, diplatinum cytostatic, Erba distamycin deriva Yakult Honsha CPT-11, crisinatol, curaderm, cytochalasin B, US 7,652,009 B2 37 38 cytarabine, cytocytin, Merz, D-609, DABIS maleate, dacar gamma-1b, interleukin-1 beta, iobenguane, irinotecan, bazine, datelliptinium, didemnin-B, dihaematoporphyrin irsogladine, lanreotide, LC 9018 (Yakult), leflunomide, ether, dihydrolenperone, dinaline, distamycin, Toyo Pharmar lenograstim, lentinan Sulfate, letrozole, leukocyte alpha inter DM-341, Toyo Pharmar DM-75, Daiichi Seiyaku DN-9693, feron, leuprorelin, levamisole--fluorouracil, liarozole, lobap docetaxel elliprabin, elliptinium acetate, Tsumura EPMTC, latin, lonidamine, lovastatin, masoprocol, melarsoprol, meto the epothilones, ergotamine, etoposide, etretinate, fenretin clopramide, mifepristone, miltefosine, mirimoStim, ide, Fujisawa FR-57704, gallium nitrate, genkwadaphnin, mismatched double stranded RNA, mitoguaZone, mitolactol, Chugai GLA-43, Glaxo GR-63178, grifolian NMF-5N, hexa mitoxantrone, molgramostim, nafarelin, naloxone-pentaZo decylphosphocholine, Green Cross HO-221, homoharringto cine, nartograstim, nedaplatin, nilutamide, noscapine, novel nine, hydroxyurea, BTG ICRF-187, ilmofosine, iso 10 erythropoiesis stimulating protein, NSC 631570 octreotide, glutamine, isotretinoin, Otsuka JI-36, Ramot K-477, Otsuak oprelvekin, osaterone, Oxaliplatin, paclitaxel, pamidronic K-76COONa, Kureha Chemical K-AM, MECT Corp acid, pegaspargase, peginterferon alfa-2b, pentosan polysul KI-81 10, American Cyanamid L-623, leukoregulin, fate Sodium, pentostatin, picibanil, pirarubicin, rabbit anti lonidamine, Lundbeck LU-23-112, Lilly LY-186641, NCI thymocyte polyclonal antibody, polyethylene glycol inter (US) MAP. marycin, Merrel Dow MDL-27048, Medco 15 feron alfa-2a, porfimer Sodium, raloxifene, raltitrexed, MEDR-340, merbarone, merocyanline derivatives, methyla rasburicase, rhenium Re 186 etidronate, RII retinamide, rit nilinoacridine, Molecular Genetics MGI-136, minactivin, uximab, romurtide, Samarium (153 Sm) lexidronam, Sargra mitonafide, mitoquidone mopidamol, motretinide, Zenyaku mostim, sizofuran, Sobuzoxane, Sonermin, strontium-89 Kogyo MST-16, N-(retinoyl)amino acids, Nisshin Flour chloride, Suramin, tasonermin, tazarotene, tegafur, temopor Milling N-021, N-acylated-dehydroalanines, nafazatrom, fin, temozolomide, teniposide, tetrachlorodecaoxide, thalido Taisho NCU-190, nocodazole derivative, Normosang, NCI mide, thymalfasin, thyrotropin alfa, topotecan, toremifene, NSC-145813, NCI NSC-361456, NCI NSC-604782, NCI to situmomab-iodine 131, trastuzumab, treosulfan, tretinoin, NSC-95580, ocreotide, Ono ONO-112, oduizanocine, Akzo triloStane, trimetrexate, triptorelin, tumor necrosis factor Org-10172, paclitaxel, pancratistatin, pazelliptine, Warner alpha, natural, ubenimex, bladder cancer vaccine, Maruyama Lambert PD-11 1707, Warner-Lambert PD-115934, Warner 25 vaccine, melanoma lysate vaccine, valrubicin, Verteporfin, Lambert PD-131141, Pierre Fabre PE-1001, ICRT peptide D, vinorelbine, VIRULIZIN, Zinostatin stimalamer, or piroXantrone, polyhaematoporphyrin, polypreic acid, Efamol Zoledronic acid; abarelix: AE 941 (Aeterna), ambamustine, porphyrin, probimane, procarbazine, proglumide, Invitron antisense oligonucleotide, bcl-2 (Genta), APC 8015 (Den protease nexin I, Tobishi RA-700, razoxane, Sapporo Brew dreon), cetuximab, decitabine, dexaminoglutethimide, diazi eries RBS, restrictin-Pretelliptine, retinoic acid, Rhone-Pou 30 quone, EL 532 (Elan), EM 800 (Endorecherche), eniluracil, lenc RP-49532, Rhone-Poulenc RP-56976, SmithKline etanidazole, fenretinide, filgrastim SD01 (Amgen), fulves SK&F-104864, Sumitomo SM-108, Kuraray SMANCS, trant, galocitabine, gastrin 17 immunogen, HLA-B7 gene SeaPharm SP-10094, spatol, spirocyclopropane derivatives, therapy (Vical), granulocyte macrophage colony stimulating spirogermanium, Unimed, SS Pharmaceutical SS-554, stry factor, histamine dihydrochloride, ibritumomab tiuxetan, ilo poldinone, Stypoldione, Suntory SUN 0237, Suntory SUN 35 mastat, IM 862 (Cytran), interleukin-2, iproxifene, LDI 200 2071, superoxide dismutase, Toyama T-506, Toyama T-680. (Milkhaus), leridistim, lintuzumab, CA 125 MAb (Biomira), taxol. Teijin TEI-0303, teniposide, thaliblastine, Eastman cancer MAb (Japan Pharmaceutical Development), HER-2 Kodak TJB-29, tocotrienol, topotecan, Topostin, Teijin and Fc MAb (Medarex), idiotypic 105AD7 MAb (CRC Tech TT-82, Kyowa Hakko UCN-01, Kyowa Hakko UCN-1028, nology), idiotypic CEA MAb (Trilex), LYM-1-iodine 131 ukrain, Eastman Kodak USB-006, vinblastine sulfate, Vinc 40 MAb (Techniclone), polymorphic epithelial mucin-yttrium ristine, Vindesine, vinestramide, Vinorelbine, Vintriptol, Vin 90 MAb (Antisoma), marimastat, menogaril, mitumomab, Zolidine, withanolides and Yamanouchi YM-534. motexafin gadolinium, MX 6 (Galderma), nelarabine, nola Alternatively, the present compounds may also be used in trexed, P30 protein, pegvisomant, pemetrexed, porfiromycin, co-therapies with other anti-neoplastic agents, such as ace prinomastat, RL 0903 (Shire), rubitecan, satraplatin, sodium mannan, aclarubicin, aldesleukin, alemtuzumab, alitretinoin, 45 phenylacetate, sparfosic acid, SRL 172 (SR Pharma), SU altretamine, amifostine, aminolevulinic acid, amrubicin, 5416 (SUGEN), TA 077 (Tanabe), tetrathiomolybdate, thali amsacrine, anagrelide, anastrozole, ANCER, ancestim, blastine, thrombopoietin, tin ethyl etiopurpurin, tira ARGLABIN, arsenic trioxide, BAM 002 (Novelos), bexaro paZamine, cancer vaccine (Biomira), melanoma vaccine tene, bicalutamide, broXuridine, capecitabine, celmoleukin, (New York University), melanoma vaccine (Sloan Kettering cetrorelix, cladribine, clotrimazole, cytarabine ocfosfate, DA 50 Institute), melanoma oncolysate vaccine (New York Medical 3030 (Dong-A), daclizumab, denileukin diftitox, deslorelin, College), viral melanoma cell lysates vaccine (Royal New dexraZoxane, dilaZep, docetaxel, docosanol, doxercalciferol, castle Hospital), or Valspodar. doxifluridine, doxorubicin, bromocriptine, carmustine, cyt Alternatively, the present compounds may also be used in arabine, fluorouracil, HIT diclofenac, interferon alfa, dauno co-therapies with VEGFR inhibitors including rubicin, doxorubicin, tretinoin, edelfosine, edrecolomab, 55 N-(4-chlorophenyl)-4-(4-pyridinylmethyl)-1-phthalazi eflornithine, emitefur, epirubicin, epoetin beta, etoposide namine; phosphate, exemestane, exisulind, fadrozole, filgrastim, fin 4-4-4-chloro-3-(trifluoromethyl)phenylaminocarbo asteride, fludarabine phosphate, formestane, fotemustine, nylaminophenoxy-N-methyl-2-pyridinecarboxamide; gallium nitrate, gemcitabine, gemtuzumab Zogamicin, gime N-2-(diethylamino)ethyl-5-(5-fluoro-1,2-dihydro-2-oxo racil/oteracil/tegafur combination, glycopine, goserelin, hep 60 taplatin, human chorionic gonadotropin, human fetal alpha 3H-indol-3-ylidene)methyl-2,4-dimethyl-1H-pyrrole-3- fetoprotein, ibandronic acid, idarubicin, (imiduimod, inter carboxamide; feron alfa, interferon alfa, natural, interferon alfa-2, inter 3-(4-bromo-2,6-difluorophenyl)methoxy-5-4-(1-pyrro feron alfa-2a, interferon alfa-2b, interferon alfa-N1, inter lidinyl)butylaminocarbonylamino-4-isothiazolecar feron alfa-n3, interferon alfacon-1, interferon alpha, natural, 65 boxamide; interferon beta, interferon beta-1a, interferon beta-1b, inter N-(4-bromo-2-fluorophenyl)-6-methoxy-7-(1-methyl-4-pi feron gamma, natural interferon gamma-1a, interferon peridinyl)methoxy-4-quinazolinamine; US 7,652,009 B2 39 40 3-5,6,7,13-tetrahydro-9-(1-methylethoxy)methyl-5-oxo Pat. No. 6,235,764, WO 01/32651, U.S. Pat. No. 6,630,500, 12H-indeno2, 1-alpyrrolo3.4-ccarbazol-12-ylpropyl U.S. Pat. No. 6,515,004, U.S. Pat. No. 6,713,485, U.S. Pat. ester N,N-dimethyl-glycine; No. 5,521,184, U.S. Pat. No. 5,770,599, U.S. Pat. No. 5,747, N-5-5-(1,1-dimethylethyl)-2-oxazolylmethylthio-2- 498, WO 02/68406, WO 02/66470, WO 02/55501, WO thiazolyl-4-piperidinecarboxamide; 04/05279, WO 04/07481, WO 04/07458, WO 04/09784, WO N-3-chloro-4-(3-fluorophenyl)methoxyphenyl-6-5-2- 02/59110, WO 99/45009, WO 00/59509, WO99/61422, U.S. (methylsulfonyl)ethylaminomethyl)-2-furanyl-4- Pat. No. 5,990,141, WO 00/12089 and WO 00/02871. quinazolinamine In some embodiments, the combination comprises a com 4-(4-Methyl-1-piperazinyl)methyl-N-(4-methyl-3-4-(3- position of the present invention in combination with at least pyridinyl)-2-pyrimidinylamino-phenylbenzamide 10 one anti-angiogenic agent. Agents are inclusive of, but not N-(3-chloro-4-fluorophenyl)-7-methoxy-6-3-(4-morpholi limited to, in vitro synthetically prepared chemical composi nyl)propoxy-4-quinazolinamine tions, antibodies, antigenbinding regions, radionuclides, and N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazo combinations and conjugates thereof. An agent can be an linamine agonist, antagonist, allosteric modulator, toxin or, more gen N-(3-((((2R)-1-methyl-2-pyrrolidinyl)methyl)oxy)-5-(trif 15 erally, may act to inhibit or stimulate its target (e.g., receptor luoromethyl)phenyl)-2-((3-(1,3-oxazol-5-yl)phenyl) or enzyme activation or inhibition), and thereby promote cell amino)-3-pyridinecarboxamide; death or arrest cell growth. 2-(((4-fluorophenyl)methyl)amino)-N-(3-((((2R)-1-methyl Exemplary anti-tumor agents include HERCEPTINTM 2-pyrrolidinyl)methyl)oxy)-5-(trifluoromethyl)phenyl)-3- (trastuzumab), which may be used to treat breast cancer and pyridinecarboxamide; other forms of cancer, and RITUXANTM (rituximab), ZEVA N-3-(AZetidin-3-ylmethoxy)-5-trifluoromethyl-phenyl-2- LINTM (ibritumomab tiuxetan), and LYMPHOCIDETM (4-fluoro-benzylamino)-nicotinamide. (epratuZumab), which may be used to treat non-Hodgkin’s 6-fluoro-N-(4-(1-methylethyl)phenyl)-2-((4-pyridinylm lymphoma and other forms of cancer, GLEEVACTM which ethyl)amino)-3-pyridinecarboxamide; may be used to treat chronic myeloid leukemia and gas 2-((4-pyridinylmethyl)amino)-N-(3-(((2S)-2-pyrrolidinylm 25 trointestinal stromal tumors, and BEXXARTM (iodine 131 ethyl)oxy)-5-(trifluoromethyl)phenyl)-3-pyridinecar to situmomab) which may be used for treatment of non boxamide: Hodgkins's lymphoma. N-(3-(1,1-dimethylethyl)-1H-pyrazol-5-yl)-2-((4-pyridinyl Exemplary anti-angiogenic agents include ERBITUXTM methyl)amino)-3-pyridinecarboxamide; (IMC-C225), KDR (kinase domain receptor) inhibitory N-(3.3-dimethyl-2,3-dihydro-1-benzofuran-6-yl)-2-((4-py 30 agents (e.g., antibodies and antigen binding regions that spe ridinylmethyl)amino)-3-pyridinecarboxamide; cifically bind to the kinase domain receptor), anti-VEGF N-(3-((((2S)-1-methyl-2-pyrrolidinyl)methyl)oxy)-5-(trif. agents (e.g., antibodies or antigen binding regions that spe luoromethyl)phenyl)-2-((4-pyridinylmethyl)amino)-3-py cifically bind VEGF, or soluble VEGF receptors or a ligand ridinecarboxamide; binding region thereof) such as AVASTINTM or VEGF 2-((4-pyridinylmethyl)amino)-N-(3-((2-(1-pyrrolidinyl) 35 TRAPTM, and anti-VEGF receptor agents (e.g., antibodies or ethyl)oxy)-4-(trifluoromethyl)phenyl)-3-pyridinecar antigenbinding regions that specifically bind thereto), EGFR boxamide: inhibitory agents (e.g., antibodies or antigen binding regions N-(3.3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-((4-pyridi that specifically bind thereto) such as ABX-EGF (panitu nylmethyl)amino)-3-pyridinecarboxamide; mumab), IRESSATM (gefitinib), TARCEVATM (erlotinib), N-(4-(pentafluoroethyl)-3-(((2S)-2-pyrrolidinylmethyl)oxy) 40 anti-Ang1 and anti-Ang2 agents (e.g., antibodies or antigen phenyl)-2-((4-pyridinylmethyl)amino)-3-pyridinecar binding regions specifically binding thereto or to their recep boxamide: tors, e.g., Tie2/Tek), and anti-Tie2 kinase inhibitory agents N-(3-((3-azetidinylmethyl)oxy)-5-(trifluoromethyl)phenyl)- (e.g., antibodies or antigen binding regions that specifically 2-((4-pyridinylmethyl)amino)-3-pyridinecarboxamide; bind thereto). The pharmaceutical compositions of the N-(3-(4-piperidinyloxy)-5-(trifluoromethyl)phenyl)-2-((2- 45 present invention can also include one or more agents (e.g., (3-pyridinyl)ethyl)amino)-3-pyridinecarboxamide: antibodies, antigenbinding regions, or soluble receptors) that N-(4,4-dimethyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)-2- specifically bind and inhibit the activity of growth factors, (1H-indazol-6-ylamino)-nicotinamide; Such as antagonists of hepatocyte growth factor (HGF, also 2-(1H-indazol-6-ylamino)-N-3-(1-methylpyrrolidin-2-yl known as Scatter Factor), and antibodies or antigen binding methoxy)-5-trifluoromethyl-phenyl-nicotinamide: 50 regions that specifically bind its receptor “c-met'. N-1-(2-dimethylamino-acetyl)-3,3-dimethyl-2,3-dihydro Other anti-angiogenic agents include Campath, IL-8, 1H-indol-6-yl)-2-(1H-indazol-6-ylamino)-nicotinamide: B-FGF, Tek antagonists (Ceretti et al., US Publication No. 2-(1H-indazol-6-ylamino)-N-3-(pyrrolidin-2-ylmethoxy)- 2003/0162712; U.S. Pat. No. 6,413,932), anti-TWEAK 5-trifluoromethyl-phenyl-nicotinamide: agents (e.g., specifically binding antibodies or antigen bind N-(1-acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2- 55 ing regions, or soluble TWEAK receptor antagonists; see, (1H-indazol-6-ylamino)-nicotinamide; Wiley, U.S. Pat. No. 6,727.225), ADAM distintegrin domain N-(4,4-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinolin-7- to antagonize the binding of integrin to its ligands (Fanslow et yl)-2-(1H-indazol-6-ylamino)-nicotinamide; al., US Publication No. 2002/0042368), specifically binding N-4-(tert-butyl)-3-(3-piperidylpropyl)phenyl 2-(1H-inda anti-eph receptor and/or anti-ephrin antibodies or antigen Zol-6-ylamino)(3-pyridyl)carboxamide: 60 binding regions (U.S. Pat. Nos. 5,981.245; 5,728,813; 5,969, N-5-(tert-butyl)isoxazol-3-yl 2-(1H-indazol-6-ylamino) 110; 6,596,852; 6.232,447; 6,057,124 and patent family (3-pyridyl)carboxamide; and members thereof), and anti-PDGF-BB antagonists (e.g., spe N-4-(tert-butyl)phenyl 2-(1H-indazol-6-ylamino)(3-py cifically binding antibodies or antigen binding regions) as ridyl)carboxamide. well as antibodies or antigen binding regions specifically Other compounds described in the following patents and 65 binding to PDGF-BB ligands, and PDGFR kinase inhibitory patent applications can be used in combination therapy: U.S. agents (e.g., antibodies or antigen binding regions that spe Pat. No. 6,258,812, US 2003/0105091, WO 01/37820, U.S. cifically bind thereto). US 7,652,009 B2 41 42 Additional anti-angiogenic/anti-tumor agents include: treMed, USA); anginex, (Maastricht University, Netherlands, SD-7784 (Pfizer, USA); cilengitide. (Merck KGaA, Ger and Minnesota University, USA); ABT 510, (Abbott, USA); many, EPO 770622); pegaptainib octasodium, (Gilead Sci AAL 993, (Novartis, Switzerland); VEGI, (ProteomTech, ences, USA); Alphastatin, (BioActa, UK); M-PGA, (Cel USA); tumor necrosis factor-alpha inhibitors, (National Insti gene, USA, U.S. Pat. No. 5,712.291); ilomastat, (Arriva, tute on Aging, USA); SU 11248, (Pfizer, USA and SUGEN USA, U.S. Pat. No. 5,892,112); emaxanib, (Pfizer, USA, U.S. USA); ABT 518, (Abbott, USA);YH16, (Yantai Rongchang, Pat. No. 5,792,783): vatalanib, (Novartis, Switzerland): China); S-3APG. (Boston Childrens Hospital, USA and 2-methoxyestradiol, (EntreMed, USA); TLCELL-12. (Elan, EntreMed, USA); MAb, KDR, (ImClone Systems, USA); Ireland); anecortave acetate, (Alcon, USA); alpha-D148 MAb, alpha5 beta1 (Protein Design, USA); KDR kinase Mab, (Amgen, USA); CEP-7055, (Cephalon, USA); anti-Vn Mab, (Crucell, Netherlands) DAC:antiangiogenic, (Con 10 inhibitor, (Celltech Group, UK, and Johnson & Johnson, juChem, Canada); Angiocidin, (In Kine Pharmaceutical, USA); GFB 116, (South Florida University, USA and Yale USA); KM-2550, (Kyowa Hakko, Japan): SU-0879, (Pfizer, University, USA); CS 706, (Sankyo, Japan); combretastatin USA); CGP-79787, (Novartis, Switzerland, EP 970070): A4 prodrug, (Arizona State University, USA); chondroitinase ARGENT technology, (Ariad, USA); YIGSR-Stealth, AC, (IBEX, Canada); BAY RES 2690, (Bayer, Germany); (Johnson & Johnson, USA); fibrinogen-E fragment, (Bio 15 AGM 1470. (Harvard University, USA, Takeda, Japan, and Acta, UK); angiogenesis inhibitor, (Trigen, UK); TBC-1635, TAP, USA); AG 13925, (Agouron, USA); Tetrathiomolyb (Encysive Pharmaceuticals, USA); SC-236, (Pfizer, USA); date, (University of Michigan, USA); GCS 100, (Wayne State ABT-567, (Abbott, USA); Metastatin, (EntreMed, USA); University, USA) CV 247, (Ivy Medical, UK); CKD 732, angiogenesis inhibitor, (Tripep, Sweden); maspin, (Sosei. (Chong Kun Dang, South Korea); MAb, vascular endothe Japan), 2-methoxyestradiol, (Oncology Sciences Corpora lium growth factor, (Xenova, UK); irsogladine (INN), (Nip tion, USA); ER-68203-00, (IVAX, USA); Benefin, (Lane Labs, USA); TZ-93, (Tsumura, Japan); TAN-1120, (Takeda, pon Shinyaku, Japan); RG 13577, (Aventis, France); WX Japan); FR-11 1142, (Fujisawa, Japan, JP 02233610); platelet 360. (Wilex, Germany); squalamine (pNN), (Genaera, factor 4. (Repligen, USA, EP 407122); vascular endothelial USA); RPI 4610. (Sirna, USA); cancer therapy, (Marinova, growth factor antagonist, (Borean, Denmark); cancer therapy, Australia); heparanase inhibitors, (InSight, Israel); KL 3106, (University of South Carolina, USA); bevacizumab (plNN), 25 (Kolon, South Korea); Honokiol, (Emory University, USA); (Genentech, USA); angiogenesis inhibitors, (SUGEN, USA); ZK CDK, (Schering AG, Germany); ZK Angio, (Schering XL 784, (Exelixis, USA); XL 647, (Exelixis, USA); MAb, AG, Germany); ZK 229561. (Novartis, Switzerland, and alpha5beta3 integrin, second generation, (Applied Molecular Schering AG, Germany); XMP 300, (XOMA, USA); VGA Evolution, USA and MedImmune, USA); gene therapy, ret 1102, (Taisho, Japan); VEGF receptor modulators, (Pharma inopathy, (Oxford BioMedica, UK); enzastaurin hydrochlo ride (USAN), (Lilly, USA); CEP 7055, (Cephalon, USA and 30 copeia, USA); VE-cadherin-2 antagonists (ImClone Sys Sanofi-Synthelabo, France); BC 1, (Genoa Institute of Cancer tems, USA); Vasostatin, (National Institutes of Health, USA); Research, Italy); angiogenesis inhibitor, (Alchemia, Austra vaccine, Flk-1, (ImClone Systems, USA); TZ93, (Tsumura, lia); VEGFantagonist, (Regeneron, USA); rBPI21 and BPI Japan); TumStatin, (Beth Israel Hospital, USA); truncated derived antiangiogenic, (XOMA, USA); PI88, (Progen, Aus soluble FLT 1 (vascular endothelial growth factor receptor 1), tralia); cilengitide (pNN), (Merck KGaA, German: Munich 35 (Merck & Co, USA); Tie-2 ligands, (Regeneron, USA); and, Technical University, Germany, Scripps Clinic and Research thrombospondin 1 inhibitor, (Allegheny Health, Education Foundation, USA); cetuximab (INN), (Aventis, France); AVE and Research Foundation, USA). 8062. (Ajinomoto, Japan); AS 1404, (Cancer Research Labo Alternatively, the present compounds may also be used in ratory, New Zealand); SG 292. (Telios, USA); Endostatin, (Boston Childrens Hospital, USA); ATN 161. (Attenuon, co-therapies with other anti-neoplastic agents, such as VEGF USA); ANGIOSTATIN, (Boston Childrens Hospital, USA); 40 antagonists, other kinase inhibitors including p38 inhibitors, 2-methoxyestradiol, (Boston Childrens Hospital, USA); ZD KDR inhibitors, EGF inhibitors and CDK inhibitors, TNF 6474. (AstraZeneca, UK); ZD 6126. (Angiogene Pharmaceu inhibitors, metallomatrix proteases inhibitors (MMP), ticals, UK); PPI 2458, (Praecis, USA); AZD 9935, (Astra COX-2 inhibitors including celecoxib, NSAID's, or CfB Zeneca, UK); AZD 2171. (AstraZeneca, UK); Vatalanib inhibitors. (pNN), (Novartis, Switzerland and Schering AG, Germany); 45 The present invention comprises processes for the prepa tissue factor pathway inhibitors, (EntreMed, USA); pegap ration of a compound of Formula I-V. tanib (Pinn), (Gilead Sciences, USA); xanthorrhizol, (Yonsei University, South Korea); vaccine, gene-based, VEGF-2, Also included in the family of compounds of Formula I-V (Scripps Clinic and Research Foundation, USA); SPV5.2, are the pharmaceutically-acceptable salts thereof. The term (Supratek, Canada); SDX 103, (University of California at “pharmaceutically-acceptable salts' embraces salts com San Diego, USA); PX 478, (Prolx, USA); METASTATIN, 50 monly used to form alkali metal salts and to form addition (EntreMed, USA); troponin I, (Harvard University, USA); salts of free acids or free bases. The nature of the salt is not SU 6668, (SUGEN, USA); OXI 4503, (OXiGENE, USA); critical, provided that it is pharmaceutically-acceptable. Suit o-guanidines, (Dimensional Pharmaceuticals, USA); motu able pharmaceutically-acceptable acid addition salts of com poramine C, (British Columbia University, Canada); CDP pounds of Formula I-V may be prepared from an inorganic 791, (Celltech Group, UK); atiprimod (plNN), (GlaxoSmith 55 acid or from an organic acid. Examples of Such inorganic Kline, UK); E 7820, (Eisai, Japan): CYC 381, (Harvard Uni acids are hydrochloric, hydrobromic, hydroiodic, nitric, car versity, USA); AE 941, (Aeterna, Canada); vaccine, angio bonic, Sulfuric and phosphoric acid. Appropriate organic genesis, (EntreMed, USA); urokinase plasminogen activator acids may be selected from aliphatic, cycloaliphatic, aro inhibitor, (Dendreon, USA); oglufamide (plNN), (Melmotte, matic, arylaliphatic, heterocyclic, carboxylic and Sulfonic USA); HIF-1alfa inhibitors, (Xenova, UK); CEP 5214, classes of organic acids, example of which are formic, acetic, (Cephalon, USA); BAY RES 2622, (Bayer, Germany); 60 adipic, butyric, propionic, Succinic, glycolic, gluconic, lactic, Angiocidin, (In Kine, USA); A6, (Angstrom, USA); KR malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, 31372, (Korea Research Institute of Chemical Technology, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, South Korea); GW 2286, (GlaxoSmithKline, UK); EHT 4-hydroxybenzoic, phenylacetic, mandelic, embonic 0101, (Exon Hit, France); CP 868596, (Pfizer, USA); CP (pamoic), methanesulfonic, ethanesulfonic, ethanedisul 564959, (OSI, USA); CP 547632, (Pfizer, USA): 786034, 65 fonic, benzenesulfonic, pantothenic, 2-hydroxyethane (GlaxoSmithKline, UK); KRN 633, (Kirin Brewery, Japan); Sulfonic, toluenesulfonic, Sulfanilic, cyclohexylaminosul drug delivery system, intraocular, 2-methoxyestradiol, (En fonic, camphoric, camphorsulfonic, digluconic, US 7,652,009 B2 43 44 cyclopentanepropionic, dodecylsulfonic, glucoheptanoic, DIBAL. diisobutylaluminum hydride glycerophosphonic, heptanoic, hexanoic, 2-hydroxy-ethane DIAD diisopropyl azodicarboxylate Sulfonic, nicotinic, 2-naphthalenesulfonic, oxalic, palmoic, DIEA diisopropylethylamine pectinic, persulfuric, 2-phenylpropionic, picric, pivalic pro DMF dimethylformamide DMAP 4-dimethylaminopyridine pionic, Succinic, tartaric, thiocyanic, mesylic, undecanoic, 5 DMSO-dimethylsulfoxide Stearic, algenic, B-hydroxybutyric, salicylic, galactaric and EDC, EDCI—1-(3-dimethylaminopropyl)-3-ethylcarbodi galacturonic acid. Suitable pharmaceutically-acceptable base imide hydrochloride addition salts of compounds of Formula I-V include metallic dppa-diphenylphosphoryl azide salts, such as Salts made from aluminum, calcium, lithium, EtOAc—ethyl acetate magnesium, potassium, Sodium and Zinc, or salts made from 10 FBS fetal bovine serum organic bases including primary, secondary and tertiary g gram amines, Substituted amines including cyclic amines, such as h—hour caffeine, arginine, diethylamine, N-ethyl piperidine, aisti HBr hydrobromic acid dine, glucamine, isopropylamine, lysine, morpholine, HCl hydrochloric acid N-ethyl morpholine, piperazine, piperidine, triethylamine, 15 HOBt—1-hydroxybenzotriazole hydrate trimethylamine. All of these salts may be prepared by con H hydrogen ventional means from the corresponding compound of the H2O hydrogen peroxide invention by reacting, for example, the appropriate acid or LiHMDS lithium bis(trimethylsilyl)-amide MCPBA meta-chloroperbenzoic acid base with the compound of Formula I-V. When a basic group MgSO magnesium Sulfate and an acid group are present in the same molecule, a com MeOH methanol pound of Formula I-V may also form internal salts. Mel—methyl iodide CHCl, DCM methylene chloride General SVnthetic Procedures NMP N-methylpyrrolidinone The compounds of the invention can be synthesized ML milliliter according to the following procedures of Schemes 1-13. 25 N. nitrogen wherein the substituents are as defined for Formulas I-V, Pd/C palladium on carbon above, except where further noted. Pd(OAc)—palladium acetate The following abbreviations are used throughout the speci Pd(OH) palladium hydroxide fication: Pd(PPh) palladium tetrakis triphenylphosphine HOAC acetic acid 30 Pd(dppf)Cl. 1,1-bis(diphenylphosphino)ferrocene palla MeCN acetonitrile dium chloride NHaCl-ammonium chloride PBS phosphate buffered saline Ar—argon POCl phosphorous oxychloride HATU O-(7-azabenzotriazol-1-yl)-N.N.N',N'-tetramethy KCO potassium carbonate luroniumhexafluorophosphate RT room temperature PyBop benzotriazol-1-yl-oxy-tripyrrolidino-phosphonium 35 NaHCO sodium bicarbonate hexafluorophosphate NaBH sodium borohydride Pd(dba) bis(dibenzylideneacetone)palladium NaOtBu—sodium tert-butoxide BINAP 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl NaOH sodium hydroxide TEAC bis(tetra-ethylammonium)carbonate NaH sodium hydride BBr boron tribromide 40 NaI sodium iodide BSA bovine serum albumin Na2SO -Sodium sulfate Br bromine TBTU O-benzotriazol-1-yl-N,N,N',N'-tetramethyluro CSCO cesium carbonate nium tetrafluoroborate CHCl chloroform THF tetrahydrofuran Cu—copper as EtsN, TEA triethylamine CuI—copper(I) iodide TFA trifluoroacetic acid EtO—diethyl ether P(t-bu) tri(tert-butyl)phosphine DBU—1.8-diazabicyclo[5.4.0]undec-7-ene HO water

Scheme 1 N N N 1) LiHMDS, DMF, 0° C. Br2, sat. NaHCO3 NH He-2) MeI, RT e Br US 7,652,009 B2 45 46 -continued N N N s^ R s^ R s^ R N N NN R1-C1 n HBr HOAC n -e- O O RNO O HO MO

Substituted pyrimidinones 6 can be prepared by the pro the 5-phenylpyridinone 4. The reaction is maintained at a cess outlined in Scheme 1. Alkylation of pyrimidinone 1 15 temperature>about 50° C., preferably at a temperature above (prepared similar to that described in WO94/26715) such as about 75° C., more preferably at about 90° C. The phenol 5 is with an alkyl halide in the presence of base (e.g. CSCO or prepared by dealkylation of the 5-(4-methoxyphenyl)pyridi LiHMDS) at a temperature of about RT yields the 3-alkylpy none 4, such as by treatment with HBr at a temperature above rimidinone 2. Bromination of the 3-alkylpyrimidinone 2, about 100° C., preferably at about 130° C. Treatment of such as with Br, in the presence of base (e.g. NaHCO) at a phenol 5 with a halo-substituted ring, Such as in the presence temperature of about RT, provides the 5-bromo-3-alkylpyri of DMAP and NMP provides compounds 6. Preferably the midinone 3. For compounds of the invention where X is O, reaction is at a temperature above RT, preferably above about coupling the 5-bromo-3-alkylpyrimidinone 3 such as with 50° C., more preferably at about 90° C. More preferably the Suzuki coupling with an appropriate boronic acid, provides reaction is heated using a microwave (150 W).

R H N S N S i) NaOH, RI, H2O He s LiHMDS, RI s NY ii) AcOH NH NH N YR, O O 8 9 Br2, clic R B(OH)2 R N S Me rr vs. N. S Nn R9 NN O Pd(dba) Br NR2

HO O

10 11

13 US 7,652,009 B2 47 48 Alternatively, compounds of the invention where Y is S can -continued be prepared by the method described in Scheme 2. Alkylation of the thione 7 (prepared following the procedure of J. Spy H chala, Syn. Comm., 27(11):1943-1949 (1997), provides the N N 2-alkylthio-pyrimidinone 8. Subsequent steps similar to that described in Scheme 1 yields the 2-substituted thio-5-(4- rsrs.N hydroxyphenyl) pyrimidinone 12. Further treatment with the NR2 halide yield compounds 13. O Scheme 3 10

15 N St

r N RNH 15 NR2 Y Compounds of the invention where Y is —NH and X is O HO O can be prepared as shown in Scheme 3. The 2-methylthi R9 12 opyrimdinone 12 is treated with the appropriate amine. Such

N N as in the presence of acid (e.g. HCl) and heated at a tempera s NR 25 N NR2 ture of above about 50° C., preferably above about 100° C., O HO 30 more preferably at about 120°C. The reaction can be heated R9 with a microwave (100 W) to form amine 14. Coupling of 14 amine 14 with the appropriate chloride, similar to the method Repua 35 described in Scheme 1 yields compound 15.

Scheme 4

N OH N S

r N r N n R2 NR2 Hes H2O-H2NCONH2 RN O RINo O O RX RX 13 16 roc

R N C N NH n

N sN NR2 R2 i R O R'NH2 R No O No H RX RX 18 17 US 7,652,009 B2 49 50 Alternatively, compounds of the invention where Y is ture above about 50° C., preferably above about 100° C., —NH and X is O can be prepared as shown in Scheme 4. more preferably at about 125°C. Treatment of the 2-chloro The 2-methylthiopyrimdinone 13 (R is CH) is derivatized to pyrimidinone 17 with the suitable amine, such as in the pres the 2-chloropyrimidinone 17 via the hydroxy intermediate 16 ence of acid (e.g. HCl) preferably at a temperature above such as by treatment of the thio compound with urea hydro- 5 about 50° C., more preferably at about 60°C., provides com gen peroxide and TFAA, preferably at about RT; followed by pounds 17. Alternatively the reaction is heated with a micro POCl and base. The chlorination is performed at a tempera- wave (60 W).

21 R-Br MeO * 1s N MeO HePCy R9 R9 19 20 21 ( ) ( )

MeO

22

N N N N 2 R Base 1. ahaloalkyl N N -RSlC N N N N

25 24 23 US 7,652,009 B2 51 52 Pyrimidine compounds of the invention can be prepared maintained at a temperature above about 100° C., preferably such as by the method described in Scheme 5. Suzuki cou at about 200° C., and preferably heated in a microwave. pling of boronic acids 19 with 2-amino-5-halopyrimidine 20, Dealkylation of the methoxy compound 22, such as with such as in the presence of a Pd catalyst (e.g. Pd(PPh)) and at thiophenol and base (e.g. KCO) in a solvent such as NMP, a temperature above about 50° C., preferably at about 80°C., at a temperature above about 100° C., preferably at about provides the bicyclic compound 21. Treatment of the amine 120° C., provides the phenol 23. The phenol 23 is coupled 21 with an appropriate halo compound, Such as an iodoben with a halo-substituted ring, such as with a catalytic amount Zene or bromo derivative, in the presence of a Pd catalyst (e.g. of DMAP at a temperature above about 100° C., preferably at Pd(OAc)), 2-biscyclohexyl 1,1-biphenyl phosphine and about 180°C., and more preferably heated in a microwave, to KO'Bu, in an appropriate solvent such as dimethylacetamide 10 provide pyridines 24. Further substitution of the amine can be and toluene yields the substituted amine 22. The reaction is achieved to provide compounds 25.

N I B(OH(OH)2 21 Suzuki -- -e- Hess N-N Br MeO MeO R9 R9 19 26 27

N21 NR N N

MeO R9 28

Rb H 2 Na N21 N NR C NR RIC1 Sa R N Base a s N N haloalkyl HO O O R9 R9 RI R9 R

31 30 29 US 7,652,009 B2 53 54 Similar to the methods described in Scheme 5, pyrimidine tuted amine 28. Dealkylation of the methoxy compound 28, compounds of the invention can be prepared Such as by the such as with thiophenol and KCO in a solvent such as NMP, method described in Scheme 6. Suzuki coupling of boronic at a temperature above about 100° C., preferably at about acids 19 with 2,5-dihalopyrimidine 26, such as in the pres 120° C., provides the phenol 29, which can be coupled with a ence of a Pd catalyst (e.g. Pd(dppf)Cl) and at a temperature halo-substituted ring, Such as with a catalytic amount of DMAP at a temperature above about 50° C., preferably at above about 50° C., more preferably at about 80°C., provides about 110°C., to provide pyridines 30. Further alkylation of the bicyclic compound 27. Treatment of halo compound 27 10 the amine can be achieved. Such as by deprotonation with with an appropriate amine, such as an aniline, in the presence strong base (e.g. NaH) at a temperature above about RT, of a Pd catalyst (e.g. Pd(OAc)2), BINAP and NaO'Bu, in an preferably at about 50° C., and treatment with haloalkyl (R- appropriate solvent such as toluene, at a temperature above 15 LG) at a temperature above about RT, preferably at about 50° about 50° C., preferably at about 100° C., yields the substi- C., to provide compounds 31.

Scheme 7 21 C B(OH) C 2 N Sa -N Pol(PPh3)4, 2M Na2CO N -- 2 N Toluene, EtOH, 80° C. MeO C N MeO R9 RX 32 33 34

BBr3, CH2Cl2 t

H C N 21 21 NR N-N N N1- N N

se-TFA, DMSO HO HO 80° C. R NH2 R9 R9 36 35

DMAP, toluene 180° C. No US 7,652,009 B2 55 56

-continued

37

Similar to the methods described above, pyridazine com 15 -continued pounds of the invention can be prepared Such as by the method described in Scheme 7. Suzuki coupling of boronic O OH NaOH,1N acids 32 with 2,5-dihalopyrimidine 33, such as in the pres RT N se NO O ence of a Pd catalyst (e.g. Pd(PPh)) and at a temperature O THF. above about 50° C., more preferably at about 80°C., provides MeOH the bicyclic compound 34. Dealkylation of the methoxy com O O pound 34. Such as with BBr (e.g. 1M) in a solvent Such as R1 R1 CHCl, at a temperature of about RT, provides the phenol 35. Where Y is NH amination of the chloro compound 34 42 41 with an appropriate amine, such as an aniline, in the presence 25 EDCI, HOBt NH ofa acid (e.g. TFA) in an appropriate solvent such as DMSO, DMF, RT R1 at a temperature above about 50° C., preferably at about 80° C., yields the substituted amine 36. The substituted amine 36 can be coupled with a halo-substituted ring, such as with Cu powder and base (e.g. NaOH) at a temperature above about 30 50° C., preferably at about 120° C., more preferably in a microwave (60 W), to provide pyridazine 37. Where Y is —CH2—, the chloro compound 34 can be alkylated, such as with B-benzyl-9-BBN and KCO in the O presence of catalytic Pd, preferably Pd(DPPF)C1, at a tem 35 perature above about 50° C., preferably at about 65° C., to Ya N V provide alkyl Substituted pyridazine compounds. R Where Y is —O—, the chloro compound 34 can be substi tuted with alcohols, such as with CsCO in the presence of DMF, at a temperature above about 100° C., preferably at 40 about 150° C., more preferably in a microwave, to provide oxy Substituted pyridazine compounds. The methoxy com pound can also be converted to the phenol by treatment with 43 pyridine hydrochloride at a temperature above about 100° C. preferably above about 150° C., more preferably at about 45 17OO C. Scheme 8 Compounds of the invention, where Y is —C(O)NH can be prepared such as by the method described in Scheme 8. 50 1-(4-Hydroxyphenyl)-5-oxo-pyrrolidine-3-carboxylic acid HO methyl ester 40 is prepared from 4-amino-phenol 38 and 38 2-methylene-succinic acid dimethyl ester 39 at a temperature MeOC 55 above about 50° C., preferably above about 100° C., more ro. preferably at about 110° C. Coupling of the phenol 40 with a 39 halide similar to that described in Scheme 3 yields the ether 60 41. De-esterification of 41, such as by treatment with base, HO yields the carboxylic acid 42. The acid 42 can be aminated 40 Such as with treatment with an amine in the presence of DMAP. Tog"a 65 coupling reagents (e.g. EDC and HOBT) provided the amide 43. US 7,652,009 B2 57 58

O OH NH2 HOC neat, 120° C. -- CO2H He O-KO MeO

R9 45 MeO

46

1. isobutyl chloroformate, Et3N, CHCl2,0° C. 2. aq. NaBH4 O ) /OH DIAD, PPh a CH2Cl2, rt MeO ROH MeO u

48 47 BBr in cite O O O-R

-- N ) / DMAP,RIC1 toluene O O -R 180° C.

HO O RI R9

49 50

Compounds of the invention, whereYis—OCH can be 45 prepared such as by the method described in Scheme 9. The Scheme 1() 5-oxopyrrolidine-3-carboxylic acid 46 an be prepared by reaction of 3-fluoro-4-methoxybenzenamine 44 with itaconic Br 50 acid 45 at a temperature above about 50°C., preferably above DMAP, Toluene RIC1 -- He about 100° C., more preferably at about 110° C. Formation of HO 160° C. the alcohol 47 is accomplished by treatment of acid 46 first 51 with isobutyl chloroformate in the presence of base, such as Br TEA, at a temperature below RT, preferably at about 0°C., 55 followed by reduction, such as with NaBH4. Treatment of the alcohol 47 with ROH, such as in the presence of DIAD and

PPhs at a temperature at about RT provided the ether 48. 60 Conversion of the methoxy compound 48 by a method similar 53 to that described in Scheme 7 provided the phenol 49. Treat ment of the phenol 49 with the appropriate halide such in the O CuI, TEAC, DMF presence of DMAP at a temperature above about 100° C. 65 8-hydroxyquinoline preferably at about 180°C., more preferably in a microwave, HN 150° C. to provide the desired ethers 50. US 7,652,009 B2 59 60 Compounds of the invention, where YR is H. can be pre -continued pared such as by the method described in Scheme 10. Treat ) ment of an appropriate halide 51 is coupled with an alcohol 52 N 5 such as with DMAP at a temperature above about 100° C., preferably at about 160° C., more preferably in a microwave, to provide the desired ether 53. Treatment of the halo com R9 10 pound 53 with the desired cyclic amine, such as pyrrolidin 2-one, in the presence of TEAC, 8-hydroxyquinoline and CuI, at a temperature above about 100° C., preferably at about 150° C., more preferably in a microwave, provides the desired RIR compounds 54.

O OH O

NH N O DPPA, EtN, BnOH N --- Toluene, 120° C.

MeO MeO

55 56

10% Wet PoC H2, EtOAc

O O O NH i NH2 N R N R C -a- O K2CO3, CH2Cl2 MeO MeO R9 R9 58 57 BBr in city

O O O X-R NH RCI NH N R DMAP, dioxane N 160° C., mv O HO O

59 60 US 7,652,009 B2 61 62 Compounds of the invention, where Y is —NHC(O)—can tection, such as with Pd/C and H yields the amine 57. Cou be prepared such as by the method described in Scheme 11. pling with an appropriate carbonyl reagent, Such as an acid cholide, in the presence of base, such as KCO, provide the Treatment of the carboxylic acid 55 such as with TEA and an desired amide 58. Conversion of the ether 58 to the alcohol alcohol, in the presence of DPPA, at a temperature above 59, by a procedure similar to that described in Scheme 7. about 50° C., preferably above about 100° C., more prefer followed by coupling with an appropriate halide provides the ably at about 120° C. forms the protected amine 56. Depro pyrrolidone 60 of the invention.

NH2

1. Itaconic acid R'MgCl, THF -- Her 2. Weinreb amide 50° C. MeO formation MeO R9 R9 44 61

O R

O-KO

MeO R9 62 actics

NO-K O DMAP, Dioxane, 160° C. NO-K O w RIC1 HO R1 R9 R9 64 63 NaBH4. voy O R O R

O-(OH O-(OMe 1:1 THF/DMF He NaH, MeI

R1 R9 RI R9 65 66 US 7,652,009 B2 63 64 Pyrrolidones of the invention, where Y is either ture above about RT, preferably at about 50° C. Conversion of —C(=O)—, —CH(OH)—or —CH(OMe)-can be prepared the ether 62 to the alcohol 63, by a procedure similar to that such as by the method described in Scheme 12. Preparation of described in Scheme 7, followed by coupling with an appro the protected carbonyl 61 such as by treatment of the amine priate halide provides the carbonyl compounds of the inven 44 with itaconic acid and N-methoxymethanamine hydro tion 64. Reduction of the carbonyls 64, such as by treatment chloride and HOBt in the presence of base, such as Et N can with NaBH at a temperature of about RT forms the alcohols be achieved at about RT. The desired substituted carbonyl 65. Alkylation of the alcohols 65, such as by treatment with compound 62 is achieved through alkylation, Such as by base (e.g. NaH) followed by reaction with the appropriate treatment with a Grignard reagent (e.g. R'MgCl) at a tempera alkyl halide yields the desired ether 66.

US 7,652,009 B2 67 68 Hydantoin compounds of the invention can be prepared in H.-D. Jakubke and H. Jescheit, “Aminosauren, Peptide, such as by the method described in Scheme 13. Preparation of Proteine' (Amino acids, peptides, proteins), Verlag Chemie, the quinolinyl ether 68, such as through the CsCO mediated Weinheim, Deerfield Beach, and Basel (1982), and in Jochen reaction of the alcohol 67 with the appropriate halo-benzene Lehmann, “Chemie der Kohlenhydrate: Monosaccharide und compound at a temperature above about RT, preferably at Derivate” (Chemistry of carbohydrates: monosaccharides about 40°C., followed by reduction of the nitro group, such as and derivatives), Georg Thieme Verlag, Stuttgart (1974). by treatment with hydrazine in the presence of a catalyst (e.g. In the additional process steps, carried out as desired, func Raney nickel) provides the amine 69. The hydantoin 70 is tional groups of the starting compounds which should not formed. Such as by addition of ethyl isocyanatoacetate and take partin the reaction may be present in unprotected form or treatment with DBU. Alkylation to form substituted hydan 10 may be protected for example by one or more of the protect toins 71 is achieved such as by treatment with an alkylhalide ing groups mentioned above under “protecting groups'. The and LiHMDS. Alternative substitution on the quinolines ring protecting groups are then wholly or partly removed accord can be achieved such as by removal of more labile groups ing to one of the methods described there. (e.g. benzyl groups) such as by treatment with PdOH/C in an Salts of a compound of Formula I with a salt-forming group appropriate solvent such as an alcohol (e.g. MeOH) and reac 15 may be prepared in a manner known per se. Acid addition tion with base (e.g. CsCO) and dihaloalkyls, and treatment salts of compounds of Formula I may thus be obtained by with the resulting haloalkyl-ether with an amine (cyclic, treatment with an acid or with a suitable anion exchange branched or straight chain) at a temperature above about RT, reagent. A salt with two acid molecules (for example a diha preferably above about 50° C., more preferably at about 60° logenide of a compound of Formula I) may also be converted C., to provide the desired compound 72. into a salt with one acid molecule per compound (for example The starting compounds defined in Schemes 1-13 may also a monohalogenide); this may be done by heating to a melt, or be present with functional groups in protected form if neces for example by heating as a Solid under a high vacuum at sary and/or in the form of salts, provided a salt-forming group elevated temperature, for example from 130 to 170° C., one is present and the reaction in salt form is possible. If so molecule of the acid being expelled per molecule of a com desired, one compound of Formula I can be converted into 25 pound of Formula I. another compound of Formula I or a N-oxide thereof; a com Salts can usually be converted to free compounds, e.g. by pound of Formula I can be converted into a salt; a salt of a treating with Suitable basic agents, for example with alkali compound of Formula I can be converted into the free com metal carbonates, alkali metal hydrogen carbonates, or alkali pound or another salt; and/or a mixture of isomeric com metal hydroxides, typically potassium carbonate or sodium pounds of Formula I can be separated into the individual 30 hydroxide. isomers. All process steps described here can be carried out under N-Oxides can be obtained in a known matter by reacting a known reaction conditions, preferably under those specifi compound of Formula I with hydrogen peroxide, oxone, or a cally mentioned, in the absence of or usually in the presence peracid, e.g. mCPBA, in an inert Solvent, e.g. CHCl, or a of solvents or diluents, preferably such as are inert to the mixture of HO and an alcohol such as MeOH or EtOH, at a 35 reagents used and able to dissolve these, in the absence or temperature between about -10-35°C., such as about 0° presence of catalysts, condensing agents or neutralizing C-RT. agents, for example ion exchangers, typically cation exchang If one or more other functional groups, for example car ers, for example in the H form, depending on the type of boxy, hydroxy, amino, or mercapto, are or need to be pro reaction and/or reactants at reduced, normal, or elevated tem tected in a compound of Formula I or in the preparation of 40 perature, for example in the range from about -100° C. to compounds of Formula I, because they should not take part in about 190° C., preferably from about -80° C. to about 150° the reaction, these are such groups as are usually used in the C., for example at about -80 to about 60°C., at RT, at about synthesis of peptide compounds, and also of cephalosporins -20 to about 40°C. or at the boiling point of the solvent used, and penicillins, as well as nucleic acid derivatives and Sugars. under atmospheric pressure or in a closed vessel, where The protecting groups may already be present in precursors 45 appropriate under pressure, and/or in an inert atmosphere, for and should protect the functional groups concerned against example under argon or nitrogen. unwanted secondary reactions. Such as acylations, etherifica Salts may be present in all starting compounds and tran tions, esterifications, oxidations, Solvolysis, and similar reac sients, if these contain salt-forming groups. Salts may also be tions. It is a characteristic of protecting groups that they lend present during the reaction of Such compounds, provided the themselves readily, i.e. without undesired secondary reac 50 reaction is not thereby disturbed. tions, to removal, typically by Solvolysis, reduction, photoly In certain cases, typically in hydrogenation processes, it is sis or also by enzyme activity, for example under conditions possible to achieve Stereoselective reactions, allowing for analogous to physiological conditions, and that they are not example easier recovery of individual isomers. present in the end-products. The specialist knows, or can The solvents from which those can be selected which are easily establish, which protecting groups are Suitable with the 55 suitable for the reaction in question include for example H.O. reactions mentioned above and hereinafter. esters, typically lower alkyl-lower alkanoates, e.g., EtOAc, The protection of Such functional groups by Such protect ethers, typically aliphatic ethers, e.g., Et2O, or cyclic ethers, ing groups, the protecting groups themselves, and their e.g., THF, liquid aromatic hydrocarbons, typically benzene or removal reactions are described for example in standard ref toluene, alcohols, typically MeCH, EtOH or 1-propanol, erence works, such as J. F. W. McOmie, “Protective Groups in 60 IPOH, nitriles, typically CHCN, halogenated hydrocarbons, Organic Chemistry”. Plenum Press, London and New York typically CHCl, acid amides, typically DMF, bases, typi (1973), in T. W. Greene, “Protective Groups in Organic Syn cally heterocyclic nitrogen bases, e.g. pyridine, carboxylic thesis”, Wiley, New York (1981), in “The Peptides”, Volume acids, typically lower alkanecarboxylic acids, e.g., AcOH, 3, E. Gross and J. Meienhofer editors, Academic Press, Lon carboxylic acid anhydrides, typically lower alkane acid anhy don and New York (1981), in “Methoden der organischen 65 drides, e.g., acetic anhydride, cyclic, linear, or branched Chemie” (Methods of organic chemistry), Houben Weyl, 4" hydrocarbons, typically cyclohexane, hexane, or isopentane, edition, Volume 15/1, Georg Thieme Verlag, Stuttgart (1974), or mixtures of these solvents, e.g., aqueous solutions, unless US 7,652,009 B2 69 70 otherwise stated in the description of the process. Such sol The compounds of this invention may also be represented vent mixtures may also be used in processing, for example in in multiple tautomeric forms, for example, as illustrated chromatography. below: The invention relates also to those forms of the process in which one starts from a compound obtainable at any stage as a transient and carries out the missing steps, or breaks off the process at any stage, or forms a starting material under the N reaction conditions, or uses said starting material in the form N O N OH of a reactive derivative or salt, or produces a compound obtainable by means of the process according to the invention 10 and processes the said compound in situ. In the preferred The invention expressly includes all tautomeric forms of embodiment, one starts from those starting materials which the compounds described herein. lead to the compounds described above as preferred. The compounds may also occur in cis- or trans- or E- or Z-double bond isomeric forms. All such isomeric forms of The compounds of Formula I, including their salts, are also 15 obtainable in the form of hydrates, or their crystals can Such compounds are expressly included in the present inven include for example the solvent used for crystallization tion. All crystal forms of the compounds described herein are (present as Solvates). expressly included in the present invention. New starting materials and/or intermediates, as well as Substituents on ring moieties (e.g., phenyl, thienyl, etc.) processes for the preparation thereof, are likewise the subject may be attached to specific atoms, whereby they are intended to be fixed to that atom, or they may be drawn unattached to of this invention. In the preferred embodiment, such starting a specific atom, whereby they are intended to be attached at materials are used and reaction conditions so selected as to any available atom that is not already Substituted by an atom enable the preferred compounds to be obtained. other than H (hydrogen). Starting materials of the invention, are known, are com The compounds of this invention may contain heterocyclic mercially available, or can be synthesized in analogy to or 25 ring systems attached to another ring system. Such heterocy according to methods that are known in the art. clic ring systems may be attached through a carbon atom or a In the preparation of starting materials, existing functional heteroatom in the ring system. groups which do not participate in the reaction should, if Alternatively, a compound of any of the formulas delin necessary, be protected. Preferred protecting groups, their eated herein may be synthesized according to any of the introduction and their removal are described above or in the processes delineated herein. In the processes delineated examples. herein, the steps may be performed in an alternate order and All remaining starting materials are known, capable of may be preceded, or followed, by additional protection/ being prepared according to known processes, or commer deprotection steps as necessary. The processes may further cially obtainable; in particular, they can be prepared using 35 comprise use of appropriate reaction conditions, including processes as described in the examples. inert Solvents, additional reagents, such as bases (e.g., LDA, Compounds of the present invention can possess, in gen DIEA, pyridine, KCO, and the like), catalysts, and salt eral, one or more asymmetric carbon atoms and are thus forms of the above. The intermediates may be isolated or capable of existing in the form of optical isomers as well as in carried on in situ, with or without purification. Purification the form of racemic or non-racemic mixtures thereof. The 40 methods are known in the art and include, for example, crys optical isomers can be obtained by resolution of the racemic tallization, chromatography (liquid and gas phase, and the mixtures according to conventional processes, e.g., by forma like), extraction, distillation, trituration, reverse phase HPLC tion of diastereoisomeric salts, by treatment with an optically and the like. Reactions conditions such as temperature, dura active acid or base. Examples of appropriate acids are tartaric, tion, pressure, and atmosphere (inert gas, ambient) are known diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric, and cam 45 in the art and may be adjusted as appropriate for the reaction. phorsulfonic acid and then separation of the mixture of dias As can be appreciated by the skilled artisan, the above tereoisomers by crystallization followed by liberation of the synthetic schemes are not intended to comprise a comprehen optically active bases from these salts. A different process for sive list of all means by which the compounds described and separation of optical isomers involves the use of a chiral claimed in this application may be synthesized. Further meth chromatography column optimally chosen to maximize the 50 ods will be evident to those of ordinary skill in the art. Addi separation of the enantiomers. Still another available method tionally, the various synthetic steps described above may be involves synthesis of covalent diastereoisomeric molecules performed in an alternate sequence or order to give the desired by reacting compounds of the invention with an optically pure compounds. Synthetic chemistry transformations and pro acid in an activated form or an optically pure isocyanate. The tecting group methodologies (protection and deprotection) synthesized diastereoisomers can be separated by conven 55 useful in synthesizing the inhibitor compounds described tional means such as chromatography, distillation, crystalli herein are known in the art and include, for example, those zation or sublimation, and then hydrolyzed to deliver the such as described in R. Larock, “Comprehensive Organic enantiomerically pure compound. The optically active com Transformations”, VCH Publishers (1989); T. W. Greene and pounds of the invention can likewise be obtained by using P. G. M. Wuts, “Protective Groups in Organic Synthesis',3' optically active starting materials. These isomers may be in 60 edition, John Wiley and Sons (1999); L. Fieser and M. Fieser, the form of a free acid, a free base, an ester or a salt. "Fieser and Fieser’s Reagents for Organic Synthesis”, John The compounds of this invention may contain one or more Wiley and Sons (1994); A. Katritzky and A. Pozharski, asymmetric centers and thus occur as racemates and racemic “Handbook of Heterocyclic Chemistry', 2' edition (2001); mixtures, scalemic mixtures, single enantiomers, individual M. Bodanszky, A. Bodanszky, “The Practice of Peptide Syn diastereomers and diastereomeric mixtures. All Such iso 65 thesis'. Springer-Verlag, Berlin Heidelberg (1984); J. Sey meric forms of these compounds are expressly included in the den-Penne, “Reductions by the Alumino- and Borohydrides present invention. in Organic Synthesis”, 2" edition, Wiley-VCH, (1997); and US 7,652,009 B2 71 72 L. Paquette, editor, “Encyclopedia of Reagents for Organic MeOH/CHCl to afford additional compound. MS (ESI pos. Synthesis”, John Wiley and Sons (1995). ion) m/z: 2010. (M+H). Calc'd for CHNO: 200.09. The compounds of this invention may be modified by appending appropriate functionalities to enhance selective Step 3: Preparation of biological properties. Such modifications are known in the art 2-benzyl-5-bromo-3-methyl-3H-pyrimidin-4-one and include those which increase biological penetration into a given biological compartment (e.g., blood, lymphatic sys Br (2.62 mL, 52 mmol) was added to 2-benzyl-3-methyl tem, central nervous system), increase oral availability, 3H-pyrimidin-4-one (Step 2, 9.3 g, 47 mmol) in CHCl (100 increase solubility to allow administration by injection, alter 10 mL) and sat NaHCO (100 mL). After 30 min, the organic metabolism and alter rate of excretion. layer was separated, dried (Na2SO) and filtered through a These detailed descriptions fall within the scope, and serve plug of silica. The filtrate was concentrated under reduced to exemplify, the above-described General Synthetic Proce pressure, and azeotroped with CHCl (2x). The crude com dures which form part of the invention. These detailed pound was dried under high vacuum for 16 h to provide the descriptions are presented for illustrative purposes only and 15 title compound. MS (ESI pos. ion) m/z: 279.0, 28.1.1. Calc’d are not intended as a restriction on the scope of the invention. for CH BrNO: 278.01. Unless otherwise noted, all materials were obtained from commercial Suppliers and used without further purification. Step 4: Preparation of 2-benzyl-5-(3-fluoro-4-meth Anhydrous solvents such as DMF, THF, CHCl and toluene oxyphenyl)-3-methyl-3H-pyrimidin-4-one were obtained from the Aldrich Chemical Company, EMD among others. 2-Benzyl-5-bromo-3-methyl-3H-pyrimidin-4-one (Step 3, 11.1 g, 39.9 mmol), 4-methoxy-3-fluorophenylboronic acid EXAMPLE1 25 (10.12 g, 59 mmol) and Pd(PPh3) (2.3 g, 1.9 mmol) in 2 M NaCO (100 mL) and dioxane (150 mL) were heated to 90° C. for 1 h. The reaction was cooled to RT, and diluted with N H2O and CH2Cl2. The organics were separated and washed 30 with brine, dried (NaSO) and filtered through a plug of NaCO silica. The filtrate was concentrated under reduced pressure. O EtO/hexane (1:1) were added and the reaction was concen O trated under vacuum to a brown solid. The solid was triturated -O s F with 20% EtO/hexane to afford the title compound as a 35 yellow solid. MS (ESI pos. ion) m/z: 325.2. Calc'd for r N11o % CHFNO: 324.13. Step 5: Preparation of 2-benzyl-5-(3-fluoro-4-hy 40 droxyphenyl)-3-methyl-3H-pyrimidin-4-one 2-Benzyl-5-3-fluoro-4-6-methoxy-7-(3-morpholin 4-yl-propoxy)-quinolin-4-yloxyl-phenyl-3-methyl HBr (40%, ACS reagent grade) was added to 2-benzyl-5- 3H-pyrimidin-4-one (3-fluoro-4-methoxyphenyl)-3-methyl-3H-pyrimidin-4-one 45 (Step 4, 9 g, 26 mmol) in HOAc (90 mL). The reaction was Step 1: Preparation of 2-benzyl-3H-pyrimidin-4-one heated to 130° C. and monitored by HPLC. After 3 h, the reaction was cooled to RT and the solid was collected by 2-Benzyl-3H-pyrimidin-4-one was prepared as filtration. The solid was washed with HO and EtO and dried described in WO94/26715 to afford the title compound as a yellow solid. MS (ESI pos. 50 ion) m/z: 311.1. Calc’d for CHFNO:310.11. Step 2: Preparation of Step 6: Preparation of 2-benzyl-5-3-fluoro-4-6- 2-benzyl-3-methyl-3H-pyrimidin-4-one methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4- yloxy)-phenyl-3-methyl-3H-pyrimidin-4-one CsCO (24.6 g. 75.7 mmol) was added to 2-benzyl-3H 55 pyrimidin-4-one (Step 1, 12.8 g) in DMF (80 mL) and THF 2-Benzyl-5-(3-fluoro-4-hydroxyphenyl)-3-methyl-3H (60 mL) at 0°C. After 10 min, Mel (4.3 mL, 68.8 mmol) was pyrimidin-4-one (Step 5, 200 mg, 0.64 mmol), 4-chloro-6- added, and the reaction was warmed to RT. After 3 h, the methoxy-7-(3-morpholinopropoxy)guinoline (217 mg, 0.64 reaction was decanted, diluted with CHCl, and washed with 60 mmol) and DMAP (39 mg, 0.32 mmol) in dioxane (3.5 mL) H2O, and aq. Sat. NaCl solution. The organic layer was dried and NMP (1.2 mL) were heated to 90° C. in a CEM micro (NaSO) and concentrated under reduced pressure. EtO and wave (150 W, 10 min, powermax). The dioxane was evapo Hexane (1:1) were added and the solvent was evaporated to rated and the crude was purified by Prep HPLC (1-95% provide a brown solid. The solid was triturated with 30' 65 CHCN/HO (0.16 TFA)) to afford the TFA salt of the title EtOAc/hexane to afford the title compound as a light brown compound as a yellow glass. MS (ESI pos. ion) m/z: 611.2. solid. The filtrate was purified by chromatography with 0-5% Calc’d for CHFNOs: 610.26.

US 7,652,009 B2 77 78

TABLE 1-continued

Mol MS Ex. Structure and Name Formula Mass (MH+) 9 C5H5FNO. 594.26 595

O

orscC) 4. pyrrollidinyl)propyl)oxy)-4- quinolinyl)oxy)phenyl)-3-methyl-2- (phenylmethyl)-4-(3H)-pyrimidinone

EXAMPLE 10 25 Step 3: Preparation of 5-bromo-3-methyl-2-methylthio-4(3H)-pyrimidinone 3-Methyl-2-methylthio-3H-pyrimidin-4-one (Step 2, 3.31 g, 21.2 mmol) was dissolved in CHCl (50 mL) and cooled to 30 0° C. under Ar. Br. (1.25 mL, 25.4 mmol) was added via syringe, and the reaction was stirred at 0°C. for 35 min, at which time TLC analysis indicated complete consumption of starting material. The reaction was quenched with 40 mL 35 saturated NaHCO, warmed to RT, and stirred overnight. The 1 reaction was extracted with CHCl (3x25 mL), and the N organic extracts were combined, dried over NaSO, filtered, 2 and concentrated to give the title compound, which did not require further purification. MS (ESI pos. ion) m/z: 236. 40 Calc’d for CHBrNOS: 233.95. 5-4-(6,7-Dimethoxy-quinolin-4-yloxy)-3-fluoro Step 4: Preparation of 5-(3-fluoro-4-methoxyphe phenyl-2-(4-fluoro-phenylamino)-3-methyl-3H nyl)-3-methyl-2-methylthio-3H-pyrimidin-4-one pyrimidin-4-one 45 Step 1: Preparation of 5-Bromo-3-methyl-2-methylthio-4(3H)-pyrimidinone 2-methylthio-3H-pyrimidin-4-one (Step 3, 14.77 g. 62.8 mmol), 3-fluoro-4-methoxyphenylbo ronic acid (20.11 g, 118.3 mmol), Pd(dba) (1.869 g, 2.04 This compound was prepared following the procedure of J. mmol), S-phos ligand (Strem Chemical, 3.45 g, 8.40 mmol) Spychala, Syn. Comm., 27(11):1943-1949 (1997). and KPO (42.27g, 199.1 mmol) were suspended in toluene (200 mL). Ar was bubbled through the solution for 5 min, and Step 2: Preparation of the reaction was placed in an oil bath (100°C.) and stirred for 3-methyl-2-methylthio-3H-pyrimidin-4-one 6.25 h, at which time LCMS analysis indicated a complete 55 reaction. The reaction was cooled to RT and allowed to stand 2-Methylthio-3H-pyrimidin-4-one (Step 1, 6.29 g, 44.2 overnight. It was diluted with CHCl (200 mL) and filtered mmol) was suspended in DMF (100 mL), cooled to 0°C., and through a 1-inch plug of silica gel which was washed exhaus additional DMF (50 mL) was added. Solid LiHMDS (9.58g, tively with MeOH, EtOAc, and CHCl2. (Some solid material 57.3 mmol) was added in one portion, and the reaction was stuck in the flask had to be taken up in water and extracted stirred at 0° C. Mel (3.6 mL, 57.8 mmol) was added via 60 Syringe, and the reaction was warmed to RT and stirred for with EtOAc separately). The filtrate (and EtOAc extracts) 20.75 h. At this time, the mixture was poured into 300 mL were all combined and concentrated, resulting in an orange HO and extracted exhaustively with EtOAc. The organic solid. This was treated with hexanes and filtered, and the extracts were combined, dried over NaSO, filtered, concen resultant light yellow solid was washed repeatedly with hex trated, and purified on silica gel (3:1->3:2-> 1:1 hexanes/ 65 anes and then put on the high vacuum overnight. The title EtOAc) to give the title compound. MS (ESI pos. ion) m/z: compound was obtained as a light yellow solid. MS (ESI pos. 157. Calc’d for CHNOS: 156.04. ion) m/z. 281. Calc'd for CHFNOS: 280.07. US 7,652,009 B2 79 80 Step 5: Preparation of 5-(3-fluoro-4-hydroxyphenyl)- EXAMPLE 11 H 3-methyl-2-methylthio-3H-pyrimidin-4-one N N F 5-(3-Fluoro-4-methoxyphenyl)-3-methyl-2-methylthio r NS 3H-pyrimidin-4-one (Step 4, 10.05 g, 35.85 mmol) was sus O pended in glacial HOAc (60 mL) and HBr (240 mL, 48%) was O added. The reaction was put in an oil bath (110°C.) and stirred -O N F for 1.5h. The reaction was heated to 120° C. and stirred for an 10 additional 1.5 h, and which time LCMS showed very little 2 starting material. The reaction was cooled to 0° C., and No N EtOAc (300 mL) was added. Saturated NaHCO, (0.2 L) was added, the reaction was transferred to a 2 L Erlenmeyer flask, 15 5-4-(6,7-Dimethoxy-quinolin-4-yloxy)-3-fluorophe nyl-2-(3-fluoro-phenylamino)-3-methyl-3H-pyrimi and 0.83 L saturated NaHCO was added. The reaction was din-4-one stirred overnight, then more NaHCOs (300 mL) and 5 N NaOH (100 mL) was added, and the reaction was stirred for Step 1: Preparation of 5-(4-(6,7-dimethoxyquinolin 4-yloxy)-3-fluorophenyl)-3-methyl-2-methylthio 30 min then filtered. The solid was collected while the pH of 3H-pyrimidin-4-one the filtrate was adjusted to about 5 using 5 N NaOH and filtered again. The solid from both filtrations was combined 5-(3-Fluoro-4-hydroxyphenyl)-3-methyl-2-methylthio-4 and dried in vacuo to give title compound. MS (ESI pos. ion) (3H)-pyrimidinone (Ex. 12, 522.7 mg, 1.963 mmol), 3,4- 25 dimethocyduinoline chloride (591 mg, 2.64 mmol), and m/z. 267. Calc’d for CHFN.O.S Mol. Wit.: 266.05. DMAP (72 mg 0.589 mmol) were suspended in 4.0 mL 1,4-dioxane and heated in a microwave at 300 W and 120° C. Step 6: Preparation of 5-(3-fluoro-4-hydroxyphenyl)- for 20 min. This process was repeated 3x using 528 mg, 528 2-(4-fluorophenylamino)-3-methyl-3H-pyrimidin-4- mg, and 536 mg of the starting material. All four reactions O 30 were combined, concentrated, and filtered through a plug of silica gel (3:1 EtOAc/hexanes) to give the title compound. 5-(3-Fluoro-4-hydroxyphenyl)-3-methyl-2-methylthio MS (ESI pos. ion) m/z. 454. Calc’d for CHFN.O.S: 453.12. 3H-pyrimidin-4-one (Step 5, 0.39 g, 1.5 mmol) was sus Step 2: Preparation of 5-(4-(6,7-dimethoxyquinolin pended in 3.6 mL p-fluoroaniline and concentrated HCl (1 35 4-yloxy)-3-fluorophenyl)-2-hydroxy-3-methyl-3H drop) was added. The reaction was heated in a microwave at pyrimidin-4-one 120° C. and 100W for 10 min (using a Powermax feature on 5-(4-(6,7-Dimethoxyquinolin-4-yloxy)-3-fluorophenyl)- a CEM microwave). The reaction was cooled to RT and 3-methyl-2-methylthio-3H-pyrimidin-4-one (Step 1, 1.048g. diluted with EtOAc (100 mL). The organic phase was 40 2.3 mmol) was dissolved in CHCN (15 mL) and TFA (1.7 extracted with 1 N NaOH (3x15 mL), and the aqueous mL) and cooled to 0°C. Urea hydrogen peroxide (290 mg. extracts were neutralized with concentrated HC1. The aque 3.09 mmol) was added, and the reaction was stirred for 5 min. trifluoroacetic anhydride (0.43 mL, 3.09 mmol) was added, ous layer was extracted with EtOAc (3x20 mL), and the and the reaction was warmed to RT and stirred for 40 min. The organic extracts were combined, dried over NaSO, filtered, 45 mixture was quenched with HO (10 mL) and EtOAc (25 mL) and concentrated to give desired compound. MS (ESI pos. and allowed to stand overnight. Saturated NaHCO (10 mL) and EtOAc were added, and the layers were separated. The ion) m/z: 330. Calc'd for CHFNO:329.10. aqueous layer was extracted with EtOAc, and the organic layers were combined, dried over NaSO filtered, concen Step 7: Preparation of 5-(4-(6,7-dimethoxyquinolin 50 trated, and purified on silica gel (EtOAc-> 1:1 EtOAc/MeOH) 4-yloxy)-3-fluorophenyl)-2-(4-fluorophenylamino)- to give title compound. MS (ESI pos. ion) m/z.: 411. Calc’d 3-methyl-3H-pyrimidin-4-one for CHFNOs: 410.39. Step 3: Preparation of 2-chloro-5-(4-(6,7-dimethox 5-(3-Fluoro-4-hydroxyphenyl)-2-(4-fluorophenylamino)- 55 yduinolin-4-yloxy)-3-fluorophenyl)-3-methylpyrimi 3-methyl-3H-pyrimidin-4-one (Step 6, 296.7 mg, 0.901 din-4(3H)-one mmol), 3,4-dimethocyduinoline chloride (313.9 mg, 1.404 mmol), and DMAP (28 mg, 0.23 mmol) were suspended in 5-(4-(6,7-Dimethoxyquinolin-4-yloxy)-3-fluorophenyl)- 1,4-dioxane (3.0 ml) and heated in a microwave at 120° C. and 2-hydroxy-3-methyl-3H-pyrimidin-4-one (Step 2, 678.8 mg, 300 W for 20 min. The reaction was cooled to RT and con 60 1.605 mmol) was dissolved in POCl (16 mL) and N,N- dimethylaniline (1.6 ml) and heated at 125°C. for 8.5 h then centrated. The mixture was purified first using reverse-phase cooled to RT and stirred overnight. The reaction was concen HPLC (10%->95% CHCN/HO with 0.1% TFA) and then trated, diluted with CHCl (125 mL) and washed with satu by filtering 2x through a 0.5 inch-1 inch plug of silica gel with rated NaHCO (25 mL, 17 mL). The organic layer was dried EtOAc. Fractions with pure compound collected and concen 65 over NaSO, filtered, and concentrated. Because of the pro trated to give the title compound. MS (ESI pos. ion) m/z: 517. pensity of title compound to hydrolysis, the crude chloride Calc’d for CHFNO. 516.16. was used for the next reaction. US 7,652,009 B2 81 82 Step 4: Preparation of 5-(4-(6,7-dimethoxyquinolin silica gel with EtOAc->2:1 EtOAc/MeOH->3:2 MeOH/ 4-yloxy)-3-fluorophenyl)-2-(3-fluorophenylamino)- EtOAc. The filtrate was concentrated and purified using 3-methyl-3H-pyrimidin-4-one reverse phase HPLC (10%->95% MeCN/HO with 0.1% TFA). Finally, the compound was filtered again through a The crude 2-chloro-5-(4-(6,7-dimethoxyquinolin-4- 5 1-inch plug of silica gel in a pipette column with EtOAc to yloxy)-3-fluorophenyl)-3-methylpyrimidin-4(3H)-one from give the title compound. MS (ESI pos. ion) m/z: 517. Calc’d Step 3 was dissolved in 15 mL 1,4-dioxane. To 5 mL of this for CHFNO. 516.16. Solution was added m-fluoroaniline (0.2 mL) and concen trated HCl (1 drop). The reaction was heated in the microwave The following Examples in Table 2 were prepared similar to at 60° C. and 60W for 5 min before being cooled to RT. The 10 the procedures described in either Example 10 or Example mixture was concentrated and filtered through a 1 inch plug of 11.

TABLE 2

Mol Mol MS Ex. Structure Formula Weight (MH+) 12 N Sn C2H2FNOS 453.12 454.0

rsrs.N YCH, O O CH-1 O N F CH3 2 No N

5-(4-((6.7-bis(methoxy)-4- quinolinyl)oxy)-3-fluorophenyl)-3- methyl-2-methylthio-4(3H)- pyrimidinone

13 N N CHFNO. 498.17 499.0

N YCH, r O CH3 O O N F CH 2 No N 5-(4-((6.7-bis(methoxy)-4- quinolinyl)oxy)-3-fluorophenyl)-3- methyl-2-(phenylamino)-4(3H)- pyrimidinone 14 F C28H2FNO. 516.16 517.0 N N

r N YCH, O CH O O N F

O 4. CH-1 5-(4-((6.7-bis(methoxy)-4- quinolinyl)oxy)-3-fluorophenyl)-2- ((2-fluorophenyl)amino)-3-methyl 4(3H)-pyrimidinone

US 7,652,009 B2 119 120 EXAMPLE 38 the resulting Suspension was filtered, and the Solid was further washed with HO. The solid was washed with hexanes to provide the title compound as a brown solid. MS (ESI pos. ion) m/z: 282. Calc'd for CHFNO: 281.10. H N N 21 Step 4: Preparation of 5-(4-(6,7-dimethoxyquinolin 4-yloxy)-3-fluorophenyl)-N-phenylpyrimidin-2- S N amine

10 A mixture of 4-chloro-6,7-dimethoxyquinoline (0.064 g, O 0.28 mmol) and 2-fluoro-4-(2-(phenylamino)pyrimidin-5-yl) phenol (Step 3, 0.48g, 0.17 mmol) in dioxane (1.0 mL) and MeO N F pyridine (0.5 mL) was treated with a catalytic amount of DMAP (0.12 g, 0.1 mmol). The mixture was heated under 2 15 microwave irradiation at 180° C. for 30 min. After cooling to MeO N RT, the mixture was diluted with NaOH (0.2N, 6 mL), and the suspension was filtered. The resulting solid was further puri fied on silica with 0-5% (NH-MeOH in DCM) to afford the 5-(4-(6,7-Dimethoxyquinolin-4-yloxy)-3-fluorophe title compound as a white solid. MS (ESI pos. ion) m/z: 469. nyl)-N-phenylpyrimidin-2-amine Calc’d for CHFNO: 468.16. Step 1: Preparation of EXAMPLE 39 5-(3-fluoro-4-methoxyphenyl)pyrimidin-2-amine

In a 500 mL round bottom flask under N, 3-fluoro-4- 25 methoxyphenylboronic acid (5.0 g, 29.4 mmol) and 5-io dopyrimidin-2-amine (5.5g, 24.9 mmol) were mixed. Tolu ene (100 mL), EtOH (40 mL) and HO (20 mL) were added, N followed by the addition of NaCO (3.0 g, 24.2 mmol). A CN stream of N was bubbled through the mixture for 5 min 30 before the catalyst Pd(PPh) (0.30 g, 0.26 mmol) was added. The mixture was heated at 80° C. under N for 20h whereby O it was cooled to RT. A solution of NaOH (5 N, 10 mL) was added to the mixture and stirring was continued for 10 min. -O 21 F The mixture was filtered and the solid was washed with H2O 35 (3x10 mL), followed by a mixture of hexanes—EtOAc (1:1, No Sn N 30 mL). The solid was dried in the air to give the title com pound. MS (ESI pos. ion) m/z: 220. Calc'd for CHFNO: 219.08. 40 {2-4-(6,7-Dimethoxy-quinolin-4-yloxy)-3-fluoro Step 2: Preparation of 5-(3-fluoro-4-methoxyphe phenyl-pyrimidin-5-yl)-phenyl-amine nyl)-N-phenylpyrimidin-2-amine Step 1: Preparation of A mixture of 5-(3-fluoro-4-methoxyphenyl)pyrimidin-2- 5-bromo-2-(3-fluoro-4-methoxyphenyl)pyrimidine amine (Step 1, 0.44g, 2.0 mmol) and bromobenzene (0.60 g, 45 4.0 mmol) in N,N'-dimethylacetamide (1.0 mL) and toluene To a mixture of 5-bromo-2-iodopyrimidine (3.0 g, 10 (1.0 mL) was placed in a microwave tube and was treated with mmol) and 3-fluoro-4-methoxyphenylboronic acid (2.0 g, 12 Pd(OAc). (0.024g, 0.1 mmol), 2-biscyclohexyl 1, 1-biphenyl mmol) in dioxane (15 mL) and H2O (5 mL) was added phosphine (Strem Chemical, 0.070 g., 0.20 mmol), and Pd(dppf)Cl. CHCl (0.1 g, 0.12 mmol) and NaCO (20g, KO'Bu (0.44g, 4.0 mmol). The mixture was degassed with N 50 19 mmol) under argon. The mixture was stirred at RT for 20 (2x) and was subject to microwave heating at 200° C. for a hand was further heated at 80° C. for 20h. The mixture was total of 20 min. After the mixture was cooled to RT, it was cooled to RT and was extracted with EtOAc. The organic filtered through a pad of Celite(R). The solid was washed with layer was washed with H.O. NHCl (sat), dried (NaSO), EtOAc (3x10 mL), and the combined organic phase was and concentrated. The crude residue was partitioned in 1:1 washed with H2O, NHCl (sat.), dried with NaSO, and 55 ether-CH2Cl and filtered to provide the title compound as a concentrated to an oil. Purification on silica using hexanes flake. The filtrate was concentrated and was triturated with EtOAc (3:1) resulted the desired compound as a yellow solid. MeOH to provide a second batch of product solid. MS (ESI MS (ESI pos. ion) m/z. 296. Calc’d for CHFNO: 295.11. pos. ion) m/z: 283, 285. Calc'd for CHBrFNO: 281.98.

Step 3: Preparation of 60 Step 2: Preparation of 2-(3-fluoro-4-methoxyphe 2-fluoro-4-(2-(phenylamino)pyrimidin-5-yl)phenol nyl)-N-phenylpyrimidin-5-amine A mixture of 5-(3-fluoro-4-methoxyphenyl)-N-phenylpy In a 50 mL round bottom flask under nitrogen was charged rimidin-2-amine (Step 2, 0.066 g., 0.22 mmol), thiophenol 5-bromo-2-(3-fluoro-4-methoxyphenyl)pyrimidine (Step 1. (0.20 g, 1.0 mmol), and KCO (0.15g, 1.1 mmol) in NMP (2 65 0.40 g, 1.41 mmol), aniline (0.28 g, 3.0 mmol), Pd(OAc), mL) was heated at 120° C. for 20 h. The mixture was cooled (0.015 g, 0.067 mmol), BINAP (0.090 g, 0.064 mmol), and to RT and diluted with HO (4 mL). After stirring for 10 min, NaO'Bu (0.27g, 2.8 mmol). Toluene (5.0 mL) was added and US 7,652,009 B2 121 122 the mixture was heated at 100° C. for 24 h. The mixture was (50%-100% EtOAc in hexanes) to afford the title compound cooled to RT and was partitioned between CHC1 and H2O. as a yellow solid. MS (ESI pos. ion) m/z: 539. Calc’d for The organic phase was dried over NaSO and concentrated. CHFNO. 538.24. Purification on silica with 1% MeOH in CHC1 afforded the title compound as a purple solid. MS (ESI pos. ion) m/z: 296. EXAMPLE 41 Calc’d for CHFNO: 295.11. Step 3: Preparation of 2-4-(6,7-dimethoxy-quino lin-4-yloxy)-3-fluoro-phenyl-pyrimidin-5-yl)-phe nyl-amine 10 21 N N A mixture of 5-(3-fluoro-4-methoxyphenyl)-N-phenylpy N1 rimidin-2-amine (Step 2, 0.23 g, 0.78 mmol), thiophenol (0.50 g, 4.6 mmol), and KCO (0.50 g, 3.6 mmol) in NMP 15 O (1.5 mL) was heated at 120° C. for 20 h. The mixture was cooled to RT and was diluted with HO (4 mL). Extraction MeO N with CHCl, followed by flash chromatography on silica (1% MeOH in EtOAc) afforded the desired phenol as a dark 2 orange film. (M+1/e: 282.) The phenol was mixed with MeO N 4-chloro-6,7-dimethoxyquinoline (0.26g, 1.2 mmol), DMAP (0.030 g, 0.25 mmol) in pyridine (1.0 mL) and dioxane (1.0 mL). The mixture was heated at 110° C. for 14 h, concen {6-4-(6,7-Dimethoxy-quinolin-4-yloxy)-phenyl trated, and heated further in toluene (5 mL). The residue was pyridazin-3-yl)-phenyl-amine purified on silica using MeOH in CHCl (0-3%). Part of the 25 product fraction was dissolved in EtOAc and was washed Step 1: Preparation of with NaOH (1 N, 2x) to yield the title compound. MS (ESI 3-Chloro-6-(4-methoxy-phenyl)-pyridazine pos. ion) m/z: 469. Calc'd for CHFNO. 468.16. 30 A mixture of 4-methoxyphenylboronic acid (3 g, 0.02 mol) EXAMPLE 40 and 3,6-dichloro-pyridazine (3.58 g., 0.024 mol) in 2 M NaCO/EtOH toluene (40 mL/20 mL/100 mL) was bubbled through N for 5 min. Pd(PPh) (1.15g, 0.001 mol) was added under N and the reaction was heated to 80°C. for 16 h. The mixture was diluted with 100 mL of EtOAc and 20 mL 35 of water. The organic phase was separated, washed with 50 mL of brine, dried over NaSO and concentrated in vacuo. The solid obtained was washed with 50% EtOAc/hexane to provide the title compound as off-white solid. MS (ESI pos. N ion) m/z: 221.0 (M+H). Calc’d Exact Mass for CHCINO: 40 220.65. N CN Step 2: Preparation of 4-(6-Chloro-pyridazin-3-yl)-phenol O 45 A solution of 3-chloro-6-(4-methoxy-phenyl)-pyridazine -O 21 F (Step 1, 2.5g, 0.0113 mol) in 1 MBBr/CHCl (34 mL) was stirred at RT for 16 h. The solution was concentrated in vacuo and the residue was re-dissolved in 100 mL of EtOAc. The No s 50 organic phase was washed with 40 mL of water followed by 40 mL of brine, dried over NaSO and concentrated in vacuo. The solid was washed with 50% EtOAc/hexane mixture to 2-(4-(6,7-Dimethoxynaphthalen-1-yloxy)-3-fluo give the title compound as a yellow solid MS (ESI pos. ion) rophenyl)-N-isopentyl-N-phenylpyrimidin-5-amine m/z: 207.2(M+H). Calc’d Exact Mass for CHCINO: 55 206.63. In a 10 mL dry flask with stirring bar was placed 2-4-(6. Step 3: Preparation of 7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl-pyrimi 4-(6-Phenylamino-pyridazin-3-yl)-phenol din-5-yl)-phenyl-amine (Example 39, 0.030 g, 0.06 mmol) under N. Anhydrous THF (1.5 mL) was added, followed by 60 To a solution of 4-(6-chloro-pyridazin-3-yl)-phenol (Step the addition of NaH (60% dispersion, 0.10g, 2.5 mmol). The 2, 1 g, 4.84 mmol) and aniline (1.35 g, 14.52 mmol) in 20 mL resulting yellow mixture was heated at 50° C. for 20 min, then of DMSO was added 5 drops of TFA. The reaction was heated cooled to RT. 1-Bromo-3-methylbutane (0.20 mL) was to 80°C. for 16 h. The solution was cooled to RT and diluted added, and the resulting yellow mixture was heated at 50° C. with 100 mL of EtOAc. The organic phase was washed with for 4.5 h. The reaction was quenched with NHCl (half sat.) 65 40 mL of water, 40 mL of brine, dried over NaSO and and the slurry was filtered, then washed with H.O.The brown concentrated in vacuo. The residue was purified by chroma solid was dissolved in CHCl and was purified on silica tography (50% EtOAc/hexane to EtOAc) to give the title US 7,652,009 B2 123 124 compound as a white solid. MS (ESI pos. ion) m/z. 264.2(M+ graph (50% EtOAc/Hexane to EtOAc) to give light yellow H). Calc’d Exact Mass for CHNO: 263.29. solid. MS (ESI pos. ion) m/z: 295.3 (M+H). Calc’d Exact Step 4: Preparation of {6-4-(6,7-Dimethoxy-quino Mass for CHFNO: 294.32. lin-4-yloxy)-phenyl-pyridazin-3-yl)-phenyl-amine Step 3: Preparation of A mixture of 4-(6-phenylamino-pyridazin-3-yl)-phenol 4-(6-Benzyl-pyridazin-3-yl)-2-fluoro-phenol (Step 3, 0.25 g, 0.95 mmol), 4-chloro-6,7-dimethoxy-quino line (0.212g, 0.95 mmol), Cu powder 0.1 g) and NaOH pellet A solution of 3-benzyl-6-(3-fluoro-4-methoxy-phenyl)- (0.1 g) in DMF/pyridine (1.5 mL/1.5 mL) was heated in a 10 pyridazine (Step 2, 1.5 g, 5.1 mmol) in 25 mL of 1 MBBr/ microwave (CEMDiscover, 60 W, 120° C. ramp 12 min, hold CHC1 was stirred at RT for 16 h. The solution was then 18 min). The reaction mixture was then diluted with 50 mL of concentrated in vacuo and the residue was re-dissolved in 100 EtOAc and washed with 20 mL of water followed by brine (20 mL of EtOAc. The organic phase was washed with 40 mL of mL). The organic phase was dried over NaSO and concen water followed by 40 mL of brine, dried over NaSO and trated in vacuo. The crude product was purified by column 15 concentrated in vacuo to give the title compound. The Solid (50% EtOAc/hexane to EtOAc) to afford the title compound has poor solubility in EtOAc and CH2Cl and was washed as a white solid. MS (ESI pos. ion) m/z.: 451.2(M+H). Calc’d with 50% EtOAc/hexane and then used in the next step (yel Exact Mass for CHNO. 450.49. low solid). MS (ESI pos. ion) m/z: 281.3 (M+H). Calc’d EXAMPLE 42 Exact Mass for CHFNO: 280.30. Step 4: Preparation of 4-4-(6-Benzyl-pyridazin-3- yl)-2-fluoro-phenoxy-6,7-dimethoxy-quinoline

25 A mixture of 4-Chloro-6,7-dimethoxy-quinoline (0.19 g, 0.85 mmol), 4-(6-benzyl-pyridazin-3-yl)-2-fluoro-phenol (Step 3, 0.2g, 0.71 mmol) and DMAP (0.1 g, 0.85 mmol) in 6 mL of toluene was heated in a microwave (Personal Chem istry, Emrys Optimizer) at 180° C. for 2 h. The mixture was 30 cooled to RT and diluted with 60 mL of EtOAc. The solution was washed with 20 mL of brine 2x, dried over NaSO and concentrated in vacuo. The residue was further purified with silica gel column chromatography (50% to 100% EtOAc in hexanes) to provide title compound as a white solid. MS (ESI 35 pos. ion) m/z. 487.3 (M+H). Calc’d Exact Mass for 4-4-(6-Benzyl-pyridazin-3-yl)-2-fluoro-phenoxy-6, CHFNO: 467.49. 7-dimethoxy-quinoline EXAMPLE 43 Step 1: Preparation of 40 3-Chloro-6-(3-fluoro-4-methoxy-phenyl)-pyridazine A mixture of 3-fluoro-4-methoxyphenylboronic acid (10g, 21 O 0.059 mol) and 3,6-dichloro-pyridazine (8.79g., 0.059 mol) in 2 M. NaCO/EtOH/toluene (80 mL/40 mL/200 mL) was 45 bubbled through N for 5 min. Cat. Pd(PPh) (3.47 g., 0.003 N-N mol) was added under N, and the reaction was heated to 80° C. for 16 h. The mixture was diluted with 200 mL of EtOAC O and 40 mL of water. The organic phase was separated, washed with 80 mL of brine, dried over NaSO and concentrated in 50 10 N F vacuo. The solid obtained was washed with 50% EtOAc/ hexane to provide off-white solid. MS (ESI pos. ion) m/z: 239.0 (M+H). Calc’d Exact Mass for CH.ClFNO: 238.65. No 4.

Step 2: Preparation of 55 3-Benzyl-6-(3-fluoro-4-methoxy-phenyl)-pyridazine 4-2-Fluoro-4-(6-phenoxy-pyridazin-3-yl)-phenoxy 6,7-dimethoxy-quinoline A solution of 3-chloro-6-(3-fluoro-4-methoxy-phenyl)- pyridazine (Step 1, 2.0 g, 8.38 mmol), B-benzyl-9-BBN (0.5 Step 1: Preparation of mL in THF, 20 mL) and KCO (3.5g, 25.1 mmol) in 30 mL 60 3-(3-Fluoro-4-methoxy-phenyl)-6-phenoxy-pyridazine of DMF was degassed with N for 5 min. Cat. Pd(DPPF)C1, (731 mg, 1 mmol) was then added and the reaction was heated at 65° C. for 3 h (preheated oil bath). The mixture was poured A mixture of 3-chloro-6-(3-fluoro-4-methoxy-phenyl)-py into ice water and extracted with 50 mL 2xEtOAc. The com ridazine (1.0 g, 4019 mmol), phenol (0.26g, 5.03 mmol) and bined organic phases were washed with 50 mL of brine and 65 CsCO, (1.64g, 5.03 mmol) in 15 mL of DMF (in microwave dried over NaSO. The solution was concentrated in vacuo tube) was heated in a microwave (Personal Chemistry, Emrys and the crude was purified by silica gel column chromato Optimizer) at 150° C. for 15 min. The mixture was cooled to US 7,652,009 B2 125 126 RT and diluted with 60 mL of EtOAc. The solution was next step without further purification. MS (ESI pos. ion) m/z: washed with 20 mL of satd. NaHCO, followed by 20 mL of 283.1 (M+H). Calc’d Exact Mass for CHFNO: 282.27. brine, dried over NaSO and concentrated in vacuo. The solid was washed with 50% EtOAc/hexanes to provide the Step 3: Preparation of 4-2-Fluoro-4-(6-phenoxy title compound as an off-white solid. MS (ESI pos. ion) m/z: pyridazin-3-yl)-phenoxy-6,7-dimethoxy-quinoline 297.3 (M+H). Calc’d Exact Mass for CHFNO: 296.30. Step 2: Preparation of A mixture of 4-chloro-6,7-dimethoxy-quinoline (0.4 g. 2-Fluoro-4-(6-phenoxy-pyridazin-3-yl)-phenol 1.79 mmol), 2-fluoro-4-(6-phenoxy-pyridazin-3-yl)-phenol (Step 2, 0.50 g, 1.79 mmol) and DMAP (0.22g, 1.79 mmol) A mixture of 3-(3-fluoro-4-methoxy-phenyl)-6-phenoxy 10 in 6 mL of toluene (in microwave tube) was heated in a pyridazine (Step 1, 0.60 g, 2.0 mmol) and pyridine hydro microwave (Personal Chemistry, Emrys Optimizer) at 180° chloride (3 g) was heated in an oil bath at 170° C. for 8 h. The C. for 1 h. sublimed pyridine hydrochloride on the top of the reaction The following Examples in Table 4 were prepared similar flask was removed, and the residue (0.65 g) was used in the to the procedures described in the above Examples.

TABLE 4

Mol MS Ex. Structure Mol Formula Weight (MH+) 43a 21 N C27H2OCIFNO SO2.12 503 N-N C O CH-1 O N F CH No N 2

6-(4-((6.7-bis(methoxy)-4- quinolinyl)oxy)-3- fluorophenyl)-N-(3- chlorophenyl)-3-pyridaZinamine

43b CH C28H23FNO3 482.18 483

N s N

O CH1. O N F CH 2 No N 6-(4-((6.7-bis(methoxy)-4- quinolinyl)oxy)-3- fluorophenyl)-N-methyl-N- phenyl-3-pyridaZinamine

43c N CHCIFNO SO2.12 503 21 DO 27112O 4v.3 N N1-N Cl

O CH1. O N F CH3 2 No N 6-(4-((6.7-bis(methoxy)-4- quinolinyl)oxy)-3- fluorophenyl)-N-(2- chlorophenyl)-3-pyridaZinamine

US 7,652,009 B2 133 134 EXAMPLE 44 Step 4: Preparation of 1-(4-(6,7-dimethoxyquinolin 4-yloxy)phenyl)-5-oxo-N-phenylpyrrolidine-3-car boxamide

5 To a solution of 1-(4-(6,7-dimethoxyquinolin-4-yloxy) phenyl)-5-oxopyrrolidine-3-carboxylic acid (Step 3, 120 mg. 0.29 mmol), aniline (55 mg 0.59 mmol), HOBt (58 mg, 0.43 mmol) in 6 mL of DMF was added EDC (82 mg, 0.43 mmol) at RT. The reaction was stirred at RT for 16h. The mixture was 10 diluted with 50 mL of EtOAc, and the resulting solution was washed with 20 mL of satd. NaHCO, followed by 20 mL of CH O brine. The organic phase was dried over NaSO and concen trated in vacuo. The crude was purified by silica gel column O 21 chromatography (30% to 100% EtOAc/hexane then to 5% 15 MeOH/EtOAc) to afford the title compound as a white solid. N MS (ESI pos. ion) m/z: 484.5 (M+H). Calc’d Exact Mass for O N CHNOs: 483.52. CH3 EXAMPLE 45

1-(4-(6,7-Dimethoxyquinolin-4-yloxy)phenyl)-5- oxo-N-phenylpyrrolidine-3-carboxamide O Step 1: Preparation of 25 1-(4-hydroxyphenyl)-5-oxo-pyrrolidine-3-carboxylic O acid methyl ester O A mixture of 4-amino-phenol (3 g, 0.027 mol) and 2-me thylene-succinic acid dimethyl ester (4.35 g, 0.027 mol) was 30 -O N F heated to 110° C. for 16 h. The dark brown glass was dis Solved in EtOAc and purified by silica gel chromatography No N 2 (20% EtOAc/hexane to EtOAC) to give the title compound as an orange oil. MS (ESI pos. ion) m/z: 236.2 (M+H). Calc’d 35 Exact Mass for CHNO. 235.24. 1-(4-(6,7-Dimethoxyquinolin-4-yloxy)-3-fluorophe nyl)-4-(phenoxymethyl)pyrrolidin-2-one Step 2: Preparation of methyl 1-(4-(6,7-dimethox yduinolin-4-yloxy)phenyl)-5-oxopyrrolidine-3-car boxylate Step 1: Preparation of 1-(3-fluoro-4-methoxyphe 40 nyl)-5-oxopyrrolidine-3-carboxylic acid A mixture of 4-chloro-6,7-dimethoxy-quinoline (1.0 g, A mixture of 3-fluoro-4-methoxybenzenamine (7.5 g. 4.45 mmol), 1-(4-hydroxyphenyl)-5-oxo-pyrrolidine-3-car 0.053 mmol) and itaconic acid (6.9 g, 0.053 mmol) was boxylic acid methyl ester (Step 1, 1.6 g. 6.7 mmol) and heated to 110° C. for 2 h. The yellow solid was dissolved in DMAP (0.55g, 4.45 mmol) in 30 mL of toluene (in 5 micro 45 100 mL of MeCH and concentrated in vacuo. The resulting wave tubes) was heated in a microwave (Personal Chemistry, solid was washed with 50% EtOAc/hexanes to give the title Emrys Optimizer) at 180°C. for 1 h. The mixture was cooled compound as a light yellow solid. MS (ESI pos. ion) m/z: to RT and diluted with 60 mL of EtOAc. The solution was 254.2 (M+H). Calc’d Exact Mass for CHFNO. 253.23. washed with 20 mL of satd. NaHCO, followed by 20 mL of brine, dried over NaSO and concentrated in vacuo. The 50 Step 2: Preparation of 1-(3-fluoro-4-methoxyphe residue was further purified with silica gel column chroma nyl)-4-(hydroxymethyl)pyrrolidin-2-one tography (100% EtOAc to 15% MeOH in EtOAc) to provide the title compound as colorless glass. MS (ESI pos. ion) m/z: To a solution of 1-(3-fluoro-4-methoxyphenyl)-5-oxopyr 423.2 (M--H). Calc’d Exact Mass for CHNO: 422.43. rolidine-3-carboxylic acid (Step 1.2g, 7.9 mmol), EtN (1.65 55 mL, 9.48 mmol) in 30 mL of CH2Cl at 0°C. was added Step 3: Preparation of 1-(4-(6,7-dimethoxyquinolin isobutyl chloroformate (1.23 mL, 9.48 mmol) via a syringe. 4-yloxy)phenyl)-5-oxopyrrolidine-3-carboxylic acid The reaction was stirred at 0°C. for 1 h. The white precipitate was removed by filtration. The filtrate was cooled to 0°C. and To a solution of methyl 1-(4-(6,7-dimethoxyquinolin-4- NaBH (0.9 g, 23.7 mmol) in water solution (3 mL) was yloxy)phenyl)-5-oxopyrrolidine-3-carboxylate (Step 2, 0.5 60 added to the reaction. After 1 h, the mixture was diluted with ng, 1.18 mmol) in MeCH/THF (2 mL: 2 mL) solution was 100 mL of EtOAc and 30 mL of satd. NaHCO, solution. The added 1.77 mL of 1 N NaOH. The reaction was stirred at RT organic phase was separated and washed with 30 mL of brine, for 8 h. The solution was concentrated in vacuo to dryness and dried over NaSO and concentrated in vacuo. The residue acidified with 1 NHC1. The white precipitate was collected by was chromatographed by a silica gel column (5% to 80% filtration and washed with 50% EtOAc/hexanes to give the 65 EtOAc/hexane) to give the title as a colorless glass. MS (ESI title compound as white solid. MS (ESI pos. ion) m/z: 409.3 pos. ion) m/z: 240.4 (M+H). Calc’d Exact Mass for (M+H). Calc’d Exact Mass for CHNO. 408.4. CHFNO. 239.24. US 7,652,009 B2 135 136 Step 3: Preparation of 1-(3-fluoro-4-methoxyphe N-(1-(4-(6,7-Dimethoxyquinolin-4-yloxy)-3-fluo nyl)-4-(phenoxymethyl)pyrrolidin-2-one rophenyl)-5-oxopyrrolidin-3-yl)benzamide To a solution of 1-(3-fluoro-4-methoxyphenyl)-4-(hy Step 1: Preparation of benzyl 1-(3-fluoro-4-methox droxymethyl)pyrrolidin-2-one (Step 2, 1.0 g, 4.18 mmol), yphenyl)-5-oxopyrrolidin-3-ylcarbamate phenol (0.786 g, 8.36 mmol) and PPhs (2.41 g, 9.2 mmol) in 50 mL of CHC1 at 0°C. was added DIAD (1.65 mL, 9.2 A solution of 1-(3-fluoro-4-methoxyphenyl)-5-oxopyrro mmol) slowly via a syringe. The reaction was warmed to RT lidine-3-carboxylic acid (1.5 g., 5.92 mmol), BnOH (1.92 g, and stirred overnight. The mixture was concentrated in vacuo 17.76 mmol), EtN (1.24 mL, 8.88 mmol) and DPPA (1.84g, and the residue was purified by chromatography (hexanes to 10 7.12 mmol) in 100 mL of toluene was heated to 120° C. for 6 50% EtOAc/hexanes) to give the title compound as a white h. The reaction was cooled to RT and concentrated in vacuo. solid. MS (ESI pos. ion) m/z: 316.2 (M+H). Calc’d Exact The residue was purified by chromatography on a silica gel Mass for C.H.FNO: 315.34. column (10% to 70% EtOAC/hexane) to give the title com pound as colorless crystal. MS (ESI pos. ion) m/z. 359.4 Step 4: Preparation of 1-(3-fluoro-4-hydroxyphenyl)- 15 (M+H). Calc’d Exact Mass for CHFNO. 358.36. 4-(phenoxymethyl)pyrrolidin-2-one Step 2: Preparation of 4-amino-1-(3-fluoro-4-meth A solution of 1-(3-fluoro-4-methoxyphenyl)-4-(phe Oxyphenyl)pyrrolidin-2-one noxymethyl)pyrrolidin-2-one (Step 3, 1.0 g, 3.17 mmol) in 15.85 mL of 1 MBBr/CHC1 was stirred at RT for 10h. The In a round-bottomed flask containing a mixture of benzyl Solution was concentrated in vacuo and the residue was 1-(3-fluoro-4-methoxyphenyl)-5-oxopyrrolidin-3-ylcar diluted with 100 mL of EtOAc. The organic phase was bamate (Step 1, 1.5 g, 4.2 mmol) and 200 mg of Pd/C in 100 washed with 40 mL of satd. NaHCOs followed by 40 mL of mL of EtOAc was applied with a H. balloon. The reaction was brine, dried over NaSO and concentrated in vacuo. The stirred at RT for 8 h, and filtered with the aid of Celite(R). The residue was purified by chromatography (5% to 60% EtOAc/ 25 filtrate was concentrated in vacuo to give the title compound hexane) to give the title compound as a light yellow foam. MS as a white solid. MS (ESI pos. ion) m/z: 225.3 (M+H). Calc’d (ESI pos. ion) m/z. 302.3 (M+H). Calc’d Exact Mass for Exact Mass for CHFNO: 224.23. CHFNO: 301.31. Step 3: Preparation of N-(1-(3-fluoro-4-methoxyphe Step 5: Preparation of 1-(4-(6,7-dimethoxyquinolin 30 nyl)-5-oxopyrrolidin-3-yl)benzamide 4-yloxy)-3-fluorophenyl)-4-(phenoxymethyl)pyrroli To a mixture of 4-amino-1-(3-fluoro-4-methoxyphenyl)- din-2-one pyrrolidin-2-one (Step 2, 0.8 g., 3.57 mmol) and KCO (0.99 g, 7.14 mmol) in 20 mL of CHCl was added benzoyl chlo A mixture of 4-chloro-6,7-dimethoxyquinoline (0.185 g, 35 ride (0.75 g, 5.35 mmol). The reaction was stirred at RT for 16 0.83 mmol), 1-(3-fluoro-4-hydroxyphenyl)-4-(phenoxym h. The solid in the reaction was removed by filtration and the ethyl)pyrrolidin-2-one (Step 4, 250 mg. 0.83 mmol) and filtrate was diluted with 20 mL of CHC1. The resulted DMAP (101 mg 0.83 mmol) in 8 mL of toluene (in a micro solution was washed with 20 mL of satd. NaHCO followed wave tube) was heated in a microwave (Personal Chemistry, by 20 mL of brine, dried over NaSO and concentrated in Emrys Optimizer) at 180° C. for 1.5 h. The mixture was 40 vacuo. The residue was purified by chromatography (30% to cooled to RT and diluted with 50 mL of EtOAc. The solution 100% EtOAc/hexane) to provide the title compound as a was washed with 20 mL of satd. NaHCOs followed by 20 mL white solid. MS (ESI pos. ion) m/z: 329.4 (M+H). Calc’d of brine, dried over NaSO and concentrated in vacuo. The residue was purified by chromatography (50% to 100% Exact Mass for CH,FNO:328.34. EtOAc/hexane) to provide the product as white solid. MS 45 Step 4: Preparation of N-(1-(3-fluoro-4-hydroxyphe (ESI pos. ion) m/z. 489.3 (M+H). Calc’d Exact Mass for nyl)-5-oxopyrrolidin-3-yl)benzamide CHFNOs: 488.51. A mixture of N-(1-(3-fluoro-4-methoxyphenyl)-5-oxopy EXAMPLE 46 rrolidin-3-yl)benzamide (Step 3, 0.9 g, 2.74 mmol) in 14 mL 50 of 1 MBBr/CHC1 was stirred at RT for 16 h. The solution was concentrated in vacuo and the residue was diluted with 50 mL of MeOH and concentrated in vacuo again. The resulting yellow solid was washed with 50% EtOAc/hexane to give a yellow solid. MS (ESI pos. ion) m/z: 315.3 (M+H). Calc’d 55 Exact Mass for CHFNO:314.31. Step 5: Preparation of N-(1-(4-(6,7-dimethoxyquino lin-4-yloxy)-3-fluorophenyl)-5-oxopyrrolidin-3-yl) benzamide 60 O A mixture of 4-chloro-6,7-dimethoxyquinoline (0.14 g, 0.6 mmol), N-(1-(3-fluoro-4-hydroxyphenyl)-5-oxopyrroli -O N F din-3-yl)benzamide (Step 4, 0.20 g, 0.6 mmol) and DMAP (78 mg, 0.6 mmol) in 2 mL of dioxane (in a microwave tube) No 4. 65 was heated in a microwave (Personal Chemistry, Emrys Opti mizer) at 160° C. for 1 h. The mixture was cooled to RT and diluted with 50 mL of EtOAc. The solution was washed with US 7,652,009 B2 137 138 20 mL of satd. NaHCO, followed by 20 mL of brine, dried chromatography (10% to 80% EtOAc/hexane) to give white over NaSO and concentrated in vacuo. The residue was solid. MS (ESI pos. ion) m/z: 314.2 (M+H). Calc’d Exact purified by chromatography (50% to 100% EtOAc in hexanes Mass for C.H.FNO: 313.32. then to 5% MeOH/EtOAc) to provide a white solid. MS (ESI pos. ion) m/z: 502.3 (M+H). Calc’d Exact Mass for Step 3: Preparation of 4-benzoyl-1-(3-fluoro-4-hy CHFNOs: 501.51. droxyphenyl)pyrrolidin-2-one A mixture of 4-benzoyl-1-(3-fluoro-4-methoxyphenyl) 10 pyrrolidin-2-one (Step 2, 1.0 g, 3.2 mmol) in 20 mL of 1 M EXAMPLE 47 BBr/CHCl was stirred at RT for 16 h. The solution was concentrated in vacuo and the residue was diluted with 50 mL of MeOH and concentrated in vacuo again. The resulting white solid was washed with 50% EtOAc/hexane to give the 15 title compound. MS (ESI pos. ion) m/z: 300.4 (M--H). Calc’d Exact Mass for CHFNO: 299.3. O Step 4: Preparation of 4-benzoyl-1-(4-(6,7- N O dimethoxyquinolin-4-yloxy)-3 fluorophenyl)pyrroli din-2-one

O A mixture of 4-chloro-6,7-dimethoxyquinoline (0.38 g. -O N F 25 1.67 mmol), 4-benzoyl-1-(3-fluoro-4-hydroxyphenyl)pyrro lidin-2-one (Step 3, 0.40 g, 1.67 mmol) and DMAP (0.204 g. No 4. 1.67 mmol) in 4 mL of dioxane (in a microwave tube) was heated in a microwave (Personal Chemistry, Emrys Opti 30 mizer) at 160° C. for 1 h. The mixture was cooled to RT and 4-Benzoyl-1-(4-(6,7-dimethoxyquinolin-4-yloxy)-3 fluorophenyl)pyrrolidin-2-one diluted with 50 mL of EtOAc. The solution was washed with 20 mL of satd. NaHCO, followed by 20 mL of brine, dried

Step 1: Preparation of 1-(3-fluoro-4-methoxyphe 35 over NaSO and concentrated in vacuo. The residue was nyl)-N-methoxy-N-methyl-5-oxopyrrolidine-3-car purified by chromatography (50% to 100% EtOAc in hexanes boxamide then to 5% MeOH/EtOAc) to provide a white solid. MS (ESI To a solution of 1-(3-fluoro-4-methoxyphenyl)-5-oxopyr pos. ion) m/z. 487.4 (M+H). Calc’d Exact Mass for rolidine-3-carboxylic acid (5 g, 19.7 mmol), N-meth 40 CHFNOs: 486.49. oxymethanamine hydrochloride (2.18 g. 22.4 mmol), HOBt (4.0g, 29.7 mmol) and EtN(4.2 mL, 29.7 mmol) in 60 mL of EXAMPLE 48 DMF was added EDC (5.7g, 29.7 mmol) at 0°C. The reaction was warmed to RT in 1 h and stirred at RT for 16 h. The 45 mixture was diluted with 100 mL of EtOAc, and the resulted solution was washed with 50 mL of satd. NaHCO, followed by 50 mL of brine. The organic phase was dried over NaSO and concentrated in vacuo. The crude residue was re-crystal O lized in 80% EtOAc/hexane to afford white solid. MS (ESI 50 pos. ion) m/z: 297.3 (M+H). Calc’d Exact Mass for N OH CHFNO. 296.29. Step 2: Preparation of 4-benzoyl-1-(3-fluoro-4-meth O Oxyphenyl)pyrrolidin-2-one 55 -O N F To a solution of 1-(3-fluoro-4-methoxyphenyl)-N-meth oxy-N-methyl-5-oxopyrrolidine-3-carboxamide (Step 1, 2g, No % 6.75 mmol) in 30 mL of THF was added 2 M phenylmagne 60 sium chloride in THF (6.75 mL) via syringe at RT. The solu tion was heated to 50° C. for 2 h. The solution was poured to 1-(4-(6,7-Dimethoxyquinolin-4-yloxy)-3-fluorophe 50 mL of satd. NHCl aq. Soln. The resulting mixture was nyl)-4-(hydroxy(phenyl)methyl)pyrrolidin-2-one extracted with 100 mL of EtOAc. The organic phase was 65 washed with 50 mL of brine, dried over NaSO and concen To a solution of 4-benzoyl-1-(4-(6,7-dimethoxyquinolin trated in vacuo. The crude was purified by a silica gel column 4-yloxy)-3-fluorophenyl)pyrrolidin-2-one (Example 47, 0.2 US 7,652,009 B2 139 140 g, 0.41 mmol) in 15 mL of MeOH was slowly added solid in DMF (40 mL) at 40°C. under N was added 3,4-difluo NaBH (50 mg, 1.32 mmol). The reaction was stirred at RT ronitrobenzene (1.6 mL, 14.2 mmol). The suspension stirred for 1 h. The reaction was quenched with 10 mL of satd. NHCl at 40° C. for 45 min. Solvent was removed under reduced solution. The solution was diluted with 100 mL of EtOAc and pressure and the residue was partitioned between CHC1. was washed with 30 mL of satd. NHCl followed by 30 mL of 5 (150 mL) and 1 N NaOH (50 mL). The organic layer was brine, dried over NaSO and concentrated in vacuo. The washed with water (50 mL) and brine (25 mL) and purified on crude solid was purified by chromatography (EtOAc to 5% silica gel yielding the title compound. Calc’d Mass for MeOH/EtOAc) to give a colorless film. MS (ESI pos. ion) CHFNOs, 420, MS (M+1) 421. m/z. 489.3 (M+H). Calc’d Exact Mass for CHFNOs: 488.51. 10 Step 2: Preparation of 4-(7-(benzyloxy)-6-methox yduinolin-4-yloxy)-3-fluorobenzenamine EXAMPLE 49 To a stirring solution of 7-(benzyloxy)-4-(2-fluoro-4-nitro phenoxy)-6-methoxyquinoline (Step 1, 4.5g, 10.7 mmol) and O 15 hydrazine (2 mL, 61 mmol) in THF (200 mL) was added Raney 2400 nickel (1 mL slurry in water). The suspension N was stirred for 30 min. The mixture was filtered through a bed OMe of Celite(R), then solvents were removed under reduced pres sure to afford the title compound. Calc’d Mass for O CHFNO 390, MS (M+1) 391. Step 3: Preparation of 3-(4-(7-(benzyloxy)-6-meth -O N F oxyquinolin-4-yloxy)-3-fluorophenyl)imidazolidine 2,4-dione 2 No N 25 To a stirring solution of 4-(7-(benzyloxy)-6-methox ycuinolin-4-yloxy)-3-fluorobenzenamine (Step 2, 1.0g, 2.6 mmol) in THF (15 mL) was added ethyl isocyanotoacetate (1 1-(4-(6,7-Dimethoxyquinolin-4-yloxy)-3-fluorophe mL, 6 mmol). After 3 h at RT, solvent was removed under nyl)-4-(methoxy(phenyl)methyl)pyrrolidin-2-one reduced pressure and the resulting residue was purified on 30 silica gel, yielding a white solid. (M-1)=520. To a solution of 1-(4-(6,7-dimethoxyquinolin-4-yloxy)-3- To the white solid (700 mg, 1.3 mmol) in dioxane (100 mL) fluorophenyl)-4-(hydroxy(phenyl)methyl)pyrrolidin-2-one was added DBU (0.3 mL, 2.0 mmol). The reaction was stirred (Example 48, 0.1 g, 0.2 mmol) in THF/DMF (1 mL:1 mL) at RT overnight. The solvent was removed under reduced was added NaH (0.1 g, 2.5 mmol) solid. The reaction was pressure to afford the title compound. Calc’d Mass for stirred at RT for 1 h. Mel (0.1 mL, 1.6 mmol) was added via 35 a Syringe and the reaction was stirred for 1 h. The reaction was CHFNOs, 473, MS (M+1) 474. quenched with 10 mL of satd. NHCl solution and 10 mL of EXAMPLE 51 water. The solution was diluted with 50 mL of EtOAc. The organic phase was separated and was washed with 30 mL of brine, dried over NaSO and concentrated in vacuo. The 40 crude oil was purified by chromatography (10% EtOAc/hex anes to EtOAc) to give colorless film. MS (ESI pos. ion) m/z: 503.5 (M+H). Calc’d Exact Mass for CHFNOs: 502.53.

EXAMPLE SO 45 N N-y O N O

O MeO N F O 2 MeO N F BO N 55 2 BO N 1-Benzyl-3-(4-(7-(benzyloxy)-6-methoxyquinolin-4- yloxy)-3-fluorophenyl)imidazolidine-2,4-dione

3-(4-(7-(Benzyloxy)-6-methoxyquinolin-4-yloxy)-3- 60 To a stirring Suspension of 3-(4-(7-(benzyloxy)-6-methoX fluorophenyl)imidazolidine-2,4-dione ycuinolin-4-yloxy)-3-fluorophenyl)imidazolidine-2,4-dione (Example 50, 200 mg, 0.42 mmol) and benzyl bromide (0.06 Step 1: Preparation of 7-(benzyloxy)-4-(2-fluoro-4- mL, 0.51 mmol) in THF (2 mL) and DMF (1 mL) was added nitrophenoxy)-6-methoxyquinoline 1 MLiHMDS in THF (0.51 mL). After 3 hat RT, the solvents 65 were removed under reduced pressure and the residue was To a stirred Suspension of 7-(benzyloxy)-6-methoxyquino purified on a silica gel to afford the title compound. Calc’d lin-4-ol (4.0 g, 14.2 mmol) and CsCO (11.5 g., 35.5 mmol) Mass for CHFNOs 563, MS (M+1) 564. US 7,652,009 B2 141 142 EXAMPLE 52 heated to 110° C. for 16 h. The dark brown glass was dis Solved in EtOAc and purified by silica gel chromatography (20% EtOAc/hexane to EtOAc) to give an orange oil. MS (ESI pos. ion) m/z: 236.2 (M+H). Calc’d Exact Mass for (C CHNO. 235.24.

O 10 O MeO N F Step 2: Preparation of Methyl 1-(4-(6,7-dimethox yduinolin-4-yloxy)phenyl)-5-oxopyrrolidine-3-car boxylate r^-so % 15 (-) A mixture of 4-chloro-6,7-dimethoxy-quinoline (1.0 g, 4.45 mmol), 1-(4-hydroxy-phenyl)-5-oxo-pyrrolidine-3-car 1-Benzyl-3-(3-fluoro-4-(6-methoxy-7-(3-mor boxylic acid methyl ester (1.6 g. 6.7 mmol) and DMAP (0.55 pholino-propoxy)guinolin-4-yloxy)phenyl)imidazoli g, 4.45 mmol) in 30 mL of toluene (in 5 microwave tubes) was dine-2,4-dione heated in a microwave (Personal Chemistry, Emrys Opti To a stirring solution of 1-benzyl-3-(4-(7-(benzyloxy)-6- mizer) at 180°C. for 1 h. The reaction mixture was cooled to RT and diluted with 60 mL of EtOAc. The solution was methoxyquinolin-4-yloxy)-3-fluorophenyl)imidazolidine-2, 25 4-dione (Example 51, 0.25 mg, 0.22 mmol) in THF (5 mL) washed with 20 mL of satd. NaHCO, followed by 20 mL of and MeOH (1 mL) over an argon atmosphere was added 20% palladium hydroxide on carbon (20 mg). The Suspension was brine, dried over NaSO and concentrated in vacuo. The stirred for 3 hat RT then filtered through a bed of Celite R. The residue was further purified with silica gel column chroma filtrate was concentrated, and to the residue (75 mg, 0.16 30 tography (100% EtOAc to 15% MeOH in EtOAc) to provide mmol) and CsCO, (67 mg, 0.21 mmol) in THF (0.5 mL) and colorless glass. MS (ESI pos. ion) m/z: 423.2 (M+H). Calc’d DMF (0.5 mL) was added 1-bromo-3-chloropropane (0.02 mL, 0.21 mmol). After 2 h at RT, solvents were removed Exact Mass for CHNO. 422.43. under reduced pressure. The resulting residue was purified on silica gel to provide a colorless film. 35 To the film (60 mg 0.11 mmol) and NaI (25 mg, 0.16 mmol) in DMF (0.5 mL) was added morpholine (0.05 mL, 0.55 mmol). The suspension was stirred at 60° C. overnight. Step 3: Preparation of 1-(4-(6,7-dimethoxyquinolin Solvent was removed under reduced pressure and the result 4-yloxy) phenyl)-5-oxopyrrolidine-3-carboxylic acid ing residue was purified on silica gel to afford the title com 40 pound. Calc’d Mass for CHFNO, 600, MS (M+1) 601. EXAMPLE 53 To a solution of methyl 1-(4-(6,7-dimethoxyquinolin-4- yloxy)phenyl)-5-oxopyrrolidine-3-carboxylate (Step 2, 0.5 45 g, 1.18 mmol) in MeCH/THF (2 mL: 2 mL) solution was added 1.77 mL of 1 N NaOH. The reaction was stirred at RT for 8 h. The solution was concentrated in vacuo to dryness and was acidified with 1 NHC1. The white precipitate was col 50 lected by filtration and was washed with 50% EtOAc/hexanes O to give the title compound as a white solid. MS (ESI pos. ion) MeO m/Z: 409.3 (M+H). Calc’d Exact Mass for CHNO: N 408.4. 55 2 MeO N

1-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-5- 60 oxo-N-phenylpyrrolidine-3-carboxamide Step 4: Preparation of 1-(4-(6,7-dimethoxyquinolin Step 1: Preparation of 1-(4-Hydroxy-phenyl)-5-oxo 4-yloxy) phenyl)-5-oxo-N-phenylpyrrolidine-3-car pyrrolidine-3-carboxylic acid methyl ester boxamide 65 A mixture of 4-amino-phenol (3 g, 0.027 mol) and 2-me To a solution of 1-(4-(6,7-dimethoxyquinolin-4-yloxy) thylene-succinic acid dimethyl ester (4.35 g, 0.027 mol) was phenyl)-5-oxopyrrolidine-3-carboxylic acid (Step 3, 120 mg. US 7,652,009 B2 143 144 0.29 mmol), aniline (55 mg 0.59 mmol), HOBt (58 mg, 0.43 Methyl (3R)-1-(4-((6.7-bis(methoxy)-4-quinolinyl) mmol) in 6 mL of DMF was added EDCI (82 mg, 0.43 mmol) oxy)-3-fluorophenyl)-5-oxo-3-pyrrolidinecarboxy at RT. The reaction was stirred at RT for 16h. The mixture was late diluted with 50 mL of EtOAc, and the resulting solution was washed with 20 mL of satd. NaHCO, followed by 20 mL of 5 EXAMPLE 55 brine. The organic phase was dried over NaSO and concen trated in vacuo. The residue was purified by silica gel column chromatography (30% to 100% EtOAc/hexane then to 5% MeOH/EtOAc) to afford the title compound as a white solid. MS (ESI pos. ion) m/z: 484.5 (M+H). Calc’d Exact Mass for 10 O NH CHNOs: 483.52. N

EXAMPLE 54 15 CH3 O V O N F

F N N O-CH Crs

CH3 O 25 1-(3-Fluoro-4-((6-(methoxy)-7-(3-(4-morpholinyl) O N propoxy)-4-quinolinyl)oxy)phenyl)-2-imidazolidi O CH3 No N2 30 The following Examples in Table 5 were prepared similar to the procedures described in the above Examples. TABLE 5

Mol Mol MS Ex. Structures Formula Weight (MH+) 56 CoH2FN2O5 516.57 517.4 O

N

O O K 1. O N F

No N 2 1-(4-((6.7-bis(methoxy)-4- quinolinyl)oxy)-3-fluorophenyl)-4- (ethoxy)(phenyl)methyl)-2- pyrrollidinone

57 C28H2FN3Os SO9.57 S10.6

O N/ N

O

O

O F

US 7,652,009 B2 165 166

TABLE 5-continued

Mol Mol MS Ex. Structures Formula Weight (MH+) 90 C27H25N3O4 455.18 456 OY

O

1. O 21

No S.N 1-(4-((6.7-bis(methoxy)-4- quinolinyl)oxy)phenyl)-3- (phenylmethyl)-2-imidazolidinone

Other compounds included in this invention are set forth in Tables 6-8 below.

TABLE 6 NN- NR3. N YCH, O CH O O 21 F RIQ N No N

i R10 ya R

91. methoxy NH

F

N N

92. methoxy 1n 1a s1 CH3 phenyl

93. methoxy -CH3 phenyl NH N

94. methoxy HO CH3 phenyl US 7,652,009 B2 167 168

TABLE 6-continued

N YCH, O CH O O 21 F RIQ N No N R 10 Ya R methoxy NH H

's-E N \ NHCH 1. N

96. methoxy NH ON-1 \ -N N(CH3)2

97. methoxy NH CH3 CH3 OD 1N1 v/ H CH3

45

TABLE 7

O 50

Ya N N R

55 CH O O N F RIQ 2 No N 60

i R 10 Ya R 98. methoxy NH phenyl 99. methoxy CH(CHOH) phenyl 65