AU2013204031B2 - c-Met modulators and methods of use - Google Patents

Abstract

C:lNRPonIbimCOJAMUII7f42_l.DOC-2627/2 0 The present invention provides compounds for modulating protein kinase enzymatic activity for modulating cellular activities such as proliferation, differentiation, programmed 5 cell death, migration and chemoinvasion. More specifically, the invention provides quinazolines and quinolines which inhibit, regulate and/or modulate kinase receptor, particularly c-Met, KDR, c-Kit, flt-3 and flt-4, signal transduction pathways related to the changes in cellular activities as mentioned above, compositions which contain these compounds, and methods of using them to treat kinase-dependent diseases and conditions. 10 The present invention also provides methods for making compounds as mentioned above, and compositions which contain these compounds.

Description

H:tecg\Imcnmcn\NR.PorlblVDCC\SCO\.3l>87ll79_l.doc-l 1/IH/20I3 2013204031 11 Apr 2013 c-Met Modulators and Method of Use

This application is a divisional application derived from Australian Patent Application No. 2010204461 which is a divisional of Australian Patent Application No. 2004275842, the entire contents of which, as originally filed, are incorporated herein by reference. 5

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U. S. provisional patent applications 60/506, 181 filed on September 26,2003, entitled"c-Met Modulators and Method of Use,"naming Bannen, Lynne et. al as inventors, 60/535, 377 filed on January 9, 2004, entitled"c-Met Modulators and 10 Method of Use,"naming Bannen, Lynne et. al as inventors and 60/577, 384 filed on June 4,2004, entitled"Synthesis of Quinoline and Quinazoline Kinase Modulators,"naming Bannen, Lynne et. al as inventors; each of which is hereby incorporated by reference in its entirety for all purposes.

15 FIELD OF THE INVENTION

[0002] This invention relates to compounds for modulating protein kinase enzymatic activity for modulating cellular activities such as proliferation, differentiation, programmed cell death, migration and chemoinvasion. Even more specifically, the invention relates to quinazolines and quinolines which inhibit, regulate and/or modulate kinase receptor signal transduction 20 pathways related to the changes in cellular activities as mentioned above, compositions which contain these compounds, methods of using them to treat kinase-dependent diseases and conditions, synthesis of the compounds as well as processes for formulating the compounds for pharmaceutical purposes.

25 BACKGROUND OF THE INVENTION

[0003] Improvements in the specificity of agents used to treat cancer is of considerable interest because of the therapeutic benefits which would be realized if the side effects associated with the administration of these agents could be reduced. Traditionally, dramatic improvements in the treatment of cancer are associated with identification of therapeutic agents acting through 30 novel mechanisms.

[0004] Protein kinases are enzymes that catalyze the phosphorylation of proteins, in particular, hydroxy groups on tyrosine, serine and threonine residues of proteins. The consequences of this seemingly simple activity are staggering; cell differentiation and proliferation; i. e. , virtually all aspects of cell life in one-way or another depend on protein kinase activity. 35 Furthermore, abnomial protein kinase activity has been related to a host of 1 WO 2005/030140 PCmJS2004/031523 2013204031 11 Apr 2013 disorders, ranging from relatively non-life threatening diseases such as psoriasis to extremely virulent diseases such as glioblastoma (brain cancer).

[0005] Protein kinases can be categorized as receptor type or non-receptor type. Receptor-type tyrosine kinases have an extracellular, a transmembrane, and an intracellular portion, while non-receptor type tyrosine kinases are wholly intracellular.

[0006] Receptor-type tyrosine kinases are comprised of a large number of transmembrane receptors with diverse biological activity. In fact, about 20 different subfamilies of receptor-type tyrosine kinases have been identified. One tyrosine kinase subfamily, designated the HER subfamily, is comprised of EGER (HBR1), HER2, HER3, and HHR4. Ligands of this subfamily of receptors identified so far include epithelial growth factor, TGF-alpha, amphiiegulin, BB-EGF, betacellulin and heregulin. Another subfamily of these receptor-type tyrosine kinases is the insulin subfamily, which includes INS-R, IGF-IR, and IR-R. The FDGF subfamily includes the PDGF-alpha and beta receptors, CSF3R, c-Kit and ELK-Π, Then there is the FLK family, which is comprised of the kinase insert domain receptor (KDR), fetal liver kinase-1 (FLK-1), fetal liver kinase-4 (FLK-4) and the . fins-like tyrosine kinase-l (fit-1). The FDGF and FLK families are usually considered together due to the similarities of the two groups. For a detailed discussion of the receptor-type tyrosine kinases, see Plowman et al., DN&P 7(6): 334-339,1994, which is hereby incorporated by reference.

[0007] The non-receptor type of tyrosine kinases is also comprised of numerous subfamilies, including Src, Frk, Btk, Csk, Abl, Zap70, Fes/Fps, Fak, Jak, Ack, and UMK. Each of these subfamilies is further sub-divided into varying receptors. For example, the Src subfamily is one of the largest and includes Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr, and Yrk. Ihe Src subfamily of enzymes has been linked to oncogenesis. For a more detailed discussion of the non-receptor type of tyrosine kinases, see Bolen, Oncogene, 8:2025-2031 (1993), which is hereby incorporated by reference.

[0008] Since protein kinases and their ligands play critical roles in various cellular activities, deregulation of protein kinase enzymatic activity can lead to altered cellular properties, such as uncontrolled cell growth associated with cancer. In addition 'to oncological Indications, altered kinase signaling is implicated in numerous other pathological diseases. These include, but are not limited to: immunological disorders, cardiovascular diseases, inflammatory diseases, and degenerative diseases. Therefore, 2 PCT/US2004/031523 2013204031 11 Apr 2013 WO 2005/030140 both receptor and non-receptor protein kinases are attractive targets for small molecule drug discovery.

[0009] One particularly attractive goal for therapeutic use of kinase modulation relates to oncological indications. For example, modulation of protein kinase activity for the treatment of cancer has been demonstrated successfully with the FDA approval of Gleevec® (imatmib mesylate, produced by Novartis Pharmaceutical Corporation of East Hanover, NJ) for the treatment of Chronic Myeloid Leukemia (CML) and gastrointestinal stroma cancers (GIST). Gleevec is a c-Kit and Abl kinase inhibitor.

[0010] Modulation (particularly inhibition) of cell proliferation and angiogenesis, two key cellular processes needed for tumor growth and survival (Matter A. Drug Disc Technol 20016,1005-1024), is an attractive goal for development of small-molecule drugs. Anti-angiogenic therapy represents a potentially important approach for the treatment cf solid tumors and other diseases associated with dysregulated vascularization, including ischemic coronary artery disease, diabetic retinopathy, psoriasis and rheumatoid arthritis. As well, cell antiproliferative agents are desirable to stow or stop the growth of tumors.

[0011] One particularly attractive target for small-molecule modulation, with respect to antiangiogenic and antiproliferative activity is c-Met. The kinase, c-Met, is the prototypic member of a subfamily of heterodimeric receptor tyrosine kinases (RTKs) which include Met, Ron and Sea. Expression of c-Met occurs in a wide variety of cell types including epithelial, endothelial and mesenchymal cells where activation of the receptor induces cell migration, invasion, proliferation and other biological activities associated with ‘invasive cell growth.” As such, signal transduction through c-Met receptor activation is responsible for many of the characteristics of tumor cells.

[0012] The endogenous ligand for c-Met is the hepatocyte growth factor (HGF), a potent inducer of angiogenisis, also known as “scatter factor” (SF). Binding of HGF to c-Met induces activation of the receptor via autophosphorylation resulting in an increase of receptor dependent signaling, which promotes cell growth and invasion. Anti-HGF antibodies or HGF antagonists have been shown to inhibit tumor metastasis in vivo (See: Maulik et al Cytokine & Growth Factor Reviews 2002 13,41-59).

[0013] Tumor growth progression requires the recruitment of new blood vessels into the tumor from preexisting vessels as well as invasion, adhesion and proliferation of malignant cells. Accordingly, c-Met overexpression has been demonstrated on a wide 3 PCT/US2004/031523 2013204031 11 Apr 2013 WO 2005/030140 variety of tumor types including breast, colon, renal, lung, squamous cell myeloid leukemia, hemangiomas, melanomas, astrocytomas, and glioblastomas. Additionally activating mutations in the kinase domain of c-Met have been identified in hereditary and sporadic renal papilloma and squamous cell carcinoma. (See: Maulik et al Cytokine & growth Factor reviews 2002 13, 41-59; Longati et al Curr Drug Targets 2001, 2, 41-55; Funakoshi et al Clinica Chimica Acta 2003 1-23). Thus modulation of c-Met is desirable as a means to treat cancer and cancer-related disease.

[0014] The Eph receptors comprise the largest family of receptor tyrosine kinases and are divided into two groups, EphA and EphB, based on their sequence homology. The ligands for the Eph receptors ate ephrin, which are membrane anchored. Ephrin A ligands bind preferentially to EphA receptors whilst ephrin B ligands bind to EphB receptors. Binding of ephrin to Eph receptors causes receptor autophosphorylation and typically requires a cell-cell interaction since both receptor and ligand are membrane bound.

[0015] Overexpression of Eph receptors has been linked to increased cell proliferation in a variety of tumors (Zhou R 1998 Pharmacol Ther. 77, 151-181; Kiyokawa E, Takai S, Tanaka M et al 1994 Cancer Res 54, 3645-3650; Takai N Miyazaki T, Fujisawa K, Nasu K and Miyakawa. 2001 Oncology reports 8, 567-573). The family of Eph receptor tyrosine kinases and their ephrin ligands play important roles in a variety of processes during embryonic development and also in pathological angiogenesis and potentially metastasis. Therefore modulation of Eph receptor kinase activity should provide means to treat or prevent disease states associated with abnormal cell proliferation such as those described above.

[0016] Inhibition of EGF, VEGF and ephrin signal transduction will prevent cell proliferation and angiogenesis, two key cellular processes needed for tumor growth and survival (Matter A. Drug Disc. Technol. 2001 6,1005-1024). EGF and VEGF receptors are previously described targets for small molecule inhibition. KDR and fit-4 are both i VEGF receptors [0017] One particularly attractive target for small-molecule modulation is c-Kit. The proto-oncogene c-Kit was first identified as the oncogenic component of the acutely transforming Hardy-Zuckerroan 4-feline sarcoma virus (Besmer et al Nature 1986 320:415-421). c-Kit (also called stem cell factor receptor or steel factor receptor) is a type 3 receptor tyrosine kinase (RTK) belonging to the platelet-derived growth factor receptor subfamily. c-Kit binds the ligand stem cell factor (SCF), and triggers its multiple signal 4 PCT/US2004/031523 2013204031 11 Apr 2013 WO 2005/030140 transduction pathways including Src family kinases, phosphatidyl-inositol 3 kinase, the Ras-Raf-Map kinase cascade, and phospholipase C (Broudy et al Blood 1999 94: 1979-1986; Lennartsson et al Oncogene 1999 18: 5546-5553 ; Tunokhina et al EMBO J 1998 17;6250-6262; Chian et al Blood 2001 98(5)1365-1373; Blnme-Jensen et al Curr Biol 1998 8:779-782; Kissel et al EMBO J 2000 19:1312-1326; Lennartsson et al. Oncogene 1999 18: 5546-5553; Sue et al Blood, 199892:1242-1149; Lev etal EMBO J1991 10:647-654). c-Kit is required for normal hematopoiesis, melanonogenesis, and gametogenesis. c-Kit is expressed in mast cells, immature myeloid cells, melanocytes, epithelial breast . cells and the interstitial cells of Cajal (ICC). In mast cells, it is required not only for the differentiation, maturation, chemotaxis, and haptotaxis but also for the promotion of survival and proliferation.

[0018] Mutations in c-Kit have been implicated in human disease. Mutations in the juxtamembrane domain am found in many human gastrointestinal stromal tumors, and mutations in the kinase domain are found in mastocytosis, germ cell tumors, acute-myeloid leukemia (AML), NK lymphoma, and other hematologic disorders (ffirota et al Science 1998 279:577-580; Singer et al J Clin Oncol 2002 203898-3905; Langley et al Proc Natl Aca Sci USA 1999: 1609-1614; Han et al Am J Pathol 1999 154:1643-1647; Beghini et al Blood 2000 95:726-727; Hongyo et al Cancer Res 2000 60:2345-2347). These mutations result in ligand-independent tyrosine kinase activity, autophosphorylation of c-Kit, uncontrolled cell proliferation, and stimulation of downstream signaling pathways. Overexpression of c-Kit and c-Kit ligand have also been described in other tumors including small-cell lung cancer, neuroblastomas, gynecological tumors, and colon carcinoma, which might result in autocrine or paracrine c-Kit activation.

[0019] The overexpression of c-Kit has also been implicated in the development of neoplasia associated with neurofibromatosis type 1 (NR). Mutations in the tumor suppressor gene NF1 lead to a deficiency in neurofibromin, a GTPase-activating protein for Ras. This deficiency results in abnormal proliferation of Schwann cells in the peripheral nervous system, and predisposes affected individuals to peripheral nerve sheath tumors (neurofibromas), astrocytomas (optic pathway gliomas), learning disabilities, seizures, strokes, macrocephaly, vascular abnormalities, and juvenile myelomonocytic leukemia (Lynch & Gutmann Neurol Clin 2002 20:841-865). Genetic experiments in mice demonstrate that haploinsuffiriency at NFJ partially rescues some of the phenotypes associated with mutations in the gene for c-Kit, indicating that these genes function along 5 WO 2005/030140 PCT/US2004/031523 2013204031 11 Apr 2013 a common developmental pathway (Ingram, et al J. Exp Med 2000 191:181-187). Also, c-Kit is expressed in schwannoma cells from NF1 patients, but not in normal schwann cells (Ryan et aL J Neurosci Res 1994 37:415-432). These data indicate that elevated c-Kit expression and sensitivity to stem cell factor may play important roles in the development of proliferative disorders associated with NF-1. Therefore, c-Kit inhibitors may be effective chemotherapeutic agents far treating patients with NF-1.

[0020] GISTs are the most common mesenchymal tumors of the gastrointestinal tract, and they are generally resistant to chemotherapy and radiation therapy. However, recent results with the c-Kit/BCR-Abl inhibitor STI571 indicate that targeting c-Kit may be an effective therapeutic strategy for this disease (Eisenberg & Mehren Expert Opm Pharmacother 2003 4:869-874). Malignant mast cell disease often suggests an extremely poor prognosis, and no reliable effective chemotherapeutic agents have been identified (Marone et al Leuk Res 2001 25:583-594). Systemic mast cell disorders have been treated with interferon-alpha, although the effectiveness of this therapy has been variable (Lehmann & Lammle Ann Hematol 1999 78:483-484; Butterfield Br J Dermatol 1998 138: 489-495). Therefore, activated c-Kit might serve as a therapeutic target in GISTs and mast cell disease, as well as other disorders associated with activated c-Kit [0021] Ht-3 is normally expressed on hematopoietic progenitor cells and a subset of mature myeloid and lymphoid cells, where it modulates cell survival and proliferation. Flt-3 is constitutively activated via mutation, either in the juxtamembrane region or in the activation loop of the kinase domain, in a large proportion of patients with AML (Reilly Leuk Lymphoma 2003 44: 1-7). Also, mutations in flt-3 are significantly correlated with poor prognosis in AML patients (Sawyers Cancer Cell 20021:413-415).

[0022] Accordingly, the identification of small-molecule compounds that specifically inhibit, regulate and/or modulate the signal transduction of kinases, particularly including c-Met, KDR, c-Kit, flt-3, and flt-4, is desirable as a means to treat or prevent disease states associated with abnormal cell proliferation and angiogenesis, and is an object of this invention.

[0023] Quinolines and quinazolines bearing substitution, for example at the two, four, six and seven positions of their fused ring system have been shown to be particularly attractive targets for kinase inhibition by a number of groups, Conventional quinoline and quinazoline kinase inhibitors typically have fairly simple substitution about the quinoline or quinazoline fused ten-membered ring system, but recently more complex molecules are 6 FCT/US2004/031523 2013204031 11 Apr 2013 WO 2005/030140 being disclosed. For example, we have previously disclosed, in U.S. provisional patent applications 60/506,181 and 60/535,377 which are both Incorporated by reference herein in their entirety for all purposes, that certain quinolines and quinazolines are particularly well suited as kinase modulators, more particularly inhibitors of for example c-Met, KDR, c-Kit, flt-3, and flt-4. These molecules in some cases are particularly complex and although they can be made via conventional methods, more efficient routes are desirable, especially in a pharmaceutical setting.

[0024] Conventional methods of making quinolines and quinazolines with the aforementioned substitution patterns usually involve linear construction of a quinoline or quinazoline template upon which relatively simple substitutions are appended. With the advent of more complex substitution about such quinolines and quinazolines (vide supra), for example side chains containing cyclic and bicyclic systems with multiple functional groups, conventional methods of synthesis become problematic due to the linear or serial reactions used. Indeed, as such molecules become more complex and the utility of such complex groups is realized, the quinoline and quinazoline ring system becomes more of a sub-structure than a main structure of such inhibitors. Thus it is desirable to find more efficient methods of synthesis, particularly convergent syntheses which axe an object of i this invention.

SUMMARY OF THE INVENTION

[0025] In one aspect, the present invention provides compounds for modulating kinase activity and methods of treating diseases mediated by kinase activity utilizing the compounds and pharmaceutical compositions thereof. Diseases mediated by kinase activity include, but are not limited to, diseases characterized in part by migration, invasion, proliferation and other biological activities associated with invasive cell growth. In particular to this invention is modulation, even more particularly inhibition, of c-Mjet, KDR, c-Kit, fit-3, and flt-4, [0026] In another aspect, the invention provides methods of screening for modulators of c-Met, KDR, c-Kit, flt-3, and flt-4 activity. ^ The methods comprise combining a composition of the invention, a kinase, e.g. c-Met, KDR, c-Kit, flt-3, or flt-4, and at least one candidate agent and determining the effect of the candidate agent on the c-Met, KDR, c-Kit, flt-3, or flt-4, activity.

[0027] In yet another aspect, the invention also provides pharmaceutical kite comprising one or more containers filled with one or mom of the ingredients of pharmaceutical % 7 2013204031 04 Oct 2016 H:\fmt\Interwoven\NRPortbl\DCC\FMT\l 1591967_l.docx-10/4/2016 compounds and/or compositions of the present invention, including, one or more kinase, e.g. c-Met, KDR, c-Kit, flt-3, or flt-4, enzyme activity modulators as described herein. Such kits can also include, for example, other compounds and/or compositions (e.g., diluents, permeation enhancers, lubricants, and the like), a device(s) for administering the compounds and/or compositions, and written instructions in a form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which instructions can also reflects approval by the agency of manufacture, use or sale for human administration.

[0028] In another aspect, the invention also provides a diagnostic agent comprising a compound of the invention and, optionally, pharmaceutically, acceptable adjuvants and excipients.

[0029] In still yet another aspect, the present invention provides processes for making compounds, and pharmaceutical compositions thereof, for modulating kinase activity and treating diseases mediated by kinase activity. In particular to this invention are methods for making quinolines and quinazolines used for modulation of kinase activity, even more particularly inhibition of kinase activity, and yet even more particularly inhibition of c-Met, KDR, c-Kit, flt-3, and flt-4.

[0029a] In a further aspect, the present invention provides a compound of Formula XXI:

XXI or a pharmaceutically acceptable salt, hydrate, or prodrug thereof, wherein, each R1 is independently selected from halogen, -OR3, -NO2, -NH2, -NR3R3, -D-R50 and optionally substituted Ci_6alkyl; w is an integer from 2 to 4; and at least one R1 is -D-R50 and at least one R1 is -OR3; wherein -D-R50 and -OR3 are interchangeably located at the 6-position and 7-position of the compound of Formula XXI; D is -O- 8 H:\fmt\Interwoven\NRPortbl\DCC\FMT\11591967_l.docx-l 0/4/2016 2013204031 04 Oct 2016 R70 is selected from -H, halogen, -OR3, -S(0)o-2R3, -NO2, -NH2, -NR3R3, and optionally substituted Ci^alkyl; J is =N- or =C(H)-; 5 10 15 20 Z is -0-; each R5 is independently selected from -H, optionally substituted Ci-6alkyl, optionally substituted aryl, and optionally substituted aryl Ci-6alkyl; Ar is para-phcnylene as defined by the substitution pattern of -Z- and -B-L-T about said phenylene; R2 is selected from -H, halogen, trihalomethyl, -CN, -NO2, -NH2, -OR3, -NR3R3, -S(O)0-2R3, -S02NR3R3, -C02R3, -C(0)NR3R3, -N(R3)S02R3, -N(R3)C(0)R3, -N(R3)C02R3, -C(0)R3, and optionally substituted Ci_6alkyl; each R3 is independently selected from -H, -Si(R5)(R5)R5, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted arylalkyl, and optionally substituted heteroarylalkyl; or two R , together with the nitrogen to which they are attached, form a four- to seven-membered heteroalicyclic, said four- to seven-membered heteroalicyclic optionally containing one additional heteroatom; when one said additional heteroatom is a nitrogen, then said nitrogen is optionally substituted with a group selected from -H, trihalomethyl, -S02R5, -S02NR5R5, -C02R5, -C(0)NR5R5, -C(0)R5, and optionally substituted lower alkyl; -B-L-T is either of formula XXV or formula XXVI,

25 30 9Π each R is independently selected from -H, halogen, trihalomethyl, -CN, -N02, -NH2, -OR3, -NR3R3, -S(0)o_2R3, -S02NR3R3, -C02R3, -C(0)NR3R3, -N(R3)S02R3, -N(R3)C(0)R3, -N(R3)C02R3, -C(0)R3, optionally substituted Ci-6alkyl, optionally substituted aryl, optionally substituted aryl Ci_6alkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclyl Ci_6alkyl; or two of R , together with the atom or atoms to which they are attached, combine to form an optionally substituted three- to seven-membered heteroalicyclic, said 8a 2013204031 04 Oct 2016 H:\fmt\Interwoven\NRPortbl\DCC\FMT\l 1591967_1 .docx-10/4/2016 optionally substituted three- to seven-membered heteroalicyclic either spiro- to, or fused to, the ring system to which it is attached; G is either an optionally substituted cycloalkyl or an optionally substituted heteroalicyclic; 5 each R30 is independently selected from halogen, trihalomethyl, -CN, -NO2, -NH2, -OR3, -NR3R3, -S(0)o-2R3, -S02NR3R3, -C02R3, -C(0)NR3R3, -N(R3)S02R3, -N(R3)C(0)R3, -N(R3)C02R3, -C(0)R3, and optionally substituted Ci-6alkyl; R13a and R13b are each independently selected from -H and optionally substituted Ci_6alkyl; 10 R50 is either R3, or according to formula XXIV;

XXIV wherein X1, X2, and optionally X3, represent the atoms of a saturated bridged ring 15 system, said saturated bridged ring system comprising up to four annular heteroatoms represented by any of X1, X2, and X3; wherein, each X1 is independently selected from -C(R6)R7-, -Ο-, -S(0)o-2-, and -NR8-; each X2 is independently an optionally substituted bridgehead methine or a bridgehead nitrogen; 20 each X3 is independently selected from -C(R6)R7-, -Ο-, -S(0)o-2-, and -NR8-; Y is either: an optionally substituted Ci^alkylene linker, between D and either 1) any annular atom of the saturated bridged ring system, except X when X is a bridgehead nitrogen, or 2) any heteroatom, represented by any of R or R ; provided there are at 25 least two carbon atoms between D and any annular heteroatom of the saturated bridged ring system or any heteroatom represented by any of R6 or R7; or Y is absent, when Y is absent, said saturated bridged ring system, is directly attached to D via an annular carbon of said saturated bridged ring system, unless D is -S02-, in which case said saturated bridged ring system, is directly attached to D via 30 an any annular atom of said saturated bridged ring system; m and p are each independently one to four; 8b 2013204031 04 Oct 2016 H:\fnU\lnterwoven\NRPortbl\DCC\FMT\l 1591967_1 .docx.-10/4/2016 n is zero to two, when n is zero, then there is a single bond between the two bridgehead X2’s; R6 and R7 are each independently selected from -H, halogen, trihalomethyl, -CN, -NH2, -N02, -OR3, -NR3R3, -S(0)o-2R3, -S02NR3R3, -C02R3, -C(0)NR3R3, 5 -N(R3)S02R3, -N(R3)C(0)R3, -NC02R3, -C(0)R3, optionally substituted Ci-6alkyl, optionally substituted aryl, optionally substituted aryl Ci-6alkyl, optionally substituted heterocyclyl, optionally substituted heterocyclyl Ci_6alkyl, and a bond to either Y or D; or R6 and R7, when taken together are oxo; or 10 R6 and R7, when taken together with a common carbon to which they are attached, form an optionally substituted three- to seven-membered spirocyclyl, said optionally substituted three- to seven-membered spirocyclyl optionally containing at least one additional annular heteroatom selected from N, O, S, and P; and R8 is selected from -R3, Y, -S02NR3R3, -C02R3, -C(0)NR3R3, -S02R3, and 15 -C(0)R3.

[0029b] In a still further aspect, the present invention provides a process for preparing a compound of Formula XXI

20 comprising reaction of a compound of Formula XXII, with a compound of Formula XXIII

(R

R 70

L'

T 25 wherein, each R1 is independently selected from halogen, -OR3, -N02, -NH2, -NR3R3, -D-R50 and optionally substituted Q^alkyl; 8c H:\fmt\Interwoven\NRPortbl\DCC\FMT\11591967_l.docx-l 0/4/2016 2013204031 04 Oct 2016 10 15 20 25 w is an integer from 2 to 4; and at least one R1 is -D-R50 and at least one R1 is -OR3; wherein -D-R50 and -OR3 are interchangeably located at the 6-position and 7-position of the compound of Formula XXII; D is -0-; R70 is selected from -H, halogen, -OR3, -S(0)o-2R3, -NO2, -NH2, -NR3R3, and optionally substituted Ci_6alkyl; J is =N- or =C(H)-; Z is either -O- or -NR5-; each R5 is independently selected from -H, optionally substituted Ci-6alkyl, optionally substituted aryl, and optionally substituted aryl Ci^alkyl; Ar is para-phcnylene as defined by the substitution pattern of -Z- and -B-L-T about said phenylene; R2 is selected from -H, halogen, trihalomethyl, -CN, -NO2, -NH2, -OR3, -NR3R3, -S(0)o-2R3, -S02NR3R3, -CO2R3, -C(0)NR3R3, -N(R3)S02R3, -N(R3)C(0)R3, -N(R3)C02R3, -C(0)R3, and optionally substituted Ci_6alkyl; each R3 is independently selected from -H, -Si(R5)(R5)R5, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted arylalkyl, and optionally substituted heteroarylalkyl; or two R3, together with the nitrogen to which they are attached, form a four- to seven-membered heteroalicyclic, said four- to seven-membered heteroalicyclic optionally containing one additional heteroatom; when one said additional heteroatom is a nitrogen, then said nitrogen is optionally substituted with a group selected from -H, trihalomethyl, -S02R5, -S02NR5R5, -C02R5, -C(0)NR5R5, -C(0)R5, and optionally substituted lower alkyl; -B-L-T is either of formula XXV,

O O XXV each R20 is independently selected from -H, halogen, trihalomethyl, -CN, -N02, -NH2, -OR3, -NR3R3, -S(0)q-2R3, -S02NR3R3, -C02R3, -C(0)NR3R3, 8d 2013204031 04 Oct 2016 H:\fmt\Interwoven\NRPortbl\DCC\FMT\l 1591967_1 .docx.-10/4/2016 -N(R3)S02R3, -N(R3)C(0)R3, -N(R3)C02R3, -C(0)R3, optionally substituted Ci_6alkyl, optionally substituted aryl, optionally substituted aryl Ci_6alkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclyl Ci-6alkyl; or 5 two of R20, together with the atom or atoms to which they are attached, combine to form an optionally substituted three- to seven-membered heteroalicyclic, said optionally substituted three- to seven-membered heteroalicyclic either spiro- to, or fused to, the ring system to which it is attached; G is either an optionally substituted cycloalkyl or an optionally substituted 10 heteroalicyclic; each R30 is independently selected from halogen, trihalomethyl, -CN, -N02, -NH2, -OR3, -NR3R3, -S(O)0-2R3, -S02NR3R3, -C02R3, -C(0)NR3R3, -N(R3)S02R3, -N(R3)C(0)R3, -N(R3)C02R3, -C(0)R3, and optionally substituted Ci-6alkyl; R13a and R13b are each independently selected from -H and optionally substituted 15 Ci_6alkyl; R50 is either R3, or according to formula XXIV;

x2 XXIV wherein X1, X2, and optionally X3, represent the atoms of a saturated bridged ring 20 system, said saturated bridged ring system comprising up to four annular heteroatoms represented by any of X , X , and X ; wherein, each X1 is independently selected from -C(R6)R7-, -Ο-, -S(0)o-2-, and -NR8-; each X2 is independently an optionally substituted bridgehead methine or a bridgehead nitrogen; 25 each X3 is independently selected from -C(R6)R7-, -Ο-, -S(0)o-2-, and -NR8-; Y is either: an optionally substituted Ciealkylenc linker, between D and either 1) any annular atom of the saturated bridged ring system, except X when X is a bridgehead nitrogen, or 2) any heteroatom, represented by any of R6 or R7; provided there are 30 at least two carbon atoms between D and any annular heteroatom of the saturated bridged ring system or any heteroatom represented by any of R6 or R7; 8e H:\fmt\Interwoven\NRPortbl\DCC\FMT\11591967_l.docx-l 0/4/2016 2013204031 04 Oct 2016 or Y is absent, when Y is absent, said saturated bridged ring system, is directly attached to D via an annular carbon of said saturated bridged ring system, unless D is -SO2-, in which case said saturated bridged ring system, is directly attached to D via an any annular atom of said saturated bridged ring system; 5 m and p are each independently one to four; n is zero to two, when n is zero, then there is a single bond between the two bridgehead X2’s; R6 and R7 are each independently selected from -H, halogen, trihalomethyl, -CN, -NH2, -NO2, -OR3, -NR3R3, -S(0)o-2R3, -S02NR3R3, -C02R3, -C(0)NR3R3, 10 -N(R3)S02R3, -N(R3)C(0)R3, -NCO2R3, -C(0)R3, optionally substituted

Ci_6alkyl, optionally substituted aryl, optionally substituted aryl Ci^alkyl, optionally substituted heterocyclyl, optionally substituted heterocyclyl Ci_6alkyl, and a bond to either Y or D; or R6 and R7, when taken together are oxo; or 15 R6 and R7, when taken together with a common carbon to which they are attached, form an optionally substituted three- to seven-membered spirocyclyl, said optionally substituted three- to seven-membered spirocyclyl optionally containing at least one additional annular heteroatom selected from N, O, S, and P; R8 is selected from -R3, Y, -S02NR3R3, -C02R3, -C(0)NR3R3, -S02R3, and 20 -C(0)R3; P1 is a suitable leaving group; and P2 is selected from -H, a metal, and a group removed in-situ when combining XXII and XXIII to make XXI.

[0029c] In a still further aspect, the present invention provides a process for preparing a 25 compound selected from Table 2.

[0030] These and other features and advantages of the present invention will be described in more detail below with reference to the associated drawings. DETAILED DESCRIPTION OF TITLE INVENTION 30 [0031] The compositions of the invention are used to treat diseases associated with abnormal and or unregulated cellular activities. Disease states which can be treated by the methods and compositions provided herein include, but are not limited to, cancer (further discussed below), immunological disorders such as rheumatoid arthritis, graft- 8f H:\fmt\Interwoven\NRPortbl\DCC\FMT\11591967_l.docx-l 0/4/2016 2013204031 04 Oct 2016 host diseases, multiple sclerosis, psoriasis; cardiovascular diseases such as artheroscrosis, myocardioinfarction, ischemia, stroke and restenosis; other inflammatory and degenerative diseases such as interbowel diseases, osteoarthritis, macular degeneration, diabetic retinopathy. 5 [0032] It is appreciated that in some cases the cells may not be in a hyper- or hypo- proliferative and/or migratory state (abnormal state) and still require treatment. For example, during wound healing, the cells may be proliferating "normally", but 8g 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523 proliferation and migration enhancement may be desired. Alternatively, reduction in "normal” cell proliferation and/or migration rate may be desired.

[0033] Thus, in one aspect the present invention comprises a compound for modulating kinase activity according to Formula I,

or a pharmaceutically acceptable salt, hydrate, or prodrug thereof, wherein, R1 is selected from -H, halogen, -OR3, -NO2, -NH& -NR3R4, and optionally substituted lower alkyl; A1 is selected from =N-, =C(H)-, and =C(CN)-; Z is selected from -S(0)o.2-, -Ο-, and -NR5-;

Ar is either a group of formula H, or of formula IH,

wherein, R2 is selected from -¾ halogen, trihalomethyl, -CN, -NO2, -NH& -OR3, -NR3R4, -S(0)o.2R3, -SOzNR^R3, -CO2R3, -CfOJNRV, -N^SOjR3, -N^QOJR3, -N(R3)C02R3, -C(0)R3, and optionally substituted lower alkyl; qis0to4; G is a group -B-L-T, wherein B is selected from absent, -N(R13)-, -N(S02R13)-, -Ο-, -S(0)o.2-, and -C(=0)-; . L is selected from absent, -C(=S)N(R13)-, -C(=NR14)N(R13)-, -SOaNfR13)-, -S02-, -C(=0)N(R13)-, -N(R13)-, -C(=0)C:.2aIkylN(R13)-, -N(R13)Ci.2alkylC(=0>, -C(=OX^.ialkylC(=0)N(R13)-, -Co^alkylene-, -C(=0)Co.iall£ylC(=0)OR3-, 9 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523 -C^NR^Co^aUtylC^O)-, -C(=0>, -C(=0)Co-ialkylC{=0)-, and an optionally substituted four to six-membered heterocyclyl containing between one and three annular heteroatoms including at least one nitrogen; and T is selected from -H, -R13, -Co^alkyl, -Co4alkylQ, -OCo^alkylQ, -CiMalkylOQ, -N(RI3)Co4alkylQ, -SOaCo^alkylQ, -C(=O)C04alkylQ, -Co4alkylN(R13)Q, and -C(=0)N(RI3)Co^alkylQ, wherein each of the aforementioned Co-4aIkyl is optionally substituted; J is selected from -S(0)o.2-. -Ο-, and -NR15-; R3is-HorR4; R4 is selected from optionally substituted lower alkyl, optionally substituted aryl, optionally substituted lower arylalkyl, optionally substituted heterocyclyl, and optionally substituted lower heterocyclylalkyl; or R3 and R4, when taken together with a common nitrogen to which they are attached, form an optionally substituted five- to seven-membered heterocyclyl, said optionally substituted five- to seven-msnibeied heterocyclyl optionally containing at least one additional annular heteroatom selected from N, O, S, and P; A2 and A3 are each independently selected from =N-, s=C(R2)-; R5 is -H or optionally substituted lower alkyl; D is selected from -Ο-, -S(O)0^-, and -NR15-; R50 is either R3, or according to formula IV;

IV wherein X1, X2, and optionally X3, represent the atoms of a saturated bridged ring system, said saturated bridged ring system comprising up to four annular heteroatoms represented by any of X1, X2, and X3; wherein, each X1 is independently selected from -CCR^R7-, -O·, -S(0)o.2-, and -NR8-; 10 PCT/US2004/031523 WO 2005/030140 each X2 is independently an optionally substituted bridgehead methine or a bridgehead nitrogen; each X3 is independently selected from -C(RS)R7-, -Ο-, -S(0)o.2-, and -NR8-; Y is either: an optionally substituted lower alkylene linker, between D and either 1) any annular atom of the saturated bridged ring system, except X2 when X2 is a bridgehead nitrogen, or 2) any heteroatam, represented by any of R6 or R7; provided there are at least two carbon atoms between D and any annular heteroatom of the saturated bridged ring system or any heteroatom represented by any of R6 or R7; or Y is absent, when Y is absent, said saturated bridged ring system, is directly attached to D via an annular carbon of said saturated bridged ring system, unless D is -SO2-, in which case said saturated bridged ring system, is directly attached to D via an any annular atom of said saturated bridged ring system; m and p are each independently 1-4; n is 0-2, when n=0, then there is a single bond between the two bridgehead X2’s; R5 and R7 are each independently selected from -H, halogen, trihalomethyl, -CN, -NH2, -NOa, -OR3, -NR^t4, -SiOJo-uR4, -SCbNR^4, -CO2R3, -C(0)NR3R4, -N(R3)SCfeR4, -NfR^C^R3, -NGQ2R3, -C(0)R3, optionally substituted tower alkyl, optionally substituted aryl, optimally substituted lower arylalkyl, optionally substituted heterocyclyl, optionally substituted tower heterocyclylalkyl, and a bond to either Y or D; or R6 andR7, when taken together are oxo; or R6 and R7, when taken together with a common carbon to which they are attached, form a optionally substituted three- to seven-membered spirocyclyl, said optionally substituted three- to seven-membered spirocyclyl optionally containing at least one additional annular ' heteroatom selected from N, O, S, andP; R8 is selected from-R3, Y, -SCytfRV, -CO2R4, -C(0)NR3R3, -SO^R4, and-C(0)R3; R13 is selected from -H, -C(=0)R3, -C(=0)OR3, -C(=0)SR3, -SO2R4, -C(=0)N(R3)R3, and optionally substituted lower alkyl, WO 2005/030140 PCT/US2004/031523 2013204031 11 Apr 2013 two R13, together with the atom or atoms to which they are attached, can combine to form a heteroalicyclic optionally substituted with between one and four of R60, said heteroalicyclic can have up to four annular heteroatoms, and said heteroalicyclic can have ’ an aryl or heteroaryl fused thereto, in which case said aryl or heteroaryl is optionally substituted with an additional one to four of R60; R14 is selected from -Η, -N02, -NH2, -N(R3)R4 -CN, -OR3, optionally substituted lower alkyl, optionally substituted heteroalicyclylalkyl, optionally substituted aryl, optionally substituted arylalkyl and optionally substituted heteroalicyclic; R15 is a group -MVM2, wherein M1 is selected from absent, -C(=S)N(R13)-, -C(=NR14)N(R13>, -SOaNCR13)-, -SOr, -C(=0)N(R13)-, -0(=0)0(=0^(¾13)^ -(V 4alkylene-, -C(=0)-, and an optionally substituted four to six-membered hetercyclyl annular containing betweenone and three heteratoms including at least one nitrogen; and M2 is selected from -H, -C^aikyl, alkoxy, -C(=0)QMalkylQ, -Co^alkylQ, -OCWalkylQ-, -N(R13)CiMalkylQ-, and -C(=0)N(R 13)Co-4alkylQ; and Q is a five- to ten-membered ring system, optionally substituted with between zero and four of R20; R20 is selected from -H, halogen, trihalomethyl, -CN, -NO2, -NHa, -OR3, -NR^t4, -S(0)o.2R3, -SOaNR3R3, -C02R3, -C(0)NR3R3, -N(R3)S02R3, -N(R3)C(0)R3, -N(R3)C02R3, -C(0)R3, and optionally substituted lower alkyl; R60 is selected from -H, halogen, frihalamelhyl, -CN, -NO2, -NH2, -OR3, -NR3R4, -S(0)o.2R3, -S02NR3R3, -COzR3, -C(0)NR3R3, -N(R3)SOaR3, -N(R3)C(0)R3, -N(R3)C02R3, -C(0)R3, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted heteroarylalkyl, and optiohally substituted arylalkyl; two of R60, when attached to a non-aromatic carbon, can be oxo; with the proviso, only when Ar is according to formula H, if Y is a Ci_g alkylene; Z is . -NH- or -N(CH3)-; R1 is a Ci^alkyl optionally substituted in the 2-position by -OH or a Ci. 4aIkoxy group; R2 is -H or halogen; n = 0; and the atoms, X1, of one bridge of the saturated bridged ring system, when combined with both bridgehead atoms, X2, of the saturated bridged ring system, represent; 1) either a pyrrolidine or a piperidine, and any atom, X1 or X2, of either of said pyrrolidine or said piperidine is attached to Y, then the other bridge of said saturated bridged ring system cannot be any one of -0C(0)CH2-, 12 WO 2005/030140 FCT/US2004/031523 2013204031 11 Apr 2013 -ch2oc(ok -oc(0)CH2CH2-, -ch2oc(0)ch2-, -ch2ch20C(o)-, OC(0)CEbNH-, -OC^CHaNfC^kyl)-, and -0C(0)CH20-; or 2) either a piperazine or a ^Ci^talkylJ-piperazine, and any atom, X1 or X2, of either of said piperazine or said 4-(Ci.4alkyl)-piperazine is attached to Y, then the other bridge of said saturated bridged ring system, only when attached via the 2- and the 3-position of either of said piperazine or said 4-(Ci ^alkylj-piperazine, cannot be one of -CH20C(0)CH2-, -CH2CH20C(0)-, and either of die two aforementioned bridges optionally substituted by one or two C].2alkyl groups; or 3) a piperazine, and any atom, X1 or X2, of said piperazine is attached to Y, then the other bridge of said saturated bridged ring system, only when attached via the 3- and die 4-position of said piperazine, cannot be one of -C(O)0CH2CH2-, -CH20C(O)CH2-, and either of the two aforementioned bridges optionally substituted by one or two Cj_2alkyl groups, and only when either of the two aforementioned bridges are attached to the 3-position of said piperazine via their left-hand end as depicted above; or 4) a 2-oxcmorpholine, said 2-oxpmatphoime attached to Y via its 4-position, then the other bridge of said saturated bridged ring system, only when attached via the 5- and the 6-position of said 2-oxomorpholine, cannot be one of -(CHaJg-, -CH2WCH2-, -CH2WCH2CHa-, and -CH2CH2WCH2-, wherein W is -Ο-, -S (0)0-2-. -JMH-, or -N(Ci4aJkyl)- wherein g is 2,3, or 4; and with the proviso that when Z is-Ο-, Ar is according to formula H, and the portion of G directly attached to Ar is selected from: Λ'ν 0 Λκ vYv νΎ8ν 0 aA γ-OLr ν'3'—V O' 13 WO 2005/030140 FCT/ES2004/031523

then R50 must be of formula IV; 2013204031 11 Apr 2013 and with the proviso that when Ar is phenylene or substituted phenylene, Z is -S(0)o.2- or -Ο-, then the portion of G directly attached to Ar cannot contain R70 R70 , when R70is selected from -¾ C^aUcyl, and Cj^alkoxyl.

[0034] In one example, the compound is according to paragraph [0033], wherein Z is either -O- or -NR5-.

[0035] In another example, the compound is according to paragraph [0034], wherein G is selected from the following: R1S R13 VR14 „13 r13 %«° i-f Q . o I ty" 0-3 .N. .N. Ur Hf o „13 r13 R13 R1S Ijt13 R13 x/NxV, O 0 R13 I , .0-4 ^ νχ O 0 r13 0 o „13 r13 o , R13 14 2013204031 11 Apr 2013

3 Ο w Mi u PCT/US2004/0315 WO 2005/030140 PCT/US2004/031523 • R13 1 / \<K2 _ 0 0 Ria Ria I I , *0-3 ^ yY** 0 n^or3 Λ^3 ° R1S r13 J / *0-2 1 R13 I / *0-2 O 0 2013204031 11 Apr 2013 wherein wherein Q, R20, and R13 ate as defined above; each E is selected from -0-, -N(R13)-, -CH2-, and -S(0)o.2-; M is selected from -Ο-, -N(R13)-, -CH2-, and -C(=OJN(R13)-; each V is independently either =N- or =C(H)-; each methylene in any of the above formulae is independently optionally substituted with R25; and R25 is selected from halogen, trihalomethyl, -CN, -N02, -NH2, -OR3, -NR3R4, -S(0)o-2R3, -SOjNR^, -C02R3, -CfOjNR^3, -NCR^SOaR3, -N(R3)C(0)R3, -N<R3)C02R3, -C(0)R3, optionally substituted aryl, optionally substituted arylalkyl, heteroarylalkyl, and optionally substituted lower alkyl; two of R25, together with the carbon or carbons to which they are attached, can combine to form a three- to seven-membered alicyclic or heteroalicycHc, two of R25 on a single carbon can be oxo.

[0036] Ια another example, the compound is according to paragraph [0035], wherein Ar is according to one of formula Ha, Hb, and Ilia.

[0037] In another example, the compound is according to paragraph [0036], wherein D is -O- and R1 is -OR3.

[0038] In another example, the compound is according to paragraph [0037], wherein -O-R50 and R1 are interchangeably located at the 6-position and 7-position of the quinazoline or quinoline according to formula I.

[0039] In another example, the compound is according to paragraph [0038], wherein R1 is -OH or -OQ-ealkyl. 16 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523 [0040] In another example, the compound is according to paragraph [0039], wherein A1 is =N- or =C(H)-.

[0041] In another example, the compound is according to paragraph [0040], wherein G is selected from: I R13 O O R13 R1s R13 1 1 / v0-3 ΛΎ” R13 R13 v'.VyYS 0 0 R13 i / \l-2 / \0-3 {R®°)o.4 Ft13 y? 11 0 0 I J R13 N jrf4 ^ II Q O 0 0 R13 R13 R13 J^E O O r13 rv? 0 Nnor3 wherein Q, R20, R13, E, and R60 are as defined above; each methylene in any of the above formulae, other than those in a depicted ring, is independently optionally substituted with R25; and R25 is selected from halogen, trihalomethyi, oxo, -CN, -NO2, -Nlfe, -OR3, -NR3R4, -SiO^zR3, -SOzNR3R3, -COzR3, -N(R3)S02R3, -N(R3)C(0)R3, -N(R3)C02R3, -C(0)R3, optionally substituted aryl, optionally substituted arylalkyl, heteroaryialkyl, and optionally substituted lower alkyl; two of R25, together with the carbon or carbons to which they are attached, can combine to form a three- to seven-membered alicyclic or beteroalicyclic.

[0042] In another example, the compound is according to paragraph [0041], wherein Q is selected from:

17 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523 wherein R20 is defined as above, and P is a five- to seven-membered ring, including die two shared carbons of the aromatic ring to which P is fused, P optionally containing between one and three heteroatoms.

[0043] In another example, the compound is according to paragraph [0042], wherein Ar is

wherein Q, R20, R13, E, and R60 are as defined above, and each methylene in any of the above formnlae, other lhan those in a depicted ring, is independently optionally substituted with R25; and R25 is selected from halogen, trihalomethyl, oxo, -CN, -NO2, -NH2, -OR3, -NR3R4, -S(0)o.2R3, -S02NR3R3, -CO2R3, -C(0)NR3R3, -NCR^SOaR3, -N(R3)C(0)R3, -N(R3)C02R3, -C(0)R3t optionally substituted aryl, optionally substituted arylalkyl, heteroarylalkyl, and optionally substituted lower alkyl; two of R25, together with the carbon or carbons to which they are attached, can combine to form a three- to seven-membered alicyclic or heteroalicyclic.

[0044] In another example, die compound is according to paragraph [0042], wherein Ar is according to formula 11b, and G is selected from*.

18

wherein Q, R20, R13, E, and R60 are as defined above» and each methylene in any of the above formulae, other than those depicted in a ring, is independently optionally substituted with R25; and R23 is selected from halogen, trihalomethyl, oxo, -CN, -NO2, -NKfe, -OR3, -NR3R4, -SiOVaR3, -SOaNR^3, -C02R3, -C(0)NR3R3, -N^SO^R3, -N(R3)C(0)R3, -N(R3)C02R3, -C(0)R3, optionally substitnted aryl, optionally substituted arylalkyl, heteroarylalkyl, and optionally substituted lower alkyl; two of R25, together with the carbon or carbons to which they are attached, can combine to .form a three- to seven-membered alicyclic or heteroalicycHc. 2013204031 11 Apr 2013 [0045] In another example, the compound is according to paragraph [0044], wherein the methylene between the two carbonyls of the depicted formulae is di-substituted with either optionally substituted lower alkyl, or an optionally substituted spirocycle.

[0046] In another example, the compound is according to either [0043] or paragraph [0044], wherein R50 is a heteroalicyKc or a Ci.<>alkyl-heteroalicyHc.

[0047] In another example, the compound is according to paragraph [0046], wherein at least one of R2 is halogen.

[0048] In another example, the compound is according to paragraph [0046], wherein R50 is according to formula IV.

[0049] In another example, the compound is according to paragraph [0048], wherein the saturated bridged ring system according to formula IV has a geometry selected from the group consisting of [4.4.0], [4.3.0], [4.2.0], [4.1.0], [3.3.0], [3.2.0], [3.1.0], [3.3.3], [3.3.2], [3.3.1], [3.2.2], [3.2.1], [2.2.2], and [22.1].

[0050] In another example, the compound is according to paragraph [0049], wherein Y is selected from -CH2CH2CH2CH2-, -CH2CH2CH2-, -CH2CH2-, -CH2-, and absent [0051] In another example, the compound is according to paragraph [0050], wherein n is 0 and the saturated bridged ring system according to formula IV has a geometry selected from the group consisting of [4.4.0], [4.3.0], [4.2.0], [4.1.0], [3.3.0], [3.2.0], and [3.1.0]. 19 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523 [0052] Ια another example, the compound is according to paragraph [0051], wherein said saturated bridged ring system contains at least one annular nitrogen or at least one annular oxygen.

[0053] In another example, the compound is according to paragraph [0052], wherein said saturated bridged ring system contains -NR8-, wherein R8 is selected from -H, optionally substituted lower alkyl, -CO2R3, -C(0)NR3R3, -SQ2R3, and-C(0)R3.

[0054] In another example, the compound is according to paragraph [0052], wherein said saturated bridged ring system is of formula V,

V wherein U1 is selected from -0-, -S(0)o.2-, -NR8-, -CR6R7-, and absent; and e is 0 or 1.

[0055] In another example, the compound is according to paragraph [0054], wherein Y is -0¾..

[0056] hi another example, the compound is according to paragraph [0055], wherein U1 is -NR8-, wherein R8 is selected from -H, optionally substituted lower alkyl, -C02R3, -0(0)101¾3. -SO2R3, and -C(0)R3.

[0057] In another example, the compound is according to paragraph [0055], wherein U1 is -0-, [0058] In another example, die compound is according to paragraph [0055], wherein U1 is absent.

[0059] In another example, the compound is according to paragraph [0052], wherein Y is selected from -CEbCHa-, -CH2-, and absent. 1 [0060] hi another example, the compound is according to paragraph [0059], wherein said saturated bridged ring system is of formula VI, R9·

R10 Rl1 20 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523

VI wherein R9, R10, and R11 are each independently selected from -H, and -OR12; or R9 is selected from -H, and -OR12, and R10 and Ru, when taken together, are either an optionally substituted alkylidene or an oxo; R12 is selected from -H, -C(0)R3, optionally substituted lower alkylidyne, optionally substituted lower arylalkylidyne, optionally substituted lower heterocyclylalkylidyne, optionally substituted lower alkylidene, optionally substituted lower alkylideneaiyl, optionally substituted lower alkylideneheterocyclyl, optionally substituted lower alkyl, optionally substituted lower alkylaryl, optionally substituted aryl, optionally substituted lower heterocyclylalkyl, and optionally substituted heterocyclyl; or two K12’s, when taken together, form 1) a corresponding spixocyclic ketal when said two Ru,s stem from R10 and R11, or 2) a corresponding cyclic ketal when said two R^’s stem from R9 and one of R10 and Rn, [0061] In another example, the compound is according to paragraph [0060], wherein one of R10 and R11 is -OR12, wherein R12 is selected from -H, -C(0)R3, and optionally substituted lower alkyl; and R9 and the other of R10 and R11 are both -H.

[0062] In another example, the compound is according to paragraph [0061], wherein Y is either -CHj- or absent, [0063] In another example, the compound is according to paragraph [0062], wherein R9 is an alkyl group containing at least one fluorine substitution thereon.

[0064] In another example, the compound is'according to paragraph [0053], wherein said saturated bridged ring system is of formula VII,

vn [0065] In another example, the compound is according to paragraph [0064], wherein Y is either -CH2- or absent [0066] In another example, the compound is according to paragraph [0065], wherein R8 is methyl or ethyl. 21 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523 [0067] la another example, the compound is according to paragraph [0053], wherein said saturated bridged ring system is of formula VDI,

R8—N

VIII

[0068] In another example, the compound is according to paragraph [0067], wherein Y is -CH2-.

[0069] In another example, the compound is according to paragraph [0068], wherein R8 is methyl or ethyl.

[0070] In another example, the compound is according to paragraph [0052], wherein said saturated bridged ring system is of formula IX

Ra

IX wherein U2 is selected from -0-, -S(0)o.2r, -NR8-, -CR6R7-, and absent.

[0071] In another example, the compound is according to paragraph [0070], wherein R3 of formula IX is selected from -Ή and optionally substituted alkyl.

[0072] In another example, the compound is according to paragraph [0071], wherein U2 is either -CR*R7- or absent [0073] In another example, the compound is according to paragraph [0072], wherein U2 is either -CEfe- or absent.

[0074} In another example, the compound is according to paragraph [0073], wherein Y is -CHZ-.

[0075] In another example, the compound is according to paragraph [0053], wherein said saturated bridged ring system is according to formula X. ·? 22 PCT/US2004/031523 2013204031 11 Apr 2013 WO 2005/030140

X

[0076] In another example, the compound is according to paragraph [0075], wherein RB is methyl or ethyl.

[0077] In another example, die compound is according to paragraph [0033], selected from Table 1.

Table 1

Entry Name Structure 1 N-[({3-fluoro-4-[(6-(methyloxy)-7-{ [(3aR,6aS> octahydrocyclopenta[c]pyrrol-5-ylmethyl]oxy)quinazdin-4-yl)oxy]phenyl}amino)carbono thioyl]-2-phenylacetamide όΑά,ιχο H r* 2 N-{[(3-flnoro-4-{[7-({[(3aR,6aS)-2-methylocJahydrocyclopenta[c] pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-yl]oxy}phenyl)amino]carbono thioylf-2-phenylacetamide f 3 N-{[(4-{[6,7-' bis(methylcxy)quino]in-4- yl]oxy}-3- Suorophenyl)(methyl)amino]c arbonothioyl}-2- phenylacetamide 4 l-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3- fluorophenyl)imidazolidin-2- one )=\ 0—^ V/Ί 5 H4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-3" (phenylmethyl)imidazolidin- 2-one 23 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523

Table 1 Entry l Name Structure 6 l-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-3- (phenylacetyl)iinidazolidin-2- one -R n_)=\ u Ό 7 ethyl [(4-{ [6,7-bis(methyloxy)qulnoIin-4-yl]oxy}-3- fhiorophenyl)ainmo] (oxo)aoet ate -0 A=\ °m° /0_^A>h ολ 8 N-{K4-{[6,7- bis(methyloxy)quinazolin-4- yl]ammo}-3- fluorophenyl)amino]carbonot hioyl} '2-phenylacetamide 9 N*-(4-{ [6,7- bis (methyloxy)quinolin-4-yl] oxy} -3 -fluorophenyl) -N-methyl-N-(2-phenylethyl)sulfamide U o 10 N-(4-{[6,7- bis(methyloxy)quinolin-4-yI]oxy} -3-fluorophenyl)-3-(phenylmethyl)-1,2,4-oxadiazol-5-amine H 11 l-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3- fluorophenyl)piperidin-2-one 24 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523

Table! Entry Name Structure 12 N-(4-{[6,7- bis(methyloxy)qumolin-4-yl]oxy }-3-flucKrophenyl>-Nl-(phenylmethyl)ethanedianiide \ /° 0-( \—NH HN—\ O 13 N-(4-{[6,7- bis(methyloxy)quinolin~4-yI]oxy}-3-fluorophfinyl)-4-phenyl- l,3“thiazol-2-aira.ne A) . H 14 N-(4-{[6,7- bis(raethyloxy)quinolin-4-yl]oxy }-3-fluQrophenyl)-N'-(2-phenyle1hyl)ethanediaiaide 15 N-(4-{[6,7- bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl>-1-phenylmethanesulfonamide -o, )=v 0-4 h—NH u M-M ^ 16 N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}“3-fluorophenyl)-2- phenylethanesulfonaimde W\ P“^~V-NH 0 ^ o 17 4-{[6,7- bis(methyloxy)quinolm-4- yl]Gxy}“3-fluoro-N- (phenylmethyl)benzenesulfon amide ** o 25 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523

Table 1 Entry Name Structure 18 4-((6,7- bis(methy]oxy)quinolin-4- yl]oxy}-3-fluoro-N-methyl-N" (phenylmethyl)benzenesulfon amide -<* }=\° γ~Ώ )== o—i ff—S—N N N—^ 19 4-((6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluoro-N-(2- phenylethyI)benzenesulfonam ide E /0K,°-Q-K b 20 4-((6,7- bis(methyloxy)quinoiin-4- yl]oxy}-3-fluoro-N-methyI-N- (2- pheny]ethyl)benzenesulfonam ide ;b-4>Kb N-y 21 4-((6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluoro~N-(3' phenylpropyl)benzenesulfona mide F. \=\ 0-( V-S-NH o 22 1-(4-( [6,7- bi s(methyloxy)quinolin-4-yI]oxy}-3- fluorophenyl)pyrrolidin-2-one F, 23 4-((6,7- bis(methy]oxy)quinolin-4- yl]oxy}phenyl (phenylmethyl)carbamate V- —o /=\ y-NH '=/ oJ=\P'\J~0 ^-Q 26 2013204031 11 Apr 2013

WO 2005/030140 PCT/US2004/031523 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523

Table! Entry Name Structure 30 N,N-(4-{[6,7~ bis(methyloxy)quinoliti'4-yl]oxy }-3-fluorophenyl)-bis-(3-phenyIpropane-l-sulfonamide) F\ °yP rtK x 7 °Tyb b 31 N-(4-{[6,7- bte(methyIoxy)quinolin-4-yl]oxy} -3-fluorophenyl)-3-phenylpropane-l-sulfonamide p rj~Q )=\ o-\"~vnh'° 32 N2-[(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3- fluorophanyl)sulfonyl]-Nl- phenylglycinamide ^-o 33 N-(6-{[6,7- bis(methyloxy)quinolin-4-yl]oxy }pyridin-3~yl)-2-pbenylacetamide H 34 N-{[(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}pyridin-3“ yl)amino]carbonothioyl} -2-phenylacetamide u'XXnXnXjO Η H 35 6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-l,3-benzothiazol-2- amine —Q /=( T /aa>n N—^ 28 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523

Table 1 Entry Name Structure 1 36 6-{[6,7- bis(methyloxy)quinolin-4-yl]oxy }-5-fluoro1,3-benzothiazol-2-amine o .YNH2 37 N-(6-{[6,7- bis(methyloxy)qwnolin-4-yl]oxy }-5-fluoro-l ,3-bertzothiazol-2-yl)-2-phenylacetamide -Q /=( X j u 38 N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluoropbenyl)-N'- (2-moipholin-4- ylethyl)ethanediamide F. Q 0 >=\ 0—6 !«Η HN—\ /—V μΖΗ 39 benzyl-{ [4-(6,17-diinethoxy-qumolin-4-yloxy)-3-fluoro-phenylcarbamoylj-methyl}-carbamic add tert-butyl ester o=( ZI ““C5 o /0-/Λ=ζ a \ 40 Nl“(4-{[6,7- ' bis(methyloxy)quinolin-4-yl]oxy}-3-fluocophenyl)-N2-(phenylmethyl)glyeinaimde A) iWmjuo H 41 N2-acetyl-N 1 -(4-{[6,7-bis(me1ilyloxy)quinoliπ-4“ yl]oxy}-3-fluarophenyl)-N2-(phenylmethyl)^ycinamide A) -SA F H 29 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523

Table 1 Entry Name Structure < 42 N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-l,3-benzothiazol-2- yl)-2-phenylacetamide _o jyV AtH0<>N U 43 benzyl-{ [6-(6,17-dimethoxy-quinolin-4-yloxy)-pyridin-3-ylcarbamoyl]-methyl} -carbamic acidtert-botyl ester ΐΓ&amp;χέο H 44 ' Nl-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy }pyridin-3-yl>-N2-(phenylmethyl)glycinaniide uriJUoQ H 45 N2-acetyl-Nl-(6-{ [6,7-bis(methyloxy)quiiK>lin-4-yl]oxy }pyridin-3-yl)-N2-(phenylmethyl)glycinamide Άχχ,ιΧΟ H 46 N-(6-{[6,7- bis(methyloxy)quino]in-4- yl]oxy}pyndin-3-yl)-3- phenylpropanamide V-, o-f V-NH O—N=/ 47 N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}pyridin-3-yl)-4- phenylbutanamide uTM___O H 30 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523

Table 1 Entry Name Structure 48 Nl-(6-{[6,7- bis(methy]oxy)qumolin-4- yl]oxy}pyridin-3-yl)-N2- metbyl-N2- (phenylmethyi)glycinainide ''"O WOguO H 49 N-(4-{[6,7- bis(methyloxy)quinoIin-4- yl]oxy}-3-fluorophenyl)-N'~ {2-[4- (methyloxy)phenyl]ethyl} etha nediamide K__0 o \=y 0—4 \—NH HN—v β—i\ Hh 50 Nl-(4-{[6,7- bis(xnethyloxy)quinolra-4- yl]oxy}-3-fluorophenyl)-N2- methyl-N2~ (pheny3methyl)glycinainide A) H 51 4-[(2-amino-l ,3-benzothiazol-6-yI)oxy]-6,7-bis(methyloxy)-l-(2-oxo-2- phenylethyljqmnolimuiii S^NH2 “O /=( T N+-^ 52 N-{ [(4-( [6,7-bis(methyloxy)quinolin-4-yl)aimno}phenyl)aimno]carbo nothioyl}-2-phenylacetamide A) jV^XUJO Η H 53 . N-(6-{[6,7- bis(methyloxy)quinolin-4-yl]oxy}-5-fluoro-l,3- ' benzothiazol-2-yl)-3 -phenylpropanamide N-/ 31 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523

Table 1 Entry Name Structure 54 N-{[(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-chloropyridin-3-yl)amino]carbQnothioyl }-2-phenylacetamide Η H 55 N-(4-{ [6,7- bis(methyloxy)qumolin-4-yl]oxy}-3-fluorophenyl)TN,“ (2,3-dihydro-lH-inden-1 -yl)ethanediamide W O—i jh-NH HN—( 1 /°Λ-Μ N—^ 56 N-(4-{[6,7- bis(methyloxy)quinolin-4-yl]oxy} -3-fluorophenyl)-N“ (2,3 -dihydro- lH-inden-2-yl)ethanediamide /^^ko 57 N-(4-{[6,7- bis(methyIoxy)quino]in-4-jd]oxy}-3-fl«orophenyl)-N'-(1,2,3,4-tetrahydronaphthalen-1 -yl)ethanediainide -, XV0 HN N-* 58 N'-(4-{[6,7- bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N-(2-phenylethyl)-N-(phenylmethyl)sulfamide F. p-i M w , 59 Nl-(4-{[6,7- bis(methyIoxy)qninoIin-4- yl]oxy}-3-fluorophenyl)-N2- (trifiuoroacetyl)glycinamide 0 F\ V/N vF A=\ 0—{ V-NH F F N-* 32 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523

Table 1 Entry Name Structure 60 N-{ [4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro~ phenylcarbanioylj-methyl}-benzamide Q 61 N-(6-{[6,7- bis(metfiyloxy)quinolin-4-yl]oxy}pyridm-3-yl)-N'-{4-fluorophenyl)propanedi amide s, Η , H 62 V N-(4-{[6,7- bis(methyloxy)quinolin-4-yl]oxy} -3-fluorophenyl)-N'-[(2S)-1,2,3,4-tetrahydronaphthalenr'2-yljetbanediamide )=\ p—ft —NH HN<"/ 63 N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-]Sr- [2-(4- methylphenyl)ethyl]ethanedia mide 64 N-(4-{[6,7- bis(methyloxy)quino]in-4- yl]oxy}-3-flutxophenyl)-lSr- (2- phenylpropyl)ethanediamide F\ °v P -q }=\ ^ o M/°-LrNH ηνλ_ 6 65 N-(4-{[6,7- bis(methyloxy)quinoUn-4-yl]oxy }-3-fiuorophenyl)-N'-[2-(4- chlorophenyl)ethyl]ethanedia mide 33' 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523

Table 1 Entry Name ----—-------— Structure 66 N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-NN'- bis(phenylmethyl)siilfamide A) cy 67 N-(4-{[6»7- bis(methyloxy)quinolin-4-yI]oxy} -3-fluorophen yl)-N,N'-bis(2-phenylethyl)sulfamide -ο K M / NH " <-0 68 ethyl [(6-((6,7-bis(methyloxy)qumoIin-4-yl]oxy}-5-chloropyridin-3-yl)amino](oxo)acetate -o, VW 69 N-(6-([6,7- bis(meth.yloxy)qumoiin-4- yl]oxy}-5-chlotopyridin-3- yl>N'-(2- phenylethyl)ethanediamide -o VVf )=\ Ρ~λ /~NH HN"~\ M_K N MU —\\ / Hr* 70 N-(6-{[6,7- bis(meihyloxy)quinolin-4- yl]oxy}-5-chloropyridin-3- yl)-N'-(4- : luorophenyl)propanediamide 71 N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-floorophenyl)-N'- (1,2,3,4-tetrahydronaphthalen- 2-yl)ethanediaroide )=\ oU~V-NH HN-/ N i 34 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523

Table 1 Entry Name Structure 72 N-(4-{[6,7- bis(methyloxy)quinolin-4-yl] oxy} -3-fluorophenyl)-ISr-[2-(l-methylpyrrolidin-2-yl)ethyl]ethanediamide -o. 3=\ °M° \ 0_h^P~YJ-m V-* 73 N-(4-{[6,7- bis(methyloxy)quinolin-4-yl]oxy} -3 -fluorophenyl)-N'-[2- (phenyloxy)ethyl]ethanediami do R ' 0 O -c, UH )=\ 0-\ ff—NH HN—II 74 N-(4-{[6,7- bis(methyloxy)quinolin-4-yl]oxy} -3-fluorophenyl)-N’-[2-hydroxy-1-(phehylmethyl)ethyl]urea '-o Η H 75 l-(4-{[6,7- bis(methyloxy)quinolin-4-yl] oxy} -3-fluorophenyl)-3-[(4-methylphenyl)sulftmyI]-4-(phenybnethyl)iimdazolidin-2-one Λ 76 N'-(4-{[6,7- bis(methyIoxy)quinoliii-4-yl] oxy) - 3-fluorophenyl)-N-methyl-N-(2- phenylethyljethanediamide R O, 0 —o )==\ 0—4 /)—NH N— 77 N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N'- {[3- (trifluoromethyl)phenyl]meth yljethanediamide -o. _K_°M° )=\ 0—4 #—NH HN”\ F F 35 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523

Table 1 Entry Name Structure 78 N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}“3-fluorophenyl)-N'- {2-13- (trifluoroinethyi)phenyl]ethyl }ethanediamide A, V<° hna__^ 79 N-(6-{[6,7- bis(methybxy)quinoIin-4~ yl]oxy}-5-chloropyridin-3- yl)-3-oxo~4- phenylbutanamide ci H 80 N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-chloropyridin-3- yl)-2-[3- (trifluoromethyl)phenyl]aceta mide "‘"Λ o? χχΑΛΑί Η / F 81 6-{[6,7- bis(methyloxy)quinolin-4-yl]oxy}-5-fluoro-N-[2-(phenyloxy)ethyl]-1,3-benzothiazol-2-arnine f Nr-* 82 6-{[6,7- bis(methyloxy)quino!in-4- yI]oxy}-5-fluoro-N-(2- piperidin-l-ylethyl)-l,3- benzothiazol-2-amiiie -ο -ΛΑη o-y 83 6-{[6,7- bis(methyloxy)quinolm-4-yl]oxy }-5-fluoro-N-methyl-N-(2-phenyletbyl> 1,3-benzothiazol-2-amine -o u 36 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523

Table 1 Entry Name - „ Structure 84 ’ 6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-fluoro-N-(2-pyrroIidin-l-ylethyl)-l,3-benzotMazol-2-amine -a 85 6-{[6,7- bis(methyloxy)quinolin.-4-yl]oxy}-5-fluoro-N-{ [3-(trifluoromethyl)phenyl]meth yl} -1,3 -benzothiazol-2-amine "S3 86 6-{t6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-fluoro-N-{2-[3- (ttifluoromethyl)phenyl]ethyl }-l,3-benzothiazol-2-amine o-4 )=( r c / / \ ψ F—j—F η-* ' F 87 N-(6-U6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-chloropyridin-3- yl)-N'-[3- (trifluoromethyl)phenyl]propa nediamide ΑλΛ ·» n Η H / F 88 N-(6-{[6,7- bis(methyloxy)quinoIin-4' yl]oxy }-5-fliioro-1,3-benzothiazol-2-yl)-2-[3-(trifluaroinethyl)phenyllaceta mide ,sY^y>° N-^ F--F F 89 Nl-(4-{[6,7“ bis{methyloxy)quinolin-4-yl] oxy} -3-fluorophenyl)-N2- {Ϊ3- (trifluoromethyl)phenyl]meth yljglycinamide 37 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523

Table 1 Entry Name Structure 90 Nl-(4-{[6,7- bis(methyioxy)quinolin-4- yI]oxy}-3-fluorophenyl).-N2- (2“phenylethyl)glycinamide r~Q E HN—' f=\ P-\ V~NH 91 Nl-(4-{ [6,7- bis(methyloxy)qurnolin-4-yl]oxy} -3-fluorophenyl)-N2-{2-[3- (trifluoromethyl)phenyl]ethyl }glycinamide _j-Q -q Jk )=\ Ρ"Λ ff HH F N—^ 92 benzyl-{ [5-chloro-6-(6,7“ dimethoxy-quinoHn-4-yloxy)-pyridin-3 -ylcarbamoyl]-mj3thyl}-carbamic acidtert-butyl ester "-Ο /0γ^ι ci XTixjXO H 93 Nl-(6-{[6,7- bis(methyloxy)quinolin-4-yl]oxy} -5-chloropyridiii-3-yl)-N2- (phenylmethyl)glycmaioide "-ο π | 94 N“(6-{[6,7- bis(methyloxy)quinolin-4-yl] oxy} -5-fluoro-l ,3-benzothiazol-2-yl)-2-[3,5-bis(trifluoromethyl)phenyl]ac etamide -a N“* F-jLF F 95 N-(6-{[6,7- bis(methyloxy)quinoIin-4-yl] oxy }-5-fluoro-l ,3-benzothiazol-2-yl)-2-[2-chloro-5- (trifluoromethyl)phenyl] aceta mide —o wVV * „ Jvy ip / F ci^ N—^ 38 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523

Table 1 Entry Name Structure 96 N-{3-fluoro-4-[(6-(methyloxy)-7-{[(l~ m6thylpiperidin-4-yl)methyl]oxy}quinoIin-4-yl)oxy]phenyl} -Ν'- (2-phenylethyl)ethanediaiaide -o 3=v3-<° &amp; 6 97 N-(4-{[6,7- bis(methyloxy)qumoIin-4-yI]oxy }-3-fluorophenyl)-N'-(1A3,4- tetrahydioisoqoinolin-1-ylmethyl)efhanediamide y/ NH HN-V /=\ ZP 98 N-(4-{[6,7- bis(methyloxy)qumolin-4-yl]oxy}-3-fluorophenyl)-N'-[(2-methyI-l,2,3,4-tetrahydroisoquinolin-1-yl)methyi] ethanediamide F. Q O -q )=\ y~( >=\ p—4 A-NH HN-\ /=\ 99 Nl-(4-{[6,7- bis(methyloxy)quinobn-4- ' yl]oxy} -3-fluorophenyl)-N2-methyl-N2-{ [3-(trifluoromethyl)phenyl]meth yl}glycinamide AijLUX: H F/F 100 Nl-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N2- methyl-N2-{2-[3- (trifluoromethy])phenyl]ethyl }glycinamide -V )=¾ p—&amp; β—NH ^ F N-/ 101 Nl-(4-{[6,7- bis(methyloxy)quinoBn-4-yl]oxy} -3-fiuorophenyl)-N2-methyl-N2-(2-phenylethyl)glycinamide \ R 0. N—' 39

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KJ u 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523 Table 1 Entry Name Structure 108 (2E>N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]°xy}phenyl)-2-[(methyIoxy)imino]propanami . de —°v /=\ y~( oh/^ ΝΛ 109 (2E)-N-(4-{[6,7- bis(methyloxy)quinolin“4- yl]oxy}phenyl)-2- [(ethyloxy)immo]propananiid e —°v /=\ y~i N—^ no (2E)-N-(4-{[6,7-bis(methylaxy)quinolin-4-yl]oxy}phenyl)-2-{[(phenylmethyl)oxy]imino}p ropanamide 111 N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}phenyl)-l- (pheny]methyl)pro]inaniide ""Ό 112 1-(4-((6,7- bis(methyloxy)quinolin-4-yl]oxy }phenyl)-3-[(4-methylphenyl)sulfonyl]-4-(phenylmethyl)imidazoIidin-2-one ^ 0 "XX 113 1-(4-( [6,7- bis(methyioxy)quinolin-4- yI]oxy}phenyl)-4- (phenylmethyl)imidazolidin- 2-one ;b_rG~pTO N-/ __ 41 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523

Table 1 Entry Name Structure 114 N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}phenyl)-4~ (phenylmethyl)-4,5-dihydro- l,3-oxazol-2-amine H 115 6,7-bis(meihyloxy)“4-( {4-[4-(phenylmethyl)piperazin-l-yl]phenyl}oxy)quinoline ^ ^ 0 1 0-O< \l—' N—^ 116 l-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}phenyl)“4- (phenylmethyl)piperazin-2“ one -Q ~ O O—i A—N N—f // 0 N—^ 117 Nl-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}phenyl)-N2- {phenylmethyl)alaninaniide -, /=\ \=v 0—^ a—NH HN—v 118 Nl-(4-{[6,7- bis(methyloxy)quinolin-4-yl]oxy}phenyI)“N2-methyl· N2- . (phenylmethyl)alamnarnide -v )s=v NH N— ^ O 119 Nl-(4-{[6,7- bis(methyloxy)quinolin-4-yljoxy} phenyl)-N2-(phenylmethyl)leucinamide —o\ /=\ y~( ^ 42 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523

Table 1 Entry Name -j-—----- Structure 120 Nl-(4-{[6/7- bis(methyloxy)quinoHn-4-yl]oxy }phen.yl)-N2-methyl-N2- (phenylmethyl)leucinaimde —q /=\ y~( ' O 121 Nl-(4-{[6,7- ' bis(methyloxy)quinolin-4-yl]oxy}phenyI)-N2-(phenylmethyl)valinainide -v /=\ vA 122 r 4-(6,7-diraethoxy-quinolin-4-ylamino)-N-(3-phenyl-propyl)-benzamide so h 0 123 4-benzyl-1-[4-(6,7-dimethoxy-quinolin-4-yloxy)-phenyI]-tetrahydro-pyrimidin-2-one -°yS iTj °T^1i 0 124 N- {3-Fluoro-4-[6-methoxy-7-(piperidln-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N'-phenethyl-oxalamide (SuAv H HNOQ 43 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523

Table 1 Entry Name Structure 125 2-(Benzyl-methyrammo)'N“ [4-(6j-dlmethoxy-quinolin-4- yloxyJ-phenyll-3-niethyI- butyramide (note: Alphabetic order of prefixes ignored while selecting parent chain) '°r\ VyVi o 126 N-[4-(6f7-Dimethoxy- quinolin-4-yloxy)-phenyl]“2- phenoxyimino-propionamide \ 1 12 A £_ 127 2-Benzyloxyhmno-N-[4-(6,7- dimethoxy-quinolm-4-yloxy)- phenyl]-2-phenyl-acetamide ‘1 '•O ^fS ^ 0 ' 128 4-[4-(4-Benzyl-piperidin-l- yl)-phenoxy]“6,7-diinethoxy- quinoline ifj °Υ!Ν| J ^OjO 129 N-[4-(6,7-Dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl] -N'-(2-isopropj4-1,2,3,4-tetrahydro-isoquinolin- l-ylmethyl)-oxalamide A) χτάχ» " Ηΐί gx 44 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523

Table 1 Entry Name Structure 130 N-[4-(6,7-Dimethoxy-qumoUn-4-yIoxy)-3-fluoro-phaiyl]-N'-(2-efiiyl-l,2,3,4-tetrahydro-isoquinolin-l-ylmethyl)-oxalamide OtAv 131 4-(4-{ 3Chloro-5-[2-(4-fluoro-phenylcarbamoyl)-acetylamino]-pyridin-2-yloxy }-6-methoxy-quinolin-7-yloxymethyO-piperidine-1-carboxylic acid tert-butyl ester so ^ " Λ F 132 N-{5-Chloro-6“[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-pyriditi“3-yl} -N-(4-fluQro-phenyl)-malonamide rAv, , o Η Η 1 Φ F 133 N- {5-Chloro-6'[6-methoxy-7-(l-methyl-piperidin-4-yImethoxy)-quinolin-4-yloxy]-pyridin-3-yl} -N-(4“ fluoro-phenyl)-malonamide r^'A, 01 v '0^ΝΧΛΝΗ | Η 1 Φ F 45 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523

Table 1 Entry Name Structure 134 N-{4-[7“(3-Diethylamino-propoxy)-6-niethoxy-quinolin-4-yloxy]-3-fluoro-phenyl }-N'-phenethyl· oxalamide rVS f S VrVS ° 1 " HI\L Or 135 N-{3-Fluoro-4“[6-methoxy-7' (3-moiphoUii-4-yl-propoxy)-quinolin-4-yloxy]-phenyl} -Ν'-phenethyl-oxalamide o h ί ' Or 136 N-{ 3-Huoro-4-[6-methoxy"7-(3-piperidin-l-yl-propoxy)-quinolin-4-yloxy]-phenyl}'N-phenethyl-oxalamide 2oA„v O * X or 137 N-{ 4- [7-(2-Diethylamino-ethoxy)-6-methoxy-quinolin-4-yloxy]-3-fiuoro-phenyI }-N'-phenethyl-oxalamide F k Tjl x*o H hA Or 46 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523

Table 1

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Table 1 Entry Name Structure 146 N-[5-Chloro-6-(6,7- dimethoxy-qumolin-4-yloxy)- pyndin-3-yI]-2,2-difluoro-N'- (4-fluoro-phenyl)-malonamide vO C! H F F 1 Φ F 147 N-Benzyl-N'- {3-fiuoro-4-[6-methoxy-7-(l-methyl-piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl }-oxalamide I H HN. 0 148 N- {3-Huoro-4-[6-methoxy-7-(piperidin-4-yimethoxy)-quinolin-4-yloxy] -phenyl} -N1-[2-(2-fluoro-phenyl)-ethyl]-oxalamide cSuVix» H “ Hll,S F Vi 149 L N-[2-(3-Chloro-phenyl)-ethyl]-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-qainolin-4-yloxy] “phenyl}-oxalamide 0°uAv H H hL 9 49 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523

Table 1 Entry Name Structure 150 N- {3-Huoro-4-[6-methoxy-7-(piperidin-4-ylxnethoxy)-quinolin-4-yloxy]“phenyl}-N’-[2-(2-methoxy-phenyl)-ethyl]-oxalamide c2oAv H . ” "-Ο 151 N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinoHn-4-yloxy]-phenyl}-N'- (2-pyridin-3-yl-ethyl)- oxalamide H H hi 152 N-Benzyl-N'-ί 3-fluoro-4-[6-methoxy-7-(piperidin-4-yJmethoxy)-quinolin-4-yloxy]-phenyl}-oxaIamide 15 H JL 0 153 N-[2“(2,5-Dimethoxy-phenyl)-ethyl]-N’“ {3-fl.uoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide H HN> --ο SO 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/D31523

Table 1 Entry Name Structure 154 N-{3-Fluoro-4-[6-methoxy-7-(piperidin-4-yhnethoxy)-qumoIin-4-yloxy]-phenyl}-N-[2-(2-trifluaromethyl-phenyl)-ethyl]-oxal amide iW. H H HISL u 155 N-[2-(2-Ethoxy-phenyl)-ethyl]“N'“ {3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quino!in-4' yloxy]-phenyl}-oxalamide H H hI j 156 N-[2-(2,4-Dimethyl-phenyl)-ethyi]-N'-{ 3-fluoro-4-[6-methoxy-7-(piperidin-4-y]methoxy)-quinolin-4-yloxy]-phenyl) -oxalamide (5uAv H H 1 XX 157 N- {3-Huoro-4-[6-methoxy-7-(piperidin-4'ylmethoxy)-quinolin-4~yloxy]-pheny] }-N-(15 -phenyl-2-p-tolyl-ethyl)“ oxalamide v n H B hA., XJ 51 2013204031 11 Apr 2013

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2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523

Table 1 Entry Name Structure 166 N-[2-(4-Ethyl-phenyl)-ethyl]-!ST-{ 3-fluoro-4-[6-methoxy-7-(piperidin-4-yImethoxy)-qninolin-4-yloxy)-phenyl }-oxalamide 'r^ArV A 167 N-[2-(4-Ethoxy-phenyl)-ethyl]-N'-{ 3-fluGro-4-[6-methoxy-7-(piperidin-4-ylme£haxy)-quinolin-4-yloxy]-phenyl}Oxalamide H H JL V0 168 N-[2-(4-Ethoxy-3-methoxy-phenyl)-ethyl]-N’-{ 3-fluoro4-[6-methoxy-7 -(piperidin-4-ylmethoxy)“quinoIin-4-yloxy]-phenyl} -oxalamide 6υΑ,ν H " HlV oc 54 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523

Table 1 Entry Name Structure , 169 N-{ 3 -Ftooro-4-[6 -methoxy-7 -(piperidin-4-ylmethoxy)-quinolm-4-yloxy]-phenyl }-N'-f2-(4-phenoxy-phenyl)-ethyl]-oxalamide V. m o H " ^NH 170 N~[2-(3-Ethoxy-4-methoxy- phenyl)-ethyl]-N'-{3~fhioro-4- [6-methoxy-7-(piperidin-4- ylmethoxy)-quinolm-4- yloxy]-phenyl}-oxalamide N. (5υάΝν H H ΗΪ ^ \x 1 171 N- {3-Huoro4-[6-methoxy~7-(piperidin-l-ylmethoxy)-quino]ia-4-yloxy]-phenyI }-N'-(2-pyridin-2-yl-ethyl)-oxalamide H H hI Ό 172 . N-{ 3-Huoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-ytoxy]-phenyl }-N'-(2-pyridin-4-yl-ethyl)-oxalaraide Vi .. . _ 55 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523

Table X Entry Name Structure 173 N-{3-Huoro-4-[6-methoxy-7 -(piperidin-4-yImethoxy)-quinoliQ-4-yloxy]-phenyl }-N'-[2-(4-fluoro-phenyl)-ethyl]-oxalamide γΑλΛ ° H " Ηΐί \x 174 N“[2-(2-Bromo-phenyl)-eihyl]~N'-{3-fluoro-4-[6-methoxy-7-(piperidm-4-yhnethoxy)-quinolin-4-yloxy]-phenyl }-oxalamide Λ ° sP1 N~^ H Br Yl 175 N-[2“C2-Chloro-6-fluoro-phenyl)-eihyl]-N,-{3-fluoro-4-[6-methoxy-7-(piperidin“4-ylmethoxy)-guinoIin-4-yloxy]-phenyl} -oxalamide A) 6υά,ν Cl > 176 N- {3“Fluoro-4-[6-methoxy“7-(piperidin-4-yhnethoxy)-quinolin-4-yloxy]-phenyl }-N'-(2#-phenyl-propyl)-oxalamide 6 uAv H H HfL 'U 56 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523

Table! Entry Name Structure 177 N- {3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl }-N'-indan- 1-yl-oxalamide ''Ο 6 H H "q 178 N-{ 3-Huoro-4-[6-methoxy-7-(l-methyl-piperidin-^ yimethoxy>quinoIin-4-yloxy]-phenyl}-N’-isobutyl-oxalandde Ύ 1 H hA /\ 179 N-{ 3-Huoro-4“[6-methoxy-7-(l-methyl-piperidin-4-ylmethoxy)-quinoliii-4-yloxy]-phenyl}-N'-(3-methyl-butyl)-oxalamide c5uAv 1 H ΗΝΓ Y >—4 oo o N-{3-Fluoro-4-[6-methoxy-7-(1 -methyl-piperidin-4“ ylmethoxy)-quinolin-4-yloxy]-phenyl}-N'-(2/f-phenyl-propyl)-oxalaimde χίνΛ · v χγ 1 h ηΛ 57 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523

Table 1 Entry Name Structure 181 N-{3-Fluoro-4-[6-methoxy-7-(1 -methyl-piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl} -ISP-(2-phenyl-prppyl)-oxalamide i k hL 182 N-{3-Fluoro*4-[6-methoxy-7- (l-methyl-piperidin-4- yImethoxy)-quinolin-4- yloxy]-phenyl}-N,-indan-2-yl“ oxalamide 0mv 1 &amp; 183 i N-{3“Ruoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-qmnolin-4-yloxy]-phenyl} -N1-(li?-phenyl-eihyl)-oxalamide 0*^ '0-Nxfi° ✓s. h h rtUU 184 N-{3-Huoro-4-[6-methoxy-7-(piperidm-4-ylmethoxy> quinolin-4“yloxy]“phenyl}-N'-(1 S-phenyl-ethyl) -oxalamide "o r°-A F Cj nj I V ^ΛνΛ^Ο ^ H H ' ~ 58 2013204031 11 Apr 2013

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Table 1 Entry Name Structure 199 N- {3“Huoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]“phenyl}-N’-[2-(4-suIfamoyl-phenyl)-ethylJ-Qxalaniide H » Ah Λ 200 N- {3-Huoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl} -N'-[2-(4-hydroxy-3 -methoxy-phenyl)-ethyl]-oxalamide c5xxAv H H Ah HCT^ 201 N- {3-Huoro-4- [6-inethoxy-7 -(pipeiidin-4-ylmethoxy)-quino]in-4-yloxy] -phenyl} -N'-[2-(3-hydroxy-4-methoxy-phenyl)-ethyl]-oxalamide c2uAv H H Ah Cu 63 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523

Table 1 Entry Name Structure 202 N-(2,4-Dichloro-benzyl)-N'- {3-fluoro-4-[6-methoxy-7- (piperidm-4-ybxietlioxy)- quinoJiti-4-yloxy]-phenyl}“ oxalamide X^Wl ° H μ c,p ct 203 N- f 3-Fluoro-4- [6-methoxy-7-(pipeiidin-4-ylmeihoxy)-quinolin-4-yloxy] -phenyl} -N-(4-fluoro-2-trifluoramethyl-benzyl)Oxal amide V. c5uAv H c H F 204 N- {3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl }-N-(l-p-tolyl-ethyl)-oxalamide 64 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523

Table 1 Entry Name Structure 205 N-{3-Huoro-4~[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl J-N1-(3-fluoro-4-trifluoromethyl-benzyl)-oxalamide " H MH Λ* cf3 206 N-(3-Chloro4-fluoro-benzyl)-N,-{3-flUQrD-4-[6-methaxy-7-(pipeiidin-4-ylmethoxy)-quinolln-4-yIoxy]-phenyi }-oxalamide H B Ih J? F 207 N-{3-Huoro-4“[6-methoxy-7- {piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-N'- [l“(3-methoxy-phenyl)-ethyl]- oxalamide 1 cimAv H " ΜΗ -jb 65 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523

Table 1 Entry Name Structure 208 N- {3-Fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl} -N-(l-naphthalen-2-yl-ethyl)-oxalamide 209 N-(4-Chloro-3-trifluoromethyl-benzyl)'N'-{3-fluoro-4-[6-methoxy-7 -(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl }-oxalamide Cl 210 N- {3-Huoro-4-[6-inethoxy-7“ (piperidin-4-ylmethoxy)-quinolin-4-yloxyJ-phenyl }-N-(l-p-tolyl-ethyl)Oxalainide H " nh "II, 9 66 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523

Table 1

67 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523

Table 1 Entry Name Structure , 214 N- {3-Huoro-4-[6-methoxy-7-(piperidm-4-ylmethoxy)-quinolin-4-yloxy]-phenyl} -NL (4-fluoro-3-trifluoromethyl-benzyl)-oxalaroide 6x?Av • « H L· ,Λ> F 215 N“(3,5-Dichloro-benzy])-N'“ {3-fluoro-4- [6-methoxy-7-(piperidin-4-ybnethoxy)-quinolin-4-yloxy]-phenyl} -oxalamide "Ό A, 216 N-{ 3-Fluoro-4-[6-methoxy-7 -(piperidin-4-ylmethoxy)-quinolin4-yloxy]-phenyl}'N'-(lR,2,3,4-tetrahydrO“ naphthalen- l-yl)-oxalamide u 217 N- {3 -Fluoro-4- [6-methoxy-7 -(piperidin-4-ylmethoxy)-quinoIin-4-yloxy]-phenyl} -N-(18,2,3,4-tetrahydro-naphthalen-l-yl)-oxalainide "ό 68 2013204031 11 Apr 2013

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Table 1 Entry Name Structure 222 N-(4-Fluoro-benzyl)-N'- {3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide F 223 N-^S'Difluoro-benzyO-N-{3-fluoro-4~[6-methoxy~7 -(piperidin-4-yImethoxy)-quinolin-4-ybxy]-phenyl}-oxalamide H h Ah X· 224 N- {3“Fluoro-4-[6-meth.oxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl} -N1-(2-phenoxy-ethyl)-oxalamide <$Wxx. a/” 225 N-(2,2-Diphenyl-ethyl)-N'-{3-fluoro-4-[6-methoxy-7-(piperidm-4-ylmethoxy)-quinolin-4-yIoxy]-phenyl} -oxalamide ""Ο cSuAx H H Ah 70 8 VO to £ to Ϊ3 to Entry S ’g-'g ? J g l-'g-s £* 1 5 p* /k ? itS'E ^ s ^ *< w i 2 a w C. v> ο O > CT a V $3 o\^ V *>*<5 A *7* ώ Α.“ B nb 0 W Λ) S ώ* a-4^(31¾ 1 r f i g [ 8 1¾ &amp;s|3* M sj r-*"* m -¾ o i u> 3 Tlf #g g. g. g. i ·# |l?fl Vt * UgUv fT tai tin s S a 3 SB 9 S f'f Sa-I·® o’g.l | X σ gi §. |S4l 1¾1 -v st^* ? g §: w 11 a ί s is ί f-U 1 ^Lv; vs ri, a. g* v g* ov &amp;tt!l • lit! Sz ’ 3 t 1 1 ϊ 1 q,^ >—\ )=° Vi W /5 b O ”CK CP q Ό-\ ζ=ζ~\-ο hP" '—v )=o Structure s? s ¢5 2013204031 11 Apr 2013 cn s hd n 1 © ©

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Table! Entry Name Structure 230 N-{ 3-Huoro-4-[6-methoxy-7-(piperidin-4-yknethoxy)-qmnoIin~4-yloxy]-phenyl }-N'-(3-fluoro-5-trifluoromethyl-benzyl)-oxalamide ""0 A, 231 N-(3,5-Difluoro-benzyl)-N'-{3-fluoro-4-[6-methoxy'7-(piperidm-4-ylmethoxy)-quinoIin-4-yloxy]-phenyl} -oxalamide *"O cSVAji.v H u L Λ 232 N-(2-Chlom-5-trifluoromethyl-benzyl)-NL {3-fluoro-4-[6-methoxy-7-(piperidm-4-ylmethoxy)-quinolin-4-yloxy]-phenyl} -oxalamide ""Ό Jr 233 N-[4-(6,7-Diinethoxy- quinolin-4-yloxy)-3-fluoro- phenyl]-N'-(2-dimethylaiiiino- 2-phenyl-ethyl)-oxalamide H L onr 72 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523

Tablet Entry Name Structure 234 N- {3-Fluoro-4- [6-methoxy-7-(piperidin-4-ylmethoxy)-quinolm-4-yloxy]-phenyl}-N'-(4-methoxy-benzyl)-oxalamide 235 1 N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-N'- (4-trifluoromethyI-benzyl)- oxalamide Φ AiV $ cf3 236 N-{ 3-Fluoro-4-[6-methoxy-7 -(piperidin-4-ylmethoxy)-qumolin-4-yloxy]-phenyl}-N’-(3-methoxy-benzyl)-oxalamide =Γ}^ , 0-- O 73 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523

Table X Entry Name Structure 237 N- {3-Huoro-4-[6-niethoxy-7-(piperidin-4-ylmethoxy)-quinolin-4“yloxy]-phenyl }-N'-(3-trifluoromethyl-’benzyl)-oxalamide ώΑΑν H " -NH 238 N-{ 3-Huoro-4-[6-methoxy-7 -(piperidin-4~ylmethoxy)~ quinolin-4-yloxy]-phenyl} -Ν'-(3-trifluoromethoxy-benzyl)-oxalamide " H Ah 239 N-{3-Fluoro-4-[6-methoxy-7’ (piperidin-4-ylmethoxy)- quinolin-4-yloxy]“phenyl}-N'- (2-methoxy-benzyl)- oxalamide "'•o ίχτό-Λ» H H -NH 240 N-{ 3“Huoro-4-[6-methoxy-7-(piperidin-4-yImethoxy)' quinolin-4-yloxy]-phenyl} -N'-(2-tofluoromethyl-benzyl)-oxalamide ό νά,ν H U L u 74 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523 I Table 1 Entry Name Structure 241 N-(3-Chloro-benzyl)-N' {3-• fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinoIin-4-yloxy]-phenyl}-oxalamide U H i H J) 242 N-{ 3-Fluoio-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-ylaxy]-phenyl }-N'-(2-trifluoron3jBthoxy-benzyl)“ oxal amide ' ^X) 1 N-(2-Chlaro-benzyl>N,-{3-fluoro-4- [6“methoxy-7- ""ο ό 'ύ'υ^γ0 H H Ah Ύ) 243 . (piperidin-4-yImethoxy)-quinolin-4-yloxy]-phenyl }-oxalamide 75 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/0315Z3

Table 1 Entry Name Structure 244 N-{ 3-Huaro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinoliii“4-yloxy3-phenyl}-N'-(4-trifluoromethoxy-benzyl)-oxalamide "Ό Φ f3ct0 245 N-{3-Huoro-4-[6-methoxy-7“ (l-methyl-piperidin-4-ylmethoxy)-quinolin-4-yloxyj-phenyl} -N'-(4-methoxy-benzyl)~oxalarnide t H .NH Φ 246 N-{3-Huoro-4-[6-methoxy-7“ (1 -methyl-piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N'-(4-trifluoromethyl-benzyl)-oxalamide χίνΛ . v i > Jh Φ cf3 76 2013204031 11 Apr 2013 3pIUIBnO|Bni-(tXU9t[d

N-{3-Huoro-4-[6-methoxy-7- (pipeddin-4-ylmethoxy)-

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2013204031 11 Apr 2013 WO 2005/030140 FCT/US2004/031523

Table 1 Entry Name Structure 251 N-[5-ChIoio-6-(6,7- dimethoxy-quinolin-4-yloxy)- pyridin-3-yl]-N'-(4-fluoro- phfinyl)-N'-methyl- malonamide /0s|M 01 utxx —N^o . Ψ F 252 N-{3-FluorO'4-[6-methoxy“7-(piperidin-4- ylmethoxy)-quinolin-4-yloxy] -phenyl }-N'-(lR-phenyl-propyl> oxalamide H H .NH b 253 N- {3-Fluoro-4- [6-meth.ox.y-7-(piperidin-4-ylmethoxy)-qwnolin-4-yloxy]-phenyl }-N'-(lR-phenyl-propyl)-oxalamide /tUt^ O 78 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523

Table 1 Entry Name Structure 254 N-(3,4-Difluoro-benzyl)-N'-{3-fluoro-4“[6-methoxy-7“ (piperidm-4-yIrnethoxy)-quinolin-4-yloxy]-phenyl }-oxalamide "Ό £ F 255 N-(2,6“Difluoro-benzyl)-N’-{3“fluoio-4-[6“inethoxy-7-(piperidin-4-yImethoxy)-quinolin-4-yloxyJ-phenyl}-oxalamide cinVAv H H Ih u' 256 N-{3-FJuoro-4-[6-methoxy-7-(l-methyl-piperidm-4-yImethoxy)-quinolin-4-yloxy]-phenyl }-N’-[2-(4-fluoro-phenyl)-ethyI> oxalamide * " .NH X> 257 N- {3-Fluoro-4-[6-methoxy-7 -(l-methyl-piperidin-4-ylmethoxy)-quino]in-4-yloxy]-phenyl }-N’-phenyl- ' oxalamide "Ό 1 σ" 79 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523

Table 1 Entry Name Structure 258 N-{ 3-Huoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl }-N-(3-fluoro-phenyl)-oxalamide rv™ H L 259 N-(4-Chloro“3-fluoro-phenyl)-N“ {3-fluoro-4-[6-methoxy-7 -(jpipeiidm-4-ylmethoxy)-quinolm-4-yloxyj-phenyl }-oxalamide o υ-~γ} c 1 o O— MY* 260 N-(3,4“Dimetboxy-phenyl)-N'-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl }-oxalamide ""Ό όσΑ/ν H Η 1 Ccr 261 N-{3-HuorO-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy] -phenyl }-N'-(3-methyl-butyl)-oxalamide " H .NH Y 80 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523

Table! Entry Name Structure 262 N-(3,3-Dimethyl-butyl)-N'-{3-fluoro-4- [6-metiioxy-7-(pipefldin-4-ylmethoxy)-quinolin-4-yIoxy]-phenyI }-oxalamide “^0 όνΑν H fl L V 263 N- {5-Chloro-6-[6-methoxy-7 -(3-piperidin-l-yl-propoxy)-quinolin-4-yloxy] -pyridiii’3-yl}-N'-(4-fluorO“pheaiyl)-malonamide ""0 i lyVji j? ΝαΛ Φ F 264 N- {3-Chloro-6-[6-methoxy-7“ (3-morpholin-4-yl-propoxy> quinoliri-4-yloxy]-pyridin-3-yl}-N'-(4-fhioro-phenyl)-malonamide _ r°YS a i «j°ySi j? XT HN^O ' Φ F 81 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523

Table 1 Entry Name Structure 265 N-{ 5-Chloro-6-[7-(3-diethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-pyridin-3-yl}-N'-(4-ftuoro-phenyl)-maIonatmde HN<X> □ F 266 N-(4-Ghloro-benzyl)-N'- {3-fluoro-4-[6“niethoxy-7“ (piperidm-4-y]methoxy)-quinolin-4-yloxyJ-phenyl} -oxal amide Ur^6-rtjo C! 267 _ N-(3,5'Diraethoxy-benzyl)-N'-{ 3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide H H L νά?. 82 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523

Table 1 Entry Name Structure 268 N-(4-ButyI-benzyl)-N - {3-fluora-4~[6-methoxy-7“ (piperidm-4-yIraethoxy)-quinolin-4-yloxy] -phenyl} -oxalamide ^o 269 N- {3-Huoio-4- [6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl }-N-(2-p-tolyl-ethyl)-oxalanide H H NH JJ 270 N-(3,5-Bis-trifluoromethyl-benzyl)-N'-{ 3-fluoio4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-y!oxy]-phenyl }-oxalamide "Ό H H L FgC^^CFg j 83 2013204031 11 Apr 2013

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WO 2005/030140 PCT/US2004/031523 2013204031 11 Apr 2013 οα 0\ --—---- to CO S3 to 00 i—* S3 00 0 Si $? Entry ^ £ O *-S ' ,¾ B* o l*> V 0¾ ·τΐ U&amp;o &amp; 0 5Γ Ο Ό 0 O S g x 0 g s I. !z; 5-(=1¾'σί β·| 11 8 |l £ * ' μΕί 5¾ gw g οχ &amp;ES Ι^ΙΓαΙ 8*3* ϊ $£? Φ· § g <3 i, s “ * w t i lew f* K^a lL· »ΐ B. I a Bits B 3· ,3 v: Λ. E- 2 ‘τ' ft* o\ 8-¾1¾. 16 iSg·^ #s&amp;a ^3½ ΐ I 1 β!λ? (a 0 ft-σ' C tr!W (L s § ? ag <S Λ. Τ' &amp; S 5 ϊ"ώ ? 8 6 &amp; a f f x fti v: *<1 —1 tgST£ ill&amp;l 8-1¾ a £ i A Oj 1" 1 Name I __/ KZA, 0\ o> /=( / /1=\ / ^J3 r^N ΐ 0. Z=/ λ—O \_r~^ W Z Λ O _/ /Λ-π o / 0 / Pi B fA r-' O * 0-^ . p- !i 12' '—\ V=o 3 Λ ^=0 0 "“0^3=° i-<0 )-' z—/ « l_ (D J-i

I WO 2005/030140 PCT/US2004/031523 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523

Table 1 Entry Name Structure 283 N-[2-(4-Amino-phenyl)-ethyl]-N’-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylrQethoxy)-quinolin-4“ yloxy]-phenyl }-oxalamide JO7 284 2-(4-Benzyl-piperidin-l -yl)~ N-{3-fluoro-4-[6-methoxy-7' (pipeiidin-4-ylmethoxy)-quinoIin-4-yloxy]-phenyl}-2-oxo-acetamide ""0 . 285 N-[4-(6J7-Dimethoxy- quinolin-4-yloxy)~phenyI]-N'- (4'fluoro-phenyl)-malonamide 'Yrax Φ F 87 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523

Table 1 Entry Name Structure 286 N-[5-ChIoro-6-(6,7-dimetiioxy-quinolm-4-yloxy)-pyridin-3 -yI]-N'-(3 -fluoro phenyl)-malonamide i 1 o °-0 * o \ 287 N-[5-Chloro-6-(6,7-dimethoxy-quinolin-4-yloxy)-pyridin-3-yl]-N'-phenyl·· i malonamide 1 o ^Z—/ \ 21 1 V // °~0? Λ 288 N-[5-Chloro-6-(6,7- dimethoxy-cpiinolin-4-yIoxy)- pyridin-3-yl]-N'-(4-fiuciio- phenyl)-2,2-dimethyl- malonamide “"Ο Cl VyvS o «J HN^O Φ F 289 N-Ethyl-N'-{3-fluaro-4-[6~ methoxy-7 -(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide ""0 88 2013204031 11 Apr 2013

WO 2005/030140 PCT/US2004/031523 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523

Table 1

[0078] In another aspect, the invention comprises a compound for modulating kinase activity of formula A-B-C, or a pharmaceutically acceptable salt, hydrate, or prodrug thereof, wherein, A is selected from: -R3 rb ox* ‘ r8 '"N^Y^O ' '1-4 OCXa -CO R10 R11 r8-0>Y2 r8-n-yVr8 t ' i-4 1 M- 4 90 2013204031 11 Apr 2013

WO 2005/030140 PCT/US2004/031523 rr^>RS /R8 °^AN\ F / N R® R®' ^-4 k* 1 R8 R3 A^ ro Λ ** 1-4 / SfO)0.2 R® ^-4 /^5(0)0-2 0=< A R8 M ' >\A B is selected from: R3_0A<^N^ r5%n/X r3_0A^Cn^ Λ S(0)o-2 }'°Τι.ϊ RS~°V'srV Hr^V1 rMVV^*' ηΛ^»4’1 Λ S(0)(>2

91 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523 0 0 (R% R5 1 ..1-2..0-3 Οτν·Λ (R2)q x V>, q{R2) O \ R5 (R2) \ RS O R5 R35 1 , .0-2 1 αΎΐ"·' (R2)q R5 ii / t0-2 / \0“3 mr (R2)q wherein R2 is selected from -H, halogen, trihalomethyl, -Of, -NH2, -NO* -OR3, -NR3!!3, -S(0)o-2R3, -S02NR3R3, -COzR3, -CiOJNR^, -NCR^SCfcR3, -N(R3)C(0)R3, -N(R3)C02R3, -C(0)R3, and optionally substituted lower alkyl; qis0to2; each R3 is independently selected from -H, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted arylalkyh and optionally substituted heteroarylalkyl; two R3, together with the nitrogen to which they are attached, form a four- to seven-membered heteroalicyclic, said four- to seven-membered heteroalicyclic optionally containing one additional heteroatom; when one said additional heteroatom is a nitrogen, then said nitrogen is optionally substituted with a group selected from -H, trihalomethyl, -S02R5, -SQ2NRsRs, -CO2R5, "C(0)NR5R5) -C(0)R5, and optionally substituted lower alkyl; each R33 is independently selected from -H, -C(=0)R3, -C(=0)OR3, -C(=0)SR3, -SOaR3, -Ct^OJNfli^R3, and optionally substituted lower alkyl; 92 PCT/US2004/031523 2013204031 11 Apr 2013 WO 2005/030140 two R35, together with the nitrogen to which they are attached, can combine to form a heteroalicyclic optionally substituted with between one and four of R60, said heteroalicyclic may have an additional annular heteroatom, and said heteroalicyclic may have an aiyl fused thereto, said aryl optionally substituted with an additional one to four of R60; A1 is selected from =N-, =C(H)-, and =C(CN)-; A2 is either =N- or =C(H)-; R5 is -H or optionally substituted lower alkyl; R8 is selected from R3, -S02NR^, -CO2R3, -CiOJNRV, -SO^3, and -C(0)R3; R9, R10, and Rn are each independently selected from -H, and -OR12; or R9 is selected from -H, and -OR12, and R10 and Rn, when taken together, are either an optionally substituted alkylidene or an oxo; and R12 is selected from -H, -C(0)R3, optionally substituted lower alkylidyne, optionally substituted lower arylaUtylidyne, optionally substituted lower heterocyclylalkylidyne, optionally substituted lower alkylidene, optionally substituted lower alkylidenearyl, optionally substituted lower alkylideneheterocyclyl, optionally substituted lower alkyl, optionally substituted lower alkylaryl, optionally substituted aryl, optionally substituted lower heterocyclylalkyl, and optionally substituted heterocyclyl; or two Rlz’s, when taken together, form 1) a corresponding spirocyclic ketal when said two R12,s stem from R10 and R11, or 2) a corresponding cyclic ketal when said two R12’s stem from R9 and one of R10 and R11; E1 is selected from -0-, -CEfe-, -N(R5)-, and -S(0)&amp;.2-; Q is a five- to ten-membered ring system, optionally substituted with between zero and four of R20; R20 is selected from -H, halogen, trihalomethyl, -CN, -NOs, -NH2, -OR3, -NR3R3, -SiO^xR3, -S02NR3R3, -CO2R3, -C(0)NR3R3, -N(R3)S02R3, -N(R3)C(0)R3, -N(R3)C02R3, -C(0)R3, and optionally substituted lower alkyl; R60 is selected from -H, halogen, trihalomethyl, -CN, -N02, -NH2, -OR3, -NR3R3, -S(0)o.2R3, -SOzNR^, -CO2R3, -^0)1^¾3. -N(R3)S02R3, -N(R3)C(0)R3, 93 2013204031 11 Apr 2013 WO 2005/030140 PCT/DS2004/D31523 -N(R3)COzR3, -C(0)R3, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted heteroarylalkyl, and optionally substituted arylalkyl; „ \ two of R , when attached to a ηαα-aromatic carbon, can be oxo; each methylene in any of the above formulae is independently optionally substituted with R23; each R23 is independently selected from halogen, trihalomethyl, -CN, -NO2, -NH2, -OR3, -NR3R3, -S(0)o-2R3, -S02NR3R3, -CO2R3, -C(0)NR3R3, -N(R3)S02R3, -N(R3)C(0)R3, -N(R3)C02R3, -C(0)R3, optionally substituted aryl, optionally substituted arylalkyl, heteroarylalkyl, and optionally substituted lower alkyl; two of R25, together with the carbon or carbons to which they are attached, can combine to form a three- to seven-membered alicycltc or heteroalicyclic, two of R on a single carbon can be oxo; with the proviso that when 5 is selected from:

V and C contains

and the remaining portion of C contains one of:

Αγ°ν o s ν-Λ ΑΛ O" yf ^ y Y''°Sx''V 94 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523 (R2)q , then A must be one of: g5c* 'ΌΟο Ο'Ύ^Ο *^ΝνΛ<} r9— R10 R11 β=-<2ι>-ηγ \> rS''n-^y®'n-^R8 ^ν·Λ<} «^V ητι , 1 /1-4 (JyA2 r . , and with the proviso that when C contains (R )q , and B is selected &amp;om. Λ S(0)o-2 ,_0YTf R3-oW -T- 31 1 r V/°\ Λ S(0)o-2 ΓΧύ 95 2013204031 11 Apr 2013 WO 2005/030140

contain

PCT/US2004/031523 then the portion of C directly attached to λ

, when R70 is selected from -H, C^aUcyl, and Ci^allroxyL

[0079] In another example the compound is according to paragraph [0078], wherein Q is selected from phenyl, napthyl, 1,2,3,4-tetrahydronaphthyl, indanyl, benzodioxanyl, benzofnranyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroisoquinolyl, pyirolyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, tetrahydropyridinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxazolidinyl, triazolyl, isoxazolyl, isoxazolidinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, isolhiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, thienyl, benzothieliyl, and oxadiazolyl; each optionally substituted with between one and four of R20; wherein each R20 is independently selected from -H, halogen, trihalomethyl, -CN, -NQj, -NH2, -OR3, -NR3R3, -COzR3, -0(0)1¾¾^ -N(R3)SOaR3, -NG^XXQJR3, -NtR^COzR3, -C(0)R3, and optionally substituted lower alkyl.

[0080] In another example the compound is according to paragraph [0079], wherein B is either of the following: 1 "V*· R3—Os. Ov?' R3-Os, h-o' }—oy wherein A1 is either =N- - or =C(H)-.

[0081] In another example the compound is according to paragraph [0080], wherein B is

96 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523 [0082]

In another example the compound is according to paragraph [0081], wherein C is selected from: \ R2 VrvJUQ IJL/ ¥ Vv S R5 R2 ^VYx>~ X R2 ° 0 H jf ,.0-3 1 jT "j l T-I-(r20)o^ x V H l U°-2 1 V 1 If l5 \ JL/(R )0-3 ° r5 ρί R2 KJ nrVV JL.\J o R5 X R2 (R60)o-4 pf .N. /V/Nvy^ i| ^0-2 0 ° Kj j 4 (rbv \ V j^rrv X R2 (R®)im |tf!ii^X-(R60)o-4 h r^r »VwNr)o-2 X\J 0 o (R60)o-4 V R2 97 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523 (R®)0-4 id a 4 <r6°)o-4 ^ V (R^cm Αλ, x^V° %n^ wherein R2, R3, R5, R20, R25 and R60 are as defined above.

[0083] In another example the compound is according to paragraph [0082], R2 is selected from halogen, trihalomethyl, -CN, -NOa, -OR3, -NR3R3, -CO2R3, -C(0)NR3R3, -N(R3)C(0)R3, -N(R3)C02R3, -C(0)R3, and optionally substituted lower alkyl [0084] lh another example the compound is according to paragraph [0083], wherein R2 is halogen.

[0085] lh another example the compound is according to paragraph [0084], wherein R2 is either fluorine or chlorine.

[0086] In another aspect, the invention comprises a compound for modulating Mnase activity according to Formula XI,

or a pharmaceutically acceptable salt, hydrate, or prodrug thereof, wherein, 98 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523 each R1 is independently selected from halogen, -OR3, -NO2, -NH2, -NR^S4, -D-R50 and optionally substituted C^aUcyl; R70 is selected from -H, halogen, -OR3, -S(0)o-2R3, -NO2, -NHa, -NR3R4, and optionally substituted Ci-galkyl; Q is selected from =N-, =C(H)-, and =C(CN)-; Z is selected from -S(0)o-2-, -0-, and -NR5-;

Ar is either a five- or six-membered aiylene or a five- or six-membered heteroarylene containing between one and three heteroatoms; G is either an optionally substituted cycloalkyl or an optionally substituted hetexoalicyclic; each R2 is independently selected from halogen, trihalomethyl, -CN, -NO2, -NH2, -OR3, -NR3R4, -S(0)o.2R3, -SOaNR^, -CO2R3, -C(0)NR3R3, -NOR^SOzR3, -N(R3)C(0)R3, -NtR^COjR3, -C(0)R3, and optionally substituted Ci^alkyl; each R3 is independently -H or R4; each R4 is independently selected fiom optionally substituted Ci-ealkyl, optionally substituted atyl, optionally substituted aryl Ci^alkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclyl Ci^alkyl; or R3 and R4, when taken together with a common nitrogen to which they are attached, form an optionally substituted five- to seven-membered heterocyclyl, said optionally substituted five- to seven-membered heterocyclyl optionally containing at least one additional annular heteroatom selected from N, O, S, and P; R5 is -H or optionally substituted C^alkyl; each D is independently selected from -0-, -S(0)o-2-, and -NR5-; each R50 is independently either R3, or according to formula ΧΠ;

ΧΠ wherein X1, X2, and optionally X3, represent the atoms of a saturated bridged ring system, said saturated bridged ring system comprising up to four annular heteroatoms represented by any of X1, X2, and X3; wherein, 99 FCT/US2004/031523 2013204031 11 Apr 2013 WO 2005/030140 each X1 is independently selected from -COR6)!?7-, -0-, -S(0)o.2-, and -NR8-; each X2 is independently an optionally substituted bridgehead methine or a bridgehead nitrogen; each X3 is independently selected from -QR^R7-, -0-, -S(0)o-2-> and -NR8-; Y is either an optionally substituted lower alkylene linker, between D and either 1) any annular atom of the saturated bridged ring system, except X2 when X2 is a bridgehead nitrogen, or 2) any heteroatom, represented by any of R6 or R7; provided there are at least two carbon atoms between D and any annular heteroatom of the saturated bridged ring system or any heteroatom represented by any of R6 or R7; or Y is absent, when Y is absent, said saturated bridged ring system, is directly attached to D via an annular carbon of said saturated bridged ring system, unless D is -S02-, in which case said saturated bridged ring system, is directly attached to D via an any annular atom of said saturated bridged ring system; m and p are each independently one to four, n is zero to two, when n equals zero, then there is a single bond between the two bridgehead X2’s; R6 and R7 are each independently selected from -H, halogen, trihalomethyl, -CN, -NH2> -N02, -OR3, -NRV, -S(0)o.2R4, -SOzNR3R4, -COzR3, -0(0)^¾4. -N(R3)S02R4, -N(R3)C(0)R3, -NGO2R3, -C(0)R3, optionally substituted Ci-eaJkyl, optionally substituted aryl, optionally substituted aryl Ci^alkyl, optionally substituted heterocyclyl, optionally substituted heterocyclyl Ci-ealkyl and a bond to either Y or D; or R6 and R7, when taken together are oxo; or R6 and R7, when taken together with a common carbon to which they are attached, form a optionally substituted three- to seven-membered spirocyclyl, said optionally substituted three- to seven-membered spirocyclyl optionally containing at least one additional annular heteroatom selected from N, O, S, and P; R8 is selected from -R3, Y, -S02NR3R4, -COaR4, -C(0)NR3R3, -SO3R4, and -C(0)R3; and 100 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523 each R30 is independently selected from halogen, trihalomethyl, -CN, -NOj, -NHj, -OR3, -mV, -SCO^wR3, -SQ2NR3R3, -CQjR3, -0(0)^¾3. -N(R3)S02R3, -N(R3)C(0)R3, -N(R3)C02R3, “C(0)R3, and optionally substituted Q.isalkyl.

[0087] In one example, the compound is accoiding to paragraph [0086], wherein Z is either-O-or-NR5-.

[0088] In another example, the compound is according to paragraph [0087], wherein at least one of R1 is -D-R50.

[0089] In another example, the compound is according to paragraph [0088], wherein D is Ό- and at least one other R1 is -OR3.

[0090] In another example, the compound is according to paragraph [0089], of formula

XmaorXmb:

xma XUIb wherein Q1 is either =N- or =C(H)-. 10091] In another example, the compound is according to paragr^h [0090], wherein R50 is selected from Ci^alkyl optionally substituted with at least one of optionally substituted amino, optionally substituted Cj^alkyl amino, optionally substituted Ci^dialkyl amino, optionally substituted heteroalicylic, and a group of formula ΧΠ.

[0092] In another example, the compound is according to paragraph [0091], wherein R3a is Ci-eaUcyl.

[0093] In another example, the compound is according to paragraph [0092], wherein Z is -0-.

[0094] In another example, the compound is according to paragraph [0093], wherein G is selected from cyclopropyl, aziradine, cyclobutyl, and azetidine, each optionally substituted with between zero and four of R30. 101 WO 2006/030140 PCT/US2004/031523 2013204031 11 Apr 2013 [0095] In another example, the compound is according to paragraph [0094], wherein Q is either =N- or =C(H)-.

[0096] In another example, the compound is according to paragraph [0095], wherein R2 is selected from -H, halogen, Cj_6 alkyl and perfluoro Cm alkyl· [0097] In another example, the compound is according to paragraph [0096], wherein -N(R3b)R4 is selected from the following: R® ^.3 R3b 1 . ,0-3 0 0^°)o-4 l*> (R6°)o-4 Λ (R6V f-jr(R®0)o-4 V\ \(w (C^E (ReV4 wherein J, is a five- to ten-membered ring, optionally substituted with between zero and five of R20; each R20 is independently selected from -H, halogen, trihalomethyl, -CN, -N02, -NH2, -OR3, -NRV, -S(0)imR3, -SQzNRV, -COzR3, -0(0^¾3. -N(R3)S02R3, -N(R3)C(0)R3, -N(R3)C02R35 -C(0)R3, optionally substituted Ci^alkyl, optionally substituted atyl, optionally substituted aryl Chalky], optionally substituted heterocyclyl, and optionally substituted heterocyclyl Ci-ealkyl; two of Rz0, together with the atom or atoms to which they are attached, combine to form an optionally substituted three- to seven-membered heteroalicyclic, said optionally substituted three- to seven-membered heteroalicyclic either spiro- to J or fused to J; E is selected from -Ο-, -NCR5)-, -CEfe-, and -S(0)o-2-; each R60 is independently selected from halogen, trihalomethyl, -CN, -N02, -NHa, -OR3, -NR3R4, -S(0)twR3, -SC>2NR3R3, -CO2R3, -C(0)NR3R3, -N(R3)SOzR3, -N(R3)C(0)R3, -N(R3)CC>2R3, -C(0)R3, optionally substituted Ci-ealkyl, optionally substituted aryl, optionally substituted heteroaryl Ci^alkyl, and optionally substituted aryl Ci^alkyl; 102 2013204031 11 Apr 2013 WO 2006/030140 PCT/US2004/031523 each methylene in any of the above formulae, other than those in a depicted ring, is independently optionally substituted with R25; and R25 is selected from halogen, trihalomethyl, oxo, -CN, -NO2, -NH2, -OR3, -NR3R4, -S(O)0-2R3, -S02NR3R3, -CO2R3, -C(0)NR3R3, -N(R3)SQ2R3, -N(R3)C(0)R3, -N(R3)C02R3, -C(0)R3, optionally substituted aryl, optionally substituted aryl C^alkyl, heteroaryl Ci^alkyl, and optionally substituted Cj^alikyl; or two of R25, together with the carbon or carbons to which they are attached, can combine to form a three- to seven-membered alicyclic or heteroalicyclic;

Rais equivalent to R3 as defined above; and R4 and R5 are as defined above.

[0098] In another example, the compound is according to paragraph [0097], of formula XlVaorXIVb:

XlVa XiVb [0099] Li another example, the compound is according to paragraph [0098], wherein R50 is Ci^alkyl optionally substituted with a group selected from optionally substituted amino, an optionally substituted alkylamino, optionally substituted diaikylamino, and optionally substituted heteroalicylic.

[0100] lh another example, the compound is according to paragraph [0099], wherein the heteroalicydic portion of said optionally substituted heteroalicyclic of R50 is selected from the group consisting of piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine 1-oxide, thiomorpholine 1,1-dioxide, 2-oxo-motpholino, pyrrolidine, and azepine.

[0101] In another example, the compound is according to paragraph [0099], wherein R50 is according to formula XII. 103 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523 [0X02] In another example, die compound is according to paragraph [0101], wherein the saturated bridged ring system according to formula ΧΠ has a geometry selected from the group consisting of [4.4.0], [4.3.0], [4.2.0], [4.1.0], [3.3.0], [3.Z0], [3.1.0], [3.3.3], [3.3.2], [3.3.1], [3.2.2], [3.2.1], [2.2.2], and [2.2.1].

[0103] In another example, the compound is according to paragraph [0102], wherein Y is selected from -G02CH2GH2CH2·-, 'CH1CH2CH2-, -CH2CH2·, -CH2-, and absent.

[0104] In another example, die compound is according to paragraph [0103], wherein n is 0 and the saturated bridged ring system according to formula ΧΠ has a geometry selected from the group consisting of [4.4.0], [4.3.0], [4.2.0], [4.1.0], [3.3.0], [3.2.0], and [3.1.0]. 1 [0105] In another example, the compound is according to paragraph [0104], wherein said saturated bridged ring system contains at least one annular nitrogen or at least one annular oxygen.

[010(i] In another example, the compound is according to paragraph [0105], wherein said saturated bridged ring system contains -NR8-, wherein R8 is‘selected from -H, optionally substituted C^alkyl, -C02R3, -C(0)NR¥, -SO^R3, and -C(0)R3.

[0107] hi another example, die compound is according to paragraph [0105], wherein said saturated bridged ring system is of formula XV,

XV wherein U1 is selected from -Ο-, -S(O)0.2-, -NR8-, -CReR7-, and absent; and e is 0 or 1.

[0108] In another example, the compound is according to paragraph [0107], wherein Y is -CHr- [0109] In another example, die compound is according to paragraph [0108], wherein U1 is -NR8-, wherein R8 is selected from -H, optionally substituted lower alkyl, -CO2R3, -C(0)NR1R3, -SO2R3, and -C(0)R3.

[0110] In another example, the compound is according to paragraph [0108], wherein U1. is -0-. 104 PCT/US2004/031523 2013204031 11 Apr 2013 WO 2005/030140 [0111] In another example, the compound is according to paragraph [0108], wherein U1 is absent [0112] In another example, the compound is according to paragraph [0103], wherein Y is selected from -CH2CH2-, -CEfe-, and absent [0113] In another example, the compound is according to paragraph [0112], wherein said saturated bridged ring system is of formula XVI,

XVI wherein R9, R10, and R11 are each independently selected from -H, and -OR12; or R9 is selected from -H, and -OR12, and R10 and Ru, when taken together, are either an optionally substituted alkylidene or an oxo; R12 is selected from -H, -C(0)R3, optionally substituted lower alkylidyne, optionally substituted lower arylalkylidyne, optionally substituted lower heterocyclylalkylidyne, optionally substituted lower alkylidene, optionally substituted lower alkylidenearyl, optionally substitated lower alkylideneheterocyclyl, optionally substituted lower alkyl, optionally substituted lower alkylaiyl, optionally substituted aryl, optionally substituted lower heterocyclylalkyl, and optionally substituted heterocyclyl; or two R12,s, when taken together, form 1) a corresponding spirocyclic ketal when said two R12’s stem from R10 and Ru, or 2) a corresponding cyclic ketal when said two Rlz’s stem from R9 and one of R10 and R1 J.

[0114] In another example, the compound is according to paragraph [0113], wherein one of R10 and R11 is -OR12, wherein R12 is selected from -H, -C(0)R3l and optionally substituted lower alkyl; and R9 and the other of R10 and Rn are both -EL

[0115] In another example, the compound is according to paragraph [0114], wherein Y is either -CH2- or absent, [0116] In another example, the compound is according to paragraph [0113], wherein R9 is an alkyl group containing at least one fluorine substitution thereon. 105 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523 [01X7] In another example, the compound is according to paragraph [0106], wherein said saturated bridged ring system is of formula XVH.

xVn [0118] In another example, the compound is according to paragraph [0117], wherein Y is either -CHp or absent [0119] In another example, the compound is according to paragraph [0118], wherein R8 is methyl or ethyl, [0120] In another example, the compound is according to paragraph [0119], wherein at least one of R2 is halogen.

[0121] In another example, the compound is according to paragraph [0106], wherein said saturated bridged ring system is of formula XVIII.

xvm [0122] In another example, the compound is according to paragraph [0121], wherein Y is -CHa-.

[0123] hi another example, the compound is according to paragraph [0122], wherein R8 is methyl or ethyL

[0124] hi another example, the compound is according to paragraph [0105], wherein said saturated bridged ring system is of formula XIX

XIX wherein U2 is selected from -Ο-, -S(0)o-2-, -NR8-, -0¾¾% and absent [0125] hi another example, the compound is according to paragraph [0124], wherein R3 of formula XIX is selected from -Ή and optionally substituted allcyl. 106 PCT/US2004/031523 WO 2005/030140 [0126] lii another example, the compound is according to paragraph [0125], wheiein U2 is either-CR^R7- or absent.

[0127] In another example, the compound is according to paragraph [0126], wherein Uz is either -CEfe- or absent.

[0128] In another example, the compound is according to paragraph [0127], wherein Y is -CH2-.

[0129] In another example, the compound is according to paragraph [0106], wherein said saturated bridged ring system is according to formula XX.

[0130] In another example, the compound is according to paragraph [0129], wherein R8 is methyl or ethyl.

[0131] In another example, the compound is according to any of paragraphs [0099] — [0130], wherein R1 is selected from alkyl, perfluoro Cj.6 alkyl, and halogen.

[0132] In another example, the compound is according to paragraph [0131], wherein R2 is selected from perfluoro C1.3 alkyl and halogen.

[0133] In another example, the compound is according to any of paragraphs [0099] — [0130], wherein R20 is selected from halogen, -CN, -N02, -NH2, -OR3, -NR3R4, -N(R3)S02R3, -N(R3)C(0)R3, -N(R3)C02R3, optionally substituted heterocyclyl, and optionally substituted heterocyclyl Ci^alkyl, and (two of R20) together with the atom or atoms to which they are attached, an optionally substituted three- to six-membered heteroalicyclic, said optionally substituted three- to six-membered heteroalicyclic fused to the phenyl as in XlVa or XTVb.

[0134] In another example, the compound is according to paragraph [0133], wherein R20 is selected from halogen, -NR3R4, optionally substituted heterocyclyl, and optionally substituted heterocyclyl Ci^alkyl, and (two of R20) together with the atom or atoms to which they are attached, an optionally substituted five- to six-membered heteroalicyclic, said optionally substituted five- to six-membered heteroalicyclic fused to the phenyl as in XTVa or XlVb. PCT/US2004/031523 2013204031 11 Apr 2013 WO 2005/030140 [0135] In another example, the compound is according to paragraph [0134], wherein R2 is selected from Cm alkyl, perfluoro Ci-6 alkyl, and halogen.

[0136] In another example, the compound is according to paragraph [0135], wherein R2 is selected from perfluoro Cu alkyl and halogen.

[0137] In another example, the compound is according to paragraph [0086], selected from Table 2.

Table 2

Entry Name Structure 1 N-(6-{[6,7- bis(methyloxy)qumolin-4- yl]oxy}-5-chlaropyridin- 3-yl)-N-(4- flnorophenyl)cyclopropan e-1,1-dicarboxamide χ/Λχχ, ooO 2 N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-chloropyridin- 3-yl)-N-(4- fluorophenyl)cyclobutane -1,1-dicarbaxamide 3 N-(6-{[6,7- bis(methyloxy)quinolin-4- yi]oxy}-5-chloropyridin- 3-ylJ-N·- (phenylmethyl)cyclopropa ne-1, l-dicarboxamide 0 Oo0 4 N-(6-{[6,7- bis(methyIoxy)quinolin-4- yl]oxy}-5-chloi»pyridin- 3-yl)-NL phenylcyctopropane-1,1- dicarboxamide XrWo "(Mn^ 108 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523

Table 2 Entry Name Structure 5 N-[3-fluoro-4-({ 6-(methyloxy)-7-[(3-moipholin-4-ylpropyl)oxy]quinolin-4-yl}axy)phenyI]-N-(4-fluorophenyl)cyclopropan e-1,l-dicarboxamide . XrWa, οοοό 6 N-[3-fluoro-4-({6- (methyloxy>7-[(3- piperidin-1- ylpropyl)oxy]qmnolin-4-yl }oxy)phenyl]-N'-(4-fluorophenyl)cyclopropan e-1, l-dicarboxamide XT Ovf V "YrS ' Wv1'/ 7 N-[3-fluoro-4-({6- (methyloxy)-7-[(3- piperidiii-1- ylpropyI)oxy]qumolin-4-yl} oxy)phenyl]-N'-(4-fluorophenyl)cyclobutane -1,1-dicarboxamide ΧϊΨί'χΧ, XC00 8 N-(6-{[6,7- bis(methyloxy)qmnolin-4- yl]oxy}-5-chloropyridin- 3-yl)-N'-(2- phenylethyl)cycloprDpane -1,1-di carboxamide '°ΥΎS ^ 9 N-(6-{[6,7- bis(methyloxy)quinolin-4-yl]oxy ί-2-methylpyridin-3-yl)-N-(4- fluorophenyl)cyclopropan e-1,1-dicarboxamide OlF χύ 10 N-f 4-[(7-chloroquinoIin-4-yl)oxy]-3-fluorophenyl} -N'-(4-fluorophenyl)cyclopropan e-1,1-dicaibaxamide XrWa, JL JL ^ 109 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523

Table 2 Entry Name ~|------ Structure 11 N-{4-[(7-chIoroquinolin-4-yl)oxy]phenyl}-N’-(4-fluorophenyl)cyclopiopan e-1,1-dicarboxamide 12 N-(4-{[6,7- bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropan e-1,1-dicarboxamide σΧΤ iX XX 13 N-(4-{[6,7- bis(methyloxy)qumazolin -4-yl]oxy }phenyI)-N'-(4-fluOTophenyl)cycIopropan e-1,1-dicarboxamide J3 XX 14 N-(4-{[6,7- bis(methyloxy)quiiiazolm -4-yl]oxy}-3-fluorophenyl)-N'-(4-fluorophenyl)cyclopropan e-1,1-dicarboxamide oXX ** XX /°yv^N 15 N-[3-fluoro-4-({ 6-(methyloxy)-7-[(3-morptiolin-4-ylpropyl)oxy]quinazolin-4-yl} oxy)phenyl]-N'-(4-: luorophenyl)cyclopropan e-1,1-dicarboxamide λ oXX XX 16 N-{5-chloro-6-[(6-(methyloxy)-7-{ [(1-methyIpiperidin-4-yl)methyl]oxyJ quinolin-4-yl)oxy]pyridin-3-y] }-N’-(4- fluorophenyl)cyclopropan e-1,1-dicarboxamide L, loo I XL jyCOC^" ' . - 110 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523

Table 2 Entry Name Structure 17 N-[5-chloro-6-({ 6-(methyloxy)-7-[(piperidin-4-ylmethyl)oxy]quinolin-4-yl} oxy)pyridin-3-yl]-N'- (4* fluorophenyl)cyclopropan e-1,1-dicarboxamide -'VrS 18 N-[5-chloro-6-({ 6-£methyloxy)-7-[(phenylmethyl)oxy]quino lin-4-yl} axy)pyridin-3-yl]-N'-(4- fluorophenyl)cyclopropan e-1, l-dicarbaxamide (yCof"'0’ 19 N-(4-{[7-{[2- (diethylairdno)ethyl]axy}- 6-(methyloxy)qumolm-4- yl]oxy}-3-fhiorophenyl)-. Ν·-(4- fluorophenyl)cyclopropan e-1,1-dicarboxamide χΛΥχχ, xooi 20 N-(4-{[7-{[2-(diethylamino)ethyl]oxy }-6-(methyloxy)quinaIin-4-yl] oxy }-3 -fluorophenyl)-N’-(4- fluorophenyi)cyc]obutane -1,1-dicarboxamide X00i 21 N-{3-fluoro-4-[(6-(methyloxy)-7-{[(l-methy]piperidin-4-yl)methyl]oxy}quinazolin -4-yl)oxy]pheriyl}-N-(4-fluorophenyl)cyclcpropan e-1,1-dicarboxamide XrWu, . 22 N-(4-{[6,7- bis(methyloxy)quinolin-4- yI]oxy}-2-methylphenyl)- N*-(4- fluorophenyl)cyclopiopan e-1,1-dicarboxamide XX Λ XX 111 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523

Table 2 Entry Name Structure 23 N-(4-fluorophenyl)-N'-[2- methyl-6-({6- (me£hyloxy)-7-[{3- morpholin-4- y]propyl)oxy]quinoIin-4“ yl}oxy)pyridin-3- yl]cyclopropane-l,l- dicarboxamide u. 0 TZ < A3 V_y 24 N-(4-{[6,7- bis(methyloxy)quinoIin-4-yl]oxy }-3-fluoiophenyl)-N'-(4- fluorophenyl)cyclopropan e-1,1-dicarboxamide XT "ϊδ XX, 25 N-(6-{[6,7- bis(methyloxy)quinoIin-4-yl]oxy }-5-chloro-2-methylpyridm-3-yl)-N'-(4- fluorophenyl)cyclopropan e-1,1-dicarboxamide JL JL ο o 1. JL 26 N-[3-fluoio-4-({7-(methyloxy)-6-[(3-m0rpholin-4-ylpicpyl)oxy]quinazo]in-4-yl}oxy)phenyl]-N'-(4-fluorophenyl)cyclopropan e-1,1-dicarboxamide νΑΧ. ίί^ rO XT ° ° TXF 27 N-(4-{[6,7- bis(methyloxy)quinolin-4-yl]oxy}-3,5-difluorophenyl)-N'-(4-fluorophenyl)cyclopropan e-1,1-dicarboxamide χ/ϊΫχχ vW 28 N-(4-{[6,7- bis(methyloxy)quinolin-4-yl]oxy}-2,5-difluorophenyl)-N'-(4-fluarophenyI)cyclopropan e-1,1-dicarboxamide XTFsi XXF COQ 112 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523

Table 2 Entry . Name Structure 29 N-[3-fluoro-4-({7-(methyloxy)-6-[(3-moipholin-4-ylpropyl)oxy]quinolin-4-yl} oxy)phenyI]-N'-{4-fluorophenyl)cyclopropan e-1,1-dicarboxamide rG° XfiiXX, scM/ 30 N-{3-fluoro-4-[(6- (meihyloxy)-7-(2-methyl octahydrocyclo- penta[c]pyrrol-5- ylmethoxy)quinazolin-4- yl)oxy]phenyI}-N'-(4- fluorophenyl)cyclopropan e-l,l-dicaiboxamide XrWo, yjCCti 31 N-{3-fluoro-4-[(7-(methyloxy)-6-{ [(1-methylpiperidin-4-yl)methyl]oxy}quinazolm -4-yZ)oxy]phenyl }-N'-(4-£luorophenyl)cyclopropan e-1,1-dicarboxamide ^ XrWxx, 32 N-[5-fluoro-2-methyl-4-({6-(raethyIoxy)-7- [(3-moipholin-4-ylpropyl)oxy]quinolin-4-yI}oxy)phenyI]-N'-(4-fluoropheriyl)cyclopropan e-1,1-dicarboxamide FV#?vV ^ cAA0 ° U, 33 N-(4-{[6,7- bis(methyloxy)quinolin-4-yljoxy [-2,3,5-trifluorophenyl)-N-(4-fluorophenyl)cyclopropan e-1,1-dicarboxamide CC0 34 N-(4-{[6,7- bis(methyloxy)quinolin-4-yI]oxy[-5-fluoro-2-methylphenyl)-N'-(4-fluorophenyl)cyclopropan e-1,1-dicarboxamide FnV!#?V ο o 113 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523

Table 2 Entry Name Structure 35 N-(4-{[6,7- bis(methyloxy)quino]in-4-yl]oxy}-2-chloro-5-methylphenyl)-N-(4-fluorophenyljcyclopropan e-1,1-dicarboxamide CoO . 36 N-(3-fluoro-4-{[6- hydroxy-7- (methyIoxy)qainoIin-4“ yl]oxy}pheny!)-N'-(4-fluorophenyl)cyclopropan e-1,1-dicarboxamide χΛΥτχ 37 N-(4-fluorophenyl)-N'-[2-methyl-4 -({6-(methyloxy)-7-[(3-morpholin-4-ylpropyl)oxy]quinolin-4-yl}oxy)pheuyl]cyclopropa ne-1,1-dicarboxamide Η \7 H 0ΛΑ0 0 V 38 N-[3-fluoro-4-({6- (methyloxy)-7-[(3- piperazin-1- ylpiopyl)oxy]quinolm-4-yl}oxy)phenyI]-N'-(4-fluorophenyl)cyclopropan e-1,1-dicarboxamide A) f" ’O" V . ώ4 NH 0 F 114 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523

Table 2 Entry Name Structure 39 N-{3-fluoro-4-[(6-(methyloxy)-7-{ [3-(4-methylpiperazin-1-yl)propyl]oxy}qumolin-4-yl)oxy]phenyl} -N'-(4-fluorophenyl)cyclopropan e-1,1 -dicarboxatnide Λ?Χ/ w \ ' 40 N-{3-fluoro-4-[(6-(niefliylaxy)-7- {[(1-methylpiperi din-4-yl)methyl]oxy}quinolin-4-yl) oxy]phenyl} -N'-(4-fluorophenyl)cyclopiopan e-1,1-dicarboxamide Λ hnO"F ΊΛ O^NH VY 41 N-(4-fluorophenyl)-N'-[4-({6-(methyloxy)-7-[(3-morpholin-4-ylpropyl)oxy]quinolin-4-yl }oxy)phenyl]cyclopropa ne-1,1-dicarboxanude <rf O O^NH ψγ YY 42 N-(4-{[7-{[3-(diethylamino)propyl]oxy }-6-(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyI)-N'-(4-fluorophenyl)cyclopropan e-1,1-dicarboxamide A.H ,-ΦΥ °yY 115 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523

Table 2 Entry Name Structure 43 N-(4-{[6,7- bis(methyloxy)quinolin-4-yl]oxy}-2-cbloro-5-fluorophenyI)-N'-(4“ fluoropheayl)cyclopropan e-1,1-dicarboxamide j οειγν°γί" 44 Ν-(4-{|;6,7-bis(methyloxy>2-(methyIthio)quinolin-4-yl] oxy} -3-fluorophenyl)-^-(4- fluorophenyljcyclopropan e-1,1-dicarboxamide yn /s 45 N-{4-flooropheayl)-N,-(4-{[2-methyl-6,7-bis (methy Ioxy)quinazolin -4- yl]oxy}phenyl)cyclopropa ne-1,1-dicarboxamide jcr A o— 46 N-(4-{[2-amino-6,7- )is(methyloxy)quinolin-4- yl]oxy}-3-fluarophenyl)- ^-(4- fluorophenyl)cyclopropan e-1,1 -dicarboxamide ηΛΛ^ γΝ 47 N-(3-fluoro-4-{ [2-(methylamino)-6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N,-(4-fluorophenyl)cyclopiopan e-1,1-dicarboxamide Yx , Xi $ »0 YvV ITvV^ V ^ H χΝΗ 116 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523

Table 2 Entry Name —i---- Structure 48 (lS,2R)-N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4-yIpropyl)oxy]quinolin-4-yl }oxy)phenyl]-N-(4-fluorophenyl)-2-methylcyclopropane-1,1-dicarboxamide r? S > r Ά o 0 XCCKXb 49 (lR,2R)-N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4-ylpropyl)oxy]quinoIin-4-yl }oxy)pheny]]-N’'(4-fluorophenyl)-2-methylcyclopropane-1,1-dicarboxamide 0 xz &amp;Q. TJ 50 N-(4-{[6-{[3-(diethylamino)propyl]oxy } -7-(methyloxy)quinolin-4-yl]oxy}-3-flaarophenyl)-N'-(4-fluorophenyl)cyclopropan e-1,1-dicarboxamide b κ tP~° 51 N-(4-{[6-{[2- (diethylamino)ethyl]oxy}- 7-(methyloxy)qainoliTi-4- yI]oxy}-3-fluorophenyl)- N'-(4- fluoropheuyl)cyclopropan e-1,1-dicarboxamide \-l(~ F ζ HN—^ )-0 /=/ 117 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523

Table 2 Entry Name Structure 52 1,1-dimethyIethyl 4-(3-{[4-[(2-fluoro-4-{ [(1- {[¢4- fiuorophenyl)amino]carbo nyl} cyclopropyl)carbonyl jamino }phenyl)oxy]-6-(methyIoxy)quino]in-7-yl]oxy }propyl)piperazine-1-carboxylate HN N V -iF 53 (lR,2R)-N-[3-fluoro-4- ({6-(methyloxy)~7-[(3- morpholin-4- ylpropyl)oxy]quinazolin- 4-yl}oxy)phenyl]-N'-(4- fluorophenyl)-2- methylcyclopropane-1,1- dicarboxamide o k "Ό -F IX 0 ΥΥ°>Λ| ο»Γ X^N FJXXnAJ===0 H 54 (lR,2R)-N-(4“{ [7-{ [2-(diethylamino)ethy]]oxy}-6-(methyloxy)qumazolin-4-yl]oxy}-3-fluorophenyl)-N-(4-fluorophenyl)-2- methylcyclopropane-1,1- dicarboxamide V/ 55 N-(4-{[7-{[3- (diethylamino)propyl]oxy }-6- (methyloxy)quinazolin-4- yI]oxy}-3-fIuoropheny])- N'-(4- fluorophenyl)cyclopropan e-1, l-dicarboxami de ry-pfV11 118 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523

Table 2 Entry Name Structure 56 N-(4-{[7-{ [3-(4-acetylpiperazin-1-yl)propyl]oxy} -6-(methyloxy)quinolm-4-yl]oxy} -3-fluorophenyl)-N'-(4- fluorophenyljcyclopropan e-1, 1-dicarboxainicte F f r $,. λJy N-\ i Ass J H ^ 57 1,1-dimethylethyl 4-(3-{[4-[(2-fluoro-4-{[((lR£R)-l-{[(4-fluorophenyl)amijio]carbo nyI}-2- methylcyclopropyl)carbon yljamino }phenyl)oxy]-6-(methyloxy)quinolin-7-yl]oxy}propyl)piperazine-1-caiboxylate Ν·^ι J 58 N-(4-{[6,7- bis(methyloxy)qmnolm-4- yl]oxy)phenyl)-N,-(4- fluorophenyl)-l- (phenylmethyl)azetidlne- 3,3-dicarboxaimde φ VNHo o ^ 119 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523

Table 2 Entry Name Structure 59 N-(4-{[6,7- bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-iluorophenyl)azetidme-3,3-dicarboxamide Φ °vNHo M-M V-|S| 60 (lR,2S)-N-{ 3-fluoro-4-[(6-(methyloxy)-7-{ [3-(4-methylpiperaziii-1-yl)propyl]oxy}quinolin-4-yl)oxy]phenyl }-N'-(4-fluorophenyl)“2-methylcyclopropane-1,1-dicarboxamide ry V, 0' 61 (lR,2R)-N-{3-fluoro-4-[(6-(methyloxy)-7 - {[3-(4-methylpiperazin-1-yl)propyl]oxy}qmnolin-4-yl)oxy]phenyl} -N'-(4-floorophenyl)-2-methyicyclopropane-1,1-dicarboxamide V) 0 H 62 (lR,2R)-N-[3-fluoro-4- ({6-(methyloxy)~7-[(3- piperazin-1- ylpropyl)oxy]quinolin-4- yl}oxy)phenyl]-N'-(4- fluorophenyl)-2- methylcyclopropane-1,1- dicarboxamide r> Ί > wF Vi _ 0 vXx^. 120 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523

Table 2 Entry Name - 1 — Structure 63 N-{3-fluoro-4-{ [7-({3-[4-(l-methylethyl)piperazin-l-yl]propyl}oxy)-6-(methyloxy)quinolin-4-yl)oxy}phenyl)-N'-(4-fluorophenyl)cyclopropan e-1,1-dicarboxamide Ί\Γ A 64 N-(4-{[7-{[3- (diethylamino)propyl]oxy }-6- (methyloxy)quinazolin-4-yl]oxy }“3-fluorophenyl)-N'-(4- fiuarophenyl)cyclopiOpan e-1,1-dicarboxamide NH ? i N^N rA 65 (lR,2R)-N-(4-{ [7-{ [3-(diethylamino)propyl3oxy }-6-(methyloxy)quinoliri-4-yl]oxy}-3-fluorophenyl)-N'-(4-fluorophenyl)-2-methylcyclopropane-1,1-dicarbctxamide &amp; ^ VyVi ?h1 *·> fMA 0 66 (lR,2R)-N-(4-{ [7-{ [2-(diethylamino)ethyl]oxy} -6-(methyloxy)quinolin-4-yl]oxy} -3-fluorophenyl)-N-(4-fluorophenyl)-2-methylcyclopropane-1,1-dicarboxamide y S 0 XLo a Ocogo-. 121 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523

Table 2 --- Entry Name Structure 67 (lR,2S)-N-(4-{ [7-{ [3-(diethylamino)propyl]oxy }-6-(methyioxy)quinoIin~ 4-yl]oxy}-3-fluorophenyl)-N'-(4-fluorophenyl)-2-methylcyciopropane-1,1 -dicarboxamide r . . S > / YX 0 68 (lR,2S)-N-(4-{ [7-( [2-(diethy]amino)ethyl] oxy} -6“(msthyloxy)quinoliti-4-yl]oxy}-3-fluorophenyl)-N'-(4-fluorophenyl)-2-methylcyclopropane-1,1-dicarboxamide S \ XLo 0 69 N-(4-{[7-{[2-(diethylamino)ethyl]oxy }-6-(methyloxy)quinazoUn-4-yI]oxy}-3-fluorophenyl)-N'-(4-fluoiophenyl)cyclobutane -1,1-dicarboxamide } jr-ΓΧ φ °J=r<^y_NHvNH F ^ 70 (lR,2S)-N-[3-fluaro-4- ({6-(methybxy)-7-[(3- piperazin-1- ylpropyI)oxy]guinolin-4~ yl} oxy)phenyl]-N'-(4-fiuorophenyl)-2-methyicyclopropane-1,1-dicarboxamide r> Υ» P’ VyV^i ohn IP 122 2013204031 11 Apr 2013 WO 2005/030140 PCT/DS2004/031523

Table 2 Entry Name Structure 71 (lR,2R,3S)-N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4-ylpropyl)oxy]qainolin-4-yl }oxy)phenyl]-N'-(4-fluorophenyl)-2,3-dimethylcyclopropane-1,1-dtearboxamide r? Xw, £ 72 (1R, 2R,3S)-N- {3-fluoro-4-[(6-(methyloxy)-7-{ [3-(4-methylpiperazin-1-yl)propyl]oxy}qumoEn-4-yl)oxy]phenyl}-N'-(4-fluorophenyI)-2,3-dimethylcyclopropane-1,1-dicarboxamide ry V, 0' VV°v^ii °HNv XyXXXy hA" 73 (lR,2R,3S)-N-[3-fluoro-4-( {6-(methyloxy)-7-[(3-morpholin-4-ylprapyl)oxy]quinazolin-4-yl}oxy)phenyl]-N'-(4-fluorophenyl)-2,3-dimethylcyclopropane-1,1-dicarboxamide X A 0' SfV 4*^ j? HI^_ Μ ρΛλΛ' 0 74 (1R,2R,3S)-N- {3-fluoro-4-[(6-(methyloxy)-7-{ [3-(4-methylpiperazin-l-yl)propyl]oxy}quinazolin-4-yl)oxy]phenyl}-N’-(4-fluorophenyl)-2,3-dimethylcyclopropane-1,1-dicarboxamide X XVyy ° X^n fXa jy=° 123 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523

Table 2 Entry Name Structure 75 N-[3-fluoro-4-({ 6-(metbyloxy)-7-[(3-moiphoJin-4-ylpropyl)oxy]qmnazolin-4-yl} oxy)phenyl]-N'-(4-fluorophenyl)cyclobutane -1,1-dicarboxamide O X lxf> V <>^n^p-NHcvNH F d 76 (2R,3R)-N-[3-fiuoro-4- ({6-(methyloxy)-7-[(3- morpholin-4- ylpropyl)oxy]quitioIin-4- yl}oxyJphenyl]-N-(4- fluorophenyl)-2,3- dimethylcycldpropane- 1,1-dicarboxamide Γ'? \s p 77 (2R,3R)-N-(4-{ [7-{ [3-(diethylamino)propyl]oxy j-6- (methyloxyjquinolin-4-yl]oxy}-3-fluorophenyl)-N'-(4-fluorophenyl)-2,3-dimethylcyclopropane-1,1-dtcarboxamide cX -s vS p 78 N-(4-{[7-{[3-(diethylamino)propyl]oxy }-6-(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl) -N'-(4-fluoraphenyl)-2,2-dimethylcyclopropane-1,1-dicarboxamide rAo 0 124 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523

Table 2 Entry Name Structure 79 N-[3-fluoro-4-({6-(methyloxy)-7-[(3-motpholin-4-ylpropyl)oxy]quinazoHn-4-yl}oxy)phenyl]-N'-(4-fluorophenyl)-2,2-dimethylcyclopropane-1,1-dicarboxanaide p 80 (lR,2R,3S)-N-(4-{ [7-{ [3-(diethylamino)propyl]oxy } -6-(methyloxy)quinolin-4-yl]axy}-3-fluorophenyl)-N'-(4-fluorophenyl)-2,3-dimethylcyclopropane-l.l-dicarboxamide (Vi o. 0 81 N-(4-{[7“{[2-(diethylamino)ethyl]oxy} -6-(methyloxy)qumoiin-4-yl] oxy) -3 -fluarophenyl)-N?-(4-fluorophenyl)-2,2-dimethylcyclopropane-1,1-dicarboxamide V, d . 82 (lR,2R,3S)-N-(4-{[7-{[2-(diethylamino)ethyrjoxy }-6-(methyloxy)quinolin-4-yl]oxy} -3-fluarophenyl)-N'-(4-fluorophenyl)-2,3-diraethylcyclopropane-1,1-dicarboxamide V A p 83 N-[3-fluoro-4-({6- (methyloxy)-7-[(3- morpholin-4- ylpropyl)oxy]quinolin-4- yl}oxy)phenyl]-N'-(4- fluorophenyl)-2,2- dimethylcyclopropane- 1,1-dicarboxainide 'v^YVl PHP ΦN J 125 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523

Table 2 Entry Name Structure 84 N-<4-{[7-{[2-(diethylamino)ethyl]oxy} 6-(methy]oxy)quinazo]in-4-yl]oxy}-3-fluorophenyl)-N'-(4-fluorophenyl)-2,2-dimethylcyclopropane-l,l“tMcarboxamide vAvi $ 85 N-(4-{[7-{[3- (diethylamino)propyl)oxy )-6- (methyloxy)quinaz61iii-4-yl]oxy} -3-fluorophenyl)-N'-(4-fl«on>phenyl)-2>2-dimethylcyclopropane-1,i-dicarboxamide /"Φγοη ° Xy' L>N ρΛΛΜΧ>° 86 Ν-(4-{ΓΜ[3- , (diethylamino)propyl]oxy >-6- (methyloxy)quinazolin~4-yl]oxy} -3-fluorophenyl)-N'-(4- fluarophenyl)cyclobutane -1,1-dicarboxamide N—\ o—^ y—NH F </ Φ 87 N- { 3-fluoro-4-[(6-(methylaxy)-7-{ [3-(4-methylpiperazin-1 -yl)propyl]oKy Jquinazolin-4-yl)oxy]phenyl}-N'-(4-fluorophenyl)cyclobutane -1,1-dicarboxamide / j—N O F Lrp Φ o-f VnhT ° 1) y~jr\ F o 1—1 88 N-[3-fluoro-4-({6- (methyloxy)-7“[(3- piperazin-1- ylpropyl)oxy]quinazolin-4-yl} oxy)phenyl]-N'-(4-fluorophenyl)cyclobutane -1,1-dicarboxaraide /—NH O [j-r\ 1 °)=/ ^^—NH Φ ,, NH 126 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523

Table 2 Entry Name Structure 89 (2R,3R)-N-[3-fluoro-4-({6-(meihyloxy)-7-[(3-moipholin-4-ylpropyl)oxy]quiiiazolin-4-yl }oxy)phenyI]-N'-(4-fluorophenyl)-2,3-dimethylcyclopropane-' 1,1-dicarboxamide Xj °Λ 0 N^N ρα^να^° 90 N“(4-{[7-{[3-(diethykmino)pr0pyl]oxy } -6-(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl>-N-(4-f!uorophenyl)cyclobutane -1,1-dicarboxamide < N~*\ ^J-Vp-NH0" NH 91 N-{3-fluoro-4-[(6-(methyloxy)-7-{ [3-(4-metbylpiperazin-1-yl)propyl]oxy}quinolin-4-yl)oxy3phenyl}-N'-(4-fluorophenyl)cyclobutane -1,1-dicarboxamide / y—N o \ /=^ O—HH°^ F ^NH 92 (lR,2R)-N-(4-{ [7- {[3-(tUethylamino)propyl]oxy }-6- (methyloxy)quinazolin-4-yl]oxy }-3-fluorophenyl)-N'-(4-fluorophenyl)-2-methylcyciopropane-1,1-dicarboxamide ΧΎ1 0 UXlMl>0 I h zx,„ 127 2013204031 11 Apr 2013 PCT/US2004/031523 WO 2005/030140 Table 2 Entry Name Structure 93 (lR,2R)-N-{ 3-fluoro-4-[(6-(methyloxy)-7-{ [3-(4-methylpiperazin-1-yl)propyI3oxy}qainazolin- 4-yl)oxy]phenyl} -N'-(4-fluorophenyl)-2-methylcyclopropane-1,1-dicarboxamide v. F S VyYi ft A o L J H 1 _ 94 (2R,3R)-N-(4-{ [7-{ [2-(diethylamino)ethyl]oxy }-6-(methyloxy)quinazolin- 4-yl]oxy}-3- Suorophenyl)-N'-(4- fiuorqphenyl)-2,3- dimethylcyclppropane- l.l-dttcarboxamide ''‘o /°yS 0 95 (2Rt3R)-N-(4-{ [7- {[3-(diethylamiiio)propyl]oxy }-6- (methyloxy)quinazolin-4-yl]axy}-3-fluoipphenyl)-N'-(4-fluorophenyl)-213-dimethylcyclopropane-1,1-tficarboxamide > wF /°yS 0 0 w°y\ 0hn .96 (lR,2R)-N-[3-fluoro-4- ({6-(methyloxy)-7-[(3- piperazin-1- ylpiopyl)oxy]quinazolin-4-yl} oxy)phenyl]-N'-(4-fluorophenyl)-2-methylcyclopropane-1,1-dicarboxamide A S Vvvs i?HN ,λ FAJ^NA0==o L J H N H 97 (2R,3R)-N-(4-{ [7-{ [2-(diethylamino)ethyl]oxy }-6-(methybxy)quinolln-4-yl]oxy}-3-Suorophenyl)-N'-(4-fluorophenyl)-2,3-dimethylcyclopropane-l.l-dttcarboxamide -o wF i /°yS 0 V SrrVi 9™C k iJ ΑΑΛγ0 128 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523

Table 2 Entry Name Structure 98 N-(4-{[6,7- bis(methyloxy)quinoli:n-4- yl]oxy}phenyl)-N'-[(4- fluorophenyl)methyl]cycl opropane-1,1- dicarboxamide F s ΧγτΟΎΪ 99 N-(4-{[6,7- bis(methyloxy)qumolin-4-yljoxy} phenyl)-N- (2-morpholin-4-ylethyljcyclopropane-1,1-dicarboxamide Q ΤτΊ Ij i rrVr 100 N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}phenyl)-N'-[2- (piperidin-1- ylmeihyl)phenyl]cyclopi:o pane-1,1-dicarboxamide $ o \3~ o / 101 N-(4-{[6,7- bis(methyl0xy)quinolm-4-yl]oxy}phenyl)-N'-[2-(pyrrolidin-1-ylmethyl)phenyl] cyclopro pane-1,1-dicarboxamide 0 σ' ct _Ar- nh o A'°YY 05^ 102 . N-(4-{[6,7- bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-[3-(morphoIin-4-ylmethyl)phenyl]cydopro pane-1,1-dicarboxamide rO <f Q NH o f'^Y' Y 0=<1νΑ^ k^N 129 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523

Table 2 Entry Name Structure 103 N-(4-{f6,7- bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-[2-(morphoIin-4-ylmethyl)phenyl]cycIopro pane-1,1-dicarboxamide H / o 104 N-(4-{f6,7- bis(methyloxy)qumolin-4- yl]oxy}phenyl)-N'- phenyIcyclqpropane-1,1- dicarboxaraide 0 105 N-[3- (aminomethyl)phenyl]-NL (4-{[6,7- bis(methyloxy)qumolin-4-yl]oxy}phenyl)cyclopropa ne-1,1-dicarboxamide rm σ' Q Λ0" NH0 106 N-(4-{[6,7- bis(raethyloxy)quinolin-4- yl]oxy}pbenyl)-N'-[3- (^iperidin-l- ylmethyl)phenyl]cyclopro pane-1,1-dicarboxamide rO Q Jr* NH ο 107 N-(4-{£6,7- bis(methyIoxy)quinoIm-4-yl]oxy}phenyl)-N'-[3-(pyrrolidin-1-ylmethyl)phenyl]cyclopro pane-1,1-dicarboxamide rO ^ Q 130 PCT/US2004/031523 2013204031 11 Apr 2013 WO 2005/030140 [0176] Another aspect of the invention is a pharmaceutical composition comprising a compound according to any one of paragraphs [0033]-[0120] and a pharmaceutically acceptable carrier.

[0177] Another aspect of the invention is a metabolite of the compound or the pharmaceutical composition according to any one of paragraphs [0022]-[0122].

[017S] Another aspect of the invention is a method of modulating the in vivo activity of a kinase, the method comprising administering to a subject an effective amount of the compound or the pharmaceutical composition according to any of paragraphs [0033]-[0121].

[0179] Another aspect of the invention is the method according to paragraph [0123], wherein modulating the in vivo activity of the kinase comprises inhibition of said kinase.

[0180] Another aspect of the invention is the method according to paragraph [0124], wherein the kinase is at least one of c-Met, KDR, c-Kit, ftt-3, and flt-4.

[0181] Another aspect of the invention is the method according to paragraph [0123], / wherein the kinase is c-Met.

[0182] Another aspect of the invention is a method of treating diseases or disorders associated with uncontrolled, abnormal, and/or unwanted cellular activities, tiie method comprising administering, to a mammal in need thereof, a therapeutically effective amount of the compound or the pharmaceutical composition as described in any one of paragraphs [0033]-[0121], [0183] Another aspect of the invention is a method of screening for a modulator of a kinase, said kinase selected from c-Met, KDR, c-Kit, flt-3, and flt-4, the method comprising combining a compound according to any one of paragraphs [0033]-[0120], and at least one candidate agent and determining the effect of the candidate agent on the activity of said kinase.

[0184] Another aspect of the invention is a method of inhibiting proliferative activity in a cell, the method comprising administering an effective amount of a composition comprising a compound according any one of paragraphs [0033]-[0120] to a cell or a plurality of cells.

[0185] As mentioned, although improved quinolines and quinazolines of the invention can be made via conventional serial methods, due to their complex structure, more efficient 131 FCT/US2004/031523 2013204031 11 Apr 2013 WO 2005/030140 routes are desirable, particularly convergent syntheses. Thus, the present invention also comprises a process for preparing a compound of Formula ΓΠ,

comprising reaction of a compound of Formula XXII, with a compound of Formula xxm

r70 p2_

(BV xxm each R1 is independently selected from halogen, -OR3, -N02, -NH2, -NR^, -D-R50 and optionally substituted Ci-ealkyl; R70 is selected from -H, halogen, -OR3, -S(OVaR3, -N02, -NHa, -NR3R3, and optionally substituted Ci^alkyl; J is selected from =N-, =C(H)-, =C(halogen)-, and =C(CN)-; Z is selected from -S(0)o-2-, -Ο-, and -NR5-; each Rs is independently selected from ~H, optionally substituted Ci^alkyl, optionally substituted acyl, and optionally substituted aryl Ci^alkyl;

Ar is either a five- to ten-membered arylene or a five- to ten-membered heteroarylene containing between one and three heteroatoms;

Rz is selected from -H, halogen, trihalomethyl, -CN, -N02, -N%, -OR3, -NR3R3, -S(0)o.2R3, -SOaNR3R3, -COzR3, -CfOJNRV, -N(R3)S02R3, -N(R3)C(0)R3, -N(R3)C02R3, -C(0)R3, and optionally substituted Q-ealkyl; 1 each R3 is independently selected from -H, -Si(R5)(Rs)R5, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted arylalkyl, and optionally substituted heteroarylalkyl; m PCT/US2004/031523 2013204031 11 Apr 2013 WO 2005/030140 two R3, together with the nitrogen to which they are attached, form a four- to seven-membered heteroalicyclic, said four- to seven-membered heteroalicyclic optionally containing one additional heteroatom; when one said additional heteroatom is a nitrogen, then said nitrogen is optionally substituted with a group selected from -H, trihalomethyl, -SO2R5, -S02NR5R5, ^COjR5, -C(0)NR5R5, -C(0)R!, and optionally substituted lower alfcyl; B is selected from absent, -N(R13)-, -N{SOaR13)-, -0-, -S(0)o.r» and-C(=0)-; L is selected from absent, -C^NCR13)-, -C^NR^NCR13)-, -SQzN(R13)-, -SO2-, -C(=0)N(R13)-, -NCR13)-, -C(=0)Ci.2allcylN(R13)-, -N(R13)C,.2aIkylC(=0)-, -C(=O)C0.1alkylC(=O)N(R13)-, -C(=0)-, -CQ4alkylene-, -C(=O)C0-ialliylC(=O)OR3-, -C(-NRw)Co-ialkylC(=0)-, -C(=0)Co.jaIlrylC(=0)-, and an optionally substituted four- to six-membensd heterocyclyl containing between one and three annular heteroatoms and comprising at least one nitrogen; T is selected from -H, -R13, -Qwalkyl, -C^alkylQ, -OCiwalliylQ, -Co^alkylOQ, -N(R13)CMalkyIQ, -SOzCo^alkylQ, -C(=O)C0.4alkylQ, -Co4alkyIN(RJ3)Q,, and -C(=aO)N(R13)C(MalkylQ, wherein each of die aforementioned Co^alkjd is optionally substituted; Q is a five- to ten-membered ring system, optionally substituted with between zero and four of R20; each R20 is independently selected from -H, halogen, trihalomethyl, -CN, -NO&amp; -NH2, -OR3, -NR^, -S(0)o.3R3, -S02NR3R3, -CQ2R3, -C(0)NR3R3, -N(R3)S02R3,

-N(R3)C(0)R3, -N(R3)C02R3, -C(0)R3, optionally substituted Ci^alkyl, optionally substituted aryl, optionally substituted aryl Cx^alkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclyl Q^alkyU two of R20, together with the atom or atoms to which they are attached, combine to form an optionally substituted three- to seven-membered heteroalicyclic, said optionally substituted three- to seven-membered heteroalicyclic either spiro- to Q or fused to Q; D is selected from -0-, -S(0)o-2-, and -NR15-; RSo is either R3, or according to formula XXTV; 133 PCT/US2004/031523 2013204031 11 Apr 2013 WO 2005/030140

wherein X1, X2, and optionally X3, represent the atoms of a saturated bridged ring system, said saturated bridged ring system comprising up to four annular heteroatoms represented by any of X1, X2, and X3; wherein, each X1 is independently selected from -CfR^R7-, -Ο-, -S(0)o.2-, and-NR8-; each X2 is independently an optionally substituted bridgehead methine or a bridgehead nitrogen; each X3 is independently selected from -CCR^R7-, -Ο-, -S(0)o.2-, and -NR8-; Y is either: an optionally substituted CVealkylene linker, between D and either 1) any annular atom of the saturated bridged ring system, except X2 when X2 is a bridgehead nitrogen, or 2) any heteroatom, represented by any of R6 or R7; provided there are at least two carbon atoms between D and any annular heteroatom of the saturated bridged ring system or any heteroatom represented by any of R6 or R7; or Y is absent, when Y is absent, said saturated bridged ring system, is directly attached to D via an annular carbon of said saturated bridged ring system, unless D is -SOr, in which case said saturated bridged ring system, is directly attached to D via an any annular atom of said saturated bridged m and p are each independently one to four; n is zero to two, when n is zero, then there is a single bond between the two bridgehead X2’s; R6 and R7 are each independently selected from -H, halogen, trihalomethyl, -CN, -NH2, -NO2, -OR3, -NRV, ~S(0)o.2R3, -SOaNRV, -CO2R3, -0(0)1¾¾3. -N^SOzR3, -N(R3)C(0)R3, -NCO2R3, -C(0)R3, optionally substituted Q^alkyl, optionally substituted aryl, optionally substituted aryl Q-ealkyl, optionally substituted heterocyclyl, optionally substituted heterocyclyl a Ci.elkyl; and a bond to either Y or D; or 134 PCT/US2004/031523 2013204031 11 Apr 2013 WO 2005/030140 R6 and R7, when taken together are oxo; or R6 and R7, when taken together with a common carbon to which they are attached, form a optionally substituted three- to seven-membered spirocyclyl, said optionally substituted three- to seven-membered spirocyclyl optionally containing at least one additional annular heteroatom selected from N, O, S, and P; R8 is selected from -R3, Y, -SOaNR3R3, -CCfcR3, -CCOJNR^, -SO2R3, and ^C(0)R3; R13 is selected from -H, -C(=0)R3, -C(=0)OR3, -C(=0)SR3, -SO2R3, -C(=0)N(R3JR3, and optionally substituted Ci-salkyl; two R13, together with the atom or atoms to which they are attached, can combine to form a heteroalicyclic optionally substituted with between one and four of Rso, said heteroalicyclic comprising up to four annular heteroatoms, and said heteroalicyclic optionally comprising an aryl or heteroaryl fused thereto, in which case said aryl or heteroaryl is optionally substituted with an additional one to four of R60; R14 is selected from -H, -N02, -ΝΗ2» -N(R3)R3, -CN, -OR3, optionally substituted Ci_6alkyl, optionally substituted heteroalicyclyl Ci-galkyl, optionally substituted aryl, optionally substituted aryl Ci^alkyl and optionally substituted heteroalicyclic; R15 is a group -M^-M2, wherein M1 is selected from absent, -C(=S)N(R13)-, -C(=MR14)N(R13)-, -SQ2N(R13K -S02-, -C(=0)N(R13)-, -C(=0)C(=O)N(R13)-, -Co^alkylene-, -C(=0)-, and an optionally substituted four to six-membered heterocyclyl containing between one and three heteroatoms but comprising at least one nitrogen; and M2 is selected from -H, -Co.ealkyl, allcoxy, -C(=0)Co.4alkylQ, -Co^alkylQ, -OCo^alkylQ-, -N(R13)C&amp;4alkylQ-, and -C(=0)N(R13)QMalkylQ; R60 is selected from -H, halogen, trihalomethyl, -CN, -N02, -NH2, -OR3, -NR3R3, -SiOVzR3, -S02NR3R3, -CO2R3, -C(0)NR3R3, -N(R3)S02R3, -N(R3)C(0)R3, -N(R3)C02R3, -C{0)R3, optionally substituted Chalky!, optionally substituted aryl, optionally substituted heteroaryl Ci^alkyl, and optionally substituted aryl Cj^alkyl; two of R60, when attached to a non-aromatic carbon, can be oxo; P1 is a suitable leaving group; and

P2 is selected from -H, a metal, and a group removed in-situ when combining XXH and ΧΧΠΙ to make XXL 135 PCT/US2004/03I523 2013204031 11 Apr 2013 WO 20057030140 [0131] In one example, the process is according to paragraph [0130], wherein Ar is para-phenylene as defined by the substitution pattern of -Z- and -B-L-T about said phenylene.

[0132] fit another example, the process is according to paragraph [0131], wherein Z is either-O-car -NR5-.

[0133] In another example, the process is according to paragraph [0132], wherein -B-L-T is selected from the following: R13 R13 %« R13 R13 I I / \0-3 Ns wO Rw r-T ^Νγ">^0 0 I-(l)12 o o i-f ^NY^Q 0 „13 ^TJhI R13 ΎΥ. „13 R13 vnyW2 . N^V |jj13 r A n«w O 0 Rl3 1 / A R13 *Vy*S O 0 R13 ^0YAH;Q3 0 R13 O 0 V u1-3 R13 Vr 0 V-Y" Ύ γ r13 ^y-Y Y Y SR13 O <£-X ,[V _«L Ύ γ r13 0 X -N. .|\L Y XR13 0 136 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523 R13 r1S S r13 r13 s 0 r-*r λ/Νγν° s s 0 Γ-Τ* Y Y R13 «h s Aw 0 r13 1 / vo^t γΝγ^ο o R13 (f^M 0 0 r <k? Y^Y^SH t (ft? χ/Ν n 0H 0 n R13 iiS t ' r0-3 R13 N (I H O I—! , γ '•RlS 0 R13 • t \Q-2 „ O 0 r-f2 *V 0 Y^t'0 A- \^)θ4 0 w U04 V n1"2 1 6 r13 R13 r13 I I, / *0-3 -YY Λ^° 0 %R3 Λ^3 0 Sir3 R13 r13 I / »0-2 I ν"Νγ^γ%13 - R13 I f *0-2 _ ^NYiTCl-6alkyl wherein Q, R20, and R13 are as defined above; each E is selected from -0-, -N(R13)-, -Cife, and -S(0)o-2-; M is selected from -0-, -N(R13)-, -CH2-, and -C(=0)N(R13)-; each V is independently either =N- or =C(H)-; each methylene in any of the above formulae is 137 PCT/US2004/031523 2013204031 11 Apr 2013 WO 2005/030140 independently optionally substituted with R25; and R25 is selected from halogen, trihalomefliyl, -CN, -N02, -NH2, -OR3, -NR^3, -S(0)o.2R3, -SOzNR^t3, -COzR3, -C(0)NR3R3, -NCR^SOiR3, -NCR^OJR3, -N(R3)C02R3, -C(0)R3, optionally substituted aryl, optionally substituted aryl Ci^alkyl, heteroaryl Ci^aBtyl, and optionally substituted Ci.6alkyl; two of R25, together with die carbon or carbons to which they are attached, can combine to form an optionally substituted three- to seven-membered alicyclic or heteroalicyclic; two of R25 on a single carbon can be oxo.

[0134] In another example, the process is according to paragraph [0133], wherein there is one of R1 that is -D-R50 and another of R1 that is -OR3*.

[0135] In another example, the process is according to paragraph [0134], wherein D is -0-.

[0136] In another example, the process is according to paragraph [0135], wherein -O-R50 and -OR3a are interchangeably located at the 6-position and 7-position of the quinazotine or quinoline according to Formula XXI.

[0137] In another example, the process is according to paragraph [0136], wherein -OR3® is selected from -OH, -OSi(R5)(R5)Rs, and optionally substituted -OCi^aOcyL

[0138] In another example, the process is according to paragraph [0137], wherein J is =N-or =C(H)-.

[0139] In another example, the process is according to paragraph [0138], wherein -B-L-T is selected from;

R13 O O FI13 r13 r13 1 1 / \0-3 r13 r13 ^YVU3 ' O 0 r13 f / a-2 / vO-3 (R%-4 B13 L ^ iTlj ^0-2 O 0 R13 1 / \0-4 O r13 t / \0-l t vO-3 v^yV'0 O 0 r13 r13 I / \(M J 138 WO 2005/030140 PCT/US2004/031523

2013204031 11 Apr 2013 wherein Q, R20, R13, E, and R®0 ate as defined above; each methylene in any of the above formulae, other than those in a depicted ring, is independently optionally substituted with R23; and R25 is selected from halogen, trihalomethyl, oxo, -CN, -NO* -NH* -OR3, -NR3R3, -S(0)o.2R3, -SOjNR^, -COzR3, -C(0)NR3R3, -N(R3)SO^R3, -N(R3)C(0)R3, -N(R3)C02R3, -C(0)R3, optionally substituted aryl, optionally substituted aryl C^aUcyl, heteroaryl Ci^alkyl, and optionally substituted Q-ealkyl; two of R25, together with the carbon or carbons to which they are attached, can combine to form a three- to seven-membered optionally substituted ahcyclic or heteroalicyclic.

[0140] In another example, the process is according to paragraph [0139], wherein Q is selected from the following three formula:

wherein R20 is defined as above, and P is a five- to seven-membered ring, including the two shared carbons of the aromatic ring to which P is fused, P optionally containing between one and three heteroatoms.

[0141] In another example, the process is according to paragraph [0140], wherein -B-L-T is either of formula XXV or formula XXVI,

wherein R20 is defined as above; G is either an optionally substituted cycloalkyl or an optionally substituted heteroalicyclic; each R30 is independently selected from halogen, trihalomethyl, -CN, -NO* -NH* -OR3, -NR3R3, -S(0)o.aR3, -SOaNR^3, -COaR3, -C(0)NR3R3, -N(R3)SOaR3, -N(R3)C(0)R3, -NCR^COaR3, -C(0)R3, and optionally 139 PCT/US2004/031523 2013204031 11 Apr 2013 WO 2005/030140 substituted C^alkyl; and R3a and R3b are each independently selected from -H and optionally substituted Ci-salkyl.

[0142] In another example, the process is according to paragraph [0141], wherein a compound of formula XXUa is combined with a compound of formula XKTIla to make a compound of formula XXIa, C^alkyl-O·. tod. (R2)o-4 XXUa xxma f 7iB^T \ (r2)cm h“<A- AA R70 XXIa wherein -B-L-T, Z, J, R50, and R2 are as defined above; R70 is selected from -¾ -NO2, -NHj, and -NRaR3; provided when Z is -N(R5)- that R5 is selected from -H, Ci.3alkyl, and aryl Ci^alkyl; P1 is selected from halogen, optionally substituted alkyl-S(0)o.2-, optionally substituted arylsulfonate, optionally substituted alkylsulfonate, a group containing boron, an azide, a group containing phosphorus, and a metal; and P2 is selected from -H and a metal.

[0143] In another example, the process is according to paragraph [0142], wherein P2 is selected from-H, lithium, sodium, potassium, cesium, copper, palladium, and titanium.

[0144] In another example, the process is according to paragraph [0143], wherein Z is -O-.

[0145] In another example, the process is according to paragraph [0144], wherein P1 is selected from chlorine, bromine, a toluene sulfonate, and trifluoromethansulfonate.

[0146] In another example, the process is according to paragraph [0145], wherein R70 is -H.

[0147] In another example, the process is according to paragraph [0146], wherein J is =C(H)-.

[0148] In another example, the process is according to paragraph [0147], wherein R2 is selected from Cj.s alkyl, perfluoro Ci* alkyl, and halogen. 140 PCT/US2004/031523 2013204031 11 Apr 2013 WO 2005/030140 [0149] In another example, the process is according to paragraph [0148], wherein XXHa and XXIIIa are heated together, optionally with a base, optionally with microwave radiation, to form XXIa.

I

[0150] In another example, the process is according to paragraph [0149], wherein the base is selected from an organic base, an inorganic base, and a combination of an organic base and an inorganic base.

[0151] In another example, the process is according to paragraph [0150], wherein the base is selected from 2,6-lutidine, 4-N^-dimethylantinopyridine, and a metal carbonate.

[0152] In another example, the process is according to paragraph [0151], wherein XXHa and XXIIIa are heated together in a solvent with said base, at between about 40°C and 200°C for between about one hour and twepty-four hours to form XXIa.

[0153] In another example, the process is according to paragraph [0152], wherein the solvent is an organic solvent.

[0154] In another example, the process is according to paragraph [0153], wherein one molar equivalent of XXIIa is combined with between about one quarter and four-molar equivalents of XXIIIa.

[0155] In another example, the process is according to paragraph [0154], wherein one molar equivalent of XXHa is combined with more than one but less than two molar equivalents of XXIIIa [0156] In another example, the process is according to paragraph [0155], wherein XXIIa is combined with XXIIIa and said base in an aromatic solvent to form a mixture, and said mixture is heated to between about 100°C and 2G0°C for between about one and ten hours to form la.

[0157] In another example, die process is according to paragraph [0156], wherein the aromatic solvent is an optionally substituted benzene.

[0158] In another example, the process is according to paragraph [0157], wherein the aromatic solvent is bromobenzene.

[0159] In another example, the process is according to paragraph [0158], wherein the base is 4-N,N-dimethylaminopyridine. 141 PCT/US2004/031523 2013204031 11 Apr 2013 WO 2005/030140 [0160] In another example, the process is according to paragraph [0159], wherein said mixture is heated to reflux for between about three and seven hours.

[0161] In another example, die process is according to paragraph [0160], wherein said mixture is heated to reflux for between about four and six hours.

[0162] Bi another example, the process is according to paragraph £0155], wherein XXfla is combined with XXlUa and said base in a non-aromatic solvent to form a mixture, and said mixture is heated to between about 40°C and 100°C for between about one and twenty hours to form XXIa.

[0163] In another example, the process is according to paragraph [0162], wherein the nonaromatic solvent comprises a functional group selected from an amide, and ether, a nitrile, a halide, an ester, an amine, and a ketone.

[0164] In another example, the process is according to paragraph [0163], wherein the nonaromatic solvent is NJsT-dimethylacetamide.

[0165] In another example, the process is according to paragraph [0164], wherein the base is potassium carbonate.

[0166] In another example, the process is according to paragraph [0165], wherein said mixture is heated to about 50°G between about ten and twenty hours.

[0167] In another example, the process is according to paragraph [0166], wherein the aromatic solvent is an optionally substituted pyridine.

[0168] hi another example, the process is according to paragraph [0167], wherein the aromatic solvent is 2,6-lutidine.

[0169] Bi another example, the process is according to paragraph [0168], wherein the base is 2,6-lutidine. ' [0170] In another example, the process is according to paragraph [0169], wherein said . mixture is heated to reflux for between about three and seven hours.

[0171] In another example, the process is according to paragraph [0170], wherein said mixture is heated to reflux for between about four and six hours.

[0172] In another example, the process is according to paragraph [0154], wherein one molar equivalent of XXJQIa is combined with more than one but less than two molar equivalents of XXHa. 142 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523 [0173] In another example, the process is according to paragraph [0172], wherein XXIIa is combined with XXJQIa and said base in an aromatic solvent to form a mixture, and said mixture is heated to between about 100°C and 200°C for between about ten and twenty hours to form XXIa.

[0174] In another example, the process is according to paragraph [0173], wherein the aromatic solvent is an optionally substituted pyridine.

[0175] In another example, the process is according to paragraph [0174], wherein the aromatic solvent is 2,6-lutidine.

[0176] In another example, the process is according to paragraph [0175], wherein the base is 2,6-lutidine.

[0177] In another example, the process is according to paragraph [0176], wherein said mixture is heated to between about 150°C and 200°C for between about fifteen and twenty hours.

[01¾] In another example, the process is according to any of paragraphs [0149] - [0177], wherein a compound of formula XXHb is substituted for the compound of formula XXTfa, and either a compound of formula XXlIIb or a compound of formula XMc is substituted for the compound of formula XXHIa, in order to make a compound of formula XXIb or a compound of formula XXIc, respectively,

XXIIb

YYTTlh xxmc 143 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523

wherein J, R50, R20 and R2 are as defined above.

[0179] In another example, the process is according to paragraph [0178], wherein R2, if present, is halogen.

[0180] In another example, the process is according to paragraph [0179], wherein R2, if present, is fluorine.

[0181] In another example, the process is according to paragraph [0180], wherein R2, if present, is up to two fluorines ortho to the oxygen of the phenylene to which R2 is attached.

[0182] In another example, the process is according to paragraph [0130], used to make a compound listed in either Table 1 or Table 2.

[0183] In another example the process is according to any of paragraphs [0130] - [0182], further comprising converting said compound to a pharmaceutically acceptable salt, hydrate, or prodrug thereof.

Definitions [0184] As used iu the present specification, the following words and phrases are generally intended to have the meanings as set forth below, except to the extent that die context in 144 2013204031 11 Apr 2013 PCT/US2004/031523 WO 2005/030140 which they are used indicates otherwise or they are expressly defined to mean something different.

[0185] The symbol **-” means a single bond, means a double bond, “s” means a triple bond. The symbol “*n/w” refers to a group on a double-bond as occupying either position on the terminus of a double bond to which the symbol is attached; that is, the geometry, E- or Z-, of the double bond is ambiguous. When a group is depicted removed from its parent formula, the symbol will be used at the end of the bond which was theoretically cleaved in order to separate the group from its parent structural formula, [0186] When chemical structures are depicted or described, unless explicitly stated otherwise, all carbons are assumed to have hydrogen substitution to conform to a valence of four. For example, in the structure on the left-hand side of the schematic below there are nine hydrogens implied. The nine hydrogens are depicted in the right-hand structure. Sometimes a particular atom in a structure is described in textual formula as having a hydrogen or hydrogens as substitution (expressly defined hydrogen), for example, -CH2CH2-. It is understood by one of ordinary skill in the art that the aforementioned descriptive techniques are common in the chemical arts to provide brevity and simplicity to description of otherwise complex structures.

[0187] In this application, some ring structures are depicted generically and will be described textually. For example, in the schematic below, if in the structure on the . left, ring A is used to describe a “spirocyclyl,” then if ring A is cyclopropyl, than are at most four hydrogens on ring A (when “R” can also be -H). In another example, as depicted on the right side of the schematic below, if ring B is used to describe a “phenylene” then there can be at most four hydrogens on ring B (assuming depicted cleaved bonds are not OH bonds).

[0188] If a group “R” is depicted as “floating” on a ring system, as for example in the formula: 145 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523

then, unless otherwise defined, a substituent “R" may reside on any atom of the ring system, assuming replacement of a depicted, implied, or expressly defined hydrogen from one of the ring atoms, so long as a stable structure is formed.

[0189] If a group <CR" is depicted as floating on a fused ring system, as for example in the formulae:

then, unless otherwise defined, a substituent “R" may reside on any atom of the fused ring system, assuming replacement of a depicted (for example the -ΝΉ- in the formula above), implied (for example as in the formula above, where the hydrogens are not shown but understood to be present), or expressly defined hydrogen (for example where in ihe formula above, “X” equals ~CH-) from one of the ring atoms, so long as a stable structure is formed. In the example depicted, the “R” group may reside on either the 5-membered or the 6-membered ring of the fused ring system, hi the formula depicted above, when y is 2 for example, thou the two “R’s” may reside on any two atoms of the ring system, again assuming each replaces a depicted, implied, or expressly defined hydrogen on the ring.

[0190] When there are more than one such depicted “floating” groups, as for example in the formulae:

where there are two groups, namely, the “R” and the bond indicating attachment to a parent structure; then, unless otherwise defined, the ‘floating” groups may reside on any atoms of the ring system, again assuming each replaces a depicted, implied, or expressly defined hydrogen on the ring.

[0191] When a group “R” is depicted as existing on a ring system containing saturated carbons, as for example in the formula: 146 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523

where, in this example, “y” can be mace than one, assuming each replaces a currently depicted, implied, or expressly defined hydrogen on the ring; then, unless otherwise defined, where the resulting structure is stable, two >cR’s” may reside on the same carbon. A simple example is when R is a methyl group; there can exist a geminal dimethyl on a carbon of the depicted ring (an “annular” carbon). In another example, two R’s on the same carbon, including that carbon, may farm a ring; thus creating a spirocyclic ring (a “spirocyclyl” group) structure with the depicted ring as for example in the formula;

[0192] “Alkyl” is intended to indude linear, branched, or cyclic hydrocarbon structures and combinations thereof, inclusively. For example, “Cg alkyl” may refer to an ra-octyl, ώσ-octyL, cydohexylethyl, and the like. Lower alkyl refers to alkyl groups of from one to six carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, j-butyl, /-butyl, isobutyl, pentyl, hexyl and the like. Higher alkyl refers to alkyl groups containing more that eight carbon atoms. Exemplary alkyl groups are those of C20 or below. Cycloalkyl is a subset of alkyl and indudes cyclic hydrocarbon groups of from three to thirteen carbon atoms. Examples of cycloalkyl groups include c-propyl, c-butyl, c-pentyl, norbomyl, adamantyl and the like. 2h this application, alkyl refers to alkanyl, alkenyl, and alkynyl residues (and combinations thereof); it is intended to include cyclohexylmethyl, vinyl, allyl, isoprenyl, and the Hke. Thus when an alkyl residue having a specific number of carbons is named, all geometric isomers having that number of carbons are intended to be encompassed; thus, for example, either ‘butyl” or “C4 alkyl" is meant to include n-butyl, jec-butyl, isobutyl, /-butyl, isobutenyl and but-2-yne radicals; and for example, "propyl” or “C3 alkyl" each indude n-propyl, propenyl, and isopropyl.

[0X93] “Alkylene" refers to straight or branched chain divalent radical consisting solely of carbon and hydrogen atoms, containing no unsaturation and having from one to ten carbon atoms, for example, methylene, ethylene, propylene, n-butylene and the like. Alkylene is a subset of alkyl, referring to the same residues as alkyl, but having two points of attachment and, specifically, fully saturated. Examples of alkylene include ethylene 147 PCT/US2004/031523 2013204031 11 Apr 2013 WO 2005/030140 (-CH2CH2-), propylene C-CH2CH2CH2-), dimethylpropylene (-CBzCiCRdiCSk.-), and cyclohexylpropylene (-C^CHaCHiCgHn)).

[0194] “Alkylidene” refers to a straight or branched chain unsaturated divalent radical consisting solely of carbon and hydrogen atoms, having from two to ten carbon atoms, for example, ethylidene, propylidene, n-butylidene, and the like. Alkylidene is a subset of alkyl, referring to the same residues as alkyl, but having two points of attachment and, specifically, double bond unsaturation. The unsaturation present includes at least one double bond [0195] “Alkylidyne" refers to a straight or branched chain unsaturated divalent radical consisting solely of carbon and hydrogen atoms having from two to ten carbon atoms, for example, propylid-2-ynyl, n-butylid-l-ynyl, and the like. Alkylidyne is a subset of alkyl, referring to the same residues as alkyl, but having two points of attachment and, specifically, triple bond unsaturation. The unsaturation present includes at least one triple bond.

[0196] Any of the above radicals, “alkylene,” “alkylidene” and “alkylidyne,” when optionally substituted, may contain alkyl substitution wbich itself contains unsaturation. For example, 2-(2-phenylethynyl-but-3-enyl)-naphthaIene (TUPAC name) contains an K-butylid-3-ynyl radical with a vinyl substituent at the 2-position of said radical.

[0197] “Alkoxy” tar “alkoxyl” refers to the group -O-alkyl, for example including from one to eight carbon atoms of a straight, branched, cyclic configuration, unsaturated chains, and combinations thereof attached to the parent structure through an oxygen atom. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like. Lower-alkoxy refers to groups containing one to six carbons.

[0198] “Substituted alkoxy” refers to the group -0-(substituted alkyl), the substitution on the alkyl group generally containing more than only carbon (as defined by alkoxy). One exemplary substituted alkoxy group is “polyalkaxy” or -O-optionally substituted alkylene-optionally substituted alkoxy, and includes groups such as -OCH2CH2OCH3, and glycol ethers such as polyethyleneglycol and -O^HaCIkO^CHb, where x is an integer of between about two and about twenty, in another example, between about two and about ten, and in a further example between about two and about five. Another exemplary substituted alkoxy group is hydroxyalkoxy or -OCH2(CH2)yOH, where y is for example an 148 PCT/US2004/031523 2013204031 11 Apr 2013 WO 2005/030140 integer of between about one and about ten, in another example y is an integer of between about one and about four.

[0199] “Acyl” refers to groups of from one to ten carbon atoms of a straight, branched, cyclic configuration, saturated, unsaturated and aromatic and combinations thereof, attached to the parent structure through a carbonyl functionality. One or mare carbons in the acyl residue may be replaced by nitrogen, oxygen or sulfur as long as the point of attachment to the parent remains at the carbonyl. Examples include acetyl, benzoyl, propionyl, isobutyryl, ί-butoxycarbonyl, benzyloxycarbonyl and the like. Lower-acyl refers to groups containing one to six carbons.

[0200] “α-Amino Acids” refer to naturally occurring and commercially available amino adds and optical isomers thereof. Typical natural and commercially available a-amino adds are glycine, alanine, serine, homoserine, threonine, valine, norvaline, leucine, isoleucine, norleucine, aspartic acid, glutamic acid, lysine, ornithine, histidine, arginine, cysteine, homocysteine, methionine, phenylalanine, homophenylalanine, phenylglycine, ortho-tyrosine, meta-tyrosine, para-tyrosine, tryptophan, glutamine, asparagine, proline and hydroxyproline. A “side chain of an α-amino add” refers to the radical found on the α-carbon of an α-amino acid as defined above, for example, hydrogen (for glycine), methyl (for alanine), benzyl (for phenylalanine), and the like.

[0201] “Amino” refers to the group -NH3. “Substituted amino,” refers to the group -N(H)R or -N(R)R where each R is independently selected from the group: optionally substituted alkyl, optionally substituted alkoxy, optionally substituted aryl, optionally substituted heterocyclyl, acyl, carboxy, alkoxycarbcsiyl, sulfanyl, sulfinyl and sulfonyl, for example, diethylamino, methylsulfonylamino, furanyl-oxy-sulfonamino.

[0202] “Aryl” refers to aromatic six- to fourteen-membered caibocyclic ring, for example, benzene, naphthalene, indane, tetralin, fhiorene and the like, univalent radicals. As univalent radicals, the aforementioned ring examples are named, phenyl, naphthyl, indanyl, tetralinyl, and fluorenyl.

[0203] “Arylene” genetically refers to any aryl that has at least two groups attached thereto. For a more specific example!, “phenylene” refers to a divalent phenyl ring radical. A phenylene, thus may have more than two groups attached, but is defined by a minimum of two non-hydrogen groups attached thereto. 149 WO 2005/030140 2013204031 11 Apr 2013 PCT/US2004/031523 [0204] “Arylalkyl” refers to a residue in which an aryl moiety is attached to a parent structure via one of an alkylene, alkylidene, or alkylidyne radical. Examples include benzyl, phenethyl, phenylvinyl, phenylallyl and the like. Both the aryl, and the corresponding alkylene, alkylidene, or alkylidyne radical portion of an arylalkyl group may be optionally substituted. “Lower arylalkyl" refers to an arylalkyl where the “alkyl” portion of the group has one to six carbons; this can also be refered to as Ci.g arylalkyl, [0205] “Exo-alkenyl" refers to a double bond that emanates from an annular carbon, and is not within the ring system, for example the doable bond depicted in the formula below.

[0206] In some examples, as appreciated by one of ordinary skill in the art, two adjacent groups on an aromatic system may be fused together to form a ring structure. The fused ring structure may contain heteroatoms and may be optionally substituted with one or more groups. It should additionally be noted that saturated carbons of such fused groups (i.e. saturated ring structures) can contain two substitution groups.

[0207] “Fused-polycyclic” or “fused ring system" refers to a polycyclic ring system that contains bridged or fused rings; that is, where two rings have more than one shared atom in their ring structures. In this application, fused-polycyclics and fused ring systems are not necessarily all aromatic ring systems. Typically, but not necessarily, fused-polycyclics share a vicinal set of atoms, for example naphthalene or 1,2,3,4-tetrahydro-naphthalene. A spiro ring system is not a fused-polycyclic by this definition, bat fused polycyclic ring systems of the invention may themselves have spiro rings attached thereto via a single ring atom of the fused-polycyclic.

[0208] “Halogen” or “halo” refers to fluorine, chlorine, bromine or iodine. “Haloalkyl” and “haloaryl” refer genetically to alkyl and aryl radicals that are substituted with one or more halogens, respectively. Thus, “dihaloaryl," “dihaloalkyl,” “trihaloaryl” etc. refer to aryl and alkyl substituted with a plurality of halogens, but not necessarily a plurality of the

I same halogen; thus 4-chloro-3-fluorophenyI is within the scope of dihaloaryl.

[0209] “Heteroarylene” genetically refers to any heteroaryl that has at least two groups attached thereto. For a more specific example, “pyiidylene” refers to a divalent pyridyl 150 PCT/US2004/031523 2013204031 11 Apr 2013 WO 2005/030140 ring radical. A pyridylene, thus may have mote than two groups attached, but is defined by a minimum of two non-hydrogen groups attached thereto.

[0210] ^eteroatom” refers to O, S, N, or P.

[0211] “Heterocyclyl” refers to a stable three- to fifteen-membered ring radical that consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, phosphorus, oxygen add sulfur. For purposes of this invention, the heterocyclyl radical may be a monocyclic, Wcyclic or tricyclic ring system, which may include fused or bridged ring systems as well as spirocyclic systems; and the nitrogen, phosphorus, carbon or sulfur atoms in the heterocyclyl radical may be optionally oxidized to various oxidation states, hi a specific example, the group -S(0)o-r, refers to -S-(sulfide), -S(0> (sulfoxide), and -SO2- (sulfone). For convenience, nitrogens, particularly but not exclusively, those defined as annular aromatic nitrogens, are meant to include their corresponding JV-oxide form, although not explicitly defined as such in a particular example. Thus, for a compound of fee invention having, for example, a pyridyl ring; the corresponding pyridyl-lV-oxide is meant to he included as another compound of the invention. In addition, annular nitrogen atoms may be optionally quatemized; and the ring radical may be partially or fully saturated or aromatic. Examples of heterocyclyl radicals include, but are not limited to, azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofuranyl, carbazoyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, puiinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazoyl, tetrahydroisoquinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxcpiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, dihydropyridinyl, tetrahydropyridinjl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazdinyl, oxazolidinyl, triazolyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolinyl, tbiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinjl, indolyl, isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl, decahydroisoqmnolyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzoxazolyl, fuiyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothieliyl, thiamorpholinyl, feiamorpholinyl sulfoxide, thiamorpholinyl sulfone, dioxaphospholanyl, and oxadiazolyl. 151 PCT/US2004/031523 2013204031 11 Apr 2013 WO 2005/030140 [0212] “Heteroalicyclic” refers specifically to a non-aromatic heterocyclyl radical. A heteroalicyclic may contain unsaturation, but is not aromatic.

[0213] “Heteroaryl” refers specifically to an aromatic heterocyclyl radical [0214] “Heterocyclylalkyl” refers to a residue in which a heterocyclyl is attached to a patent structure via one of an alkylene, alkylidene, or alkylidyne radical. Examples include (4-methylpiperazin-l-yl) methyl, (moipholin-4-yl) methyl, (pyridine-4-yl) methyl, 2-(oxazolin-2-yl) ethyl, 4-(4-methyIpiperazin-l-yl)-2-butenyl, and the like. Both the heterocyclyl, and the corresponding alkylene, alkylidene, or alkylidyne radical pardon of a heterocyclylalkyl group may be optionally substituted. “Lower heterocyclylalkyl” refers to a heterocyclylalkyl where the “alkyl” portion of the group has one to six carbons. ‘Beteroalicyclylalkyl” refers specifically to a heterocyclylalkyl where the heterocyclyl portion of the group is non-aromatic; and “heteroarylalkyl” refers specifically to a heterocyclylalkyl where the heterocyclyl portion of the group is aromatic Such terms may be described in more than one way, for example, “lower heterocyclylalkyl” and “heterocyclyl Chalky!” are equivalent terms.

[0215] “Optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not One of ordinary skill in" the art would understand that, with respect to any molecule described as containing one or more optional substituents, that only statically practical and/or synthetically feasible compounds are meant to be included. “Optionally substituted” refers to all subsequent modifiers in a term, for example in the term “optionally substituted arylCi.g alkyl,” optional substitution may occur on both the “Cj_8 alkyl” portion and the “aryl” portion of the molecule; and for example, optionally substituted alkyl includes optionally substituted cycloalkyl groups, which in turn are defined as including optionally substituted alkyl groups, potentially ad infinitum. A list of exemplary optional substitution are listed below in the definition of “substituted.” [0216] “Saturated bridged ring system” refers to a bicyclic or polycyclic ring system that is not aromatic. Such a system may contain isolated or conjugated unsaturation, but not aromatic or heteroaromatic rings in its core structure (but may have aromatic substitution thereon). For example, hexahydro-furo[3,2-b]furan, 2,3,3a,4,7,7a-hexahydrD-lH-mdene, 7-aza-bicyclo[2.2.1]heptane, and l,2,3,4,4a,5,8,8a-0ctahydro-naphthalene are all included in the class “saturated bridged ring system.” 152 PCT/US2004/03I523 2013204031 11 Apr 2013 WO 2005/030140 [0217] “Spirocyclyl” or “spirocyclic ring” refers to a ring originating from a particular annular carbon of another ting. For example, as depicted below, a ling atom of a saturated bridged ring system (rings B and B’)> but not a bridgehead atom, can be a shared atom between the saturated bridged ring system and a spirocyclyl (ring A) attached thereto. A spirocyclyl can be caibocyclic or heteroaUcyclic.

[0218] “Substituted” alkyl, aryl, and heterocyclyl, refer respectively to alkyl, aryl, and heterocyclyl, wherein one or more (for example up to about five, in another example, up to about three) hydrogen atoms are replaced by a substituent independently selected from; optionally substituted alkyl (for example, fluoromethyl), optionally substituted aryl (for example, 4-hydnoxyphenyl), optionally substituted arylalkyl (for example, 1-phenyl-ethyl), optionally substituted heterocydylalkyl (far example, l-pyridin-3-yl-ethyl), optionally substituted heterocyclyl (for example, 5-chlaro-pyridin-3-yl or 1 -methyl-piperidin-4-yl), optionally substituted alkoxy, alkylenedioxy (for example methylenedioxy), optionally substituted amino (for example, alkylamino and dialkylamino), optionally substituted amidino, optionally substituted aryloxy (for example, phenoxy), optionally substituted arylalkyloxy (for example, benzyloxy), carboxy (-CO2H), cafboalkoxy (that is, acyloxy or -OC(=OJR), carboxyalkyl (that is, esters or -CO2R), carboxamido, benzyloxycarbonylamino (CBZ-amino), cyano, acyl, halogen, hydroxy, nitro, sulfanyl, sulfinyl, sulfonyl, thiol, halogen, hydroxy, oxo, carbamyl, acylamino, and sulfonamide.

[0219] “Suitable leaving group” is defined as the term would be understood by one of ordinary skill in the art; that is, a carbon with such a group attached, upon reaction wherein a new bond is to be formed, loses such a group upon formation of the new bond. The invention pertains particularly with respect convergent synthesis, to reactions where such a. leaving group is bonded to a reaction partner that is aromatic, undergoes a bond-forming reaction and remains aromatic. A typical example of such a reaction is a nucleophilic aromatic substitution reaction, as would be understood by one of ordinary skill in the art. However, the invention is not limited to such mechanistic restrictions; for example, reactions where there is, for example, an insertion reaction (for example by a transition metal) into the bond between the aromatic reaction partner and its leaving group 153 PCT/US2004/031523 2013204031 11 Apr 2013 WO 2005/030140 followed by reductive coupling can also be used within the scope of the invention. Examples of suitable leaving groups include halogens, optionally substituted aryl or alkyl sulfonates, phosphonates, azides, RS(0)o-2- where R is, for example optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl.

[0220] “Sulfanyl" refers to the groups: -S-(optionally substituted alkyl), -S-(optionally substituted aryl), and -S-(optiona31y substituted heterocyclyl).

[0221] “SulfinyT refers to the groups: -S(0)-H, -S(0)-(optionally substituted alkyl), -S(0)-optionally substituted aryl), and -S(0)-(optionally substituted heterocyclyl).

[0222] “Sulfonyl” refers to the groups: -SfOjHoptionally substituted alkyl), -S(02)-optionally substituted aryl), -S(02>(optionally substituted heterocyclyl), -S(02)-(optionally substituted alkoxy), -S(C>2)"Optionally substituted aryloxy), and -S(02)-(optionally substituted heterocyclyioxy).

[0223] “Yield” for each of tiie reactions described herein is expressed as a-percentage of the theoretical yield [0224] Some of the compounds of the invention may have imino, amino, oxo or hydroxy substituents off aromatic heterocyclyl systems. For purposes of tins disclosure, it is understood that such imino, amino, oxo or hydroxy substituents may exist in their corresponding tautomeric form, i.e., amino, imino, hydroxy or oxo, respectively.

[0225] Compounds of the invention are named according to systematic application of the nomenclature rules agreed upon by the International Union of Pure and Applied Chemistry (IUPAC), International Union of Biochemistry and Molecular Biology (IUBMB), and the Chemical Abstracts Service (CAS).

[0226] The compounds of the invention, or their pharmaceutically acceptable salts, may have asymmetric carbon atoms, oxidized sulfur atoms or quatemized nitrogen atoms in their structure.

[0227] The compounds of the invention and their pharmaceutically acceptable salts may exist as single stereoisomers, racemates, and as mixtures of enantiomers and diastereomers. The compounds may also exist as geometric isomers. AH such single stereoisomers, racemates and mixtures thereof, and geometric isomers are intended to be within the scope of this invention.

I 154 PCT/US2004/031523 2013204031 11 Apr 2013 WO 2005/030140 [0228] It is assumed that when considering generic descriptions of compounds of the invention for the purpose of constructing a compound, such construction results in the creation of a stable structure. That is, one of ordinary skill in the art would recognize that there can theoretically be some constructs which would not normally be considered as stable compounds (that is, sterically practical and/or synthetically feasible, supra).

[0229] When a particular group with its bonding structure is denoted as being bonded to two partners; that is, a divalent radical, for example, -OCH2-, then it is understood that either of the two partners may be bound to the particular group at one end, and the other partner is necessarily bound to the other end of the particular group, unless stated explicitly otherwise. Stated another way, divalent radicals are not to be construed as limited to the depicted orientation, for example “-OCH2-” is meant to mean not only “-OCH2~” as drawn, but also "-CH2O-.” [0230] Methods for the preparation and/or separation and isolation of single stereoisomers from racemic mixtures or non-racemic mixtures of stereoisomers are well known in the art. For example, optically active (R)- and (S)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. Enantiomers (R-and S-isomers) may be resolved by methods known to one of ordinary skill in the art, for example by: formation of diastereoisomeric salts or complexes which may be separated, for example, by crystallization; via formation of diastereoisomeric derivatives which may be separated, for example, by crystallization, selective reaction of one enantiomer with an enantiomer-specific reagent, fox example enzymatic oxidation ox reduction, followed by separation of the modified and unmodified enantiomers; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support, such as silica with a bound chiral ligand or in the presence of a chiral solvent. It will be appreciated that where a desired enantiomer is converted into another chemical entity by one of the separation procedures described above, a further step may be required to liberate the desired enantiomeric form. Alternatively, specific enantiomer may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting on enantiomer to the other by asymmetric transformation. For a mixture of enantiomers, enriched in a particular enantiomer, the major component enantiomer may be further enriched (with concomitant loss in yield) by recrystallization.

[0231] “Patient” fur the purposes of the present invention includes humans and other animals, particularly mammals, and other organisms. Thus the methods are applicable to 155 PCT/US2004/031523 2013204031 11 Apr 2013 WO 2005/030140 both human therapy and veterinary applications. In a preferred embodiment the patient is a mammal, and in a most preferred embodiment die patient is human [0232] “Kinase-dependent diseases or conditions" refer to pathologic conditions that depend on the activity of one or mote protein kinases. Kinases either directly or indirectly participate in the signal transduction pathways of a variety of cellular activities including proliferation, adhesion, migration, differentiation and invasion. Diseases associated with kinase activities include tumor growth, the pathologic neovascularization that supports solid tumor. growth, and associated with other diseases where excessive local vascularization is involved such as ocular diseases (diabetic retinopathy, age-related, macular degeneration, and the like) and inflammation (psoriasis, rheumatoid arthritis, and the like).

[0233] While not wishing to be bound to theory, phosphatases can also play a role in “kinase-dependent diseases or conditions7’ as cognates of kinases; that is, kinases phosphorylate and phosphatases dephosphorylate, for example protein substrates. Therefore compounds of the invention, while modulating kinase activity as described herein, may also modulate, either directly or indirectly, phosphatase activity. This additional modulation, if present, may be synergistic (or not) to activity of compounds of the invention toward a related or otherwise interdependent kinase or kinase family, in any case, as stated previously, the compounds of the invention are useful for treating diseases characterized in part by abnormal levels of cell proliferation (i.e. tumor growth), programmed cell death (apoptosis), cell migration and invasion and angiogenesis associated with tumor growth.

[0234] “Therapeutically effective amount” is an amount of a compound of the invention, that when administered to a patient, ameliorates a symptom of the disease. The amount of a compound of the invention which constitutes a “therapeutically effective amount” will vary depending on the compound, the disease state and its severity, the age of the patient to be treated, and the like. The therapeutically effective amount can be determined routinely by one of ordinary skill in the art having regard to his own knowledge and to this disclosure.

[0235] “Cancer” refers to cellular-proliferative disease states, including but not limited to; Cardiac; sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung; bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), 156 PCT/US2004/031523 2013204031 11 Apr 2013 WO 2005/030140 alveolar (faronchlolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hanlartoma, inesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaiposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary tract: kidney (adenocarcinoma, Wilm’s tumor' [nephroblastoma], lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangjocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osieochronftoma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis defomians), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, geiminoma Jpinealoma], glioblastoma multiform, oligodendrogliama, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma);. Gynecological: uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma [serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma], granulosa-thecal cell tumors, SertoliLeydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma], fallopian tubes (carcinoma); Hematologic: blood (myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma [malignant lymphoma]; Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaiposi's sarcoma, moles dysplastic nevi, lipoma, angioma· 157 PCT/US2004/031523 2013204031 11 Apr 2013 WO 2005/030140 dermatofibroma, keloids, psoriasis; and Adrenal lands: neuroblastoma. Thus, the team “cancerous cell” as provided herein, includes a cell afflicted by any one of the above-identified conditions.

[0236] “Pharmaceutically acceptable acid addition salt” refers to those sails that retain the biological effectiveness of the free bases and that are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrohromic add, sulfuric add, nitric acid, phosphoric acid, and the like, as well as organic acids such as acetic add, trifluoroacetic add, propionic acid, glycolic acid, pyruvic add, oxalic add, maleic add, malonic add, succinic add, fumaric acid, tartaric acid, citric add, benzoic add, cinnamic acid, mandelic add, methanesulfonic acid, ethanesulfonic add, p-toluenesulfbnic add, salicylic acid and the like.

[0237] “Pharmaceutically acceptable base addition salts” include those derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Exemplary salts are the ammonium, potassium, sodium, calcium, and magnesium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylammoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. Exemplary organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. (See, for example, S. M. Berge, et al., "Pharmaceutical Salts,” J. Pharm. Sci., 1977;66:1-19 which is incorporated herein by reference.) [0238] “Prodrug” refers to compounds that are transformed (typically rapidly) in vivo to yield the parent compound of the above formulae, for example, by hydrolysis in blood. Common examples include, but are not limited to, ester and amide forms of a compound having an active form bearing a carboxylic acid moiety. Examples of pharmaceutically acceptable esters of the compounds of this invention include, but are not limited to, alkyl esters (for example with between about one and about six carbons) wherein the alkyl group is a straight or branched chain. Acceptable esters also include cycloalkyl esters and 158 PCT/US2004/031523 2013204031 11 Apr 2013 WO 2005/030140 arylalkyl esters such as, but not limited to benzyl. Examples of pharmaceutically acceptable amides of the compounds of this invention include, but are not limited to, primary amides, and secondary and tertiary alkyl amides (for example with between about one and about six carbons). Amides and esters of the compounds of the present invention may be prepared according to conventional methods. A thorough discussion of prodrugs is provided in T. Efiguehi and V. Stella, “Pro-drugs as Novel Delivery Systems," Vol 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Fergamon Press, 1987, both of which are incorporated herein by reference for all purposes.

[0239] “Metabolite” refers to the break-down or end product of a compound or its salt produced by metabolism or biotransformation in the animal or human body; for example, biotransformation to a more polar molecule such as by oxidation, reduction, or hydrolysis, or to a conjugate (see Goodman and Gilman, "The Pharmacological Basis of . Therapeutics" 8.sup.th Ed., Pergamon Press, Gilman et al. (eds), 1990 for a discussion of biotransformation). As used herein, the metabolite of a compound of the invention or its salt may be the biologically active form of the compound in the body. In one example, a prodrug may be used such that the biologically active form, a metabolite, is released in vivo. In another example, a biologically active metabolite is discovered serendipitously, that is, no prodrug design per se was undertaken. An assay for activity of a metabolite of a compound of the present invention is known to one of skill in the art in light of the present disclosure.

[0240] In addition, the compounds of the present invention can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention.

[0241] In addition, it is intended that the present invention cover compounds made either using standard organic synthetic techniques, including combinatorial chemistry or by biological methods, such as bacterial digestion, metabolism, enzymatic conversion, and the like.

[0242] "Treating” or “treatment" as used herein covers the treatment of a disease-state in a human, which disease-state is characterized by abnormal cellular proliferation, and invasion and includes at least one of: (i) preventing the disease-state from occurring in a human, in particular, when such human is predisposed to the disease-state but has not yet 159 PCT/US2004/031523 2013204031 11 Apr 2013 WO 2005/030140 been diagnosed as having it; (ii) inhibiting the disease-state, i.e., attesting its development; and (iii) relieving the disease-state, i.e., causing regression of the disease-state. As is known in the art, adjustments for systemic versus localized delivery, age, body weight, general health, sex, diet, time of administration, drug interaction and the severity of the condition may be necessary, and will be ascertainable with routine experimentation by one of ordinary skill in the art.

[0243] One of ordinary skill in the art would understand that certain crystallized, protein-ligand complexes, in particular c-Met, c-Kit, KDR, flt-3, or flt-4-ligand complexes, and their corresponding x-ray structure coordinates can be used to reveal new structural information useful for understanding the biological activity of kinases as described herein. As well, the key structural features of the aforementioned proteins, particularly, the shape of the ligand binding site, are useful in methods for designing or identifying selective modulators of kinases and in solving the structures of other proteins with similar features. Such protein-ligand complexes, having compounds of the invention as their ligand i component, are an aspect of the invention.

[0244] As well, one of ordinary skill in the art would appreciate that such suitable x-ray quality crystals can be used as part of a method of identifying a candidate agent capable of binding to and modulating the activity of kinases. Such methods may be characterized by the following aspects: a) introducing into a suitable computer program, information defining a ligand binding domain of a kinase in a conformation (e,g. as defined by x-ray structure coordinates obtained from suitable x-ray quality crystals as described above) wherein the computer program creates a model of the three dimensional structures of the ligand binding domain, b) introducing a model of the three dimensional structure of a candidate agent in the computer program, c) superimposing the model of the candidate agent on the model of the ligand binding domain, and d) assessing whether the candidate agent model fits spatially into the ligand binding domain. Aspects a-d are not necessarily carried out in the aforementioned order. Such methods may further entail: performing rational drug design with the model of the three-dimensional structure, and selecting a potential candidate agent in conjunction with computer modeling.

[0245] Additionally, one skilled in the art would appreciate that such methods may further entail: employing a candidate agent, so-determined to fit spatially into the ligand binding domain, in a biological activity assay for kinase modulation, and determining whether said candidate agent modulates kinase activity in the assay. Such methods may also include 160 PCT/US2004/031523 2013204031 11 Apr 2013 WO 2005/030140 administering the candidate agent, determined to modulate kinase activity, to a mammal suffering from a condition treatable by kinase modulation, such as those described above.

[0246] Also, one skilled in the art would appreciate that compounds of the invention can be used in a method of evaluating the ability of a test agent to associate with a molecule or molecular complex comprising a ligand binding domain of a kinase. Such a method may be characterized by the following aspects: a) creating a computer model of a kinase binding pocket using structure coordinates obtained from suitable x-ray quality crystals of the kinase, b) employing computational algorithms to perform a fitting operation between the test agent and the computer model of the binding pocket, and c) analyzing the results of the fitting operation to quantify the association between the test agent and the computer model of the binding pocket

General Administration [0247] Administration of the compounds of die invention, or their pharmaceutically acceptable salts, in pure form or in an appropriate pharmaceutical composition, can be carried out via any of the accepted modes of administration or agents for serving similar utilities. Thus, administration can be, for example, orally, nasally, parenterally (intravenous, intramuscular, or subcutaneous), topically, transdermally, intravaginally, intravesically, intracistemally, or rectally, in the form of solid, semi-solid, lyophilized powder, or liquid dosage forms, such, as for example, tablets, suppositories, pills, soft elastic and hard gelatin capsules, powders, solutions, suspensions, or aerosols, or the like, preferably in unit dosage forms suitable for simple administration of precise dosages. / [0248] The compositions will include a conventional pharmaceutical carrier or excipient and a compound of the invention as the/an active agent, and, in addition, may include other medicinal agents, pharmaceutical agents, carriers, adjuvants, etc. Compositions of the invention may be used in combination with anticancer or other agents that are generally administered to a patient being treated for cancer. Adjuvants include preserving, wetting, suspending, sweetening, flavoring, perfuming, emulsifying, and dispensing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form 161 PCT/US2004/031523 2013204031 11 Apr 2013 WO 2005/030140 can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.

[0249] If desired, a pharmaceutical composition of the invention may also contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, antioxidants, and the like, such as, for example, citric acid, sorbitan monolanrate, triethanolamine oleate, butylalted hydroxytoluene, etc.

[0250] Compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.

[0251] One preferable route of administration is oral, using a convenient daily dosage regimen that can be adjusted according to the degree of severity of the disease-state to be treated.

[0252] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage farms, the active compound is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or (a) tillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders, as for example, cellulose derivatives, starch, alignates, gelatin, polyvinylpyrrolidone, sucrose, and gum acacia, (c) humectants, as for example, glycerol, (d) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, croscarmellose sodium, complex silicates, and sodium carbonate, (e) solution retarders, as for example paraffin, (f) absorption accelerators, as for example, quaternary ammonium compounds, (g) wetting agents, as for example, cetyl alcohol, and glycerol monostearate, magnesium stearate and the like (h) adsorbents, as for example, kaolin and bentonite, and (i) lubricants, as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof, hi the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. 162 WO 2005/030140 PCT/US2004/031523 2013204031 11 Apr 2013 [0253] Solid dosage fauns as described above can be prepared with coatings and shells, such as enteric coatings and others well known in the art. They may contain pacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedded compositions that can be used are polymeric substances and waxes. The active compounds can also be in microencapsulated farm, if appropriate, with one or more of the above-mentioned excipients.

[0254] Liquid dosage farms far oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. Such dosage forms are prepared, for example, by dissolving, dispersing, etc., a compound(s) of the invention, or a pharmaceutically acceptable salt thereof, and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol and the Hke; solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol, dimethylformamide; oils, in particular, cottonseed oil, groundnut oil, com germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid esters of sorbitan; or mixtures of these substances, and the like, to thereby form a solution or suspension.

[0255] Suspensions, in addition to the active compounds, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.

[0256] Compositions for rectal administrations are, for example, suppositories that can be prepared by mixing the compounds of the present invention with for example suitable non-irritating excipients or carriers such as cocoa butter, polyethyleneglycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt while in a suitable body cavity and release the active component therein.1 [0257| Dosage forms for topical administration of a compound of this invention include ointments, powders, sprays, and inhalants. The active component is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as may be required. Ophthalmic formulations, eye ointments, powders, and solutions are also contemplated as being within the scope of this invention. 163 PCT/US2004/031523 2013204031 11 Apr 2013 WO 2005/030140 [0258] Generally, depending on the intended mode of administration, the pharmaceutically acceptable compositions will contain about 1% to about 99% by weight of a compound(s) of the invention, or a pharmaceutically acceptable salt thereof, and 99% to 1% by weight of a suitable pharmaceutical excipient. In one example, the composition will be between about 5% and about 75% by weight of a componnd(s) of the invention, or a pharmaceutically acceptable salt thereof, with the rest being suitable pharmaceutical excipients.

[0259] Actual methods of preparing such dosage forms are known, or will be apparent; to those skilled in this art; for example, see Remington's Pharmaceutical Sciences, 18th Ed., (Mack Publishing Company, Easton, Pa., 1990). The composition to be administered will, in any event, contain a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, for treatment of a disease-state in accordance with the teachings of this invention.

[0260] The compounds of the invention, or their pharmaceutically acceptable sails, are administered in a therapeutically effective amount which will vary depending upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of the compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular disease-states, and the host undergoing therapy. The compounds of the present invention can be administered to a patient at dosage levels in the range of about 0.1 to about 1,000 mg per day. For a normal human adult having a body weight of about 70 kilograms, a dosage in the range of about 0.01 to about 100 mg per kilogram of body weight per day is an example. The specific dosage used, however, can vary. For example, the dosage can depend on a number of factors including the requirements of the patient, the severity of the condition being treated, and the pharmacological activity of the compound being used. The determination of optimum dosages for a particular patient is well known to one of ordinary skill in the art.

Utility of compounds of the invention as screening agents [0261] To employ the compounds of the invention in a method of screening for candidate agents that bind to, for example c-Met, KDR, c-Kit, fit-3, or flt4, the protein is bound to a support, and a compound of the invention is added to the assay. Alternatively, the 164 PCT/US2004/031523 2013204031 11 Apr 2013 WO 2005/030140 compound of the invention is bound to the support and the protein is added. Classes of candidate agents among which novel binding agents may be sought include specific antibodies, non-natural binding agents identified in screens of chemical libraries, peptide analogs, etc. Of particular interest are screening assays for candidate agents that have a low toxicity for human cells. A wide variety of assays may be used for this purpose, including labeled in vitro protein-protein binding assays, electrophoretic mobility shift assays, immunoassays for protein binding, functional assays (phosphorylation assays, etc.) and the like.

[0262] The determination of the binding of the candidate agent to, for example, c-Met, KDR, c-Kit, flt-3, or flt-4 protein may be done in a number of ways. In one example, the candidate agent (the compound of the invention) is labeled, for example, with a fluorescent or radioactive moiety and binding determined directly. For example, thus may be done by attaching all or a portion of the c-Met, KDR, c-Kit, flt-3, or flt-4 protein to a solid support, adding a labeled agent (for example a compound of the invention in which at least one atom has been replaced by a detectable isotope), washing off excess reagent, and determining whether the amount of the label is that present on the solid support. Various blocking and washing steps may be utilized as is known in the art.

[0263] By “labeled” herein is meant that the compound is either directly or indirectly labeled with a label which provides a detectable signal, e.g., radioisotope, fluorescent tag, enzyme, antibodies, particles such as magnetic particles, chemiluminescent tag, or specific binding molecules, etc. Specific binding molecules include pairs, such as biotin and streptavidin, digoxin and antidigoxtn etc. For the specific binding members, the complementary member would normally be labeled with a molecule which provides for detection, in accordance with known procedures, as outlined above. The label can directly or indirectly provide a detectable signal.

[0264] In some embodiments, only one of the components is labeled. For example, c-Met, KDR, c-Kit, flt-3, or flt-4 protein may be labeled at tyrosine positions using 125I, or with fluorophores. Alternatively, more than one component may be labeled with different labels; using 1251 for the proteins, for example, and a fluorophor for the candidate agents.

[0265] The compounds of the invention may also be used as competitors to screen for additional drug candidates. “Candidate bioactive agent” or “drug candidate” or grammatical equivalents as used herein describe any molecule, e.g., protein, oligopeptide, small organic molecule» polysaccharide, polynucleotide, etc., to be tested for bioactivity. 165 PCT/US2004/031523 2013204031 11 Apr 2013 WO 2005/030140

They may be capable of directly or indirectly altering the cellular proliferation phenotype or the expression of a cellular proliferation sequence, including both nucleic acid sequences and protein sequences. In other cases, alteration of cellular proliferation protein binding and/or activity is screened. In the case where protein binding or activity is screened, some embodiments exclude molecules already known to bind to that particular protein. Exemplary embodiments of assays described herein include candidate agents, which do not bind the target protein in its endogenous native state, termed herein as “exogenous" agents. In one example, exogenous agents further exclude antibodies to c-Met, KDR, c-Kit, fit-3, orflt-4.

[0266] Candidate agents can encompass numerous chemical classes, though typically they are organic molecules having a molecular weight of more than about 100 daltons and less than about 2,500 daltons. Candidate agents comprise functional groups necessary for structural interaction with, proteins, particularly hydrogen bonding and lipophilic binding, and typically include at least an amine, carbonyl, hydroxyl, ether, or carboxyl group, for example at least two of the functional chemical groups. The candidate agents often comprise cyclical carbon or heterocyclyl structures and/or aromatic or polyaromatic structures substituted with one or more of the above functional groups. Candidate agents are also found among biomolecules including peptides, saccharides, fatty acids, steroids, purines, pyrimidines, derivatives, structural analogs, or combinations thereof.

[0267] Candidate agents are obtained from a wide variety of sources including libraries of synthetic or natural compounds. For example, numerous means are available for random and directed synthesis of a wide variety of organic compounds and triomolecules, including expression of randomized oligonucleotides. Alternatively, libraries of natural compounds in the form of bacterial, fungal, plant and animal extracts are available or readily produced. Additionally, natural or synthetically produced libraries and compounds are readily modified through conventional chemical, physical and biochemical means. Known pharmacological agents may be subjected to directed or random chemical modifications, such as acylation, alkylation, esterification, amidification to produce structural analogs.

[0268] In one example, the binding of the candidate agent is determined through the use of competitive binding assays. Iu this example, the competitor is a binding moiety known to bind to c-Met, KDR, c-Kit, flt-3, or flt-4, such as an antibody, peptide, binding partner, ligand, etc. Under certain circumstances, there may be competitive binding as between the 166 PCT/US2004/031523 2013204031 11 Apr 2013 WO 2005/030140 candidate agent and the binding moiety, with the binding moiety displacing the candidate agent

[0269] in some embodiments, the candidate agent is labeled. Either the candidate agent or the competitor, or both, is added first to for example c-Met, KDR, c-Kit fit-3, or flt-4 for a time sufficient to allow binding, if present. Incubations may be performed at any temperature that facilitates optimal activity, typically between 4°C and 40°C

[0270] Incubation periods ate selected for optimum activity, but may also be optimized to facilitate rapid high throughput screening. Typically between 0.1 and 1 hour will be sufficient. Excess reagent is generally removed or washed away. The second component

I is then added, and the presence or absence of the labeled component is followed, to indicate binding.

[0271] In one example, the competitor is added first, followed by the candidate agent Displacement of the competitor is an indication the candidate agent is banding to c-Met, KDR, c-Kit, flt-3, or flt-4 and thus is capable of binding to, and potentially modulating, the activity of the c-Met, KDR, c-Kit, flt-3, or flt-4. In this embodiment either component can be labeled. Thus, for example, if the competitor is labeled, the presence of label in the wash solution indicates displacement by the agent Alternatively, if the candidate agent is labeled, the presence of the label on the support indicates displacement [0272] In an alternative embodiment, the candidate agent is added first, with incubation and washing, followed by the competitor. The absence of binding by the competitor may indicate the candidate agent is bound to c-Met KDR, c-Kit, flt-3, or flt-4 with a higher affinity. Thus, if the candidate agent is labeled, the presence of the label on the support, coupled with a lack of competitor binding, may indicate the candidate agent is capable of binding to c-Met KDR, c-Kit flt-3, or flt-4.

[0273] It may be of vialue to identify the binding site of c-Met, KDR, c-Kit, flt-3, or flt-4. This can be done in a variety of ways. In one embodiment once c-Met KDR, c-Kit flt-3, or flt-4 has been identified as binding to the candidate agent, the c-Met KDR, c-Kit, flt-3, or flt-4 is fragmented or modified and the assays repeated to identify the necessary components for binding.

[0274] Modulation is tested by screening for candidate agents capable of modulating the activity of c-Met, KDR, c-Kit, flt-3, or flt-4 comprising the steps of combining a candidate agent with c-Met, KDR, c-Kit, flt-3, or flt-4, as above, and determining an alteration in the 167 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523 biological activity of the c-Met, KDR, c-Kit, flt-3, or flt-4, Thus, in this embodiment, the candidate agent should both bind to (allhough this may not be necessary), and alto: its biological or biochemical activity as defined herein. Hie methods include both in vitro screening methods and in vivo screening of cells for alterations in cell viability, morphology, and the like.

[0275] Alternatively, differential screening may be used to identify drug candidates that bind to native c-Met, KDR, c-Kit, flt-3, or flt-4, but cannot bind to modified c-Met, KDR, c-Kit, flt-3, or flt-4.

[0276] Positive controls and negative controls may be used in the assays. For example, all control and test samples are performed in at least triplicate to obtain statistically significant results. Incubation of samples is for a time sufficient for the binding of the agent to the protein. Following incubation, samples are washed free of non-specifically bound material and the amount of bound, generally labeled agent determined. For example, where a radiolabel is employed, the samples may be counted in . a scintillation counter to determine the amount of bound compound.

[0277] A variety of other reagents may be included in the screening assays. These include reagents like salts, neutral proteins, e.g., albumin, detergents, etc which may be used to facilitate optimal protein-protein binding and/or reduce non-specific or background interactions. Also reagents that otherwise improve the efficiency of the assay, such as protease inhibitors, nuclease inhibitors, anti-microbial agents, etc., may be used. The mixture of components may be added in any order that provides for the requisite binding.

Abbreviations and their Definitions [0278] The following abbreviations and terras have the indicated meanings throughout.

Abbreviation _Meaning

Ac acetyl ATP adenosine triphosphate BNB 4-bromomethyl-3-nitrobenzoic acid Boc t-butyloxy carbonyl 168 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523 Abbreviation Meaning br broad Bii butyl °C degrees Celsius c- cyclo CBZ CarboBenZoxy = benzyloxycarbonyl d doublet dd doublet of doublet dt doublet of triplet DBU Diazabicyclo[5.4.0]undec-7 -ere DCM dichloromethane = methylene chloride = CH2CI2 DCE dichloroethylene DEAD . diethyl azodicarboxylate DIC diisopropylcarbodiimide DBA Ν,Ν-diisopropylethyl amine DMAP ^NJ^-dimethylaminopyridine DMF N,N-dimethylfonnamide DMSO dimethyl sulfoxide DVB 1,4-divinylbenzene EEDQ 2-eihoxy-l-ethoxycarbonyl-l,2-dihydroqumoline El Electron Impact ionization Et ethyl Bnoc 9-fluorenybnethoxycarbonyI g gram(s) GC gas chromatography h or hr • hour(s) HATU 0-(7-Azabenzotriazol-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate HMDS hexametliyldisilazane HOAc acetic acid HOBt hydroxybenzotriazole HPLC high pressure liquid chromatography 169 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523 Abbreviation Meaning L Iiter(s) M molar or molarity in multiplet Me methyl mesyl methanesulfonyl mg milligram(s) MHz megahertz (frequency) Min minute(s) xnL miIliUter(s) mM millimolar mmol miUimole(s) . 1 mol mole(s) MS ' mass spectral analysis ΜΓΒΕ methyl t-butyl ether N normal or normality I NBS N-hromosuccinimide NCS N-chlorosuccinimide nM . nanomolar NMO N-methylmorpholine oxide NMR nuclear magnetic resonance spectroscopy PEG polyethylene glycol pEY poly-glutamine, tyrosine Ph phenyl PfaOH phenol PfP pentafluorophenol PfPy pentafluoropyridine PPTS Pyridinium p-toluenesulfonate Py pyridine PyBroP biomo-tris-pymilidino-phosphonium hexailuorophosphate quartet 170 WO 2005/030140 PCT/US2004/031523

Abbreviation _Meaning RT Room temperature Sat’d saturated s singlet s- 1 secondary t- tertiary tortr triplet TBDMS t-butyldimethylsilyl TBS triethylsilane TFA trifluoroacetic acid THF tetrahydroforan TMOF trimethyl orthofonnate TMS trimethylsilyl tosyl p-toluenestdfbnyl Trt triphenylmethyl uL . microliter(s) uM Micromole(s) or micromolar 2013204031 11 Apr 2013

Synthesis of Compounds [0279] Schemes 1 and 2 depict general synthetic routes for compounds of the invention and are not intended to be limiting. More specifically, Scheme 1 depicts synthesis of i quinazoline compounds, and Scheme. 2 depicts synthesis of quinoline compounds. Specific examples are described subsequently to these general synthetic descriptions so as to allow one sldlled in the art to make and use dither quinazolines or quinolines of the invention.

Scheme 1 171 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523

[0280] Referring to Scheme 1, a benzoic ester 1, where R is typically but not necessarily a methyl radical and P is typically but not necessarily an alkyl group, is O-alkylated at the oxygen para to the carboxylate group with an electrophile to afford a substituted derivative 2, P is typically a lower alkyl group, but may be a protecting group that is removed later in a synthesis. When P is a lower alkyl group it may possess functionality initially, or be derivitized to contain such functionality at various stages of the synthesis. The gronp, E1, may represent either a protecting group, e.g. benzyl, or a group that either has moieties present in compounds of the invention or possesses functionality that serve as a precursors to such groups. Aromatic ring nitration and reduction of the corresponding nitro group are carried out in a regie- and chemoselective manner by methods well known in the art to give anthranilate derivative 3. Formation of quinazolin-4-one 4 is carried out by methods well known in the art, for example by heating 3 in farmamide solution in the presence of ammonium formate or far example by heating directly with fonnamidine hydrochloride. Introduction of 4-position functionality groups is carried out by methods known in the art. For example, quinazolin-4-one 4 is converted to an intermediate quinazoline 5, where “L” represents a leaving group, e.g. chlorine. Quinazoline 5 is then converted to 6 by reaction with a range of nucleophiles, e.g. amines, alcohols, and thiols. After formation of 6, group “Z" is either left “as is” or converted at some subsequent stage to a derivative thereof. For example when Z is -NH-, then the hydrogen on the nitrogen 172 PCT/US2004/031523 2013204031 11 Apr 2013 WO 2005/030140 may optionally be replaced with an alkyl group, or when Z is sulfur, then that sulfur atom may be oxidized to, for example, a sulfone. Structure 6 may represent compounds of the invention or, for example when E1 serves as a protecting group, E1 may be removed to provide phenol 7. Introduction of a group E2 is carried out by methods well established in the art; for example alkylation with an appropriately derivatized alkyl halide (or mesylate or the like) to give 8 which also represents compounds of the invention.

Scheme 2

(0281] Scheme 2 shows a general route used to make exemplary quinolines of the invention. For example, compound 9 contains an alkyl group, R1, a protecting group, P. The arrangement of the protected and alkylated phenolic oxygens may vary from the pattern depicted in compound 9. Compound 9 is nitrated to provide compound 10. The nitro group of compound 10 is reduced to give aniline 11. Compound 11 is treated, for example, with ethyl formate under basic conditions followed by acidification and isolation to form 4-hydroxy quinoline 12. Quinoline 12 may be converted to compounds of the invention in a number of ways. For example, the 4-oxygen is used as a nucleophile in a nucleophilic aromatic substitution reaction to term quinoline-aryl-ether 13. In another example, compound 13 is further derivatized, via removal of .protecting group P, to afford compound 14. The 7-hydroxy of compound 14 is alkylated, for example with electrophile E, to provide a compound of the invention. As discussed in relation to Scheme 1, 173 PCT/US2004/031523 2013204031 11 Apr 2013 WO 2005/030140 variations on any of the above steps ate possible, and intermediates in these schemes, for example compounds 12,13, and 14 may also be compounds of the invention according to formula 1. Also, for example, the 4-hydroxy quinoline compound 12 are converted to a corresponding 4-nitrogen or 4-sulfur quinoline using chemistry known in the art to make compounds of the invention, or alternatively the corresponding 4-nitrogen or 4-sulfur quinolines are made via routes analogous to that depicted in Schemes 1 and 2.

[0282] Schemes 1 and 2 are illustrative of quinolines and quinazolines having oxygen substitution at their respective 6- and 7-positions; the invention is not so limited, but rather is intended to encompass quinolines and quinazolines not necessarily having substitution, oxygen or otherwise, at their respective 6- or 7-positions.

[0283] Schemes 3 and 4 depict generalized synthetic routes to show the process of the invention to make compounds of formua XXI and is not intended to be limiting. More specifically, Schemes 3 and 4 depict convergent syntheses of quinoline and quinazoline compounds as described herein. Specific examples are described subsequently to this general synthetic description so as to allow one of ordinary skill in the art to practice the invention.

[0284] Referring to Scheme 3, a benzoic ester 16 for example, where E is typically but not necessarily a methyl radical and Rl is typically but not necessarily one or more alkoxy or hydroxy groups, hi a typical synthesis, at least one of R1 within Scheme 3 is a hydroxyl which is converted (or protected )via one or more steps to a group important to the activity of the compounds as described as kinase modulators (in the case that -OH itself is desired in the final compound, then deprotection affords the -OH, vide supra). Preferably, but not necessarily, this group is complete once the synthesis of XXII is complete. By building desired complexity into XXII prior to combination with XXlli, convergent syntheses’ advantages over serial syntheses are realized more folly. Regioselective aromatic ring nitration, and reduction of the corresponding nitre group, are carried out in a regio- and chemoselective manner by methods well known in the art to give anthranilate derivative 17. Formation of quinazoline or quinoline 4-oae 18 is carried out by methods well known in the art. Far example by heating 17 in foxmamide solution in the presence of ammonium formate, or by heating 17 with formamidine hydrochloride, the quinazoline-4-one analog is made. In another example 17 is treated, for example, with ethyl formate under basic conditions followed by acidification and isolation to form the 4-hydroxy quinoline analog (a tautomer of the 4-one). In this scheme Γ represents either carbon or nitrogen atom with 174 PCT/US2004/031523 2013204031 11 Apr 2013 WO 2005/030140 the appropriate number of hydrogens to fill their respective normal valence braiding schemes; J’ is a precursor to J. Radicals J and R70 are in accord with formula XXL Introduction of 4-position functionality is earned out by methods known in the art For example, 4-one IS is converted to ΧΧΠ, where “P1” represents a suitable leaving group (in accord with fomrnla XXI), e.g. chlorine (via dehydration/chlarination of 18 to give ΧΧΠ). In another example, a 4-hydroxy analog is converted to a sulfonyl ester, e.g. the trifluoromethane sulfonate.

ΧΧΠ [0285] Scheme 4 shows a general route used to make compounds of formula XXHL For example, aromatic compound 19, where “X" is a leaving group, such as fluorine and Έ” is an electron withdrawing group such as nitro, is converted to 20 by reaction with a range of nucleophiles, e.g. amines, alcohols, and thiols (where “Z" is oxygen, nitrogen (substituted or not), or sulfur). In this case, “R” represents a removable group, for example benzyl. In a typical synthesis, after formation of 20, group Έ" is either left “as is" or converted at some subsequent stage to a derivative thereof. In the example depicted, E is converted to B', a precursor to B in accord with formula XXI, to make 21. For example if E is a nitro, then B’ could might be an amino group, made via reduction of the nitro group. Structure 21 may be further derivitized by synthesis of -B-L-T in accord with formula XXL In scheme 4, this is depicted as a serial process whereby L’, a precursor to L, is introduced to give 22, followed by introduction of Τ' (a precursor to T) to give 23. In some cases, -L-T is preformed and appended to B, One of ordinary skill in the art would appreciate that variations on any of the above steps are possible. Compound 23 is converted to ΧΧΠΙ via conversion of Τ’ to T and introduction of P2 (for example, when R is benzyl, removal of the benzyl after completion of -B-L-T). 175 2013204031 11 Apr 2013 WO 2005/030140 Scheme 4 PCT/US2004/031523 X m 1 _ ·νφ"· - (R2)0-4 (R2)o-4 (R2)o-4 19 20 21

xxm [0286] As discussed above, one aspect of the invention encompasses combination of ΧΧΠ and ΧΧΠΙ to make compounds of formula XXI. Because of the diversity and complexity of compounds described for kinase modulation {vide supra), methods of the invention provide advantages to serial synthesis.

Examples [0287] The following examples serve to more fully describe the manner of using the above-described invention, as well as to set forth the best modes contemplated for carrying out various aspects of the invention. It is understood that these examples in no way serve to limit the true scope of this invention, but rather are presented for illustrative purposes. All references cited herein are incorporated by reference in their entirety. Generally, but not necessarily, each example set out below describes a multi-step synthesis as outlined above. 176 2013204031 11 Apr 2013 WO 2005/030140

PCT/US2004/031523

Quinoline and Quinazoline Syntheses

Example 1

oc [0288] Synthesis _of l-f4-BeiiZVloxv-5-methoxv-2-nitro-oheDvlVethancme. 1-(4-Benzyloxy-3-methoxy-phenyl)-ethancne (200 mmol, 51.3 g) dissolved in DCM (750ml) and the mixture cooled to 0° C. Nitric acid (90%, 300 mmol, 14 nil) was added dropwise to the cooled solution over 20 minutes. Sulfuric acid (96.2%, 300 mmol, 8.75 ml) was then added dropwise over 40 minutes at 0° C.

[0289] Additional nitric acid (200 mmol, 9.4 ml) was added dropwise over 20 minutes. The reaction mixture was diluted with water (300 ml) and wash with water (3 X 200 ml), Sat. NaHC03 (4 X 200 ml, or until neutral). The organic layer was dried over Na2S04 and concentrated.

[0290] The crude mixture was recrystallized with DMF to give 22.5 g of the nitro product. The DMF layer was concentrated and recrystallized with ethyl acetate to give additional 8.75g of the product The ethyl acetate layer was concentrated and purified on silica column using 20% EtOAc/hexanes to gave another 4.75 g of the product. Total yield is 36 g, (-60%). 1HNMR (CDCI3): 7.647 (1¾ s), 7.446-7.333 (5H, m), 6.745 (1H, s), 5.210 (2¾ s), 3.968 (3¾ s), 2.487 (3¾ s).

Example 2

Δ [0291] Synthesis of l-(2-Amino-4-benzvloxv-5-methoxv-ph£nvl)-ethanone. A Mixture of iron powder (477 mmol, 27 g), ammonium acetate (500 mmol, 31,g), 1 -(4-Benzyloxy-5-methoxy-2-nitro-phenyl)-ethanone (120 mmol, 36 g), toluene (500 ml) and water (500 ml) was refluxed overnight, or until completion. The mixture was filtered through celite and 177 2013204031 11 Apr 2013 WO 2005/030140

Example 3

PCT/US2004/031523 washed with EtOAc. The organic layer was washed with water and Sat NaCl, dried over Na2SCM, and concentrated to afford the product 90%. 1H NMR (CDC33): 7.408-7.298 (5¾ m), 7.130 (1H, s), 6.155 (2H, hr), 6.104 (1¾ s), 5.134 (2H, s), 3.834 (3¾ s), 2.507 (3¾ s). LC/MS (M+l = 272).

[0292] Synthesis of 7-Benzvloxv-6-methox v-quinolin^ol. To a solution of l-(2-Amino-4-benzyloxy-5-methoxy-phenyl)-ethanone (108 mmol, 29.3 g) in DME (700 ml) was added sodium methoxide (432 mmol, 23.35 g). The mixture was stirred for 30 minutes. Ethyl formate (540 mmol, 44 ml) was added and the mixture was stirred overnight. (Additional sodium methoxide may he needed if reaction is not complete as monitored by LC/MS.) After the reaction was completion, the mixture was diluted with water (40 ml) and acidified to neutral with 1M HC1. The precipitate was filtered and washed with water, dried in vacuo to afford 22g (72%) of 7-benzyloxy-6-methoxy-quinolin-4- ol. 1H NMR (CDC33): 10.7 (1¾ hr), 7.703 (1¾ s), 7.493-7.461 (1¾ t), 7.431-7.413 (2¾ br d), 7.372-7.333 (2¾ t), 7.296-7.283 (1H, d), 6.839 (1¾ s), 6.212-6.193 (1¾ d), 5.212 (2¾ s), 3.965 (3¾ s). LC/MS (M+l = 282).

Example 4

[0293] 7-Benzvtoxv-4-/2-fhmro-4-mtro-uhennxY)-6-methoxv-amnolme. To a round bottom flask equipped with a magnetic stir bar was added 7-Benzyloxy-6-methoxy- 1H-quinolin-4-one (12.2 g, 43.3 mmol, 1.0 eq.), acetonitrile (150ml), DMF (150ml) and 178 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523 cesium carbonate (28.2 g, 86.5 mmol, 2.0 eq). The mixture was stirred at room temperature for 30 minutes at which time 1,2-difluoro-4-nitro-benzene (7.57 g, 47.6 mmol, 1.1 eq) was added over a 10 minute period. After 2 hours the reaction was complete at which time 75% of the MeCN and DMF was removed and the resulting solution was poured over into ice water. The solid was filtered and dried and further columned with a biotage system. The eluent was 1:3 ethyl acetato/hexane. Removal of the solvent afforded 7-Benzyloxy-4-(2-fluoro-4-nitro-phenoxy)-6-methoxy“quinoline as a pale green solid (7.4 g, 41% yield). ‘HNMR (400 MHz, CDCfe): 8.53 (d, 1H), 8.42 (dd, 1H), 8.16 (m, IB), 7.5 (m, 8H), 6.76 (d, 1H), 5.31 (s, 2H), 3.92 (s, 3H); MS (BI) for CsH^PNaOj: 421 (MB4).

Example 5 .Noa

NOa [0294] 4-('2-Fluoro-4-nitro-phenoxvV6--methoxv-qiiinolin-7-ol. To a round bottom flask equipped with a magnetic stir bar was added 7-benzyloxy-4-(2-fluoro-4~nitro-phenoxy)-6“ methoxy-quinoline (2.9 g, 6.9 mmol, 1.0eq) and 33% HBr in acetic add (30 ml). The mixture was stirred at room temperature for 3 hours and diluted with ether to give a pale white solid. The solid was filtered, washed with ether and dried to yield 4-(2-Huar0'4-mtra-phenoxy)-6-methoxy“qmnolin“7-ol as a pale white solid (2.74 g, 97.5% yield). 1H NMR (400 MHz, CDC13): 11.89 (bs, 1H), 8.87 (d, 1H), 8.57 (d, 1H), 8.30 (d, 1H), 7.89 (m, 1H), 7.73 (s, IH), 7.55 (s, 1H), 4.03 (s, 3H); MS (El) for C16HUEN205:421 (M+H4).

Example 6

CbzN

179 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523 [0295] 5-r4-f2-FIuoro-4-iiitro-phepoxv)-6-mBthQXV-aiiinolin-7-vlQxvmethvl7-hexahvdro-cvclcmentaTclpvrroIe-2-carboxvlic acid benzyl ester. To a round bottom flask equipped with a magnetic stir bar was added 4-(2-Huoro-4-nitro-phenoxy)-6-methoxy-quinolin-7-ol (2.74 g, 6.7 mmol, 1.0 eq.), DMA (30ml) and cesium carbonate (6.6 g, 20.2 mmol, 3.0 eq). The mixture was stirred at room temperature for 30 minutes at which time 5-methanesu]fonyloxymethyl-hexahydro-cyclopaita[c]pyrrole-2-carboxylic acid benzyl ester (2.6 g, 7.3 mmol, 1.1 eq) was added. The reaction was heated to 75° C and allowed to stir overnight. After allowing the reaction to cool to room temperature the reaction was poured into water. The solid was filtered and was then dissolved in EtOAc and washed 2X water, IX brine and dried over NaSC>4. The solvent was removed to yield 5-[4-(2-Huoro-4-nitro-phenoxy)-6-methoxy-qumolin-7-yloxymethyI]-hexahydrO" cyclopenta[c]pyrrole-2-carboxylic acid benzyl ester as a cream solid (3.7 g, 94% yield). JH NMR (400 MHz, CDC13): 8.55 (d, 1H), 8.15 (d, 1H), 8.09 (d, 1H), 7.32 (m, 8H), 6.52 (d, 1H), 5.11 (d, 2H), 4.13 (d, 2H), 3.95 (s, 3H), 3.57 (m, 2H), 3.43 (m, 2H), 2.93 (m, 3H), 2.16 (m, 2H), 1.39 (m, 2H); MS (El) for C32H30EN3O7: 588 (M+H4).

Example 7

[0296] 4-f2-Fluoro-4-nitro-phenoxvl-6-iriethoxv-7-foctahvdro-cvclopaitarclpvrrol-5-vlmethoxvVquinolitift. To a round bottom flask equipped with a magnetic stir bar was added 5“[4-(2-Fluoro-4-nitio-phenoxy)-6-methoxy“quinolin-7-yloxymethyl]- hexahydiocyclopenta-[c]pyrrole-2-carboxylic add benzyl ester (2.5 g, 4.1 mmol, 1.0eq), 33% HBr in acetic add (5 ml) and acetic add (5 ml). The mixture was stirred at room temperature for 1 hour and diluted with EtOAc to give a pale orange solid. The solid was filtered, washed with EtOAc and dried, giving 4-(2-Hucsro-4-nitro-phenoxy)-6-methoxy-7-(octahydro-cydopenta[c]pyrrol-5-ylmethoxy)-quinoline (2.1 g, 95% yield). JHNMR (400 MHz, CDCI3): 8.83 (d, 1H), 8.32 (m, 2H), 8.02 (s, 1H), 7.76 (t, 1H), 7.65 (s, 1H), 6.89 (d, 180 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523 1H), 5.3 (d, 2H), 4.11 (m, 3H), 3.26 (m, 4H), 2.95 (m, 2H), 2.68 (m, 3H), 236 (m, 2H), 1.68 (m, 2H); MS (El) for QmHmHNsOj: 454 (M+lT).

Example 8

[0297] 4-f2-Huoio-4-nitro-phenoxv]-6-metfaoxv-7-f2-methvl-octahvdro-cvclooentafc1pvnpl-5-vlmethoxv)-ouinoIine. To a round bottom flask equipped with a magnetic stir bar was added 4-(2-Fluoro-4-nitrO“phenoxy)-6-methoxy“7-(octahydro-cyclopenta[c]pytrol-5-yImethoxy)-quinoline (2.1 g, 3.9 mmol, 1.0 eq.) and acetonitrile/water 1:1 (5ml, 5ml). The reaction mixture was then cooled to 0° C and 37% solution of formaldehyde in water was added (0.2 g, 7.8 mmol, 2.0 eq). While keeping the temperature at 0°C Na(OAc)sBH was added (4.4g, 20.7 mmol, 3.0 eq). After 1 hour the pH was adjusted to 10 and the aqueous was extracted 2 x DCM (100 ml). Removal of the PCM resulted in a white solid. The compound was further purified with a biotage system using an eluent EtOAc and 5% MeOH, affording 4-(2-Huoro-4-nitro-phenoxy>6-methoxy-7-(2-methyl-octahydiocyclopenta-[c]pynOl-5-ylmethoxy)-quinoline (0.9 g, 50% yield).). *H NMR (400 MHz, CDC13): 8.57 (d, 1H), 8.14 (dd, 1H), 8.12 (dd, 1H), 7.41 (s, 2H), 7.34 (t, 1H), 6.54 (d, 1H), 4.19 (d, 2H), 4.01 (s, 3H), 2.61 (m, 4H), 2.43 (m, 1H), 2.33 (s, 3H), 2.11 (m, 4H), 1.32 (m, 2H); MS (El) forCasHfcFNaOj: 468 (M+H4).

181 2013204031 11 Apr 2013 WO 2006/030140 PCT/US2004/031523 [0298] 3--FluQrQ-4-r6-metfaoxv-7-r2-methvl-octahvdro-cvclopeiitafc1pvrm1-S-vlmRthnyv1-quinolin-4-vIoxvl-pheDvlamine· To a par hydrogenation reaction vessel was added 4-(2-fluoro-4~nitro-phenoxy)-6-methoxy-7-(2-methyl-octahydro-cyclopeuta[c]pyrrol-5-ylmethoxy)-quinoline (0.800 g, 1.6 mmol, 1.0 eq.), DMF (50 ml), EtoAc (50ml), MeOH (50ml), TEA (5ml) and 10% Pd/C (200 mg). The vessel was placed on the par hydrogenator at 35 psi overnight, The Pd was filtered and the solvent removed to give 3-fluoro-4-[6-methoxy-7-(2-methyl-octahydrO“Cyclopenta[c]pyrrol-5-ylmethoxy)“qumolin-4-yloxy]-phenylamine as an off yellow solid (0.78 g, 99% yield.). NMR (400 MBs, CDCls): 8.45 (d, 1H), 7.57 (s, 1H), 7.36 (s, 1H), 7.05 (t, 1H), 6.54 (m, 2H), 6.39 (d, 1H), 4.16 (d, 2H), 4.01 (s, 3H), 3.81 (m, 3H), 2.61 (m, 3H), 2.41 (m, IB), 2.29 (s, 3H), 2.23 (m, 2H), 1.32 (m, 2H); MS (El) for C25H2BFN3Q3:438 (M+tf).

Example 10

[0299] 1-13-Fluoro4~r 6-methoxv-7-/,2-methvl-octahydro-cvclonentafclnvm>l-5- vlmethoxv)-quinolin-4-vloxv7-Dhenvll-3-phenvlacetvl-fluourea. To a round bottom flask equipped with a magnetic stir bar was added 3-fluoro-4- [6-methoxy-7-(2-methyl-octahydro-cyck>penta[c]pyrrol-5-ylmdhoxy)-quinoIin-4-yloxy]-phenylamme (0.78 mg, 1.7 mmol, 1.0 eq.), toluene (10ml), ethanol (10ml) and phenyl-acetyl isothiocyanate ¢1.64 g, 9.2 mmol, 4.5 eg). The reaction mixture was stirred at roam temperature overnight. After removal of the solvent ihe product was purified with a biotage system using an eluent EtOAc and 4% TEA (2L) then EtOAc, 4% TEA, 1% MeOH (1L). The solvent was removed to give l-{3-fluoro-4-[6-meftaxy-7-(2-methyl-octahydro-cyclopenta[c]pyirc>l-5-ylmetiioxy)-quinoIin-4-yloxy]-phenyl}-3-phenylacetyl-thiourea (0.5 g, 50% yield). JH NMR (400 MHz, DMSO): 8.48 (d, 1H), 7.92 (dd, IB), 7.53 (s, 1H), 7.40 (m, 4H), 7.33 (d, 2H), 7.23 (m, 2H), 6.54 (d, 2H), 6.39 (d, 1H), 4.21 (d, ZED, 4.02 (s, 3H), 3.81 (ra, 3H), 182 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523 2.87 (d, 29), 2.73 (m, 4H), 2.53 (m, 1H), 2.27 (m, 2H), 2.01 (s, 3H), 1.36 (m, 2H); MS (El) for QiBbmAS: 615 (M+H*).

Example 11

[0300] 6-fr6.7-DTTnetboxv-QuinoIin-4-vloxv)-5-fluoro-benzothifl7:ol-‘2-vlaTnir7P. 4-(6,7-dimethoxy-qmnolm-4--yloxy)-3-fluoro-phenylainirie (l.OOg, 3.18mmol) was dissolved in , AcOH (8.0ml), to whidi was added NH4SCN (486mg, 6.38mmol) and the mixture cooled in an ice bath. Br2 (0.33ml, 6.42mmol) in AcOH (0.33ml) was added dropwise with stimng. After addition was complete, the reaction mixture was stirred at room temperature. After one hour, more NH4SCN (l.Og, 13.1mmol) was added, followed by more Br2 (0.33ml, 6.42mmol) in AcOH (0.33ml), dropwise with stimng. The reaction mixture was then heated to reflux for several minutes. Upon cooling to room temperature, solids were filtered and washed with AcOH, followed by HjjO. The volume of the filtrate was reduced in vacuo and the pH adjusted to pH 9-10 with 1.0N NaOEL The resulting solids were filtered, washed with H20, and dried under high vacuum to give 6-(6,7-dimethoxy-quinolin-4-yloxy)-5-fluorD-benzothiazoI“2-ylainine (568mg, 48%). *H-NMR (400MHz, DMSO): 8.45 (d, 1H), 7.82 (d, 1H), 7.73 (br s, 2H), 7.53 (s, 1H), 7.38 (m, 2H), 6.44 (d, 1H), 3.94 (s, 6H). LC/MS Calcdfor [M+H]+ 372.1, found 372.2

Example 12

[0301] N-r6-(6.7-Dimethoxv-quinolm-4-vloxv)-5-fiuoro-benzothiazol-2-vn-2-phenvl-acetamide, 6-(6,7-dimethoxy-quinolin-4-yloxy)-5-fluoro-benzothiazol-2-ylamine (95mg, 183 PCT/US2004/031523 2013204031 11 Apr 2013 WO 2005/030140 0.25mmol), Et3N (0.10ml, 0.72nunal), phenylacetyl chloride (0.044ml, O.33mmol), and THF (1.0ml) were combined and stirred at room temperature for 1 hr. Additional phenylacetyl chloride (p.Q44ml, 0.33mmol) was added and the mixture heated to reflux for 1- 2 hrs. After cooling to room temperature, the reaction mixture was diluted with 1:1 AcCN:H20 (1.0ml) and die resulting solids filtered, washed with 1:1 AcCN-TfeO and dried under high vacuum to give N-[6-(6,7-dimethoxy-quinolin-4-ylaxy)-5-fluoio-henzothiazol- 2- yl)-2-phenyl-acetamide (72mgs, 59%). ^-NMR (400MHz, DMSO): 12.80 (s, 1H), 8.54 (d, 1H), 8.18 (d, 1H), 7.91 (d, 1Ή), 7.60 (s, 1H), 7.45 (s, 1H), 7.34 (m, 4H), 7.28 (m, 1H), 6.60 (d, 1H), 3.98 (s, 3H), 3.$6 (s, 3H), 3.86 (s, 2H). LC/MS Calcd for [M+B]+ 490.1, found 490.0.

Example 13

CBZ CBz [0302] 5-[4-(4-Amino-2-fIuoro-phenoxy)-6-methoxy-quinazolin-7-yloxymethyl]- hexahydro-cyclopenta[c]pyiTole-2-carboxylic acid benzyl ester. 4-Amino-2-fluoro-pheinol (1.53g, 12.Qmmol) was dissolved in dry DMF (30ml) to which was added 60% NaH (774mg, 19.3mmol). After the mixture was stirred at room temperature for several minutes, a suspension of 5-(4-chloro-6-methoxy-quinazolin-7-yloxymethyl)-hexahydro-cyclopenta[c]pyrroIe-2-cart>axylic add benzyl ester (4.70g, 6.7mmol) in dry DMF (40ml) was added. The reaction mixture was stirred at room temperature for 1-2 hrs, then diluted with EtOAc and washed wilh sat’d NaHCQs (3x), H2O (lx), sat’d NaCl (lx), dried (NazSCU), and concentrated in vacuo to give crude 5-[4-(4-amino-2~fluoro-phenoxy)-6-methoxy-quinazolin-7-yloxymethyl]-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid benzyl ester (5.6g, ~100%) which was used in the next reaction without further purification. talMR (400MHz, DMSO): 8.50 (s, 1H), 7.48 (s, 1H), 7.34 (m, 5H), 7.28 (m, 1H), 7.02 (t, IB), 6.48 (dd, IB), 6.40 (dd, 1H), 5.40 (hr s, 2H), 5.05 (s, 2H), 4.16 (d, 2H), 3.92 (s, 3H), 3.48 (m, 2H), 3.30 (m, 2H), 2.65 (m, 2H), 2.52 (m, IB), 2.10 (m, 2H), 1.30 (m, 2H), LC/MS Calcd for [M+Hf 559.2, found 559.4. 184 PCT/US2004/031523 WO 2005/030140

2013204031 11 Apr 2013 [0303] 5-14-F2-Hucffo-4-f3-phenvlaceWl-tMoureidoVphenoxvT-<T“metlroxv-atimazalin-7- vloxvmethvll-hexahvdro-cvclopentafclpvrrole-2-carboxvlic add benzyl ester. Fhenylacetyl chloride (2.65ml, 20.Qmmol) and AgSCN (4.92g, 29.6mmol) were combined in dry toluene (50ml) and heated to reflux for 2 hrs. The reaction mixture was allowed to cool to room temperature, the solids were filtered through celite and the filtrate concentrated in vacuo. The resulting oil was combined with 5-[4-(4-amino-2-fluoro~ phenoxy)-6-methoxy-quinazolin-7-yloxymethyl]-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid benzyl ester (5.6g, lOromol) in 1:1 EtOH:toluene (100ml) and the mixture stirred at room temperature for 1-2 hrs. The reaction mixture was diluted with EtOAc and washed with sat’d NaHC03 (3x), HzO (lx), sat’d NaCl (lx), dried (NajSO^, and concentrated in vacuo. The resulting oil was purified by flash chromatography (3:1 £tOAc:hexanes) to give 5-{4-[2-fluoro-4-(3-phenylacetyl-thioureido>phenoxy]-6-methoxy-quinazolin-7-yloxymethyl}-hexahydrocyclopenta[c]pyrrole-2-carboxylic acid benzyl ester (3.6 Ig, 49%) as a dark brown foam. aH-NMR (400MHz, DMSO): 12.44 (s, 1H), 11.80 (s, 1H), 8.54 (s, IB), 7.90 (m, 1H), 7.53 (s, 1H), 7.48 (m, 2H), 7.38 (s, 1H), 7.34 (m, 7H), 7.28 (m, 3H), 5.05 (s, 2¾). 4.16 (d, 2H), 3.94 (s, 3H), 3.72 (s, ZB), 3.48 (m, 2H), 3.30 (m, 2H), 2.65 (m, 2H), 2.52 (m, IB), 2.10 (m, 2H), 1.30 (m, 2H). LC/MS Calcd for [M+H]+ 736.2, found 736.0.

185 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523 [0304] l-{ 3-HuorD“4-[6-methoxy-7-(octahydro-cyclopenta[c]pynDl-5“ylmBthoxy)- qrtinazohn4-yloxy]-phenyl}-3-pheiiylacet)fl-thiouiea, dhydrobromide salt. 5-{4-[2-Fluoro-4-(3-phenylacetyl-thioureido)-phenoxy]-6“methoxy-quinazolin-7-yloxymethyl}-hexahydto-cydopenta[c]pyiroIe-2-caxboxy]ic add benzyl ester (3.3g, 4.5mmol) was dissolved in AcOH (70ml) to which was added 33%HBr in AcOH (12ml). The reaction mixture was stirred at room temperature for 1 hr, diluted with BtzO (1000ml) and the resulting solids filtered, washed with Et20, and dried under high vacuum to give the l-{3-fluoro-4-[6-methoxy-7-(octahydro-cyclopenta[c]pym)l-5-yhnethoxy)-quinazolin-4-yloxy]-phenyI}-3-phenylacetyl-thiourea, dihydrohromide salt (3.4g, 100%). !H-NMR (400MHz, DMSO): 12.42 (s, 1H), 11.80 (s, 1H), 8.84 (br s, 2H), 8.64 (s, 1H), 7.92 (m, 1H), 7.59 (s, 1H), 7.49 (m, 2H), 7.41 (s, 1H), 7.33 (m, 4H), 7.27 (m, 1H), 4.17 (d, 2H), 3.95 (s, 3H), 3.73 (s, 2H), 3.17 (m, 2H), 3.10 (m, ZH), 2.83 (m, 2H), 2.45 (m, 1H), 2.15 (m, 2H), 1.30 (m, 2H). LC/MS Calcd for [M+Hj+ 602.2, found 602.1.

Example 16

[0305] 1- {3^ηατσ4-[6-ηιβ&amp;οχ7-7-(2^βΰΐ7ΐ'θοΐ3ΐΐ3ίϊ1πΜ:7θ1ορβηΐΒ[ο]ρ3ΤΕΓο1-5- ylmethoxy)-qmnazolin-4-yloxy]-phenyl}-3-phenylacetyl-thiourea. l-{3-Fluoro-4-[6-methoxy-7-(octahydro-cydopenta[c]pyrral-5-ylinethoxy)-quinazolin4-yloxy]-phenyI}'3-phenylacetyl-thiourea, dihydxobromide salt (3.4g, 4.5mmol) was dissolved in in a combination of AcCN (100ml), HfeO (30ml), and AcOH (2.45ml). Formaldehyde (37% in H2O, 855ml, lO.Smmol) was added and the mixture cooled in an ice bath. Na(OAC)3BH (2.99g, 14.1mmol) was added and the reaction mixture was stirred at 0 C for 1 hr, followed by stirring at room temperature for 2 hrs. The reaction mixture was neutralized with the addition of sat'd NaHC03 and then concentrated in vacuo. The resulting aqueous mixture was extracted with CH2CI2 (3x). The combined extractions were washed with sat’d NaHCOs (lx), sat’d NaCl (lx), dried (NajSO^, and concentrated in vacuo. The 186 2013204031 11 Apr 2013 WO 2005/030140 PCTYUS2004/031523 resulting residue was purified by flash chromatography (100% EtOAc, followed by 4% EtgN in EtOAc) to give the free base of l-{3-fluoro-4-[6-methoxy-7-(2-methyl“OCtahydro-cyclopenta[c3pyrrol-5-yimethQxy)-quinazolin-4-yloxy]-phenyl}“3-phenylacetyl“thiourea (1.13g, 40%). The free base was converted to the HC1 salt by dissolving the flee base in a mixture of 1:1 AcCN.'KfeO containing 2-3 equivalents of 1 N HC1 and lyophilizing to give the HG1 salt of l-{3-fluoro-4-[6-methoxy-7-(2-methyl-octahydro-cyclopenta[c]pyirol-5-ylmethoxy)-quinazoIin-4-ylaxy]-phenyl}-3-phenylacetyl-thiouiea as a white solid. *Η-NMR (4O0Mfiz, DMSO): 12.44 (s, 1H), 11.83 (s, 1H), 10.24 (br s, 1H), 8.59 (s, 1H), 7.93 (m, 1H), 7.59 (s, 1H), 7.50 (m, 2H), 7.42 (s, 1H), 7.36 (m, 4H), 7.30 (m, 1H), 4.20 (m, 2H), 3.95 (s, 3H), 3.73 (s, 2H), 3.39 (m, 2H), 3.06 (m, 2H), 2.95-2.77 (m, 5B), 2.35 (m, 1H), 2.15 (m, 2H), 1.45 (m, 2H). LC/MS Calcd for ΡΜ+ΗΓ 616.2, found 616.2. Alternatively, the free base was converted to the acetate salt by dissolving the flee base in a mixture of MeOH and CH2CI2 to which was added 3 equivalents of acetic add. The resulting mixture was concentrated in vacuo and the resulting residue lyophilized from 1:1 AcCN.HaO to give die acetate salt of l“{3-fluoro-4-[6-methoxy-7-(2-methyl-octahydro-cyclopenta[c]pyrrol-5-ylmethoxy)-quinazolin~4“yloxy]-phenyl}-3-phenylacetyl-1iiiourea as a white solid. ^-NMR (400MHz, CDCfe): d 12.45 (s, 1H), 8.65 (s, 1H), 7.98 (dd, 1H), 7.50 (s, 1H), 7.40 (m, 4H), 7.29 (m, 4H), 4.17 (d, 2H), 4.05 (s, 3H), 3.75 (s, 2H), 2.93 (m, 2H), 2.80 (m, 2H), 2.72 (m, 2H), 2.53 (s, 3H), 2.47 (m, 1H), 2.25 (m, 2H), 2.02 (s, 3H), 1.35 (m, 2H). LC/MS Calcd for [M+Hf 616.2, found 616.2.

Example 17

[0306] (6.7-Dimethoxy-(minazo]in-4-vlW2-flirorO“4-Mtro-phenv1VarmTie- A mixture of 4-chloro-6,7-dimethoxy-quinazoline (548mg, 2.4mmol), 2~fluoro-4-mtro-phenylamine (392mg, 2.5mmol), AcCN (10ml), and conc’d HQ (0.050ml) was heated to reflux for several hrs. After the reaction mixture was allowed to cool to room temperature, the resulting solids were filtered, washed with AcCN and air-dried to give (6,7-dimethoxy-quinazolin-4-yl)-(2-fluoro-4-nitro-phenyl)-amine (673mgs, 80%). ΐΐ-ΝΜΕ (400MHz, 187 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523 DMSO): 12.18 (hr s, 1H), 8.91 (s, 1H), 8.45 (s, 1H), 8.36 (dd, 1H), 8.24 (dd, 1H), 7.91 (dd, 1H), 7.44 (s, 1H), 4.04 (s, 3H), 4.Q2 (s, 3H). LC/MS Calcd for |M+HT 345.1, found 345.4.

Example 18

[0307] NV6.7-Dimethoxv-auinazolin-4-vlV2-fliiO!ro-benzai&amp;-1.4-diarniTie. (6,7-

Diinethoxy-quinazolin-4-yl)-(2“fluoro-4-ratro-phenyl)-aniine (673mg, 1.95mmol) was dissolved in a combination of DMF (20ml) and MeOH (20ml), to which was added 10% Pd/C (227mg). The mixture was shaken under an atmosphere of Ha on a Parr hydrogenator at 40psi for 3hrs. The reaction mixture was filtered through celite and the filtrate concentrated in vacuo. The restilting residue was triturated in EtOAc/EtjO. The resulting solids were filtered, washed with Et20, and dried under vacupm to give N'-(6,7-dimethoxy-quinazolin-4-yl)-2-fluoro-benzene-l,4-dlamine (398mg, 65%) which was used in the next reaction without further purification. ^-NMR (400MHz, DMSO): 10.80 (br s, 1H), 10.30 (br s, 1H), 8.63 (s, 1H), 8.15 (s, 1H), 7.33 (s, 1H), 7.15 (m, 1H), 6.45 (m, 1H), 3.96 (s, 6H). LC/MS Calcd for [M+H]+ 315.1, found 315.4.

Example 19

[0308] l-14-(6.7-Dimethoxv-quinazolin-4-vlaminnV3-fluoro-phenvn-3-phenvlacetvl-thiourea. Fhenylacetyl chloride (0.18ml, 1.4mmol) and AgSCN (338mg, 2.0mmol) were 188 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523 combined in dty toluene (5ml) and heated to reflux for 2 hrs. The reaction mixture was allowed to cool to room temperature, the solids were filtered through celite and the filtrate concentrated in vacuo. The resulting oil was combined with 1^-(6,7-Dimethoxy-qmnazoHn-4-yl)-2-fluoro-benzene-l,4-diamine (398mg, 1.3mmol) in 1:1:2

EtOH:tohiene:MeOH (30ml) and the mixture stirred at room temperature overnight. The resulting solids were filtered and washed with toluene, followed by hexanes. The solids were dissolved/suspended in a mixture of EtOAc/MeOH. Insoluble material was filtered and the filtrate concentrated in vacuo. The resulting solids were once again dissolved/suspended in a mixture of EtOAc/MeOH, In soluble material was filtered and die filtrate concentrated in vacuo to give l-[4-(6,7-dimethoxy-quinazolin-4-ylammo)-3-fiuoro-phenyl]-3-phenylacetyl-thiourea (105mg, 17%). ^-NMR (4Q0MHz, DMSO): 12.53 (s, 1H), 11.86 (s, 1H), 11.44 (hrs, 1H), 8.81(s, 1H), 8.25 (s, 1H), 7.94 (dd, 1H), 7.54 (m, 2H), 7.16 (m, 5H), 7.10 (m, 1H), 4.02 (s, 6H), 3.84 (s, 2H). LC/MS Calcd for [Μ+Η]+ 492.1, found 492.4.

Example 20

NCfe [0309] 6.7-Dimethoxv-4-(5-nitro-Dvridin-2-vloxv)-qiiiTioljne. To a round bottom flask equipped with a magnetic stir bar was added 6,7-dimethoxy-lfi-quinolin-4-one (1.8 g, 8.77 mmol, 1.0 eq.), anhydrous acetonitrile (90 mL) and CS2CO3 (3.13 g, 9.65 mmole, 1.1 eq.). The reaction mixture was stirred at roam temperature for 5 minutes. Then, 2-0-5-nitropyridine (1.53 g, 9.65 mmol, 1.1 eq.) was added. The reaction mixture was stirred at room temperature for 16 hours. Hie solids were then filtered off and the filtrate was concentrated via rotary evaporation. The resulting material was taken up in EtOAc, and again the solids were filtered off. The EtOAc filtrate was concentrated. Purification was dime on Biotage with solvent system EtOAc 100%. The collected pure fractions were concentrated and dried on high vacuum overnight to give 6,7-dimethaxy-4-(5-nitro-pyridm-2-yloxy)-quinoline as a yellow foam solid (0.902 g, 31.4% yield). XH NMR ¢400 189 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523 MHz, CDC13): 9.08 (d, IB), 8.74 (d, 1H), 8.60 (dd, IB), 7.49 (s, 1H), 7.26 (d, 1H), 7.16 (s, 1H), 7.07 (d, 1H), 4.06 (s, 3H), 3.95 (s, 3H); MS (El) for 328 (M+H*).

Example 21

[0310] 6-(6.7-Pimedioxv-quiiiolin-4-vloxvVpvridiii-3-vlaTnine· To a round bottom flask equipped with a magnetic stir bar was added 6,7-dimethoxy-4-(5-mtio-pyridiii-2-yloxy)“ quinoline (0.46 g, 1,41 mmol, 1.0 eq.), and THF (10 mL), MeOH (4 mL), DMF (2 mL), and TEA ¢2 mL). Hie 6,7-Drmethoxy-4-(5-nitro-pyridin-2-yIoxy)-quinolme was dissolved completely in the above solution mixture, and was flushed with nitrogen for at least 5 minutes. The Pd/C (10% by weight) (0.090 g, 20% by weight) was then added. A balloon Ailed with H2 was connected to the flask after the nitrogen was vacuumed out. The reaction mixture was stirred at room temperature for 4 hours. The palladium was filtered out through Celite, and the filtrated was collected and concentrated via rotary evaporation. The resulting oil-like product was taken up into 5 mL of water and 1 mL of acetonitrile and lyophilized to yield 6-(6,7-dimethoxy-quinolin-4-yloxy)-pyridin-3-ylamine as a light brown solid (0.411 g, 98.1%). JHNMR (400 MHz, CDC13): 8.54 (d, 1H), 7.85 (d, 1H), 7.53 (s, 1H), 7.41 (s, 1H), 7.18 (dd, 1H), 6.96 (d, 1H), 6.61 (d, 1H), 4.05 (s, 3H), 4.03 (s, 3H), 3.73 (s, 2H); MS (ED for Ci6Hi5N303:298 (M+H*).

Example 22

[0311] l-r6-(6.7-Dimethoxv-auinolin-4-vbxvVovridin-3-vll-3-phenvlacetvl-thiourea. To a round bottom flask equipped with a magnetic stir bar was added 6-(6,7-dimethoxy-quinolin-4-yloxy>pyridin-3-ylamine (85 mg, 0.0285 mmol, 1.0 eq.), and Phenyl-acetyl 190 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2O04/O31S23 isothiocyanate (256 mg, 1.44 mmol, 5.0 eq.) dissolved in EtOAc/MSeOH 50:50 (2 mL). The reaction mixture was sittred at room temperature for 12 hours, and the solvent was evaporated via rotary evaporation. Purification was done on Biotage with solvent system 95% EtOAc, 4% TEA and 1% MeOH. The combined pure fractions were concentrated and dried under vacuum overnight to yield l-[6-(6,7-dimethoxy-quinolin~4-yloxy)-pyridin-3-yl]-3-phenylacetyl-thiourea as a light yellow solid (40.4 mg, 29.1%). !H NMR (400 MHz, CDC13): 8.65 (d, 1H), 8.33 (d, 1H), 8.27 (dd, 1H), 7.35 (m, 7H), 7.15 (d, 1H), 6.92 (d, 1H), 4.05 (s, 3H), 3.99 (s, 3H), 3.76 (s, 2H); MS (ED for C25H22N4O4S: 475 (M+H1).

Example 23

[0312] N-r4-f6.7-Dimethoxv-auinolin-4-vloxvl-3-fluQro-nhenvll-N,-phenethvI-oxalannide. To a solution of 4-(6,7-dimethoxy-qmnolin-4-yloxy)-3-fluoro-phenylamine (263 mg, 0.83 mmol) andEtjN ¢0.223 ml, 1.67 mmol) in CHaCfe (10 mL) was added dropwise a solution of ethyl oxalyl chloride in CH2C12 (1 mL). The stirring was continued far 0.5 h at rt. The reaction mixture was then washed with aqueous saturated NaHCOs and dried over NaSO* Removal of the solvent gave the erode oxamate, which was treated with neat phenethylamine (1.0 g, 8.3 mmol) at 80 °C for 3 h. Purification by flash column chromatography (hexanes:EtOAc = 1:3) gave N-[4-(6,7-djmethoxy-quinolin-4-ytoxy)-3-fluoro-phenylJ-N'-phenethyl-oxalamide (310 mg, 76%). 'Η NMR (400 MHz, CDCI3) δ 9.35 (br s, 1H), 8.70 (d, 6.3 Hz, 1H), 7.83 (dd, 11.9,2.5 Hz, 1H), 7.60-7.54 (m, 2 H), 7.43 (s, 1H), 7.38-7.32 (m, 3 H), 7.30-7.20 (m, 4 H), 6.41 (d, J = 5.3 Hz, 1H), 4.07 (s, 3 H), 4.05 (s, 3 H), 3.67 (dt, J= 7.0,7.0Hz, 2H), 2.92 (t, J= 7.2Hz, 2H). LC-MS: 490 [M+H]+ 191 PCT/US2004/031523

Example 24

2013204031 11 Apr 2013 WO 2005/030140 [0313] N434fluoro446-meflroxv-741“methvl-pipeririin-4-vtmethoxyVcpiinolin-4-vloxvl-phenvl)-N,-phenethvl-oxalaTnidR To a flask containing 7-benzy]oxy-4-(2-£LuQro-4-nitro-phenoxy)-6-methoxy-quinoline (850 mg, 2.0 mmol) was added 20 mL of 30% HBr in AcOH. The resulted solution was stirred for 4 h at it; at this time, a large amount of precipitate fanned. The crude product was filtered, washed with Et20 and dried in air, giving 4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-74iydioxyquinoline (609 mg, 92% yield).

[0314] To a solution of the 4-(2-fluoro-4-niiro-jAenoxy)-6-inethoxy-7-hydroxyqiinioline (609 mg, 1.8 mmol) in DMF (9 mL) was added K4CO3 (1.24 g, 9.0 mmol) and N-Boc-4-piperidinemethanol mesylate (732 mg, 2.5 mmol). The mixture was then stirred at 80 °C for 2.5 h. After it was cooled to rt, the mixture was loaded directly to a Biotage column, and eluted with solvents (hexanesrEtOAc = 1:3). The resulting product, 4-[4-(2-fluoro-4-mtro-phenoxy)-6-methoxy-quinoIin-7-yloxymethyl]'pipeiidine-l'Carboxylic acid tert-butyl ester, was obtained as a solid (556 mg, 56%). , [0315] To a solution of 4-[4-(2-fluoro-4-dtro-phenoxy)-6-methoxy-quinolin-7-yloxymethyl]-piperidine-l-carboxylic acid teat-butyl ester (305 mg, 0.58 mmol) in CEfcCfe (1 mL) was added 0.4 mL of TFA. The reaction mixture was stirred for 1.5 h and the solvents were removed under reduced pressure. The crude product was treated with NaBH(OAc)3 (381 mg, 1.80 mmol) and formaldehyde (0.5 mL, 37% in H2O). The stirring was continued for 12 h. The reaction was quenched with sat. aqueous NaHCC>3. 15% 1 NaOH was added until PH = 14. The product was extracted with EtOAc. Removal of the solvent in vacuo gave the crude product, 4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-7-(l-methyl-piperidin-4-ylmethoxy)“quinoline, (240 mg, 93%), which was used directly in the next reaction.

[0316] To a solution of 4-(2-Fluoro-4-nitro-phenoxy)-6-methoxy-7-(l-methyl-piperidin“4-ylmethoxyj-quinoline (240 mg, 0.54 mmol) in EtOH (20 mL) was added 10% Pd/C (50 192 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523 mg). The mixture was then hydrogenated on a Parr hydrogenator (40 psi) for 10 h. AcOH was added to dissolve the intermediate (mostly the hydroxylamine) and the hydrogenation was continued for additional 12 h. LC-MS was used to monitor the reaction progress. The solvents were removed under reduced pressure and the resulting crude product of 3-fluoro-4-[6-methoxy^7-(l-inethyl-piperidm-4-ylmethoxy)-quinolin-4-yloxy]-phenylainine (about 220 mg) was used directly in the next reaction.

[0317] To a 0 °C solution of 3-fluoro-4-[6-methoxy-7-(l-methyl~piperidin-4-ylmethaxy)-quinolin-4-yloxy]-phenylamine (66 mg, 0.13 mmol) and EfeN (0.34 mL) in CH2CI2 (6 mL) was added slowly ethyl oxalyl chloride (98 mg). The reaction mixture was stirred at rt for 30 min, then diluted with CS2G2 and washed with sat. aqueous NaHC03. After dried over MgS04 and concentrated, the crude ethyl oxamate was reacted with phenethylamine (80 mg, 0.64 mmol) at 80 °C for 2 h. Purification by HPLC gave product, N-{3-fluoro-4-[fi-meihoxy-T-il-nmthyl-piperidm^ylinethoxyJ-quinolin-d-ytoxyl-phenylJ-N'-phenethyl-oxalamide (52 mg, 68% yield). *H NMR (400 MHz) δ 9.38 (hr s, 1H), 8.48 (d, J = 5.2 Hz, 1H), 7.83 (dd, J = 11.7,2.6 Hz, 1H), 7.59 (t, J=6.2 Hz, 1H), 7.55 (s, 1H), 7.40-7.20 (8 H), 6.39 (d, J = 5.3 Hz, 1H), 4.06 (d, J « 6.6 Hz, 2 H), 4.04 (s, 3 H), 3.67 (q, J=6.8 Hz, 2 H), 2.98 (br d, J = 11.5 Hz, 2 H), 2.92 (t, J = 7.0 Hz, 2 H), 2.34 (s, 3 H), 2.10-1.80 (m, 5 H), 1.60-1.54 (m, 2 H).

Example 25

[0318] l-(4-Fluoro-phenylcarbamovD-cvclopropanecarboxvlic acid. The title compound was prepared based on a modified procedure of Shih and Rankin [Synthetic Communications, 1996, 26(4), 833-836]: To a mixture of cyclopropane-1,l-dicarboxylic acid (21.2 g, 0.163 mol, 1.0 eq.) in anhydrous THF (200 mL) under nitrogen was added dropwise triethylamine (16.49 g, 0.163 mol, 1.0 eq.) with stirring for 30 minutes at 0°C, followed by the addition of thionyl chloride (19.39 g, 0.163 mol, 1.0 eq.) with stirring for another 30 minutes at 0°C. To the resulting mixture under nitrogen was added dropwise a solution of 4-fluaroaniline (19.92 g, 0.179 mol, 1.1 eq.) in anhydrous THF (100 mL) with stirring for 1.5 hours at 0°C. The reaction mixture was diluted with ethyl acetate and 193 2013204031 11 Apr 2013 PCT/US2004/031523 WO 2005/030140 washed with IN NaOH. The layers were separated, and the ethyl acetate layer was concentrated in vacuo to give a brownish solid. The brownish solid was washed with small amount of cold ethyl acetate, filtered and dried under vacuum to yield l-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic add as a white solid (23.71 g, 65.18%). ]H NMR (400 MHz, CD3OD): 7.57-7.53 On, 2H), 7.05-7.00 (m, 2H) 1.46-1.43 (m, 2H), 1.40- 1.37 (m, 2H).

Example 26

[0319] l-t4-Eluoro-phenvlcarhamnvlVcvcIobutanecarboxvlic add. To a mixture of cyclobutane-l,l-dicarboxylic add (10.0 g, 69.4 mmol, 1.0 eq.) in anhydrous THF (100 mL) under nitrogen was added dropwise triethylamine (7.02 g, 69.4 mmol, 1.0 eq.) with stilling for 30 minutes at 0°C, followed by the addition of thionyl chloride (8.25 g, 69.4 mmol, 1.0 eq.) with stirring for another 30 minutes at 0°C. To the resulting mixture under nitrogen was added dropwise a solution of 4-fluoroaniline (8.48 g, 76.3 mmol, 1.1 eq.) in anhydrous THF (50 mL) with stirring for 1.5 hours at 0°C. The reaction mixture was diluted with ethyl acetate and extracted with 2N NaOH. The aqueous phase was titrated with 2N HC1 to pH 1-2 and then extracted with ethyl acetate. The organic phase was dried with sodium sulfate and concentrated in vacuo to give l-(4-fluoro-phenylcarbamoyl)- cyclobutanecarboxylic add as a light pink solid (5.75 g, 34.9%). *H NMR (400 MHz, CDCI3 w/ldrop CD3OD): 7.53-7.48 (m, 2H), 7.06-7.00 (m, 2H), 2.81-2.63 (m, 4H), 2.14-2.02 (m, 2H).

Example 27

[0320] 1-Benzvbaihamnvl-cvclopropanecarboxvlic add. The title compound was prepared based on a modified procedure of Shih and Rankin [Synthetic Communications, 1996, 26(4), 833-836]: To a mixture of cyclopropane-1,1-dicarboxylic add (5.0 g, 38,4 194 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523 mmol, 1.0 eq.) in anhydrous THF (50 mL) under nitrogen was added dropwise triethylamine (3.89 g, 38.4 mmol, 1.0 eq.) with stirring for 30 minutes at 0°C, followed by the addition of thiohyt chloride ¢4.57 g, 38.4 mmol, 1.0 eq.) with stirring for another 30 minutes at 0°C. To the resulting mixture under nitrogen was added dropwise a solution of benzylaroine 5 (4.53 g, 42.3 mmol, 1.1 eq.) in anhydrous THF (25 mL) with stirring for 1.5 hours at 0°C. The reaction mixture was diluted with ethyl acetate and extracted with 2N NaOH (to pH 10). The aqueous phase was titrated with 2N HC1 to pH 1-2 and then extracted with ethyl acetate. The organic phase was dried with sodium sulfate and concentrated in vacuo to give 1-Benzyicarbamoyl-cyclopropanecarboxylic add as a white solid (4.39 g, 52.15%). NMR (400 MHz, CDC13): 8.44 (hr s, 1H), 7.37-7.33 (m, 2B), 7.32-7.26 (m, 3H), 1.82-1.70 (m, 4H).

Example 28

[0321] 1-Phenvlcarbamovl-cvclopropanecaiboxvlic add. To a mixture of cyclopropane- 1,1-dicarboxylic acid (5.29 g, 40.7 mmol, 1.0 eq.) in anhydrous THF (50 mL) under nitrogen was added dropwise triethylamine (4.12 g, 40.7 mmol, 1.0 eq.) with stirring for 30 minutes at 0°C, followed by the addition of (hionyl chloride (484 g, 40.7 mmol, 1.0 eq.) with stirring for another 30 minutes at 0°C. To the resulting mixture under nitrogen was added dropwise a solution of phenylamine 9 (4.17 g, 44.8 mmol, 1.1 eq.) in anhydrous THF (25 mL) with stirring for 1.5 hours at 0°C. The reaction mixture was diluted with ethyl acetate and extracted with 2N NaOH (to pH >10). The aqueous phase was titrated with 2N HCI to pH 1-2 and then extracted with ethyl acetate. The organic phase was dried with sodium. sulfate and concentrated in vacuo to give 1-phenylcarbamoyl-cyclopropanecarboxylic acid as a white solid (5.08 g, 60.8%). XH NMR (400 MHz, CDCI3): 10.50 (br s, IB), 7.56-7.54 (m, 2H), 7.35-7.31 (m, 2H), 7.15-7.10 (m, 1H), L94- 1.91 (m, 2H), 1.82-1.79 (m, 2H). 195 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523

Example 29

[0322] 7-Benzvloxv-4-chloro-6-methoxv-gtilno1ine. Dry DMF (8.0ml, 103mmol) was dissolved in dry CHCI3 (40ml) and cooled in an ice bath. Oxalyl chloride (9.0ml, lOSmmol) in CHbCfc (10ml) was added dropwise with stirring at OC. When the bubbling had ceased, this solution was added slowly to an ice-cold solution of 7-benzyloxy-6-methoxy-3H-quinazolin-4-one (lO.Og, 35.4mmol) in dry CHCI3 (60ml) and the mixture was then heated to reflux for 2-3hrs. After cooling to room temperature, H2O (100ml) was added and the phases were separated. The aqueous phase was further extracted with CHCI3 (2x). The combined CHC13 extractions were washed with sat’d NaCl (lx), dried (Na2S04) and concentrated in vacuo. The resulting residue was purified by flash chromatography (1:1 hexanes:EtOAc, followed by 100%EtOAc) to give 7-benzyloxy-4-chloro-6-methoxy-quinoline (5.11 g, 48%). LC/MS Calcd far [M+H|+ 301.1, fo.und 301.1.

Example 30

[0323] Cvclopropane-l.l-dicarboxvlic acid r3-fluoro-4-i7-hvdroxv-6-metboxv-qninolin-4-vloxv)-nbenvn-amidef4-fluoro-phen vll-amide. To a solution of cyclopropane-1,1- dicarboxylic acid [4-(7-benzyloxy-6-methoxy-qumolin-4-yloxy>-3-fluoro-phenyl]-amide (4-fiuoro-phenyl>amide (1.18g, 2,0 mmol) in EtOH (20 mL) was added 1,4-cyclohexadiene (2.0 mL, 20 mmol) and 10% Pd/C (300 mg). The reaction mixture was then heated to reflux and the stirring was continued far 2 h. It was cooled to room temperature, filtered through celite and washed with MeOH. The MeOH solution was then concentrated under reduced pressure. The residue was taken into EtOAc (200 mL). 196 FCX/US2004/031523 2013204031 11 Apr 2013 WO 2005/030140

The EtOAc solution was washed with water, and dried over NazSCL. Removal of the solvent under reduced pressure gave 900 mg (89%) of the crude product (90% purity by analytical HPLC), which was used in the next reaction without further purification.

Example 31

[0324] N-(4-f f7-f F3-<TKftthv1aminolethvnoxvl-6-fmefhvloxvlquinoIin-4-ynoxv)-3- fluorophenvl')-N’-('4-flutnOPhenvl)cvcloproDane-Ll-dicaifaoxaTnide· To a mixture of cyclopropane-1,1-dicarboxylic add [3-fluaro-4-(7-hydroxy-6-methoxy-quinolin-4-yloxy)-phenjd]-amide(4-fluoro-phenyl)-amide (186 mg, 0.36 mmol) in CH2CI2 (10 mL) was added 2-(diethylamino)ethanol (63 mg, 0.54 mmol), and PPI13 (141 mg, 0.54 mmol). DIAD (109 mg, 0,54 mmol) was then added as a CH2CI2 (1 mL) solution. The resulted solution was stirred at room temperature for 2 h and the solvent was removed under reduced pressure. To the residue was added 1 N HC1 (50 mL), and it was washed with EtOAc (50 mL x 2). The aqueous phase was basified by adding 15% NaOH aqueous solution until pH =11-13, and then extracted with ether (50 mL x 2). The combined organic layer was dried (MgS04), and concentrated in vacuo. The residue was purified on preparative HPLC to give N-(4-{[7-{[2-(diethylammo)ethyl]oxy}-6-(methyloxy)quinolin-4-yl]oxy}-3-fluomphenyl)-N'-(4-fluoro-pheny])cyclopropane-l,l-dicaiboxamide (74 mg, 34%) as a pale yellow solid. *H NMR (400 MHz, DMSO-fife) δ 10.40 (br s, 1H), 10.02 (br s, 1 H), 8.47 (d, 7= 5.2 Hz, 1H), 7.91 (hr d, 7 = 13.9 Hz, 1 H), 7.54-7.52 (m, 2 H), 7.55- 7.50 (m, 1H), 7.52 (s, 1H), 7.50-7.40 (m, 1H), 7.41 (s, 1H), 7.16 (br t, 7 = 8.7 Hz, 2 H), 6.41 (br d, 7=4.7 Hz, 1H), 4.18 (t, 7= 6.0 Hz, 2 H), 3.94 (s, 3 H), 2.87 (br t, 7=6.3 Hz, 2 H), 2.59 (q, 7= 7.1 Hz, 4 H), 1.47 (br s, 4 H), 1.00 (t, 7= 7.0 Hz, 6 H). 197 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523

Example 32

[0325] l-f4-Benzvloxv-3-methoxvphenvl)ethanone· A solution of 4-hydroxy-3-methoxyacetophenone (40 g, 240 mmol), benzyl bromide (31.4 mL, 260 mmol) and potassium carbonate (99.6 g, 360 mmol) in DMF (800 mL) was heated to 40 °C overnight The solution was cooled to room temperature, poured over ice and (he resultant solid was filtered. This material was washed with water and dried to give l-(4-benzyloxy-3-methoxyphenyl)ethanone (61 g, 99 %).

[0326] l-f4-Bea3zvloxv-5-methoxv-2-nittophenvl'teflianone· A stirred solution of 1-(4-benzyloxy-3-methoxyphenyl)ethanone (51.3 g, 200 mmol) in dichloromethane (750 mL) was cooled to 0 °C. Nitric add (90 %, 14 mL, 300 mmol) was added dropwise to the cooled solution over 20 min. Sulfuric acid (96.2 %, 16.3 mL, 300 mmol) was then added dropwise over 40 min at 0 °C. Additional nitric add (9.4 mL, 200 mmol) was added dropwise over 20 min. The reaction mixture was washed with water (3 x 200 mL), and saturated sodium bicarbonate (4 x 200 mL, or until neutral). The organic layer was dried over Na2S04 and concentrated The crude mixture was recrystaUized from DMF to give l-(4-benzyloxy-5-methoxy-2-nitnophenyl)ethanone (36 g, 60 %). *11NMR (400 MHz, CDCI3): δ 7.65 (s, 1H), 7.45-7.33 (m, SB), 6.74 (s, 1H), 5.21 (s, 2H), 3.97 (s, 3H), 2.49 (s, 3H).

[0327] l-(2-Amino-4-benzvtoxv-5-methnxvphenvDethanone. A mixture of iron powder (27 g, 0.48 g atoms), ammonium formate (31 g, 500 mmol), l-(4-benzyloxy-5-methoxy-2-nitmphenyl)ethanone (36 g, 120 mmol), toluene (500 mL) and water (500 mL) was heated to reflux overnight. The mixture was filtered through celite and washed with ethyl acetate. The combined organic layers were washed with water and brine. The organic layer was 198 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523 dried over NajSCh and concentrated to afford 1 -(2-amino-4-benzyloxy-5-methoxyphenyl)ethanone (29.3 g, 90 %). ^NMR (CDa3): δ 7.41-7.30 (m, 5H), 7.13 (s, 1H), 6.16 (hr s, 2H), 6.10 (s, 1H), 5.13 (s, 2H), 3.83 (s, 3H), 2.51 (s, 3H). LC/MS (M+H= 272).

[0328] 7-Ben2vloxv-6-methoxvfliiinnlin-4-ol· Sodium ethoxide (74.8 g, 1.1 mol) was added to a solution of l-(2-ammo-4-benzyloxy-5-inethoxyphenyl)ethanone (29.3 g, 108 mmol) in DMB (700 mL) and stirred for 30 min. Ethyl foonate (44 mL, 540 mmol) was added and the mixture was stirred overnight (in case of incomplete reaction, additional sodium ethoxide can be added and the reaction monitored by LCZMS). After the reaction was complete, the mixture was diluted with water (40 mL) and acidified to neutral pH with 1M HC1. The solid was filtered, washed with water and dried to afford 7-benzyloxy- 6-methoxyquinolin-4-ol (22 g, 72%). *H NMR (400 MHz, CDC13): δ 10.7 (hr s, IB), 7.70 (s, 1H), 7.49-7.46 (t, 1H), 7.43-7.41 (hr d, 2H), 7.37-7.33 (t, 2H), 7.30-7.28 (d, 1H), 6.84 (s, 1H), 6.21-6.19 (d, 1H), 5.21 (s, 2H), 3.96 (s, 3H). LC/MS (M+H=282).

[0329] 7-BenzvloxV“4-chlaro-6-methoxvquinoIme. Phosphorus oxychloride (300 mL) was added to 7-benzyloxy-6-methoxyquinolin-4-ol (40 g, 140 mmol) and the mixture heated to reflux for 2 h. The mixture was carefully poured into a mixture of ice and sodium carbonate. The solution was adjusted to pH 8 with the addition of solid sodium bicarbonate and stirred at room temperature overnight The solid was filtered and washed with water and dried to give 7-benzyloxy-4-chloro-6-methoxyqmnoline as a pale brown solid (40.2 g, 95%). *H NMR (400 MHz, dg-DMSO): δ 8.61 (s, 1H), 7.57-7.37 (m, 8H), 5.32 (s, 2H), 3.98 (s, 333); 13C NMR (100 MHz, ^-DMSO): δ 152.4,151.5, 148.5,146.2, 139.6,137.0, 129.2, 128.8, 121.7, 120.4, 110.1, 101.9, 70.8, 56.5; IR (cm'1): 2359, 2341, 1506,1456,1435,1252,1227,1146,999, 845,752,698,667; LOMS (M+H = 300).

Example 33

[0330] Trifluoromethanesulfonic acid 7-benzvloxv-6-methoxv-quinolin-f-vl ester. To a dry 2L RBF containing 7-benzyloxy-6-methoxyquinolin-4-ol (75.3 g, 267 mmol) was added DCM (1L), 4-dimethylaminopyridine (3.28 g, 26.8 mmol) and 2,6-lutidine (62 mL, 199 2013204031 11 Apr 2013 WO 2003/030140 PCT/US2004/031523 534 mmol). The mixture was cooled to -20°C by controlled addition of dry ice to an acetone bath. Tiifluoromethanesulfonyl chloride (37 mL, 350 mmol) was added dropwise to the cooled solution with magnetic stirring over 25 minutes. After addition was complete, the mixture was stirred in bath for 20 minutes, then at room temperature for 3 hours. LCMS indicated reaction completion. The reaction mixture was concentrated in vacuo and placed under high vacuum to remove residual 2,6-lutidine. To the resulting brown solids was added methanol (3.5 L). The resulting slurry was stirred with mechanical stirrer for 30 min before adding water (1.5 L). The solids were isolated by filtration, followed by a water wash. Hie resulting solid was dried under high vacuum overnight yielding trifluoromethanesulfonic acid 7-benzyloxy-6-methoxy-quinolin-4-yl ester as a light brown solid (92.2 g, 83.8%). JHNMR (400MHz, DMSO, ds): δ 8.82 (d, 1H), 7.67 (s, 1H), 7.59 (d, 1H), 7.54-7.52 (m, 2H), 7.46-7.42 (m, 2H), 7.39-7.36 (m, 1H), 7.23 (s, 1H), 5.35 (s, 2H), 3.97 (s, 3H). LC/MS: M+H=414.

Example 34

[0331] Trifluoromethanesulfonic acid 6.7-dimethoxvaainolin-4-vl ester from 6.7-Dimethoxv-qumoliD-4-ol. To a dry 1L RBF containing 6,7-dimethoxy-quinolin-4-ol (20.9 g, 102 mmol), which can be prepared according to the procedure of Riegel, B. (J, Amer. Chem. Soc. 1946, 68, 1264), was added DCM (500 mL), 4-dimethylaminopyridine (1.24 g, 10 mmol) and 2,6-lutidine (24 mL, 204 mmol). The mixture was vigorously stirred at RT. Trifluoromethanesulfbnyl chloride (14 mL, 132 mmol) was added dropwise to the solution. After addition was complete, the mixture was stirred ice bath for 2 to 3 hrs. On LC/MS indicating the reaction completion, the reaction mixture was concentrated in vacuo and placed under high vacuum to remove residual 2,6-lutidine. To the resulting brown solids was added methanol (250 mL). The resulting slurry was stirred for 30 min before adding water (1L). The solids were isolated by filtration, followed by a water wash. The resulting solid was dried under high vacuum overnight yielding trifluoromethanesulfonic add 6, 7-dimethoxy-quinolin-4-yl ester as a light brown solid (27 g, 80%). *H NMR (400MHz, DMSO, de): δ 8.82 (d, 1H), 7.59 (m, 2H), 7.20 (s, 1H), 3.97 (d, 6H). LC/MS: M+H = 338. 200 PCT/US2004/031523

Example 35

2013204031 11 Apr 2013 WO 2005/030140 [0332] l-Benzvloxv-2-fluoro-4-mtrobenzene· A solution of 2-fluoro-4-nitropheno] (50.0 g, 318 mmol), benzyl bromide (42 mL, 350 mmol) and potassium carbonate (66.0 g, 478 mmol) in DMF (200 inL) was heated to 40 °C overnight. The solution was cooled to room temperature, poured ova: ice and the resultant solid was filtered This material was washed with water and dried to give l-benzyloxy-2-fluoro-4-mtrobenzeue (75.0 g, 95 %). NMR (400 MHz, dfi-DMSO): δ 8.19-8.11 (m, 2H), 7.53-7.37 (m, 6H), 5.36 (s, 2H); 13C NMR (100 MHz, <fc-DMSO): δ 152.8, 152.4, 149.9, 140.9, 136.1, 129.3, 129.1, 128.7, 122.0,115.2,112.8,112.6,71.6; IR (cm'1): 1499,1346,1279, 1211,1142,1072,986, 885, 812, 789,754,742,700,648, 577.

[0333] 4-Beiizvloxv-3-fluQroaniiine. A mixture of iron powder (45.2 g, 0.809 g atoms), ammonium formate (53.6 g, 0.850 mol), l-benzyloxy-2-fluoro-4-nitrobenzene (50.0 g, 0.200 mol), toluene (400 mL) and water (400 mL) was heated to reflux overnight. The mixture was filtered through Celite and washed with hot ethyl acetate. The combined organic layers were washed with water and brine, then dried over sodium sulfate and concentrated to afford 4~benzyloxy-3-fluoroaniline (44 g, 100 %). JH NMR (400 MHz, ri6-DMSO): δ 7.43-7.26 (m, 5H), 6.90 (dd, 1H), 6.49 (dd, 1H), 6.34 (m, 1H), 4.99 (hr s, 2H), 4.98 (s, 2H); 13C NMR (100 MHz, d5-DMSO): δ 171.1,155.1,152.7, 144.9,138.0, 137.2, 129.6,129.0,128.5, 118.9, 110.0,102.9, 72,5; IR (cm'1): 1510,1454,1277,1215, 1126,1007,957,843,800,789,739,694,604; LC/MS (M+H = 218).

[0334] Ethvl r(4-benzvloxv-3“fluoroDhenvliaminoIfoxo)acetate. Ethyl oxalyl chloride (44 mL, 390 mmol) was added to a solution of 4-benzyloxy-3-fluoroanilme (44 g, 180 mmol) in diisopropylethylamine (69 mL, 400 mmol) and stirred at room temperature for 15 min. The mixture was extracted with dichloromethane and washed with water and brine. The organic layer was dried over sodium sulfate and concentrated to afford ethyl [(4- 201 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523 benzyloxy-3-Quorophenyl)amino](oxo)acetate (58.4 g, 100 %). 1H NMR (400 MHz, DMSO): 510.87 (s, 1H), 7.73 (d, 1H), 7.69 (d, IB), 7.53 (d, 1H>, 7.46-7.40 (m, 4H), 5.17 (s, 2H), 4.31 (q, 2H), 1.31(t, 3H); IR (cm'1): 1732, 1705, 1558, 1541, 1508, 1456,1273, 1186,1167,1101,999,858,741,694; LC/MS (M+H=318).

[0335] iV-f4-Benzvloxv-3-£louiPPheaivl)-jy,-(2-DhenvlethvnRriignertiHmide. Phenethyl-amtne (33 mL, 520 mmol) was added to ethyl [(4-benzyloxy-3-fluorophenyl)amino](oxo)acetate (81 g, 260 mmol) and the mixture was sonicated at room temperature for 30 min. The resulting solid was filtered, washed with water and dried to give JV-(4-benzytoxy-3-fiourophenyl)-i\r-(2-phenylethyl)ethanedianiide (100 g, 99 %), *H NMR (400 MHz, ife-DMSO): 610.72 (hr s, 1H), 9.05 (m, IB), 8.78 (m, 1H), 7.77 (m, 1H), 7.59 (m, 1H), 7.46-7.19 (m, 8H), 5.16 (m, 2H), 3.45 (m, 2H), 2.83 (m, 2H); IR (cm" l): 2980, 2883, 1653, 1522, 1506, 1441, 1385’ 1221, 1122, 951, 808, 746, 696, 584; LC/MS (M+H-393).

[0336] ALr3-Pluoro-4-hvdroxvphenvI)-jV,-f2-DhenvlethvlWtiangHinmtHft A mixture of N-(4-benzyIoxy-3-flourophenyI)-/V'’-(2-phenylethyl)ethanediamide (40 g, 100 mmol) and 38% hydrobromic acid in acetic acid (250 mL) was stirred at room temperature overnight. The resulting solid was filtered, washed with water and dried to give JV-(3-fluoro-4-hydroxyphenyl>JV’-(2-phenylethyI)ethanediamide as a slightly yellow solid (30.6 g, 99 %yield). *Η NMR (400 MHz, (fc-DMSO): 510.60 (s, 1H), 9.02 (t, 1H), 7.70 (d, 1H), 7.47 (d, 1H), 7.32-7.20 (m, 3H), 6.91 (t, 1H), 3.43 (m, 2H), 2.81 (m, 2H); 13CNMR (100MHz, ds-DMSO): 5160.5,158.8, 152.0,149.6,142.2,139.8,130.3,129.3, 129.0,126.8,118.1, 117.4,109.6,109.3 IR (cm'1): 3279,1653,1518,1456,1279,1190,742,696,584; LC/MS (M+H = 303).

Example 36

202 PCT/US2004/031523 2013204031 11 Apr 2013 WO 2005/030140 [0337] l-Benzvloxv-2-fluoro-4-nitro-benzene. To a slurry of sodium hydride (60% dispersion is oil, 693 mmol, 27.7 g) and dimethylacetamide ¢600 ml) was added benzyl alcohol (462 mmol, 48 ml) dropwise with stirring under N2. The mixture was stirred for 1 hour at RT and then cooled to 0°C. 3,4-difluoronitrobenzene (508 mmol, 56.2 ml) was added to the cooled solution and stirred far 1 hour. Reaction mixture poured onto saturated ammonium chloride solution (800 ml) and stirred for 30 minutes, filtered and washed with water. The solid was stirred in ethyl acetate ¢500 mL), and filtered to give 54g of product The ethyl acetate filtrate, after concentrated in vacuo, was triturated with diethyl ether (500 mL), sonicated for 2 hours, and filtered to give another 30g of product. The ether layer was concentrated and column purified using 5% EtOAc/hexanes as eluent to gave additional 15g of product. The total yield of l-benzyloxy-2-fluoro-4-nitro-benzene was 95g (83%). (Note: the product contains ca. 5% of 3,4-Bis-benzyloxy-nitrobenzene, which is carried into the next step without further purification.) NMR. (400MHz, CDCI3); δ 8.04-8.00 (m, 2H), 7.43-7.37 (m, 5H), 7.08 (t, 1H), 5.26 (s, 2H).

[0338] 4-Benzvloxv-3-fluoro-phenv1 amine. A mixture of l-benzyloxy-2-fluoro-4-mtro-benzene (44g, 178 mmol), tolume ¢400 ml), ammonium formate (35 g), iron (30 g), and water (400 ml) was heated to reflux with stirring overnight The reaction mixture was filtered through celite and washed with ethyl acetate (400ml). The organic layer was separated and washed with brine ¢300 ml), dried over sodium sulfate and concentrated to give 4-benzyloxy-3-fluoro-phenyIamine as an oil (33.7 g, 87%). lH NMR (400MHz, CDCI3): 67.41-7.29 (m, 5H), 6.79 (t, 1H), 6.45 (dd, 1H), 6.14 (dd, 1H), 5.02 (s, 2H), 3.50 (s, 2H). LC/MS: (M+l) 218.

[0339] Cvctonropane-l.l-dicarboxvfic acid f4-benzvloxv-3-fluoro-phenv1Vflmirip. 64-fluoro-nhenvll-amide. To a stirred mixture of 4-benzyloxy~3-fluoro-phenylamine (155.3 mmol, 33.7 g), l-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid (170.8 mmol, 38.13 g) and anhydrous dichloromethane (600 ml) was added ED Cl ¢233.9 mmol, 44.7 g) in portions. After stirring at RT for 1 hr, the reaction mixture was diluted with saturated sodium bicarbonate (400 ml) and stirred for 30 minutes. Hie precipitate was filtered and air dried to give the 1st crop of product. The biphasic filtrate was separated, and the organic phase was washed with brine (300 ml), dried over sodium sulfate, and concentrated. The residue was taken up in DCM (100 ml), stirred for 15 minutes, and filtered to give a 2nd crop of product. The combined yield of cycIopropaiie-1,1-dicarboxylic acid (4-benzyloxy-3-fluoro-phenyl)-amide (4-flnoro-phenyl)-amide was 64.5 203 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523 g (98%). JH NMR (400MHz, CDCI3): δ 8.92 (br s, 1H), 8.88 (br s, 1H), 7.50-7.32 (m, 8H), 7.06-7.02 (m, 3H), 6.97-6.92 (t, IH), 5.13 (s, 2H), 1.65 (s, 4H). LC/MS: (M+l) 423.

[0340] Cvclooropane-l.l-dicarboxvlic acid G-fluoro^hvdroxv-phenvl'i-a-mide M-fhinm-phgnvlI-flTnidft- A mixture of cyclopropane-1,1-dicarboxylic add (4-benzyloxy-3-fluoro-phenyl)-ainide (4-fluoro-phenyl)-amide (152.8 mmol, 64.5), ethanol (800 ml), cyclohexadiene (764 mmol, 71 ml), and 10% Pd/C (2 g) was refluxed for 2 hoars. t

Reaction mixture cooled and filtered through celite and washed with methanol. The combined filtrate was concentrated and stirred in 10% EtOAc/ether (350 ml). The resulting precipitate was filtered and washed with ether to give a 1st crop of product. The filtrate was concentrated and stirred in DCM (150 ml) to give another precipitate, which was then filtered to give a 2nd crop of product. The combined yield of cyclopropane-1,1-dicarboxylic acid (3-fluoro-4-hydroxy-phenyl)-amide (4-fiuoro-phenyl)-amide was 43 g (85%) in 95% purity by HPLC (UV @ 254 nm). NMR (400MHz, DMSO-D6): δ 10.07 (hr s, 1H), 9.92 (br s, 1H), 9.64 (br s, 1H), 7.64-7.60 (m, 2H), 7.55-7.51 (m, IB), 7.17-7.12 (m, 3H), 6.89-6.84 (t, 1H), 1.43 (s, 4H). LC/MS: (M+l) 333.

Example 37

[0341] Cyclopropane-1.1-dicarboxvlic add (4-benzvloxv-phenvl)-amide (4-fluoro- phenvD-aimde. To a 0 °C suspension of 4-benzyloxyaniline hydrochloride (47.0 g, 200 mmol) and l-(4-fluoro-phenylcarbamoyl)-cyclopropanecaiboxyIic acid (49.1 g, 220 mmol) in CH2CI2 (400 mL) was added ED Cl (38.2 g, 200 mmol). Stirring was continued at rt for 2-4 h until the reaction was complete. CH2CI2 was removed under reduced pressure. H20 (300 mL) and MeOH (200 mL) were added, and the resulting mixture was stirred at rt for 30 min. After filtration and wash with HfeO, the solid was transferred to another flask containing 300 mL of sat. aqueous NaHCOs solution. The mixture was stirred for another 30 min. The solid was filtered, washed with water, and dried over night 204 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523 on a lyophilizer, affording cyclopropane-1,1-dicafboxylic add (4-benzyloxy-phenyl)-amide (4-fluoro-phenyl)-amide (75.8g, 95% yield) as an off-white solid [0342] Cvclopropane-l.l-dicarboxvlic acid (4-fluoro-nhenvlWmidti (4-hvdroxv-ohenvl)-amide. To a refluxing mixture of cyclopropane-l,l-dicatboxylic add (4-benzyloxy-phenyl)-amide (4-fluoro-phenyl)-amide (46 g, 113 mmol), 10% Fd/C (2 g) in EtOH (400 mL) was added dropwise 1,4-cyclohexadiene (62.7 mL, 678 mmol). Stirring was continued for 2-5 h until die reaction was complete. The mixture was cooled to it, filtered through celite, and washed with EtOH. The solution was then concentrated under reduced pressure. To the flask containing the crude product was added CHCI3 (200 mL). The resulting suspension was stirred for 15 min at rt. The solid was filtered, and dried in the air to give cydopiopane-l,l-dicaiboxylic acid (4-fhioro-phenyl)-amide (4-hydroxy-phenyl)-amide (34.4 g, 95%, yield).

Example 38

[0343] Alternate Synthesis of Cvclopronane-l.l-dicarboxvlic acid (4-fluoro-phenvD-amide (4-hvdroxv-phen vlVamids. To a solution of 4-aminophenol (2.93 g, 26.9 mmol) and l-(4-fluoro-phenylcafbamoyl)-cycloprqpanecarboxy]ic acid (5.00 g, 22.4 mmol) in DMA (30 mL) was added EDCX (5.15 g, 26.9 mmol). The mixture was stirred vigorously until the reaction was complete (~ 3 h). With vigorous stirring, die reaction mixture was then poured into a flask containing sat. aqueous NaHCO^ solution (200 mL). The stirring was continued for 1 h. The resulting suspension was then filtered. Hie solid was washed with water (50 mL), chloroform (50 mL) and dried under vacuum, affording l-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid (6.22g, 88% yield) as a powder (>95% purity by HPLC and *H NMR). 205 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523

Example 39

[0344] A^-^4-rf7-Benzvloxv^-mefliDxvauinQlin-4-vl>oxvr3-ilutMOfdifiaivl>-iy-f2- phenvlethvl^ethanftriiamitte. A mixture of 7-benzyloxy-4-chloro-6-methoxyquinoline (30 g, 100 mmol), iVL(3“fluoro-4-hydroxyphenyl)-i7’-(2“phenylethyl)etlianediaimde (32 g, 106 mmol), DMAP (125 g, 1.02 mol) and bromobenzene (500 mL) was heated to reflux for 6 h. The mixture was cooled to room temperature and the bromobenzene was removed under reduced pressure. Methanol (500 mL) was added to the residue and the mixture was stirred at room temperature for 2 h. The resulting solid was filtered, washed with methanol and dried to give iV-{4-[(7-benzyloxy-6-methoxyquinolin-4-yl)oxy]-3-fluorophenyl}-lV'“ (2-phenylethyl) ethanediamide (34 g, 61 %). ^NMR (400 MHz, <&amp;-DMSO): δ 11.05 (s, 1H), 9.15 (s, 1H), 8.47 (d, 1H), 8.05 (d, 1H), 7.84 (d, IB), 7.56-6.36 (m, 13H), 6.46 (d, 1H), 5.32 (s, ZH), 3.97 (s, 3H), 3.47 (q, 2H), 2.86 (t, 2H); 13C NMR (100 MHz, d6-DMSO): 6160.5, 160.2, 159.9, 159.5, 155.2, 152.7, 152.2, 150.3, 149.6, 146.9, 139.7, 137.4, 137.3,137.2,137.1, 129.3, 129.2, 129.1,129.0, 128.9,128.7,128.6, 126.9, 124.8, 117.9,115.3,109.9,102.8, 99.8,70.6, 56.5,41.3,35.2; IR (cm1): 1657,1510,1481,1433, 1416,1352,1310,1252,1215,1609,986, 891,868, 850,742,696;LC/MS (M+H= 566).

Example40

[0345] 7V-(3-Fluoro-4-ri7-hvdroxv-6-methoxvamnolin-4-vl)oxvfohenvl)-iV,-('2-phenvlethviy.thanertiamide,- To a solution of iV-{4-[(7-benzyloxy-6-methoxyquinolin-4- 206 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523 yl)oxy]-3-fluorophenyl}-Ar’-(2-phenylethyl)ethanediamide (32 g, 56 mmol) in methanol (200 mL), DMF (100 mL), dichloromethane (100 mL), ethyl acetate (100 mL) and acetic acid (5 mL) was added palladium hydroxide (4.2 g) and the mixture was shaken on a Fair hydrogenator under a hydrogen pressure of 45 psi for 4 h. The resulting suspension was filtered through celite and the solid residue was washed with boiling dichloromethane (2 L) and acetone (2 L). The combined filtrates were evaporated to yield JV-{3-fluoio4-[(7-hydroxy-6-methoxyquinolm-4-yI)oxy]phenyl}-l\T-(2-pbenylethyl)elhanedianiide as an off-white solid (25.6 g, 95 %). Ή NMR (400 MHz, 4-DMSO): 511.06 (s, 1H), 10.25 (hr s, 1H), 9.12 (t, 1H), 8.40 (d, 1H), 8.01 (dd, 1H), 7.50-7.44 (m, 2H), 7.31-7.23 (m, 6H), 6.39 (d, 1H), 3.95 (s, 3H), 2.85 (t, 2H), 2.50 (m, 2H); JR (cro-1): 1666,1624,1585,1520,1481, 1427,1377,1256,1211,1194,1022, 880,850,839, 802, 750,700; LCZMS (M+H=476).

Example 41

vnoxvlphenvL-iy’-re-phenylethvDethaTiediaTnirie- A solution of iV“{3-fluc!ro-4-[(7-hydroxy-6-methoxyqimiolin“4-yl)oxyJphenyl}-AP-(2-phenylethyl)ethanediamide (25.6 g, 54 mmol), iV-(3-chloropropyl)morphoIine hydrochloride (11.7 g, 592 mmol) and potassium carbonate (16.6 g, 120 mmol) in DMF (300 mL) was heated to 80 °C overnight. Upon cooling, a majority of die DMF (250 mL) was removed on a rotary evaporator, 5% aqueous LiCl (300 mL) was added and the mixture was sonicated at room temperature. The solid was filtered, suspended in IN HCl and washed with ethyl acetate (2 x 300 mL). The solution was adjusted to pH 14 using 2N sodium hydroxide and subsequently extracted with dichloromethane (3 x 200 mL). The organic layer was dried over sodium sulfate, filtered and evaporated to give JV-(3-fluoro-4-{[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinolin-4-yl]oxy}phenyl)-j\r-(2-phenylethyl)ethanediaimde as a yellow solid (24 g, 74 %). *H NMR (400 MHz, CDC13): 5 9.37 (s, 1H), 8.46 (d, 1H), 7.81 (dd, 1H), 7.57 (t, 1H), 7.53 (s, 1H), 7.42 (s, 2H), 7.34-7.20 (m, 6H), 6.39 (d, 1H), 4.27 (t, 2H), 4.03 (s, 3H), 3.71 (m, 4H), 3.65 (q, 2H), 2.91 (t, 2H), 2.56 (br s, 4¾ 2.13 (m, 2H); 13C NMR (100 MHz, dff-DMSO): 5160.1,160.0, 159.5, 155.2, 152.7, 152.6, 150.2,149.5, 147.1, 207 PCT/US2004/031523 2013204031 11 Apr 2013 WO 2005/030140 139.7, 137.3, 137.1, 129.3, 129.1, 126.9, 124.8, 117.9, 115.1, 109.2, 102.7, 99.6, 67.4, 66.9, 56.5, 55.5, 54.1, 41.3, 35.2, 26.4; IR (tan·1): 1655, 1506, 1483, 1431, 1350, 1302, 1248,1221,1176,1119,864,843,804,741,700; LCVMS (M+H=603).

Example 42

[0347] Cvclopropane-l.l-dicarboxvlic add r4-(7-benzvIoxv-6-methoxv-oirinoliii-4-vloxvV3-fluoro-phenvll--amide f4-fluoro-phenvl%amide. To a flask containing cyclopropane-1,1-dicarboxylic acid (3-fluoro-4-hydroxy-phenyl)-amide (4-fluoro-phenyl)-amide ¢2.25 g, 6.7 mmol) and trifluoromethanesulfoiiic add 7-benzyloxy-6-methoxy-quinolin-4-yl ester (1.87 g, 4.5 mmol) was added dry 2,6-lutldine (9 mL). The reaction mixture was heated to reflux (143°C) with vigorous stirring. The reaction progress was monitored by LC-MS. 2,6-Lutidine was removed under reduced: pressure when the reaction was complete (about 6 h). The residue was treated with charcoal (1.5 g) in refluxing EtOAc (50 mL) for 15 min, and filtered through celite. The volume of the filtrate was reduced to about 20 mL and was added 20 mL of 1N HC1. The crude product precipitated as the HC1 salt, which was filtered and washed with EtOAc and HzO (88% purity by analytical HPLC). The HC1 salt was free-based with saturated aqueous NaHC03 solution. Farther purification by column chromatography (hexans:EtOAc = 1:4) gave cyclopropane-1,1-dicarboxylic acid [4-(7-benzyloxy-6-methoxy-quinolin-4-yioxy)-3-fluoro-phenyl]-amide (4-fluoro-phenyl)-amide as an off-white solid (1.3 g, 48% yield. NMR (400 MHz, DMSO, d6): 10.41 (s, 1H), 10.02 (s, 1H), 8.48 (d, 1H), 7.92 (dd, 1H), 7.65 (m, 2H), 7.54 (m, 5H), 7.41 (m, 4H), 7.17 (m, 2H), 6.43 (d, 1H), 5.32 (s, 2H), 3.97 (s, 3H), 1.48 (m, 4H). LC/MS Calcd for |M+H3+ 596.2, found 596.3. 208 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523

Example 43

[0348] Cvclopropane-l.l-dicarbaxvlic acid ra-fluoro-4-(7-hydroxv-6-me1hoxv-qninolin-4-vIoxv)-phenvn-amide (4-fluorn-phenvD-amide· To a solution of the cyclopropane-1,1-dicarboxylic acid [4-(7-benzyloxy-6-methoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-ainide (4-fluoro-phenyl)-amide (22.4 g, 37.6 mmol) in BOH (340 mL) was added 1,4-cyclohexadiene (35 mL, 376 mmol) and 10% Pd/C (2,08 g). The reaction mixture was then heated at 65°C with stirring for 3 h (Caution; Ha gas is released horn the reaction). It was then allowed to cool to room temperature, and filtered through celite follwed by a MeOH wash. The solution was then concentrated under reduced pressure. The yellow residue was taken into EtOAc (1 L). The EtOAc solution was washed with water (IX), brine (2X), dried over MgSC>4 and concentrated in vacuo. Cyclopropane-1,1-dicarboxylic acid [3-fiuoro-4-(7-hydroxy-6-methoxy-gumalm^-yloxy)-phenyl]-armde (4-fluoro-phenyl)-amide was obtained as a yellow solid (17.3 g, 91.1% yield), which were carried on to the next reaction without further purification. *Η NMR (400 MHz, DMSO, d6): 10.39 (s, IB), 10.15 (s, IB), 10.00 (s, 1H), 8.38 (d, 1H), 7.88 (dd, 1H), 7.63 (m, 2H), 7.50 (m, 2H), 7.40 (t, 1H), 7.27 (s, IB), 7.14 (m, 2H), 6.33 (d, 1H), 3.95 (s, 3B), 1.47 (m, 4H). LC/MS Calcd for [Μ+·Η]+ 506.2, found 506.3. Anal.HPLC: 99.4% pure.

Example 44

vlloxv)phenvn-jy-f4-fluorophenvllcvclopropane-l.l-dicarboxamide· To a mechanically stirred slurry of cyclopropane-1,1-dicarboxylic acid [3-fluoro-4-(7-hydroxy^6-methoxy-quinolin-4-ylaxy)-phenyl]-amide (4-fluom-phenyl)-amide (16.6 g, 32.8 mmol) and 209 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523 potassium carbonate (13.6 g, 98.6 mmol) in DMF (250 mL) was added 4-(3-chloropropyl)-moiphoKne hydrochloride (13, 7.92 g, 39.6 mmol). The resulting mixture was heated at 90°C for 5 hours (until phenol completely consumed). The reaction mixture was allowed to cool to room temperature, then dumped into water (900 mL), followed by extraction with EtOAc (3X). The combined extracts were washed with 5% LiCl (aq.) (3X) and brine (IX) followed by drying over MgS04 and concentration in vacuo. The crude (18.8g) obtained as brown solid was further purified by flash chromatography [silica gel, 4-stage gradient system: 1) EtOAc; 2) EtOAc:MeOH:7N NEfe/MeOH (95:5:0.5); 3) DCM:MeOH:7N NH3/MeOH (95:5:0.5); 4) DCM:MeOH: 7N NH3/M^OH (93:8:1)], affording N-[3-fhmro-4-({6-(metoyloxy)-7-[(3-morphohn-4-ylpropyl)oxy]qumolin-4-yl}oxy)phenyl]-N-(4-fluorophenyl)cyclopropane-l,Ldlicarboxaniide was obtained as an off white solid (15.0 g, 72% yield). 1H NMR (400 MHz, DMSO-d6): 10.41 (s, 1H), 10.02 (s, 1H), 8.47 (d, 1H), 7.91 (dd, 1H), 7.65 (m, 2H), 7.53 (m, 2H), 7.42 (t, 1H), 7.40 (s, 1H), 7.16 (m, 2H), 6.42 (d, 1H), 4.20 (t, 2H), 3.96 (s, 3H), 3.59 (t, 4H), 2.47 (t, 2H), 2.39 (br, s, 4H), 1.98 (m, 2H), 1.48 (m, 4H). LC/MS Calcd for [M+H]+ 633.3, found 633.0.

Example 45

[0350] Cvcloprooane-l.l-dicafboxvlic acid r4-f7-henzvlaxv-6-methoxv-auinazolm-4-vloxvV3-fluoro-phenv11-amide (4-fluQro-phenvO-amide: A mixture of 7-benzyloxy-4-chloro-6-methoxy-quinazoline (5 g, 16.67 mmol), cyclopropane- 1,1-dicarboxylic acid (3-fluoro-4-hydroxy-phenyl)-amide (4-fluoro-phenyl)-amide (8.3 g, 25 mmol), potassium carbonate (125 mmol, 17.25 g), and dimethylacetamide (125 ml) was heated 50° C with stirring for 16h. Reaction mixture was poured onto ice/water (600 ml) and stirred for 30 minutes, and filtered. The solid was dissolved in ethyl acetate and washed with water (lx), brine, and concentrated. The erode was purified on silica get column eluting with 30% acetone in hexanes to yield cyclopropane-1,1-dicarboxylic acid [4-(7-benzyIoxy-6- 210 2013204031 11 Apr 2013 WO 2005/030140 PCT/DS2004/O31523 methoxy-quinazoIin-4-yloxy)-3-fluoro-phenyl]-amide (4-fluOTo-phenyl)-amide (7.5 g. 76%). *HNMR (CDa3): 8.64 (1H, hr. s), 8.55 (1¾ s), 8.33 (1¾ hr. s), 7.74-7.71 (1¾ dd), 7.54 (1H, s), 7.48-7.33 (8¾ m), 7.31-7.24 (2H, m), 7.06-7.02 (2H, m), 5.32 (2¾ s). 4.06 (3¾ s). 1.77-1.74 (2¾ m), 1.63-1.61 (2¾ m).

Example 46

[0351] Cvclonropane-l.l-dicarboxvlic add r3-fluoro-4-(7-hvdroxv-6-methoxv-quinazolia-4-vloxvVphenvI1-amide (4-flupro-phenvD-amide. To a mixture of cyclopropane-1,1-dicarboxylic acid [4-(7-benzyloxy-6-methoxy-quinazolin-4-yloxy)-3-fluoro-phenyl]-amide (4-fluoro-phenyl)-amide (7.5 g, 12.6 mmol), acetic acid (few drops), dichloromethane (50 ml) and methanol (100 ml) was added 10% Pd/C (700 mg). The mixture was agitated in hydrogen gas (40 psi) until the reaction was complete (ca. 4 hr). The solution was filtered through celite and concentrated to give a crude product as a solid. The crude product was triturated with ether, and filtered. The filter cake was dried in vacuo to yield cyclopropane-1,1-dicarboxylic add [3-fluoro-4-(7-hydroxy-6-methoxy-quinazolin-4-yloxy)-phenyl]-amide (4-fluoro-phenyl)-amide (6.1 g, 95% yield). ’HNMR (dmso-d6): 10.86 (1H, br. s), 10.34 (1H, br. s), 10.04 (1¾ br. s), 8.46 (1H, s), 7.84-7.80 (1¾ dd), 7.66-7.62 (2¾ m\ 7.55 (1¾ s), 7.47-7.45 (1¾ m), 7.41-7.37 (1¾ m), 7.24 (1¾ s), 7.18-7.13 (2¾ t), 3.98 (3¾ s), 1.46 (4¾ s).

Example 47

[0352] N-f3-Huoro-4-f i 6-ftneithvloxv)-7-r('3-morpholin-4-vbroDvr)oxvlquinazolin-4- vlloxy)phenvn-N'-(4“fluorophenvl)cvclopropane-l.l-dicarboxamide· To a mixture of 211 2013204031 11 Apr 2013 WO 2005/090140 PCT/US2004/031523 cyclopropane- 1,1-dicarboxylic acid [3-Quoro-4-(7-hydroxy-6-methoxy-quinazolin-4~ yloxy)-phenyl]-amide (4-fluoro-phenyl)-amide (1.5 g, 2.96 mmol), 4-(3-hydroxypropyl)mDrpholiQe (0.623 mL, 4.5 mmol), triphenylphosphine (1.18 g, 4.5 mmol), and dichloromethane (50 mL) was added diisopropyl azodicarboxylate (0.886 mL, 4.5 mmol). Hie mixture was stirred at room temperature for 16 h, monitored by LCMS. After removal of solvent, the mode mixture was separated by flash column chromatography (silica), eluting with 5% methanol in dicbloromethane to give N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4-ylpropyl)oxy]quinazolhi-4-yl} oxy)phenyl]-N’-(4-fluorophenyl)cyclopn>pane-l,l-dicarbox-amide (890 mg, 47% yield). 1HNMR (400MHz, DMSOd6): d 10.36 (hr s, 1H), 10.05 (br s, 1H), 8.55 (s, 1H), 7.83 (m, 1H), 7.64 (m, 2H), 7.57 (s, 1H), 7.44 (m, 3H), 7.18 (t, 2H), 4.27 (m, 2H), a99 (s, 3H), 3.61 (m, 6H), 2.40 (m, 4H), 2.01 (m, 2H), 1.47 (m, 4H). LOMS Calcd for [M+H|+ 634.2, found 634.3.

Example 48

[0353] N-(4-fr6.7-bisfmethvloxvlauinolin-4-vlloxylphBnvl')-Nl-(4-fluorophenvl)cvclo-propane-l.l-dicarboxamide· To a solution of cyclopiopane-l,l-dicarboxylic acid ¢4-fluoro-phenyl)-amide (4-hydroxy-phenyl)-amide (6.98 g, 22.2 mmol) in anhydrous 2,6-lutidine (50 mL) was added trifluoromethanesulfonic add 6, 7-dimethoxy-quinolin-4-yl ester (5 g, 14.8 mmol). The reaction mixture was heated at 165°C in a sealed pressure tube with stirring for 18 h. The reaction mixture was concentrated an high vacuum to completely remove lutidine. The resulting solid material was dissolved in DCM (250 mL), and washed several times with 1N sodium hydroxide to remove the excess phenol. The crude mixture was loaded on a silica gel flash column and eluted with 75% EtOAc-hexanes, affording N-(4~{[6,7-bis(methyloxy)quinoIin-4-yl]oxy}pheny])-N'-(4-fluorophenyl)cyclopropane-l,l-dicarboxamide (3.2 g, 44%). ‘H NMR (400 ΜΗκ, de-DMSO): δ 10.2 (s, IB), 10.05 (s, 1H), 8.4 (s, 1H), 7.8 (m, 2H), 7.65 (m, 2H), 7.5 (s, 1H), 212 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523 7.35 (s, 1H), 7.25 (m, 2H), 7.15(m, 2H), 6.4 (s, 1H), 4.0 (d, 6H), 1.5 (s, 4H). LCMS: M+H= 502.

[0354] 4·7-ΡίοΜθΓοαΐίίηο11π6. Phosphorus oxychloride (4mL, 429 mmol) was added to 7-chloro-4-hydroxyquinaline 2.86g, 15.9mmol) in a round bottom flask equipped with a reflux condenser. The mixture was heated to reflux for 2h, then allowed to cool to room temperature. The solution was concentrated in vacuo to a thick oil, then dumped over cracked ice. The resulting solution was neutralized with saturated NaHCOs (aq). The slurry was filtered and washed with water. The solids were dried under vacuum, afforded 4,7-dichIoroquinoline as a white solid (2.79g, 88.5% yield).

Example 50

[0355] 4-r4-<'2“FIuoro-4-fri-(,4-fIuoro-phenvlcaibannnvlVcvclot)rot)anecarbonvn-anitno^ phenoxv’)-6-methoxv-Quinazolin-7-vloxvmethvn"pioeridine-l-carboxvlic add tert-butvl ester. Cyclopropane-1,1 -dicarboxylic acid [3-fluoro-4-(7-hydroxy-6-methoxy-quinazolin-4-yloxy)-phenyl]-amide (4-fluoro-phenyl)-amide (325 mg, 0.64 mmol), 4-methanesulfonyloxymethyl-piperidine-l-carboxylic add tert-butyl ester (193 mg, 0.66 mmol), K2CO3 (181 mg, 1.31 mmol) were combined in DMF (5 ml) and heated to 80°C overnight The reaction was not complete and more 4-methanesulfonyloxymethyl-piperidine-1 -carboxylic add tert-butyl ester (90 mg, 0.31 mmol) and K2CO3 (90 mg, 0.65 mmol) were added and heating at 80°C continued for another night. The reaction mixture 213 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523 was allowed to cool to room temperature, then diluted with EtOAc and washed with H20 (3x), sat’d Nad (lx), dried (NauSCU) and concentrated in vacuo. The resulting crude material was purified by flash chromatography (1;1 hexanes:EtOAc, followed by 1:3 hexanes:EtOAc) to give 4-[4-(2-fluoio-4- {[l-(4-fluoro-phenylcarbainoyl)- cyclopropanecarbonyl]“ainino}-phenoxy)-6-iDethoxy-quinazolin-7-yloxymethyl]-piperidine-l-carboxylic acid tert-butyl ester (273 mg, 60%). LC/MS Calcd for |M+H]+ 704.3, found 704.4.

Example 51

[0356] Cvclopronane-1.1-dicarboxvlic acid 1 3-fluoro-4-r6-methoxv-7-('piperidin-4- v]methoxv)-quinazolin-4-vloxv1-pbRnvn-aniide f4-fhioro-phenvl)-amide. TFA salt. 4-[4-(2-Huoro-4-{[l-(4-fluoro-phenylcarbamoyl)-cycloprDpanecarbonyl}-amino}-phenoxy)-6-methoxy-quinazolin-7-yloxymethyl]-piperidine-l-carboxylic acid tert-butyl ester (273 mg, 0.39 mmol) was dissolved in CH2CI2 (8 ml) to which was added TFA (8 ml) and the mixture stirred at room temperature for lhr. The reaction mixture was concentrated in vacuo and the resulting oil triturated with Et20· The resulting solids were filtered, washed with Et20 and dried under high vacuum to give cyclopropane-1,1-dicarboxylic add {3-fluoro-4-[6-mefooxy-7“(jriperidin-4-yMeithoxy)-quinazolin-4-yloxy]-phenyl}-ainide (4-fluoro-phenyl)-amide, TFA salt (222 mg, 80%). LC/MS Calcd for (M+HJ+ 604.2, found 604.3.

Example 52

[0357] N-(3-Fluoro-4-r(6-fmethvloxvV7-fra-methvlpiperidm-4-vl)methvnoxvlguin- azolin-4-vl')oxvlphenvll-N,-('4-fluorophenvIlcvcloprQpane-l.l-<hcarhnxamide· 214 PCT/US2004/031523 2013204031 11 Apr 2013 WO 2005/030140

Cyclopropane-1,1-dicarboxylic acid {3-fluoro-4- [6-metfaoxy-7-(piperidin-4-ylmethoxy)-quinazolin-4-yloxy]-phenyl}-amide (4-fluoro-phenyl)-amide, TFA salt (222 mg, 0.31 mmol), H2O (3 ml), 37% formaldehyde in H2O (0.18 ml) and acetic acid (27 drops) were combined in acetonitrile (9 ml) to which was slowly added triacetoxyborohydride (561 mg, 2.65 mmol). The mixture was stirred at room temperature for 1-2 hr, then diluted with IN NaOH and H2O and extracted with CH2CI2 (3x). The combined CH2CI2 extractions were washed with sat’d NaCl (lx), dried (Na2S04) and concentrated in vacuo. The resulting residue was dissolved in a minimum of 1:1 dioxane:EtOAc I» which was added 4M HQ in dioxane (1-2 ml). The resulting solids were filtered, washed with EtOAc and dried under high vacuum to give N-{3-fluaro-4-[(6-(methyloxy)~7-{ [(1-methylpiperidin-4-yl)methyl]oxy}qumazolin-4-yl)oxy] phenyl}-N'-(4- fluorophenyl)cyclopropane-l,l-dicarboxamide, HQ salt (167 mg, 83%). 1HNMR (400MHz, DMSO-dc): δ 10.40 (s, 1H), 10.17 (hr s, 1H) 10.07 (s, 1H), 8.61 (s, 1H), 7.85 (m, 1H), 7.65 (m, 2H), 7.48 (m, 2H), 7.42 (t, 1H), 7.16 (t, 2H), 4.12 (2,2H), 4.00 (s, 3H), 3.46 (m, 2H), 2.99 (m, 2H), 2.73 (d, 3H), 2.13 (m, 1H), 2.01 (m, 2H), 1.63 (m, 2H), 1.47 (m, 4H). LC/MS Calcd for [M+H]+ 618.2, found 618.3.

Synthesis of Bridged Bicyclics [0358] The following describes synthesis of bridged bicyclics with appended leaving groups for use as, for example, alkylating agents, fa the context of this invention, these alkylating agents are used, for example, to alkylate the quinazoline or quinolines on the 6-or 7-oxygens to make compounds of the invention. The invention is not limited to alkylation chemistry to append such bridged bicyclics, but rather the aforementioned description is meant only to be illustrative of an aspect of the invention.

Example 53 [0359] 1.4:3.6-dianhvdro-2-0-methvl-5-fMmethvlai3fonvl)-D-glndtol: To a solution of l,4:3,6-dianhydro-2-<9-meth)4-I>-glucitol (1.19¾ 7.4 mmol) in dichloromethane was added pyridine (lmL, 12.36 mmol) followed by methanesulfonyl chloride (0.69mL, 8.92 mmol) and the mixture was allowed to stir at room temperature over 12 hours. The solvent was removed and the amorphous residue was partitioned with ethyl acetate and 0.1M aqueous hydrochloric acid. The aqueous phase was extracted once with additional 215 PCT/US2004/031523 2013204031 11 Apr 2013 WO 2005/030140 ethyl acetate and the combined organic layers were washed with saturated aqueous sodium chloride then dried over anhydrous magnesium sulfate. Filtration and concentration followed by drying in vacuo afforded l,4:3,6-dianhydro-2-0-methyl-5-0-(methylsulfonyl)-D-glucitol (1.67g, 94% yield) as a colorless oil. GC/MS calculated for CgHwSOe: 238 (M^).

Example 54 [0360] 1.4:3.6-dianhvdro-5-0-fahanvlcaifaonvlVD-fructose ethvlene elvcol acetal: A solution of 1,4:3,6-dianhydro-5-G-(phenylcarbonyl)-D-fructose (2.00g, 8.06 mmol), ethylene glycol (5.00g, 80.6 mmol), and p-totaenesulfonic acid (1.53g, 8.06 mmol) in benzene (lOOmL) was refluxed for 90 min using a Dean-Stark Trap apparatus. The reaction mixture was diluted with ethyl acetate (lOOmL), washed with saturated aqueous sodium bicarbonate (2 x 50mL) then brine (50mL), and dried over anhydrous sodium sulfate. Filtration, concentration and column chromatography on silica (1:1 hexane/ethyl acetate) provided 1.44g (61% yield) of 1,4:3,6-dianhydro-5-<9-(phenylcarbonyl)-D-ffuctose ethylene glycol acetal as a colorless solid. !H NMR (400 MHz; CDCfe): 8.08 (m, 2H), 7.58 (m, 1H), 7.54 (m, 2H), 5.38 (dd, 1H), 4.97 (t, 1H), 4.21-4.02 (m, 7H), 3.86 (d, 1H), 3.75 (d, 1H).

Example 55 [0361] 1.4:3.6-dianhvdro-D-fnictose ethvlene elvcol acetal: To a solution of 1,4:3,6-dianhydro-5-<9-(phenylcarbonyl)-D-fructose ethylene glycol acetal (1.44g, 4.93 mmol) in methanol (4GmL) was added 50% aqueous sodium hydroxide (0.38 g, 4.75 mmol) and the mixture was stirred at room temperature for 30 minutes. Neutralization with 1M HC1, followed by concentration and column chromatography on silica ¢1:2 hexane/ethyl acetate) provided 0.74g (80% yield) of l,4:3,6-dianhydrD-D-fructose ethylene glycol acetal as a colorless solid. ]H NMR ¢400 MHz; CDCI3): 4.60 (t, 1H), 4.32 (m, 1Ή), 4.14 (d, 1H), 4.05-3.98 (m, 5H), 3.82 (s, 2H), 3.62 (dd, 1H), 2.65 (d, 1H).

[0362] 1.4:3.6“dianhvdro-5-Q-(me<hvlsulfonvl)-D-fnictose ethylene elvcol acetal: To a solution of l,4:3,6-dianhydro-D-fructose ethylene glycol acetal (0.74g, 3.93 mmdl) and triethylamine (1.20g, 11.86 mmol) in dichloromethane (40mL) was added 216 PCT/US2004/031523 2013204031 11 Apr 2013 WO 2005/030140 methanesulfonyl chloride (0.90g, 7.88 mmol) at 0°C under nitrogen. The solution was wanned to room temperature and stirred for 13 h, Dichloromethane (50mL) was added, and the organic layer was washed with saturated aqueous sodium bicarbonate (30mL),

I water (30mL), and brine (30mL) then dried over anhydrous sodium sulfate. Filtration and concentration provided 1.02g (97%) of 1,4:3,6-dianhydrO“5-0-(methylsulfonyl)-D-ftuctose ethylene glycol acetal as a yellow oil. NMR ¢400 MHz; CDCI3): 5.08 (m, 1H), 4.82 (t, 1EQ, 4.13 (dd, 1H), 4.04 (m, 4H), 3.93 (dd, 1H), 3.87 (d, 1H), 3.81 (d, 1H), 3.13 (s, 3H).

Example 56 [0363] 1.4:3.6-dianhvdm-2^deoxV"2-niethvlidene-D-ura&amp;mo-he3dtol: To a solution of l,4:3,6-dianhydro-2-deoxy-2-nxethylidene'5-<7-(phenylcarbonyl)-D-flrflfe/no-hexitol (329mg, 1.34 mmol) in methanol (lOmL) was added 50% aqueous sodium hydroxide (95mg, 1.19 mmol) and the mixture was stirred at room temperature for 30 minutes. Neutralization with 4M hydrogen chloride in 1,4-dioxane followed by concentration and column chromatography on silica (1:1 hexane/ethyl acetate) provided 141mg (74%) of l,4:3,6-dianhydro-2-deoxy-2-methyhdene-D-ara&amp;m0-hexitol as a colorless solid. *H NMR (400 MHz; CDCI3): 5.37 (m, 1H), 5.20 (m, 1H), 4.80 (m, 1H), 4.54 (m, 2H), 4.43 (m, 1H), 4.26 (m, 1H), 3.95 (dd, 1H), 3.54 (dd, 1H), 2.70 (d, 1H).

[0364] 1.4:3.6-<iiarthvdro-2-deoxv-2-methvliden6-5-0-(methvlsuIfonvri-D-amh/?iQ-hexitol: To a solution of 1,4:3,ti-dianhydro^-decKy^metiiylidene-D-^anzhzno-hexitol

I (135mg, 0.95 mmol) and triethyiamine (288mg, 2.85 mmol) in dichloromethane (lOmL) was added methanesulfonyl chloride (222mg, 1.94 mmol) at 0°C under nitrogen. Hie solution was warmed to room temperature and stirred for 18 h. Dichloromethane (50mL) was added and the organic layer was washed with saturated aqueous sodium bicarbonate (2 x 25mL), water (25mL) and brine (25mL) then dried over anhydrous sodium sulfate. Hltration and concentration provided 213mg (72%) of l,4:3,6-dianhydro-2-deoxy-2-methylidene-5-<7-(methylsulfonyl)-D-um&amp;ino-hexitol as a yellow oil. *H NMR (400 MHz; CDCI3): 5.40 (m, 1H), 5.23 (m, 1H), 5.04 (m, 1H), 4.85 (m, 1H), 4.73 (t, 1H), 4.58 (m, IB), 4.41 (m, 1H), 4.08 (dd, 1H), 3.86 (dd, 1H), 3.14 (s, 3H). 217 PCT/US2004/031523 2013204031 11 Apr 2013 WO 2005/030140

Example 57 [0365] 1.4:3.6-(Manhvdro-2-deoxv-5-0-fohenvkarbonvIVL-flri2fcfoo-hex-l-enitol.‘ To a mixture of l,4:3,6-dianhydro-5-0-(phenylcarbonyl)-(D)-gIycitoI (4.32g, 17.3 mmol), triethylamine (4.91 mL, 35.3 mmol) and 4-dimethylammopyridme (0.63g, 5.2 mmol) in dichloromethane (50 mL) at -10 0 to -15° was added trifluromethanesulfonic anhydride (3.48mL, 20.7 mmol) dropwise over ten minutes and the resulting mixture was stined at this temperature for 3 hours. The mixture was poured into 100 mL of ice-water and extracted with dichloromethane (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered then concentrated. The crude triflate was suspended in toluene (50 mL) followed by addition of 1,8-diazabicyclo[4,5,0]undec-7-ene (5.25 mL, 34.6 mmol) and the mixture was stirred at room temperature for 18 hours. The reaction mixture was poured into ice-water and partitioned then Hie aqueous portion was extracted with dichloromethane (3 x 50 mL). The combined organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flashed chromatography (silica gel, 5-20% ethyl acetate-hexane) to give l,4:3,6-dianhydro-2-deoxy-5-0-(phenyIcarbonyl)-L-arahfho-hex-l-emtol, as a white solid, 3.10g, 77% yield. Ή NMR (400MHz; CDCI3): 8.08-8.06 (m, 2H), 7.61-7.57 (m, 1H), 7.56-7.43 (m, 2H), 6.62-6.61 (d, 1H), 5.48-5.46 (m,lH), 5.32-5.26 (m,lH), 5.13-5.10 (m, 2H), 4.18-4.14 (tr.lH), 3.61-3.56 (tr, 1H),

Example 58 [0366] Melhvl 3.6-anhvdro-5-Q-fuhenvlcarbonvl)-B-L-eiucofuranoside: To a solution of l,4:3,6-dianhydro-2-deoxy-5-£>-(phenylcafbony])-L-arabino-hex-l-enitol (l.OOg, 4.3 mmol) in methanol (17 mL) at -4°C was added 3-chloroperoxybenzoic acid (85%, 1.35g, 8.6 mmol), and the resulting mixture was slowly warmed to room temperature and stirred for 18 hours. The reaction mixture was concentrated, diluted with dichloromethane (50 mL), washed with saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 25-60% ethyl acetate-hexane) to give methyl 3,6-anhydro-5~0-(phenylcarbonjd)-P-L-glucofuranoside as a white solid, 1.03g, 83% yield. XH NMR (400MHz; CDCI3): 8.11-8.08 (d, 2H), 761-7.56 (tr, 1H), 7.48-7.44 (m, 2H), 5.24-5.17 218 WO 2005/030140 PCT/US2004/031523 2013204031 11 Apr 2013 (m, 2H), 4.96 (s, 1H), 4.57-4.56 (d, ffi), 4.27 (s, 1H), 4.22-4.18 (dd, IB), 4.08-4.04 (dd, IB) 3.36 (s, 3H).

[0367] Methyl 3.6-anhvdro-2-C>-methvl-5-0-faheiivlcari)cmyl)-B-L-gIuccifaninoside; A mixture of methyl 3,6-anhydm-5-0-(phenylcarbonyl)-0-L-glucofuranoside (1.03g, 3.7 mmol), silver ¢1) oxide (0.85g, 3.7 mmol) and methyl iodide (0.34 mL, 5.5 mmol) in DMF (2 mL) was heated at 60°C for 1 hour. After cooling to room temperature the reaction mixture was diluted with ethyl acetate (50 mL), filtered over celite, adsorbed on silica gel (lOg) and purified by flash chromatography (silica gel, 5-30% ethyl acetate-hexane) to give melhyl 3,6-anhydro-2-O-mefliyI-5-O-(phenylcarbonyl)-0-L-glucofuranoside as a colorless oil, 0.82g, 76% yield. NMR (40GMHz; CDCI3): 8.11-8.09 (d,2H), 7.60-7.56 (m, 1H), 7.46-7.44 (m, 2H), 5.24-5.20 (m, IB), 5.18-5.09 (tr, 1H), 4.99 (s, 1¾. 4.61-4.60 (d, IB), 4.21-4.17 (tr, 1H), 4.08-4.03 (tr, IB), 3.81 (s, 1H), 3.40 (s, 3H), 3.57 (s, 3B).

[0368] Methyl 3.6-anhvdro-2-Q-methvl-K-D-idofuranoside.‘ A solution of methyl 3,6-anhydro-2~0-methyl-5-0-(phenylcarbonyl)-0-L-glucofuranoside (820mg, 3.1mmol) and 50% sodium hydroxide (248 mg, 3.1 mmol) in methanol (lOmL) was stirred at room temperature for 30 minutes. The material was adsorbed on silica gel (5g) and passed through a short column (15% ethyl acetate in hexanes to 5% methanol in ethyl acetate) to give methyl 3,6-anhydro-2-0-methyl-a-D-idofuranoside as a colorless oil, 420 mg, 85% yield. NMR (400MHz; CDCI3): 5.04 (s, 1H), 5.84-5.81 (tr, 1H), 4.44-4.42 (tr, IB), 4.25-4.19 (m, 1H), 3.85-3.75 (m, 1H), 3.49 (s, 3H), 3.43 (s, 3H), 2.75-2.72 (d, 1H).

[0369] Methyl 3.6-anhvdro-2-<9-methvl-5-0-(methvlsulfonvli-S-L-eIucofuranoside: Methyl 3,6-anhydro-2-£?-methyl-ot-D-idofuranoside (420 mg, 2.6 mmol) was dissolved in dichloromethane (10 mL) and pyridine (0.36 mL, 3.7 mmol) at 0°C, Methanesulfonyl chloride (0.14 mL, 3.1 mmol) was added and the resulting mixture was stirred at 0°C for 1 hour then at room temperature for 2 hours. The reaction mixture was washed with water and saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered and concentrated to give methyl 3,6-anhydro-2-£?-methyl-5-O-(methylsulfonyl>-0-L-glucofuranoside as a colorless oil, 669mg, 95% yield, which was used without further purification. 219 WO 2005/03014« PCT/US2004/031523 2013204031 11 Apr 2013

Example 59 [0370] 3.6-anhvdro-5-Q~(DhenvIcarbonvl)-a-L-glucofuranose: A mixture of osmium tetroxide (4% in water, 0.25 ruL, 0.03 mmol) and N-methylmorpholine (505 mg, 4.3 mmol) in 3 mL of 50% acetone in water was wanned to 60%. A solution of 1,4:3,6-dianhy(ko-2-deoxy-5-0-(phenylcarbonyl)~L-ara&amp;mo-hex-l-enitol (2.00g, 8.6 mmol) in 6 mL of 50% acetone in water was added over 3 hours. During this time an additional amount of N-methylmorpholine (l.Olg, 8.6 mmol) was added in small portions periodically. Upon completion of the addition process the reaction was stirred for another hour and cooled to room temperature. The crude mixture was applied to a column of silica gel and flashed (0-6% methanol in 1:1 ethyl acetate:hexane) to give 3,6-anhydro-5-0-(phenylcarbonyl)-a-L-glucofuranose as a white solid, 1.5g, 65% yield 1H NMR (400MHz; DMSO-de): 8.01-7.95, (m, 2H), 7.68-7.66 (m, 1H), 7.57-7.53 (m, 2H), 5.18- 5.11 (m, 2H), 4.854.81 (m, 1H, m), 4.37-4.35 (m, 1H), 4.05-3.96 (m, 2H), 3.85-3.83 (m, 1H).

[0371] 3.6-anh vdro-2- O-methvl-5- 0-(t»hen vie aihonvl Va-L-glucofuranoside: 3,6-

Anhydro-5-0-(phenylcarbonyl)-a-L-glucofuranose (576 mg, 2.2 mmol) was added to a mixture of sodium hydride (60% oil dispersion, 346 mg, 8.7 mmol) and methyl iodide (0.54mL, 8.7 mmol) in 5 mL of DMF at 0°C and the resulting mixture was stirred for 1 hour. The reaction mixture was diluted with ethyl acetate and quenched with water (5 mL). The aqueous portion was extracted with ethyl acetate (3x5 mL). The combined organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered, and' concentrated The residue was purified by flashed chromatography (silica gel, 5-20% ethyl acetate in hexane) to give 3,6-anhytfro-2-0-methyl-5-CKphenylcarbonyl)-a-L-glucofuranoside as a white solid 270 mg, 42% yield Ή NMR (400MHz; CDCI3): 8.09- 8.07 (m, 233), 7.6,1-7.57 (m, 1H), 7.48-7.27 (m, 2H), 5.25-5.22 (m, 1H), 5.07-5.06 (d, 1H), 4.94-4.91 (m, 1H), 4.73-4.71 (m, IB), 4.204.16 (m, 1H), 3.96-3.94 (m, 1H), 3.85-3.83 (tr, 1H), 3.50 (s,3H), 3.42(s, 3H).

[0372] Methyl 3.6-anhvdro-2-0-methvl-5-O-fmethvlsulfonvll-oc-L-glucofuranoside: A solution of methyl 3,6-anhydro-2-0-methyl-5-0-(phenylcarbonyl)-a-L-glucofuranoside (230mg, 0.92 mmol) and 50% sodium hydroxide (74 mg, 0.92 mmol) in methanol (5 mL) was stirred at room temperature for 30 minutes. The mixture was adsorbed on silica gel (2g) and passed through a short column (15% ethyl acetate in hexanes to 5% methanol in ethyl acetate) to afford a colorless oil which was employed directly in the next step, 140 220 PCT/US2004/031523 2013204031 11 Apr 2013 WO 2005/030140 mg, 0.72 mmol, 95% yield. The alcohol was dissolved in dichloromethane (5 mL) and pyridine (121 pL, 1.03 mmol) was added at 0°C. Methanesulfonyl chloride (27|iL, 0.88 mmol) was added and the resulting mixture was stirred at 0°C for 1 hour then at room temperature for 2 hours. The reaction mixture was washed with water and saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated to give methyl 3,6-anhydro-2-0-methyl~5-0-(methylsulfonyl)-a-L-glucofuranoside as a colorless oil, 190 mg, 96% yield

Example 60 [0373] 3.6-Anhvdro-1.2-0-fl-methvlethvlideneV5-Q-fphenvlcarbonvlVa-L-gluco-furanoso: A mixture of 3,6-anhydro-5-0-(phenylcarbonyI)-a“L-glucofuranose (l.OOg), 2,2-dimethoxy propane (0.63 mL), p-toluenesulfonic add (20 mg) and benzene (10 mL) was heated at reflux for 3 hours. The reaction mixture was cooled then adsorbed on silica gel (lOg) and purified by flash chromatography (silica gel, 5-35% ethyl acetate in hexanes) to give 3,6-anhyfro-l,2-0-(l-methylethylidene)-5-O-(phenylcatbanyI)-o&amp;-L-glucofuranose as colorless oil, 0.85g, 74% yield aH NMR (400MHz; CDCI3): 8.08-8.06 (d, 2H), 7.59-7.56 (tr, 1H), 7.46-7.42 (m, 2H), 5.99-5.98 (d, 1H), 5.35-5.31 (tr, 1H), 5.10- 5.08 (d, 1H), 4.66-4.65 (d, 1H), 4.61-4.60 (d, 1H), 4.20-4.16 (dd 1H), 3.91-3.74 (tr, 1H,), 1.50 (s, 3H), 1.34 (s,3H).

[0374] 3.6-Anhvdro-1.2-Q-fl-methvIethvlideneV5-<7-fmethvlsulfonvI)-a-L-gIuco-furanose; A solution of 3,6-anhydro-l,2-0-(l-methylethylidene)-5-0-(phenylcarbonyl)-Ci-L-glucofuranose (850mg) and 50% sodium hydroxide (111 mg) in methanol (lQmL) was stirred at room temperature for 30 minutes. The mixture was then adsorbed on silica gel (5g) and passed through a short column (15% ethyl acetate in hexanes to 5% methanol in ethyl acetate) and the alcohol intermediate, 390 mg, 70% yield was used immediately in the next step. The alcohol was dissolved in dichloramethane (10 mL) and pyridine (0.32 mL) at 0°C. Methanesulfonyl chloride (0.12 mL) was added and the resulting mixture was stirred at 0°C for 1 hour then at room temperature for 2 hours. The reaction mixture was washed with water and saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered and concentrated to give 3,6-anhydro-l,2-0-(1-methy]ethyhdene)-5-0-(methylsuIfonyI)-a-L-glucofuranose as a colorless oil, 485 mg, 90% yield, which was immediately employed in the next step. 221 PCT/US2004/031523 2013204031 11 Apr 2013 WO 2005/030140

Example 61 [0375] (3£8a5)-3-/Chloiomethvl)hexahvdro-lff-pvmoIor2.1-cirL41axazine.· (5)-(+)-Prolinol (6.00 g, 59.3 mmol) was added to epichlorohydrin (47 mL, 600 mmol) at 0°C. The solution was stirred at 40°C for 0.5 h and then concentrated in vacuo. The residual oil was cooled in an ice bath and concentrated sulfuric acid (18 mL) was added dropwise with stirring. The mixture was heated at 170-180°C far 1.5 h, poured into ice (300 mL) and then basified with sodium carbonate to pH~8. The mixture was partitioned with ethyl acetate/hexanes and filtered. The filtrate was separated and the aqueous portion was extracted twice with ethyl acetate. The combined organic portion was dried over sodium sulfate, filtered and concentrated in vacuo to afford oil that was purified by column chromatography (ethyl acetate for less polar product and then 30% methanol in ethyl acetate). (3S,8aS)-3-(ChIoromethyl)hexahydro-lH-pynolo[2,l-c][l,4]oxazine (less polar product) ¢1.87 g, 10.7 mmol, 18% yield): *H NMR (400 MHz, CDCI3): 4.06 (dd, ffi), 3.79-3.71 (m, 1H), 3.60-3.48 (m, 2H), 3.36 (dd, 1H), 3.15 (dd, 1H), 3.13-3.06 (m, 1H), 2.21-2.01 (m, 3H), 1.90-1.68 (m, 3H), 1.39-1.24 (m, 1H); MS (El) for CeEfcNOO: 176 (MET). (3/?,8a5)-3-(Chloromethyl)hexahydro-lli-pyrrolo[2,i-c3[l,4]oxazme (1.54 g, 8.77 mmol, 15% yield): Ή NMR (400 MHz, CDCfe): 3.94-3.77 (m, 4H), 3.55 (dd, 1H), 3.02- 2.93 (m, 2H), 2.45 (dd, 1H), 2.29-2.15 (m, 2H), 1.88-1.64 (m, 3H), 1.49-1.38 (m, 1H); MS (El) for QsHmNOCI: 176 (MH+).

[0376] Using the same or analogous synthetic techniques and/or substituting with alternative starting materials, the following were prepared: [0377] (3jK.8aR)-3-fChinrnrnethvl)hexahvdro-lf/-pvrrolof2.1-cin.41oxazme: *H NMR (400 MHz, CDCI3): 4.05 (dd, 1H), 3.79-3.70 (m, 1H), 3.61-3.48 (m, 2H), 3.35 (dd, 1H), * 3.15 (dd, 1H), 3,13-3.07 (m, 1H), 2.21-2.01 (m, 3H), 1.89-1.67 (m, 3H), 1.39-1.25 (m, 1H); MS (El) for CgH^OCh 176 (MiT).

[0378] (35.8ag)-3-(Chloramethvl)hexahvdrD“lH-Dvtrolof2.1-cl Γ 1.41oxazme: *H NMR ¢400 MHz, CDCI3): 3.93-3.77 (m, 4H), 3.55 (dd, 1H), 3.02-2.93 (m, 2H), 2.45 (dd, 1H), 2.30-2.15 (m, 2H), 1.88-1.64 (m, 3H), 1.49-1.37 (m, 1H); MS (El) for QHuNOCl: 176 (MET). 222 PCT/US2004/031523 2013204031 11 Apr 2013 WO 2005/030140

Example 62 [0379J (35.8affVH8xahvdra-lff-pvrrolor2.1-ciri.41oxazin-3-vlinethvl acetate: (35,8a5)-3-(Chloromethyl)hexahydro-l£T-pynrolo[2,l-c][l,4]oxazine (2.30 g, 13.1 mmol) and potassium acetate (12.8 g, 131 mmol) were stirred in dimethylforraamide (25 mL) at 140°C for 20 h. Hie mixture was partitioned between ethyl acetate and water. The organic portion was washed twice with water, then with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford (3£,8a5)-hexahydro-li7-pyrrolo[2,1 -c] [1,4]oxazin-3-yImethyI acetate as a brown oil (2.53 g, 12.7 mmol, 97% yield). !HNMR (400 MHz, CDCI3): 4.14-4.02 (m, 3H), 3.81-3.72 (m, 1H), 3.37-3.31 (m, 1H), 3.09 (dt, 1H), 3.00 (dd, 1H), 2.21-2.00 (m, 3H), 2.10 (s, 3H), 1.90-1.67 (m, 3H), 1.39-1.24 (m, 1H); MS (ED for Q0H17NQ3:200 (MH4).

[0380] <'3S.8aS)-Hexahvdio-lg-pvnolor2.1-dri.41oxazin-3-vlmethanol: (3S,8aS)-

Hexahydro-lH-pyrrolo[2,l-c][l,4]oxazin-3-ylmethyl acetate (2.36 g, 11.9 mmol) was treated with sodium methoxide (25 wt% solution in methanol; 2.7 mL) for 0.5 h. The mixture was cooled in an ice bath and a solution of 4M HC1 in 1,4-diaxane (3 mL, 12.0 mmol) was added slowly. The mixture was stirred at room temperature for 5 minutes and then was concentrated in vacuo to afford a suspension which was diluted with dichloromethane, filtered and the filtrate was concentrated in vacuo to afford (3S,8aS)-hexahydro-lff-pyrrolo[2,1-c] [1,4] oxazin-3-ylmethanol as a brown oil (1.93 g, >100% yield). JH NMR (400 MHz, GDCI3): 4.05 (dd, 1H), 3.73-3.65 (m, 2H), 3.62-3.56 (m, 1H), 3.39-3.34 (m, 1H), 3.10 (dt, 1H), 3.00-2.95 (m, 1H), 2.24-1.98 (m, 4H), 1.97-1.70 (m, 3H), 1.44-1.28 (m, 1H); MS (El) for CgHisNC^: 158 (MH4).

[0381] f3S.8aSVhexafavdm-lff-pvirotor2.1-ciri.41oxaan-3-vhnethvl methanesulfonate: (3S,8aiS)-Hexahydro-lH-pyrrolo[2,l-c][l,4]oxazin-3-ylmethanol (1.00 g, 6.37 mmol) was dissolved in dichloromethane (10 mL) and triethylamiiie (2.4 mL, 17.3 mmol) was added at 0°C followed by dropwise addition of methanesulfonyl chloride (0.93 niL, 12.0 mmol). The solution was wanned to room temperature and stirred for 1.25 h and then was concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic portion was washed with saturated sodium bicarbonate solution. The combined aqueous portion was extracted witii ethyl acetate. The combined organic portion was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford (35,8a5)-hexahydro-lH-pyrrolo[2,1 -c] [1,4]oxazin-3- 223 PCT/US2004/031S23 2013204031 11 Apr 2013 WO 2005/030140 ylmethyl methanesulfonate as an orange-brown oil (1.20 g, 5.1 mmol, 80% yield). MS (El) for C9H17NO4S: 236 (MH*).

Example 63 [0382] Octahvdro-2g-quinolizm-3-vlmethanol: Ethyl octahydro-2ff-quinolizine-3-carboxylate (2.35 g, 11.1 mmol) was added dropwise to a stiired suspension of lithium aluminum hydride (1M solution in tetrahydrofuran, 33 mL, 33 mmol) in tetrahydrofuran (50 mL) at 0°C. The reaction was stirred at room temperature for 3 h. The mixture was cooled in an ice bath and ethyl acetate (6 mL) was added slowly, followed by water (1.25 mL), 15% aqueous sodium hydroxide solution (5 mL) and water (1.25 mL). The mixture was filtered through a pad of celite and washed with ether. The filtrate was concentrated in vacuo and dried rigorously to afford ociahydro-2H-qmnolizin-3-ylmethanol as a yellow oil (1.66 g, 9.82 mmol, 88% yield). MS (El) for C10H19NO: 170 (MB*).

[0383] Octahvdro-2ff-qmnolizm-3-vlmethvl methanesulfonate: Octahydro-2ff-qumolizin- 3-ylmethanol (600 mg, 3.55 mmol) was dissolved in dichloromethane (8 mL) and triethylamine (1.5 mL, 10.8 mmol) was added at 0°C followed by dropwise addition of methanesulfonyl chloride (0.56 mL, 7.16 mmol). The solution was wanned to ro'om temperature and stirred for 1.25 h and then was concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The aqueous portion was extracted with ethyl acetate. The combined organic portion was washed with brine, dried over sodium sulfate, filtered and concentrated m vacuo to afford octahydro-2H-quinolizm-3-yImethyl methanesulfonate as an orange oil (796 mg, 3.22 mmol, 91% yield). MS (El) for C11H21NO3S: 248 (MH*).

Example 64

[0384] (3S.8aS)-3-(Hvdroxvmeth^)hexahvdropvnolori-2-fl]pvrflzin-lf2ff>-one: A solution of methyl l-[(25)-3-hydroxy“2-( {[(phenylmethyl)oxy]caibonyl} amino)propyl] -L~ prolinale (3.50 g, 10.4 mmol) in methanol was added to 5% palladium on carbon (50 wt.% in water) in methanol and treated with hydrogen at 40 psi for 1 h. The mixture was filtered and the filtrate was brought to reflux briefly and then cooled and concentrated in vacuo to afford (3S,8aS)-3-(hydroxymethyl)hexahydropyrrolo[l,2^a]pyrazin-l(2H)-one as 224 WO 2005/030140 PCT/US2004/031523 2013204031 11 Apr 2013 a colorless solid (1.50 g, 8.83 mmol, 85% yield). *HNMR (400 MHz, CDC13): 7.28-7.22 (m, 1H), 3.83-3.75 (m, 1H), 3.69 (dd, 1H), 3.56 (dd, 1H), 3.31 (t, 1H), 3.08 (dd, 1H), 2.92 (dt, IB), 2.76-2.70 (m, 1H), 2.66 (dd, 1H), 2.28-2.16 (m, 1H), 2.02-1.73 (m, 3H); MS (El) forC8Hi4N202:171 (ΜΗ1).

[0385] f3S.8a5')-3-<' /Γ/11 -DimethvlflthvTIfdf methvllsilvlloxv Imethyllhexahydro- uvrroloi 1.2-alovrazin-1 (2fl)-one: To a solution of (3S,8a5)-3-(hydroxymethyl) hexahydropyrrolo[l,2-a]pyrazin-l(217)-one (1.49 g, 8.82 mmol) in dimethylfarmamide (20 mL) was added triethylamine (2.45 mL, 17.6 mmol) and 4-dimethylaminopyridine (90 mg, 0.882 mmdl). The solution was cooled in an ice bath and fert-butyldimethylsilyl chloride (2.66 g, 17.6 mmol) was added. The mixture was warmed to room temperature and stirred fen: 14 h. The mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The aqueous portion was extracted twice with ethyl acetate. The combined organic portion was dried over sodium sulfate, filtered and concentrated in vacuo to afford a pale brown solid which was triturated with ethyl acetate to afford (3S,8a<5)-3-({ [(1, l-dimfitiiylethyl)(dimethy])silyl]oxy}methyl) hexahydropyrrolo[l,2-a]pyrazin-l(2#)-one as an off-white solid (1.74 g, 5.84 mmol, 66% yield). lK NMR (400 MHz, CDC13): 6.09-5.90 (m, 1H), 3.86-3.76 (m, IB), 3.63 (dd, 1H), 3.44 (dd, 1H), 3.25 (t, 1H), 3.10 (ddd, 1H), 2.98-2.90 (m, 1H), 2.68-2.60 (m, 1H), 2.52 (dd, 1H), 2.28-2.18 (m, 1H), 2.06-1.95 (m, IB), 1.93-1.74 (m, 2H), 0.90 (s, 9H), 0.07 (s, 6H); MS (El) for Q^gNaOiSi: 285 (MET1).

[0386] (3S.8a5)-3-(irfl.l-DimethvlefhviydimftthvlVsUvlloxvlmethvl)-2-methvIhexalivdrD pyrrolof 1,2-alpyrazin-l(2ff)-one: (3S,8aS)-3-({ [(l,l-Dimethylethyl)(dimethyl)silyl]oxy} methyl)hexahydropynolo[l,2-a]pyrazin-l(2ff)-one (1.51g, 5.32mmol) in dimethylformamide (8 mL) was added to an ice-cooled suspension of sodium hydride (60 wt.% dispersion in oil; 213 mg, 5.32 mmol) in dimethylformamide (8 mL). The mixture was stirred at 0°C for 0.25 h and then iodomethane (0.332 mL, 5.32 mmol) was added dropwise. The mixture was stirred at room temperature for 0.5 h and then was stirred at 70°C for 2 h. The mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The aqueous portion was extracted with ethyl acetate. The combined organic portion was dried over sodium sulfate, filtered and concentrated in vacuo to afford (35, 8aS)-3-({ [(1, l-dimethylethyl)(dimethyl)silyl]oxy}methyl)-2- methylhexahydropyirolo[l,2-fl]pyrazin-l(2fl)-one as a yellow oil (1.552 g, 5.21 mmol) which was dissolved in tetrahydrofuran (20 mL) and treated with tetrabutylammonium 225 PCT/US2004/031523 WO 2005/030140 fluoride (1.0M solution in tetrahydrofuran; 10.4 mL, 10.4 mmol) for 2 h at mom temperature. The mixture was concentrated m vacuo and purified by column chromatography (10% methanol in dichloromethane) to afford (3S,8aS)-3-(hydroxymethyl)-2“methylhexahydropyrrolo[l^-a]pyrazin-l(2fl)-one as a yellow oil (496mg, 2.7Qmmol, 51% yield from (35,8aS)-3-({ [(1,1- dimethylethyl)(dimethyI)silyl]oxy} methyl)hexahydropyrrolo[l,2-a]pyrazin-l(2ff)-one). JHNMR (400 MHz, CDC13): 3.98-3.93 (m, 1H), 3.86 (dd, IB), 3.61-3.55 (m, 1H), 3.29- 3.25 (m, 1H), 3.09-3.03 (m, 1H), 3.03-2.97 (m, IB), 3.02 (s, 3H), 2.93 (dd, IB), 2.87-2.79 (m, 1H), 2.32-2.21 (m, 1H), 2.00-1.86 (m, 2H), 1.83-1.64 (m, 1H); MS (BI) for C9H16N202.· 185 (MB4).

Example 65 [0387] 1.2-Dideoxv- l-[(2S)-2-(methoxvcarbanvD- 1-pvrroHdtn vl 1-2-ΓΓfphenvlmethoxvl carbonvll aminol-D-g/vcgro-hexitol: To a solution of 2-deoxy-2-{[(phenylmethyloxy) carbonyl]amino}-D-glycero-hexopyranose (5.0 g, 0.016 mol) in methanol (500 mL) was added L-proline methyl ester hydrochloride (2.8 g, 0.022 mol) and sodium cyanoborohydride (3.4 g, 0.054 mol). The solution was heated to 64 °C for 14 h. After cooling to room temperature, the reaction mixture was concentrated in vacuo to afford 1,2-. dideoxy-l-[(2S)-2-(methoxycarbonyl)-l-pyrrolidinyl]-2-[[(phenylmethoxy)caihonyl] ammo]-D-g?ycera-hexitol (6.81 g, 100%) as a clear and colorless oil. MS (El) for CaoHsiNjOe: 427 (ΜΗ*).

Example 66 [0388] Methvl 1-Γf2S)-3-hvdraxv-2-( (rfohenvlmethvltoxvlcarbon vl l aramolpropvli-L- ptolinate: l,2-dideoxy-l-[(25)-2-(methoxycarbonyl)-l-pyrrolidinyl]-2-[[(phenylmethoxy) carbonyl]amino]-D-giycero-hexitol (6.81 g, 0.016 mol) was taken into water (100 mL) and the resulting solution was cooled to 0°C. Sodium periodiate (14.8 g, 0.069 mol) dissolved in water was added dropwise and the resulting mixture was steed at 0°C for 2 h. The reaction mixture was partitioned with dichloromethane (3x100 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was taken up in methanol (200 mL) and the resulting solution was cooled to 0°C. Sodium borohydiide WO 2005/030140 PCT/US2004/03I523 2013204031 11 Apr 2013 (1.98 g, 0.052 mol) was added and the reaction mixture was stirred for 1 h at 0°C. The reaction mixture was concentrated in vacuo and partitioned with dichloromethane and saturated aqueous ammonium chloride. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The resulting crude product was purified by column chromatography (5% methanol in dichloromethane) to yield methyl 1-[(ZS)-3-hydroxy-2-{{ [(phenylmethyl)oxy]caibonyl }amino)propyl]T^prolmate (4.9 g, 92%) as a white solid. MS (El) for Q7H25N2O5:337 (MH*). £0389] Methvl 1-Γ(25)-3-Γ(methvlsulfonvl)oxvl-2-fl rfphenvlmethvflaxvlcarhonvt lammol 1 proDvll-L-nmliTiate.· Methyl l-[(2S)-3-hydroxy-2-({[(phenylmethyl)axy]carbonyl}amflio) propyl]-L-prolinate (200 mg, 0.594 mmol) was dissolved in dichloromethane (5 mL) fallowed by the addition of 4-(dimethylamino)pyridine (3.6 mg, 0.039 mmol) and triethylamine (0.125 mL, 0.891 mmol) and the resulting mixture was cooled to' 0 °C. Methanesulfonyl chloride (0.060 mL, 0.773 mmol) was added diopwise and the reaction mixture was stirred for 1 h at 0°C. The mixture was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford methyl l-[(2S)-3-[(methylsulfonyl)oxy]-2“({[(phenylmethyl)oxy]carbonyl}amino)propyl]-L-prolinate (246 mg, 100%) as a clear and colorless oiL MS (El) for C1&amp;H27N2O7S: 415 (ΜΗ4).

Example 67 [0390] 1.1-Dinaethvlethvl (3afl.6aS)-5-(hvdroxvmethvl)hexahvdrocvclopentarclpvErole-2f UD-carboxvlate: Under a nitrogen atmosphere, borane tetrahydrofuran complex (1M in THF, 42 mL, 41.9 mmol) was diluted with tetrahydrofuran (42 mL) and cooled with an ice bath. Neat 2,3-dimethylbut-2-ene (5.0 mL, 41.9 mmol) was added in portions over 0.25 h and the solution was stirred at 0°C for 3 h. A solution of 1,1-dimethylethyl (3aK,6aS)-5-methyhdenehexahydrocyclopenta[c]pyrrole-2(lH)“Carboxylate (1.98 g, 8.88 mmol) in tetrahydrofuran (10 mL) was added slowly,* and the solution was warmed to room temperature and stirred 12 h. After cooling to 0°C, 10% aqueous sodium hydroxide (17 mL, 41.7 mmol) was added slowly, followed by 30% aqueous hydrogen peroxide (13 mL, 128 mmol) and the solution was warmed to room temperature. The solvent was removed in vacuo and the solution was partitioned between water and diethyl ether. The layers were separated and the aqueous layer was further extracted (3 x 50 mL diethyl ether). The 227 WO 2005/030140 PCT/US2004/031523 2013204031 11 Apr 2013 combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to provide 2.04 (95%) of 1,1-dimethylethyl (3a/?,6aS)-5-(hydroxymethyl)hexahydrocyclopenta[c]pyrroIe-2(lfl)-carboxylate, which was used without purification. 1H NMR (400 MHz, CDCI3): 8.50 (broad s, 1H), 3.66-3.46 (m, 3H), 3.20-3.00 (m, 2H), Z70-2.59 (m, 2H), 2.37-2.18 (m, 1H), 2.04 (m, 1H), 1.84 (broad s, 1H), 1.70-1.55 (m, 1H), 1.46 (s, 9H), 1.17 (m, 1H), 0.93 (m, 1H).

[0391] 1.1 -Ptmethvlethvl (3aR.6a5)-5-f Γ fmethvisulfonvlloxvTmethvllhexahvdrocvclo- penta Γdpvtrole-2(l ffl-carboxylate: Methanesulfonyl chloride (0.2mL, 2.48mmol), was added dropwise to a solution of 1,1-dimethylethyl (3a/?, 6a^-5~(hydroxymethyi)hexahydro cyclopenta[c] pyrrole-2(127)-carboxylate (0.40 g, 1,65 mmol) and triethylamine (0.69 mL, 4.95 mmol) in 20 mL dichloromethane at 0°C and the reaction mixture was stirred for 1 h at room temperature. The solvent was evaporated, the resulting crude mixture was diluted with 100 mL ethyl acetate and washed with water (30 mL), 1M aqueous sodium hydroxide, brine, 1M aqueous hydrochloric acid and brine again. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting 1,1-dimethylethyl (3aft,6a5)-5-{ [(methylsulfonyl)oxy]meihyl}hexahydrocyclo- penta[c]pyrrole-2(lH)-carboxylate was used without further purification. MS (El) for C14HZ5NO5S: 320 (ΜΕί), 264 (M-tBu).

Example 68 [0392] 1.1-Dimethvlethvl (3ag.6alSfl-5-(hvdroxv)-hexahvdrocvclopentarcl pvnole-2flHV· carboxvlate: Sodium borohydride (0.15 g, 4.00 mmol), was added to a solution of 1,1-dimethylethyl (3aR,6aS)-5-oxo-hexahydrocyc]0penla[c] pyrrole-2(122)-carboxylate (0.45 g, 2.00 mmol) in 10 mL methanol at 0°C and the reaction mixture was stirred for 1 h at this temperature. The solvent was evaporated, the crude mixture was diluted with 100 mL ethyl acetate and washed with water (30 mL), 1M aqueous hydrochloric acid and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give 1,1-dimethylethyl (3aJ?,6aS)-5-(hydroxy)-hexahydrocyclopenta[c] pyrroIe-2( 1/7)-carboxylate (0.44g, 98%). NMR (400 MHz, de-DMSO): 4.08 (m, 1H), 3.40 (m, 2H), 3.30 (m, ZH), 2.50 (m, 2H), 1.98 (m, 2H), 1.40 (s, 9H), 1.30 (m, 2H). MS (El) for C12H21NO3:228 (MEf). 228 WO 2005/030140 PCT/US2004/031523 2013204031 11 Apr 2013 [0393] 1,1-Djxnethvlethyl_(3BR.6aS)-5-( Kmethylsulfanvltoxvi Ihexahvdrocvclo- pentardpvrfole-2CUn-carboxvlate: Methanesulfonyi chloride (0.18 mL, 2.33 mmol), was added dropwise to a solution of 1,1-dimethylethyl (3a/?,6aS)-5-(hydroxy)-hexahydrocyclopenta[c] pyrrole-2(lZ?)-carboxylate (0.44 g, 1.94 mmol) and triethylamine ¢0.81 mL, 3.81 mmol) in 10 mL dichloromethane at 0°C and die reaction mixture was stirred for 1 h at room temperature. The solvent was evaporated, the resulting crude mixture was diluted with 100 mL ethyl acetate and washed with water (30 mL), brine, 1M aqueous hydrochloric acid and brine again. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The resulting crude 1,1-dimethylethyl (3aR,6aS)-5-{ [(methylsulfonyI)axy] }hexahydrocyclopenta[c]pyrrole-2(lfl)-carboxylate was used without further purification. MS (El) for CJ3H23NO5S: 306 (MH*).

[0394] 3-fChloromethvHhexahvdro-lff-ri-41oxazinor3-4-ciri-4lr»cazine: A solution of (3R)-morpholin-3-yImethanol (4.21 g, 36.0 mmol) in 2-(chloromjethyl)oxirane (28.2 mL, 0,360 mol) was heated to 40°C for 3 h and then the solution was concentrated in vacuo. The intermediate was cooled in an ice bath and treated with 30.0 mL of concentrated sulfuric acid. The mixture was heated to 170°C for 2 h and then allowed to cool to room temperature. The mixture was poured into ice-water and solid sodium bicarbonate was carefully added until the solution was basic. 10% methanol in ethyl acetate was added and the biphasic mixture was filtered. The layers were separated and the aqueous layer was extracted (3 x 100 mL 10% methanol in ethyl acetate). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography (S1O2, 2:5 hexanes:ethyl acetate) provided 3-(chloromethyl)hexahydro-ΙίΗΙ,4]oxazino[3,4-c][ 1,4]oxazine 2.44g (35%) as two separated diastereomers. (3i?,9aS)-3-(chloromethyl)hexahydro-lH-[l,4]oxazino[3,4-c][l,4]oxazine: (0.886 g, 13% yield): NMR (400 MHz, CDC13): 3.91 (m,3H), 3.82 (m, 1H), 3.68 (dt, 1H), 3.61 (dd, 1H), 3.47 (dd, 1H), 3.35 (t, 1H), 3.19 (t, 1H), 2.80 (d, 1H), 2.54 (m, 2H), 2.40 (m, 2H); MS (El) fdr CbHmN03C1: 192 (MET4}. (3S,9ai)-3-(chlommethyl)hexahydro-l//- [l,4]oxazmo[3,4~c][l,4]oxazine: (1.55 g, 22% yield): Ή NMR (400 MHz, CDC13): 3.85 (m, 2H), 3.73 (m, 3H), 3.50 (m, 2H), 3.29 (t, 1H), 3.18 (t, 1H), 2.85 (dd, 1H), 2.64 (dd, 1H), 2.40 (m, 2H), 2.17 (t, IB); MS (El) for CaHi^NOaCI: 192 (MH+). 229 WO 2005/030140 PCT/US2004/031523 2013204031 11 Apr 2013 [0395] Hexahvdro-lg-ri.41oxazinQr3.4~ciri.41oxa2iii-3-vImethvl acetate: A suspension of (3R,9a$-3-(chlraomethyl)hexahydro-lff-[l,4]oxazino[3,4-c][l,4]oxazine (1.97 g, 10.3 mmol) and potassium acetate (10.1 g, 102 mmol) in DMF ¢20.0 mL) was stirred at 140% for 16 h, and then at 150°C for another 12 h. The reaction mixture was partitioned between water (250 mL) and ethyl acetate (250 mL), the organic layer was washed with 5% lithium chloride (2 x 100 mL) and brine (100 mL) then dried over anhydrous sodium sulfate and concentrated in vacuo. Column chromatography (SiOz, 1:1 hexane:ethyl acetate, then 100% ethyl acetate) afforded 0.92 g (42%) of hexahydro-lff- [1.4] oxaano[3,4-c][l,4]oxazm-3-ylmethyl acetate as a yellow oil. Distinct diastereomers as described above were converted in this step to give: (3jR,9a5)-hexahydra-LH- [1.4] oxazino[3,4-c][l,4]oxazin-3'ylmethyl acetate: !H NMR (400 MHz, CDCfe): 4.18 (dd, 1H), 4.00 (m, 1H), 3.80 (dd, 1H), 3.68 (di, 1H), 3.60 (dd, 1H), 3.46 (m, 2H), 3.22 (t, ffi), 2.64 (dd, IH), 2.53 (m, 2H), 2.43-2.35 (m, 2H), 2.10 (s, 3H), and (3S,9aS> hexahydro-lH-[l,4]oxazino[3,4-c][l,4]oxazin-3-ylmethyI acetate: *Η NMR (400 MHz, CDCI3): 4.09 (d, 2H), 3.90-3.82 (m, 2H), 3.75-3.64 (m, 3H), 3.27 (t, 1H), 3.18 (t, 1H), 2.69 (dd, 1H), 2.63 (m, 1H), 2.46-2.33 (m, 2H), 2.16 (t, 1H), 2.10 (s, 3H).

[0396] l'3R.9aiy>-Bexahvdro- ΙΗ-Γ1.41oxazmoF3.4-cl Γ l-41nxazm-3-vImethvl methane- sulfonate: To a solution of (3R,9aS)-hexahydrD-Lff-[l,4]oxazino[3,4-c][l,4]oxazin-3-ylmethyl acetate (0.922 g, 4.28 mmol) in methanol (14.0 mL) was added 1.03 mL (4.50 mmol) of sodium methoxide (25% wt. in methanol) dropwise at room temperature. After 5 min., 1.6 mL (6.43 mmol) of 4.QM hydrogen chloride in dioxane was added and a pink precipitate formed The solution was concentrated in vacuo and the pink solid was taken up in 30.0 mL dichloromethane. This slurry was cooled in an ice bath and triethylamine (3.0 mL, 21.5 mmol) was added, followed by methanesulfonyl chloride (0.37 mL, 4.71 mmol). The resultant yellow solution was stirred far 30 minutes at room temperature. The mixture was then partitioned between dichloromethane and saturated aqueous sodium 1 bicarbonate then the aqueous layer was extracted (3 x 50 mL dichloromethane). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to provide crude (3R,9a5)-hexahydro-lfl-[l,4]oxazino[3,4-c][l,4]oxazin-3-yImethyI methanesulfonate which was taken on to the following reaction without purification. 230 PCT/US2004/031523 2013204031 11 Apr 2013 WO 2005/030140

Example 70

[0397] ('8aR)-6-fChloromethvl)tetcahvdrQ-lg-ri.37thiazolor4.3-cin.41oxay.ine· A solution of (4A)- l,3-thiazolidin-4-yImothanol (0.300 g, 2.52 mmol) in 2-(chloromethyl)oxirane (2.0 mL, 25.5 mmol) was heated under nitrogen to 40°C for 12 h. The solution was then cooled to room temperature and 2-(chloromethyl)oxirane was removed in vacuo. The crude intermediate was cooled in ice, and was taken up in 2.0 mL of concentrated sulfuric acid. The resulting mixture was heated to 200°C for 0.5 h then poured carefully onto wet ice, which was allowed to melt. The aqueous solution was carefully made basic using solid sodium bicarbonate and the resulting mixture was filtered using water and 10% methanol in ethyl acetate as eluent The layers were separated and the aqueous layer was extracted with 10% methanol in ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 11.6 mg (2.4% yield) of crude (8aR)-6-(chlaroinethyl)tetrahydro- 1Ή- [l,3]thiazolo[4,3-c][l,4]axazine as a mixture of diastereomers which was directly taken on to the next step.

Example 71 [0398] 1.1-Dimethvlethvl f3-eniibV3-f2-rfmeihvlsnlfonvltoxvlethvn-8-azabicvclof3.2· 11 octane-8-carboxvlate: To a solution of 1,1-dimethylethyl (3-enafo)-3-(2-hydrQxyethyl)-8-azabicyclo[3.2. l]octane-8-carboxylale (30.3 mg, 1.19 mmol) in dichloromethane (4.0 mL), was added triethylamine (0.5 mL, 3.56 mmol) and the solution was cooled to 0°C under nitrogen. Methanesulfonyl chloride (0.11 mL, 1.42 mmol) was added slowly and mixture was allowed to warm to room temperature and stirred for lh. The reaction mixture was partitioned between dichloromethane and water. The aqueous phase was extracted with ) dichloromethane (2 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to provide 35.1 mg (89%) of 1,1- / dimethylethyl (3-e«do>3-{ 2-[(methylsulfonyl)oxy] ethyl }-8-azabicyelo[3.2. l]octane- 8- carboxylate, which was carried forward for alkylation without purification. 231 PCT/US2004/031523 2013204031 11 Apr 2013 WO 2005/030140

Example 72

PS-PPh3

DEAD

[0399] N-r3-Fluoro-4-( [ 7-fmethvloxvV6-r ('3-mQrDho]in-4-vtomovl1oxvlauinazolin-4- vl 1 oxv1phenvll-N-f4-fluorophenvl)cvclopropane-l. 1-dicarhnxamide. Crude cyclopropane-1,1-dicarboxylic acid [3-fluoro-4-(6~hydroxy-7-methoxy-quinazolin-4- yloxy)-phenyl]-amide (4-fluoro-phenyl)-armde (333mg, 0.66nmiol), PS~PPh3 resin, (loading = 2.33imno]/g, 797mg, 1.86mmol), 3-moipholin-4-yI-propan-l-ol (0.26ml, 1.88mmol), and DEAD (0.31ml, 1.91mmol) were combined in CH2CI2 (10ml) and stirred at room temperature for l-2hrs. The reaction mixture was filtered and the resin thoroughly washed with CH2CI2. The filtrate was concentrated in vacuo and the resulting residue was dissolved in EtOAc and washed with H2O (4x) and sat'd NaCl (lx) and then extracted with IN HC1 (3x). The combined IN HO extractions were washed with EtOAc (2x). Hie acidic aqueons phase was then basified with IN NaOH and extracted with EtOAc (3x). The combined EtOAc extractions were washed with H20 (lx), sat’d NaCl (lx), dried (Na2S04>, and concentrated in vacuo. The resulting residue was purified by preparative reverse phase HPLC (25mM NHtOAc/acetonitnle) and the pure fractions were lyophilized to give cyclopropane-1,1-dicarboxylic acid {3-fluaro-4~[7-methoxy-6~(3-morpholin-4-yl-

I propaxy)-quinazolin-4-yloxy]-phenyl} -amide (4-fluoro-phenyl)-amide (42.6mg, 10%). 1HNMR (400MHz, DMSO-d6): d 10.37 (hr s, 1H), 10.05 (br s, 1H), 8.55 (s, 1H), 7.84 (m, 1H), 7.65 (m, 2H), 7.58 (s, 1H), 7.43 (m, 3H), 7.16 (t, 2H), 4.27 (m, 2H), 4.00 (s, 3H), 3.60 (m, 6H), 2.39 (m, 4H), 1.99 (m, 2H), 1.47 (m, 4H). LC/MS Calcd for [M+H]+ 634.2, found 634.1.

[0400] Using the same or analogous synthetic techniques and/or substituting with alternative starting materials, the following were prepared: [0401] N-(3-fluorD-4-rf7-fmethvloxvl-6-fr(l-methvlpioeridin-4-vllmethvnoxvl0uin-azolin-4-vlbxvlphenvl 1 -N'-f4-fluorophenvllcvclopropan&amp;-l. 1 -dicarboxamide: *H NMR (400MHz, CDCI3): 5 9.67 (s, 1H), 8.59 (s, 1H), 8.43 (s, 1H), 7.75 (d, 1H), 7.52 (s, 1H), 232 2013204031 11 Apr 2013 WO 2005/030140 FCT/US2004/031523 7.46 (m, 2H), 7.31 (s, 1H), 7.20 (m, 2¾. 7.06 (t, 2H), 4.04 (d, 2H), 4.03 (s, 3H), 2.98 (d, 2H), 2.34 (8,3H), 2.12-2.1.95 (m, 5H), 1.76 (m, 2B), 1.64 (m, 2H), 1.57 (m, 2H). t

Example 73 h2n^. HO'

[0402] Preparation of l-r4-f6.7-riTTTiethnxv-aumoIin-4-vloxv)-DhCTvlcarhflmnvn-cvclonropanecarboxvlic acid. To the cyclopropyl di-carboxylic acid (449 mg, 3.45 mmol) in THF (3.5 mL) was added TEA (485 pL, 3.45 mmol). The resulting solution was stirred at roam temperature under a nitrogen atmosphere for 40 minutes before adding thienyl chloride ¢250 pL, 3.44 mmol). Hie reaction was monitored byLCMS for the formation of mono acid chloride (quenched the sample with MeOH and looked for corresponding mono methyl ester). After 3 hours stirring at room temperature, 4-(6,7-dimethoxy-quinolin-4~ yloxy)-pheuylamine (1.02 g, 3.44 mmol) was added as a solid, followed by more THF (1.5 mL). Continued to stir at room temperature for 16 hours. The resulting thick slurry was diluted with EtOAc (10 mL) and extracted with IN NaOH. The biphasic slurry was filtered and the aqueous phase was acidified with cone. HCI to pH = 6 and filtered. Both solids were combined and washed with EtOAc, then dried under vacuum. The desired product, l-[4-(6,7-dimethoxy-quinolin-4-ylaxy)-phenylcarbamoyl]-cyclopropanecarboxylic acid, was obtained (962 mg, 68.7% yield, 97% pure) as a white solid. JH NMR (DzO/NaOH): 7.97 (d, 1H), 7.18 (d, 2H), 6.76 (m, 4H), 6.08 (d, 1H), 3.73 (s, 3H), 3.56 (s, 3H), 1.15 (d, 4H).

Example 74

OH h2n

hatu/diea/dma F

233 PCT/US2004/031523 WO 2005/030140 10403] ‘N-(4-f f 6.7-BisrmethvloxvV|uinnlin-4-vlloxv!phenvI')-Nl-rf4-fluorophenvl'>methvl1 cyclopropane-l.l-dicafbnxaiTaide- Tn a solution of l-[4-(6,7-dimethoxy-qumolin-4-yloxy)-phenylcarbamjoylJ-cyclopropanecarboxylic acid ¢74.3 nag, 0.182 mmol), 4-Fhiaro benzylamine (25 pL, 0.219 mmol), DIEA (90.0 pL> 0.544 mmol) in DMA (1.0 mL) was added HATU (203 mg, 0.534 mmol). The resulting solution was stirred at room temperature for 1 hour before adding dropwise to water (10 mL) with stirring. The slurry was sonicated, filtered and the solids were washed with 1 N NaOH followed by water. After air drying, the solids were further purified by prep HPLC, affording Ή-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N,-[(4-fluorophenyl)methyl]cyclopropane-l,l-dicarboxamide (33 mg, 35% yield, 98% pure) as a white solid. !H NMR (DMSO, de): 10.82 (s, 1H), 8.80 (d, 1H), 8.50 (t, 1H), 7.83 (d, 2H), 7.74 (s, 1H), 7.56 (s, 1H), 7.30-7.38 (m, 4H), 7.15 (t, 2H), 6.80 (d, 1H), 4.32 (d, 2H), 4.04 (s, 3H), 4.03 (s, 3H), 1.42 (s, 4H).

[0404] The following confounds were prepared, in a similar manner as above, from the coupling of l-[4-(6,7-dimethoxy-quinoIm-4-yloxy)-phenylcarbamoyl]-cyclopropane carboxylic add with a corresponding alkylamine or arylamine.

[0405] N-(44 Γ6.7-Bis(methvIoxv)quinolin-4-vlloxvlphenvn-N'-f2-foiperidm-l-vlmethvlbhenvllcyclopropane-1. l-dicarhoxamide. 1H NMR (DMSO-d6): 10.62 (s, 1H), 8.79 (d, 1H), 8.24 (t, 1H), 7.83 (d, 2H), 7.72 (s, 1H), 7.58 (s, 1H), 7.37 (d, 2H), 6.76 (d, 1H), 4.04 (s, 3H), 4.03 (s, 3H), 3.98 (m, 2H), 3.66 (m, 2B), 3.49 (m, 4H), 3.25 (t, 2H), 3.13 (hr., 2H), 1.42 (d,4H).

[0406] N“('4-ir6.7-Bis('methvloxv~)auinolin-4-vnoxvlphenvll-N'-r2-fpiperidin-l-vlmethvDphenvncvclopropane-l.l-dicHrhnyamide. 1H NMR (DMSO-d6): 10.78 (s, 1H), 10.53 (s, 1H), 8.43 (d, 1H), 8.12 (d, IB), 7.82 (d, 2H), 7.49 (s, 1H), 7.37 (s, 1H), 7.20-7.28 (m, 3H), 7.15 (dd, 1H), 7.01 (td, 1H), 6.35 (d, 1H), 3.93 (s, 3H), 3.92 (s, 3H), 3.47 (a, 2H), 2.17 (br., 4H), 1.49 (m, 4H), 1.41 (m, 4H), 1.32 (br., 2H).

[0407] lN-f4-ir6.7-Bis(methvloxv>lquinolin-4-vlloxv]phenvl)-N'-r2-fpviTolidin-l-vImethvl>phenvncvclopropane-l.l-tltcarbOTfamide. 1H NMR (DMSO-d6): 10.98 (s, 1H), 10.56 (s, 1H), 8.42 (d, 1H), 8.10 (dd, 1H), 7.81 (m, 2H), 7.49 (s, 1H), 7.37 (s, 1H), 7.17-Ί2Ί (m, 4H), 7.01 (td, 1H), 6.35 (d, 1H), 3.93 (s, 3H), 3.92 (s, 3H), 3.61 (s, 2H), 2.30 (br., 4H), 1.47 (br., 4H), 1.43 (m, 4H).

[0408] 'N-(4-f Γ6.7-Bis(melhvlaxv)auinolin-4-vlloxv]phenvl)-Nl-r3-(morphplin-4; vlmethvl)phenvllcvclopropane-l.l-dicarboxamide. 1H NMR (DMSO-d6): 10.12 (s, 1H), 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523 10.03 (s, 1H), 8.44 (d, 1H), 7.74 (d, 2H), 7.57 (s, 1H), 7.53 (d, 1H), 7.48 (s, 1H), 7.37 (s, 1H). 7.21 On, 3H), 6.98 (d, 1H), 6.40 (d, 1H), 3.93 (s, 3H), 3.92 (s, 3H), 3.56 (t, 4H), 3.41 (s, 2H), 2.34 (br„ 4H), 1.48 (s, 4H).

[0409] lN-f4-(r6.7-Bisfm6thvIoxv)qumolin-4-vllQxvlphenvl,)-N,-r2-/niorpholin-4-vlmethvBphenvncvclopropane-l.l-dicarhoxaTTiide· 1H NMR (DMSO-d6): 10.54 (s, 1H), 10.47 (s, 1H), 8.43 (d, 1H), 8.08 (d, 1H), 7.78 (d, 2H), 7.49 (a, 1H), 7.37 (d, 1H), 7.18- 7.30 (m, 4H), 7.03 (t, 1H), 6.37 (d, 1H), 3.94 (s, 3H), 3.93 (s, 3H), 3.50 (s, 2H), 3.44 (br., 4H), 2.20 (br., 4H), 1.48 (d, 4B).

[0410] *N-f4-f r6.7-Bisfmgthvloxv~)auino]in-4-vlloxvlphenvD-Nl-r3-rpiparidin-l -vlmetfavDphenvllcvclopropane-1.1-dicarboxamfde. 1H NMR (DMSO-d6): 10.0-10.2 (br., 2H), 8.46 (d, 1H), 7.76 (d,2H), 7.53 (m, 3H), 7.39 (s, IB), 7.24 (m, 3B), 6.98 (d, 1H), 6.43 (d, 1H), 3.95 (s, 3H), 3.93 (s, 3H), 3.37 (s, 2H), 2.31 (br., 4H), 1.48 (m, 8H), 139 (br., 2H).

[0411] 1N-f4-ir6.7-Bisfmethvloxv)ouinolin-4-vlloxvlphenvl)-N,-r3-fpvtrolidin-l-vlmethvBphenvlIcvcIoDropane-Ll-dicarhoxaTnidft· 1H NMR (DMSO-d6): 10.0-10.2 (br., 2H), 8.46 (d, 1H), 7.77 (d, 2H), 7.59 (s, 1H), 7.53 (d, 1H), 7.51 (s, 1H), 7.39 (s, 1H), 7.23 (m, 3H), 6.99 (d, 1H), 6.43 (d, 1H), 3.95 (s, 3H), 3.93 (s, 3B), 3.52 (s, 2H), 2.42 (br., 4H), 1.69 (br,4H), 1.48 (s,4B).

Example 75

235 WO 2005/030140 PCT/US2004/031523

2013204031 11 Apr 2013

[0412] Synthesis of N-(4~jr6.7-his(mefovloxv)-2-(metfavifoin^qiiiTinliii--4-vr]oxvl-3-flnoionhen^VN'-f^fiuQroDhenvDcvcloprQpane-l.l-dicarboxamide Commercially available 5-(bis-methylsulfanyl-methylene)-2,2-dimethyl-[l,3]dioxane-4,6-clione (3.5 g, 14 mmol) and 3,4-dimethoxyoaniIme (2.2 g, 14 mmol) were reflux in EtOH (20 mL) for 2 hours. The EtOH was removed under reduced pressure and EtOAc was added to the residue. The product was filtered and washed with cold EtOAc (3X). 5-[(3,4-dimethoxy-phenylanuno)-inethylsulfanyl-methylene]-2,2“dimethyE[l,3]dioxane-4,6-dioiie was obtained as a white solid (1.7 g, 47% yield) and used wilhout further purification. LCMS: m/z 352 (M-H)'.

[0413] A mixture of 5-[(3,4-dimethoxy-phenylammo)-methylsulfanyl-methylene]-2,2-dimethyI-[l,3]dioxane-4,6-dione (1.7 g, 6.6 mmol) and diphenylether (3.5 g, 21 mmol) were heated at 260 °C for 10 minutes. Hie mixture was cooled to room temperature and heptane was added. 6,7-Dimethoxy-2-methylsulfanyl-quinolin-4-ol was filtered and isolated as an orange solid and used without further purification (1.4 g, 83% yield). LCMS: m/z 352 (M+H)+.

[0414] A mixture of 6,7-dimethoxy-2-methylsulfanyl·quiπcllm-4-ol (1.0 g, 4.0 mmol), 3,4-difluoronitrobenzene (0.48 mL, 4.3 mmol), cesium carbonate (26 g, 8.0 mmol), and DMF (15 mL) was stirred at room temperature for 12 hours, after which time, the mixture was filtered. The filtrate was extracted with DCM, washed with 10% LiG(aq.)s water, (IX) and brine (IX), followed by drying over NazSCU and concentration in vacuo. The crude solids were purified by flash chromatography (silica gel, 5% MeOH in DCM), affording the nitroquinoline (1.3 g, 85.8% yield) as an orange solid, LCMS: m/z 391 (M+H)-1'. A mixture of nitroquinoline (0.33 g, 0.85 mmol), 5% Pt/S on carbon (0.050 g), ammonium formate (0.40 g, 6.3 mmol) in EtOH (5 mL) was heated at 80 °C for 1 hour The mixture was cooled to room temperature and the solvent removed under reduced pressure. The residue was dissolved in DCM, the mixture filtered, and the precipitate discarded. Removal of the organic solvent afforded 4-(6,17-dimethoxy-2-methylsulfanji-quinolin-4-yloxy)-3-fluoro-pheaijlamine as an orange aU (220 mg, 73% yield). LCMS: m/z 361 (M+H)+. 236 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523 [0415] To a mixture of 4-(6,7-dimethoxy-2-methylsuIfanyI-quinolin-4-yloxy)-3-fluoro-phenylamine (0.22 g, 0.61 mmol) and l-(4-Huoro-phenylcarbamoyl)-cyclopropanecarboxylic acid (0.16 g, 0.73 mmol) in DMF (5 mL) was added TEA (0.25 mL, 1.8 mmol) followed by HATU (0.57 g, 1.5 mmol). The resulting solution was stirred overnight at room temperature. The reaction mixture was dumped into water and extracted with DCM (2X). The combined extracts were washed with 5% LiCl^q.) (3X), water, (IX) and brine (IX), followed by drying over Na2S04 and concentration in vacuo. The crude solids were purified by preparatory HPLC with ammonium acetate, affording N-(4-{[6,7-his(methyloxy)“2-(methylthio)quinolin-4-yl]oxy}-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (0.39 g, 11% yield) as a white solid. XH NMR (DMSOnifc) δ 10.34 (s, 1H), 9.94 (s, 1H), 7.83 (d, 1H), 7.59 (m, 2H), 7.56 (m, 1H), 7.40 (m, 2H), 7.23 (s, 1¾. 7.09 (t, 2H), 6.12 (s, 1H), 3.88 (s, 3H), 3.85 (s, 3H), 2.48 (s, , 3H), 1.40 (m, 4H).

Example 76

[0416) Synthesis of N-f4-fr2-amino-fi.7-bis('methvloxv)qumolin-4-vlloxvl-3“ fluorophenvD-N'^-fluoionhenvDcvclopropane-l. 1 -dicarhnxamide. A mixture of 5-[(3,4-dimethoxy-phenylamino)-methylsulfanyl-methylene]-2,2-diinfithyl-[l,3)diaxane-4,6-dione (1.0 g, 2.8 mmol), 30% ammonium hydroxide (8.5 mL), HgCk (0.76 g, 2.8 mmol) in THF (5 mL) was stirred at room temperature for 30 minutes. The mixture was extracted with DCM and water (3X) and dried with Na2SQ*. Concentration m vacuo afforded 5-[amino-(3,4-dimethoxy-pheiiylamino)-methylene]-2,2-dimethyl-[l,3]dioxane-4,6-dione as a white solid (0.90 g, 97% yield) and this compound was used without further purification. LCMS: m/z 321 (M-H)\ 237 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523 [0417] A mixture of 5-[amino-(3,4-dimethoxy-phenylamino)-methylene]-2,2-dim0thyl- [l,3]dioxane-4s6-dione (0.90 g, 2.8 mmol) and diphenylether (3.0 g, 18 mmol) was heated at 260 °C for 30 minutes. The mixture was cooled to room temperature and heptane was added. Product 2~amino-6,7-dimethoxy-quinoIin-4-oI was filtered and isolated as an orange solid and used without further purification (0.31 g, 33% yield). LCMS: m/z 221 (M+H)+.

[0418] 4-(4-Amino-2-fluoro-phenoxy)-6,7“dimethoxy-quinolin-2-ylamine was synthesized from 2-amino-6,7-dimethoxy-quinolin-4-ol in a similar manner as 4-(6,7-dimethoxy-2-methylsulfanyl-quinolin-4-yloxy)-3-fluoro-phenylainine, and obtained as a white solid (4.0% yield). LCMS: m/z 330 (M+H)+.

[0419] N-(4-{ [2-amino-6,7-bis(methyloxy)qumolin-4-yl]oxy}-3-fluQrophenyl)-N'-(4-fluorophenyl)cyclopropane-l,l-dicarbQxamide was synthesized from 4-(4-amino-2-fluoro-phenoxy)-6,7-dimethoxy-quinolin-2-ylamine in a similar manner as N-(4-{[6,7-bis(methyloxy)-2-(methylthio)quinohn-4-yl]oxy}-3-fluQrophenyl)-N'-(4-fluorophenyl)cyclopropane-l,1-dicarboxamide. It was purified by preparatory HPLC using ammonium acetate and isolated as a white solid (4.0% yield). JHNMR (DMSO-dg) δ 10.34 (s, 1H), 9.95 (s, 1H), 7.82 (d, 1H), 7.58 (m, 2H), 7.44 (d, 1¾. 7.33 (t, 1H), 7.25 (s, 1H), 7.09 (t, 2H), 7.07 (s, 1H), 6.17 (br s, 2H), 5.66 (s, 1H), 3.79 (s, 3H), 3.77 (s, 3H), 1.40 (d, 4H). LCMS: m/z 535 (M+H)+.

Example 77

[0420] Synthesis of T4-(3-fluoro4-fr2-6nethviamino]-6.7-bis(methvloxv’)Quinolin-4-vnoxvlphenvl)-Nl-f4-fluoroDhenvl,lcvclopiopane-l.l-dicarboxamide. A mixture of 5-238 2013204031 11 Apr 2013 PCT/US2004/031523 WO 2005/030140 [(3,4-dimethoxy-phenylainino>methyIsuIfanyl-inetityIene]-252-dimethyl-[l,3]dioxane“4,6' dione (0.50 g, 1.4 mmol), methylamine (2 M in TBF, 0.75 mL.> 1.5 mmol), BgCh (0.38 g, 1.4 mmol) in THF (5 mL) was stirred at room temperature far 30 minutes. The mixture was extracted with DCM and water (3X) and dried with Na2SC>4. Concentration m vacuo afforded 5-[(3,4-dimethoxy-phenylamino)-methylamino-methylene]-2,2-dimethyl- [l,3]dioxane-4,6-dione as a yellow solid (0.48 g, 99% yield) and this compound was used without further purification. LCMS: m/z 335 (M-H)".

[0421] A mixture of 5-[(3,4-dimethoxy-pheny]amino}-methylammo-rnethylene]-2)2-dimethyl-[l,3]dioxane-4,6-dione (0.40 g, 28 mmol) and diphenyletiier (3.0 g, 18 mmol) was heated at 260 °C for 15 minutes. The mixture was cooled to room temperature and heptane was added. Product 6,7-dimethoxy-2-mdhylamino-quinolm-4-Ql was filtered and isolated as a tan solid and used without further purification (0.30 g, quantitative yield). LCMS: m/z 235 (M+H)+.

[0422] [4-(4-Amino-2-fluoro-phenoxy)-6,7-dimethoxy-qumoIin-2-yl]-methyl-amine was . ) synthesized from 6,7-dimethoxy-2-methylanuno-quinolin-4-ol in a similar manner as 4-(4-Amino-2-fluoro-phenoxy)-6,7-dimethoxy-qumolin-2-yIamme, and isolated as a yellow oil (58% yield). LCMS: m/z 330 (M+H)+.

[0423] ’N-(3-fluoro-4-{[2-(methylaxmno)“6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-l,l-dicarboxamide was synthesized from [4-(4-amino-2-fluoro-phenoxy)-6,7-dimethoxy-quinolin-2-yl]-methyl-arnine in a similar manner as N-(4-{[6,7-bis(methyloxy)-2-(methyIthio)quinolin-4-yl]oxy}-3-fluorophenyl)-N'“(4-fluoro-phenyl)cyclopropane-l, 1-dicarboxamide, It was purified by preparatory HPLC using ammonium acetate and isolated as a white solid (6.0 mg, 4.0% yield). Ή NMR (DMSO-dg) δ 10.42 (s, 1H), 9.91 (s, 1H), 7.88 (dd, 1H), 7.56 (m, 2H), 7.44 (m, 4H), 7.09 (t, ZB), 5.90 (s, 1H), 3.88 (s, 3H), 3.85 (ε, 3H), 3.39 (hr s, 1H), 2.92 (s, 3H), 1.41 (dt, 4H). LCMS: m/z 535 (M+H)+.

Example 78

239 2013204031 11 Apr 2013 WO 2005/030140 FCT/US2004/031523· [0424] N-(4-( Γ6-Ι [3-fί1ΐΒίΗνΐΑηιϊηο)ρΓορνηοχνΐ-7-('ΐΡ6ΰινΙοχν')ςαίηοϋη-4-νηοχνί-3- fluarophenyfi-N'-f4-fluororihflnvl')cvctoDropane-1. l-dicarboxamide. To a sluny of cyclopropane-1,1-dicarboxylic add [3-fluaro-4-(6-hydroxy-7-methoxy-quinolin-4-y]oxy)-phenyl]-amide (4-flooro-phenyl)-amide ¢0.12 g, 0.23 mmol), hydroxypropyldiethylamine (0.090 mL, 0.61 mmol), triphenylphosphine (0.20 g, 0.76 mmol) in DCM (10 mL) was added DIAD ¢0.17 mL, 0.86 mmol). Hie resulting mixture was stirred at room temperature for 12 hours, after which time, the solvent was removed under reduced pressure. The residue was extracted with EtOAc and IN HC1 (6X) and brine (IX) followed by drying with Na2S(>4. Concentration of the organic fraction in vacuo afforded 'N-(4-{ [6-{ [3-(diethylamino)propyl]oxy}-7-(metiiyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N'-(4-fIuarophenyl)cycIopropane-l,1-dicarboxamide as a yellow oil (0.18 g, wet, ca 95% purity by analytical HPLC). Further purification by preparatory HPLC using ammonium acetate afforded the product in 99% purity by analytical HPLC. LCMS: m/z 619 (M+H)+. !H NMR (DMSO-dff) δ 10.37 (br s, 1H), 10.00 (s, 1H), 8.44 (d, 1H), 7.87 (d, 1H), 7.62 (m, 2H), 7.49 (m, 2H), 7.41 (m, 2H), 7.13 (t, 2H), 6.40 (d, 1H), 4.17 (t, 2H), 3.93 (s, 3H), 2.59 (t, 2H), 2.49 (m, 6H), 1.91 (m, 4H), 0,94 (t, 6H).

Example 79

240 PCT/US2004/031523 2013204031 11 Apr 2013 WO 2005/030140 [0425] K-(4-flUorophenyl)-NW4-J[2-mftthvl-fi|7-hisfmeth'rioxvlqmnazolin-4- ylloxy luhenvllcvclopropane-1.1-di carboxamides. Commercially available 2-amino-4,5-dimethoxy-benzoic add methyl ester (3g, 0.014 mol) and acetic anhydride (4.03 mL, 0.0426 mol) were heated in heptane at 100°C for 3 hours. After removal of heptane in vaccuo, the crude product of 2-acetylamino-4,5-dimethoxy-ben2oic acid methyl ester was obtained and used without further purification. LCMS: m/z 254 (M+H).

[0426] To the erode 2-acetylaminq-4,5-dimethoxy-benzoic add methyl ester obtained above was added ammonium acetate (7.98g 0.104 mol) and acetic acid (10 mL). The mixture was heated at reflux in a pressure tube until the formation of the desired cyclization product, as indicated by LC/MS: m/z 221 (M+H). After cooling to RT, the reaction mixture was diluted with water, and extracted with EtOAc 3 times. The combined organic phase was basified with aq. NaOH solution, and washed 3 times with EtOAc. The aqueous layer was then addified with aq. HC3 and extracted three times with EtOAc. The combined organic extract was dired over Na2S04 and concentrated in vacuo, affording 6,7-dimethoxy-2-methyl-quinazolin-4-ol (0.15g), which was used without further purification. LC/MS: m/z 221 (M+H).

[0427] A mixture of 6,7-dimethoxy-2-methyl-quinazoIin~4-ol obtained from previous step (0.15g, 0.68 mmol) and POC13 (1.59 mL, 17.04 mmol) was heated at reflux for 48 hours. The reaction mixture was poured into ice water, neutralized with NaHCOj, and adjusted to basic with K2CO3. The mixture was cooled to 0°C with stirring The resulting predpitate was filtered, giving 4-chloro-6,7-diinethoxy-2-methyl-quinazoline (0.094g), which was used without further purification.

[0428] A mixture of the chloro quinazoline (0.094g, 0397 mmol) obtained above, 4-nitrophenol (O.llg, 0.795 mmol) and bromobenzene (3mL) was heated at 160°C for 48 hours. The solvent was then removed and the reaction was taken up in MeOH. Et20 was added and the reaction stirred 30 min and the predpitate was filtered, affording 6,7-dimethoxy-2-me)hyl-4-(4-nitro-phenoxy)-quinazoline (0.08 lg) as a very light yellow solid. LC/MS: m/z 342 (M+H).

[0429] A mixture of 6,7-dimethoxy-2-methyl-4-(4-Mteo-pheuoxy)-quinazo!line (0.08lg, 0.236 mmole), Pt/S (0.008g, 15 mol%), ammounium formate (0.098g 1.56 mmol) and EtOH (3mL) was heated with stirring at 70°C for 3 hours. The reaction mixture was then filtered while hot and washed with hot EtOH. The crude product of 4-(6,7-dimethoxy-2- 241 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523 methyl-quinazoIin-4-yloxy)-phenylamine (0.924g) was obtained as a yellow solid, which was used in the next reaction without farther purification. LC/MS: m/z 312 (M+H).

I

[0430] To a mixture of 4-(6,7-dimethoxy-2-methyl-quinazolin-4-yloxy)-phenylamine (0.100g, 0.321 mmol) and l-(4-fluoro-phenylcarbamoyl)-cycIopropanecaiboxyIic acid (O.056g, 0.386 nunol) in DMP was added DIEA (0.168 mL, 0.963 mmol), followed by HATU (0.183g, 0.482 mmol). The reaction mixture was stirred at RT for 15 hours. The mixture was diluted with EtOAc, washed with 5% LiCl aq solution three times, dried over Na2S04, and concentrated m vacuo. The crude product was purified on preparative HPLC to give ,N-(4-fluorophenyl)-N'-(4-{[2-methyl-6,7-bis(methylQxy)qumazolin-4' yl]oxy}phenyl)cyclopropane-l,1-dicarboxamide (3.2 mg) as a white solid. 1H NMR (DMSO-d6) 10.15 (bs, 1H), 10.01 (bs, 1H), 7.69-7.75 (m, 2H), 7.61-7.68 (m, 2H), 7.52 (s, 1H), 7.32 (s, 1H), 7.23-7.29 (m, 2H), 7.12-7.19 (m, 2H), 3.93 (d, 6H), Z43 (s, 3H), 1.53 am

Example 80

[0431] Preparation of l-(4-Huoro-uhenvlcaifamiovlV2-methvl-cvcloDropanecarboxvlic acid. 2-Methylcyclopropane-1,1-dicarboxylic acid methyl ester was prepared by following die literature procedure (Baldwin, J. K; Adlington, R. M.; Rawlings, B. J. Tetrahedron Lett. 1985, 481.) The carboxylic add (700 mg, 4.4 mmol) was dissolved in CH2CI2 (10 mL). To the resulting solution was added 4-fhioroaniline (590 mg, 5.3 mmol), HOBt (890 mg, 6.6 mmol) and EDO (2.5 g, 13.2 mmol), the stirring was continued for 3 h at rt. CH2CI2 (30 mL) was added to the reaction mixture, and the resulting solution was washed with brine, and dried over Na2S04. CH2CI2 was removed under reduced pressure. Further purification by column chromatography gave 635 mg (57%) of the desired amide. 242 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523 [0432] The methyl ester obtained above was then treated with LiOH*H20 (116 nig, 2.78 mmol, 1.1 eqiv.) in THF (2 mL) and BfeO (1 mL) for 3h at rt. THF was removed under reduced pressure. The aqueous solution was diluted with 20 mL of H20, washed with ether (10 mL), and acidified with 1 N HC1. The solid was filtered, dissolved in EtOAc, and dried over Na2S04. Removal of EtOAc gave the crude product of l-(4-fluoro-phenylcarbamoyl)-2-methyl-cyclopropane-carboxy]ic acid, which was used in the next reaction. :H NMR (400 MHz, DMSO-de) δ 12.99 (br s, 1H), 10.33 (br s, 1H), 7.59 (dd, J = 9.0, 5.0 Hz, 2 H), 7.11 (dd, J = 9.0, 9.0 Hz, 2 H), 1.86-1.78 (m, 1 H), 1.43 (dd, J = 9.0, 4.2 Hz, 1H), 1.30 (dd, J = 7.8,4.3 Hz, 1H), 1.19 (d, J = 6.3 Hz, 3H).

Example 81

[0433] Synthesis of (lS,2R)-N-[3-fluoro-4-({6-(mfithyloxy)-7-[(3-inotpholin-4-ylpropyl) oxy]quinolin-4-yl}oxy)phenyl]-N,-(4-fluorophenyl)-2-mBthylcyclopropane-l,l-dicarboxamide. To a solution of 4-(7-benzyloxy-6-methoxy-quinolin-4-yloxy)-3-fluoro-phenylamine (150 mg, 0.38 mmol) in CH2C12 (3 mL) was added D1EA (341 mg, 2.64 mmol), l-(4-fluoro-phenylcarbamoyl)-2-methyI-cyclopropanecarboxylic acid (120 mg, 0.49 mmol) and PyBOP (686 mg, 1.32 mmol), The reaction mixture was stirred at rt for 6 h. After standard workup, the crude product was purified by column chromatography.

[0434] The coupling product (130 mg, 0*21 mmol) obtained above was dissolved in EtOH (2 mL). 1,4-cyclohexadiene (170 mg, 2.1 mmol) and 10% Pd/C (10 mg) were added. The 243 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523 mixture was stirred for 2 h under reflux. After cooling, the mixture was filtered through Celite, and washed with MeOH. Removal of the solvents gave the crude product (136 mg), which was used in the next reaction.

[0435] To a solution of the 7-hydroxyquinoline (136 mg, 0.26 mmol) in DMF (2 mL) was added 4-(3-chloropropyI)morpholine hydrochloride (70 mg, 0.35 mmol) and K2CO3 (69 mg, 0.50 mmol). The reaction mixture was then stirred at 80 °C for 5 h. After cooling, EtOAc (20 mL) was added. The EtOAc solution was washed twice with brine, and dried over Na2S(>4. Removal of EtOAc and purification by column chromatography (CH2CI2: MeOH - 10:1) gave ’(lS^R)-N-[3-fluoro4-({6-(methyloxy)-7-[(3-morpholin-4- ylpropyl)oxy]quinoUn-4-yl }oxy)phenyl]-N'-(4-flnorophenyl)-2-methylcycloprppane-l ,1 -dicarboxamide. The product was then dissolved in ethyl ether, and treated with 1.5 equiv. of 1N HCl/ether. Filtration and lyophilizatian gave the HC1 salt of ’(lS,2R)-N-[3-fluoro- 4-( {6-(methyloxy}-7- [(3-morpholin-4-ylpropyl)oxy]quinolin-4'yl }oxy)phenyl]-N,-(4-fluarophenyl)-2-methylcyclopropane-l,l-dicarboxamide: *H NMR (400 MHz, DMSO-de) δ 10.49 (hr s, 1H), 10.26 (br s, 1H), 10.15 (hr s, 1H), 8.74 (br s, 1H), 7.95 (hr d, J= 13.2 Hz, 1H), 7.8-7.5 (m, 6 H), 7.16 (t, J = 8.9 Hz, 2 H), 6.82 (br s, 1H), 4.34 (t, J = 5.9 Hz, 2 H), 4.02 (s, 3 H), 3.99 (br s, 2 H), 3.77 (br t, J = 12.0 Hz, 2 H), 3.56-3.30 (m, 4 H), 3.17- 3.07 (m, 2 H), 2.40-2.30 (m, 2 H), 2.04-1.95 (m, 1H), 1.45 (dd, J = 7.2,4.7 Hz, 1H), 1.36 (dd, J = 8.5,4.5 Hz, 1H), 1.09 (d, J = 6.2 Hz, 3 H). /

Example 82

244 l WO 2005/030140 PCT/US2004/031523 2013204031 11 Apr 2013 [0436] Synthesis of <'!R.2R')-N-r3-fluoro-4-(/6-imethvloxv'l-7-r<'3-morDholin-4-vbronvlloxvl-quinolin-4-vl 1οχν^6ηνΐνΝ'Τ4^1υαΓθΡΐΐ6ηνΙ]-2-ηΐΕΰιν1ονο1οιη:ορΒηΒ-1.1-dicarhnxamidR To a solution of 4-(74jenzyloxy^-methoxy-quinolin-4-yloxy)-3-fLuQro-phenylamine ¢322 mg, 0.82 mmol) and 2-Methyl-cyclopropane-l, 1-dicarboxylic acid methyl ester (195 mg, 1.23 mmol) in CH2CI2 (4 mL) was added HOBt (61 mg, 0.32 mmol) and EDGE (211 mg, 1.64 mmol). The stirring was continued for 12 h at it. The reaction mixture was then diluted with HO Ac and washed with brine. Removal of organic solvents in vacuo and further purification by column chromatography gave the desired coupling product (153 mg).

[0437] The product (153 mg, 0.29 mmol) obtained above was treated with LiOEMfeO (15 mg, 0.35 mmol) in TUP (1 mL) and H2O (1 mL) for 2 h. THF was removed. 10 mL of HaO was added to (he mixture. Hie aqueous solution was washed with ether, and acidified with 1N HC1. The solid was then filtered and dried under vacuum.

[0438] The crude carboxylic acid (118 mg, 0.23 mmol) and 4-fluoroaniline (111 mg, 0.27 mmol) web dissolved in DMF (2 mL). To this solution was added D1EA (178 mg, 1.38 mmol) and PyBOP (358 mg, 0.69 mmol). The mixture was stirred overnight at rt. It was then diluted with EtOAc, washed twice with brine. Removal of EtOAc and column chromatography gave the desired product.

[0439] The product (66 mg, 0.11 mmol) obtained above was dissolved in EtOH (2 mL). 1,4-cyclohexadiene (80 mg, 1,1 mmol) and 10% Pd/C (10 mg) were added. The mixture was stirred for 2 h under reflux. After cooling, the mixture was filtered through Celite, and washed with MeOH. Removal of the solvents gave the crude product (70 mg), which was used in the next reaction.

[0440] To a solution of the 7rhydraxyquinoline (80 mg, 0.15 mmol) in DMF (2 mL) was added 4- (3-chloropropyl)morpholine hydrochloride (62 mg, 0,31 mmol) and K2CO3 (64 mg, 0.46 mmol). The reaction mixture was then stirred at 80 °C for 5 h. After cooling, EtOAc (20 mL) was added. The EtOAc solution was washed twice with brine, and dried aver Na2S04. Removal of EtOAc and purification by column chromatography (CH2CI2 : MeOH = 10:1) gave '(lR,2R>N-[3-fluoro-4-({6-Cmethyloxy)-7-[(3-morpholin-4- ylpropyl)oxy]quinolin-4-yl} oxy)phenyl]-N'-(4-fluorophenyl)-2-methylcyclopropane-1,1-dicarboxamide. The product was then dissolved in ethyl ether, and treated with 1.5 equiv, of 1N HCl/ether. Filtration and lyophilization gave the HC1 salt of '(lR,2R)-N-[3-fl.uoro-4-({6-(metiiyloxy)-7-[(3-morphoHn-4-ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N,-(4~ 245 2013204031 11 Apr 2013 WO 2005/030140 FCT/US2004/031523 fluoiophenyl)-2-methylcyclopropane-l,l-dicarboxamide: Ή NMR (400 MHz, DMSO-ds) δ 10.65 (br s, 1H), 10.54 (br s, 1H), 9.74 (s, 1H), 8.75 (br s, 1H), 8.01 (br d, J -12.9 Hz, 1H), 7.80-7.50 (m, 6 H), 7.20-7.10 (m, 2 H), 6.84 (br s, 1H), 4.34 (br t, J = 5 Hz, 2 HD, 4.04 (s, 3 B), 4.05-3.95 (m, 2 H),' 3.77 (br t,J = 11 Hz, 2 H), 3.52 (br d, J = 12.7 Hz, 4 H), 3.12 (br q, J = 9.0 Hz, 2 H), 2.40-2.30 (m, 2 HO, 2.10-1.95 (m, 1 H), 1.40-1.30 (m, 2 H), 1.10 (d, J=6.2 Hz, 3 H).

Example 83

NaOH, MeOH, HgO 80°C, 5 h

0 0

[0441] Synthesis of Y2R.3R~)-N-r3-fluoro-4-/ (6-fmethvloxvV7-f(3-inorpholin-4- vlpropvl)oxvl-quinolin-4-vlloxv')phenvIl-Nl-('4-fluorophenvl>-2.3-dimflthv1cvcIopropane-1.1-djcarboxamide. 2,3-trans-Dimethyl-cyclopropane-l,l-dicarboxylic acid diethyl ester was prepared by following the literature procedure. (Ohishi, J. Synthesis, 1980,690.) To a solution of 2,3-trans-dimethyl-cyclopropane-l,l-dicarboxyIic acid diethyl ester (6.75 g, · 31.5 mmol) in MeOH (30 mL) was added 33 mL of 1 N NaOH aqueous solution. The mixture was stirred at 85 °C for 5 h. MeOH was removed under reduced pressure; the residue was diluted with 40 mL of H20. The aqueous solution was washed with 20 mL of 246 PCT/US2004/031523 2013204031 11 Apr 2013 WO 2005/030140 ether, and acidified with 1N HC1. Filtration and drying under vacuum gave 4.72 g 80 %) of the desired carboxylic acid.

[0442] The aniline (1.08 g, 2.78 mmol) and the carboxylic acid (518 mg, 2.78 mmol) prepared above were dissolved in GEfeCfe (15 raL). HATU (2.11 g, 5.56 mmol) andDUSA (1.8 mL, 11.1 mmol) were added. The reaction mixture was stirred at rt overnight. It was then concentrated and diluted with EtOAc. The EtOAc solution was then washed with 5% NaOH and brine. Removal of EtOAc gave the crude coupling product, which was hydrolyzed to the corresponding carboxylic acid by treatment with IiOH»H20 (175 mg, 4.17 mmol) in THF (100 mL) -H20 (50 mL) at 60 °C for 10 h.

[0443] The carboxylic acid (850 mg, 1.60 mmol) and 4-fluoroaniline (355 mg, 3.20 mmol) were dissolved in DMF (8 mL). HATU (3.89 g, 3.2 mmol) and DIEA (1.1 ml, 6.4 mmol) were added. The reaction mixture was stirred at rt overnight. HaO (10 mL) was added to the reaction, and a precipitate formed. The solid was filtered, washed with aqueous sat. Na2C03 and ether. Further purification by column chromatography gave 596 mg (60%) of the desired product. Debenzylation was done by following the standard procedure. r [0444] To a solution of the 7-hydroxyquinoIine (261 mg, 0,49 mmol) in DMF (5 mL) was added 4-(3-chloropropyl)marpholine hydrochloride (195 mg, 0.98 mmol) and K2CO3 (202 mg, 1.46 mmol). The reaction mixture was then stirred at 80 °C for 4 h. After cooling, EtOAc (20 mL) was added. The EtOAc solution was washed twice with brine, and dried over Na2S04.. Removal of EtOAc and purification by column chromatography (CH2CI2 : MeOH = 10:1) gave 122 mg (37%) of '(2R,3R)-N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4-ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N,-(4-fluorophenyl)-2,3-dimethyl*· cyclopropane-1, l-dicarboxamide. *HNMR (400 MHz, CDCI3) δ 8.44 (d, J= 5.1 Hz, 1 H), 8.11 (br s, 1H), 7.77-7.70 (m, 2 H), 7.53 (s, 1H), 7.50-7.44 (m, 2 H), 7.40 (s, 1 H), 7.22- 7.16 (m, 2 H), 7.06-6.98 (m, 2 H), 6.36 (br d, J = 5.1 Hz, 1 H), 4.26 (t, J = 7.0 Hz, 2 H), 4.02 (s, 3 H), 3.72 (t, J = 4.4 Hz, 4 H), 2.57 (t, J = 7.3 Hz, 2 H), 2.50-2.42 (m, 4 H), 2.18- 2.10 (m, 2 H), 1.80-1.66 (m, 2 H), 1.304.24 (m, 6 H). 247 PCT/US2004/031523

Example 84

2013204031 11 Apr 2013 WO 2005/030140 [0445] Synthesis of 74-(4-1 r6.7-trisfmfidiv1oxvlqninoifn-4-vlloxv lDhenvlVN'-(4- fluorophenvlVl-fDhenvlmethvl')a2etidine-3.3-riif'.flrhnyannidfi· l-Benzyl-azetidine-3,3-dicarboxylic acid was prepared by following the literature procedure (Miller, R. A.; et al. Syn. Comm. 2003, 33, 3347). To a solution of 4-(6,7-dimethoxy-quinolin-4-yloxy)-phenylamine (4.2 mmol, 1 equiv.) and 4-fluoroaniline (4.2 mmol, 1 equiv.) in DMF (20 mL) was charged with DIEA (12.6 mmol, 3 equiv.) and a solution of l-benzyl-azetidine- 3,3-dicarboxylic add ( 4.2 mmol, 1 equiv.) in DMF (10 mL). The reaction mixture was allowed to stir at RT and monitored by LCMS. The reaction was complete in. 6 h. The reaction mixture was diluted with ethyl acetate and washed with 10% LiCl (3x), brine (3x), dried with sodium sulfate, filtered and the solvent Was reduced in vacuo. The crude product was purified by silica gel chromatography eluting with 2% of MeOH in EtOAc. The fractions containing the desired product were further purified using preparative HPLC to give lN-(4-{[6,7-bis(nKthyloxy)quinolm-4-yl]oxy}phenyl)-N,-(4-fluorophenyl)-l-(phenylmethyl)azetidine-33-dicart)oxamide (300 mg, 12% yield) as a white solid. 1HNMR (DMSO-d6): 10.0 (s, 1H), 9.90 (s, 1H), 8.45 (d, 1H), 7.80 (d, 2H), 7.70 (m, 2H), 7.50 (s, ffl), 7.40 (s, 1H), 7.48-7.15 (m, 9H), 3.95 (s, 6H), 3.70 (s, 4H), 3.60 (s, 2H). LCMS (POS): 607.2 (M+H).

[0446] N-(4-{[6,7-bis(inethyloxy)qainoIin-4-yI]oxy}phenyl)-N'-(4-fluoiqphenyl) azetidine-3,3-dicarboxamide. To a solution of TSi-(4-{ [6,7-bis(methyIoxy)quinolin-4-yl]oxy}phenyl)-N,-(4-fluorophenyl)-l-(phenylmethyl)a2etidme-3,3-dicarboxainide (300 mg, 0.5 mmol) in MeOH (50 mL) was charged with Pd/C (50% wet, 10% mmol, 265 mg) and acetic acid (2 mL). The reaction mixture was subjected to hydrogenolysis condition under H2 (50 psi) on a Parr Hydrogenator for 16 hr. The reaction mixture was filtered through celite and washed with MeOH, After removal of solvent in vacuo, the crude product was purified using preparative HPLC (solvent system: MeCN/H20/NH4OAc), affording N-(4-{ [6,7-bis(inethyloxy)quinolm-4-yl]oxy}phenyl)-N'-(4-fluorophenyl) 248 PCT/US2004/031523 2013204031 11 Apr 2013 WO 2005/030140 az»tidine-3,3-dicarboxamide (82 mg, 32% yield) as a white solid ’HNMR (DMSO-d6): 8.46 (d, 1H), 7.84 (d, 28), 7.70 (m, 28), 7.50 (s, 1H), 7.40 (s, 1H), 7.24 (d, 28), 7.20 (t, 28), 6.44 (d, 1H), 4.03 (s, 48), 3.95 (s, 6H), 1.90 (s, 3H, acetate salt). LCMS (POS): 517.3 (M+H).

Example 85

[0447] N-f 3-fluorp-4-r(6-(inethvloxv)-7-f rfl-methv1piperidin-4-vllmjedi-v41oxvloiiiaoli]i-4-vl')oxvlphenvll-N,-(,4-fluoroDhenvl)cvclopropaiie-l.i-dir.arhnxaTntda· To a solution of cyclopropane-1, l-dicarboxylic acid {3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl }-amide (4-fluoro-phenyl)-aiiiide, TFA salt (~500 mg, 0.71 mmol) in ClCH^Cl (8 mL) were added 30% formaldehyde (4 mL) and NaBH(OAc)3

I (752 mg, 3.55 mmol). The reaction mixture was stirred overnight It was then quenched with aqueous sat NaHC03, extracted with EtOAc. The organic phase was washed with brine and dried over NazSO^. Drying salts were filtered, washed with EtOAc and the filtrate concentrated in vacuo to give 21Qmgs of crude product. The resulting residue was redissolved in EtOAc and any insoluble material filtered. To the filtrate was added 4M HC1 in dioxane (200μΙ) and the mixture was stirred at room temperature for 1 hour. Solids were filtered, washed with EtOAc, dried under high vacuum, dissolved in 50% aqueous AcCN and lyophilized to give 'N-{3-fluQro-4-[(6-(methyloxy)-7-{[(l-methylpiperidin-4-yl)methyl]oxy}quinolin-4-yl)oxy]phenyl}-Nl-(4-fluorophenyI)cyclopropane-l,l-dicarhox-amide, HC1 salt (113 mg, -25% yield). 1HNMR (400MHz, DMSO-d6): δ 10.51 (s, 1H), 10.30 (hr. s, 1H), 10.04 (s, 1H), 8.80 (d, 1H), 7.99 (dd, 1H), 7.55 (m, 28), 7.67-7.53 (m, 4H), 7.16 (t, 28), 6.89 (d, 1H), 4.13 (d, 28), 4.05 (s, 38), 3.47 (m, 28), 3.00 (m, 28), 2.74 (d, 38), 2.17 (m, 1H), 2.03 (m, 28), 1.68 (m, 28), 1.49 (m, 4H). LC/MS Calcd for [M+Hf 617.3, found 617.4. Anal. HPLC (8 min gradient): 98% pure, 3.11 min. 249 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523

Example 86

F

[0448] (lR.2R.3S)-N-(4-i Γ7-Ι r2-fdiethvlammo)ethvlloxYl-6-/methvloxv)auinolin-4- vll oxv I -3 -fluoroohen vlV-N’-f4-fluoroDhenvlV2.3 -dimethvIcvcloproDan&amp;-1.1-dinarhnxamirie- 2,3-Dimethyl-cyclopropane-1,1 -dicarboxylic acid [3-fluoro-4-(7-hydroxy- 6-methoxy-quinolin-4-yloxy)-phEnyl]-ainide (4-fluoro-phenyl)-amide (210 mg, 0.39mmol), DMA (2mls), (2-chloro-ethyl)-diethyl-amine, HQ salt (73 mg, 0.42mmol) and KZC03 (136 mg,. 0.98mmol) were combined and heated at 80C overnight. The reaction mixture was then diluted with H^O and sonicated. The resulting solids were filtered, washed with HjjO and dried under high vacuum. Hie crude product was then purified by preparative HPLC using an ammonium acetate buffer system and lyophilized to give '(lR,2R,3S)-N-(4-{[7-{[2-(diethylamino)ethyl]oxyJ-6-(tnethyloxy)qumolin-4-yl]oxy}-3' fluorophenyl)-N'-{4-fluorophenyl)-2,3-dimethylcyclopropane-l,1-dicarboxamide (39 mg, 16% yield). 1HNMR (400MHz, DMSO-d6): δ 10.14 (s, 1H), 9.61 (s, 1H), 8.46 (d, 1H), 7.87 (dd, 1H), 7.67 (m, 2H), 7.57 (m, 1H), 7.51 (s, 1H), 7.42 (s, 1H), 7.39 (m, 11¾. 7.15 (t, 2H), 6.41 (d, 1H), 4.20 (m, 233), 3.94 (s, 3H), 2.87 (m, 233), 2.60 (m, 4H), 1.80 (m, 2H),

1.18 (s, 3H), 1.17 (s, 3H), 1.01 (m, 6H). Note: 0.5eq of AcOH is present by NMR. · LC/MS Calcd for [MfHJ+ 633.3, found 633.4. Anal. HPLC (25 min gradient): 96% pure, I 18.52 min.

Example 87

HCI 250 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523 [0449] Ν-(4-ίΓ7-ί r2-(diethvIamTiMWhvnQxv}..6-<methvloxvlQuinazolin-4-vrioxv}-3- fluQrnoheavlVN,-r4-fluorQDhenvlV2.2-dfmp.thvlcvclopropaDe-l.l-flirjiitinyaTnide- 2,2-Dimethyl-cyclopropane-1,1 -dicarboxylic acid [3-fluoro-4-(7-hydroxy-6-methoxy- qumazolin-4-ylQxy)-phenyl]-amide (4-fluoro-phenyl)-amide (203 mg, O.38mmol), DMA (2mls), (2-chloro-ethyl)-diethyl-ainine, HO salt (73 mg, 0.42mmol) and K2CO3 (146 mg, l.OSmmol) were combined and heated at 80C overnight. The reaction mixture was then diluted with H2O and extracted with CH2CI2 (3x). The combined CH2CI2 extractions were washed with sat’d NaHCCb (lxX sat’d NaCl (lx), dried (Na2S04), and concentrated in vacuo. The resulting crude product was purified by flash chromatograghy (Silica Gel 60, 100% EtOAc, followed by 10% MeOH, 1% triethylamine in EtOAc), then dissolved in 50% aqueous AcCN and Iyophilized to give 7^-(4-^7-( [2-(diethylamino)ethyl]oxy}-6-(xnethyIoxy)quinazolin-4-yl]oxy}-3-flu0rophenyl)-N,-(4“fluorophenyI)-2,2-dimethyl-cyclopropane-1, l-dcarboxamide (70 mg, 29% yield). ‘HNMR (400MHz, DMSO): δ 10.24 (s, 1H>, 10.00 (s, 1H), 8.54 (s, 1H), 7.84 (dd, 1H), 7.66 (m, 2H), 7.56 (s, 1H), 7.51 (m, 1H), 7.43 (m, 2H), 7.18 (t, 2H), 4.26 (m, 2H), 3.98 (s, 3H), 2.88 (m, 2H), 2.59 (m, 4H), 1.58 (m, 2H), 1.18 (s, 6H), 1.00 (t, 6H). LCZMS Calcd for [M+Hf 634.3, found 634.4. Anal. HPLC (25 min gradient): 94% pure, 24.08 min.

Example 88 o2n

nh2 \ [0450] Synthesis of lN-r3-(annnomethvllphenvll-Nl-f4-ifSJ-bisfmethvloxvlauinoiin-^ vlloxv ]phenvDc vclopronane-1.1-dicarboxamide. (4-Nitro-benzyl)-carbamic acid tert-butyl ' ester. 4-Nitro-benzyIamine, HC1 salt (5.19g, 27.5mmol) was dissolved in dioxane j (lOGmls). NaOH (3.4g, 85.0mmol) in H2O (20mls) was added, followed by Boc 251 WO 2005/030140 PCT/US2004/031523 2013204031 11 Apr 2013 anhydride (7.6g, 34.8mmol). The mixture was stirred at room temperature. After 3hrs, the reaction mixture was diluted with EtOAc and washed with H2O (3x), sat’d Nad (lx), dried (Na2S04), and concentrated in vacuo. The resulting residue was triturated with hexanes, the resulting solids filtered, washed with hexanes and dried under vacuum to give (4-nitro-benzyI)-carbamic acid tert-butyl ester (6.34g, 91% yield). LC/MS Calcd for [M+Hj+ 253.1, found 197.0 (minus t-butyl).

[0451] (4-Amino-benzyl)-carbamic acid tert-butyl ester. (4-Nitro-benzyl>carbamic add tert-butyl ester (6.34g, 25.1mmol), iron powder (6.5g, Ιΐβτητηοΐ), ammonium formate (13.Og, 206mmol), H2O (75mls), and toluene (75mls) were combined and heated to reflux. After 3hrs the reaction mixture was allowed to cool and filtered through Celite with thorough washing with EtOAc. The filtrate was transferred to a separatory funnel and the phases separated. The organic phase was further washed with H2O (lx), sat’d NaCl (lx), dried (Na2S04), and concentrated in vacuo to give (4-amino-benzyl)-carbamic acid tert-butyl ester (5.02g, 90% yield). LC/MS Calcd for [M+H|+ 223.1, found 167.1 (minus t-butyl).

[0452] [3-({ 1 -[4-(6,7 -Diraethoxy-quinoKn-4-y!oxy)-phenylcarbamoyl]-cycloprepane-carbonyl}-amino)-benzyl]-carbamic add tert-butyl ester. l-[4-(6,7-Dimetfaoxy-quinolin~ 4-yloxy)-phenylcarbamoyl]-cyclopropanecaiboxylic acid (254 mg, 0.62mmol), (4-amino-benzyl)-carbamic acid tert-butyl ester (164 mg, 0.74mmol), dry DMA (lOmls), HATU (714 mg, 1.88mmol), and D1EA (325ml, 1.86mmol) were combined and stirred at room temperature. After 2hrs, the reaction mixture is diluted with H20 and the resulting solids are filtered, washed with H2O, followed by sat’d NaHC03, and dried under high vacuum to give erode [3-({ l-[4-(6,7-dimethoxy-quinolin-4-yloxy)-phenylcarbamoyl]-cyclopropanecarbonyI}-amino)-benzyl]-carbamic acid tert-butyl ester (301 mg, 79% yield) which was used in the next reaction without further purification. LC/MS Calcd for [Μ+ΗΓ 613.3, found 613.1.

[0453] N-[3-(Aminomethyl)phenyl]-N'-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl) cyclopropane-1,1-dicaiboxamide, TFA salt. [3-({ l-[4-(6,7-Ilimethoxy^quinoIin-4- yloxy)-phenylcarbamoyI]-cyclopropanecari)onyl}-ainino)-benzyl]-carbamic acid tert-butyl ester (50 mg, 0.081mmol) was dissolved in 50% TFA in CH2CI2 (lOmls) and stirred at room temperature. After 2hrs, the reaction mixture was concentrated in vacuo and the resulting residue was triturated with EtaO. The resulting solids were filtered, washed with Et20 and dried under high vacuum to give 'N-[3-(aminomethyl)phenyl]-N'-(4-{[6,7- 252 FCT/US2004/031523 2013204031 11 Apr 2013 WO 2005/030140 bis(methyloxy)quinolin-4-yl]oxy}phenyl)cydopiopme-l,l-dicarbaxamide as the TFA salt (54 mg, 100%). 1HNMR (400MHz, DMS0-d6): δ 10.28 (s, 1H), 10.19 (s, 1H), 8.77 (m, 1H), 8.21 (m, 3H), 7.84 (m, 2H), 7.76 (m, 1Ή), 7.71 (m, 1H), 7.58 (m, 2H), 7.38 (m, 3H), 7.19 (m, 1H), 6.76 (m, 1H), 4.03 (s, 6H), 3.39 (m, 2H), 1.53 (m, 4H). Note: all peaks are very broad and unresolved. LC/MS Calcd for [Μ+ΗΓ 513.2, found 513.4. Anal. HPLC (25 min gradient): 88% pure, 12.39 min.

[0454] Table 3 contains !H-NMR data for selected compounds of the invention.

Table 3

Entry Name ‘H-NMR 1 N-[3-fluoro-4-({ 6-(methyloxy)-7-[(3-piperazin-l-ylpropyl)oxy]quinolin-4-yl }oxy)phenyl) -N'-(4-fluarophenyl)cyclapropane-l, 1-dicarboxamide 1HNMR (DMSO-d6): 10.52 (s, 1H), 10.02 (s, 1H), 9.38 (br., 3H), 8.79 (d, IB), 7.98 (dd, 1H), 7.74 (s, 1H), 7.65 (m, 3H), 7.54 (m, 2H), 7.15 (t, 2H), 6.86 (d, 1H), 4.33 (t, 2B), 4.04 (s, 3H), 3.17-3.50 (m, 9H), 2.27 (br., 2H), 1.79 (m, IB), 1.48 (m, 4H). Note: The peak at 59.38 includes 2 TFA equivalents. 2 N-{3-fluoro-4-[(6-(methyloxy)-7-{ [3-(4-methylpiperazin-l-yl)propyl] oxy }quinolin-4-yl)oxy]phenyl }-N-(4-fluorophenyl)cyclopropane-l, 1-dicarboxamide 1HNMR (DMSO-d6): 10.41 (s, 1H), 10.03 (s, 1H), 8.47 (d, 1H), 7.90 (dd, 1H), 7.64 (m, 2H), 7.52 (s, 2H), 7.42 (t, 1H), 7.39 (s, 1H), 7.16 (t, 2H), 6.41 (d, 1H), 4.18 (t, 2H), 3.95 (s, 3B), 2.47 (t, 2H), 2.6-2.8 (br., 8H), 2.17 (s, 3H), 1.97 (m,2H), 1.48 (s,4H). 3 N-{3-fluoro-4-[(6-(methyloxy)-7-{ [(l-methylpiperidin-4-yl)methyl]oxy}quincilin-4-yl)oxy]phenyl }-N'-(4-fluoiophenyl)cyclopropane-l,l-dicarboxamide 1HNMR (400MHz, DMSO-d6): d 10.51 (s, 1H), 10.30 (br. s, 1Ή), 10.04 (s, 1H), 8.80 (d, 1H), 7.99 (dd, 1H), 7.55 (m, ZH), 7.67-7.53 (m, 4H), 7.16 (t, 2B), 6.89 (d, IB), 4.13 (d, 2H), 4.05 (s, 3H), 3.47 (m, 2H), 3.00 (m, 2H), 2.74 (d, 3H), 2.17 (m, 1H), 2.03 (m, 2H), 1.68 (m, 2H), 1.49 (m, 4H). 4 N-(4-fluorophenyl)-N'-[4-({ 6-(methyloxy)-7-[(3-morpholin-4-ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]cyc]opropane-1,1-dicaxboxamide !H NMR (400 MHz, DMSO-d6): 8.47 (d, 1H), 8.30 (m, 1H), 8.15 (m, 1H), 7.8 (m, 2H), 7.62 (s, 1H), 7.45 (m, 2H), 7.2 (m, 3B), 7.10 (m, 2H), 6.7 (d, 1H), 4.5 (in, 2H), 4.3 (m, 2H), 4.01(s, 3H), 3.5 (hr, 2H), 3.3 (m, ZH), 3.1 (m, 2H), 2.51 (m, 2H), 1.9 (m, 2H) 1.6 (m, 4H). 5 N-(4-{[7-{[3- (diethylamino)pn>pyi]oxy}-6-(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N'-(4-fluorophenyl)cyclopropane~l, 1 - ' dicarboxamide i ‘HNMR (400 MHz, DMSO-d6): 10.58 (s, 1H), 10.31 (bs, 1H), 10.04 (s, 1H), 8.75 (d, 1H), 7.99 (d, 1H), 7.74 (s, 1H), 7.63 (m, 4H), 7.19 ;t, 2H), 6.91 (m, 1H), 4.39 (t, 2H), 4.19 (s, 3H), J.21 (m, 7H), 2.29 (m, 2H), 1.46 (d, 4H), 1.15 t,6H). 253 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523

Table 3 Entry Name *H-NMR 6 N-(4~{[6,7- bis(methyloxy)qumolin-4-yl]oxy}-2-chloro-5-fluorophen)d)-N,-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 1H NMR (DMSO-d6): 11.56 (s, 1H), 9.77 (s, 1H), 8.50 (d, 1H), 8.32 (d, 1H), 7.82 (d, 1H), 7.59 (m, 2H), 7.51 (s, 1H), 7.42 (s, 1H), 7.20 (t, 2H), 6.55 (d, 1H), 3.95 (s, 3H), 3.94 (s, 3H), 1.73 (m,2H),‘3.65 (m,2H). 7 N-(4-{ [6,7-bis(methyloxy)-2-(methyltMo)quinolin-4-yl}oxy}-3-flnatophenyl)-N-(4-flnorophjenyl)cyclopropane-l, 1-dicatboxamide 1H NMR (DMSO-dff) d 10.34 (s, IB), 9.94 (s, 1H), 7.83 (d, ffi), 7.59 (m, 2H), 7.56 (m, 1H), 7.40 (m, 2H), 7.23 (s, 1H), 7.09 (t, 2H), 6.12 (s, 1H), 3.88 (s, 3H), 3.85 (s, 3H), 2.48 (s, 3H), 1.40 (m, 4H). 8 N-(4-fluorophenyl)-lSr-(4- {[2-methyl-6,7- bis(methyloxy)quinazolm-4- yl]oxy}phenyl)cyclopiopane- 1,1-dicarboxaniide ^NMR (DMSO-de) 10.15 (bs, 1H), 10.01 (bs, 1H), 7.69-7.75 (m, 2H), 7.61-7.68 (m, 2H), 7.52 (s, 1H), 7.32 (s, 1H), 7.23-7.29 (m, 2H), 7.12-7.19 (m, 2H), 3.93 (d, 6H), 2.43 (s, 3H), 1.53 (s,4H). 9 N-(4-{ [2-araino-6,7-bis (methyloxy)quinolin-4-yl]oxy} -3-fluorophenyl)-N1-(4-fluorophenyl)cydopropane-l,l-dicarboxamide 1H NMR (DMSO-d6) d 1034 (s, 1H), 9.95 (s, 1H), 7.82 (d, IB), 7.58 (m, 2H), 7.44 (d, 1E0, 7.33 (t, 1H), 7.25 (s, 1H), 7.09 (t, 2H), 7.07 (s, 1H), 6.17 (br s, 2H), 5.66 (s, 1H), 3.79 (s, 3H), 3.77 (s,3H), 1.40 (d,4H). 10 N-(3-fluoro-4-{ [2-(methylamino)-6,7-bis(methyloxy)quinolin-4-yl]oxy}phenylJ-N'-(4-fluorophenyl)cyclopiopane-1,1-dicarboxamide ‘HNMR (DMSO-dff) d 10.42 (s, 1H), 9.91 (s, 1H), 7.88 (dd, 1H), 7.56 (m, 2H), 7.44 (m, 4H), 7.09 (t, 2H), 5.90 (s, 1H), 3.88 (s, 3H), 3.85 (s, 3H), 3.39 (br s, 1H), 2.92 (s, 3H), 1.41 (dt, 4H). 11 (lS,2R>N-[3-fluoro-4-({6-(methyloxy)-7-[(3-maipholiii-4-! ylpropyl)oxy3quinolin-4-yl }oxy)phenyl]-N'-(4- ! fluorophenyl)-2- [ methylcyclopropane-1,1- ; dicarboxamide Ϊ lHNMR (400 MHz, DMSO-dg) d 10.49 (br s, 1H), 10.26 (br s, 1H), 10.15 (br s, 1H), 8.74 [br s, 1H), 7.95 (brd, J= 13.2 Hz, 1H), 7.8-7.5 (m, 6 H), 7.16 (t, J = 8.9 Hz, 2 H), 6.82 (br i, 1H), 4.34 (t, J = 5.9 Hz, 2 H), 4.02 (s, 3 H), i.99 (br s, 2 B), 3.77 (br t, J = 12.0 Hz, 2 H), i.56-3.30 (m, 4H), 3.17-3.07 (m, 2 H), 2.40-1.30 (m, 2 H), 2.04-1.95 (m, 1H), 1.45 (dd, 3 = 12,4.7 Hz, 1H), 1.36 (dd, J = 8.5,4.5 Hz, 1 1), 1.09 (d, J = 6.2 Hz, 3 H). 254 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523

Table 3 Entrj Name *H-NMR 12 (lR,2R)-N-[3-fluoro-4-({6-(methyIoxy)-7-[(3-morpholin-4 ylpropyl)oxy]quinoliri-4-yl }oxy)phenyl]-N'-(4-fluorophenyl)-2-methylcyclopiopane-1,1-dicarboxamide XH NMR (400 MHz, DMSO-dfi) d 10.65 (hr s, 1H), 10.54 (br s, 1H), 9.74 (s, 1H), 8.75 (hr s, - 1H), 8.01 (br d, J = 12.9 Hz, 1H), 7.80-7.50 (m, 6 H), 7.20-7.10 (m, 2 H), 6.84 (br s, 1H), 4.34 (br t, J = 5 Hz, 2 H), 4.04 (s, 3 H), 4.05-3.95 (m, 2 H), 3.77 (br t,J = 11 Hz, 2 H), 3.52 (br d, J = 12.7 Hz, 4 H), 3.12 (br q, J=9.0 Hz, 2 H), 2.40-2.30 (m, 2 H),2.10-1.95 (m, 1H), 1.40-1.30 (m, 2 H), 1.10 (d,J = 6.2 Hz, 3 H). 13 N-(4-{[6-{[3- (diethylainino)propyl]oxy}-7- (methyloxy)quinolin-4-yl]oxy}- 3-fluorophenyl)-N'-(4- fluorophenyl)cyclopropane-l,l- dicarboxamide XH NMR (DMSO-ie) d 10.37 (hr s, 1H), 10.00 (s, 1H), 8.44 (d, 1H), 7.87 (d, 1H), 7.62 (m, 2H), 7.49 (m, 2H), 7.41 (m, 2H), 7.13 (t, 2H), 6.40 (d, 1H), 4.17 (t, 2H), 3.93 (s, 3H), 2.59 (t, 2H), 2.49 (m, 6H), 1.91 (m, 4H), 0.94 (t, 6H). 14 N-(4-{ [6- {[2- (diethylamino)ethyl]oxy }-7-(methyIoxy)qwnolm-4-yl]oxy} -3-fluarophenyl)-N-(4-fluorophenyl)cyclopropane-l, 1-dicarboxamide XH NMR QOMSO-dg) d 10.36 (br s, 1H), 9.99 (s, 1H), 8.44 (d, 1H), 7.88 (dd, 1H), 7.62 (m, 2H), 7.57 (m, 2H), 7.41 (m, 2H), 7.13 (t, 2H), 6.40 (d, 1H), 4.17 (t, 2H), 3.93 (s, 3H), 2.85 (t, 2H), 2.56 (q, 4H), 2.49 (m, 4H), 0.98 (t, 6H). 15 1,1-dimethylethyl 4-(3-( [4-[(2-fluαro-4-{[(l-{[(4-fluorophenyl)aimno]carbonyl}c yclopropyl)carbonyl]aimno}phe nyl)oxy]-6- (methyloxy)quinolin-7-yl] oxy }propyl)piperazine-l-carboxylate XH NMR (400 MHz, CDC13): 10.05 (s, 1H), 8.49-8.27 (t, 1H), 7.79-7.76 (d, 1H), 7.57 (s, 1H), 7.47-7.43 (m, 3H), 7.27-7.20 (m, 1H), 7.09-7.04 (m, 2H), 6.40-6.39 (d, 1H), 4.28-4.25 (t, 2H), 3.50 (s, 3H), 3.47-3.44, (t, 4H), 2.62-2.59 (t, 2H), 2.46-2.44 (t, 4H), 2.18-2.11 (m, 2H), 2.09 (s, 1H), 1.83-1.81 (t, 2H), 1.64-1.61 (t,2H), 1.47 (s,9H). 16 (lR,2R)-N-[3-fluoro-4-({ 6-(methyloxy)-7-[(3-morpho]in-4-ylpropyl)oxy]quiiiazo]in-4-yl }oxy)phenyl]“N,-(4-fluorophenyl)-2-methylcyclopropane-1,1- ' dicarboxamide ‘HNMR (DMSO-dtf) d 10.40 (s, 1H), 9.65 (s, IH), 8.45 (s, 1H), 7.79 (dd, 1H), 7.53 (m, 2H), 7.47 (s, 1H), 7.36 (m, 1H), 7.31 (m, 2H), 7.05 [t, 2H), 4.17 (t, 2H), 3.91 (s, 3H), 3.51 (t, 4H), Ϊ.40 (t, 2H), 2.36 (m, 4H), 1.90 (m, 3H), 1.30 [m, 2H), 1.02 (d, 3B). 17 (lR,2R)-N-(4-{ [7-((2-(diefhylamlno)ethyl]axy}-6- . (methylaxy)quinazolin-4-yl]oxy} -3-fluorophenyl)-N’-(4- , fluorophenyl)-2- ' methylcyclopropane-1,1- . dicarboxamide 1 H NMR (DMSO-d6) d 10.49 (s, 1H), 9.73 (s, .H), 8.52 (s, 1H), 7.85 (dd, 1H), 7.61 (m, 2H), r.54 (s, 1H), 7.41 (m, 3H), 7.12 (t, 2H), 7.23 (t, iH), 3.96 (s, 3H), 2.86 (t, 2H), 2.56 (q, 4H), .98 (m, IH), 1.34 (m, 2H), 1.07 (d, 3H), 0.97 t, 6H). 255 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523

Table 3 Entrj Name ^-NMR 18 /a- tu , [3' , Λ 1H NMR (DMSO-d6) 8.51 (s, 1H), 7.78-7.84 (cbeihylaimno)propyl]Qxy}-6- L 1H) 7.58.7,54 (mj 2H), 7.53 (s, 1H), 7.34- dicarboxamide 1-39(1,6¾. 19 PH NMR (400 MHz, CDC13): 10.04 (s, 1H), N-(4-{ [7-{ [3-(4-acetylpiperazin-l8.48-8.47 (d, 1H), 8.21 (s, 1H), 7.79-7.76 (d, l-yl)propyl]oxy}-6- 1H), 7.57 (s, 1H), 7.52-7.44 (m, 3H), 7.28-7.20 (methyloxy)qamolin-4~yljcKy}- j(m, 2H), 7.09-7.05 (t, 2H), 6.40-6.39 (d, 1H), 3-fluorophenyD-N'-(4- 14.30-4.26 (t, 2H), 4.04 (s, 3H), 3.64-3.62 (t, fluorophenyl)cyclopropane-l,l- [2¾. 3.49-3.47 (t, 2H), 2.62-2.58 (t, 2H), 2.50-dicaiboxamide 12.44 (m, 4H), 2.17-2.12 (m, 2H), 2.10 (s, 3H), 1.84-1.81 (t, 2H), 1.64-1.61 (t, 2H). 20 rHNMR W-54(S, 1H), ftoOT^-{ (C1^2R)-HK^ Ln( 1H) 8.4,.8.46 (d. 1H),7,96-7.« (dd, fluorophenyl)ommo]carbonyl}. ^ (m_ 2H)> ,S2 jj,^ , ^ A . . * . n 7.40 (d, 2H), 7.17-7.12 (t, 2H), 6.44-6.42 (d, methylcyclopropyl)carbonyl]am 1422.4,18 (t, 2H), 3.95 (s, 3H), 3.42-140 L 2H), 2.36-2.26 (m, 8H), 2.00-1.98 (m, 3H), b* <m· **140 ®>· u°·109 catbaxylate 21 N-(4-{[6,7- bis(methyloxy)quinolin-4- IlHNMR (DMSO-d6): 10.0 (s, 1H), 9.9 (s, yl]oxy}phenyl)-N’-(4- 1H), 8.45 (d, 1¾. 7.8 (d, 2H), 7.7 (m, 2H), 7.5 fluorophenyl)-l- (s, III), 7.4 (s, 1H), 7.48-7.15 (m, 9H), 3.95 (s, (phenylnKthyl)azetxdiiie-3,3- 6H), 3.7 (s, 4H), 3.6 (s, 2H). dicarboxamide j 22 .,, 1- „ IlHNMR (DMSO-d6): 8.46(d, 1H),7.84(d, K 7·70 «“ «>7'50 <s- “*>·1M (“ “Ο· ftSSStoSl· 7.24 (d, 213), 7.20 ft 2H), 644 (d, 113),4.03(¾ ^), 3.95 (¾ 6H), 1.90 (a, 3H, acetate sah). 23 (lR,2S)-N-{3-fiuoio-4-[(6-(methyloxy)-7-{ [3-(4-methylpiperazin-1 -yl)propyl]oxy}quinolin-4-yl)oxy3phenyl}-N'-(4-fluorophenyl)-2-methylcyclopropane-1,1-dicarboxamide PH NMR (400 MHz, DMSO-ife): 10.26 (s, 1H), 9.75 (s, 1H), 8.47-8,46 (d, 1H), 7.91-7.87 (dd, ! 1H), 7.70-7.66 (m, 2H), 7.56-7.51 (m, 2H), 7.43-7.38 (m, 2H), 6.42-6.41 (d, 1H), 4.20-4.16 (t, 2H), 3.95 (s, 3H), 2.47-2.43 (m, 2Ή), 2.40-2.24 (m, 5H), 2.14 (s, 3H), 2.03-1.93 (m, 3H), 1.89 (s, 3H), 1.45-1.42 (m, 1H), 1.38-1.35 (m, 1H), 1.10-1.08 (d,3H). 256 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523

Table 3 En.tr;) τ Name JH-NMR 24 (lR,2R)-N-{3-fluoro-4-[(6-(methyloxy)-7-{ [3-(4-methylpiperazin-l-yl)propyl]oxy}quinolin-4-y])oxy]phenyl}-N'-(4-fluorophenyl)-2-methylcyclop!ropane-l,l-dicarboxamide *HNMR (400 MHs, DMSO-4f): 10.56 (s, IB), 9.75 (s, 1H), 8.47-8.46 (d, 1H), 7.96-7.93 (d, 1H), 7.68-7.61 (m, 2H), 7.53-7.52 (m, 2B), 7.44-7.39 (m, 2H), 7.18-7.12 (m, 2H), 6.44-6.42 (d, IB), 4.20-4.17 (t, ZH), 3.95 (s, 3H), 3.42-3.30 (m, 3H), 2.46-2.44 (m, 2H), 2.33 (br s, ZH), 2.15 (s, 3H), 2.05-1.94 (m, 2H), 1.89 (s, 5H), 1.40-135 (m, 1H), 1.10-1.09 (m, 3H). 25 (lR,2R)-N-[3-fluoro-4-({6-(methyloxy)-7-[(3-piperazin-l-ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N'-(4-fluorophenyl)-2-methylcydopropane-1,1-dicarbaxamide ]HNMR (400 MHz, DMSO-dfc): 10.55 (s, 1H), 9.72 (s, 1H), 8.47-8.46 (d, 1H), 7.96-7.93 (d, 1H), 7.68-7.61 (m, 2H), 7.52 (br s, 2H), 7.44-7.40 (m, 2H), 7.17-7.12 (m, 2H), 6.44-6.43 (d, 1H), 4.21-4.18 (t, 2H), 3.95 (s, 3H), 2.79 (br s, 4H), 2.47-2.44 (t, 2H), 2.38 (brs, 3H), 2.04-1.95 (m, 3H), 1.40-1.35 (m, 2H), 1.11-1.09 (m, 5H). 26 N-(3-fluaro-4-{ [7-({3-[4-(l-methylethyl)piperazin-l-yl]propyl}oxy>6-(methyloxy)qmnoIin-4-yl]oxy}phenyl)-N-(4-fluorophenyl)cyclopropane-l, 1-dicarboxamide :HNMR (400 MHz, DMSO-ife): 10.40 (s, 1H), 10.02 (s, 1H), 8.47-8,46 (d, 1H), 7.92-7.89 (d, 1H), 7.66-7.63 (m, 2H), 7.52-7.51 (d, 2H), 7.44-7.39 (m, 2H), 7.19-7.14 (m, 2H), 6.42-6.41 (d, 1H), 4.20-4.17 (t, 2H), 3.95 (s, 3B), 2.70-2.68 (m, 1H), 2.62-2.55 (m, 2H), 2.46-2.33 (m, 8H), 1.99-1.94 (m, 2H), 1.47 (s, 4H), 1.00-0.95 (m,6H). 27 N-(4-{[7-{[3- (diethyIamiiio)propyl]oxy}-6-(methyloxy)quinazo]in-4-yl]oxy} -3-fluoropheny])-N'- (4-fluorophenyl)cyclopiopane-l,l-dicarboxamide XH NMR (DMSO-d6)10.34 (s, 1H), 10.01 (s, 1H), 8.50 (s, 1H), 7.81 (dd, 1H), 7.55-7.68 (m, 2H), 7.51-7.55 (m, 2H), 7.33-7.48 (in, 3H), 7.12 (t, 2H), 4.22 (t, 2H), 3.94 (s, 3H), 2.52-2.61 (m, 2H), 2.49-2.51 (m, 4H), 1.83-1.94 (m, 2H), 1.42 (s,4H), 0.95 (t,6H). 28 (lR,2R)-N-(4-{ [7-{ [3-(diethylamino)propyl]oxy}-6-(mefliyloxy)quinoliii-4-yl]oxy}-3-fluorophenyl)-N'-(4-fluarophenyl)-2- 1 meihylcyclapropane-l,l- ‘ dicarboxamide lHNMR (DMSO-dff) d 10.52 (s, 1H), 9.70 (s, 1H), 8.44 (d, 1H), 7.92 (dd, 1H), 7.61 (m, 2H), 7.50 (m, 2H), 7.43 (m, 2H), 7.12 (t, 2H), 6.41 [d, IB), 4.17 (t, 2H), 3.93 (s, 3H), 2.55 (m, ΪΗ), 2.31 (m, 4H), 1.98 (m, 1H), 1.88 (m, 2H), L.35 (m, 2H), 1.07 (d, 3H), 0.94 (t, 6H). 29 (lR,2R)-N-(4-{ [7-{[2- , (diethylamino)ethyl]oxy}-6- 1 methyloxy)guinolin-4-yl]oxy}- „ 3-fluorophenyl)-N-(4- -fluorophenyl)-2- ) methylcycloprqjane-1,1- . dicarboxamide ^ HNMR (DMSO-di) d 10.52 (s, 1H), 9.70 (s, H), 8.44 (d, 1H), 7.78 (dd, 1H), 7.61 (m, 2H), .51 (m, 2H), 7.41 (m, 2H), 7.12 (t, 2H), 6.41 d, 1H), 4.17 (t, 2H), 3.93 (s, 3H), 2.85 (t, 2H), ,.57 (q, 4H), 1.98 (m, 1H), 1.34 (m, 2H), 1.07 d,3H),0.98(t,6H). 257 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523

Table 3 Entry Name ‘H-NMR 30 (lR,2S)-N-(4-{ [7-{ [3-(diethylamino)propyl]oxy}-6-(methylaxy)quinoIin-4-yl]oxy} 3-fiuoroph0nyl)-N'-(4-fluorophenyl)-2-methylcyclopropane-1,1-dicarboxamide ‘HNMR (DMSO-de) d 10.17 (s, 1H), 9.97 (s, 1H), 8.39 (d, 1H), 7.80 (dd, 1H), 7.62 (m, 2H), 7.45 (m, 2H), 7.31 (m, 2H), 7.09 (t, 2H), 6.34 (d, 1H), 4.12 (t, 2H), 3.88 (s, 3H), 2.46 (m, 2H), 2.40 (m, 4H), 1.92 (m, 1H), 1.84 (m, 2H), 1.37 (m, 1H), 1.29 (m, 1H), 1.01 (d, 3H), 0.89 (t,6H). 31 (lR,2S)-N-(4-{ [7-{ [2-(diethylamino)ethyl]oxy }-6-(methyloxy)quinolin-4-yl] oxy} -3-fiuorophenyl)-N'-(4-fluorophenyl)-2-methylcyclopropane-1,1-dicarboxamide ^NMR (DMSO-ife) d 10.22 (s, 1H), 10.01 (s, 1H), 8.44 (d, 1H), 7.86 (dd, 1H), 7.66 (m, 2H), 7.49 (m, 2H), 7.39 (in, 2H), 7.14 (m, 2B), 6.39 (d, 1H), 4.18 (m, 2H), 3.92 (s, 3H), 2.85 (t, 2H), 2.57 (q, 4H), 1.97 (m, 1H), 1.42 (m, 1H), 1.35 (m, 1H), 1.06 (d, 3H), 0.98 (t, 6H). 32 N-(4-{[7-{[2- (diethyiamino)ethyl]oxy}-6-(methyloxy)quinazoIin-4-yl]oxy} -3-fluoropheny])-N'-(4-fluorophenyl)cyclobutane-l, 1-dicarboxamide JHNMR (CDCls) 8.57 (s, 1H), 8.12 (s, 1H), 7.73-7.81 (ra, 2H), 7.48-7.53 (m, 2H), 7.32 (s, 1H), 6.98-7.08 (m, 3H), 4.28 (t, 2H), 4.04 (s, 3H), 3.25 (t, 2Π), 2.76 (q, 4H), 2.67 (q, 4H), 2.01-2.15 (m, 2H), 1.10 (t, 6H). 33 ,(UR,2S)-N-[3-fluoio-4-({6-(methyloxy)-7-[(3-piperazin-l-ylpropyI)axy]qamolin-4-yl}oxy)phenyl]-N,-(4-fluorophenyl)-2-methylcyelopropane-1,1-dicarboxamide XHNMR (400 MHz, DMSO-ifc): 10.28 (s, 1H), 9.80 (s, IB) 8.47-8.46 (d, 1H), 7.90-7.88 (d, 1H), 7.70-7.62 (m, 2H), 7.56-7.52 (m, 2H), 7.44-7.39 (m, 2H), 7.18-7.12 (m, 2H), 6.44-6.41 (t, 1H), 4.20-4.17 (t, 2H), 3.95 (s, 3H), 2.74-2.72 (t, 3H), 2.46-2.42 (m, 1H), 2.35 (br s, 3H), 2.03-1.93 (m, 3H), 1.87 (s, 4B), 1.43-1.35 (m,2H), 1.09-1.08 (ra,3H). 34 (k,2R,3S)-N-[3-fluaro-4-({6-(mediyloxy)-7-[(3-morpholin-4-ylpropyl)oxy]qaino]in-4-yl}oxy)phenyl]-N,-(4-fluorophenyl)-2,3-dimethylcyclopropane-1,1-dicarboxamide 1 1HNMR (DMSO-d6): 1H (10.12 ppm, s), 1H (9.6 ppm, s), 1H (8.46 ppm, d), 1H (7.88 ppm, dd), 2H (7.68 ppm, m), 1H (7.56 ppm, d), 1H (7.51 ppm, s), 2H(7.4 ppm, m), 2H (7.13 ppm, t), 1H (6.4 ppm, d), 2H (4.2 ppm, t), 3H (3.94 >pm, s), 4H ( 3.6 ppm, t), 2H (2.45 ppm, t), 4H [2.37 ppm, m), 2H (1.97 ppm, t), 2H (1.8 ppm, n), 6 H(1.28 ppm, d). 35 (lr,2R,3S)-N-{ 3-fluoro-4-[(6-(methyloxy)-7-{ [3-(4-methylpiperazin-1 - c yl)propyl]axy}quinolin-4-yl)oxy3phenyl}-N'-(4-fluorophenyl)-2,3- p dime£hylcyclopropan&amp;-l, 1 - 2 dicarboxamide p IHNMR (DMSO-d6): 1H (10.12 ppm, s), 1H 9.6 ppm, s), 1H (8.46 ppm, d), 1H (7.88 ppm, id), 2H (7.69 ppm, m), 1H (7.58 ppm, d), 1H 7.51 ppm, s), 2H (7.4 ppm, m), 2H (7.13 ppm, ), 1H (6.4 ppm, d), 2H (4.2 ppm, t), 3H (3.95 pm, s), 10H (2.35 ppm, m), 3H (2.14 ppm, s), H (1.97 ppm, t), 2H (1.8 ppm, m), 6H (1.28 pn, d). 258 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523

Table 3 Entry Name *Η-ΝΜΚ 36 N-[3-fluoro-4-({6-(methyloxy) 7-[(3-morphoIin-4-ylpropyI)oxyJqumazolin-4~ yl }oxy)phenyl]-N,-(4-fluorophenyl)cyclobutane-l, 1-dicarboxamide *H NMR (400 MHz, DMSO-d6): 8.45 (d, 2 H), 8.15 (d, 1H), 7.8 (d, 1H), 7.45 (m, 3H), 7.25 (m, 3H), 7.0 (m, 2B), 4.20 (t, 2H), 4.0 (s, 3H), 3.7 (m, 4H), 2.67 (m, 4H), 2.45 (m, 6H), 2.0 (m,4H). 37 (2R,3R)-N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpho]in-4-ylpropyl)oxyjquinoIin-4-yl }oxy)pheny]]"N'-(4“ fluorophenyI)“2,3" dimethylcyclopropane-1,1-dicarboxamide Ή NMR (400 MHz, CDQ3) d 8.44 (d, J = 5.1 Hz, 1H), 8.11 (br s, 1H), 7.77-7.70 (m, 2 H), 7.53 (s, 1H), 7.50-7.44 (m, 2 H), 7.40 (s, 1H), 7.22-7.16 (m, 2H), 7.06-6.98 (m, 2H), 6.36 (br d, J = 5.1 Hz, 1H), 4.26 (t, J = 7.0 Hz, 2 H), 4.02 (s, 3 H), 3.72 (t, J = 4.4 Hz, 4 H), 2.57 (t, J = 7.3 Hz, 2H), 2.50-2.42 (m, 4H), 2.18-2.10 (m, 2 H), 1.80-1.66 (m, 2 H), 1.30-1.24 (m, 6 H). 38 (2R,3R)-N-(4- {[7- { [3-(diethylamno)propylj oxy} -6 -(methyloxy)quinolin-4-yl] oxy} -3-fiuorophenyl)-N,-(4-fluorophenyl)-2,3-dimethylcyclopropane-l, 1-dicarboxamide JH NMR (400 MHz, DMSO-de) d 10.34 (s, 1 H), 10.05 (s, 1H), 8.46 (br s, 1H), 7.93 (br d, J = 4.7 Hz, 1H), 7.54-7.52 (m, 2 H), 7.52-7.50 (m, 2 H), 7.50-7.30 (m, 2 H), 7.20-7.10 (m, 2 H), 6.47 (br s, 1H), 4.30-4.20 (m, 2 H), 3.95 (s, 31¾. 3.40-3.10 (m, 6 H), 2.60-2.40 (m, 2 H), 1.90-1.80 (m, 2H), 1.30-1.10 (m, 12 H). 39 N-(4-{[7-{[3- (diethylamino)propyl]oxy}-6-(methyloxy)qulnolin-4-yl] oxy} -3-fluorophenyl)-N'-(4-fluoropheny!)-2,2-dimethylcyclopropane-1,1 -dicarboxanude 1H NMR (400MHz, DMSO-d6): d 10.47 (s, 1H), 10.16 (s, 1H), 8.43 (d, 1H), 722 (dd, 1H), 7.67 (m, 2H), 7.58 (m, 1H), 7.52 (s, 1H), 7.41 (m, 2H), 7.15 (t, 2H), 6.44 (d, 1H), 4.25 (t, 2H), 3.95 (s, 3H), 3.10 (m, 6H), 2.17 (m, 2H), 1.91 (s, 3H, acetate salt), 1.52 (m, 2H), 1.18 (m, 12H). 40 N-[3-fluoro-4-({6-(methyloxy)-7- [(3-morpholm-4-ylpropyl)oxy]quinazolin-4-yl}oxy)phenyl]-N'-(4- i fluorophenyl)-2,2-dnnethyIcyclopropane-1,1- i dicarboxamide ' 1HNMR (400MHz, DMSO-d6): d 10.21 (s, 1H), 9.97 (s, 1H), 8.51 (s, 1H), 7.81 (dd, 1H), 7.64 (m, 2H), 7.54 (s, 1H), 7.48 (m, 1H), 7.41 ;m, 1H), 7.38 (s, 1H), 7.15 (t, 2H), 4.24 (t, 2H), 3.97 (s, 3H), 3.58 (m, 4H), 2.45 (t, 2H), 2.38 [m, 4H), 1.97 (m, 2H), 1.58 (m, 2H), 1.18 (s, JH), 1.17 (s, 3H). 41 (lR,2R,3S)-N-(4-{[7-{[2- : (diethylamino)ethyl]axy}-6- ; inethyloxy)quinolin-4-yl]oxy} - ( 3-fluorophenyi)-N,-(4“ : fluorophenyl)-2,3-dimethylcyclopropane-1,1- ' dicarboxamide ' P iHNMR (400MHz, DMSO-d6): d 10.14 (s, [H), 9.61 (s, IB), 8.46 (d, 1H), 7.87 (dd, 1H), r. 67 (m, 2H), 7.57 (m, 1H), 7.51 (s, 1H), 7.42 s, 1H), 7.39 (m, 1H), 7.15 (t, 2H), 6.41 (d, H), 4.20 (m, 2H), 3.94 (s, 3H), 2.87 (m, 2H), .60 (m, 4H), 1.80 (m, 2H), 1.18 (s, 3H), 1.17 s, 3H), 1-01 (m, 6H). Note: 0.5eq of AcOH is resent by NMR. 259 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523

Table 3 Entry Name 1H-NMR 42 N-(4-{[7-{[2“ (diethylamino)ethyl]oxy}-6-(methyloxy)quinazolin-4-yl]oxy}-3-fluarophenyl)"N'-(4-fluorophenyl)-2,2-dimethylcyclopropane-1, 1-dicarboxamide 1H NMR (400MHz, DMSO): d 10.24 (s, 1H), 10.00 (s, 1H), 8.54 (s, 1H), 7.84 (dd, 1H), 7.66 (m, 2H), 7.56 (s, 1Ή), 7.51 (m, 1H), 7.43 (m, 2H0,7.18 (t, 2H), 4.26 (m, 2H), 3.98 (s, 3H), 2.88 (m, 2H), 2.59 (m, 4H), 1.58 (m, 2H), 1.18 (s, 6H), 1.00 (t,6H). 43 N-(4-{[7-{[3- (diethylambio)propyl]oxy}-6-(methyloxy)quinazoliii-4· yl]oxy}-3-fluorophenyl)-N,-(4-fluorophenyl)-2,2-dimethylcyclopropane-1,1-dicarbaxamide 1HNMR (400MHz, DMSO-d6): d 10.21 (s, 1H), 9.97 (s, 1H), 8.51 (s, 1H), 7.82 (dd, 1H), 7.64 (m, 2H), 7.54 (s, 1H), 7.48 (m, 1H), 7.41 (m, IH), 7.37 (s, IB), 7.15 (t, 2H), 4.23 (t, 2H), 3.97 (s, 3H), 2.56 (m, 2H), 2.46 (m, 4H), 1.91 (m, 2H), 1.58 (m, 2H), 1.18 (s, 6H), 0.96 (t, 6¾. 44 N-(4-{[7-{[3- (diethylamino)propyl]oxy}-6-(metfiyloxy)quinazolin-4-yl]oxy} -3-fluorophenyl)-N'-(4-fluorophenyl)cyclobutane-1,1-dicarbaxamide 1HNMR (CDC13): 8.57 (s, 1H), 8.50 (s, 1H), 8.11 (s, IH), 7.81 (dd, 1H), 7.53 (m, 3H), 7.28 (m, 4H), 7.04 (t, 2H), 4.24 (t, 2H), 4.04 (s, 3H), 2.95 (t, 2H), 2.84 (q, 4H), 2.75 (m, 4H), 2.21 (m, 2H), 2.02 (m, 2H), 1.18 (t, 6H). 45 N-{3-fluoro-4-[(6-(methyloxy)-7-{ [3-(4-methylpiperaziii-l-yl)propyI]oxy }quinazolin-4-yI)oxy]phenyl}-N,-(4-fluorophenyl)cyclobutane-l, 1 -dicarboxamide 1HNMR (CDCL3): 8.57 (s, IH), 8.49 (s, IH), 8.10 (s, IH), 7.80 (d, IH), 7.70 (br., IH), 7.52 (m, 3H), 7.31 (m, 3H), 7.04 (t, 2H), 4.26 (t, 2H), 4.04 (s, 3H), 2.62-2.77 (m, 14H), 2.40 (s, 3H), 2.13 (m, 2H), 2.01 (m, 2H). 46 (2R,3R)-N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4-yIpropyl)oxy]quinazolln-4-yl }oxy)phenyl]-N’- (4-fluaropfaenyl)-2,3-dimetbylcyclopropane-1,1-dicarboxamide lB NMR (400 MHz, CDCI3) d 8.59 (s, 1H), 8.11 (br s, 1H), 7.80-7.76 (m, 2H), 7.53 (s, 1 H), 7.50-7.46 (m, 2 H), 7.34 (s, 1H), 7.26-7.24 (m; 2 H), 7.06-7.00 (m, 2 H), 4.28 (t, J - 6.6 Hz, 2 H), 4.05 (s, 3 H), 3.73 (br t, J=4.4 Hz, 4 H), 2.57 (t, J = 7.0 Hz, 2 H), 2,52-2,45 (m, 4 H), 2.18-2.10 (m, 2 H), 1.80-1.68 (m, 2 H), L.28-1.20 (m, 6 H). 47 N-(4-{[7-{[3- ’ {diethylamino)propy]]oxy} -6- : methyloxy)quinolin-4-yl]oxy} - ; 3-fIuorophenyl)-N-(4- . fluorophenyl)cyclobutane-1,1- , dicarboxamide . ( HNMR (400 MHz, DMSO-ife): 9.98 (s, IB), ).72 (s, IH), 8.45-8.43 (d, IH), 7.97-7.94 (dd, -H), 7.73-7.69 (m, 2H), 7.65-7.52 (m, 3H), ?.44-7.39 (m, IH), 7.18-7.14 (m, 2H), 6.43-i.42 (d, IB), 4.20-4.19 (t, 2H), 3.95 (s, 3H), ,.70-2.66 (m, 6H), 2.45 (hrs, 2H), 1.91-1.84 m, 6H), 0.98 (br s, 6H). 260 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523

Table 3 Entry Name XH-NMR 48 N- {3-fluoro-4- [(6-(methyloxy)· 7-{ f3-(4-methylpiperazin-l-yl)propyl]oxy}quindin-4-yl)oxy]phenyl}-N'-(4-fluorophenyl)cyclobutaae-l ,1-dicarboxaraide ^NMR (400 MHz, DMSO-^): 9.99 (s, 1H), 9.73 (s, 1H), 8.45-8.43 (d, 1H), 7.97-7.93 (dd, 1H), 7.73-7.69 (m, 2H), 7.65-7.52 (m, 2H), 7.44-7.38 (m, 2H), 7.18-7.14 (m, 2H), 6.43-6.42 (d, 1H), 4.19-4.16 (t, 3H), 3.95 (s, 3H), 2.70-2,66 (m, 4H), 2.47-2.33 (m, 8H), 2.15 (s, 3H), 1.98-1.94 (m, 2H), 1.90-1.84 (m, 4H). 49 (2R,3R)-N-(4-{ [7-{ [2-(diethykmino)ethyr!oxy}-6-(methyloxy)quinazoHn-4-yl]oxy} -3-fluorophenyl)-N'-(4-fluorophenyl)-2,3 -dimethylcyclopropane-1,1-dicarboxamide JH NMR (400 MHz, CDCI3) d 8.59 (br s, 1H), 8.29 (hr s, 1H), 7.93 (s, 1H), 7.77 (d,J = 10.8 Hz, 1H), 7.53 (s, 1H), 7.50-7.45 (m, 2 H), 7.32 (s, 1H), 7.26-7.22 (m, 2H), 7.05-6.99 (m, 2H), 4J27 (t, J = 6.6 Hz, 2 H), 4.04 (s, 3 H), 3.03 (t, J = 6.5 Hz, 2 H), 2.67 (q, J = 7.0 Hz, 4 H), 1.80-1.70 (m, 2 H), 122 (br t, J=5.3 Hz, 6 H), 1.09 (hr t, J = 7.2 Hz, 6 H). 50 t (2R,3R)-N-(4-{ {7-{ [3-(diethyIamiiio)propyl]oxy }-6-(methyloxy)quinazolin-4-yi]oxy}-3-fluorophenyl)-N'-(4-fluoropheriyl)-2,3-dimethylcyclopropane-1,1-dicarboxamide XHNMR (400 MHz, CDCI3) d 8.58 (s, 1H), 8.40-8.36 (m, 1H), 8.02-7.96 (m, 1H), 7.80-7.75 (m, 1H), 7.53 (s, 1H), 7.52-7.50 (m, 2 H), 7.31 (s, 1H), 7.28-7.20 (m, 2H), 7.02 (t, J - 8.5 Hz, 2 B), 425 (t, J = 6.3 Hz, 2 H), 4.04 (s, 3 H), 3.00-2.90 (m, 2 H), 2.88-2.80 (m, 4 H), 2.30-2.20 (m, 2 H), 1.76-1.68 (m, 2 H), 1.25-1.15 (m, 12 H). 51 (2R,3R)-N-(4-{ [7-{ [2-(diethylamino)ethyl]oxy }-6-(methyloxy)qainolin-4-yl]oxy} -3-fluorophenyl)-N'-(4-fluorophenyl)-2,3-dimethylcyclopropane-l, 1-dicarboxamide XHNMR (400 MHz, CDCI3) d 8.47 (d, J = 5.2 Hz, 1H), 8.17 (hr s, 1H), 7.80-7.74 (m, 2 H), 7.55 (s, 1H), 7.52-7.46 (m, 2 H), 7.42 (s, 1H), 7.247^0 (m, 2 H), 7.05 (t, J=8.6 Hz, 2 B), 6.38 (hr d, J = 5.4 Hz, 1H), 4.27 (t, J=6.4 Hz, 2H), 4.03 (s, 3 H), 3.04 (hr t, J = 7.2 Hz, 2H), 2.68 (q, J=6.8 Hz, 4 H), 1.80-1.68 (m, 2 H), 1.26 (d, J=6.4 Hz, 6 H)’, 1.09 (hr t, J - 7.2 Hz, 6H). 52 N-(4-{[6,7- his(methyloxy)guinoIm-4-yl]oxy}phenyI)-N,-[(4-fluorophenyl)methyl]cyclopropa ( ne~ 1,1-dicarboxamide LHNMR (DMSO-d6): 10.82 (s, 1H), 8.80 (d, IH), 8.50 (t, 1H), 7.83 (d, 2H), 7.74 (s, 1H), 7.56 (s, 1¾ 7.30-7.38 (m, 4H), 7.15 (t, 2H), j.80 (d, IB), 4.32 (d, 2H), 4.04 (s, 3H), 4.03 (s, 3H), 1.42 (s,4H). 53 N-(4-{[6,7- bis(methyloxy)quiiiolin-4-yl]oxy}phenyl)-N'-(2- 1 morpholin-4- Ξ ylethyl)cyclopropane-1,1- 3 dicarboxamide ( IH NMR (DMSO-d6): 10.62 (s, 1H), 8.79 (d, LH), 8.24 (t, IH), 7.83 (d, 2H), 7.72 (s, IH), r.58 (s, IH), 7.37 (d, 2H), 6.76 (d, IH), 4.04 (s, SH), 4.03 (s, 3H), 3.98 (m, 2H), 3.66 (m, 2H), .49 (m, 4H), 3.25 (t, 2H), 3.13 (br., 2H), 1.42 d,4H). 261 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523

Table 3 Entry Name XH-NMR 54 N-(4-{[6,7- bis(methyloxy)quinoIin-4- yl]oxy}phenyl)-N-E2- (piperidin-1- ylmethyl)phenyl]cyclopropane- 1,1-dlcarboxamide 1HNMR (DMSO-d6): 10.78 (s, 1H), 10.53 (s, 1H), 8.43 (d, 1H), 8.12 (d, 1H), 7.82 (d, 2H), 7.49 (s, 1H), 7.37 (s, 1H), 7.20-7.28 (m, 3H), 7.15 (dd, 1H), 7.01 (id, 1H), 6.35 (d, 1H), 3.93 (s, 3H), 3.92 (s, 3H), 3.47 (s, 2H), 2.17 (br., 4H), 1.49 (m, 4¾ 1.41 (m, 4H), 1.32 (hr., 2H). 55 N-(4-{[6,7- bis(metbyloxy)qumolin-4- yl]oxy}phenyl)-N'-[2- (pynoHdin-l- ylmethyl)phenyl]cyclopiopane- 1,1-dicarboxamide 1HNMR (DMSO-d6): 10.98 (s, 1¾ 10.56 (s, 1H), 8.42 (d, 1H), 8.10 (dd, 1H), 7.81 (m, 2H), 7.49 (s, 1H), 7.37 (s, 1H), 7.17-7.27 (m, 4H), 7.01 (td, IB), 6.35 (d, 1H), 3.93 (s, 3E), 3.92 (b, 3H), 3.61 (s, 2H), 2.30 (br., 4H), 1.47 (br., 4H), 1.43 (m, 4H). 56 N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}phenyI)-N'-[3- (morpholin-4- ylmethyl)phenyl] cyclopropane-1,1-dicaiboxamide 1HNMR (DMSO-d6): 10.12 (s, 1H), 10.03 (s, 1H), 8.44 (d, 1H), 7.74 (d, 2H), 7.57 (s, 1H), 7.53 (d, 1H), 7.48 (s, 1H), 7.37 (s, 1H), 7.21 (m, 3B), 6.98 (d, 1H), 6.40 (d, 1H), 3.93 (s, 3H), 3.92 (s, 3H), 3.56 (t, 4H), 3.41 (s, 2H), 2.34 (br., 4H), 1.48 (s, 4H). 57 N-(4-{[6,7- bis(methyloxy)qoinolin-4- yl]oxy}phenyl)-N'-[2- (morpholin-4- y!methyl)phenyI]cyclopropane- 1,1-dicarboxamide 1HNMR (DMSO-d6)r 10.54 (s, 1H), 10.47 (s, 1H), 8.43 (d, 1H), 8.08 (d, 1H), 7.78 (d, 2H), 7.49 (s, 1H), 7.37 (d, 1H), 7.18-730 (m, 4H), 7.03 (t, 1H), 6.37 (d, 1H), 3.94 (s, 3H), 3.93 (s, 3H), 3.50 (s, 2H), 3.44 (br., 4H), 2.20 (br., 4H), 1.48 (d, 4H). 58 N-(4-{[6,7- bis(methyloxy)quinolin-4~ ylJoxyJphenyD-N'- phenylcyclopropane-1,1- dicarboxamide 1HNMR (DMSO-d6): 10.14 (s, 1H), 10.03 (s, IB), 8.44 (d, 1H), 7.74 (d, 2H), 7.62 (d, 20), 7.48 (s, 1H), 7.37 (s, 1H), 7.27-7.31 (m, 2H), 7.19-7.23 (m, 2H), 7.05 (t, 1H), 6.41 (d, 1H), 3.93 (s, 6H), 3.92 (s, 3H), 1.48 (s, 4H). 59 N-[3-(aminomethyl)phenyl]-N'- (4-(16,7- bis(methyloxy)quinolin-4-yl]oxy}phenyl)cyclopropane-' 1,1-dicarboxamide . 1HNMR (400MHz, DMSO-d6):d 1028 (s, 1H), 10.19 (s, IB), 8.77 (m, 1H), 8.21 (m, 3H), 7.84 (m, 2H), 7.76 (m, 1H), 7.71 (m, 1H), 7.58 . [m, 2H), 7.38 (m, 3H), 7.19 (m, 1H), 6.76 (m, LH), 4.03 (s, 6H), 3.39 (m, 2H), 1.53 (m, 4H). ^ote: all peaks are very broad and unresolved. 60 N-(4-{[6,7- bis(methyloxy)quinoIin-4- ; yl]oxy}phenyl)-N'-[3- ' (piperidin-1- . ylmethyl)pheiiyl]cyclopropane- , 1,1-dicarboxamide LH NMR (DMSO-d6): 10.0-10.2 (br., 2H), i.46 (d, 1H), 7.76 (d, 2H), 7.53 (m, 3H), 7.39 s, 1H), 7.24 (m, 3H), 6.98 (d, 1H), 6.43 (d, H), 3.95 (s, 3H), 3.93 (s, 3H), 3.37 (s, 2H), ,.31 (br., 4H), 1.48 (m, 8H), 1.39 (br., 2H). 262 PCT/US2004/031523

Table 3

Entry Name 61 N-(4-{ [6,7- bis(methyloxy)quinolin-4- yl]Qxy}phenyl)-N'-[3- (pyrrolidin-1- ylmethyl)phenyl]cyclopropane-1,1-dicarboxamide 1H NMR (DMSO-d6): 10.0-10.2 (br., 2H), 8.46 (d, 1H), 7.77 (d, 2H), 7.59 (s,.lH), 7.53 (d, 1H), 7.51 (s, IB), 7.39 (s, 1H), 7.23 (m, 3H), 6.99 (d, 1H), 6.43 (d, 1H), 3.95 (s, 3H), 3.93 (s, 3H), 3.52 (s, 2H), 2.42 (br., 4H), 1.69 (br, 4H), 1.48 (s,4H). 2013204031 11 Apr 2013 WO 2005/030140

Assays [0455] Kinase assays were performed by measurement of incorporation of γ~33Ρ ATP into immobilized myelin basic protein (MBP). High binding white 384 well plates (Greiner) were coated with MBP (Sigma #M-1891) by incubation of 60ul/well of 20pg/ml MBP in Tris-buffered saline (TBS; 50mM Ids pH 8.0,138mM Nad, 2.7mM KCI) for 24 hours at 4° C. Plates were washed 3X with 100μ1 TBS. Kinase reactions were carded out in a total volume of 34μ1 in kinase buffer (5mM Hepes pH 7.6,15mM NaCI, 0.01% bovine gamma globulin (Sigma #1-5506), lQmM MgCk, ImM DTT, 0,02% TritonX-100). Compound dilutions were performed in DMSO and added to assay wells to a final DMSO concentration of 1%. Each data point was measured in duplicate, and at least two duplicate assays were performed for each individual compound determination. Enzyme was added to final concentrations of lOnM or 20nM, far example. A mixture of unlabeled ATP and γ-33P ATP was added to start the reaction (2xl06 cpm of Y-33P ATP per well (3000Ci/mmole) and either 10μΜ or 30μΜ unlabeled ATP, typically. The reactions were carded out for 1 hour at room temperature with shaking. Plates were washed 7x with TBS, followed by the addition of 50pl/well scintillation fluid (Wallac). Hates were read using a Wallac Trilux counter. This is only one format of such assays, various other formats are possible, as known to one skilled in the art.

[0456] The above assay procedure can be used to determine the ICjo for inhibition and/or the inhibition constant, Kj. The IC50 is defined as the concentration of compound required to reduce the enzyme activity by 50% under the conditions of the assay. Exemplary compositions have IC50S of, for example, less than about 100 μΜ, less than about 10 μΜ, less than about 1 μΜ, and further for example having ICso’s of less than about IOO nM, and still further, for example, less than about 10 nM. The Ki for a compound may be 263 2013204031 11 Apr 2013 WO 2005/030140 PCT/US2004/031523 determined from die IC50 based on three assumptions. First, only one compound molecule binds to the enzyme and them is no cooperatiyity. Second, the concentrations of active enzyme and the compound tested are known (i.e., there are no significant amounts of impurities or inactive forms in the preparations). Third, the enzymatic rate of the enzyme-inhibitor complex is zero. The rate (i.e., compound concentration) data are fitted to the equation: /- (E0 +I0+Kd)-J(E0 + /„ + Kd)2-4Vo 2En where V is the observed rate, V^, is the rate of the free enzyme, Io is the inhibitor concentration, Ho is the enzyme concentration, and Kj is the dissociation constant of the enzyme-inhibitor complex.

Kinase specificity assays: [0457] Kinase activity and compound inhibition am investigated using one or mom of the three assay formats described below. The ATP concentrations for each assay are selected to be close to the Michaelis-Menten constant (Km) for each individual kinase. Dose-response experiments are performed at 10 different inhibitor concentrations in a 384-well plate format. The data are fitted to the following four-parameter equation: Y=Min + (Max -Min) / (1 + (XTC50)AH) where Y is the observed signal, X is the inhibitor concentration, Min is the background signal in the absence of enzyme (0% enzyme activity), Max is die signal in the absence of inhibitor (100% enzyme activity), IC50 is the inhibitor concentration at 50% enzyme inhibition and H represents the empirical Hill’s slope to measure the cooperativity. Typically H is dose to unity. c-Met Assay [0458] c-Met biochemical activity was assessed using a Luciferase-Coupled Chemiluminescent Kinase assay (LCCA) format as described above. Again, kinase activity was measured as the percent ATP remaining following the kinase reaction. 264 PCT/US2004/031523 2013204031 11 Apr 2013 WO 2005/030140

Remaining ATP was detected by hiciferase-ludferin-coupled chemiluminescence. Specifically, the reaction was initiated by mixing test compounds, ΙμΜ ATP, ΙμΜ poly-EY and lOnM c-Met (baculovirus expressed human c-Met kinase domain P948-S1343) in a 20uL assay buffer (20mM Tris-HCL pH7.5, lOmM MgCl2, 0.02% Triton X-100, lOOmM DTT, 2mM MhCfe). The mixture is incubated at ambient temperature for 2hours after which 20uL iu cdferase-luciferin mix is added and tiie chemiluminescent signal read using a Wallac Victor2 reader. The lucaferase-ludferin mix consists of 50 mM HEPES, pH 7.8, 8.5ug/mL oxalic acid (pH 7.8), 5 (or 50) mM DTT, 0.4% Triton X-100,0.25 mg/ml-coenzyme A, 63 uM AMP, 28 ug/mL luciferin and 40,000 units of light/mL luciferase. KDR Assay [0459] KDR biochemical activity was assessed using a Luciferase-Coupled Chemiluminescent Kinase assay (LCCA) format. Kinase activity was measured as the percent ATP remaining following the kinase reaction. Remaining ATP was detected by luciferase-luciferin-coupled chemiluminescence. Specifically, the reaction was initiated by mixing test compounds, 3 μΜ ATP, 1.6 μΜ poly-EY and 5 nM KDR (baculovirus expressed human KDR kinase domain D807-V1356) in a 20uL assay buffer (20mM Tris-HCL pH7.5, lOmM MgClz, 0.01% Triton X-100, ImM DTT, 3mM MaCl^. The mixture is incubated at ambient temperature for 4 hours after which 20uL luciferase-luciferin mix is added and the chemiluminescent signal read using a Wallac Motor2 reader. The luciferase-luciferin mix consists of 50 mM HEPES, pH 7.8, 8.5ug/mL oxalic add (pH 7.8), 5 (or 50) mM DTT, 0.4% Triton X-100,0.25 mgftriL coenzyme A, 63 uM AMP, 28 ug/mL luciferin and 40,000 units of light/mL luciferase. flt-4 Assay [0460] Biochemical activity for flt-4 was assessed using an Alphascreen Tyrosine Kinase protocol. AlphaScreen™ (Perkin Elmer) technology is a proximity assay employing microparticles. Singlet oxygen derived from a donor bead following laser exdtation results in chemiluminescence when in proximity (100 A) to an acceptor bead due to biomolecular interactions. For the Flt-4 assay, donor beads coated with streptavidin and acceptor beads coated with PY100 anti-phosphotyrosine antibody were used (Perkin Elmer). Biotinylated poly(Glu,Tyr) 4:1 (Perkin Elmer) was used as the substrate. 265 PCT/US2004/031523 2013204031 11 Apr 2013 WO 2005/030140

Substrate phosphorylation was measured by addition of donor/acceptor beads by chemiluminescence following donor-acceptor bead complex formation. Test compounds, 5 μΜ ATP, 3 nM biotinylated poly(Glu, Tyr) and 1 nM Ht-4 (baculovirus expressed human Ht-4 kinase domain D725-R1298) were combined in a volume of 20 pL in a 384-well white, medium binding microtiter plate (Greiner). Reaction mixtures were incubated for 1 hr at ambient temperature. Reactions were quenched by addition of 10 uL of 15-30 mg/mL AlphaScreen bead suspension containing 75 raM Hepes, pH 7.4, 300 mM NaCl, 120 mM EDTA, 0.3% BSA and 0.03% Tween-20, After 2-16 hr incubation at ambient temperature plates were read using an AlphaQuest reader (Perkin Elmer). IC50 values correlate well with those determined by radiometric assays.

Ht-3 Assay [0461] Biochemical activity for flt-3 was assessed using a Luciferase-Coupled Chemiluminescent Kinase assay (LCCA) format. Kinase activity was measured as the percent ATP remaining following the kinase reaction. Remaining ATP was detected by luciferase-luciferin-coupled chemiluminescence. Specifically, the reaction was initiated by mixing test compounds, 5 μΜ ATP, 3 μΜ poly-EY and 5 nM Flt-3 (baculovirus expressed human Flt-3 kinase domain R571-S993) in a 20uL assay buffer (20mM Tris-HCL pH7.5, lOmM MgCfe,0.01% Triton X-100, ImM DTT, 2mM MnCl2). The mixture is incubated at ambient temperature for 3 hours after which 20uL luciferase-luciferin mix is added and the chemiluminescent signal read using a Wallac Victor2 reader. The luciferase-luciferin mix consists of 50 mM HEPES, pH 7.8, 8.5ug/mL oxalic acid (pH 7.8), 5 (or 50) mM DTT, 0.4% Triton X-100,0.25 mg/mL coenzyme A, 63 uM AMP, 28 ug/mL luciferin and 40,000 units of light/mL luciferase. c-Kit Assay

[0462] c-Kit biochemical activity was messed using AlphaScreen tm (Perkin Elmer) -technology, described above. Test compounds, ATP, biotinylated poly(Glu, Tyr) and c-Kit kinase were combined in a volume of 20 //L in a 384-well white, medium binding microtiter plate (Greiner). Reaction mixtures were incubated for 1 hr at ambient temperature. Reactions were quenched by addition of 10 uL of 15-30 mg/mL AlphaScreen bead suspension containing 75 mM Hepes, pH 7.4, 300 mM NaCl, 120 mM 266 PCT/US2004/031523 2013204031 11 Apr 2013 WO 2005/030140 EDTA, 0.3% BSA and 0.03% Tween-20. After 16 hr incubation at ambient temperature plates were read using an AlphaQuest reader (Perkin Elmer).

Structure Activity Relationships [0463] Table 4 shows structure activity relationship data for selected compounds of the invention. Inhibition is indicated as IC$o with foe following key: A = ICjo less than 50 xiM, B = IC50 greater than 50 nM, but less than 500 nM, C = IC50 greater than 500 nM, but less than 5000 nM, and D = IC50 greater than 5,000 nM. Depending upon the functionality about foe quinazoline or quinoline, exemplary compounds of foe invention exhibit selectivity for any of c-Met, KDR, c-Kit, flt-3, and fit-4. Abbreviations for enzymes listed in Tables 2-3 are defined as follows: c-Met refers to hepatocyte growth factor receptor kinase; KDR refers to kinase insert domain receptor tyrosine kinase; flt-4, fins-like tyrosine kinase-4, representative of foe ELK family of receptor tyrosine kinases; c-Kit, also called stem cell factor receptor or steel factor receptor; and flt-3, fins-like tyrosine kinase-3. Empty cells in foe tables indicate lack of data only.

Table 4

Entry Name c-Met KDR U ύ i 1 N-[({ 3-fluoro-4-[(6-(methyloxy)-7-{ [(3aR,6aS)-octahydrocyclopenta[c]pyrrol-5-yhnethyl]oxy}quinazolin-4-yl)oxy] phenyl} amino)carbonothioyl]-2-phenylacet amide A A 2 N-{ [(3-fluoro-4-{ [7-({ [(3aR,6aS)-2-mefoyloctahydrocyclopenta[c]pyrrol-5-yl]mefoyl}oxy)-6-(methyloxy)quinazolin-4-yl]oxy}phenyl)amino]carbonothioyl}-2~ phenylacetamide A A A A 3 N-{ [(4-{ [6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)(methyl)amino]carbonothioyl}-2-phenyiacetamide C 4 l-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3- fluorophenyl)imidazolidin-2-one C C C 5 l-(4-{[6,7-bis(mefoyloxy)quinoIin-4-yl]oxy}-3- fluorophenyt)-3-(phenylmethyl)imidazolidiii-2-one C B c 6 l-(4-{[6,7-bis(methj4oxy)quinolin-4-yl]oxy}-3- fluorophenyl)-3-(phenylacetji)imidazolidin“2-ane B 267 2013204031 11 Apr 2013 to o\ K $2 to u> κ to 1—4 g 1—4 NO P-4 00 1—4 1—4 ON 1—4 Oi 1—4 1—4 l·—* to 1—4 1—4 1—4 O so OO -4 1 ON V s: ce •&amp;Ϊ T2 * It if f a I ¥* I t* if B ΐ V5 1 ft S'ft 0 ON 3 ** i f £ 3 A v; 5 a g. ^¾. fl p ’•ft' hO S- E-S* o 1 S' cp τ a- O tmU a u fr| 1 U> 1 1 B o! i* H· T 03 g? if § a \s.£ It a| ft S ^ 8 s' GQ ft I" 9 ω 3 lL· i £ CL § Ο O * -fL J σϊ V ff ? S'# St St ii S ss v: «-IF-» t 1 (^1 ON <1 s: ce li ts if ° CD V Cl 'O' |c i?i-a S; 11 s. ·-< S' ΰ 0 * v: 1 § •s. P-4 1 Ϊ os &amp; V g sr. 3 w ’g.f g £ vj vj ΐ?4 ft S'a 1¾ gl· tfj B !| 1 t!o 1 Jh pi ~|J y> f· &amp;f s g. ►s H 0 ^ 43 s¥ w e cr “· a sr 8 -U· a ^ κ J=i is i s, I V» CD JHj 1 4L. 1 B 5 -j Έ § Έ3 0· *d ^ B* o a * vft jQ If f g If gs |i 3 u> l| £ 4L. t os 0 Έ3 ί fcB It 6=-4 ft* s^l sS- o* C3 ft >** 1 CD k g r &amp; ^ g^ ·ο g X B ϋ Cl ω n (b 0 1 £ a 'οϊ 5 <i 6 o* Ά 6r If B O *5 m &amp;I- M o If as s s 1¾ § (!)J i. &amp; 1 as ps ©I rf ^ &amp; B ^ &amp;| St P o’ W i s a ^ tf j* 1 2! g1? 3 ^ 1¾ s§ w a Ό &amp; B* &amp; s a &amp;§ » B" O g4 if IS 81¾ l U» 0 JL, Ί ^ B* -4 CD ", a s *<, K P-l Λν P II git Si, CD E" 52 O &amp;f § s 1 a lr u> 1 ffi § t* •3 ft S' F" § -r1 n< ty 'ζ? S" •S’ ϊ. ri v O- S*"0 a a ^ s* 11 fi II ? Ο Λ Is* &amp; O li Sf nb &amp; a s* •5 w ^-¾ (—* ja v 'TS ^ Ιέ | a | ?* f rs 1 a 54¾ CD V u» i Ιά S- os S V v- σ* D—1 ML« ν' » 11 ft i &amp; fs a c ar ’ft5 *=i li if B p* *-1-· 8* ώ 1—4 1 J p\ if It If « o «·< If fi Sf CD I u> 1 &amp; S 2 5 -$ •8 f1 S*ft 8 ?1 >< 0 2# it at E2 'ώι ft* B CD ^ ° ΪΛ g V 3 f_l O ¥ f Is 6 g a -¾ 0 T V ω (Λ ι 1 ? Ή-? sv ^ EC l* W II 1! ss- T3 a a- B· 3 0 1-f tt ftu V £3 §1 e. ώ 8“ 1 £ ft 1 aft C os i V 4 s cr co „§3 III tit I&amp;&amp; 8* i | a| ti ^ Ϊ B 0 1 LO t ? ffs 3 £ "S. £ ΕΓ &amp; CD O 0 3 Μ 1 If £.¾ ft ¥ | a *? a f CD v; .1 1 U» 1 o ta O o o o o Π o o o o O > o w o Π o 1 > u a ► ta w w n Π n Π Π o o Π > Π ta o ω n n ta o o o Π - o w o w o Π η 0 * ta ta ω to o ® o o 1-4 £ * n

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-χ ‘x-3nBdojdoioXoiXipaanp-£‘3-(iXuaijdojonu-i?) -j^-(^iraqdaxonij-e-{Xxo[pC-iraito2ramb(jixoiAqi3ai) -9-{Xxo[iXdojd(outaretXi03ip)-£] }-β ΗΟ-Ν-ΟΐεΈΖ) 2013204031 11 Apr 2013 10 CAMRri)fibllDCC\WAM\3e>5l{|(;9_I.DOC-2(V»7ail|0 - - 293A - [0455] The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general 5 knowledge in the field of endeavour to which this specification relates.

[0456] Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

Claims (31)

1. THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS:

   1. A compound of Formula XXI:

   XXI or a pharmaceutically acceptable salt, hydrate, or prodrug thereof, wherein, each R1 is independently selected from halogen, -OR3, -NO2, -NH2, -NR3R3, -D-R50 and optionally substituted Ci_6alkyl; w is an integer from 2 to 4; and at least one R1 is -D-R50 and at least one R1 is -OR3; wherein -D-R50 and -OR3 are interchangeably located at the 6-position and 7-position of the compound of Formula XXI;; D is -0-; R70 is selected from -H, halogen, -OR3, -S(0)o-2R3, -NO2, -NH2, -NR3R3, and optionally substituted Ci_6alkyl; J is =N- or =C(H)-; Z is -0-; each R5 is independently selected from -H, optionally substituted Ci_6alkyl, optionally substituted aryl, and optionally substituted aryl Ci_6alkyl; Ar is para-phcnylcnc as defined by the substitution pattern of -Z- and -B-L-T about said phenylene; R2 is selected from -H, halogen, trihalomethyl, -CN, -NO2, -NH2, -OR3, -NR3R3, -S(0)o-2R3, -S02NR3R3, -C02R3, -C(0)NR3R3, -N(R3)S02R3, -N(R3)C(0)R3, -N(R3)C02R3, -C(0)R3, and optionally substituted Ci_6alkyl; each R3 is independently selected from -H, -Si(R5)(R5)R5, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted arylalkyl, and optionally substituted heteroarylalkyl; or two R3, together with the nitrogen to which they are attached, form a four- to seven-membered heteroalicyclic, said four- to seven-membered heteroalicyclic optionally containing one additional heteroatom; when one said additional heteroatom is a nitrogen, then said nitrogen is optionally substituted with a group selected from -H, trihalomethyl, -S02R5, -S02NR5R5, -C02R5, -C(0)NR5R5, -C(0)R5, and optionally substituted lower alkyl; -B-L-T is either of formula XXV or formula XXVI,

   XXV XXVI each R20 is independently selected from -H, halogen, trihalomethyl, -CN, -N02, -NH2, -OR3, -NR3R3, -S(0)o-2R3, -S02NR3R3, -C02R3, -C(0)NR3R3, -N(R3)S02R3, -N(R3)C(0)R3, -N(R3)C02R3, -C(0)R3, optionally substituted Ci_6alkyl, optionally substituted aryl, optionally substituted aryl Ci^alkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclyl Ci-6alkyl; or two of R20, together with the atom or atoms to which they are attached, combine to form an optionally substituted three- to seven-membered heteroalicyclic, said optionally substituted three- to seven-membered heteroalicyclic either spiro- to, or fused to, the ring system to which it is attached; G is either an optionally substituted cycloalkyl or an optionally substituted heteroalicyclic; each R30 is independently selected from halogen, trihalomethyl, -CN, -N02, -NH2, -OR3, -NR3R3, -S(0)o-2R3, -S02NR3R3, -C02R3, -C(0)NR3R3, -N(R3)S02R3, -N(R3)C(0)R3, -N(R3)C02R3, -C(0)R3, and optionally substituted Ci^alkyl; R13a and R13b are each independently selected from -H and optionally substituted Ci-ealkyl; R50 is either R3, or according to formula XXIV;

   XXIV wherein X1, X2, and optionally X3, represent the atoms of a saturated bridged ring system, said saturated bridged ring system comprising up to four annular heteroatoms represented by any of X1, X2, and X3; wherein, each X1 is independently selected from -C(R6)R7-, -0-, -S(0)o-2-, and -NR8-; each X2 is independently an optionally substituted bridgehead methine or a bridgehead nitrogen; each X3 is independently selected from -C(R6)R7-, -0-, -S(0)o-2-> and -NR8-; Y is either: an optionally substituted Ci-6alkylene linker, between D and either 1) any annular atom of the saturated bridged ring system, except X2 when X2 is a bridgehead nitrogen, or 2) any heteroatom, represented by any of R6 or R7; provided there are at least two carbon atoms between D and any annular heteroatom of the saturated bridged ring system or any heteroatom represented by any of R or R ; or Y is absent, when Y is absent, said saturated bridged ring system, is directly attached to D via an annular carbon of said saturated bridged ring system, unless D is -SO2-, in which case said saturated bridged ring system, is directly attached to D via an any annular atom of said saturated bridged ring system; m and p are each independently one to four; n is zero to two, when n is zero, then there is a single bond between the two bridgehead X2’s; R6 and R7 are each independently selected from -H, halogen, trihalomethyl, -CN, -NH2, -NO2, -OR3, -NR3R3, -S(0)o-2R3, -S02NR3R3, -C02R3, -C(0)NR3R3, -N(R3)S02R3, -N(R3)C(0)R3, -NC02R3, -C(0)R3, optionally substituted Ci_6alkyl, optionally substituted aryl, optionally substituted aryl Ci-6alkyl, optionally substituted heterocyclyl, optionally substituted heterocyclyl Ci-6alkyl, and a bond to either Y or D; or R6 and R7, when taken together are oxo; or R6 and R7, when taken together with a common carbon to which they are attached, form an optionally substituted three- to seven-membered spirocyclyl, said optionally substituted three- to seven-membered spirocyclyl optionally containing at least one additional annular heteroatom selected from N, 0, S, and P; and R8 is selected from -R3, Y, -S02NR3R3, -C02R3, -C(0)NR3R3, -S02R3, and -C(0)R3.
2. 2. The compound of claim 1 which is a compound of formula XXIa:

   XXIa
3. 3. The compound of claim 2, wherein: -B-L-T is of formula XXV,

   XXV each R is independently selected from -H and halogen; G is an optionally substituted cycloalkyl; and R50 is R3.
4. 4. The compound of claim 2, wherein R is selected from -H and halogen. 50 3
5. 5. The compound of claim 3, wherein -O-R is O-R .
6. 6. The compound of claim 3, wherein -O-R50 is O-Me. 70
7. 7. The compound of claim 6, wherein R is -H and J is =C(H)-.
8. 8. The compound of claim 7, wherein: G is cyclopropyl; and (R30)o-4 is (R30) which is fluoro.
9. 9. A compound of Formula XXIb

   XXIb or a pharmaceutically acceptable salt or hydrate thereof, wherein, J is =N- or =C(H)-; R21S selected from Ci_6 alkyl, perfluoro Ci_6 alkyl, and halogen; Of) each R is independently selected from -H, halogen, trihalomethyl, -CN, -NO2, -NH2, -OR3, -NR3R3, -S(0)o-2R3, -S02NR3R3, -CO2R3, -C(0)NR3R3, -N(R3)S02R3, -N(R3)C(0)R3, -N(R3)C02R3, -C(0)R3, optionally substituted C l ealkyl, optionally substituted aryl, optionally substituted aryl Ci-6alkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclyl Ci-6alkyl; or two of R20, together with the atom or atoms to which they are attached, combine to form an optionally substituted three- to seven-membered heteroalicyclic, said optionally substituted three- to seven-membered heteroalicyclic either spiro- to, or fused to, the ring system to which it is attached; R50 is either R3 which is -H, -Si(R5)(R5)R5, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted arylalkyl, and optionally substituted heteroarylalkyl; wherein each R5 is independently selected from -H, optionally substituted Ci-6alkyl, optionally substituted aryl, and optionally substituted aryl Ci-6alkyl; or R50 is according to formula XXIV;

   XXIV wherein X1, X2, and optionally X3, represent the atoms of a saturated bridged ring system, said saturated bridged ring system comprising up to four annular heteroatoms represented by any of X1, X2, and X3; wherein, each X1 is independently selected from -C(R6)R7-, -0-, -S(0)o-2-, and -NR8-; each X2 is independently an optionally substituted bridgehead methine or a bridgehead nitrogen; each X3 is independently selected from -C(R6)R7-, -0-, -S(0)o-2-, and -NR8-; Y is either: an optionally substituted Ci-6alkylene linker, between 0 and either 1) any annular atom of the saturated bridged ring system, except X when X is a bridgehead nitrogen, or 2) any heteroatom, represented by any of R6 or R7; provided there are at least two carbon atoms between 0 and any annular heteroatom of the saturated bridged ring system or any heteroatom represented by any of R or R ; or Y is absent, when Y is absent, said saturated bridged ring system, is directly attached to 0 via an annular carbon of said saturated bridged ring system; m and p are each independently one to four; n is zero to two, when n is zero, then there is a single bond between the two bridgehead X2,s; R6 and R7 are each independently selected from -H, halogen, trihalomethyl, -CN, -NH2, -NO2, -OR3, -NR3R3, -S(0)o-2R3, -S02NR3R3, -CO2R3, -C(0)NR3R3, -N(R3)S02R3, -N(R3)C(0)R3, -NCO2R3, -C(0)R3, optionally substituted Ci-ealkyl, optionally substituted aryl, optionally substituted aryl Ci-6alkyl, optionally substituted heterocyclyl, optionally substituted heterocyclyl Ci-6alkyl, and a bond to either Y or O; or Re and R7, when taken together are oxo; or Re and R7, when taken together with a common carbon to which they are attached, form an optionally substituted three- to seven-membered spirocyclyl, said optionally substituted three-to seven-membered spirocyclyl optionally containing at least one additional annular heteroatom selected from N, 0, S, and P; and Rs is selected from -R3, Y, -S02NR3R3, -CO2R3, -C(0)NR3R3, -SO2R3, and -C(0)R3.
10. 10. The compound of claim 9, wherein J =C(H)-.
11. 11. The compound of claim 10, wherein R50 is R3.
12. 12. The compound of claim 11, wherein R50 is methyl.
13. 13. The compound of claim 12, wherein R , if present, is halogen.
14. 14. The compound of claim 12, wherein R2, if present, is fluoro. 2
15. 15. The compound of claim 14, wherein R , if present, is up to two fluorines ortho to 2 the oxygen of the phenylene to which R is attached.
16. 16. A process for preparing a compound of Formula XXI

    XXI comprising reaction of a compound of Formula XXII, with a compound of Formula XXIII

    XXII XXIII wherein, each R1 is independently selected from halogen, -OR3, -NO2, -NH2, -NR3R3, -D-R50 and optionally substituted Ci_6alkyl; w is an integer from 2 to 4; and at least one R1 is -D-R50 and at least one R1 is -OR3; wherein -D-R50 and -OR3 are interchangeably located at the 6-position and 7-position of the compound of Formula XXII; D is -0-; R70 is selected from -H, halogen, -OR3, -S(0)o-2R3, -NO2, -NH2, -NR3R3, and optionally substituted Ci_6alkyl; J is =N- or =C(H)-; Z is -0-; each R5 is independently selected from -H, optionally substituted Ci_6alkyl, optionally substituted aryl, and optionally substituted aryl Ci-6alkyl; Ar is /;ara-phcnylene as defined by the substitution pattern of -Z- and -B-L-T about said phenylene; R2 is selected from -H, halogen, trihalomethyl, -CN, -NO2, -NH2, -OR3, -NR3R3, -S(O)0-2R3, -S02NR3R3, -C02R3, -C(0)NR3R3, -N(R3)S02R3, -N(R3)C(0)R3, -N(R3)C02R3, -C(0)R3, and optionally substituted Ci-6alkyl; each R3 is independently selected from -H, -Si(R5)(R5)R5, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted arylalkyl, and optionally substituted heteroarylalkyl; or two R3, together with the nitrogen to which they are attached, form a four- to seven-membered heteroalicyclic, said four- to seven-membered heteroalicyclic optionally containing one additional heteroatom; when one said additional heteroatom is a nitrogen, then said nitrogen is optionally substituted with a group selected from -H, trihalomethyl, -S02R5, -S02NR5R5, -C02R5, -C(0)NR5R5, -C(0)R5, and optionally substituted lower alkyl; -B-L-T is either of formula XXV,

    XXV each R20 is independently selected from -H, halogen, trihalomethyl, -CN, -N02, -NH2, -OR3, -NR3R3, -S(0)o-2R3, -S02NR3R3, -C02R3, -C(0)NR3R3, -N(R3)S02R3, -N(R3)C(0)R3, -N(R3)C02R3, -C(0)R3, optionally substituted Ci^alkyl, optionally substituted aryl, optionally substituted aryl Ci-6alkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclyl Ci-6alkyl; or two of R20, together with the atom or atoms to which they are attached, combine to form an optionally substituted three- to seven-membered heteroalicyclic, said optionally substituted three- to seven-membered heteroalicyclic either spiro- to, or fused to, the ring system to which it is attached; G is either an optionally substituted cycloalkyl or an optionally substituted heteroalicyclic; each R30 is independently selected from halogen, trihalomethyl, -CN, -NO2, -NH2, -OR3, -NR3R3, -S(0)o-2R3, -S02NR3R3, -C02R3, -C(0)NR3R3, -N(R3)S02R3, -N(R3)C(0)R3, -N(R3)C02R3, -C(0)R3, and optionally substituted Ci-6alkyl; R13a and R13b are each independently selected from -H and optionally substituted Ci_6alkyl; R50 is either R3, or according to formula XXIV;

    XXIV wherein X1, X2, and optionally X3, represent the atoms of a saturated bridged ring system, said saturated bridged ring system comprising up to four annular heteroatoms represented by any of X1, X2, and X3; wherein, each X1 is independently selected from -C(R6)R7-, -0-, -S(0)o-2-, and -NR8-; each X2 is independently an optionally substituted bridgehead methine or a bridgehead nitrogen; each X3 is independently selected from -C(R6)R7-, -0-, -S(0)o-2-, and -NR8-; Y is either: an optionally substituted Chalkylene linker, between D and either 1) any annular atom of the saturated bridged ring system, except X2 when X2 is a bridgehead nitrogen, or 2) any heteroatom, represented by any of R6 or R7; provided there are at least two carbon atoms between D and any annular heteroatom of the saturated bridged ring system or any heteroatom represented by any of R6 or R7; or Y is absent, when Y is absent, said saturated bridged ring system, is directly attached to D via an annular carbon of said saturated bridged ring system, unless D is -SO2-, in which case said saturated bridged ring system, is directly attached to D via an any annular atom of said saturated bridged ring system; m and p are each independently one to four; n is zero to two, when n is zero, then there is a single bond between the two bridgehead X2’s; R6 and R7 are each independently selected from -H, halogen, trihalomethyl, -CN, -NH2, -NO2, -OR3, -NR3R3, -S(0)o-2R3, -S02NR3R3, -C02R3, -C(0)NR3R3, -N(R3)S02R3, -N(R3)C(0)R3, -NC02R3, -C(0)R3, optionally substituted Ci-6alkyl, optionally substituted aryl, optionally substituted aryl Ci-6alkyl, optionally substituted heterocyclyl, optionally substituted heterocyclyl Ci-6alkyl, and a bond to either Y or D; or R6 and R7, when taken together are oxo; or R6 and R7, when taken together with a common carbon to which they are attached, form an optionally substituted three- to seven-membered spirocyclyl, said optionally substituted three- to seven-membered spirocyclyl optionally containing at least one additional annular heteroatom selected from N, O, S, and P; R8 is selected from -R3, Y, -S02NR3R3, -C02R3, -C(0)NR3R3, -S02R3, and -C(0)R3; P1 is a suitable leaving group; and P2 is selected from -H, a metal, and a group removed in-situ when combining XXII and XXIII to make XXI.
17. 17. The process according to claim 16, wherein a compound of formula XXIIa is combined with a compound of formula XXIIIa to make a compound of formula XXIa,

    XXIIa XXIIIa

    XXIa wherein R70 is selected from -H, -N02, -NH2, and -NR3R3; P1 is selected from halogen, optionally substituted alkyl-S(0)o-2-, optionally substituted arylsulfonate, optionally substituted alkylsulfonate, a group containing boron, an azide, a •λ group containing phosphorus, and a metal; and P is selected from -H and a metal. 2 * *
18. 18. The process according to claim 17, wherein P is selected from -H, lithium, sodium, potassium, cesium, copper, palladium, and titanium; Z is -0-; P1 is selected from chlorine, bromine, a toluene sulfonate, and trifluoromethansulfonate; R70 is -H; J is =C(H)-; and R2 is selected from Ci-6 alkyl, perfluoro Ci-6 alkyl, and halogen.
19. 19. The process according to claim 17 or claim 18, wherein XXIIa and XXIIIa are heated together, with a base, to form XXIa wherein: the base is selected from an organic base, an inorganic base, and a combination of an organic base and an inorganic base selected from 2,6-lutidine, 4-N,N-dimethylaminopyridine, and a metal carbonate; XXIIa and XXIIIa are heated together in a solvent with said base, at between about 40°C and 200°C for between about one hour and twenty-four hours to form XXIa; the solvent is an organic solvent.
20. 20. The process according to claim 19, wherein the process further comprises heating XXIIa and XXIIIa with microwave radiation.
21. 21. The process according to any of claims 16-20, further comprising converting said compound to a pharmaceutically acceptable salt, hydrate, or prodrug thereof.
22. 22. A process for preparing a compound of Formula XXIb,

    XXIb comprising reaction of a compound of Formula XXIIb, with a compound of Formula XXIIIb

    XXIIb XXIIIb wherein, J is =C(H)-; R2 is selected from Ci_6 alkyl, perfluoro Ci_6 alkyl, and halogen; each R20 is independently selected from -H, halogen, trihalomethyl, -CN, -NO2, -NH2, -OR3, -NR3R3, -S(0)o-2R3, -S02NR3R3, -C02R3, -C(0)NR3R3, -N(R3)S02R3, -N(R3)C(0)R3, -N(R3)C02R3, -C(0)R3, optionally substituted Ci-6alkyl, optionally substituted aryl, optionally substituted aryl Ci^alkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclyl Ci^alkyl; or two of R20, together with the atom or atoms to which they are attached, combine to form an optionally substituted three- to seven-membered heteroalicyclic, said optionally substituted three- to seven-membered heteroalicyclic either spiro- to, or fused to, the ring system to which it is attached; each R3 is independently selected from -H, -Si(R5)(R5)R5, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted arylalkyl, and optionally substituted heteroarylalkyl; or two R3, together with the nitrogen to which they are attached, form a four- to seven-membered heteroalicyclic, said four- to seven-membered heteroalicyclic optionally containing one additional heteroatom; when one said additional heteroatom is a nitrogen, then said nitrogen is optionally substituted with a group selected from -H, trihalomethyl, -S02R5, -S02NR5R5, -C02R5, -C(0)NR5R5, -C(0)R5, and optionally substituted lower alkyl; each R5 is independently selected from -H, optionally substituted Ci-6alkyl, optionally substituted aryl, and optionally substituted aryl Ci-6alkyl; R50 is either R3, or according to formula XXIV;

    XXIV wherein X1, X2, and optionally X3, represent the atoms of a saturated bridged ring system, said saturated bridged ring system comprising up to four annular heteroatoms represented by any of X , X , and X ; wherein, each X1 is independently selected from -C(R6)R7-, -0-, -S(0)o-2-, and -NR8-; each X2 is independently an optionally substituted bridgehead methine or a bridgehead nitrogen; each X3 is independently selected from -C(R6)R7-, -0-, -S(0)o-2-, and -NR8-; Y is either: an optionally substituted Ci_6alkylene linker, between 0 and either 1) any annular atom of the saturated bridged ring system, except X2 when X2 is a bridgehead nitrogen, or 2) any heteroatom, represented by any of R6 or R7; provided there are at least two carbon atoms between 0 and any annular heteroatom of the saturated bridged ring system or any heteroatom represented by any of R or R ; or Y is absent, when Y is absent, said saturated bridged ring system, is directly attached to 0 via an annular carbon of said saturated bridged ring system; m and p are each independently one to four; n is zero to two, when n is zero, then there is a single bond between the two bridgehead X2’s; R6 and R7 are each independently selected from -H, halogen, trihalomethyl, -CN, -NH2, -N02, -OR3, -NR3R3, -S(0)o-2R3, -S02NR3R3, -C02R3, -C(0)NR3R3, -N(R3)S02R3, -N(R3)C(0)R3, -NC02R3, -C(0)R3, optionally substituted Ci-6alkyl, optionally substituted aryl, optionally substituted aryl Ci^alkyl, optionally substituted heterocyclyl, optionally substituted heterocyclyl Ci^alkyl, and a bond to either Y or O; or R6 and R7, when taken together are oxo; or R6 and R7, when taken together with a common carbon to which they are attached, form an optionally substituted three- to seven-membered spirocyclyl, said optionally substituted three- to seven-membered spirocyclyl optionally containing at least one additional annular heteroatom selected from N, 0, S, and P; R8 is selected from -R3, Y, -S02NR3R3, -C02R3, -C(0)NR3R3, -S02R3, and -C(0)R3; and P1 is selected from chlorine, bromine, a toluene sulfonate, and trifluoromethansulfonate; wherein XXIIb and XXIIIb are heated together, with a base, to form XXIb, wherein: the base is selected from an organic base, an inorganic base, and a combination of an organic base and an inorganic base selected from 2,6-lutidine, 4-N,N-dimethylaminopyridine, and a metal carbonate; XXIIb and XXIIIb are heated together in a solvent with said base, at between about 40°C and 200°C for between about one hour and twenty-four hours to form XXIb; the solvent is an organic solvent.
23. 23. The process according to claim 22, wherein the process further comprises heating XXIIa and XXIIIa with microwave radiation.
24. 24. The process according to claim 22 or claim 23, wherein R , if present, is fluorine.
25. 25. The process according to claim 24, wherein R , if present, is up to two fluorines ortho to the oxygen of the phenylene to which R is attached.
26. 26. A process for preparing a compound selected from Table 2: _ Table 2_

    said compound being represented by Formula XXI,

    XXI said process comprising reaction of a compound of Formula XXII, with a compound of Formula XXIII

    XXII XXIII wherein, each R1 is independently selected from halogen, -OR3, -NO2, -NH2, -NR3R3, -D-R50 and optionally substituted Ci_6alkyl; w is an integer from 2 to 4; and at least one R1 is -D-R50 and at least one R1 is -OR3; wherein -D-R50 and -OR3 are interchangeably located at the 6-position and 7-position of the compound of Formula XXII; D is -0-; R70 is selected from -H, halogen, -OR3, -S(0)o-2R3, -NO2, -NH2, -NR3R3, and optionally substituted Ci-6alkyl; J is =N- or =C(H)-; Z is -0-; each R5 is independently selected from -H, optionally substituted Ci^alkyl, optionally substituted aryl, and optionally substituted aryl Ci-6alkyl; Ar is para-phenylene as defined by the substitution pattern of -Z- and -B-L-T about said phenylene; R2 is selected from -H, halogen, trihalomethyl, -CN, -NO2, -NH2, -OR3, -NR3R3, -S(O)0-2R3, -S02NR3R3, -C02R3, -C(0)NR3R3, -N(R3)S02R3, -N(R3)C(0)R3, -N(R3)C02R3, -C(0)R3, and optionally substituted Ci-6alkyl; each R3 is independently selected from -H, -Si(R5)(R5)R5, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted arylalkyl, and optionally substituted heteroarylalkyl; or two R3, together with the nitrogen to which they are attached, form a four- to seven-membered heteroalicyclic, said four- to seven-membered heteroalicyclic optionally containing one additional heteroatom; when one said additional heteroatom is a nitrogen, then said nitrogen is optionally substituted with a group selected from -H, trihalomethyl, -SO2R5, -SC>2NR5R5, -CO2R5, -C(0)NR5R5, -C(0)R5, and optionally substituted lower alkyl; -B-L-T is of formula XXV,

    XXV each R20 is independently selected from -H, halogen, trihalomethyl, -CN, -NO2, -NH2, -OR3, -NR3R3, -S(0)o-2R3, -S02NR3R3, -C02R3, -C(0)NR3R3, -N(R3)S02R3, -N(R3)C(0)R3, -N(R3)C02R3, -C(0)R3, optionally substituted Chalky I, optionally substituted aryl, optionally substituted aryl Ci-6alkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclyl Ci-6alkyl; or two of R20, together with the atom or atoms to which they are attached, combine to form an optionally substituted three- to seven-membered heteroalicyclic, said optionally substituted three- to seven-membered heteroalicyclic either spiro- to, or fused to, the ring system to which it is attached; G is either an optionally substituted cycloalkyl or an optionally substituted heteroalicyclic; each R30 is independently selected from halogen, trihalomethyl, -CN, -NO2, -NH2, -OR3, -NR3R3, -S(0)o-2R3, -S02NR3R3, -C02R3, -C(0)NR3R3, -N(R3)S02R3, -N(R3)C(0)R3, -N(R3)C02R3, -C(0)R3, and optionally substituted Ci^alkyl; R13a and R13b are each independently selected from -H and optionally substituted Ci_6alkyl; R50 is either R3, or according to formula XXIV;

    XXIV wherein X1, X2, and optionally X3, represent the atoms of a saturated bridged ring system, said saturated bridged ring system comprising up to four annular heteroatoms represented by any of X1, X2, and X3; wherein, each X1 is independently selected from -C(R6)R7-, -0-, -S(0)o-2-, and -NR8-; each X2 is independently an optionally substituted bridgehead methine or a bridgehead nitrogen; each X3 is independently selected from -C(R6)R7-, -0-, -S(0)o-2-, and -NR8-; Y is either: an optionally substituted Ci-6alkylene linker, between D and either 1) any annular atom of the saturated bridged ring system, except X2 when X2 is a bridgehead nitrogen, or 2) any heteroatom, represented by any of R6 or R7; provided there are at least two carbon atoms between D and any annular heteroatom of the saturated bridged ring system or any heteroatom represented by any of R or R ; or Y is absent, when Y is absent, said saturated bridged ring system, is directly attached to D via an annular carbon of said saturated bridged ring system, unless D is -SO2-, in which case said saturated bridged ring system, is directly attached to D via an any annular atom of said saturated bridged ring system; m and p are each independently one to four; n is zero to two, when n is zero, then there is a single bond between the two bridgehead X2’s; R6 and R7 are each independently selected from -H, halogen, trihalomethyl, -CN, -NH2, -N02, -OR3, -NR3R3, -S(0)o-2R3, -S02NR3R3, -C02R3, -C(0)NR3R3, -N(R3)S02R3, -N(R3)C(0)R3, -NC02R3, -C(0)R3, optionally substituted Ci-6alkyl, optionally substituted aryl, optionally substituted aryl Ci-6alkyl, optionally substituted heterocyclyl, optionally substituted heterocyclyl Ci-6alkyl, and a bond to either Y or D; or R6 and R7, when taken together are oxo; or R6 and R7, when taken together with a common carbon to which they are attached, form an optionally substituted three- to seven-membered spirocyclyl, said optionally substituted three- to seven-membered spirocyclyl optionally containing at least one additional annular heteroatom selected from N, O, S, and P; R8 is selected from -R3, Y, -S02NR3R3, -C02R3, -C(0)NR3R3, -S02R3, and -C(0)R3; P1 is a suitable leaving group; and P is selected from -H, a metal, and a group removed in-situ when combining XXII and XXIII to make XXI.
27. 27. The process according to claim 26, wherein: the compound of Formula XXI is:

    the compound of Formula XXII is:

    and the compound of Formula XXIII is:
28. 28. The process according to claim 26 for making

    , comprising: (a) combining 1,1-cyclopropane dicarboxylic acid with thionyl chloride to form the acid chloride, and treating the resulting acid chloride with 4-fluoroaniline to form

    > (b) (i) combining

    with

    to form

    , and removing the Bn group in

    to form

    or (b) (ii) combining

    with

    to form

    ; and (c) combining a mixture of

    and

    in lutidine.
29. 29. The process according to any one of claims 22-28, further comprising converting said compound to a pharmaceutically acceptable salt or hydrate thereof.
30. 30. A compound of Formula XXI prepared by the process of any one of claims 16 to 29.
31. 31. A compound according to any one of claims 1 to 15 and 30 or a process according to any one of claims 16 to 29 substantially as hereinbefore described with reference to the Figures and/or Examples.